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==== Front Appl Acoust Appl Acoust Applied Acoustics. Acoustique Applique. Angewandte Akustik 0003-682X 1872-910X Elsevier Ltd. S0003-682X(21)00676-9 10.1016/j.apacoust.2021.108582 108582 Article Impact of COVID-19 lockdown on ambient noise levels in seven metropolitan cities of India Garg N. a⁎ Gandhi V. b Gupta N.K. b a CSIR-National Physical Laboratory, New Delhi 110 012, India b Central Pollution Control Board, Delhi 110 032, India ⁎ Corresponding author. 18 12 2021 1 2022 18 12 2021 188 108582108582 25 10 2020 18 11 2021 5 12 2021 © 2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. The paper analyzed the impact of lockdown on the ambient noise levels in the seventy sites in the seven major cities of India and ascertained the noise scenario in lockdown period, and on the Janta Curfew day in comparison to the pre-lock down period and year 2019 annual average values. It was observed that the majority of the noise monitoring sites exhibited a decrement in ambient day and night equivalent noise levels on the national Janta Curfew day and Lockdown period as compared with the normal working days attributed to the restricted social, economical, industrial, urbanization activity and reduced human mobility. A mixed pattern was observed at a few sites, wherein the ambient day and night equivalent noise levels during Janta curfew day and Lockdown period had been reported to be higher than that on the normal working days. The study depicts the noise scenario during the lockdown and pre-lockdown period for seventy sites in India and shall be instrumental in analyzing the consequences and implications of imposing lockdowns in future on the environmental noise pollution in Indian cities. Keywords National Ambient Noise Monitoring Network (NANMN) Day equivalent sound level, Lday Night equivalent sound level, Lnight ==== Body pmc1 Introduction Noise pollution is evidently a serious health hazard apart from air and water pollution as analyzed in many research studies [1], [2], [3]. Thus, the continuous monitoring, reporting and analysis of the ambient noise levels in the urban scenario is necessary for devising and implementing suitable control and abatement measures for noise pollution prevention and control and reducing the associated health hazards. The entire world had been facing the wide spreading of Coronavirus (COVID 19) disease since the starting of the year 2020. The World Health Organization declared it as a ‘global pandemic’ on 11th March 2020. Subsequently, many countries imposed complete lockdown so as to prevent the spreading of this disease at an alarming rate. In India, a 14 h voluntary public curfew on 22nd March 2020 called as national ‘Janta curfew’ was observed followed by a much targeted nationwide lockdown initially for three weeks starting from 24th March to 14th April 2020, extended up to 3rd May 2020 followed by further extension till 31st May 2020. The government of India announced a ‘Janta Curfew’ from 7 am to 9 pm on Sunday, 22nd March to stop the spread of coronavirus disease, wherein people were urged not to step out of their homes except for those working in essential services like healthcare, security or media. As a result, the lockdown rules were imposed by the Ministry of Home Affairs (MHA), India so as to prevent the rapid outbreak of pandemic. Also, all places of social gatherings, schools, colleges, offices, transportation systems including rail, road and air and industries were restricted with only few exceptions for necessary and essential services only. The details of all the consolidated activities permitted and prohibited during the Janta curfew day and in the national lock down period had been summarized in a recent Maharashtra Pollution Control Board (MPCB) report [4]. The studies had revealed that the air quality improved in India during the lockdown period due to considerable reduction in the concentration of particulate matter and gases like carbon monoxide as well as nitrogen dioxide [5], [6], [7], [8]. A recent study conducted in Eastern India revealed that the particulate matter concentration reduced by three to four times, surface temperature reduced by 3–5 °C and noise levels (from 8 am to 4 pm) reduced from 85 dB(A) to 65 dB(A) amid lockdown [9]. There had been several studies reported on the effect of lockdown on air and noise pollution in many countries. A recent study in Dublin, Ireland observed a significant reduction in noise pollution at all the twelve noise monitoring stations [10] in the pandemic situation. The sound environment introduced by the lockdowns modified them not only in ambient noise levels, but also by the present sources and as such natural sounds were heard again [11]. Aletta et al., 2020 [12] reported an average reduction of 5.4 dB(A) in the equivalent continuous sound levels for the eleven locations in London city, with reduction ranging from 1.2 dB to 10.7 dB. The imposition of quarantine closed all the commercial activities thus affected the environmental parameters directly associated to the human health [13]. A recent study presented by Somani et al., 2020 [14] also discussed about the reduced air and noise pollution in India in the pandemic period. These studies thus revealed the reduced air and noise pollution levels during the lockdown period due to restricted human activities. Thus, it is imperative in national and international scenario to monitor and analyze the ambient noise levels in the cities and devise Noise Action Plans (NAPs) for the abatement and control of ambient noise levels so as to improve the health and quality of life. In India, the Central Pollution Control Board (CPCB), India established the National Ambient Noise Monitoring Network (NANMN) since the year 2011 with the prime objective of establishing the real-time continuous noise monitoring systems in the seventy sites in seven major cities of India [15], [16], [17], [18], [19]. This study analyzed the noise monitored data available from the seventy sites of seven major cities of India during the pre-lockdown period and lockdown period with an objective of:• ascertaining the noise scenario and the annual average ambient noise levels of the seventy sites for the lockdown and pre-lockdown period and compare them with the ambient noise limits of India (Table 1 [18]),Table 1 Ambient noise limits of India[18]. Category of area/ zone Limits in dB(A) Day time (6 a.m. to 10p.m.) Night time (10p.m. to 6 a.m.) Industrial Area 75 70 Commercial Area 65 55 Residential Area 55 45 Silence zone 50 40 • identify the noisy hot spots amongst the seventy sites and the requirements of implementation of Noise Action Plans, • ascertain the status of compliance of the residential and silence zone sites with the ambient noise limits during the lockdown and pre-lockdown period, and • analyze the severity of night equivalent noise levels in comparison to the day equivalent noise levels in lock down and pre-lockdown period. Although the ten noise monitoring stations installed in one city can never describe the true picture of noise scenario in that city, yet the analysis of ambient noise levels acquired from the seventy sites in totality in this study shall be very helpful for understanding the noise scenario during different periods (annual average year 2019 values, Janta curfew day, pre-lockdown and lockdown period); planning for suitable noise control measures and analyzing the consequences and implications of imposing future lockdowns on the ambient noise levels in India. 2 Materials and methods The permanent Noise Monitoring Terminals (NMTs) at the seventy sites reported in the study have been stationed in the seven major cities of India since year 2011 with each state having ten noise monitoring stations. The seven cities are: Bengaluru, Chennai, Delhi, Hyderabad, Kolkata, Lucknow and Mumbai. The seventy sites cover 25 commercial, 16 residential sites, 17 silence zone sites and 12 industrial sites. The network developed is a unique and one of the largest noise monitoring network in the entire Asian continent reported so far. The explicit details of all the Noise Monitoring Terminals including the instrumentation employed and the methodology and procedure followed for ambient sound levels data acquisition, transmission, analysis and reporting had been discussed in details previously [15], [16], [17]. Fig. 1 shows the pictorial view on map of India of all the seven cities and seventy sites whereby these permanent NMTs had been installed and deployed for continuous noise monitoring throughout the year [20], [21].Fig. 1 Pictorial view on Map of India of seventy noise monitoring stations permanently situated in the seven major cities of India [20]. 3 Results and discussion The ambient day and night equivalent noise levels were measured for the seventy sites in the seven major cities of India during the following periods: annual average year 2019 day and night equivalent sound levels, pre-lockdown period, Janta curfew day and lockdown period. Table 2a, Table 2b, Table 3a, Table 3b (a) and (b) enlists the details of the seventy sites and average day and night equivalent sound levels measured at the seventy sites in seven major cities of India during these different periods. These values were compared with the ambient noise standards for all the zones in order to ascertain their compliance and identify the noisy hot spots.Table 2a Average ambient levels, Lday and Lnight for the twenty sites in the four major cities during normal days and lockdown period. Name of Site City Latitude Longitude Site characteristics Annual Average equivalent sound levels for year 2019 Business-As-Usual (Pre-Lockdown days) Lockdown period Janta Curfew Lday Lnight Lday Lnight Lday Lnight Lday Lnight Dilshad Garden Delhi 28°40′ 53.76′' N 77°19′ 6.2′' E Silence 68.7 68.4 66.9 67 66 66 66 66 CPCB HQ. 28°39′ 20.99′' N 77°17′ 39.91′' E Commercial 66.5 56.7 66.3 57.6 58.4 51.6 57 53 DTU, Bawana 28°44′ 44.49′' N 77°5′ 1.56′' E Silence 62.2 57.9 58.9 57.3 59.7 57.6 59 58 ITO 28°37′ 41.21′' N 77°14′ 27.22′' E Commercial 75.1 73.5 73.6 73.3 74.7 74.2 – – NSIT Dwarka 28°36′ 14.46′' N 77°2′ 28.78′' E Silence 57.9 54.2 58.8 55 54.2 49.8 57 54 Gomti Nagar Lucknow 26°52′ 58.02′' N 80°59′ 58.02′' E Silence 66.9 60.2 64.9 58.6 60.9 54.1 55 53 Hazrat Ganj 26°51′ 0.66′' N 80°56′ 51.59′' E Commercial 74.0 73.2 69.9 62.7 57.3 53.1 56 55 Indira Nagar 26°53′ 25.08′' N 80°59′ 57.29′' E Residential 50.6 44.7 66.9 58.3 63.4 55.6 64 60 PGI Hospital 26°45′ 17.68′' N 80°55′ 59.53′' E Silence 66.7 67 83.9 88.4 86.3 85.2 86 86 Talkatora Industrial Area 26°50′ 2.44′' N 80°53′ 30.25′' E Industrial 63.7 62.3 66.7 58.4 59.8 55 62 64 Kasba Gole Park Kolkata 22°31′ 1.2′' N 88°24′ 15.8′' E Industrial 64.4 61.1 67.9 61.5 70.8 65.5 69 68 New Market 22°33′ 41.4′' N 88°21′ 10.4′' E Commercial 72.9 76.3 64.1 62.4 61.8 62.5 63 66 Patauli 22°28′ 21.07′' N 88°23′ 29.71′' E Residential 73.4 72.4 69.2 68.8 66.2 66.2 70 68 SSKM Hospital 22°32′ 19.58′' N 88°20′ 35.29′' E Silence 70.4 69.6 43 – 42.3 44 43 75 WBPCB HQ 22°33′ 42.67′' N 88°24′ 32.46′' E Commercial 63.4 57.0 62.3 56.4 53.6 49.5 54 56 AS HP Mumbai 19°1′ 15.83′' N 72°51′ 33.24′' E Silence – – 47.7 47.3 46.6 46.8 48 47 Bandra 19°3′ 20.77′' N 72°49′ 49.41′' E Commercial 67.5 66.9 57.4 58 61.7 62.3 57 56 MPCB HQ. 19°6′ 42.73′' N 73°0′ 43.80′' E Commercial 70.2 67.3 68.5 67.4 62 59.7 58 60 Thane MCQ 19°0′ 57.38′' N 72°51′ 29.24′' E Commercial 69.1 69.1 67.6 69.6 67.7 67.6 68 69 Vashi Hospital 19°4′ 45.49′' N 73°0′ 0.12′' E Silence 75.8 74.2 66.2 66.4 57 57.8 67 62 Table 2b Average ambient levels, Lday and Lnight for the fifteen sites in the three major cities during normal days and lockdown period. Name of Site City Latitude Longitude Site characteristics Annual Average equivalent sound levels for year 2019 Business-As-Usual (Pre-Lockdown days) Lockdown period Janta Curfew Lday Lnight Lday Lnight Lday Lnight Lday Lnight Abids Hyderabad 17°23′ 27.42′' N 78°28′ 25.59′' E Commercial 73.1 65.7 72.6 65.8 60.4 52.1 58 59 Jeedimetla 17°30′ 44.12′' N 78°28′ 10.43′' E Industrial 72.6 73.2 65.7 65.9 70 69 68 69 Jubilee Hills 17°26′ 22.08′' N 78°23′ 58.28′' E Residential 59.7 53.8 62.1 56.4 58.5 50.9 – – TSPCB 17°25′ 27.77′' N 78°27′ 3.74′' E Commercial 69.8 62.9 69.2 63.3 61.7 55.2 60 61 Zoo Park 17°22′ 8.44′' N 78°28′ 17.42′' E Silence – – 50.3 50.8 48.6 48.2 40 40 BTM Bengaluru 12°54′ 30.36′' N 77°35′ 10.96′' E Residential 64.7 64.7 64.5 65.2 63.2 62.8 63 67 Marathahalli 12°54′ 45.45′' N 77°34′ 34.58′' E Commercial 73.1 72.7 78.6 77.1 76.2 75.3 79 77 Nisarga Bhawan 12°59′ 0.54′' N 77°35′ 40.15′' E Residential 76.4 79.1 51.5 50.8 55.4 54.6 54 58 Parisar Bhawan 12°58′ 32.18′' N 77°36′ 12.38′' E Commercial 67.2 62.1 65.6 61.5 57.2 51.3 57 57 Peeniya 13°1′ 4.28′' N 77°30′ 11.45′' E Industrial 63.4 58.4 62.1 59.5 58.7 59.3 61 61 Eye Hospital Chennai 13°6′ 16.13′' N 80°17′ 3.35′' E Silence 69.2 61.0 58.8 60.7 57.9 57.6 58 58 Guindy 13°0′ 42.79′' N 80°13′ 9.46′' E Industrial 80.1 78.2 86.1 86.2 78.6 79.7 85 86 Perambur 13°6′ 43.46′' N 80°14′ 16.85′' E Commercial 74.4 71.6 61.6 60 57.6 51 62 51 T. Nagar 13°2′ 24.34′' N 80°13′ 57.44′' E Commercial 77.3 73.0 69.8 70.2 67 68.2 70 68 Triplicane 13°3′ 17.91′' N 80°16′ 28.44′' E Residential 60.9 59.0 57.4 58.7 60.8 61.8 60 59 Table 3a Average ambient levels, Lday and Lnight for twenty new sites in the four major cities during normal days and lockdown period. Name of Site City Latitude Longitude Site characteristics Annual Average equivalent sound levels for year 2019 Business-As-Usual (Pre-Lockdown days) Lockdown period Janta Curfew Lday Lnight Lday Lnight Lday Lnight Lday Lnight Civil Lines Delhi 28°40′ 55.97′' N 77°13′ 25.75′' E Commercial 61.7 58.3 60.8 57.5 58.3 54.3 57 54 R. K. Puram 28°33′ 46.23′' N 77°11′ 12.4′' E Residential 66.8 61.6 60.9 58.7 59.7 54.7 – – Anand Vihar 28°38′ 51.22′' N 77°18′ 57.02′' E Commercial 65.6 61.9 65.4 63 53.8 52.3 60 57 Mandir Marg 28°38′ 11.41′' N 77°12′ 2.36′' E Silence 65.4 54.8 59.1 52.6 59.1 53.1 58.5 47.6 Punjabi Bagh 28°40′ 12.83′' N 77°7′ 54.14′' E Residential 61.3 52.4 56.6 51 54.1 47.6 – – Chinhat Lucknow 26°54′ 17.09′' N 81°03′ 13.08′' E Industrial 67.3 60.0 67.7 51.2 62.6 50.4 56 50 IT College 26°52′ 22.47′' N 80°56′ 30.28′' E Silence 64.7 59.5 65.5 59.1 59.6 52.4 54 53 CSS Airport 26°45′ 55.41′' N 80°53′ 10.91′' E Commercial 76.3 67.0 62.8 57.6 61.6 50.9 68 50.6 RSC Aliganj 26°53′ 21.89′' N 80°56′ 24.43′' E Commercial 65.1 57.6 65.5 60.9 58.8 53.9 78 – UPPCB HQ 26°52′ 6.75′' N 81°00′ 12.54′' E Residential 63.9 62.2 66.5 59.5 60.2 53.6 56 56 Birati N. Kolkata 22°40′ 13.99′' N 88°26′ 1.74′' E Residential 79.1 77.9 70.9 55.3 59.5 51.7 64 68 R G Kar 22°36′ 16.18′' N 88°22′ 43.20′' E Silence 63.7 62.2 55.5 61.3 48.8 71.2 68 73.3 Tollygunge 22°29′ 56.48′' N 88°20′ 43.79′' E Commercial 66.8 62.9 65.2 62.9 60.5 56.5 61 60 Bag Bazar 22°36′ 4.61′' N 88°22′ 1.01′' E Residential 87.2 90.1 75.4 74.2 78 72.5 81 77 Tartala 22°30′ 56′' N 88°18′ 19.2′' E Industrial 75.3 73.1 68.5 64.1 61.8 56.5 64 69 M&M Kandivali Mumbai 19°12′ 3.87′' N 72°52′ 12.14′' E Industrial 60.4 52.6 59.6 52.9 54 47.5 53 47 CST 18°56′ 0.67′' N 72°49′ 29.61′' E Commercial 74.5 70.3 73.6 70 68 59.4 70 63 L&T Powai 19°7′ 18.31′' N 72°53′ 34.27′' E Industrial 59.4 55.1 59.1 52.6 58.2 46.6 58 48 Pepsico Chembur 19°2′ 52.89′' N 72°54′ 37.12′' E Residential 68.1 61.3 68.2 62.2 62.4 57.9 61 59 Andheri 19°6′ 44.49′' N 72°51′ 20.71′' E Industrial 78.9 78.0 75.2 74.8 75.3 77.3 75 83 Table 3b Average ambient levels, Lday and Lnight for the fifteen new sites in the three major cities during normal days and lockdown period. Name of Site City Latitude Longitude Site characteristics Annual Average equivalent sound levels for year 2019 Business-As-Usual (Pre-Lockdown days) Lockdown period Janta Curfew Lday Lnight Lday Lnight Lday Lnight Lday Lnight Tarnaka Hyderabad 17°25′ 43.57′' N 78°32′ 15.83′' E Residential 81.4 81.7 63.7 50.6 71.4 67.9 69 66 Gaddapothram 17°36′ 4.1′' N 78°22′ 19.8′' E Industrial 83.3 74.0 66.7 67.7 70.9 73.9 79 82 Gachibowli 17°27′ 36.1′' N 78°20′ 3.3′' E Silence 60.0 58.2 60.9 58.7 60.3 56.9 59 55 Paradise 17°26′ 36.7′' N 78°29′ 15.9′' E Commercial 81.4 80.3 79.4 76.3 71.3 66.5 68 72 Kukatpalli 17°29′ 45.3′' N 78°23′ 39′' E Commercial 69.9 66.7 69.2 67.4 63.1 58.4 62 63 Yeshwantpur Bengaluru 13°1′ 5.04′' N 77°33′ 28.13′' E Commercial 72.1 64.0 71.4 65.1 65.8 59 63 61 R.V.C.E 12°55′ 23.15′' N 77°29′ 58.5′' E Silence 67.4 65.9 56.2 52.5 50 48.7 49 49 Whitefield 12°58′ 38.47′' N 77°45′ 5.18′' E Industrial 66.2 61.1 65.5 60.7 58.8 53.9 57 57 Dolmur 12°57′ 48.86′' N 77°38′ 17.78′' E Residential 64.3 59.3 62.2 57.7 60.9 53.5 57 55 Nihmans 12°56′ 15.27′' N 77°35′ 32.95′' E Silence 72.0 74.1 66.6 72.8 62.3 70.7 75 81 Pallikarnai Chennai 12°56′ 14.67′'N 80°12′ 55.27′' E Commercial 84.4 78.6 62.1 55.8 69.5 80.3 81 73 Velachery 12°58′ 35.09′' N 80°13′ 15.27′' E Residential 65.5 59.7 62.6 55.7 58.1 50.9 58 51 Washermanpet 13°7′ 53.84′' N 80°16′ 43.95′' E Commercial 75.6 71.5 74.5 74.4 75.1 74.9 75 76 Anna Nagar 13°5′ 21.45′' N 80°13′ 23.93′' E Silence 75.0 77.8 62.2 89.1 56.7 85.4 77 88 Sowcarpet 13°5′ 42.4′' N 80°16′ 32.2′' E Residential 62.3 60.2 64.2 63.9 59.3 59 65 66 3.1 Annual average ambient noise levels in year 2019 The analysis of ambient day and night equivalent noise levels for the year 2019 revealed that eight sites including seven industrial and one residential site meet the ambient noise standards. Table 4 shows the frequency distribution of noise descriptors, day equivalent noise level, L day; night equivalent noise level, L night; 24 h equivalent sound level, L Aeq,24h and day-night average sound level, L dn in dB(A) for seven major cities (70 sites) during the different periods. It was observed that majority of sites: 49 sites (70 %) registered ambient day equivalent noise levels between 60 and 75 dB(A). 39 sites (55.7 %) registered night equivalent noise levels between 55 and 70 dB(A). 49 sites (70 %) registered L Aeq,24h levels between 60 and 75 dB(A), while 40 sites (57.1 %) registered L dn levels between 65 and 80 dB(A). Some of the sites showed very high ambient noise levels and thus immediately require the implementation of appropriate noise action plans. No commercial or the silence zone site complied with the ambient noise limits for the year 2019. The zone wise analysis showed that majority of sites lying in commercial zone (80%), residential zone (66.7%), silence zone (80%) and industrial zone (58.4%) registered day equivalent noise levels in range 60 to 75 dB(A). Also, the majority of sites lying in commercial zone (64%) and silence zone (66.7%) registered night equivalent noise levels in range 55 to 70 dB(A), while 66.7 % residential sites and 58.4 % of industrial sites registered night equivalent noise levels in range 50 to 65 dB(A). 2 residential sites, 2 silence zone sites, 2 industrial zone sites and no commercial zone site showed day equivalent levels up to 60 dB(A). Also, 3 residential sites, 2 silence zone sites, 2 industrial zone sites and no commercial zone site showed night equivalent noise levels up to 55 dB(A).Table 4 Frequency distribution of Lday, Lnight, LAeq,24h and Ldn in dB(A) for the seventy sites during year 2019 annual average, Business-As-Usual (Pre-Lockdown days), Janta curfew day and lockdown period. Range of noise descriptors Lday Lnight Ldn LAeq,24h No of sites Year 2019 Pre-Lock down days Janta curfew Lock-down period Year 2019 Pre-Lock down days Janta curfew Lock-down period Year 2019 Pre-Lock down days Janta curfew Lock-down period Year 2019 Pre-Lock down days Janta curfew Lock-down period 35 < Leq ≤ 40 dB(A) 0 0 1 0 0 0 2 0 0 0 0 0 0 0 0 0 40 < Leq ≤ 45 dB(A) 0 1 1 1 0 1 2 1 0 1 0 1 0 1 1 0 45 < Leq ≤ 50 dB(A) 0 1 2 4 1 1 5 8 0 0 1 1 1 0 0 2 50 < Leq ≤ 55 dB(A) 1 2 5 5 6 10 10 22 0 0 1 1 0 3 3 4 55 < Leq ≤ 60 dB(A) 5 11 20 22 14 21 15 15 1 1 3 5 7 4 15 12 60 < Leq ≤ 65 dB(A) 17 16 13 19 14 14 7 4 3 7 10 16 21 19 14 27 65 < Leq ≤ 70 dB(A) 19 26 12 8 11 12 12 8 11 15 16 21 14 21 11 7 70 < Leq ≤ 75 dB(A) 13 6 3 5 12 6 3 6 18 22 10 7 14 12 10 8 75 < Leq ≤ 80 dB(A) 8 4 5 5 8 2 3 3 11 12 13 8 6 5 3 6 80 < Leq ≤ 85 dB(A) 4 1 3 0 1 0 3 1 13 7 2 5 4 2 6 2 85 < Leq ≤ 90 dB(A) 1 1 1 1 1 3 3 2 7 3 5 3 1 3 3 2 90 < Leq ≤ 95 dB(A) – – – 0 – – – 0 4 2 2 2 0 – – – 3.2 Ambient noise levels in pre-lockdown period The analysis of ambient noise levels in pre-lockdown period (Business-As-Usual or normal) days were analyzed for the period of 7th March 2020 to 21th March 2020. Only ten industrial sites complied with the ambient noise standards in pre-lockdown period. It can be observed from Table 4 that 53 sites (75.7%) registered day equivalent noise levels between 55 and 70 dB (A) and 45 sites (64.3%) registered night equivalent noise levels between 50 dB(A) to 65 dB(A). 52 sites (74.3%) registered L Aeq,24h levels between 60 dB(A) to 75 dB(A) and 49 sites (70%) registered L dn levels between 65 and 80 dB(A). No residential/commercial/silence zone site complied with the ambient noise limits for this period. Table 5 shows the zone wise analysis of frequency distribution of day and night equivalent sound levels for the different periods. The zone wise analysis (Table 5) showed that majority of sites in pre-lockdown period lying in commercial zone (87.4 %) registered day equivalent noise levels in range 60 to 75 dB(A), while 80 % of residential zone sites, 86.7 % of silence zone sites and 83.3 % of industrial zone sites registered day equivalent noise levels in range 55 to 70 dB(A). Also, the majority of sites lying in commercial zone (83.4 %) registered night equivalent noise levels in range 55 to 70 dB(A), while 87.5 % of residential zone sites, 60 % of silence zone sites and 66.7 % of industrial zone sites registered night equivalent noise levels in range 50 to 65 dB(A). 1 commercial zone site, 3 residential sites, 9 silence zone sites and 2 industrial zone sites showed day equivalent noise levels up to 60 dB(A). Also, 4 residential sites, 5 silence zone sites, 3 industrial zone sites and no commercial zone site showed night equivalent noise levels up to 55 dB(A).Table 5 Frequency distribution of day and night equivalent noise levels for the seventy sites during different periods: Pre-Lockdown period, Janta curfew day and lockdown period. Variation of Lday and Lnight values in dB Percentage of noise monitoring locations in various zones Commercial Residential Silence Industrial Pre-lockdown Janta curfew day Lockdown Pre-lockdown Janta curfew day Lockdown Pre-lockdown Janta curfew day Lockdown Pre-lockdown Janta curfew day Lockdown Lday Lnight Lday Lnight Lday Lnight Lday Lnight Lday Lnight Lday Lnight Lday Lnight Lday Lnight Lday Lnight Lday Lnight Lday Lnight Lday Lnight 40 < Leq ≤ 45 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 6.7 6.7 6.7 0.0 6.7 6.7 0.0 0.0 0.0 0.0 0.0 0.0 45 < Leq ≤ 50 0.0 0.0 0.0 0.0 0.0 4.2 0.0 0.0 0.0 0.0 0.0 6.2 0.0 0.0 6.7 13.3 13.3 13.3 0.0 0.0 0.0 25.0 0.0 25.0 50 < Leq ≤ 55 0.0 0.0 4.3 21.7 8.3 37.5 6.7 25.0 7.7 15.4 13.3 43.8 0.0 20.0 13.3 26.7 6.7 20.0 0.0 25.0 8.3 0.0 8.3 16.7 55 < Leq ≤ 60 4.2 29.2 39.1 30.4 25.0 20.8 13.3 43.8 30.8 38.5 33.3 18.7 40.0 26.7 33.3 13.3 46.7 26.7 16.7 16.7 25.0 8.3 33.3 16.7 60 < Leq ≤ 65 33.3 29.2 21.8 17.4 29.2 8.3 40.0 18.7 38.5 0.0 33.3 12.5 20.0 13.3 0.0 6.7 13.3 0.0 8.3 25.0 25.0 16.7 16.7 0.0 65 < Leq ≤ 70 33.3 25.0 21.8 13.0 16.7 12.5 26.7 6.2 15.4 38.5 6.7 12.5 26.7 13.3 20.0 6.7 6.7 6.7 58.3 16.7 16.7 25.0 8.3 16.7 70 < Leq ≤ 75 20.8 8.3 4.3 8.7 16.7 12.5 13.3 6.2 0.0 0.0 6.7 6.2 0.0 6.7 6.7 13.3 0.0 13.3 8.3 8.3 8.3 0.0 25.0 8.3 75 < Leq ≤ 80 8.3 8.3 4.3 8.7 4.2 0.0 0.0 0.0 0.0 7.7 6.7 0.0 0.0 0.0 6.7 0.0 0.0 0.0 0.0 0.0 8.3 0.0 8.3 16.7 80 < Leq ≤ 85 0.0 0.0 4.3 0.0 0.0 4.2 0.0 0.0 7.7 0.0 0.0 0.0 6.7 0.0 0.0 6.7 0.0 6.7 0.0 0.0 8.3 16.7 0.0 0.0 85 < Leq ≤ 90 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 13.3 6.7 13.3 6.7 6.7 8.3 8.3 0.0 8.3 0.0 0.0 3.3 Ambient noise levels on Janta Curfew day On the day of Janta Curfew i.e. 22nd March 2020, restricted vehicles on the roads and opening of only essential commercial units [7] was permitted by the authorities. Thus, fourteen sites including nine industrial sites, four commercial sites and one silence zone site complied with the ambient noise levels on day of Janta Curfew. It was observed (Table 4) that 45 sites (64.3 %) registered day equivalent noise levels between 55 and 70 dB(A) and 32 sites (45.7 %) registered night equivalent levels between 50 and 65 dB(A). 39 sites (55.7 %) registered L dn levels between 65 and 80 dB(A), while 40 sites (57.1 %) registered L Aeq,24hr levels between 55 and 70 dB(A). No site lying in residential zone complied with the ambient noise standards. The zone wise analysis (Table 5) showed that the majority of the sites on Janta curfew day lying in commercial zone (82.7 %), residential zone (84.7 %), silence zone (53.3 %) and industrial zone (66.7%) registered day equivalent noise levels in range 55 to 70 dB(A). Also, the majority of the sites lying in commercial zone (69.5 %) and residential zone (53.9 %) registered night equivalent noise levels in range 50 to 65 dB(A), while 53.3 % of silence zone sites registered night equivalent noise levels in range 45 to 60 dB(A). It was also observed that 5 residential sites, 11 silence zone sites, 4 industrial zone sites and 10 commercial zone sites showed day equivalent levels up to 60 dB(A). Also, 2 residential sites, 8 silence zone sites, 3 industrial zone sites and 5 commercial zone sites showed night equivalent noise levels up to 55 dB(A). 3.4 Ambient noise levels in lockdown period The ambient noise levels in the lockdown period were analyzed for the period of 23rd March 2020 to 7th April 2020. It was observed that nineteen sites including nine industrial sites and ten commercial zone sites complied with the ambient noise standards. None of the silence or the residential zone sites surprisingly complied with the ambient noise limits. It can be observed from Table 4 that 49 sites (70 %) registered day equivalent noise levels between 55 dB(A) to 70 dB (A) and 41 sites (58.6 %) registered night equivalent noise levels between 50 dB(A) to 65 dB(A). 46 sites (65.7 %) registered L Aeq,24h levels between 55 dB(A) to 70 dB(A) and 44 sites (62.9 %) registered L dn levels between 60 and 75 dB(A). 39 sites (55.7 %) met the target of 60 dB L day in lockdown period, while 32 sites (45.7 %) met the target of 55 dB L night in lockdown period. The zone wise analysis as shown in Table 5 showed that majority of sites in lockdown period lying in commercial zone (70.9 %) registered day equivalent noise levels in range 55 to 70 dB(A), while 80 % of residential zone sites, 66.7 % of silence zone sites and 58.3 % of industrial zone sites registered day equivalent noise levels in range 50 to 65 dB(A). Also, the majority of sites lying in commercial zone (66.6 %), residential zone (75 %) and silence zone (46.7 %) registered night equivalent noise levels in range 50 to 65 dB(A), while 58.4 % of industrial zone sites registered night equivalent noise levels in range 45 to 60 dB(A). 4 Comparison of the ambient noise levels for the different periods The comparison of ambient day and night equivalent noise levels measured for the different periods were analyzed for the seventy sites in order to understand the noise scenario in the different periods and analyzing the change in noise scenario during the Janta curfew and lockdown in comparison to the pre-lockdown days and the annual average ambient day and night equivalent noise levels observed in the year 2019. The analysis of comparison of day and night equivalent noise levels for the different periods is presented in this section. 4.1 Comparison of ambient noise levels on the Janta curfew day with pre-lockdown period Fig. 2 (a) and (b) show the difference between the day and night equivalent noise levels on the Janta curfew day and average ambient noise levels during the pre-lockdown period for the seventy sites. The analysis of ambient day and night equivalent noise levels in comparison to the pre-lockdown period shows that 33 sites (47.1 %) registered decrement in both the day and night equivalent noise levels. 41 sites (58.6 %) registered decrement in the day equivalent noise levels, while 43 sites (61.4 %) registered a decrement in the night equivalent noise levels. 24 sites registered decrement in day equivalent level by ≥ 5 dB(A), while 15 sites registered a decrement in night equivalent noise levels by ≥ 5 dB(A). 9 sites registered decrement in day levels ≥ 10 dB(A), while only one site showed decrement in night level ≥ 10 dB(A). However, 9 sites showed an increment in the day equivalent noise levels by ≥ 5 dB(A), while 11 sites registered increment in night equivalent noise levels ≥ 5 dB(A). Overall, 16 commercial sites, 10 silence zone sites, 7 residential sites and 8 industrial sites showed reduction in day equivalent noise levels in the range of 0 to 15 dB(A). Also, 20 commercial sites, 13 silence zone sites, 5 residential sites and 5 industrial sites showed decrement in night equivalent noise levels in range 0 to 15 dB(A). It was observed that the majority of the sites lying in the commercial and silence zone registered decrement in the ambient day and night equivalent noise levels.Fig. 2 (a) and (b). Difference in day equivalent noise levels, Lday and night equivalent noise levels, Lnight in dB(A) on the Janta curfew day and the average day and night equivalent noise levels in Business As Usual (Pre-Lockdown) period in year 2020. 4.2 Comparison of ambient noise levels in lockdown period with pre-lockdown period Fig. 3 (a) and (b) show the difference in average day and night equivalent noise levels of lockdown period with the pre-lockdown period for the seventy sites. The analysis of average ambient day and night equivalent noise levels in lockdown period in comparison to the pre-lockdown period shows that 50 sites (71.4 %) showed a decrement in both day and night equivalent noise levels. 53 sites (75.7 %) showed the decrement in day equivalent noise levels, while 55 sites (78.6 %) showed decrement in night equivalent noise levels. 30 sites (42.9 %) showed decrement in day equivalent noise levels ≥ 5 dB(A), while 29 sites (41.4 %) showed a decrement in night equivalent noise levels ≥ 5 dB(A). 4 sites showed a decrease in day equivalent noise levels ≥ 10 dB(A), while 6 sites showed a decrease in night equivalent noise levels ≥ 10 dB(A). Overall, 20 commercial sites, 14 silence zone sites, 11 residential sites and 8 industrial sites showed reduction in day equivalent noise levels in the range of 0 to 15 dB(A). Also, 20 commercial sites, 14 silence zone sites, 13 residential sites and 8 industrial sites showed decrement in night equivalent noise levels in range 0 to 15 dB(A). It was observed that the majority of the sites registered decrement in the ambient day and night equivalent noise levels.Fig. 3 (a) and (b). Difference in average day equivalent noise levels, Lday and night equivalent noise levels, Lnight in dB(A) during Lockdown period and Business As Usual (Pre-Lockdown period) in year 2020. 4.3 Comparison of ambient noise levels on Janta curfew day with year 2019 annual average levels Fig. 4 (a) and (b) show the difference in ambient day and night equivalent noise levels observed on the Janta Curfew day and year 2019 annual average day and night equivalent noise levels for the seventy sites. The comparison of the ambient day and night equivalent levels on the Janta Curfew day with year 2019 annual average noise levels revealed that 38 sites (54.3 %) showed a decrement in both day and night equivalent noise levels. 44 sites (62.9 %) showed decrement in day equivalent noise levels, while 43 sites (61.4 %) showed decrement in night equivalent noise levels. 28 sites (40 %) showed a decrease in day equivalent noise levels ≥ 5 dB(A), while 27 sites (38.6 %) showed a decrease in night equivalent noise levels ≥ 5 dB(A). Also, 19 sites (27.1 %) showed a decrease in day equivalent noise levels ≥ 10 dB(A), while 12 sites (17.1 %) showed a decrease in night equivalent noise levels ≥ 10 dB(A). However, it can be observed that 7 sites showed an increase in day equivalent noise levels by ≥ 5 dB(A), while 13 sites showed an increase in night equivalent noise levels by ≥ 5 dB(A). Overall, 20 commercial sites, 8 silence zone sites, 8 residential sites and 8 industrial sites showed reduction in day equivalent noise levels in the range of 0 to 15 dB(A). Also, 18 commercial sites, 9 silence zone sites, 8 residential sites and 6 industrial sites showed decrement in night equivalent noise levels in range 0 to 15 dB(A). It was observed that the majority of the commercial zone sites registered decrement in the ambient day and night equivalent noise levels.Fig. 4 (a) and (b). Difference in day equivalent noise levels, Lday and night equivalent noise levels, Lnight in dB(A) on Janta Curfew day and annual average ambient day and night equivalent noise levels observed in year 2019. 4.4 Comparison of ambient noise levels in lockdown period with year 2019 annual average levels Fig. 5 (a) and (b) show the difference in ambient day and night equivalent noise levels observed during lockdown period with the year 2019 annual average day and night equivalent levels for the seventy sites. The comparison of the ambient day and night equivalent noise levels in lockdown period with the annual average year 2019 levels showed that 57 sites (81.4 %) showed a decrement in both day and night equivalent noise levels. 61 sites (87.1 %) showed a decrement in day equivalent noise levels, while 55 sites (78.6 %) showed decrease in night equivalent noise levels. 43 sites (61.4 %) showed a decrement in day equivalent noise levels ≥ 5 dB(A) and 38 sites (54.3 %) showed decrement in night equivalent noise levels ≥ 5 dB(A). 22 sites showed a decrement in day equivalent noise levels ≥ 10 dB(A), while 18 sites showed a decrement in night equivalent noise levels ≥ 10 dB(A). Overall, 22 commercial sites, 8 silence zone sites, 12 residential sites and 11 industrial sites showed reduction in day equivalent noise levels in the range of 0 to 15 dB(A). Also, 18 commercial sites, 9 silence zone sites, 11 residential sites and 8 industrial sites showed decrement in night equivalent noise levels in range 0 to 15 dB(A). It was observed that the majority of the commercial and industrial zone sites registered decrement in the ambient day and night equivalent noise levels.Fig. 5 (a) and (b). Difference in average day equivalent noise levels, Lday and night equivalent noise levels, Lnight in dB(A) during the Lockdown period and annual average ambient day and night equivalent noise levels observed in year 2019. 5 Overall noise scenario in different periods The zone-wise analysis for the seventy sites under consideration as shown in Table 5 revealed that the majority of sites lying in each zones showed the day equivalent noise levels ranging from 55 to 65 dB(A) in lockdown period and on the Janta curfew day, while in the pre-lockdown period, majority of sites registered day equivalent noise levels ranging from 60 to 70 dB(A). Also, the majority of sites in each zone showed the night equivalent noise levels ranging from 50 to 60 dB(A) in lockdown period and on the Janta curfew day, while in the pre-lockdown period, majority of sites showed night equivalent noise levels ranging from 55 to 65 dB(A). It was observed that only 19 sites (27.1 %) complied with the ambient noise limits for the lockdown period. Table 6 shows the status of compliance of all the 70 sites with respect to the ambient noise standards for the year 2019 annual average values, Janta curfew day, pre-lockdown and lockdown period. It can be observed that no residential zone or silence zone site met the ambient noise standards in lockdown period. Table 6 also shows the status of compliance of day and night equivalent sound levels explicitly for the various sites with ambient noise standards of India. Interestingly, some of the sites partially complied with either day or night noise limits. It can be observed that 33 sites (47.1 %) complied with day equivalent noise limits, while only 19 sites (27.1 %) complied with the night equivalent noise limits for the lockdown period. Similarly, on the Janta curfew day, 31 sites (44.3 %) complied with day equivalent noise limits, while only 14 sites (20 %) complied with the night equivalent noise limits. This is different to the scenario of the pre-lock down period, whereby 23 sites (32.9 %) complied with day equivalent noise limits, while only 10 sites (14.3 %) complied with the night equivalent noise limits. Thus, even in the lockdown situation, only 10 additional sites complied with day equivalent noise limits and 9 additional sites complied with night equivalent noise limits. 32 sites (45.7 %) only met the target of 55 dB L night in lockdown period and 18 sites (25.7 %) on the Janta curfew day as 55 dB L Aeq,outside had been recommended as an interim goal by WHO [22]. In accordance with the U.S Department of Housing and Urban Development (HUD) recommended limits of the noise scenario of 49 < L Aeq ≤ 62 dB(A) as normally acceptable [23]; 44 sites (62.9 %) met the criteria in lockdown period and 35 sites (50 %) on the Janta curfew day. Also, taking into account the criteria of L dn ≤ 65 dB(A) as acceptable, 42 sites (60 %) met the criteria in the lockdown period and 32 sites (45.7 %) on the Janta curfew day.Table 6 Status of compliance of various sites with the ambient noise limits. Period Number of sites meeting legal limits for both day and nigght time Name of the sites Number of Compliant Stations: Day and Night Time exclusively Year 2019 annually Eight (Seven industrial and One residential) sites Whitefield, Gole Park, Talkatora, Peeniya, Indira Nagar, Chinhat, Kandivali and L&T Powai Day time limits: 12 sites (1 residential, 1 commercial and 10 industrial sites) Night time limits: 8 sites (1 residential and 7 industrial sites) Business-As-Usual (Pre-Lockdown days) Ten (Ten industrial sites) Peeniya, Whitefield, Jeedimetla, Gaddapothram, Gole Park, Tartala, Talkatora, Chinhat, Kandivali and L&T Powai Day time limits: 23 sites (3 silence, 1 residential, 9 commercial and 10 industrial sites) Night time limits: 10 industrial sites Janta curfew Fourteen (Nine Industrial sites, Four commerical sites and One silence zone site) Peeniya, Whitefield, Parisar Bhawan, Perambur, CPCB headquareters, Civil lines, Jeedimetla, Zoo, Gole Park, Tartala, Talkatora, Hazrat Gunj, Chinhat, Kandivali and L&T Powai Day time limits: 31 sites (4, silence, 2 residential, 15 commercial and 10 industrial sites) Night time limits: 14 sites (1 silence, 4 commercial and 9 industrial sites) Lockdown period Nineteen (Nine industrial and Ten commercial zone sites) Peeniya, Whitefiled, Parisar Bhawan, Perambur, CPCB Headquarters, Civil Lines, Anand Vihar, Abids, TSPCB, Jeedimetla, Gole Park, Kolakata Head Quarter, Tartala, Talkatora, Hazrat Gunj, Chinhat, CSS Airport, Kandivali and L&T Powai Day time limits: 33 sites (2 silence, 5 residential, 15 commercial and 11 industrial sites) Night time limits: 19 sites (9 commercial and 10 industrial sites) Table 7 shows the frequency distribution (in %) of difference of average (L day − L night) for the 70 sites. It was revealed that the majority of difference between the day and night equivalent noise levels in each period varied from −5 to 10 dB. Very few sites (<5.8 %) only showed the difference greater than 10 dB. It can be observed (Table 7) that he difference in the day and night equivalent noise levels within ± 5 dB(A) were observed for 42 sites (60 %) in pre-lock down period and 52 sites (74.3 %) in year 2019 as evident from the annual average values. However, during the lockdown period and on Janta curfew day, the difference between day and night noise levels within ± 5 dB(A) were observed for 40 sites (57.1 %) in lockdown period and 50 sites (71.4%) on Janta curfew day. Thus, the night equivalent noise levels were not as severe in the lockdown period as were observed in the year 2019 annual average values, while on the Janta curfew day, there was only a marginal impact on night equivalent noise levels in comparison to the year 2019 annual average values. Also, in order to ascertain the most severely affected zone, the noise limit exceedance factor for each zone and in each period was analyzed as shown in Table 8 . The noise limit exceedance factor (NEF) was calculated as the ratio of the ambient noise level (day/night) observed at the site to the noise limit recommended by the ambient noise standards. The average of noise limit exceedance factor (NEF) for all the sites lying in one zone is called as the Average Exceedance Factor (AEF) as analyzed in Table 8 [24], [25], [26]. Some of the interesting observations analyzed from the analysis of ambient noise levels during pre-lockdown period, lockdown period and Janta curfew day as listed in Table 6, Table 7, Table 8 are as follows:• Overall, the percentage of stations complying with noise standards during day-time increased from 32.9 % during normal working days to about 47.1 % during lockdown period and 44.3 % on the Janta curfew day. This can be attributed to restricted industrial/commercial activities as well as vehicular movements during the lockdown period. The highest increase in percentage of stations complying with day ambient noise standards was observed in commercial areas. It was observed that the percentage of stations complying with noise standards increased from 12.9 % to 21.4 % due to the lockdown restrictions imposed. • 60 dB(A) L day can be considered as NOAEL (no observed adverse effect level) for correlation between road traffic noise and myocardial infarction (MI); the risk of MI increases incessantly for noise levels higher than 60 dB(A) [22], [27]. It can be observed that for the year 2019, only 8.9 % of the monitoring sites and during the pre-lockdown period, only 21.4 % of monitoring sites meet the 60 dB(A) L day limit. However, during the lockdown period, 45.7 % of the monitoring sites and 41.4 % of the monitoring sites on Janta curfew day meet the 60 dB(A) L day limit. The WHO Regional Office for Europe recent guidelines recommended 53 dB L den and 45 dB L night as the threshold for road traffic noise [28], [29]. A recent study by Garg (2019) recommended the use day-night average sound level and day-evening-night sound level descriptors without night time or evening time adjustments in Indian perspectives [30]. Thus, 53 dB(A) L Aeq,24h limit can be considered analogous value ignoring the 5 dB evening and 10 dB night time corrections. It was observed that only 8 sites during the lockdown period and 5 sites on Janta curfew day meet the 53 dB(A) L Aeq,24h limit. Also, only one site during the lockdown period and two sites on Janta curfew day meet the 45 dB(A) L night limit. • Marginal increase in percentage of stations complying with the ambient noise limits during day-time was observed in the residential areas. The percentage of complying stations increased from 1.4 % on the normal working day to 2.9 % during Janta curfew day and 7 % during Lockdown period in the residential areas. This can be attributed to the fact that noise emissions in the residential areas is mainly due to various factors such as the household appliances, vehicular movements etc. During the Janta curfew/lockdown period, although the vehicular movement was minimal; the background sound due to the household activities remained the same, and to some extent increased as most of the people were at home and hence marginal impact of Janata curfew/ lockdown observed in percentage of stations complying with noise standards. Also, on the Janta curfew day, the authorities encouraged common masses to clap and ring bells at 5 pm in evening as a show of appreciation for the doctors, nurses, policemen and staff deployed for fighting the pandemic, which may be a reason for escalated evening equivalent noise levels of the residential zone sites. • In the silence zones, the percentage of stations complying with noise standards during the day-time even reduced during the lockdown period. The percentage of complying stations decreased from 4.3 % during normal working days to 2.9 % during the lockdown period in silent zones. This can be attributed to the fact that it is mainly the hospitals which are located in silence zones and activities contributing to noise generation remain unchanged in an around hospital area during lockdown period, some sites even witnessing an increase in these activities. • A marginal increase in percentage of stations complying with noise standards during day- time was observed in the industrial areas. In the industrial areas, the percentage of complying stations increased from 14.3 % during normal working days to 15.7 % during the lockdown period. A marginal increase in the percentage of stations complying with ambient noise standards was observed in industrial area as some of the sources of noise pollution such as vehicular movements etc. had been prevailing even during the Janta curfew and the lockdown period. • Analysis of night equivalent noise levels showed a marginal increase in the percentage of stations complying with noise standards during the night-time. The percentage of complying stations increased from 14.3 % during normal working days to 27.1 % during the lockdown period and 20 % during the Janta curfew day. In the residential, silence and industrial zones, the number of stations complying with the ambient noise limits were the same, which can be attributed to the fact that the activities carried out during night-time remained unchanged in all three categories viz. normal working day, Janta curfew and lockdown period. It was observed that for the commercial areas, the percentage of stations complying with ambient limits increased to 12.9 % in lockdown period and 5.7 % on Janta curfew day. This can be attributed to the closure of some of the commercial activities such as malls, banquet halls, restaurants, markets, shops etc. • An important observation on the average exceedance factor (AEF) analyzed during the different periods (Table 8) was that the silence zone is the most affected zone and showed excessive violation of the limits, wherein the night equivalent noise levels were observed to be 1.5 to 1.6 times the ambient night noise limits. The day equivalent noise levels were observed to be 1.2 to 1.3 times the ambient day noise limits for silence zones. The residential zone experienced an average exceedance factor of 1.3 to 1.4 times the ambient night noise limits during each period, while the commercial zone experienced an average exceedance factor of 1.2 to 1.4 times the ambient night noise limits during each period. The average exceedance factor for the day-time for commercial zone was observed to be in range of 1.0 to 1.1 in lockdown, pre-lockdown period, while that for the residential zone AEF value was in range of 1.1 to 1.2. As obvious, the industrial zone registered the lowest average exceedance factor of 0.9 in each case for day and night equivalent noise levels. It was observed that the silence zones with AEF 1.2–1.6 were the noisiest zones followed closely by residential (AEF 1.1–1.4) and commercial (AEF 1.0–1.1) zones and industrial zones, the least (AEF 0.9–1.0). A similar findings pertaining to the range of AEF values for the four zones had been presented earlier by Kalawapudi et al., 2020 [26] study for the Mumbai Metropolitan Region (MMR) of India. It may be noted that mixed category zone is prevalent in some of the sites. Some sites lying in residential and silence zones have close proximity to the road/metro train networks, markets and other commercial and industrial establishments, vehicular movements, honking noise, loudspeaker noise and even prone to aircrafts noise, which is the prime cause for the accentuated ambient noise levels. Table 7 Frequency distribution (in %) of difference of average (Lday - Lnight) values in dB for the 70 sites. Range of (Lday − Lnight) in dB Year 2019 annually Business-As-Usual (Pre-Lockdown days) Janta curfew Lockdown period No. of sites No. of sites (in %) No. of sites No. of sites (in %) No. of sites No. of sites (in %) No. of sites No. of sites (in %) −20 < (Lday - Lnight) ≤ -15 dB 0 0 0 0 1 1.4 1 1.4 −15 < (Lday - Lnight) ≤ -10 dB 0 0 0 0 1 1.4 0 0 −10 < (Lday - Lnight) ≤ -5 dB 0 0 2 2.9 3 4.3 2 2.9 −5 < (Lday - Lnight) ≤ 0 dB 15 21.4 14 20.0 25 35.7 13 18.6 0 < (Lday - Lnight) ≤ 5 dB 37 52.9 28 40.0 25 35.7 27 38.6 5 < (Lday - Lnight) ≤ 10 dB 18 25.7 21 30.0 6 8.6 23 32.9 10 < (Lday - Lnight) ≤ 15 dB 0 0 2 2.9 1 1.4 4 5.7 15 < (Lday - Lnight) ≤ 20 dB 0 0 2 2.9 0 0 0 0 Table 8 Average Exceedance Factor (AEF) for different zones in year 2019, pre-lockdown period, lockdown period and Janta curfew day. Year 2019 annual average values Category Lday Lnight Maximum value Minimum value AEF Maximum value Minimum value AEF Industrial Area (n = 12) 1.1 0.8 0.9 1.1 0.8 0.9 Commercial Area (n = 25) 1.3 1.0 1.1 1.5 1.0 1.2 Residential Area (n = 16) 1.6 0.9 1.2 2.0 1.0 1.4 Silence zone (n = 17) 1.5 1.2 1.3 2.0 1.4 1.6 Pre-Lockdown period Category Lday Lnight Maximum value Minimum value AEF Maximum value Minimum value AEF Industrial Area (n = 12) 1.1 0.8 0.9 1.2 0.7 0.9 Commercial Area (n = 25) 1.2 0.9 1.0 1.4 1.0 1.2 Residential Area (n = 16) 1.4 0.9 1.2 1.6 1.1 1.3 Silence zone (n = 17) 1.7 1.0 1.2 2.2 1.2 1.6 Lockdown period Category Lday Lnight Maximum value Minimum value AEF Maximum value Minimum value AEF Industrial Area (n = 12) 1.0 0.7 0.9 1.1 0.7 0.9 Commercial Area (n = 25) 1.2 0.8 1.0 1.5 0.9 1.1 Residential Area (n = 16) 1.4 1.0 1.1 1.6 1.1 1.3 Silence zone (n = 17) 1.7 0.9 1.2 2.1 1.2 1.5 Janta curfew day Category Lday Lnight Maximum value Minimum value AEF Maximum value Minimum value AEF Industrial Area (n = 12) 1.1 0.7 0.9 1.2 0.7 0.9 Commercial Area (n = 25) 1.2 0.8 1.0 1.8 0.9 1.2 Residential Area (n = 16) 1.5 1.0 1.1 1.7 1.1 1.4 Silence zone (n = 17) 1.7 0.7 1.2 2.5 0.9 1.5 It is evident that although lockdown had a prominent effect on the reduction of the day and night equivalent noise levels, yet only few sites complied with the ambient noise limits. The silence zone witnessed an increase in the activities which resulted in marginal effect of Janta curfew/lockdown. None of the residential zone or silence zone sites met the ambient noise standards even in the lockdown period. These observations also suggest a retrospective and prospective view on the ambient noise limits for the residential and silence zones in India. It is rightly pointed out in the European Night Noise Guidelines (2009) report that the limits could be a reasonably high value, but firmly imposed or a stringent limit with no legal obligation whatsoever [22]. Fig. 6 suggests the flow chart of reducing the noise pollution in the residential and silence zone sites in Indian cities. Demarcation of all the silence zone and residential zone sites in cities, and no-honking zones and the implementation of land-use planning especially for the new developments in Master Plan Document shall be some of the pivotal steps for reducing the ambient noise levels. Planning and execution of various Noise Action Plans (NAPs) such as erection of noise barriers, restricted movement of heavy vehicles in residential and silence zones, prohibiting honking noise, traffic management and control, installation of green belts, vegetation and trees, enhancing the sound insulation of windows and facades and developing enhanced acoustic balcony [31], [32] especially in the sites witnessing high traffic, road surface improvement or replacement [33] can substantially reduce the ambient noise levels as recommended in various studies [34], [35], [36], [37]. However, while devising the suitable noise control measures, the economic considerations, cost-benefit analysis plays an important role and thus the initiation of the Best Practicable and Economical Option (BPEO) must be considered. Also, an action plan should define the actions in a ‘smart’ way (specific, measurable, achievable, realistic, time related) and should not merely be a policy statement, but should be accountable and clearly define the estimated noise level reductions to be accomplished [38]. Noise mapping of various sites in the cities, identification of the noisy hotspots and periodic review and assessment of noise scenario after fixed intervals (say three years) by the concerned authorities shall be indispensable to analyze, understand, devise and execute suitable long-term and short-term noise action plans [39]. Also, the enactment of some legal measures such as type approval noise testing of vehicles, horns, noise labeling of domestic appliances, machines and construction equipments [40], strict enforcement of National Building Codes, land-use planning and management policy, improving the urban soundscapes by vegetation, musical water fountain etc. shall be instrumental in noise control in residential and silence zones [41], [42], [43]. Thus, the analysis of ambient noise levels during the lockdown and pre-lockdown period presented in this study shall be beneficial for consideration of imposing lockdowns, traffic control plans (odd–even rule) etc. for noise pollution prevention and control in the metropolitan cities in India [44], [45], [46], [47], [48], [49], [50].Fig. 6 Flow chart of recommended noise pollution control strategy in silence and residential zone sites in the metropolitan cities of India. 6 Conclusions and recommendations The study presented the noise scenario during the lockdown period, pre-lockdown period and on the day of Janta curfew. The impact of lockdown on the ambient noise levels for the seventy sites in the seven major cities of India was analyzed. The lockdown imposed to curtail the spread of COVID-19 pandemic was unique and never witnessed in past in India. The study revealed that the reduction in noise levels was more pronounced during the day-time for majority of the sites as compared to night-time due to reduced economic activities. 50 sites (71.4 %) registered a decrement in both day and night equivalent noise levels in lockdown period when compared to the pre-lock down period. 30 sites (42.9 %) showed a decrement in day equivalent noise levels ≥ 5 dB(A), while 29 sites (41.4 %) showed decrement in night equivalent noise levels ≥ 5 dB(A) in lockdown period in comparison to the pre-lockdown period. The analysis of ambient day and night equivalent noise levels on Janta curfew day in comparison to the pre-lockdown period shows that 33 sites (47.1 %) registered a decrement of both day and night equivalent noise levels. 24 sites (34.3 %) registered decrement in day equivalent level by ≥ 5 dB(A), while 15 sites (21.4 %) registered a decrement in night equivalent noise levels by ≥ 5 dB(A) on Janta curfew day. The reduced ambient noise levels at majority of the sites was primarily due to the restricted social, economical, industrial, urbanization activity, reduced human mobility, low traffic volumes on the roads and reduction in honking noise. However, the accentuated day equivalent noise levels at some sites in lockdown period and on the day of Janta curfew may be attributed to the execution of some specific activities like policing, increased activities near the hospital areas in pandemic situation, announcements on the loudspeakers, vehicular movements and other domestic noise due to restricted human mobility. Thus, suitable noise control action plans are required to be implemented and executed for such sites for bringing the ambient levels below the limits. An interesting observation in the present study on ascertaining the compliance of the ambient day and night equivalent noise levels in the lockdown period and on the Janta curfew day in comparison to the ambient noise standards showed that only nineteen sites comprising of nine industrial and ten commercial zone sites complied with the ambient noise limits in the lockdown period. Also, on the day of Janta curfew, Fourteen sites including nine industrial sites, four commercial sites and one silence zone site met the noise limits. No site lying in silence zone and residential zone complied with the ambient noise standards during the lockdown period. 33 sites (47.1 %) complied with day-time noise limits, while 19 sites (27.1 %) complied with night-time noise limits in lockdown period. On the day of Janta curfew, 31 sites (44.3 %) complied with day-time noise limits, while 14 sites (20 %) complied with night-time noise limits. It is thus evident that even imposition of lockdown in some sites is not enough in bringing the ambient day and night equivalent noise levels within the limits. The analysis of ambient noise levels observed for the different zones revealed that a marginal increase in percentage of stations complying with noise standards during day-time was observed in industrial and residential zones. The highest increase in percentage of stations complying with day ambient noise standards was observed in commercial areas due to the restricted social and economical activities. However, for the silence zones, the percentage of stations complying with the ambient noise limits during day-time even reduced during the lockdown period. The percentage of complying stations decreased from 4.3 % during normal working days to 2.9 % during the lockdown period in silence zones. This may be attributed primarily due to increase activities near the hospital areas in pandemic situation. The analysis of night equivalent noise levels showed a marginal increase in the percentage of stations complying with noise standards during the night-time. The percentage of complying stations increased from 14.3 % during the normal working days to 27.1 % during the lockdown period and 20 % during the Janta curfew day. The non-compliance of the ambient noise limits for the residential and silence zone sites in the lockdown period revealed that even such measures are in-effective in reducing the ambient noise levels below the limits. This is primarily due to the mixed category zone prevalent for the majority of these locations. Thus, the implementation of Best Practicable and Economical Options amongst the different noise action plans (NAPs) as described in Fig. 6 can be very helpful in reducing the ambient noise levels below the recommended limits. Thus, future developments on Smart Cities and townships should consider these aspects at the conceptualization and designing stages for reducing the noise pollution and developing sustainable cities promoting good health and quality of life. CRediT authorship contribution statement N. Garg: Conceptualization, Methodology, Writing – review & editing. V. Gandhi: Investigation, Writing – review & editing. N.K. Gupta: Investigation. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgements Authors express sincere gratitude towards the Central Pollution Control Board, India authorities for their consent to publish this work. 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==== Front Appl Ergon Appl Ergon Applied Ergonomics 0003-6870 1872-9126 Published by Elsevier Ltd. S0003-6870(21)00319-7 10.1016/j.apergo.2021.103672 103672 Article The effect of sound environment on spatial knowledge acquisition in a virtual outpatient polyclinic Dalirnaghadeh Donya ∗ Yilmazer Semiha Bilkent University, Faculty of Art, Design and Architecture, Department of Interior Architecture and Environmental Design, Bilkent, Ankara, 06800, Turkey ∗ Corresponding author. 28 12 2021 4 2022 28 12 2021 100 103672103672 18 4 2021 13 12 2021 14 12 2021 © 2021 Published by Elsevier Ltd. 2021 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. This study examines the impact of the sound environment on spatial knowledge acquisition in a virtual outpatient polyclinic. Outpatient polyclinics have a salient role in determining early outpatient treatments of COVID-19 to prevent hospitalization or death and reduce the burden on hospitals. However, they have not been widely investigated in the literature. The studies on spatial knowledge have identified environmental elements mainly related to vision with no focus on sound. Currently, there is limited research on the effect of sound environment on spatial knowledge acquisition in virtual outpatient polyclinics. In this study, a virtual simulated outpatient polyclinic has been created with varying levels of visual and audio cues. Eighty participants were assigned to one of the four groups: a control (no visual signage), a visual (visual signage), an only audio (no landmarks and no visual signage), and an audio-visual group. The virtual environment was presented as a video walkthrough with passive exploration to test spatial knowledge acquisition with tasks based on the landmark-route-survey model. The results showed that a combination of visual signage and sound environment resulted in higher spatial knowledge acquisition. No significant difference was found between the performance of the visual group and the control group that shows that signage alone cannot aid spatial knowledge in virtual outpatient polyclinics. Data from the only audio group suggests that landmarks associated with sound can compensate for the lack of visual landmarks that may help design a wayfinding system for users with visual disabilities. Keywords Landmark-route-survey model Outpatient polyclinics Sound environment Spatial knowledge Virtual environments ==== Body pmc1 Introduction Spatial knowledge development is one of the four theories of wayfinding (Jamshidi and Pati, 2021). Human spatial knowledge is linked to and defined by finding and following routes from one destination to another (Kuipers, 1990). Hospitals are among the most complex environments that the public accesses (Zijlstra et al., 2016). Better acquisition of spatial knowledge in hospitals leads to better wayfinding performance (Gärling et al., 1981; Siegel and White, 1975) that benefits patients, institutions, and medical outcomes (Rodrigues et al., 2020). It reduces lost staff and patient time and users' dissatisfaction because of being disoriented, enhances staff concentration for not being interrupted to provide directions, and minimizes the costs of delayed or missed appointments. In hospitals and other healthcare units, wayfinding is generally emergency with patients or visitors aiming to find their destination as quickly as possible, either for an appointment or finding the emergency unit, or visiting a patient (Greenroyd et al., 2018). In this process, unfamiliarity with the setting and crowdedness puts the visitors in a stressful situation as they try to navigate and find their way within the space (Baskaya et al., 2004). In the case of outpatient polyclinics, complex floor layouts make wayfinding daunting for familiar and unfamiliar users. Navigating between diagnosis and analysis units of an outpatient polyclinic can be difficult because of poor signage, poor layout design and crowdedness (Baskaya et al., 2004). Being disoriented or uncertain of one's location can cause anxiety and distress in unfamiliar spaces (Gibson, 2009). This has gained even more importance with the outbreak of the COVID-19 virus and the increased anxiety and stress levels in healthcare units (Hau et al., 2020). Acquisition of spatial knowledge is a cognitive process involved in locating targets, estimating distance and directional associations, and perceiving objects’ orientation and position (Lawton, 2010). The landmark-Route-Survey (LRS) model of spatial knowledge, described by Siegel and White (1975), is still among the most accepted theories of spatial representation. Landmark knowledge refers to the identity of places (landmarks) and objects based on their salience, appearances, and subjective importance without knowing their relative spatial relationship (Iachini et al., 2009). It requires the acquisition of sensory and semantic information, storage of the representation in long-term memory, and the retrieval of the memory when prompted (Parong et al., 2020). Route knowledge connects the landmarks that are necessary to reach one point from another (Siegel and White, 1975). Survey knowledge (or configurational knowledge) is knowledge of the spatial layout and spatial relationships between objects and places. Survey knowledge demands the acquisition, storage, and retrieval of landmarks and routes and their orientations from long-term and working memory. Successful wayfinding requires all three types of spatial knowledge. A variety of tasks have been used to measure spatial knowledge such as cue recognition, object recall, pointing task, scene recognition task (Carassa et al., 2002), route drawing (Iaria et al., 2009), chronological scene classification, and sketch-mapping tasks (Gaunet et al., 2001; Lapeyre et al., 2011). Wayfinding is the real-world application of spatial knowledge that corresponds with spatial abilities such as spatial perception and mental rotation (Choi et al., 2006). Wayfinding relies on environmental cues such as landmarks and signage (spatial cues such as arrows, color coding, and directional texts) (Morag and Pintelon, 2021; Rodrigues et al., 2020). However, this system can be confusing because of the hospitals’ complex layouts and the overwhelming number of signs (Passini, 1984). Plan configuration, spatial landmarks, spatial differentiation, signage, and room numbers are cited as the factors that aid wayfinding (Weisman, 1981). Although these environmental cues ease wayfinding, there are also difficulties related to their use, such as highly reflective decorative elements, misleading lighting, and signage size and placement (Rousek and Hallbeck, 2011). Studies conducted on the use of signage as wayfinding aids suggest that signage alone cannot overcome architectural failures (Arthur and Passini, 1992), furthermore, increasing the number of signage has been found to decrease wayfinding performance (Carpman, 1984). Even well-designed signs may not provide enough cues for efficient wayfinding (Lee et al., 2014; Rousek and Hallbeck, 2011). The problems associated with the use of visual environmental cues exacerbate with visual impairment and cognitive decline associated with aging (Bosch and Gharaveis, 2017). Thus, in recent years, there has been a growing emphasis on the use of alternative methods such as digital wayfinding systems (Morag and Pintelon, 2021) and the use of auditory and haptic cues for all users, especially in spaces with a proliferation of visual signage (Devlin, 2014). Spatialized sounds emitted from specific decision points or landmarks are also among methods proposed by the literature (Bosch and Gharaveis, 2017). Although there has been developments in information and communication equipment, accessible wayfinding is still hard to achieve for the blind and partially sighted (Chandler and Worsfold, 2013). The attention devoted to spatial learning is among the factors that determine the successful acquisition of spatial knowledge (Albert et al., 1999). In the last 30 years, there has been a great deal of research on the automatic capture of spatial attention following the presentation of spatially nonpredictive cues (Spence and Santangelo, 2009). While the majority of the work has focused on the capture of spatial attention by visual cues (Wright and Ward, 1994, 2008), an increasing number of studies have started to investigate the attention-capturing properties of auditory cues (Ho and Spence, 2005; Spence and Driver, 1994). Research on crossmodal links in spatial attention indicates that the presentation of a cue from different modalities (e.g., vision and hearing) from the same spatial location facilitates spatial attention (Spence et al., 2004). Perception of space relies on integrating information from different modalities (Driver and Spence, 1998). Based on crossmodal links between different modalities, sudden sounds attract not only auditory attention but also visual and tactile attention to their location; likewise, abrupt touches attract auditory and visual attention towards them (Driver and Spence, 1998). Furthermore, recent studies suggest that sound has a leading effect on visual elements’ noticeability in a way that variations in sound level correspond with changes in visual attention (Liu et al., 2020). Regarding the importance of visual elements in acquiring spatial knowledge, it should be noted that visual reference points (e.g., church) are characterized by sound signals (e.g., church bells) (Karimpur and Hamburger, 2016). Thus, pairing visual cues with audio cues may help spatial knowledge acquisition. Designers of virtual worlds utilize various visual and auditory cues to draw attention towards a point of interest or a spatial goal. Nonverbal audio and spatial placement of audio in virtual spaces have been used as navigational cues in prior studies (Burkins and Kopper, 2015; Dodiya and Alexandrov, 2008; Lokki and Grohn, 2005; McMullen and Wakefield, 2014). Lokki and Grohn (2005) explored the use of audio and visual cues in a 3D virtual environment and found that audio cues were as helpful as visual cues. In another virtual environment, Burkins and Kopper (2015) investigated the effect of 3D sound as a wayfinding tool. They found that participants were faster in finding the correct target and had a higher performance in pointing tasks in the maze with audio cues. Hamburger and Röser (2014) compared recognition and wayfinding performance for verbal, visual, and acoustic landmarks (animal sounds) in a virtual environment and found a good recognition and wayfinding performance for acoustic landmarks. Another study found that an interactive exploration in a virtual environment with environmental sound provided sufficient spatial mental maps (Picinali et al., 2014). Marples et al. (2020) explored the effect of landmark, auditory, and illumination cues on player navigation in virtual mazes. The findings indicated that both lighting and audio cues reduced solve time when used in isolation; however, no reinforcement interaction was detected when they were used together. In another study, instead of using auditory cues, Chandrasekera et al. (2015) investigated the use of soundscape as auditory landmarks in wayfinding tasks. They found that soundscape provided navigation aids and enhanced immersion in virtual environments. In their study, a church, a market place, and a school soundscape were used in a virtual maze as auditory landmarks. Based on the studies mentioned above, it can be concluded that the addition of audio cues in a virtual environment would lead to better performance in spatial knowledge tasks. As can be seen in the mentioned studies, virtual environments are widely used in answering questions about spatial cognitive processes (Memikoğlu and Demirkan, 2020; Tang et al., 2009). Virtual environments provide an accurate representation of real environments (Westerdahl et al., 2006) while allowing systematic environmental manipulations that cannot be easily implemented in real environments (Kuliga et al., 2015). To achieve environmental comparability, it is vital to simulate naturalistic experiences in virtual environments (Bell et al., 2001). Sketches, photographs, and slide shows are traditional approaches to provide a natural setting in virtual environments (Bateson and Hui, 1992). Desktops and laptops are among common presentation devices that produce comparable results with high immersive virtual systems (Kalff and Strube, 2011; Kuliga et al., 2015) because they provide sufficient visual realism in spatial knowledge tasks (Green and Jacob, 1991; Parong et al., 2020; Sayers, 2004). It has also been stated that more immersive systems may lead to less behavioral realism because of the difficulties with controls. Virtual environments can be explored either passively or actively (Chrastil and Warren, 2013). A passive exploration model is recommended for indoor public spaces with predetermined routes (Cao et al., 2019). Theoretical framework The sound environment contains different sounds simultaneously (Raimbault and Dubois, 2005). Some of these sounds may attract the listener's attention more than others based on the physical characteristic of the signals and the meanings they carry (Papadopoulos et al., 2012). The sound environment of hospitals is generally described as chaotic and noisy (Löf et al., 2006), with high levels that fluctuate over time (Johansson et al., 2012), populated by speech and a variety of mechanical noises such as paging systems, floor cleaners, beeping alarms and air-conditioning systems (Ryherd et al., 2008). Through an exploratory study, the effect of the available sound sources in an outpatient polyclinic on spatial knowledge acquisition when combined with visual signage were investigated. The logic behind this is based on the findings on multisensory representation, characteristics of auditory attention, and auditory input processing. Multisensory representation suggests that a congruent appearance (in terms of time, location, and meaning) of sound stimuli with a visual target leads to better attention, perception, and memory because of providing more detail in comparison to unisensory presentations (Lehmann and Murray, 2005; Spence et al., 2004; Talsma et al., 2010; Werkhoven et al., 2014). Furthermore, the representation of sound objects in memory is more long-lasting than visual objects. Additionally, auditory input processing occurs earlier than visual input processing (Zimmermann et al., 2016). The information from different modalities is stored and processed in the working memory before being sent to long-term memory (Baddeley, 1992). The working memory comprises a visuospatial sketch pad, a central executive, and a phonological loop. The phonological loop holds speech-based and acoustic information while the visuospatial sketch pad processes visual and spatial information. In this sense, audio information provided by the sound environment of the outpatient polyclinic would be processed in the phonological loop, while the visual information would be processed in the visuospatial sketchpad. In that sense, if one of the modalities fails to encode or retrieve information, the second may still be successful (Butler et al., 2011). Previous research has shown that visual and spatial components of working memory are involved in acquiring landmark, route, and survey knowledge (Wen et al., 2011). Here, the aim was to assess whether receiving information from two different modalities (visual and audio) would aid the acquisition of spatial knowledge. Although the literature has stated the benefits of multisensory presentations on attention and memory, there are limited studies that have focused on the effect of multisensory presentations on spatial knowledge. The available ones have only looked at the effect of multisensory presentations on wayfinding and not on spatial knowledge tasks. With this gap in mind, the theoretical framework of the study presented in Fig. 1 was prepared. Based on this framework, the context provides environmental stimuli that can be visual, auditory, or tactile. The information from these modalities results in auditory and visual memory representations that are assessed independently. The phonological loop processes auditory information while visuospatial information is processed by the visuospatial sketchpad (Baddeley, 1992). These components of working memory lead to landmark, route, and survey knowledge that induce spatial knowledge acquisition (Wen et al., 2011). Within this context, it was hypothesized that the sound sources available in the acoustic environment of an outpatient polyclinic would lead to a better spatial knowledge acquisition when combined with visual signage.Fig. 1 The theoretical framework of the study. Fig. 1 What distinguishes this study from others is that while the majority of the studies have been conducted in virtual mazes with animal or object sounds as audio cues, this study has used audio and visual information derived from a real outpatient polyclinic in a simulated virtual environment. The motivation of this study is twofold. First, it aims to contribute to the studies conducted on spatial knowledge by looking at the role of the sound environment. Secondly, it is intended to provide grounds for using the sound environment as a design element to promote spatial knowledge by analyzing the physical and perceptual characteristics of the sound. In that sense, the following research questions are proposed.Q1 Is there any association between spatial knowledge acquisition among different components (control group, visual group, audio group, audio-visual group)? Q2 Is there any association between the sound sources and the remembered landmarks in the spatial knowledge tasks? 2 Materials and methods 2.1 Participants In this study, a convenience sample of 80 healthy students and employees from Bilkent University, Turkey was used. Analysis of the data in all tasks showed a statistical power of higher than 0.80; thus, this sample size was sufficient to detect significant effects. Since familiarity with the setting could be a determining factor in task performance, the experiment was conducted with parIntegrated Health Campus. The participants were randomly divided into four experimental groups that varied in the level of visual (signage) and audio (sound environment) stimuli, with 20 people (10 women and 10 men) in each group. Although the gender ratio is equal in all groups, participants' assignment to groups was random. All the participants were informed about the study protocol, voluntarily participated in the study, and filled a written consent form. The participants’ age distribution ranged from 19 to 40 years (mean = 27.16 years, SD = 4.527). Gender, age, education level, major, and nationality were collected as sample demographic information, shown in Table 1 .Table 1 Demographic characteristics of the participants in each experiment group. Table 1 Gender Education level Age Department Nationality F M University Masters/PhD M SD Engineer Design Science Other Turkish Iranian Other Group 1 10 10 5 15 28.6 4.97 11 2 5 2 8 9 3 25.0% 75.0% 55.0% 10.0% 25.0% 10.0% 40.0% 45.0% 15.0% Group 2 10 10 2 18 27.2 3.82 13 3 0 4 7 9 4 10.0% 90.0% 65.0% 15.0% 0 20.0% 35.0% 45.0% 20.0% Group 3 10 10 13q 7 24.65 3.93 7 5 1 7 15 5 0 65.0% 35.0% 35.0% 25.0% 5.0% 35.0% 75.0% 25.0% 0 Group 4 10 10 5 15 28.2 4.51 13 5 2 0 9 10 1 25.0% 75.0% 65.0% 25.0% 10.0% 0 45.0% 50.0% 5.0% Total 40 40 25 55 27.16 4.52 44 15 8 13 39 33 8 2.2 Virtual environment In this study, the outpatient polyclinic of Bilkent Integrated Health Campus in Ankara was simulated to create a desktop virtual environment with predetermined routes that did not involve active wayfinding tasks. This hospital is the largest city hospital in Turkey (Kerman et al., 2012; Özkan, 2018) and serves as one of the hospitals to treat COVID-19 patients. This outpatient polyclinic has a large area and complex layout that make it a suitable choice for study. Fig. 2 presents the schematic plan of the outpatient polyclinic with the traveled route. A detailed description of the visual signage is provided in Appendix D.Fig. 2 The outpatient polyclinic plan shows the entrance, the traveled route, the elevators, the escalators, and the patient administration desks. The interior pictures were taken from 1, 2, and 3. All the landmarks assessed (and omitted in group 3) are shown in the figure. The escalators and the elevators had distinct sounds. Fig. 2 The real outpatient polyclinic was visited to capture a visual and audio recording of a route starting from the main entrance leading up to the neurology department. A Canon Power Shot G10 equipped with a binaural microphone was used to collect the real environment's visual and audio data. Fig. 3 shows interior pictures of the space.Fig. 3 Interior pictures of the real environment showing the escalators, the staircases, and the patient administration desks. Fig. 3 Chief Architect Premier X11 was used to create a 3D simulation of the space. The scenes were rendered in real-time at a speed of 20 frames per second (Min and Ha, 2020). A video of the specified route was created by using the Walkthrough path tool for passive exploration. This route was similar to the one that was recorded in the real environment. Similar to previous virtual environments, the route was shown with a plain ceiling with sufficient contrast between the floor and the walls. No light sources were used to avoid directional cues from shadows (Sharma et al., 2017). The route was made of uniform and undistinguishable paths and neutral-colored walls so that the walls did not provide wayfinding cues (Lingwood et al., 2015). A simple model with grey-scale textures and little detail was preferred to assess users’ performance in isolation from other factors as recommended by the literature (Kuliga et al., 2015; Natapov et al., 2015; Von Stulpnagel et al., 2014). Fig. 4 presents renderings of the virtual environment.Fig. 4 Interior renders of the simulated virtual environment representing the skylight, the escalators, and patient administration desks. Fig. 4 2.3 Experimental stimuli Three different videos were created with the walkthrough path tool. One of the videos had the exact visual signage and landmarks from the real environment. The other one was wiped of all the available signage to create the control group's experiment setting, and the last video was wiped of all the visual signage and landmarks to create the set up for the only audio group. The presented and omitted landmarks and signage are depicted in Fig. 2. The escalators, admission desks, elevators, and staircases were the landmarks. The escalators and visitor elevators had a distinct sound that stood out against the background sound. The justification for removing the signage and the landmarks was assessing the effect of sound environment on spatial memory when used in isolation versus when it was used in combination with visual signage and landmarks to see if the effect of audio and visual cues on spatial knowledge acquisition interacts with each other. The videos with the visual signage and the one with no landmarks were reproduced by adding audio to them with Cyberlink Power Director editing software. Clapping was used to synchronize the video and sound information. Overall, four different experimental models were created that are:• Group 1 (control group): No visual and no audio information was provided in the virtual environment. • Group 2 (visual group): Visual signage was provided in the virtual environment. • Group 3 (only-audio group): All landmarks and visual signage were removed from the virtual environment. Only the sound environment was available. • Group 4 (audio-visual group): Visual signage and polyclinic sound environment were provided in the virtual environment. It should also be mentioned that the original study included groups 1,2 and 4. After analyzing the data, in order to enhance the study, group 3 was added later. The models were animated with a wide-angle lens following the route to provide a 65-degree field of view and a more immersive virtual environment (Lee and Kline, 2011). Fig. 5 represents screenshots of each experiment group.Fig. 5 Created videos for each experiment group from left to right: Control group, Visual group, only-audio, and audio-visual group. Fig. 5 The simulated eye height was set to 1.60 m from the floor, and walking speed was a constant of 1.1 m/s (Haq et al., 2005; Lee and Kline, 2011; North, 2002). The video duration was 185 s (including stops before the intersections). The route was identical for the different conditions, with a length of 154 m and eight direction changes (three times left, five times right). A 17-inch Asus personal computer was used (2.59 GHz, 16 Gb RAM with an nVidia GeForce GTX 960) as an apparatus to provide visual information. The laptop was placed on a desk, and the participants sat in a chair approximately 50 cm from the screen. Each participant undertook the test individually and without interruption in the experimenter's office with closed doors and windows. Binaural signals of the soundscape were delivered by computer through headphones (ROG Strix Fusion 300 7.1) (Shu and Ma, 2018). 2.4 Procedure The scenario of the test was introduced to the participants before the test. Participants were asked to watch a video of a route and recall details such as where to turn and certain architectural elements. A questionnaire (See Appendix A and B) was handed out to each participant before viewing the video. Before watching the video, the participants were asked to answer demographic information about themselves. The participants’ hearing was tested with the Widex online hearing test. All the participants had normal hearing. Although there were no sound stimuli in the control group (group 1) and visual group (group 2), all the participants were asked to wear headphones for standardization and to create a feeling of presence (Liu et al., 2020; Marples et al., 2020). After the hearing test and filling in demographic information, the participants watched the video. The video started from the outpatient polyclinic entrance, traveled across the patient admission desks and elevators, and finally arrived at the destination, the neurology department. The plan of the space was not available to the participants during the learning phase. Fig. 6 presents a schematic flowchart of the procedure.Fig. 6 Schematic flowchart of the study. Fig. 6 2.5 Performance tasks After watching the video, all groups were asked to do five different spatial memory tasks using the Landmark-Route-Survey model representation (Cogné et al., 2018). A landmark placement task was used to measure landmark knowledge. In this task, the participants were presented with a schematic plan of the outpatient polyclinic that showed the beginning of the route. They were asked to place the escalator, the staircases, the elevators, and the patient administration desks on the blank plan as accurately as possible similar to previous studies (Meneghetti et al., 2017; Muffato et al., 2017). For scoring purposes, the completed sketch maps were scanned and uploaded each plan to Gardony Map Drawing Analyzer (GMDA version 1.2) (Gardony et al., 2016). This software is based on a bidimensional regression method (Friedman and Kohler, 2003) and compares the landmarks' location on the map and their Cartesian coordinates previously calculated on the target layout. The program generates several parameters. Like previous studies, the canonical organization's square root (SQRT-CO), ranging from 0 to 1, as a global index of accuracy was considered (Muffato et al., 2017). A higher score indicates a better performance. See Appendix C for details of the tasks. A direction choosing and scene sorting task were used to measure route knowledge. For the direction choosing at different decision points, the participants were asked to watch the video again, but this time the video would pause at each decision point, and the participants were asked to choose the correct direction (straight, right, and left) at each point (6 points to choose), on the questionnaire. Feedback was provided to the participants after answering each question, similar to previous studies (Muffato et al., 2020). Percentages of correctly taken directions were considered for scoring purposes similar to previous studies (Wen et al., 2011). In the scene sorting task, the participants were presented with eight pictures taken along the route and asked them to sort them chronologically, similar to previous studies (Wallet et al., 2011). In this task, the sorting errors were counted. This score was then compared to the best possible score (i.e., 8) to obtain percentages. A sketch mapping and a pointing task were used to measure survey knowledge. In the sketch-mapping task, the participants were presented with the plan showing the escalators' location, the staircases, and other architectural elements and asked them to draw the route they had watched on the video (Wallet et al., 2011). A pass or fail method was used to analyze the data (Cogné et al., 2018). In the pointing task, the participants were asked to imagine standing at a given landmark, facing another, and pointing to a third (Muffato et al., 2017). For scoring purposes, the circular mean of the minimum angles between each participant's response and the correct direction (0–180°) was considered (Borella et al., 2015; Muffato et al., 2017). The final pointing score consisted of the mean error score for the four pointing tasks. Additionally, the participants in groups 3 and 4 filled in “Method A” of ISO/TS 12913–2:2018 questionnaire on the sound environment (Acun and Yilmazer, 2018, 2019; ISO, 2018; Orhan and Yilmazer, 2021). The first part of the questionnaire classifies the sound sources into four categories: traffic noises, other sounds, sounds from human beings, and natural sounds on a scale from “1-not at all to 5-dominates completely”. The second part examines the sound environment's perceived affective quality based on eight perceptual attributes (pleasant, chaotic, vibrant, uneventful, calm, annoying, eventful, and monotonous) on a scale from “1-strongly disagree to 5-strongly agree”. The perceived affective quality is based on a two-dimensional model proposed by Axelsson et al. (2010). This modal is defined by four bipolar factors: the two orthogonal factors, Pleasantness and Eventfulness, which are located at a 45° (degrees) rotation from the second set of orthogonal factors, Calmness, and Excitement. According to this model, an exciting soundscape is pleasant and eventful, whereas a calm soundscape is pleasant and uneventful. In the same way, a chaotic soundscape is unpleasant and eventful, whereas a monotonous soundscape is unpleasant and uneventful. The data is generally presented on a radar graph to demonstrate the association between the attributes based on each attributes' mean score. The third part of the questionnaire assesses the sound environment on a scale from 1-very bad to 5-very good, and the fourth part analyzes the appropriateness of the sound environment on a scale from 1-not at all to 5-perfectly. 2.6 Data analysis The Statistical Package for the Social Sciences (SPSS 25.0, IBM, USA) was used to analyze the data. All tasks showed good internal reliability (Cronbach's α from 0.70 to 0.88). Leven's test in all tasks indicated homogeneity of variance; thus, parametric tests were used to analyze the data. A one-way ANOVA was used to analyze the data between the groups in all tasks except the sketch mapping task. A Scheffe Test was used as a post-hoc test to make pairwise comparisons between the groups. In the sketch mapping task, since the data was categorical (fail or pass), a chi-square test was used to make pairwise comparisons between the groups. 3 Results 3.1 Spatial knowledge performances in each task Task 1 (Landmark placement on a sketch) analysis: The results indicated a significant difference between the subjects’ performance; F (3,76) = 17.037, p < 0.001, ƞ2 = 0.402 (observed power = 1.000). Scheffe Post Hoc Test was applied to compare performance in a pairwise fashion. There was a significant difference between group 1 and group 4, p < 0.001, and between group 2 and group 4, p < 0.001, and between group 3 and 4, p < 0.001; however, there was no significant difference between group 1 and group 2 (p = 1.000), group 1 and 3 (p = 0.138), and 2 and 3 (p = 0.149). The participant in group 4 scored higher (mean score = 0.777) than group 2 (mean score = 0.497), group 1 (mean score = 0.499) and group 3 (mean score = 0.355). See Fig. 7 for the representation of the data analysis between the experiment groups in task 1. Crosstabs were also prepared on the association between the remembered landmarks and the experiment groups, as seen in Table 2 .Fig. 7 Mean scores in the landmark placement (Task 1) across the four experimental groups. Each panel displays performance for the control, visual group, only audio group, audio-visual group conditions. Significant differences are indicated by asterisks that denote a significance level of p < 0.05. Fig. 7 Table 2 Association between the remembered landmarks and the experiment groups. Table 2 Escalator Admission 1 Admission 2 Elevator 1 Elevator 2 Staircase 0 1 0 1 0 1 0 1 0 1 0 1 Group 1 2 18 12 8 12 8 13 7 18 2 9 11 10.0% 90.0% 60.0% 40.0% 60.0% 40.0% 65.0% 35.0% 90.0% 10.0% 45.0% 55.0% Group 2 4 16 7 13 12 8 10 10 19 1 11 9 20.0% 80.0% 35.0% 65.0% 60.0% 40.0% 50.0% 50.0% 95.0% 5.0% 55.0% 45.0% Group 3 5 15 14 6 20 0 14 6 20 0 20 0 25.0% 75.0% 70.0% 30.0% 100.0% 0.0% 70.0% 30.0% 100.0% 0.0% 100.0% 0.0% Group 4 0 20 3 17 7 13 2 18 11 9 8 12 0.0% 100.0% 15.0% 85.0% 35.0% 65.0% 10.0% 90.0% 55.0% 45.0% 40.0% 60.0% Total 11 69 36 44 51 29 39 41 68 12 48 32 13.8% 86.3% 45.0% 55.0% 63.7% 36.3% 48.8% 51.2% 85.0% 15.0% 60.0% 40.0% In the landmark placement task, the escalators were correctly placed on the plan by at least 75% of the participants in all groups. The first admission desk was missed by at least 60% of the participants in the control and only audio group, while more than 65% of the participants in the visual and audiovisual group placed it correctly on the plan. In the case of the visitor's elevator (elevator 1), more than half of the participants in group 1 missed this landmark while 50% of the participants in the visual group placed it correctly. 70% of the participants in the only audio group had misplaced the visitor's elevator while 90% of the audio-visual group placed the elevators correctly. The second elevators were missed by more than 90% of the participants in group 1, 2 and 3 while 55% of the participants in the audio-visual group remembered it correctly. The second admission desk was missed by 60% of the participants in group 1 and 2 and all the participants in the only audio group. 65% of the participants in the audiovisual had placed it correctly. The staircase was missed by 45% and 55% of the participants in group 1 and 2 respectively. All the participants in the only audio group had missed the staircase while 60% of the participants in the audiovisual group had remembered it correctly. Task 2 (Direction choosing at decision points) analysis: Comparison of the percentages of correct answers showed a significant difference between the groups in this task. F (3,76) = 3.843, p = 0.013, ƞ2 = 0.131 (observed power = 0.802). Scheffe Post Hoc Test was applied to compare performance in a pairwise fashion. There was a significant difference between group 1 and group 4, p = 0.022. There was no significant difference between group 1 and group 2 (p = 0.391), group 1 and 3 (p = 0.913), 2 and 3 (p = 0.792), 2 and 4 (p = 0.553), and 3 and 4 (p = 0.115). The bar graph shows the mean scores in group 4 (mean score = 95.832), group 2 (mean score = 87.49), group 3 (mean score = 81.64), and group 1 (mean score = 77.94). Fig. 8 presents the mean scores across all four groups.Fig. 8 Mean scores in direction choosing (Task 2) across the experiment groups. Fig. 8 Task 3 (Sorting task) analysis: Comparisons of percentages of correctly ordered pictures indicated a significant effect of the experiment group on performance; F (3,76) = 5.183, p = 0.003, ƞ2 = 0.170 (observed power = 0.912). Scheffe post hoc test indicated a difference between group 1 and group 4 (p = 0.009) and group 2 and group 4 (p = 0.026). No difference was detected between group 1 and group 2 (p = 0.984), 1 and 3 (p = 0.299), 2 and 3 (p = 0.507), and 3 and 4 (p = 0.469). The mean scores, as shown on Fig. 9 , show a trend towards group 4 (mean score = 86.875) performing better than group 3 (mean score = 71.87), group 2 (mean score = 57.50), and group 1 (mean score = 53.75).Fig. 9 Mean scores in the sorting task (Task 3) across the experiment groups. Each panel displays performance for the control, visual group, only-audio and audio-visual group. Significant differences are indicated by asterisks that denote a significance level of p < 0.05. Fig. 9 Task 4 (Sketch-mapping) analysis: In this task, the aim was to analyze whether the experiment group had any impact on passing or failing drawing the sketch map. Since the data were categorical, a Chi-square test was used to analyze the data. Results showed a significant difference between the groups, X2 = 13.759, p = 0.003. Z scores were compared to see where the significance existed; p-values were adjusted with the Bonferroni method to avoid type 1 error (Beasley and Schumacker, 1995). The results suggested a significant difference between passed or failed sketch maps in group 1 and group 4 (X2 = 12.379, P < 0.001), 2 and 4 (X2 = 8.640, p = 0.003), 3 and 4 (X2 = 5.584, p = 0.018). However, no difference existed between groups 1 and 2 (X2 = 0.440, P = 0.507), 1 and 3 (X2 = 1.667, p = 0.197), 2 and 3 (X2 = 0.404, p = 0.525) in the proportion of passed or failed drawn sketch maps. The percentages of the correct answers within each group were compared. 30.0% in group 1, 40.0% in group 2, 50% in group 3, and 85.0% of the participants in group 4 successfully drew the sketch mapping task. Table 3 presents the percentages of the correct and the wrong sketch maps.Table 3 Number and percentages of correct and wrong sketch-maps (Task 4) across the groups. Table 3 Control group Visual group Only-Audio group Audio-visual group Wrong 14 12 10 3 Within Groups 70.0% 60.0% 50.0% 15.0% Correct 6 8 10 17 Within Groups 30.0% 40.0% 50.0% 85.0% Table 4 Summary of ANOVA and mean scores across all tasks. Table 4Tasks df F p Experiment Groups Scores Landmark placement 3 17.037 p < 0.001 Control group 0.499 Visual group 0.497 Only audio group 0.355 Audio-visual group 0.777 Direction choosing 3 3.843 0.01 Control group 77.94 Visual group 87.49 Only audio group 81.64 Audio-visual group 95.83 Scene sorting 3 5.183 0.003 Control group 53.75 Visual group 57.50 Only audio group 71.87 Audio-visual group 86.87 Sketch mapping 3 13.759a 0.003 Control group 30b Visual group 40 Only audio group 50 Audio-visual group 55 Pointing task 3 13.285 p < 0.001 Control group 92.60 Visual group 54.18 Only audio group 37.62 Audio-visual group 17.99 a X2 values have been reported here. b Is the percentages of correctly drawn sketch maps. Task 5 (Pointing task) analysis: The results indicated a significant effect of experiment group on performance; F (3,76) = 13.285, p < 0.001, ƞ2 = 0.344 (observed power = 1.000). Scheffe test indicated a significant difference between group 1 and group 2 (p = 0.026), between group 1 and group 3 (p < 0.001), 1 and 4 (p < 0.001), and 2 and 4 (p = 0.041). There was no significant difference between groups 2 and 3 (p = 0.613), and 3 and 4 (p = 0.470). The average deviation from the correct direction was the lowest for group 4 with 17.99°, followed by group 3 with 37.62° and group 2 with a 54.18-degree deviation. Group 1 had the worst performance with a 92.60-degree deviation. Fig. 10 represents the data analysis in the pointing task.Fig. 10 Mean scores in the pointing task (Task 5) across the experiment groups. Each panel displays performance for the control, visual, only-audio, and audio-visual conditions. Significant differences are indicated by asterisks that denote a significance level of p < 0.05. Fig. 10 Overall, the results indicate a significant effect of the experiment group on acquiring spatial knowledge. Table 4 summarizes the ANOVA results and mean scores of the tasks across the experiment groups. 3.2 Perceptual analysis of the sound environment To understand participants’ perception of the overall sound environment, the participants in groups 3 and 4 were asked to watch the video again and fill in Method A of the ISO/TS 12913–2:2018 (ISO, 2018) questionnaire after finishing the spatial knowledge tasks. Fig. 11 shows the categories of the sounds heard by the participants in both groups. Human sounds were the dominant sounds in both groups.Fig. 11 Classification of sounds heard in the soundscape. Fig. 11 The radar graph presented in Fig. 12 shows the participants’ perception towards the sound environment through two orthogonal components of valence (annoying-pleasant) and activation (uneventful-eventful). Any perceptual outcome in the pleasant region is a positive sound environment (pleasant, calm, vibrant), while outcomes located in the annoying region make up a negative sound environment. The emotional assessment of the sound environment shows convergence towards the eventful-chaotic-annoying region that presents a negative sound environment.Fig. 12 Two-dimensional model of perceived affective quality based on means. Fig. 12 Fig. 13 and Fig. 14 present participants' assessment of the sound environment and its appropriateness, respectively. The majority of the participants in group 3 rated the sound environment as neither good nor bad, while the majority of the participants in group 4 rated it as good. In terms of the sound environments’ appropriateness, the majority of the participants in both groups rated it as either moderate or very much.Fig. 13 Assessment of the sound environment. Fig. 13 Fig. 14 Appropriateness of the sound environment. Fig. 14 3.3 Physical analysis of the sound environment This section discusses the role of the sound environment and its mechanism on how it may have promoted spatial knowledge by analyzing the recorded sound's content. To provide an empirical analysis of the sound environment, a detailed time-frequency analysis, not limited to temporal ones, was conducted, depicted in Fig. 15 . The spectrogram reveals the changes in the frequency content of the signal over time. The Fourier coefficient of each time-frequency pixel has been encoded in color in which the dark red and blue indicate two extremes of high and low coefficient amplitude, respectively. Based on this time-frequency content, the spectrogram has been divided into several temporal segments indicated by dashed red vertical red lines. The first segment (0–31s) is a temporal portion of the signal from the entrance to the escalators, which shows specific high-frequency content around 400 Hz with a wide bandwidth. The second segment (31s–75s) has a different time-frequency pattern indicating less prominent high-frequency content. This part of the route is from the escalators to the beginning of the patient admission desks. The third segment (75s–92s) has lower frequency variations and less prominent features in the frequency content that matches the acoustic experience of the participants along the patient administration desks. In the next segment (92s–132s), the elevator area has unique tones, which can be seen as short-term bursts around frequencies 0.5 kHz and 1.2 kHz. The fifth segment (132s–156s) indicates the transient time from the elevator area toward the neurology department entrance, which has distinct patterns than previous ones. This segment has a low amplitude auditory event and is generally quieter than previous segments. The final segment (156s–185s) has distinct frequency content and patterns in low and mid frequency levels along the neurology department. If the analyzed segments are matched to the route's video, it can be seen that each sound segment has taken place in a different space of the outpatient polyclinic. A change in the sound environment's content takes place with a change in the route's direction. The change in amplitude and frequency of the sound environment along the route may have attracted the participants' attention towards the route and other visual elements, resulting in better performance in the spatial knowledge task.Fig. 15 Short-time frequency transform (STFT) of the sound signal. Fig. 15 4 Discussion This study examined whether adding the sound environment would enhance spatial knowledge task performance in a virtual outpatient polyclinic. A significant effect of the experiment group on spatial knowledge acquisition was found in all of the tasks. The audio-visual group had the best performance among the groups in all of the tasks. Another interesting finding of the study was no significant difference between the performance of the only audio group and the visual group. Although the video that the only audio group watched was wiped of all the landmarks such as escalators, admission desks, and elevators, the performance of the participants was comparable to the other groups. In the landmark placement task, the audiovisual group had a significantly higher performance than all the other groups. At the same time, there was no difference between the performance of the only audio group and the visual and control group. Considering that no landmarks were available in this group, it can be concluded that the sound environment is sufficient to provide landmark knowledge. Based on the percentages reported in Table 2 and Fig. 15, it can be seen that the landmarks with sound were remembered better in the only audio and audiovisual group. In the direction choosing task, the control group had a significantly lower performance than the audiovisual group, but the visual group, only audio and audiovisual group, had a similar performance. In the sorting task, groups 1 and 2 had a significantly lower performance than the audiovisual group. Again, the only audio group had similar performance with the audiovisual group. The audiovisual group had a significantly higher performance. Considering the unavailability of landmarks in the only audio group, the existence of the sound environment has been found sufficient to achieve route knowledge similar to landmark knowledge. In the sketch-mapping task, similar to the previous tasks, the audiovisual group had a significantly higher performance. There was no significant difference between the performance of the control, visual and only audio groups. In the pointing task, the control group had a significantly lower performance than the other groups. While the visual group had a lower performance than the audiovisual group, there was no difference between the performance of the only audio group and the audiovisual group. Thus, similar to landmark and route knowledge, survey knowledge can also be achieved through the sound environment in the absence of visual cues. This finding indicates that spatial knowledge can be gained without landmarks, which is in line with the findings of Allen (1988). It should also be mentioned that there was no significant difference between the visual and control group except for the pointing task. This shows that visual signage used in isolation does not necessarily enhance performance as stated in the introduction (Lee et al., 2014; Rousek and Hallbeck, 2011). The audiovisual group's significantly higher performance is consistent with the theoretical framework in Fig. 1 that suggests gathering information from different modalities would lead to a better memory and, therefore, better spatial knowledge. In the audiovisual group, both the phonological loop (sound environment) and visuospatial sketchpad (signage and the surrounding visual environment) are processing information. The dual processing of information may explain the high performance of the audiovisual group in comparison to the other groups. Another speculation is that the sound environment, with its fluctuations across the route, had a better pop-out effect, which is one of the characteristics of good landmarks (Lynch, 1960). The simulated virtual polyclinic is visually uniform with no lighting and color contrast between different route sections, while the sound environment has unique and discernible peaks and dips that may have made the visually uniform spaces distinguishable from each other. However, rather than any environmental sound, the exact sound environment of the traveled route in the outpatient polyclinic with its own unique physical and perceptual characteristics was used. Based on the short-time frequency transform analysis of the signal, it can be seen that the frequency and amplitude of the signal change along the route. Loudness or amplitude, a subjective characteristic of sound, is a perceptual cue for humans and allows them to distinguish different sounds and is related to pressure level and energy distribution in frequency and time (Buus et al., 1997; Jepsen et al., 2008; Secchi et al., 2017). The changes in frequency and amplitude of the signal along the route may have attracted the participants' attention towards the decision points that helped them perform better in spatial knowledge tasks. Another explanation could be that visual cues add semantic context for the audio cues leading to a better performance in spatial knowledge tasks. Stimulation of the auditory cortex leads to increased activation in the visual cortex (Tranel et al., 2003). The addition of the sound environment may have enhanced activation of the visual cortex leading to a better performance in the audiovisual group. Furthermore, as the radar graph in Fig. 12 indicates, the sound environment was perceived as chaotic and annoying, associated with arousal. Based on the findings of Thompson et al. (2001), a sound stimulus that is moderately arousing can enhance spatial abilities. The arousing nature of the sound environment may be another reason why the sound environment led to a higher spatial knowledge performance. It should also be mentioned that although the sound environment is perceived negatively, the participants have assessed it as appropriate because appropriate differs from desired (Axelsson, 2015; Orhan and Yilmazer, 2021). Audio and visual information in the built environment interact and affect one another (Jeon and Jo, 2020). Audio stimuli that correspond with visual stimuli have a leading effect on visual attention (Liu et al., 2020). In our study, the availability of certain sounds in the sound environment that correspond with a visual element may have attracted the participants’ attention, leading to higher performance in spatial knowledge tasks. An example of this audio-visual interaction can be seen in the elevators. The elevator is seen and the sound of its doors opening and closing is heard, in addition to floor announcements and beeping in the background. Furthermore, considering the use of sound in isolation, a significantly better performance of the audio-visual group can be seen, while in most tasks, there was no significant difference between the visual and only audio group and only audio and audiovisual group. While the combination of visual and audio cues has led to better performance, there is no difference between the performance of the visual and the only audio group. Thus, the sound alone does not lead to a better performance than visual signage, which is in line with the findings of Liu et al. (2020). In their study in railway stations, Liu et al. (2020) conclude that audiovisual interactions and the leading effect of sounds on visual elements can be used in the process of wayfinding system design. An active wayfinding task was not conducted, but good spatial knowledge leads to good wayfinding performance. The findings are also consistent with those of Werkhoven et al. (2014). They compared the effect of visual, auditory, and audiovisual landmarks on spatial memory and navigation in a virtual maze and found better performance in maze drawing, adjacency, and wayfinding tasks for the audiovisual group. Another study with comparable results to ours was conducted by Hamburger and Röser (2014). They compared wayfinding performance for verbal, visual, and acoustic landmarks (animal sounds) in a virtual environment. In their study, acoustic landmarks resulted in good recognition and performance. In contrast to our findings, Chandrasekera et al. (2015) found no significant effect of soundscape on wayfinding in a virtual maze. The first experiment group int their study had only soundscape landmarks, the second group had only visual landmarks and the third had both visual and soundscape landmarks. The effect of soundscape was significant on immersion however it did not have any significant effect on wayfinding. The reasons behind the contrasting findings can be that in this study the sound environment of the outpatient polyclinic was used as a whole, representing an existing/naturalistic environment, while they used a church, a market place and a school as visual and soundscape landmarks. Another difference is that while we used different tasks to measure aspects of spatial knowledge, they only used mean time to reach the goal as a measure for wayfinding performance. Another interesting finding of the study is that there was no significant difference between the performance of the visual group and the control group in all of the tasks except for the pointing task. This may be explained by Arthur and Passini (1992) ‘s work that states adding signage to facilitate wayfinding does not overcome architectural failures because the ability to read the space is more critical than in situ sign system and signage (Carpman and Grant, 1995; Erkan, 2018). Rousek and Hallbeck (2011) and Lee et al. (2014) indicate that even well-designed signs do not provide enough information to ease wayfinding. Some studies suggest that users ignore graphical expressions and sign objects during wayfinding (Dogu and Erkip, 2000) because the visual system is already occupied with the route's information (Hamburger and Röser, 2014). In the pointing task, individual factors, visuospatial working memory, and rotation abilities affect task performance (Meneghetti et al., 2018). This may explain the significant difference between the groups in this task. More research needs to be done about the other factors that may have caused this significant difference. Overall, the study confirms the existence of a difference between spatial knowledge acquisition among different experiment groups. The audiovisual group's high performance demonstrates the beneficial effect of sound environment on spatial knowledge acquisition. One limitation of the study is that it cannot be determined whether adding any type of sound would lead to similar results. Other routes and other complex interior spaces such as airports and shopping malls need to be investigated to see if similar results would be achieved. Other limitations of our study are having a non-immersive virtual environment and tasks that are solely based on passive exploration. Although passive exploration has yielded similar results to active exploration studies, adding a task based on active exploration may have enriched our study. Despite these limitations, our study contributes to the available research on spatial knowledge in hospitals. 5 Conclusions A developed spatial knowledge leads to improved wayfinding performance. Thus, it is essential to investigate alternative and cost-efficient factors other than visual stimuli that affect spatial knowledge acquisition. Modalities apart from vision are suitable for developing mental spatial images that lead to successful navigation. Visual information can be ignored simply by looking in another direction; however, this is not the case for audio information. Thus, it is easier to use sound as a resource for spatial knowledge acquisition. This may be important for the aging population and patients with visual disabilities who rely on hearing for spatial information. As mentioned earlier, the participants in the audiovisual group had a significantly higher performance than the other groups; furthermore, the group with only audio had similar or better performance than the visual group. This indicates that even without visual landmarks, the sound environment can compensate and provide sufficient cues for acquiring spatial knowledge. The landmarks that were placed correctly on the sketch map were generally the ones with a unique sound. This finding can be used to create soundmarks that aid spatial knowledge and thus wayfinding. Considering navigation issues associated with visual elements such as signage and the positive effect of adding the sound environment in spatial knowledge tasks, more studies should consider the role certain sound sources can play as soundmarks. Hospitals are generally associated with high sound levels due to reflections from hard surfaces and noise from equipment and people with little consideration on designing the sound environment. The sound environment of the outpatient polyclinic in this study was perceived negatively; however, its addition to the virtual environment aided spatial knowledge acquisition. Thus, even adverse components of the sound environment can be used positively. From a design perspective, our study is a stepping stone for future studies that would focus on sound characteristics such as loudness, pitch, and affective qualities on the formation of soundmarks that can be employed at crossroads, transition spaces, or joint points to aid spatial knowledge acquisition. Based on the results following conclusion can be drawn.1. A combination of visual signage and sound environment resulted in higher performance across landmark, route, and survey tasks. 2. No significant difference was found between the performance of the visual group and the control group that shows that signage alone cannot aid spatial knowledge in virtual outpatient polyclinics. 3. The sound environment would be an efficient tool in enhancing spatial knowledge in virtual outpatient polyclinics. 4. The landmarks associated with a sound can compensate for the lack of visual landmarks that can help design a wayfinding system for users with visual disabilities. Author contributions Conceptualization, S.Y, and D.D.; Methodology, S.Y.; Software, D.D.; Visualization, D.D.; Formal analysis, D.D.; Investigation, D.D.; Data curation, D.D.; Resources, S.Y.; Writing—original draft preparation, D.D.; Writing—review and editing, D.D. and S.Y.; Supervision, S.Y. Funding “This research received no external funding”. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Appendix A Supplementary data The following is the Supplementary data to this article:Multimedia component 1 Multimedia component 1 Acknowledgments The authors would like to thank Sadid Sahami for his assistance in preparing the sound signal diagrams. We also thank graduates and employees of Bilkent University who participated in the study. This research is conducted as part of a Ph.D. study in I.D. Bilkent University. Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.apergo.2021.103672. ==== Refs References Acun V. Yilmazer S. A grounded theory approach to investigate the perceived soundscape of open-plan offices Appl. Acoust. 131 2018 28 37 Acun V. Yilmazer S. 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==== Front Public Organiz Rev Public Organization Review 1566-7170 1573-7098 Springer US New York 694 10.1007/s11115-022-00694-x Article Digital Transformation: Exploring big data Governance in Public Administration http://orcid.org/0000-0003-2999-2982 Yukhno Alexander [email protected] grid.445043.2 0000 0001 1431 9483 Institute of Public Administration and Civil Service of the Russian Presidential Academy of National Economy and Public Administration, 76, Prospect Vernadskogo, 119454 Moscow, Russia 13 12 2022 115 30 7 2022 17 11 2022 8 12 2022 © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. As economies become increasingly data-driven, big data technologies and software products are turning into key tools for managing technological processes in real time for more efficient delivery of public services to citizens. The change in the interaction between the state and society implies the creation of a unified state digital ecosystem, centered around big data. Such paradigm calls for rethinking of public administration principles ensuring the transition from an electronic state to a digital one. As a result, the likelihood of creating values that meet the shifting expectations of citizens in relation to public services increases. Keywords Artificial intelligence Big data Digital transformation Public administration ==== Body pmcIntroduction Nowadays big data technologies and software products are turning into key tools for managing digital transformation. The development of the state and society interaction implies the creation of a unified state digital ecosystem with dig data placed in the center. The global big data market is projected to grow to US$ 103 billion by 2027, more than double the market size in 2018. At the same time software will become the largest big data market segment by 2027 with a share of 45% (Mlitz, 2021). Investments in big data, artificial intelligence and machine learning technologies (Yukhno, 2019) are essential for the development of this area. Its volume depends on the industry and market segment. For example, the 2021 Global Data survey shows that for the pharmaceutical industry, big data (51%) and artificial intelligence (51%), along with APIs and digital platforms (39%), will be the most important investments in the next two years (Big data and AI are likely to lead emerging technology investments: Survey, 2021). Surveys show that most of these investments spent on the budget for ICT solutions (55%), training employees (48%), hiring new employees (30%) and paying for external technical consultants (26%). Financing of such investments mainly comes from the IT budget (46%), implying that big data is still considered a technical issue (Big data is a job engine, n.d). The COVID-19 pandemic has contributed to the implementation into practice the tools and processes for working with big data, which reflects the key technological trends of state and corporate development and have the greatest potential impact on the competitive advantages of states and organizations in the coming years. Methodology The current study presents a comprehensive analysis of big data governance in public administration. The author applies empirical and comparative analysis, expert assessments, synthesis, deduction, and induction to draw the conclusions. Big data is becoming an increasingly important intangible asset for states and organizations that affects the implementation of their strategies and competitive advantages in the market. Thus, the key technological trends in a state and corporate development concerning data-driven public administration in the post-Covid period were examined.In this context the following aspects of big data application were studied: the main features of big data and reasons for introducing it to public administration, the critical challenges to its efficient application and a data-driven public sector. Based on the results obtained, the need to create a unified state digital ecosystem with data and algorithms in the center is logically justified. The article begins with a brief overview section. The next part presents the analysis and findings about efficient big data application. It is followed by discussion on a path to efficient data-driven public administration and its implications for states and organizations. The article is concluded with final remarks and discissions for further research. Big Data As a New Effective Tool For States and Organizations Altough big data existed in the past, the widespread adoption of the term is credited to C.Lynch, the editor of the Journal Nature, who used it in 2008 in an issue dedicated to the explosive growth of the world’s information (Lynch, 2008). Gartner understands big data as high-volume, -velocity and -variety information assets that demand cost-effective, innovative forms of information processing for enhanced insight and decision making (Sicular, 2013). ISO/IEC 20546:2019 (Information technology — Big data — Overview and vocabulary) defines big data as extensive datasets — primarily in the data characteristics of volume, variety, velocity, and/or variability — that require a scalable technology for efficient storage, manipulation, management, and analysis (GOST R ISO/IEC 20546 – 2019. Information technology. Big data. Overview and vocabulary, 2020). In essence, the term describes the exponentially increasing volume and variety of data belonging to organizations and states that cannot be processed using conventional tools (Bennett, 2017, p. 462). The main sources of big data include mobile and social platforms, streaming data that comes from the Internet of Things (IoT), public data from open sources, cloud data, databases (Oracle, SQL, Amazon Simple, etc.), ERP systems, data warehouses, etc. (Big data: what is it and why it matters, n.d; Joshi, 2017). In most cases, data is generated by an extremely heterogeneous user base and social and organizational mechanisms that differ significantly from the technical models that have traditionally been used in economic life. The situation is further complicated by the fact that users of the Internet and social networks often do not belong to the organizations or networks to which they transmit data (Constatiou and Kallinikos, 2015, pp.4–5). In this regard, the issue of ensuring its confidentiality becomes extremely relevant. In recent years, researchers have developed various features of big data that characterize this term and reveal its content1. The author proposes to highlight the key ones among them: Volume - the amount of big data created, collected, copied, and consumed around the world is growing exponentially and will reach 180 zettabytes by 2025 (Holst, 2021). Velocity - big data is created at a tremendous speed and requires real time processing, storage, and analysis. Variety - big data is formed from various types of data in a wide variety of formats (structured, semi-structured and unstructured data, text data, speech data, video data, etc.). Veracity - big data must be characterized by accuracy, truthfulness, and reliability, otherwise they can lead to incorrect decisions. Variability - understanding the meaning of big data requires consideration of the chosen context. Visualization - for greater accessibility of perception of big data, its visualization is required. Value - the analysis of big data allows you to derive value to solve the problems of specific users (Ishwarappa, 2015; Sicular, 2013; Rialti et al., 2016). Nowadays big data is used in almost all sectors of the economy and is finding new areas of application, such as identifying consumer buying habits, personalized marketing, health monitoring using data from wearable devices, road mapping for autonomous vehicles, customized health plans for cancer patients, traffic analysis to reduce congestion in cities, production optimization, real-time data monitoring and cybersecurity protocols, etc. T.H. Davenport and J. Dyché highlight the following among the main reasons for using big data technologies: cost and task execution time reduction, development of new products and offerings, and support of internal business decisions (Davenport and Dyché, 2013, pp. 3–8). This position could be complemented by such benefits as identifying potential risks that can improve the quality and effectiveness of the risk management system, the ability to create targeted products and services for a specific market, retaining and attracting new customers (Mills, 2019). The COVID-19 has only accelerated the indicated trends, demonstrating the key role of big data in promptly responding to emerging challenges and making decisions that affect all or most people in states and organizations2. It has rapidly influenced many aspects of governments and organizations activities, significantly increasing the role of artificial intelligence and machine learning in big data analytics in the public and private sectors. Due to the need to collect, segment and promptly interpret huge amounts of data related to the spread of the virus, the important role of artificial intelligence algorithms in this process was revealed (Marr, 2020). In addition, due to the use of artificial intelligence, states and organizations received a functional tool which can predict, detect, diagnose and treate various viruses for the coming years in real-time mode (Ibid). At the same time, states and organizations are facing problems in the field of data protection (issues of confidentiality, security, data leakage, etc.), which have underlined the need for new approaches to regulating this area of our life. A Path to Efficient Big Data Application Big data usability depends on two key factors, which are the main goals of the applied business processes: the ability to create value from it and the quality of such data (Hilb, 2019, p. 60). V.D. Milovidov notes that the presence of a large amount of data and technologies for its processing does not have “any pronounced correlation with the economic results of economic activity.“ As a confirmation of this thesis, the author points out that “the total volume of accumulated data in American companies practically does not correlate with the indicators of their market capitalization” (Milovidov, 2019, p. 288). In reality, the presence of a large amount of generated data does not always allow to determine at first glance potential options for extracting value from it and using it for solving practical problems. On average, from 60 to 73% of all data in an organization is not used for analytics, which considering the specifics of data-driven economy may lead to a decrease in competitiveness (Gualtieri, 2016). Moreover, the intended effects of data analysis cannot be verified retrospectively, and the transparency of the data can cause controversy among the participants in the digital ecosystem. The Organization for Economic Cooperation and Development (OECD), while noting the inexhaustibility of data, emphasizes that it can be reused to open up significant growth opportunities or create benefits for the whole society in ways that could not have been foreseen when they were first created (Enhancing Access to and Sharing of Data: Reconciling Risks and Benefits for Data Re-use across Societies, 2019). With more data being produced today than ever before, the ability to use it becomes the key competitive advantage for states and organizations. Understanding and interpretation of the data can provide them with valuable information needed to improve its performance (forecasting demand, potential problems, etc.). The issue of data quality is one of the key areas of activity of states and organizations, not just their ICT departments (Yukhno, 2021). During the coronavirus pandemic, the low quality of data did not allow the use of various artificial intelligence models for diagnosing the disease and predicting risks for patients, as they were not suitable for clinical use. Thus, it becomes clear that poor data quality jeopardizes the achievement of state goals and largely depends on the quality of the process for data obtaining, as well as on the quality of the processes for its storing, managing, transferring, and presenting (GOST R 54524 – 2011/ISO/TS 8000 – 100:2009. Data quality. Part 100. Master data. Exchange of characteristic data. Overview, 2012). At the same time, according to GOST R 56214 – 2014 / ISO / TS 8000-1: 2011, data quality affects only those data that are involved in making any decision, while preventing the repetition of data defects and reducing unnecessary costs (GOST R 56214 – 2014/ISO/TS 8000-1:2011. Data quality. Part 1. Overview, 2015). In this regard, interaction in the field of data management should include stakeholders with a clear division of areas of responsibility and be directly linked to the development priorities of states and organizations (Goasduff, 2020). A report by Precisely and Corinium Global Intelligence shares that data reliability implies three characteristics: accuracy, consistency, and context. The integration of cloud technologies helps improve the quality of collection and analysis of big data. However, 82% of data leaders find it difficult to provide a constant stream of reliable data that is suitable for making informed business decisions. In addition, 9 out of 10 managers face a shortage of workers with the right skills (Data Integrity Trends: Chief Data Officer Perspectives in 2021, 2021; Precisely: 82% of data executives cite data quality as a barrier, 2021).In the digital era, data quality needs to be directly linked to the KPIs of governments and organizations (Moore, 2018b). Data collection requires certain costs and clear regulations for assessing the use and profitability of acquiring various types of data for specific tasks. However, according to Gartner, about 60% of organizations do not even measure the annual financial costs (lost revenue opportunities, reduced organizational efficiency and productivity, etc. (Barrett, 2022) on low quality data (Moore, 2018b). Governments and organizations need to clearly understand the relationship between additional data, improving forecasting accuracy and creating added value (Heath, 2019, p. 46). It also means quantifying the financial benefits of big data, as well as the costs (and consequent savings) of investing in risk management in this area (Bennett, 2017). That said, according to a Gartner survey, 42% of data analytics leaders do not measure or track metrics in this area. Those who do carry out such activities are mainly focused on achieving compliance goals (Goasduff, 2020). In this regard, it is recommended that states and organizations: establish a unified approach to data; measure the values of big data indicators; identify key data workers; optimize the cost of data quality management tools; set realistic time frames for deploying data quality tools (Moore, 2018b); implement a quality control system for big data; create a unified repository of big data and provide access to it for all employees in accordance with internal regulations; develop a corporate culture of working with big data; implement employee-friendly big data analytics tools. Big data is becoming an increasingly important intangible asset (The world’s most valuable resource is no longer oil, but data: Regulating the Internet giants, 2017) for states and organizations, contributing to the creation of added value in various sectors of the economy. Such approach contributes to digital transformation (Dremel et al., 2017, p. 97) and gaining competitive advantages in the market (Ibid) by predicting needs and responding to changes in the economy (Strengthening Digital Government, 2019, p. 3). In other words, big data needs to be viewed as an asset and both its value and the value it stores should be measured. In this regard, states and organizations need to implement measurable indicators that will allow to trace the relationship between data analytics and ongoing initiatives and projects to create value and achieve their goals and objectives. Specifically, they are invited to: determine the key priorities of activities; approve KPIs (financial, operational, reputation, etc.) in achieving goals and objectives using big data analytics; determine the current level of quality of existing big data and its impact on their activities; approve the target state of data quality to achieve the set goals (Moore, 2018a). Currently the importance of solutions that allow monitoring of real time data quality metrics is growing. States and organizations are now using artificial intelligence and machine learning to support more complex data management tasks, including data cataloging, metadata managing, and displaying and anomalies detecting (Hunt, 2021). In addition, the use of artificial intelligence and machine learning contributes to significant improvements in the quality of the data itself as an intangible asset. At the same time, high-quality and compatible data is required, for the efficient operation of artificial intelligence (Artificial Intilligence. Towards a choice of strategy, 2019, p. 56). In this regard, states and organizations, first of all, need to systematically consider the issue of introducing strategies and tools for managing such data. It is noted that aligning strategies for big data, cloud computing and mobile technologies leads to a 53% economic growth in comparison to competitors that do not use these technologies (Columbus, 2015). High data quality provides the ground for an effective data management structure, supports business initiatives, minimizes emerging risks, and ensures the reliability, completeness, uniqueness, and relevance of data itself. In practice, the main tools for improving the quality of data are as follows: adopting a data management strategy, data profiling, data checking as it is entered, data cleaning, data quality monitoring and controlling, building interaction between organizational units, making changes to the organizational structure (for example, the introduction of data manager position or the creation of a data quality control center) with the setting of appropriate business processes, roles, functionality, stakeholder responsibilities and realistic deadlines for the implementation of these tools in practice. At the same time, the widespread introduction of tools to improve data quality, as a rule, is undermined by their high cost (Moore, 2018b). With the exponential scaling of the volume of big data moving between nations and organizations, value chains will become more complex and analytical tools more and more diversified. Thus, states and organizations need to carry out continuous and comprehensive work to systematize and control big data quality used to create in order to form an appropriate corporate culture of big data management for further transition to big data-based decision-making. Moving to a Data-Driven Public Sector The OECD classifies a data-driven public sector as one of the six dimensions of the OECD Digital Government Framework (The OECD Digital Government Policy Framework: Six dimensions of a Digital Government, 2020, p. 6), highlighting that a mature digital state is a data-driven state (Ibid, p. 14) and calls for a shift from information-driven states to a data-driven public sector3. In real life, the implementation of big data technologies in public administration faces three main issues: technical and practical problems (insufficient amount of quality data, lack of common standards and level of interaction between various public and private ICT systems, etc.); limited resources and opportunities (insufficient funding for necessary research, low qualifications of civil servants and digital literacy in society, etc.); the presence of barriers in society and the state (institutional, legislative, cultural, etc.) (Ubaldi et al., 2019, p. 53). To simplify and improve the abovementioned practices, the OECD recommends that states develop strategies to support data-driven public sector development (Strengthening Digital Government, 2019, p. 1). Typically, such a strategy focuses on three main areas: the needs of citizens and society, obtaining, analyzing, and making decisions based on big data, mobility, and speed of sharing big data and decision making (Akatkin et al., 2017, p. 19). In addition, the data-driven state focuses on its use to create social value by predicting and planning possible changes, improving the quality of public services, implementing public policy and responding to public requests, as well as assessing and monitoring its use (The OECD Digital Government Policy Framework: Six dimensions of a Digital Government, 2020, p. 15). In practice, this means that the development of approaches in which new technologies and big data become instruments for achieving the state’s goals and objectives. At the same time, the very transition to strategic management of big data at the state level, as a rule, presupposes the presence of three major elements: nationwide data architecture; digital transformation of public administration; human resources (The state as a platform. People and technology, 2019, p. 8–11). In addition, the analysis shows that the shift to data-driven governance can be facilitated by a government strategy focusing on two main areas: leveraging existing data from different sources through aggregation and analysis and building real-time data exchange networks to deliver improved public service (Real-Time, Data-Driven Government. Develop Forward-Thinking, Citizen-Centric Programs, 2021, p. 9). The change in the format of interaction between the state and society necessitates the creation of a unified state digital ecosystem with data and algorithms in the center. The currently implemented platform approach in public administration4 will significantly increase the speed of provision of public services, and feedback from citizens in real time will significantly increase the requirements for the quality of their provision. Such a paradigm of relations presupposes a rethinking of the principles of the public administration system, ultimately ensuring the transition from an electronic state to a digital one (The OECD Digital Government Policy Framework: Six dimensions of a Digital Government, 2020, p. 6). The goal of this process should be the transformation of all areas of the state’s activities, including internal processes and standards for the provision of public services, the organizational structure of public administration, internal corporate culture, the necessary skills and competencies of civil servants, the format of interaction with citizens and receiving feedback, etc. As a result, the likelihood of creating values that meet the increased expectations and requirements of citizens regarding the results of their interaction with the state increases. Thus, in the digital era, the digital transformation of the state necessitates the adaptation and use of new technologies and big data in state activities in order to “reset” public administration. In this regard, World Bank’s “World Development Report 2021: Data for Better Lives” is proposing a new social contract to address data governance challenges that will: increase the use and reuse of data to extract more value; ensure more equitable access to the benefits that data creates; build trust by creating mechanisms to protect citizens from data risks; prepare the ground for the creation of an integrated national data system (World Development Report 2021: Data for Better Lives, 2021). An integrated national data system includes three groups of actors: states and international organizations, individuals and civil society, and the private sector, which cooperate in an environment where data is safely produced, exchanged, and used. Despite the need for close interaction between the parties, such a system does not require an obligatory centralized management system and storage of all data in it (Ibid). The introduction of the term “unified national data system” into scientific research reflects a new stage in the development of the digital environment. The system is built on the basis of four pillars (Table 1). Table 1 Four pillars of a unified national data system Pillar Specifications Infrastructure policy provides equal access to data for states and people; contributes to the development of internal data infrastructure, which allows for local storage, processing and exchange of data within the state. Data Regulations trust in data transactions is supported by strong laws and regulations; factors facilitating the exchange of data are usually more developed for publicly available data, where government policy and legislation establish rules for access and exchange of such data, than for private data, where governments have more limited influence. Economic policy measures growing role of data in the business models of digital platforms is changing competition, trade and taxation in the real economy, posing risks for low- and middle-income states; security measures and data processing tools developed by states will have an impact on the real economy (antitrust regulation, tax issues, trade in services based on data); low- and middle-income states often lack the institutional capacity to manage the policy problems posed by data-driven economies. Data Management Institutes institutions to manage data have four main functions: strategic planning, setting rules and standards, compliance and enforcement, and gaining the knowledge and evidence needed to understand and address emerging issues; a targeted, participatory approach to data management and oversight can help institutions keep pace with the ever-evolving data ecosystem and enhance their legitimacy, transparency and accountability (World Development Report 2021: Data for Better Lives, 2021). Both states and organizations that want to be effective during the period of active digital transformation of the economy, when moving to data-centric management, are recommended to take into account the above factors. The priority of using big data for the state in the Russian Federation is consolidated in regulatory documents. The decree of the President of the Russian Federation of 05/09/2017 N 203 “On the Strategy for the Development of the Information Society in the Russian Federation for 2017–2030” defines the digital economy as “an economic activity in which the key production factor is digital data, processing of large volumes and the use of the analysis results of which, in comparison with traditional forms of management, can significantly increase the efficiency of various types of production, technologies, equipment, storage, sale, delivery of goods and services” (Strategy of the Information Society Development in the Russian Federation for 2017–2030, 2017). On June 3, 2019, by Order of the Government of the Russian Federation No. 1189-r, the Concept for the Creation and Operation of a National Data Management System (NDMS) and a roadmap for the creation of an NDMS for 2019–2021 were approved. According to the Big Data Association, compared to 2019, the introduction of big data in the Russian Federation under the optimistic scenario can provide 1.8% of GDP growth (1.2% under the baseline scenario), as well as the growth of the big data market to 160 billion rubles (100 billion rubles - under the baseline scenario) by 2024. At the same time, in order to expand the possibilities of using big data, the Association proposes to overcome five groups of barriers (lack of specialists for the mass adoption of big data, limited infrastructure and data availability, difficulties in research and innovation in the field of big data, lack of large-scale implementation of big data in sectors of the economy) (Strategy for the Big Data market development by 2024, 2019). Currently, in order to be competitive, both states and organizations need to use a wide range of internal and external information resources. This means increasing the volume of different types of data by closer collaboration with different stakeholders (Judah, 2021). It seems that effective data management does not occur in isolation, but in close interaction with other participants of the digital ecosystem, who are collectively responsible for the final result. In this regard, it is necessary to work out in detail the issue of the availability of open and common tools (for example, open standards, APIs, algorithms) that can facilitate overall integration both inside and outside the organization (The Path to Becoming a Data-Driven Public Sector, 2019). Considering the problem from the state point of view, the establishment of partnerships outside the public sector will allow it to: take advantage of digital private sector solutions to improve, optimize and modernize public sector data infrastructure (e.g. cloud solutions); facilitate the publication of data produced by civil society organizations on government open data platforms or the publication of open government data on non-government data portals; support the exchange of data between multiple stakeholders from different sectors and strengthen the control and power of data owners over the exchange and use of their data for common policy objectives (Ibid). For example, the practice of collecting big data is gaining popularity in order to maintain economic statistics used to monitor the economic situation in the state (in Indonesia, tourism statistics are monitored using data from cellular operators, Azerbaijan uses data from electronic databases of retail for statistical purposes, in Australia statistics on jobs and gross wages are analyzed using payroll data, etc.) (Bernal et al., 2021). Concluding Discussions This paper aims to fill the knowledge gap around big data and data-driven public administration in the post-Covid period. The pandemic has intensified the key role of big data in responding to emerging challenges and decision-making that affects states and societies, significantly increasing the role of artificial intelligence and machine learning in big data analytics in the public and private sectors. The author states that the volume of analyzed big data is constantly growing and requires the creation and maintenance of an appropriate technological architecture and ICT infrastructure, as well as an increase in the scale of its storage, analysis, and transmission. At the same time, the fact of having big data does not automatically impy that it can be used to solve real problems. The main value of big data lies not in itself, but in the conclusions, products and services that appear as a result of its processing and analysis (Davenport and Dyché, 2013, p. 30). In fact, organizational productivity improvements and competitive advantage arise from analytic models that identify new opportunities and enable states and organizations to predict and optimize their performance (Barton and Court, 2012). The author stresses that data reliability implies such characteristics as accuracy, consistency, and context. The issue of data quality is one of the key areas of activity of states and organizations and needs to be directly linked to their KPIs. However. the widespread introduction of tools to improve data quality nowadays is constrained by their high cost. The analysis reveals problems in the field of data protection. The use of big data leads to a reset of the risk management system both within the state and organizations, allowing it to be processed in real time to obtain more accurate results, improve the quality of work and feedback from citizens and counterparties. The main task in the field of big data is finding a balance between emerging risks and its value for the state and organizations in the context of the constant increase in volume and the development of new technologies that ensure its cheaper storage. In addition, the growth in big data can lead to an information gap between the strategic and operational levels of government and corporate governance. In this regard, one of the important consequences of the digital transformation of an organization is the need to build processes that could be managed in real time. Mechanisms for managing big data, on the one hand, have to protect it from factors that can destroy or limit its value, on the other hand, to exclude situations in which states and organizations will not be able to take of advantage of the value of their data (Tallon, 2013 p. 26). It is noted that a mature digital state is a data-driven state that encompasses three major elements: nationwide data architecture, digital transformation of public administration and human resources. The shift to data-driven governance implies the creation of a unified state digital ecosystem with data and algorithms in the center building real-time data exchange networks to deliver improved public service. Such approach calls for rethinking of public administration principles unltimately ensuring the transition from an electronic state to a digital one to increase its efficiency. Thus, the effectiveness of the use of big data largely depends on the development of the digital environment and the ability to move data quickly and at low cost among a potentially unlimited number of participants in a government-regulated framework. Funding Information Not applicable Declarations The author has no relevant financial or non-financial interests to disclose. Conflicts of Interest Not applicable Ethics Approval Not applicable Informed Consent Not applicable 1 In practice, there are more than 50 characteristics of big data. For example, Dhamodharavadhani, S., Gowri, R., Rathipriya, R. (2018, March). Conference: First International Conference on Computer Vision,Networks and Informatics. Unlock Different V’s of Big Data for Analytics. International Journal of Computer Sciences and Engineering, 06 (04), 183–190. 2 For example, working with big data has enabled the FTS of Russia to effectively provide targeted support measures to citizens and organisations in a short period of time. Federal Tax Service (2020, November 12). Na obshchestvennom sovete pri FNS Rossii obsudili rabotu Sluzhby vo vremya pandemii [The Public Council of the Russian FTC discussed its work during the pandemic]. Retrieved May 21, 2022, from https://www.nalog.ru/rn77/news/activities_fts/10154705/. 3 In practice, the terms “data” and “information” are often used interchangeably. However, it is useful to distinguish between them. Data consists of bits and bytes, which are created by computer systems. Information comes from data, after the data has been organised, analysed and presented in a particular context. 4 For example, Petrov, M., Burov, V., Shklyaruk, M., Sharov, A. (2018, April). The State as a Platform: People and Technology. 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The Economist The world’s most valuable resource is no longer oil, but data: Regulating the Internet giants. Retrieved May 24, 2022, from https://www.economist.com/leaders/2017/05/06/the-worlds-most-valuable-resource-is-no-longer-oil-but-data The Russian Presidential Academy of National Economy and Public Administration (2019). Iskusstvennyi intellekt. K vyboru strategii [Artificial Intilligence. Towards a choice of strategy]. The education center for digital transformation teams and CDTOs. Retrieved May 24, 2022, from https://www.ranepa.ru/images/News/2019-05/30-05-2019-AI-report-2019.pdf The Russian Presidential Academy of National Economy and Public Administration (2019). Gosudarstvo kak platforma: Lyudi i tekhnologii [The state as a platform. People and technology] The education center for digital transformation teams and CDTOs. Retrieved May 24, 2022, from https://files.data-economy.ru/Docs/GovPlatform.pdf Ubaldi, B., Le Fevre, E. M., Petrucci, E., Marchionni, P., Biancalana, C., Hiltunen, N., Intravaia, D. M., & Yang, C. (2019). State of the art in the use of emerging technologies in the public sector. OECD Working Papers on Public Governance, OECD Publishing. No. 31. 10.1787/932780bc-en VentureBeat Precisely: 82% of data executives cite data quality as a barrier. Retrieved May 24, 2022, from https://venturebeat.com/2021/06/25/precisely-82-of-data-executives-cite-data-quality-as-a-barrier/ World Bank (2021). World Development Report 2021: Data for Better Lives. 10.1596/978-1-4648-1600-0 Yukhno, A. S. (2019). Prospects for the use of artificial intelligence in corporate governance. Insurance law, no. 4(85), 26–32. Yukhno, A. S. (2021). Corporate governance of information and communication technologies in the digital era. 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==== Front Wien Klin Wochenschr Wien Klin Wochenschr Wiener Klinische Wochenschrift 0043-5325 1613-7671 Springer Vienna Vienna 2125 10.1007/s00508-022-02125-9 Editorial 2022 update to “The start of the Austrian response to the COVID-19 crisis: a personal account” Müller Markus [email protected] grid.22937.3d 0000 0000 9259 8492 Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria 13 12 2022 2022 134 23-24 813814 9 11 2022 © The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature 2022 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. issue-copyright-statement© Springer-Verlag GmbH Austria, part of Springer Nature 2022 ==== Body pmcTwo years after my first personal account in this journal [1], Austria faces the fading of the 7th COVID wave. As of October 2022, since the beginning of the pandemic 21,000 Austrian patients had died from COVID and more than 90% of Austrians have developed immunity by infection or vaccination. The availability of highly protective mRNA vaccines and antiviral drugs and the evolution of various, increasingly infectious subtypes of the original Wuhan SARS-CoV‑2 strain, in particular alpha, delta and omicron, have led to a markedly different situation as compared to the beginnings of the pandemic. The overall estimations from February 2020 remain essentially valid today and the drastic response measures from March 2020, which were implemented in the absence of vaccines and therapeutic options, are hardly a matter of dispute. The early enthusiasm about the “Swedish approach” which led to “ten times higher COVID-19 death rates compared with neighbouring Norway and elderly people being administered morphine instead of oxygen” is mainly discussed in an ethical context [2]. Overall, immunity has developed in most countries worldwide by infection or vaccination, probably except for China where a zero COVID strategy is pursued, which still leads to lockdowns and severe interruption of supply chains worldwide. The public attention has moved on to the Ukrainian-Russian war and despite high case numbers, with few exceptions, only few mandatory public measures are effectively in place. The burden of disease in terms of intensive care unit (ICU) patients and hospital admission remains relatively low due to a decoupling of cases and morbidity. In retrospect, it is surprising how quickly the COVID pandemic became a worldwide source of energy for political debates, media attention and business interests. Despite a severe lack of initial preparedness, the initial success of public measures is undisputable for the first weeks of the pandemic; however, from May 2020 onwards, a substantial proportion of political representatives, media channels and even medical doctors opposed the implementation of measures like face masks, NPIs and vaccines. In a 2022 election for the chamber of physicians an anti-COVID measures party, which named COVID a “running nose pandemic” gained 7% of the electorate of practitioners. This led to discussions about an unusually high rate of “critical thinkers” and adherents to conspiracy theories (sometimes with anti-Semitic attitudes) among the Austrian population and even among doctors and the roots of this line of thinking in Austrian history [3]. Historical comparisons to a cholera pandemic in Vienna 1873 where headlines on “hygiene terror” and “doctor dictatorship” appeared in newspapers in response to public health measures or belittling Austrian media reports in 1918 on the Spanish Flu (“benign disease”), an infection which was named after Spain, one of the few countries without media censorship, come to mind. The extremely polarized COVID media frenzy was heated up by remarkable numbers of publicly acclaimed experts, pseudo-experts and celebrities, which presented misleading or even false information and misused the term “evidence” in hitherto unknown ways, which also showed a lack of basic research understanding [4]. The polarized public sentiment also led to murder threats to physicians, nurses and protests in front of hospitals, a situation which stood in stark contrast to the initial public acclaim of healthcare workers as “pandemic heroes”. Although similar trends, e.g. HIV deniers or Lyme disease extremists have emerged before, the extent of irrationality in the context of COVID defies any historical comparison. In the context of the rapid development of mRNA vaccines (Operation Warp Speed or Project lightspeed) a wave of public “vaccine envy” following market authorization in December 2020 was followed by “vaccine and pandemic fatigue” in the summer of 2021. In September 2022 a Lancet commission paper on lessons for the future from the COVID 19 pandemic was published [5]. It rightfully argues that the WHO acted too slowly, most governments around the world were inadequately coordinated and that pandemic control was seriously hindered by public opposition and lack of social trust. These conclusions can certainly also be drawn for Austria, a nation which experienced 3 Ministers of Health in office since the beginning of the pandemic and 9 Ministers of Health in the last 8 years. Austria was one of the few countries worldwide, which implemented mandatory COVID vaccination and extremely costly high-density testing (approximately 10 times the testing density of Germany at a cost of approx. € 2 billion) without measurable effect on outcome parameters. From the beginning of the pandemic, case tracing to keep cases below the “Merkel number” of 50/100,000 was never effectively pursued and in fall 2021 a political bargain was made by joining another hard nationwide lockdown with mandatory vaccination. This only further undermined public trust in healthcare policies and aggravated the polarized public sentiment. Thus, political instability, lack of leadership and consistency and poor national coordination substantially hindered coping with the consequences of the pandemic. Lack of clarity is also apparent in the current “Epidemic Act”, a law, which dates back to 1913 and, until 2020, mostly dealt with historical infectious diseases like cholera. Due to numerous amendments in the last 2 years the “Epidemic Act” now consists of an old, historical part and a meanwhile much larger part with extremely detailed COVID regulations. Whether this reactive legal approach will be a sufficient framework to deal with future epidemic crises is questionable. On the structural side, a former Minister of Science took up a proposal of the Medical University of Vienna and promoted the establishment of a “one stop shop” for pandemic crisis coordination by founding an Austrian Ignaz Semmelweis Institute for Research on Infectious Disease, a project, which is currently being developed (www.bmbwf.gv.at/Ministerium/Presse/20211201.html). Overall, with the exception of a number of Asian nations, most pandemic measures were reactive rather than proactive. Anthony Fauci pointed out this dilemma by commenting: “if and when the infections will come, and they will come … Wayne Gretzky doesn’t go where the puck is. He goes where the puck is going to be. We want to go where the virus is going to be”. Thus, the quote “If you fail to prepare, you are preparing to fail” (Benjamin Franklin) is now probably as valid as at the beginning of the pandemic. Conflict of interest M. Müller declares that he/she has no competing interests. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ==== Refs References 1. Müller M The start of the Austrian response to the CoV19 crisis: a personal account Wien Klin Wochenschr 2020 132 353 355 10.1007/s00508-020-01693-y 32533439 2. Brusselaers N Steadson D Bjorklund K Breland S Stilhoff Sörensen J Ewing A Bergmann S Steineck G Evaluation of science advice during the COVID-19 pandemic in Sweden Humanit Soc Sci Commun 2022 91 1 17 3. Lackner H, Zielinski C. Die Medizin und ihre Feinde. Wie Scharlatane und Verschwörungstheoretiker seit Jahrhunderten Wissenschaft bekämpfen. 2022. https://www.ueberreuter.at/shop/die-medizin-und-ihre-feinde/. Accessed: 28 Nov 2022. 4. Yeh RW Valsdottir LR Yeh MW Shen C Kramer DB Strom JB Secemsky EA Healy JL Domeier RM Kazi DS Nallamothu BK PARACHUTE Investigators Parachute use to prevent death and major trauma when jumping from aircraft: randomized controlled trial BMJ 2018 13 363 363 k5094 5. Sachs JD Karim SSA Aknin L Allen J Brosbøl K Colombo F Barron GC Espinosa MF Gaspar V Gaviria A Haines A Hotez PJ Koundouri P Bascuñán FL Lee JK Pate MA Ramos G Reddy KS Serageldin I Thwaites J Vike-Freiberga V Wang C Were MK Xue L Bahadur C Bottazzi ME Bullen C Laryea-Adjei G Amor YB Karadag O Lafortune G Torres E Barredo L Bartels JGE Joshi N Hellard M Huynh UK Khandelwal S Lazarus JV Michie S The Lancet Commission on lessons for the future from the COVID-19 pandemic Lancet 2022 400 10359 1224 1280 10.1016/S0140-6736(22)01585-9 36115368	36512128	PMC9747073	NO-CC CODE	2022-12-15 23:21:58	no	Wien Klin Wochenschr. 2022 Dec 13; 134(23-24):813-814	utf-8	Wien Klin Wochenschr	2,022	10.1007/s00508-022-02125-9	oa_other
==== Front Peer Peer Netw Appl Peer Peer Netw Appl Peer-to-Peer Networking and Applications 1936-6442 1936-6450 Springer US New York 1410 10.1007/s12083-022-01410-8 Article Tamper-proof multitenant data storage using blockchain http://orcid.org/0000-0001-6504-5742 Sharma Aditi [email protected] Aditi Sharma is currently working as well as pursuing PhD from Jaypee Institute of Information Technology, Noida and has an academic experience of over 8 years. She received M.Tech. (Computer Science and Engineering with Specialization in Data Engineering), from Indraprastha Institute of Information Technology, Delhi (IIIT-Delhi) and B.Tech. (Computer Science and Engineering) from GBTU, Lucknow. Her research interests include Data Mining, Information Retrieval, Data Warehousing, Database Management System and Distributed Systems. Kaur Parmeet [email protected] Parmeet Kaur is currently working in Jaypee Institute of Information Technology, NOIDA and has an academic experience of over 18 years. She received PhD(Comp Engg) from NIT Kurukshetra , M.Tech.(CSc) from Kurukshetra University and B.E.(Hons)(CompSc & and Engg.) from P.E.C., Chandigarh. Her research interests include distributed systems, cloud & edge computing and big data systems. She has published more than 50 papers in various reputed indexed journals, peer reviewed conferences and book chapters. Two students have been awarded PhD under her supervision and 3 students are pursuing research in domains of distributed computing and big data. grid.419639.0 0000 0004 1772 7740 Jaypee Institute of Information Technology, Noida, India 13 12 2022 119 19 11 2021 3 11 2022 © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. Technologies like Internet of Things (IoT), cloud, artificial intelligence, blockchain etc. have become a perceptible part of our lives resulting in the generation of enormous amounts of data. Consequently, the systems used for storage and processing of this data are required to be scalable for handling the huge volumes of data. A shared, multitenant system such as a cloud-based storage-as-a-service provides scalability of storage as well as economics of sharing. However, there is a risk of data tampering when multiple tenants work in a shared environment. The benefits of a multitenant solution can be leveraged only if tenants’ data is isolated from each other. Further, prevention of data tampering from malicious tenant nodes is also required. Therefore, the paper proposes the use of a private blockchain for an implementation of a multi-tenant-based storage system. The objective is to develop a scalable system where tenants’ data is not at a risk of tampering. The efficacy of the proposed system has been demonstrated with synthetic data of multiple tenants using a Software as a Service (SaaS) healthcare application. Keywords Multi tenancy Distributed database Storage Blockchain Tenants ==== Body pmcIntroduction The widely popular Software as a Service (SaaS) cloud computing model employs a multi-tenant architecture to achieve cost efficiency along with scalability and flexibility. SaaS applications are commonly based on multi-tenant data storage where resources as well as datastore schema are shared among different tenants. In contrast, a different instance of a single tenant application is created for each user or tenant; thereby increasing the service cost as well as the maintenance cost for the tenants and the providers respectively. Consequently, sharing of resources in multi-tenancy leads to lowered cost for all [1, 2]. Despite this advantage, a multitenant architecture faces a challenge related to data security. As multiple tenants share the same storage, there is a higher possibility of data infringement if tenants’ data is not isolated from each other. A malicious tenant can attack other tenant’s data by sending malicious information, initiating illegitimate transactions or denying transactions among different tenants. Therefore, building a secure system is required to avoid data tampering in such a multi-tenant system. Flexibility and data isolation are the two most important features required in a multi-tenant application. A recent technology that can be used for implementing tamper-free data storage for multi-tenant applications is the blockchain technology. Apart from its frequent use in cryptocurrency, it is emerging as a prominent technology for building secure and immutable storage systems [3]. Blockchains or Distributed Ledgers eliminate risk of alteration in data once stored through the use of decentralization and cryptographic hashing. Thus, blockchain storage is designed to save any data or transactions forever and in an immutable matter, i.e., without any modification. Moreover, the private or permissioned blockchains only allow identifiable participants to be admitted to the blockchain network [4]. Such blockchains provide an immediate and transparent view of stored data stored on an immutable ledger to the permissioned network members. The use of blockchain by a multitenant SaaS application for prevention of tampering and allowing auditing of transactions between different tenants is bound to build trust among tenants. Therefore, this paper proposes a single blockchain- based scalable system to handle shared data among multiple tenants while preventing data tempering between tenants. Specifically, tenant data is stored offline while its record or metadata is stored on the blockchain using the platform, namely Multichain [5]. This allows efficient data storage, efficient querying as well as complete validation of a data storage or retrieval operation. Further, the Multichain-based blockchain is a permissioned network where any data can be stored or accessed only by authorized users or tenants. This makes the system apt for data storage by multiple tenants of a SaaS application without the risk of any unauthorized data access or tampering. The system proposed in the paper endeavours to improve upon other related blockchain based storage systems in the following aspects:Support for multi-tenant applications: The proposed system’s main objective is to provide a multi-tenant storage system where different tenants can store and share data in the same blockchain. Scalability: The proposed system is a scalable storage system due to the use of blockchain along with an off-chain storage for tenants’ data. Tamper-proof: To build trust among the tenants, a permissioned blockchain framework-MultiChain is used for the implementation which provides security as well as tenant data isolation. Query processing time: The proposed system is using off-chain storage for tenant data and employing the blockchain to store only the meta data. This is unlike most existing systems that store the entire data on the blockchain resulting in high query processing time. The rest of the paper is structured as follows: An overview of blockchain technology along with the related work is discussed in Sect. 2. Design of the proposed system is presented in Sect. 3. Results of implementation are described in Sect. 4 along with a threat model. Finally, we conclude the article. Background and related work Overview of blockchain technology The blockchain technology is being used in varied applications ranging from cryptocurrencies, transaction management to record keeping for digital assets. Blockchain is a distributed ledger that consists of a chain of blocks in which transaction details or records are stored. The first block in the blockchain is termed as the Genesis block. Each block contains hash of the previous block along with a timestamp and transaction data or record [3, 6]. Figure 1 illustrates the structure of a blockchain.Fig. 1 Blockchain structure In a blockchain, every block has its own unique nonce and hash. Each block also references the hash of the previous block in the chain. This makes mining of a block difficult especially on large chains. Miners use special software to solve the incredibly complex math problem of finding a nonce that generates an accepted hash. Since the nonce is only 32 bits and the hash is 256, there are approximately four billion nonce-hash combinations that must be mined before the right one is identified. Only after that, a miner’s block is added to the chain [7]. Once a block is successfully mined, the change is accepted by all of the nodes on the network. Making a change to any block previously added in the chain requires re-mining not just the block with the change, but all of the blocks that are subsequent to this block. Therefore, it is extremely difficult to manipulate data or transactions added to the blockchain. Apart from its property to store data practically in an immutable manner, the growing number and variety of blockchain applications is also due to its decentralised nature. Blockchain allows building of transparent, secure and scalable systems where users can view and check any action performed on the chain. There are different variations of blockchains available, like Consortium and Hybrid blockchains but Public and Private blockchain are the two most popular blockchains. Table 1 depicts how these two blockchains differ from each other.Table 1 Public v/s Private blockchain Properties Public Blockchain Private Blockchain Participants It is permissionless, anyone can participate/join the blockchain It is permissioned and only invited participants can join the blockchain Access Permissions Read/ Write access to everyone Restricted/customized access permissions to different users Network Open Network, Decentralized Invitation only network, partially decentralized Operational Speed Low High Trust among participants Trustless Trusted participants Level of Data Transparency High (completely transparent) Moderate (partially transparent, only to authorized members) Verifiability Validity of each record on blockchain can be verified Validity of each record on blockchain can be verified Blockchain Platforms Bitcoin, Ethereum Hyperledger, Corda, Multichain MultiChain: open source blockchain platform A substantial number of open-source and commercial platforms, such as Ethereum, Ripple, MultiChain, Sidechain, IBM Blockchain, Hyperledger Fabric, Hyperledger Sawtooth, R3 Corda etc., are available for creation of blockchains. The proposed work has used MultiChain platform to create blockchain based data storage system for SaaS applications. MultiChain is an open-source platform for the creation and deployment of enterprise blockchain, referred to as a private blockchain [5]. It can be used to develop a blockchain to be used either within one or between multiple organizations. MultiChain supports all the prevalent operating systems such as Windows, Linux and Mac and can be used to store any kind of digital asset. The primary advantage of MultiChain platform over other related platforms is the implementation freedom that comes with the use of MultiChain. Blockchain users are given the privilege to define blockchain parameters and an ability to store multiple assets on their blockchain [5, 8]. While designing new blockchains, developers can configure the following parameters of a block: release timing, transaction rate, proof-of-work requirement, mining diversity, active permission types, level of consensus required for creating/removing administrators and miners, maximum block size and maximum metadata per transaction. Unlike some other platforms like Bitcoin Core, MultiChain provides ease to configure different blockchains at the same time. Further, Multichain supports a number of programming languages such as Python, C#, PHP, JavaScript or Ruby. Some significant features of MultiChain are summarized below [9]:Permissioned: To access this blockchain, permission is required since it is an invite-based network. Table 3 illustrates some of the access-level permissions granted by MultiChain. MultiChain Stream: Streams provide data retrieval, timestamping and archiving of data that can be used to implement shared immutable key-value, time-series and identity- driven databases. Assets: A MultiChain asset is the term referring to an item/token having some value, that can be transferred between blockchain users via a transaction. MultiChain handshake protocol: Since blockchains are decentralized, a peer-to-peer connection is established between the nodes in a blockchain via handshaking by MultiChain. Scalability: MultiChain provides flexibility in storing information on a stream, it can be on-chain or go off-chain any time according to the administrator. The dual chain storage method further leads to scalability of the system. Mining: Mining of data blocks in MultiChain is performed by a set of pre-assigned or identifiable members of the blockchain only. Here, in mining process, instead of computing any mathematical puzzle or hash by multiple nodes, these pre-assigned block validators can add new blocks in the blockchain. The above features and flexibility provided by MultiChain motivates its use as the blockchain platform for the implementation of a private blockchain in this work. Literature review Significant research is being performed in multidisciplinary domains utilizing blockchain technology. The work in [10] has tried to address the problem of online piracy in movie industry by developing a blockchain-based anti-piracy system, “Vanguard”. This system substitutes the conventional Intellectual property (IP) registration system and keeps track of the owners IP rights to ensure that there is no illicit distribution of their data. Blockchain technology and certificateless cryptography have been used in [11] to implement a data storage system for managing and protecting huge amounts of IoT data. Authors of [12] have utilized blockchain in the design of approaches to be used for data sharing in smart cities. A Blockchain Tree to store information from smart Id cards has been proposed in [13]. This system provides multilevel security by integrating blockchain at lower level to that of higher level. The work in [4] focusses on the implementation of blockchain for various applications in food industry like food tracing, land registrations, customer awareness programs, agriculture insurance etc. Authors have used the open-source platform- MultiChain for the implementation of the proposed system. One of the main advantages of using blockchain is to prevent forgery or frauds as it is immutable and transparent. One such scenario has been discussed in [14], where blockchain based system is used for preventing property frauds such as frauds involving bank loans etc. Ping End-to-end Reporting (PingER) is a framework developed by the SLAC National Accelerator Laboratory USA for worldwide end-to-end internet performance measurement [15]. The work proposes a decentralized blockchain based data storage system for PingER. Here, instead of centralized storage of data, all the data files are distributed among multiple locations using Distributed Hash Tables (DHT) and only metadata of these files is stored on the blockchain. A new terminology, Blockchain-as-a-Service (BaaS), similar to SaaS has been discussed in paper [16]. It is a cloud-based service which eases blockchain set-up, provides platform to run applications, security and some other core features of blockchain. Authors of [17] have proposed a blockchain based system for multitenant architecture. Each tenant has individual permissioned blockchain which in turn is connected to a main chain. This work has been carried out with Laava ID Pty Ltd (Laava) and implementation is done using Ethereum. The present work considers an important application area for blockchain, i.e., the healthcare sector. Significant existing work performed for application of blockchain in the healthcare sector is summarized in Table 2. For instance, authors in [18] have included blockchain technology in digital services like online consultations. They have used a decentralized solution to provide security in the healthcare sector. Use of blockchain has added transparency in the user-client, here doctor- patient communication. Also, authors have presented three different case studies in this field, namely; Telemedicine, patientory and medblock. Paper [19] is a survey paper which highlights the work done in the field of electronic heath record (EHR) systems using blockchain technology. Authors have discussed various consensus algorithms to be used in public blockchain, such as; Practical Byzantine Fault Tolerance replication algorithm (PBFT), RAFT, Proof of Authority (PoA), Proof of Capacity (PoC) and Proof of Elapsed Time (PoET). A privacy preserving system-MediBchain has been proposed in [20] for healthcare data using blockchain technology. For encrypting private data, they have applied Elliptic Curve Cryptography (ECC).Table 2 Comparison of proposed system with related work in healthcare domain S.No Related Work Overview/Issues Addressed SaaS Application & Multitenancy Storage in Blockchain Techniques/Implementation 1 MedRec [21] • Fragmented data • System interoperability No encodes metadata Ethereum blockchain 2 MediChain [22] • Addresses scalable asset (data) storage demands • Has developed a web application “Trioova” to improve user interface No Patients’ medical data Hyperledger Composer 3 MedicalChain [23] • Handles issues like record tampering, lack of transparency • Uses MedTokens to share healthcare information at a marketplace No Health records Hyperledger Fabric 4 MediBChain [24] • Privacy preserving mechanism for the health care data No Patients’ data Blockchain is used as a storage and protocol using cryptographic functions has been proposed 5 Medicohealth [25] • Implemented an immutable database of doctors which is linked to a licensing authority • Provides secure data storage and access management No Physicians’ data Storj, OpenEHR 6 MedX [26] • Decentralized registry of physicians using Smart contracts No Physicians’ data Ethereum 7 MedChain [27] • Handles data security and interoperability by developing a multi-crypto-token framework Yes Patients’ data Hyperledger Fabric blockchain framework is used to implement Medchain and MedChain Security Token is deployed on Ethereum 8 Proposed System • Prevents privacy and data tampering and provides transparency along with tenant isolation Yes Metadata information about the assets MultiChain Framework A mobile application has been developed using blockchain technology for storing data of cognitive behavioral therapy for insomnia patients [28]. Data is stored in Hyperledger Fabric blockchain network in JSON format. This blockchain based system provides data transparency and accessibility without risk of data tampering. Blockchain has been integrated with artificial intelligence systems in [29] to design a predictive system for COVID-19 infection for a better clinical risk management. The improvements made by the proposed system are listed in Table 2. Threat model We analyse the security of our proposed system using a threat model as described in this section. Threat modelling is an organized procedure for identification of probable threats, potential vulnerabilities and listing a corresponding mitigation plan. In a cloud environment, data is distributed among several servers across different locations, thus it is highly likely to suffer from inevitable security threats [30]. Therefore, the main idea of threat model utilized in our work is to propose a systematic analysis of different possible attacks, vulnerabilities, and its possible defence mechanism in a cloud storage environment. This work, uses the STRIDE framework [31] developed by Microsoft, to create an effective threat model for the blockchain based multitenant system. STRIDE model covers the following threats:(i) Spoofing: This is a threat to authentication where the attacker pretends to be an authorised user and uses his identity to access his/her clinical data added in the cloud or blockchain network. (ii) Tampering: This is a threat to integrity where the attacker performs some unauthorised modification of the data, thus violating the integrity of the data stored on the system. (iii) Repudiation: Repudiation is a breach of contract, in which a user can deny that a certain transaction was not performed by him. (iv) Information Disclosure: This is a threat to confidentiality where the attacker tries to access the information from the storage system without any authorization. (v) Denialof Service: This is threat to availability where attacker can flood the cloud environment resources with heavy amount of fake data packets, so that the system is unavailable to handle real data traffic. (vi) Elevated privileges: This is a threat to authorization where some already authorised user tries to access data of some other user without significant permission. Further discussion and security threat analysis are covered under Sect. 4.2. Multi-tenant tamper-proof storage The section presents the design and implementation of a tamper-proof storage for a multi-tenant SaaS application related to healthcare. Management of healthcare data is a critical task as it involves confidential and sensitive information related to patients. Along with the secure storage of the patient’s data, its efficient retrieval is also imperative. For instance, timely fetching of data is required to haste up the treatment process after diagnostic by the doctor or for simplifying the insurance claims. Motivation Blockchain technology has lately emerged as one of the most promising solutions for secure and efficient data storage. Data can be directly stored in the form of transaction on the blockchain network. These transaction data and records are stored in the form of hash digest in a Merkle tree; thus, making it difficult to decode the content using the hashed data. Only the authenticity of the data can be checked by verifying the hash of the block with the stored hash making the blockchain immutable. Despite the advantages provided by blockchain, it faces challenges related to data privacy and query processing time. Firstly, the transaction data stored in a block is visible to every node associated with that particular blockchain network. However, there can be the need for some data to be hidden from certain subset of nodes. Existing solutions to provide data privacy on the blockchain rely on asymmetric encryption of stored data. Transaction data is encrypted with an encryption key and stored on the blockchain. For retrieving the data, decryption key is provided to only the subset of nodes who are authorized to access this data; thus, the data remains hidden form the remaining nodes. The proposed work builds a multitenant storage system that provides privacy to tenant nodes by isolating their data from each other and giving access to only authorized tenants. Another challenge that needs to be considered is related to degradation in query response time as the blockchains grow in size. The proposed work is based on horizontal scaling of blockchains which implies that new nodes can be added to the blockchain network depending on the system requirement as it is a decentralized network. However, scalability has a negative impact on time spent in retrieval of data stored on the blockchain, i.e., the query processing time. Although blockchain is used to store transaction data in blocks, it does not support any query language unlike relational databases. Applications that have small data can easily store entire data on-chain. However, if data grows in size, it will take more time in retrieving data from the chain resulting in a high cost. Using a blockchain to save the entire data of a large-scale application is time-consuming and not scalable too. Therefore, the proposed system employs an off-chain storage (databases or dedicated file systems) for actual application data and stores only the meta data on the blockchain. A similar approach has been implemented by systems like StorJ [32], Filecoin [33] etc. though these are not focused on multi-tenant data storage. The proposed storage system is based on a private blockchain developed using the Multichain platform. However, instead of storing complete documents on the blockchain, the proposed system stores only the metadata information such as transaction time, summary of all transactions in a block, reference to previous block hash along with the hash of a document on the blockchain. Off-chain data storage is used for storing complete documents in order to reduce the blockchain’s (a) space overhead in storing large documents (b) time overhead in retrieving and storing data. In contrast, storing only the hash value of the document on a blockchain makes the system secure and improves system performance drastically by saving storage space and time. A multi-tenant SaaS healthcare application A multitenant SaaS application is utilized by a set of users or tenants. The considered SaaS application is based on healthcare sector where patient’s data is stored on the blockchain and can be accessed by different nodes involves in the blockchain network- Health insurer, healthcare provider, research institutes, supply chain and the government are multiple tenants associated with this system. The tenants in the proposed application can be classified according to their role in the system as follows [34]:Data Contributor (DC) A Data contributor is any individual or a group of individuals who intend to collect and share their own data or data collected by them among different nodes. Data Readers (DR) Data readers are individuals or a group of individuals who plan to use the shared data provided by data-contributors through the blockchain to fulfill their information requirements. A permissioned blockchain allows the grant of different access level permissions to its users, as depicted in Table 3. By default, all the privileges are granted to DC, which can subsequently grant permissions to other tenants such as DRs. Miners Miners in a blockchain are those nodes which have permission to add transaction blocks in the network. Thus, in addition to DC, there can be multiple other miner nodes chosen by DC. This implies that a DR can act as a miner if DC grants ‘Mine’ permission to it. In the proposed system if a node is a miner, then its miner_status is 1 else 0. Table 3 Access-level permissions by MultiChain Permission Description Connect Using this permission, one node can connect to another node in the blockchain and can access blockchain contents Send This permission allows the node to send data to other nodes via a transaction Receive It allows the node to receive data from another node, which are reflected on transaction. In MultiChain, send and receive permissions are granted to the first node, thus by default DC has all access permissions Issue Using this permission, a user can create new assets which can be later transferred to some other user as needed Activate By default, DC has the Activate permission. Using this permission, a node can change connect, send and receive permissions of other nodes Mine This permission allows nodes to add a new block in the blockchain network. Nodes which have this permission are termed as Miners Create Using this permission, a user can create new data streams Admin This is the most important permission, which has all the admin controls. By default, DC has this permission. Using this, a node can change all permissions of other nodes Custom Apart from defined set of permissions, MultiChain allows the admin node to create custom permissions. The node with admin permission can create a set of custom permissions Creation of blockchain The work employs a private blockchain for developing a tenant-based storage system. Individual patient stores the metadata of medical record in the form of a transaction on a single blockchain. There is a separate blockchain for each patient. Suppose a patient X undergoes some tests from an unknown disease. Now, to store information about this patient (such as his personal details etc.), a new blockchain will be created with the creation of a genesis block, i.e., the first block of this blockchain. Next, the first node, i.e., the patient data node will add the metadata of X’s tests’ results as transaction data on the block (see Fig. 1). Similarly, all his medical records like doctor’s prescription, vaccination certificate etc. can be added as subsequent blocks on this blockchain. The actual data of the patient is stored off-chain in a database [35]. MultiChain platform has been used for the implementation of a private or permissioned blockchain. Unlike a public blockchain network which requires tedious mathematical computation for the proof of work mining to create a new block, here some pre-authorized members, i.e., “Miners” are authorized to add a new block in the blockchain [9]. Health insurer, healthcare provider, research institutes, supply chain and the government are the multiple tenants, also known as tenant nodes who can see this X’s data in the blockchain. Here, the first node i.e. patient who is adding his/her data in the blockchain acts as the DC (and the default miner node) and the other remaining tenants’ nodes are DR. Figure 2 depicts the role of multiple tenants sharing patient’s data in the proposed system. MultiChain uses sha256 cryptographic secure hash functions to calculate header hashes. Additionally, MultiChain uses smart filters for validating the transaction data. Also, to prove that the certificate issued to patient exists, Proof of Existence (POE) is provided to the user. In order to provide POE to tenants that the particular file or patient’s record existed on the stated date and time, document ‘s hash and timestamp are linked with it [36].Fig. 2 Multiple Tenants sharing Patient’s record in the Proposed System Data validation Algorithms 1–5 have been proposed to allow retrieval of patient’s medical record by other tenants of the application. To access the patient’s record, which is the primary data contributor (DC) for our application, tenants who are data readers need to have access level permissions provided by MultiChain platform (refer Table 3). Initially all the nodes have connect permission using which each node can connect to the other nodes and can read the data stored in the blockchain. All the remaining permissions such as send, issue, activate, mine, create etc. are granted by the admin node or the first node in our case on request to the tenant node. Validate(txn-id) function used in Algorithm 1–5 uses transaction filters supported by the MultiChain platform. A transaction filter validates a transaction by considering the input, output and metadata of the transaction. The transaction needs to pass this smart filter validation test. A failure of this test implies an invalid transaction which is therefore rejected. This ensures timely and tamperproof access of the X’s data whenever required. For instance, consider a text file with a patient’s test results. In our application, this text file will be stored on the cloud and only the hash of the contents of this file will be stored on the blockchain. Suppose, an intruder manages to access and modify this file. Using the SHA 256 hash function, the hash of this file content can be recalculated and compared to the hash stored on the blockchain. If these two hash values do not match, it will be clearly evident that the file has been tampered. Thus, the proposed system is able to prevent any tampering of the data stored on the cloud using the hash value of the data stored on the blockchain. Data validation by different tenants (A) Healthcare Provider Each individual patient has control over his blockchain. In case, patient X needs to visit a new hospital or healthcare provider, he can provide it access to his blockchain. Storing medical data on blockchain not only provides security in comparison to paper-based record keeping but also reduces redundant clinical tests. Algorithm 1 corresponds to record fetching by healthcare provider who gets access to a patient’s record which is tamper-proof and can also add a new block (for e.g. including prescription data) to the patient’s blockchain. For adding prescription as a new block in the blockchain, healthcare provider is granted send, receive and mine permission. Thus, this tenant will now act as a DC in the blockchain. (B) Health Insurance Companies Using blockchain technology, it will be easier for health insurance companies to verify the medical claims and avoid forgery of documents. Algorithm 2 depicts the record fetching by a health insurance company. This tenant is not mining or adding data in the blockchain, thus it remains as a DR. (III) Research institutes and Supply chain or pharmacy For research on new diseases and development of new drugs, a large corpus of patient’s data is required. After prior approval from patients, their tamperproof medical data that is stored on blockchain can be supplied to research institutes and supply chain or pharmacy. Algorithm 3 and 4 illustrates the patient’s record fetching by research institutes and supply chain respectively. Both of these tenants are utilizing the blockchain data for research and analysis, these tenants are not adding any data in the blockchain, thus they remain as a DR. (IV) Government Governments of most of the countries have made a transition from paper-based health record keeping to electronic health records. “MyHealthRecord” is the National Health Portal hosted by Centre for Health Informatics (CHI), set up at National Institute of Health and Family Welfare (NIHFW), by the Ministry of Health and Family Welfare (MoHFW), Government of India [37, 38]. This has helped health experts to study various disease trends and propose its eradication policies. The recent menace to the world health is the outbreak of the novel Coronavirus Disease (COVID-19). The only possible solution to eliminate COVID-19 which WHO can think of right now is effective vaccination of the population. Indian government has also started its vaccination drive against this pandemic. Using the proposed work, government can make available person X vaccination certificate on the blockchain and thus, preventing forgery or tampering of the certificate. For adding a vaccination certificate as a new block in the blockchain, government will be granted send, receive and mine permission. Thus, this tenant will now also act as a data contributor in the blockchain. Algorithm 5 depicts the record fetching by government. Security analysis This section examines how the proposed system mitigates the potential threats associated with the cloud storage system; as listed by STRIDE model and discussed in Sect. 2.4 [30]. The proposed blockchain based multitenant system tackles the threats as follows:Authentication and access control: The proposed system uses permissioned blockchain for its implementation. Thus, all the users are added to the network after subsequent authentication process and only authorised users are allowed to access the data. Depending on the requirement each user or tenant is a DC or DR and is accordingly granted different access permissions to control, read, send, mine etc. (see Table 3). Integrity: The verification procedure to check the integrity of the data stored in the blockchain is handled by a hash tree popularly known as Merkle tree which is a tree-based data structure in which the hash of the child node is stored in non-leaf node. Using the Merkle tree, user can confirm whether the transaction is legitimate or not by verifying the hashes. Repudiation: Non-repudiation is an important property for secure communication made available by blockchain networks. Confidentiality: The proposed system allows only the authorised users to access the data stored, thus ensuring data confidentiality. Instead of complete data, only the hashed meta data is stored in the blockchain network; therefore, restricting unauthorised access of data to an extent. Key Security: The proposed system uses Elliptic Curve Digital Signature Algorithm (ECDSA): a public key cryptography encryption algorithm for key generation in the MultiChain blockchain network [39]. Results This section describes the results of implementation of the proposed model. Simulation setup The initial implementation of the proposed system is performed on a Windows server with an Intel Core i5 CPU (1.60 GHz) and 8 GB of DDR3 memory. For the deployment of the private blockchain, MultiChain an open-source platform is used along with Amazon Elastic Compute Cloud (Amazon EC2) [40]. It is one of the most popular web services by Amazon, which offers computational capacity to run applications on the cloud. EC2 provides easy scaling and flexibility in configuring features like memory size, processors etc. EC2 also has an elastic load balancer which can automatically divide incoming data load to multiple available instances as required, here instances are virtual computing environments. We have used Ubuntu Server 16.04 LTS (HVM), SSD Volume Type for implementing multiple tenant nodes in the proposed Multichain system. Initially, the blockchain has five nodes in the network. One of them is data contributor (DC), in our case it is an individual whose medical record will be shared on the blockchain. The other nodes are the data readers (DR). The procedure of implementation is listed as follows:(A) Launching and connecting to EC2 Server using AWS account to set up DC In the first step, an EC2 Server is launched and connected using AWS account to set up the DC. An Ubuntu Server 16.04 LTS (HVM), SSD Volume Type has been used and connection to this sever has been made using putty through its .pem file (named as Multichain-key.pem) with the command. ssh -i “Multichain-key.pem” ec2-3-144-147-56.us-east 2.compute.amazonaws.com (B) Creating blockchain and Genesis block Once MultiChain is successfully installed, using the DC node created in the step 1, a blockchain, referred to as Chain1, for the first patient is created. Fig. 3 demonstrates the MultiChain core daemon which initiates the server and mines the first block, referred to as Genesis block in the network. Fig. 4 illustrates the details of the created blockchain. Similarly, all the other tenant nodes are added into the network. (C) Connecting tenants in a Blockchain and defining permissions to each node Multiple EC2 servers were used for creating multiple tenant nodes and all these tenants were connected to a blockchain Chain1. After successful connection to chain1, admin node, here node1 granted different access level permissions as explained in Table 3 to each tenant. Fig. 5 illustrates the information about the peers connected to a tenant node and Fig. 6 shows the permissions granted to the tenant node. Fig. 3 MultiChain Core Demon Fig. 4 Information about created MultiChain Chain1 Fig. 5 Information about the peers connected to Chain1 Fig. 6 Permissions assigned to node Table 4 lists all the details of implemented nodes including the private IP and public IP DNS which is used for establishing connection using ssh client. The column, node address shows the address of each tenant node using which nodes can connect to each other along with its best computed block hash.Table 4 Details of implemented nodes Nodes Private IP Public IP DNS Node Address Best Block Hash Node 1 172.31.34.236 ec2-3-144-147-56.us-east-2.compute.amazonaws.com [email protected]:2901 00007468a9049bbe42424babae3d411610d463c96d5c753dff83cb3b2ae51f19 Node 2 172.31.39.239 ec2-18-188-112-203.us-east-2.compute.amazonaws.com [email protected]:2901 0000ee7f5bf9df9d224789905770f4015d80fd081a27a0795260b863f77e0677 Node 3 172.31.15.114 ec2-18-118-122-1.us-east-2.compute.amazonaws.com [email protected]:9699 00000009d8f46a8a57f351bcd725706b22a31e29738b9fa51f15e44bd608acf2 Node 4 172.31.14.23 ec2-18-219-154-138.us-east-2.compute.amazonaws.com [email protected]:9705 0000f4e39670be22b912a2f27b79ee4bb72d39b0fdf3bfbc4309085883b9f802 Node 5 172.31.21.207 ec2-18-117-236-216.us-east-2.compute.amazonaws.com [email protected]:5747 0000d545e12937a58974df77175e3f5b4c40f73c5a4bec1a087bed5d199f839a Node 6 172.31.30.202 ec2-3-16-183-7.us-east-2.compute.amazonaws.com [email protected]:6473 0000f5f6435ae1eb2a058f7d371c7e70310107406a75962dd8480d78626de61b Node 7 172.31.17.166 ec2-3-17-148-157.us-east-2.compute.amazonaws.com [email protected]:2645 0000e63cac94021e053633bfb934840e196c17add54a8a03f79b2812f156c256 Further we assess the scalability of the proposed system by adding multiple nodes in the blockchain. The subsequent experiments were carried out on NVIDIA DGX- Workstation having 20-core intel Xeon e5-2698 v4 2.2 GHz processor and 256 GB DDR4 memory. We utilized Containerization to implement 100 nodes in the MultiChain network, each node in a separate container. Containerization helps to achieve significantly lighter weight implementation as compared to the use of virtualization in the earlier experiments. We have used Docker [41] an open-source containerization platform that allows users to encapsulate all the application code with libraries and necessary dependencies into isolated containers. Figure 7 shows a sample list of multichain nodes installed on docker containers.Fig. 7 Information about Containers acting as peers in blockchain For creating multiple nodes, we initiated multiple docker instances. The blockchain is created on the first node called as the seed node and all the remaining nodes are connected to this blockchain as peers. Each node has its own private key generated using ECDSA. We assigned proper permissions (see Table 3) for the nodes to send, connect, create or mine blocks in the network. Figure 8 depicts how different peer nodes are connected to a tenant node.Fig. 8 Information about the peers connected to Chain1 using containers We have instigated the network for 100 nodes and the system can be further scaled up. Since only metadata is being stored, hundreds of transactions and data streams can be processed per second. Single MultiChain node can proficiently handle millions of data load but the same node is not capable to store millions of addresses or users in its own MultiChain wallet [5]. Evaluation metrics The performance of the proposed storage system has been evaluated using tests, namely, the admin elasticity test, tenant isolation test and scalability test [32].Admin elasticity test A blockchain network can have combination of different nodes having admin permissions. In this test, we shut down some servers hosting the admin nodes and then tested whether new nodes can connect to the network. This test was performed ranging from few admin nodes to no admin nodes in the network. Table 5 illustrates the significance of admin nodes in the network since no new nodes can be added if there is no existing admin node. However, it is possible that there are multiple admin nodes in a blockchain. Tenant isolation test There are multiple nodes that are tenants in the blockchain network. In this test, we shut down some servers hosting tenant nodes. After performing this test, it was observed that all tenants are isolated from each other. Table 6 illustrates that even if some nodes were taken off, the system continues to work properly, remaining tenant nodes were still capable to process the transactions required to communicate in the network. Scalability test All the above tests were carried out at different sized networks to check the scalability of the system. We started with 7 nodes network and scaled up to 25 nodes using AWS. It was observed from Table 7 that the proposed system is scalable and new nodes can be added or removed from the blockchain network without hindering the working of the remaining blockchain network. Further to assess scalability, the system performance was checked for 100 nodes by creating docker containers and performing the admin elasticity test and tenant isolation test with these nodes. We initially divided the nodes in a ratio of 40:60 where 40 nodes are given admin permissions and 60 nodes are tenants. Then to perform the admin scalability test, we shut down admin nodes till there was no admin node in the network. It was observed, that at least one admin node is required for proper functionality of the permissioned blockchain network. Similarly, on the same nodes we performed tenant isolation test by shutting down some tenant nodes ranging from few nodes to no tenant node in the network. As already stated, the blockchain is created on the first node and all the remaining nodes are added to this blockchain as its peers. Thus, it is not required to connect each node to the remaining nodes, all peers are independent. As expected, after performing this test, it was observed that all tenants are isolated from each other and even after breakdown of some nodes, remaining nodes accomplished the transactions in the network without affecting the working of the proposed system. Table 5 Admin elasticity test Number of Admin Nodes Number of Tenants Nodes Can New Nodes connect 3 4 Yes 2 4 Yes 1 4 Yes 0 4 No Table 6 Tenant Isolation test Number of Nodes Number of Tenants Nodes Can New Nodes communicate/send transaction 3 5 Yes 3 4 Yes 3 3 Yes 3 2 Yes 3 1 Yes 3 0 Yes Table 7 Scalability test TEST Number of Admin Nodes Number of Tenant Nodes Can New Nodes connect Can New Nodes communicate/send transaction Admin elasticity test 10,9,8,7,6 15 Yes - 5,4,3,2,1 15 Yes - 0 15 No - Tenant isolation test 5 15,14,13,12,11,10 - Yes 5 9,8,7,6,5,4,3,2,1 - Yes 5 0 - Yes Conclusion The paper has presented the design and implementation of a Blockchain based data storage system that prevents data tampering in a multitenant environment. The blockchain is used for validating access to data by tenants while the actual tenant data is stored offchain for efficient query processing. The efficacy of the system has been investigated using data from a case study of healthcare sector. Further. a threat model has also been utilized for showing that the system can effectively handle the possible security threats. The proposed system leverages benefits of blockchain technology by providing scalability of the system along with data isolation among different tenants in the system. The proposed storage system was successfully implemented and evaluated using three different tests- the admin elasticity test, tenant isolation test and scalability test. It was observed that data of each tenant was independent of the other tenants and accessible only to the authorized users. Even if some tenants were shut down, the system continued to function properly since the remaining working nodes could communicate with each other effectively. Declarations Conflict of interest Authors declare that they do not have any conflict of interest/competing interest. 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==== Front Educ Inf Technol (Dordr) Educ Inf Technol (Dordr) Education and Information Technologies 1360-2357 1573-7608 Springer US New York 11516 10.1007/s10639-022-11516-4 Article Post-Covid Lockdown Assessment of Blended Learning Approach for Distance Education in Ghana: implications for human resource managers and curriculum implementers http://orcid.org/0000-0003-0065-2183 Segbenya Moses [email protected] 1 MensahMinadzi Vincent 2 1 grid.413081.f 0000 0001 2322 8567 Department of Business Studies, College of Distance Education, University of Cape Coast, Cape Coast, Ghana 2 grid.413081.f 0000 0001 2322 8567 Department of Education, College of Distance Education, University of Cape Coast, Cape Coast, Ghana 13 12 2022 119 30 8 2022 10 11 2022 5 12 2022 © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. This study assessed the blended learning approach for distance education and its implications for human resource managers and curriculum implementers. The study used the descriptive survey design from the quantitative approach. A sample of 552 was drawn from a study population of 2208 postgraduate students pursuing their distance programme countrywide with public universities. Data was collected with a self-developed questionnaire and was analysed with Partial Least Square Structural Equation Modelling (PLS-SEM). It was found that there was a significant relationship between challenges with face-to-face and the usefulness of face-to-face, challenges with online learning intention and the usefulness of online intention (decision to continue or discontinue with online learning as against the traditional face-to-face mode). Also, there was a significant relationship between the challenges of online intentions and the usefulness of online learning; the usefulness of face-to-face and usefulness of online learning, and the usefulness of online learning and challenges with online learning. It was further found that challenges with both face-to-face sessions and online learning needed to be resolved to ensure successful blended learning for postgraduate distance learners. It was therefore recommended that the human resource managers and curriculum implementors should ensure that the right type of courses are taught on the online platform and the remaining courses are taught using the face-to-face mode. It was further recommended that more postgraduate study centres be opened to reduce challenges associated with face-to-face sessions. Also supports in terms of online tools, internet data and requisite skills should be provided to minimise challenges associated with online learning among postgraduate distance learners. Keywords Blended learning Face-to-face session Online learning Postgraduate learners ==== Body pmcIntroduction The emergence of the Covid-19 pandemic since the latter part of 2019 affected higher education institutions worldwide (Buheji & Buheji, 2020). Safety protocols such as social distancing, lockdown, among others, put in place by governments across the globe to curb and reduce infections led to the closure of educational institutions (Upoalkpajor & Upoalkpajor, 2020). Some higher education institutions in Ghana-University of Ghana, University of Education, Winneba, University of Cape Coast, and Kwame Nkrumah University of Science and Technology have resorted to online as an alternative to the traditional face-to-face interaction in their quest to continue the academic calendar while ensuring quality education delivery to students (Upoalkpajor & Upoalkpajor, 2020). Thus, usage of online platforms to deliver educational content has flourished during Covid-19 than before (Oliver, 2020). Over time, the reduction in the infection rate of Covid-19 has given some educational institutions the opportunity to either fully continue with dedicated online learning, revert to the traditional face-to-face approach, or adopt a blended approach (Nambiar, 2020). Blended learning relates to a combination of both traditional face-to-face and online modes of instruction (Kassner, 2013). Blended learning allows both teachers and students to collaborate, benefit from both traditional face-to-face and online classes, thus increasing students’ engagement in instruction in a varied manner (Abbasi et al., 2020). Blended learning on the distance mode affords learners the opportunity to harness the benefits associated with the two approaches whiles using the merit of one approach to reduce the negative impact of the other (Paechter & Maier, 2010). Segbenya et al. (2022) revealed that distance learners in developing economies are confronted with challenges associated with online learning including irregular electricity, requisite skills to participate in online learning platforms, internet facilities, and challenges with the availability and functionality of online tools. These challenges, therefore, serve as barriers to distance learners in developing countries to fully harness the benefits or usefulness of online learning (González-Gómez et al., 2016). Meanwhile, the traditional face-to-face approach where the distance learners will have to converge in a geographic area or classroom for teaching and learning to take place is also not without challenges (Ryan et al., 2016). These challenges include cost and risk associated with transportation to study centres, cost of accommodation, the possibility of missing out on lecture/classes, or reporting for face-to-face late (Segbenya et al. 2019). Thus, the blended approach where both face-to-face and online learning approaches are adopted could be very helpful for distance learners in reducing the challenges faced by these learners during and after the pandemic (Paechter, Maier, & Macher, 2010; Albelbisi & Yusop, 2019; Segbenya et al. 2019). Meanwhile, the adoption of the blended approach places enormous responsibilities not only on distance learners and their facilitators, as earlier studies have revealed (Segbenya et al., 2022; Nambiar, 2020) but also on human resource managers and curriculum implementors. This is because human resource managers play a critical role in the admission of students and the recruitment of course facilitators (Segbenya & Ansah, 2020). Curriculum implementors also determine the curriculum to be taught and which aspect should be taught online and face-to-face (Makewa & Ngussa, 2015). Curriculum implementors in this study are managers of distance institutions, study centre coordinators and course facilitators who directly developed and teach the contents of the academic programmes (Letshwene, & du-Plessis, 2021; Ng, 2018). Existing studies on the impact of COVID-19 on education by Segbenya et al. (2022); Upoalkpajor & Upoalkpajor (2020); Buheji, & Buheji (2020) have all been centred on basic schools and undergraduate students and online learning. Little has therefore been empirically done during and after the COVID-19 lockdown in Ghana to seek distance postgraduate learners’ perspectives on blended learning and the implications for human resource managers and curriculum implementors (Segbenya et al., 2022). Thus, there is dearth of research on blended learning at the postgraduate level in Ghana. Within this background, this study was carried to examine the post covid lockdown assessment of the blended learning approach adopted for postgraduate distance learners and their implications for human resource managers and curriculum implementors. The five hypotheses that guided the study were: Hypotheses H01: Challenges with face-to-face tutorials sessions has significant relationship with usefulness of face-to-face. H02: Challenges with online learning has a statistically significant relationship with usefulness of face-to-face. H03: Challenges with online learning has significant relationship with usefulness of online learning in a blended distance education. H04: Usefulness of face-to-face has significant relationship with usefulness of online learning in a blended distance education system. H05: Usefulness of online learning has significant relationship with continuity of online learning in a blended distance education system. Literature review Conceptual review Face-to-face or online learning (blended learning) have several common features including student-student and student-instructor interactions, instructor support and mentoring, lecture/content delivery quality, course content and social networking tools. All other things being equal, the semblance within the two modes is likely to influence students to opt for any of the modes. Blended learning though not a new phenomenon however, it has gained prominence as a result of Covid-19 emergence. In recent times, many empirical investigations have been conducted into the blended learning mode so as to ascertain learners’ preferences or otherwise. Successful implementation of educational programmes in higher education institutions depends on a large extent its usefulness to the students (Almaiah, 2018). Literature indicates that one of the factors influencing successful implementation of blended learning approach in high education institutions is students’ acceptance. Students are the major beneficiaries of teaching approaches be it traditional face-to -face, purely online or both. It therefore means that when students perceived teaching approach to be beneficial to them, it is most likely that they would embrace it. So, when students think that the online learning approach would not affect the quality of content delivery and when they find the online platform easy to use, they would accept it (Ho, Tsung-Hsien, & Binshan, 2010). However, if students feel the online platform would affect quality delivery, they would prefer the traditional face-to-face method. We argue therefore that if students weigh the two approaches to be similar in quality, they would gladly adopt it since they would not lose anything. Studies have been conducted to explore factors that influence higher institution students’ acceptance of the blended learning mode. A study conducted by Khan, Kamal, Illiyan, and Asif (2021) showed that learners had the least preference for online learning as compared to traditional face-to-face teaching. It could be inferred that the challenges students had with online learning influenced their preference for the face-to-face mode of learning. These challenges were not different from what Segbenya et al., (2022) revealed in their study: unreliable power supply, erratic internet connectivity, lack of collaboration, and motivation. It can also be said that there was the relationship between the usefulness of online learning and the intention to continue with online learning. If students realised how useful and fascinating online learning is, they would want to continue with it (Mahyoob, 2020). Another study by Mahyoob (2020) revealed that the majority of students surveyed were not satisfied with continuing online learning because they could not fulfil the expected learning outcomes or performance. Their dissatisfaction was premised on the fact that they had challenges with online learning. For instance, respondents indicated that they could not use all the blackboard services for online learning, join online classes, participate effectively, and submit their assignments. They also revealed they were unable to complete their examinations online. The finding agrees with that of Aguilera-Hermida (2020), who found that learners had the least preference for online learning as compared to traditional face-to-face teaching. However, the finding was in contrast with a study carried out by Muthuprasad et al., (2021); Hasan and Khan (2020), who revealed that students were more comfortable with the online learning approach since according to the students it is more flexible compared to the traditional face-to-face interaction. Bali & Liu (2018) conducted an investigation into face-to-face and online learning approaches and revealed that there was no statistically significant difference between online and face-to-face learning. The results further indicated that even though respondents were satisfied with face-to-face learning, most of them chose online learning over the face-to-face method due to its convenience, ease of time, and the opportunity to work at any time they wished. Moreover, online learning is proven to be cost-effective and flexible which enables them to work at their own pace (Zheng, Bender and Lyon’s (2021). It is clear beyond reasonable doubt that face-to-face and online learning play a complementary role since they create opportunities for students to experience different learning contexts. However, Syarah et al. (2020); Kuset et al. (2021) and Kemp and Grieve (2014) found a non-significant difference in students’ performance in the two modes of learning. Theoretical review The researchers adopted technology acceptance models (TAM) to explore and explain the factors that influence blended mode acceptance among postgraduate students’ population (Kemp, Palmer, & Strelan, 2019; Teran-Guerrero, 2019). The TAM attempts to explain students’ willingness and the continuous use of technology in the teaching and learning process. Experts believe that certain factors influence students’ attitudes towards the use of educational technologies in higher education institutions. Ali (2020) asserts that students’ attitudes towards educational technology directly affect their learning process. Other factors such as affect and motivation have an influence on students’ behaviour towards adopting online learning. Affect includes the user enjoyment and satisfaction with the prior use of a platform, the affect toward the use of technology, and the individual’s emotional state (Kemp et al., 2019). Motivation connotes the perceived relevance of an activity that impacts behavioural intention. Research shows that there is a relationship between motivation and self-regulation skills and online learning. Albelbisi and Yasop, (2019) assert that when there’s a lack of motivation, it could result in individuals spending extra time completing assignments, turning in late assignments, or overall poor-quality work. Based on the theoretical and conceptual review, a conceptual framework has been developed showing the relationship between the variables of the study as well as the interconnectedness of the hypotheses guiding the study (See Fig. 1). Fig. 1 Conceptual framework showing the relationship between the variables of the study.(Key: CHFTF = challenges with face-to-face sessions, UFTF = usefulness of Face-to-face sessions, CHOLI = challenges with online learning intention, UOLI = usefulness of online learning intention, COLI = continuity with online learning intentions.) Methodology The study employed the descriptive survey design from the quantitative approach and sampled 552 from a study population of 2208 graduate students pursuing their distance programme with public universities from study centres across all regions countrywide. The sample represents 25% of the study population which gave a better representation as compared to the 336 suggested by the Cochran formula for sample determination (Segbenya et al., 2021). Sampling techniques deployed for the study was multistage sampling technique, including stratified and simple random techniques to sample the respondents to the research instrument. The simple random was used to ensure that all 2208 postgraduate students had an equal chance of being selected to arrive at the 552 respondents. The stratified sampling component was also used to cater for ensuring respondents selected fall under both male and female categories, education and business programmes, and both first and second-year categories. Measures Data were collected with a self-developed questionnaire measured on a four-point Likert scale: strongly disagree, disagree, agree, and strongly agree. The two parts of the questionnaire comprised demographic characteristics of respondents for part one and part two focused on the variables captured under the research hypotheses. Reliability and validity values were above the minimum threshold, suggesting that the instrument was good to use. Data were analysed with Partial Least Square-Structural Equation Modelling (PLS-SEM) for testing of the hypotheses. Analysis and findings The initial part of the presentation of the results in this section is the demographic data of the respondents for this study and the second part focused on the presentation of the main findings for the study’s five hypotheses. Demographic data The demographic characteristics of respondents in terms of gender, category of programme and level of academic programme formed the preliminary analyses of the results. The results as presented in Table 1 indicate that majority of respondents were male postgraduate students (51.4%), pursuing business masters programmes (46.4%) and were in their second year (final year) of their academic programmes (66.1%). Table 1 Demographic characteristics of respondents Demographic Characteristics Frequency Percent Gender Male 284 51.4 Female 268 46.6 Total 552 100.0 Category of academic programme Education 220 39.9 Business 256 46.4 Others 76 13.7 Total 552 100.0 Level of academic programme 1st Year 187 33.9 2nd Year 365 66.1 Total 552 100.0 Field survey (2022) Measurement model Confirmatory factor analysis by the PLS algorithm was primarily carried out to estimate the internal consistency measure of the model. Individual items forming the variables or factors of the study was used for the measurement, and this can be seen in the reflective model presented in Fig. 2. From Fig. 2, the minimum loading of 0.652 and above for each item measuring the factors was achieved, as suggested by Hair et al. (2017) and Segbenya et al. (2022). Fig. 2 Figure 2: An algorithm for confirmatory factor analysis Source: Field survey (2022). Measure for internal consistency for the analysis The PLS path model’s internal consistency measures for this study were done with four main indicators- rho A, Cronbach’s Alpha, Composite Reliability and Average Variance Extracted (AVE) (Hair et al. 2017) and the results are presented in Table 2. The results in Table 2 show that a Composite Reliability value ranged between 0.772 and 0.881 for all the factors. The Average Variance Extracted (AVE) values were between 0.598 and 0.742, above the minimum threshold of 0.50 recommended by Kline (2015). A rho-A value ranged between 0.608 and 0.858 was achieved for all factors of the study. Additionally, a Cronbach’s Alpha value between 0.601 and 0.832 for all variables was also obtained. The results suggest that all the variables achieved the minimum threshold recommended by Hair et al. (2017) and that the model achieved both reliability and validity standards of analysis. Table 2 Construct Reliability and Validity Cronbach’s Alpha rho_A Composite Reliability Average Variance Extracted (AVE) CHFTF 0.834 0.858 0.881 0.598 CHOLI 0.723 0.738 0.842 0.640 COLI 0.602 0.608 0.821 0.697 UFTF 0.601 0.680 0.772 0.635 UOLI 0.702 0.706 0.852 0.742 Source: Field survey (2022) Discriminant validity A discriminant validity using the Heterotrait-Monotrait Ratio (HTMT) as suggested by Henseler, Ringle and Sarstedt (2015) was carried out with the purpose of establishing the uniqueness of each variable in the study. The result as presented in Table 3 suggest that all diagonal loadings for the same variable were zero and between variables of the study were below 0.85 thresholds (Henseler, Ringle & Sarstedt, 2015), suggesting that discriminant validity was achieved for the PLS path model. Table 3 Heterotrait-Monotrait Ratio (HTMT) CHFTF CHOLI COLI UFTF UOLI CHFTF 0 CHOLI 0.818 0 COLI 0.405 0.366 0 UFTF 0.406 0.435 0.836 0 UOLI 0.333 0.301 0.828 0.812 0 Source: Field survey (2022) Multicollinearity The existence of multicollinearity according to Segbenya (2012) could influence validity of the results obtained by the path significance test. Thus, the presence of multicollinearity was checked with the use of the variance inflated factors (VIF) as suggested by Hair et al. (2017) with threshold values below 3.3 suggesting that the reflective model was a multicollinearity-free model. The results shown in Table 4 suggested no multicollinearity issues since all the inner values were below 3.3 thresholds. Table 4 Inner VIF Values CHFTF CHOLI COLI UFTF UOLI CHFTF 1.898 CHOLI 1.898 1.088 COLI UFTF 1.088 UOLI 1.000 Source: Field survey (2022) Structural model and hypotheses testing Testing for the significance of the hypotheses for paths analysis was done with the Bootstrapping sequence of 5000 samples utilised in the PLS bootstrap procedure as recommended by Hair et al. (2017) and Segbenya et al. (2022). The results can be seen in Fig. 3. Fig. 3 Bootstrapping results for path analysis Source: Field survey (2022). Results of path analysis Table 5 presents the detailed results for the path significance determined from the PLS bootstrapping sequence. The first part of the results highlights the R2 (R-square) values supported by the adjusted R2 values, as presented in Table 5. The R2 values explained the variance in the dependent variable predicted by the independent variables (Hair et al., 2017). Thus, the structural model explained about 0.286variances in the continuity of online learning intention (COLI), 0.094 variances in the usefulness of face-to-face interaction (UTFT) and 0.237 variances in the usefulness of online learning intention (UOLI) among postgraduate distance learners. Table 5 Path Coefficients R Square R Square Adjusted COLI 0.286 0.285 UFTF 0.094 0.091 UOLI 0.237 0.234 Beta Sample Mean Standard Deviation T Statistics P Values Confidence Intervals f 2 2.5% 97.5% 1 CHFTF -> UFTF -0.162 -0.161 0.060 2.707 0.007* -0.272 -0.039 0.015 2 CHOLI -> UFTF -0.173 -0.173 0.060 2.857 0.004* -0.296 -0.045 0.017 3 CHOLI -> UOLI -0.092 -0.096 0.040 2.284 0.023* -0.171 -0.009 0.010 4 UFTF -> UOLI 0.452 0.458 0.041 10.960 0.000 0.383 0.535 0.246 5 UOLI -> COLI 0.535 0.537 0.032 16.908 0.000 0.475 0.600 0.401 Source: Field survey (2022); *p < 0.000, p < 0.05 supported The second part of the results presented in Table 5 shows the significance of path analysis results for the variables of the study in terms of testing for the five hypotheses of the study. The path analysis results suggested that all the five hypotheses guiding this study achieved statistical significance. Thus, there was a statistically significant negative relationship between challenges with face-to-face sessions (CHFTF) and the usefulness of Face-to-face sessions (UFTF) at (β=-0.162, t = 2.707, p = 0.007) for hypothesis one. Also, there was a statistically significant negative relationship between challenges with online learning intention (CHOLI) and usefulness of face-to-face session (UTFT) at (β=-0.173, t = 2.857, p < 0.004) for hypothesis two; and challenges with online learning intention (CHOLI) and usefulness of online learning intention (UOLI) at (β=-0.092, t = 2.284, p < 0.023) for hypothesis three. For hypothesis four, the results show that there was a significant positive relationship between the usefulness of Face-to-face (UFTF) and the usefulness of online learning intention (UOLI) at (β=-0.452, 10.960, p < 0.000). Furthermore, the model also established a statistically positive significant relationship between the usefulness of online learning intention and continuity of online learning at (β = 0.535, t = 16.908, p < 0.000) for hypothesis five of the study. The effect sizes obtained for each of the significant paths were also favourable based on Cohen (1988) suggestion that an effect size of 0.010 to 0.401 was acceptable. The unidimensional nature of the confidence intervals for the variables for all significant paths also revealed valid and reliable significance. Additionally, the significant results were further strengthened by the confidence level of 95%, with a minor error margin of only 5% indicated by the statistics obtained from the upper and lower boundaries, respectively. Importance performance map analysis (IPMA) PLS Importance Performance Map Analysis (IPMA) was further conducted to give further emphasis to the PLS estimates of the structural model variable relationships. The IPMA gave additional information on the performance and relevance of each latent variable in the model (Hair et al., 2017). Ringle and Sarsted (2016), as well as Segbenya et al. (2022), posit that the total effects represented the sum of direct and indirect effects; thus, the unstandardised effects were drawn upon by the IPMA to enable a “ceteris paribus” interpretation of predecessor constructs’ impact on the target construct. This meant that the size of the total unstandardised effect increased the performance of the target construct’s performance when there was an increase in certain predecessor construct’s performance. Thus, the relevance and importance of the relationships indicated in the model were determined with the PLS IPMA analysis separately for the usefulness of online learning (UOLI) and the results can be referenced from Table 6. Table 6 Performance index values and total effects (UOLI) Total Effect (Importance) Index Values (Performance) CHFTF 0.073 58.108 CHOLI 0.170 59.595 UFTF 0.452 29.414 Source: Field survey (2022) The results, as shown in Table 6, revealed that challenges with online learning (CHOLI) had the strongest and highest value in terms of performance (59.595). However, CHOLI was not the most relevant in predicting the usefulness of online learning (UOLI) in the model since the total effect (Importance) of CHOLI was the second lowest with a value of 0.170. Rather, the most important predictors of the usefulness of online intention/learning among distance postgraduate learners in the model was rather usefulness of face-to-face (UFTF) of 0.452. Figure 4 further highlight the importance and performance map of the usefulness of online learning. Fig. 4 Importance and Performance Map of OLI Source: Field survey (2022). Graphical representation of the PLS IPMA path results The results presented in Fig. 5 is the pictorial view of the PLS path model for IPMA conducted. Ringle and Sarstedt (2016) and Segbenya et al. (2022) recommended that analysts and readers pay attention to the differences between the graphical PLS-SEM results and the graphical representation of IPMA as totally different PLS outputs. The differences advanced were firstly, that the performance values of each latent variable of the IPMA shown instead of the R2 values of the endogenous latent variables shown in the PLS path model. The second difference was that the IPMA results highlighted the unstandardised and recalled the outer weights of the measurement models (formative and reflective) and not the standardised outer loading or weights. Thus, in this study, the results of the beta values highlighted in the outer model in Fig. 5 revealed each item’s importance to the construct and not the loading. The inner values also determined the performance values of the constructs in the individual construct in relation to the endogenous variable and not the total variance explained. Fig. 5 Importance and Performance Map of OLI Source: Field survey (2022). Discussion and implications The study’s findings for the first hypothesis that there was a significant negative relationship between challenges with face-to-face sessions (CHFTF) and the usefulness of face-to-face (UFTF) needs further deliberation. The results mean that a percentage increase in the students’ frustrations herein termed as challenges associated with face-to-face sessions will lead to the same percentage decrease in the usefulness of the face-to-face sessions for postgraduate distance students. Thus, the usefulness of face-to-face tutorial sessions as a component of the blended learning on the distance programmes during the emergence of the Covid-19 can only be heightened or sustained if challenges associated with the face-to-face tutorial sessions are reduced to their barest minimum. Some of the challenges that postgraduate distance learners face regarding face-to-face include financial, institutional, instructional, and work and life balance. These challenges can influence distance learners’ punctuality and regularity to face-to-face and consequently affect their academic performance on the distance mode. The results of this study thus, corroborate the findings of Bali & Liu (2018) that face-to-face challenges for distance learners affect their appreciation for face-to-face tutorial sessions. The findings for the study’s second hypothesis that a significant relationship between challenges with online learning (CHOLI) and usefulness of face-to-face (UFTF) needs to be explained further. The findings suggest that a percentage increase in challenges with online learning among postgraduate distance learners will lead to the same percentage increase in appreciation for face-to-face tutorial sessions. Challenges with online learning such as internet connectivity, cost of data bundle and regular electricity have the propensity to reduce students’ likeness for online learning among postgraduate distance learners. Thus, such challenges with online learning make distance learners gravitate towards the traditional face-to-face tutorial component of the blended learning adopted by distance education institutions during the Covid-19. Alternatively, a decrease in distance learners’ difficulties with online learning will lead to decrease appreciation for face-to-face learning and increase students’ appreciation for online learning during a pandemic. Thus, Mahyoob (2020) findings that challenges associated with online learning among distance students in developing economies have compelled distance education institutions to continue using the traditional face-to-face facilitation mode to deliver their distance education programmes were upheld by this study. This study also found that there was a statistically negative relationship between challenges with online learning (CHOLI) and the usefulness of online learning (UOLI) for the study’s third hypothesis guiding the study. The explanation for the significance recorded in the relation between the two variables suggests that the higher the challenges with online learning among postgraduate distance learners, the lower their interest in continuing with online learning on the distance mode. Thus, continuity and higher appreciation of online learning as a component of blended learning in the distance mode depend on how providers of distance education can resolve students’ challenges associated with the online mode of learning. The findings, therefore, are in tandem with the findings of Khan, Kamal, Lllivan, and Asif (2021) that unresolved students’ challenges with online learning could be blamed for the low level of appreciation for online learning in developing economies. The study further found for hypothesis four that face-to-face sessions significantly related to the usefulness of online learning among postgraduate distance learners. The explanation for this result is that a percentage increase in the use of face-to-face sessions can lead to the same percentage increase/improvement in the usefulness of online learning. Generally, distance learners would have preferred one over the other. However, the results suggest that distance education institutions can use the face-to-face session as a launchpad to enhance their online education for blended learning. A successful and well-coordinated face-to-face session could be used to prepare students for online learning, and the challenges with one method/approach could be minimised by the other. Thus, effective blended learning where learners are satisfied with both face-to-face sessions and online learning could enhance students’ performance on the distance mode. Therefore, the findings of this study agree with that of Kemp and Grieve (2014) successful blended learning in the distance mode largely depends on the usefulness of both face-to-face sessions and useful online learning approaches. Lastly, the findings for the fifth hypothesis showed a strongly positive and significant relationship between the usefulness of online learning and the continuity of online learning among postgraduate distance learners that needs further explanation. The findings suggest that a percentage increase in the usefulness of online learning will result in the same percentage increase in distance learners’ decision to continue with online learning. Thus, until online learning becomes useful to distance learners, its continuity cannot be guaranteed. Thus, to improve upon the dedication/loyalty of distance learners for online learning, distance education institutions would need to ensure that students derive the maximum benefits from the online education provided. Alternatively, a reduction in the usefulness of online education for distance learners would make it very difficult for distance education institutions to continue with online education for students. The results agree with the findings of Hasan and Khan (2020) that deriving the maximum benefits from online education has the propensity to influence students continuous support for online education, especially during any pandemic. 5.1 Practical implications for HR managers and curriculum implementers The significant relationships between variables measuring blended learning for distance education after post covid lockdown have several implications for human resource managers in developing economies like Ghana. The two main components of the blended learning examined were face-to-face sessions and online learning, and their usefulness within the blended learning approach depended on the ability to reduce challenges associated with them. For this reason, the role of human resource managers and curriculum implementers in distance education institutions is crucial for the successful running of blended learning. The implication of the findings for HR managers and curriculum implementers will focus on the two blocks of the blended learning-face-to-face session and online learning. Human resource managers and curriculum implementers need to play a critical role in reducing challenges associated with face-to-face sessions (Bali & Liu, 2018).The use of hired and franchised facilities of other non-tertiary institutions hosting distance programmes of distance education institutions pose several institutional challenges, including the suitability of furniture, washrooms, among others, during a face-to-face session at these facilities (Grieve, 2014).Thus, HR managers need to ensure that conducive facilities that promote comfort for learning are hired/provided or built for face-to-face learning for their postgraduate learners. Additionally, face-to-face tutorials also demand that students spend on transportation with the associated risks to commute to their study centres for academic work. Some distance learners also travel a long distance to their study centres and must pay for accommodation for a day or two to be able to participate in face-to-face sessions (Segbenya & Anokye, 2022). Furthermore, successful face-to-face sessions are dependent on the availability of committed and competent part-time/hired academic staff referred to as facilitators (Segbenya & Anokye, 2022). Thus, human resource managers and curriculum implementers are to ensure that part-time facilitators hired are committed and competent for the successful delivery of course content in the face-to-face mode. Another challenge with face-to-face tutorial sessions is the dependency or the use of print media or modules/course pack for teaching and learning (Segbenya et al., 2019). Thus, delays in supplying these modules could distort the academic calendar and hamper smooth face-to-face sessions for distance learners (Segbenya & Anokye, 2022). Thus, HR managers and curriculum implementers have the peculiar and arduous task of ensuring early or timely production and supply of course modules. These modules should be free from typographical errors to facilitate easy understanding among learners. HR managers and curriculum implementers also have responsibilities toward resolving challenges associated with online learning among distance postgraduate learners. This component of blended learning also comes with several challenges. Key among these challenges is the cost of data for online learning (Almaiah, 2018; Segbenya et al., 2022). Distance learners mostly struggle to pay their school fees, and the additional cost of buying internet data/bundles for online learning poses a financial burden on distance learners (Segbenya et al., 2022). Thus, HR managers will need to ensure that distance learners and their facilitators can have access to zero-rated subscriber identity modules to be able to participate in online learning. A closely related challenge to the cost of internet data is the availability and functionality of online gadgets among facilitators and students to participate in online learning. Without the availability and functioning of online tools, online learning intention would be mirage or fantasy (Mahyoob, 2020; Segbenya et al., 2022). Thus, HR managers will have to ensure that possession of these online tools would serve as a condition for hiring facilitators or distance learners. Additionally, due to low Information Communication and Technological skills, it is also possible to possess the online tools and still be unable to use them for online learning due to a lack of adequate competence or skills on how to use these online tools (Khan, Kamal, Illiyan, & Asif, 2021; Segbenya et al., 2022). Hence, HR managers of distance education institutions need to either provide basic skills on how to use online tools to participate in online learning or ensure that online participation skills become a prerequisite for admitting online learners and hiring part-time course tutors. Another challenge with online learning, which affects the continuity on the online component of blended learning on the distance mode, is the availability of consistent internet facilities for effective online learning (Segbenya et al., 2022). Thus, the support of managers in this perspective will be very necessary. Human resource managers and curriculum implementors also need to evaluate their academic programmes and courses offered to determine which courses or components of the course contents should be taught online or face-to-face (Letshwene, & Plessis, 2021).This is because calculation subjects such as (Mathematics, Accounting among others) can be very challenging when taught on online platforms without an online board for calculations and demonstrations. Theoretical implication The findings of this study have theoretical implications for the running of blended learning approach. The findings showed that for blended learning approach to be successful, students who are major stakeholders must accept the learning mode. Students’ acceptance and intention to continue with a particular learning mode is premised on the fact that students would not have serious impediments as they adopt the approach. Students’ attitudes and motivation towards particular learning context depends on what they make of it. If the students feel that the disadvantages outweigh the advantages of a particular mode, they will not accept it. Therefore, HR managers and curriculum implementers should pay attention to the theory of Technology Acceptance Model if they want to experience hustle-free blended implementation. Policy implications The results obtained from the performance analysis of the variables of the study had policy implications. The study revealed that the two blocks of blended learning-face-to-face sessions and online learning can only be useful to distance postgraduate learners depending heavily on how distance education institutions minimise the challenges associated with online learning and face-to-face sessions. Thus, HR managers, and curriculum implementers need to pay attention to important factors such as challenges and usefulness of online learning and face to face sessions to ensure the continuity of online learning and face-to-face sessions for successful blended learning during pandemics. Conclusion and recommendations This study assessed the post covid locked down blended learning among postgraduate learners and the implications for human resource managers and curriculum implementors. It can be concluded that a successful implementation of blended learning model is hinged on factors that influence students’ acceptance. It was established that the usefulness of the blended mode and challenges associated with the blended mode influenced students’ intention to continue or otherwise. Thus, the study established that there was a relationship between challenges with face-to-face and usefulness of face-to-face; challenges with online learning intention and usefulness of online intention; challenges of online intentions and usefulness of online learning; usefulness of face-to-face and usefulness of online learning; and usefulness of online learning and challenges with online learning. These findings have implications for both the human resource managers and curriculum implementors. Thus, it is recommended that management of the distance education institutions should partner with their human resource managers and curriculum implementors to ensure that postgraduate courses offered on the distance mode are really examined to know which of them should be taught on online or on face-to-face mode. This will help to reduce challenges that distance learners have with blended learning during face-to-face or online learning. Calculation, sciences and practical-related courses or components of courses offered could be taught face-to-face while the remaining components or courses are taught using the online platforms. It is also recommended that more postgraduate study centres be opened or established closer to learners to reduce the distance they have to cover to attend their face-to-face component of the blended learning. Course facilitators are very instrumental for both the face-to-face and the online components of the distance learning programmes for postgraduate students in Ghana. It is therefore recommended that competent facilitators who have the requisite skills for teaching on both face-to-face mode and online platform be hired for teaching at the postgraduate level. Providers of postgraduate distance programmes in Ghana should partner with telecommunication companies in the country to provide zero-rated SIM (subscriber identity modules) for distance learners on their postgraduate programmes to enable them fully to participate in the online lectures. Additionally, management and human resource managers will also need to develop the skills and competence of both the learners and the facilitators to be able to participate and use the online learning platforms. It is also recommended that the management of institutions providing distance education in Ghana support both distance learners and facilitators to acquire online learning tools or facilities to be able to participate in online learning. Thus, managers’ ability to ensure reduction in the challenges confronting both face-to-face sessions and online learning components of the blended learning introduced by distance education providers in Ghana during and after the COVID-19 is a catalyst for successful blended learning in Ghana. Limitations and future research directions This study was limited to postgraduate distance learners in one country, which limited the generalisation of the findings of the study with circumspection. Thus, further studies could consider undertaking a similar study but involving postgraduate facilitators to get their perspective on blended learning. Future studies could also consider a qualitative or a mixed approach. Finally, the sample could be expanded to include other higher education institutions offering distance education models. Funding Not available Data availability The datasets for the current study are available from the corresponding author upon a reasonable request. List of abbreviations CHFTF Challenges with Face-to-Face sessions UFTF Usefulness of Face-to-Face sessions CHOLI Challenges with Online Learning Intention UOLI Usefulness of Online Learning Intention COLI Continuity with Online Learning Intentions CFA Confirmatory Factor Analysis HTMT Heterotrait-Monotrait Ratio PLS Partial Least Squares PLS-SEM Partial Least Squares Structural Equation Modelling SEM Structural Equation Modelling SIM Subscriber Identification Module (SIM) TAM Technology Acceptance models (TAM) VIF Variance Inflated Factor Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ==== Refs References Abbasi, S., Ayoob, T., Malik, A., & Memon, S. I. (2020). Perceptions of students regarding E-learning during Covid-19 at a private medical college. Pak J Med Sci., 36 (COVID19-S4)), S57–S61. 10.12669/pjms.36.COVID19-S4.2766. Aguilera-Hermida, A. P. (2020). 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==== Front Technol Forecast Soc Change Technol Forecast Soc Change Technological Forecasting and Social Change 0040-1625 0040-1625 Published by Elsevier Inc. S0040-1625(22)00777-6 10.1016/j.techfore.2022.122256 122256 Article Sports entrepreneurship during COVID-19: Technology as an ally to maintain the competitiveness of small businesses González-Serrano María Huertas a Alonso Dos Santos Manuel bc⁎ Sendra-Garcia Javier d Calabuig Ferran a a Department of Physical Education and Sport, University of Valencia, Valencia, Spain b University of Granada, Faculty of Economics and Business Administration, Marketing and Market Research Department, Granada, Spain c Universidad Católica de la Santísima Concepción, Faculty of Economy and Business Administration, Administration Department, Concepción, Chile d ESIC University, Spain ⁎ Corresponding author at: University of Granada, Faculty of Economics and Business Administration, Marketing and Market Research Department, Granada, Spain. 13 12 2022 2 2023 13 12 2022 187 122256122256 27 12 2021 27 8 2022 4 12 2022 © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. The sports sector, specifically the field of personal trainer entrepreneurship, has been severely affected by the COVID-19 crisis. However, there are still few empirical studies that analyze how the actions taken before and during this crisis can affect sports entrepreneurs' performance. This research aims to analyze which combinations of sports entrepreneurs' personal characteristics and actions performed have been most and least effective in minimizing the negative impact of COVID-19 on their businesses. A validated online questionnaire was administered to personal trainer entrepreneurs from May to June 2020 before they reopened their facilities. Fuzzy-set qualitative comparative analysis (fsQCA) was performed to assess the impacts. The results show that both post-COVID measures (adaptation of the business model) and previous strategic orientation seemed essential. Specifically, high levels of sports entrepreneurs' resilience and innovation/R&D when competing against their closest competitors before the COVID-19 pandemic and the increased use of technologies (sports services digitization) during the pandemic have been essential to maintaining the performance of the sports business. Thus, improvements in the digital competencies of personal trainers' sports entrepreneurs, the development of strategic plans and activities related to innovation/R&D and process improvements are important measures to maintain the competitiveness of small sports businesses during crises. Keywords Sports entrepreneurship SME Technology Strategic orientation Business model adaptation ==== Body pmc1 Introduction Entrepreneurship has been considered an essential and novel force for the competitiveness of sports industries and their socioeconomic positioning in society (Jones et al., 2017). Indeed, sports are considered entrepreneurial by nature, and if their competitiveness is to be maintained, entrepreneurship is vital when managing businesses (Ratten, 2012). The initial theory, proposed by Ratten (2011), is based on the idea that the sports sector involves more innovation and risk-taking activities than do other sectors due to the emphasis on competitiveness (Pellegrini et al., 2020). However, even though the sports industry represents one of the most entrepreneurial economic sectors in the global economy, the coronavirus pandemic (COVID-19) has hindered its ability to remain competitive (Parnell et al., 2020). Due to the massive spread of the new coronavirus (SARS-CoV-2), many European governments have enacted regulations and legislation to reduce social interactions and contain its spread (Mutz and Gerke, 2020). Restrictive measures were taken in terms of social distance, capacity maintenance, and—in some cases—closure of these sports businesses, as they were considered nonessential activities. Due to those restrictive measures, the fitness industry has lost a total of €1.505 billion during the pandemic (Valgo, 2021). Thus, sports businesses that are slow or unwilling to react to a crisis are likely to exhibit lower performance levels (Ratten, 2020a). Therefore, due to the COVID-19 crisis, the importance of sports entrepreneurship has increased because of its deep connection to change (Ratten, 2020b). Sports entrepreneurship is especially important during COVID-19, as all sports companies, athletes, managers, fans, and consumers must make use of it to act creatively in the face of unexpected events. According to the same author, doing so will help combat the discomfort and uncertainty associated with the COVID-19 crisis. During times of crisis, the sports industry must use its unique business ecosystem to foster proactive collaboration that leads to value cocreation (Ratten et al., 2021). In the specific case of the sports industry, there are some businesses that play a key role during the COVID-19 crisis. Such a key role is filled by entrepreneurs of personal training centers, as they play a vital role in promoting physical activity in the population. Physical sports practices contribute to improving people's health and immunity. Moreover, these practices bring enormous benefits to cognitive functioning and wellbeing (Mandolesi et al., 2018). During the COVID-19 pandemic, people with both normal health and chronic disease activate, maintain, and advance their physical activity for 30 to 60 min on most days of the week within the limits of social distancing (Denay et al., 2020). Recent studies show that continued sports practice increases survival in relation to COVID-19 (Salgado-Aranda et al., 2021). Therefore, entrepreneurs of personal training centers in the sports industry face the challenge of continuing to offer their services. Hence, it is vital to discover which strategies are the most effective to diminish the adverse effects of the COVID-19 crisis on the performance of these centers. According to crisis management literature, innovation, and creativity, as well as the resilience of entrepreneurs, are often key to overcoming crises. Creative people are those who exhibit creative behaviors, such as inventing, designing, devising, composing and planning activities (Guilford, 1950). Innovation is defined as the creation of new processes, products or services for the market, which improve the overall competitiveness in the market (Li and Atuahene-Gima, 2001). Therefore, creative people are more likely to develop innovative behaviors. Resilience is defined as the ability to maintain reliable functioning despite adversity (Williams et al., 2017). According to these authors, linking crises and resilience can provide a more complete understanding of the organization. All these individual capabilities can help entrepreneurs manage their businesses more efficiently in general and mainly during times of crisis. In terms of management aspects, the strategic orientation of entrepreneurs when managing their businesses—in this case, during and prior to crisis management—can be considered a critical element of the innovation process (Adams et al., 2019). Strategic orientation refers to “principles that direct and influence the activities of a firm and generate the behaviors intended to ensure its viability and performance” (Hakala, 2011, p. 199). In this case, the creativity, innovation and resilience of entrepreneurs can help improve their strategic orientation. Moreover, during times of crisis, business adaptation is often key, with technology sometimes being a key ally. Indeed, Trischler and Li-Ying (2022) note that in times of unprecedented change related to the ongoing digital transformation of businesses and society at large, a contemporary management challenge is to recognize and translate these changes into digital business model innovation. Digitization affects almost all industries, creating opportunities and challenges for established companies, large, digital, nascent and small start-ups (Volberda et al., 2021), with the sports industry being no exception. As COVID-19 continues to affect everyone's lives and consumer behaviors, the digital transformation process has experienced unprecedented growth that may not abate—even after the pandemic has passed (Kim, 2020). COVID-19 has challenged many companies to turn toward digital solutions for their survival (Modgil et al., 2022). During 2020 and 2021, there was an increase in technological change and a push for digital entrepreneurship in many parts of the world to address different challenges (Iivari et al., 2020; Secundo et al., 2021). During the last two decades, the phenomenon of digital entrepreneurship fueled by COVID-19 has been driven by technological assets ranging from internet tools to communication and information technologies (Abubakre et al., 2021; Bai et al., 2021). Furthermore, although the long-term effects of the COVID-19 crisis for small businesses are still unknown, in the short term, it is becoming increasingly clear that more digital capabilities are needed to survive (Ratten and Thompson, 2021). Therefore, making use of creativity and innovation and the resilience of sports entrepreneurs is key during COVID-19, with technology being their ally. Specifically, technological innovation is a complex and multidimensional construct that refers to innovations associated with an organization's operations, such as the introduction of new/improved products or processes (Singhal et al., 2020). These authors point out that scholars demonstrate the importance of technological innovation in a firm's ability to gain a sustainable competitive advantage. However, although interest in sports entrepreneurship has been growing in recent years (González-Serrano et al., 2020), studies have not yet incorporated a crisis management approach (Ratten, 2020b) focusing on the creativity, innovation and resilience capabilities of sports entrepreneurs. Neither have they focused on digital and business model transformation and strategic orientation aspects due to the COVID-19 crisis. Some studies address the crisis management approach theoretically (DiFiori et al., 2020; Ratten, 2020b; Weed, 2020); however, empirical studies using this approach are practically nonexistent (Escamilla-Fajardo et al., 2020; Hammerschmidt et al., 2021). Furthermore, no empirical study addresses this approach from the perspective of the for-profit sector and, more specifically, personal training centers, whose role is key to the maintenance and improvement of society's health and survival in the face of this virus. This investigation is also important because these companies are usually small in size (Jones et al., 2017). Previous studies already highlight their concern over the effect of COVID-19 on small companies (Thorgren and Williams, 2020). Therefore, this study aims to determine which combination of internal characteristics of sports entrepreneurs (creativity and innovation, and resilience) and strategies (strategic orientation and business model adaptation) that they adopted (both previous strategies and strategies during the crisis) have been more effective and less effective for their businesses' performance during times of crisis. For this purpose, the fsQCA methodology is used because the complexity of entrepreneurial phenomena exceeds traditional methods' capability to reflect important aspects of their heterogeneity (Douglas et al., 2020). This paper contributes to the literature in different ways. First, it focuses on crisis management in the sports sector—studies on which are practically nonexistent. There is a need to deepen knowledge in this area of crisis management in the sports sector (Ratten, 2020a). Second, a dual approach was used in this study. Hence, this study contributes to addressing the fact that most studies focus only on analyzing the postcrisis measures taken by companies without considering the precrisis measures taken (Doern, 2016). Thus, in this study, the actions taken by sports entrepreneurs both before (strategic orientation) and during (business model adaptation) the COVID-19 crisis are analyzed to discover their impact on business performance. The findings highlight that not only corrective measures (during the crisis) but also preventive measures (such as previous strategic orientation and innovation and creativity) could diminish the harmful effects of crises on small and medium-sized enterprises (SMEs) in the sports business. Third, this research presents specific measures that could diminish the harmful effects of crises. Regarding personal characteristics, the resilience capability of sports entrepreneurs is of vital importance in diminishing the harmful effects of COVID-19. Regarding previous measures taken before a crisis, the introduction of innovation/R&D when competing against the closest competitors and for continuous process improvement are essential. Moreover, during a crisis, business model adaptation measures mainly based on the introduction of new technology and the intensification of existing partnerships, the search for new suppliers and the reorganization of operational processes are essential to diminish the negative effects of the crisis. However, it is not the measures taken in isolation but the combination of these measures with the personal characteristics of sports entrepreneurs that can reduce the negative effects of crises. In this way, this study deepens the knowledge of crisis management in small companies in the sports sector, proposing operating guidelines that can help reduce future crises' negative impacts on these companies. 2 Theoretical framework 2.1 COVID-19 and its impact on the sports industry in Spain The COVID-19 pandemic originated in December 2019 in China (specifically, the city of Wuhan was the epicenter) and spread rapidly to all parts of the world (Parnell et al., 2020). Since then, the first outbreaks in Spain, Italy, France, Germany, and the United Kingdom led the WHO Director-General to declare on March 13, 2020, that Europe had become the epicenter of the virus (Weed, 2020). Subsequently, the spread COVID-19 throughout the Americas meant that people worldwide were confronted with a virus for which there was neither a vaccine nor a treatment, and blocking measures had to be implemented to cope with a global pandemic. The World Health Organization (WHO, 2019) declared a pandemic of a global scope and stated that no continent is exempt (WHO, 2019). As of June 13, 2021, this pandemic caused approximately 3,816,651 deaths worldwide (Worldometer, 2021). With specific regard to Spain, on March 15, Royal Decree 463/2020, issued on March 14, declared a state of alarm for the management of the health crisis caused by COVID-19 (p. 25390–25,400) and decreed the confinement of this country. This decree led to a nearly complete paralysis of the fitness and sports facilities sector. This sector is among those suffering the most from the effects of this health crisis and the consequences of the measures implemented by competent authorities to help alleviate it (Valgo, 2020). Between April 2020 and March 2021, each sports center suffered on average a 64 % reduction in turnover because of closures and restrictions of facilities, resulting in a loss of €1.505 billion during the pandemic (Valgo, 2021). This situation is worrisome, since the COVID-19 crisis is an unprecedented situation that remains ongoing, and it is unknown when it will end (He and Harris, 2020). Moreover, unlike other crises, the COVID-19 pandemic has dramatically changed society and has altered current business practices (Ratten, 2020a). These changes have been reflected in the economy and people's behavior because it is a highly contagious virus, so social distancing, hygiene, and the use of masks, among other measures, are crucial. This fact has meant that fitness centers have had to adapt and reconsider the services they offer. 2.2 Crisis management and entrepreneurship A crisis refers to an event that is considered relatively unpredictable, threatens important stakeholder expectations, and can significantly negatively impact an organization's performance (Coombs, 2014). The literature on crisis management focuses on the “association between planning and the enhancement of preventative actions and/or responses to organizational failures, accidents, and disruptions” (Herbane, 2013). However, most research on crisis management focuses on natural disasters or financial events (Grewal and Tansuhaj, 2001; McEntire et al., 2002; Ratten, 2020c), so the business literature discusses crisis management from an economic rather than behavioral perspective. Specifically, the coronavirus crisis has affected companies' abilities to carry out their activities, introducing changes in behaviors such as working from home and social distancing (Ratten, 2020a). This same author points out that this combination has posed challenges to many companies' survival, particularly those in the service economy. Therefore, improvisation and acceptance of digital technology have been two of the behaviors promoted by this pandemic (Sheth, 2020). Moreover, the repercussions of a crisis on small businesses can be particularly remarkable due to their lack of preparation and resources, which make them more vulnerable (Runyan, 2006). In general, smaller organizations tend to suffer above-average during crises due to a lack of resources, limited experience, and less formalized crisis management planning (Doern, 2016). While COVID-19 is affecting nearly every person and organization in the world, there is particular concern over how the consequences of the pandemic and the various government responses to it (lockouts, social distancing guidelines, etc.) will affect small and medium-sized enterprises (SMEs) (Thorgren and Williams, 2020). However, there is very little research on how crises affect how small firms are managed (Galbraith and Stiles, 2006; Herbane, 2013). This research gap is striking because small firms are more likely to be affected by crises and have to struggle more to recover from them (Asgary et al., 2012). Typically, the most effective measures to resolve crises are analyzed during a crisis and exhibit their effects after the crisis is resolved. Most research in this area focuses on the postcrisis period and identifies obstacles to recovery (Doern, 2016). Moreover, studies that attempt to uncover characteristics that predict firms' successful recovery after crises are inconsistent in identifying the key factors responsible for recovery (Corey and Deitch, 2011). According to Dobrowolski (2020), it is necessary to test actions' effectiveness before they occur. For this reason, there have been several calls for organizational research to better explore what we know about crisis-organization interactions, including how to develop organizational resilience not only as a critical response to adversity but also how to mitigate it before it arises (Van Der Vegt et al., 2015; Williams and Shepherd, 2016). However, the most effective measures on how firms should act in the face of a crisis do not seem to be precise (Johansen et al., 2012). The literature highlights that the nature of a crisis and its responses are multifaceted (Dobrowolski, 2020). 2.2.1 Resilience Although each discipline offers a different definition and perspective of resilience, the common aspect among these definitions is that resilience responds to unexpected or unanticipated changes and disturbances and an ability to adapt and respond to those changes (Erol et al., 2010). Gallopín (2006) discusses enterprise resilience as an enterprise's adaptive capacity and ability to cope with, adapt to, and recover after a disruption. In the literature, flexibility has become an emerging construct of resilience (Stevenson and Spring, 2007). Resilience suggests that a system's adaptive capacity in the case of a disruption can be increased by designing, planning, and building flexibility in systems (Sheffi and Rice, 2005; Walker et al., 2004). An enterprise with high resilience is most likely to cope with problems that arise every day and successfully manage all aspects that cause the crisis (Sanchis Gisbert and Poler Escoto, 2013). Sheffi and Rice (2005) state that building resilience should be a strategic initiative that changes the way an enterprise increases its competitiveness. Enterprises need to be as resilient as possible to face disruptions (Sanchis Gisbert and Poler Escoto, 2013). Barroso et al. (2008) define a disruption or its synonymous disruptive event as a foreseeable or unforeseeable event, directly affecting an enterprise's usual operation and stability. Resilience helps businesses survive longer by improving their ability to persist and adapt to environmental changes (Gittell et al., 2006; Markman and Venzin, 2014; Ortiz-de-Mandojana and Bansal, 2016). A resilience-focused approach leads organizations to improve disaster management through awareness, flexibility, training and preparedness, engagement of managers and staff, and participation in a broader network of stakeholders (Gimenez et al., 2017). To be sustainably successful, entrepreneurs' need to have the resilience to overcome critical situations and even emerge from failures and crises is more robust than before (Duchek, 2018). Thus, sports entrepreneurs' resilience is essential to combat the COVID-19 crisis. Hence, the following proposal is presented:Hypothesis 1 Resilience is positively related to positive (or less harmful) COVID-19 impacts. 2.2.2 Innovation and creativity Creativity occurs at the individual level, while innovation occurs at the organizational level (Kapucu and Ustun, 2018). The majority of researchers agree with the standard definition that a creative product is a novel and valuable product (Runco and Jaeger, 2012). Subsequently, some recent definitions add a third criterion, such as surprise (Boden, 2004) or nonobviousness (Simonton, 2012). Innovation is defined as the creation of new processes, products or services for the market that improve the overall competitiveness in the market (Li and Atuahene-Gima, 2001). Innovation is vital during crises, partly because of the new demands imposed by different stakeholders and partly because of the risk of standing still, which can lead to business failure (Amankwah-Amoah, 2021). Crises are usually associated with adverse effects among required changes but can also positively affect innovation (Faulkner, 2001; Roy et al., 2018). Adversity and crises incentivize some firms to innovate, which can reduce the negative effects of crises (Heinonen and Strandvik, 2020). Crises have affected many sectors, presenting uncertainty in markets and driving waves of innovation activities (Amankwah-Amoah, 2021). Innovation is a coping strategy that has sustainable effects and can make a company stronger in the future (Wenzel et al., 2020). These process innovations are often characterized by minimizing errors and defects and discarding obsolete routines (Schilling and Shankar, 2019). This situation has been the case for COVID-19, which, although challenging organizations, many have demonstrated their ability to innovate through the crisis to become more resilient in the future (Fretty, 2020). In fact, according to Heinonen and Strandvik (2020), the COVID-19 pandemic prompted even the most efficient organizations to explore new ways to innovate, known as “CoviNovation”. Several authors demonstrate the positive effects of creativity and innovation on business performance in general (Kariv, 2010; Munizu and Hamid, 2018) and during crises (Al-Ameedee and Abd Alzahrh, 2021). Hence, in this situation, the capacity for the innovation and creativity of sports entrepreneurs became a tool to combat the negative effects of COVID-19. Therefore, the following proposal arises:Hypothesis 2 Innovation and creativity are positively related to positive (or less harmful) COVID-19 impacts. 2.2.3 Strategic orientation Strategic orientation is defined as the firm's strategic tendencies, which characterize its activities and behaviors and seek to help the organization achieve a sustainable competitive advantage and improve performance (Hakala, 2011). The positive relationship between strategic orientation and business performance is assessed in previous research (Al-Ansaari et al., 2015). Published research linking strategic orientation and crisis assessment in SMEs is limited (Parnell et al., 2015). Preble (1997) point out that strategic management and crisis management have been evolving in isolation and separately despite their synergistic potential. This author points out that combining the crisis management approach with the strategic market positioning orientation can strengthen organizations' strategic management. In this vein, He and Harris (2020) highlight that postpandemic research will focus on how different strategic orientations benefit or constrain organizational responses. Along the same vein, Wenzel et al. (2020) highlight that perseverance is a good strategy, although it is advisable to make strategic changes if a crisis lasts too long. Kraus et al. (2020), in their study of European family businesses, point out that some companies will have to make strategic changes to their future orientation if a crisis is prolonged. Penco et al. (2022) show how entrepreneurial orientation copes with the changing environment and helps address market opportunities. Thus, the following proposals are presented:Hypothesis 3 Companies' use of innovation/R&D strategies when competing against their closest competitors before the COVID-19 crisis is positively related to positive (or less harmful) COVID-19 impacts. Hypothesis 4 Strategies related to process improvement before the COVID-19 crisis are positively related to positive (or less harmful) COVID-19 impacts. 2.2.4 Business model adaptation Business model adaptation is likely to happen under external threat conditions (De Reuver et al., 2013). According to Teece (2010), a business model can be defined as a “management's hypothesis about what customers want, how they want it, and how the enterprise can organize to meet those needs best, get paid for doing so, and make a profit” (p. 172). Adaptive capacity is a concept that has also been frequently associated with resilience (Gallopín, 2006; Stevenson and Spring, 2007). Walker et al. (2002) define adaptive capacity as an aspect of resilience that reflects learning, the flexibility to experiment and adopt novel solutions, and the development of generalized responses to broad classes of challenges. How firms adapt their business models to external threats and opportunities is still poorly understood (Saebi et al., 2017). However, some authors point out that the fit between the firm's business model and its environment can influence business profitability (Lawrence and Lorsch, 1967). Prospect theory (Kahneman and Tversky, 1979) is used to predict behavior in the face of different stimuli. This theory indicates that managers are more inclined to engage in risky behaviors in the face of external threats, such as adapting the company's business model, than under favorable conditions. A study conducted by Saebi et al. (2017) found that the more severe the external threat is, the more likely firms are to engage in business model adaptation. In a recent analysis of the reactions of family firms in five European countries to the COVID-19 crisis, Kraus et al. (2020) identifies temporary business model innovation as a possible solution to recovery from the crisis. In this vein, He and Harris (2020) notes that during COVID-19, production orientations and strategic flexibility are needed, while postpandemic competitive advantages are likely to ensue to organizations able to respond better to gain a first-mover advantage. For instance, Ceesay et al. (2021) analyze the importance of social entrepreneurship alliances and find that this type of alliance varies from other business relationships due to the social mission and the orientation of partners to the social cause; however, in the future, they may pursue commercial interests. In addition, in the case that investors are needed, it is recommended that institutional investors be sustainable, as they contribute to the environmental performance of companies (Kordsachia et al., 2022). These are some examples of possible business model adaptations and measures that could be taken to combat crises. Therefore, the adaptation of the business model through different initiatives, such as collaborations with other entities, the search for new suppliers or investors, and the introduction of new processes, among others, may be key to responding to the needs generated by the COVID-19 crisis. Therefore, the following proposal is presented:Hypothesis 5 Intensifying existing partnerships, using new suppliers, or reorganizing operational processes during COVID-19 are positively related to positive (or less harmful) COVID-19 impacts. COVID-19 has rapidly driven digitization in many industries that have continued to operate thanks to various digital platforms (Barnes, 2020). Digitization is defined as using digital technologies, such as information, communication, computing, and connectivity technologies, to promote organizational change (Sebastian et al., 2017). This process has the potential to help SMEs react effectively to public crises by stimulating their dynamic abilities (Vial, 2021). Indeed, SMEs that have used various digital technologies to cope with the COVID-19 crisis have improved their performance (Guo et al., 2020). The current COVID-19 crisis, coupled with technological advances, has created a favorable environment for companies to transform their value chains and innovate (Amankwah-Amoah, 2021). Primarily, the importance of digital technology has become visible due to the need for small businesses to respond to customer needs during the COVID-19 crisis, which has brutally disrupted small businesses and necessitated rapid change (Ratten and Thompson, 2021). Moreover, in the specific case of the sports industry, which has been affected by unprecedented changes because of social distancing, the use of new technologies to offer services is vital (Ratten, 2021). In this vein, He and Harris (2020) highlight that industries that once revolved around face-to-face interaction have found ways and means to engage and survive through online media, and it seems likely that much of this change will continue to be driven using online media. This has also been the case in the sports industry, where some sports businesses adopted the digitization of services and processes during the COVID-19 crisis to continue offering their services and products. Thus, the following proposal is presented:Hypothesis 6 Increased use of technology during COVID-19 is positively related to positive (or less harmful) COVID-19 impacts. 3 Methodology 3.1 Participants The sample was composed of 65 entrepreneurs in the sports sector who were running their businesses during the COVID-19 pandemic in a European country (Spain). These entrepreneurs created their personal training centers. They had a mean age of 32.86 years (SD = 5.18), comprising 23.10 % women and 76.90 % men. Regarding their academic training, 89.20 % were graduates or undergraduates in physical activity and sports sciences, 3 % had vocational training in sports, 3.10 % had no training, and 4.60 % had other nonregulated training. Regarding the size of their businesses, the mean number of employees was 4.42 (SD = 3.92), and they were small businesses. 3.2 Instrument A structured questionnaire composed of the different scales presented below was used. - Strategic orientation: This scale comprised six items and was extracted from Saebi et al. (2017). It captured the market development orientation of the entrepreneurs. The items were related to the measures that the entrepreneurs carried out before the crisis. Two items were selected from this scale: (1) innovation/R&D when competing against the closest competitors and (2) process improvement. These questions were answered with a dichotomous (yes/no) response. - Resilience commitment: This scale was extracted from Lee et al. (2013) and was composed of three items that measure the ethos of commitment to resilience. These aspects were related to (1) the capacity of sports centers to respond to the unexpected, (2) the capacity to seek an appropriate balance between short- and long-term priorities, and (3) the capacity to learn from mistakes or problems. A five-point Likert scale was used to measure this variable, where one meant strongly disagree, and five meant strongly agree. The Cronbach's alpha of this scale was 0.60. - Innovation and creativity: Three items composed this scale, which was extracted from Lee et al. (2013). This scale measured the entrepreneur's capacity to create an entrepreneurial culture in its center to foster both innovation and creativity. The items were related to the capacity of the sports entrepreneur to (1) encourage people to challenge and develop themselves through their work, (2) use their knowledge in new ways, and (3) reward thinking outside the box. A five-point Likert scale was used to measure this variable, where one meant strongly disagree and five meant strongly agree. The Cronbach's alpha of this scale was 0.63. - Business model adaptation: Five items compose this scale, which was extracted from Saebi et al. (2017). This scale measured the extent to which firms adapted their business models during the crisis. Only one item and another adapted item were used. The following initiatives were assessed with this scale: (1) intensify existing partnerships, use new suppliers or reorganize operational processes and (2) increase the use of technology. These questions were answered with a dichotomous (yes/no) response. - Type of impact: This scale was extracted from Saebi et al. (2017) and measured the type of external impact posed by the COVID-19 crisis. The sports entrepreneurs were asked to indicate their response on a 5-point Likert scale to the question, “To what extent was your personal trainer center affected by the COVID-19 crisis?” The response options were (1) strongly and severely negatively affected, (2) significantly negatively affected, (3) moderately negatively affected, (4) not affected, and (5) positively affected. Finally, participants were asked a series of sociodemographic questions (gender, age, educational level, and company size). 3.3 Procedure The data analyzed in this study were collected through a questionnaire sent online via the University of Valencia's platform (LimeSurvey 2.5). The links were sent to different sports institutions and shared on social media to attract the attention of these sports entrepreneurs. Data were collected weeks after the entrepreneurs' businesses were closed due to COVID-19 and before they reopened in adherence to the new measures. Data were collected from May 5, 2020, to June 7, 2020. The research was performed in accordance with the Helsinki and University of Valencia guidelines. 3.4 Common method bias The language of the items comprising the questionnaire was kept as simple as possible to ensure no common method bias. To this end, double-barreled questions were avoided, and variables were reported before their measurement items to help structure the respondents' responses (Podsakoff and Organ, 1986). Two post hoc tests were used to assess common method bias: (i) Harman's single-factor test (Podsakoff and Organ, 1986) and (ii) the full collinearity test (Kock, 2015). First, Harman's single-factor test was performed to test whether the variance explained by the 17 items grouped into a single factor was <50 %. In this case, the variance explained was 20.34 %, which was below the reference value limit and certifies that the study is not affected by common method bias (Podsakoff and Organ, 1986). Subsequently, the full collinearity evaluation method was performed. Variance inflation factor (VIF) values above 3.30 are considered an indicator of collinearity and that the data are possibly contaminated by method bias. Only if the VIFs (factor levels) of the test are equal to or <3.30 can the absence of common method bias be assured (Kock, 2015). In this study, all VIFs values for the factors were lower than 3.30, confirming that this study lacks common method bias. 3.5 Data analysis First, Cronbach's alpha of the scales was calculated for internal consistency. Cronbach and Shavelson (2004) note that Cronbach's alpha (α) values ≥0.70 are considered high, those ≥0.60 are considered adequate, and those <0.60 are considered low. Then, to provide a deeper understanding of this phenomenon, a nonsymmetric method was used: fuzzy-set qualitative comparative analysis (fsQCA). fsQCA helps provide finer-grained insights into the complexity of entrepreneurial phenomena (Douglas et al., 2020). Its application in this field has experienced remarkable growth in recent years (Kraus et al., 2018). Traditionally, QCA is helpful when analyzing a small number of cases (Woodside, 2013). fsQCA is based on the idea that relationships between constructs are “frequently better understood in terms of set-theoretic relations rather than correlations” (Fiss, 2011). This method is based on complexity theory and uses an inductive research method that relies on the principles of (1) conjunction, (2) equifinality, and (3) causal asymmetry (Misangyi et al., 2017). Conjunction refers to the fact that the antecedent conditions within a configuration operate in an interdependent way instead of a discrete way. Equifinality is related to the existence of multiple effective combinations of conditions that lead to the same outcome. Causal asymmetry means that the conditions found to be related to the outcome in one combination of conditions (configuration) may be unrelated or even inversely related in another configuration. However, both are associated with the same outcome. To perform fsQCA, the first step was to transform the raw data responses into fuzzy-set responses; thus, all missing data were deleted. Before performing the analysis, the analysis values were recalibrated because their values must be between 0 and 1. To calibrate the continuous variables (variables with more than two values), it is necessary to consider three thresholds. The literature recommends establishing the 10th, 50th, and 90th percentiles as thresholds (Woodside, 2013). Thus, the continuous variables of this study (innovation and creativity and resilience) were calibrated using the following thresholds: percentile 90 (high levels), percentile 50 (intermediate levels), and percentile 10 (low levels). The dummy variables (strategic orientation and business adaptation model variables) were calibrated using two values: 0 (entirely outside) and 1 (fully inside). The next step was to calculate the necessary and sufficient condition tests to evaluate the effects of the different conditions on a particular outcome (COVID-19 impact) and the absence of the output (~COVID-19 impact). A condition is necessary when it must always be present for the occurrence of a particular outcome and when the consistency value is higher than 0.90 (Ragin, 2009). However, a sufficient condition expresses a combination of conditions (configurations) that can lead to a particular outcome. However, this particular outcome can also be achieved by other configurations (equifinality). To calculate sufficient conditions, fsQCA involves two stages (Eng and Woodside, 2012). First, a truth table algorithm transforms the fuzzy-set membership scores into a truth table that presents all logically possible configurations and their possible outcomes. Regarding the frequency cutoff, Fainshmidt (2020) suggests that a frequency of one is appropriate for small to medium sample sizes but should be higher if the sample is larger. Thus, due to our sample's small size (n = 65), a threshold of one observation was selected. Selecting a frequency cutoff of one means that the configuration is considered if it is present in at least one case. Second, fsQCA presents the three possible solutions: (1) complex, (2) parsimonious, and (3) intermediate. The complex solution is the most restrictive of the three solutions, while the parsimonious solution is the least restrictive. However, Ragin (2009) suggests including the intermediate solution, which is thus the solution presented in this study. In the sufficient analysis, solution coverage refers to how much variance is explained (number of observations that can be explained for the combination of conditions). Meanwhile, solution consistency represents the reliability that a model could have. Hence, to discover the most critical configuration, raw coverage should be considered. fsQCA 3.0 software was used to perform the analysis. 4 Results First, the descriptive results are presented, in which the degree to which these personal trainers' businesses have been affected can be observed. As shown in Table 1 , 23.10 % of businesses were strongly and severely negatively affected, 29.20 % were significantly negatively affected, 36.90 % were moderately negatively affected, 6.20 % were not affected, and 4.60 % were positively affected. (See Fig. 1.) Table 1 The extent to which sports entrepreneurs were affected. Table 1Type of impact Frequency Percentage Strongly and severely negatively affected 15 23.10 Significantly adversely affected 19 29.20 Moderately adversely affected 24 36.90 Not affected 4 6.20 Positively affected 3 4.60 Total 65 100 Fig. 1 Fuzzy plot of Model 1 using data from the holdout sample. Fig. 1 4.1 fsQCA results Second, the descriptive statistics and calibration values of the variables are shown. Table 2 shows the calibration of the study's continuous variables: resilience commitment, innovation and creativity, and COVID-19 impact.Table 2 Calibration values for the variables of resilience commitment, innovation and creativity, and COVID-19 impact. Table 2 Resilience commitment Innovation and creativity COVID-19 impact N 65 65 65 Mean 69.35 71.00 2.40 SD 31.39 35.56 1.06 Minimum 12.00 6.00 1.00 Maximum 125.00 125.00 5.00 Percentiles 10 36.00 24.00 1.00 50 64.00 64.00 2.00 90 125.00 125.00 4.00 The strategic orientation and business model adaptation variables were calibrated dichotomously as 1 (yes) and 0 (no). Regarding strategic orientation, before the COVID-19 pandemic, most of these sports entrepreneurs had improved their business processes (87.70 %). Before the pandemic, approximately half had innovated or conducted R&D (58.80 %) when competing against their closest competitors. Concerning the measures taken during COVID-19 by these entrepreneurs, half of them had intensified existing partnerships, used new suppliers, or reorganized their operational processes (50.80 %). In addition, during COVID-19, many of these entrepreneurs had increased the use of technologies in their businesses (86.40 %). Table 3 shows the results.Table 3 Calibration values for strategic orientation and business model adaptation. Table 3 Percentage Yes No Strategic orientation (Pre-COVID-19 measures) Use of innovation/R&D in competition against the closest competitors (SO1) 58.50 41.50 Process improvement (SO2) 87.70 12.30 Business Model Adaptation (COVID-19 measures) During the crisis, our company intensified existing partnerships, used new suppliers, or reorganized its operational processes. (BMA1) 50.80 49.20 During the crisis, our company has increased the use of technology. (BMA2) 86.40 15.40 4.2 Necessary analysis of the impact of COVID-19 precrisis measures (strategic orientation) The necessary analysis was performed to discover whether any of the conditions were necessary for the positive (or less negative) and negative impacts of COVID-19 on the performance of personnel trainers' centers considering precrisis measures. A condition is necessary when the consistency is >0.90 (Ragin, 2009). The results obtained for both high and low levels of COVID-19 impact show no necessary condition. These results are shown in Table 4 .Table 4 Necessary conditions for positive (or less negative) and negative COVID-19 impacts considering precrisis measures (strategic orientation). Table 4 COVID-19 ~COVID-19 Consistency Coverage Consistency Coverage Innovation and creativity 0.62 0.69 0.68 0.59 ~Innovation and creativity 0.63 0.72 0.64 0.57 Resilience 0.61 0.75 0.57 0.55 ~Resilience 0.63 0.66 0.74 0.60 SO1 0.66 0.63 0.49 0.37 ~SO1 0.34 0.46 0.51 0.54 SO2 0.87 0.56 0.89 0.44 ~SO2 0.13 0.60 0.11 0.40 Note: SO1-Innovation/R&D when competing against the closest competitors; SO3-Reduction in operating costs; SO2-Process improvement. 4.3 Sufficiency analysis of the impact of COVID-19 on precrisis measures (strategic orientation) Then, a sufficiency analysis was performed with the conditions presented above. First, the two variables related to firms' strategic orientation before the COVID-19 pandemic were considered, i.e., presence and creativity and innovation and resilience. Ragin (2008) recommends a minimum consistency threshold of 0.75 when performing sufficient analysis in the truth table. The threshold for a positive COVID-19 impact was 0.85. A fsQCA model is informative when consistency is higher than 0.74 (Eng and Woodside, 2012). Five solutions were found that were able to explain 67 % of the cases of high levels of positive COVID-19 performance (consistency: 0.81; coverage: 0.67). The most important configuration for a positive COVID-19 impact was high levels of resilienceinnovation/R&Dprocess improvement (consistency: 0.83; raw coverage: 0.42). The second most explanatory configuration was high innovation levelshigh levels of resilienceno innovation/I + D (consistency: 0.88; raw coverage: 0.37). The third combination was low levels of innovation innovation/I + process improvement (consistency: 0.83; raw coverage: 0.35). The fourth combination was low levels of innovationhigh levels of resilienceprocess improvement (consistency: 0.92; raw coverage: 0.35). Finally, the fifth solution was high levels of innovationhigh levels of innovationno process improvement (consistency: 0.87; raw coverage: 0.03). These solutions were able to explain 42 %, 37 %, 35 %, 35 % and 3 % of the variance, in the positive or less negative impact of COVID-19. On the other hand, two solutions were proposed to explain the negative impact of COVID-19, which explained 34 % of the cases. In these circumstances, the variables related to firms' strategic orientation before the COVID-19 pandemic were considered, i.e., absence and creativity, innovation, and resilience. When performing sufficient analysis, Ragin (2009) recommends a minimum consistency threshold of 0.75 in the truth table. The threshold for a negative COVID-19 impact was 0.78. The two solutions for the negative impact of COVID-19 are presented in Table 5 . The most explanatory configuration for a negative COVID-19 impact was high levels of innovationno innovation/R&D process improvement (consistency: 0.81; raw coverage: 0.27). The second most explanatory configuration was high innovation levelslow levels of resilienceno innovation/I + Dprocess improvement (consistency: 0.78; raw coverage: 0.07). These solutions were able to explain 27 % and 7 % of the variance in the negative impact of COVID-19.Table 5 Sufficient conditions (intermediate solution) for positive (or less negative) and negative COVID-19 impacts considering precrisis measures (strategic orientation). Table 5Cutoff frequency: 1 COVID-19 impact Cutoff consistency: 0.85 ~COVID-19 impact Cutoff consistency: 0.78 1 2 3 4 5 1 2 Innovation and creativity ● ○ ○ ● ● ● Resilience ● ● ● ● ○ SO1 ● ● ● ○ ○ SO2 ● ● ● ○ ● ● Consistency 0.83 0.88 0.83 0.92 0.87 0.81 0.78 Raw coverage 0.42 0.37 0.35 0.35 0.03 0.27 0.07 Unique coverage 0.01 0.00 0.11 0.11 0.03 0.27 0.07 Total solution consistency 0.81 0.81 Total solution coverage 0.67 0.34 Note: SO1-Innovation/R&D in competition against the closest competitors; SO2-Process improvement; ● = presence of condition, ○ = absence of condition; Expected vector for COVID-19 Impact: 1.1.1.1 (0: absent; 1: present); Expected vector for ~COVID-19 impact: 0.0.0.0 using the format of Fiss (2011). The notation employed by Fiss (2011) was used to present the results. Black circles indicate the presence of a condition, while white circles indicate the absence of a condition. The predictive validity test was conducted following the recommendations of Pappas and Woodside (2021). The procedure was as follows: (1) the database was divided into two subsamples with an equal number of cases (sample size); (2) the first subsample was used to perform the fsQCA with the same criteria as in the original analysis with the total data sample (please see Table 5); (3) the fuzzy set models (configurations) were taken from the first subsample and were tested on the holdout sample (second subsample); (4) the different models were tested on the holdout sample, generating an XY plot; and (5) steps 3 and 4 were performed again using the holdout sample to test the models of the first subsample. Finally, the consistency and coverage values of the two subsamples were compared. The consistency and coverage values of the models from subsample 1 should be similar to those from the holdout sample for the different models presented on the plot. In this way, high predictive validity could be ensured. The XY plot from Model 1 was tested using the holdout sample (Fig. 1). Models with consistency above 0.80 are useful and can serve to advance the theory (Woodside, 2017). In this case, the 0.911 value indicates high consistency, while the 0.416 value indicates coverage. These values indicate that the data are largely consistent (91 %) with the argument that Model 1 is a subset of the COVID-19 impact that covers 42 % of the cases. Thus, this test demonstrates that the solutions have high predictive capacity. Finally, the robustness of the results was evaluated. The test to analyze changes in the frequency and consistency thresholds was evaluated (Muñoz and Kibler, 2016). The results did not differ drastically from the initial set, although small changes may generate significant changes in the final solution (Gonçalves et al., 2016). The results with consistency thresholds of 0.87 were as follows: (1) high levels of resilienceinnovation/R&Dprocess improvement (consistency: 0.83; raw coverage: 0.42) and low levels of innovationhigh levels of resilienceprocess improvement (consistency: 0.92; raw coverage: 0.35). In conclusion, all of the tests corroborate the predictive validity and robustness of the results presented. 4.4 Necessary analysis of COVID-19 impact crisis measures (business model adaptation) The necessary analysis was performed to determine whether any of the conditions were necessary for the positive (or less negative) and negative impacts of COVID-19 on the performance of personal training centers. To consider a condition as necessary, the consistency must be >0.90 (Ragin, 2009). Focusing on the results obtained, for both high and low levels of COVID-19 impact, there is no necessary condition. These results are shown in Table 6 .Table 6 Necessary conditions for positive (or less negative) and negative COVID-19 impacts considering crisis measures (business model adaptation). Table 6 COVID-19 ~COVID-19 Consistency Coverage Consistency Coverage Innovation and creativity 0.62 0.69 0.68 0.58 ~Innovation and creativity 0.63 0.72 0.64 0.57 Resilience 0.62 0.75 0.57 0.55 ~Resilience 0.63 0.66 0.74 0.60 BMA1 0.55 0.61 0.82 0.43 ~BMA1 0.45 0.51 0.18 0.50 Technology 0.86 0.57 0.45 0.39 ~Technology 0.06 0.57 0.55 0.49 Note: BMA1-During the crisis, our company intensified existing partnerships, used new suppliers or reorganized its operational processes. 4.5 Sufficiency analysis of COVID-19 impact crisis measures (business model adaptation) Then, a sufficiency analysis was performed with the conditions related to the measures implemented during the crisis. First, the variables related to firms' business model adaptation, resilience commitment, and innovation and creativity were considered present. A minimum consistency threshold of 0.75 was used when performing a sufficient analysis in the truth table (Ragin, 2009). The threshold for a positive or less negative COVID-19 impact was 0.80. Three solutions were found that were able to explain 63 % of the cases of high levels of positive or less negative COVID-19 performance (consistency: 0.80; coverage: 0.63). The most important configuration for a positive or less negative COVID-19 impact was increased use of technology during the pandemichigh levels of resilienceintensified existing partnerships, used new suppliers, or reorganized operational processes (consistency: 0.86; raw coverage: 0.31). The second main configuration was increased use of technology during the pandemiclow levels of innovation and creativityno intensified existing partnerships, used new suppliers or reorganized operational processes (consistency: 0.73; raw coverage: 0.27). The third combination was no increased use of technology during the pandemiclow levels of innovation and creativityno intensified existing partnerships, used new suppliers or reorganized operational processes (consistency: 1.00; raw coverage: 0.05). These solutions were able to explain 21 %, 27 %, and 5 % of the variance in the positive or less negative impact of COVID-19. In contrast, two solutions proposed to explain the negative impact of COVID-19 were able to explain 27 % of the cases. The condition related to the firms' measures during the COVID-19 pandemic (business model adaptation) considered absence, creativity and innovation, and resilience. The threshold for a negative COVID-19 impact was 0.81. This threshold is in line with the recommendation of Ragin (2008) that a minimum consistency threshold of 0.75 in the truth table is recommended. The most explanatory configuration for a negative COVID-19 impact was high levels of innovation and creativityhigh levels of resiliencenot intensifying existing partnerships, using new suppliers, or reorganizing operational processes (consistency: 0.84; raw coverage: 0.22). The second most explanatory configuration was no increased use of technology during the pandemichigh levels of innovation and creativityintensifying existing partnerships, using new suppliers, or reorganizing operational processes (consistency: 0.72; raw coverage: 0.05). These solutions explained 22 % and 5 % of the variance in the negative impact of COVID-19 (see Table 7 ).Table 7 Sufficient conditions (intermediate solution) for positive (or less negative) and negative COVID-19 impacts considering crisis measures (business model adaptation). Table 7Cutoff frequency: 1 COVID-19 impact cutoff consistency: 0.80 ~COVID-19 impact cutoff consistency: 0.81 1 2 3 1 2 Innovation and creativity ○ ○ ○ ● Resilience ● ● BMA1 ● ○ ● ○ ● Technology ● ● ○ ○ Consistency 0.86 0.73 1.00 0.84 0.72 Raw coverage 0.31 0.27 0.05 0.22 0.05 Unique coverage 0.31 0.27 0.05 0.22 0.05 Total solution consistency 0.80 0.81 Total solution coverage 0.63 0.27 Note: BMA1-During the crisis, our company intensified existing partnerships, used new suppliers or reorganized its operational processes; ● = presence of condition, ○ = absence of condition; Expected vector for COVID-19 impact: 1.1.1.1 (0: absent; 1: present); Expected vector for ~COVID-19 impact: 0.0.0.0 using the format of Fiss (2011). The notation employed by Fiss (2011) was used to present the results. White circles indicate the absence of a condition, while black circles indicate the presence of a condition. As in the previous analysis, the predictive validity test was conducted following the recommendations of Pappas and Woodside (2021). This procedure was as follows: (1) the database was divided into two subsamples with an equal number of cases (size sample); (2) the first subsample was used to perform the fsQCA with the same criteria as in the original analysis with the total data sample (see Table 7); (3) the fuzzy set model was taken from the first sample, and the solutions were calculated as a model in the second sample (holdout sample); (4) the models were tested in the holdout sample, running an XY plot; and (5) steps 3 and 4 were performed again using the holdout sample to test all of the models of the first subsample. Finally, the consistency and coverage values were compared. The consistency and coverage values of the models from subsample 1 should be similar to those from the holdout sample for the different models presented in the plot to ensure high predictive validity. Fig. 2 shows the XY plot from Model 1 tested in the holdout sample. Models with consistency above 0.80 are useful and can serve to advance the theory (Woodside, 2017). The 0.980 value indicates high consistency, while the 0.180 value indicates coverage. These calculations indicate that the data are largely consistent (98 %), and Model 1 is a subset of the COVID-19 impact that covers 18 % of the cases. The predictive capacity of the models is ensured.Fig. 2 Fuzzy plot of Model 1 using data from the holdout sample. Fig. 2 Finally, the robustness of the results was tested. As in the previous fsQCA, changes in the frequency and consistency thresholds were evaluated (Muñoz and Kibler, 2016). The new solutions improving the consistency threshold did not differ substantially from the initial set, although small changes may yield significant changes in the final solution (Gonçalves et al., 2016). The results with a consistency threshold of 0.87 were the following: (1) increased use of technology during the pandemichigh levels of resilienceintensified existing partnerships, used new suppliers, or reorganized operational processes (consistency: 0.86; raw coverage: 0.31), (2) no increased use of technology during the pandemiclow levels of innovation and creativityno intensified existing partnerships, used new suppliers or reorganized operational processes (consistency: 1.00; raw coverage: 0.05), and (3) increased use of technology during the pandemiclow levels of innovation and creativity*high levels of resilience (consistency: 0.92; raw coverage: 0.32). In conclusion, all of the tests corroborate the predictive validity and robustness of the results. 5 Discussion COVID-19 was an unexpected event for sports entrepreneurs. Most of them were not prepared for such a disruptive event, as reflected in the reduction in their performance levels. This reduction could have been due to the lack of existing knowledge about crisis management in the sports industry (Ratten, 2020b). Only a small percentage of sports entrepreneurs indicated that their businesses were not affected or were positively affected. These findings are in line with Parnell et al. (2020), who point out that, although the sports industry is enterprising, the coronavirus pandemic (COVID-19) has hampered its ability to remain competitive. These findings are also in line with those of the COVID-19 Impact Report on Sports Facilities (Valgo, 2020), which shows that Spain's fitness centers have been affected to a large extent by this pandemic. However, not all personal training centers have been affected in the same way. This difference exists because firms can respond to an economic downturn in various ways, by initiating either internally focused actions to adapt to changing environmental pressures or externally focused actions to modify their environments (Chattopadhyay et al., 2001). This study's findings show that a combination of different internal and external measures was necessary for this type of entrepreneur to be little affected by COVID-19. Commitment is one of the key internal factors to being a sports entrepreneur characterized by high resilience levels. This finding is in line with Duchek (2018), who notes that entrepreneurs' resilience enables them to overcome critical situations and emerge from failures and crises stronger than before to achieve sustainable success. In the same vein, various authors highlight resilience as a critical capacity to successfully manage all aspects of a crisis (Sanchis Gisbert and Poler Escoto, 2013). Therefore, according to Sheffi and Rice (2005), resilience should be a strategic initiative to increase companies' competitiveness. Thus, increasing sports entrepreneurs' resilience is vital to maintaining competitiveness during times of crisis. In addition, sports entrepreneurs' necessary actions before the COVID-19 crisis that minimized the harmful effects of the crisis were innovation/R&D when competing against their closest competitors, and these actions were quite important. In addition, making process improvements before the crisis was also vital. These data are in line with Dobrowolski (2020), who point out the need to analyze the most effective measures before the crisis occurred. Furthermore, the results highlight the importance of entrepreneurship to maintain competitiveness in this sector, as previous studies also point out (González-Serrano et al., 2020). Therefore, continuously adopting a strategic orientation can help reduce the negative impact of unexpected events, such as crises of various kinds. In contrast, sports entrepreneurs of personal training centers that were most affected generally had high levels of creativity and innovation, had not undertaken innovation/R&D actions when competing against their closest competitors, and had improved some processes before the COVID-19 pandemic. Thus, strategic orientation prior to the crisis could help organizations achieve sustainable competitive advantages and improve performance (Hakala, 2011), making innovation essential in this case (Roy et al., 2018; Wenzel et al., 2020). Regarding the measures taken during the COVID-19 crisis, the increased use of technologies during COVID-19 and the intensification of existing partnerships, the use of new suppliers and the reorganization of operational processes were two of the most important adaptations. Therefore, the COVID-19 crisis has highlighted the importance of technology in continuing to offer sports services. In the same vein, Hayduk (2020) points out that for sports entrepreneurship to maintain and increase its impact, more attention needs to be paid to the role of technology in sports. Therefore, it can be observed that the sports sector is trending toward digitalization (Ratten and Jones, 2020), which is one of the most critical factors driving international competitiveness in this industry (Jones et al., 2020). Furthermore, in a study on the COVID-19 crisis, Al-Omoush et al. (2020) highlight that social media have played a significant role; this observation also applies to the sports industry. However, according to the latest DESI report (The Digital Economy and Society Index), Spain exhibits relatively weak performance in the digitization of companies, especially SMEs, and is below the EU average in human capital indicators (European Commission, 2020). Therefore, in the present and future, sports entrepreneurs of personal training centers should improve their digital competencies and those of their employees. However, these measures are not the only combinations of strategies that can generate this lower impact of COVID-19 on companies' performance. These data are in line with Muñoz et al. (2020), who point out that there is no easy solution for how policy makers or decision makers in SMEs should think and act to cope with or reorient business policies during a crisis. However, the measures presented above should be taken into consideration. Hence, these findings highlight the importance of entrepreneurship within contemporary society (Ferreira et al., 2019). Sports entrepreneurs whose training centers were most affected showed high levels of innovation, creativity, and resilience. However, if they did not intensify existing partnerships, use new suppliers, or reorganize their operational processes, their performance was reduced during the COVID-19 crisis. Additionally, not increasing the use of technology during the pandemic was reflected in reducing personal centers' performance. This finding is in line with Ratten (2020b), who notes that sports businesses that are slow or unwilling to react to a crisis are likely to exhibit lower performance levels. This finding also highlights the vital role of technology during COVID-19. This pandemic has brought information and communications technologies to the forefront of human life (Barnes, 2020). Therefore, although perseverance is a good strategy, if the crisis lasts too long (as with COVID-19), it is worthwhile making strategic changes (Wenzel et al., 2020). In this case, intensifying existing partnerships, using new suppliers, reorganizing operational processes, and increasing the use of technology are vital. Thus, digital transformation is currently one of the greatest challenges for businesses of all sizes and ages (Kraus et al., 2019). The actions carried out to respond to COVID-19 by sports entrepreneurs vary. However, entrepreneurship and resilience are of vital importance for this type of sports entrepreneur. Innovative actions are forced by crises, and an entrepreneurial approach and the encouragement of intrapreneurship in employees are fundamental for these entrepreneurs to respond efficiently to unexpected events and reduce the negative impact on their businesses' performance. Along these lines, Donthu and Gustafsson (2020) point out that effort should be made to learn from the consequences of pandemic outbreaks to prepare society for when this kind of outbreak happens again. Training in technological competencies for the digitization of sports services and the continuously promoting an entrepreneurial spirit in their employees are two of the most important lessons that sports entrepreneurs should take away from the COVID-19 crisis. These results can be of great use to the sports industry during future crises that may arise, since they are cyclical and tend to repeat over time (Potter, 2001). 6 Conclusions and implications Most entrepreneurs in the fitness industry have been greatly affected by the COVID-19 pandemic. These entrepreneurs have taken numerous measures that have caused their businesses to have been affected to a greater or lesser extent by this pandemic. For personal training business owners to be less affected by future crises, developing strategies to enhance the commitment to resilience in their businesses is paramount. Therefore, these entrepreneurs should improve their centers' ability to respond to the unexpected, seek an appropriate balance between short- and long-term priorities, and learn from mistakes and problems. To this end, strategic planning and continuous employee training can be of great importance. In addition, introducing new technologies can be of great help due to the behavioral changes resulting from this pandemic. Additionally, strategies or measures taken during and before a crisis are essential. Among them, the development of activities related to innovation/R&D and process improvement stand out as the most important for this type of business to reduce the impact of a crisis. However, all of these strategies must be carried out as a whole and in combination with others if more extraordinary results are to be obtained. Therefore, it is not a question of specific actions at specific times but of a strategic and entrepreneurial orientation over time. During a crisis, the measures carried out by intensifying existing partnerships, using new suppliers, or reorganizing operational processes have proven to be key strategies to reducing the harmful effects of this crisis. As mentioned above, it is not taking measures in isolation but, instead, combining these different measures that leads to better results. However, it should be emphasized that having a strategic orientation to the operation of personal training centers is nearly as crucial as taking such measures to adapt a business due to a crisis. Therefore, the importance of innovation and entrepreneurship in this type of business is highlighted. In addition, personal training centers' digitization seems to be a current and future necessity if competitiveness in the sports industry is to be maintained. Due to the closure of personal training centers, the sudden outbreak of this crisis forced these sports entrepreneurs to use technologies that have appeared to stay. The maintenance of these online training services and the introduction of new online services are among the most critical strategies available to these sports entrepreneurs. This study has several limitations that need to be highlighted. First, the sample size is small, and the sports entrepreneurs in the sample are from only one country, so these results should be interpreted with caution and cannot be generalized. Future studies should replicate this research with larger samples of personal training center owners from different countries. Additionally, the variables analyzed are limited. In future studies, new variables should be introduced to explain a more significant percentage of the variance in these companies' performance. Finally, this study has a cross-sectional design. In the future, it would be interesting to conduct longitudinal studies to analyze the impact of these measures over time. CRediT authorship contribution statement María Huertas González-Serrano: conceptualization, investigation, writing-original paper; methodology, software, writing - review & editing; Ferran Calabuig: supervision, writing - review & editing; Manuel Alonso-Dos-Santos: writing - review & editing, data curation and formal analysis; Javier Sendra-García: conceptualization, writing- review & editing. María Huertas González-Serrano is Assistant Professor in the Department of Physical Education and Sport at University of Valencia. She is specialist in sports management and entrepreneurship. Her PhD is in physical activity and sport (sport entrepreneurship specialization). She has participated in several research projects in sports management and has published several articles about sport entrepreneurship and intrapreneurship in prestigious journals such as are Journal of Business Research, International Entrepreneurship and Management Journal, Sport in Society among others. Manuel Alonso Dos Santos holds a Ph.D. in Marketing and Consumer Behavior. His areas of interest are sports marketing, consumer behavior, and social marketing. He currently works at the University of Granada. Has published articles in international journals about satisfaction, education, digital marketing, and intention to attend sporting events. He has >56 papers (e.g., Psychology & Marketing, Journal of Business Research, Entrepreneurship & Regional Development, Sustainable Production and Consumption, Knowledge Management Research & Practice, Physiology & Behavior, Industrial Management & Data Systems) and 65 international conferences (e.g., GIKA, AMS, AEMARK). Manuel is a member of the editorial board for the IJSMS and ARLA. Javier Sendra-Garcia is at PepsiCo from 1995 to 2020, currently at the PepsiCo bottler Ahembo in the Canary Islands. His profile is combined with experience in academia, having published several articles in indexed-ranked journals, such as Technological Forecasting & Social Change, Journal of Business Research, Review of Managerial Science, or Economic Research. He has participated in a number of international conferences, and serves as an ad-hoc reviewer for several academic journals. Ferran Calabuig is Associate Professor at University of Valencia. He leads the Sport Management & Innovation Research Group. His main lines of research are related to sport consumer behavior, sport marketing, sponsorship, entrepreneurship and sport tourism. He publishes regularly in prestigious international journal such are Journal of Business Research, Industrial Management and Data Systems, Int. J. of Sports Marketing and Sponsorship, International Entrepreneurship and Management Journal, Technological Forecasting and Social Change among others. 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Retrieved from: https://www.valgo.es/2do-informe-impacto-covid-19-en-las-instalaciones-deportivas/ 2020 Valgo 3er Informe Abril 2021 Impacto Económico COVID-19 en las Instalaciones Deportivas Fitness (3rd Report April 2021 COVID-19 Economic Impact on Sports Fitness Facilities) Retrieved from: https://www.valgo.es/impacto-covid-19-en-instalaciones-deportivas 2021 Van Der Vegt G.S. Essens P. Wahlström M. George G. Managing Risk and Resilience 2015 Academy of Management Briarcliff Manor NY Vial G. Understanding digital transformation: a review and a research agenda Managing Digital Transformation 2021 13 66 Volberda H.W. Khanagha S. Baden-Fuller C. Mihalache O.R. Birkinshaw J. Strategizing in a digital world: overcoming cognitive barriers, reconfiguring routines and introducing new organizational forms Long Range Plan. 54 2021 102110 Walker B. Carpenter S. Anderies J. Abel N. Cumming G. Janssen M. Lebel L. Norberg J. Peterson G.D. Pritchard R. Resilience management in social-ecological systems: a working hypothesis for a participatory approach Conserv. Ecol. 6 2002 14 30 Walker B. Holling C.S. Carpenter S.R. Kinzig A. Resilience, adaptability and transformability in social–ecological systems Ecol. Soc. 9 2004 5 14 Weed M. The role of the interface of sport and tourism in the response to the COVID-19 pandemic J. Sport Tour. 24 2 2020 79 92 Wenzel M. Stanske S. Lieberman M.B. Strategic responses to crisis Strateg. Manag. J. 41 2020 7 18 Williams T.A. Shepherd D.A. Building resilience or providing sustenance: different paths of emergent ventures in the aftermath of the Haiti earthquake Acad. Manag. J. 59 2016 2069 2102 Williams T.A. Gruber D.A. Sutcliffe K.M. Shepherd D.A. Zhao E.Y. Organizational response to adversity: fusing crisis management and resilience research streams Acad. Manag. Ann. 11 2017 733 769 Woodside A.G. Moving beyond multiple regression analysis to algorithms: calling for adoption of a paradigm shift from symmetric to asymmetric thinking in data analysis and crafting theory J. Bus. Res. 66 2013 463 472 10.1016/j.jbusres.2012.12.021 Woodside A.G. The Complexity Turn: Cultural, Management, and Marketing Applications 2017 Springer World Health Organization Coronavirus disease 2019 (COVID-19) Situation Report 43, 3March, 2019 2019 https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200303-sitrep-43-covid-19.pdf?sfvrsn=2c21c09c_2 Worldometer COVID-19 Coronavirus Pandemic: Total Deaths Retrieved March 29th, 2021, from 2021 https://www.worldometers.info/coronavirus/	0	PMC9747137	NO-CC CODE	2022-12-15 23:21:59	no	Technol Forecast Soc Change. 2023 Feb 13; 187:122256	utf-8	Technol Forecast Soc Change	2,022	10.1016/j.techfore.2022.122256	oa_other
==== Front Lancet Glob Health Lancet Glob Health The Lancet. Global Health 2214-109X The Author(s). Published by Elsevier Ltd. S2214-109X(22)00516-2 10.1016/S2214-109X(22)00516-2 Correspondence Universal health coverage is the vital link when health care is a public health good Hatefi Arian a a Department of Medicine, Institute for Global Health Sciences, and Philip R Lee Institute for Health Policy Studies, University of California—San Francisco, San Francisco, CA 94143, USA 13 12 2022 1 2023 13 12 2022 11 1 e30e30 © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license 2023 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcThe COVID-19 pandemic has exposed vulnerabilities in both national health systems as well as the global health governance system. As described by Arush Lal and colleagues (November, 2022),1 universal health coverage (UHC) is inextricably linked and paramount to building health system resilience. Basic definitions of economic goods help clarify this link. Diagnostic testing is foundational to understanding and responding to epidemics, as demonstrated by the COVID-19 pandemic. Identifying the main beneficiary of testing—that is, whether it is a public or private good—is of critical importance because of its implications for optimising supply and demand. Diagnostic testing is mainly performed as health care, provided to an individual to guide disease-specific treatment for that individual. That is, diagnostic testing is in this sense primarily a private good because it provides benefit first and foremost to the individual who consumes the test. Demand and consumption are therefore rational. Further, providers of care have an incentive to provide diagnostic testing for health care when their services are adequately covered and paid for (and, too often, vice versa). This is the basic premise of health-care financing: people have a health need that generates demand, and financing mechanisms raise and pool revenue in order to purchase services that match demand with supply. UHC deals with the extent of health financing, as it aspires to provide coverage for essential health services to the full population with financial risk protection. However, the COVID-19 pandemic exposed a vulnerability of the health-care model of diagnostic testing. Particularly early in the pandemic before COVID-19-specific treatment options existed, care was entirely supportive.2 A positive test largely did not change case management, but it was nonetheless essential—not for the individual, but for public health. Although diagnostic testing had little impact on case management, it unquestionably provided the backbone of disease surveillance to break chains of transmission, guiding measures such as precautions and isolation, quarantine, contact tracing, and other public policy. Testing, in other words, was more public than private good; some private benefit was incurred, but society was an outsize beneficiary of testing an individual. Within this publicness is the major challenge for policy makers: markets fail to produce public goods when individuals must absorb costs but share benefits. In the case of COVID-19, the benefit to an individual was often insufficient to absorb the costs (in time, money, comfort, or effort) of being tested. Compounding the challenge was the lack in many countries of a commensurate response to such a low incentive to be tested. Health-care conceptions do not deal adequately with the public nature of infectious diseases, since they still treat them as primarily privately held. COVID-19 testing was orphaned in a no-man's land between health care and public health, lacking enough demand to overcome individual costs while lacking enough financing to overcome low demand. This no-man's land—an unacceptable failure to link health care and public health—was a market failure that greatly undermined health security. Market failures are prime targets for public intervention. The public benefit of testing for real-time disease surveillance is true irrespective of the universality of health coverage, but the inclusive nature of UHC opens the possibility for creating large risk pools of public finance that can be leveraged for their redistributive capacity—the power to cross-subsidise among low and high need, such as among healthy and sick or young and old.3 Redistributive capacity can also be leveraged to cross-subsidise between private and public health goods, bridging the health-care and public health divide, particularly to cover low-demand, truly public health-care services such as some communicable disease testing. Thus, redistributive capacity within a UHC scheme is the natural—indeed, vital—financing mechanism that can link the often disparate worlds of individual health care, which is so often about “private” benefit, and public health, which, as the name implies, benefits all. I declare no competing interests. ==== Refs References 1 Lal A Abdalla SM Chattu VK Pandemic preparedness and response: exploring the role of universal health coverage within the global health security architecture Lancet Glob Health 10 2022 e1675 e1683 36179734 2 WHO Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected: interim guidance 12 January 2020 https://www.who.int/publications/i/item/10665-332299 2020 3 Mathauer I Vinyals Torres L Kutzin J Jakab M Hanson K Pooling financial resources for universal health coverage: options for reform Bull World Health Organ 98 2020 132 139 32015584	36521949	PMC9747167	NO-CC CODE	2022-12-15 23:21:59	no	Lancet Glob Health. 2023 Jan 13; 11(1):e30	utf-8	Lancet Glob Health	2,022	10.1016/S2214-109X(22)00516-2	oa_other
==== Front Lancet Glob Health Lancet Glob Health The Lancet. Global Health 2214-109X The Author(s). Published by Elsevier Ltd. S2214-109X(22)00463-6 10.1016/S2214-109X(22)00463-6 Articles Novel FujiLAM assay to detect tuberculosis in HIV-positive ambulatory patients in four African countries: a diagnostic accuracy study Huerga Helena PhD a* Bastard Mathieu MSc a Lubega Alex Vicent MBChB c Akinyi Milcah APGDCR e Antabak Natalia Tamayo MD f Ohler Liesbet MPH g Muyindike Winnie MMed h Taremwa Ivan Mugisha MSc d Stewart Rosanna MBBS g Bossard Claire MSc a Nkosi Nothando DPSN g Ndlovu Zibusiso MSc i Hewison Catherine MPH j Stavia Turyahabwe MPH k Okomo Gordon MPH l Ogoro Jeremiah Okari MSc m Ngozo Jacqueline MPH n Mbatha Mduduzi MD o Aleny Couto MD p Wanjala Stephen MD e Musoke Mohammed MD e Atwine Daniel PhD c Ascorra Alexandra BSc b Ardizzoni Elisa MSc q Casenghi Martina PhD r Ferlazzo Gabriella MD i Nakiyingi Lydia PhD s Gupta-Wright Ankur PhD t Bonnet Maryline PhD u a Department of Field Epidemiology, Epicentre, Paris, France b Department of Research, Epicentre, Paris, France c Department of Medicine, Epicentre, Mbarara, Uganda d Laboratory of Mycobacteriology, Epicentre, Mbarara, Uganda e Department of Medicine, Médecins Sans Frontières, Nairobi, Kenya f Department of Medicine, Médecins Sans Frontières, Maputo, Mozambique g Department of Medicine, Médecins Sans Frontières, Eshowe, South Africa h Department of Medicine, Mbarara Regional Referral Hospital, Mbarara, Uganda i Southern African Medical Unit, Médecins Sans Frontières, Cape Town, South Africa j Department of Medicine, Médecins Sans Frontières, Paris, France k National Tuberculosis and Leprosy Control Services, Ministry of Health, Kampala, Uganda l Department of Health Services, Ministry of Health, Homa Bay, Kenya m National Tuberculosis and Leprosy Control Services, Ministry of Health, Nairobi, Kenya n KwaZulu-Natal Department of Health, Durban, South Africa o King Cetswayo District Office, Department of Health, Eshowe, South Africa p National STI, HIV/AIDS Control Program, Ministry of Health, Maputo, Mozambique q Mycobacteriology Unit, Institute of Tropical Medicine, Antwerp, Belgium r Department of Innovation and New Technology, Elizabeth Glaser Pediatric AIDS Foundation, Geneva, Switzerland s Department of Medicine, Makerere University College of Health Sciences, Kampala, Uganda t Institute for Global Health, University College London, London, UK u Université de Montpellier, TransVIHMI, INSERM, IRD, Montpellier, France * Correspondence to: Dr Helena Huerga, Department of Field Epidemiology, Epicentre, Paris 75019, France 13 12 2022 1 2023 13 12 2022 11 1 e126e135 © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license 2023 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Background Development of rapid biomarker-based tests that can diagnose tuberculosis using non-sputum samples is a priority for tuberculosis control. We aimed to compare the diagnostic accuracy of the novel Fujifilm SILVAMP TB LAM (FujiLAM) assay with the WHO-recommended Alere Determine TB-LAM Ag test (AlereLAM) using urine samples from HIV-positive patients. Methods We did a diagnostic accuracy study at five outpatient public health facilities in Uganda, Kenya, Mozambique, and South Africa. Eligible patients were ambulatory HIV-positive individuals (aged ≥15 years) with symptoms of tuberculosis irrespective of their CD4 T-cell count (group 1), and asymptomatic patients with advanced HIV disease (CD4 count <200 cells per μL, or HIV clinical stage 3 or 4; group 2). All participants underwent clinical examination, chest x-ray, and blood sampling, and were requested to provide a fresh urine sample, and two sputum samples. FujiLAM and AlereLAM urine assays, Xpert MTB/RIF Ultra assay on sputum or urine, sputum culture for Mycobacterium tuberculosis, and CD4 count were systematically carried out for all patients. Sensitivity and specificity of FujiLAM and AlereLAM were evaluated against microbiological and composite reference standards. Findings Between Aug 24, 2020 and Sept 21, 2021, 1575 patients (823 [52·3%] women) were included in the study: 1031 patients in group 1 and 544 patients in group 2. Tuberculosis was microbiologically confirmed in 96 (9·4%) of 1022 patients in group 1 and 18 (3·3%) of 542 patients in group 2. Using the microbiological reference standard, FujiLAM sensitivity was 60% (95% CI 51–69) and AlereLAM sensitivity was 40% (31–49; p<0·001). Among patients with CD4 counts of less than 200 cells per μL, FujiLAM sensitivity was 69% (57–79) and AlereLAM sensitivity was 52% (40–64; p=0·0218). Among patients with CD4 counts of 200 cells per μL or higher, FujiLAM sensitivity was 47% (34–61) and AlereLAM sensitivity was 24% (14–38; p=0·0116). Using the microbiological reference standard, FujiLAM specificity was 87% (95% CI 85–89) and AlereLAM specificity was 86% (95 CI 84–88; p=0·941). FujiLAM sensitivity varied by lot number from 48% (34–62) to 76% (57–89) and specificity from 77% (72–81) to 98% (93–99). Interpretation Next-generation, higher sensitivity urine-lipoarabinomannan assays are potentially promising tests that allow rapid tuberculosis diagnosis at the point of care for HIV-positive patients. However, the variability in accuracy between FujiLAM lot numbers needs to be addressed before clinical use. Funding ANRS and Médecins Sans Frontières. ==== Body pmcIntroduction Tuberculosis accounts for 1·5 million deaths worldwide annually and remains the leading cause of death in people with HIV.1 Tuberculosis diagnosis is key in combating the disease. The large decrease in people newly diagnosed with tuberculosis linked to health service disruptions caused by the COVID-19 pandemic has increased mortality due to tuberculosis.1 The development of biomarker-based tests that can diagnose tuberculosis using non-sputum samples, which enables initiation of tuberculosis treatment on the same day, is a high priority for tuberculosis control.2 The first point-of-care test endorsed by WHO was the Alere Determine TB-LAM Ag test (AlereLAM; Abbott, Waltham, MA, USA), a lateral flow assay that detects the mycobacterial lipoarabinomannan (LAM) antigen in urine. The use of urine samples is a key advantage since some patients (14–63%), particularly those who are seriously ill, cannot produce sputum samples.3, 4 The AlereLAM assay increases tuberculosis diagnosis,3, 4, 5, 6, 7, 8 reduces mortality among symptomatic patients admitted to hospital,9, 10 is well accepted by test users,11 and is cost-effective.12, 13, 14 In a meta-analysis, AlereLAM sensitivity was 42% in patients with symptoms of tuberculosis (45% in patients with CD4 counts of <200 cells per μL, 16% in those with CD4 counts of ≥200 cells per μL, and 29% in ambulatory settings), with 92% specificity.15 WHO currently recommends AlereLAM to assist in tuberculosis diagnosis in people with HIV with signs and symptoms of tuberculosis, and in severely immunosuppressed patients irrespective of symptoms (ie, among people admitted to hospital with advanced HIV disease, or ambulatory with CD4 counts of <100 cells per μL).16 Despite these recommendations, AlereLAM uptake by national programmes has been slow.17 Research in context Evidence before this study The Fujifilm SILVAMP TB LAM (FujiLAM) is a novel point-of-care assay that detects the mycobacterial lipoarabinomannan (LAM) antigen in urine to identify tuberculosis. FujiLAM can detect lower LAM concentrations than the currently WHO-recommended urine-based point-of-care Alere Determine TB-LAM Ag test (AlereLAM; Abbott, Waltham, MA, USA). In a meta-analysis, AlereLAM sensitivity was estimated at 42% in HIV-positive patients with symptoms of tuberculosis (29% in ambulatory settings) with 92% specificity.We searched PubMed Central from database inception to Aug 23, 2022, for studies or reports of lipoarabinomannan for the diagnosis of tuberculosis. We used the search terms “(“tuberculosis” OR “tb”) AND (“lipoarabinomannan” OR “lam”) AND (“Fuji”) AND (“HIV”)”. No language restrictions were applied. Our search identified five relevant publications that reported results on the accuracy of the FujiLAM assay for diagnosis of tuberculosis in adults with HIV. One study done in South Africa, one in Ghana, and one in Nigeria used previously collected clinical and laboratory data and stored frozen urine samples from HIV-positive patients. A meta-analysis included the studies conducted in South Africa and Ghana and an additional dataset from Viet Nam. One prospective study that included a small sample of HIV-positive patients in Zambia (n=68) used fresh urine samples. Reported sensitivities ranged between 71% and 75% and specificities between 89% and 93%. No data were available from large prospective studies. Added value of this study This is the first large multicentre prospective study to assess the diagnostic accuracy of the novel FujiLAM urine assay for the diagnosis of tuberculosis in adults with HIV. Diagnostic accuracy was assessed using microbiological and composite reference standards and compared with AlereLAM. In post-hoc analyses, FujiLAM accuracy was assessed by test lot number. Ambulatory HIV-positive patients with signs and symptoms of tuberculosis irrespective of their CD4 count and asymptomatic patients with advanced HIV disease were included from four countries in sub-Saharan Africa (Uganda, Kenya, Mozambique, and South Africa) with a high prevalence of HIV and tuberculosis. We found that FujiLAM identified a considerable proportion of HIV-positive patients who had microbiologically confirmed tuberculosis and that it was more sensitive than the currently recommended AlereLAM across all CD4 count strata and in both groups of patients, with similar specificity. However, FujiLAM sensitivity and specificity varied by lot number. Implications of all the available evidence Next-generation, higher sensitivity urine-LAM assays, are promising tests that can potentially improve the diagnosis of tuberculosis in patients with HIV. However, the variability in accuracy between FujiLAM lot numbers needs to be addressed before clinical use. The Fujifilm SILVAMP TB LAM (FujiLAM; Fujifilm, Tokyo, Japan) is a new point-of-care urine-based test that can detect lower LAM concentrations than AlereLAM using high affinity monoclonal antibodies directed towards largely Mycobacterium tuberculosis-specific LAM epitopes. Two studies in South Africa and Ghana assessing the diagnostic accuracy of FujiLAM in HIV-positive patients have reported higher FujiLAM sensitivities than AlereLAM when using frozen urine samples and previously collected clinical or laboratory data (70% vs 42% in South Africa; 74% vs 53% in Ghana) and slightly lower FujiLAM specificities compared with AlereLAM (91% vs 95% in South Africa; 89% vs 96% in Ghana).18, 19 A retrospective study in Nigeria and a prospective study in Zambia with a small number of people with HIV (70 and 68 patients, respectively) have reported similar accuracy.20, 21 These results suggest that the assay has the potential to improve tuberculosis diagnosis in people with HIV. However, to date, no evidence is available from large, prospective, diagnostic accuracy studies. We aimed to assess the accuracy of the FujiLAM assay to diagnose tuberculosis from fresh urine samples in people with HIV at high risk of tuberculosis (either with symptoms of tuberculosis or asymptomatic with advanced HIV disease) in four countries in sub-Saharan Africa (Uganda, Kenya, Mozambique, and South Africa). Methods Study design and participants We did a diagnostic accuracy study comparing FujiLAM and AlereLAM assays against microbiological and composite reference standards of tuberculosis at five outpatient public health facilities (HIV and tuberculosis clinics attached to referral hospitals and primary health-care clinics) in four countries: Uganda, Kenya, Mozambique, and South Africa (appendix p 2). We consecutively approached and enrolled HIV-positive ambulatory individuals (aged ≥15 years) with signs or symptoms of tuberculosis irrespective of their CD4 T-cell count (group 1), and asymptomatic patients with advanced HIV disease (group 2). Signs and symptoms of tuberculosis were defined as cough, fever, weight loss, night sweats (of any duration), or signs of extrapulmonary tuberculosis. Asymptomatic patients were those without any of these signs and symptoms. Advanced HIV disease was defined as a CD4 count of less than 200 cells per μL, or HIV clinical stage 3 or 4 at the time of the consultation.22 Patients receiving tuberculosis treatment were excluded. The study protocol was approved by the National Ethics Committees in each country and by Médecins Sans Frontières Ethics Review Board (appendix p 3). Written informed consent (or assent for minors aged 15–17 years) was obtained from all study adult participants and from parents or guardians. This study follows guidance for non-sputum tests diagnostic accuracy evaluations23 and conformed to the Standards for Reporting of Diagnostic Accuracy Studies reporting guidelines (appendix pp 4–5). Procedures At the initial consultation, all participants underwent clinical examination, chest x-ray, and blood sampling, and were requested to provide a fresh urine sample, and two sputum samples at an interval of at least 30 min. Patients unable to produce a sputum sample spontaneously were offered sputum induction. Sex was self-reported by the participants (male or female). FujiLAM and AlereLAM urine assays, Xpert MTB/RIF Ultra assay (Xpert Ultra; Cepheid, Sunnyvale, CA, USA) on sputum or urine, sputum culture for M tuberculosis, and CD4 count were systematically carried out for all patients at this consultation. Xpert Ultra was performed on urine for patients unable to produce two sputum samples, and on other non-respiratory samples for patients with signs of extrapulmonary tuberculosis. In South Africa, M tuberculosis culture was occasionally performed on urine on clinician request. In Uganda, sputum smear microscopy was systematically performed. Retinoscopy and thoracic or abdominal ultrasound were occasionally done in addition to other investigations for extrapulmonary or disseminated tuberculosis. Clinicians made decisions regarding patients’ management and tuberculosis treatment based on the results of the assessments, with the exception of the FujiLAM assay. Patients with symptoms of tuberculosis who had not started on tuberculosis treatment were re-assessed after 7 days. All patients were followed up for 6 months after enrolment. Urine FujiLAM and AlereLAM tests were performed at the point of care on fresh urine immediately after clinician assessment, following each manufacturer's instructions. The LAM tests were independently done by trained clinical, laboratory, or lay workers, who were masked to clinical and microbiological results, and to the results of the other LAM test. The FujiLAM test was also read by a second reader, masked to the first reading results, to assess inter-reader agreement. A schema of the testing procedures is shown in the appendix (pp 6–7). In the case of invalid results, the test was repeated up to two times. Xpert Ultra was performed on one of the two sputum samples collected, on urine, and on extrapulmonary specimens if indicated. Additionally, the two sputum and extra-pulmonary samples were cultured using the Mycobacterial Growth Indicator Tube liquid culture (Becton Dickinson, Franklin Lakes, NJ, USA) and on the Lowenstein-Jensen solid culture medium (sputum only). The Bioline TB Ag MPT64 test (Abbott) or Standard Q TB MPT64 Ag (SD Biosensor, Suwon, South Korea) were used to differentiate M tuberculosis complex from non-tuberculous mycobacteria. The personnel performing Xpert Ultra and culture were masked to FujiLAM and AlereLAM results. CD4 T-cell count was performed using the Pima Analyser (Abbott) or the FacsCalibur Flow Cytometer (Becton Dickinson). Clinicians interpreted chest x-ray results using a checklist, which consisted of the most common tuberculosis radiological findings, with a pictogram and a final interpretation of the chest x-ray as: suggestive of tuberculosis, abnormal not suggestive of tuberculosis, and normal. Two external radiologists, masked to the clinical and laboratory information, read the x-rays at a later stage. In case of discordant interpretation by clinicians and one external radiologist, a third reading by the other radiologist was performed and the interpretation with at least two concordant results was used for the classification of the patients as probable tuberculosis using a composite reference. Data were collected on paper forms and entered into an electronic database using the REDCap software (Vanderbilt University, Nashville, TN, USA) at the study site. Outcomes The primary outcome of the study was the diagnostic accuracy of FujiLAM compared with the microbiological reference standard. Secondary outcomes were the diagnostic accuracy of FujiLAM compared with the composite reference standard, the diagnostic accuracy of AlereLAM against both reference standards, and the FujiLAM inter-reader agreement. For the microbiological reference standard, confirmed tuberculosis was defined as at least one positive Xpert Ultra or M tuberculosis culture result from any sample; tuberculosis-negative cases were defined as at least two negative Xpert Ultra or culture results, including at least one sputum; all others were defined as unclassifiable. For the composite reference standard, confirmed tuberculosis or probable tuberculosis defined tuberculosis. Patients with probable tuberculosis were those who did not meet the definition of confirmed tuberculosis, for whom a decision to treat for tuberculosis was made by the clinician and who had one or more of the following: positive sputum smear microscopy, chest x-ray suggestive of tuberculosis, ultrasound or retinoscopy suggestive of tuberculosis, or clinical diagnosis of extrapulmonary tuberculosis. Tuberculosis-negative cases were those with at least one negative result on Xpert Ultra or culture on at least one sample (respiratory sample for patients with symptoms and any sample if asymptomatic) who did not meet the criteria for probable or confirmed tuberculosis, without a chest x-ray suggestive of tuberculosis and with no clinician's decision to treat tuberculosis; unclassifiable patients were those remaining. For both reference standards, only samples obtained, investigations performed, and treatment decisions made within 30 days after enrolment were used to classify patients. Patients with positive Xpert or culture results in samples obtained after 30 days were deemed unclassifiable. For FujiLAM and AlereLAM, only tests done at initial consultation were considered. None of the index tests were included in the reference standards. Statistical analysis A sample size of 88 individuals with confirmed tuberculosis was required to estimate a FujiLAM sensitivity of 70% against the microbiological reference standards with a 95% CI width of 10%. For group 1, based on the assumption of a 10% tuberculosis prevalence and assuming that 10% of patients had no results, the final sample size was 990 patients. For group 2, due to the low proportion of asymptomatic patients with advanced HIV disease during interim data review, we estimated that it was feasible to enrol at least 500 patients. Based on an expected tuberculosis prevalence of 4%, this would allow a sensitivity of 70% to be estimated with 95% CI width of 20%. Continuous variables were summarised as median and IQR and categorical variables as counts and percentages. Patients were classified as seriously ill if they had a temperature higher than 39°C, a respiratory rate higher than 30 respirations per minute, cardiac rate of less than 120 beats per min, or inability to walk unaided.16 The FujiLAM and AlereLAM diagnostic accuracies were assessed in patients with valid results for both tests, by calculating the sensitivity and specificity against the microbiological and composite reference standards, and stratified by CD4 count in all patients, and separately in patients from group 1 and group 2. All proportions were calculated and reported with their 95% CIs. In sensitivity analyses, all unclassifiable patients were considered tuberculosis-negative to avoid excluding any patient from analysis. After study completion, the Foundation for Innovative Diagnostics (FIND) and the FujiLAM manufacturer reported variability of FujiLAM accuracy by lot number.24 Therefore, we performed post-hoc analyses of the accuracy of FujiLAM against the microbiological reference standard by lot number. In additional exploratory analyses, we compared the intensity of the positive FujiLAM (weak or strong as interpreted by the reader) and AlereLAM results (grades 1–4 as per the manufacturer scale) according to the microbiological reference standard and assessed the association between the intensity of the positive FujiLAM results and semi-quantitative Xpert Ultra results (in any sample) as a proxy for tuberculosis burden. We used the McNemar's test for paired samples to compare the sensitivity and specificity of FujiLAM and AlereLAM, and the χ2 test to compare independent proportions. FujiLAM test inter-reader agreement was assessed by calculating the κ statistic. p values of 0·05 or less were considered to indicate statistical significance. Double data entry and data cleaning were performed regularly during the whole study duration. Data were analysed using R (version 4.1.3.) and Stata (version 17.0). Role of the funding source The study funders had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. Results Between Aug 24, 2020 and Sept 21, 2021, 1575 patients (823 [52·3%] women) were included in the study: 1031 patients in group 1 and 544 patients in group 2 (figure 1 ). The median CD4 count was 528 cells per μL (IQR 272–770) in group 1 and 128 cells per μL (66–181) in group 2, 927 (89·9%) of 1031 patients in group 1 and 495 (91·0%) of 544 patients in group 2 were on antiretroviral therapy (ART), and 60 (5·8%) patients in group 1 and eight (1·5%) patients in group 2 were seriously ill (table ).Figure 1 Study flowchart Group 1 included HIV-positive ambulatory individuals (aged ≥15 years) with signs or symptoms of tuberculosis irrespective of their CD4 T-cell count. Group 2 included asymptomatic patients with advanced HIV disease. FujiLAM=Fujifilm SILVAMP TB LAM assay. AlereLAM=Alere Determine TB-LAM Ag test. Table Patient characteristics and diagnostic tests results Group 1 (n=1031) Group 2 (n=544) Sex Women 590 (57·2%) 233 (42·8%) Men 441 (42·8%) 311 (57·2%) Age, years 43 (35–53) 37 (30–45) CD4 count, cells per μL 528 (272–770) 128 (66–181) CD4 range, cells per μL <200 193/1026 (18·8%) 467/543 (86·0%) 200–349 137/1026 (13·4%) 22/543 (4·1%) 350–499 152/1026 (14·8%) 20/543 (3·7%) ≥500 544/1026 (53·0%) 34/543 (6·3%) On ART 927 (89·9%) 495 (91·0%) Seriously ill 60 (5·8%) 8 (1·5%) Tuberculosis suggestive symptoms Cough 965 (93·6%) NA Fever 453 (43·9%) NA Night sweats 404 (39·2%) NA Weight loss 345 (33·5%) NA Difficulty breathing 250 (24·2%) NA Haemoptysis 30 (2·9%) NA Chest x-ray Suggestive of tuberculosis 212 (20·6%) 63 (11·6%) Abnormal with other signs 254 (24·6%) 150 (27·6%) Normal 510 (49·5%) 276 (50·7%) Not done 55 (5·3%) 55 (10·1%) Extrapulmonary tuberculosis diagnosis 6 (0·6%) 4 (0·7%) Decision to treat for tuberculosis 236 (22·9%) 72 (13·2%) At least one urine-based test result available† 1027 (99·6%) 543 (99·8%) At least one sputum-based test result available‡ 929 (90·1%) 335 (61·6%) Sputum spontaneously produced 753/929 (81·0%) 43/335 (12·8%) Sputum induced 159/929 (17·1%) 278/335 (83·0%) No information on successful sputum collection method 17/929 (1·8%) 14/355 (4·2%) FujiLAM Positive 166 (16·1%) 81 (14·9%) Negative 856 (83·0%) 461 (84·7%) Invalid 5 (0·5%) 1 (0·2%) Not done 4 (0·4%) 1 (0·2%) FujiLAM positive intensity Light line 125/166 (75·3%) 62/81 (76·5%) Dark line 41/166 (24·7%) 19/81 (23·5%) AlereLAM Positive 179 (17·4%) 78 (14·3%) Negative (no line) 755 (73·2%) 420 (77·2%) Negative (line lighter than grade 1) 93 (9·0%) 45 (8·3%) Invalid 0 0 Not done 4 (0·4%) 1 (0·2%) AlereLAM positive grade 1 147/178 (82·6%) 70/76 (92·1%) 2 13/178 (7·3%) 1/76 (1·3%) 3 6/178 (3·4%) 3/76 (3·9%) 4 12/178 (6·7%) 2/76 (2·6%) Xpert Ultra (sputum samples) M tuberculosis detected 83 (8·0%) 12 (2·2%) M tuberculosis not detected 825 (80·0%) 313 (57·5%) Invalid, error, or no result 5 (0·5%) 3 (0·6%) Not done 118 (11·5%) 216 (39·7%) Xpert Ultra (non-respiratory samples) M tuberculosis detected 12 (1·2%) 6 (1·1%) M tuberculosis not detected 187 (18·1%) 467 (85·9%) Invalid, error, or no result 3 (0·3%) 7 (1·3%) Not done 829 (80·4%) 64 (11·8%) M tuberculosis culture in sputum Positive 71 (6·9%) 7 (1·3%) Negative 763 (74·0%) 311 (57·2%) Non-tuberculous mycobacteria 7 (0·7%) 4 (0·7%) Contaminated 18 (1·8%) 3 (0·6%) Not done 172 (16·4%) 219 (40·3%) Microbiological reference§ Confirmed tuberculosis 96/1022 (9·4%) 18/542 (3·3%) Not tuberculosis 680/1022 (66·5%) 312/542 (57·6%) Unclassifiable 246/1022 (24·1%) 212/542 (39·1%) Composite reference§ Confirmed tuberculosis 96/1022 (9·4%) 18/542 (3·3%) Probable tuberculosis 41/1022 (4·0%) 8/542 (1·5%) Not tuberculosis 657/1022 (64·3%) 441/542 (81·4%) Unclassifiable 228/1022 (22·3%) 75/542 (13·8%) Data are n (%), median (IQR), or n/N (%). Group 1 included HIV-positive ambulatory individuals (aged ≥15 years) with signs or symptoms of tuberculosis irrespective of their CD4 T-cell count. Group 2 included asymptomatic patients with advanced HIV disease. ART=antiretroviral therapy. NA=not applicable. FujiLAM=Fujifilm SILVAMP TB LAM assay. AlereLAM=Alere Determine TB-LAM Ag test. Xpert Ultra=Xpert MTB/RIF Ultra assay. M tuberculosis=Mycobacterium tuberculosis. * Patients were classified as seriously ill if they had a temperature of >39°C, a respiratory rate of >30 respirations per min, a cardiac rate of >120 beats per minute, or inability to walk without help. † Urine-based FujiLAM or AlereLAM results. ‡ Sputum-based Xpert Ultra or M tuberculosis culture laboratory results. § Microbiological and composite reference classification for patients with valid FujiLAM and AlereLAM results and included in the accuracy analyses. FujiLAM was positive in 166 (16·1%) of 1031 patients in group 1 and 81 (14·9%) of 544 patients in group 2. FujiLAM was invalid in 18 (1·1%) of 1571 tested patients on the first attempt and in six (0·4%) of 1571 patients after repeating the test. FujiLAM results inter-reader agreement was 98·0% (κ=0·94 [95% CI 0·91–0·96]; appendix p 8). AlereLAM was positive in 179 (17·4%) of 1031 patients in group 1 and 78 (14·3%) of 544 patients in group 2. 1022 patients in group 1 and 542 patients in group 2 had both FujiLAM and AlereLAM results, of whom 96 patients (9·4%) in group 1 and 18 patients (3·3%) in group 2 had confirmed tuberculosis, and 41 patients (4·0%) in group 1 and eight patients (1·5%) in group 2 had probable tuberculosis. In total, 458 (29·3%) of 1564 patients were unclassifiable as per the microbiological reference standard and 303 (19·4%) of 1564 patients were unclassifiable as per the composite reference standard. Among unclassifiable patients, five had positive Xpert or culture results in samples obtained after 30 days, of whom three were FujiLAM positive and none was AlereLAM positive. Using the microbiological reference standard, FujiLAM sensitivity was 60% (95% CI 51–69) compared with 40% (31–49) for AlereLAM (p<0·0007). Among patients with CD4 counts of less than 200 cells per μL, FujiLAM was 69% (95% CI 57–79) and AlereLAM sensitivity was 52% (40–64; p=0·0218), and among patients with CD4 counts of 200 cells per μL or higher, FujiLAM sensitivity was 47% (34–61) and AlereLAM sensitivity was 24% (14–38; p=0·0116; figure 2 ).Figure 2 Sensitivity and specificity of FujiLAM and AlereLAM diagnostic accuracy against the microbiological reference standard in patients with HIV Sensitivity and specificity of FujiLAM and AlereLAM by CD4 count for both groups combined, group 1, group 2, and sensitivity and specificity of FujiLAM for both groups combined by assay lot number. Group 1 included HIV-positive ambulatory individuals (aged ≥15 years) with signs or symptoms of tuberculosis irrespective of their CD4 T-cell count. Group 2 included asymptomatic patients with advanced HIV disease. FujiLAM=Fujifilm SILVAMP TB LAM assay. AlereLAM=Alere Determine TB-LAM Ag test. TP=true positive. FP=false positive. FN=false negative. TN=true negative. Using the microbiological reference standard, in group 1, FujiLAM sensitivity was 59% (95% CI 49–68) and AlereLAM sensitivity was 44% (34–54; p=0·0112), and in group 2, FujiLAM sensitivity was 61% (39–80) and AlereLAM sensitivity was 22% (0·09–0·45; p=0·0082). Among patients in group 1, FujiLAM sensitivity was similar in patients with CD4 counts of less than 200 cells per μL (71% [56–83]) and 200–349 cells per μL (68% [43–87]), and lower among patients with CD4 counts of 350 cells per μL or higher (35% [18–54]). AlereLAM sensitivity was 63% (47–76) in patients with CD4 counts of less than 200 cells per μL, and lower in patients with CD4 counts of 200–349 cells per μL (37% [16–62]) and CD4 counts of 350 cells per μL or higher (17% [6–36]). Using the microbiological reference standard, FujiLAM specificity was 87% (95% CI 85–89) and AlereLAM specificity was 86% (84–88; p=0·8828). Using the composite reference standard, FujiLAM sensitivity was 48% (95% CI 40–56) and AlereLAM sensitivity was 38% (31–46; p=0·0237) and FujiLAM specificity was 90% (95% CI 88–92) and AlereLAM specificity was 95% (94–96; p<0·0001; figure 3 ). In sensitivity analyses in which unclassifiable tuberculosis cases were considered as tuberculosis-negative, FujiLAM specificity against the microbiological reference standard and composite reference standard was similar. However, AlereLAM specificity against the composite reference standard was lower than in primary analyses (appendix pp 9–10).Figure 3 Sensitivity and specificity of FujiLAM and AlereLAM against the composite reference standard in patients with HIV Sensitivity and specificity of FujiLAM and AlereLAM by CD4 count for both groups combined, group 1, and group 2. Group 1 included HIV-positive ambulatory individuals (aged ≥15 years) with signs or symptoms of tuberculosis irrespective of their CD4 T-cell count. Group 2 included asymptomatic patients with advanced HIV disease. FujiLAM=Fujifilm SILVAMP TB LAM assay. AlereLAM=Alere Determine TB-LAM Ag test. TP=true positive. FP=false positive. FN=false negative. TN=true negative. In post-hoc analyses of four different FujiLAM lot numbers used in the study, the FujiLAM accuracy point estimates against the microbiological reference standards varied by lot number. Sensitivity varied from 48% (95% CI 34–62) to 76% (57–89) and specificity from 77% (95% CI 72–81) to 98% (93–99; figure 2; appendix p 11). A third of patients with confirmed tuberculosis (36 [31·6%] of 114 patients) were identified by the two LAM tests (figure 4 ). Additionally, among the 114 patients with confirmed tuberculosis, FujiLAM alone identified tuberculosis in 32 (28·1%) patients and AlereLAM alone identified tuberculosis in ten (8·8%) patients. Among 992 patients without tuberculosis, 42 (4·2%) had positive FujiLAM and AlereLAM results, 91 (9·2%) had only FujiLAM positive results, and 93 (9·4%) had only AlereLAM positive results (appendix p 12). Of the 11 patients with non-tuberculous mycobacteria isolated in sputum without M tuberculosis, three were both FujiLAM and AlereLAM positive.Figure 4 FujiLAM and AlereLAM results among patients with confirmed tuberculosis and patients without tuberculosis as per the microbiological reference standard Group 1 included HIV-positive ambulatory individuals (aged ≥15 years) with signs or symptoms of tuberculosis irrespective of their CD4 T-cell count. Group 2 included asymptomatic patients with advanced HIV disease. FujiLAM=Fujifilm SILVAMP TB LAM assay. AlereLAM=Alere Determine TB-LAM Ag test. As per the microbiological reference standard, weakly positive FujiLAM results and grade 1 AlereLAM results were more frequent among patients who did not have tuberculosis than patients with confirmed tuberculosis. Among patients with positive FujiLAM results, 120 (90·2%) of 133 patients without tuberculosis had weakly positive results compared with 34 (50·0%) of 68 patients with confirmed tuberculosis (p<0·0001). Among patients with positive AlereLAM, 121 (91·0%) of 133 patients without tuberculosis had grade 1 results compared with 29 (64·4%) of 45 patients with confirmed tuberculosis (p<0·0001; appendix pp 12–13). The intensity of positive FujiLAM results was associated with semi-quantitative Xpert Ultra results (appendix p 14). Among patients with high or medium Xpert Ultra results, a higher proportion had strongly positive FujiLAM results than did those with low, very low, or trace Xpert Ultra results (p=0·0012). Discussion In this diagnostic accuracy study, the FujiLAM assay identified a considerable proportion of symptomatic ambulatory HIV-positive patients and asymptomatic patients with advanced HIV disease who had microbiologically confirmed tuberculosis. FujiLAM was more sensitive than AlereLAM across all CD4 count strata and both study groups. Specificity was similar for both tests. As notified after study completion by FIND and the FujiLAM manufacturer, we found variability in FujiLAM accuracy among lot numbers, which affected both sensitivity and specificity. Further investigations are required before clinical use of FujiLAM. Exploratory analyses suggest that the intensity of the FujiLAM positive results might be associated with tuberculosis bacterial load based on semi-quantitative Xpert Ultra results, and that false positive FujiLAM results might be more frequent among patients with weakly positive results. The sensitivity of FujiLAM was high in patients with CD4 counts of less than 200 cells per μL and in patients with CD4 counts of 200–350 cells per μL, while the sensitivity of AlereLAM was lower in patients with CD4 counts of 200–350 cells per μL than in patients with CD4 cells counts of less than 200 cells per μL. FujiLAM sensitivity at higher CD4 counts would be a substantial advantage compared with the AlereLAM test. A meta-analysis of studies using previously collected data and stored urine samples found higher FujiLAM sensitivity at lower CD4 counts (87% in patients with CD4 counts <100 cells per μL) than higher CD4 counts (44% in patients with CD4 counts ≥200 cells per μL).25 However, neither this nor other studies have reported FujiLAM sensitivity in patients with CD4 counts between 200 and 350 cells per μL or higher than 500 cells per μL. In our study, among symptomatic patients with CD4 counts of 350 cells per μL or higher, FujiLAM sensitivity was lower (35%) than reported in HIV-negative symptomatic patients (53%) in a multicentre study,26 and in two smaller studies (66% and 75%).20, 21 This difference might be explained by the higher proportion of HIV-negative patients with advanced or disseminated tuberculosis disease in these studies. We report the first prospective diagnostic accuracy results of FujiLAM in asymptomatic patients with advanced HIV disease. The prevalence of tuberculosis was high in this group (3% with microbiologically confirmed and 5% with probable or confirmed tuberculosis) and FujiLAM detected around 65% of cases. A study in Ghana19 including patients referred for ART initiation identified the majority of confirmed tuberculosis cases among symptomatic patients after the WHO symptom screen. As previously reported, we found FujiLAM specificity tended to be lower in immunosuppressed patients18, 19, 25 and slightly higher with the composite reference standards. These findings question the suitability of using only sputum microbiology results to define tuberculosis-negative cases among patients with low CD4 cell counts. FujiLAM is expected to produce fewer cross-reactions with non-tuberculous mycobacteria than AlereLAM due to highly specific antibodies.18, 20, 27 We found most false positive FujiLAM results were weakly positive and occurred in specific lot numbers. One hypothesis is that some false positive results could also be due to cross-reactions with other pathogens producing weakly positive results. However, we also found an association between FujiLAM result intensity and bacterial load by Xpert Ultra. Some FujiLAM positive tests might also have been misclassified as false positive in patients with low tuberculosis bacterial load not detected by Xpert Ultra or culture. We found differences in the FujiLAM diagnostic accuracy by lot number. One lot number (representing 30% of the tests) showed high sensitivity and suboptimal specificity whereas two lot numbers had lower sensitivity and high specificity. The cause of this variability is currently under investigation by the manufacturer, and clinical use will not be possible until this variability in performance has been addressed. Urine samples were easily produced by almost all patients, while only three-quarters of symptomatic and less than 10% of asymptomatic patients could spontaneously produce sputum. Therefore, urine-based tuberculosis tests have a clear added value for tuberculosis diagnosis. Furthermore, as we have reported elsewhere, urine sampling for tuberculosis investigations is mostly preferred to sputum sampling by patients.28 The FujiLAM test is considered easy to perform, including by lay health-care workers.29 The main limitation of our study is the possible misclassification of patients with non-microbiologically confirmed tuberculosis as tuberculosis-negative cases, which might have led to underestimation of LAM specificity against the microbiological reference standards.23 To maximise tuberculosis detection, we systematically performed Xpert Ultra and culture in two sputum samples for all patients, Xpert Ultra in urine for patients with less than two sputum samples, and Xpert Ultra in extra-pulmonary samples if indicated. Additionally, our definition of tuberculosis-negative cases included two sputum Xpert Ultra or culture-negative results. Although this strict definition resulted in a high proportion of unclassifiable patients, LAM specificity against the microbiological reference standards in primary and sensitivity analyses (unclassified patients considered as tuberculosis-negative) was similar. Since the microbiological reference standards might yield overestimates for LAM sensitivity, we used a composite reference standard that combined clinical and pathological tests to identify patients with tuberculosis. We defined a short timeframe (30 days) between the index tests and the reference to decrease the possibility of bias. Another limitation was the precision of the FujiLAM sensitivity by CD4 count as the sample size was calculated for overall accuracy by patient group. Finally, the variability of the accuracy between FujiLAM lot numbers limits the interpretation of the overall diagnostic accuracy of FujiLAM. Strengths of the study include the study setting of four countries with a high HIV burden with similar conditions to those of its intended use. Symptomatic patients were eligible irrespective of their CD4 count, and consequently, large numbers of patients with high CD4 counts were included, which represents the current ambulatory HIV population in many African clinics. Clinicians in low-resource settings often rely on clinical judgement to diagnose tuberculosis due to poor availability of x-rays, difficulties in obtaining sputum samples, and delays in obtaining rapid molecular test results. Next-generation, higher sensitivity urine-LAM assays are promising tests that allow rapid tuberculosis diagnosis at the point of care for people with HIV with symptoms of tuberculosis and for asymptomatic patients with advanced HIV disease. However, the variability in accuracy between FujiLAM lot numbers needs to be addressed before clinical use. Data sharing Data collected for the study will be made available on request after manuscript publication. Data will include individual deidentified participant data and the data dictionary. Requests can be addressed to the corresponding author ([email protected]). Requests will be examined by a committee of relevant people involved in the study. The scientific aspects of the proposal as well as the ethical and legal implications of the data sharing will be considered. Data will be shared after approval of the proposal and after signing a data sharing agreement by all parties involved. Declaration of interests We declare no competing interests. Supplementary Material Supplementary appendix Acknowledgments We would like to acknowledge the patients who participated in this study, the study personnel, and supportive staff in the four study sites. We also thank the external radiologists and the imaging advisors for support with the study. We would like to thank Médecins Sans Frontières, Epicentre, the Ministry of Health, and the National Tuberculosis Program in Uganda, Kenya, South Africa, and Mozambique. We also thank Tony Reid for the final edits of the Article. This study was funded by the ANRS (grant number 20314) and Médecins Sans Frontières. FujiLAM tests were donated by the Foundation for Innovative Diagnostics. Contributors HH and MBa designed the study with input from WM, NTA, LO, IMT, ZN, and CH. HH oversaw and coordinated the multicentre study. NTA, LO, and WM oversaw the study in the study sites. AVL, MA, NTA, RS, and NN supervised the study implementation in the study sites. IMT, CB, TS, GO, JOO, JN, MMb, CA, SW, MMu, DA, and AA provided support to the study implementation in the study sites. IMT and EA provided support to the laboratory procedures. ZN, CH, GF, LN, MC, AG-W, and MBo provided scientific support. MBa did the statistical analysis. HH wrote the manuscript draft. AG-W and MBo provided substantial input in the manuscript. All authors had full access to all data in the study and contributed to the interpretation of data, the revision of the Article, approved the final version of the manuscript, and had final responsibility for the decision to submit for publication. HH and MBa had access to and verified all the data. ==== Refs References 1 WHO Global tuberculosis report 2021 2021 World Health Organization Geneva 2 WHO High-priority target product profiles for new tuberculosis diagnostics: report of a consensus meeting 2014 World Health Organization Geneva 3 Lawn SD Kerkhoff AD Burton R Diagnostic accuracy, incremental yield and prognostic value of Determine TB-LAM for routine diagnostic testing for tuberculosis in HIV-infected patients requiring acute hospital admission in South Africa: a prospective cohort BMC Med 15 2017 67 28320384 4 Huerga H Mathabire Rucker SC Cossa L Diagnostic value of the urine lipoarabinomannan assay in HIV-positive, ambulatory patients with CD4 below 200 cells/μL in 2 low-resource settings: a prospective observational study PLoS Med 16 2019 e1002792 5 Drain PK Gounder L Sahid F Moosa MYS Rapid urine LAM testing improves diagnosis of expectorated smear-negative pulmonary tuberculosis in an HIV-endemic region Sci Rep 6 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Perspectives and perceptions of urine sampling and urine-based TB testing among patients in Kenya and Uganda. World Conference on Lung Health; Oct 19–22, 2021 (virtual; abstr EP-27-366). 29 Chenai Mathabire Rücker S Lissouba P Akinyi M Feasibility and acceptability of using the novel urine-based FujiLAM test to detect tuberculosis: a multi-country mixed-methods study J Clin Tuberc Other Mycobact Dis 27 2022 100316	36521944	PMC9747168	NO-CC CODE	2022-12-15 23:23:24	no	Lancet Glob Health. 2023 Jan 13; 11(1):e126-e135	utf-8	Lancet Glob Health	2,022	10.1016/S2214-109X(22)00463-6	oa_other
==== Front Curr Res Ecol Soc Psychol Curr Res Ecol Soc Psychol Current Research in Ecological and Social Psychology 2666-6227 The Authors. Published by Elsevier B.V. S2666-6227(22)00012-0 10.1016/j.cresp.2022.100045 100045 Article Heavy crisis, new perspectives? Investigating the role of consumption, time wealth and meaning construction during countrywide Covid-19 lockdown in Germany Hüppauff Tilmann ⁎ Richter Nadine Hunecke Marcel Faculty of Applied Social Sciences, University of Applied Sciences and Arts Dortmund, Germany ⁎ Corresponding author: Tilmann Hüppauff, Emil-Figge Straße 38a, 44227 Dortmund, Germany. 27 4 2022 2022 27 4 2022 3 100045100045 28 6 2021 28 1 2022 23 4 2022 © 2022 The Authors. Published by Elsevier B.V. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. The COVID-19 pandemic profoundly changed the way we live and consume. One open question is whether the crisis provides an opportunity to increase alternatives to materialistic consumption. We characterize these alternatives as sustainable leisure behaviour. Our study aimed to analyse: (i) Changes in behaviour frequency of consumption and sustainable leisure before and during lockdown. (ii) How potential changes in behaviours are appraised and if there are intentions to keep changed behaviour. (iii) Influence of Time Wealth (an alternative model of affluence that potentially promotes low consumption life styles) and Life Reflection (fundamental reflection processes stimulated by the Covid-19 crisis) on consumption and sustainable leisure behaviour during lockdown. We collected data from 947 participants in Germany, using an online survey. Participants reported behaviour frequencies of consumption and sustainable leisure before and during lockdown. Furthermore, participants evaluated potential behaviour changes and rated statements regarding their future intentions. Main findings: (i) Pairwise t-tests revealed reduced consumption behaviour in Electronics and Clothes. All sustainable leisure behaviours increased during lockdown. (ii) Increases in sustainable behaviour received positive evaluation and were intended to extend into the future. Consumption behaviour results were mixed. (iii) In multiple regression analysis, Time Wealth and Life Reflection were positively related to most sustainable leisure behaviour. Sustainable leisure behaviour correlated positively with Life Satisfaction and Presence of Meaning. We discuss future research ideas regarding the promotion of sustainable wellbeing in a post COVID society. Graphical abstract Image, graphical abstract Keywords Time wealth Meaning Sustainable consumption Sustainable leisure Covid-19, Wellbeing ==== Body pmc1 Introduction The Covid-19 crisis has turned the world upside-down. To prevent the collapse of health care systems drastic lockdown regulations were imposed by the German government. The measurements taken included social distancing, closing down shops and businesses and introducing stay-at-home regulations for work and private-life sphere. Thus, the crisis is a huge changemaker for individual lifestyles. Yet, it remains unclear what potential positive and negative impact the crisis has for adopting environmentally friendly behaviour. The goal of the current study is to investigate changes of consumption behaviour and behaviour that poses an alternative to buying and consuming products, which we call sustainable leisure behaviour. Furthermore, we examined Time Wealth and Life Reflection as relevant factors connected to behaviour alternative to consumption. Reese et al. (2020) presented research questions connecting the Covid-19 crisis to pro-environmental behaviour, wellbeing and potential influencing factors. Overall, the question stands out as to whether the Covid-19 crisis “can be helpful for understanding and even supporting a social-ecological transformation” (Reese et al., 2020, p. 2). Life interventions created by Covid-19 might provide opportunities to change habits towards more sustainable behaviours (DeAngelis, 2020; Reese et al., 2020; Whitmarsh et al., 2021). From our point of view this connects to the broader question of how less resource intensive lifestyles can create wellbeing (Hunecke, 2018; Kasser, 2017; Raymond & Raymond, 2019). 1.1 Environmental impact of consumerism The consumption of products, clothes and services are amongst the main drivers for climate pollution and resource consumption in industrialised countries such as Germany (Ivanova et al., 2016). Increasing wealth and mass advertising shifted consumption motives from satisfying human necessities towards social status, distinctiveness and luxury (Jackson, 2009, pp. 98–102; Kasser, 2016). The production of clothes and manufactured products are amongst the main drives for growing resource demands including GHG emissions (Wood et al., 2018). One reason might be the increased consumption of electronics, clothes and household items such as furniture (Steen-Olsen et al., 2016; Wood et al., 2018). In a consumerist culture such as Germany, the average German lifestyle requires resources for three planets (Global Footprint Network, 2021), although consumption might be unevenly distributed (Gore, 2020). Consequently, one key factor for solving the climate crisis is to enable and encourage alternative ways of as well as alternatives to material consumption. 1.2 Change in consumption and leisure through Covid-19 lockdown Lockdown measurements altered ways of consumption through social distancing and the shutdown of shops and firms. Even though online shopping options were still available, consumption levels decreased worldwide (Jo et al., 2021). In Germany, social welfare policies were imposed by to prevent the risk of unemployment (Christ et al., 2021; COVID-19 Snapshot Monitoring [COSMO], 2021). In turn, lowered consumption levels might indicate that people spent time committing to alternative leisure activities. In our present study, we therefore focused on behaviour that can be associated with sustainable leisure (Bedfort et al., 2011). Ropke and Godskesen (2007) characterized sustainable leisure as requiring low levels of resources, being time consuming, close to home, using shared facilities and focusing on one thing at a time. Corley et al. (2021) for example showed that garden use increased during Covid-19 and is connected to better health amongst older adults. Furthermore, activities linked to spending time outdoors (Lemmey, 2020) and sustainable food consumption (Borsellino et al., 2020; Whitmarsch et al., 2020) increased. 1.3 Time wealth One influencing factor regarding the emergence of sustainable leisure behaviour during the pandemic might be the amount of time people feel to have on hand. This subjective feeling can be conceptualized as personal Time Wealth (Reisch, 2001) or Time Affluence (Kasser & Sheldon, 2009). The main indicator for feeling “affluent of time” is the amount of time that is perceived to be free from obligatory tasks (Goodin et al., 2005; Kasser & Sheldon, 2009; Von Jorck et al., 2019). Von Jorck et al. (2019) furthermore suggest tempo, plannability, synchronisation, sovereignty as relevant indicators of Time Wealth. For a socially beneficial sustainability transformation, having time might represent an alternative model of wealth instead of exclusively focusing on material growth (Kasser & Sheldon, 2009; Reisch, 2001). Increasing Time Wealth e.g. through reducing working time is therefore argued to have a triple dividend namely providing “sustainability, social equity and enhanced life satisfaction” (Buhl & Acosta, 2016, p.1). Time Wealth might enable more sustainable lifestyles since experiencing lack of time is reported as a major barrier for sustainable behaviour (Kasser, 2009; Speck & Hasselkuss, 2015; Young et al., 2010). Chai et al. (2015) could show that people who enjoyed more free time could address the value-action gap concerning environmental behaviour more successfully. However, it is uncertain if Time Wealth promotes more sustainable lifestyles per se. Other studies found that higher levels of Time Wealth were not necessarily associated with lower resource consumption (Buhl & Acosta, 2016), but with higher wellbeing and social engagement (Buhl & Acosta, 2016; Kasser & Sheldon, 2009). Therefore, investigating the role of Time Wealth regarding the adoption of sustainable leisure behaviour during the Covid-19 lockdown might provide further insights concerning the relationship between Time Wealth and sustainable behaviour. 1.4 Meaning, crisis and reflection “In times of crisis, people reach for Meaning. Meaning is strength. Our survival may depend on our seeking and finding it.” This quote associated to existential psychologist Viktor Frankl as cited in Schaffner (2020) might be applicable to the climate crisis as well as the current Covid-19 crisis. As Schnell (2021) illustrates “What was long taken for granted is now called into question by reality: The primacy of growth and progress is crumbling in the face of a pandemic, economic crisis, climate change and widening income gaps.” (p. 238). Research has identified two fundamental meaning processes. Seeking meaning (search) and having meaning (presence) (Steger et al., 2006). People actively search for meaning when existing meaning assumptions are challenged (Park, 2010). Although searching for meaning can be accompanied by negative emotions it holds potential for the adaption needed for solving a crisis (Schnell, 2021, pp. 105–106). In the context of climate crisis, the active construction of meaning might be an important psychological resource for developing sustainable lifestyles (Hunecke, 2018; Hunecke & Richter, 2019). Meaning Construction describes the conscious reflection about experiences made by making efforts to integrate those experiences into personal meaning systems (Delle Fave, 2020; Park, 2010). However, such deliberative and active reflection requires considerable resources. In daily life, decisions are mostly guided by habitual thinking and acting (Kahneman, 2003). Covid-19 as a major life incident has disrupted daily habits and created circumstances where some people might reflect more profoundly on their values and choices. Thus, we tested whether reflections stimulated by Covid-19 are connected to a less resource intensive lifestyle. 1.5 Consumerism and individual wellbeing Following philosophical traditions, psychological research generally distinguishes between hedonic and eudaimonic wellbeing (Aristotele, 2001; Heintzelman, 2018). Hedonic wellbeing might be conceptualised as “pleasure” in form of maximising positive affect, while minimising negative affect (Kahneman et al., 1999). With his concept of subjective wellbeing, Diener (1985) additionally proposed a cognitive component of hedonic wellbeing in the form of satisfaction with one's life as a whole. Eudaimonic approaches describe wellbeing as living according to self-determined values and goals (Ryan et al., 2008) and experiencing meaning (Heintzelman, 2018). Although findings suggest that consuming new products may give a hedonic boost (Babin et al., 1994), valuing material wealth and status through consumption is associated negatively with individual wellbeing (Kasser, 2016). Acting more sustainable on the other hand has the potential to increase eudaimonic and hedonic wellbeing (Venhoeven et al., 2013), especially if it is autonomous and valued intrinsically (Brown & Kasser, 2005; Kasser, 2017; Venhoeven et al., 2017). Therefore, sustainable leisure behaviour may be positively related to individual wellbeing. 1.6 The present study Based on the reviewed literature, the focus of the present study lies on the following research questions: [RQ 1] Firstly, we investigated whether Covid-19 measurements have changed consumption behaviour as well as behaviour of sustainable leisure. Thus, we tested whether Covid-19 measurements led to a decrease in consumption behaviour frequency [RQ 1a] and if Covid-19 measurements led to an increase in sustainable leisure behaviour frequency [RQ 1b]. [RQ 2] How were potential changes in consumption and sustainable leisure behaviour evaluated? In order to explore this question, we analysed if increasing sustainable leisure behaviours [RQ 2a] and decreasing consumption behaviours [RQ 2b] were associated with positive evaluations of behaviour. [RQ 3] Furthermore, we investigated whether there are intentions to continue potential behaviour-specific changes. Specifically, we tested whether increasing sustainable leisure behaviour [RQ 3a] and decreasing consumption behaviour [RQ 3b] could be linked to higher intentions to keep behaviour change in the future. [RQ 4] We investigated the role of Time Wealth for less resource-intensive lifestyles during Covid-19. We tested if Time Wealth during Covid-19 lockdown was connected to higher levels of sustainable leisure behaviour [RQ4a] and lower levels of consumption behaviour [RQ4b]. [RQ 5] In a similar way we tested if Meaning Construction in the form of Life Reflection during lockdown was linked to a stronger commitment in sustainable leisure behaviour [RQ 5a] and lower levels of consumption behaviour [RQ 5b]. [EXPLORATORY ANALYSES] In an exploratory analysis we checked whether sustainable leisure behaviours were connected to indicators of wellbeing during Covid-19 lockdown. This might hold implications for future research on how sustainable lifestyles and individual wellbeing can be reconciliated. 2 Method 2.1 Procedure Using SoSci Survey (https://www.soscisurvey.de), the cross-sectional survey was carried out in Germany from April 21 to May 10, 2020 during the national lockdown, which was imposed on March, 23. On average participants experienced 36 days (range: 29–48) of lockdown regulations which were gradually lifted by May. We used a convenience sampling with no compensation for study participation. Informed consent was obtained from all participants included in the study. In the first section we assessed life circumstances related to Covid-19 together with questions assessing individual wellbeing, Time Wealth, Meaning Construction and Personal Ecological Norm. In a next step, a list of behaviour descriptions was presented. The participants were instructed to indicate (t1) how often they used to perform the behaviour prior to the lockdown (t2) how often they perform the behaviour since the lockdown regulations were imposed. Furthermore, participants were asked how they evaluate the behaviour change and whether they intend to keep the behaviour change in the future. These items were shown only if participants rated different behaviour frequencies on t1 and t2. In a last section we assessed sociodemographic data. 2.2 Sample In order to determine the necessary sample size for our multiple regression analysis we performed a priori power analysis using GPower 3.1.9.4 (Faul et al., 2007) based on alpha = 0.05 and power = 0.80 including 7 predictor variables. We estimated small effect sizes of f² = 0.02. Estimations revealed a sample size needed of N = 485 or higher. We collected data from 947 participants. In total we excluded N = 27 participants from the analyses. Seven participants were excluded due to a too fast completion of the questionnaire (< 5 minutes). Additionally, two participants were excluded using quality indicators provided by SoSci Survey software for extremely fast completion (Leiner, 2019; SoSci Survey, 2020). One participant was excluded due to age being younger than 16. Due to the increasing lift of lockdown restrictions, we stopped data collection after the 10th of May and excluded subjects who completed the questionnaire after this date (N = 17). Overall, N = 920 participants were thus included in the analysis. N = 652 identified themselves as female, N = 246 indicated their gender as male and N = 7 were diverse. Because of the small group of diverse participants, they were excluded from analysis using gender as a variable. The average age was M age= 38.25 (SD = 14.37). Most of the participants reported holding a (bachelor's or master's) university degree (57.4%), 33.6% had a higher level of secondary education, 8.7% had a general level of secondary education and 0.3% had no certificate of secondary education (so far). Average income level was between 2501–3000 Euro. An overview of missing data is in the Appendix A. 2.3 Study material The next section describes the operationalisation of the variables included in the analysis. The survey also assessed other variables that are not part of the present investigation: Policy acceptance, mobility behaviour, social environment perception, social diffusion, Covid-19 stress, one-item satisfaction with life scale and perceived solidarity. 2.3.1 Sociodemographics For sociodemographics we assessed age, gender, education, relationship status, profession and income. Furthermore, we asked for county, postal code and living conditions that might influence the appraisal of the lockdown situation. This included household size, access to private outside areas, childcare during Covid-19 and workplace changes (home office, short-time work). Participants also had the chance to write about their feelings and thoughts concerning the onset of the Covid-19 wave. 2.3.2 Time wealth For assessing Time Wealth we orientated towards the Time Affluence scale used by Kasser and Sheldon (2009). The scale focuses mainly on subjective feelings of tempo (“my life is too rushed”) and the amount of free time (“I have enough time to do the things that are important to me”). Building on recent advancements in measuring Time Wealth (Von Jorck et al., 2019), we furthermore added the facet sovereignty (“I can use my time self-determined”). Mostly due to limited space in the questionnaire, we did not include more items measuring plannability and synchronisation. Additionally, the synchronisation of daily appointments would have been difficult to assess under lockdown conditions since daily routines were fundamentally disrupted. All items were measured on a scale from 1 (“strongly disagree”) to 5 (“strongly agree”). To analyse the factorial structure of time wealth, confirmatory factor analysis (CFA) was conducted using lavaan (Rosseel, 2012). A bifactor model with the three dimensions tempo, sovereignty, free time and a general factor yielded the best fit after excluding one item of the tempo dimension, which was not significantly related to the tempo factor and showed a negative variance (CFI = 0.990, TLI = 0.997, RMSEA = 0.040, SRMR = 0.012). A s – 1 model with free-time as a common factor as suggested by Geiger et al., (2021) showed a poorer fit after excluding one item for the reasons described above (CFI = 0.968, TLI = 0.936, RMSEA = 0.102, SRMR = 0.029). Based on these findings we decided for the best fitting model and computed the mean of time wealth following the symmetrical bifactor model. The detailed path weights can be found in the online supplementary materials. The final 8-item scale had an internal consistency of ω = 0.94 (McDonald's omega) and α = 0.91. 2.3.4 Life reflection To investigate the role of Meaning Construction in the context of Covid-19 and alternative consumption behaviour, we used the Life Reflection scale by Lüders et al. (2021). The scale measures fundamental reflection processes stimulated by events or objects. We framed the questions explicitly with regard to the Covid-19 crisis. Item examples are “the coronavirus and its consequences make me think about what sort of person I want to be” or “the coronavirus and its consequences encourage me to think about in which world I want to live in”. Internal consistency was at α = 0.91 (ω = 0.91). Items were measured on a scale from 1 (“strongly disagree”) to 5 (“strongly agree”). 2.3.5 Consumption behaviour To measure consumption behaviour, we used single items asking purchasing behaviour of Electronics (“purchase of electronic devices”), Clothes (“purchase of clothes”) and House & Garden (“purchase of Items for House & Garden”). We chose these types of behaviour because they have a high environmental impact (see Section 1.1), but are performed quite regularly by people regardless of their socio-economic status. Furthermore, these behaviours were still possible to be executed under lockdown regulation e.g. via online shopping. We also included Streaming (“streaming media services”) as it also has a significant environmental impact (Shehabi et al., 2014) and might be highly relevant during the lockdown phase. Participants were asked to indicate behaviour frequency before lockdown measures and during lockdown measures separately on a scale from 1 (“rarely/not at all”) to 5 (“very often/always”). 2.3.6 Sustainable leisure behaviour To assess sustainable leisure behaviour, we asked for the frequency of Outdoor Activities (“outdoor activities [excursion, walks, sports]”), Crafting Activities (“crafting activities in the house, flat or garden [repairing, renewing, maintaining]”), Creative Activities (“creative activities [sewing, building, painting, making music]”) as well as Food Preparation (“food preparation [cooking, baking]”) using single items. We chose these behaviours because they were not inferred strongly by lockdown regulations and can be at the same time defined as sustainable leisure behaviour (Ropke & Godskesen, 2007). Because social contact restrictions were part of the lockdown measures, we did not include behaviours that make use of shared facilities. Again, participants were asked to indicate their behaviour frequency before and during lockdown on a scale from 1 (“rarely/not at all”) to 5 (“very often/always”). 2.3.7 Evaluation of behaviour change As described in Section 1.5, one aim was to measure how participants evaluated potential behaviour changes in consumption and sustainable leisure. Thus, if measured behaviour frequency during lockdown differed from behaviour frequencies before lockdown, we asked subjects to evaluate these behaviour changes on a scale from 1 (“very negative”) to 5 (“very positive”). 2.3.8 Future intentions of behaviour change To assess intentions to maintain behaviour frequencies that changed during Covid-19 lockdown we asked participants to rate the statement “I intend to keep my behaviour changes for the future” on a scale from 1 (“does not apply at all”) to 5 (“fully applies”) for each changed behaviour. 2.3.9 Personal norm As personal ecological norms are an important predictor of pro-environmental behaviour (Bamberg & Möser, 2007), we included this variable as a control. The 4 items included statements such as “I feel responsible that I should contribute to climate protection through my choice of transport” and “To protect the environment I feel obliged to save energy at home”. Items were adapted from Hunecke et al. (2007) and measured on a scale from 1 (“strongly disagree”) to 5 (“strongly agree”). Internal consistency was at α = 0.87 (ω = 0.87). 2.3.10 Life satisfaction We also included the Satisfaction with Life Scale (Diener et al., 1985) to assess current life satisfaction. When necessary, we adapted the items to the current pandemic situation (e.g. “The current situation does not hinder me from getting the import things I want in life”). Internal consistency was α = 0.79 (ω = 0.79), scale anchors ranged from 1 (“strongly disagree”) to 5 (“strongly agree”). 2.3.11 Presence of meaning To measure Presence of Meaning, we used the presence subscale of the Meaning Life Questionnaire by Steger et al. (2006). The MLQ assesses the presence of Meaning using items such as “I have discovered a satisfying life purpose” and “I understand my life's meaning”. Cronbach's alpha was 0.90 (ω = 0.91). Items were assessed on a scale from 1 (“strongly disagree”) to 5 (“strongly agree”). 3 Results The next section provides statistical results for testing the proposed research questions. In order to mitigate alpha error accumulation, we tested our assumptions against the p = .001 level of significance using two-tailed tests. Furthermore, our results were predominantly in the direction predicted by the proposed research questions making alpha error accumulation less likely. 3.1 Behaviour change [RQ1] Fig. 1 shows changes in consumption behaviour before and after lockdown. Pairwise comparisons revealed a significant decrease in consumption behaviour for Clothes, t(919) = 23.17, p < .001, Bca 95% CI [0.72, 0.86], d = -0.88, and Electronics, t(919) = 10.46, p < .001, Bca 95% CI [0.20, 0.29], d = -0.31. In contrast Streaming behaviour increased significantly, t(919) = -14.74, p < .001, Bca 95% CI [-0.48, -0.37], d = 0.34. House & Garden consumption did not differ significantly, t(919) = 0.89, p < .376, Bca 95% CI [-0.04, 0.10], d = -0.002.Fig. 1 Behaviour frequencies of consumption behaviour before and during lockdown. Fig. 1 Frequency of sustainable leisure behaviour increased in all behaviour categories. Effect was the largest for Food Preparation, t(919) = -18.44, p < .001, Bca 95% CI [-0.65, -0.52], d = 0.55, as well as Crafting Activities, t(919) = -19.68, p < .001, Bca 95% CI [-0.69, -0.56], d = 0.55, followed by Creative Activities, t(919) = -11.32, p < .001, Bca 95% CI [-0.43, -0.31] d = 0.30, and Outdoor Activities, t(919) = -6.48, p < .001, Bca 95% CI [-0.37, -0.20], d = 0.26. Effects are illustrated in Fig. 2 .Fig. 2 Behaviour frequencies of sustainable leisure behaviour before and during lockdown. Fig. 2 3.2 Appraisal of behaviour change [RQ2; RQ3] As described in Section 2.1, we asked participants with respect to behaviours, that changed in their frequency due to Covid-19, how they would evaluate these changes and whether they intended to keep this changed behaviour in the future. To be able to connect behaviour change with evaluation and behaviour intention we created difference scores between behaviour frequency during the pandemic (t2) and before the pandemic (t1). We performed Spearman's rho correlation analysis to test whether a stronger increase in behaviour frequency can be connected to higher evaluation and intention. Table 1 depicts correlation analyses for consumption behaviour. Negative relationships between behaviour change and evaluation of change indicate that decreasing behaviour frequencies were evaluated positively. We observed this pattern for the consumption of Clothes, Electronics and Streaming although effects failed to reach significance on the 0.001 level. Positive relationships between behaviour change and evaluation of change indicate that increasing behaviour correlates with higher appraisal of change. House & Garden consumption revealed a small significant positive relationship indicating that increasing consumption was evaluated positively. For future behaviour intentions correlations were weak for all the tested behaviours and failed to cross the 0.001 significance level.Table 1 Correlation of behaviour Change, Evaluation and Future Intentions for consumption behaviours including descriptive statistics. Table 1 N M SD 1 2 3 1. BC 920 -0.79 1.04 – Clothes 2. E 551 3.21 1.01 -0.09 – 3. FI 551 3.01 1.10 -0.04 .57⁎⁎⁎ – 1. BC 920 -0.25 0.71 – Electronics 2. E 295 3.14 .98 -0.16⁎⁎ – 3. FI 295 3.06 1.21 -0.15* .65⁎⁎⁎ – 1. BC 920 -0.03 1.04 – House & Garden 2. E 413 3.19 0.84 .17⁎⁎⁎ – 3. FI 413 3.07 0.94 .02 .49⁎⁎⁎ – 1. BC 920 0.43 0.88 – Streaming 2. E 373 2.97 0.96 -0.16⁎⁎ – 3. FI 373 2.87 1.11 -0.09 .58⁎⁎⁎ – Table 2 depicts evaluation and future intention for sustainable leisure behaviour change. Spearman's correlation effects between behaviour change and evaluation were all positive and highly significant on the 0.001 significance level. Overall, this indicates that increasing sustainable leisure activity was evaluated positively. Correlations were strong for Outdoor Activities and small for Food Preparation, Crafting Activities and Creative Activities. Furthermore, Future intention was positively correlated with behaviour change, although effects were smaller. This means that the greater the increase in behaviour, the more participants intended to keep behaviour patterns.Table 2 Correlation of behaviour Change, Evaluation and Future Intentions for sustainable leisure behaviours including descriptive statistics. Table 2 N M SD 1 2 3 1. BC 920 0.59 0.96 – Food Prep. 2. E 441 4.08 0.99 .19⁎⁎⁎ – 3. FI 441 3.90 1.04 .14⁎⁎⁎ .68⁎⁎⁎ – 1. BC 920 0.63 0.96 – Crafting Act. 2. E 443 3.79 0.99 .27⁎⁎⁎ – 3. FI 443 3.54 1.09 .24⁎⁎⁎ .65⁎⁎⁎ – 1. BC 920 0.28 1.31 – Outdoor Act. 2. E 584 4.00 1.25 .50⁎⁎⁎ – 3. FI 584 3.92 1.30 .39⁎⁎⁎ .70⁎⁎⁎ – 1. BC 920 0.37 0.99 – Creative Act. 2. E 394 3.92 1.08 .30⁎⁎⁎ – 3. FI 394 3.79 1.12 .27⁎⁎⁎ .67⁎⁎⁎ – 3.3 Testing connection of time wealth and life reflection on consumption behaviour and sustainable leisure behaviour [RQ 4; RQ 5] To test relationships between Time Wealth, Life Reflection, consumption and sustainable leisure behaviour, we conducted hierarchical regressions. Consumption and sustainable leisure behaviour were included as dependant variables. We controlled for demographic variables (Gender, Education and Age). We also included t1 behaviour frequencies to control for the influence of pre-pandemic behaviour habits. In a next step we added the Personal Ecological Norm to control for the influence of eco-friendly mindsets. Relations of Time Wealth and Life Reflection to sustainable leisure behaviour at Time 2 are depicted in Table 3 . Time Wealth showed a positive relationship with all four categories of sustainable leisure behaviour: Outdoor Activities, Crafting Activities, Creative Activities, and Food Preparation. Following Cohen (1992), beta weights indicating effect sizes were small (p Outdoor Activities < 0.001, βOutdoor Activities = 0.14; p Crafting Activities < 0.001, βCrafting Activities = 0.16; p Creative Activities < 0.001, βCreative Activities = 0.16) and negligible (p Food Preparation = 0.002, βFood Preparation = 0.08). Life Reflection showed a highly significant positive relationship with a small weight on Food Preparation (p Food Preparation < 0.001, βFood Preparation = 0.12). We found statistically significant effects of Life Reflection on Crafting and Creative Activities, but effect sizes were negligible (p Crafting Activities = 0.001, βCrafting Activities = 0.09; p Creative Activities = 0.004, βCreative Activities = 0.07).Table 3 Hierarchical Regressions for Time Wealth and Life Reflection on sustainable leisure behaviour at Time 2, controlled for demographics and Personal Norm. Table 3IV DVs: Sustainable Leisure Behaviors, Time 2 Outdoor Act. Food Preparation Crafting Act. Creative Act. Β95% CI[LL; UL] ∆R2 Β95% CI[LL; UL] ∆R2 Β95% CI[LL; UL] ∆R2 Β95% CI[LL; UL] ∆R2 Step 1 .12⁎⁎⁎ 39⁎⁎⁎ .41⁎⁎⁎ .48⁎⁎⁎ Behaviour t1 0.35⁎⁎⁎ [0.28; 0.43] 0.55⁎⁎⁎ [0.50; 0.60] 0.77⁎⁎⁎ [0.71; 0.84] 0.78⁎⁎⁎ [0.72; 0.83] Gender -0.23⁎⁎ [-0.40; -0.06] -0.38⁎⁎⁎ [-0.51; -0.25] -0.14 [-0.28; 0.01] -0.32⁎⁎⁎ [-0.47; -0.18] Age -0.01⁎⁎⁎ [-0.02; -0.01] -0.001 [-0.01; 0.03] -0.002 [-0.01; 0.002] -0.01⁎⁎⁎ [-0.01; -0.005] Education 0.15⁎⁎ [0.05; 0.25] 0.13⁎⁎ [0.06; 0.21] 0.02 [-0.06; 0.11] -0.03 [-0.11; 0.06] Step 2 .01* .01⁎⁎⁎ .004* .01⁎⁎ Personal Norm 0.11⁎⁎ [0.02; 0.20] 0.12⁎⁎⁎ [0.05; 0.19] 0.09⁎⁎ [0.02; 0.17] 0.12⁎⁎ [0.04; 0.20] Step 3 .02⁎⁎⁎ .02⁎⁎⁎ .04⁎⁎⁎ .03⁎⁎⁎ Life Reflection 0.20 [-0.06; 0.10] 0.13⁎⁎⁎ [0.08; 0.19] 0.11⁎⁎ [0.05; 0.18] 0.01⁎⁎ [0.03; 0.16] Time Wealth 0.17⁎⁎⁎ [0.09; 0.24] 0.09* [0.03; 0.14] 0.21⁎⁎⁎ [0.14; 0.27] 0.22⁎⁎⁎ [0.16; 0.29] Note. N = 875 ∆R2 = Change in R2 compared to previous step, p<.05. ⁎⁎p<.01. ⁎⁎⁎p<.001 Gender: 0 = female; 1 = male IV = Independent Variable; DV = dependant Variable Concerning consumption behaviour, only House & Garden (p House & Garden = 0.002, βHouse & Garden = 0.09) and Streaming related to Time Wealth (p Streaming < 0.001, βStreaming = 0.09). Only Streaming was related to Life Reflection (p Streaming < 0.001, βStreaming = 0.08). All weights were negligible. 3.4 Exploratory analyses: sustainable leisure activities and indicators of wellbeing To test whether sustainable leisure behaviour correlates with individual wellbeing during the pandemic, we conducted exploratory correlational analyses including consumption behaviour, sustainable leisure behaviour, Life Satisfaction and Presence of Meaning. We tested whether higher behaviour frequencies of sustainable leisure were connected to higher Presence of Meaning as well as higher Life Satisfaction. We found highly significant correlations of Outdoor Activities, Food Preparation and Crafting Activities with Life Satisfaction (r sOutdoor Activities(918) = 0.17, p Outdoor Activities < 0.001; r sFood Preparation(918) = 0.14, p Food preparation < 0.001; r sCrafting Activities(918) = 0.11, p Crafting Activities < 0.001) and Presence of Meaning (r sOutdoor Activities (917) = 0.12, p Outdoor Activities < 0.001; r sFood Preparation (917) = 0.16, p Food preparation < 0.001; r sCrafting Activities (917) = 0.14, p Crafting Activities < 0.001). We found no highly significant correlations of Consumption behaviour with wellbeing measures except for the purchase of items for House & Garden being correlated with Life Satisfaction, r s(918) = 0.13, p House & Garden < 0.001. 4 Discussion 4.1 Discussion of findings 4.1.1 Changes in consumption behaviour and sustainable leisure during lockdown [RQ 1] Even though clothes and electronic devices were available during the lockdown via online shopping, consumption decreased. Consumption of Items for house and garden however remained at the same level. The higher frequency of streaming is consistent with previous studies that found strongly increased streaming hours (Bloomberg, 2020) as well as increased mediated communication (Brown & Greenfield, 2021). All sustainable leisure behaviour investigated increased, suggesting a change towards more time consuming, but less material intensive activities during lockdown. Data from first lockdown in England reporting a rise in “low carbon recreation” points in a similar direction (Whitmarsch et al., 2020). Using big data analysis, Evers et al. (2021) revealed an increased prevalence of food preparation, making and repairing clothes, growing vegetables as well as maintenance activities in the house. These findings were replicated empirically in two large American samples during stay-at-home orders in May 2020 (Greenfield et al., 2021). 4.1.2 Evaluation of changes in consumption and sustainable leisure [RQ 2] With regards to consumption of Streaming, Clothes, and Electronics, the correlation of decreasing frequencies with positive appraisals was weak and failed to reach the aspired level of high significance, except for House & Garden consumption showing a positive appraisal of increased consumption. On the other hand, the participants did not seem to perceive the experienced decrease of consumption during the lockdown negatively. The positive evaluation of the change towards more sustainable leisure activities suggests an approval of performing less material consuming activities. Taken together, these findings indicate the increased importance of sustainable leisure compared to consumption behaviour during the lockdown. 4.1.3 Intentions to sustain the increase of sustainable leisure behaviour and the decrease of consumption behaviour [RQ 3] We observed no clear intention to sustain the change of consumption levels. As intention is an important predictor of behaviour (Bamberg & Möser, 2007), this result points out, that participants may not maintain buying less clothes as well as spending more time streaming. In contrast, all changes towards sustainable leisure behaviour were correlated with a future intention to sustain the change. This points out again, that people not only appraise the changes positively, but also plan to maintain the higher frequency of sustainable leisure behaviour in the future. Similarly, Whitmarsch et al. (2020) found that 19% of the survey respondents reported that they intend to continue recreational activities when Covid-19 restrictions are lifted. 4.1.4 Time wealth as a predictor for sustainable leisure behaviour and consumption behaviour [RQ 4] Previous studies suggested Time Wealth as an important factor both enabling wellbeing and low consumption lifestyles (Kasser, 2009; Kasser & Brown, 2003). Our results indicate that during Covid-19 lockdown, Time Wealth is relevant for sustainable leisure, while it is not for the consumption of material goods. Even though consumption levels of electronics and clothes decreased significantly, lower levels were not associated with higher Time Wealth. This might indicate that other factors may be responsible for variance such as variables determining the willingness to shop online (Haridasan & Fernando, 2018) or the general mood for consumption (Jung et al., 2021). Streaming was correlated positively with Time Wealth. In combination with the stay-at-home policy and more free time, this connection seems plausible and may be an expression of the increased digitalisation of life spheres through the pandemic (Brown & Greenfield, 2021; Echegaray, 2021). The positive connection between Time Wealth and sustainable leisure behaviour indicates that participants who feel time affluent spent their time more often with sustainable leisure behaviour. With the changed circumstances in the lockdown, the barrier of a lack of time for some sustainable behaviour may have been temporarily reduced. Studies have shown that home office and the absence of a daily work commute during lockdown was associated with greater time wealth (Gerold & Geiger, 2020) and better work-life balance (Ipsen et al., 2021). Therefore, time-intensive activities might be easier to integrate into daily life. Gerold and Geiger (2020) reported that people mainly used increased Time Wealth during Covid-19 for resting, care work, household maintenance and leisure while collectively organised sustainability behaviour decreased. This underlines the role of Time Wealth as an enabler of sustainable behaviour when this behaviour is motivated and free from environmental constraints (Geiger et al., 2021). 4.1.5 Meaning reflection as predictor for sustainable leisure behaviour and consumption behaviour [RQ 5] Small positive relationships between Life Reflection and sustainable leisure activities indicate that people who reflected more on their meaning in life due to the Covid-19 crisis, decided to spend their time more often with low-resource consuming activities. However, effects were only highly significant for Food Production and the explained variance was small. One possible reason is that Life Reflection triggered by the current crisis might not always result in behaviour related to sustainability. Hunecke (2013) for example points out that meaning construction might not necessarily lead to goals related to sustainability because it is an open process. However, other findings indicate that aspirations to acquire a life of luxury were dampened through the Covid-19 crisis while collectivistic and frugal values increased (Evers et al., 2021; Greenfield et al., 2021). Regarding consumption behaviour we found no connection between Life Reflection caused by the pandemic crisis and the consumption of Clothes, House & Garden and Electronics. The positive correlation of meaning reflection and Streaming might be explained through streamed media content. Streaming broadcast services for example could have led to an enhanced reflection concerning the current pandemic situation. We think that more research is needed to further investigate which lifestyle pathways emerge from the disrupting experiences of the Covid-19 lockdown. These pathways could range from increased frugality to new forms of materialism (Echegaray, 2021). 4.1.6 Exploratory analysis: relationships between wellbeing and sustainable leisure activities during lockdown Recent studies focused on mechanisms linking sustainable behaviour to wellbeing (Kasser, 2017; Raymond & Raymond, 2019). In our data, consumption behaviour did not or negatively relate to wellbeing measures except for purchasing Items for House & Garden. This effect could be connected to the substantial correlation with Crafting Activities (see Section 3.4). Consumption during lockdown (e.g. buying building material) that enables meaningful activity (maintenance work in the house) may lead to enhanced wellbeing, although further research would be needed to clarify this connection. The results also revealed small relationships between sustainable leisure behaviour and wellbeing during the lockdown. Data from a large English panel study found similar connections, indicating positive associations of outdoor, crafting and creative leisure behaviour with mental wellbeing (Bu et al., 2020). One possibility is that this behaviour is compatible with living according to intrinsically orientated values (Brown & Kasser, 2005; Kasser, 2017). Furthermore sustainable leisure behaviour might go along with flow experiences (Csikszentmihalyi, 1992), which offers a way to increase wellbeing with low-environmental impact activities (Isham et al., 2019). 4.2 Limitations Several limitations should be noted regarding our measurement design. Although we investigated behavioural changes between two time points, the data was cross-sectional and therefore no causal conclusions can be drawn. Furthermore, behaviour frequencies prior to the pandemic were reported in hindsight which increases the probability of inaccurate behaviour assessments. We also assessed behaviour using single item measurement which has limitations regarding its psychometric properties (Churchill, 1979). Concerning the assessment of Time Wealth it should be noted that both tested models showed a negative item variance which could indicate measurement problems (Eid et al., 2017). One reason might be because different items and fewer facets were included compared to Geiger et al. (2021). Another limitation is the use of a convenience sample, which, on average was highly educated and showed a high ecological awareness. Thus, a generalisation of the study results might be restricted, although other study findings point in a similar direction (Bu et al., 2020; Evers et al., 2021; Greenfield et al., 2021). Furthermore, it is important to note that the investigated sustainable leisure behaviour is susceptible to environmental rebound effects. In general, the market economy has the tendency to commodify intrinsic rewarding activities leading to “escalating leisure” through materialism, social comparison and hyper-mobility (Bedfort et al., 2011). 4.3 Future directions In our data we found no clear evidence that reduced consumption behaviour impairs wellbeing. However, a great challenge is the maintenance of motivation for individuals to reduce consumption on the long-term, especially because there is currently a strong tendency to shift consumption to e-commerce (Statistisches Bundesamt, 2021). Hodbod et al. (2021) showed that consumption preferences remained changed also after lockdown restrictions were lifted. In their study, lacking motivation to consume (“not missing it”) was the second most powerful driver for reduced consumption while socio-economic status seemed less relevant. Building on this trend, ways of consuming and living should be developed which create wellbeing while staying within global resource capacities. In this respect the shift toward sustainable leisure activities seems promising. This crisis revealed that many people preferred to spend more time outdoors, preferred preparing meals at home, performed more crafting activities and engaged in creative activities more often. Sustainable leisure should also be further investigated as a strategy to support resilience during the Covid-19 crisis (Bu et al., 2020; Corley et al., 2021) and may be an important factor to respond to the climate crisis as well. A continued investigation is needed to examine what types of changed lifestyles emerge from the Covid-19 crisis (Echegaray, 2021). Our study findings suggest promoting Time Wealth might be a starting point. As the feeling of having enough time is an important precondition for self-determined behaviour (Kasser & Sheldon, 2009), a common problem is the observed and actual higher tempo in daily life due to increased time pressure (Garhammer, 2002) that leaves no room for time intensive activities connected to sustainable leisure. Future studies could explore how sustainability behaviour can be supported by measurements to enhance time sovereignty such as the possibility to work in home office (Ipsen et al., 2021) and by reducing working hours (Kasser, 2017; Nässén & Larsson, 2015). Future studies should also provide a more detailed investigation of how meaning construction processes relate to different sources of meaning such as materialistic or social orientated values (Hunecke, 2018; Kasser, 2016) in order to enhance explanatory value of the construct. In this way new insights can be created on how "inner transformation“ can support the necessary social-ecological transformation to come (Woiwode et al., 2021, p.1). 4.4 Conclusion The future challenges of climate and environmental change call for a reduction of consumption and for alternatives to consumerism. Low material-consuming sustainable leisure activities have the potential to increase wellbeing while decreasing negative ecological consequences and therefore constitute one step on the way to realise a “double dividend in sustainable consumption” (Jackson, 2005, p. 1). The present study offers several insights concerning consumer behaviour, sustainable leisure behaviour, Time Wealth and meaning construction. Regarding the question whether the Covid-19 crisis might provide important lessons for supporting a social-ecological transformation (Reese et al., 2020), the first countrywide lockdown in Germany might offers a “moment of change” (Whitmarsh et al., 2021, p. 78) regarding everyday consumption behaviour. Discussion of ethics All procedures performed in studies involving human participants were in accordance with the ethical standards of the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed Consent: Informed consent was obtained from all individual participants included in the study. Informed Consent included purpose, procedure an expected duration of the study. Participants furthermore were explained their rights concerning the collected data. Debriefing: Contact details of the study conductors were provided after study completion. Funding This work was supported by the Federal Ministry of Education and Research (BMBF), Germany [grant number 01UR1801B] CRediT authorship contribution statement Tilmann Hüppauff: Conceptualization, Methodology, Formal analysis, Investigation, Data curation, Writing – original draft. Nadine Richter: Conceptualization, Methodology, Writing – original draft, Writing – review & editing. Marcel Hunecke: Conceptualization, Methodology, Writing – review & editing, Supervision, Funding acquisition. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Apendix A Overview of missing values in Sociodemographics variablesVariable NValid NMissing Age 917 3 Gender 905 15 Income 850 70 Education 892 28 Appendix B Intercorrelations and descriptives of Items included in the analysis Table B1 Spearman's Correlation effects and between sustainable leisure behaviour, consumption behaviour, Presence of Meaning, Life Satisfaction, Life Reflection, Time Wealth and Personal Ecological Norm. Table B1Var 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 1. Cla – 2. Clb .34 – 3. Clc -0.58 .52 – 4. Ela .28 .16 -0.14 – 5. Elb .17 .29 .09 .58 – 6. Elc -0.10 .17 .25 -0.40 .48 – 7. HGa .34 .17 -0.15 .34 .19 -0.14 – 8. HGb .20 .28 .06 .18 .33 .17 .54 – 9. HGc -0.07 .15 .20 -0.09 .19 .30 -0.26 .63 – 10. Stra .12 .15 .03 .14 .14 .01 .02 .10 .11 – 11. Strb .17 .14 -0.02 .13 .14 .04 .04 .14 .14 .74 – 12. Strc .07 .01 -0.05 -0.01 -0.004 .03 .01 .06 .05 -0.22 .44 – 13. OAa .04 -0.07 -0.07 -0.01 -0.04 -0.02 .13 .01 -0.10 -0.13 -0.13 -0.03 – 14. OAb .02 .04 .03 -0.09 -0.04 .06 .05 .12 .10 -0.02 .01 .04 .29 – 15. OAc -0.001 .10 .07 -0.09 -0.002 .08 -0.06 .10 .18 .10 .12 .08 -0.54 .60 – 16. FPa .11 .11 .01 .07 .03 -0.03 .17 .13 -0.02 .07 .03 -0.06 .27 .12 -0.13 – 17. FPb .11 .07 -0.04 .04 .04 .01 .16 .14 -0.002 .04 .07 .04 .16 .21 .06 .58 – 18. FPc -0.01 -0.06 -0.07 -0.04 .002 .04 -0.04 .01 .04 -0.02 .06 .13 -0.14 .10 .23 -0.48 .36 – 19. CAa .10 .08 -0.01 .17 .08 -0.07 .40 .25 -0.07 -0.04 -0.07 -0.06 .19 .07 -0.12 .23 .15 -0.11 – 20. CAb .14 .08 -0.05 .14 .11 -0.01 .36 .44 .18 -0.04 .03 .09 .10 .14 .04 .16 .24 .08 .63 – 21. CAc .07 .03 -0.03 .01 .07 .06 .06 .30 .29 .02 .12 .16 -0.09 .12 .20 -0.06 .14 .24 -0.19 .59 – Var 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 22. CrAa -0.01 .03 .02 .07 .04 -0.02 .13 .07 -0.04 .02 .01 -0.02 .09 .04 -0.05 .20 .14 -0.09 .29 .20 -0.05 – 23. CrAb .04 .04 -0.01 .04 .04 .01 .08 .15 .09 .04 .09 .08 -0.02 .09 .11 .13 .17 .03 .17 .30 .19 .71 – 24. CrAc .07 .002 -0.06 .002 .01 .01 -0.03 .12 .15 .05 .14 .15 -0.14 .08 .22 -0.04 .08 .16 -0.10 .19 .34 -0.12 .57 – 25. PoM .08 .02 -0.05 .09 .04 -0.04 .12 .08 -0.01 -0.15 -0.11 .02 .16 .12 -0.02 .10 .16 .04 .13 .14 .02 .11 .06 -0.06 – 26. LS -0.02 .02 .03 .06 .08 .03 .09 .13 .05 -0.04 -0.06 -0.01 .12 .17 .05 .06 .14 .08 .05 .11 .09 .03 .05 .02 .43 – 27. LR .08 .02 -0.07 .02 -0.04 -0.08 .04 .03 -0.02 .02 .11 .13 -0.02 .07 .10 .03 .20 .18 .003 .13 .16 .11 .18 .17 .04 .01 – 28. TW .02 .03 .02 -0.03 .01 .04 -0.03 .07 .11 .02 .12 .15 -0.03 .12 .13 -0.01 .09 .10 -0.01 .18 .22 .02 .18 .22 .11 .17 .14 – 29. PN -0.25 -0.13 .12 -0.13 -0.17 -0.05 -0.03 -0.03 -0.02 -0.08 -0.09 -0.01 .17 .15 -0.01 .15 .17 .07 .08 .11 .06 .15 .16 .07 .05 .16 .27 .03 Note.Cl: Clothing, El: Electronics, HG: Items for House & Garden, Str: Streaming, OA: Outdoor Activities, FP: Food Production, CA: Crafting Activities, CrA: Creative Activites, PoM: Presence of Meaning, LS: Lifes Satisfaction, LR: Life Reflection, TW: Time Wealth, PN: Personal Ecological Norm a Behaviour t1, b Behaviour t2, c Difference Value (t2-t1) Correlations in bold are significant at p < .01 N = 920 Table B2 Descriptive statistics of sustainable leisure behaviour, consumption behaviour, Presence of Meaning, Life Satisfaction, Life Reflection, Time Wealth and Personal Ecological Norm. Table B2Var M SD Clothesa 2.51 0.94 Clothesb 1.72 0.86 Clothesc -0.79 1.04 Electronicsa 1.84 0.78 Electronicsb 1.59 0.81 Electronicsc -0.25 0.71 House & Gardena 2.32 0.94 House & Gardenb 2.29 1.16 House & Gardenc -0.03 1.04 Streaminga 2.84 1.22 Streamingb 3.26 1.30 Streamingc 0.43 0.88 Outdoor Act.a 3.44 1.02 Outdoor Act.b 3.72 1.17 Outdoor Act.c 0.28 1.31 Food Prep.a 3.45 1.10 Food Prep.b 4.03 1.05 Food Prep.c 0.59 0.96 Crafting Act.a 2.54 1.03 Crafting Act.b 3.17 1.23 Crafting Act.c 0.63 0.96 Creative Act.a 2.37 1.13 Creative Act.b 2.73 1.31 Creative Act.c 0.37 0.99 Presence of Meaning 3.82 0.88 Life Satisfaction 3.51 0.80 Life Reflection 3.56 0.98 Time Wealth 3.49 0.97 Personal Norm 3.96 0.86 Appendix C Supplementary materials Image, application 1 Acknowledgement We thank Franziska Fowles for proof reading in English grammar and writing. 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How Has COVID-19 Impacted Low-Carbon Lifestyles and Attitudes Towards Climate action? (CAST Briefing Paper 04) 2020 Center for Climate Change and Social Transformations https://cast.ac.uk/wp-content/uploads/2020/08/CAST-Briefing-04-Covid-low-carbon-choices-1.pdf Venhoeven L.A. Bolderdijk J.W. Steg L. Explaining the paradox: how pro-environmental behaviour can both thwart and foster well-being Sustainability 5 4 2013 1372 1386 https://www.mdpi.com/2071-1050/5/4/1372 Whitmarsh L. Poortinga W. Capstick S. Behaviour change to address climate change Curr. Opinion Psychol. 42 2021 76 81 10.1016/j.copsyc.2021.04.002 https://doi.org/https://doi.org/ Woiwode C. Schäpke N. Bina O. Veciana S. Kunze I. Parodi O. Schweizer-Ries P. Wamsler C. Inner transformation to sustainability as a deep leverage point: fostering new avenues for change through dialogue and reflection Sustainab. Sci. 16 3 2021 841 858 10.1007/s11625-020-00882-y Wood R. Stadler K. Simas M. Bulavskaya T. Giljum S. Lutter S. Tukker A. Growth in environmental footprints and environmental impacts embodied in trade: Resource Efficiency Indicators EXIOBASE3 22 3 2018 553 564 https://doi.org/https://doi.org/10.1111/jiec.12735 Young W. Hwang K. McDonald S. Oates C.J. Sustainable consumption: green consumer behaviour when purchasing products Sustain. Develop. 18 1 2010 20 31 https://doi.org/https://doi.org/10.1002/sd.394	0	PMC9747204	NO-CC CODE	2022-12-15 23:21:59	no	Curr Res Ecol Soc Psychol. 2022 Apr 27; 3:100045	utf-8	Curr Res Ecol Soc Psychol	2,022	10.1016/j.cresp.2022.100045	oa_other
==== Front Asian J Psychiatr Asian J Psychiatr Asian Journal of Psychiatry 1876-2018 1876-2026 Elsevier B.V. S1876-2018(22)00409-9 10.1016/j.ajp.2022.103411 103411 Article COVID-19 vaccine-related psychiatric adverse events: correspondence Sookaromdee Pathum a⁎ Wiwanitkit Viroj b a Private Academic Consultant, Bangkok Thailand b Honorary professor, Dr DY Patil Vidhyapeeth, Pune, India ⁎ Corresponding author. 14 12 2022 14 12 2022 10341120 11 2022 7 12 2022 12 12 2022 © 2022 Elsevier B.V. All rights reserved. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcDear Editor, we would like to share ideas “COVID-19 vaccine-related psychiatric adverse events: Mechanisms and considerations (Mopuru and Menon, 2022).” According to Mopuru and Menon (2022), the observed correlation between COVID-19 vaccines and unfavorable psychiatric reactions may be explained by mechanisms such as vaccine-triggered proinflammatory response, autoimmune encephalitis, stress, and inhibition of psychotropic metabolism leading to cessation of treatment (Mopuru and Menon, 2022). Because it is impossible to establish a causal connection between the two given the uncontrolled nature of the available observations, Mopuru and Menon noted that these reports should not be used as justification for avoiding getting the COVID-19 vaccine (Mopuru and Menon, 2022). We both believe that the potential for psychiatric side effects from the COVID-19 vaccination exists. It's critical to rule out any previous asymptomatic episodes because COVID-19 is a common clinical entity (Joob and Wiwanitkit, 2020) that can be difficult to diagnose from a clinical history. In a crisis, it can be challenging to provide mental health care, as Rohanachandra (2022) pointed out. The diagnosis and therapeutic management may be impacted by a number of circumstances. The ability to identify the issue is actually a crucial quality that a practitioner must possess (Patra, 2022). The immune response to the COVID-19 vaccine is affected by genetic factors (Chen et al., 2022). More prospective studies that can account for confounding factors ought to be conducted. Acknowledgement none Financial disclosure noe Conflict of interest None ==== Refs References Chen D.P. Wen Y.H. Lin W.T. Hsu F.P. Association between the side effect induced by COVID-19 vaccines and the immune regulatory gene polymorphism Front Immunol 13 2022 Oct 26 941497 Joob B. Wiwanitkit V. Letter to the Editor: Coronavirus Disease 2019 (COVID-19), Infectivity, and the Incubation Period. J Prev Med Public Health. ;53 2020 70 Mar Mopuru R. Menon V. COVID-19 vaccine-related psychiatric adverse events: Mechanisms and considerations Asian J Psychiatr. 2022 Nov 12;79:103329. doi: 10.1016/j.ajp.2022.103329. Online ahead of print. Patra S. Competency-based child and adolescent psychiatry curriculum for Indian medical graduates: Need of the hour Jun Asian J Psychiatr 72 2022 103150 10.1016/j.ajp.2022.103150 Rohanachandra Y.M. Impact of economic crisis on child and adolescent mental health services (CAMHS): Experience from Sri Lanka Dec Asian J Psychiatr 78 2022 103288 10.1016/j.ajp.2022.103288	0	PMC9747226	NO-CC CODE	2022-12-15 23:22:53	no	Asian J Psychiatr. 2022 Dec 14;:103411	utf-8	Asian J Psychiatr	2,022	10.1016/j.ajp.2022.103411	oa_other
==== Front J Microbiol Immunol Infect J Microbiol Immunol Infect Journal of Microbiology, Immunology, and Infection 1684-1182 1995-9133 Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. S1684-1182(22)00283-3 10.1016/j.jmii.2022.12.002 Review Article COVID-19-associated candidiasis and the emerging concern of Candida auris infections Tsai Chin-Shiang abcd Lee Susan Shin-Jung ef Chen Wan-Chen g Tseng Chien-Hao h Lee Nan-Yao cdi Chen Po-Lin cdi Li Ming-Chi cdi Syue Ling-Shan cd Lo Ching-Lung cd Ko Wen-Chien ci∗ Hung Yuan-Pin ijk∗∗ a Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan b Department of Internal Medicine, National Cheng Kung University Hospital, Dou-Liou Branch, College of Medicine, National Cheng Kung University, Yunlin, Taiwan c Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan d Center for Infection Control, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan e School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan f Division of Infectious Disease, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan g Department of Pediatrics, Changhua Christian Children's Hospital, Changhua City, Taiwan h Division of Infectious Diseases, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan i Department of Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan j Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan k Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan ∗ Corresponding author. Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, Tainan, Taiwan ∗∗ Corresponding author. Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare, Tainan, 700, Taiwan 14 12 2022 14 12 2022 31 5 2022 28 9 2022 4 12 2022 © 2022 Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. The incidence of COVID-19-associated candidiasis (CAC) is increasing, resulting in a grave outcome among hospitalized patients with COVID-19. The most alarming condition is the increasing incidence of multi-drug resistant Candida auris infections among patients with COVID-19 worldwide. The therapeutic strategy towards CAC caused by common Candida species, such as C. albicans, C. tropicalis, and C. glabrata, is similar to the pre-pandemic era. For non-critically ill patients or those with a low risk of azole resistance, fluconazole remains the drug of choice for candidemia. For critically ill patients, those with a history of recent azole exposure or with a high risk of fluconazole resistance, echinocandins are recommended as the first-line therapy. Several novel therapeutic agents alone or in combination with traditional antifungal agents for candidiasis are potential options in the future. However, for multidrug-resistant C. auris infection, only echinocandins are effective. Infection prevention and control policies, including strict isolation of the patients carrying C. auris and regular screening of non-affected patients, are suggested to prevent the spread of C. auris among patients with COVID-19. Whole-genome sequencing may be used to understand the epidemiology of healthcare-associated candidiasis and to better control and prevent these infections. Keywords Candidemia Candida albicans Candida auris fluconazole echinocandins COVID-19 infection ==== Body pmc	0	PMC9747227	NO-CC CODE	2022-12-15 23:21:59	no	J Microbiol Immunol Infect. 2022 Dec 14; doi: 10.1016/j.jmii.2022.12.002	utf-8	J Microbiol Immunol Infect	2,022	10.1016/j.jmii.2022.12.002	oa_other
==== Front Appl Nurs Res Appl Nurs Res Applied Nursing Research 0897-1897 1532-8201 Elsevier Inc. S0897-1897(22)00106-9 10.1016/j.apnr.2022.151664 151664 Article Fear of COVID-19 and social distancing on the health behavior of coronary heart disease patients Kim Kyungsook a Yu Jungok b⁎ a Dong-A University Hospital, Busan, Republic of Korea b College of Nursing, Dong-A University, Busan, Republic of Korea ⁎ Corresponding author. 13 12 2022 2 2023 13 12 2022 69 151664151664 15 8 2022 25 9 2022 6 12 2022 © 2022 Elsevier Inc. All rights reserved. 2022 Elsevier Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Purpose This study aimed to provide basic data to improve the health behavior of patients diagnosed with coronary artery disease during pandemics such as that caused by coronavirus disease 2019 (COVID-19) by identifying the fear of COVID-19 and the degree of social distancing behavior of coronary patients. Methods In this study, 162 patients diagnosed with coronary artery disease who received follow-up care at the cardiovascular center of Dong-A University Hospital in Busan were selected. The variables examined in this study included subjects' general characteristics and disease-related characteristics, fear of COVID 19, social distancing behavior, and health behavior. Data were collected from June 8–25, 2021, and data analysis was performed using the IBM SPSS26.0 program. Results The results showed that older participants, those who were religious, those with cohabitants, and those who showed better compliance with social distancing showed better health behavior practice. Factor with the greatest influence on the health behavior of patients with coronary artery disease was social distancing behavior (β = 0.299, p < .001). Conclusion After the COVID-19 pandemic, it is necessary to develop a health care program to promote the health behavior of high-risk patients, including coronary artery disease, in preparation for the COVID-19 era. The younger the patient, the fewer health activities are undertaken when living alone, so appropriate education and support for these individuals should increase the rate of implementation of health activities for coronary artery disease. Keywords Coronary artery disease Fear of COVID-19 Social distancing behavior Health behavior ==== Body pmc1 Introduction The World Health Organization, on March 11, 2020, declared the coronavirus disease 2019 (COVID-19) pandemic as the incidence and mortality of COVID-19 increased worldwide (World Health Organization, 2020). Many nations have implemented stringent social distancing policies to minimize the spread of COVID-19, and more people stayed at home for longer periods. Although patients with chronic diseases, including those with coronary artery disease (CAD), should make regular hospital visits to check their health condition and get prescriptions, planned hospital admissions and outpatient visits were canceled due to fear of infection of COVID-19 (Sokolski et al., 2021). CAD is the number one cause of death, disability, and human suffering globally (Khan et al., 2020). Due to the nature of the disease, patients with CAD are at high risk of recurrence and require continuous management (Meier & Timmis, 2012). Active health behavior of patients with CAD is essential to prevent the mortality and recurrence rates from increasing (Korea Center for Disease Control and Prevention Agency, 2021a, Korea Center for Disease Control and Prevention Agency, 2021b). Fear of COVID-19 positively affected infection prevention behavior, such as hand washing and social distancing (Harper et al., 2020). Fear of COVID-19 also negatively affected health behavior as smoking and drinking increased with higher fear of COVID-19 (Nguyen et al., 2020). Social distancing is an effective and key way to prevent COVID-19 infection (Painter & Qiu, 2021). One study showed that patients with illnesses complied more with social distancing than health professionals or the general public by postponing or canceling going out, gathering, or traveling and coming straight home after their business if they had to go out (Kim, 2020). However, people have suffered from mental health problems, such as psychological stress, anxiety, and depression due to social distancing (Brooks et al., 2020), and daily and physical activities decreased (Schuch et al., 2020). Isolation restrictions increased the intake of delivered food at home and led to irregular eating habits, increasing obesity (Ahmed, 2020). These are associated with an increased risk of cardiovascular diseases (Lavie et al., 2018). Health behaviors, such as quitting smoking, stopping drinking, physical activities, dietary control, and exercise for managing obesity and maintaining a healthy weight, reduce mortality and the risk of recurrence in patients with CAD. However, it is not known how the COVID-19 pandemic affects health behaviors in these patients. This study aimed to investigate how the fear of COVID-19 and social distancing behaviors affect health behaviors in patients with CAD. 2 Methods 2.1 Study design This was a cross-sectional study conducted in a single institution to identify the effects of fear of COVID-19 and social distancing behaviors on health behaviors in patients with CAD. 2.2 Participants The study included patients diagnosed with CAD and received follow-up at an outpatient clinic of the Cardiovascular center of Dong-A University Hospital located in Busan. The inclusion criteria included subjects: 1) aged ≥20 years; 2) diagnosed with angina or myocardial infarction per the International Classification of Disease, Tenth Revision; 3) who were receiving drug therapy or being followed at our outpatient clinic after percutaneous coronary intervention (PCI) or coronary artery bypass grafting; 4) who fully understood the purposes of the study and voluntarily agreed to participate in the study. The minimum sample size for multiple regression analysis was calculated to be 157, Using G*power software, considering the effect size (f) of 0.15, significance level (α) = 0.05, power = 0.90, and 12 variables. In the present study, 162 copies of a questionnaire were distributed. Since there were no missing answers, all 162 participants were included in the final analysis. 2.3 Measures Different measures were used to achieve the objectives of this study. These include the Fear of COVID-19, social distancing behaviors and cardiovascular-related health behaviors. 2.4 Fear of COVID-19 To assess fear of COVID-19, the Fear of COVID-19 Scale, which consists of a total of seven items and was developed by Ahorsu et al. (2020), was considered; we used its Korean version translated by Seong et al. (2020), and its validity and reliability were tested. Higher scores on this scale indicate a higher level of fear of COVID-19. Cronbach's α was 0.87 in a study by Seong et al. (2020), while Cronbach's α was 0.86 in the present study. 2.5 Social distancing behaviors To assess social distancing behaviors against COVID-19, a scale with 15 items, developed by Heo et al. (2021), was used. Higher scores indicate better compliance with social distancing behaviors against COVID-19. Reliability testing of the scale in a study by Heo et al. (2021) revealed a Cronbach's α of 0.91. In this study, Cronbach's α was 0.90. 2.6 Health behaviors To assess health behaviors, the Health Promoting Lifestyle Profile, first developed by Walker et al. (1987), was considered: we used its modified version with added cardiovascular-related health behaviors by Song et al. (2018). The scale comprises 21 items (health responsibility: five items; exercise: four; diet: six; stress management: three; and smoking: three), and higher scores indicate better compliance with health behaviors. Cronbach's α for this measure was 0.83 in the study by Song et al. (2018) and 0.85 in the present study. 2.7 Ethical considerations This study was conducted after approval by the Institutional Review Board of Dong-A University Hospital (DAUHIRB-21-119). 2.8 Data collection Data were collected from June 8 until 25, 2021. The study included patients being followed up for CAD at the outpatient clinic of our Cardiovascular Center. With the cooperation of responsible doctor and the nursing department, we described the purposes and methods of the study directly to the patients and obtained their consent to participate in the study. Participants completed the questionnaire while they were waiting for the doctor. It took approximately 10–20 min to complete the questionnaire. 2.9 Data analysis The collected data were analyzed as follows using the IBM SPSS 26.0 program. The frequency, percentage, mean, and standard deviation (SD) were used to analyze the participants' domographic and disease-related characteristics, fear of COVID-19, social distancing behaviors, and health behaviors. Differences in the level of fear of COVID-19, social distancing behaviors, and health behaviors by demographic and disease-related characteristics were analyzed by a t-test and an analysis of variance. Scheffe's test was used for posthoc testing. The correlation between fear of COVID-19, social distancing behaviors, and health behavior was analyzed using Pearson's correlation coefficient. A multiple regression analysis was performed to identify factors affecting participants' health behavior. 3 Results 3.1 Participants characteristics Participants' demographic and disease-related characteristics are summarized in Table 1 . A total of 162 participants (107 [66.0 %] men and 55 [34.0 %] women) engaged in this study and the average age was 66.9 (±12.23) years. Most participants (118 [72.8 %]) lived with a family, while 44 participants (27.2 %) lived alone. Regarding participants' vaccination status, 84 (51.9 %) were unvaccinated, while 78 (48.1 %) were vaccinated. 111 participants (68.5 %) were diagnosed with CAD 1 year ago or before.Table 1 Differences in health behaviors according to the participants' general characteristics (N = 162). Table 1Characteristics Categories n % COVID-19 fear Social distancing Health Behavior Mean ± SD t or F p Mean ± SD t or F p Mean ± SD t or F p 16.44 ± 5.84 65.38 ± 8.79 65.61 ± 9.71 Gender Male 107 66 15.28 ± 5.45 −3.64 <0.001 64.44 ± 9.12 −1.91 0.580 65.26 ± 9.72 1.19 0.236 Female 55 34 18.69 ± 5.95 67.21 ± 7.87 63.34 ± 9.67 Age (years) 20–40a 4 2.5 11.75 ± 5.50 0.77 0.380 56.25 ± 12.84 8.71 0.004 (b,c,d > a) 46.75 ± 5.05 9.23 0.003 (b,c,d > a) 41–60b 42 25.9 16.28 ± 5.46 63.59 ± 9.00 61.85 ± 9.75 61–80c 93 57.4 16.70 ± 6.09 65.79 ± 8.66 66.79 ± 9.05 81–90d 23 14.2 16.47 ± 5.84 68.60 ± 6.80 63.91 ± 8.59 Educational level None 5 3.1 17.60 ± 8.14 1.04 0.308 64.40 ± 7.40 3.65 0.580 55.20 ± 2.58 2.00 0.158 Elementary 23 14.2 16.82 ± 4.40 66.91 ± 8.22 62.91 ± 9.46 Middle school 31 19.1 17.48 ± 6.22 67.25 ± 9.13 66.00 ± 9.06 High school 59 36.4 15.94 ± 6.06 65.94 ± 7.85 65.06 ± 10.11 ≥College 44 27.2 16.04 ± 5.79 62.63 ± 9.82 64.97 ± 9.89 Living alone Yes 44 27.2 15.95 ± 6.82 0.65 0.516 64.88 ± 9390 0.44 0.658 61.72 ± 9.90 2.33 0.021 No 118 72.8 16.62 ± 5.45 65.57 ± 8.38 65.68 ± 9.46 Religion Yes 105 64.8 16.50 ± 5.88 −0.17 0.859 66.01 ± 8.70 −1.23 0.217 66.58 ± 9.50 −3.63 <0.001 No 57 35.2 16.33 ± 5.81 64.22 ± 8.92 60.98 ± 9.10 Occupation No 87 53.7 17.26 ± 5.83 1.81 0.071 67.17 ± 7.86 2.91 0.004 65.48 ± 8.26 5.68 0.213 Yes 75 46.3 15.60 ± 5.69 63.20 ± 9.41 63.51 ± 11.19 Monthly income (10,000 won) <100 53 32.7 17.58 ± 5.73 1.36 0.244 67.43 ± 7.09 7.41 0.007 62.73 ± 8.65 0.53 0.466 100–199 37 22.8 15.08 ± 5.25 66.21 ± 9.05 67.35 ± 10.21 200–299 35 21.6 17.00 ± 6.02 64.28 ± 10.14 64.37 ± 9.84 ≥300 37 22.8 15.44 ± 5.84 62.67 ± 8.87 64.78 ± 10.25 Covid-19 Vaccine Yes 78 48.1 16.69 ± 6.14 0.51 0.604 65.83 ± 8.34 1.62 0.537 65.97 ± 9.11 1.73 0.085 No 84 51.9 16.21 ± 5.57 64.97 ± 9.23 63.34 ± 10.13 Diagnosis (Months) <3 14 8.6 16.71 ± 5.63 0.58 0.447 67.71 ± 7.45 0.01 0.891 64.21 ± 11.28 0.50 0.478 3 ∼ 6 12 7.4 17.75 ± 5.83 64.58 ± 6.96 62.08 ± 11.04 6 ∼ 12 25 15.4 16.92 ± 5.13 62.84 ± 8.66 64.32 ± 11.16 >12 111 68.5 16.16 ± 6.05 65.75 ± 9.11 65.00 ± 9.10 Comorbidities Yes 71 43.8 14.97 ± 5.85 −2.89 0.005 64.09 ± 9.59 −1.65 0.990 63.98 ± 9.77 −0.72 0.471 No 91 56.2 17.59 ± 5.60 66.39 ± 8.03 65.09 ± 9.69 3.2 Level of fear of COVID-19, social distancing behaviors, and health behavior in patients with CAD In patients with CAD, the mean score for the level of fear of COVID-19 was 2.15 ± 1.10/5 points, while the mean score for social distancing behaviors was 4.35 ± 0.86/5 points. The mean score for health behavior was 3.07 ± 0.88/5 points. Among the sub-categories of health behavior, the highest score was 3.79 ± 0.46 points for smoking, followed by 3.18 ± 0.57 points for diet, 3.04 ± 0.66 points in health responsibility (health monitoring), 2.69 ± 0.79 for exercise, and 2.69 ± 0.71 points for stress management. 3.3 Differences in the level of fear of COVID-19, social distancing behaviors, and health behavior by general and disease-related characteristics In terms of differences in fear of COVID-19 by demographic and disease-related characteristics, gender and presence of comorbidities were found to be significantly influential factors. In terms of differences in social distancing behaviors by demographic and disease-related characteristics, age, occupation, and income were significantly influential factors. In terms of differences in health behavior by demographic and disease-related characteristics, age, living alone, and religion were significantly influential factors (Table 1). 3.4 Correlations between fear of COVID-19, social distancing behaviors, and health behavior Correlations between fear of COVID-19, social distancing behaviors, and health behavior in patients with CAD revealed that health behavior was positively correlated with social distancing behaviors. Fear of COVID-19 was not seen to be significantly correlated with either health behavior or social distancing behaviors (Table 2 ).Table 2 Correlation between the fear of COVID-19, social distancing behavior, and health behavior (N = 162). Table 2Variables Fear of COVID-19 r(p) Social distancing behavior r(p) Fear of COVID-19 Social distancing behavior 0.127 (0.106) Health behavior 0.001 (0.990) 0.366 (<0.001) 3.5 Factors affecting health behavior in patients with CAD The tolerance and variance inflation factor (VIF) were calculated to investigate factors affecting health behavior in patients with CAD to test collinearity among independent variables. The tolerance of each variable was 0.922–0.996 (≤1.0) and the VIF was 1.004–1.085 (≤10), indicating that there was no multicollinearity among independent variables. Since the Durbin Watson statistic was 2.019, indicating that autocorrelation did not exist, regression analysis results were reliable. The variable with the greatest influence on health behavior adherence in patients with CAD was social distancing behaviors, followed by religion, age, and living alone. The total explanatory power of the variables was 22.5 % (F = 12.67, p < .001, R2 = 0.244, Adjusted R2 = 0.225; Table 3 ).Table 3 Factors influencing health behaviors of patients with coronary artery disease (N = 162) Table 3 B SE β t p Social distancing behavior 0.330 0.079 0.299 4.16 <0.001 Religion (ref: no) 4.319 1.429 0.213 3.02 0.003 Age 0.135 0.057 0.170 2.34 0.020 Living alone (ref: no) −3.36 1.514 −0.155 −2.22 0.028 4 Discussion This study aimed to provide basic information for improving health behavior in patients with CAD in the COVID-19 pandemic by assessing the level of fear of COVID-19 and social distancing behavior and determining how the factors affect health behavior in patients with CAD. The mean score for the level of participants' fear of COVID-19 in this study was 2.15/5 points. The mean score was 3.54 in a study in healthy adults using the same scale (Seong et al., 2020), and it was 3.15 in a study in older adults aged ≥65 years (Kwon & Seong, 2021). The reason the mean fear of COVID-19 score reported in this study was lower than that from previous studies is that data were collected during the period when infection control was stable; and the number of daily confirmed COVID-19 cases was approximately 500 (Korea Center for Disease Control and Prevention Agency, 2021b) due to the government's successful quarantine response. This discrepancy may also be attributable to the fact that the study was conducted after COVID-19 vaccination began and before variants, such as the delta variant, emerged when participants' fear of COVID-19 was relatively mild. In a study on fear of COVID-19 by country (Lin et al., 2021), among 10 countries, the highest scores were reported in Iran, at 3.9 points, and the lowest score was reported in New Zealand, at 2.02 points. These results are deemed to be associated with infection control; the number of confirmed COVID-19 cases and the mortality rate were high in Iran with poor infection control measures, resulting in high fear of COVID-19, while the confirmed cases and mortality rates were low in New Zealand with good infection control measures. Since the 2015 Middle East Respiratory Syndrome outbreak, the Korean Government designated central and local hospitals specializing in infectious diseases, made the designation of temporary isolation facilities by city and province mandatory, and expanded the number of epidemiological investigation centers as part of the government's reform plan for effective countermeasures against novel infectious diseases (Ministry of Health and Welfare, 2015). With a high-quality medical system and countermeasures, the mortality rate due to COVID-19 was low in Korea, which might have contributed to the low levels of fear of COVID-19 in this study, similar to those seen in New Zealand. In terms of fear of COVID-19 according to participants' characteristics, women showed higher levels of fear of COVID-19 than men, consistent with the results of several previous studies (Kwon & Seong, 2021). In one study, since women were more likely than men to be psychologically vulnerable, women showed higher levels of stress, anxiety, depression, and sleep problems during the COVID-19 pandemic (Broche-Pérez et al., 2020), and fear of COVID-19 can be interpreted in the same context. Patients with co-morbidities (hypertension, diabetes and dyslipidemia) had higher levels of fear of COVID-19 than without comorbidities. The higher level of fear of COVID-19 may have resulted from information stating that patients with chronic diseases were more vulnerable to COVID-19 infection than the healthy population (Bae et al., 2021). The mean score for social distancing behaviors in participants in this study was 4.35/5 points. In a previous study, which used the same scale as in this study to assess social distancing behaviors in patients, healthy persons, and healthcare professionals (Heo et al., 2021), the mean scores were 4.61, 4.39, and 4.35 points in patients, healthcare professionals, and healthy individuals, respectively. Han and Choi (2021) reported that since social distancing behaviors are important to prevent the spread of infection during the pandemic period, Korea, with a strongly collectivist culture, may have adopted social distancing behaviors without resistance amid the COVID-19 pandemic. The high social distancing behavior score in this study was thought to result from such norms' effects on social distancing behaviors. The level of compliance with social distancing was relatively lower among younger participants with jobs and relatively high incomes. The level of compliance with social distancing in Korean adults assessed in a study (Han & Choi, 2021) is consistent with that in adults in North America and Europe assessed in a previous study (Coroiu et al., 2020). Since young people are more involved in social and economic activities than older adults, it is more difficult for them to comply with a code of conduct that promotes isolation. In this study, the participants' mean health behavior score was 3.07/4 points, similar to that in recent studies using the same scale to assess health behaviors in patients with CAD. The mean score was 3.13 in a study by Jeong (2021) and 2.92 in a study by Jung et al. (2021). Compliance is high regarding health behaviors related to smoking and eating habits in patients with CAD. However, compliance was low for health behaviors related to exercise, showing that exercise was not performed sufficiently or regularly. Education on the importance of exercise and continuous public relations and education for practicing exercise even during the COVID-19 pandemic are thought to be required to promote healthy behavior in patients with CAD. Health behavior according to participants' characteristics was significantly influenced by age, cohabitants, and religion. Fear of COVID-19 was not significantly correlated with health behavior, but social distancing behavior has the greatest impact on health behavior. Isolation due to social distancing promotes a decrease in daily activities, such as work, leisure activity, shopping, and walking (Schuch et al., 2020), and can cause obesity due to increased intake of delivered food and irregular eating habits (Ahmed, 2020). But, in this study, the level of practice of health behavior was higher as the level of compliance with social distancing behaviors was better, contrary to the results from previous studies. Individuals who attempt to willingly comply with health behavior, such as social distancing, during the epidemic are also willing to comply with other health behaviors for CAD. In a previous study assessing the significant effects of religion, religion was not clearly associated with health behavior in patients with CAD. However, in a study investigating the effects of religion in older adults on health-promoting behavior (Yi & Kim, 2016), regardless of the type of religion, those who attended any worship were more likely to better comply with health behavior than those without religion, supporting the results of this study. Participants with a spouse or child were found to practice better health behavior than those living alone. This is consistent with the results from a previous study (Jeong, 2021) and implies that family members' practical help and emotional support contribute to improving health-promoting behavior. Accordingly, specific and practical health-promoting policies and support for patients who live alone during the pandemic are required. This study has some limitations. First, this study collected the data for assessment after vaccination against COVID-19 began and before any viral variants emerged when the participants' fear of COVID-19 was relatively mild, which should be considered when interpreting the study results. Second, since participants in this study overcame their fear of COVID-19 and were willing to visit the hospital during the pandemic, we did not include those who could not visit the hospital. CAD patients who did not visit the hospital during the COVID-19 pandemic may have higher fear of COVID-19 than patients who visited the hospital, and the characteristics of diseases such as CAD severity scores may be different. Third, this study collected data about patients with CAD who visited the outpatient clinic of one university hospital, so the study findings cannot be generalized to explain the health behaviors of every patient with CAD. Therefore, future studies are required by expanding participants. Despite these study limitations, this study is significant in that it provides basic data to improve health behavior in patients with CAD during the COVID-19 pandemic by determining the level of fear of COVID-19 and compliance with social distancing in these patients and investigating how those variables affect health behavior. 5 Conclusion This study was conducted to provide basic data to improve health behavior in patients with CAD in pandemic situations, such as COVID-19, by determining the levels of fear of COVID-19 and compliance with social distancing and identifying how those variables affect health behaviors. The results showed that older participants, those who were religious, those with cohabitants, and those who showed better compliance with social distancing showed better health behavior practices. Based on this study's results, we would like to make the following suggestions: first, patients with CAD showed poorer health behaviors at younger ages and when living alone. For those patients, a program of appropriate education and support should be developed to improve their health behaviors. Second, since there is a lack of studies on the effects of fear of COVID-19 and social distancing behaviors on health behaviors in patients with CAD, repeated and expanded studies are required to elucidate this. Lastly, a health management program should be developed to promote health behaviors in patients with CAD, which is appropriate for the COVID-19 endemic era following the COVID-19 pandemic. Ethical considerations This study was conducted after approval by the Institutional Review Board of Dong-A University Hospital (DAUHIRB-21-119). CRediT authorship contribution statement K.S. Kim conceptualized and designed the study, designed the data collection instruments, collected data, draf- ted the initial manuscript, and reviewed and revised the manuscript. J.0.Yu assisted with design of the study and data collection instruments, drafted initial manuscript and reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. Declaration of competing interest There are no conflicts of interest to declare. Acknowledgments The authors would like to thank all patients who participated in this study. ==== Refs References Ahmed H.O. The impact of social distancing and self-isolation in the last corona COVID-19 outbreak on the body weight in sulaimani governorate-Kurdistan/Iraq, a prospective case series study Annals of Medicine and Surgery 59 2020 110 117 10.1016/j.amsu.2020.09.024 32963773 Ahorsu D.K. Lin C.Y. Imani V. Saffari M. Griffiths M.D. Pakpour A.H. The fear of COVID-19 scale: Development and initial validation International Journal of Mental Health and Addiction 20 2020 1 9 10.1007/s11469-020-00270-8 Bae S. Kim S.R. Kim M.N. Shim W.J. Park S.M. 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==== Front J Infect Public Health J Infect Public Health Journal of Infection and Public Health 1876-0341 1876-035X The Author(s). Published by Elsevier Ltd on behalf of King Saud Bin Abdulaziz University for Health Sciences. S1876-0341(22)00346-X 10.1016/j.jiph.2022.12.007 Original Article Analysis of SARS-CoV-2 Genomic Surveillance Data During the Delta and Omicron Waves at a Saudi Tertiary Referral Hospital Obeid D. ab Al-Qahtani A. ac Almaghrabi R. d Alghamdi S. e Alsanea M. a Alahideb B. a Almutairi S. e Alsuwairi F. a Al-Abdulkareem M. a Asiri M. a Alshukairi A. cf Alkahtany J. e Altamimi S. g Mutabagani M. g Althawadi S. g Alanzi F. ch Alhamlan F. acg⁎ a Department of Infection and Immunity, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia b Public Health laboratories, Public Health Authority, Riyadh, Saudi Arabia c College of Medicine, Alfaisal University, Riyadh, Saudi Arabia d Organ Transplant Center of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia e Infection Control & Hospital Epidemiology Department, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia f Department of Medicine, King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia g Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia h Paediatric Critical Care, Paediatric Department, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia ⁎ Corresponding author at: Department of Infection and Immunity, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia, Fax: 966 11 442 4519, 14 12 2022 14 12 2022 © 2022 The Author(s). Published by Elsevier Ltd on behalf of King Saud Bin Abdulaziz University for Health Sciences. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Background Studying the genomic evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may help determine outbreak clusters and virus transmission advantages to aid public health efforts during the pandemic. Thus, we tracked the evolution of SARS-CoV-2 by variant epidemiology, breakthrough infection, and patient characteristics as the virus spread during the Delta and Omicron waves. We also conducted phylogenetic analyses to assess modes of transmission. Methods Nasopharyngeal samples were collected from a cohort of 900 patients with positive polymerase chain reaction (PCR) test results confirming COVID-19 disease. Samples underwent real-time PCR detection using TaqPath assays. Sequencing was performed with Ion GeneStudio using the Ion AmpliSeq™ SARS-CoV-2 panel. Variant calling was performed with Torrent Suite™ on the Torrent Server. For phylogenetic analyses, the MAFFT tool was used for alignment and the maximum likelihood method with the IQ-TREE tool to build the phylogenetic tree. Data were analyzed using SAS statistical software. Analysis of variance or t tests were used to assess continuous variables, and χ2 tests were used to assess categorical variables. Univariate and multivariate logistic regression analyses were preformed to estimate odds ratios (ORs). Results The predominant variants in our cohort of 900 patients were non–variants of concern (11.1%), followed by Alpha (4.1%), Beta (5.6%), Delta (21.2%), and Omicron (58%). The Delta wave had more male than female cases (112 vs. 78), whereas the Omicron wave had more female than male cases (311 vs. 208). The oldest patients (mean age, 43.4 years) were infected with non–variants of concern; the youngest (mean age, 33.7 years), with Omicron. Younger patients were mostly unvaccinated, whereas elderly patients were mostly vaccinated, a statistically significant difference. The highest risk for breakthrough infection by age was for patients aged 30–39 years (OR=12.4, CI 95%: 6.6-23.2), followed by patients aged 40–49 years (OR=11.2, CI 95%: 6.1-23.1) and then 20–29 years (OR=8.2, CI 95%: 4.4-15.4). Phylogenetic analyses suggested the interaction of multiple cases related to outbreaks for breakthrough infections, healthcare workers, and intensive care unit admission. Conclusion The findings of this study highlighted several major public health ramifications, including the distribution of variants over a wide range of demographic and clinical variables and by vaccination status. Keywords COVID-19 Variant of Concern (VOC) Delta Omicron SARS-CoV-2 Genomic Surveillance Breakthrough Infections (BTI) ==== Body pmc1 Introduction Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The continued evolution of SARS-CoV-2, especially in regions with high levels of vaccination, highlights the importance of genomic surveillance. The ancestral virus strain emerged in Wuhan, China, and spread globally [1]. As of September 28, 2022, the total number of cases of COVID-19 infection worldwide exceeded 615 million, and the overall death toll was 6.5 million people [2]. Genetic changes in RNA viruses are common, even predicted, especially at the spike and receptor binding domain regions [3]. Those changes in SARS-CoV-2 may provide a natural selection advantage for variants that affect virus transmissibility, disease severity, immune escape, and therapeutic escape [4]. Since the pandemic started, the virus has been mutating slowly but steadily, with many variant sets classified as lineages. The World Health Organization has been monitoring and assessing the emerged lineages, classifying them according to their risk at a global public health level. The classified lineages are considered variants of interest or variants of concern (VOCs) so that their monitoring and research will be prioritized to build the best response to the pandemic [5]. The main lineages (VOCs) showing the biggest global threats include the Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529) variants. Most of those lineages started as a single community transmission that went on to compete with the extant dominant subtype. The Omicron variant, which has been the dominating lineage in 2022, has five classified subtypes, starting with BA.1, which emerged in South Africa during the 2021-2022 winter. Vaccination-based immunity is the most effective public health weapon against infectious diseases. Remarkably, during the COVID-19 pandemic, several vaccine types, including an RNA, a subunit, and a viral vector vaccine, were developed and tested within a year, preventing the death of 19.8–31.3 million people worldwide [6], [7]. The global challenge requiring more attention from public health authorities today is breakthrough infections (BTIs), which are increasing in countries with good vaccination coverage and vaccine accessibility. Inequality in COVID-19 vaccination accessibility due to limited resources and income is predicted to introduce immune escape variants [8]. According to the US Centers for Disease Control and Prevention, the definition of a BTI is infection with the virus that causes COVID-19 following vaccination with either a primary series or a primary series plus a booster [9]. These infections are a substantial concern in developed countries although many studies have shown lower disease severity, viral load, and death in this population than in the unvaccinated population [10], [11], [12]. The BTI rate was high when the Omicron variant first emerged because a two-dose vaccine elicited poor neutralization [13]. However, the addition of a booster vaccination was sufficient to obtain strong neutralization, which led to many health officials recommending it as a primary dose, especially in high-risk groups. The Omicron variant harbors 34 mutations in the spike gene, accounting for the virus's efficiency in infecting more cells than the other variants [14]. The highest numbers of BTIs have been found among people who are older or who have comorbidities regardless of their vaccination status [15], [16]. Another high-risk group is people who are immunocompromised. Chronic infections in such patients have driven significantly more SARS-CoV-2 genetic diversity, including the generation of mutations commonly found in VOCs [17]. Individuals who are unvaccinated, elderly, immunocompromised, or have comorbidities are most vulnerable to severe COVID-19 disease and have the highest potential to enable the emergence of new variants that may evolve to escape immunity. The genetic diversity of SARS-CoV-2 in Saudi Arabia has important global ramifications because the country hosts millions of Muslim pilgrims annually. In Saudi Arabia, the total number of COVID-19 cases has exceeded 816,000, with 9,300 deaths [2]. To date, 25.3 million people (72.6% of the population) in Saudi Arabia were fully vaccinated [2]. The genetic diversity of SARS-CoV-2 evolved during the implementation of public health actions [18]. In Saudi Arabia, the first cases were detected in February 2020, and the first appearance of the Alpha and Beta VOCs was in early 2021 [19]. Studying the genomic evolution of SARS-CoV-2 at the level of community transmission may identify outbreak clusters, transmission advantages, and high-risk groups. Examining the evolution of SARS-CoV-2 at a single location may identify host factors and clusters with considerable effects on viral transmissibility. In this study, we aimed to tracked the evolution of SARS-CoV-2 during the Delta and Omicron waves at a tertiary referral hospital in Riyadh, Saudi Arabia. This hospital offers primary and highly specialized inpatient and outpatient medical care for immunocompromised patients in Saudi Arabia, as it has advanced treatments for oncology, organ transplantation, and cardiovascular disease. Our objectives in this study were to (1) track variant epidemiology by clinical variables, (2) evaluate vaccination status and dose by patient demographic and clinical characteristics, (3) identify risk factors for BTIs and intensive care unit (ICU) admission, and (4) conduct phylogenetic and cluster formation analyses for outbreaks by BTI, ICU admission, and vaccination status. 2 Methods 2.1 Collection of samples and clinical and demographic data Samples were collected from 900 patients visiting the hospital with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 by using a nasopharyngeal swab. The positive samples were sent to us from the Molecular Virology Section of the Pathology and Laboratory Medicine Department at King Faisal Specialist Hospital and Research Centre. Electronic medical records containing deidentified patient data were obtained from the Infection Control and Hospital Epidemiology Department. Variables assessed included demographic characteristics, vaccination history, comorbidities, symptoms, laboratory reports, and ICU admission. The inclusion criteria included all samples received from April 2021 to January 2022 that passed quality control metrics of sample integrity to be processed and analyzed by next-generation sequencing. We excluded all samples with poor quality control metrics. 2.2 Sample preparation Nasopharyngeal samples (200 µL) underwent total nucleic acid RNA extraction using the MagMAX™ Viral/Pathogen II (MVP II) Nucleic Acid Isolation Kit. The RNA integrity was assessed using a Nanodrop system, with an accepted 260/280 ratio of approximately 2. Real-time PCR was performed targeting N (nucleocapsid), ORF1ab (open reading frame of 1ab), and S (spike) genes using TaqPath™ COVID-19 CE-IVD RT-PCR Kits by following the manufacturer's instructions. Real-time PCR was conducted using a 7500 Fast Real-Time PCR system and software (Applied Biosystems, California, USA). All samples positive for SARS-CoV-2 were converted to cDNA using SuperScript™ IV VILO™ Master Mix. 2.3 Sequencing and bioinformatics analysis We conducted next-generation sequencing using an Ion GeneStudio S5 System (Thermo Fisher Scientific, USA). The cDNAs were amplified using the Ion AmpliSeq™ SARS-CoV-2 Insight Research Assay by following the manufacturer's instructions. Amplified products were ligated with unique barcode adaptors using the Ion Xpress Barcode Adaptors 1-16 kit and purified with Agencourt AMPure XP Reagent (1.5×; Beckman Coulter, USA). Constructed libraries were normalized to 33 pM using nuclease-free water, and up to 16 libraries were equally pooled. Pooled libraries were used as a template input for emulsion PCR and enrichment of template-positive particles using the Ion Chef automated system with the Ion 510 & Ion 520 & Ion 530 Kit-Chef kit according to the manufacturer's instructions. Enriched template-positive ion sphere particles were loaded onto an Ion 530 chip, and sequencing was performed with an Ion GeneStudio using Ion S5 sequencer. The obtained data were primarily processed (base calling and quality, alignment, assembly, and variant calling) with Torrent Suite™ software on the Torrent Server, version 5.12. De novo assembly of the contigs was performed using the assembly Trinity plugin (v1.2.1), and consensus sequences of each sample were generated using the IRMA plugin (v1.2.1). Variant call files were analyzed using the COVID-19 SnpEff plugin to identify and annotate variants with public and private databases. 2.4 Phylogenetic analysis FASTA file names that we used were annotated to reflect patient information (sample identification, variant, month of infection, vaccinated or unvaccinated, healthcare worker [HCW] or not, and ICU admission or regular case). Sequences were then aligned against the reference (NC_045512.2) using the MAFFT (v 7.490) tool and 6merpair method to create a consensus alignment file [20]. For phylogenetic analyses, we used the maximum likelihood method with the IQ-TREE tool (v2.2.0-beta COVID-edition) [21]. We used the ModelFinder tool (within IQ-TREE) to select the best model for our samples, which was determined to be the TIM2+F+I nucleotide substitution model [22]. To visualize the phylogenetic trees, we used FigTree software (v1.4.4) (http://tree.bio.ed.ac.uk/software/figtree/). All generated sequences were submitted to the GISAID database. 2.5 Ethics approval and consent The Research Advisory Council (Clinical Research Committee) at King Faisal Specialist Hospital and Research Centre approved this study (RAC #220 0009) and granted a waiver for the requirement of obtaining informed consent owing to the use of deidentified samples. 2.6 Statistical analysis All collected data were stored and analyzed using SAS, version 9.4, and Prism, version 9.0 (GraphPad). Inferential and ‎descriptive statistics were conducted to study clinical variables. Analysis of variance or t tests were used to assess continuous variables, and χ2 tests were used to assess categorical variables. Univariate and multivariate logistic regression analyses were preformed to estimate the odds ratios (ORs) for BTIs and for ICU admission by patient clinical and demographic characteristics, and a global χ2 p-value is presented for each variable. All reported P-values were two-tailed and were considered to be statistically significant at <0.05. 3 Results 3.1 Patient demographic and clinical characteristics The mean (SD) age of 900 SARS-CoV-2–infected patients who contributed samples to this study was 36.6 (15.8) years; the youngest patient was 4 months of age, and the oldest patient was 102 years. Most patients were female (54.5%), Saudi (65.3%), and hospital employees (59%). Only 17 patients were infected prior to travel. Most patients (75%) received ≥1 dose of any available COVID-19 vaccine, including BNT162b2 (49.5%), ChAdOx1 (31.2%), and a mix of vaccines and other types (19.3%). Most BTI cases were detected after the second vaccine dose (50.5%), followed by after the first dose (45.6%) and after a booster (3.9%). Regarding comorbidities, 49.9% of patients had a previous clinical burden, 9.2% had hypertension, and 8.2% had diabetes mellitus. A total of 21 patients (2.7%) were admitted to the ICU. Using whole genome sequencing, we detected four lineages clustered into five groups: Alpha (B.1.1.7) (4.1%), Beta (B.1.351) (5.6%), Delta (B.1.617.2) (21.2%), and Omicron (B.1.1.529) (58%) variants, and non-VOCs (11.1%). No Gamma lineage cases were detected in this cohort. 3.2 Detected variants and lineages by patient demographic and clinical characteristics The first aim of this study was to track variant epidemiology by clinical variables. To that end, sample variants were called using the classification documentation of the World Health Organization (https://www.who.int/activities/tracking-SARS-CoV-2-variants) [5]. Fig. 1 A shows the timeline for the distribution of the variants detected in samples received from April 2021 to January 2022. The first cases were positive for non-VOCs, followed in the order presented herein by the Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), and Omicron (B.1.1.529) variants. This variant evolution was similar to that reported worldwide: non-VOC infections followed by other variants (Alpha, Beta), followed by the Delta wave in the summer of 2021, followed by the Omicron wave in winter of 2021–2022.Fig. 1 Distribution of SARS-CoV-2 variants over time, by age and by vaccination dose. A) Density plot showing the percentage of samples with each variant over time: the first cases detected were non-VOCs; Delta dominated from November to the end of December; and Omicron began dominating in January. B) Distribution of variants by age group. C) Distribution of variants by vaccination status and dose. Fig. 1 Table 1 shows the analysis of patient clinical and demographic data for each variant. A significant association was detected by gender, with more male than female patients infected with Delta, but more female than male patients infected with Omicron. The mean age differed significantly by variant, with the oldest patients infected with non-VOCs (mean age, 43.4 years), whereas the youngest patients were infected with Omicron (mean age, 33.7 years). Most non-VOC, Alpha, and Delta variant infections were in patients aged 30–39 years; most Beta variant infections were in patients aged 40–49 years; and most Omicron variant infections were in patients aged 20–29 years (Fig. 1 B). No association was detected by symptom although most asymptomatic patients were infected with the Omicron variant. ICU admission was significantly associated with variant type, with the highest ICU admissions for patients infected with Delta and non-VOCs. A significant association between variant type and comorbidity was also found. Patients with no comorbidity were infected mainly with non-VOC, Alpha, and Beta variants, whereas patients with comorbidities were infected mainly with Omicron. There was no association between variant type and hypertension or diabetes. There was also no association between variant type and vaccination status. However, a significant association was detected between variant type and vaccine type, with patients who received BNT162b2 and mixed vaccines infected primarily with the Omicron variant, and patients who received ChAdOx1 infected primarily with Delta. A significant association was also found between variant type and number of vaccine doses, with the Delta variant detected primarily in patients after one dose, and Omicron being most common after the second and booster doses (Fig. 1 C).Table 1 Demographic and clinical characteristics of 900 PCR-confirmed SARS-CoV-2–infected patients with genomic samples sequenced, by detected variant. Table 1Characteristica Variant, No. (%) of 900 samples P-Value Non-VOC (n=100,11.1%) Alpha (n=37,4.1%) Beta(n=50,5.6%) Delta(n=191,21.2%) Omicron (n=522,58%) Gender Male (n=407) 51(5.7) 15(1.7) 21(2.4) 112(12.5) 208(23.2) (0.0002)b Female (n=488) 48(5.4) 22(2.5) 29(3.2) 78(8.7) 311(34.8) Age (Mean, SD), years 43.4(15.5) 40.7(18.4) 35.9(14.7) 40.4(12.9) 33.7(16) (0.0001)b Age Group, years 0-19 (n=98) 1(0.1) 2(0.22) 6(0.7) 5(0.60) 84(9.4) (0.0001)b 20-29 (n=203) 16(1.8) 10(1.1) 13(1.5) 28(3.1) 136(15.2) 30-39 (n=251) 29(3.2) 11(1.2) 10(1.1) 67(3.1) 134(15.0) 40-49 (n=177) 21(2.3) 3(0.33) 14(1.6) 55(6.1) 84(9.4) 50-59 (n=102) 19(2.1) 7(0.8) 5(0.60) 20(2.2) 51(5.7) 60-102 (n=65) 13(1.5) 4(0.5) 2(0.2) 15(1.7) 31(3.5) Symptomatic Yes (n=825) 99(11) 35(3.9) 49(5.4) 182(20.2) 487(54.11) (0.140) No (n=48) 1(0.11) 2(0.22) 1(0.11) 9(1) 35(3.9) Intensive Care Unit Admittance Yes (n=21) 7(0.90) 0 1(0.13) 10(1.30) 3(0.40) (0.0001)b No (n=516) 42(5.4) 29(3.8) 38(4.9) 128(16.5) 516(66.7) Comorbidity Yes (n=359) 25(2.8) 4(0.44) 7(0.80) 47(5.2) 276(30.7) (0.0001)b No (n=540) 74(8.2) 33(3.70) 43(4.8) 144(16.0) 246(27.4) Diabetes Mellitus Status No (n=825) 90(10.0) 36(4.0) 49(5.5) 177(16.7) 473(52.6) (0.25) Yes (n=74) 9(1.0) 1(0.1) 1(0.1) 14(1.6) 49(5.5) Hypertension Status No (n=816) 90(10.0) 34(3.8) 49(5.5) 176(19.6) 467(52.0) (0.32) Yes (n=83) 9(1.0) 3(0.33) 1(0.11) 15(1.7) 55(6.1) CT Value Range High (n=100) 8(1.2) 5(0.7) 8(1.2) 20(2.9) 59(8.6) (0.0001) b Low (n=154) 13(1.9) 2(0.30) 8(1.2) 42(6.1) 89(13.0) Moderate (n=430) 14(2.1) 17(2.5) 14(2.1) 63(9.2) 322(47.1) Vaccination Status Vaccinated (n=584) 57(7.3) 23(2.9) 35(4.50) 146(18.8) 323(41.6) (0.22) Unvaccinated (n=193) 21(2.7) 10(1.3) 7(0.90) 36(4.6) 119(15.3) Type of Vaccine BNT162b2 (n=281) 23(4.1) 3(0.5) 14(2.5) 60(10.6) 181(31.9) (0.0001)b ChAdOx1 (n=177) 34(6.0) 16(2.8) 20(3.5) 83(14.6) 24(4.2) Mixture of vaccines and other types (n=110) 0 0 0 3(0.5) 107(18.8) Vaccine Breakthrough Post first dose (n=241) 53(10.0) 19(3.6) 30(5.7) 111(21.0) 28(5.3) (0.0001)b Post second dose (n=267) 2(0.40) 2(0.4) 5(1.0) 25(4.7) 233(44.1) Post Booster (n=21) 0 0 0 0 21(3.97) Abbreviations: PCR, polymerase chain reaction; VOC, variant of concern a Not all characteristics sum to 900 patients owing to missing data. b Denotes statistical significance at P < 0.05. 3.3 Vaccination status and dose by patient characteristic and clinical manifestation Our second aim was to evaluate vaccination status and dose by patient demographic and clinical characteristics ( Table 2). There was a significant difference by age: unvaccinated patients were younger (mean age, 33.4 years), and vaccinated patients were older (mean age, 37.3 years). No significant difference was detected for gender or for cycle threshold (Ct) by vaccination status, with the mean Ct for both vaccinated and unvaccinated patients approximately 23. A significant association was found between vaccination status and age group, with fewer vaccinated patients in the 0–19 years age group but more vaccinated patients in all other age groups. An association was also detected between vaccination status and nationality, with a low proportion of unvaccinated non-Saudi patients (2.4%). ICU admission was significantly associated with vaccination status, with unvaccinated patients having higher ICU admission than vaccinated patients (1.2% vs. 0.7%). Regarding comorbidities, among unvaccinated patients, a higher percentage had comorbid conditions (14%), whereas among vaccinated patients, most patients did not have comorbidities (52%). No significant association was found between vaccination status and patient symptom, diabetes, and hypertension.Table 2 Patient demographic and clinical characteristics by vaccination status and dose. Table 2Characteristica Vaccination Status(n=777, UNK=123) Breakthrough infection after vaccine dose (n=529, UNK=55) Unvaccinated(n=193,24.8%) Vaccinated (n=584,75.2%) (P-value) First dose (n=241,45.6%) Second dose(n=267, 50.5%) Booster (n=21,3.9%) (P-value) Age (mean, SD) years 33.4(20.3) 37.3(11.5) (0.0011) b 37.6(9.9) 36.9(12.3) 38.6(9.6) (0.022)b Ct (mean, SD) 23.9(6.2) 23.6(5.5) (0.57) 23.6(5.6) 23.4(5.4) 25(4.3) (0.45) Gender (n=773) Male (n=354) 84(10.9) 270(34.9) (0.56) 133(25.6) 99(19.0) 12(2.3) (0.0002)b Female (n=419) 107(13.8) 312(40.4) 106(20.4) 162(31.2) 8(1.5) Age Group (n=774) years (0-19) (n=67) 46(5.9) 21(2.7) (0.0001)b 2(0.4) 11(2.11) 0 (0.13) (20-29) (n=186) 39(5.0) 147(19.0) 57(10.9) 70(13.4) 3(0.6) (30-39) (n=233) 35(4.5) 198(25.6) 89(17.1) 90(17.2) 8(1.5) (40-49) (n=160) 25(3.2) 135(17.4) 62(11.9) 53(10.2) 8(1.5) (50-59) (n=87) 27(3.5) 60(7.8) 27(5.2) 26(3.9) 2(0.4) (60-102) (n=41) 18(2.3) 23(3.0) 3(0.60) 12(2.3) 1(0.2) Nationality (n=715) Saudi (n=438) 147(20.6) 291(38.7) (0.0001)b 142(28.9) 100(20.3) 11(2.2) (0.0001)b Non-Saudi (n=277) 17(2.4) 260(36.4) 90(18.3) 142(28.9) 7(1.4) Symptoms Observed (n=777) Asymptomatic (n=45) 10(1.3) 35(4.5) (0.67) 10(1.9) 16(3.1) 3(0.60) (0.11) Symptomatic (n=732) 183(23.6) 549(70.7) 230(44.1) 246(47.1) 17(3.3) ICU Admission (n=672) No (n=659) 167(24.9) 492(73.2) (0.0032)b 158(36.0) 258(58.8) 20(4.5) (0.54) Yes (n=13) 8(1.2) 5(0.7) 2(0.46) 1(0.2) 0 Comorbidity (n=777) No (n=488) 84(10.8) 404(52.0) (0.0001)b 221(42.3) 144(27.6) 14(2.7) (0.0001)b Yes (n=289) 109(14.0) 180(23.2) 19(3.6) 118(22.6) 6(1.2) Hypertension (n=777) No (n=707) 175(22.5) 532(68.5) (0.85) 234(44.8) 229(43.8) 19(3.6) (0.0001)b Yes (n=70) 18(2.3) 52(6.7) 6(1.2) 33(6.3) 1(0.2) Diabetes Mellitus (n=777) No (n=712) 175(22.5) 537(69.1) (0.57) 235(45) 232(44.4) 19(3.6) (0.0001)b Yes (n=65) 18(2.3) 47(6.1) 5(1.0) 30(5.6) 1(0.2) Ct Value Range (n=607) High (Ct>30) (n=86) 23(3.8) 63(10.4) (0.73) 28(7.0) 23(5.7) 3(0.8) (0.0002)b Low (20<Ct) (n=144) 33(5.4) 111(18.3) 46(11.4) 51(12.7) 4(1.0) Moderate (20-30) (n=377) 98(16.1) 279(46.0) 64(15.9) 172(42.8) 11(2.7) Ct indicates cycle threshold; ICU, intensive care unit; UNK, unknown. a Not all characteristics sum to 900 patients owing to missing data. b P values <0.05 considered statistically significant. We further investigated patient demographic and clinical characteristics among vaccinated patients with BTIs by the number of vaccine doses they received ( Table 2 ). Age was significantly associated with vaccine dose, with the oldest patients (mean age, 38.6 years) receiving a booster dose, and the youngest (mean age, 36.9 years) receiving a second dose. By Ct group classification, a significant difference was detected, with the group having a Ct value >30 composed mainly of patients receiving a single vaccine dose. A significant association was found for gender: BTIs were highest in male patients after the first and second doses, whereas BTIs were highest in female patients after the second dose. Nationality status was also significantly associated with BTIs. Many Saudi patients were infected after the first and second doses, whereas most non-Saudi patients were infected after the second dose. Although no significant association was found for ICU admission, no ICU cases were reported for patients with a booster dose. A significant association was found for comorbidity status. Most patients with comorbid conditions were infected after the second dose. For hypertension and diabetes, many patients were infected after the second dose, and only one patient with hypertension and one patient with diabetes were infected after a booster dose. 3.4 BTI and ICU admission risks by patient demographic and clinical characteristics Our third aim was to identify risk factors associated with BTIs and with ICU admission ( Table 3 ). We conducted binary/univariate logistic regression analysis to estimate ORs. For risk of BTI, a significant association was found by age group, with the highest odds found in the age group of 30–39 years (OR=12.4 CI 95%: 6.6-23.2), followed by 40–49 years (OR=11.2, CI 95%: 6.1-23.1), and 20–29 years (OR=8.2, CI 95%: 4.4-15.4). Higher risk of BTI was found for non-Saudi patients (OR=7.7, CI 95%: 4.6-13.1) compared with Saudi patients and for patients with no comorbidity history (OR=2.9, CI 95%: 2.1-4.1), but not for gender, Ct classification, hypertension, diabetes, or symptoms. Global multivariate analysis was conducted to calculate adjusted ORs (age and comorbidity as confounder variables). The analysis showed that the global model was significant, with higher risk of BTI among non-Saudi patients (OR=3.8, CI 95%: 1.8-8.4) and reduced risk for patients with no hypertension (OR=0.06, CI 95%: 0.005-0.77).Table 3 Estimated odds of ICU admission and breakthrough COVID-19 infection by patient demographic and clinical characteristics. Table 3Characteristic Breakthrough infection ICU Admission OR (95% CI) (P-value) AOR (95% CI) Global (P-value) OR (95% CI) (P-value) AOR (95% CI) Global (P-value) Gender Male 1 (0.56) 1 (0.0013)a 1 (0.1) 1 (0.055) Female 0.91(0.7-1.3) 1.0(0.58-1.9) 0.48(0.19-1.17) 0.18(0.016-2.04) Age Group, years (0-19) 1 (0.0001)a b 1 (0.0001)a b (20-29) 8.2(4.4-15.4) NA (30-39) 12.4(6.6-23.2) 2.4(0.27-20.4) (40-49) 11.2(6.1-23.1) 2.5(0.27-22.6) (50-59) 4.9(2.4-9.7) 2.4(0.2-26.7) (60-102) 2.8(1.3-6.3) 17.3(2.1-140.2) Nationality Non-Saudi 7.7(4.6-13.1) (0.0001)a 3.8(1.75-8.4) NA NA NA Saudi 1 1 NA NA Ct Value Range High 1 (0.72) 1 0.62(0.1-5.1) (0.83) 1.6(0.11-22.8) Low 1.2(0.66-2.3) 0.90(0.36-2.3) 1.2(0.31-4.7) 1.4(0.1-16.9) Moderate 1.0(0.6-1.8) 1.3(0.56-2.9) 1 1 Hypertension No 1.1(0.6-1.8) (0.85) 0.06(0.005-0.77) 0.17(0.07-0.42) (0.0001)a NA Yes 1 1 1 Diabetes Mellitus No 1.2(0.65-2.1) (0.58) 5.7(0.53-65) 0.12(0.05-0.31) (0.0001)a NA Yes 1 1 1 Comorbidity (0.001)a b NA b No 2.9(2.1-4.1) NA Yes 1 NA Symptoms (0.67) Asymptomatic 1.2(0.56-2.4) 2.3(0.66-7.8) NA NA NA Symptomatic 1 1 NA CI indicates confidence interval; Ct, cycle threshold, OR, odds ratio; AOR, adjusted odds ratio; ICU, intensive care unit; and NA, data not available and not included in statistical analysis. a P values <0.05 considered statistically significant. b AOR calculated from multivariate analysis using age and comorbidity as confounders. For risk of ICU admission, a significant association was found by age group, with the highest odds found in the age group 60–102 years (OR=17.3 CI 95%: 2.1-140.2). Lower risk of ICU admission was found for patients without hypertension (OR=0.17, CI 95%: 0.07-0.42) and for patients without diabetes (OR=0.12, CI 95%: 0.05-0.31). There was no significant risk of ICU admission by gender or Ct classification. All admitted ICU patients were Saudi, all had comorbidities, and all presented with symptoms. Global multivariate analysis was conducted to calculate adjusted ORs, with age and comorbidity as confounder variables. The analysis showed that the global model was not significant after adjusting for the confounders. 3.5 Variants in the spike gene by patient demographic and clinical characteristics and by vaccination status and dose Samples with good quality and coverage for variant calling were analysed by patient characteristics. The main spike variants detected with high frequency in our cohort were H69del, Y144del, K417N, N440K, L452R, S477N, T478K, E484K, N501Y, D614G, and P681R ( Fig. 2 ). The variants with the highest frequencies were D614G (82.6%), T478K (61.6%), K417N (55.6%), H69del (55.1%), and N440K (50.9%). The least frequent variants were E484K (7.2%), Y144del (19.9%), and P681R (23.1%).Fig. 2 Heatmap showing spike variants by patient demographic and clinical characteristics. Heatmap columns represent detected variants, and rows represent the indicated characteristic. The frequency of each variant is shown in each square according to the color gradient given in the key, with purple being the lowest frequency and yellow being the highest. Fig. 2 A summary of each variant by patient demographic and clinical characteristics and by vaccination status and dose is given in Supplementary Table S1. Our analysis by age indicated that all but two spike variants were found in younger patients. Variants H69del, K417N, N440K, S477N and N501Y (Group A) were found primarily in younger patients (P<0.05), whereas, L452R and P681R (Group B) were found primarily in older patients (P<0.05). Group A variants had higher odds of being found in female patients, whereas group B variants showed lower odds. Group A variants were detected mostly in Saudi patients, and group B variants were detected mostly in non-Saudi patients. The highest viral load (i.e., lowest Ct) was found in patients with H69del, K417N, and D614G variants, and the lowest viral load (i.e., highest Ct) was found in patients with E484K, and N501Y variants. Only three variants were significantly associated with vaccination status. Variant N440K was found primarily in unvaccinated patients (OR=1.5, 95% CI 1.1-2.1), whereas L452R (OR=1.6, 95% CI 1.1-2.4) and P681R (OR=1.9, 95% CI 1.1-3.1) were found primarily in vaccinated patients. Our analysis by vaccination dose indicated that after a booster shot, L452R, E484K, P681R were not detected in any patient. After the second dose, all variants except L452R, P681R, and E484K were associated with higher risk for BTI. 3.6 Phylogenetic analysis in outbreaks The fourth aim of this study was to conduct phylogenetic and cluster formation analyses for outbreaks by BTI, ICU admission, and vaccination status. Fig. 3 shows the phylogenetic tree generated using the TIM2+F+I substitution model. The analysis was conducted to reveal any patient interaction with multiple patient groups in nosocomial outbreaks. The tree differentiates into two major nodes: one node with Delta samples and the other with mostly Omicron samples. The first cluster (highlighted in light red in Fig. 3) indicated an outbreak in the hospital involving three ICU cases with four HCWs and seven unvaccinated individuals. The next cluster (highlighted in light brown) is divided into three main branches, with cases involving HCWs and regular cases detected in January. The third main cluster (highlighted in light green) starts with vaccinated HCWs and a regular case, and then branches into nine outbreaks. The next cluster (highlighted in Tiffany-blue) includes 7 HCWs, of which 3 were unvaccinated. The next cluster (highlighted in lavender) has two main branches. Of the five patients in the first branch, three were HCWs; of the 18 patients in branch B, 13 were HCWs. The second branch also shows HCW-HCW transmission as well as HCW-regular case transmission. In the next cluster (highlighted in light violet) of 23 patients, the first group has two regular cases that were vaccinated patients and a single HCW case, followed by the second group, which has mostly regular cases of vaccinated individuals. The second group has the most regular case to regular case transmission between vaccinated individuals. The next clusters (highlighted in light pink) branch from the same node to give rise to eight minor nodes. The first nodes have a couple of HCW-HCW transmissions giving rise to other clusters and cases related to vaccinated regular case to regular case transmission. The later nodes in the same cluster also involve 18 unvaccinated patients, which was the highest number across all other clusters. The last cluster in this analysis (highlighted in yellow) has more than 16 minor nodes within the same cluster. The cluster begins with a vaccinated HCW, who gives rise to multiple outbreaks of HCW-HCW transmissions and regular case to HCW transmissions; the majority of the cases in this cluster were vaccinated, with only 18 unvaccinated patients.Fig. 3 Phylogenetic analysis of transmission in a single center. The sequences shown in the figure are annotated to reflect patient data: sample ID, variant, month of infection, vaccinated (V) or unvaccinated (UV), healthcare worker (HCW) or not (N), and intensive care unit (ICU) or (R) regular case. Overall, there were 8 main clusters using the TIM2+F+I model. Fig. 3 To further investigate clusters, we conducted the analysis again using the IQ-TREE-2 tool but with the TIM2+F+I model. The visualized model is shown in Fig. 4. The total cluster with 21 patients has 2 major nodes: one node has the most cases (red); the other node has only three cases (yellow). The first minor node (yellow) has a total of three patients carrying the Delta variant, of whom two were vaccinated and none was an HCW. The second minor node (red and purple) has 18 patients comprising three ICU cases, five unvaccinated patients, and four HCWs. ICU case sample number 161 was closely related to case sample number 40, which was an unvaccinated patient. The second ICU case, sample number 50, was very close to HCW case sample number 69 and to unvaccinated case sample number 550. The third ICU case, sample number 28, was related closely to a vaccinated patient (sample number 48), who was not an HCW. Overall, Our analysis highlights the interactions among multiple cases associated with nosocomial outbreaks for ICU cases, unvaccinated individuals, and HCWs.Fig. 4 Phylogenetic analysis for outbreaks including ICU patients. The sequences shown in the figure were annotated to reflect patient data: sample ID, variant, month of infection, vaccinated (V) or unvaccinated (UV), healthcare worker (HCW) or not (N), and intensive care unit (ICU) or (R) regular case. Overall, there were 21 patients, and the estimated tree was constructed using the TIM2+F+I model. The estimated branch length is shown in each node. Fig. 4 4 Discussion The outcome of this study showed the SARS-CoV-2 community transmission and genomic evolution during the Delta and Omicron waves at a tertiary hospital in Saudi Arabia. We were able to track variant epidemiology by clinical variables, evaluate vaccination status and dose by patient demographic and clinical characteristics, identify risk factors for BTIs and ICU admission, and conduct phylogenetic analysis and cluster formation for outbreaks by patient group. Variant distributions by patient demographic and clinical characteristics were significantly different in our cohort. By gender, the Delta wave had more male than female cases, whereas more female than male cases were detected in the Omicron wave. The oldest patients were infected with non-VOCs, whereas the youngest cases were infected with Omicron strains. Another study comparing Delta and Omicron waves conducted in France also observed Omicron infections predominantly in younger, female, and vaccinated patients [23]. That study also noted that compared with Delta infection, Omicron infection was independently associated with lower risk for ICU admission, mechanical ventilation, and in-hospital admission. Similar observations have been reported in many other countries, including the United States, Denmark, Qatar, and England, suggesting that the Omicron wave is associated with less disease severity than the Delta wave [22], [23], [24], [25]. However, a comparison of the vaccination coverage indicated that the Omicron wave infected populations with higher vaccination coverage than the Delta wave. Vaccination remains one of the most critical factors in COVID-19 disease severity. Interestingly, on the basis of the findings in our cohort, the Delta and Omicron waves in the Saudi population showed significantly different patient characteristics and disease severity. However, the comparison of severity may be biased because during the Omicron wave, the population had a higher percentage of vaccine coverage, reaching 70% in 2022. In our cohort, younger patients were mainly unvaccinated, whereas elderly patients were mostly vaccinated; this difference was statistically significant. The highest risk for BTIs by age in our cohort was found in the group 30–39 years of age, followed by 40–49 years and 20–29 years. This risk profile may be explained in part by the Saudi government's vaccination priority list, which opened first for elderly and high-risk groups. Similar results for BTIs were also observed in a population in the United States [24]. ICU admission was significantly associated with vaccination status, with the highest ICU admissions reported for unvaccinated patients, and no ICU cases reported among individuals who received a booster. Other studies have also found that patients with boosters were more protected than unvaccinated patients and patients who received only two vaccine doses; this association was found for both Omicron and Delta variants [28]. The BTIs among hospitalized patients tend to be in elderly individuals with comorbidities [29]. Additionally, the higher risk for Omicron infection suggests less protection against the Omicron than the Delta variant. Although the many variants of Omicron make the virus efficient and able to cause BTIs, most Omicron cases were associated with fewer deaths and lower hospital admission rates [30]. The variants most frequently detected in our cohort were D614G (82.6%), followed by T478K (61.6%), and K417N (55.6%). In our previous work, we also reported a high percentage of D614G variants in a Saudi population with a higher risk of hospital admission [18] . In the present study, we observed variant sets that were associated with specific patient characteristics. For example, the H69del, K417N, N440K, S477N, and N501Y variants were primarily found in younger, female, and Saudi (vs. non-Saudi) patients. By contrast, L452R and P681R variants were mostly found in elderly, male, and non-Saudi patients. The highest viral load was found in patients with H69del, K417N, and D614G variants. Most BTI cases in our cohort had either the L452R or P681R variant. No samples with variants H69del, L452R, E484K, P681R, and D614G were from patients who received a booster dose. This finding indicates that receipt of a booster vaccine in our cohort was effective against variants that harbor those mutations. The results from other studies have indicated that spike variants N501Y and H69del increase disease severity and virus transmissibility [31], and that the L452R variant increases virus infectivity and is associated with escape from neutralizing antibodies [32]. Several variants found in Omicron (i.e., H69del, Y144del, K417N, T478K, N501Y, D614G, and P681R) have been linked to immune escape elicited by previous infection or vaccine [33]. Our phylogenetic analysis highlighted the interactions among multiple cases associated with outbreaks for BTIs, ICU admission, and HCWs. We identified eight distinctive clusters. The first cluster included all the Delta cases and had all the ICU admission cases. In this outbreak, most ICU cases were closely related to unvaccinated individuals. Most HCW outbreaks were found in clusters, primarily evolving through HCW-HCW transmission that then moved to other individuals. Unvaccinated patients also significantly transmitted the virus by regular case-to-unvaccinated transmission, HCW-to-vaccinated transmission, and unvaccinated-to-unvaccinated transmission. In a large meta-analysis study that included 230,398 HCWs, the estimated prevalence of SARS-CoV-2 infection was 11% [34]. The most frequently affected personnel were nurses working in hospitalization/non-emergency wards during the screening phase. Another study that evaluated suspected risk factors for outbreaks among HCW staff recognized a higher risk of failing to use personnel protective equipment while caring for patients with COVID-19 infection [35]. HCW transmission to hospitalized patients caused approximately a fifth of identified cases among hospitalized patients with COVID-19 in the “first wave” in England [36]. In many countries, current surveillance underestimates the strength of outbreaks [37]. Using modeling, one study found that exposure to an infectious patient with hospital-acquired SARS-CoV-2 or to an infectious HCW was associated with an additional 0.8 infections per 1,000 susceptible HCWs per day [38]. By contrast, exposure to an infectious patient with community-acquired SARS-CoV-2 was associated with less than half the reported risk. These results indicate the importance of genomic surveillance in health care setting to limit community-acquired SARS-CoV-2 infections. 5 Study Limitations A key limitation in our study was that we did not conduct epidemiological/tracing interviews to confirm the transmission modes and whether the infections among HCWs were acquired in the hospital or community. Samples sizes for the analysis of patient distribution by variant was not equal, which could bias our results due to having more vaccinated Omicron cases than others. Future studies assessing additional data on HCW roles and their interaction with patients would enhance hospital infection control procedures. In our future work to further investigate virus evolution, we plan to conduct genomic surveillance at the hospital alongside epidemiologic interviews to create a phylogenetic database that links patients involved in outbreaks. 6 Conclusions To the best of our knowledge, this is the largest SARS-CoV-2 genomic surveillance study conducted in the region. Our findings on the distribution of Delta and Omicron variants across patient demographic and clinical characteristics and by vaccination status have several important public health implications. Our cohort included many BTIs, enabling investigation of the genomic evolution of the virus. Our data highlight the importance of vaccination, especially to reduce the severity of COIVD-19 disease. These results emphasize the importance of genomic surveillance for infectious diseases, especially in healthcare settings. Ethics approval The study protocol was approved by The Research Advisory Council (Clinical Research Committee) (RAC #220 0009). Funding This work was supported by King Faisal Specialist Hospital and Research Centre grant number 220 0009, 2020]. Competing interests The authors declare that the research was conducted in the absence of any potential conflict of interest. Uncited references [26]; [27] Appendix A Supplementary material Supplementary material Data availability The data and codes used in this study are available upon request. In addition, the SARS-CoV-2 sequences are deposited in GISAID website. Appendix A Supplementary data associated with this article can be found in the online version at doi:10.1016/j.jiph.2022.12.007. ==== Refs References 1 Zhou P. Yang X.-L. Wang X.-G. Hu B. Zhang L. Zhang W. 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==== Front Comput Biol Med Comput Biol Med Computers in Biology and Medicine 0010-4825 1879-0534 Elsevier Ltd. S0010-4825(22)00972-6 10.1016/j.compbiomed.2022.106264 106264 Article TEMPO: A transformer-based mutation prediction framework for SARS-CoV-2 evolution Zhou Binbin ad1 Zhou Hang ab1 Zhang Xue c Xu Xiaobin c Chai Yi g Zheng Zengwei ad Kot Alex Chichung h Zhou Zhan cef∗ a Department of Computer Science and Computing, Zhejiang University City College, No. 48 Huzhou Street, Hangzhou, 310015, China b College of Computer Science and Technology, Zhejiang University, Hangzhou, 310027, China c Innovation Institute for Artificial Intelligence in Medicine and Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China d Industry Brain Institute, Zhejiang University City College, Hangzhou, 310015, China e The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, 322000, China f Alibaba-Zhejiang University Joint Research Center of Future Digital Healthcare, Hangzhou, 310058, China g ZJU-UoE Institute, Zhejiang University, Haining, 314400, China h School of Electrical and Electronic Engineering, Nanyang Technological University, 639798, Singapore ∗ Corresponding author. Innovation Institute for Artificial Intelligence in Medicine and Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. 1 These authors have contributed equally to this work. 14 12 2022 14 12 2022 10626418 9 2022 16 10 2022 30 10 2022 © 2022 Elsevier Ltd. All rights reserved. 2022 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. The widespread of SARS-CoV-2 presents a significant threat to human society, as well as public health and economic development. Extensive efforts have been undertaken to battle against the pandemic, whereas effective approaches such as vaccination would be weakened by the continuous mutations, leading to considerable attention being attracted to the mutation prediction. However, most previous studies lack attention to phylogenetics. In this paper, we propose a novel and effective model TEMPO for predicting the mutation of SARS-CoV-2 evolution. Specifically, we design a phylogenetic tree-based sampling method to generate sequence evolution data. Then, a transformer-based model is presented for the site mutation prediction after learning the high-level representation of these sequence data. We conduct experiments to verify the effectiveness of TEMPO, leveraging a large-scale SARS-CoV- 2 dataset. Experimental results show that TEMPO is effective for mutation prediction of SARS- CoV-2 evolution and outperforms several state-of-the-art baseline methods. We further perform mutation prediction experiments of other infectious viruses, to explore the feasibility and robustness of TEMPO, and experimental results verify its superiority. The codes and datasets are freely available at https://github.com/ZJUDataIntelligence/TEMPO. Keywords SARS-CoV-2 Viral evolution Natural language processing transformer-based method phylogenetic tree Mutation prediction ==== Body pmc1 Introduction Since the first report of coronavirus disease (COVID-19) in late December 2019, which was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), more than 600 million infection cases have been reported from more than 200 countries or regions around the world, according to the World Health Organization (WHO) [1]. The widespread of SARS-CoV-2 presents a significant threat to human life, as well as public health and economic development, over 6.48 million lives have been lost in the COVID-19 outbreak and unquantifiable economic losses up to July 2022 [2]. Extensive efforts have been put out and implemented to battle against the pandemic, including the development of pharmaceutical interventions, such as drugs, antibodies, and vaccines, as well as non-pharmaceutical approaches, such as quarantine and keeping a physical distance [[3], [4], [5], [6], [7], [8]]. Vaccination has been widely used as a public anti-epidemic strategy since it has been proven to be a promising approach. However, the efficacy of current vaccines would be diminished by the emerging SARS-CoV-2 variants. With the spread of the pandemic, SARS-CoV-2 has continued to evolve and mutate, with an increasing number of mutations arising. According to the RCoV19 dataset [9], the variation frequency of the medium value of SARS-CoV-2 reached 0.264% and more than 1851 lineages [10] have emerged up to July 2022. The mutations will make it more difficult for the virus to be identified by human antibody-mediated vaccinations, which will either render the vaccines ineffective or inhibit diagnostic detection [[11], [12], [13], [14], [15]]. Tracking the evolution of SARS-CoV-2 could provide a thorough insight into viral evolution dynamics and early detection of variants of concern (VOCs). Virus evolution is primarily driven by mutations, both genetically and antigenically. Bai et al. successfully forecasted that some certain mutations of the spike protein at N501 may result in a stronger binding of angiotensin converting enzyme 2 (ACE2), prior to the emergence of the UK mutant (SARS-CoV-2 VOC 202012/01) on December 1, 2020 [16]. Starr et al. investigated the impact of amino acid mutations to the receptor binding domain (RBD) on the expression of folded protein as well as its affinity for ACE2, and showed that the N501Y mutation in the Alpha variant strengthens binding to ACE2 [17]. Tegally et al. presented a new lineage of the Beta variant of SARS-CoV-2 with three residues in the binding site (K417 N, E484K and N501Y), which has spread incredibly quickly and become one dominant lineage in a few weeks [18]. Similar to the B.1.351 variant, the Gamma variant, which possesses independent K417T, E484K and N501Y mutations, is quickly spreading over regions [12]. The fast spread of the Delta variant (B.1.617.2) that exploded in early 2021 was investigated, and the results revealed that it was caused by the evasion of antibodies, growing activity, and higher transmissibility [19,20]. Accurate and efficient prediction of genetic mutations of the SARS-CoV-2 has attracted significant attention, which could contribute to better identifying vulnerabilities for antibody-based treatments, vaccines, and diagnostics, as well as increasing the window of opportunity for developing proactive responses [[21], [22], [23], [24]]. With the advent of highthroughput technologies and the availability of massive sequence data, numerous computational models for viral evolution have been developed in recent years. Xia et al. designed a statistical mutual information-based approach to calculate the variance correlations of sites, and used the most recently mutated sites to infer the future most probable mutated sites [25]. Bai et al. evaluated the free energy change of different kinds of single site or combinedsite mutations and predicted possible mutation sites [26]. Yin et al. modeled the temporal sequence of sites and employed a long short-term memory (LSTM) model with an attention mechanism to predict mutations at each single target site [27]. Maher et al. predicted the possible mutations in SARS- CoV-2 contributing to future variants by using a variety of methods, such as a bidirectional LSTM model, to evaluate mutational effects, and identified the key biological drivers of intrapandemic evolution [28]. In addition, using natural language models as a powerful computational model to handle biological sequence data has become a popular idea due to its rapid development and effectiveness. As an example, Hie et al. proposed a self-supervised learning approach to learn the sequence representation of proteins to maximize the immune escape capability while ensuring the fitness of protein sequences [29]. However, despite a large number of studies using computational models to predict viral evolution, most of the previous work does not take into account the phylogeny of viral evolution, which significantly reflects the development process of variants. In addition, due to the complexity of the evolutionary process and the diversity of evolutionary lengths, it is necessary to design models with more expressive power and computational efficiency. Therefore, we choose to design methods for this mutation prediction problem based on the transformer model, within which the attention architecture is naturally conducive to better capturing long-range dependencies and facilitating large-scale parallel computation. In this paper, we propose a transformer-based mutation prediction framework (TEMPO) for SARS-CoV-2 evolution. TEMPO can learn a high-level representation of historical prior sequence data that are constructed from the phylogenetic tree (PT) structure data of SARS-CoV-2, and afterwards predict the mutation probability of sites. More specifically, we first design a systematic PT-based sampling method to generate the sequence of viral amino acid sequences combined with temporal information, in which the temporal nature of viral evolution can also be portrayed. Second, we employ an embedding method ProtVec [30] for the residue representation. After that, a transformer structure is introduced to encode the embedded sequence to extract and learn complex correlations, and a fully connected layer is performed for the final site variants prediction. In addition, we devise an architecture to predict the mutations at each single site. We conduct experiments to verify the effectiveness of our proposed model TEMPO on the mutation prediction of SARS-CoV-2 evolution leveraging the SARS-CoV-2 dataset. Experimental results demonstrate that TEMPO is effective and outperforms several state-of-the-art baseline methods. We further explore the feasibility and robustness of TEMPO by performing mutation prediction experiments of other infectious viruses leveraging three influenza datasets, including the H1N1, H3N2 and H5N1 subtypes. The results indicate that our model is not only effective for the mutation prediction of SARS-CoV-2, but also informative for the evolutionary analysis of a broader range of viruses. We anticipate that the proposed TEMPO can provide significant insight into the evolution of SARS-CoV-2 and contribute to the early detection of VOCs in the next stage. 2 Materials and methods 2.1 Datasets 2.1.1 Data collection For SARS-CoV-2, we collected the amino acid sequence data of its spike protein from the GISAID database [31] and its phylogenetic tree data from the RCoV19 database [9]. The phylogenetic tree was generated by Pangolin software (Pangolin:4.1.2, PangoLearn: 2022-04-09). Table 1 presents the statistical information of SARS-CoV-2 spike protein sequence data and a total of 7389216 sequences were used after data cleaning. Mutation prediction in Spike proteins is our target, since Spike is the focus of antibody-mediated immunity and is the principal antigen in existing vaccines [32]. In addition, HA protein sequence data of influenza subtypes H1N1, H3N2 and H5N1 were also collected for additional experimental validation, following Yin's work [27]. Since these datasets contain series with different time spans, the SARS-CoV-2 dataset is split by month, while the three influenza virus datasets are by year.Table 1 The number of the available SARS-CoV-2 spike protein sequences from 2020.01 to 2022.02. Table 1Month 2020.01 2020.02 2020.03 2020.04 2020.05 2020.06 2020.07 2020.08 2020.09 756 1800 56,173 57,978 29,898 33,283 42,785 43,198 46,589 Month 2020.10 2020.11 2020.12 2021.01 2021.02 2021.03 2021.04 2021.05 2021.06 79,322 108,871 149,285 253,874 276,977 431,163 443,089 343,410 284,341 Month 2021.07 2021.08 2021.09 2021.10 2021.11 2021.12 2022.01 2022.02 547,335 854,129 706,695 653,010 798,758 625,360 288,256 232,881 2.1.2 Data preprocessing Because our method performs single site mutation prediction, sequence alignment is required to ensure the consistency of site numbering in different samples. Multiple sequence alignment (MSA) was performed on the protein sequences using MAFFT [33]. The SARS-CoV-2 dataset contains more than 8 million sequences in total, so it is impractical to perform multiple sequences directly on the entire dataset. Due to the high similarity between the SARS-CoV-2 sequences, we compared each sequence in the SARS-CoV-2 dataset with the standard reference sequence pairwise rather than a direct multiple sequence comparison. To facilitate the subsequent phylogenetic-tree-based sampling method, some additional information, such as lineage and sequence quality, is added to each sequence from the metadata based on the unique sequence ID. Sequences without these additional information will be excluded.Algorithm 1 PT-based Sampling Method.Image 1 2.2 PT-based sampling method To predict virus mutation based on evolutionary information, the first step is to generate evolutionary historical sequences from discrete protein sequences in the dataset. More explicitly, each historical sequence is composed of multiple protein sequences. The historical sequences can be used to reflect the evolution of the virus to better predict future mutation trends. A simple approach to obtain historical sequences is sampling from the dataset sequentially in chronological order based on the submission time of the sequences. However, the chronological order of sequence submission does not always coincide with the evolutionary order. For example, some of the most recently submitted sequence data may belong to a lineage that is early in the evolution of the virus, while some relatively earlier submitted sequences may also belong to a lineage that has just emerged at that time and they are at the further back in the evolutionary order, which we should pay more attention to. Therefore, we propose a phylogenetic tree (PT) based method sequentially sampling viral sequences to construct historical sequences that better reflect the virus evolutionary order, as shown in Algorithm 1. A phylogenetic tree is a branching diagram that depicts the evolution of various species or lineages from a common ancestor. This can help understand what occurred throughout evolution. Specifically, the phylogenetic tree data were obtained from the RCoV19 database [9] which is based on Phylogenetic Assignment of Named Global Outbreak Lineages (PANGO). First, a depth-first search (DFS) method is performed on the evolutionary tree to retrieve the set of evolutionary paths, where each evolutionary path corresponds to a path from the root node to a leaf node of the phylogenetic tree. Second, we generate multiple samples in each evolutionary path. These samples can be treated as historical sequences since they reflect the historical evolution process. When generating a single sample, each node on the path is selected in turn according to the order from the root node to the leaf node, and the amino acid sequence with the same lineage is discovered and added to the sample. The generation process of one sample would be completed when it reaches the last leaf node on the evolutionary path. The length distribution of sampled historical sequences is shown in Fig. 1 . The results show that the path lengths of the generated sequences are all less than 10, and most are concentrated between 4 and 8, which indicates that the phylogenetic tree is wide and shallow. To avoid evolutionary paths that are too short to reflect virus evolutionary characteristics, we selected evolutionary paths of length 5 to 8 for sampling. We also discard sequences whose evolutionary paths are longer than 8 because they are too few to construct a valid dataset which may also cause overfitting.Fig. 1 Length distribution of the sampled historical sequences (i.e., the number of nodes in the corresponding evolution path). Fig. 1 2.3 The proposed transformer-based model TEMPO With these sampled historical sequence data, we develop a transformer-based model TEMPO for mutation prediction of SARS-CoV-2 evolution. The framework of this model has been presented in Fig. 2 . We would elaborate on it as below.Fig. 2 The framework of the proposed model TEMPO for mutation prediction of SARS-CoV-2. L represents the evolutionary path length. Fig. 2 2.3.1 Sequence encoding Sequence sampling is simply the process of obtaining historical series data of amino acid sequences from a dataset. To perform mutation prediction using machine learning models, amino acid sequences (encoded with character ‘ACDE … ’) need to be encoded as vectors of real numbers, and the protein language pre-trained model ProtVec [ 30] is used to complete this process. The specific steps are shown in Fig. 3 . First, we split the whole sequence into subsequences and generate the embedding matrix of 3-g based on ProtVec [30]. Inspired by Tempel [27], we break these sequences into shifted overlapping residues in the window of 3 shown in Fig. 3. For example, in SARS-CoV-2, each spike protein sequence is depicted as 1273 lists of 3-g that are embedded in a 1273100 dimensional vector space based on ProtVec [30], where a 3-g is represented by a 100-dimension vector space. The ‘unknown’ vector from ProtVec will be assigned to denote the subsequence if it contains ‘-’ at any positions. To predict the mutation for each site, we utilize three overlapping 3-g, shown in Fig. 3, and focus on the center position as the target site. The three overlapping 3-g would be represented as the summation of the individual 3-g embedding vector. Therefore, each training case incorporates n sequential 3-3-g, embedded in 100n dimensions, where n is the length of the evolutionary path. An example of generating the representation of historical sequences can be found in Supplementary Material.Fig. 3 Sequence encoding process. Each 3-g is represented by a 100 dimension vector. Representations of three 3-g around the target site are summed to generate the final feature vector. Fig. 3 2.3.2 Transformer encoder model After sequence encoding, we use a transformer-based architecture to learn the evolutionary features of each target site in the entire input historical sequences, as presented in Fig. 2. Due to the complexity of the evolutionary process and the diversity of evolutionary lengths, models with more expressive power and computational efficiency are needed. Transformer is one popular sequence model architecture in the field of natural language processing recently. Compared to RNN, its internal attention mechanism is inherently computationally parallelizable and has better representation capabilities for especially long sequences, which is very suitable for virus evolution prediction tasks on large-scale datasets with evolutionary paths of various lengths. Correspondingly, in the task of virus mutation prediction, the evolutionary path of the target site in historical sequences can be viewed as a sentence, where each amino acid residue at the target site is considered as a word or a token. So predicting whether mutation will occur along this evolutionary path at the target site is transformed into a binary classification problem for a sentence. Unlike classical time-series models such as RNN and LSTM, it is generally believed that transformer outperforms those methods due to two properties itself. First, it uses attention mechanism to adaptively learn the weights (i.e., the degree of influence on the features of next layer) of each element of the sequence for the feature embedding. Second, the pure attention architecture is designed to better capture long-range dependencies and facilitate large-scale parallel computation, which makes it easier to train larger parametric models in less time and improve the expressiveness of the model. The original transformer is designed in the encoder-decoder architecture for machine translation tasks. In our task, since we only need to learn the features of the input sequence and make prediction based on the sequence feature, there is no need to generate a sequence in a transduction manner as translation tasks. Therefore, only the encoder part of the transformer architecture is reserved in our model. Specifically, the model input is a vector of L100 dimensions, where L is the length of evolutionary path (referred as sentence later) in a historical sequences sample. The output obtained after the last layer of the transformer encoder is a vector of Ld dimensions, where d is the hidden layer dimension, a hyperparameter. These L*d-dimensional vectors can be viewed as the corresponding feature representations of each of the L target sites (referred to as tokens later) in the input historical sequence learned by the model. Since we view the mutation prediction task as a sentence classification problem, we need to obtain the representation of the whole sentence from the representation of these L “words”. Two common solutions are tried here: one is to take the average of representations of these L words as the representation of the whole sentence, and the other is to select only representation of the last word. It is worth mentioning that although the second approach only employs the representation corresponding to the last word, this representation also contains information about the whole sentence because the attention mechanism takes into account all the words in the sentence during the computation. The experimental results show that the latter method is more effective. We believe that the reason for this phenomenon may be that the attention mechanism itself assigns a weight to each word in the sentence. When using the mean value of the representation of each word as the sentence representation, the operation of averaging suppresses the variability in the degree of contribution of each word to the sentence representation, thus making it more difficult to train the model to obtain a better sentence representation, whereas when only the representation of the last word is taken as the sentence representation, the sentence representation is computed by the pure attention mechanism, thus avoiding the problem of averaging suppression. Finally, the representation of the sentence is fed into a fully connected neural network, and the final prediction is obtained through a Softmax layer. The cross-entropy loss function is used to train the parameters in the network because cross-entropy is commonly used to measure the difference between two probability distributions and is therefore well suited as an objective function for the binary classification task. In addition, there are some details worth mentioning in training processes. In order to train the network in a supervised manner, it is necessary to give a label to each input sequence. We generate labels based on whether the last two protein sequences in the input historical sequence (i.e., the last two nodes on the evolutionary path) have the same amino acids at the target site. When the amino acids of the last two protein sequences at the target site cannot be determined (taking the value X or missing), this sample will be ignored and excluded from the training process. 2.4 Experiments 2.4.1 Dataset settings We collected in excess of 8 million SARS-CoV-2 sequences from January 2020 to February 2022 from the GISAID database, and generated a total of 15,200 samples with 5 samples for each evolutionary path to evaluate the effectiveness of our method. Specifically, we first preprocess the dataset to filter abnormal sequences and add additional information needed, and then use the proposed PT-based sampling method to generate training samples. 2.4.2 Baselines Two types of baselines are set up for prediction, as follows: 2.4.2.1 Traditional machine learning methods • SVM [34]: Support vector machine (SVM) is a generalized linear classifier for binary classification. The embedding of the target site at the penultimate node on the evolution path is fed to predict mutation at the leaf node. • LR [35]: Logistic regression (LR) is a traditional machine learning method which maps the input embedding features at the penultimate node to a scalar in (0,1) with the logistic function which corresponding to the classification probability. • RF [36]: Random forest (RF) is an ensemble learning method which uses multiple decision trees to do the classification task. The input and output settings are the same as SVM and LR. 2.4.2.2 RNN-based methods • RNN [37]: Recurrent neural network (RNN) is a specialized neural network for sequences, which allows variable length sequences as input and output. Specifically, the sequence of target node embedding with the sequence length N is used as the model input, where N is the length of the corresponding evolution path. And the output is a 2-dimensional vector which indicates the probability of mutation or not. • LSTM [38]: LSTM is an RNN-type network which can capture features of longer sequences with several well designed gating mechanism. • Tempel [27]: Tempel is a LSTM-based model with an attention mechanism to capture more complex correlations in the input sequence. 2.4.3 Implementation details All the approaches are performed with Scikit-learn [39] and Pytorch [40]. Note that the path from the root node to the leaf node in the phylogenetic tree is denoted as the evolutionary path. In the implementation, we use all the nodes without leaf nodes on the evolutionary path to predict the mutation of the leaf node. Specifically, we divide the dataset into a training data and a testing data according to a ratio of 4:1. In the training dataset, we generate the evolutionary historical sequence data based on the phylogenetic tree. In order to forecast the ultimate mutation, we first remove the leaf nodes from the phylogenetic tree and use the data from all other nodes, aside from the leaf nodes, as input for the proposed transformer-based model. The training objective is to minimize cross-entropy loss. We train the model for 100 epochs to achieve the convergence. With the trained model, we input the testing data without the leaf nodes, to predict whether the leaf nodes would witness a mutation. For all RNN-based models, we apply stochastic gradient descent with a minimum batch size of 256 for optimization. The learning rate is 0.001 with 128 hidden units in the encoder. We use cross-entropy as the objective function. The strategy with a drop-out of 0.5 is carried out and all the models are fit for 200 training epochs. We implement all baselines and our model on the environment with one AMD EPYC 7502P CPU @ 3.35GHZ and NVIDIA RTX3090 24 GB card. 2.4.4 Evaluation metrics We use five commonly used metrics, i.e., Accuracy, Precision, Recall, F-score and Matthews correlation coefficient (MCC), for classification model performance evaluation, among which the most important metrics are Accuracy, F- score and MCC. The detailed calculation formula for these metrics are shown in the Supplementary Material. Overall, a higher accuracy indicates a better precision rate of the prediction while a higher F-score value indicates a better trade-off of accuracy and completeness for positive sample prediction. The MCC is generally considered a more balanced indicator and can be applied even when the sample of the two categories differs significantly (i.e., category imbalance), which matches our scenario well because mutation will not occur in most cases. 3 Results and discussion 3.1 The workflow of TEMPO We present a workflow, as shown in Fig. 4 , to demonstrate the implementation steps of our method for mutations prediction at specific individual sites. Our objective is to predict whether there will be mutations in each site at the next stage of the evolution process, which is represented by the bottom leaf node of the phylogenetic tree as shown Fig. 2. The sampled historical residue information in sequence following the phylogenetic tree structure is mapped as the path from the root node to the penultimate node. Given historical sequences S 1 to S k generated by the PT-based sampling method, we produce historical embedding sequences S1pos=i to Skpos=i for each target site position i. Then we feed all the samples into the TEMPO model to obtain final mutation prediction results for each target site.Fig. 4 The workflow of mutation prediction of SARS-CoV-2 at specific sites using TEMPO. Fig. 4 3.2 Performance evaluation of TEMPO for SARS-CoV-2 mutation prediction To evaluate the effectiveness of the proposed model, we conduct comparison experiments on the mutation prediction between our model TEMPO and various baseline methods, using a large-scale SARS-CoV-2 dataset. The experimental results are shown in Table 2 . All the results are averaged over 10 random trails with a fixed random seed. The experimentalTable 2 Experiment results on the SARS-CoV-2 dataset. Table 2Method Accuracy Precision Recall F-score MCC SVM 0.530 0.519 0.588 0.551 0.063 LR 0.542 0.530 0.575 0.552 0.085 RF 0.544 0.534 0.561 0.547 0.089 RNN 0.609 0.581 0.720 0.643 0.226 LSTM 0.648 0.619 0.731 0.670 0.302 Tempel 0.648 0.618 0.743 0.675 0.305 TEMPO 0.655 0.658 0.614 0.636 0.309 results show that TEMPO achieves the best prediction performance in terms of multiple evaluation metrics, including accuracy, precision, and MCC, with an improvement of 1.1%, 6.5%, 1.3% compared with baseline methods. This can be attributed to the attention architecture of the transformer encoder layer in TEMPO, which is able to capture the complicated correlations between the lineages throughout the evolution path and learn the importance of the impact of each lineage on the final mutation probability. We can observe that TEMPO has a lower recall performance, which may be attributed to the overfitting issue with more parameters in the transformer layers. In addition, SVM has the worst prediction performance. The possible reason may be that this baseline method is not feasible for effectively learning time-series information. Moreover, we observe that TEMPO and other RNN-based methods outperform other baselines significantly. This may be because non-sequential models have difficulty utilizing the history of the sequence evolution, which in turn proves that the evolution path of the target lineage plays an important role in the mutation prediction. This is determined by the strong correlations between the ancestor node and the child nodes on the phylogenetic tree, which can be captured effectively by the proposed PT-based sampling method. Among all the sequential models, Tempel and LSTM obtain comparable prediction performance, which can be explained by the similarity of their whole architecture. 3.3 Performance evaluation of TEMPO for influenza mutation prediction We further explore the feasibility and robustness of our proposed TEMPO model by performing mutation prediction experiments with other infectious viruses. Three influenza datasets are used, including influenza subtypes H1N1, H3N2 and H5N1. These datasets are downloaded from Influenza Virus Resource [41], containing the full-length HA sequences between 1991 and 2016. Finally 161,000, 132,000 and 102,000 sequential samples of H1N1, H3N2 and H5N1 were used for the experiment, respectively. Note that we do not take the SVM method into consideration, owing to its significant time complexity on the large datasets. It should also be noted that when using the influenza dataset for virus evolution prediction, we did not use a PT-based sampling method, but a time-sequence-based sampling method due to the lack of relevant influenza phylogenetic tree data. Experiments on these influenza datasets are designed to verify the generalization and robustness of TEMPO, so the sampling method used to generate the dataset is not the main concern here. Experimental results are demonstrated in Table 3 . From the table, we find that TEMPO outperforms these baseline methods consistently, in terms of various evaluation metrics, including Accuracy, F-score, and MCC. We also observe that TEMPO obtains comparable mutation prediction performance in terms of Precision and Recall. This reflects the good generalization ability of our model. This TEMPO model can be used as a general framework for mutation prediction on various types of viruses, including SARS-CoV-2 and these influenza viruses.Table 3 Experiment results on influenza datasets. Table 3Datasets Method Accuracy Precision Recall F-score MCC H1N1 LR 0.823 0.685 0.418 0.519 0.438 RF 0.904 0.805 0.764 0.784 0.723 RNN 0.897 0.773 0.774 0.774 0.707 LSTM 0.902 0.799 0.761 0.780 0.717 Tempel 0.902 0.798 0.763 0.780 0.717 TEMPO 0.905 0.803 0.774 0.788 0.727 H3N2 LR 0.938 0.47 0.043 0.079 0.128 RF 0.962 0.812 0.504 0.622 0.623 RNN 0.953 0.709 0.408 0.518 0.516 LSTM 0.961 0.782 0.515 0.621 0.616 Tempel 0.961 0.780 0.521 0.625 0.619 TEMPO 0.963 0.826 0.510 0.631 0.633 H5N1 LR 0.987 0.872 0.210 0.338 0.424 RF 0.989 0.826 0.426 0.562 0.589 RNN 0.986 0.971 0.105 0.189 0.317 LSTM 0.990 0.870 0.414 0.561 0.596 Tempel 0.990 0.895 0.395 0.548 0.591 TEMPO 0.990 0.863 0.429 0.573 0.605 3.4 Parameter experiments To study the impact of different hyperparameter values on the mutation prediction performance, we analyze the performance of models on the SARS-CoV-2 dataset by varying three significant hyperparameters, including the number of encoder layers, number of attention heads and learning rate. The hyperparameter study results are depicted in Fig. 5 .Fig. 5 Hyperparameter study of TEMPO. Fig. 5 From the figure, we observe that the best prediction performance is obtained when the number of encoder layers equals to 2. An appropriate value of the number of encoder layers improves the model's ability to effectively capture evolutionary historical information. We also choose different values of the number of attention heads n from 1 to 5 in the experiments, and find that the best F-score result is obtained when n = 4. When n < 4, the performance worsens due to the lack of representation ability. In addition, we search for the learning rate from 0.0001 to 0.1, and confirm the value 0.001 with the best performance in our model. 3.5 Mutation prediction results We utilize all the data available up to February 2022 to predict the future mutation. Specifically, using all the data, we generate sampled sequence data and input it into the TEMPO model to forecast future mutations, following the same process as for the prediction framework described above. It should be noted that TEMPO only predicts the mutation probability of the target site and does not predict the specific type of mutation. We sorted the mutation prediction results at certain sites with more than 6 sampled sequence data, and presented a list of high-probability (p ≥ 0.5) predicted mutation sites, as shown in Table 4 . We compared the prediction results of TEMPO with the actual mutations according to the RCoV19 database v4.0 [9] and found that TEMPO can effectively predict mutations at certain sites where new variants arise. These new mutations have been illustrated in the bond font. For instance, according to our model, site 215 has a 0.75 chance to get a new mutation in the near future. Later real data documented in the RCoV19 database confirm the variants.Table 4 A list of high-probability (p ≥ 0.5) predicted mutation sites in descending order. Table 4Site Prediction probability Variant after February 2022 796 1.00 D796Y 452 0.94 L452R, L452Q, L452M 950 0.82 – 501 0.80 N501Y 484 0.78 E484A 859 0.78 – 681 0.75 P681H 215 0.75 D215E 144 0.69 – 936 0.67 – 156 0.67 – 142 0.62 G142D 222 0.60 – 19 0.59 T19I 158 0.57 – 157 0.56 F157L 478 0.54 T478K 145 0.50 TH145–146- 477 0.50 S477 N In addition, we can see that TEMPO can be used to predict mutations at sites that have not yet emerged, with 22 successfully predicted mutations among all the 39 newly emerged mutations, as shown in the Supplementary Material. Note that some mutations are predicted with few sampled sequence data. For example, site 259 has not undergone a mutation since February 2022, and according to our model, it has a probability of 0.75 to witness a mutation soon, which has been confirmed by the RCoV19 database. This is a challenging task, and we believe our model provides a promising step toward predicting new mutations. 4 Conclusion Mutation prediction for SARS-CoV-2 evolution is a challenging and essential task. In this paper, we aim to predict future mutations in sites using historical spike protein data. We designed a phylogenetic tree-based sampling method to generate sequence data with full consideration of the tree-structure of SARS-CoV-2 evolution data. We propose a novel transformer-based model TEMPO that can fully utilize the prior sequence information and effectively learn high-level representations to enhance prediction performance. Experimental results on a large-scale SARS-CoV-2 dataset prove the effectiveness of our model for mutation prediction of SARS-CoV-2 evolution. To explore the feasibility and robustness of this model, we conducted further experiments on mutation prediction of other infectious viruses, leveraging three influenza datasets. The results verify the superiority of our proposed model. Despite having obtained many research results, there still remain limitations. First, we did not take the phylogenetic tree construction method into consideration due to the construction computation difficulty in the large SARS-CoV-2 dataset. Thus, one open future work is to investigate the sensitivity of phylogenetic uncertainty when phylogenetic trees constructed by various methods are available. Second, we did not consider the global information of protein sequences. One of the future works will be to incorporate global information of proteins and investigate the effects on mutation prediction. Data availability statement The datasets and codes in this study can be found in the online repository https://github.com/ZJUDataIntelligence/TEMPO. Funding This work is supported by the 10.13039/501100001809 National Natural Science Foundation of China (Grant No. 62102349), the Key R&D Program of Zhejiang Province (Grant No. 2020C03010), and the Huadong Medicine Joint Funds of the 10.13039/501100004731 Zhejiang Provincial Natural Science Foundation of China (Grant No. LHDMZ22H300002). Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Appendix A Supplementary data The following is the Supplementary data to this article:Multimedia component 1 Multimedia component 1 Acknowledgments The authors would like to acknowledge the Supercomputing Center of 10.13039/501100004835 Zhejiang University City College, the Information Technology Center and State Key Lab of CAD&CG of 10.13039/501100004835 Zhejiang University , and Alibaba Cloud for the support of the advanced computing resources. 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==== Front Public Health Pract (Oxf) Public Health Pract (Oxf) Public Health in Practice 2666-5352 The Authors. Published by Elsevier Ltd on behalf of The Royal Society for Public Health. S2666-5352(22)00129-X 10.1016/j.puhip.2022.100353 100353 Article Engaging businesses and faith-based organizations in public health interventions: Lessons learned from a COVID-19 and flu vaccine detailing program in the Northeast Bronx☆ Diallo Fatoumata ∗ Paulino Lissette Shiman Lauren Freeman Kim Brooks Brandon Banson Diana Reyes Anita ∗ Corresponding author. Bureau of Bronx Neighborhood Health, 1826 Arthur Avenue, Bronx, NY, 10457, USA. 13 12 2022 13 12 2022 10035321 9 2022 15 11 2022 12 12 2022 © 2022 The Authors. Published by Elsevier Ltd on behalf of The Royal Society for Public Health. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Objectives The NYC Department of Health and Mental Hygiene conducted a COVID-19 and flu vaccine community detailing program to influential businesses and faith-based organizations in the Northeast Bronx in 2022 to increase COVID-19 and flu vaccine knowledge and uptake among residents of the area. Study design program evaluation. Methods The program was piloted in the Northeast Bronx, a geography selected based on prior low COVID-19 and flu vaccination rates and high COVID-19 case positivity rates. Barbershops, hair salons, beauty salons, nail salons and faith-based organizations were selected as potential partners because their owners or staff typically spend at least an hour in interactions with clients. From January 2022 through April 2022, two detailing visits were conducted by engagement staff: an initial visit to all potential partners in the selected geography, and a follow up visit to those who committed to be champions of health. Results Out of 113 identified businesses/organizations, 70 met the criteria to be potential partners in the program. After being contacted by health department staff, 45 (64%) potential partners committed to be champions of health. During the four months of the pilot, zip codes with the highest level of program engagement experienced greater percent increases in COVID-19 vaccination rates during the program period compared to NYC and Bronx averages. Flu vaccination rates during the program period were not available. Conclusion Supplementing other local public health efforts, the community detailing pilot program demonstrates a model of dissemination of health information through local business leaders, and provides lessons learned to increase champion commitment. Keywords Health promotion Vaccine hesitancy Community engagement Program evaluation ==== Body pmc1 Introduction New York City's Department of Health and Mental Hygiene (NYC Health Department) has used place-based health initiatives to support neighborhoods unjustly burdened with premature morbidity and mortality. After many years of developing place-based initiatives and building strong relationships in three historically excluded neighborhoods with high premature mortality, the NYC Health Department launched Bureaus of Neighborhood Health in these communities [1]. Situated in the South Bronx, the Bureau of Bronx Neighborhood Health aims to promote health equity and reduce health disparities through place-based initiatives, research, and programming. Generations of structural racism, including the lasting impacts of redlining, have resulted in the Bronx having a high burden of health challenges and premature deaths. This vibrant and diverse borough is home to over 1.4 million residents; 56.0% identify as Hispanic or Latino, 38.6% identify as Black, and 34.6% were born outside of the United States [2]. It has also been ranked the least healthy county in the state annually since the County Health Rankings launched in 2010 [3]. Pre-existing chronic conditions, overcrowded housing, and other health and socio-economic factors have made Bronx residents more vulnerable to the direct and indirect impacts of the COVID-19 pandemic [4]. COVID-19 cases, hospitalizations, and death rates in the Bronx are among the highest in NYC [5]. Hispanic and Black residents, who are highly represented in the Bronx, have been disproportionately affected by the COVID-19 pandemic [6]. Nevertheless, between 75%-82% of residents living in the Northeast Bronx received at least one dose of a COVID-19 vaccine, compared to 88% of residents across NYC [7]. Reduced vaccination rates might stem from historical examples of oppression which has led to residents’ public distrust of government and scientific sources. Hence, providing accurate information about the COVID-19 vaccine through direct engagement of at-risk Bronx communities is critical. The NYC Health Department has operated a Public Health Detailing program since 2003 to engage healthcare providers in sharing information about specific health topics with their patients. Modeled after pharmaceutical detailing, the Public Health Detailing program was designed to address gaps in provider knowledge and promote the use of essential preventive services by primary care providers [8]. Detailing efforts by the NYC Health Department to primary care providers have shown to increase knowledge and implementation of recommended practices [8,9], as well as improve clinical management, lifestyle modification, and behavior change [10]. To reach historically excluded populations burdened with preventable health disparities, trusted health information may come from community leaders beyond healthcare providers. Previous health promotion interventions have engaged barbershops, hair salons, and places of worship; these community-based businesses and organizations are highly accessible and are considered to be safe spaces by community members. A systematic review of obesity interventions in African American faith-based organizations (FBOs) found improvements in participants’ weight and health behaviors [11]. Barbershops and salons have been shown to increase recommended health screenings and improve chronic disease management in community members [12,13]. A literature review of health promotion conducted in salons and barbershops found that businesses reported already sharing important health information with their customers, and that their customers were interested in receiving the health information from their stylists or barbers or in salons or barbershops [14]. To address vaccine hesitancy and increase vaccination rates, the Bureau of Bronx Neighborhood Health piloted a community detailing program in the Northeast Bronx. The program addressed both COVID-19 and flu vaccines since the detailing took place during flu season and there are symptom similarities between the two viruses. The program met with business leaders while NYC's Public Health Detailing program detailed healthcare providers in the same neighborhoods to saturate the Northeast Bronx community with accurate information about COVID-19 and flu vaccines. To the authors' knowledge, this is the first public health detailing program to jointly engage health providers and business leaders in public health promotion. This article describes the community detailing model and program evaluation results, and explores lessons learned. 2 Methods 2.1 Program planning 2.1.1 Developing list of potential champions As shown in Fig. 1 , four zip codes in the Northeast Bronx (10466, 10469, 10470, 10475) were selected for the intervention based on low flu vaccination rate data from the 2020 NYC Community Health Survey and low COVID-19 vaccination [15] and high COVID-19 case positivity rates as of September, 2021 [16]. The program selected barbershops, hair salons1 , beauty salons2 , nail salons, and FBOs as potential champions because these businesses are highly accessible by their communities and consistently spend at least an hour interacting with clients or community members. Businesses were identified through merged and deduplicated lists from Google Maps, the NY State Barber License, and the NYC Health Department's salesforce platform, Public Health Partners Connect. During initial visits, businesses or places of worship marked as temporarily or permanently closed, and those found to be in residential buildings, were excluded from the list. A map was created in GIS Mapping Software (ESRI). Initial and follow-up surveys were programmed into a data collection application (Survey123) and integrated into the ESRI map.Fig. 1 Map of the COVID-19 and flu vaccines community detailing program area. Fig. 1 2.1.2 Preparing detailing staff and materials The NYC Health Department's Public Health Detailing program team conducted two days of intensive training for the community detailing project team, a bilingual Bronx-based team of community health workers and health promoters with members fluent in both English and Spanish. The training guided staff on how to introduce and frame the issue to businesses, how to provide recommendations and promote materials, how to overcome barriers and objections during visits, and how to gain commitments and close the visit. Project materials disseminated during initial visits included: a letter from the NYC Commissioner of Health, informational flyers, brochures, and palm cards on COVID-19 and flu. At the initial visit, potential partners were also provided with personal protective equipment (PPE including surgical masks, KN95 and N95 masks, and hand sanitizer) and at-home COVID-19 test kits. 2.2 Program implementation Project team members were assigned to specific neighborhood areas to minimize travel between visits. The detailing visits began at the end of December 2021. However, because of a COVID-19 surge and businesses’ limited capacity to engage during the December holiday season, the project was paused and relaunched in mid-January 2022. Visits occurred between January–April 2022. During the initial visit, the team requested to speak with a decision-maker and provided an introduction and program overview. The project team member administered an oral survey and recorded responses into Survey123, collecting information about community perceptions of the COVID-19 and flu vaccines and documenting the partner's commitments to champion the importance of these immunizations. Businesses were invited to become champions of health by committing to one or more of the following: (1) speaking with their customers about the COVID-19 and flu vaccines and offering supporting materials to help answer any questions of concerns, (2) displaying posters and brochures that encourage vaccination, (3) hosting a Health Department staff person to table at the business to share information and answer customer's questions, or (4) any other activity suggested by the business relevant to COVID-19 and flu vaccine promotion. Between visits, the team completed requests including providing additional resources or PPE and tabling at the champion's site to communicate directly with clients and passing residents. A month after the initial visit, sites that agreed to become champions of health received a follow-up visit and were invited to complete a follow-up survey to learn about their experiences participating in the program. 3 Results 3.1 Engagement in the program 3.1.1 Identified partners Fig. 2 details business/FBO engagement throughout the community detailing program. A total of 113 unique barbershops, hair salons, beauty salons, nail salons, and FBOs were identified. Of these, 43 were excluded during initial visits because they were found to be in a private home, temporarily or permanently closed, or had hours of operation that were incompatible with the project, yielding 70 potential partners. Most excluded sites were FBOs (n = 29) which had closed their sites and were only conducting online worship.Fig. 2 Business/FBO engaged in the COVID-19 and flu vaccines community detailing program [N(%)]. Fig. 2 During the initial visit, twenty sites refused participation in the program (15.7%). Among those who committed as champions, sixteen sites refused the follow-up visit (8.8% actively, 26.7% passively) and two were found to be closed after multiple visit attempts. When sites refused to participate or complete the program, the community detailing teams were able to engage with them about the reason for their refusal. Sites that actively refused visits expressed distrust in government or stated that there were too many regulations at the time and were not sure if the detailing staff intentions were motivated by health or regulatory concerns. Sites were considered to have passively refused participation if they said that they were busy and did not have time to speak with the detailing staff, and that there was no good time to visit, or they were not sure when they owner would come in. When the detailing teams introduced the possibility of speaking about other health topics distinct from COVID-19 or flu vaccines in the future, most sites who refused participation in this project were willing to have health department staff attempt future engagement. 3.1.2 Commitments to be champions of health In total, 45 of the 70 potential partners committed to being champions of health. However, only 27 (60.0%) fully completed the program by agreeing to a follow-up visit and participating in the follow-up survey. Although one FBO agreed to be a champion and followed through on its commitment to host a health department staff, it passively refused the follow-up survey and consequently did not complete the program. As shown in Table 1 , most sites that committed to being champions elected to display materials in their site (74.0%), though many committed to have vaccine conversations and offer materials (44.0%), or to host a health department staff person for tabling (34.0%). None suggested an alternate activity, an option included to create a more equitable partnership and give sites greater agency as program participants. Almost all sites accepted materials to distribute to residents (95%); 84.0% accepted flu posters and flyers and 74.0% accepted COVID-19 posters and flyers.Table 1 Sites commitments to be champions of health and their adherence to the commitments. Table 1 Sites That Made Commitment N (%)a Sites Documented as Completing Commitment N (%)b Finishing program: engaging in follow up visit and completing survey 45(90.0) 27(60.0) Commitment 1: Having vaccine conversations and offering supporting materials 22(44.0) 8(36.4) Commitment 2: Displaying posters and brochures that encourage vaccination 37(74.0) 7(18.9) Commitment 3: Hosting a Health Department staff person to table at the business 17(34.0) 13(76.5) a Represents results from the 50 surveyed businesses/FBOs during the initial visit. b Completing commitments 1 and 2 could only be assessed among champions that agreed to a follow-up visit and completed the follow-up survey. Among champions who made commitment 1, thirteen were assessed in a follow-up visit and nine were lost to follow-up. Among champions who made commitment 2, twenty-three were assessed in a follow-up visit and fourteen were lost to follow-up. Attempts were made to engage all sites which committed to being champions in a follow-up visit and post-survey. The timing between completion of the initial and the follow-up visit was 26 days on average; sites engaged later in the project lifespan had a shorter time between the initial and follow-up visits. No association was found between the initial to follow-up visit time interval and whether champions completed their commitments. At the initial visit, 37 (74.0%) champions committed to displaying COVID-19 and flu vaccine flyers in their store. Among the 23 champions who made this commitment and completed the post survey, only seven (18.9%) had them hanging in their site at follow-up. Compliance in hanging posters and flyers among businesses who refused the follow-up visit could not be assessed. During initial visits, 17 (34.0%) champions committed to host a health department staff member at their site for a tabling event. Engagement staff followed up on those champions and scheduled tabling at the sites. However, after multiple scheduling attempts, four of the champions ultimately declined following through on their tabling requests. Tabling events were completed for the remaining 13 champions who committed to this activity during initial visits; during these events staff engaged directly with a total of approximately 245 residents. Two adjacent tabling events were scheduled simultaneously; during this time a COVID-19 mobile vaccine van was stationed outside of a champion business so that NYC Health Department staff could answer questions and refer interested residents directly to the mobile vaccination site. At the initial visit, 22 (44.0%) champions committed to having vaccine conversations with their customers or community members. During the second visit, only 8 of these champions reported following through on this commitment (9 champions were lost to follow-up and 5 reported that they had not had conversations with their clients about the vaccines). As detailed in Table 2 , most leaders focused on COVID-19 vaccines in their conversations; only two champions reported also having conversations about flu vaccines.Table 2 Vaccine conversations: changing perceptions from initial visit to follow-up visit. Table 2 Initial Visit N (%) Follow-up Visit N (%) Vaccine hesitancya What are the most common reasons that you have heard from your customers or other people in your community why they do not want to get the COVID-19 vaccine? 30(100) 13(100) Long-term effects are not known 3(10.0) 0(0.0) Vaccines developed too quickly/waiting on full FDA approval 2(6.7) 2(15.4) Might not do a good job of preventing transmission 4(13.3) 0(0.0) Side effects 3(10.0) 1(7.7) Not necessary if already had COVID 5(16.7) 2(15.3) Current vaccines do not protect against new variants 1(3.3) 1(7.69) Some other reasonc 11(36.7) 4(30.8) Don't know 10(33.3) N/A Did not talk to people since last meeting N/A 5(38.5) What is the most common reason that you have heard from your customers or other people in your community why they do not want to get the Influenza vaccine? Long-term effects are not known 2(6.7) 0(0.0) Might not do a good job of preventing transmission 1(3.3) 0(0.0) Side effects 3(10.0) 0(0.0) Not necessary if already had flu 1(3.3) 0(0.0) Some other reasond 23(76.7) 2(15.4) Don't know 0(0.0) N/A Did not talk to people since last meeting N/A 11(84.6) Confidence levelsb When people share their concerns with you about COVID-19 or flu vaccines, how confident do you feel in talking with them about those concerns using information that you trust? 30(100) 27(100) Very Confident 13(43.3) 9(33.3) Somewhat Confident 9(30.0) 4(14.8) Neutral/No Opinion 7(23.3) 11(40.7) Not Very Confident 1(3.3) 2(7.4) Not Confident at All 0(0.0) 1(3.7) a Responses from the initial visit represent businesses that were already having vaccine conversations with their clients. Results from the follow-up visit include only the champions that committed to having vaccine conversations and completed the post survey. b Responses from the follow-up visit includes all champions that completed the follow-up survey including those that did not commit to having vaccine conversations. c Responses for some other reason for COVID-19 vaccine hesitancy included public distrust in government, religion, misinformation on social media, or stubbornness during the initial visit. For the follow-up visit, other reasons for COVID-19 vaccine hesitancy included lack of trust of vaccine ingredients, lack of interest in the booster shot, and disapproval of mandates from government and businesses. d Responses for some other reason for flu vaccine hesitancy was religion during the initial visit. As for the follow up visit, the two businesses that had flu vaccine conversations did not provide another reason for flu vaccine hesitancy but expressed that their clients had either already taken the flu vaccine or did not mention concerns about it. 3.2 Changing perceptions over time 3.2.1 Vaccine hesitancy As respected leaders in their community, site leaders were able to share perceptions about vaccine hesitancy. During the initial visit, among the 30 site leaders who reported that they had been having conversations with people about vaccines prior to the intervention, most did not perceive hesitancy in their community to be due to previously reported common concerns such as unknown long-term effects of the vaccine or the speed at which vaccines were developed [17]. Rather, a third of these leaders stated that they did not know the most common reasons for vaccine hesitancy, and 36.7% cited some other reason such as public distrust in government, religion, misinformation on social media, or stubbornness. During the follow-up visit, champions cited other reasons for COVID-19 vaccine hesitancy including lack of trust of vaccine ingredients, lack of interest in the booster shot, and disapproval of mandates from government and businesses. 3.2.2 Confidence level of businesses Twenty-two sites felt confident talking to people about COVID-19 and flu vaccine concerns before participating in the project. Notably, the overall confidence level among surveyed leaders decreased by the follow-up visit, which may be a result of conflicting messaging from government. When asked during the follow-up survey if there was anything that would have helped them to feel more comfortable talking to their customers about the COVID-19 and flu vaccines, 100% of the respondents said “No”. Reasons cited included already feeling comfortable talking to people, the perception that COVID-19 is now over, and people are no longer willing to talk about it, and the sentiment that it is customers’ personal choice whether they should take the vaccine or not. 3.3 Community-level changes Although the program sought to engage businesses/FBOs across four zip codes, engagement by zip code varied. Most champions were in 10466 and 10469; most tabling events were also completed there. As shown in Table 3 , these two zip codes experienced higher percent increases in residents with at least one dose of a COVID-19 vaccine than the Bronx and NYC averages during the project period. The zip codes with less engagement in the program, 10470 and 10475, experienced percent changes in vaccinated residents closer to borough and citywide averages. Changes in flu vaccination rates during the project period were not available and therefore could not be assessed.Table 3 Percent change in COVID-19 vaccination rate compared to champions’ commitments and program completion by zip code. Table 3 Populationb Champions Commitments N(%) COVID-19 Vaccinationa Number of Champions Committed Number of Tabling Events Completed Number of Champions who Finished Programc Percent of all residents vaccinated pre-program (January 1, 2022) Percent of all residents vaccinated post-program (May 1, 2022) Percent Change in COVID-19 Vaccination Rate (January 1 to May 1, 2022) 10466 75,000 21(46.6) 6(46.2) 11(40.7) 68.3% 74.2% +8.7% 10469 73,000 12(26.6) 4(30.8) 9(33.3) 69.0% 74.2% +7.6% 10470 16,000 9(20.0) 2(15.4) 5(18.5) 75.6% 80.8% +6.9% 10475 44,000 3(6.6) 1(7.69) 2(7.4) 73.1% 77.2% +5.6% Bronx 1,425,000 (--) (--) (--) 76.7% 82.7% +7.2% NYC 8,468,000 (--) (--) (--) 81.8% 87.0% +5.6% a Percent of residents all ages who have received at least one dose of a COVID-19 vaccine, per New York City Department of Health Citywide Immunization Registry [7]. b Population estimates rounded to the nearest thousand, per U.S. Census Bureau July 1, 2021 [2]. c Engaged in follow-up visit and completed follow up survey. 3.4 Champions’ experiences When business leaders were asked about their overall experience as champions of health during the follow-up visit, they shared challenges as well as aspects of the program that worked well. Challenges included mixed messaging about COVID-19 and difficulty or discomfort in having conversations about the vaccines, detailed in Table 4 . Champions also identified aspects of the program that were successful, noting that: the materials and resources were helpful, they were grateful to have access to PPE, and that they would be willing to talk to their customers about other health topics in the future. Out of the 27 businesses that completed the post survey, 16 were interested in future partnerships with the health department (4 declined and 7 hesitated).Table 4 Results from the follow-up visit when champions were asked of their overall experiencea participating in the program. Table 4Mixed messaging about COVID-19 has led to misinformation and public distrust• COVID-19 mandates and restrictions limited businesses • It is hard to change client views • Most people are not concerned about COVID-19 • The COVID-19 virus is overrated • COVID-19 is over Difficulty and discomfort in having vaccine conversations• It is difficult to talk about COVID-19 with clients • Did not engage in COVID-19 and flu vaccine conversations • Not comfortable having COVID-19 conversations, unless started by clients Helpfulness of resources• Flyers were very helpful in sharing information when clients needed them • Handed out flyers to clients when asked about COVID-19 • Distributed PPE to employees and clients Interest in promoting other health messaging• Open to discussing other topics and resources in the near future • Do not mind the Health Department tabling in front of their business on other health topics • Interested in health promotion related to chronic illnesses (ex: health screenings, mental health resources) • Not interested in partnering with the health department in the future because they are busy a Even though the detailing intended to discuss both COVID-19 and flu vaccines, engaged business leaders were more interested in talking about COVID-19. 4 Discussion To mitigate vaccine hesitancy and increase vaccination rates, the Bureau of Bronx Neighborhood Health implemented a hyperlocal community detailing program to educate community members through influential business owners and faith-based leaders. The intervention successfully engaged many potential partners and developed a network of champions of health in the neighborhood. Greater percent increase in COVID-19 vaccination rates were observed in the zip codes with more involvement in the detailing program and these increases were higher than the Bronx and city averages. 4.1 Limitations The evaluation of this effort is subject to several notable limitations. First, the evaluation was designed to show contribution of the program's efforts on overall vaccination rates, not attribution. Many simultaneous efforts, including the NYC Health Department's Public Health Detailing to providers and tireless efforts of community-based organizations in these neighborhoods, also seek to increase COVID-19 and flu vaccinations in the same zip codes. Citywide factors may also confound the relationship between this program and changing vaccination rates over time, particularly if those efforts were received and/or enforced differently by different communities. They include citywide public health messaging campaigns and the enforcement of vaccine mandates by private and public employers, which caused many residents to receive vaccinations to retain employment. Second, during the program duration, available information about the COVID-19 vaccinations continued to develop. The community detailing program focused on businesses that mostly reach adult clients, but some of these adults may be parents who received information about vaccines for youth. For this reason, the evaluation purposely considers vaccination rates for all-ages, but information about vaccine efficacy and safety for different age groups may have been received differently. At the time of this project, COVID-19 vaccines were not available for children under 4 years old. Finally, the small sample size of engaged champions limits ability to demonstrate effectiveness of the program. 4.2 Lessons learned This project represented an intentional geographic departure from the Bureau of Bronx Neighborhood Health Action Center's typical catchment area in the South Bronx to concentrate resources in the Northeast Bronx, where COVID-19 and flu vaccine rates lagged behind other NYC neighborhoods. The businesses/FBOs engaged were new partners and allowed an opportunity to develop novel relationships. Since these business types often work with health inspectors, some had a preconceived perception that staff were visiting for enforcement purposes. In general, vaccine-related engagement in historically excluded communities requires repeat encounters and allocating ample time for discussion. In some cases, business owners actively refused participation in the survey, but the detailing teams were able to engage in long conversations with staff about their concerns and questions. Even when explicit objectives are not met (i.e., completed surveys, commitments as champions), important information can be shared, and misinformation or fear addressed. Despite hesitancy talking about vaccines, most sites were eager to receive PPE from staff; some even visited the bureau's building after the initial engagement to pick up additional PPE. Such benefits of this program extend beyond reported evaluation findings. FBOs were not ideal for this detailing model. After multiple visit attempts, only 3 out of 32 originally identified FBOs engaged because many were closed or were conducting all worship virtually and none finished the program. Consequently, future iterations of this model should focus on businesses like barbershops, beauty salons, and other influential business types or attempt to engage FBOs when they return to in person service. Due to the demographics of the Northeast Bronx community, having bilingual project staff was essential for engaging businesses, organizations, and community members. Many barbershops who became champions of health were only able to participate because the team could speak with the owner or manager in Spanish. Nevertheless, since many other languages are spoken in the community, detailing teams encountered language barriers when interacting with some sites which hindered the engagement level. Future detailing programs should leverage interpretation resources. Although the intention of the project was to promote both COVID-19 and flu vaccinations, following the lead of business or FBO leaders, most engagement and discussion centered around COVID-19 vaccinations; therefore, future iterations might be best when focused on a single topic at a time, especially when dealing with controversial and politicized topics as they might dominate other topics during conversations. The program itself was limited by inconsistent COVID-19 public messaging by federal, state, and local government that made sustained engagement challenging. The lack of follow-through on champions’ commitments and interest in completing the follow-up visit and survey may be, in part, a result of the external political and social environment with respect to the COVID-19 pandemic. Many champions expressed that “COVID is over” or that people are tired of talking about COVID-19. Between the initial and follow-up visits, policies such as Key to NYC which required proof of COVID-19 vaccination to enter certain establishments and other local COVID-19 preventions such as mask mandates were suspended. Compounded with federal, state, and local messaging about “return to normalcy” and the end of the “pandemic phase”, this hindered efforts to engage with businesses and FBOs about vaccines. During this time, the existing vaccines were also demonstrated to be less effective in preventing infection against Omicron compared to prior variants. Sixteen businesses that initially committed to become champions refused the follow-up survey, potentially due to the shift in perceived importance of increasing vaccination rates. Nonetheless, zip codes with more engaged champions demonstrated increased COVID-19 vaccination coverage, indicating that business leaders can be influential champions for health in their communities. 4.3 Conclusion The COVID-19 and flu community detailing project was the first of its kind in NYC. The project offered insight about ways to engage Bronx community members and partners in health messaging. Future planned iterations of the project include replicating the model with a chronic disease health lens and expanding potential champions to include other influential community leaders beyond business owners and FBOs. Statements of ethical approval This work was determined not human subjects research by the NYC Health Department's Institutional Review Board and therefore not subject to ethical approval. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgements The authors wish to acknowledge the Bureau of Bronx Neighborhood Health engagement staff and community health workers, the Bureau of Chronic Disease Public Health Detailing team, and the community champions of health who engaged in the program. ☆ This work was done by the Bureau of Bronx Neighborhood Health within the Center of Health Equity and Community Wellness of the NYC Department of Health and Mental Hygiene. 1 Hair salons offer only hair services and products. 2 Beauty salons may offer hair services and products but also provide extended services including services related to skin health, facial aesthetics, foot care, nail manicures, aromatherapy, meditation, oxygen therapy, or mud baths. ==== Refs References 1 Dannefer R. The neighborhood as a unit of change for health: early findings from the east harlem neighborhood health action center J. 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==== Front J Anxiety Disord J Anxiety Disord Journal of Anxiety Disorders 0887-6185 1873-7897 Elsevier Ltd. S0887-6185(22)00133-5 10.1016/j.janxdis.2022.102660 102660 Article Intolerance of uncertainty, anxiety sensitivity, and health anxiety during the COVID-19 pandemic: Exploring temporal relationships using cross-lag analysis Bredemeier Keith a⁎ Church Leah D. b Bounoua Nadia b Feler Bridget a Spielberg Jeffrey M. b a Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA b Department of Psychology, University of Delaware, Newark, DE, USA ⁎ Correspondence to: 3535 Market Street, Suite 626, Philadelphia, PA 19104, USA. 14 12 2022 1 2023 14 12 2022 93 102660102660 29 8 2022 23 11 2022 9 12 2022 © 2022 Elsevier Ltd. All rights reserved. 2022 Elsevier Ltd Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Intolerance of uncertainty (IU) and anxiety sensitivity (AS) have been widely discussed and explored as factors that may contribute to health anxiety. We propose that IU and AS are salient issues for many during the COVID-19 pandemic, and may play a role in the development or exacerbation of health anxiety during the pandemic. Studies have examined links between IU and AS with health anxiety during the pandemic, but these relationships have not been tested together using a longitudinal study design. In the present study, measures of IU, AS, and health anxiety were collected from 301 adults at two time points 6 months apart during (early stages of) the COVID-19 pandemic using an online survey platform. Cross-lagged analysis was utilized to simultaneously estimate cross-sectional and longitudinal associations between these three variables. Robust cross-sectional associations were observed, and IU prospectively predicted changes in both health anxiety and AS. No other statistically significant prospective associations emerged. Present findings support the putative role of IU in health anxiety, suggesting that some observed links between AS and health anxiety could be driven by shared variance with IU. IU may be an important factor to monitor and target in health anxiety interventions during the pandemic. Keywords Health anxiety Intolerance of uncertainty Anxiety sensitivity Pandemic COVID-19 ==== Body pmc1 Introduction Health or illness anxiety is a common problem, affecting up to 6 % of the general population during the course of their lives, and up to 20 % of medical outpatients (Tyrer, 2018). Health anxiety is characterized by excessive worries about health and fears of developing a disease, resulting in hypervigilance for signs of illness and maladaptive information seeking and safety behaviors. The impact of health anxiety on well-being and service utilization can result in substantial healthcare costs – for example, a naturalistic longitudinal study by Fink, Ørnbøl, and Christensen (2010) found that individuals with severe health anxiety used 41–78 % more healthcare per year. There has been extensive research exploring cognitive and behavioral factors theorized to be associated with risk for excessive health anxiety (see Asmundson, Abramowitz, Richter, & Whedon, 2010; Asmundson & Fergus, 2019; Salkovskis & Warwick, 2001; Taylor, 2004). Two factors that have been widely discussed, examined, and shown to be linked with health anxiety in the literature are intolerance of uncertainty and anxiety sensitivity (e.g., Fergus & Bardeen, 2013; Fetzner et al., 2014; Gerolimatos & Edelstein, 2012; Horenstein, Rogers, Bakhshaie, Zvolensky, & Heimberg, 2019; Norr, Albanese, Oglesby, Allan, & Schmidt, 2015; Wright, Lebell, & Carleton, 2016). Although definitions of intolerance of uncertainty (IU) have changed over time, recent and influential work defines IU as “an individual's dispositional incapacity to endure the aversive response triggered by the perceived absence of salient, key, or sufficient information, and sustained by the associated perception of uncertainty” (p.31, Carleton, 2016). IU may contribute to distress in responses to uncertainty triggered by the experience of potential risks (e.g., exposures) and symptoms of disease or illness, which in turn can lead to problematic ways of coping with feelings of uncertainty with known links to health anxiety, such as information seeking or avoiding medical appointments/tests (e.g., Baerg & Bruchmann, 2022; Bottesi, Marino, Vieno, Ghisi, & Spada, 2021). Anxiety sensitivity (AS) is a trait characterized by aversive emotional reactions to feelings or symptoms of anxiety. AS may contribute to the tendencies to be hyper-vigilant to bodily sensations and experience distress when such sensations occur, which are established aspects of the health anxiety cycle (e.g., see Warwick & Salkovskis, 1990; Abramowitz , Olatunji, & Deacon, 2007). We propose that both IU and AS are particularly salient during the COVID-19 pandemic, which may contribute to increased health anxiety during the pandemic (see also Freeston et al., 2022 and Funkhouser, Klemballa, & Shankman, 2022). The pandemic has involved a great deal of uncertainty for all, including uncertainty about how the pandemic will evolve and the risks associated with different circumstances and behaviors, which may have led to substantial distress and maladaptive coping in individuals with high levels of IU (for supporting evidence about specific maladaptive coping behaviors, such as information seeking and reassurance seeking, see Bottesi et al., 2021, Jagtap, Shamblaw, Rumas, & Best, 2021, and Sauer, Jungmann, & Witthöft, 2020; see also Taha et al., 2014 for similar findings from the H1N1 pandemic). Likewise, increased attention to bodily sensations as potential signs of illness has been reinforced (e.g., by daily symptom monitoring/reporting requirements), which may have caused even greater distress amongst individuals with elevated AS (see Asmundson & Taylor, 2020). Consistent with our hypotheses, IU has been linked with a range of problems and symptoms in studies conducted during the pandemic (Akbari et al., 2021, Bakioğlu et al., 2021, Beck and Daniels, 2022, Bottesi et al., 2021, Del-Valle et al., 2022, Di Blasi et al., 2021, Fitzgerald et al., 2022, McCarty et al., 2022, Mertens et al., 2020, Parlapani et al., 2020, Rettie and Daniels, 2021, Sauer et al., 2020, Sohrabzadeh-Fard et al., 2021; Saulnier et al., 2022; Smith, Twohy, & Smith, 2020; Tull et al., 2020; Valle et al., 2020; Wheaton, Messner, & Marks, 2021), including health anxiety (Bottesi et al., 2021, Rettie and Daniels, 2021, Sohrabzadeh-Fard et al., 2021, Tull et al., 2020) and fear of COVID (Baerg & Bruchmann, 2022; Bakioğlu et al., 2021; Çelik et al., 2022; Mertens et al., 2020; Satici, Saricali, Satici, & Griffiths, 2020). Likewise, some recent studies have reported links between AS and problems/symptoms during the pandemic (Manning et al., 2021, Morriss et al., 2021, Rogers et al., 2021, Saulnier et al., 2022; Warren et al., 2021), including COVID fear/anxiety (Çelik et al., 2022; Moghadam, Choukami, & Mousavi, 2021; Rogers et al., 2021; Saulnier et al., 2022; Shabani et al., 2022; Warren et al., 2021). Of note, Saulnier and colleagues (2022) also examined and found support for an interactive effect of IU and AS predicting COVID-related worries and safety/avoidance coping behaviors. Importantly, only a few previous studies during the pandemic have examined the relationships between IU, AS, and/or health anxiety prospectively (Di Blasi et al., 2021, Paluszek et al., 2021, Tull et al., 2020), and no studies have tested these relationships simultaneously. Notably, a recent study published by Paluszek and colleagues (2021) found that AS (as well as disgust sensitivity) predicted the “COVID stress syndrome” (including contamination fears), yet only IU was tested as a hypothesized moderator of those relationships and a significant moderating effect of IU was not observed in that study. Moreover, the present study builds upon previous work by Tull and colleagues (2020), which examined prospective associations between IU and health anxiety, but not AS, in a sample of adults in the United States across a one-month period. Testing prospective associations between IU and AS at the same time in prospective studies would be valuable to confirm if one or both variables can predict changes in symptoms of health anxiety over time, at the same time accounting for cross-sectional links (which are well established), temporal stability, and shared variance. To this end, the present study examined cross-sectional and prospective associations between IU, AS, and health anxiety using cross-lagged panel analysis in an international sample. Specifically, we analyzed online survey data collected from adults at two assessment time points over 6 months during the early stages of the COVID-19 pandemic. Examining changes in IU, AS, and health anxiety over a 6-month period may allow for greater understanding of the interplay between these variables over time, building upon previous cross-sectional and prospective work published during the COVID-19 pandemic. Based on the extant literature, we hypothesized that both IU and AS would both independently predict later levels of health anxiety, after accounting for initial levels of health anxiety and the cross-sectional relationships between these variables. 2 Materials & methods 2.1 Participants The initial sample consisted of 308 participants who completed both initial and follow-up assessments as part of a larger study examining the relationship between symptoms of anxiety and distress, putative risk factors, and coping/safety behaviors during the early stages of the COVID-19 pandemic (for more information, see Church, Bounoua, Rodriguez, Bredemeier, & Spielberg, 2022). Participants were recruited from countries wherein governments recommended COVID-related guidelines similar to those recommended in the US, including Canada, the European Union, and Australia. Due to missing data on all key study variables, seven participants (2.2 %) were removed from the sample. The final sample consisted of 301 adults (42.9 % female, ages 18–65, mean age = 30.9). Most participants were from European countries (89.3 %), and the remaining participants were in the US (6.7 %) or other countries (4.0 %). The only study eligibility requirements were: 1) fluency in English; and 2) residence in a country wherein the government had recommended COVID-related guidelines similar to those recommended in the US, including Canada, the European Union, and Australia. Approximately 3.5 % of the participant sample reported having contracted COVID-19 at the time of data collection. 2.2 Measures The Intolerance of Uncertainty Scale-short version (IUS-12; Carleton, Norton, & Asmundson, 2007) was used to measure responses to uncertainty, the future and ambiguous situations. The IUS-12 is composed of 12 items and has two factors; ‘Prospective IU’ (7 items; e.g., “I always want to know what the future has in store for me”) and ‘Inhibitory IU’ (5 items; e.g., “When I am uncertain I can’t go forward”) (Carleton et al., 2007, McEvoy and Mahoney, 2011). Participants rate each item using a 5-point Likert scale ranging from 1 (“not at all characteristic of me”) to 5 (“entirely characteristic of me”). As demonstrated by the total and subscale scores, the IUS-12 has good internal consistency as well as convergent and divergent validity (Carleton et al., 2007, McEvoy and Mahoney, 2011). Because the two factors are highly correlated (rs >0.62; see Hale et al., 2016 for evidence supporting a bifactor or hierarchal factor structure for the IUS) and we did not have unique hypotheses about them, total scale scores were used in analysis for the current study. Internal consistencies (Cronbach’s alpha) in the current sample were good (time 1: α = 0.87; time 2: α = 0.89). The Anxiety Sensitivity Index-3 (ASI-3; Taylor et al., 2007) is an 18-item self-report questionnaire that measures anxiety sensitivity, or the reflection of one’s tendency to view anxiety-related sensations as aversive. There are three six-item subscales: physical (“It scares me when my heart beats rapidly”), cognitive (“It scares me when I am unable to keep my mind on a task”), and social concerns (“I worry that other people will notice my anxiety”). Items are rated using a five-point Likert scale and range from 0 (very little) to 4 (very much). Like the IUS-12, the ASI-3 subscale scores were strongly correlated (rs >0.48), consistent with the observed hierarchal factor structure of the ASI-3 (consisting of a single “higher order” factor; Rodriguez, Bruce, Pagano, Spencer, & Keller, 2004). Thus, total scale scores from the ASI-3 were used to test a priori hypotheses described above. Evidence supports the internal consistency and factorial validity of the ASI-3 scale, as well as the convergent and discriminant validity of scores (Jardin et al., 2018, Kemper et al., 2012, Taylor et al., 2007). Internal consistencies (Cronbach’s alpha) in the current sample were excellent (time 1: α = 0.90; time 2: α = 0.91). The Short Health Anxiety Inventory (SHAI; Salkovskis, Rimes, Warwick, & Clark, 2002) is an 18-item short version questionnaire derived from the original 64-item Health Anxiety Inventory (HAI; Salkovskis et al., 2002) to assess symptoms over the past 6 months. Example items include “I am often afraid that I have a serious illness” and “I frequently have images of myself being ill”. Each item of the SHAI has four response options that allow individuals to choose what best reflects their feelings over the past 6 months. When creating the SHAI, Salkovskis and colleagues used 14 items from the full HAI with the highest item-total correlations from a sample of patients with hypochondriasis. The remaining 4-items of the SHAI were developed to measure theoretical consequences of having a serious illness. In the present study, the 14 items related to fears of becoming ill and the 4-item negative consequences (of illness) subscale were summed to create total SHAI scores. Research has shown that the SHAI possesses internal consistency, as well as convergent, divergent, factorial and criterion validity that is supported by existing evidence (Abramowitz et al., 2007, Alberts et al., 2013). Internal consistencies of the 18-item SHAI (Cronbach’s alpha) in the current sample were excellent (time 1: α = 0.90; time 2: α = 0.90). To explore whether predictors of changes in health anxiety might be accounted for by coinciding changes in general anxiety, we measured changes in self-report tendencies to worry using the Penn State Worry Questionnaire (PSWQ; Meyer, Miller, Metzger, & Borkovec, 1990). This scale has strong evidence for reliability and validity, and is widely used in basic and applied research on etiology and treatment of generalized anxiety (Brown et al., 1992, Meyer et al., 1990, Startup and Erickson, 2006). Internal consistencies of the PSWQ in the current sample were excellent (time 1: α = 0.94; time 2: α = 0.95). 2.3 Procedures Participants were recruited using an online crowdsourcing platform (Prolific Academic, https://www.prolific.co) in June of 2020 amidst the COVID-19 pandemic. Previous work has indicated that Prolific Academic participants are more diverse than other crowdsourcing platforms, such as Amazon’s Mechanical Turk, therefore increasing the likely representativeness of Prolific samples (Newman et al., 2021, Peer et al., 2017). Follow-up data were collected after a 6-month interval in December 2020. A total of 520 participants completed the 1st wave of data collection and were invited for the 2nd wave. Given anticipated attrition as well as potential variance in the quality of data, a larger participant sample was recruited for the time 1 collection. Additionally, fewer participants were recruited to complete data collection at time 2 due to the study constraints and the increased statistical power of repeated measures designs to test prospective relationships. For the 2nd wave, data was collected from the first 300 individuals who consented to participate. However, due to a technical error, data was collected from 301 individuals. We conducted follow-up independent samples t-tests to examine differences at baseline in key study variables. Results revealed no significant differences between those who completed the 2nd data collection and those who did not on the ASI (p = .246), IUS (p = .743), and SHAI (p = .092). Mean study completion time was approximately 41 min. Thus, to address concerns about the quality of data validity, individuals who completed data collection in less than 20 min (i.e., less than half the mean completion time) at Time 1 (n = 27) were excluded from invitation to participate in the follow-up assessment. Participants provided written consent, obtained through Prolific Academic. All procedures were approved by the University of Delaware Institutional Review Board. Study data were collected and managed using REDCap (Research Electronic Data Capture) tools, a secure, web-based software platform, hosted at the University of Delaware (Harris et al., 2009, Harris et al., 2019). 3 Calculation We explored potential bidirectional effects using cross-lagged panel model analyses. Cross-lagged structural equation modeling was conducted using MPlus v.8 (Muthén & Muthén, 1998) to examine predictive relationships between intolerance of uncertainty (indexed via the IUS-12), anxiety sensitivity (indexed via ASI-3), and health anxiety (indexed via SHAI). Importantly, we planned to examine all three variables within the same cross-lag model in order to estimate cross-sectional and prospective relationships between each set of variables, simultaneously taking into account shared variance among the measures. As noted above, total scale scores were examined from all three measures because our a priori research questions and hypotheses related to the overall constructs rather than facets of these constructs (based on some previous studies of IU and AS during the pandemic which have not shown consistent findings with subscales of the measures; e.g., Tull et al., 2020; Warren et al., 2021). Thus, testing all subscales of the measures may reduce statistical power to address our research questions (because of lower reliability and degrees of freedom). Within the cross-lagged model, autoregressive paths were included, and the variables were allowed to covary within each time point. Of note, two participants were missing SHAI data at Time 2. In order to include all participants with at least partial data, missing data were estimated using maximum likelihood estimator with robust standard errors (MLR). Standardized results are reported below. Follow-up (sensitivity) hierarchal regression analyses were conducted including changes in PSWQ scores as a predictor in step 1, in order to explore whether any observed prospective associations might be driven by changes in generalized anxiety during the early phases of the pandemic. To examine effect sizes, standardized betas may be interpreted similar to correlation coefficients wherein small = 0.1, medium = 0.3 and large = 0.5 (Cohen, 1992). 4 Results Descriptive statistics for the three primary measures at times 1 and 2 are presented in Table 1, and distributions for IU and AS scores (histograms) are presented in Fig. 1, Fig. 2. Notably, 30 participants (10 %) scored greater than or equal to the proposed clinical cutoff of 27 on the SHAI (see Abramowitz et al., 2007) at Time 1, and 33 participants (11 %) scored at or above the clinical cutoff at time 2, suggested elevated levels of health anxiety were not uncommon in our study sample.Table 1 Sample means (and SDs) for total scores from the three study measures at initial administration (T1) and 6-month follow-up (T2). Table 1 T1 T2 IUS-12 34.53 (8.89) 34.18 (9.36) ASI-3 22.05 (12.51) 21.99 (12.96) SHAI 15.51 (7.96) 15.72 (8.37) PSWQ 50.26 (14.91) 50.36 (15.52) Fig. 1 Histograms illustrating distributions of: (top panel A) Intolerance of Uncertainty Scale (IUS) total scores at Times 1 (baseline) and 2 (6 month follow-up); and (bottom panel B) Anxiety Sensitivity Index (ASI) total scores at Times 1 and 2. Fig. 1 Fig. 2 Cross-lagged associations between intolerance of uncertainty, anxiety sensitivity, and health anxiety across six months of the COVID-19 pandemic Note: N = 301. Standardized beta coefficients depicted. Bolded lines represent significant cross-lagged associations of interest, * p < .05. Lines on the left (with corresponding beta coefficient values) represent cross-sectional associations between the three variables at Time 1 (baseline), lines on the right represent correlated residuals between the variables at Time 2 (6 months follow-up), and lines in the middle represent prospective (cross-lagged, from Time 1 to Time 2) associations between variables. Fig. 2 Results from the cross-lagged analysis are presented in Fig. 1. As anticipated based on prior research, all cross-sectional relationships between key study variables were statistically significant at both time points (ps <.01). When examining prospective associations, we found a statistically significant positive association between IU at time 1 and health anxiety at time 2 (β =[ 0.13 p <[ 0.01. Further, we found a statistically significant positive association between IU at time 1 and AS at time 2 (β = .17, p <[ 0.01. In contrast, we found no statistically significant associated between time 1 health anxiety and time 2 IU or AS (ps >.30), nor was time 1 AS statistically significantly associated with time 2 IU or health anxiety (ps >;0.10. All cross-sectional associations were in the medium to large range (βs ==0.30–0.63, and the statistically significant prospective associations were small effects. Scatterplot illustrating the associations between IU at time 1 and health anxiety at time 2 (panel A) and AS (panel B) are shown in Fig. 3.Fig. 3 Scatterplot of the associations between (top panel A) Intolerance of Uncertainty Scale (IUS) scores at Time 1 with Short Health Anxiety Inventory (SHAI) scores at Time 2 (6 month follow-up); and (bottom panel B) IUS scores at Time 1 and Anxiety Sensitivity Index (ASI) scores at Time 2. Fig. 3 Interactions between IU, health anxiety, and AS were not examined in the model because moderation was not part of our research questions/hypotheses. Instead, a post hoc (hierarchal regression) analysis was conducted to explore the interaction between IU and AS predicting health anxiety at follow-up (beyond variance accounted for by baseline health anxiety), based on some recently published findings (e.g., Paluszek et al., 2021; Saulnier et al., 2022). Results from post-hoc analysis did not support an interactive effect of key study variables (β <[ 0.01 p >[ 0.90. In the present regression model, the results for the main effects of IU and AS were very consistent with those from the primary (cross-lag) analysis described above (IU: β = .13, p <[ 0.01 AS: β = .07, p =[ 0.15. Likewise, two sensitivity analyses were conducted using hierarchal regression modeling to predict time 2 health anxiety and time 2 AS with changes in PSWQ scores entered in step 1 (in addition to time 1 health anxiety and AS). In these models, IU scores from time 1 remained a statistically significant predictor of time 2 health anxiety; β = .14, p <[ 0.01 and also time 2 AS; β = .18, p <[ 0.01 5 Discussion The present study explored cross-sectional and longitudinal associations between intolerance of uncertainty (IU), anxiety sensitivity (AS), and health anxiety reported at two time points over 6 months during the early stages of the COVID-19 pandemic. We found that initial levels of IU predicted both health anxiety and AS at follow-up, after accounting for the shared variance among the variables. In contrast, AS and health anxiety did not prospectively predict each other or IU at follow-up when all relationships between key study variables were tested simultaneously. Although the observed prospective effects were small, present study findings provide novel insights into the relationships between IU, health anxiety, and AS in the context of an ongoing global pandemic. The prospective association between IU and health anxiety is consistent with previous work (e.g., Fergus & Bardeen, 2013; Tull et al., 2020), and supports the putative role of IU as a risk factor for health anxiety. Indeed, the consistency of rapidly emerging findings in the past year supporting the role of IU in health anxiety during the pandemic seems to highlight the robustness of this relationship (see also Korte et al., 2021). In addition to substantially increased health risks, a salient aspect of the early stages of the pandemic was the uncertainty of such health risks (in general, and in different contexts; see Freeston, Tiplady, Mawn, Bottesi, & Thwaites, 2020 and Funkhouser et al., 2022). In turn, individuals with elevated IU may have been more likely to overestimate such health risks (e.g., Bredemeier & Berenbaum, 2008; Pepperdine, Lomax, & Freeston, 2018; see Funkhouser et al., 2022) and/or engage in safety behaviors linked with health anxiety (e.g., pathological information seeking, increased attention and reactivity to physical symptoms/sensations) during times of increased uncertainty. Additional research is needed to test IU as a proposed mechanisms and explore whether the present findings pattern have persisted later in the pandemic. In contrast, the lack of a significant prospective association between AS and health anxiety was inconsistent with our predictions and some previous work (e.g., Fergus & Bardeen, 2013; Warren et al., 2021; Wheaton, Berman, & Abramowitz, 2010; but see also Blakey & Abramowitz, 2017 and Olatunji et al., 2009). The present (null) finding will be important to replicate in independent samples, to bolster confidence that the finding is not a Type II error. Together, the current findings may suggest that previous evidence for a temporal link between AS and health anxiety may be driven by unaccounted for shared variance with IU. Indeed, the potential role of IU on the link between AS and health anxiety is bolstered by the observed prospective association between initial levels of IU and both AS and health anxiety at follow-up in the present study, suggesting that IU could contribute to the development or exacerbation of both AS and health anxiety, potentially accounting for some of the shared variance between those constructs (see also Çelik et al., 2022, O’Bryan & McLeish, 2017, O’Bryan et al., 2022, and Wright et al., 2016). Further, the prospective link between initial IU and changes in AS may suggest that individuals with elevated IU tended to become more vigilant (and reactive) to bodily sensations during the pandemic, perhaps as a way to cope with their uncertainty during the ongoing pandemic. More generally, given that both AS and IU are transdiagnostic constructs that may reflect “fundamental fears” (Carleton et al., 2007, Carleton, 2016), and given that the two are moderately correlated, we propose that both AS and IU may be important to study and examine simultaneously in studies of outcomes linked to both (see also Carleton, Fetzner, Hackl, & McEvoy, 2013). The present results build on previous studies examining the correlates and potential consequences of elevated IU and/or AS during the pandemic (e.g., Paluszek et al., 2021; Rettie & Daniels, 2021; Saulnier et al., 2022; Tull et al., 2020; Warren et al., 2021). Indeed, AS may very well contribute to symptoms of emotional distress (including health anxiety) in other ways not captured by our prospective analyses (e.g., pre-pandemic levels of AS may contribute to initial levels of health anxiety). Further, AS may contribute to other related but distinct problems during the pandemic, either independently or interactively with IU (e.g., catastrophizing; Saulnier et al., 2022). The present study has some notable strengths, including the longitudinal study design and sample size (to ensure good statistical power). Of course, the study also has limitations to consider when interpreting the results and planning further research. First, the study relied exclusively on self-report measures, which could lead to some spurious associations attributed to shared method variance. Future studies should utilize other methods to measure one or more key study constructs, such as clinical interviews/ratings. Further, the study used an internet survey platform – although online data collection has important strengths (e.g., diversifying samples, efficiency), the use of online crowdsourcing platforms carries some elevated risk of invalid responding, even when methods are used to limit or identify such data (e.g., based on short survey completion times). Further, the extent to which present study findings can be generalized to other samples, or other times remains unclear. The lack of demographic information such as participant ethnicity, occupation, or SES limits our conclusions and confidence about the generalizability of present study findings, as well as our ability to conduct further analyses across different subgroups (e.g., education, socioeconomic status, or health status) which may highlight unique differences in the relationship between key study variables. Prospective studies over longer time periods, and with more than two observation points, would permit testing more complex models of the temporal links between IU, AS, and health anxiety, including mediational models. Notably, the extent to which baseline SHAI scores from the current study captured levels of pre-pandemic vs. early pandemic health anxiety remains unclear, particularly given the timeframe assessed by the SHAI (past 6 months). Indeed, pre-pandemic sentiment of health anxiety may give support to the relationships explored in the current study by providing unique insight into the maintenance and exacerbation of health anxiety within the context of a global pandemic. Additionally, our measure of health anxiety did not specifically address COVID-specific health anxiety (which was not examined due to the lack of established measures when this study was initiated), and therefore it remains unclear the extent to which the relationship between intolerance of uncertainty and anxiety sensitivity may uniquely or differentially related to COVID-specific health anxiety. More generally, collection of baseline data prior to the onset of the pandemic would have supported more definitive conclusions about pre-pandemic relations between IU, health anxiety, and AS as well as changes in these variables associated with pandemic conditions. Further, small effects like those observed in the present study are expected and common in longitudinal research in the field, however more research is needed to explore/confirm the clinical significance of these prospective relationships. Last, but most importantly, the prospective analyses and results provide stronger evidence for theorized causal links than cross-sectional data alone but are by no means sufficient to establish causality. More prospective studies are needed, and importantly, future studies should aim to measure these constructs more times and/or over a longer timeframe, and critically, should include and examine other important variables known or hypothesized to contribute to health anxiety. Advancing research on health anxiety, particularly doing a global pandemic, could illuminate potential mechanisms driving associations between IU and increases in health anxiety. If supported in future research, findings from the present study may have some valuable clinical implications. In particular, present study findings highlight the potential utility of focusing attention and efforts on elevated IU in programs to reduce or prevent health anxiety during the pandemic. For example, IU may be a valuable target in the treatment of health anxiety, perhaps utilizing IU-focused intervention that have been developed and tested for treating generalized anxiety (see Robichaud & Dugas, 2006 and Hebert & Dugas, 2019). Indeed established cognitive-behavioral therapy approaches for health anxiety have shown promise during the pandemic (e.g., see Sharrock et al., 2021), however there is potential for cognitive-behavioral treatment programs/protocols to be bolstered by incorporating IU-focused strategies developed by Dugas and colleagues for improving uncertainty tolerance. Measuring IU as a method for identifying individuals at risk for health anxiety could also have value, though the utility of IU as a risk factor is likely to be contingent of the magnitude of relationship between these variables. Although effect sizes observed in the present study were small, the smaller sizes could be due in part to the short timeframe of the follow-up and/or limitations of the measures. In addition to work aiming to replicate our results and addressing the limitations discussed above, future studies should aim to directly test speculative clinical implications. 6 Conclusion In summary, the present study tested prospective links between intolerance of uncertainty, anxiety sensitivity, and health anxiety over 6 months during the early stages of the pandemic using cross-lagged analysis. Results revealed that initial levels of intolerance of uncertainty predicted levels of health anxiety 6 months later, as well as anxiety sensitivity 6 months later. Although questions remain about the nature and time course of the relationships between IU and health anxiety, present study findings may have important implications for theories and treatment of health anxiety. Funding statement This research did not receive any specific funding from agencies in the public, commercial, or not-for-profit sectors. During the time that this manuscript was written, KB received funding from the 10.13039/100006093 Patient-Centered Outcomes Research Institute (CER-2020C1-19382) and the 10.13039/100000025 National Institute of Mental Health (R21 MH123888-01A1). LDC received funding from the 10.13039/100000001 National Science Foundation (2021317035), and NB received funding from the 10.13039/100000025 National Institute of Mental Health (F31MH120936). Ethical approval statement Study procedures were approved by the University of Delaware Institutional Review Board. Participants provided written consent, obtained through Prolific Academic. Conflict of interest The authors have no conflicts of interest to disclose. Data availability Data are available from the authors by request. ==== Refs References Abramowitz J.S. Deacon B.J. Valentiner D.P. 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==== Front J Environ Psychol J Environ Psychol Journal of Environmental Psychology 0272-4944 0272-4944 The Author(s). Published by Elsevier Ltd. S0272-4944(22)00188-8 10.1016/j.jenvp.2022.101943 101943 Article Anthropause appreciation, biophilia, and ecophilosophical contemplations amidst a global pandemic Kolandai-Matchett Komathi a∗ Milne Barry a McLay Jessica b von Randow Martin a Lay-Yee Roy a a COMPASS Research Centre, School of Social Sciences, Faculty of Arts, University of Auckland, New Zealand b Department of Statistics, University of Auckland, New Zealand ∗ Corresponding author. 13 12 2022 13 12 2022 1019432 8 2022 7 12 2022 9 12 2022 © 2022 The Author(s). Published by Elsevier Ltd. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. In 2020, COVID-19 mitigation measures, including lockdowns and travel bans to curtail disease transmission, inadvertently led to an “Anthropause” – a unique global pause to anthropogenic activities. While there was a spike in ecological studies measuring Anthropause effects on environmental indicators, people's experiences of the Anthropause or its potential to inspire change were hardly considered. Hence, we aimed to measure people's appreciation of the environmental outcomes of the Anthropause, ecophilosophical contemplations about the pandemic, and experiences of lockdown-triggered biophilia (human's innate love for and draw towards nature) and test the hypothesis that these experiences would be consistently more prominent among the already environmentally inclined. To that end, we developed and tested three measures on a representative sample of 993 New Zealanders. Anthropause Appreciation received the highest overall mean ratings, followed by Lockdown-Biophilia and Eco-Contemplation. Pre-existing pro-environmental dispositions and behaviours did not consistently influence our three measures as expected. Demographic variables had little influence, while experiences of financial and mental health impacts due to COVID-19 had no influence. We interpreted the limited influence of explanatory variables as indicative of a degree of uniformity in people's experiences. High appreciation of Anthropause benefits suggests that the public may be supportive of policies and ways of living that can lead to similar outcomes post-pandemic – offering environmental policymakers and communicators a basis for action. Ecophilosophical contemplations and biophilic draw among the public suggest an awareness of the significance of the human-nature relationship – offering a symbolic global keystone for communicating and advocating conservation and the many values of pauses in life to connect with nature. Building women's environmental leadership capabilities and the ongoing greening of Christianity may be essential steps for global post-pandemic environmental behaviour transformations. Keywords Anthropause Ecophilosophy Biophilia Environmental attitudes Environmental perceptions Post-pandemic environmental behaviour Handling Editor: W. Schultz ==== Body pmc1 Background While the present study aimed to measure environmental perceptions and experiences within the context of the Coronavirus Disease-2019 (COVID-19) pandemic, we first acknowledge the immeasurable ensuing global suffering. For humans, it is not just illness and countless deaths but also distress over extensive social disruptions and economic slowdowns (Katz, McInerney, Ravindran, & Gold, 2021; Nicola et al., 2020). Non-human animals endured a more silent suffering in the form of abandonment and neglect due to being perceived as virus transmitters and death through hasty mass culling due to being detected with virus mutations (Fantini, Devaux, Yahi, & Frutos, 2022; Frutos & Devaux, 2020; Parry, 2020). With an estimate of 3.4 billion single-use facemasks being discarded daily, the pandemic has also been environmentally detrimental (Benson, Bassey, & Palanisami, 2021). However, the unique global cessation of human activities due to COVID-19 mitigation measures (lockdowns and travel restrictions), coined as the “Anthropause” by Rutz et al. (2020), led to favourable environmental outcomes such as reduced air pollution and environmental noise (Sarkar, Debnath, & Reang, 2020; Zambrano-Monserrate, Ruano, & Sanchez-Alcalde, 2020). A quieter and less polluted environment; the increased presence of birdlife; and nature's opportunity to regenerate were among the positive aspects of the pandemic identified by survey respondents in the US and New Zealand (Every-Palmer et al., 2020; Haasova, Czellar, Rahmani, & Morgan, 2020; M. Jenkins et al., 2021) – providing some indication of public appreciation of the Anthropause. Ecophilosophical musings, defined as contemplations about nature and our relationship with it (Fairweather, 1993), became pronounced during the pandemic. For instance, that the pandemic is an ‘Earth-cleansing blessing in disguise’ that would allow plant and animal life to reclaim their land and ‘Mother Earth to heal, recharge, replenish and rebalance’, were among metaphors and expressions referring to the need to end unkind treatment of animals and mitigate anthropogenic damage to ecosystems (Choudhary, 2020; Kamdi & Deogade, 2020; Khan & Yadav, 2020). Biophilia, the innate emotional affiliation that humans have with non-human life forms (Wilson, 1984, 2017), became indirectly evident during lockdowns. Globally, there was an increase in demand for urban parks during the pandemic (Geng, Innes, Wu, & Wang, 2020). Increased visits to densely covered trails, forest reserves, and other green spaces were recorded in Norway, Germany, Hong Kong, Singapore, Tokyo, and Seoul (Derks, Giessen, & Winkel, 2020; Lu, Zhao, Wu, & Lo, 2021; Venter, Barton, Figari, & Nowell, 2020), and also reported in public surveys in the US and the UK (Grima et al., 2020; Robinson, Brindley, Cameron, MacCarthy, & Jorgensen, 2021). Inability to access desired nature venues during lockdowns led to feelings of nature deprivation, which was in turn associated with reduced emotional health and wellbeing (Tomasso et al., 2021; Wheaton, Waiti, Olive, & Kearns, 2021) – suggesting signs of unfulfilled biophilia (Wilson, 1984, 2017). Within ecological and conservation sciences, the Anthropause was regarded as a natural experiment, offering scientists an unprecedented opportunity to measure changes in natural ecosystems and animal behaviour in the absence of environmentally damaging human activity (Bates, Primack, Moraga, & Duarte, 2020; Montgomery, Raupp, & Parkhurst, 2021) – partly explaining the spike in studies documenting lockdown effects on environmental indicators (see Loh et al., 2021). By comparison, within the social sciences, there is a dearth of studies examining public appreciation of the Anthropause. While lockdown-related ecophilosophical musings were expressed by scholars, we have little understanding of the extent to which members of the public experienced similar contemplations. Increased green space visits during the pandemic implied a biophilic draw – the innate love and attraction that humans have for nature and non-human lifeforms (Wilson, 1984, 2017). However, experiences of lockdown-related biophilia were hardly directly measured. At the time of research conceptualisation, we did not identify any preceding research that had considered New Zealanders' views in these regards. A strict nationwide COVID-19 lockdown was implemented between 25 March and 27 April 2020 in New Zealand – providing its residents 33 days of complete Anthropause. This was followed by less restrictive lockdowns from 28 April to 13 May 2020 nationwide and between 12 and 30 August 2020 in Auckland (New Zealand's largest city), where some movement was allowed – providing additional days of partial Anthropause. We developed three item-sets to measure people's appreciation of the positive environmental outcomes of the Anthropause, COVID-19-related ecophilosophical contemplations, and experiences of biophilia during lockdown. The item-sets (presented as matrix questions) were added to the International Social Survey Programme (ISSP) Environment questionnaire, which measured general environmental perceptions, values, and behaviour, while also eliciting an extensive range of demographic details (see Supplementary Document 1). In this paper, we consider how these unique COVID-19-related environmental perceptions and experiences, and the associated predictors might help shape post-pandemic environmental behaviour change. 2 Preceding research, measures, and hypotheses In this section, we first describe recent and past research that guided our development of items to measure people's appreciation of the Anthropause, ecophilosophical contemplations about the COVID-19 pandemic, and feelings of biophilia during the COVID-19 lockdown in 2020. Next, we present a set of theory-based hypotheses about how the sample might respond to these item-sets. 2.1 Beneficial outcomes of the anthropause The most notable Anthropause outcome was an 8.8% reduction in global carbon emission in the first half of 2020, coinciding with COVID-19 lockdowns (Liu et al., 2020). Decreases in vehicular traffic and industrial activity reduced atmospheric pollutants and particulate matter concentrations in heavily populated cities and regions (Kumari & Toshniwal, 2020; Le et al., 2020; Liu et al., 2020), including in the city of Auckland, New Zealand (H. Patel, Mondal, & Ghosh, 2020). Walking and cycling increased during periods of lockdown (Morse, Gladkikh, Hackenburg, & Gould, 2020; van Leeuwen, Klerks, Bargeman, Heslinga, & Bastiaansen, 2020), suggesting a positive change in mobility behaviour. In some regions, reduced industrial discharge, tourism activities and motorboat use led to cleaner rivers and waterways (Braga, Scarpa, Brando, Manfè, & Zaggia, 2020; Patel, Mondal, & Ghosh, 2020), improved coastal water quality, and cleaner beaches (Cherif et al., 2020; Coll, 2020; Okuku et al., 2020; Ormaza-Gonzaìlez, Castro-Rodas, & Statham, 2021). Noise pollution, regarded by the World Health Organization as the third most harmful type of environmental pollution, lessened – benefitting humans and wildlife (Bahukhandi, Agarwal, & Singhal, 2020; Basu et al., 2021; Coll, 2020). Increased terrestrial wildlife movement observed in different parts of the world; reduced roadkill; changes in birdlife communication behaviour and higher breeding success; and increased sightings of marine and freshwater species during the Anthropause were indicative of nature's restorative capacity and how a better environment for wildlife can be achieved with reduced vehicles, human presence, human mobility, and anthropogenic noise (Bar, 2021; Coll, 2020; Derryberry, Phillips, Derryberry, Blum, & Luther, 2020; Manenti et al., 2020; Silva-Rodríguez, Gálvez, Swan, Cusack, & Moreira-Arce, 2020). Albeit temporary, the Anthropause offered real environmental outcome indicators that may affect how people respond to environmental issues post-pandemic. We designed eight items to measure Anthropause Appreciation (see Section 3.2). 2.2 COVID-19-related ecophilosophical contemplations Ecophilosophy may be defined as “thinking about nature and our relationship with it, and as such has been the intellectual underpinning of environmentalism” (Fairweather, 1993, p. 5). Contemplative attention to the natural world is not only a spiritually significant act in its own right but can also engender ethical actions (Eggemeier, 2014). Reflecting on the pandemic, scholars from different disciplines called for a rethinking of people's relationship with and treatment of nature and animals:• “To my introspective mind, this chapter of COVID-19 pandemic … represents … a reflective and contemplative moment of our collective consciousness to ponder on the symbiotic interconnectedness of human environment-animal (wildlife) interface and in a broader perspective ‘The Earth-Human System’ interactions. We need to question the “human hubris of anthropocentrism,” the very purpose of human existence, in relation to ecosystems health, and realize how we are on a collision course between the human species and environmental and nature's ecosystems.” Bhaskara Shelley, Physician (Shelley, 2020, p. 2). • Running out of patience with us, I imagine Mother Nature saying to us, “…I'm sending a lethal virus to remind you of the unitary nature of your consciousness and its inseparability with the natural world. Perhaps these life-and-death conditions will shock you into an awakening. Under social lockdown and isolation, perhaps you will rediscover your capacity to communicate beyond the reach of your senses.” Larry Dossey, Physician (Dossey, 2020, p. 345). • The COVID-19 pandemic “shows the impacts of the ‘human-nature’ dichotomy of the Anthropocene era. Therefore, it calls for personal, societal, and global changes and transformations.” Anastasia Zabaniotou, Chemical engineer (Zabaniotou, 2020, p. 122). • Considering how past calls for lifestyle changes have not been taken seriously despite ongoing environmental deterioration, “nature herself has forced humans through COVID-19 to adjust in favour of environmental health.” Peter Bisong, Philosophy and business management scholar (Bisong, 2020, p. 126). Open-ended responses in a New Zealand-based survey also hinted at ecophilosophical contemplations, with participants expressing hope that the positive environmental outcomes of COVID-19 would be long-lasting and that the pandemic would prove to be a blessing for humankind (M. Jenkins et al., 2021). Among Indigenous communities in Australia, references to ‘Mother Earth’ resurged, emphasising the essentiality of nature for not only human wellbeing but also human survival (Weckert, 2020). The idea that COVID-19 is nature's message to humankind was a metaphor directing attention to ecological symptoms that call for a more careful treatment of nature – in other words, a wake-up call to humanity (Weckert, 2020). In the US, some survey respondents held perceptions of the pandemic as bearing a higher-order purpose (i.e. a message that humans are not in control over nature, a warning from nature, and punishment for humankind's transgressions) (Haasova et al., 2020). They also identified strengthened social ties with family and friends, and collective values such as altruism and being helpful, as positive outcomes of the pandemic (Haasova et al., 2020) – values that are known contributors to human happiness (Kesebir & Diener, 2009). The distinction between “essential” and “non-essential” services in official communications and the closure of shopping outlets during mandated lockdowns may have provided people with a never-before-experienced “pause” to reflect on actual needs and happiness. People may have mused over non-material sources of happiness – distinguishing it from the fleeting happiness gained from commercially-induced needs-transcending consumption (Binswanger, 2006; Kolandai-Matchett, 2009; Lane, 1994; Ricard, 2017; Sachs, 2012). This was regarded as an important contemplation, considering that escalating production and consumption is a major contributor to environmental decline (IPBES, 2019; Lorek & Vergragt, 2015) and materialism has been associated with environmental apathy (Good, 2007; Kilbourne & Pickett, 2008). Scholars also proposed that lessons learned from the pandemic, that can be used for addressing global environmental problems such as climate change and biodiversity loss, include the value of collective and early action (Bouman, Steg, & Dietz, 2020; Jin, 2020; Perkins, Munguia, Ellenbecker, Moure-Eraso, & Velazquez, 2021; Rousseau & Deschacht, 2020). Collective behaviours were pivotal for the success of COVID-19 mitigation measures, and official public health messages emphasised shared responsibility and collective action (Sutton, Renshaw, & Butts, 2020; Wolf, Haddock, Manstead, & Maio, 2020). Our second item-set thus aimed to measure COVID-19-related Ecophilosophical Contemplation (Eco-Contemplation) during lockdown (see Section 3.2). 2.3 Lockdown-triggered biophilia The biophilia hypothesis, which posits that humans have an innate emotional affiliation with non-human life forms (Wilson, 1984, 2017), has been supported by a considerable number of studies (see, Annerstedt & Währborg, 2011; Gillis & Gatersleben, 2015; Howell & Passmore, 2013; Joye, 2007). The biophilic draw becomes particularly pronounced during disasters and hazardous situations, as humans seek doses of nature-connectedness to establish resilience to cope with the calamity they face (Tidball, 2012). People thus feel an immediate biophilic draw toward nature following mandated COVID-19 lockdowns (Gillis, 2020) – which likely explains the global increase in visits to urban parks and green spaces during the pandemic (Derks et al., 2020; Geng et al., 2020; Lu et al., 2021; Venter et al., 2020). This increase would be unsurprising to Eco-Existential Positive Psychology proponents, who have contended that cultivating the innate biophilic tendency through nature-connectedness helps address six fundamental existential anxieties: meaning in life, death, isolation, freedom, identity, and happiness (Passmore & Howell, 2014). In the US and the UK, people reported enhanced feelings of nature-connectedness and awareness of nature's importance for coping with the pandemic and maintaining mental wellbeing (Grima et al., 2020; Lemmey, 2020; Morse et al., 2020; Robinson et al., 2021). The importance of urban green spaces for the psychological wellbeing of city dwellers (Barton & Rogerson, 2017; Houlden, Weich, Porto de Albuquerque, Jarvis, & Rees, 2018; McCunn, 2020; Ugolini et al., 2020) became notable as access to such spaces helped people better cope with mandated stay-at-home orders (Dzhambov et al., 2021; Pouso et al., 2021). We developed a third item-set to measure Lockdown-triggered Biophilic draw (Lockdown-Biophilia) during a period of mandated stay-at-home order (see Section 3.2). 2.4 Research objectives and hypotheses First, we aimed to gauge the extent to which people (i) appreciated the positive outcomes of the Anthropause and experienced (ii) Eco-Contemplations and (iii) Lockdown-Biophilia during lockdown. Second, we aimed to test six theory-based hypotheses. Considering observations in preceding studies, we expected pre-existing pro-environmental dispositions and behaviour to be consistently associated with higher Anthropause Appreciation (H1), Eco-Contemplation (H2), and Lockdown-Biophilia (H3) ratings. In the US, nature-connectedness was associated with positive thoughts about the pandemic's environmental benefits (Haasova et al., 2020), and in Italy, a pro-environmental attitude was associated with a tendency towards making sustainable purchases during the pandemic (Peluso, Pichierri, & Pino, 2021). To test H1–H3, we selected nine ISSP variables to represent multiple domains of pro-environmental dispositions and behaviours (Larson, Stedman, Cooper, & Decker, 2015; Truelove & Gillis, 2018) – attitude towards environmental problems (environmental concern), connectedness with nature (nature enjoyment, engagement in nature activities), private environmental behaviour (recycling, product avoidance, non-consumption of meat), public environmental behaviour (past-5-year environmental actions, environmental group membership), and political orientation (voting for the Green party). In view of the influence of self-efficacy and scepticism on collective environmental actions (Bamberg, Rees, & Seebauer, 2015; Lauren, Fielding, Smith, & Louis, 2016; Zhou, 2014), we expected that environmental self-inefficacy (H4) and scepticism (H5) would be negatively associated with Eco-Contemplation-item#3 (contemplations about collective action for nature protection as a learning from COVID-19 responses). We examined this item separately, considering that the efficacy of quick and collective action against the global threat of COVID-19 was a unique learning from COVID-19 with implications for addressing global issues such as climate change and biodiversity (Bouman et al., 2020). Not being able to shop and the opportunity to self-reflect on essential needs and happiness under lockdown (Eco-Contemplation-item#4) was another unique COVID-related experience that we sought to examine in more depth, considering that needs-transcending consumption is often the root cause of environmental problems (Lorek & Vergragt, 2015). As women tend to shop as a pastime and are more prone to compulsive buying (Black, 2007; Campbell, 2000; Neuner, Raab, & Reisch, 2005; Tarka, Harnish, & Babaev, 2022), we hypothesised that women (vs men) would have experienced a greater degree of personal reflections concerning shopping during lockdown as described in Eco-Contemplation-item#4 (H6). The influences of demographic variables on environmental attitudes and behaviour have been mixed and, to some extent, dependent on the specificity of outcomes being measured (Fisher, Bashyal, & Bachman, 2012; Jones & Dunlap, 1992). Although most studies show females to be more inclined towards environmentally-conscious behaviour than males, a few show the opposite trend or a lack of gender difference (see Fisher et al., 2012; Hunter, Hatch, & Johnson, 2004). Given the novelty of the Anthropause Appreciation, Lockdown-Biophilia and Eco-Contemplation item-sets, we explored the influence of demographic variables (gender, ethnicity, area of dwelling, religion, age, and qualification) without prior hypotheses. Additionally, considering the scale of economic (Brodeur, Gray, Islam, & Bhuiyan, 2021; Nicola et al., 2020) and mental health impacts of COVID-19 (Rajkumar, 2020; Xiong et al., 2020), we explored if personal experiences of impact on income and mental health due to COVID-19 affected ratings on our three item-sets. 3 Method 3.1 Survey implementation and sample Data were collected between 22 February and 30 June 2021, primarily using a mail survey method with the option of completing the survey online. Invitations with an information sheet, the questionnaire, and pre-paid return envelopes were sent to a stratified random sample of 5388 individuals selected from the New Zealand Electoral Roll, which resulted in 993 responses. Responses were weighted to represent the population (see von Randow, Kolandai, & Milne, 2021 for details). The questionnaire (see Supplementary Document 1) and research methods were approved by the University of Auckland Human Participants Ethics Committee (Ref. 3136). Appendix A provides the descriptive statistics of our sample. 3.2 Dependent variables We used a deductive approach (based on recent and past literature detailed in Section 2) for item generation (see Table 1 ). For each item-set, a 10-point anchored rating scale was used with a “can't choose” answer option added to ensure elicitation of actual experiences and perceptions. The Anthropause Appreciation item-set asked respondents to rate the value of eight environmental outcomes during COVID-19 lockdowns. In the Eco-Contemplation item-set, respondents indicated the extent to which four ecophilosophical statements concerning the pandemic represented their perceptions. In the Lockdown-Biophilia item-set, respondents indicated the extent to which three statements denoting biophilia were reflective of their feelings.Table 1 Dependent variables. Table 1Anthropause Appreciation Eco-Contemplation Lockdown-Biophilia 1 = Not at all valuable 1 = Not at all 1 = Not at all 10 = Highly valuable 10 = To a great extent 10 = To a great extent #1 Reduced carbon emissions #1 I believe the COVID-19 pandemic is Mother Nature's way of forcing us to stop and contemplate our existence #1 I felt a greater need to be in nature (e.g. park, beach, community garden) during COVID-19 lockdown #2 Cleaner air #2 I believe the COVID-19 pandemic is proof that our wellbeing is linked with that of other lifeforms #2 I felt a stronger connection to nature during COVID-19 lockdown #3 Increased sustainable travel (e.g. walking, cycling) #3 I believe the COVID-19 crisis showed us that collective action works, and we should do the same to protect nature #3 Being in nature during COVID-19 lockdown contributed to my feelings of mental/emotional wellbeing #4 Cleaner rivers/waterways #4 Not being able to go shopping under COVID-19 lockdown made me reflect on real needs and happiness #5 Cleaner beaches #6 Reduced noise pollution (e.g. lack of traffic noise) #7 Better environment for wildlife #8 Restoration of ecological systems Given the reliable internal consistency of the Anthropause Appreciation (α = 0.953, n = 841), Eco-Contemplation (α = 0.771, N = 861), and Lockdown-Biophilia item-sets (α = 0.919, N = 933), these were treated as scales in our analyses. 3.3 Independent variables Adding our item-sets to the ISSP Environment questionnaire enabled us to examine responses based on two types of predictor variables – pre-existing pro-environmental dispositions and behaviour (Table 2 ) and demographics which included two measures on COVID-19 financial and mental health impacts (Table 3 ).Table 2 Environmental predisposition variables. Table 2Variable Description Environmental concern “How concerned are you about environmental issues?“, elicited response in a 5-point scale anchored by 1, not at all concerned and 5, very concerned Nature enjoyment “How much, if at all, do you enjoy being outside in nature?“, elicited ranked ordinal responses: not at all, to a small extent, to some extent, to a great extent, to a very great extent. Considering the small number of “not at all” responses (n = 6), these were merged with the “to a small extent” group, creating four categories. Engagement in nature activities “In the last twelve months, how often if at all have you engaged in any leisure activities outside in nature, such as hiking, bird watching, swimming, skiing, other outdoor activities, or just relaxing?“, elicited ranked ordinal responses: never, several times a year, several times a month, several times a week, daily. Recycling “How often do you make a special effort to sort glass or tins or plastic or newspapers and so on for recycling?“, elicited ranked ordinal responses: never, sometimes, often, always. Considering the small number of “never” responses (n = 13), these were merged with the “sometimes” group creating three categories. Product avoidance “How often do you avoid buying certain products for environmental reasons?“, elicited ranked ordinal responses: never, sometimes, often, always. Non-consumption of red meat “In a typical week, on how many days do you eat beef, lamb, or products that contain them?“, elicited responses on a 0–7 scale. Responses were recoded to a dichotomous variable – meat consumption: yes (1–7), no (0). Past-5-year environmental actions A set of three yes/no dichotomous questions asked respondents if “in the last five years” they had “signed a petition about an environmental issue”, “given money to an environmental group”, “taken part in a protest or demonstration about an environmental issue”. These were summed into a single variable indicating the number of actions ranging from zero to three. Environmental group membership “Are you a member of any group whose main aim is to preserve or protect the environment?“, elicited a dichotomous response: yes, no Voting for the Green Party “For which party did you cast your party vote at the 2020 General Election?“, requested respondents to select from a list of six New Zealand political parties, specify a different party, or indicate if they had chosen not to vote or were not eligible to vote. Responses were recoded to a dichotomous variable – Green party voting: yes, no. Environmental self-efficacy Two items measuring self-efficacy (see Pisano & Lubell, 2015), “It is just too difficult for someone like me to do much about the environment” and “I find it hard to know whether the way I live is helpful or harmful to the environment”, elicited Likert scale responses: agree strongly, agree, neither agree nor disagree, disagree, disagree strongly. Environmental scepticism Two items measuring scepticism (see Zhou, 2014), “Many of the claims about environmental threats are exaggerated”, and “There are more important things to do in life than protect the environment”, elicited Likert scale responses: agree strongly, agree, neither agree nor disagree, disagree, disagree strongly. Table 3 Demographic variables and personal impact of COVID-19 measures. Table 3Variable Description Gender Responses to an open-ended question, “What is your gender?” were transformed into a dichotomous variable – Gender: female, male. Ethnicity A multiple select question, “To which of the following ethnic groups do you belong”, enabled respondents to select one or more of twelve ethnicities – a method that complies with the Statistical Standard for ethnicity in New Zealand. These were recoded into five non-mutually exclusive dummy variables (New Zealand Māori, European, Pacific, Asian, Other). Dwelling A single select question, “Would you describe the place where you live as…“, asked respondents to select from five categories: a big city, the suburbs or outskirts of a big city, a town or small city, a country village, a farm or home in the country. Responses were recoded to a dichotomous variable, dwelling: country (the first three categories), city (the last two categories). Religion A single select question, “Which one of these categories describes your current religion?“, elicited nominal responses: No religion, Christian, Buddhist, Hindu, Muslim, Jewish, Another religion. The small number of “Jewish” responses (n = 2) were merged with the “Another religion” category. Age Respondents were asked to indicate their year of birth. Age was calculated and categorised into four age bands for analysis: 19–24, 25–44, 45–64, and ≥65. Qualification level A single selection question, “Which one of these categories best describes your highest formal qualification?“, asked respondents to select from eight ranked categories ranging from no formal qualification through to postgraduate or higher. These were re-grouped into six ordered categories: no formal qualification, primary school completed; secondary school qualification; trade or professional certificate or diploma below degree level; undergraduate degree; postgraduate or higher. COVID-19 financial and mental health impacts “How would you rate the impacts COVID-19 has had on you personally? (1) Impact on my usual income, (2) Impact on my emotional/mental wellbeing”, elicited ranked ordinal responses: very negative, slightly negative, neither negative nor positive, slightly positive, very positive. 3.4 Analyses Analyses were performed with Stata-SE17 and SPSS 27, using survey weights in all instances (see von Randow et al., 2021). First, to provide an overview of the extent to which people appreciated the Anthropause and experienced Eco-Contemplations and Lockdown-Biophilia, we considered the overall mean ratings for the three scales. We also considered the percentage of respondents providing high (mean ≥ 8), moderate (mean 3.1–7.9), and low (mean ≤ 3) ratings in the 1–10 scales of our measures. Next, Spearman's correlations were used to assess the collinearity of all explanatory variables except for the nominal variable, religion (see the bivariate correlation matrix in Appendix B). The association strengths between some pre-existing environmental disposition variables were moderate (.3–0.4), while most other associations were low (<0.3). Then, multiple regression analyses were performed to test the hypotheses that pre-existing pro-environmental dispositions and behaviours would be consistently associated with higher Anthropause Appreciation, Eco-Contemplation, and Lockdown-Biophilia (H1–H3), and to explore the influence of demographic and COVID-19 personal impact variables on the scales' ratings. All nine environmental predisposition and eight demographic predictor variables were entered into the models simultaneously. A backwards-elimination approach of sequential removal of the least significant variable at each stage was used to generate the final models. Missing values were not included as categories in the models for dichotomous and ranked ordinal predictor variables. For the nominal variable, religion, which had 27 missing values, missing was treated as a category in the models, and regression-based pairwise comparisons were examined. Squared semi-partial correlation coefficients (sr2) were computed for the final models to provide indications of the unique amount of variance contributed by each independent variable. To give an overview of the raw relationships between each predictor variable and our three dependent measures, plots based on bivariate regression analyses are provided in Supplementary Document 2 – these detail the most significant predictors as well as less significant and non-significant predictors, the inspection of which is instrumental for an accurate interpretation of the multivariable analysis (Gilliver & Valveny, 2016). Bivariate linear regression models were used to test H4 and H5, which posited that higher environmental self-efficacy and lower environmental scepticism would be associated with stronger reflections about collective environmental action as a learning from COVID-19 (Eco-Contemplation-item#3). We tested H4 with two predictor variables denoting environmental self-efficacy, and H5 with two variables denoting environmental scepticism individually rather than as scales. Although measuring similar constructs (see Table 2), they showed low reliability with coefficients of 0.442 and 0.636, respectively, when tested with Spearman-Brown reliability tests for two-item scales (Eisinga, Grotenhuis, & Pelzer, 2013). An independent-samples t-test (and Cohen's D as an effect size measure) was used to test H6, which proposed that women would provide higher Eco-Contemplation item#4 ratings than men. 4 Results 4.1 Overall responses Anthropause Appreciation received the highest overall mean ratings (M = 8.02), followed by Lockdown-Biophilia (M = 6.27) and Eco-Contemplation (M = 6.18) (see Appendix C for descriptive statistics). Anthropause Appreciation ratings were high (mean ratings ≥8) among a majority (61.3%) and moderate (mean ratings 3.1–7.9) in over a third (36.1%) – suggesting a prominent appreciation of Anthropause-related environmental outcomes. Over a third (35%) experienced an extreme biophilic draw during the lockdown, while close to half (47.5%) experienced this at a moderate level. Over a quarter (26.8%) experienced high Eco-Contemplations about the pandemic, while a majority (62.6%) experienced this moderately. Only a minority provided low-end ratings (mean ratings ≤3) in the three scales – 2.6%, 10.6%, and 17.4%, respectively. 4.2 Hypothesised predictors Collectively, the predictor variables accounted for 25.7% (F (11, 902) = 22.66, p < 0.001, R 2 = 0.2566) of the variance in the Anthropause Appreciation ratings. There was little support for H1 as only three environmental predisposition variables retained significance in the final multiple regression model (see Table 4 ). Increases in environmental concern, in particular, and frequency of engagement in nature-based activities, and frequency of product avoidance were associated with increases in Anthropause Appreciation.Table 4 Multiple regression associations of Anthropause Appreciation with environmental predisposition and demographic variables. Table 4Predictor variables β SE t p 95% CI sr2 Constant 4.622 0.694 6.66 <0.001 3.259 5.984 Environmental concern 0.625 0.143 4.37 <0.001 0.344 0.906 0.0916 Nature-based activities frequency 0.171 0.071 2.42 0.016 0.032 0.311 0.0089 Product avoidance frequency 0.307 0.108 2.84 0.005 0.095 0.520 0.0155 Gender (0 = male, 1 = female) 0.595 0.177 3.37 0.001 0.248 0.942 0.0241 Age −0.327 0.070 −4.67 <0.001 −0.465–0.190 0.0237 Religion: Hindu vs No religion 0.975 0.263 3.71 <0.001 0.460 1.490 0.0064 Religion: Hindu vs Christian 0.908 0.266 3.42 0.001 0.387 1.429 0.0055 Religion: Hindu vs Another religion 1.182 0.482 2.45 0.014 2.128 0.236 0.0178 Religion: Buddhist vs No religion 0.399 0.204 1.95 0.051 0.002 0.800 0.0008 An interesting observation when we consider the bivariate associations (Fig. S1, Supplementary Document 2) was the relatively high Anthropause Appreciation ratings (Means between 6.7 and 8.3) even among those with lower or lowest-end environmental predispositions in all predictor scenarios except for environmental concern where the mean rating among those in the “not at all” category was 4.8. Overall, predictor variables accounted for 20.5% (F (7, 904) = 15.05, p < 0.001, R 2 = 0.2049) of the variance in Eco-Contemplation ratings. There was little support for H2. Only environmental concern, nature-based activities, and product avoidance retained significance in the final multiple regression model with increases in these scales associated with increases in Eco-Contemplation ratings (see Table 5 ).Table 5 Multiple regression associations of Eco-Contemplation with environmental predisposition and demographic variables. Table 5Predictor variables β SE t p 95% CI sr2 Constant 5.709 0.866 6.59 <0.001 4.009 7.410 Environmental concern 0.654 0.106 6.17 <0.001 0.446 0.862 0.0652 Nature-based activities frequency 0.266 0.081 3.27 0.001 0.106 0.425 0.0132 Product avoidance frequency 0.392 0.151 2.6 0.009 0.096 0.687 0.0171 Ethnicity: Māori (0 = yes, 1 = no) −0.583 0.255 −2.28 0.023 −1.084–0.082 0.0085 Ethnicity: Pacific (0 = yes, 1 = no) −0.793 0.316 −2.51 0.012 −1.414–0.173 0.0055 Ethnicity: Asian (0 = yes, 1 = no) −1.314 0.231 −5.68 <0.001 −1.768–0.860 0.0318 Ethnicity: Other (0 = yes, 1 = no) −1.821 0.616 −2.95 0.003 −3.031–0.612 0.0124 Interestingly, Eco-Contemplation ratings were moderate (Means between 3.9 and 6.1) even among those with lower or lowest-end environmental predispositions in all predictor scenarios when we consider the bivariate associations (Fig. S3, Supplementary Document 2). Predictor variables accounted for 28.6% (F (14, 874) = 25.18, p < 0.001, R2 = 0.2856) of the variance in Lockdown-Biophilia ratings. Increases in the environmental concern, nature enjoyment, nature-based activities, and product avoidance scales were associated increases in Lockdown-Biophilia (see Table 6 ). Contrary to expected, an increase in recycling frequency was associated with a decline in Lockdown-Biophilia. Hence, H3, as well, was hardly supported.Table 6 Multiple regression associations of Lockdown-Biophilia with environmental predisposition and demographic variables. Table 6Predictor variables β SE t p 95% CI sr2 Constant −0.305 0.702 −0.43 0.664 −1.683 1.073 Environmental concern 0.492 0.152 3.23 0.001 0.193 0.790 0.0248 Nature enjoyment 0.620 0.175 3.54 <0.001 0.276 0.963 0.024 Nature-based activities frequency 0.507 0.114 4.46 <0.001 0.284 0.731 0.0295 Recycling frequency −0.415 0.176 −2.36 0.018 −0.759–0.070 0.0083 Product avoidance 0.506 0.147 3.44 0.001 0.217 0.795 0.019 Gender (0 = male, 1 = female) 0.923 0.217 4.26 <0.001 0.498 1.348 0.0278 Ethnicity: Asian (0 = yes, 1 = no) −0.835 0.273 −3.06 0.002 −1.370–0.299 0.0076 Qualifications 0.188 0.089 2.12 0.035 0.014 0.363 0.0066 Religion: Buddhist vs No religion 1.127 0.542 2.08 0.038 0.062 2.191 0.003 Religion: Muslim vs No religion 1.651 0.640 2.58 0.01 0.395 2.908 0.0031 Religion: Muslim vs Christian 1.326 0.638 2.08 0.038 0.074 2.577 0.002 Those whose pre-existing pro-environmental attitudes and behaviour were at the low or lowest end levels provided moderate Lockdown-Biophilia ratings (means between 3.4 and 6.2) in all predictor scenarios (see Fig. S5, Supplementary Document 2). Particularly interesting was that those who indicated “not at all/small extent” for nature enjoyment provided a 5.2 Lockdown-Biophilia mean rating (panel (b), Fig. S5). We found no support for H4, which posited a negative linear association between environmental self-inefficacy and contemplations about collective action for nature protection as a learning from COVID-19 responses (Eco-Contemplation-item#3 rating). As shown in Fig. 1 , although significant in the model, the perception that it is too difficult to do much about the environment (F(1, 966) = 7.35, p < 0.01) showed more of a U-shaped association with collective action for nature protection and explained just 1.37% of the variance in ratings. The second self-inefficacy variable, on uncertainty about the environmental impacts of one's own lifestyle, did not influence contemplations about collective action (F(1, 954) = 0, p = 0.9586, R 2 = 0).Fig. 1 Mean scores, confidence intervals and regression trendlines for the Eco-Contemplation-item#3 scale (0–10) by environmental self-efficacy: “It is just too difficult for someone like me to do much about the environment”. Fig. 1 We found some support for H5 that environmental scepticism would be negatively associated with contemplation about collective action for nature protection (Eco-Contemplation-item#3 rating). As shown in Fig. 2 , a perception of exaggerated environmental threats (F(1, 945) = 36.46, p < 0.001) was associated with decline in collective action mean ratings, as expected. This environmental scepticism explained 10.7% of the variability in contemplation about collective action. However, although significant in the model, a substantial deviation of one point from the trend line weakened the association between the perception that there are more important things to do in life than protect the environment (F(1, 956) = 48.89, p < 0.001) and collective action mean rating. This second measure of environmental scepticism explained 8.5% of the variability in contemplation about collective action.Fig. 2 Collective action as learning from COVID-19 responses (Eco-Contemplation-item#3) by environmental scepticism. Panels show mean scores, confidence intervals and regression trendlines for the Eco-Contemplation-item#3 scale (1–10) by (a) “Many of the claims about environmental threats are exaggerated” and (b) “There are more important things to do in life than protect the environment”. Fig. 2 As hypothesised (H6), reflections concerning real needs and happiness from the inability to shop during lockdown (Eco-Contemplation-item#4) was significantly higher for women (M = 6.02, SD = 3.029) than men (M = 5.20, SD = 2.777), t(954) = 4.368, p < 0.001, d = 0.283). 4.3 Demographic predictors Only gender, age and religion were predictive of Anthropause Appreciation (see Table 4). Women provided higher Anthropause Appreciation ratings than men while appreciation declined with increased age. Hindus’ Anthropause Appreciation was significantly higher than those identifying as Christians, another religion, and having no religion. Albeit less significantly, the rating by Buddhists was associated with higher Anthropause Appreciation than those indicating no religion. Ethnicities were the only demographic variables that retained significance in the final multiple regression model for Eco-Contemplation (Table 5). Māori, Pacific, Asian and Other ethnicities were associated with higher Eco-Contemplation ratings relative to those not identifying with these ethnicities. Gender, ethnicity, qualifications, and religion were predictive of Lockdown-Biophilia (Table 6). Women provided higher Lockdown-Biophilia ratings than men, while ratings by Asians were higher compared to non-Asians. Increase in qualification levels was associated with increase in Lockdown-Biophilia. Buddhists' and Muslims’ ratings were higher than the ratings of those indicating no religion. Ratings by Muslims was higher than ratings by Christians. 5 Discussion This study retrospectively assessed the prevalence and predictors of, (i) Anthropause Appreciation, (ii) COVID-19-related Ecophilosophical Contemplation, and (iii) Lockdown-triggered Biophilia during the 2020 pandemic. Pre-existing pro-environmental dispositions and behaviour did not lead to consistently higher ratings on the three scales’ ratings as we hypothesised. Demographic variables had limited influence while experiences of financial and mental health impacts due to COVID-19 had no bearings on the scales. This limited influence of explanatory variables suggests that Anthropause appreciation and experiences of ecophilosophical musings and biophilic draw during the COVID-19 lockdown were not restricted to those who were already environmentally inclined, but rather occurred broadly across society. Over half of our survey respondents (61.3%) expressed a high degree of Anthropause Appreciation (a rating of 8 or higher on a 1–10 scale) and this appreciation was high even among those with low pro-environmental dispositions and behaviour. Having directly observed the benefits of a pause to environmentally detrimental activities, it is likely that the public may be supportive of policies and ways of living that can lead to similar outcomes post-pandemic. For instance, in Australia, COVID-19-related anthropomorphism (ascribing human characteristics to non-human entities) was predictive of support for pro-environmental pandemic recovery policies and travel restrictions (Borovik & Pensini, 2022; Pensini & McMullen, 2022). In Borovik and Pensini's (2022) study, support was unexpectedly stronger among those experiencing financial insecurity during the pandemic – suggesting a shift in how people typically prioritise their needs. Hence, rather than solely focusing on economic recoveries, “policymakers should acknowledge and attempt to preserve societal changes which have simultaneously benefited human wellbeing and biodiversity” (Cooke et al., 2021, p. 113). The environmental indicators data collected during the Anthropause could guide pandemic recovery plans. With careful consideration, the Anthropause may serve as a widely resonating and effective metaphor that inspires conservation actions because its symbolic undertone “that humans have taken too much from nature and set the relationship out of balance” holds an appeal that crosses cultural boundaries (Young, Kadykalo, Beaudoin, Hackenburg, & Cooke, 2021, p. 275). The Anthropause has made environmental solutions less abstract (Young et al., 2021) and reduced the temporal psychological distance typically associated with environmental outcomes being in the future or for future generations (Sparkman, Lee, & Macdonald, 2021). Albeit momentary, the Anthropause offered a taste of possibilities, by bringing ecological benefits and better life quality to the here and now (Young et al., 2021). It thus offers the opportunity for impactful science communication based on the efficacious environmentally relevant behavioural adaptations during the Anthropause and optimism about nature's recovery (Forti, Japyassú, Bosch, & Szabo, 2020; Riera, Rodríguez, McAfee, & Connell, 2022). Although only 26.8% in our study experienced strong ecophilosophical contemplation during lockdown, a majority (62.6%) experienced this at a moderate level. Comparable contemplations were noted in other countries. When asked if lockdowns affected their views about nature, UK respondents reported enhanced affinity with and appreciation of nature, increased motivation towards environmental preservation, a realisation of human impacts on the environment, and optimism about the efficacy of collective changes (Lemmey, 2020). Similarly, in Vermont, participants' valuing of nature during lockdown included nature's contribution to mental wellbeing and feelings of nature connectedness (Morse et al., 2020). These observations emphasise the value of pauses in life to contemplate our relationship with nature. The Anthropause, if preserved as a global keystone to symbolically promote human and environmental wellbeing, could lead to “a greater appreciation for noise reduction, tranquillity, and reflection (a collective physical and spiritual ‘pause’), and to underlining the benefits of a radical break with past practices” (Young et al., 2021, p. 276). The cultivation of Anthropause-like contemplative practice could thus be an impactful addition to current environmental conservation tools. Environmental scepticism is likely to be a persisting barrier, as demonstrated in the lower ratings for contemplations about ‘collective nature protection actions as a learning from COVID-19’, by those holding this disposition in our study. Addressing this dilemma would require mitigating factors such as alarmist media communication, perceptions about expert disagreement, and scientific and political uncertainty that contribute to scepticism (Corner, Whitmarsh, & Xenias, 2012; Whitmarsh, 2011). Contrary to our expectation, environmental self-efficacy was not meaningfully associated with contemplation about COVID-inspired collective nature protection actions. Nevertheless, another New Zealand survey showed that socio-political efficacy (group efficacy) increased after lockdown, and in turn increased pro-environmental attitudes (Milfont, Osborne, & Sibley, 2022). Hence, considering the role of social norms and collective efficacy for enhancing self-efficacy and pro-environmental behaviour appear critical (Doherty & Webler, 2016; Jugert et al., 2016). An extreme Lockdown-triggered biophilic draw was experienced by 35.1%, while 47.5% experienced this moderately. What was a more interesting observation was that the biophilic draw experience was relatively high even among those whose pre-existing level of nature enjoyment was lowest. Observations of green space visit increases in New Zealand and elsewhere during lockdown, indirectly corroborate our findings (Derks et al., 2020; MacKinnon, MacKinnon, Pedersen; Venter et al., 2020; Zari, Glensor, & Park, 2022). The stronger biophilic draw felt by those with higher frequency of engagement in nature activities in our study may be partly explained by New Zealand's lockdown policies, which did not permit risky nature-based activities like ocean swimming or tramping. Nature deprivation was felt particularly strongly in New Zealand by surfers, who realised the importance of their previously taken-for-granted access to coasts for their wellbeing (Wheaton et al., 2021). In the present study, area of dwelling (city-based vs. country-based) did not affect the degree of biophilic draw experienced during lockdown. This may be partly explained by New Zealand's lockdown policies which permitted driving to an outdoor space such as urban parks for exercise, which, in turn, may partly explain the lack of association between mental health and Lockdown-triggered Biophilia in our study. Mental wellbeing, being the most frequently cited reason for visiting a green space during lockdown in Wellington, New Zealand, was regarded as a sign of ‘urgent biophilia’ (MacKinnon, MacKinnon, Pedersen Zari, Glensor, & Park, 2022). Studies elsewhere demonstrated how access to such spaces, even a window view of greenery, helped people better cope mentally with mandated social isolation during lockdowns (Dzhambov et al., 2021; Pouso et al., 2021; Ribeiro et al., 2021). In Israel inequities in access to green spaces during lockdown due to location meant that some suffered wellbeing declines more than others (Colléony, Clayton, & Shwartz, 2022). Similarly, inequities in access to urban green spaces for the psychological wellbeing of city dwellers in Croatia, Israel, Italy, Slovenia, Lithuania, and Spain became more notable during mandated social isolation (Ugolini et al., 2020). Collectively, these findings reiterate the importance of human-nature relationships for wellbeing and town planning that ensures conservation and equitable access to urban green and blue spaces (Astell-Burt & Feng, 2021; Ribeiro et al., 2021; Seymour, 2016). It also suggests an opportunity to encourage a more reciprocal relationship with nature. This may require public awareness of biophilia. It may be that the public experience biophilia but do not define it as an ‘innate affinity with nature’. Further development and testing of inventories to measure biophilic attitudes (Letourneau, 2013) and biophilic draw within and beyond the context of lockdowns appear warranted. Women provided higher Anthropause Appreciation and Lockdown-Biophilia ratings than men. Additionally, in our sample, the inability to shop during lockdown was associated with reflection on real needs and happiness for women more so than men. The overall gender difference appears in line with findings from most of the literature examining environmental attitudes and behaviour (Dhenge, Ghadge, Ahire, Gorantiwar, & Shinde, 2022; Fisher et al., 2012). While this may suggest the importance of female environmental advocates, change agents, and decision-makers, from a global standpoint, such responsibility placed on women's shoulders is laden with challenges, given women's social positions in society and vulnerabilities (for in-depth discussions, see Nasrin, 2012; Resurrección, 2013; Shanley, Silva, Trilby, & Silva, 2018; Shinbrot, Wilkins, Gretzel, & Bowser, 2019; Tran, 2021). In addition to patriarchal structures, hidden aspects such as a lack of self-confidence can impede women's access to environmental leadership roles (Shinbrot et al., 2019). Nevertheless, research suggests that better environmental decisions tend to be made when women are in decision-making positions alongside men, in some contexts (Glass, Cook, & Ingersoll, 2016; Hollindale, Kent, Routledge, & Chapple, 2019). Hence, education and training to build women's environmental leadership capabilities (Segovia-Pérez, Laguna-Sánchez, & de la Fuente-Cabrero, 2019) may be an important step in actualising a greener post-COVID world. Those identifying as Christian or as having no religion provided lower Anthropause Appreciation and Lockdown-Biophilia ratings than those identifying with other major religions. We interpret our religion-related findings with caution, given the relatively small representations of non-Christian religions in our sample (between 1.1 and 2.5%). Nevertheless, it appears to reflect studies in the US and Australia, which concluded that compared to non-Christians, Christians have lower levels of environmental concern (Clements, McCright, & Xiao, 2013; Reid, 2014). Literal beliefs in the Bible were associated with lower general and ecocentric environmental concern in a multinational study (Schultz, Zelezny, & Dalrymple, 2000). However, there were some denominational differences within Christianity, with Orthodox Christians and Catholics being the most concerned (Reid, 2014). Since earlier condemnations of the dominion theory in the Book of Genesis as being responsible for environmental decline (Toynbee, 1972; White, 1967), Christian environmental ethics and values concerning environmental guardianship and stewardship have prompted support for environmental causes, including environmental education (see Bouma-Prediger, 2016; Cass, 2020; Hitzhusen, 2007; W. Jenkins, 2013; Wardekker, Petersen, & van Der Sluijs, 2009). With Christianity being the world's largest religion (Pew Research Centre, 2017), its ongoing greening appears important for global post-pandemic environmental behaviour transformations. Theology scholars examining the religion-environment interface could consider the underlying contexts that contribute to denominational differences in COVID-related environmental concern, to provide transformative insights for greening Christianity. Advocates of a greener post-pandemic recovery could consider religious leaders for the role of change agents. This is already occurring to some extent. Churches in New Zealand and other Pacific nations, already advocating environmental care, are now calling for a green COVID-19 recovery (Cass, 2020). In the US, Pope Francis's words significantly influenced public perceptions about a moral obligation to expedite climate change action (Schuldt, Pearson, Romero-Canyas, & Larson-Konar, 2017; Shin & Preston, 2019), and environmental actions among Christians, Muslims, and Jewish people appear partly shaped by the beliefs and practices of their respective religious institutions (Vaidyanathan, Khalsa, & Ecklund, 2018). This suggests a valuable arena for values-based environmental advocacy, considering that many religious values (e.g. selflessness, gratitude, empathy, non-violence, compassion) are relevant to reciprocal human-nature relationships and dispositions of care towards nature (Abu-Hola, 2009; Dien, 1997; Gross, 1997; Guelke, 2004; Kureethadam, 2016; Renugadevi, 2012; Sahni, 2007; Woodhouse, Mills, McGowan, & Milner-Gulland, 2015). Such advocacy appears promising, considering how environmental attitudes were influenced by religious attitudes and awareness of faith-based environmental stewardship (Crowe, 2013; Simeon, 2021). Merging of religious and environmental values may lead to enduring self-transcending environmental motivations based on benevolence, altruism, and concern for the wellbeing of others and of nature (Schwartz, 2012) – universal values that are essential for sufficiency as a basis for reducing environmental impacts alongside efficiency (Kurz, 2019). The Anthropause was experienced globally and appears to be a defining event in the 21st century which evidenced how “relatively minor changes to our lifestyles can potentially have major benefits for ecosystems”, wildlife, and humans (Rutz et al., 2020, p. 1158). Its many lessons offer practicable approaches for sustaining the ecological benefits of lockdowns (Celin, Bhanot, & Kalsi, 2022). It may be seen as an opportunity for a post-pandemic new normality – a departure from the old routines of ecologically destructive living (Searle, Turnbull, & Lorimer, 2021) and the present study suggests public support for such an outcome. Our study was limited in several ways. First, although nationally representative by age, gender, and ethnicity, relationships with predictors may have been missed due to the relatively small sample size. Second, as the beneficial outcomes of the Anthropause were measured retrospectively, post-lockdown, there may have been an element of recall bias. Due to the already-extensive ISSP questionnaire and the need to minimise respondent burden, we did not measure direct experiences of lockdown-related ecological benefits. Repetition of the Anthropause Appreciation scale in future research would benefit from additional questions measuring knowledge about Anthropause environmental outcomes and the sources of that knowledge. Space constraints also limited the scope of our COVID-related Eco-Contemplation and Lockdown-Biophilia scales. Pensini and McMullen's (2022) items for assessing anthropomorphism within the context of COVID-19, Haasova and colleagues' (2020) items on higher-order beliefs about the pandemic and the present Eco-Contemplation items could be merged to form a more comprehensive item-set in future research. Finally, given the low COVID-19 case numbers at the time of data collection in New Zealand, we did not consider COVID-19 contraction as a potential predictor variable in our study. This variable may need to be accounted for when considering our measures in jurisdictions with higher COVID-19 severity. Despite limitations, our study offers a preliminary account of possible relationships and the lack thereof between measures of Anthropause Appreciation, COVID-19-related Ecophilosophical Contemplations, and Lockdown-triggered Biophilia, and demographic characteristics and environmental predispositions. Similar research carried out internationally might help shed light on unique Anthropause-related perceptions and values that have strong implications for human-nature relationships, and the choices we might make to prevent future pandemics and achieve a greener post-pandemic world. Funding This study was partly funded by the Faculty of Arts, 10.13039/501100001537 University of Auckland Performance-Based Research Funds. CRediT author statement Komathi Kolandai: Conceptualisation, Methodology, Investigation, Formal analysis, Project Administration, Writing – original draft. Barry Milne: Funding acquisition, Methodology, Investigation, Supervision; Writing – review & editing. Jessica McLay: Formal analysis, Writing - review & editing. Martin von Randow: Methodology, Investigation, Project Administration, Data curation, Writing – review & editing. Roy Lay-Yee: Funding acquisition; Writing – review & editing. Uncited references Post, 2005. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Appendix A Sample statistics Variables Description N (%) Gender Male 485 (48.9) Female 507 (51.1) Excluded: One respondent indicating a non-binary gender Age 19–24 years 92 (9.4) 25–44 years 314 (32.2) 45–64 years 321 (32.9) ≥65 years 250 (25.6) Excluded: 16 missing Ethnicity Māori 160 (16.4) European 743 (76.1) Pacific 50 (5.1) Asian 127 (13.0) Other 20 (2.0) Excluded: 16 missing Qualification level No formal qualification 22 (2.3) Primary school completed 53 (5.4) Secondary school qualification 305 (31.3) Trade or Professional Certificate or Diploma below degree level 271 (27.8) Undergraduate degree 182 (18.7) Postgraduate or higher 141 (14.5) Excluded: 19 missing Dwelling Country 150 (15.3) City 830 (84.7) Excluded: 13 missing Religion No religion 465 (46.8) Christian 418 (42.1) Buddhist 23 (2.3) Hindu 25 (2.5) Muslim 11 (1.1) Another religion 24 (2.4) Missing 27 (2.8) Appendix B Bivariate correlation matrix (predictor variables) (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (1) Environmental concern 1 (2) Nature enjoyment .194 1 (3) Nature activities .100 .439 1 (4) Recycling .201 .140 .095 1 (5) Product avoidance .434 .147 .106 .267 1 (6) Meat consumption .137** −.02 −.063* .01 .188 1 (7) Environmental actions .343 .271 .157 .131 .301 .087 1 (8) Environmental group member .210 .144 .105 .096 .190 .038 .340 1 (9) Voting for the Green Party .212 .066* −.057 .042 .171 .188 .257** .086* 1 (10) Gendera .080* .088** .077* .045 .066* .016 .048 −.022 .004 1 (11) Ethnicity: Māorib −.038 .026 .037 .123 .027 .062 −.122 −.029 .003 −.029 1 (12) Ethnicity: Europeanb .033 −.197 −.236 −.171 −.01 .138 −0.03 −.057 −.075* −.001 −.093 1 (13) Ethnicity: Pacificb .003 −.007 .037 .126 .015 .008 −0.015 −.003 .042 −.02 −.054 −.290 1 (14) Ethnicity: Asianb .004 .222 .280 .098 .01 −.203 .116 .064* .043 −.002 −.167 −.685 −.042 1 (15) Ethnicity: Otherb −.012 −.002 −.051 .045 .053 .047 .054 .052 .012 .025 −.062 −.234 −.03 −.056 1 (16) Dwelling .013 −.059 −.198 .008 .017 .037 .038 −.078* .026 .029 .007 .169** −.077* −.152 −.06 1 (17) Age .046 −.047 .096 .177 .083 −.063* −.116 −.016 −.182 −.042 .157 −.148 .059 .128** .068* −.192** 1 (18) Qualifications .078* .055 −.046 .002 .079* .097 .119 .072* .127 .108 .046 .122 .089 −.210 −.118 .099 −.173 1 (19) COVID-19 financial impacts .028 .018 −.011 −.042 .055 .098** .038 −.023 −.035 .078* −.033 .085** .016 −.03 −.003 .003 .025 .028 1 (20) COVID-19 mental health impacts −0.036 .052 −.018 .014 .034 .05 −.048 .007 −.082* −.015 −.124** .033 −.026 −.011 .076* −.03 .091 −.104 .283** 1 Note: aGender: 0 = male, 1 = female. bEthnicity: 0 = yes, 1 = no. Bolded values show moderate associations. * Correlation is significant at the 0.05 level (2-tailed). ** Correlation is significant at the 0.01 level (2-tailed). Appendix C Frequency of mean ratings for the Anthropause Appreciation, Eco-Contemplation, and Lockdown-Biophilia scales Image 1 Appendix D Supplementary data The following are the Supplementary data to this article:Multimedia component 1 Multimedia component 1 Multimedia component 2 Multimedia component 2 Acknowledgement We thank Professor Niki Harré, who reviewed our measures and provided valuable feedback during their development. We thank Janet von Randow, Laila Kanon, Catherine Bodnar, and our colleagues at COMPASS for their help in preparing the questionnaires for mailing. Last, but not least, we thank the participants of our study for the voluntary contribution of their time. Appendix D Supplementary data to this article can be found online at https://doi.org/10.1016/j.jenvp.2022.101943. ==== Refs References Abu-Hola I. 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==== Front Comput Commun Comput Commun Computer Communications 0140-3664 1873-703X Elsevier B.V. S0140-3664(22)00454-6 10.1016/j.comcom.2022.12.004 Article COVID-19 health data analysis and personal data preserving: A homomorphic privacy enforcement approach Dhasarathan Chandramohan a Hasan Mohammad Kamrul b⁎ Islam Shayla c⁎ Abdullah Salwani b Mokhtar Umi Asma b Javed Abdul Rehman d Goundar Sam ef a Thapar Institute of Engineering & Technology, ECED, Department of Computer Science & Engineering, Punjab, India b Faculty of Information Science and Technology, Universiti Kebangsaan Malaysia (UKM), 43600 Bangi, Selangor, Malaysia c Institute of Computer Science and Digital Innovation, UCSI University, Malaysia d Department of Cyber Security, Air University, Islamabad, Pakistan e School of Computing and Innovative Technologies, British University Vietnam, Viet Nam f RMIT University Vietnam, Viet Nam ⁎ Corresponding authors. 14 12 2022 14 12 2022 1 7 2022 13 11 2022 1 12 2022 © 2022 Elsevier B.V. All rights reserved. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. COVID-19 data analysis and prediction from patient data repository collected from hospitals and health organizations. Users’ credentials and personal information are at risk; it could be an unrecoverable issue worldwide. A Homomorphic identification of possible breaches could be more appropriate for minimizing the risk factors in preventing personal data. Individual user privacy preservation is a must-needed research focus in various fields. Health data generated and collected information from multiple scenarios increasing the complexity involved in maintaining secret patient information. A homomorphic-based systematic approach with a deep learning process could reduce depicts and illegal functionality of unknown organizations trying to have relation to the environment and physical and social relations. This article addresses the homomorphic standard system functionality, which refers to all the functional aspects of deep learning system requirements in COVID-19 health management. Moreover, this paper spotlights the metric privacy incorporation for improving the Deep Learning System (DPLS) approaches for solving the healthcare system’s complex issues. It is absorbed from the result analysis Homomorphic-based privacy observation metric gradually improves the effectiveness of the deep learning process in COVID-19-health care management. Keywords Deep learning system Homomorphic Healthcare Privacy preserving Privacy metrics Security ==== Body pmc1 Introduction A multidisciplinary machine learning approach can diagnose COVID-19 with a scientific paradigm to personalize the distribution of significant medical symptoms. Patient health ecosystem building should be decentralized in an ideal environment. Virus transmission was noted in clinical trials from previous pandemics. The patient’s symptoms are monitored, analyzed, and predicted as prior information for possible viral infection. In the past ten decades, many viral infections have been caused by a variety of flu worldwide. The Daily life of societal functionality gets affected due to multivariate viruses, which leads to the global pandemic. Holistic studies of crowd monitoring, social spreading cause research, diagnosing fake news delivery, predicting virus infection and its peak analysis. The machine learning technique allows personalizing promising health eco-system analysis and prediction. To make smart integration for gathering the history of virus-infected patients and empowering the flu tracking and appearance of new variants prediction and its risk. Personal health data pattern concerns multiple factors with appropriate isolation, correlated to reducing risk factors. The Internet of Things (IoT) utilizes for accessing, tracing, screening, monitoring, and diagnosing corresponding symptoms for prediction and clinical trials. Predicting COVID-19 by analyzing the blood sample and various symptoms minimizes the spread of vulnerable viruses. The Multi-filtering process helps to diagnose typical spreading among patients and the public as a victim and gets infected. Scanning chest X-rays and CT offers radiation safety measures with certain limitations. Researchers highlight cleanliness as the key promo for avoiding the spreading chain. It is observed that untreated wastewater management in regional-level surveillance could boost the estimation of specific flu spreading and lead to pandemics. Prognosis evaluation by hematological features identifying hybrid genetic algorithm-based machine learning techniques. Clinical symptoms of patient data are normalized, and it might be validated into a statistically trained data set for feature selection to identify the best relevant patient data for treatment. The severity of symptoms is extracted for discriminant analysis and intubation risk based on ML evaluation criteria. When users store their data in the cloud, a TPA (Third Party Administer) will be allotted to check the integrity of the data. A lightweight encryption scheme for COVID-19 health data needs to focus on a secure range and query for confidential data. Section 1 deals with the protection of personal data, the importance of privacy in COVID-19 patients, and the need for data to be encrypted. So, mobile users should be able to query data and get the results per their requests. Timestamp routing by various intelligent optimization techniques to analyze the COVID-19 patient data is expressed in Section 2. In Section 3, we designed and proposed a Homomorphic privacy protection enforcement and its metrics to build a system that uses the optimization model by incorporating the artificial bee colony approach in the framework. The need for a data analytics system for analyzing the COVID-19 data collected from various patients and hospitals for testing and formulating a protective mechanism. The analytical result analysis is discussed, and the efficiency variations are illustrated and plotted in Section 4. In Section 5 we concluded the privacy metric needed for a COVID-19 healthcare system, and enhancement features for future research are discussed. 2 Literature study [1] contemporary interrelated pandemic research with digital technology help to discover COVID-19 symptoms analysis and prediction. The paper discusses the risk factors, drug development, early prediction, and alerting the global spreading. However, it focuses on AI-based developments in COVID-19 pandemic research. [2] to meet the global pandemic, machine learning is the best technology to adopt and improve the situations argued in the world at complete lockdown. Mobility of human activity expects few daily survival needs are exempted from shutting down. Machine learning is one of the most potent pandemic problem solvers and improves the mitigation of the spread of flu in a different form. [3] to diagnose the symptoms of COVID-19 using machine learning by filtering the datasets with original and normalized values. Features selection is used for diagnosing positive clinical symptoms are directed to a trusted prediction. It minimizes the health risk for practitioners and the public to safeguard themselves from the infection. [4] predict the inhabitation of patients with mild and moderate symptoms for disease severity and neutralize the persistence of COVID-19. It is observed from the data collected from various hospitals with privacy concerns regarding patient health information. A Spike of virus infection is observed from the disease severity, and the monitoring process helps to anti-Spike less flu infection. [5] Uniform Manifold Approximation And Projection (UMAP) technique is followed to cluster essential medical data to filter the diagnostic process, and its outcome is observed. A systemic hematological fraction to discover the illness and new patterns of infection. [6] correlations and coefficient of regular blood sample testing sensitive medical data and artificial intelligent interpretation among samples are illustrated. Its accuracy mainly focuses on clinical blood samples applying a statistical t-test for filtering unique pandemic diagnosis tools for positive cases. [7] 3D representation empirical mode decomposition techniques for classification and extracting block of backbone components using deep CNN approach. Context-aware attention classifies the main features of pneumonia cases which helps to detect COVID-19. [8] wastewater quantification concentration by mitigating environmental correlation for an early prediction and detection of SARS-CoV-2 from the clinical data of public health monitoring system. Sampling scientific data with limited availability of numerous flu infection provide prior warning to the public noted symptoms. [9] decision tree estimation of the severity of patients by adaptive boost machine learning algorithm to reduce the effect of spreading COVID-19 with competitive accuracy prediction by using advanced ML algorithm. To fight against the global virus, a random selection model was used in the COVID-19 test study for unveils and fight against the medical complexities. Risto Miikkulainen et al. (2018) World is unprepared to face COVID-19 restless information collection about the community spread. They were monitoring the quality predictors and reducing trade-offs among NPI simulators. The proposed epidemiological models help the system with a trustworthy explanation to improve the interactive symptoms collected for COVID prediction. The synchrophasor measurements identify the classification of regression modeling in all transmission lines. The magnetic flux from the transmission lines is in ideal condition for the projects with faults location. Privacy-preserving in a distributed web service environment with a framework dealing with an ad-hoc scenario. The service requester’s demands are not fulfilled by the quality of retrieved services [10]. Privacy policy extensibility is applicable for the service providers in all constraint-based satisfactions. It is validated by optimization algorithms to check efficiency. Fog-enabled environmental services are delayed, and their load is estimated [11] in a shared service. The requirements are tested in real-time test cases and industrial standards to check their efficiency. Virtual and physical validation is verified in a contemporary data environment. The delay in transmission delay gets improved, and the optimization approaches improve the delivery rate. Patient-care amenities related to healthcare services are taken into intensive care by Edge of Things (EoT) [12] as persuasive healthcare management. The edge computing service providers (ECSP) and cloud computing service providers (CCSP) observe the patient’s health at regular intervals and get all health information using body area networks (BAN). The article proposed a portfolio optimization solution based on the virtual machine (VM) with the deliverable cloud service. To achieve service distribution, centralized service monitoring and EoT introduces portfolio optimization. It supports a cost-effective system in personalized healthcare management system using VM-supportable techniques to improve innovative healthcare services. Moreover, it improves intelligent devices and mobile applications to support healthcare services in secure and safe incarceration. The patient details would be categorized based on the data analytics techniques [13] for identifying the low-power devices utilized in real-time microbiome monitoring. The portable devices are neutral; it has an ambiguous architecture that needs ubiquitous analysis in all diversified environments. To process the data collectively integrated from resources of the universal environment, devices have a vast amount of relevant and irrelevant data that needs to be communicated and converted into useful information. A scheduling mechanism is adopted for reliable communication to pipeline the cloud-based services and edge computing devices. It is proposed that efficient information interaction, multimodal data fusion, and automatic production [14] improve edge computing. The interaction-based systems are highly in demand utilizing e-health services in a robotic architectural neutral system management. The cognitive control of multimodal fusion is carried out in traditional and real-time scenarios. The artificial intelligent driving force highlights resource scheduling. Edge computing techniques expand all computing resources to promote economic growth. Sentimental analysis is endorsed as unsupervised learning, with artificial intelligence (AI) as the core competitiveness. The efficiency of cognitive manufacturing adopts a highly interconnected structure and composition to improve chip assembly significantly. The article discussed the need for a multi-agent-based cloud service endorsement in ubiquitous computing scenarios [15]. The agents would analyze the possibilities of proper communications with minimum resource utilization in all circumstances. The cloud-enabled devices would share the device information with all service providers on demand. It could increase the privacy issue of the device owners and put them at personal risk—multi-agent-based service utilization with proactive privacy-preserving measures and ineffective resource sharing and communication. Internet of Things (IoT) -based learning for network communications to improve human–computer interaction [16] for the betterment of enormous service sharing and utilization. It involves vast sensible data processing and transformation in every service cattalo. The researchers are forecasting proper and rescindable research has been highlighted with limited privacy-preserving information. There is a need to concentrate on contextual and content-based privacy preservation in IoT-based communications. It is focused on identity-based encryption schemes based on resource availability for data transfer. Healthcare emergency monitoring using a bio-inspired approach has a predictive measure for the effective recovery of patients from health risks, as illustrated by [10], [17], [18]. The current study dealt with the contemporary computing and routing architecture which inculcate randomly and cannot develop trust in cooperative systems. It has crypto mechanisms for ensuring the handshake process between the devices. There is a need to create a privacy metric with a collaboration of mathematical approach, statistical data, privacy policy customized, and advanced encryption mechanism to better the user’s trust. Security is focused on high priority by designing protocols with current industrial needs, [19] discussed enhancing the intelligent control IoT security to handle critical challenges by the cryptographic lightweight process. Encryption and decryption are tested in a real-time network for their efficiency. Dynamic global communication [20] proposed an intelligent grid for effective data processing and transmission to collect and analyze the power grid [17], [18], [19]. Genetic Deep Learning Convolutional Neural Network (GDCNN) [21], [22] designed an approach to predict COVID-19 with a partial swam intelligent optimization model and huddle particle swarm optimization. Numerous techniques and methodologies were proposed in the literature study for personal data prevention ([23]; Mhayuddin et al., 2020; [24]). Statistical data collaboration and indicating the cause of information breaches are challenging. Researchers face different attacks on stored data, and there is a need for an advanced approach to balance data prevention and computation. The homomorphic encryption technique is one such approach that could balance data encryption and analysis, which fulfills current needs and gives a tricky time for attackers. Patients affected by COVID-19 health condition is tested for marginal deviations in the immune system [25]. The patients who follow the regular diet and physical activity are noticed with perfect immune systems, whereas the rest are found dangerous for take-ups in the next wave. A deep learning-based fake news filtering to get the real news. It uses classification concerning COVID-19 awareness and checks the correctness of information spreading in social media and communication [26] sentimental feature extraction as an information fusion. 3 The homomorphic privacy protection enforcement The homomorphic encryption system description level metric states the activities involved in the description level with the help of the following parameters development, application, and publication. Fig. 1. states that the development parameter includes the integration of agent idea ida, dynamics dyn, and its documentation doc.developmentdev=ida+dyn+doc. The application displays the documentation doc of various users. applicationapp=doc0n. Publication measures the marketing aspect mkas of multi-agent systems and the user acceptance accuser of agent systems publicationpub=mkas+accuser. (1) PPM(x,y)=1PM∑i=1P∑j=1M(xi−μx)(yij−μy)σxσy PPM→ Privacy Preserving model similarity metrics PM→ Privacy Metrics x, y are two-way request and response μxandμyareaveragerequestandresponse σxσyarestandarddeviationsofxandyrespectively P and M are privacy, metrics for user (2) P∗=argMaxTPPM(MSLm,1,MSL(Pl,−1)) Where ‘m’ is mathematical induction and ‘l’ is privacy law. MSL→ Metric Security Level Where, (M, l) is health patient data-related to privacy law. Pis privacy endurance that produces the alignment pair (m, P(l)). D: P→ A { Data- D, Privacy-P, Authorised user-A, m ∈ P, l ∈ A.} (3) PLɛ=∑Ωμɛ(PAU,l) Privacy law → PLɛ Privacy (Authorized User)→P(AU) Law enforcement → l (4) PPAUx,y=(2μxiμyj+Ux)(2σij+Uy)(μ2xiμ2yj+Ux)(σ2ij+σ2yij+Uy) PPAUx,y→ Privacy-preserving for an authorized user Ux, Uy→ User request σ2yij,σ2ij→ Unauthorized request μxiμyj→ Mathematical inclusion, statistical metrics μ2xiμ2yj→ Privacy law, mathematical inclusion, statistical metrics HomomorphicSystemdesinglevel=size+componentstructure+complexity+function (5) HomomorphicSystemdesinglevel=∑i=1nacta+mtr+orghr+orgfn+re,env,ph,soc+fnsreq (6) Homomorphicsystemworkinglevel=communication+interaction+knowledge+lifeness+conflictmanagement+community+management+application+stability+performance+organization (7) Homomorphicsystemworkinglevel==langsofa+othera+act+mdtysofa+othera+learoutc+adpa+ssmaineff+nega+systs+comma0ncollba+coorasstra+appar+coop0n+∑selrpa+perf+perfa+r(cu,pl,ar,md,comm,ob,dmk) Data metrics are followed to ensure the encryption standard is given in Eqs. Eq. (1)–(7) respectively. The privacy-preserving relevant frameworks have an adequate methodology for healthcare to maintain the coordinators’ and the tradeoff between energy-efficient architectural interfaces. It cannot organize and sustain the coordinator’s private information safety and trust. Identifying the appropriate user’s privilege and confidentiality level needs to be considered more concerned with the support of multi-level computing. A Peer-to-Peer opportunistic computing and routing system also socializes with tolerable message transmission with privacy metrics. The software interface for effective machine optimization would support the critical emergence of COVID-19 health monitoring. An emergency is caused in any circumstance to handle it with cooperative information sharing to the centralized system for the betterment of recovery. To monitor the regular activity with intensive care and react in time to speed up the monitoring and medication process. The monitoring activity could be organized periodically to collect the patient medical data for appropriate treatment and action. A specified agent could regularize the movement of a patient to monitor the active process. Multiple agents cooperatively monitor the process for an organized medication process to prolong the COVID-19 health integral structure. COVID-19 health monitoring is a good activity for a balanced medication process for complex maintenance integrated by multi-agent cooperation. Each agent monitors the patient health activity and periodically reports to the COVID-19 health centralized agent for medication by appropriate experts in time. To collect a patient’s regular exercise, the deployed agents run all time as an active depict. The main objective is the proper treatment at the right time to avoid a patient’s critical situation. The medication must be processed during exceptional cases with a cooperative multi-agent hierarchy approach. Emergency and urgent COVID-19 health organizations with multi-agent unified monitoring by on-demand computing lead to a risk of collaborative device participation in the communication for appropriate medication. The devices handle the critical situations provided by agreeing to the multi-agent terms and conditions. To develop an acceptable feature to improve the confidentiality level Fig. 1 with algorithm 3.1 would act as a trust for the devices participating in the cooperative task which handles the emergencies. Participative agent’s data privacy-preserving strategy by adopting the mathematical approach, statistical information, information policy act, and encryption techniques to ensure the multi-agent coordination with privacy metrics.Fig. 1 Private data metrics using homomorphic enforcement for COVID-19 big data. 3.1 Algorithm for homomorphic enforcement and working principle for data protection Fun_Setup_Selection Web User Group – (WUG) WUG1, WUG2, WUG3, … WUGn {whereas WUG1, WUG2 belongs to web user such that <WUG1> = WU1, <WUG2>=WU2, which describes and define the bonding of participative users (PU): PU: WU1 X WU2 → WUn on applying electrical cryptographic (ECC) hash functions such as ECCH1, ECCHz, and ECCH it will give ECCH1: {T, F} → {T, F}n, ECCHz: {T, F} δ x {T, F}* → {T, F}n, for z ∈ {T, F} δ and n ∈ no.of. UsersRequest, and ECCH:WUn→WU2,WUn→WUz Return UsersData (UD)≔{u,WUG1, WUG2, WU1, WU2, pu, ECCH1,ECCHz,ECCH} End Fun_Setup_Selection Fun_Key_Generation (UD,W)α T → Transaction, R → Request, T,R∈rUpu∗ t←pu(WUG1,WUG2)j Function Data LatenceyUserRequest UR: fun_Privacy_Sustainability Input: UR Service Input: UR Node Input: CloudUserCredential User Service ← Null; For Users in the UR Service list of CloudDataContainers do If CloudDataStorage is not present on CloudProvider, then User Service ← Verifying the CloudDataStorage; End End CloudBandWidth ← UserBandwidth[UserIdentity][UserDevice]; AccessPermission ← UserService/ CloudServiceBandwidth; Return AccessPermission; While Data Intruder is identified do Pi ← Private Data identification ∼ Pi ← False User Private Request Identification (Px, Distributed Request- DR) DR= GenerateDistributedService(Px, DR, ∼ Pi) If DR Navigates as DistributedService then do BlockRequest= DR[0] sum of DR[n] Else if DR Navigates as AuthenticatedDistributedService Then AllowRequest= DR[0] sum of DR[n+i] Else if DR Navigates as UnAuthenticatedDistributedService Then BlockRequest= DR[0] sum of DR[n+i] Else if DR Navigates as UnKnownAuthenticatedDistributedService Then BlockRequest= DR[0] sum of DR[n+i] Else if DR Navigates as KnownAuthenticatedSimillarDistributedService Then BlockRequest= DR[0] sum of DR[n+i] Else if DR Navigates as UnKnownAuthenticatedSimillarDistributedService Then BlockRequest= DR[0] sum of DR[n+i] Else EndService= ServiceRequest[0, n+i] End while End fun_Privacy_Sustainability Send to DS Return VaidService End ⇒ IC (HU1, HU2, HU3, …, HUn) ⇒; Where, HUn=HUx * HUx11HUx12HUnHUx21HUx22⋮HUx31HUy32⋮⋮⋮⋮HUxm…HUmn* [d, p, b, m] HUxij* HUd11HUp12HUb13HUm14HUd21HUp22HUb23HUm24HUd31HUp32HUb33HUm34⋮⋮⋮⋮HUdm1HUpm2HUbm3HUmmHUd11HUp12HUb13HUm14HUd21HUp22HUb23HUm24HUd31HUp32HUb33HUm34⋮⋮⋮⋮HUdm1HUpm2HUbm3HUmm⋯HUd1⋯HUm1⋮⋱⋮HUdm⋯HUmmn EON =HUxij [∵ (xi)j => i ={d,p,b,m}and j= {number of mobile opportunistic nodes}] MONxMONyMON∞MONx1MONy1⋮MONx2MONy2⋮⋮⋮⋮MONxnMONynMON∞HUd11HUp12HUb13HUm14HUd21HUp22HUb23HUm24HUd31HUp32HUb33HUm34⋮⋮⋮⋮HUdm1HUpm2HUbm3HUmmHUd11HUp12HUb13HUm14HUd21HUp22HUb23HUm24HUd31HUp32HUb33HUm34⋮⋮⋮⋮HUdm1HUpm2HUbm3HUmm⋯HUd1⋯HUm1⋮⋱⋮HUdm⋯HUmmn Different algorithms are used to analyze the COVID-19 data, and its result variations are noted carefully. It is illustrated in Table 2. Moreover, improving the analyzing strategy, a deep learning-based approach would improve. It is also used in the proposed approach, as shown in algorithm 3.1. Electronic health records of patients affected by COVID-19 are collected from various open-source datasets and validated by different available algorithms and techniques highlighted in the literature study. Every algorithm is designed to solve one particular issue, such as one algorithm for patient identification with symptoms and another for analyzing the possibility of spreading and the cause. From the study, it is clear that to target solve issues related to electronic health data prediction, analysis, and prevention of personal information of COVID-19 patients hybrid model is needed to address these issues. Homomorphic enforcement of data prevention hybrid algorithm outperforms these perspectives illustrated in Section 3.1. ⇒ EONxij (x dpbm)n[∵ (xi)j] ⇒ ICn.∏n=1∞HUn ∴EmergencyHealthInformation=ICn.∏n=1∞HUn The algorithm at 3.1 describes the information of energy getting used in all circumstances and is highlighted with homomorphic privacy metrics. Fig. 2. shows the structure of collective on-demand classification of nodes with the help of the Multi-Agent system working level deals with the agent communication, level of agent interaction, knowledge, lifelessness, conflict management, community, management, application, stability, performance, and organization. Agent communication is stated as the various communication languages of other agents and the action to be carried out communicationcomm=[langsofa+othera+act]. Interaction states the type of interaction with the software agent and another agent, interactionint=mdty(sofa+othera). Knowledge refers to the outcome of agent learning knowledgekng=learoutc. Liveness refers to the agent’s adaptation symbolizing system maintenance efforts lifeneslif=(adpa+ssmaineff). Conflict management deals with agent negotiation and system tasks. conflictmangementconfmg=(nega+systs). Community refers to the different levels of agent communication regarding agent collaboration. communitycmty=[comma0ncollba]. Management level refers to the various level of agent coordination concerning agent system structures. managementlevelmg=(coorasstra). Application level refers to the application area and different agent role cooperation. applicationlevelapp=(appar+coop0n). The stability level states the measure of agent self-reproduction. stabilitylevelstb=∑selrpa. Performance level states the performance and performance of an environment. performancelevelprf=(perf+perfa). Organization-level parameters deal with an agent’s roles, such as customer, planner, archivist, mediator, communicator, observer, and decision-maker. organizationlevelorg=r(cu,pl,ar,md,comm,ob,dmk).Fig. 2 Deep learning-based privacy preserving system for a Health Care Management Model. Homomorphic system description level for DPLS Homomorphicsystemdescriptionlevel=development+application+publication (8) Homomorphicsystemdescriptionlevel=ida+dyn+doc+doc0n+(mkas+accuser) Homomorphicdevelopmentlifecycle=phaselevel+milestonelevel+requirementworkflowlevel (9) Homomorphicdevelopmentlifecycle=str,sz,c+∑i=1nmsa+[reqa] The homomorphic development method level states the various stages involved in the development method level and its parameters, such as methodology level, paradigm level, and case level. The methodology level tries to find out suitable development method for agent implementation Dmda.methodolgylevelmth=∏Dmda. Paradigm levels used to identify the relevance of selected development paradigm Dmdpard, paradigmlevel=∏Dmdpard. Case-level parameters state the tools that support tlsp for the agent implantation. Homomorphicdevelopmentmethodlevel=methodologylevel+paradigmlevel+caselevel (10) Homomorphicdevelopmentmethodlevel=∏Dmda+∏Dmdpard+tlsp The homomorphic development management level metric deals with all management level activity parameters, project management level as shown in Eqs. (8), (9) and (10), configuration management level, and quality management level. Project management level state the developer risks devrs and the method ma involved in the agent development.projectmangementlevelprojmgl=devrs+ma. Configuration management level states the success of the version control concerning the agent. Thus configurationmanagementlevel=(nk)pkqn−k, where ‘n’ stands for the number of trails, ‘k’ denotes the number of success, n−k represents the number of failures, p indicates the probability of success of version control based on the agent in one trail, q=1−p probability of failures in one trail. Quality management level parameter state the quality assurance technique qteca involves in software agents. qualitymanagementlevelqmgl=[qteca]. Homomorphic developer-level metrics state the parameters involved in the development of an agent, such as skill level, communication level, and productivity level. Agent skill level involves the developer skill devsk and implementation of agent impa. skilllevelskl=(devsk+impa). Agent communication level parameter deals with the work advance based on collaboration collb and cooperation coop.communicationlevelcomml=wkadv(collb+coop). Productivity level states the amount of work done w=f∗d. Agentdevelopmentmanagementlevel=projectmanagementlevel+configurationmanagementlevel+qualitymanagementlevel (11) Agentdevelopmentmanagementlevel=devrs+ma+nkpkqn−k+[qteca] Homomorphicdeveloperlevel=skilllevel+communicationlevel+productivitylevel (12) Homomorphicdeveloperlevel=devsk+impa+wkadvcollb+coop+(f∗d) The homomorphic software resource level states the necessary resource required for the development of agent software and is based on the parameters paradigm level, performance level, and replacement level. The paradigm level, as shown in Eqs. (11), (12), states the relevance of the selected development paradigm devprg. paradigmlevelprgl=∏devprg. Performance level represents the component comp and effectiveness eff.performancelevelperfl=(comp+eff). The replacement level parameter states the version of adaptation adp when using various software replacementlevelrepl=[adp]vr. Homomorphic software resource level for DPLS Agent hardware resource level metric deals with reliability, performance, and availability. Reliability level states the reliable hardware plafa required for running an agent. relaiblitylevelrell=[plafa]0n. Fig. 3. shows the performance level deals with the various platform used by the software agent performancelevel=plata=1n. Availability level states the availability of various platforms avil.availablitylevel=[avil]plat Homomorphicsoftwareresourcelevel=paradigmlevel+performancelevel+replacementlevel (13) Homomorphicsoftwareresourcelevel=∏devprg+comp+eff+[adp]vr Homomorphichardwareresourcelevel=Realibilitylevel+Performancelevel+Availabilitylevel (14) Homomorphichardwareresoucelevel=[plafa]0n+plata=1n+[avil]plat HomomorphicSystemdevelopmentlifecycle=phaselevel+milestonelevel+requirementworkflowlevel (15) HomomorphicSystemdevelopmentlifecycle=str,sz,c+∑i=1nmsmas+[reqmas] Homomorphic System Development Method level for DPLS HomomorphicSystemdevelopmentmethodlevel=methodologylevel+paradigmlevel+caselevel (16) HomomorphicSystemdevelopmentmethodlevel=∏Dmdmas+∏Dmdpard+tlsp HomomorphicSystemdevelopmentmanagementlevel=projectmanagementlevel+configurationmanagementlevel+qualitymanagementlevel (17) HomomorphicSystemdevelopmentmanagementlevel=devrs+mmas+nkpkqn−k+[qtecmas] The coordinator-specific intra-cluster information system for a health management system is demonstrated in Fig. 3. The virtual coordinators have a limitation with static boundaries for communication. It searches for an appropriate resource for effective communication in deprived regions, and the management level of data protection and privacy levels are illustrated in Eqs. (13), (14). Homomorphic and Development life cycle, Method, developer, and management level for DPLS. The Homomorphic System Development life cycle and Development management level for DPLS as shown in Eqs. (15), (16), and (17), respectively.Fig. 3 DPLS - A coordinator-specific Intra-cluster Information Updating system. 4 Result evaluation and discussion Homomorphic system development model to analyze the COVID-19 data for managing the entire life cycle of hardware resource monitoring. Resource allocation under developer model and methods with software description. To remain safe and protected and complete maximum efficiency with minimum futile effort or disbursement communication system under network problems which intrude an event activity without believing a reliable another part is still persistent as a challenging issue. In three parts, the user’s data investigator scrutinizes a crime locomotive as the core of a careful trailing obstructive contrivance. The number of file block facsimiles has no meaning in the design of manifold users with the sole data center. The number of potential electronic health information needs to be prevented from various breach activities and influencing unusual activity. The number of tags is noted from individual responses identified from various symptoms collectively illustrated in Fig. 4. The hit ratio of different ranges concerning COVID-19 data is tested under fifty degrees of other circumstances as defined by user 1 to user n. The on-demand request is calculated based on the recall value of the patient’s f1-score to improvise personal data during critical scenarios. The readiness of users after homomorphic encryption is also noticed, as shown in Fig. 5. Data security is a mandatory research work that needs immediate consideration without any delay. Researchers focus rather than reactively; it would be better to be proactive in data preservation. There are cryptographic techniques to solve these issues actively in preventing data breaches. Mathematical imposed models give a high probability of protection in all scenarios. Elliptical curve cryptography (ECC) is a secure encryption and decryption standard algorithm that can serve the issue until a few hits. Similarly, hashing-based techniques resemble hash tables to protect a few more attempts from data breaches. Comparatively, homomorphic encryption standard algorithms (HMA) prove with the help of distributed mathematical model in-built to withhold maximum hit ratio and attacks to prevent the data identity. It motivated us to incorporate the model into the proposed approach to solve privacy issues, specifically in the healthcare system.Fig. 4 COVID patient analysis eligible to prevent personal information. Suppose there is an opportunity to collaborate with various users to perform a computation. In that case, it might help a critical health user recover from danger as a homomorphic metric-based health cooperation analysis is illustrated in Fig. 6.Fig. 5 Homomorphic enforcement in critical scenario. Preventing user information whenever a critical attack is initiated on the storage region is noted for possible breach. Health users having credentials to various features of storage regions might lead to improper guidance in handling precious data. An electric health record holder would use multiple applications that might provide free access to the rest of the world by agreeing to the vendors’ terms and agreements. The agreement is not so easy to explore the users from time to time, leading to mishandling of the data by the application owner and their partnering agency. To avoid exploring inside electronic information without the concern of providers or users, a multi-constrained access control mechanism is used as a shield to protect all data from intruders. Service requests are generated and validated by multi-environment protection levels deployed on top of the storage region by incorporating necessary homomorphic prevention mechanisms.Fig. 6 Opportunistic health data analysis and homomorphic metric for COVID patients. Privacy metrics are collectively used to reduce the risk factors of health informatics for individual users to improve effective personal data prevention. Fig. 7. shows the eligible metrics adopted by incorporating the homomorphic standard for preventing the data breach. Figs. 4, 5, 6 and 7 illustrate the multi-objective opportunity of COVID-19 analysis prediction and homomorphic enforcement to avoid user’s information. The homomorphic system adapts to solving complex tasks more optimally by splitting the problem into various sub-tasks. To maintain the system’s reliability, suitable quality metrics should be represented as agents and supports for empirical analysis. The deep learning process would be applied with appropriate metrics for improving DPLS performance, specialization, Interaction, learning, negotiation, and self-reproduction in various fields. A vast area of research needs to be addressed, and available analysis calls for the digital world.Fig. 7 Homomorphic opportunistic computing with eligible privacy metrics. Privacy metrics system evaluation under different scenarios for searching and identifying the nodes which need critical care and emergency computing. They are notably tested for information preservation identified from the sharable participative nodes. Table 1 illustrates the process of random access, searching, and identification of resource sharing to perform emergency communication. Data breaches and computing observed by SPOC, PPBOC, DPLS, and CSOHM are tested, and their metrics are noted with different scenarios. Results show improved performance to do cooperative tasks comparatively high respectively.Table 1 Deep learning based privacy metrics system tested under different scenarios (DS). Different Critical/ Emergency computing- Kbps Critical/ Emergency computing- Kbps scenarios Random SPOC PPBOC DPLS CSOHM Random SPOC PPBOC DPLS CSOHM DS1 7576.7 5992 2231 1915 1241 6573.3 4691 2927 1915 1032 DS2 8853.89 4232 3421 2323 2241 6253.33 3382 3594 2829.03 1174 DS3 10746.45 5442 3952 2424 3141 8303.33 7743 3105 2637.33 1092 DS4 18594.74 9215 4841 3342 4035 13269.33 11215 3182 2102.82 1047 DS5 17978 6456 4315 3562 5221 15449.35 14826 3215.5 2948 1210 DS6 13087.33 7020 2532 4888 6214 11768.97 10420 3853 2008.88 1038 DS7 23527 9983 3123 5333 6533 22341 21983 4013 3133.33 1104 Data privacy can be addressed with various methodologies, Such as mathematical models, statistical algorithm analysis, cryptographic logic, and advanced encryption algorithms. Blockchain technologies are one of the advanced technology to be adapted for distributed data storage and decentralized managing strategy. A future extension of the proposed work is further improved by using blockchain-based information protection. Since healthcare patient data is controlled by hospital management or doctors in the current perspective, it can be framed as a decentralized model without disturbing core healthcare management. Homomorphic encryption techniques can be inculcated into blockchain technology to prevent the block of data in the chain. Data created in a genesis block would consist of original patient data where it needs to be stopped. Inside the blockchain, a cryptographic algorithm must be incorporated to generate hashing of every block. Privacy metrics in the healthcare management system is evaluated for the betterment of privacy-preserving; it is compared with various algorithms, privacy policy, encryption techniques, statistical analysis, and mathematical model for effectiveness. It is observed that the proposed privacy metric has a comparatively high data-preserving rate in all circumstances. Table 2 shows various parameters and their illustration with algorithms testing and manipulation of statistical and thematical models wrapped with the privacy policy as a backbone. Encryption techniques adopted for end-to-end data preserving with high risk and low data breaches to achieve a cent percent data delivery. The vast increase in resource sharing would increase the scalability risk, so deep learning-based data navigation needs to reduce the failure rate in information prevention.Table 2 Privacy metrics evaluation of cooperative system tested in the healthcare system. Performance criteria Privacy-preserving metrics Privacy policy & encryption Statistical analysis Mathematical model Random SPOC PPBOC DPLS CSOHM Random SPOC PPBOC DPLS CSOHM Random SPOC PPBOC DPLS CSOHM Confidentiality ✗ ✔ ✔ ✔ ✔ ✗ ✔ ✔ ✔ ✔ ✗ ✔ ✔ ✔ ✔ Integrity ✗ ✔ ✔ ✔ ✔ ✗ ✔ ✔ ✔ ✔ ✗ ✔ ✔ ✔ ✔ Availability ✗ ✔ ✔ ✔ ✔ ✗ ✔ ✔ ✔ ✔ ✗ ✔ ✔ ✔ ✔ Accountability ✗ ✗ ✗ ✗ ✔ ✗ ✗ ✗ ✗ ✔ ✗ ✗ ✗ ✗ ✔ Service Assurance ✗ ✗ ✗ ✗ ✔ ✗ ✗ ✗ ✗ ✔ ✗ ✗ ✗ ✗ ✔ Data Reliability ✗ ✗ ✔ ✔ ✔ ✗ ✗ ✔ ✔ ✔ ✗ ✗ ✔ ✔ ✔ Scalability ✗ ✗ ✔ ✔ ✔ ✗ ✗ ✔ ✔ ✔ ✗ ✗ ✔ ✔ ✔ Fault tolerance ✗ ✗ ✔ ✔ ✔ ✗ ✗ ✔ ✔ ✔ ✗ ✗ ✔ ✔ ✔ Robustness ✗ ✗ ✗ ✔ ✔ ✗ ✗ ✗ ✔ ✔ ✗ ✗ ✗ ✔ ✔ Search time ✗ ✗ ✗ ✔ ✔ ✗ ✗ ✗ ✔ ✔ ✗ ✗ ✗ ✔ ✔ Computing time ✗ ✗ ✗ ✔ ✔ ✗ ✗ ✗ ✔ ✔ ✗ ✗ ✗ ✔ ✔ Privacy Risk Factor ✗ ✗ ✔ ✔ ✔ ✗ ✗ ✔ ✔ ✔ ✗ ✗ ✔ ✔ ✔ Preserving Strategy ✗ ✗ ✗ ✔ ✔ ✗ ✗ ✗ ✔ ✔ ✗ ✗ ✗ ✔ ✔ Data delivery rate ✗ ✗ ✔ ✔ ✔ ✗ ✗ ✔ ✔ ✔ ✗ ✗ ✔ ✔ ✔ Node Coordination ✗ ✗ ✔ ✔ ✔ ✗ ✗ ✔ ✔ ✔ ✗ ✗ ✔ ✔ ✔ Service assurance is an essential preserving strategy in node coordination which help for building trust among providers and to do practical computing. The future research focus might be more concerned with the data prevention mechanism coupled with a framework in-built with deep learning and an artificial intelligence-based approach that would improvise the trust factor. Table 3 illustrates the COVID-19 prediction data collected from hospital management. Moreover, various disease symptoms and patients’ illnesses are shown in the table. Patient data is analyzed with all possible opportunities and the prediction mechanism, as shown in Fig. 8a, 8b, and 8c.Table 3 COVID-19 data analysis and illustration with various diseases. SL.No Sex Pneumonia Age Pregnancy Diabetes COPD Asthma Inmsupr Hypertension Other_disease Cardiovascular Obesity Renal_chronic Tobacco 1. F 2 71 2 2 2 2 2 1 2 2 2 1 2 2. M 2 38 +VE 2 2 2 2 2 2 2 1 2 2 3. F 2 49 2 1 2 2 2 1 2 2 1 2 2 4. M 1 67 NA 2 2 2 2 1 2 2 2 2 2 5. F 1 56 2 2 2 2 2 1 2 2 2 2 2 6. M 2 45 NA 2 2 2 2 2 2 2 2 2 2 7. M 1 51 NA 2 2 2 1 1 1 1 2 1 2 8. F 2 48 2 1 2 2 2 1 2 2 2 2 2 9. M 2 77 NA 1 2 2 2 1 2 2 2 2 1 10. F 2 30 2 2 2 2 2 2 2 2 1 2 2 11. M 1 68 NA 1 2 2 2 2 2 2 2 2 2 12. F 2 42 2 2 2 2 2 2 1 2 1 2 2 13. M 2 49 NA 2 2 2 2 2 2 2 2 2 2 14. F 2 59 2 1 2 2 2 1 2 2 2 2 2 15. M 1 29 +VE 2 2 2 2 2 2 2 2 2 2 16. M 1 89 NA 1 2 2 2 1 2 2 2 2 2 17. F 1 67 2 2 2 2 2 2 2 2 2 2 2 18. M 1 52 NA 2 2 2 2 2 2 2 2 2 2 19. M 1 63 NA 2 2 2 2 2 2 2 2 2 2 20. M 2 48 NA 2 2 2 2 2 2 2 2 2 2 21. F 1 76 2 2 2 2 2 1 2 2 1 2 2 22. M 2 36 +VE 2 2 2 2 2 2 2 1 2 2 23. M 2 52 NA 2 2 2 2 2 2 2 1 2 2 24. M 2 48 NA 1 2 2 2 2 2 2 2 2 2 25. M 1 60 NA 2 2 2 2 1 2 2 1 2 2 26. M 2 25 +VE 1 2 2 2 2 2 2 2 2 2 27. M 1 67 NA 2 2 2 2 2 2 2 2 2 2 28. M 2 40 NA 2 2 2 2 2 2 2 2 2 2 29. F 2 54 2 2 2 2 2 2 2 2 2 2 2 The literature study explores the need for personal health data prevention from various perspectives. There is a research gap in personal heal record prevention. Available prevention mechanisms are holding the breach for notable iterations because of the vibrant advantages and the adequate performance of the advanced approach to preventing personal data motivated to propose a system that enhances the prevention mechanism in critical cases. Healthcare issues can be handled with homomorphic encryption-based data protection. The multi-constrain data prevention would support the electronic health report holders to collaborate with exemplary practitioners in relevant research communities worldwide. Fig. 8a, Fig. 8b, Fig. 8c show the prediction mechanism and its analysis in all scenarios mainly based on the metrics utilized for developing a unique model by incorporating standard homomorphic encryption. COVID-19 patients data is analyzed with acute symptoms of those with other notable diseases under medication.Fig. 8a COVID-19 patient data analysis. Fig. 8b COVID-19 prediction. It is observed from the literature study that virus infection and its vast spreading led to a global pandemic that destroyed all nations’ economies. Many cases have come across from time to time with a different virus, which caused much human life in this world. From the study, it is must to predict the cause and procedure to prevent the wide spreading of any virus to the next level or the rest of the world. A research gap is identified in predicting the virus cause, and the chance of affecting internal organs or disturbing the functionality of routine work may lead to critical danger. Patient health information is highly confidential and must be protected by hospitals and doctors. Electronic health records are stored in many hospitals, and cloud storage creates a critical risk for patients’ health data. Much research concentrates on personal health record protection by using standard approaches. In the proposed model, the utilization of homomorphic encryption shows an improved performance in personal health record maintenance. The article tested the COVID-19 dataset to evaluate the proposed approach’s effectiveness. The unexpectedly presented system outperformed in all perspectives and showcased the need for applying such methods to prevent the COVID-19 patient details and predict the wide spread of the virus in stipulated time.Fig. 8c COVID-19 health data metric privacy performance compared with other approaches. 5 Conclusion A deep learning approach for analyzing user requests on demand with an appropriate search process and identifying the right resource is challenging. This paper demonstrates and describes the mining process by coordinator-specific bee colony-based architecture. In decentralized maintenance under virtual coordination, searching and allocating the resource in a wireless region is unmanageable. The nomadic agent supports the knowledgebase with sufficient resources based on the artificial bee colony behavior as the nature-inspired deep learning approach for searching and identifying eligible resources. In this article, it is brought to the notice of the research forum that there is a need for a deep learning process to map the fitness of the learning system using multi-agent. However, deep learning systems might reach a better era if the applicability and maintenance could be performed by improving the efficiency, portability, trustworthiness, functionality, reusability, testability, and security of current social impacts. Observation and future work The proposed homomorphic encryption strategy could be more suited to include in the block to improve the prevention mechanism. Cooperative Secure Opportunistic Homomorphic Management (CSOHM) for data integrity encourages health users’ awareness to address data breaches. Data protection in various research criteria would be evaluated based on a few parameters considered the highest metrics to mitigate privacy breaches. Metrics that have the most priority like Confidentiality, Integrity, Availability, Accountability, Service assurance, Data Reliability, Scalability (Comparatively High), Fault Tolerance (Very low, Low, Medium/Average, High, Very High), Robustness (Very low, Low, Medium/Average, High, Very High), Search time (ms), Computing time (Kbps), Privacy Risk Factor (Very low, Low, Medium/Average, High, Very High), Preserving Strategy (Very low, Low, Medium/Average, High, Very High), Reliability (Very low, Low, Medium/Average, High, Very High), Data delivery rate %, Node Coordination in %, No. of opp. nodes to do a collaborative task. These privacy metrics must determine adequate personal data protection in various storage services. The performance evaluation is illustrated in Table 2 and its plotting is shown in Figs. 8a, 8b, and 8c evidence of which outperformance of the proposed approach with concrete proof of the proposed system’s effectiveness. CRediT authorship contribution statement Chandramohan Dhasarathan: Conceptualization, Methodology, Writing – original draft, Software, Validation. Mohammad Kamrul Hasan: Data curation, Analysis, Writing – original draft, Writing – review & editing, Funding. Shayla Islam: Visualization, Investigation, Software. Salwani Abdullah: Writing – review & editing, Software. Umi Asma Mokhtar: Writing – reviewing and editing. Abdul Rehman Javed: Writing – reviewing and editing. Sam Goundar: Writing - analysis, Reviewing and editing. Uncited References [27], [28], [29] Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Data availability The dataset used is made available as an open source for the research community. The proposed system preserves patient health records during the pandemic and in all situations. Relevant healthcare data sets are considered for testing the proposed approach’s effectiveness, as illustrated in the result and discussion section. Dataset: Chandramohan D, May 25, 2022, “Privacy_COVID”, IEEE Dataport, doi: https://doi.org/10.21227/scr5-pr80. Acknowledgment This work is supported by the Universiti Kebangsaan Malaysia (UKM) under FRGS/1/2020/ICT03/UKM/02/6, and Thapar Institute of Engineering & Technology, ECED, Patiala, Punjab, India . ==== Refs References 1 Firouzi F. Harnessing the power of smart and connected health to tackle COVID-19: IoT, AI, robotics, and blockchain for a better world IEEE Internet Things J. 8 16 2021 12826 12846 10.1109/JIOT.2021.3073904 35782886 2 Rahman M.M. Paul K.C. Hossain M.A. Ali G.G.M.N. Rahman M.S. Thill J.-C. 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==== Front Sci Afr Sci Afr Scientific African 2468-2276 The Author(s). Published by Elsevier B.V. on behalf of African Institute of Mathematical Sciences / Next Einstein Initiative. S2468-2276(22)00408-2 10.1016/j.sciaf.2022.e01504 e01504 Article A Look at the Global Impact of COVID-19 Pandemic on Neurosurgical Services and Residency Training Kuo Cathleen C. 1 Aguirre Alexander O. 1 Kassay Andrea 2 Donnelly Brianna M. 3 Bakr Hebatalla 4 Aly Mohamed 5 Ezzat Ahmed A.M. 6 Soliman Mohamed A.R. 67⁎ 1 Jacobs School of Medicine and Biomedical Sciences at University at Buffalo, Buffalo, New York, USA. 2 Department of Neurosurgery, Western University, Windsor, Canada. 3 Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hofstra University, Hempstead, New York, USA. 4 Department of Radiology, Giza Scan, Giza, Egypt. 5 Department of Radiology, National Heart Institute, Giza, Egypt. 6 Department of Neurosurgery, Faculty of Medicine, Cairo University, Cairo, Egypt. 7 Department of Neurosurgery, Jacobs School of Medicine and Biomedical Sciences at University at Buffalo, Buffalo, New York, USA. ⁎ Corresponding Author, Faculty of Medicine, Cairo University, Cairo, Egypt, Tel 732-924-1637 14 12 2022 14 12 2022 e01504© 2022 The Author(s). Published by Elsevier B.V. on behalf of African Institute of Mathematical Sciences / Next Einstein Initiative. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. BACKGROUND : The COVID-19 pandemic has left an indelible effect on healthcare delivery and education system, including residency training. Particularly, neurosurgical departments worldwide had to adapt their operating model to the constantly changing pandemic landscape. This review aimed to quantify the reduction in neurosurgical operative volume and describe the impact of these trends on neurosurgical residency training. METHODS : We performed a comprehensive search of PubMed and EMBASE between December 2019 and October 2022 to identify studies comparing pre-pandemic and pandemic neurosurgical caseloads as well as articles detailing the impact of COVID-19 on neurosurgery residency training. Statistical analysis of quantitative data was presented as pooled odds ratio (OR) and 95% confidence intervals (CI). RESULTS : A total of 49 studies met the inclusion criteria, of which 12 (24.5%) were survey-based. The case volume of elective surgeries and non-elective procedures decreased by 70.4% (OR=0.296, 95%CI 0.210–0.418) and 68.2% (OR=0.318, 95%CI 0.193–0.525), respectively. A significant decrease was also observed in functional (OR=0.542, 95%CI 0.394–0.746), spine (OR=0.545, 95%CI 0.409–0.725), and skull base surgery (OR=0.545, 95%CI 0.409–0.725), whereas the caseloads for tumor (OR=1.029, 95%CI 0.838–1.263), trauma (OR=1.021, 95%CI 0.846–1.232), vascular (OR=1.001, 95%CI 0.870–1.152), and pediatric neurosurgery (OR=0.589, 95%CI 0.344–1.010) remained relatively the same between pre-pandemic and pandemic periods. The reduction in caseloads had caused concerns among residents and program directors in regard to the diminished clinical exposure, financial constraints, and mental well-being. Some positives highlighted were rapid adaptation to virtual educational platforms and increasing time for self-learning and research activities. CONCLUSION : While COVID-19 has brought about significant disruptions in neurosurgical practice and training, this unprecedented challenge has opened the door for technological advances and collaboration that broaden the accessibility of resources and reduce the worldwide gap in neurosurgical education. Keywords Covid-19 Education Neurosurgery Pandemic Residency Training Abbreviations CNS, Congress of Neurological Surgeons CI, confidence interval HIC, high income countries LMIC, low- and middle- income countries OR, odds ratio PPE, personal protective equipment Editor: DR B Gyampoh ==== Body pmcINTRODUCTION COVID-19, the disease caused by SARS-CoV-2, has been characterized by the World Health Organization as a public health emergency and later declared as global pandemic. [1] To date, more than 625 million people worldwide have tested positive for COVID-19 and at least 6.5 million deaths have been attributed to it. [2] Resources required to care for this patient population and the overwhelming demands have strained the healthcare systems rapidly in many countries. [3] The prioritization of surgical services has also shifted: non-urgent elective surgical cases and outpatient clinics were placed on hold, while emergent cases continued but with revised management protocols. [4], [5], [6] Within neurosurgical care, many procedures are time-sensitive or semi-urgent – treating sooner may prevent long-lasting neurological deficits and potentially benefit more from surgical intervention. [7] Triaging non-elective neurosurgical indications, therefore, presented an unprecedented challenge under the constantly changing pandemic landscape that required meticulous weighing of the risks and benefits. [8] In addition to the impact on case volume, quality of neurosurgical residency training is another aspect that has been negatively influenced by the COVID-19 pandemic. [9] Many programs underwent temporary restructuring of their services to both minimize the number of residents exposed to COVID-19 as well as to maintain workflow to allow urgent reallocation of hospital resources. [10] While the training time for neurosurgical residency is long (ranging from 5 to 8 years), even three months of reduction in surgical activities and clinical experiences may have far-reaching effects on training. [9] Adaptive measures reported to supplement resident training included the use of webinar-type online platforms for conferences, at-home microsurgical skill training programs, surgical stimulation sessions, and research activities that can be performed remotely. [11], [12], [13], [14] Prior to the COVID-19 pandemic, disparity in neurosurgical training between high-income countries (HIC) and low- and middle-income countries (LMICs) was already a prominent problem leading to maldistribution of neurosurgeons and neurosurgical care. [15] The outbreak of COVID-19 further deepened the existing disparities. [16] For instance, despite the abovementioned innovative platforms for neurosurgical training and education can be distributed rapidly across the world, LMICs would have limited ability to implement those novel technologies. [13,14] There has also been a reduction in international training opportunities, including observership programs, elective rotations, clinical and research fellowship positions, and in-person conferences. [17] Understanding the impact of the COVID-19 pandemic on neurosurgical training can provide insight for program directors and faculty members to discern which aspects of residency training are most vulnerable to changes and to recognize what modifications can help to maintain consistency in training quality as well as to help guide response to future pandemics. In this study, we sought to quantify the reduction in neurosurgical case volume and to ascertain the associated effect on residency training worldwide through a systematic review of relevant published articles and further analysis of the results. METHODS The manuscript was prepared in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. [18] Search strategy, selection criteria, and outcome measures were determined in advance. Search Strategy A comprehensive systematic search was conducted through PubMed (National Library of Medicine) and EMBASE (Elsevier) from December 2019 to September 2022. Terms synonymous with “COVID-19”, “neurosurgery” and “residency training” were utilized with Boolean operators to maintain high inclusivity for the initial search. We also performed manual searches of the bibliographies to identify relevant studies. The search was limited to English language publications and human subjects. Full search strategy can be found in supplementary table 1. Selection Criteria The search results were entered into Rayyan (https://www.rayyan.ai/) (Rayyan Systems Inc, Cambridge, Massachusetts, USA), which is a web mobile application for systematic review. [19] Two authors independently screened titles and abstracts of all identified studies with a third author who provided an assessment in case of any disagreement. We included studies that directly compared neurosurgical case volume in pre-COVID-19 era and COVID-19 era as well as articles detailing the impact of COVID-19 on neurosurgical residency training worldwide. Studies were excluded if they did not provide comparative data, compared the wrong time periods, focused on methodological or technological innovations rather than residency training, and did not provide separate data from other surgical specialties. Conference abstracts, commentaries, and cadaver or animal studies were also excluded. Of note, we included letters to the editor and editorials as most of the neurosurgery journals were accepting studies as only editorials during the COVID-19 pandemic. Data Collection and Quality Assessment Following the finalization of the included studies, relevant data including first author, title, publication date, country of the enrolled population, study design, and pandemic period reported were extracted into a standardized, pilot-tested template. The primary outcome of interest was the impact on neurosurgical residency training, which could be measured in terms of caseloads, redeployment, work hours, research activities, change in educational sessions (e.g. morbidity and mortality conference, grand rounds, and board review), and solution implemented to cope with these difficulties. The quality of included cohort or case control studies was evaluated using the 9-star Newcastle-Ottawa Quality Assessment Scale (NOS). [20] Statistical Analysis Studies with data available for case volumes in the pre-COVID-19 era and COVID-19 era were included in the quantitative meta-analysis. Effect sizes were presented as odds ratio (OR) with their corresponding 95% confidence interval (CI) and displayed in the form of a forest plot. We assessed heterogeneity across individual studies by inspecting forest plots and with I2 index and Cochran's Q statistical test. If I2 was >50% and p-value <0.05, a random-effects model (DerSimonian and Laird method) was chosen; otherwise, the fixed-effect model was used to pool the estimate. Potential publication bias was evaluated using the Eggers’ regression asymmetry test. We considered a two-sided p-value <0.05 statistically significant. All statistical analyses were performed using RStudio (https://www.r-project.org/) (RStudio, Boston, Massachusetts, USA). Results Study Identification A systematic search of the literature yielded a total of 606 and 628 articles from PubMed and Embase, respectively. After removing duplicates, 935 articles were left; their titles and abstracts were screened, and 78 relevant articles were identified for full-text review. Overall, this study collated data and information from 49 articles, [11,12,17,[21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65]] with 25 of them included in the quantitative synthesis (Figure 1 ). Twenty-two of these articles were retrospective in nature, two had data collected both retrospectively and prospectively, one was both a retrospective cohort study and a survey. The remaining 14 articles were surveys and were included in the qualitative synthesis. By country involved, most studies enrolled patients from the United States (n=21), followed by India (n=4), Egypt (n=4), United Kingdom (n=3), and Spain (n=3). For quality assessment, the mean Newcastle-Ottawa scale was 6.2 ± 0.9 (range, 5 to 8), suggesting that majority of the included cohort studies were of moderate methodological quality. Study characteristics of the included articles are summarized in Table 1 .Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram showing the number of articles identified and excluded at each stage of the literature search. Figure 1 Table 1 Descriptive Summary of Included Studies in Systematic Review and Meta-Analysis. Table 1Author, Year Country Involved Study design Pandemic Period Reported Impacts on Residency Training NOS Alhaj et al. 2020 [32] Kuwait, Canada, USA, Saudi Arabia, Italy, Serbia Cross-sectional survey N/A 98% felt training was affected 90% felt mental health was affected 100% reported their social life was affected N/A Aljuboori et al. 2021 [12] USA Retrospective cohort and survey Mar 2020 – Apr 2020 87.5% stated didactics moved to online only 37.5% felt surgical skills was negatively affected 87.5% reported more time for research activities 7 Almufarriji et al. 2021 [35] Saudi Arabia Survey N/A 58.8% reported stopping all educational activities 35.8% increase in on-call duties 9.5% redeployed N/A Arnaout et al. 2020 [56] USA Letter to the editor N/A Actively reduced elective surgical cases and in-person visits Restructured services: residents contributed to daily patient care remotely, implemented a coverage model similar to a weekend coverage Eliminated “double” scrubbing by senior residents and junior residents Moved educational activities virtually 50% redeployed N/A Ashkan et al. 2021 [27] United Kingdom Retrospective and Prospective cohort Jan 18, 2020 – May 15, 2020 55.6% reduction in overall operative volume 31.5% increase in proportion of emergency operations 8 Ashry et al. 2020 [21] Egypt Survey N/A 56% reported reduction of actual role in surgical steps 10% redeployed 88% stated transition to virtual educational methods 100% felt suffering from financial strains 68% reported burnout symptoms Significant increase in research hours N/A Azab et al. 2021 [37] Egypt Retrospective cohort Mar 2020 – Dec 2020 Decrease in mean operative time (pre: 98±8.3 vs. during: 94.3±11.4 minutes) 6 Bambakidis et al. 2020 [57] USA Editorial N/A Decreased resident staffing to 50% of normal (1-week on and 1-week off model) Significant drop in elective and nonessential surgical volume Limited surgical cases to a single resident to preserve PPE Transitioned to virtual conferences N/A Bajunaid et al. 2020 [38] Saudi Arabia Retrospective cohort Mar 31, 2020 – May 20, 2020 44% reduction in overall operative volume 6 Benner et al. 2022 [41] USA Retrospective cohort Apr 1, 2020 – Apr 30, 2020 58.5% reduction in overall operative volume 6 Burks et al. 2020 [31] USA Retrospective cohort Apr 1, 2020 – Apr 30, 2020 Operative case totals were lower at all levels of training Significant decrease in the number of residents participating in each case (p<0.01) Significant decrease in cases compared to the year before (p<0.01) 7 Bray et al. 2020 [58] USA Letter to the editor N/A Held weekly online “town-hall meetings” Service subdivided to 2 working teams (2-week cycle) Transitioned to telemedicine for all outpatient visits Redeployed to neurological Critical Care team N/A Cerda-Vargas et al. 2021 [42] Spain, Mexico, Argentina, Brazil Cross-sectional survey N/A 66.2% felt training was affected 86.3% felt either or both of their physical and mental health were affected 20.1% reported increase in weekly academic hours N/A Cheserem et al. 2020 [43] Egypt, Zimbabwe, South Africa Cross-sectional survey Apr 16, 2020 – May 21, 2020 Marked reduction in clinical activities (-80% of elective surgery, -83% of clinics, -38.5% of emergency surgery) 61.0% reported receiving online teaching 57.72% had examinations postponed and 19.51% had examinations cancelled 11.38% redeployed 32.52% reported training rotation suspended 23.58% stated not receive a formal salary N/A Dash et al. 2020 [44] India Cross-sectional survey May 7, 2020 – May 16, 2020 67.5% reduction in the average number of surgeries performed per month 32.6% reduction in the number of academic sessions 61.02% reported shift to online videoconferencing sessions 13.56% had academic sessions stopped 88.14% felt training in terms of clinical and operative skills were adversely impacted 53.39% feared being less competent 48.30% felt increase in work-related stress N/A Deora et al. 2020 [45] India Retrospective cohort Mar 1, 2020 – Jul 31, 2020 57% reduction in overall operative volume 5 ElGhamry et al. 2021 [46] United Kingdom Retrospective cohort Mar 20. 2020 – Aug 31, 2020 Significant reduction in referral and operative caseloads (p<0.001) 7 Eichberg et al. 2020 [16] USA Letter to the editor N/A Halted all elective cases but continue to schedule urgent and emergent cases 75% diminished in overall surgical volume Implemented telehealth technology integrated into electronic medical record All in-person conferences have been replaced by video teleconferences Devised rotating resident schedules to minimize viral exposure and burnout N/A EI-Ghandour et al. 2020 [59] International (96 countries) Letter to the editor Mar 20, 2020 – Apr 3, 2020 71.4% reported decreased workload 62.5% reported financial burden 26.7% reported cessation of research activities N/A Galarza et al. 2020 [60] Spain Letter to the editor N/A Redeployed to serve on COVID-19 teams Reduced to 27 to 35 surgical cases per day N/A Goyal et al. 2020 [47] India Retrospective cohort Mar 25, 2020 – May 31, 2020 52.2% reduction in overall operative volume 6 Jean et al. 2020 [62] International (60 countries) Survey N/A 46.1% reported operative volume dropped more than 50% N/A Khalafallah et al. 2020 [26] USA Retrospective cohort Mar 4, 2020 – Apr 17, 2020 97.12% reduction in in-person clinic visits 44.68% reduction in inpatient census 15.4% redeployed Transition of grand rounds and M&M to online videoconference 50% increase in educational session attendance 75% felt didactics were negatively affected 87.5% reported didactics transited to online only 8 Khalafallah et al. 2020 [22] USA Survey N/A 74.8% reported decreased weekly work hours 67.6% reported decreased ability to meet ACGME operative case minimums 15.3% redeployed 82.0% participated in remote didactic lectures 66.7% reported increase in research activities N/A Khan et al. 2021 [24] USA Retrospective cohort Mar 16, 2020 – May 8, 2020 Decreased resident coverage to a 1 week on and 1 week off model Decreased operative volume in spine cases and functional cases (p<0.001) 6 Kilgore et al. 2021 [30] USA Retrospective cohort Mar 2020 – June 2020 77% reduction in neurosurgical volume Significant increased incidence of multiple residents scrubbing the same case (p=0.011) 6 Laskay et al. 2020 [61] USA Letter to the editor N/A Restructured resident coverage to 7-day cycle Department issued an official requirement for all nonessential cases to be cancelled Initiated teleconsultation program for trauma patients with nonurgent or nonoperative pathology Limited in-person conference attendance to 10 individuals Utilized educational resources offered by the Congress of Neurological Surgeons N/A Lubansu et al. 2020 [48] Belgium Retrospective cohort Mar 6, 2020 –May 10, 2020 50% reduction in overall operative volume 6 Meybodi et al. 2020 [49] Iran Retrospective cohort Mar 2020 – Jun 2020 31% reduction in overall surgical cases Considerable reduction in subspecialized educational surgeries 6 Nabil et al. 2022 [50] Egypt Retrospective cohort Jan 2020 – Jun 2020 38% reduction in overall operative volume 5 Pannullo et al. 2020 [63] USA Letter to the editor N/A Cancelled all elective surgeries 65.6% reduction in operative volume 50% clinic visits moved to telehealth 42.9% redeployed Halted all basic and translational experiments Transited to virtual grand rounds, M&M conferences, resident journal club, and department webinars N/A Patel et al. 2020 [51] USA Retrospective cohort Mar 23, 2020 –May 8, 2020 40% reduction in weekly procedural volume 28% decrease in weekly neurosurgical consultation 47% decrease in outpatient clinic encounters 6 Pelargos et al. 2020 [11] USA, Canada Survey Apr 17, 2020 – Apr 30, 2020 35.1% providing non-specialty care to COVID-19 patients 82% reduction in inpatient and outpatient volumes 91% reported decrease in work responsibility, with significant decrease in work hours (p<0.0001) 33.7% felt residency education was negatively affected, with senior trainees more likely to be concerned 26.5% concerned limit ability to get desired employment or fellowship Significant increase in number of trainees spending >4 hours on didactics p<0.0001 N/A Petr et al. 2022 [52] Austria, the Czech Republic Retrospective cohort Jan 2020 – Dec 2021 Reduction in number of traumatic brain injuries, spine conditions, and chronic subdural hematomas 5 Saad et al. 2020 [28] USA Retrospective cohort Mar 16, 2020 –Apr 15, 2020 80% reduction in case volume 59% decrease in numbers of bedside procedures 20% reduction in occupancy of neurointensive care unit bed Transition of M&M to virtual conference 7 Sahin et al. 2021 [53] Turkey Survey N/A 54.8% felt theoretic education was negatively affected 21.3% reported transition to completely online teaching sessions 38.3% had teaching sessions not held at all 78.7% felt surgical training was negatively affected, with decreased case volume (60.9%) being the most cited reason 42.1% felt increased concerns about residency training and future career N/A Sarpong et al. 2021 [54] USA Retrospective cohort Mar 8, 2020 – Jun 8, 2020 61.0% reduction in case volume 7 Sudhan et al. 2021 [40] India Retrospective cohort Mar 15, 2020 – Sep 15, 2020 42.75% reduction in caseloads No significant difference in overall incidence of emergency and essential surgeries (p=0.482) 6 Suryaningtyas et al. 2020 [23] Indonesia Retrospective cohort Apr 2020 – Jun 2020 50% reduction in overall case volume Reorganized the residents for service in 10-20 schemes (10-day on service, followed by 20-day off hospital) 7 Tavanaei et al. 2021 [39] Iran Retrospective and Prospective case control Jun 1, 2020 – Sep 1, 2020 30% reduction in overall case volume 6 Theofanis et al. 2020 [64] USA Letter to the editor N/A Devised a new call schedule with 2 teams Mandated residents who were not working stay home Redeployed to “Line Service in intensive care units N/A Tzerefos et al. 2021 [33] Greece, Switzerland, Spain, United Kingdom Survey N/A 88.8% felt education was negatively influenced 92.5% reported a reduction in hands-on surgical exposure 92.5% participated in online educational activity 29.9% redeployed 44.8% reported more time for research work 65.7% reported more time for self-study N/A Velnar et al. 2022 [34] Slovenia Retrospective cohort Mar 2020 – Apr 2021 No important decline of the number of operated patients 5 Wali et al. 2020 [36] USA Retrospective cohort Mar 16, 2020 – Jul 6, 2020 Only moderate diminish of daily total cases (pre: 6.9 vs. during: 5.8 cases) 5 Weber et al. 2020 [55] USA Letter to the editor N/A Transitioned from 12-hour call periods to 24-hour call to minimize face-to-face sign-out Implemented a daily lecture curriculum (1.5 hours every day) led by senior residents Transitioned from pre-COVID resident group fitness to in home exercise routines Established a dedicated weekly meeting in which the Program Director and Chairman run a “Town Hall” session for resident concerns, ideas, and questions N/A Weiner et al. 2021 [65] International Survey Mar 27, 2020 – Apr 4, 2020 35.6% respondents identified as “high telehealth users” 80.1% were interested in online education N/A Wittayanakorn et al. 2020 [17] Indonesia, Malaysia, Philippines, Singapore, Thailand Survey May 22, 2020 – May 31, 2020 82% reduction in elective operations 62% reduction in emergency operations 76% felt training was significantly impacted Transition to virtual meetings for grand rounds and M&M 33% noted a decrease in research productivity N/A Zhang et al. 2022 [29] USA Retrospective cohort Jan 2020 – Dec 2020 58% decrease in caseloads for junior residents and 45% for senior residents 6 Zoia et al. 2020 [25] Italy Survey Mar 2020 – May 2020 72.4% reported reduced time in neurosurgical department 78.6% performed less operations 16.1% performed no operations 55.7% reported increased production of scientific papers N/A Abbreviation: M&M, morbidity and mortality; N/A, not applicable; NOS, Newcastle Ottawa scale; USA, United States of America. Elective and Non-elective Neurosurgical Services Eight studies reported the case volume of elective neurosurgical procedures performed both before and during the COVID-19 pandemic. [27,[37], [38], [39], [40],47,50,54] Collectively, the number of elective surgeries decreased by 70.4% (OR=0.296, 95% CI 0.210–0.418, p<0.001) (Figure 2 A). A comparison of non-elective neurosurgical procedures was reported in 9 studies, with an overall decrease of 68.2% (OR=0.318, 95% CI 0.193–0.525, p<0.001) (Figure 2B). [12,27,[37], [38], [39], [40],[46], [47], [48]] Significant publication bias was observed for both elective and non-elective case volumes (p=0.034 and p=0.001, respectively).Figure 2 Forest plot for comparison of number of (A) elective and (B) non-elective neurosurgical procedures before and during COVID-19 pandemic. OR, odds ratio; CI, confidence intervals. Figure 2 Neurosurgical Subspecialty Experience Among the neurosurgical subspecialties, functional services experienced the highest reduction in case volume (45.81% reduction; OR=0.542, 95% CI 0.394–0.746, p<0.001; Figure 3 A) followed by spine cases (45.5% reduction; OR=0.545, 95% CI 0.409–0.725, p<0.001; Figure 3B), and skull base surgery (30.6% reduction; OR=0.695, 95% CI 0.572–0.845, p<0.001; Figure 3C). No statistically significance in case volume between pre-pandemic and pandemic era was found for neurosurgical oncology (OR=1.029, 95% CI 0.838–1.263; Figure 4 A), neuro-trauma (OR=1.021, 95% CI 0.846–1.232, p=0.833; Figure 4B), neurovascular surgery (OR=1.001, 95% CI 0.870–1.152, p=0.991; Figure 4C), and pediatric neurosurgery service (OR=0.589, 95% CI 0.344–1.010, p=0.055; Figure 4D). Except for spine (p=0.449), skull base (p=0.132), neuro-trauma (p=0.471), and neurovascular surgery (p=0.398), potential publication were observed for all other subspecialty pooled estimates (all p<0.05).Figure 3 Forest plot for case volume comparison of (A) functional, (B) spine, and (C) skull base service before and during COVID-19 pandemic. OR, odds ratio; CI, confidence intervals. Figure 3 Figure 4 Forest plot for case volume comparison of (A) neurosurgical oncology, (B) neuro-trauma, (C) neurovascular, and (D) pediatric service before and during COVID-19 pandemic. OR, odds ratio; CI, confidence intervals. Figure 4 Possible Effects of COVID-19 Pandemic on Neurosurgery Residency Training The collated data of impacts on residency training are summarized in brief in Table 1 and the modifications implemented are presented in Table 2 . Majority of the included studies observed a significant decrease in overall caseloads, both surgical and non-surgical, resulting in diminished clinical exposure for residents. [12,[21], [22], [23], [24], [25], [26], [27], [28],[30], [31], [32], [33],35,[37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54],[56], [57], [58], [59], [60], [61], [62], [63], [64], [65]] Ashry et al. found that 56% of the residents had a reduction in their actual role in the surgical steps and the number of residents scrubbing in the same procedure had been decreased to the minimum for preservation of personal protective equipment (PPE). [21] A survey completed by El-Ghandour and colleagues revealed that elective surgery/clinic cancellation occurred more frequently in African countries and that theyr were utilizing PPE significantly less commonly in LMICs (OR=0.441, 95% CI 0.216-0.900, p<0.05). [59] Some studies suggested restructuring their resident rotations to incorporate altered working patterns: Suryaningtyas et al. proposed a 10-day on and 20-day-off model, whereas Khan et al. reported a decrease in the resident coverage to one week-on service and one week-off hospital. [23,24] Fifth studies reported a formal reduction of resident presence, with a significant decrease in working hours and responsibility. [21,22,26,[30], [31], [32],35,40,44,50,[56], [57], [58],62,64] However, some residents experienced increased burdens and anxiety due to the extra work caused by the pandemic, including redeployment to help manage COVID-19 patients or COVID-related problems when needed. [12,21,42,44] Moreover, the reduction in operative volumes and clinical experiences has caused concern amongst residents about meeting their annual training requirements. [22,26]Table 2 Modifications implemented on neurosurgical services and residency training of each included studies Table 2Image, table 2Image, table 2 Abbreviation: HIC, high income country; LMIC, low-middle income country. Color code: green signifies that the change has been adopted in the study; red signifies that the change has not been adopted in the study. Aside from changes to clinical activity, educational and academic pursuits have also been impacted. [21,42,56] There is a rapid increase in popularity of online conferences and telemedicine. [58] Some residency programs took advantage of the various complementary virtual didactic lectures, such as American Association of Neurologic Surgeons webinars, Congress of Neurological Surgeons (CNS) Online Grand Rounds, CNS Virtual Visiting Professor, and ad hoc national and international virtual conferences. [11] For many residents, this transition to digital platforms has improved the access to educational materials. [12,57] It is worth noting that surveys conducted in HICs reported a higher percentage of technological shift in comparison to LMICs (87.5% vs. 61.5%, respectively). [17,26,53] Furthermore, the decrease in case volumes and working hours at the neurosurgical department allowed more time for preparation of board examination and research activities. [17,22,33,59] In Italy, for instance, 71.9% of responders affirmed increased time spent for studying and 55.7% reported an increase in research productivity. [25] However, in LMIC, 33.0% of residents noted a decline in their research output and 71.0% reported missing out on opportunity for education and training. [17] Discussion The COVID-19 pandemic has presented an unprecedented challenge for virtually every aspect of healthcare worldwide, with all healthcare systems grappling with limitations in resources, space, and staffing. [66] In an attempt to contain transmission and conserve resources, clinical team underwent temporary restructuring and adopted a new workflow to meet the demands of the pandemic. [67] Residents are an indispensable part of any institution's workforce and, therefore, were the most and first affected by the spread of COVID-19 infections. [68] To the best of the authors’ knowledge, this is the first study of its kind to quantify the global impacts of the COVID-19 pandemic on neurosurgical services and the associated effect on residency training. All selected articles had seen a decrease in operative volume, with some reporting concerns over residents’ ability to meet Accreditation Council for Graduate Medical Education operative case requirements and about future career prospects. Redeployment to non-neurosurgical roles varied across studies, ranging from 0% to 36.0% of the residents. [17,26,33,60,63,64] While these restructurings affected the operative skills and clinical experience, adapting to the new normal provided an opportunity for new technologies and additional time for research and self-directed studying. Impact on Elective and Non-Elective Cases Perhaps most obviously, the COVID-19 pandemic placed a substantial impact on the operative component of neurosurgical training. [22,26] A steep decline in operative volume was noted during the COVID-19 period in comparison to pre-COVID-19 times, with elective cases decreasing by 70.4% and non-elective surgeries decreased by 68.2%. There were multiple factors that could contribute to the case reduction. First, patients may defer or avoid medical attention due to fear of contracting COVID-19 in healthcare settings. [69] Second, residents and physicians were redeployed to aid frontline workers in managing the overwhelming COVID-19 patient load. [70] The redeployment rate of residents had been noticed to be higher in LMICs, according to a multi-country survey. [17] The lack of personnel in the neurosurgical department forced non-essential surgeries to get postponed or canceled. [70] Moreover, the widespread uncertainty in regard to PPE availability, transmission risk, disease management, and planning to prioritize intensive care unit beds had led the Centers for Medicare & Medicaid Service to place a moratorium on postponing all non-emergent, elective surgeries. [71] These challenges were even more pronounced in LMICs given their limited PPE access and significant shortage of supplies, such as ventilators and test reagents [59] HICs had the financial and diplomatic resources to obtain PPE, medical equipment, diagnostic tests, and healthcare workers at the detriment of LMICs. [72] The reduction in surgical volume, however, was less in LMICs, as they carry a disproportionate share of the global burden of surgical cases that cannot be postponed safely. [73] African countries, for example, contain 15% of the global volume of neurosurgical diseases, but their healthcare facilities have access to less than 1% of neurosurgeons worldwide, making training capable and competent neurosurgeons a fundamental step in achieving equal access. [74] The emergent procedures were also expected to decrease, as traffic volumes, social events, sports activities, and assaults were all decreased due to lockdowns and stay-at-home orders. [75] Impact on Neurosurgical Subspecialty Cases When analyzing by neurosurgical subspecialties, we observed a pronounced reduction in caseloads for spine, functional, and skull base surgery. These findings are expected given spine, functional, and skull base cases were relatively less likely to be emergent in comparison to neurosurgical oncology, neuro-trauma, neurovascular surgery, and pediatric neurosurgery service. [24,27] The disproportionate decrease in spine, functional, and skull base cases may carry significant implications for both the patients and the trainees. Delays in surgical intervention or adoption of a more conservative approach increases the risk of neurological deterioration, permanent loss of function, and treatment failure in these patient populations. [7,28] For trainees, junior residents were among the most impacted as the bulk of their operative volume was routine elective procedures and learning the basics of operative techniques. [24,28,29] Kilgore et al. also suggested that one may see a rise in the number of residents pursuing fellowships in the coming years as a result of a steep decline in elective cases. [30] In addition, our study found a substantial between-study heterogeneity for the rate of neurosurgical oncology procedures. Patients with tumors, such as cerebellar metastasis or glioblastoma, and presenting symptoms, such as acute hydrocephalus or cerebral herniation, are generally considered a priority and should have surgery scheduled in a timely manner. [62,76] However, for patients with benign or low-grade tumors that are asymptomatic, surgical intervention may be postponed until a safer time. [76] Cessation of majority of the endoscopic endonasal procedures due to concerns of disseminating COVID-19 infection may be another reason leading to the discrepancy in neurosurgical oncology case volume between studies. [28] Negative Impact on Neurosurgical Residency Training Due to a significant reduction in the number of surgical cases, bedside procedures, and outpatient clinic encounters, neurosurgical residents have been hit hard by the COVID-19 pandemic from an educational and training perspective. [12,31,77] A common theme across the included studies was the widespread worry about failing to meet case number requirements and operative competency. Those obstacles were not only faced by neurosurgical residents but also echoed by residents in other specialties. [77,78] Another phenomenon observed was the decline in mental health and increase in burnout symptoms, with as high as 90% of the neurosurgical residents worldwide reported being affected. [32] Some contributing factors may include the fears of being infected and transmitting to family members, little social support due to quarantine, shortage of staff and personal protective equipment, redeployment in haste without adequate training and supervision, altered rotation schedules, and financial strains. [21,22,33,79] Neurosurgery Residency Program Adaptations and Solutions As part of an effort to combat the loss of clinical experience, various assisted teaching methods were suggested. Grand rounds, morbidity and mortality conference, board reviews, and lecture series were provided via digital platform. [11,28,63,80] Some programs initiated streaming of procedures online and utilized virtual reality-based surgical stimulators to practice psychomotor surgical techniques. [81,82] However, these immersive technologies were often not available in Sub-Saharan Africa and other LMICs. [59] Online meeting has also been used for collaborations between geographically distant programs to discuss cases, new initiatives, and research projects. [11] While the use of virtual platforms increased the accessibility and affordability of educational resources for trainees at LMICs, the uptake of new technologies has been slower in LMICs than in HICs and may be limited by variability in internet speed, time zones, and language barrier. [12,44] Poor internet connectivity could result in high frequency of disconnection, poor sound and image quality, and long question-response lag time. [83] One proposed solution to circumvent these barriers was posting videos on free online platforms, such as YouTube, or those that provide live translations. [84] Furthermore, there is now an effort within the global surgery community to increase access to safe and affordable surgical care and to advocate for strengthening the training system in LMICs as a part of pandemic preparedness strategy. [85] Specifically, the Global Neurosurgery Initiatives started in 2018 may be a resource to assist resident training at LMICs, compensating for loss of training during the pandemic. [86] As the impacts of the COVID-19 pandemic on healthcare system continue to evolve, it is imperative to continually evaluate how resident training is affected and explore novel approaches to improve clinical, surgical, and educational experiences as well as prepare for similar future pandemics. Future Recommendations COVID-19 may be the deadliest viral outbreak the world has experienced in more than a century, but it will not be the last pandemic in our lifetime. In face of these many uncertainties, programs need to reassess their adaptive strategies, create action plans to improve on areas of deficiency, and integrate sustainable initiatives to supplement resident training, which often requires flexibility, innovation, and creativity. The heterogeneity between the included studies signified the importance of adopting a more individualized approach, one that is tailored to the program, the year of residency, and country. Furthermore, the neurosurgical community at large such as the global neurosurgery initiatives should step up and provide openly accessible educational materials during such pandemics to ensure adequate training for the next generation of neurosurgeons around the globe especially trainees from lower income countries such as Sub-Saharan Africa. As the impacts of the COVID-19 pandemic on healthcare systems continue to evolve, it is imperative to continually evaluate how resident training is affected and explore novel approaches to improve clinical, surgical, and educational experiences as well as prepare for similar future pandemics. Limitations This systematic review and meta-analysis have several limitations to consider. First, the patient populations enrolled in the selected articles were mainly from the United States and European countries. Insufficient data from other regions, including countries that were hit hard by COVID-19, could prevent our study from drawing a meaningful conclusion. Second, 32.4% of the selected articles involved the use of surveys and may have not been validated due to the time constraint. Biases, such as subjective questions, voluntary responses, and heterogenous respondents and institutions, could have limited the generalizability of our results. Third, multiple pooled estimates had substantial between-study heterogeneity and publication bias. We suspect that, in the setting of COVID-19 pandemic, variation in state legislation, institutional policy, hospital baseline caseloads, the peak of pandemic between countries, the time periods studies were conducted, and the rate of exposure may all contribute to the heterogeneity. Similarly, each neurosurgical residency program around the globe varies widely in terms of workload, caseload, and structure. This may lead to different adaptability to the pandemic and result in variable impact on the training and learning outcome. Furthermore, no study has compared the operative skill and theoretical knowledge of residents between pre-COVID-19 and COVID-19 periods, and thus the true impact of COVID-19 on neurosurgical training remains unknown. Long-term impacts of the COVID-19 pandemic on neurosurgical trainees, including operative competency, mental health, and career advancement, merit further investigation. Conclusion The landscape of neurosurgery worldwide has been dramatically transformed by the COVID-19 pandemic, forcing a paradigm shift in both neurosurgical practice and training. Reduction of clinical and surgical exposure has adversely impacted educational provision, which was more pronounced in LMICs. Nevertheless, these unprecedented challenges have rendered an opportunity to rethink the conventional patterns of residency training and identify potentials for collaboration and increase accessibility and affordability for educational resources. It would be of paramount interest to reevaluate, in the near future, the impact of these newly adopted technologies and educational resources on neurosurgical training. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Ethical Considerations This study was not research involving human subjects and that their review and approval was not required. Data Sharing The data that support the findings of this study are available from the corresponding author on reasonable request. Potential Conflicting Interests All authors have no personal, financial, or institutional interest in the materials or devices described in this manuscript. 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==== Front Build Environ Build Environ Building and Environment 0360-1323 1873-684X The Authors. Published by Elsevier Ltd. S0360-1323(22)01154-4 10.1016/j.buildenv.2022.109924 109924 Article New dose-response model and SARS-CoV-2 quanta emission rates for calculating the long-range airborne infection risk Aganovic Amar a∗ Cao Guangyu b Kurnitski Jarek c Wargocki Pawel d a Department of Automation and Process Engineering, UiT The Arctic University of Norway, Tromsø, Norway b Department of Energy and Process Engineering, Norwegian University of Science and Technology - NTNU, Trondheim, Norway c REHVA Technology and Research Committee, Tallinn University of Technology, Tallinn, Estonia d Department of Civil Engineering, Technical University of Denmark, Copenhagen, Denmark ∗ Corresponding author. 14 12 2022 14 12 2022 1099248 11 2022 12 12 2022 13 12 2022 © 2022 The Authors. Published by Elsevier Ltd. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Predictive models for airborne infection risk have been extensively used during the pandemic, but there is yet still no consensus on a common approach, which may create misinterpretation of results among public health experts and engineers designing building ventilation. In this study we applied the latest data on viral load, aerosol droplet sizes and removal mechanisms to improve the Wells Riley model by introducing the following novelties i) a new model to calculate the total volume of respiratory fluid exhaled per unit time ii) developing a novel viral dose-based generation rate model for dehydrated droplets after expiration iii) deriving a novel quanta-RNA relationship for various strains of SARS-CoV-2 iv) proposing a method to account for the incomplete mixing conditions. These new approaches considerably changed previous estimates and allowed to determine more accurate average quanta emission rates including omicron variant. These quanta values for the original strain of 0.13 and 3.8 quanta/h for breathing and speaking and the virus variant multipliers may be used for simple hand calculations of probability of infection or with developed model operating with six size ranges of aerosol droplets to calculate the effect of ventilation and other removal mechanisms. The model developed is made available as an open-source tool. Keywords Virus airborne infection Infection control Wells-Riley model Quanta emission rate SARS-CoV-2 ==== Body pmc1 Introduction SARS-CoV-2 is spread by exposure to respiratory fluids carrying the infectious virus [1]. The virus-carrying respiratory droplets and aerosols can be produced through all expiratory activities including breathing, talking, coughing, and sneezing from both symptomatic and asymptomatic individuals [1]. These infectious aerosols and droplets may come into direct contact with susceptible individuals by inhalation from the surrounding air or indirect contact when the susceptible individual touches a surface contaminated by infectious respiratory fluid [2]. Although disputed at the start of the pandemic, the evidence for direct airborne transmission of SARS-CoV-2 has grown as the pandemic progressed [[3], [4], [5]]. It is now widely accepted that airborne transmission of SARS CoV-2 may be the leading cause of super-spreading events that are recognized as the pandemic's primary drivers [6]. Once recognized as the main route of COVID-19 spread, identifying the relative importance of different engineering controls targeting the spread of COVID-19 in indoor environments requires accurate prediction of the transmission risk. In this context, there is a need for predictive risk assessment tools for better understanding when planning effective strategies to minimize risks associated with airborne transmission. The concept behind the mathematical tools used so far for modeling airborne transmission risk is based on coupling dose-response models with a box model containing a source and sink of contaminants. The infection risk inside the box can be modeled either using i) a simplified approach by analytically solving the conservation of mass equations for the contaminants under quasi-ideal and quasi-uniform assumptions/conditions (not considering the airflow dynamics inside the box) ii) a complex approach by numerically solving full conservation of mass and energy equations of the airflow dynamics and contaminant transport using numerical solvers, i.e., computational fluid dynamics (CFD). Whilst the latter generates more accurate predictions it requires an experienced user with expertise in using CFD tools. The computationally demanding CFD modeling approach is also limited by a time-consuming simulation process, taking a long time to run even in small indoor spaces. Hence, CFD models are neither easily applied to new rooms nor suited for rapid simulations, which may be essential for fast-evolving pandemic conditions. In addition, in comparison to the complex approach, the simplified approach can be implemented in the form of open-access digital tools that are straightforward, fast, and simple to use for epidemiologists, virologists, immunologists, and other public health experts without previous background expertise on airborne transmission risk modeling. Although extensively used during the pandemic, there is yet still no consensus on a universal simplified approach, which may create misinterpretation of results, confusion among public health experts, etc. In this context, a short history described through mathematical development of the dose-response model coupled is presented in the next chapter. 2 Modeling background In general, the dose-response models predict the probability of an infection or illness of a proportion of the susceptible population when exposed to a given dose, i.e. number of viral copies of a specific respiratory virus. These models are based on two principles: the estimation of the intake dose of the infectious agent and the estimation of the probability of infection under a given intake dose. The two most commonly used dose-response models for calculating the infection risk of respiratory viruses are the exponential and beta-Poisson models [7]. Both models assume a random distribution of the number of copies in the exposed medium (ambient air) described by the Poisson probability distribution. If the exposed medium (ambient air) contains a known mean number of n viral copies, the probability that the susceptible person would ingest exactly m number of viral copies (per hour) would equal:(1) P(m;n)=e−n∙nmm! The number of viral copies k that will survive from the ingested copies m and cause an infection will depend on the survival probability p (%) of a single viral copy that differs depending on the host susceptibility, i.e. each host may have an equal or different probability of getting infected from the same number of viral copies. The probability P that exactly k number of m ingested viral copies will survive the host response and cause infection is determined by the binomial probability distribution:(2) P(k;m,p)=(mk)∙pk∙(1−p)m−k The exponential model assumes that each host has an equal probability of getting infected from a single viral copy defined as: =1v ; where v (−) is defined as the number of ingested viral copies that will cause an infection, i.e. the infectious dose (ID). So, the total infection probability defined by the exponential model is calculated according to the following transformations:(3) P(k;m,n,p)=∑m=k∞{(mk)∙pk∙(1−p)m−k}∙{e−n∙nmm!}=∑m=k∞m!(m−k)!∙k!∙pk∙(1−p)m−k∙e−n∙nmm!∙nknk⇒P(k;m,n,p)=(np)k∙e−nk!∙∑m=k∞((1−p)∙n)m−k(m−k)!=(np)k∙e−nk!∙e(1−p)∙n The probability that at least one viral copy will be ingested is valid for all k>0:(4) P(1≤k<∞)=1−P(0)=1−e−p∙n In summary, given known parameters in both the exponential or the beta-Poisson dose-response model as well as the mean number of n viral copies in the exposed ambient air allows the calculation of the airborne transmission risk. To simplify the infection risk models by avoiding the use of parameters, Riley et al. [8] implemented Wells's concept of one quantum [9], which is defined as the number of inhaled infectious virus-laden aerosols n = v required to infect at least 63.21% percent of the susceptible persons defined through the exponential model:(5) P=1−e−p∙n=1−e−1v∙v=1−e−1=63.21% Under the assumption that the number of airborne quanta is constant in the ambient air, one may express the exponential dose-response model by using the total number N of inhaled quanta (each quanta containing v number of viral copies) as:(6) P=1−e−p∙n=1−e−N∙1v∙v=1−e−N Riley et al. [9] further expanded the exponential dose-response model by assuming that if the quanta-carrying aerosols are evenly distributed in a ventilated room with a quanta concentration n(t)[quantam3] , the total amount of quanta inhaled n in the room under steady-state conditions (dn(t)dt=0) for an exposure time t equals:(7) N=IR∙∫0tn(t)dt=IR∙n∙t Further assuming that the only source of quanta is through exhalation from I number of infected persons with an average quanta production rate of q, the quanta concentration n in the room under steady-state conditions (dn(t)dt=0) becomes:(8) V∙dn(t)dt=S−Q∙n(t)=>n=SQ=I∙qQ then infection risk probability can be expressed in the following form:(9) P=1−e−N=1−e−IR∙n∙t=1−e−I∙IR∙q∙tQ Equation (9) is known as the classical/conservative form of the Wells-Riley equation. However, this original version assumed steady-state conditions, i.e. constant concentration of aerosolized quanta in the surrounding air. Gammaitoni and Nucci [10] introduced a model capable of incorporating non–steady-state quanta concentrations by solving equation (8) for dn(t)dt≠0 . Given known initial quanta concentrations n0 and known removal mechanisms ∑λ allows evaluating the amount of quanta concentration in an indoor environment at any time interval:(10) V∙dn(t)dt=S−V∙n(t)∙∑λ=>n(t)=n0∙e−∑λ∙t+SV∙∑λ∙(1−e−∑λ∙t) However, as in the original Wells-Riley model, the Gammaitoni and Nucci model [10] also considered the ventilation rate as the only removal/sink term in the equation. Therefore, the equation has been upgraded in later models to incorporate other removal mechanisms and control measures that can affect the infection risk, i.e., the biological decay of the airborne pathogen [11] and deposition loss of the infectious particles due to gravitational settling [12] but also the optional removal mechanisms such as ultraviolet radiation and supply air filtration in the case of a recirculating ventilation system [[13], [13]]. However, the input processing of these removal mechanisms may be troublesome: the data unavailability of the biological decay rates for certain viruses and the data uncertainty for the deposition rates due to the broad spectrum of both the amount and size ranges of the aerosol-carrying particles may misestimate the infection risk calculation. In addition, the input values of the source term described by the average quanta production rate have so far been based on quite limited literature data and vary not only on the type of disease for different viruses but also on the original epidemiological case study for the same virus type. Furthermore, the classical Wells Riley model is limited to fully and ideally air mixing in a single zone. Consequently, the airborne infection risk could be under-or overestimated. These issues remained unsolved until the recent COVID-19 pandemic. As no standardized WR model exists, airborne transmission risk studies used different variations of the WR model; most often the conservative WR model with only the ventilation rate as the removal mechanism. Such simplification may not only misestimate the infection risk calculation but also miscalculate the potential effects of all existing removal mechanisms besides ventilation and their susceptibility to indoor environmental parameters. The specific objective of this study is to improve the classical WR-model by resolving the specific issues: i) develop an aerosol and droplet production rate model from the source, I.e. infected person for different expiratory modes and virus variants ii) expand the classical model with all potential removal mechanisms iii) propose a method to account for the incomplete mixing conditions. To reach these specific objectives, we decided to perform a comprehensive review of all the Wells-Riley models that have been used to model the infection risk in research studies published after the start of the pandemic in early 2020. By resolving the specific issues, the overall aim of this study is to develop and propose an advanced Wells Riley model for future and retrospective indoor infection risk assessments. 3 Methodology The Medline database was searched for all original articles modeling the airborne transmission risk using the Wells-Riley model. A comprehensive list of search terms, i.e. “Wells-Riley model”, “airborne transmission risk ”, and “infection risk model”, was used, including Medical Subject Headings (MeSH). The search was limited to English-language articles published after 01.01.2020. The last search was conducted on 24th August 2022. Finally, 21 articles [[13], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34]] were considered eligible for inclusion in the present review study. Data from the included studies were extracted using a predesigned spreadsheet. From each study, the following data were extracted: source details, authors, year of publication, whether the WR model was solved for a steady/non-steady state, whether fully mixing conditions were assumed or not, types of removal mechanisms, and information on source modeling regarding quanta emission rate including the droplet production rate. 3.1 Source: Quanta emission rate The quanta emission rate was reported to be calculated as either directly estimated from previous epidemiological studies or derived from the volume emission rate, viral load, and quanta-response relationship. 3.1.1 Directly estimated from epidemiological studies for previous species of coronaviruses This method was used in four risk assessment studies published during the pandemic and has also been used before the pandemic for assessment risk calculations for other respiratory viruses. This method is not new and has been used before the current pandemic to estimate the quanta emission for other infectious respiratory viruses including measles [8], tuberculosis [10], and influenza [37]. The method was used by six studies when estimating the quanta emission rate for SARS-CoV-2 [15,21,23,24,29,32,35,36]. The method is based on fitting the quanta emission rate S in equation (10) for a derived steady-state value of quanta concentration in air n that was back-calculated from the infection risk equation (9) P reported in previous outbreaks of SARS-CoV-2:(11) P=1−e−IR∙n∙t=>n=−ln⁡(1−P)IR∙t The source is then back-calculated from equation (7):(12) S=−∑λ∙(ln(1−P)IR∙t+n0∙e−∑λV∙t)1−e−∑λV∙t This method requires considerable input information from the observed outbreaks, and additional building system details such as the amount of recirculated air, filter efficiency, ventilation rates, on rates, space volume, and exposure time of infected persons but also additional building system details such as the amount of recirculated air, filter efficiency, etc. With insufficient input details, the uncertainty risk may be too large for the quanta estimation rate S to be used for both future and retrospective infection risk assessments. 3.1.2 Derived from the droplet volume emission rate (mlh), the viral load (RNAml) and the quanta-response relationship (quantaRNA) This is a novel methodology for calculating the quanta emission rate that was reported in 15 studies [13,14,[16], [17], [18], [19], [20],[25], [26], [27], [28],30,31,34] and can be summarized in the following expression:(13) S=cv∙ci∙Vexh cv – viral load in the respiratory tract [RNAmL] ci – the quanta-response relationship is defined as the ratio between one infectious quantum and the infectious dose expressed in viral copies, i.e. the number of viral RNA copies required to infect at least 63.21% of susceptible persons, [quantaRNA] Vexh− the total volume of respiratory fluid exhaled per unit time, [mlh] 3.1.2.1 Respiratory aerosol and droplet volume emission rate models Three original methods/equations have so far been used to calculate Vexh:a) The method by Buonnano et al. [17]. (14) Vexh=IR∙∑i=14(Ni,j∙Vi) IR- breathing rate [m3h] Vi– the spherical volume of a single droplet in the ith bin [mL] Ni,j- Droplet number concentration in the ith bin of four aerosol droplet diameters during four different expiratory activities (j) as measured by Morawska et al. [36] [particlescm3] as presented in Table S1 of supplementary materials. A similar approach was used by Aganovic et al. for speaking. The size distribution (Table S2) for speaking is determined experimentally by the works of Morawska et al. [38] for droplet aerosols ≤ 2 μm and Chao et al. [39] for respiratory droplets ≥ 2 μm [38]. However, instead of using the spherical volume of a single droplet, they used the following expression to calculate the total volume from a size bin:(15) Vi(D)=π∙(Dmax4−Dmin4)24∙(Dmax−Dmin) where Dmax and Dmin denote the bin's lower and upper diameter values, according to Nicas [40].b) The method by Schjiven et al. [15]. Schjiven et al. [[13], [13]] developed two equations for calculating Vbr depending on the type of expiratory activity:i) Breathing The total volume of aerosol droplets exhaled per hour of breathing was calculated as:(16) Vbreath=60∙10N(μbr,σbr)∙10−12∙π6∙∑i=16(di3∙10N(μi,σi)) N(μbr,σbr) – lognormal distribution of the breathing rate as measured by Fabian et al. [39] [Lmin] with mean μbr=log10(6.8) and standard deviation (SD) σbr=0.05 di– droplet diameter in the ith bin of six aerosol droplet diameters as measured by Fabian et al. [41] [mL] N(μi,σi) – lognormal distribution of the concentration of di[particlesmin] with mean μi and SD σi for each bin given in Table S3.ii) Speaking and singing According to Schjiven et al. [[13], [13]], the total volume of aerosol droplets exhaled per hour of speaking and singing was calculated by summing nsp,si samples of volumes of each aerosol diameter from the aerosol diameter data set d(μm) as follows:(17) Vsp,si=3∙10−12∙nsp,si∙π6∙∑i=1ksp,sidi3 di– droplet diameter in the ith bin of ksp=13 and ksp=5 aerosol droplet diameters for loud-voiced counting [42] and singing [43] as in Table S4. nsp,si - lognormal distribution of expelled aerosol d droplets calculated based on mean μsp=2.2 and standard deviation σsp=0.29 from measured data during speaking [45] and μsi=5.0 and σsi=0.28 for singing [43]:(18) nsp,si=10N(μsp,si,σsp,si)+0.5 c) The method by Nordsiek et al. [16]. Instead of using measured data on droplet concentration in different size distributions, the model developed by Nordsiek et al. [14] utilized probability density functions (pdfs) of the droplet diameter. These functions were obtained using the tri-modal lognormal distribution derived by Johnson et al. [45]. The model is known as the bronchiolar-laryngeal-oral (B-L-O) tri-modal model, as it considers droplet production associated with three distinct modes: one occurring in the lower respiratory tract, another in the larynx, and a third in the upper respiratory tract and oral cavity, respectively. The number concentration of droplets of size k produced in each of the modes is given as a sum over each mode i [45]:(19) dCnkdlog10dp=ln⁡(10)∙∑i=13[(Cni2∙π∙ln⁡(GSDi))∙e(−(lndp−lnCMDi)22∙(lnGSDi))2)] The model parameters for dehydrated aerosols produced during speaking [43] are presented in Table S5. The notation dCnkdlog10dp represents the number concentration in each bin of particle diameters (dCnk) normalized by a bin width (k to k+1) that is constant in log space, i.e. dlog10dp =  log⁡(dp,k+1dp,k), where k represents a discretization of the dp space. The volume of particles of a given diameter is represented as a concentration [μm3cm3] , assuming all particles are spherical, is given by:(20) Vexh=IR∙dCnk∙π∙dp,k36 All three methods presented in a), b) and c) are compared to corresponding experimental data measurements for breathing, speaking, and singing as measured by Fleischer [46] as presented in Table 1 . Both volume droplet emission rate models by Bunonano et al. [16], and Schjiven et al. [[13], [13]] showed relatively good agreement with the data measurements by Fleishcer et al. [46] for both fine aerosols ≤5μ m and both fine and coarse aerosols ≤20 μ m. The volume emission rate measured by Fleischer et al. [46] for singing was within the range of volume rates generated by the model by Schjiven et al. model [[13], [13]] for singing. The model output by Nordsiek et al. underestimated the volume emission by speaking.Table 1 Comparison of droplet volume emission rate models for different expiratory activities against experimental data. Table 1 Size range Ddry (μ m) Breathing Vbr[pLh] Speaking Vsp[pLh] Singing Vsi[pLh] Model Bunonano et al. [16] ≤5.5 157 748 – Schjiven et al. [[13], [13]] ≤20 132a (0–54000) 1080a (0–54000) 12900a (930–123000) Nordsiek et al. [14] ≤20 – 142 – Experimental data Fleischer et al. [446] ≤5 332 1289 6487 ≤20 332 1390 10963 a mean (min-max) computed after running 10 000 Monte Carlo samples. Based on these observations, we decide to introduce a new model for breathing, singing, and speaking similarly to Bunonano et al. [16] as follows:(21) Vexh=3600∙106∙∑i=16Pi,br,sp,si∙Vi(D) Pi- particle emission rate [particless] in the ith bin of six aerosol droplet diameters during three different expiratory activities (br,sp,si) as measured by Fleischer et al. [46] and presented in Table S6 of supplementary materials. Vi(D) is the total volume from each size bin as calculated in equation (15). 3.1.2.2 Viral load cv[RNAmL] The viral load in respiratory aerosol reflects the virion concentration in the fluid where the particles originate. The infected respiratory droplets may originate through sputum expelled from the lower respiratory tract (the trachea, the bronchi and bronchioles, and the alveoli) or the saliva generated in the upper respiratory tract (nasal cavity, throat/pharynx, or voice box/larynx). The respiratory droplets emitted by breathing are generated in the lower respiratory tract while the droplets produced by speaking are generated in the upper respiratory tract [47]. The amount of RNA gene copies emitted by an infected person depends both on the volumetric flow rate exhaled per unit time and the viral load at the origin of production (upper or lower respiratory tract) and so the total amount of RNA gene copies expelled will differ for different expiratory activities, such as speaking and breathing. When released from either the lower or upper respiratory tract (assumed to have ∼100% RH), droplets experience rapid evaporation and shrinkage upon encountering the unsaturated ambient air. Depending on the relative humidity value, the initial size of a hydrated respiratory droplet (∼100% RH) can be 2–3 times larger than the dehydrated droplet [48]. Therefore, the evaporation process may have a significant effect on the total calculated volume of the droplets and consequently on the number of viral RNA copies contained in dehydrated fine aerosols ≤ 5 μ m as the data used for cv [RNAmL] is based on the viral load reported directly from respiratory tract samples (sputum or saliva). The studies utilizing the quanta emission rate based on viral load have so far used the initial viral load reported in sputum or saliva, assuming that the initial proportionality RNAmL accounts even after evaporation. However, this is not the case as shown by a recent study [49] that measured viral RNA in different-sized respiratory aerosols emitted by infected patients. It found that aerosols ≤ 5 μ m contained more viral copies than aerosols ≥ 5 μ m so that 93% and 54% of the viral load in this study was detected in aerosols ≤ 5 μ m for talking and breathing, respectively. Thus, it is crucial to calculate the viral copies cv,(Ddry≤5μm) contained in fine dehydrated aerosols. This may be done using the following procedure based on the balance equation of RNA copies, i.e. RNA copies are not affected by the short evaporation process and stay constant before and after evaporation that lasts some time Δtevap:(22) cv,0∙Vexh,0∙Δtevap=cv,dry∙Vexh,dry∙Δtevap=>cv,0∙π6∙∑i=1nni,0∙di,03=cv,dry∙π6∙∑i=1nni,dry∙ddry3 The number of droplets in each size bin will remain the same before and after evaporation, i.e. ni,0=ni,eq and if we now use the shrinkage factor for evaporation due to dehumidification of the initial hydrated droplet from Table S9 so that di,eq≈0.4∙di,0 , we can further write that:(23) cv,0∙∑i=1n(ddry0.4)3=cv,dry∙∑i=1nddry3=>cv,dry=15.6∙cv,0 The total number of RNA copies expelled during some time interval Δt can be expressed as:(24) cv,dry∙Vexh,dry∙Δt=cv,dry(≤5μm)∙Vexh,dry(≤5μm)∙Δt+cv,dry(≥5μm)∙Vexh,dry(≥5μm)∙Δt Based on the viral loads in fine and coarse aerosols reported in Ref. [49] the viral load contained in dehydrated respiratory aerosols ≤ 5 μ m [RNAmL] for breathing, speaking and singing can be calculated as:(25) cv,breath,dry(≤5μm)∙Vbreath,dry(≤5μm)=0.54∙cv,dry∙Vbreath,dry (26) cv,speak,dry(≤5μm)∙Vspeak,dry(≤5μm)=0.93∙cv,dry∙Vspeak,dry (27) cv,sing,dry(≤5μm)∙Vsing,dry(≤5μm)=0.83∙cv,dry∙Vsing,dry Using (23) we get:(28) cv,breath,dry(≤5μm)=8.4∙cv,0∙Vbreath,dryVbreath,dry(≤5μm) (29) cv,speak,dry(≤5μm)=14.5∙cv,0∙Vspeak,dryVspeak,dry(≤5μm) (30) cv,sing,dry(≤5μm)=13.0∙cv,0∙Vsing,dryVsing,dry(≤5μm) Where Vbreath,dry , Vspeak,dry and Vsing,dry [mLh] are the total volumetric flowrates of all dehydrated respiratory aerosols and droplets exhaled by breathing, speaking, and singing respectively, while Vbreath,dry(≤5μm) , Vspeak,dry(≤5μm) and Vsing,dry(≤5μm) are the volumetric flow rate of only dehydrated respiratory aerosols ≤ 5 μ m in size. The correlation Vbreath,eqVbreath,eq(≤5μm)=1.04 was found using equation (16). Finally:(31) cv,breath,eq(≤5μm)=8.7∙cv,0 Similarly, the expression for the viral load in dehydrated aerosols for speaking and singing was derived using equation (17) respectively:(32) cv,speak,eq(≤5μm)=78.7∙cv,0 (33) cv,sing,dry(≤5μm)=26.0∙cv,0 3.1.2.3 The quanta-RNA relationship ci (quantaRNA) In absence of data for SARS-CoV-2, most infection risk models [14,[16], [17], [18],20,[25], [26], [27],30,31] at the start of the pandemic relied on the exponential dose-response relationship derived for the SARS-CoV virus by Watanabe et al. [50] as ci=1410quantaRNA. This dose-response model was based on data for several viruses besides SARS-CoV, including human coronavirus HcoV229, murine hepatitis virus (MHV), swine virus (HEV), and brouchitis IBV for both animal and human hosts. Schjiven et al. estimated based on the data for a Dutch variant of SARS-CoV-2 that 1440 copies result in an infection, and this quanta response relationship was used in the other three studies [18,28,34]. This estimation was based on the data for a beta variant of SARS-CoV-2 (B.1.351) 3.13 · 109 RNA/mL that allegedly matched 5.62 · 107 TCID50, i.e. 1TCID50≈ 56 RNA copies. Unfortunately, no research data or reference was provided supporting this relationship. As the pandemic progressed new dose-response model emerged. Most recently, Miura et al. [51] derived the following dose response for HCoV-229E based on human challenge data:(34) P(n)=1−(0.17∙e−4.2∙10−9∙n+(1−0.17)∙e−k∙n) So far only one dose-response research study has been performed for SARS-CoV-2 [52] for which 18/34 (52%) young adults were infected after being intranasal inoculated with 10 TCID50 doses of a pre-alpha variant. For k=−0.1 => P(10)=52%. Therefore as P(14)=63.2% we will define 14 TCID50 as equal to 1 quanta. Sender et al. [53] analyzed human challenge data reported for a wild pre-alpha variant and concluded a relationship of 1TCID50≈104RNA copies, or 1quanta=14∙104 RNA copies. Based on the quanta-RNA relationship for the original Wuhan strain, we derived also the quanta-RNA for several successive strains as shown in Table 2 .Table 2 Estimated quanta-RNA relationship for various strains of SARS-CoV-2. Table 2Strain of SARS-CoV-2 Infectivity compared to variant in the previous row ci(quantaRNA) Virus variant quanta multiplier (−) Original (Wuhan) – 14000 1.0 Alpha (B.1.1.7) +90% [54] 7400 1.9 Delta (B 1.617.2) +150% [55] 5000 2.8 Omicron (B.1.1.529) +420% [56] 1200 11.7 When comparing the quanta-emission rates (quanta/h) to the previous model by Buonanno et al. [16], there are differences are more than tenfold even for the the same expiratory activities and viral load, as shown in Table 3 . This significant difference is due to the difference between the values used to describe quanta-RNA relationship ci. Buonanno et al. [16] used ci = 2 ⋅10−2 (quantaRNA), based on data for SARS-CoV-1. In other words, Buonanno et al. [16] assumed that it would be needed to ingest at least 200 viral copies to to infect at least 63.2% of the susceptible population, compared to our derived values of 14 000 viral copies of the original SARS-CoV-2 strain to cause infection.Table 3 Average quanta emission rates (quanta/h) for SARS-CoV-2 original strain. Table 3Activity Buonanno et al. [16]a Viral load 107 RNA/mL This study Viral load 107 RNA/mL This study Viral load 108 RNA/mL Breathing 0.72 0.01 0.13 Speaking 9.7 0.38 3.8 Singing 62 0.90 9.0 a In the case of Buonanno we refer to 66th percentile values. In our study, in the case of a viral load of 107 RNA/mL and 108 RNA/mL we refer to 35th and 56% percentile values, respectively. We have opted only for selecting representative quanta values depending on the purpose, as the viral load is a parameter with large variation. If the purpose is to model some event with a super spreader, extremely high values are to be used. In our application, we are interested in adequate ventilation in shared indoor spaces. In such a case, the aim is not to eliminate, but reduce the infection risk: an infectious person should infect no more than one person during the infectious period – therefore median values of the viral load are justified to use. 3.2 Sinks: Removal mechanisms Altogether nine potential removal mechanisms were identified in the studies using the Wells-Riley model: ventilation λvent [[13], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36]], deposition λdep [[14], [15], [16], [17], [18],[20], [21], [22], [23], [24], [25], [26], [27], [28],[31], [32], [33], [34]], viral inactivation by relative humidity λRH [[13], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29],[31], [32], [33], [34]], portable air cleaner λPAC [22,27,35,36], inactivation by ultraviolet germicidal irradiation of the recirculated air from the ventilation system or portable air cleaners λUVGI [21,22,27,32], respiratory tract absorption rate λresp [13,14,18,28,34], filtration of portable air cleaner or recirculated air ηfilt−rec [15,27,29,36], filtration by use of a face mask ηfm [14,22,27,35]. The following sections present an overview of the removal mechanisms. 3.2.1 Ventilation λvent (auxiliary) Ventilation λvent is the only removal mechanism included in the original Wells-Riley model, and thus in all following WR versions considered. Although not all buildings have installed mechanical ventilation systems, there is always an infiltration rate due to air leakage through the building envelope ranging from 0.6 to 3 ACH depending on standards [57]. Its removal rate is dependent on the good mixing assumption of the WR model, for which the airborne quanta is assumed to be equal across the space considered. It is the type of ventilation system that defines the airflow distribution, and hence the mixing conditions. So far, there have been two modeling approaches [25,34] that have tried to account for the mixing conditions in the WR model. Both utilize the concept of ventilation efficiency ε [58] defined as:(35) ε=nexh(t)−nsup(t)n(t)−nsup(t) n(t) – quanta concentration in the indoor environment at the time (t), quantam3 nsup(t) – quanta concentration in the supply/outdoor at the time (t), quantam3 nexh(t) – quanta concentration in the exhaust at the time (t), quantam3 The ventilation efficiency can be simplified in case of no recirculation of ventilated air and as there is no airborne virus in outdoor air nsup(t)=0=>ε=nexh(t)n(t) . The following two methods are presented below:a) The method by Shen et al. [25]. Expanding equation (10):(36) V∙dn(t)dt=S−V∙n(t)∙∑λ=S+Qvent∙nsup(t)−Qvent∙nexh(t)−V∙n(t)∙∑λrest Where λrest=∑λ−λvent are all the removal mechanisms excluding ventilation only. Further as nsup(t)=0, λvent=QventV and inserting ε=nexh(t)n(t) one gets:(37) V∙dn(t)dt=S−Qvent∙ε∙n(t)−n(t)∙∑λrest=S−V∙n(t)∙ε∙λvent−V∙n(t)∙∑λrest=s−V∙n(t)∙(∑λrest+ε∙λvent) And the solution for transient conditions is then:(38) n(t)=n0∙e−(∑λrest+ε∙λvent)∙t+SV∙(∑λrest+ε∙λvent)∙(1−e−(∑λrest+ε∙λvent)∙t) b) The method by Aganovic et al. [34]. The method proposed by Aganovic et al. [34] is based on dividing the indoor space into two zones to depict incomplete mixing. This concept has been introduced for airborne contaminants by Sandberg [58] and the model has shown to have good agreements with tracer gas measurements. Fig. 1 shows a schematic presentation of a two-zone exposure model of the imperfect room mixing loosely based on the two-zone models for imperfect mixing used earlier in literature [59,60]. In the exposure model, the space under consideration is divided horizontally into two perfectly mixed zones with uniform quanta concentrations in each zone ni(t) and nj(t): the occupied zone i reaching hoccup.=1.8m above the floor and the rest is the unoccupied zone nj(t).Fig. 1 Schematic representation of a simplified two-zone exposure model [34]. Fig. 1 The quanta balance for the lower occupied zone i can be expressed in the following form:(39) Vi∙dni(t)dt=S+β∙Q∙nj(t)−β∙Q∙ni(t)−∑λi,rest∙ni(t)∙Vi (40) Vj∙dnj(t)dt=Q∙nj,sup−Q∙nj(t)+β∙Q∙ni(t)−β∙Q∙nj(t)−∑λj,rest∙nj(t)∙Vj Where ∑λi,rest and ∑λj,rest are the rest of the sum of removal mechanisms except for ventilation in rooms i and j respectively. The volume of the occupied zone can be expressed as Vi=1.8H∙V, where H is the height of the space, while the volume of the unoccupied zone is Vj=(1−1.8H)∙V. As for infectious airborne contaminants nsup≈0 it is possible to derive the expression for the mixing factor β as a function of the contaminant removal effectiveness for steady state conditions ε=njni: (41) β=ε1−ε∙Q∙H+(k+D)∙(H−1.8)∙VQ∙H The differential equations for the change in the quanta concentrations in zones i and j, i.e. the pair of equations (39), (40) for incomplete/imperfect mixing ventilation can be written in the following forms:(42) dni(t)dt=A1∙ni(t)+B1∙nj(t)+C1 (43) dnj(t)dt=A2∙ni(t)+B2∙nj(t)+C2 Where the constant coefficients A 1,A 2,B 1,B 2, C 1 and C 2 for the ventilation systems are presented in Table S7. The unique solutions to this set of first-order differential equations (42), (43):(44) ni(t)=K1∙(r1A2∙er1∙t−B2A2∙er1∙t)+K2∙(r2A2∙er2∙t−B2A2∙er2∙t)−B2A2∙C1∙A2−C2∙A1A1∙B2−A2∙B1−C2A2 (45) nj(t)=K1∙er1∙t+K2∙er2∙t+C1∙A2−C2∙A1A1∙B2−A2∙B1 Where r1=A1+B2+(A1+B2)2−4∙(A1∙B2−A2∙B1)2 and r2=A1+B2−(A1+B2)2−4∙(A1∙B2−A2∙B1)2 The coefficients K2 and K1 can be calculated using initial conditions ni(0)=0 and nj(0)=0:(46) K2=(C1∙A2−C2∙A1)∙(r1−B2)+C1∙B2−C2∙B1(r2−r1)∙(A1∙B2−A2∙B1) (47) K1=−K2−C1∙A2−C2∙A1A1∙B2−A2∙B1 3.2.2 Virus inactivation by relative humidity λRH at the ambient temperature of 20–25 °C Ambient temperature and humidity strongly affect the inactivation rates of enveloped viruses, including SARS-CoV-2 [61]. To characterize the impact of relative humidity on the inactivation rate λRH for SARS-CoV-2 in aerosols, data on the aerosolized virus survival times at different relative humidities were obtained from experimental studies performed at indoor air temperatures 20–25 °C [[62], [63], [64]]. The reported values for virus nebulized in artificial saliva, and for virus cultivated in the standard tissue culture medium are presented in Table S8. Previous studies have shown that the viral inactivation rates at different RH values for other enveloped viruses strongly depend on the complex composition of the respiratory droplet. While the exact salt to protein ratio is hard to identify, it has been assumed based on previous studies that the ratio is 1:1. The inactivation rates λRH reported in Table S7 are shown for two distinct saliva/dry solutes compositions: an artificial medium-dry solute composition of 13.1 g/L salts and 3.6 g/L (3.6:1.0) proteins and a culture medium-dry solution composition consisting of 17.1 g/L salts and 6.8 g/L proteins (2.5:1.0). Therefore it is difficult to recommend whether values reported for artificial media or standard medium to be used separately [28] or to merge the values and use the mean [18]. 3.2.3 The deposition rate λdep The deposition rate of virus-carrying aerosols and droplets is determined by the settling or terminal velocity, which itself is dependent on droplet size. When released from the respiratory tract (assumed to have ∼99.5% RH), droplets experience rapid evaporation and shrinkage upon encountering the unsaturated ambient atmosphere. The dependence of the dry equilibrium size of an aqueous droplet (Ddry) containing dry solutes on RH can be derived from the separate solute volume additivity (SS-VA) model for multi-component particles by Mikhailov et al. [48]. For the sake of brevity, the equations are not repeated here. All the equations can be found in a recent study by Aganovic et al. [28] on the relationship between indoor RH and infection risk using the Wells-Riley model. The Ddry/D0 ratios calculated according to the SS-VA model for the respiratory droplet initial size range of 0.3−10.0μm are presented in Table S9 ratios The impact of RH on the size of dehydrated droplets with an initial size of 5 μm of different compositions (protein to salt ratios) as derived from the SS-VA model is shown in Fig. 2 .Fig. 2 The impact of RH on Ddry with an initial size of 5 μm of different compositions (protein to salt ratios) at an indoor air temperature range 20–25 °C. Fig. 2 The deposition rate λdep of a virus-laden droplet can be expressed as follows:(48) λdep=vsHperson Hperson – the average height of the infected person(s), m The gravitational settling velocity of the droplets vs and ms can be determined from the following:(49) vs=∑i=1nCc∙ρd∙Deq,i2∙g18∙μ g – gravitational acceleration, ms2 ρd – density of droplets, kgm3 μ – viscosity of air, gcm∙s Deq,i – mean droplet equilibrium diameter for n = 6 size bins (Table S6), m Cc− Cunningham Slip correction factor (−) and can be determined by the existing empirical expression [63]:(50) Cc=1+λgDeq∙(2.51+0.80∙e−0.55∙Deqλg) λg− mean free path (μm) 3.2.4 Virus inactivation by ultraviolet germicidal irradiation (UVGI) λUVGI−R of the recirculated air from the ventilation system or portable air cleaners The virus-carrying aerosols can also be inactivated by ultraviolet germicidal irradiation (UVGI) zones in ducts or filters of the recirculation ducts and air cleaners that are placed in the space and can be calculated as:(51) λUVGI−R=ηUVGI∙(QrecorQPAC)=1−e−k∙Ir∙τr In both cases, the median virus inactivation efficiency ηUVGI [−] can be computed from expected flow rates according to the same principle [66]:(52) ηUVGI=1−e−k∙Ir∙τr k – UVGI inactivation constant (obtained from experimental data) [cm2∙mW−1∙s−1] Ir- inactivation rate constant [μWcm2](53) Ir=PrAr,50∙Lr Pr− the power of the UVGI device [W] τr− residence time of room air passing through UVGI [s] (54) τr=Lrvr Lr− length of the UVC device [m] vr− velocity at the cross-section of the recirculation duct or the PAC fan 3.2.5 Inactivation – upper room UVGI removal factor λUVGI−UP The second type of inactivation focused on in this model is upper room UVGI. A sufficient dosage of UV radiation will inactivate viruses (by photochemical disruption of viral RNA upon absorbing UV photons). Upper room applications of this technology make use of UV radiation generating lamp sources (low/medium pressure mercury vapor lamps or UV-C - LEDs), either wall mounted or suspended from the ceiling, to irradiate upper air zones of individual spaces while shielding the lower occupied zones from harmful UV radiation. According to Harmon and Lau [22] the removal rate due to upper room UVGI is calculated as:(55) λUVGI−UP=Ir−UP∙ZUP ZUP- upper room susceptibility constant [m2J] (ZUP≈0.377m2J[67]) Ir−UP – upper room average irradiance [μWcm2] (Ir−UP≤0.2μWcm2− supper permissible limit of irradiance at eye height [68]) 3.2.6 The respiratory tract absorption rate, λresp The respiratory tract absorption rate, λresp is a function of droplet diameter and tidal volume size [69] and can be calculated according to the following equation:(56) ζ=N∙k∙IRV IR is the inhalation rate of the exposed subject (which was assumed to be the inhalation rate for resting and standing averaged) at 0.52 m3h , and k (−) is a function of droplet diameter and tidal volume, the volume of air inhaled per breath [70]. We will use k=0.54 as in Ref. [69]. 3.2.7 Portable air cleaners λPAC Portable air cleaners (PAC) may be helpful for spaces with inadequate ventilation or when increased ventilation with outdoor air is not possible without compromising thermal comfort (temperature or humidity). PAC systems are mobile ventilation units that are commonly equipped with high-efficiency particulate air (HEPA) filters that capture at least 99.97% of particles of the maximum penetrating size (i.e., 0.3 μm in diameter). Under the assumption of fully mixing conditions, the removal rate of a HEPA-equipped PAC can be calculated as:(57) λPAC=QPACV QPAC - clean air delivery rate (CADR) of a PAC unit [m3h] V - room volume [m3] 3.2.8 Filtration of recirculated air λfilt For building HVAC systems the particle removal efficiency of filters is rated by the minimum efficiency reporting values (MERVs). MERVs rating standard specifies the filtration efficiency for three different ranges of particle sizes that follow a rating system with values ranging from 1 on the low end up to 16 (Table S10). The removal rate of a recirculating air filter can be calculated as:(58) λfilt=ηfilt∙Qrec To incorporate different removal efficiencies for different droplet size distributions, the quanta concentration equation (10) can be adjusted in the following manner:(59) n(t)=n0∙e−(∑λrest+∑inηfilt,i∙Qrec)+SV∙(∑λrest+∑inηfilt,i∙Qrec)∙(1−e−(∑λrest+∑inηfilt,i∙Qrec)∙t) Where ∑λrest are the rest of the removal mechanisms except for filtration by recirculated air and ηfilter,i – filter efficiency for different size bins according to Table S10., [%] 3.2.9 Filtration by face masks ηfm Face masks provide air filtration of the virus-carrying aerosols and droplets in the surrounding air. The particle-size weighted removal efficiencies of different masks can be estimated based on the assumed infectious particle size distribution [25] (Table S11). The facemask removal efficiency is included in source rate S in the following manner:S=cv∙ci∙3600∙106∙∑i=16Pi,br,sp,si∙Vi(D)∙(1−ηmask,i) ηmask,i – efficiency for different size bins according to Table S11., [%] 4 Results and discussion To assess the relative impact of different modes of sources and removal mechanisms on the airborne transmission risk, a simple case study was investigated with the same dimension characteristics and number of persons present for each case considered. The simple scenario consisted of a classroom with an area of 64 m2 and 3 m height with one infected and twenty susceptible persons present. As only long-distance airborne transmission risk is considered all the persons were distanced 1.5 m, as shown in Fig. 3 . The time exposure considered was 60 minutes. The indoor temperature was in the range of 20–25 °C.Fig. 3 The layout of the classroom case scenario considered. Fig. 3 4.1 The impact of the source characteristics The impact of four different source production characteristics was assessed for the case scenario conditions described. Only outdoor supplied mechanical ventilation was considered; i.e. no recirculation or use of PAC systems. Neither the infected nor the susceptible person wore a facemask. Fig. 4 indicates the importance of considering the input characteristics of expiratory modes, type of SARS-CoV-2 variants, amount of viral load in the infected person, and the number of persons infected. For the particular classroom case scenario, the infection risk of long-distance airborne transmission after 180 minutes may be up to 40 times higher when the infected person is singing compared to breathing, and two times higher compared the case when the person is speaking (Fig. 4 a)). The calculated high infection risk for singing is supported by several previous singing-related COVID-19 outbreaks: the karaoke-related outbreaks in bars in Sapporo and Otaru (Japan) [71], the indoor choir rehearsals in Whir au Val (France) [72], Amsterdam (The Netherlands) [73] and Skagit County (USA) [74]. As the pandemic progressed, new and more infectious variants of SARS-CoV-2 emerged. Their impact on the infection risk was estimated as shown in Fig. 3 b). If again considering the exposure time after 180 minutes, the infection risk for the latest variant of Omicron is up to 8 times higher for identical indoor conditions compared to the original Wuhan strain that initiated the pandemic. The last two scenarios were considered for an infected person with a viral load of 108RNAmL, which is close to the median viral load reported in a recent study [75] in non-vaccinated (median 108.1RNAmL) and vaccinated people (median 107.8RNAmL). W while the infection risk for the Omicron variant at a viral load of 108RNAmL is relatively high at ∼ 23% after 180 minutes, a tenfold increase in the viral load (108RNAmL) would result in an infection of most probably all of the 20 susceptible persons (P ∼ 96%) from long-airborne transmission by virus-laden aerosols ≤5μm in size (Fig. 3 c)). Though a rarity, viral loads >109RNAmL have been reported [76,77], and considering our predicted infection simulations are probably the main drivers of super-spreading events in poorly ventilated conditions. The impact of more persons being infected than a single one is shown in Fig. 4 d).Fig. 4 The impact of quanta generation characteristics on the airborne infection risk: a) impact of expiratory modes (breathing, speaking, and singing) b) the impact of SARS-CoV-2 variants (speaking only) c) impact of viral load (speaking only) d) impact of the number of persons infected (speaking only). Fig. 4 Fig. 4. The impact of removal mechanisms on the airborne infection risk: a) ventilation rate b) filtration efficiency in case of recalculated air c) face mask d) upper room UVGI radiation. 4.2 The impact of removal mechanisms Fig. 5 compares four different removal mechanisms for the same setup conditions, amount of viral load in the infected person, expiratory mode (speaking), and virus variant (Omicron). The baseline scenario is shown in blue color in poorly ventilated conditions (0.5 ACH), RH = 53%, and no use of a face mask.Fig. 5 The impact of removal mechanisms on the airborne infection risk: a) ventilation rate b) filtration efficiency in case of recalculated air c) face mask d) upper room UVGI radiation. Fig. 5 It is clear, that except for relative humidity, it is possible to reduce the infection risk below 10% with ventilation (6 and 12 ACH), face mask (N 95), or upper room UVGI (0.2 μWcm2) after three hours of exposure compared to the baseline infection risk of 23%. High ventilation rates of 6 and 12 ACH and a highly efficient N 95 mask reduce the infection risk below 5% after 180 minutes. On the other hand, controlling relative humidity may decrease the infection risk slightly by reducing it to 20% or by increasing it to 70%. However, both of these RH values or on the end of the range allowed by leading standards for indoor air quality [79,80]. The next Fig. 6 shows the relative effect of applying the different removal mechanisms for the baseline scenarios for reducing the infection risk after 180 minutes.Fig. 6 The relative decrease in long distance-airborne infection risk after 180 minutes by applying different measures compared to the baseline scenario (no mask, no UVGI, ventilation rate = 0.5 h−1, RH = 53%). Fig. 6 4.2.1 The impact of ventilation efficiency The single-zone (equation (38)) and two-zone model (equation (44) and (45)) were compared for three different ε (0.50, 0.75, and 1.00) values lower than 1, as the two-zone model for incomplete mixing ventilation is limited to ε<1. Fig. 7 . Shows that for a low ventilation rate (0.5 h−1), the single-zone model underestimates the infection risk and this difference increases as the ventilation efficiency become lower. After 360 minutes, the maximum relative difference for the baseline scenario at 0.5 h−1 is up to 15% at ε= 0.5 and up to 8% at ε= 0.75 (see Fig. 8).Fig. 7 The impact of ventilation efficiency on the infection risk generated by a single-zone and two-zone model at a relatively low ventilation rate (0.5 h−1). Fig. 7 Fig. 8 The impact of ventilation efficiency on the infection risk generated by a single-zone and two-zone model at a relatively high ventilation rate (6 h−1). Fig. 8 While the relative difference between a lower ventilation rate and lower ventilation efficiency ε value is relatively high to be ignored (>5%), the maximum relative difference at higher ventilation rates (6.0 h−1) is around 2% for ε= 0.75 and up to 5% for ε= 0.5 after 360 minutes of exposure. So low relative differences between the results obtained by the single- and two-zone models imply that the single-zone model may be used without losing significantly on accuracy and a relatively high ventilation rate (>6 h−1). The impact of a variety of ventilation efficiency values to 0.5<ε<1.5 on the infection risk at 6 h−1 are shown in Fig. 9 . This implies the importance of a possible misestimation of the infection risk for completely mixing conditions (ε=1) at higher ventilation rates.Fig. 9 The impact of increased ventilation efficiency on the infection risk at a relatively high ventilation rate (6 h−1) generated by the single-zone model. Fig. 9 5 Limitations The model is still subject to several limitations. Unfortunately, the validation of the generated model against previous outbreaks is still not possible due to missing considerable input information from the observed events, and additional building system details such as the viral load of the infected person, expiratory modes (speaking or singing event), ventilation rates, space volume, and exposure time of infected persons but also additional building system details such as the amount of recirculated air, filter efficiency, etc. With insufficient input details, any validation process is futile. Future outbreak reports should include this information for validated retrospective infection risk assessments. Another major limitation is that model is only limited to long-airborne transmission risk assessment (>1.0-meter social distance). Short-range airborne transmission may not be dealt with due to the main assumption that once released the droplets are instantaneously mixed evenly in every point of the room environment. This may be impossible to overcome by using the conventional dose-response approach based on quanta balances of open black boxes. Other limitations that may not be solved without using either expensive CFD simulations or on-site experimental measurements involve the inclusion of convective flows within the space, the impact of the activity and movement of occupants, and the change of pace and mode of expiration (breathing vs. talking). Hence future work should try to capture the physical processes as much as possible but also try to develop and run the dynamic models to arrive at realistic estimates. 6 Conclusions This study reviewed the airborne infection models based on the Wells-Riley concept of quanta to provide the most suitable model for both retrospective and future long-distance airborne risk assessment. The model presented in this study presents an extended and improved Well-Riley model as a result of compiling and comparing all source and sink/removal terms reported during the COVID-19 pandemic. The used approaches for calculating the source and sink mechanisms published during the recent pandemic were reviewed and new data was utilized to characterize the viral load and removal mechanisms. Based on identifying unresolved issues for each sink and source term we improved the classical WR model by introducing the following novelties i) developing a new model to calculate the total volume of respiratory fluid exhaled per unit time ii) developing a novel viral dose-based generation rate model for dehydrated droplets after expiration iii) deriving a novel quanta-RNA relationship for various strains of SARS-CoV-2 iv) proposing a method to account for the incomplete mixing conditions. We show that the quanta emission rate reported in previous studies were overestimated even by factor 10 because of using data and assumptions being based on SARS-CoV-1. Recent studies have confirmed medium viral load for both vaccinated and unvaccinated persons about 108 RNA copies in mL for the alpha and delta strains allowing to determine new average quanta emission rates including omicron variant. These quanta values for original strain of 0.13 and 3.8 quanta/h for breathing and speaking and the virus variant multipliers determined in this study may be used for simple hand calculations of probability of infection or to be used with developed model operating with six size ranges of aerosol droplets to calculate the effect of ventilation and other removal mechanisms. Overall, our new model allows for changing more than four source input parameters (expiratory mode, virus variant, viral load, and several infected persons) as well as six potential removal mechanisms by ventilation, viral inactivation by relative humidity, ventilation by using a portable air cleaner, inactivation by UVGI of the recirculated air from the ventilation system or portable air cleaners, upper room UVGI filtration of portable air cleaner or recirculated air and the filtration by use of a face mask. In addition, the model introduces the concept of ventilation efficiency for evaluating incomplete mixing conditions. By resolving these specific issues, an advanced and integrated Wells-Riley model was developed, tested, and recommended for future and retrospective indoor infection risk assessments. The model developed is made available as an open-source interactive computational tool. Uncited references [44]; [65]; [67]; [78]. CRediT authorship contribution statement Amar Aganovic: Writing – original draft, Methodology, Formal analysis, Conceptualization. Guangyu Cao: Writing – review & editing, Conceptualization. Jarek Kurnitski: Writing – review & editing, Conceptualization. Pawel Wargocki: Writing – review & editing, Conceptualization. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Appendix A Supplementary data The following is the Supplementary data to this article:Multimedia component 1 Multimedia component 1 Data availability Data will be made available on request. Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.buildenv.2022.109924. ==== Refs References 1 Wang Chia C. Airborne transmission of respiratory viruses Science (New York, N.Y.) 373 6558 2021 eabd9149 10.1126/science.abd9149 2 Scientific Brief: SARS-CoV-2 Transmission CDC COVID-19 Science Briefs 7 May 2021 Centers for Disease Control and Prevention (US) 3 Lednicky JA, Lauzard M, Fan ZH et al. Viable SARS-CoV-2 in the Air of a Hospital Room with COVID-19 Patients. 4 Zhang R. Li Y. Zhang A.L. Wang Y. Molina M.J. Identifying airborne transmission as the dominant route 12 for the spread of COVID-19 Proc. Natl. Acad. Sci. 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==== Front J Acad Consult Liaison Psychiatry J Acad Consult Liaison Psychiatry Journal of the Academy of Consultation-Liaison Psychiatry 2667-2979 2667-2960 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. S2667-2960(22)00314-7 10.1016/j.jaclp.2022.08.006 Letter to the Editor: Brief Case Report Posttraumatic Stress Disorder and Hyperventilation in Post-COVID-19 Syndrome: An Underestimated Association Benzakour L. M.D. 1∗ Psychiatry Liaison Unit, Psychiatry Department, Geneva University Hospitals, Geneva, Switzerland Voruz P. 1 Faculty of Medicine, University of Geneva, Geneva, Switzerland Clinical and Experimental Neuropsychology Laboratory, Faculty of Psychology, University of Geneva, Geneva, Switzerland Neurology Department, Geneva University Hospitals, Geneva, Switzerland Lador F. Ph.D. Faculty of Medicine, University of Geneva, Geneva, Switzerland Division of Respiratory Medicine, Medicine Department, Geneva University Hospitals, Geneva, Switzerland Guerreiro I. M.D. Division of Respiratory Medicine, Medicine Department, Geneva University Hospitals, Geneva, Switzerland Kharat A. M.D. Division of Respiratory Medicine, Medicine Department, Geneva University Hospitals, Switzerland Assal F. M.D. Faculty of Medicine, University of Geneva, Geneva, Switzerland Neurology Department, Geneva University Hospitals, Geneva, Switzerland Péron J.A. Ph.D. Clinical and Experimental Neuropsychology Laboratory, Faculty of Psychology, University of Geneva, Geneva, Switzerland Neurology Department, Geneva University Hospitals, Geneva, Switzerland ∗ Send correspondence and reprint requests to Lamyae Benzakour, MD, University Hospital Geneva: Hopitaux Universitaires Geneve, Psychiatry, Geneve, Switzerland 1 These authors contributed equally to this work. 1 These authors contributed equally to this work. 14 12 2022 November-December 2022 14 12 2022 63 6 637638 26 7 2022 10 8 2022 15 8 2022 © 2022 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved. 2022 Academy of Consultation-Liaison Psychiatry Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcIntroduction Hyperventilation syndrome (HVS) is a dysfunctional breathing syndrome in which minute ventilation exceeds metabolic demands, resulting in hemodynamic and chemical changes. Recent data suggest that HVS incidence is high in the post-COVID-19 condition,1 and its management may involve consultation-liaison (CL) psychiatry considering the presence of functional symptoms. In our clinical practice, we observed an association between posttraumatic stress disorder (PTSD), which is also prevalent in the post-COVID-19 condition,2 and HVS that could be explained by a traumatic experience during the acute phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. These 2 phenomena have so far only been studied separately in the post-COVID-19 condition despite the evidence of their interaction in other pathologies. In the present letter case, we would like to highlight the possible interaction between HVS and PTSD in post-COVID-19 condition. Case Report Ms. G was a 44-year-old nurse working in a general medicine unit. She had no medical or surgical history and was referred to a CL psychiatrist at 5 months after infection for COVID-19 because she had anxiety. Three months after the SARS-CoV-2 infection, although Ms. G complained of palpitations and dyspnea, a cardiological evaluation including rhythm and echocardiographic parameters was normal. Pulmonary function tests showed reduced diffusing capacity for carbon monoxide (71%) and normal spirometry (forced expiratory volume, 87%). A thoracic computed tomography scan revealed discrete bilateral subpleural ground-glass opacities. The 6-minute walking test showed 580 m (96% predicted distance), and SpO2 was between 97% and 99%, with a peak dyspnea of 9/10 on the Borg scale. The Nijmegen score was 37/64 (cutoff at 20 for HVS). At 5 months, the psychiatric assessment revealed anxiety and a feeling of insecurity with hyperarousal symptoms, as well as exaggerated startle reactions, nightmares with sleep disturbance, flashbacks, and avoidance behaviors related to the period she was infected by SARS-CoV-2. Ms. G described derealization, poor sleep, and severe fatigue. All these symptoms began after she felt the fear of death when she was infected by SARS-CoV-2 herself and after she was greatly affected by the death of a young person due to COVID-19 infection at work during the same period. The PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders, fifth edition, score was 43 (cutoff at 33 for PTSD); anxiety and depression scores were 9 and 10, respectively, on the Hospital Anxiety and Depression Scale (cutoff at 11 for anxiety and 11 for depression). Concerning previous relevant traumatic life events, during her childhood, she lived with her mother who was diagnosed with bipolar disorder. Ms. G witnessed episodes of agitation, and her mother made several suicidal attempts. Neuropsychological functions assessed 6 months after infection revealed mild executive difficulties (inhibition, programming, mental flexibility, lexical availability), and severe self-reported fatigue. Ms. G was diagnosed with post-COVID-19 condition, dissociative subtype PTSD, and HVS. She received specific physiotherapy and psychotherapeutic approaches based on a multimodal treatment in 3 phases using eye movement desensitization and reprocessing (EMDR) and cognitive behavioral therapy. She had 12 sessions of EMDR in total dealing with desensitization of her traumatic events and then preparation of future scenarios concerning her work. The cognitive behavioral therapy approach consisted of cognitive restructuring and identification of emotions. An antidepressant was initiated with particular attention to the risk of treatment emergent mania, given her family history: first paroxetine 20 mg without any therapeutic response after 1 month, and then a switch to escitalopram 20 mg. The patient greatly improved and returned to work at part time (20%). Five months later, we observed a worsening around the date of her COVID-19 infection. Moreover, the arrival of the fifth wave of COVID-19 triggered a panic attack. Ms. G stopped working and received intensive psychiatric follow-up with complementary EMDR sessions targeting the fifth wave. She slowly improved both physically and mentally: she continued to suffer from fatigue and dyspnea from exercise to a very lesser extent with no symptoms of PTSD and no new panic attacks. Discussion Specific knowledge about HVS in post-COVID-19 condition is scarce, especially regarding interaction with psychiatric symptoms. HVS has been previously associated with psychiatric symptoms such as anxiety and depressive symptoms.3 However, these studies were not able to demonstrate a causal link between the two, and the nature of their interactions remains unknown. In our clinical experience, PTSD is common in patients who have experienced HVS in the post-COVID-19 condition, and this association needs to be investigated in future studies. A robust literature highlights dyspnea as a predictor of PTSD: the presence of dyspnea during the acute phase of COVID-19,4 and acute respiratory distress syndrome requiriing admission to the intensive care unit, no matter the etiology,5 increased the risk of PTSD. There is a need for greater awareness of PTSD in clinical practice when assessing patients with unexplained dyspnea. Closer cooperation between psychiatrists, physiotherapists, medical staff of intensive care unit, and lung specialists in the evaluation of this frequent symptom is recommended. Institutional Review Board Statement: This case report was approved by the Ethics Committee of Geneva. Informed Consent: Written informed consent has been obtained from the patient to publish this paper. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Disclosure: The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. ==== Refs References 1 Taverne J. Salvator H. Leboulch C. High incidence of hyperventilation syndrome after COVID-19 J Thorac Dis 13 2021 3918 34277081 2 Yuan Y. Liu Z.-H. Zhao Y.-J. Prevalence of post-traumatic stress symptoms and its associations with quality of life, demographic and clinical characteristics in COVID-19 survivors during the post-COVID-19 era Front Psychiatry 12 2021 665507 34093279 3 Margraf J. Hyperventilation and panic disorder: a psychophysiological connection Adv Behav Res Ther 15 1993 49 74 4 Einvik G. Dammen T. Ghanima W. Heir T. Stavem K. Prevalence and risk Factors for post-traumatic stress in Hospitalized and Non-Hospitalized COVID-19 patients Int J Environ Res Public Health 18 2021 2079 33672759 5 Worsham C.M. Banzett R.B. Schwartzstein R.M. Dyspnea, acute respiratory Failure, Psychological Trauma, and post-ICU mental Health: a Caution and a Call for research Chest 159 2021 749 756 33011205	36522036	PMC9747240	NO-CC CODE	2022-12-15 23:21:59	no	J Acad Consult Liaison Psychiatry. 2022 Dec 14 November-December; 63(6):637-638	utf-8	J Acad Consult Liaison Psychiatry	2,022	10.1016/j.jaclp.2022.08.006	oa_other
==== Front J Acad Consult Liaison Psychiatry J Acad Consult Liaison Psychiatry Journal of the Academy of Consultation-Liaison Psychiatry 2667-2979 2667-2960 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. S2667-2960(22)00312-3 10.1016/j.jaclp.2022.08.004 Letter to the Editor: Brief Case Report Patients With Schizophrenia-Spectrum Disorders as Vulnerable Populations in an Age of Misinformation: A Case Report of Ivermectin-Related Liver Failure Fioravante Nicholas BS ∗ Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD Kozak Zofia M.D. Glovinsky David M.D. Department of Psychiatry, University of Maryland Medical Center, Baltimore, MD ∗ Send correspondence and reprint requests to Nicholas Fioravante, BS, University of Maryland School of Medicine, Baltimore, MD 14 12 2022 November-December 2022 14 12 2022 63 6 639640 22 7 2022 9 8 2022 11 8 2022 © 2022 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved. 2022 Academy of Consultation-Liaison Psychiatry Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcIntroduction The COVID-19 pandemic has seen a surge in medical misinformation. In particular, popular media has amplified misinformation regarding the use of the antiparasitic drug ivermectin for prophylaxis and treatment of COVID-19. Here, we present the case of a patient, Mr. A, with a schizophrenia-spectrum disorder (SSD) who had been using ivermectin for this purpose. He was evaluated by the psychiatric consultation service after presenting in fulminant liver failure requiring emergent hepatic transplant. Case Mr. A, with a charted diagnosis of schizophrenia, was admitted to the hospital in fulminant liver failure after taking escalating daily doses of ivermectin for the past 6 months (up to 100 mg in the days leading to admission), in addition to supplements taken for years (including ashwagandha, uva ursi, chi shao, serrapeptase, burdock, schisandra, mullein, bladderwrack, dandelion, neem leaf, nettle leaf, niacin, candidase). Mr. A ordered ivermectin online, seemingly without a prescription. He had no history of addiction and a negative urine toxicology screen on admission. After liver transplant, the consult-liaison (CL) psychiatry team was consulted for recommendations on starting a daily antipsychotic, as the primary transplant team was concerned Mr. A's charted history of schizophrenia would pose a risk to his transplant. Chart review revealed several emergency room visits for strange concerns (i.e., feeling parasites “wiggle”), and 1 inpatient psychiatric admission 4 years prior for suicidal ideation, disorganized thought, and odd statements regarding metaphysics. He was discharged on olanzapine but was nonadherent and subsequently received no antipsychotics. No functional decline was noted since. Evaluation revealed a linear and organized thought process. He confirmed his motivation for taking supplements was to reduce his risk of parasitic and viral infection, denying this was an immediate concern. He had insight that the ivermectin and supplement use led to his liver failure. Collateral from the Mr. A's mother revealed years of social isolation, paranoia, and belief in various conspiracy theories. He reportedly drank bleach when a former President suggested it may be a viable treatment for COVID-19. Subsequent evaluations consistently revealed no active parasitosis or hallucinations. The CL team felt that Mr. A's long-standing pattern of paranoid thinking, odd beliefs, parasitosis, metaphorical speech, and lack of close confidants was most congruent with schizotypal personality disorder. The CL psychiatry team recommended against standing antipsychotics. Discussion Since the beginning of the COVID-19 pandemic, a general sense of uncertainty has provided optimal conditions for the rise of COVID-19-related misinformation. Despite evidence that ivermectin is not an appropriate prophylaxis option for COVID-19, the Centers for Disease Control and Prevention has documented a rapid increase in ivermectin prescriptions and associated serious illnesses in the United States.1 A case report of liver failure in a patient taking 1 dose of ivermectin2 demonstrates its potential for hepatotoxicity. However, it is not possible to definitively conclude ivermectin was the cause of Mr. A's liver failure in the setting of his polysupplement use. Systemic ivermectin is approved for treatment of parasitic worms in humans. According to the Food and Drug Administration, toxicity of ivermectin can manifest as nausea, vomiting, diarrhea, hypotension, allergic reactions, dizziness, ataxia, seizures, coma, and possible death. Ivermectin can be purchased online, as evident in the case of Mr. A. It is not clear which media sources Mr. A was exposed to; however, social media has been identified as a major driver for ivermectin use,3 which poses a strong argument for holding social media platforms accountable for reducing the spread of medical misinformation. Some countries consider dissemination of misinformation a legal offense and fine those who spread it.4 When misinformation proliferates, vulnerable populations can be severely and negatively affected. This case highlights that patients with SSDs may be at increased risk of poor outcomes in a digital ecosystem rampant with misinformation. Social pressure can sway what those with schizophrenia believe to be true.5 Although this finding has not been studied in those with SSDs, it is an important consideration for the clinician working with patients with these conditions. Clinicians should be careful to avoid using leading questions and should consider screening at-risk patients' beliefs in harmful misinformation, especially in times of enormous risk such as during the current pandemic. A recent peer-reviewed commentary suggests physicians must take more active roles in disseminating correct information on social media and participate in visible public debates regarding the validity of purported treatments.3 We believe Mr. A's SSD made him susceptible to medical misinformation, ultimately costing him both his health and liver. Many more patients like him exist. To reduce morbidity, mortality, and health care costs, more must be done to understand the effect of misinformation on patients with SSDs. Conflicts of Interest: The authors declare that they have no conflict of interest. Informed Consent: Patient consent was not available; no personally identifiable information was included. ==== Refs References 1 CDC Health Alert Network Rapid Increase in Ivermectin Prescriptions and Reports of Severe Illness Associated with Use of Products Containing Ivermectin to Prevent or Treat COVID-19 2021 Centers for Disease Control and Prevention CDCHAN-00449 https://emergency.cdc.gov/han/2021/han00449.asp 2 Veit O. Beck B. Steuerwald M. Hatz C. First case of ivermectin-induced severe hepatitis Trans R Soc Trop Med Hyg 100 2006 795 797 3 Taccone F.S. Hites M. Dauby N. From hydroxychloroquine to ivermectin: how unproven “cures” can go viral Clin Microbiol Infect. Published online February 2022 4 Ogunleye O.O. Basu D. Mueller D. Response to the Novel Corona Virus (COVID-19) pandemic across Africa: Successes, Challenges, and Implications for the Future Front Pharmacol 11 2020 1205 5 Peters M.J.V. Moritz S. Tekin S. Jelicic M. Merckelbach H. Susceptibility to misleading information under social pressure in schizophrenia Compr Psychiatry 53 2012 1187 1193	36522037	PMC9747241	NO-CC CODE	2022-12-15 23:21:59	no	J Acad Consult Liaison Psychiatry. 2022 Dec 14 November-December; 63(6):639-640	utf-8	J Acad Consult Liaison Psychiatry	2,022	10.1016/j.jaclp.2022.08.004	oa_other
==== Front J Acad Consult Liaison Psychiatry J Acad Consult Liaison Psychiatry Journal of the Academy of Consultation-Liaison Psychiatry 2667-2979 2667-2960 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. S2667-2960(22)00330-5 10.1016/j.jaclp.2022.08.009 Letter to the Editor: Subjects of Interest to C-L Psychiatry Possibility of Age and Prior Psychiatric Illnesses Affecting the Study Design on Cognitive Dysfunction, Psychiatric Distress, and Functional Decline After SARS-CoV-2 Infection Ahmed H. Shafeeq ∗ Bangalore Medical College and Research Institute, Bangalore, India ∗ Send correspondence and reprint requests to H. Shafeeq Ahmed, Bangalore Medical College and Research Institute, K.R Road, Bangalore 560002, Karnataka, India. 14 12 2022 November-December 2022 14 12 2022 63 6 643644 1 4 2022 29 8 2022 © 2022 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved. 2022 Academy of Consultation-Liaison Psychiatry Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: The research paper by Vannorsdall et al.1 was quite interesting in that the authors attempted to prospectively analyze the cognitive abilities, mental health symptoms, and functioning at approximately 4 months after the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The study does take a different approach compared to the conventional COVID-19 studies in that it compared the well-being of the non-intensive care unit (ICU) versus the post-ICU patients. One of the most noticeable characteristics from this study is that there seems to be a slight disparity with regards to the mean age between the non-ICU and post-ICU patients. The post-ICU patients seem to be older (mean 58 years) than the non-ICU patients (mean 49.5 years). This study further shows the possible association between age and the cognitive function and mental health functions of the post-ICU patients, which seems to be lower in all aspects than that of the non-ICU patients except the Oral Trail Making Test Part B. Studies indicate that with increasing age, there will be an accelerated rate of neuronal dysfunction, neuronal loss, and cognitive decline, with many persons developing cognitive impairments.2 Furthermore, since more number of older patients show severe SARS-CoV-2 disease manifestations, they are more often admitted to ICUs.3 This could be one of the main reasons for the association of decreased cognitive and mental functions to post-ICU patents compared to non-ICU patients. The authors used the Quick Dementia Rating Scale (QDRS) for the measurement of mental health and functioning. But in truth, the scale focuses on dementia and cognitive ability rather than a measure of mental health and functioning, so it would have been more appropriate to use the QDRS scale for measuring cognitive ability.4 Using QDRS appropriately as a test for cognitive function would definitely yield more value. The authors themselves mentioned in the Materials and Methods section that the QDRS scale would be used for analyzing the “10 domains of cognition, mood, and daily functioning”. Therefore, the functional significance of the QDRS could have been better apprised and used in the study to provide more accurate results. In the result analysis section of mental ability and functioning, we see a different turn of events where one can notice that in this scenario, the post-ICU patients scored less on three scales including Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, and QDRS than the non-ICU patients, making the mental health disorder less severe in post-ICU patients versus non-ICU patients. Such findings truly provide us with more in-depth analyses of the results. Since the investigators did not exclude participants with previous cases of cognitive impairment, mental health issues, or other psychiatric and/or psychological illnesses, one cannot confirm whether certain candidates had a prior diagnosis of the same. Studies have indicated that people with mental illnesses are more prone to having comorbidities, and hence a more severe case of SARS-CoV-2 infection and need for hospitalization.5 It is entirely possible that some or several participants from the post-ICU patients group had cognitive impairments and/or mental health illnesses which would have inadvertently tainted the study population and hence possibly even the result analysis. Since the study had no well-defined inclusion or exclusion criteria, there is no way to know whether any patient had psychiatric or psychological comorbidities prior to the SARS-CoV-2 infection. Appropriate questionnaires for the right function and a more well-defined age-based categorization of the patients could prove to be more beneficial for result analysis of the study findings. Especially having an age-matched study population will give us adequate results. Having a proper exclusion and inclusion criteria while taking into consideration the factors being studied in the research, will give a better study population. Conflicts of Interest: The author declares that he has no conflict of interest. Funding: None. ==== Refs References 1 Vannorsdall T.D. Brigham E. Fawzy A. Cognitive dysfunction, psychiatric distress, and functional decline after COVID-19 J Acad Consult Liaison Psychiatry 63 2022 133 143 34793996 2 Murman D.L. The impact of age on cognition Semin Hear 36 2015 111 121 27516712 3 Hu C. Li J. Xing X. Gao J. Zhao S. Xing L. The effect of age on the clinical and immune characteristics of critically ill patients with COVID-19: a preliminary report PLoS One 16 2021 e0248675 33735325 4 Galvin J.E. The Quick Dementia Rating System (qdrs): a rapid dementia staging tool Alzheimers Dement (Amst) 1 2015 249 259 26140284 5 Egede C. Dawson A.Z. Walker R.J. Garacci E. Campbell J.A. Egede L.E. Relationship between mental health diagnoses and COVID-19 test positivity, hospitalization, and mortality in Southeast Wisconsin Psychol Med 2021 1 9	36522039	PMC9747242	NO-CC CODE	2022-12-15 23:21:59	no	J Acad Consult Liaison Psychiatry. 2022 Dec 14 November-December; 63(6):643-644	utf-8	J Acad Consult Liaison Psychiatry	2,022	10.1016/j.jaclp.2022.08.009	oa_other
==== Front J Acad Consult Liaison Psychiatry J Acad Consult Liaison Psychiatry Journal of the Academy of Consultation-Liaison Psychiatry 2667-2979 2667-2960 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. S2667-2960(22)00270-1 10.1016/j.jaclp.2022.05.001 Letter to the Editor: Subjects of Interest to C-L Psychiatry Reply to Letter to Editor by Ahmed HS, et al re: Possibility of Age and Prior Psychiatric Illnesses Affecting the Study Design Vannorsdall Tracy D. Ph.D. ∗ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD Parker Ann M. M.D., Ph.D. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD Outcomes After Critical Illness and Surgery (OACIS) Research Group, Johns Hopkins University School of Medicine, Baltimore, MD Oh Esther S. M.D., Ph.D. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD Johns Hopkins University School of Nursing, Baltimore, MD ∗ Send correspondence and reprint requests to Tracy D. Vannorsdall, PhD, Johns Hopkins Hospital, 600 N. Wolfe Street, Meyer 218, Baltimore, MD 21287 14 12 2022 November-December 2022 14 12 2022 63 6 645646 © 2022 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved. 2022 Academy of Consultation-Liaison Psychiatry Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: We thank Ahmed (2022)1 for highlighting features of our recent article in which we report and contrast the rates of cognitive dysfunction, emotional distress, and functional decline approximately 4 months after acute coronavirus disease 2019 (COVID-19) illness in those who did and did not require intensive care unit (ICU) admission.2 Ahmed (2022)1 pointed out that patients in our sample who received care in the ICU were older than non-ICU patients and proposed that this discrepancy may have contributed to the generally lower cognitive composite test scores observed among those requiring more intensive treatment. It was similarly noted that the ICU patient group seemed to exhibit less psychiatric distress than their non-ICU peers and that it remains unclear the extent to which either cognitive dysfunction or psychiatric symptoms were present prior to COVID-19 illness. A question was also raised as to the nature and interpretation of a self-report instrument. Older adults appear at greater risk of more severe COVID-19 illness and are more likely to have pre-existing diminution in cognitive functioning due to normal and/or pathologic aging.3 We addressed this potential confound in our data by analyzing age-adjusted cognitive test performances that account for the contribution of age to cognitive test scores. We also employed statistical adjustments for this and other nonmedical characteristics that are frequently associated with cognitive test performances (i.e., sex, racial/ethnic minority status, educational attainment, and estimated IQ). Our finding that those receiving care in the ICU continued to demonstrate poorer global cognition after such adjustments suggests that more severe COVID-19 illness and/or factors associated with ICU admission, rather than systematic biases in our clinical groups, may underly the poorer cognitive outcomes observed in ICU survivors. Our findings that cognitive functioning was not associated with the severity of mental health symptoms or functional decline and that neuropsychiatric symptoms were frequent regardless of the need for ICU care are important, as they highlight the role of routine assessment of mental health symptoms after COVID-19 regardless of initial illness severity. We noted that ours was a descriptive study of the neuropsychiatric features characterizing those adults who are likely to receive care in a post-COVID-19 pulmonary clinic. It was not designed to address the underlying etiologies for the neuropsychiatric symptoms we observed. However, we agree with Ahmed (2022)1 that studies employing control groups well matched for pre-existing medical, cognitive, and mental health features are needed in order to more clearly identify the extent to which COVID-19 exerts an independent effect on neuropsychiatric outcomes, identify those at greatest risk, and to guide management. Recent data from hospitalized adults in Wuhan, China, demonstrate that older patients with severe illness, when compared with non-COVID-19 controls and those with less severe illness, are more likely to show persistent and progressive cognitive decline over the first year after the illness.4 Such individuals may represent a particularly at-risk group and may require ongoing neuropsychiatric specialty care. In contrast, clinical data from studies of patients seeking neuropsychological services at post-COVID-19 condition clinics in the United States5 suggest that such groups disproportionately had middle-aged (mean age <50 y) and female (84%) populations and report high rates of pre-existing psychiatric conditions (57%). In such samples, subjective cognitive dysfunction is more pronounced than the generally mild deficits observed in formal neuropsychological testing and tends to be associated with the severity of mood/anxiety symptoms.5 Those findings suggest that among clinically referred patient groups, there may be a primary role for psychologic and psychiatric interventions aimed at improving patient distress and functioning. Finally, Ahmed (2022)1 suggests that the Quick Dementia Rating Scale be employed as a measure of mental health symptoms and would more appropriately be interpreted as an index of cognitive ability. Here, we respectfully disagree as this instrument was employed to assess the extent of patient-reported decline in daily functioning attributable to subjective changes in cognition, mood, and ability to perform other activities of daily living. Thus, the Quick Dementia Rating Scale served as an adjunct to, rather than a direct measure of, cognition and psychiatric symptoms. Disclosures: A.M.P. declares receiving legal consulting fees; receiving speaker fees/honoraria from Vizient, Johns Hopkins, ASHA, HCL Healthcare India, and Global Tracheostomy Collaborative; and being in the Data Safety Monitoring/Advisory Board sponsored by Universidad de Chile. The other 2 authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. ==== Refs References 1 Ahmed H.S. Possibility of age and prior psychiatric illnesses affecting the study design on cognitive dysfunction, psychiatric distress, and functional decline after SARS-CoV-2 infection J Acad Consult Liaison Psychiatry 63 2022 643 644 2 Vannorsdall T.D. Brigham E. Fawzy A. Cognitive dysfunction, psychiatric distress, and functional decline after COVID-19 J Acad Consult Liaison Psychiatry 63 2022 133 143 34793996 3 Chen Y. Klein S.L. Garibaldi B.T. Aging in COVID-19: vulnerability, immunity and intervention Ageing Res Rev 65 2021 101205 33137510 4 Liu Y.H. Chen Y. Wang Q.H. One-year trajectory of cognitive changes in older survivors of COVID-19 in Wuhan, China: a longitudinal cohort study JAMA Neurol 79 2022 509 517 35258587 5 Whiteside D.M. Basso M.R. Naini S.M. Outcomes in post-acute sequelae of COVID-19 (PASC) at 6 months post-infection part 1: cognitive functioning Clin Neuropsychol 36 2022 806 828 35130818	36522040	PMC9747243	NO-CC CODE	2022-12-15 23:21:59	no	J Acad Consult Liaison Psychiatry. 2022 Dec 14 November-December; 63(6):645-646	utf-8	J Acad Consult Liaison Psychiatry	2,022	10.1016/j.jaclp.2022.05.001	oa_other
==== Front J Acad Consult Liaison Psychiatry J Acad Consult Liaison Psychiatry Journal of the Academy of Consultation-Liaison Psychiatry 2667-2979 2667-2960 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. S2667-2960(22)00270-1 10.1016/j.jaclp.2022.05.001 Letter to the Editor: Subjects of Interest to C-L Psychiatry Reply to Letter to Editor by Ahmed HS, et al re: Possibility of Age and Prior Psychiatric Illnesses Affecting the Study Design Vannorsdall Tracy D. Ph.D. ∗ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD Parker Ann M. M.D., Ph.D. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD Outcomes After Critical Illness and Surgery (OACIS) Research Group, Johns Hopkins University School of Medicine, Baltimore, MD Oh Esther S. M.D., Ph.D. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD Johns Hopkins University School of Nursing, Baltimore, MD ∗ Send correspondence and reprint requests to Tracy D. Vannorsdall, PhD, Johns Hopkins Hospital, 600 N. Wolfe Street, Meyer 218, Baltimore, MD 21287 14 12 2022 November-December 2022 14 12 2022 63 6 645646 © 2022 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved. 2022 Academy of Consultation-Liaison Psychiatry Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: We thank Ahmed (2022)1 for highlighting features of our recent article in which we report and contrast the rates of cognitive dysfunction, emotional distress, and functional decline approximately 4 months after acute coronavirus disease 2019 (COVID-19) illness in those who did and did not require intensive care unit (ICU) admission.2 Ahmed (2022)1 pointed out that patients in our sample who received care in the ICU were older than non-ICU patients and proposed that this discrepancy may have contributed to the generally lower cognitive composite test scores observed among those requiring more intensive treatment. It was similarly noted that the ICU patient group seemed to exhibit less psychiatric distress than their non-ICU peers and that it remains unclear the extent to which either cognitive dysfunction or psychiatric symptoms were present prior to COVID-19 illness. A question was also raised as to the nature and interpretation of a self-report instrument. Older adults appear at greater risk of more severe COVID-19 illness and are more likely to have pre-existing diminution in cognitive functioning due to normal and/or pathologic aging.3 We addressed this potential confound in our data by analyzing age-adjusted cognitive test performances that account for the contribution of age to cognitive test scores. We also employed statistical adjustments for this and other nonmedical characteristics that are frequently associated with cognitive test performances (i.e., sex, racial/ethnic minority status, educational attainment, and estimated IQ). Our finding that those receiving care in the ICU continued to demonstrate poorer global cognition after such adjustments suggests that more severe COVID-19 illness and/or factors associated with ICU admission, rather than systematic biases in our clinical groups, may underly the poorer cognitive outcomes observed in ICU survivors. Our findings that cognitive functioning was not associated with the severity of mental health symptoms or functional decline and that neuropsychiatric symptoms were frequent regardless of the need for ICU care are important, as they highlight the role of routine assessment of mental health symptoms after COVID-19 regardless of initial illness severity. We noted that ours was a descriptive study of the neuropsychiatric features characterizing those adults who are likely to receive care in a post-COVID-19 pulmonary clinic. It was not designed to address the underlying etiologies for the neuropsychiatric symptoms we observed. However, we agree with Ahmed (2022)1 that studies employing control groups well matched for pre-existing medical, cognitive, and mental health features are needed in order to more clearly identify the extent to which COVID-19 exerts an independent effect on neuropsychiatric outcomes, identify those at greatest risk, and to guide management. Recent data from hospitalized adults in Wuhan, China, demonstrate that older patients with severe illness, when compared with non-COVID-19 controls and those with less severe illness, are more likely to show persistent and progressive cognitive decline over the first year after the illness.4 Such individuals may represent a particularly at-risk group and may require ongoing neuropsychiatric specialty care. In contrast, clinical data from studies of patients seeking neuropsychological services at post-COVID-19 condition clinics in the United States5 suggest that such groups disproportionately had middle-aged (mean age <50 y) and female (84%) populations and report high rates of pre-existing psychiatric conditions (57%). In such samples, subjective cognitive dysfunction is more pronounced than the generally mild deficits observed in formal neuropsychological testing and tends to be associated with the severity of mood/anxiety symptoms.5 Those findings suggest that among clinically referred patient groups, there may be a primary role for psychologic and psychiatric interventions aimed at improving patient distress and functioning. Finally, Ahmed (2022)1 suggests that the Quick Dementia Rating Scale be employed as a measure of mental health symptoms and would more appropriately be interpreted as an index of cognitive ability. Here, we respectfully disagree as this instrument was employed to assess the extent of patient-reported decline in daily functioning attributable to subjective changes in cognition, mood, and ability to perform other activities of daily living. Thus, the Quick Dementia Rating Scale served as an adjunct to, rather than a direct measure of, cognition and psychiatric symptoms. Disclosures: A.M.P. declares receiving legal consulting fees; receiving speaker fees/honoraria from Vizient, Johns Hopkins, ASHA, HCL Healthcare India, and Global Tracheostomy Collaborative; and being in the Data Safety Monitoring/Advisory Board sponsored by Universidad de Chile. The other 2 authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. ==== Refs References 1 Ahmed H.S. Possibility of age and prior psychiatric illnesses affecting the study design on cognitive dysfunction, psychiatric distress, and functional decline after SARS-CoV-2 infection J Acad Consult Liaison Psychiatry 63 2022 643 644 2 Vannorsdall T.D. Brigham E. Fawzy A. Cognitive dysfunction, psychiatric distress, and functional decline after COVID-19 J Acad Consult Liaison Psychiatry 63 2022 133 143 34793996 3 Chen Y. Klein S.L. Garibaldi B.T. Aging in COVID-19: vulnerability, immunity and intervention Ageing Res Rev 65 2021 101205 33137510 4 Liu Y.H. Chen Y. Wang Q.H. One-year trajectory of cognitive changes in older survivors of COVID-19 in Wuhan, China: a longitudinal cohort study JAMA Neurol 79 2022 509 517 35258587 5 Whiteside D.M. Basso M.R. Naini S.M. Outcomes in post-acute sequelae of COVID-19 (PASC) at 6 months post-infection part 1: cognitive functioning Clin Neuropsychol 36 2022 806 828 35130818	0	PMC9747250	NO-CC CODE	2022-12-15 23:21:59	no	ästhet dermatol kosmetol. 2022 Dec 14; 14(6):6	latin-1	null	null	null	oa_other
==== Front J Acad Consult Liaison Psychiatry J Acad Consult Liaison Psychiatry Journal of the Academy of Consultation-Liaison Psychiatry 2667-2979 2667-2960 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. S2667-2960(22)00270-1 10.1016/j.jaclp.2022.05.001 Letter to the Editor: Subjects of Interest to C-L Psychiatry Reply to Letter to Editor by Ahmed HS, et al re: Possibility of Age and Prior Psychiatric Illnesses Affecting the Study Design Vannorsdall Tracy D. Ph.D. ∗ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD Parker Ann M. M.D., Ph.D. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD Outcomes After Critical Illness and Surgery (OACIS) Research Group, Johns Hopkins University School of Medicine, Baltimore, MD Oh Esther S. M.D., Ph.D. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD Johns Hopkins University School of Nursing, Baltimore, MD ∗ Send correspondence and reprint requests to Tracy D. Vannorsdall, PhD, Johns Hopkins Hospital, 600 N. Wolfe Street, Meyer 218, Baltimore, MD 21287 14 12 2022 November-December 2022 14 12 2022 63 6 645646 © 2022 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved. 2022 Academy of Consultation-Liaison Psychiatry Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: We thank Ahmed (2022)1 for highlighting features of our recent article in which we report and contrast the rates of cognitive dysfunction, emotional distress, and functional decline approximately 4 months after acute coronavirus disease 2019 (COVID-19) illness in those who did and did not require intensive care unit (ICU) admission.2 Ahmed (2022)1 pointed out that patients in our sample who received care in the ICU were older than non-ICU patients and proposed that this discrepancy may have contributed to the generally lower cognitive composite test scores observed among those requiring more intensive treatment. It was similarly noted that the ICU patient group seemed to exhibit less psychiatric distress than their non-ICU peers and that it remains unclear the extent to which either cognitive dysfunction or psychiatric symptoms were present prior to COVID-19 illness. A question was also raised as to the nature and interpretation of a self-report instrument. Older adults appear at greater risk of more severe COVID-19 illness and are more likely to have pre-existing diminution in cognitive functioning due to normal and/or pathologic aging.3 We addressed this potential confound in our data by analyzing age-adjusted cognitive test performances that account for the contribution of age to cognitive test scores. We also employed statistical adjustments for this and other nonmedical characteristics that are frequently associated with cognitive test performances (i.e., sex, racial/ethnic minority status, educational attainment, and estimated IQ). Our finding that those receiving care in the ICU continued to demonstrate poorer global cognition after such adjustments suggests that more severe COVID-19 illness and/or factors associated with ICU admission, rather than systematic biases in our clinical groups, may underly the poorer cognitive outcomes observed in ICU survivors. Our findings that cognitive functioning was not associated with the severity of mental health symptoms or functional decline and that neuropsychiatric symptoms were frequent regardless of the need for ICU care are important, as they highlight the role of routine assessment of mental health symptoms after COVID-19 regardless of initial illness severity. We noted that ours was a descriptive study of the neuropsychiatric features characterizing those adults who are likely to receive care in a post-COVID-19 pulmonary clinic. It was not designed to address the underlying etiologies for the neuropsychiatric symptoms we observed. However, we agree with Ahmed (2022)1 that studies employing control groups well matched for pre-existing medical, cognitive, and mental health features are needed in order to more clearly identify the extent to which COVID-19 exerts an independent effect on neuropsychiatric outcomes, identify those at greatest risk, and to guide management. Recent data from hospitalized adults in Wuhan, China, demonstrate that older patients with severe illness, when compared with non-COVID-19 controls and those with less severe illness, are more likely to show persistent and progressive cognitive decline over the first year after the illness.4 Such individuals may represent a particularly at-risk group and may require ongoing neuropsychiatric specialty care. In contrast, clinical data from studies of patients seeking neuropsychological services at post-COVID-19 condition clinics in the United States5 suggest that such groups disproportionately had middle-aged (mean age <50 y) and female (84%) populations and report high rates of pre-existing psychiatric conditions (57%). In such samples, subjective cognitive dysfunction is more pronounced than the generally mild deficits observed in formal neuropsychological testing and tends to be associated with the severity of mood/anxiety symptoms.5 Those findings suggest that among clinically referred patient groups, there may be a primary role for psychologic and psychiatric interventions aimed at improving patient distress and functioning. Finally, Ahmed (2022)1 suggests that the Quick Dementia Rating Scale be employed as a measure of mental health symptoms and would more appropriately be interpreted as an index of cognitive ability. Here, we respectfully disagree as this instrument was employed to assess the extent of patient-reported decline in daily functioning attributable to subjective changes in cognition, mood, and ability to perform other activities of daily living. Thus, the Quick Dementia Rating Scale served as an adjunct to, rather than a direct measure of, cognition and psychiatric symptoms. Disclosures: A.M.P. declares receiving legal consulting fees; receiving speaker fees/honoraria from Vizient, Johns Hopkins, ASHA, HCL Healthcare India, and Global Tracheostomy Collaborative; and being in the Data Safety Monitoring/Advisory Board sponsored by Universidad de Chile. The other 2 authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. ==== Refs References 1 Ahmed H.S. Possibility of age and prior psychiatric illnesses affecting the study design on cognitive dysfunction, psychiatric distress, and functional decline after SARS-CoV-2 infection J Acad Consult Liaison Psychiatry 63 2022 643 644 2 Vannorsdall T.D. Brigham E. Fawzy A. Cognitive dysfunction, psychiatric distress, and functional decline after COVID-19 J Acad Consult Liaison Psychiatry 63 2022 133 143 34793996 3 Chen Y. Klein S.L. Garibaldi B.T. Aging in COVID-19: vulnerability, immunity and intervention Ageing Res Rev 65 2021 101205 33137510 4 Liu Y.H. Chen Y. Wang Q.H. One-year trajectory of cognitive changes in older survivors of COVID-19 in Wuhan, China: a longitudinal cohort study JAMA Neurol 79 2022 509 517 35258587 5 Whiteside D.M. Basso M.R. Naini S.M. Outcomes in post-acute sequelae of COVID-19 (PASC) at 6 months post-infection part 1: cognitive functioning Clin Neuropsychol 36 2022 806 828 35130818	0	PMC9747252	NO-CC CODE	2022-12-15 23:21:59	no	ästhet dermatol kosmetol. 2022 Dec 14; 14(6):43	latin-1	null	null	null	oa_other
==== Front Can J Anaesth Can J Anaesth Canadian Journal of Anaesthesia 0832-610X 1496-8975 Springer International Publishing Cham 2360 10.1007/s12630-022-02360-8 Reports of Original Investigations Persistent diaphragm dysfunction after cardiac surgery is associated with adverse respiratory outcomes: a prospective observational ultrasound study Association entre dysfonctionnement persistant du diaphragme après une chirurgie cardiaque et issues respiratoires indésirables : une étude échographique prospective observationnellehttp://orcid.org/0000-0002-3204-4636 Laghlam Driss MD [email protected] 13 Naudin Cecile PhD 2 Srour Alexandre MD 1 Monsonego Raphael MD 1 Malvy Julien MD 1 Rahoual Ghilas MD 1 Squara Pierre MD 13 Nguyen Lee S. MD, PhD 13 Estagnasié Philippe MD 13 1 Department of Cardiology and Critical Care, Neuilly-sur-Seine, France 2 grid.477172.0 Recherche et Innovation Clinique Ambroise Paré (RICAP), Neuilly-sur-Seine, France 3 grid.477172.0 CERIC, Clinique Ambroise Paré, 27 Boulevard Victor Hugo, 92200 Neuilly-sur-Seine, France 13 12 2022 19 25 3 2022 21 7 2022 26 7 2022 © Canadian Anesthesiologists' Society 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. Background Transient diaphragm dysfunction is common during the first week after cardiac surgery; however, the precise incidence, risk factors, and outcomes of persistent diaphragm dysfunction are not well described. Methods In a single-centre prospective cohort study, we included all consecutive patients over 18 yr who underwent elective cardiac surgery. Diaphragm function was evaluated with ultrasound (M-mode) by recording the excursion of both hemidiaphragms at two different time points: preoperatively and after the seventh postoperative day in patients breathing without assistance. Significant diaphragm dysfunction after the seventh day of the index cardiac surgery was defined as a decrease in diaphragm excursion below the lower limit of normal: at rest, < 9 mm for women and < 10 mm for men; after a sniff test, < 16 mm for women and < 18 mm for men. Results Overall, 122 patients were included in the analysis. The median [interquartile range (IQR)] age was 69 [59–74] years and 96/122 (79%) were men. Ten (8%) patients had diaphragm dysfunction after the seventh postoperative day. We did not identify risk factors for persistent diaphragm dysfunction. Persistent diaphragm dysfunction was associated with a longer median [IQR] duration of noninvasive (8 [0–34] vs 0 [0–0] hr; difference in medians, 8 hr; 95% confidence interval [CI], 0 to 22; P < 0.001) and invasive mechanical ventilation (5 [3–257] vs 3[2–4] hr; difference in medians, 2 hr; 95% CI, 0.5 to 41; P = 0.008); a higher reintubation rate (4/10, 40% vs 1/112, 0.9%; relative risk, 45; 95% CI, 7.1 to 278; P < 0.0001), a higher incidence of pneumonia (4/10 [40%] vs 7/112 [6%]; relative risk, 6; 95% CI, 2 to 16; P < 0.001), and longer median [IQR] length of stay in the intensive care unit (8 [5–29] vs 4 [2–6] days; difference in medians, 4 days; 95% CI, 2 to 12; P = 0.002). Conclusion The incidence of persistent diaphragm dysfunction was 8% in patients undergoing elective cardiac surgery and was associated with adverse respiratory outcomes. Study registration ClinicalTrials.gov (NCT04276844); prospectively registered 19 February 2020. Supplementary Information The online version contains supplementary material available at 10.1007/s12630-022-02360-8. Résumé Contexte Un dysfonctionnement transitoire du diaphragme est fréquent au cours de la première semaine après une chirurgie cardiaque. Toutefois, l’incidence précise, les facteurs de risque et les devenirs liés à un dysfonctionnement persistant du diaphragme ne sont pas bien décrits. Méthode Dans une étude de cohorte prospective monocentrique, nous avons inclus tous les patients consécutifs de plus de 18 ans qui ont bénéficié d’une chirurgie cardiaque non urgente. La fonction du diaphragme a été évaluée à l’échographie (mode M) en enregistrant l’excursion des deux hémidiaphragmes à deux moments différents : avant l’opération et après le septième jour postopératoire chez les patients respirant sans assistance. Un dysfonctionnement significatif du diaphragme après le septième jour de la chirurgie cardiaque initiale a été défini comme une diminution de l’excursion diaphragmatique en dessous de la limite inférieure de la normale, soit : au repos, < 9 mm pour les femmes et < 10 mm pour les hommes; après un test de reniflement, < 16 mm pour les femmes et < 18 mm pour les hommes. Résultats Au total, 122 patients ont été inclus dans l’analyse. L’âge médian des patients (écart interquartile [ÉIQ]) était de 69 ans [59-74] ans et 96/122 (79 %) étaient des hommes. Dix (8 %) patients ont présenté un dysfonctionnement du diaphragme après le septième jour postopératoire. Nous n’avons pas identifié de facteurs de risque de dysfonctionnement persistant du diaphragme. Un dysfonctionnement persistant du diaphragme était associé à : une durée médiane [ÉIQ] de ventilation non invasive (8 [0–34] vs 0 [0–0] h; différence dans les médianes, 8 heures; intervalle de confiance [IC] à 95 %, 0 à 22; P < 0,001) et de ventilation mécanique invasive (5 [3–257] vs 3[2–4] h; différence dans les médianes, 2 heures; IC 95 %, 0,5 à 41; P = 0,008) plus longues, un taux de réintubation plus élevé (4/10, 40 % vs 1/112, 0,9 %; risque relatif, 45; IC 95 %, 7,1 à 278; P < 0,0001), une incidence plus élevée de pneumonie (4/10 [40 %] vs 7/112 [6 %]; risque relatif, 6; IC 95 %, de 2 à 16; P < 0,001), et une durée de séjour médiane [ÉIQ] plus longue à l’unité de soins intensifs (8 [5-29] vs 4 [2–6] jours; différence en médianes, 4 jours; IC 95 %, 2 à 12; P = 0,002). Conclusion L’incidence de dysfonctionnement persistant du diaphragme était de 8 % chez les patients bénéficiant d’une chirurgie cardiaque non urgente et était associée à des issues respiratoires indésirables. Enregistrement de l’étude ClinicalTrials.gov (NCT04276844); enregistrée prospectivement le 19 février 2020. Keywords acute respiratory failure cardiac surgery diaphragm dysfunction ==== Body pmcDiaphragm dysfunction (DD) after cardiac surgery is closely related to frequent respiratory complications.1,2 It has been associated with pneumonia and difficulty weaning from mechanical ventilation in critical ill patients3,4 and in cardiac surgery patients.5–7 Its incidence is unclear, ranging from 1% to 60%.8 It may be the consequence of mechanical ventilation leading to both diaphragmatic atrophy and injury leading to contractile dysfunction.9,10 It may also occur during cardiac surgery, for example, because of phrenic nerve injury caused by ice-cardioplegia solution or the surgical technique. There may also be an ischemic mechanism with ligation of the diaphragmatic blood supply during internal mammary dissection.11 Early postoperative DD has been found to be frequent, but data are controversial regarding its consequence on short-term and mid-term outcomes.5,12–16 Ultrasonography is now recognized as an easy and accurate method to noninvasively evaluate diaphragmatic function at the bedside in the intensive care unit (ICU) for assessment and monitoring of DD.17 Nevertheless, the definition of DD assessed by ultrasound is not standardized and the methods of diagnosis are variable. The latter include diaphragmatic excursion after the sniff test or after deep inspiration in M-mode, measuring the thickness of the diaphragm and the thickening fraction, and, recently, tissue Doppler.18 Our main objective was to investigate the incidence of DD one week after cardiac surgery, assessed by diaphragm excursion measured by ultrasound at the bedside. We hypothesized that DD was frequently persistent after cardiac surgery and could worsen respiratory outcomes. Methods This observational, single-centre prospective study was approved by the responsible ethics committee (8 February 2020; Comité de Protection des Personnes Nord-Ouest III, CNRIPH: 20.01.08.52326) and registered at ClinicalTrials.gov (NCT04276844). Informed consent was obtained from all participants. Patients All consecutive patients admitted to the cardiothoracic surgery department of the Clinique Ambroise Paré (Neuilly-Sur-Seine, France) prior to elective cardiac surgery were screened for enrollment; all adult patients who underwent elective cardiac surgery were eligible for inclusion. Exclusion criteria included contraindication to preoperative functional respiratory assessment, pregnancy, active COVID-19 pneumonia, and inability to give consent. All variables, demographic data, comorbidities, surgical data, and postoperative data were prospectively recorded. Surgical and perioperative management Perioperative management was standardized. All patients were fitted with a right internal jugular central venous catheter. All procedures involved a full sternotomy approach. Mammary arteries and saphenous veins were used as coronary bypass grafts. Myocardial protection was provided using normothermic continuous blood cardioplegia solution. During surgery (except the cross-clamping period), mechanical ventilation was set at a tidal volume of 6 mL·kg-1 of predicted body weight and a positive end-expiratory pressure (PEEP) level of 5 cm H2O, the respiratory rate was adjusted to maintain normocapnia, and the inspired fraction of oxygen (FIO2) was set to keep the arterial partial pressure of oxygen (PaO2) below 100 mm Hg. In the ICU, the ventilation protocol was lung-protective with a tidal volume of 6 mL·kg-1 of the ideal body weight, a PEEP of 5 cm H2O, an FIO2 set to obtain a PaO2 above 100 mm Hg, and an inspiration/expiration time ratio of 1:2. Physicians were free to adjust the ventilatory parameters according to patient needs, including adjustment of PEEP level in case of postoperative hypoxia due to atelectasis. Other therapies were left to the discretion of the ICU intensivists. After surgery, patients were transferred to the ICU where absence of bleeding, respiratory and hemodynamic stability, and normothermia were determined before stopping sedatives drugs and performing a spontaneous breathing trial. Ultrasound measurements The excursion of both hemidiaphragms was measured sequentially in each patient at two different time points: preoperatively (the day before surgery) and from the seventh postoperative day in patients breathing without assistance (extubated or on pressure support mode with zero PEEP); if patients were not breathing without assistance, the ultrasound evaluation was deferred. In case of respiratory failure with clinical suspicion of DD, a supplementary echography evaluation was performed before the seventh postoperative day. Ultrasound examinations of diaphragm excursion were performed at the bedside with the patient in a 45° semirecumbent position during quiet and unassisted breathing, using an ultrasound platform (Philips CX50®, Amsterdam, The Netherlands) connected to a 1–5-MHz phased-array transducer. Diaphragm excursion was evaluated at rest and after a sniff test, using anatomical motion (M)-mode through a lateral approach from the midaxillary line.14,19 As an exploratory measurement, we also examined the value of each hemidiaphragm peak after the sniff test using tissue doppler imaging velocity. The excursion value of each hemidiaphragm was the average measurement of three consecutive respiratory cycles (separately at rest and after the sniff test) (see example on Fig. 1). Diaphragm dysfunction after the seventh day after cardiac surgery was defined, in M-mode, by a decrease in amplitude of the movement of the diaphragm below the lower limit of normal for at least one of the following measurements: 1) at rest, < 9 mm for women and < 10 mm for men; and 2) after the sniff test, < 16 mm for women and < 18 mm for men.20Fig. 1 Right hemidiaphragm ultrasound. Visualization of the right hemidiaphragm in B-mode from the subcostal view (Panel B). Then, application of an M Mode to record diaphragm motion. Panel A shows normal inspiratory diaphragm excursion at rest while panel B shows normal inspiratory diaphragm excursion after the sniff test. Outcomes The main outcome was the incidence of persistent postoperative DD after seven days following the index surgery. Secondary outcomes included respiratory complications (pneumonia, atelectasis requiring bronchial clearing by fibroscopy, reintubation rate, prolonged mechanical ventilation [> 24 hr], or prolonged noninvasive ventilation [> 48 hr]), length of ICU stay, and pulmonary function tests in patients diagnosed with persistent postoperative DD. Statistical analysis Continuous variables are expressed as mean (standard deviation [SD]) when normally distributed or median [interquartile range (IQR)] elsewhere. Categorical variables are expressed as n (%) and were compared using Fisher’s exact test. Shapiro–Wilk tests were used to test the normality of the distribution of the studied variables. Differences between the two groups were compared using Student’s t test for normally distributed data and the Mann–Whitney U test for nonnormally distributed numerical data. Comparisons of median diaphragmatic excursion between the day before surgery and after seven days following surgery were performed using a paired Wilcoxon test, to test for within-group differences. Since this nonparametric test works with ranks, it is usually not possible to obtain a confidence interval (CI) with exactly 95% confidence of the difference in medians. The statistical software computes an approximate confidence level, which is reported in Tables 2 and 3 as 95% CI of difference in medians. The significance threshold adopted was P < 0.05. The sample size was estimated by hypothesizing a 30% incidence of persistent DD after seven days according to a previously published study.13 We powered this study to detect the same incidence in elective patients. We needed 100 participants to obtain an effect size of 30%, an incidence with 80% power, and a two-tailed alpha of 0.05. Statistical analysis was performed using MedCalc® version 14 (MedCalc Software Ltd, Ostend, Belgium). Results During the study period, we included 157 patients, 122 of whom were included in the final analysis (33 patients were excluded because of incomplete pre- or postoperative echographic measurements including poor echogenicity; one patient withdrew his consent; and one patient was not operated) (Electronic Supplementary Material [ESM] eFigure). In the whole cohort, the median [IQR] age was 69 [59–74] years, 96/122 (79%) were men, the median [IQR] body mass index was 25.6 [23.0–28.8] kg·m-2, and 16/122 (13%) patients had chronic obstructive pulmonary disease. No patient had COVID-19 pneumonia. Baseline characteristics and surgical data are displayed in Table 1. Overall, 10/122 (8%) patients had DD after the seventh day following surgery: six with left hemidiaphragm dysfunction, three with right hemidiaphragm dysfunction, and one with bilateral dysfunction.Table 1 Baseline characteristics and surgical data No DD N = 112 Persistent DD N = 10 P value Baseline characteristic Age, median [IQR] 69 [59–75] 65 [56–74] 0.50a Male sex, n/total N (%) 88/112 (79%) 8/10 (80%) 1.00b BMI (kg·m-2), median [IQR] 25.6 [23.0–28.7] 27.1 [23.4–35.6] 0.26a Diabetes, n/total N (%) 33/112 (30%) 5/10 (50%) 0.32b Dyslipidemia, n/total N (%) 65/112 (58%) 4/10 (40%) 0.44b Arterial hypertension, n/total N (%) 67/112 (60%) 6/10 (60%) 0.74b Smoker status, n/total N (%) 46/112 (41%) 4/10 (40%) 0.79b COPD, n/total N (%) 16/112 (14%) 0/10 (0%) 0.36b Surgery Isolated CABG, n/total N (%) 60/112 (54%) 6/10 (60%) 0.95b Isolated valve surgery, n/total N (%) 31/112 (28%) 1/10 (10%) 0.45b AVR, n/total N (%) 16/112 (14%) 1/10 (10%) 1.00b MVR or MVP, n/total N (%) 15/112 (13%) 0/10 (0%) 0.61b Tricuspid valve surgery, n/total N (%) 0/112 (0%) 0/10 (0%) - Ascendant aortic surgery, n/total N (%) 2/112 (2%) 0/10 (0%) 1.00b AVR plus ascendant aortic surgery, n/total N (%) 3/112 (3%) 1/10 (10%) 0.29b Combined CABG + valve surgery, n/total N (%) 7/112 (6%) 1/10 (10%) 0.51b Combined valve surgery, n/total N (%) 9/112 (8%) 1/10 (10%) 0.59b Number of grafts, median [IQR] 3 [2, 3] 3 [2–4] 0.39a Left mammary artery, n/total N (%) 66/112 (59%) 7/10 (70%) 0.73b Right mammary artery, n/total N (%) 59/112 (53%) 5/10 (50%) 0.87b Saphenous vein, n/total N (%) 1/112 (1%) 0/10 (0%) 1.00b CPB time (min), median [IQR] 73 [56–87] 71 [59–118] 0.61a ACC time (min), median [IQR] 59 [46–68] 60 [52–95] 0.32a Pleural drains after surgery, n/total N (%) 63/112 (56%) 7/10 (70%) 0.61b aMann–Whitney test bFisher’s exact test ACC = aortic cross clamping; AVR = aortic valve replacement; BMI = body mass index; CABG = coronary artery bypass grafting; CPB = cardiopulmonary bypass; DD = diaphragm dysfunction; IQR = interquartile range; MVP = mitral valvuloplasty; MVR = mitral valve replacement Risk factors for developing diaphragm dysfunction after surgery We compared patients who developed DD with those who did not. There was no difference in preoperative characteristics in patients who developed DD compared with those who did not. Procedural variables were not different either (median [IQR] cardiopulmonary bypass time, 73 [58–88] min and median [IQR] aortic cross-clamping time, 59 [46–70] min) in both groups). The type of procedure did not affect the incidence of postoperative DD either. There was no difference in the occurrence of DD between the different surgeons (surgeon 1: 5/82 [6%]; surgeon 2: 2/17 [12%]; surgeon 3: 3/23 [13%]; P = 0.48). Evolution of hemidiaphragm excursion over time In patients without DD, according to the chosen definition, there was a significant decrease in both left and right hemidiaphragm excursion at rest and after the sniff test on the seventh postoperative day compared with the day before surgery (Table 2, Fig. 2).Table 2 Evolution of diaphragm excursion before and one week after surgery No DD N = 112 Persistent DD N = 10 D-1 D+7 Difference in medians (95% CI) P value D-1 D+7 Difference in medians (95% CI) P value Left hemidiaphragm Diaphragm excursion at rest (mm), median [IQR] 25 [18–29] 21 [16–27] -2 (-3 to -0.2) 0.03a 28 [15–33] 12 [8–17] -16 (-21 to 8) 0.04a Diaphragm excursion after sniff test (mm), median [IQR] 42 [34–52] 34 [28–43] -8 (-10 to -4) < 0.001a 37 [33–49] 16 [12–23] -25 (-35 to 9) 0.02a TDI after sniff test (cm·s-1), median [IQR] 12 [9–15] 10 [8–13] -2 (-2 to -1) 0.001a 11 [7–13] 9 [6–13] 1 (-5.7 to 5) 1.00a Right hemidiaphragm Diaphragm excursion at rest (mm), median [IQR] 24 [18–30] 20 [17–24] -3 (-5 to -1) < 0.001a 20 [17–25] 16 [10–23] -6.5 (-14 to 7) 0.28a Diaphragm excursion after sniff test (mm), median [IQR] 42 [32–49] 33 [26–41] -6 (-10 to -4) < 0.001a 41 [24–49] 24 [12–42] -7.5 (-36 to 18) 0.16a TDI after sniff test (cm·s-1), median [IQR] 11 [9–14] 10 [7–14] -1 (-2 to -0.9) 0.03a 10 [8–14] 16 [6–20] 2.5 (-7 to 21) 0.40a Each hemidiaphragmatic excursion was evaluated in unassisted patients in M-mode at rest, i.e., during calm spontaneous breathing, and after the sniff test. Each hemidiaphragmatic function was evaluated in unassisted patients in TDI mode after the sniff test. aPaired Wilcoxon test CI = confidence interval; D-1 = day before surgery; D+7 = after the seventh postoperative day in patients during unassisted breathing; DD = diaphragmatic dysfunction; IQR = interquartile range; TDI = tissue doppler imaging Fig. 2 Evolution of diaphragmatic excursion of each hemidiaphragm before and one week after surgery in patients without persistent diaphragm dysfunction. Each hemidiaphragm excursion was evaluated in patients during unassisted breathing at rest, i.e., during calm spontaneous breathing, and after sniff test. P values are from paired Wilcoxon tests for comparisons of excursion evolution within left and right hemidiaphragm groups, between D-1 and D+7. D-1 = day before surgery; D+7 = after the seventh postoperative day in patients during unassisted breathing In patients with persistent DD, the excursion of the impaired hemidiaphragm was severely decreased (Table 2, Fig. 3).Fig. 3 Evolution of diaphragmatic excursion of each hemidiaphragm before and one week after surgery in patients with persistent diaphragm dysfunction. Each hemidiaphragm excursion was evaluated in patients during unassisted breathing in M-mode at rest, i.e., during calm spontaneous breathing, and after sniff test. Each symbol represents the same patient for the evaluation of the two hemidiaphragms. P values are from paired Wilcoxon tests for comparisons of excursion evolution within left and right hemidiaphragm groups, between D-1 and D+7. D-1 = day before surgery; D+7 = after the seventh postoperative day in patients with unassisted breathing Secondary clinical outcomes Secondary outcomes are displayed in Table 3. Patients with persistent DD after the seventh postoperative day experienced a significant impairment of postoperative respiratory outcomes. Persistent DD was associated with a longer median duration of noninvasive and mechanical invasive ventilation, a higher reintubation rate, more frequent episodes of pneumonia, and a longer median length of stay in the ICU. Mortality did not significantly differ between both groups.Table 3 Secondary outcomes Outcome No DD N = 112 Persistent DD N = 10 P value Relative risk (95% CI) NIV or HFO > 48 hr (days), n/total N (%) 3/112 (3%) 4/10 (40%) 15 (4 to 52) < 0.001a Mechanical ventilation > 24 hr, n/total N (%) 1/112 (1%) 4/10 (40%) 45 (7 to 278) < 0.001a Pneumonia, n/total N (%) 7/112 (6%) 4/10 (40%) 6 (2 to 16) 0.006a Reintubation, n/total N (%) 1/112 (1%) 4/10 (40%) 45 (7 to 278) < 0.001a Atelectasis requiring bronchoscopy, n/total N (%) 2/112 (2%) 3/10 (30%) 17 (4 to 75) 0.004a Mortality, n/total N (%) 0/112 (0%) 1/10 (10%) - 0.08a Difference in medians (95% CI) Duration of NIV or HFO (hr), median [IQR] 0 [0–0] 8 [0–34] 8 (0 to 22) < 0.00b Duration of mechanical ventilation (hr), median [IQR] 3 [2–4] 5 [3–257] 2 (1 to 41) 0.008b Postoperative Us-troponin peak, median [IQR] 2.4 [1.2–4.3] 2.4 [1.3–5.0] 0.1 (-1.3 to 1.9) 0.82b Postoperative creatine kinase, median [IQR] peak 495 [340–809] 666 [357–1,114] 171 (-151 to 477) 0.38b Length of stay in ICU (days), median [IQR] 4 [2–6] 8 [5–29] 4 (2 to 12) 0.002b Length of stay in hospital (days), median [IQR] 10 [8–12] 11 [8–29] 0.5 (-1 to 12) 0.24b aFisher’s exact test bMann–Whitney test CI = confidence interval; DD = diaphragm dysfunction; HFO = high-flow oxygen; ICU = intensive care unit; IQR = interquartile range; NIV = noninvasive ventilation In patients with persistent DD, a pulmonary function test was performed before and after surgery in 4/10 patients; the median [IQR] forced vital capacity post/pre ratio was 0.81 [0.67–0.90], the median [IQR] forced expiratory volume in the first second post/pre ratio was 0.77 [0.61–0.84], and the median [IQR] total lung capacity post/pre ratio was 0.85 [0.82–1.10] (n = 3) (see ESM eTable). Discussion In this prospective observational cohort study in cardiac surgery patients, we observed an incidence of 8% of persistent DD after the postoperative seventh day, which was associated with worsened respiratory outcomes compared to patients without DD. Overall, patients presented an average 15% decrease in diaphragm excursion at rest and 19% decrease after sniff test on day 7. Overall, DD was associated with a 33% incidence of respiratory complications. We identified no preoperative and procedural risk factors for persistent DD. Most patients undergoing cardiac surgery show an early and transient DD.5,15,16 Indeed, transient diaphragm impairment can be caused by many factors, including sternotomy pain, mechanical factors affecting the chest and mediastinum, electrolyte disorders (such as hypophosphatemia), and pleural or pericardial effusion. Our findings revealed two important issues associated with DD in cardiac surgery patients. First, we found that a significant proportion of these patients developed severe postoperative DD, which was persistent after the seventh postoperative day. Most studies have evaluated DD in the early perioperative days.5,15,16 Only one study by Pasero et al. assessed, in a prospective and observational study of 24 patients, the diaphragmatic thickness fraction at 24 hr before elective surgery and within one week after surgery. The authors reported 21% and 25% right and left DD, respectively.13 This difference in incidence compared to our study could be explained by the use of ice-cold cardioplegia solution in Pasero’ study and the different methods of ultrasound assessment (diaphragmatic thickness vs excursion). Second, whether persistent DD worsens respiratory outcomes is still under debate. Here, we report poorer respiratory outcomes in these patients as DD was associated with a longer duration of noninvasive and mechanical invasive ventilation, a higher reintubation rate, higher episodes of pneumonia, and longer length of stay in the ICU. We did not observe differences in terms of preoperative characteristics in patients with and without persistent DD, especially the incidence of diabetes. Moreover, there was no significant difference in the incidence of DD between patients undergoing coronary bypass grafting procedures compared with those undergoing other procedures. Nevertheless, we found that, even in patients without severe persistent DD, there was a significant decrease of both hemidiaphragm excursion after the seventh postoperative day, which suggests a bilateral involvement of the muscle, excluding an exclusive surgical phrenic nerve injury. In this work, we chose to evaluate diaphragmatic excursion after the sniff test, as described by Boussuges et al.20 to define DD because this approach matched the expertise of the investigators and is known to be a reproducible method. Excursion and the thickening fraction are frequently used and accurately examined diaphragm function in critically ill individuals during a spontaneous breath trial.17 Ultrasonographic diaphragmatic excursion and the thickening fraction are correlated in cardiac surgery patients during unassisted breathing.16 Nevertheless, excursion seems to be a more feasible and reproducible method in this population (interobserver reliability yielded a bias below 0.1 cm with limits of agreement [LOA] of ± 0.3 cm for excursion and −2% with LOA of ± 21% for thickening fraction).16 Finally, while ultrasound accurately evaluates diaphragm function, the electrical activity of the diaphragm is still considered the gold standard diagnosis method.11,21 We acknowledge several limitations to this study. First, the single-centre nature of this study may impact the generalizability of the results. Nevertheless, the existence of persistent DD and its consequences are consistent with the literature. Moreover, we previously showed consistency with external cohorts of patients who are treated in our centre.12,22 Second, we observed a lower incidence of DD at day 7 than was reported by Pasero et al., who described a 30% incidence but used diaphragm thickness criteria.13 While our study may have been underpowered to determine risk factors of persistent DD, we observed significant differences between both groups, in terms of postoperative complications. The exclusion of patients with incomplete data from the final analysis due to poor echogenicity may also have led to an underestimation of DD incidence. Third, a significant number of patients were excluded from the study because of the COVID-19 pandemic, which reduced operator or machine availability. Furthermore, we did not report the incidence of pleural effusion on day 7, which could be linked to DD. Finally, we chose to define DD as a decrease of excursion under the lower limit of at least one measurement of spontaneous breathing or the sniff test, but not both. Although there is no consensus definition of DD, this may reduce the generalization of our results. Conclusion In this observational ultrasound study, persistent DD after the seventh postoperative day, evaluated utrasonographically by diaphragmatic excursion, occurred in 8% of patients undergoing elective cardiac surgery. This was associated with prolonged mechanical ventilation and length of stay in the ICU. Further larger studies are needed to fully explore the risk factors and consequences of DD after cardiac surgery. Supplementary Information Below is the link to the electronic supplementary material.Supplementary file1 (PDF 182 kb) Author contributions Driss Laghlam, Cecile Naudin, and Philippe Estagnasié have substantially contributed to the conception and the design of the study and were major contributors in writing the original manuscript. Lee S. Nguyen and Pierre Squara have also substantially contributed to the conception and the design of the study and were contributors in revision of the manuscript. Driss Laghlam, Alexandre Srour, Raphael Monsonego, Ghilas Rahoual, and Julien Malvy have substantially contributed to the acquisition and analysis of the data. Acknowledgements Thank you to all the team of the Department of Clinical Research, particularly to Elefteria Sideris, Fatma Bouaziz, Djamiath, Thiamiyou, Steve Novak, and Messaouda Merzoug. Disclosures The authors declare that they have no competing interests. Funding statement Support was provided solely from institutional and/or departmental sources from the department of Clinical Research, CMC Ambroise Paré, Neuilly-sur-Seine, France. Data availability statement The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Editorial responsibility This submission was handled by Dr. Philip M. Jones, Deputy Editor-in-Chief, Canadian Journal of Anesthesia/Journal canadien d’anesthésie. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ==== Refs References 1. Diehl JL Lofaso F Deleuze P Similowski T Lemaire F Brochard L Clinically relevant diaphragmatic dysfunction after cardiac operations J Thorac Cardiovasc Surg 1994 107 487 498 10.1016/S0022-5223(94)70094-X 8302068 2. Ge X Wang W Hou L Yang K Fa X Inspiratory muscle training is associated with decreased postoperative pulmonary complications: evidence from randomized trials J Thorac Cardiovasc Surg 2018 156 1290 1300 10.1016/j.jtcvs.2018.02.105 29705543 3. Dres M Goligher EC Dubé BP Diaphragm function and weaning from mechanical ventilation: an ultrasound and phrenic nerve stimulation clinical study Ann Intensive Care 2018 8 53 10.1186/s13613-018-0401-y 29687276 4. Kim WY Suh HJ Hong SB Koh Y Lim CM Diaphragm dysfunction assessed by ultrasonography: influence on weaning from mechanical ventilation Crit Care Med 2011 39 2627 2630 10.1097/ccm.0b013e3182266408 21705883 5. Bruni A Garofalo E Pasin L Diaphragmatic dysfunction after elective cardiac surgery: a prospective observational study J Cardiothorac Vasc Anesth 2020 34 3336 3344 10.1053/j.jvca.2020.06.038 32653270 6. Engoren M Buderer NF Zacharias A Long-term survival and health status after prolonged mechanical ventilation after cardiac surgery Crit Care Med 2000 28 2742 2749 10.1097/00003246-200008000-00010 10966245 7. Nguyen LS Estagnasie P Merzoug M Low tidal volume mechanical ventilation against no ventilation during cardiopulmonary bypass in heart surgery (MECANO): a randomized controlled trial Chest 2021 159 1843 1853 10.1016/j.chest.2020.10.082 33217416 8. Jellish WS Oftadeh M Peripheral nerve injury in cardiac surgery J Cardiothorac Vasc Anesth 2018 32 495 511 10.1053/j.jvca.2017.08.030 29248326 9. Jaber S Petrof BJ Jung B Rapidly progressive diaphragmatic weakness and injury during mechanical ventilation in humans Am J Respir Crit Care Med 2011 183 364 371 10.1164/rccm.201004-0670oc 20813887 10. Hooijman PE Beishuizen A Witt CC Diaphragm muscle fiber weakness and ubiquitin-proteasome activation in critically ill patients Am J Respir Crit Care Med 2015 191 1126 1138 10.1164/rccm.201412-2214oc 25760684 11. Aguirre VJ Sinha P Zimmet A Lee GA Kwa L Rosenfeldt F Phrenic nerve injury during cardiac surgery: mechanisms, management and prevention Heart Lung Circ 2013 22 895 902 10.1016/j.hlc.2013.06.010 23948287 12. Laghlam D Lê MP Srour A Diaphragm dysfunction after cardiac surgery: reappraisal J Cardiothorac Vasc Anesth 2021 35 3241 3247 10.1053/j.jvca.2021.02.023 33736912 13. Pasero D Costamagna A Marchisio A Diaphragmatic dysfunction following cardiac surgery: observational study Eur J Anaesthesiol 2019 36 612 613 10.1097/eja.0000000000000969 31274546 14. Lerolle N Guérot E Dimassi S Ultrasonographic diagnostic criterion for severe diaphragmatic dysfunction after cardiac surgery Chest 2009 135 401 407 10.1378/chest.08-1531 18753469 15. Moury PH Cuisinier A Durand M Diaphragm thickening in cardiac surgery: a perioperative prospective ultrasound study Ann Intensive Care 2019 9 50 10.1186/s13613-019-0521-z 31016412 16. Tralhão A Cavaleiro P Arrigo M Early changes in diaphragmatic function evaluated using ultrasound in cardiac surgery patients: a cohort study J Clin Monit Comput 2020 34 559 566 10.1007/s10877-019-00350-8 31278543 17. Zambon M Greco M Bocchino S Cabrini L Beccaria PF Zangrillo A Assessment of diaphragmatic dysfunction in the critically ill patient with ultrasound: a systematic review Intensive Care Med 2017 43 29 38 10.1007/s00134-016-4524-z 27620292 18. Soilemezi E Savvidou S Sotiriou P Smyrniotis D Tsagourias M Matamis D Tissue doppler imaging of the diaphragm in healthy subjects and critically ill patients Am J Respir Crit Care Med 2020 202 1005 1012 10.1164/rccm.201912-2341oc 32614246 19. Pasero D Koeltz A Placido R Improving ultrasonic measurement of diaphragmatic excursion after cardiac surgery using the anatomical M-mode: a randomized crossover study Intensive Care Med 2015 41 650 656 10.1007/s00134-014-3625-9 25573500 20. Boussuges A Gole Y Blanc P Diaphragmatic motion studied by m-mode ultrasonography: methods, reproducibility, and normal values Chest 2009 135 391 400 10.1378/chest.08-1541 19017880 21. Merino-Ramirez MA Juan G Ramón M Electrophysiologic evaluation of phrenic nerve and diaphragm function after coronary bypass surgery: prospective study of diabetes and other risk factors J Thorac Cardiovasc Surg 2006 132 530 536 10.1016/j.jtcvs.2006.05.011 16935106 22. Nguyen LS Baudinaud P Brusset A Heart failure with preserved ejection fraction as an independent risk factor of mortality after cardiothoracic surgery J Thorac Cardiovasc Surg 2018 156 188 193 10.1016/j.jtcvs.2018.02.011 29530566	36513852	PMC9747253	NO-CC CODE	2022-12-15 23:21:59	no	Can J Anaesth. 2022 Dec 13;:1-9	utf-8	Can J Anaesth	2,022	10.1007/s12630-022-02360-8	oa_other
==== Front ästhet dermatol kosmetol A¨sthetische Dermatologie & Kosmetologie 1867-481X 2198-6517 Springer Medizin Heidelberg 2244 10.1007/s12634-022-2244-7 Fortbildung Komplikationen bei Behandlung mit injizierbaren Fillern Rzany Berthold Medizin am Hauptbahnhof, Karl-Popper-Straße 8/203, 1100 Wien, Österreich 14 12 2022 2022 14 6 2225 © Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2022 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. issue-copyright-statement© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2022 ==== Body pmcDie Injektion von Füllmaterialien ist ein äußerst beliebtes Verfahren zur Hautverjüngung in der ästhetischen Medizin. Dass dies jedoch gewisse Risiken birgt, sollte Dermatologinnen und Dermatologen bewusst sein. Neben Überkorrekturen sind vaskuläre und immunologische Reaktionen typische Komplikationen, die bei der Behandlung mit Fillern auftreten können. Injizierbare Füllmaterialien, vor allem hyaluronsäurehaltige Filler (HA-Filler), sind aus der ästhetischen Medizin nicht mehr wegzudenken [1]. Sie sind einfacher und vielseitiger anwendbar als zum Beispiel Eigenfett. Wer mit Fillern behandelt, sollte sich der möglichen Komplikationen einer solchen Behandlung bewusst sein und - wenn sie auftreten - diese erkennen und behandeln können. Neben Überkorrekturen, die nicht Thema dieses Artikels sind, können immunologische und vaskuläre Reaktionen auftreten [2]. Dadurch, dass diese Reaktionen selten sind, beruhen die Empfehlungen zur Prävention und Behandlung im günstigsten Fall auf Fallberichten und Fallserien, häufig jedoch nur auf Expertenwissen. Dies sollte man vor Augen haben, wenn man sich mit diesem Thema auseinandersetzt. Arterielle Okklusion Die arterielle Okklusion ist eine seltene unerwünschte Wirkung auf injizierbare Füllmaterialien und die Verpflanzung von Eigenfett (Lipofilling). Sie tritt gleichermaßen nach der Behandlung mit Kanülen und mit Nadeln auf. Bei einer ausgedehnten Okklusion kann es - wenn diese bei einem HA-Präparat nicht rechtzeitig erkannt wird beziehungsweise bei Verwendung eines Nicht-HA-Präparats - zu einer Nekrose der Haut oder der darunterliegenden Strukturen mit anschließender Narbenbildung kommen. Ist die Arteria (A.) centralis retinae beteiligt, können Patientinnen und Patienten in sehr seltenen Fällen auch erblinden. Diese schweren unerwünschten Reaktionen treten vor allem bei der Behandlung der Glabella, der Nase und der Nasolabialfalte auf - also in Regionen, wo ein arterieller Verschluss nicht durch kommunizierende arterielle Gefäße kompensiert werden kann (▶Abb. 1). Wenn die Okklusion auf einen HA-Filler zurückzuführen ist, ist die Injektion von Hyaluronidase im Bereich des behandelten Areals und des Ausbreitungsgebiets der betroffenen Arterien die Therapie der ersten Wahl. Die Hyaluronidase sollte dabei großzügig und wiederholt (innerhalb von Stunden/Tagen) eingesetzt werden, bis die Symptome (z.B. Schmerzen) rückläufig sind. Wird sie sehr schnell angewendet (innerhalb weniger Stunden), sind die unerwünschten Wirkungen vielfach reversibel [2]. Folglich kommt es gar nicht erst zu einer Nekrose mit gegebenenfalls subsequenter Narbenbildung (▶Tab. 1). Jedoch sollte auch bei Patientinnen und Patienten mit einer Okklusion, die zum Beispiel erst vier Tage nach Injektion eines HA-Fillers auftritt, noch eine Behandlung mit Hyaluronidase durchgeführt werden, um die Perfusionsbedingungen zu verbessern.Zeitpunkt Symptome Therapie Sofort Starke Schmerzen1 Hyaluronidase2 "Blanching" eines arteriellen Gefäßes Innerhalb von Stunden Netzartige livide Verfärbung Hyaluronidase2 Bildung steriler Pusteln3 Innerhalb von Tagen Nekrosenbildung und Ulzeration Stadiengerechte Wundbehandlung 1 Wurde eine lokale Betäubung oder ein mit Lokalanästhetikum versetzter Filler verwendet, kann dieses Zeichen manchmal akut fehlen, es setzt erst später nach Rückgang der anästhesierenden Wirkung ein. 2 Hylase® Dessau off-label, 1:150 auf 1 ml verdünnt im Bereich der Injektionstellen und des vermutlichen Ausbreitungsgebietes des Fillerthrombus, bis zu 10 ml, Wiederholung bis sich die Schmerzen beziehungsweise Zeichen der vaskulären Okklusion zurückbilden 3 keine antibiotische oder antivirale Therapie indiziert Prävention arterieller Okklusionen Da diese unerwünschte Wirkung selten ist - die Inzidenz wird auf 1:6.410 pro 1 ml Filler geschätzt -, fällt es nicht leicht, Empfehlungen zu formulieren, wie arterielle Okklusionen vermieden werden können [3]. Wichtig ist, ausreichende Kenntnisse über die anatomischen Verhältnisse zu besitzen, um gerade in Risikoarealen vorsichtig zu behandeln. Es erscheint logisch, das injizierbare Füllmaterial langsam zu applizieren und große Volumina zu vermeiden, insbesondere im Bereich der Glabella. Es gibt keinen Hinweis dafür, dass die Aspiration des Fillers Okklusionen vermeiden kann. Rolle der Sonografie Dem aktuellen Hype um mobile Ultraschallgeräte sollte man mit Vorsicht begegnen. Arterielle Okklusionen sind selten und die kleineren Handultraschallgeräte nach wie vor unhandlich. Sie können aber dazu verwendet werden, eine arterielle Okklusion zu diagnostizieren und den Therapieverlauf zu überwachen [4]. Vaskuläre Okklusion nach Behandlung mit Nicht-HA-Filler Keine der in diesem Bereich existierenden Empfehlungen überschreitet das Niveau einer Expertenmeinung [5]. Letztendlich macht es wohl trotz aller postulierten Interventionen wahrscheinlich wenig Unterschied, ob abgewartet wird oder Patientinnen und Patienten mit zum Beispiel Taldalafil 20 mg oder Acetylsalicylsäure 500 mg behandelt werden. Daher sollten sich Ärztinnen und Ärzte bei der Auswahl eines Fillers primär fragen, ob ein propagierter Nicht-HA-Filler wirklich einem HA-Filler überlegen ist. Immmunologische Reaktionen Immunologische Reaktionen können auf alle injizierbaren Füllmaterialien auftreten. Unterschieden werden akute, subakute und verzögerte Reaktionen, wobei es zu Schwellungen, Abszessen und Knotenbildung kommen kann (▶Abb. 2). Die Therapie der immunologischen Reaktionen hängt von der Art des injizierten Fillers, der Reaktion und des Triggers ab. Wichtig ist es, im Vorfeld den verantwortlichen Filler und mögliche Auslöser wie eine Impfung zu identifizieren. Bei unklarer Anamnese und Verdacht auf das Vorhandensein eines permanenten Fillers ist eine Biopsie zu empfehlen. Wichtig ist, dass diese durch erfahrene (Dermato-)Pathologinnen und -pathologen beurteilt wird. Dann gelingt es, das verantwortliche Fillermaterial zu bestimmen [6]. Abszesse Bei Abszessen steht die Inzision im Vordergrund, wobei immer eine bakteriomykologische Untersuchung durchgeführt werden sollte. Jedoch lassen sich in den meisten Fällen bei solchen Unverträglichkeitsreaktionen keine pathologischen Keime nachweisen. Knotenbildung: Fillerdepot und Fremdkörperreaktion Zu einer Knotenbildung kann es bei allen Füllmaterialien kommen. Sie kann auf ein Fillerdepot und/oder eine Fremdkörperreaktion auf den Filler hinweisen. Letztere ist ein immunologischer Prozess, dem eine immunmodulierende Therapie folgen muss. Bei HA-Fillern steht hier in erster Linie der Einsatz von Hyaluronidase im Vordergrund, um die Depots aufzulösen. Im nächsten Schritt folgt eine systemische Behandlung mit oralen Steroiden (als Stoßtherapie) und/oder Doxycyclin. Doxycyclin wird dabei mit 40-50 mg pro Tag meist ähnlich wie in der Therapie der Akne oder Rosazea dosiert. Steroide (Trimacinolon) oder 5-Fluorouracil können auch injiziert werden. Jedoch besteht die Möglichkeit, dass hier lokale Lipoatrophien auftreten. Mittel der ersten Wahl bei Fremdkörperreaktionen auf permanente Filler, wie Polymethylmethacrylat oder Silikon, beziehungsweise verzögert abbaubare Filler ist Methotrexat [7, 8]. Zumeist reicht eine orale Gabe von 10-15 mg pro Woche aus, gefolgt von 5 mg Folsäure am nächsten Tag. Die Dosierung orientiert sich an der S3-Leitlinie zur Therapie der Psoriasis vulgaris [9]. Vor der Therapie sollten eine aktive Tuberkulose und weitere Kontraindikationen ausgeschlossen werden. Knotenbildungen auf Filler dauerhaft mit Antibiotika wie Clindamycin zu behandeln, ist nicht indiziert. Das ursprüngliche Argument für die Gabe von Antibiotika war die mittlerweile nicht mehr präsente Biofilmhypothese. Es gibt allerdings keinerlei Evidenz, dass sich dadurch die Knotenbildung beeinflussen lässt. Wohlgemerkt haben die zahlreichen Nebenwirkungen von Fillern auf die COVID-19-Vakzine eindrucksvoll gezeigt, dass Fillerreaktionen überwiegend immunologischer Natur sind und keine Infektionen, die antibiotisch behandelt werden müssen [10]. Wahl der Produktfamilie nach eine Fillerreaktion Bei einer Reaktion auf einen HA-Filler einer Produktfamilie, zum Beispiel der Vycross-Familie, sollte man nach Auflösen des Fillers und der Therapie der immunologischen Reaktion nicht erneut mit einem Filler aus derselben Familie behandeln. Hierdurch kann sonst eine Reaktion erneut getriggert werden. Wenn eine weitere Filler-Korrektur erwünscht ist, wird also empfohlen, einen Filler aus einer anderen Produktfamilie zu wählen. Das heißt, wenn es zum Beispiel zu einer Reaktion auf Juvéderm® Voluma® kam, sollte für die erneute Korrektur zum Beispiel Belotero® Volume verwendet werden. Fazit Bei der Behandlung mit injizierbaren Füllmaterialien treten unerwünschte Reaktionen auf - bei einigen Fillern mehr als bei anderen. Unverträglichkeitsreaktionen auf Filler können vaskulärer oder immunologischer Art sein. Bei vaskulären Reaktionen kommt es zu einem arteriellen Verschluss, der zu einer Nekrose der Haut und benachbarter Strukturen führen kann. Wurde ein HA-Filler verwendet, sollte zeitnah Hyaluronidase im Bereich des behandelten Areals und der verschlossenen Gefäße injiziert werden. Bei immunologischen Reaktionen (z.B. Schwellungen oder Knotenbildung) sollte mit oralen Steroiden (als Stoßtherapie) oder anderen immunmodulierenden Therapien wie niedrigdosiertem Doxycyclin behandelt werden. Bei Reaktionen auf HA-Filler sollte Hyaluronidase eingesetzt werden, um Depots aufzulösen. Bei granulomatösen Reaktionen auf permanente Filler, wie Polymethylmethacrylat oder Silikon, und abbaubare Nicht-HA-Filler, kommt Methotrexat zur Anwendung. Eine Dauertherapie mit Antibiotika wie Clindamycin ist nicht indiziert. Unerwünschte Reaktionen sollten, wann immer möglich, vermieden werden. Voraussetzung dafür sind gute Kenntnisse des Präparates und der Anatomie. Prof. Dr. med. Berthold Rzany, M. Sc. Medizin am Hauptbahnhof Wahlarztzentrum für Dermatologie & Venerologie Karl-Popper-Straße 8/203 1100 Wien [email protected] @b_rzany_berlin_wien SpringerMedizin.de Ausgabe verpasst? Jetzt als ePaper lesen! Lesen Sie ästhetische dermatologie & kosmetologie jetzt auch digital auf Ihrem Tablet oder Smartphone - jederzeit und überall. SpringerMedizin.de hält für Sie alle Ausgaben der letzten elf Jahre als ePaper bereit, auf die Sie kostenfrei zugreifen können. Highlights der letzten Ausgabe S2k-Leitlinie zu Diagnostik und Therapie der Rosazea Haarerhaltende Therapien der androgenetischen Alopezie Hautpflege bei Bestrahlung Hidradenitis suppurativa - Pathogenese, Diagnostik und Therapie Kongressbericht vom 21. EADV-Kongress 2022 in Mailand www.springermedizin.de/aesthetische-dermatologie ==== Refs Literatur 1. De Maio M et al. Injectable fillers in aesthetic medicine. Berlin, Heidelberg: Springer, 2014 2. Rzany B et al. Understanding, avoiding, and managing severe filler complications. Plast Reconstr Surg 2015;36:196S-203S 3. Alam M et al. Rates of vascular occlusion associated with using needles vs cannulas for filler injection. JAMA Dermatol 2021;157:174-80 4. Schelke LW et al. Ultrasound-guided targeted vs regional flooding: a comparative study for improving the clinical outcome in soft tissue filler vascular adverse event management. Aesthet Surg J 2022;https://doi.org/jjbj 5. van Loghem J et al. Managing intravascular complications following treatment with calcium hydroxylapatite: An expert consensus. J Cosmet Dermatol 2020;19:2845-58 6. Dadzie OE et al. Adverse cutaneous reactions to soft tissue fillers - a review of the histological features. J Cutan Pathol 2008;35:536-48 7. Pérez-Ruiz C et al. Adverse granulomatous reaction to silicone filler treated with methotrexate. Dermatol Surg 2019;45:489-92 8. Philibert F et al. Eruptive granuloma after injection of Ellansé® successfully treated using methotrexate. Ann Dermatol Venereol 2018;147:525-9 9. Nast A et al. S3 Guideline for the treatment of psoriasis vulgaris, update - Short version part 1 - Systemic treatment. J Dtsch Dermatol Ges 2018;16:645-69 10. Washrawirul C et al. Global prevalence and clinical manifestations of cutaneous adverse reactions following COVID-19 vaccination: A systematic review and meta-analysis. J Eur Acad Dermatol Venereol 2022;36:1947-68	0	PMC9747256	NO-CC CODE	2022-12-15 23:21:59	no	ästhet dermatol kosmetol. 2022 Dec 14; 14(6):22-25	utf-8	null	null	null	oa_other
==== Front Aesthetic Plast Surg Aesthetic Plast Surg Aesthetic Plastic Surgery 0364-216X 1432-5241 Springer US New York 3199 10.1007/s00266-022-03199-6 Original Article Quality of Life, Body Image and Personality Traits Among Women Receiving Botulinum Toxin Type a for Cosmetic Purposes Azadeh Mafi Negin 1 Nahidi Yalda 2 Layegh Pouran 2 Khadem Rezayian Majid 3 http://orcid.org/0000-0002-5743-661X Nahidi Mahsa [email protected] 4 1 grid.411583.a 0000 0001 2198 6209 Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran 2 grid.411583.a 0000 0001 2198 6209 Cutaneous Leishmaniasis Research Center, Mashhad University of Medical Sciences, Mashhad, Iran 3 grid.411583.a 0000 0001 2198 6209 Clinical Research Development Unit, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran 4 grid.411583.a 0000 0001 2198 6209 Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran 13 12 2022 18 17 9 2022 16 11 2022 © Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. Background The demand for minimally invasive cosmetic procedures has rampantly increased in recent decades. The aim of this study was to evaluate the body image, personality traits and quality of life (QoL) in women consuming botulinum toxin type A for cosmetic purposes. Methods This case–control study was conducted on 89 participants referring to outpatient dermatology clinics in Mashhad from 2019 to 2021. All participants completed a checklist of demographic and clinical characteristics, as well as three other questionnaires, including the World-Health-Organization Quality of Life-Short Form, Big 5 Inventory-10 (BFI-10) and Yale-Brown Obsessive-Compulsive Scale modified for body dysmorphic disorder (Y-BOCS-BDD). A control group of 101 sex and age-matched people from the general population also completed the questionnaires online. Results All participants were females, and most of them in the case group were 31–50 years old (n = 68, 77.1%). Among the case group, QoL was reported higher in all domains; however, this was only significant in ‘physical’ (P = 0.003) and ‘psychological’ (P = 0.036) aspects. After considering the confounding factors, the case group was able to significantly predict increased QoL in the ‘physical’ (P = 0.019) and ‘environmental’ (P = 0.015) domains. In terms of BFI-10 scores, conscientiousness was notably higher among the case group (P < 0.001), while the control group scored slightly but significantly higher than the case group in neuroticism (P = 0.019). The control group scored significantly higher in Y-BOCS-BDD (P < 0.001). Conclusions In clients receiving botulinum toxin injection for cosmetic purposes, QoL was higher than in the control group. No signs of body dysmorphia or pathological personality traits were found in these individuals. Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. Keywords Personality Quality of life Body image Botulinum toxin http://dx.doi.org/10.13039/501100004748 Mashhad University of Medical Sciences 971246 Nahidi Mahsa ==== Body pmcIntroduction The demand for cosmetic procedures has significantly increased in the past decades for both genders. According to American Society of Plastic Surgeons, total cosmetic procedures increased 1.7-fold by 2010 and 2.3-fold by 2020 in comparison with 2000 [1]. Considering its population, Iran has one of the highest rates of cosmetic procedures with over 175,000 cases reported in 2017 [2]. Even though women are the primary seekers of these interventions, the number of men is on the rise among cosmetic clients as well [3]. The population of noninvasive cosmetic clients, however, is not studied in Iran yet. It is important to investigate whether clients demanding these interventions share common features like high neuroticism and low self-esteem or exhibit positive characteristics that encourage their attempts for increasing their life quality and self-acceptance. Understanding the motivating forces behind this rising demand has multidisciplinary advantages for both psychiatrists and aesthetic physicians as it can provide valuable insight into psychopathologic issues associated with this growing trend, as well as helping clinicians recognize their patients’ needs. Various factors may have influenced the growth of aesthetic medicine. The almost unattainable aesthetic goals in modern culture could be partly guided by the growth of effective adverts that capitalize on human’s innate desire for beauty and perfection. Studies show that increasing popularity of Internet search terms like ‘Botox,’ ‘Juvéderm’ and ‘Radiesse’ is correlated with the number of Instagram and Facebook users [4]. Failing to reach these high standards can negatively influence mental health, infesting individuals with appearance-based rejection sensitivity and negative body image. Therefore, it is not surprising to observe a reduced quality of life (QoL) among people with these negative cognitions. For this reason, seeking cosmetic procedures may have undeniably positive effects on QoL, acting as a strong motivation for these treatments. Considering that the motivating forces behind cosmetic treatments are mostly internal concepts that may not always be evident to an outside view, they signify the relevance of psychology to aesthetic medicine. Personality psychometrics such as BFI-10 [5] can provide valuable insight into fundamental similarities between these individuals by grouping their general traits into ‘openness,’ ‘conscientiousness,’ ‘neuroticism,’ ‘extraversion’ and ‘agreeableness.’ It has been shown that neurotic people are more likely to mention body-related topics in their self-narrative use of language [6] and that those with body dysmorphic disorder show high scores of neuroticism while they are in a low range for conscientiousness and extraversion scores [7]. Even so, cultural differences prevent from drawing absolute conclusions about personality traits; therefore, further research is still required in these fields. As a common minimally invasive procedure, studying Clostridium botulinum toxin type A (BT) injections can be an attractive choice for many cosmetic clients. With various applications for eyebrow ptosis, horizontal and vertical glabellar rhytids, crow’s feet and eyelid hooding [8], BT experienced remarkable growth by 584% in the 2000s, significantly higher than any other form of minimally invasive procedure [1]. Cosmetic BT has mainly resonated with adults > 34 years old [9]; considering the reports indicating decreased prevalence of body dysmorphic disorder in > 44 year old adults [10], BT provides an opportunity to investigate these age-related presentations of body dysmorphic symptoms. In this case–control study, we aimed to investigate the difference between clients receiving BT injections and those who have never received such injections in terms of personality traits, QoL and body dysmorphic symptoms. The results of our study may help aesthetic clinicians find commonalities among their clients’ personalities and connect with their needs more effectively, while potentially reducing dissatisfaction with the outcome by means of proper communication and consultation. Furthermore, psychiatrists may come closer to answering the question of whether cosmetic procedures should be categorized as enforcers of dysfunctional cognitions or beneficial treatments to psychologic conditions. Methods Study Settings and Approval This case–control study was conducted in 2019 and lasted for two years across outpatient dermatology clinics of Imam Reza and Ghaem Hospitals of Mashhad, Iran, as well as private dermatology clinics. Informed consent was obtained from all participants and the authors ensured their confidentiality. This study was in accordance with the Declaration of Helsinki. Ethics Committee of Mashhad University of Medical Sciences approved this study (IR.MUMS.MEDICAL.REC.1397). Participants The case group included females referred to receive botulinum toxin for cosmetic purposes who were selected through the convenience sampling method considering the following inclusion criteria: (1) 18–68 years of age, (2) absence of congenital craniofacial defects or other facial scars, (3) lack of major psychiatric conditions or admission in psychiatry service and (4) literacy to complete surveys. Due to COVID-19 restrictions, our control group was selected from among sex-matched online survey respondents who had never received botulinum toxin for cosmetic purposes. Since cosmetic interventions are not covered by insurance companies, no distinction was made between clients who referred to private institutions as opposed to public ones. Participants who had answered < 80% of questions were excluded, resulting in a total of 190 female participants (89 in case group, 101 in control group). Survey Tools The previously validated Persian translation of World Health Organization Quality of Life: Brief Version (WHOQOL-BREF) was used to evaluate QoL among both groups [11]. Using items designed based on five-point Likert scale, this 26-item questionnaire measures QOL in four different domains: physical health, psychological well-being, social relationships and environment. WHOQOL-BREF is scored in a positive direction (higher scores indicating higher QOL), while the results may be transformed into either a 4–20 or 0–100 range, and the latter method of scoring was used in our study. We assessed body dysmorphic symptoms using the self-report Yale-Brown Obsessive-Compulsive Scale Modified for Body Dysmorphic disorder (Y-BOCS-BDD). This questionnaire consists of 12 ordinal items (each ranging 0–4) concerned with two domains of obsessions and compulsions. The cumulative score may range from 0 to 48, with higher scores indicating more severe body dysmorphic symptoms. We used the Persian translation of Y-BOCS-BDD, which was validated in 2010 [12]. The short-form big five inventory (BFI-10), which is the briefest personality questionnaire, was used to analyze personality traits in the five major domains of openness, conscientiousness, neuroticism, extraversion and agreeableness. Each of these domains is scored in a range of 2–10 and determined by two Likert-based items (ranging 1–5). Some items were reverse-scored since they were negatively worded. This scale has been previously translated into Persian, and the validity and reliability of it have been confirmed [13]. Demographic details of each participant, including age, sex, education, job, income and marital status were documented for analysis along with their questionnaire responses. The participants self-reported their previous cosmetic treatments, recent major life events and past psychiatric history (i.e., history of any outpatient psychiatric visit or treatment). The time required to complete the surveys was approximately one hour, and all participants could receive a detailed explanation of their results via e-mail. Statistical Analysis Data were analyzed using SPSS, version 16 (IBM Statistics, Chicago, IL, USA). Qualitative variables were described by frequency and percentage, while quantitative variables were described by mean and standard deviation. Independent samples student t-test and Mann–Whitney test were used to compare quantitative variables between two groups based on their normal distribution. The case and control groups were not matched for some features; therefore, there was large heterogeneity in a number of characteristics. This was controlled by building backward stepwise linear regression models of the dependent variables, and the variables were removed based on P ≥ 0.1 at each step. According to a recent study by Garrusi and Baneshi, the prevalence of dissatisfaction with body image among the Iranian population was reported to be around 34% [14]. While the frequency of dissatisfaction with body image has not been reported among those receiving botulinum toxin injections, it is assumed to be nearly 15% based on anecdotal observations of the authors. The sample size was calculated 81 in each group with respect to alpha of 0.05 and a beta of 0.2 using PASS (PASS 2019 Power Analysis and Sample Size Software, NCSS, LLC; Kaysville, Utah, USA), which was increased to 90 in each group considering a 10% dropout. Results Demographic and Clinical Features In total, 190 female participants were included in this study (89 cases, 101 controls). Most cases and controls were 31–50 years old (77.1 and 86.1%, respectively) (Table 1). The difference in marital status, employment, income level and perceived financial status was statistically significant between the two groups (P < 0.001). Table 2 summarizes the psychological features of participants as well as their cosmetic history. Out of 89 participants in case group, 29 (39.8%) had ≥ 4 four BT injections in the past. The case group reported significantly higher frequency of soft tissue filler use (P < 0.001). The control group visited a psychiatrist more frequently (31.7% vs. 16.5%; P = 0.018), but was less commonly treated for psychiatric problems (6.9% vs. 7.1%; P > 0.99). The two groups were not statistically different in terms of recent major life events.Table 1 Demographic features of the participants Demographic feature Groups P-value* Case N = 89 Control N = 101 Age (Years) 18–30 13 (14.9%) 14 (13.9%) 0.087 31–50 68 (77.1%) 87 (86.1%) 51–60 8 (8.0%) 0 (0.0%) Marital status Single 19 (21.34%) 49 (48.51%) < 0.001 In relationship 65 (73.03%) 38 (37.62%) Married 1 (1.12%) 10 (9.90%) Divorced or widowed 4 (4.49%) 4 (3.96%) Education (years) Primary 1 (1.1%) 0 (0.0%) 0.312 Secondary 1 (1.1%) 0 (0.0%) Associate degree 14 (15.7%) 12 (11.9%) Bachelor 42 (47.2%) 43 (42.6%) Master degree 22 (24.7%) 26 (25.7%) Doctoral 9 (10.1%) 20 (19.8%) Employment Unemployed 18 (20.9%) 39 (45.9%) < 0.001 Part-time 4 (4.7%) 16 (18.8%) Freelance 16 (18.6%) 9 (10.6%) Private 32 (37.2%) 16 (18.8%) Governmental 13 (15.1%) 5 (5.9%) Retired 3 (3.5%) 0 (0.0%) Income level Low 6 (7.9%) 47 (45.6%) < 0.001 Average 41 (53.9%) 31 (30.7%) High 29 (38.2%) 23 (22.8%) Perceived financial state Poor 0 (0.0%) 9 (8.1%) 0.035 Struggling 14 (15.7%) 17 (16.8%) Average 55 (61.8%) 52 (51.5%) Comfortable 19 (21.3%) 19 (18.8%) Well-off 5 (5.0%) 1 (1.1%) Chi-square test Table 2 Comparison of psychiatric and cosmetic history of participants Clinical features Groups P-value Case N = 89 Control N = 101 Abdominoplasty 2 (2.2%) 1 (1.0%) 0.601 Eyebrow lift 3 (3.4%) 1 (1.0%) 0.342 Rhinoplasty 18 (20.2%) 12 (11.9%) 0.162 Liposuction 5 (5.6%) 1 (1.0%) 0.100 Skin resurfacing/hair removal laser 38 (42.7%) 33 (32.7%) 0.177 Soft tissue fillers (face) 24 (27.0%) 4 (4.0%) < 0.001 Psychiatric visit 14 (16.5%) 32 (31.7%) 0.018 Currently under psychiatric treatment 6 (7.1%) 7 (6.9%) > 0.999 Psychiatric hospitalization 0 (0.0%) 0 (0.0%) – Past year’s Major life events Marriage 6 (6.7%) 8 (7.9%) 0.789 Child birth 6 (6.7%) 2 (2.0%) 0.150 Divorce 1 (1.1%) 4 (4.0%) 0.373 * Chi-square test Survey Results Table 3 summarizes the results of WHOQOL-BREF and BFI-10 among the case and control groups. The mean QoL scores among the case group were higher in all domains; however, this increase was statistically significant in ‘physical’ and ‘psychological’ domains (P = 0.003 and P = 0.036, respectively), while the difference in ‘social relationships’ and ‘environment’ domains was not statistically significant. In terms of the big five personality traits, conscientiousness was notably higher in the case group (7.37 ± 1.79 vs. 5.87 ± 1.86, P < 0.001). In terms of neuroticism, the control group scored slightly but significantly higher than the case group (P = 0.019). Other aspects of BFI-10 were not significantly different between the two groups. The mean Y-BOCS-BDD score was significantly higher in the control group (24.14 ± 8.12 vs. 12.73 ± 7.54, P < 0.001).Table 3 Survey results, compared between the case and control groups Feature Group P-value * Case N = 89 Control N = 101 WHOQOL-BREF Physical 53.65 ± 11.26 48.19 ± 13.46 0.003 Psychological 59.75 ± 12.15 55.98 ± 12.41 0.036 Social relationships 63.97 ± 21.45 58.13 ± 20.27 0.055 Environment 64.19 ± 17.51 60.19 ± 16.29 0.105 Big Five Agreeableness 6.97 ± 1.54 6.66 ± 1.78 0.195 Conscientiousness 7.29 ± 1.79 5.79 ± 1.66 < 0.001 Neuroticism 5.49 ± 1.66 5.79 ± 1.66 0.019 Openness 6.77 ± 1.95 7.25 ± 1.91 0.088 Extraversion 6.05 ± 1.74 5.70 ± 1.94 0.189 * Independent samples t-test Regression Analysis Since the groups were only sex- and age-matched, backward stepwise linear regression was used to identify potential independent predictors of the study outcomes out of the following candidate independent variables: group, employment, income level, soft tissue filler use and psychiatric visit. The resulting regression models are summarized in Table 4. The study group was a predictor of ‘physical’ and ‘environment’ QoL domains, Y-BOCS-BDD score, conscientiousness and neuroticism (P < 0.05). Conscientiousness was also predicted by a history of psychiatric visit (unstandardized beta = 0.59, 95% Cl [ − 0.001 1.19], P = 0.05). Income level was a positive predictor of ‘physical,’ ‘psychological’ and ‘environment’ aspects of QoL.Table 4 Summarized results of stepwise linear regression Dependent variable model Independent variable (predictors) Adjusted sum of R-squared Unstandardized beta 95% Confidence interval P-value Physical QoL Case–control* 0.085 − 4.8 [ − 8.95 − 0.081] 0.019 Income level 6.27 [1.88 10.66] 0.005 Psychological QoL Case–control 0.082 − 3.42 [ − 7.48 0.64] 0.099 Income level 5.91 [1.55 10.26] 0.008 Psychiatric visit 4.08 [ − 0.40 8.56] 0.074 Environment QoL Case–control 0.064 8.76 [ − 15.81 − 1.72] 0.015 Income level 8.31 [2.32 14.30] 0.007 Social relationships QoL Case–control 0.039 − 6.66 [ − 13.36 0.041] 0.051 Psychiatric visit 6.78 [ − 0.70 14.26] 0.075 Y-BOCS-BDD Case–control 0.311 10.71 [8.18 13.24] < 0.001 Extraversion Job 0.056 − 0.742 [ − 1.40 0.08] 0.028 Agreeableness Income level 0.012 0.48 [ − 0.07 1.04] 0.089 Conscientiousness Case–control 0.221 − 1.65 [ − 2.19 − 1.11] < 0.001 Psychiatric visit 0.59 [ − 0.001 1.19] 0.050 Neuroticism Case–control 0.048 0.62 [1.20 0.03] 0.038 QoL Quality of life; Y-BOCS-BDD Yale-brown obsessive-compulsive symptoms scale adjusted for body dysmorphic disorder *A positive Beta defines a positive association with being in the control group Discussion In the current study, we investigated the psychological condition of women receiving cosmetic BT injections. Cultural aesthetic standards can leave individuals in a state of dissatisfaction with their body, affecting their mental health, well-being and QoL. The demand for minimally invasive cosmetic procedures has increased significantly since the 2000s [1], and it is essential for both aesthetic physicians and psychiatrists to understand the forces encouraging this demand, as well as its implications on cosmetic clients. Understanding the common personality traits of cosmetic clients is important in catering for their needs. We found that the clients receiving BT injections scored significantly higher in conscientiousness and lower in neuroticism from among the Big Five traits [5]. Our stepwise linear regression model for neuroticism indicated that variables other than the group do not account for any further variance, while a history of psychiatric visit can predict conscientiousness. Neuroticism refers to a general tendency for negative thoughts, which might seem natural to overlap with negative body image in some cases. However, the relationship between neuroticism and body dissatisfaction is more complex and depends on multiple variants. Studies suggest that in women with lower levels of neuroticism, feminine personality traits (based on bem sex role inventory) are associated with higher self-evaluated sexual attractiveness, while in high levels of neuroticism, masculine traits are associated with better body image [15]. In other words, the effect of neuroticism on body image is reliant on other personality traits as well. Interestingly, some reports in China that resembles the Iranian culture compared to the West suggest that conscientiousness is strongly associated with masculinity traits [16, 17]. According to these studies, females with high neuroticism may be less prone to body dissatisfaction if they have high conscientiousness; however, no study has directly examined this possibility. We observed higher levels of conscientiousness and lower neuroticism in clients seeking BT cosmetic treatment, while they did not demonstrate body dysmorphic tendencies. The personality features in our study may be influenced by the minimally invasive nature of BT injections because one study on invasive facial cosmetic surgeries in Iran (e.g., rhinoplasty) reported that conscientiousness and agreeableness are notably lower among these patients than in the general population [18]. Nonetheless, with respect to neuroticism, our study is counteractive to some reports that indicate higher levels in cosmetic clients [19, 20]. It is worth noting that the results of such questionnaires may be biased by the situation in which they were completed, that is, when patients are waiting for a medical procedure in a stressful environment. The implications of cosmetic procedures on well-being and life satisfaction are arguably the most important aspects of aesthetic medicine. We found that according to Y-BOCS-BDD, individuals who received BT injections showed significantly less body dysmorphic tendencies than the control group, which is consistent with the lower levels of neuroticism observed in the case group. This difference in Y-BOCS-BDD score may be attributed to several causes, which we will discuss later. However, it is important to note that the results of control group were obtained via online surveys and included those who may have experienced cosmetic procedures other than BT injections (even though there was no statistical difference between the case and control groups in terms of past cosmetic procedures other than facial fillers). Thus, it is not without merit to assume that some individuals from the control group consider receiving BT injections in the future. Furthermore, the financial status of our case group was significantly better than the control group, although stepwise regression eliminated income as an independent variable affecting Y-BOCS-BDD; in other words, income level cannot predict body dysmorphic symptoms. More importantly, though, our case group completed surveys before their injections, and the data were not analyzed based on whether it was their first injection or not. Accordingly, the evidence does not directly suggest BT cosmetic procedure as the cause of reduced body dysmorphic tendencies in the case group. One could imagine that individuals with low body dysmorphic tendencies may be seeking BT due to other motivating factors, negating the relevance of underlying psychopathologies related to body image. A study by Schaschmidt et al. on cosmetic clients receiving BT found no significant association between body dysmorphic symptoms and BT injection [20]. Even though we found fewer body dysmorphic symptoms in those who were receiving BT, the report by Schaschmidt et al. is consistent with our conclusion that body dysmorphia is not a factor encouraging BT injection. However, studies on other forms of cosmetic interventions have revealed a significant relationship between negative body image and aesthetic plastic surgery [21]. This may be explained by the invasive nature of plastic surgery, which requires patients to be influenced by strong motivating factors such as negative body image. We found that the case group not only showed lower body dysmorphic symptoms but also demonstrated a higher QoL in all WHOQOL-BREF domains. However, multivariate regression analyses revealed that only the ‘environment’ and ‘physical well-being’ domains of QOL were significantly higher in the case group. Stepwise regression models also found ‘social well-being’ to be the sole domain that was not predicted by income. Our results replicated the findings of Schaschmidt et al. in this regard, which similarly indicated higher QoL scores in the ‘environment’ and ‘physical health’ domains of people receiving BT [20]. Similarly, Molina et al. reported that following BT injection, clients experience an increase in their QoL [22]. These are all consistent with previous observations about the importance of physical appearance on individuals’ QoL after cosmetic treatments, which affects self-esteem and interpersonal relationships [23–25]. Our study was conducted with a large sample size, and for the first time evaluated the psychological characteristics of those receiving BT in Iran; however, several limiting factors were present. Firstly, due to COVID-19 limits, our control group was selected through online surveys, and most importantly, it was not matched based on some characteristics; however, we used stepwise regression models to mitigate this aspect. Secondly, the timeframe of injections was not considered and no distinctions were made between people who were experiencing their first BT injection and those who received them for a long time; this limited our ability to analyze the cause-and-effect relationship of cosmetic procedures on well-being. Future prospective studies on BT injections with a focus on differences before and after the injection may provide new insight into the psychiatric aspects of this cosmetic procedure. Conclusion The present study provided insight into psychological aspects of cosmetic clients receiving BT injections in Iran. Our case group scored significantly lower in neuroticism and higher in conscientiousness while displaying fewer symptoms associated with body dysmorphic disorder. We report that seeking cosmetic BT injection need not alarm physicians of underlying major psychopathologies, although care should be taken for susceptible clients. Our study supports the fact that BT injections are associated with higher physical and environmental QoL. Acknowledgements This study was based on a thesis by Negin Azadeh Mafi for the doctor of medicine (MD) degree from Mashhad University of Medical Sciences (grant no.971246). Declarations Conflict of interest The authors declare that they have no conflicts of interest to disclose. Ethical Approval This study was in accordance with the Declaration of Helsinki. The Ethics Committee of Mashhad University of Medical Sciences approved this study (IR.MUMS.MEDICAL.REC.1397). Informed Consent Informed consent was obtained from all participants. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ==== Refs References 1. American Society of Plastic Surgeons [Internet] National Clearinghouse of Plastic Surgery Procedural Statistics (2020) Available from: https://www.plasticsurgery.org/documents/News/Statistics/2020/plastic-surgery-statistics-full-report-2020.pdf. Accessed 4 Apr 2022 2. Zare B Javadi F Naseri S Does it make me beautiful? A focus group discussion on cosmetic surgery Int J Appl Sociol 2014 4 5 126 132 3. 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==== Front Circ Econ Sustain Circ Econ Sustain Circular Economy and Sustainability 2730-597X 2730-5988 Springer International Publishing Cham 243 10.1007/s43615-022-00243-0 Review Paper Circular Economy in the Food Chain: Production, Processing and Waste Management Gonçalves Maria Luiza M. B. B. http://orcid.org/0000-0002-3252-3004 Maximo Guilherme J. [email protected] grid.411087.b 0000 0001 0723 2494 School of Food Engineering, University of Campinas (FEA/UNICAMP), Monteiro Lobato St., 80, Campinas, São Paulo 13083-862 Brazil 14 12 2022 119 15 3 2022 28 11 2022 © The Author(s), under exclusive licence to Springer Nature Switzerland AG 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. Food processing, from agricultural production to domestic consumption, is responsible for generating great amounts of waste per year, resulting in soil, water, and air pollution. These pollutants, together with the uses of petrochemical process inputs such as solvents, additives, or fuels, increase the food chain’s environment impacts resulting in wasted resources. In response to this scenario, the circular economy (CE) theory is presented in literature as a liable alternative for the design of more sustainable production chains. In this context, this work was aimed at evaluating the literature’s approach on the CE concept within the food processing and food waste management. The works show the centrality of “food waste” as a focus for the application of the CE. However, despite the relevance of management, reuse, or valuation of food waste, particularly due to its contribution to carbon footprint and decrease of food safety, studies have found other strategies for improvement of CE in the food chain. In this case, works in literature were allocated within the framework presented by the Ellen Macarthur Foundation called ReSOLVE, with proposals for modification of production chain to promote the CE. Among the proposals, one should highlight: modification of productive systems for mitigation of environmental impacts and greenhouse emissions, processes optimization for decreasing the use of natural resources and wastes, use of 4.0 Industry such as IoT, big data, or machine learning techniques for improvement of the whole supply chain, development of collaborative platforms for production and market, use of residues or co-products by design of intra- or inter-chain loops, and exchange of process or inputs with high environmental impacts for greener ones. Keywords Sustainability Food products Green alternatives Bioeconomy http://dx.doi.org/10.13039/501100001807 Fundação de Amparo à Pesquisa do Estado de São Paulo 2014/21252-0 Maximo Guilherme J. http://dx.doi.org/10.13039/501100002322 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior 001 ==== Body pmcIntroduction According to Food and Agriculture and Organization, in 2018, one-third of the global agricultural land, calculated in 4.8 billion hectares [1], were designated to cropland. From post-harvest to distribution, losses of this production are estimated in up to 25%, depending on the food chain [2]. Indeed, food chains are responsible for the generation of a large amount of waste, as well as environmental impacts along their productive stages. This includes land production, animal farming, food processing, transport, market, and consumption, responsible for the disposal of organic residues, packages, greenhouse gases, waste waters, among others, throughout the route, representing wasted potential resources. In 2019, the farming contribution in the global food chain carbon footprint was calculated in 13.35% of CO2 equivalent of greenhouse gases, land use change in 6.49%, and pre- and post-production in 10.79% [1], being the main contributors in the food chain environmental emissions. To deal with this, global initiatives have been made for reducing global impacts and achieving sustainable production systems. In 2015, through the Paris Agreement, during COP21, the signatory countries agreed to offer financial, technical, and infrastructural support to mitigate global climate change for decreasing 2 °C by 2030, promoting technological and social changes to achieve low carbon emissions. In this context, the United Nations gathered 17 Sustainable Developments Goals (SDG) for sustainable development, concerning the socio-economical and environmental changes necessary to achieve sustainable production models with zero-carbon emission, waste generation, and unrenewable resources use decrease [3]. Through the 12th SDG, namely “Responsible Consumption and Production,” alternative economical models of producing were proposed to reduce the use of natural resources without detriment of economic growth [4–7]. It means that, together with the food losses, consumption and production of non-renewable materials and energy sources during food production and processing should be targeted. In this context, literature, governments, and national and international organizations have paid attention to the so-called circular economy (CE). As opposed to the traditional economical and production model, in which resources are used for product manufacturing and products are discarded, generating waste and pollution with net carbon emissions, the CE proposes a more circular model, in which resources are used more than once, prioritizing minimum or no use of no-renewable resources, as well as waste generation [8]. This model enables producers to address the matter ensuring production without detriment of the environment. Other alternative models have been also explored in literature. Examples are the “Industrial Ecology,” in which goods production are based on the natural systems, considering the interaction among industrial production, environmental, and society, targeting the reducing of natural resources by reusing and recycling principles [9, 10]; the “Buen Vivir” (Living Well – free translation), a Latin American theory that questions the actual model of goods production and usage of natural resources (not be considered “resources” by this theory), directly dialoguing with indigenous cosmologies, economy undergrowth, and colonial perspectives [11]; the “Food-Energy-Water” (FEW) Nexus, an approach that considers food, energy, and water consumption/production are interrelated with a focus on (re)utilization of food waste by converting it to energy or other high valued chemicals [12]. Lately, gradual changes have been performed in several manufacturing chains, by promoting the CE concept. To ensure proper application of it, quantitative and qualitative tools have been developed to evaluate the level of circularity of production chains. Life Cycle Assessment (LCA) is one of the most used methods for evaluation of the environmental impacts of a production system, particularly in case of food systems. The assessment, described in the ISO 14,040 and 14,044 standards, is performed from “cradle to grave,” i.e., from raw materials to product consumption, with the calculation of environmental impacts categories such as global warming, land and water use and fossil resources depletion [13]. Other strategies as proposed by the “ReSOLVE” framework [14] described by Ellen Macarthur Institute, consists of “rules” or strategies to reach a full or partial circularity in the goods production, including the performance of up to six actions or “modifications” throughout the productive chain to REgenerate environment, Share processes and products, Optimize the systems, create Loops in the chain, Virtualise services and processes, and Exchange non-renewable and high environmental impact materials [15]. Therefore, considering the novelty of the concept and the important role displayed in the way of re-thinking productive systems and the economy itself, particularly in case of food systems, this work was aimed at performing bibliographical research on the occurrence of studies on CE applied to food production and food waste management, including works published in the last 5 years, evaluation of the main focuses. Also, considering the centrality of the theme “food waste” in the works, food waste was conceptualized by presenting three main categories, food waste itself, food surplus and food loss including the best environmental management options for each one. Finally, based on the ReSOLVE framework proposed by the Ellen Macarthur Foundation, works in literature were categorized within one of the six business actions of it, highlighting potential alternatives for enhancement of the circularity within the food chain. Circular Economy in the Food Chain and Food Waste Management: Occurrence in Literature To assess the context and how often the literature has addressed the topic of CE in the food chain, bibliometric research was performed using two main academic databases, namely “Web of Science” (all databases) and “Scopus.” The keywords used in the research were “Circular Economy” associated with the terms “Food Chain” or “Food Waste” or “Agricultural Waste” or “Waste Valorisation” or “Food Processing.” “Food Chain” is the obvious main term in this research. Though the expressions “Food Waste” and “Agricultural Waste” do not represent the same concept, they are most likely to represent the same idea of “waste” in the food industry. The term “Valorisation” was chosen due to the frequency found in the works within the CE concept and therefore, it was also used in the research. The “Food Processing” term can most likely appear in the context of studies on the food manufacturing stage of the food chain, reason why it was used in the research. The period of analysis was the last 5 years (from 2017 to June, 2022) as an attempt to make the review as contemporary as possible. The type of document considered was original articles, reviews, conference papers, book chapters and editorials indexed in those two databases. Patents deposited within that period were also considered in the research in order to incorporate innovations and technological advances in the area. The flowchart presented in Fig. 1 shows how the bibliographical research was performed. Fig. 1 Flowchart regarding how bibliometric research was conducted in this study The number of results found in each database was 858 for Web of Science, 427 for Scopus from 2017 to June of 2022. Duplicates appeared when each base was cross-linked. The results were downloaded in the Excel software [16], the duplicates were excluded at the worksheet and data divided according to the theme. Some works, according to each category, will be further detailed in the next section. Also, works based on the ReSOLVE framework [14], further detailed in the next section, were highlighted. Excluding duplicates and unrelated work, the total works found was 1005. The distribution of citations per year, for keyword selected, and the distribution of documents published per country is shown in Fig. 2A and B. Figure 3 shows a tree map with the fields of knowledge of the journals that published the articles. Fig. 2 a Distribution of documents per year and b distribution of documents published per country (research origin) Fig. 3 Tree map with the fields of knowledge of the journals The number of documents significantly increased within 2017 to 2019, peaking by 2021. Considering that for year 2022 research was performed until June, the total number of works published, must probably increase possibly overcoming 2021. Considering the top 10 subject areas in the search, “Environmental Science” is the field of knowledge with the greatest number of works, reviews, or original articles, followed by “Energy” and “Engineering.” Subject areas more likely to study CE, particularly in Food Systems, such as “Economics, Econometrics and Finance” and “Agricultural and Biological Sciences” showed a low presence of works in this specific subject. “Chemistry” also appeared as the last of this list. Although the bibliographical research in CE showed an increase in publication, the total quantity regarding “Food Production” is still lower when compared to other fields of knowledge. Otherwise, results suggested a great contribution of the academic works on more sustainable technological development. Studies on theoretical application of the circular model into the industry were commonly found in “Business, Management and Accounting” and “Economical, Econometric and Finance” areas. Public policies towards a more circular economy, such as those with the principles of “green cities,” strategies for development of local markets, local farmers or producers have been also investigated, especially in the context of agricultural waste management and food processing. Considering the countries where research on CE was performed in food chain (Fig. 2B), three main contributors were identified. Italy was the country with the greater production regarding the application of CE concepts in food waste management in the food production, followed by United Kingdom and Spain. These countries follow the European Directives for waste management and have specific policies to implement changes in the food chain to achieve the UN Sustainable Development Goals. Among the targets of such directives are the increase of at least 50% by weight of re-use and recycle of waste from households by 2020 with an increasing of the values by 2035. The United Kingdom is not a member of the European Union but has committed to the SDG and the Sustainable Development Agenda with investments in research and innovation in this area [17]. In 2020, particularly, a “Circular Economy Package Policy Statement” was developed by the UK Department for Environment, Food and Rural Affairs to ensure introduction of the CE concepts in the country. China, USA, and Brazil were also listed among the top 10 countries focusing on CE studies for more sustainable food production and food waste management practices. These countries correspond to the largest food producers and consumers in the world, having the largest contribution to the waste generation and disposal throughout the food chain compared to other regions. China has governmental policies for waste collection recovery, with a centralized system for cities and small villages, as well as examples of public-private partnerships initiatives regarding the waste management of rural solid waste. However, the resistance of villagers is a bottleneck for reaching recycling targets [18] as well as market demands and fiscal transparency issues [19]. In USA, the US Environmental Protection Agency published a guidance for waste management of hazardous, non-hazardous, and solid waste, with recycling guidelines [20]. The guidelines include alternative methods for recycling material, solid waste and hazardous wastes, reuse and recovery, principles of CE and waste management. In 2010, a joint initiative between USA and Brazil were implemented, called “National Solid Waste Policy.” This policy is a public-private partnership and acts on the improvement of recycling policies, application of new technology for recycle, reuse and recovery of waste. The increase in organic waste digestors, composting and packing disposal techniques was one of main the goals of this policy [20]. In Brazil, an important program for more sustainable industrial practices was the RENOVABIO program, implemented in 2016 by the Ministry of Mines and Energy of the Brazilian Government. This program stimulates companies to implement renewable energy technologies in exchange of Decarbonization Credits (CBIO), proportional to the amount of renewable energy produced [21] with includes the use of agricultural wastes for energy production. In this context, more technologies for the integration of biomasses within the Industrial Processes have been encouraged during past years, giving rise to the concept of “Bio-refinery” [22]. Within this concept the main products obtained by using wastes or biomasses are second generation bio-fuels from non-food crops or residues, biogas from industrial wastes, or lignocelluloses materials from agriculture and forestry, third generation bio-fuels using aquatic microorganism or fourth generation fuels by combining fuel production and CO2 capturing and storing [23, 24]. Indeed, the application of bio-refineries is considered highly feasible in Brazil that, within the CE values, are also highly encouraging in the context of other developing countries [23, 25]. Food Waste and Their Management As observed in the literature review, there are few research regarding food production or processing systematically associated to CE. Most of the works indicates, as possible alternative for a circular production, the reuse/recycle of output streams (mainly food wastes) for manufacturing of valued products, followed by replacement of processes or feedstock for those with lower environmental impact [26–29]. Few works consider the full circularity concept, with the reintroduction of output streams in the same chain, what CE call as “closed-loops,” or the use of these outputs to another productive cycles, what CE call as “open-loops.” Reuse of water through wastewater treatment [30], use of bagasse [31] or other biomasses for energy generation [32–35] as well as replacement of volatile solvents by greener ones [36–38], are other CE alternatives proposed in literature for food production in the CE context. Food waste and technologies for their management are still presented as one of the main focuses in the context of applying CE in the food chain. However, the comprehension of what is a food waste could influence in the choice of the best environmental alternative for their management. In fact, definition of waste in the food chain varies in literature, despite several attempts observed to harmonize such definition. In this context, a particular highlight could be given to the work of Teigiserova, Hamelin and Thomsen [39]. The authors divide “wastes” in food system in 5 categories: (1) agricultural production, (2) post-harvest activities, (3) processing and manufacturing, (4) retail and wholesale, (5) consumption and services. They also distinguished food surplus from food waste and food loss. According to them, after harmonization of literature works, the first refers to food for human consumption that are not expected to be “wasted,” most represented as household and food service leftovers, but also processed food with expired date not retailed or consumed. It also considers food bound to be wasted during its lifecycle whether by not being appealing to consumers, or for its bad appearance, such as deformed fruits and vegetables. The second group refers to some distinguish types: (i) inedible organic residues that is not expected or inappropriate to be eaten by humans, due to either natural inedibility or inedibility due to processing, such as leaves, bones, bagasse or frying oil; (ii) edible parts of fruits and vegetables or edible organic residues resulted from processing or consumption, such as peels, seeds, or whey; (iii) and spoiled food due poor storage conditions in households and retailing. The last refers to food unintentionally lost due spoilage throughout the food system (previous to household consumption or retailing storage) as a result of inappropriate post-harvest conditions, improper storage (temperature, atmosphere composition, time of storage), bad practices of logistic management or transportation. Based on these concepts, the authors proposed a hierarchy of alternatives for the management of each type of “waste.” The scheme proposed is sketched in Fig. 4. It is an inverted pyramid in which the best-environmental alternatives are closer to its top. By this hierarchy, management of food surplus are placed as the focus, focused on prevention of food disposal in households and retailing by allocating it for human consumption. Possibilities, in this context, are food banks for people in need, reinventing food dishes from leftovers, use of misshaped fruit and vegetable for cooking, encouraging their commercialization. Food processing is also considered an important and interesting alternative in this case, with the increasing in shelf-life of still edible fruits, vegetables or meets. Food waste is placed in the middle of the pyramid. In this case, depending on the waste quality, generally characterized by its edibility or inedibility, they should be designated firstly for animal feed followed by their uses in adding-value processes. Recycling of materials for production of other goods such as bio-plastics, composite materials or chemicals as well as the recovery of bio-compounds by extraction technologies are the main proposals. Renewable energy production is placed as the last option for management of food wastes, in contrast with the frequency of works found in literature. Food losses are in the bottom of the inverted pyramid, in which disposal should be avoided. Indeed, considering that food losses can be avoided by good post-harvest, storage, and transportation practices, from farming to retailing, their existence is questionable. Fig. 4 Inverted Pyramid showing a hierarchy of actions for food waste management, adapted from [39]. Green actions for food surplus, orange and yellow actions for wastes, and red for losses As observed reuse/recycling is the most spread practice within literature works but also within the public polices for urban routines worldwide, considering the management of food “wastes” and mitigation of their environmental impacts. Indeed, avoidance or reduction of waste generation, and the recycling of waste into alternative products are often premises for waste management. Beyond management of disposed food packages, reuse/recycling activities mainly includes practices of composting, and more recently bio-energy production. According to the European Environment Agency (2021), 28 European countries recycle around 55% of total urban waste per year, in which residues from food consumption represents a significant fraction. In China, around 73% of total urban solid waste are reused and governances have planned to achieve 79% until 2025 [40]. In Brazil, only 3% of the recyclable solid waste is effectively recycled per year, approximately, despite the country has approved in 2010 the National Policy of Solid Waste, where reuse and recycle of waste, and reduction of landfills were some of the main targets of the law. In the USA, 35.2% of municipal solid waste are recycled or use for composting. However, up to 2017, in USA, most of the solid waste was still thrown out in landfills (139 million) and the minority recycled, composted (94 million), or combusted (34 million) [41]. Indeed, recycling alternatives had been growing throughout decades. During 1970s, the environmentalist movement was strengthened with the evolution of public opinion towards reduction of water, land, and fossil fuel consumption [42, 43]. The problematic of waste management also arose in governmental and personal actions, motivated by popular opinion trough society movements and Non-Governmental Organizations (ONGs) environmental driven, such as Greenpeace and many others created at 1980s. Recycling became the substitute for landfills. Then, further in the late 1970s, the energy crisis provoked by the shortage of petroleum available, increased the fossil fuel prices and promoted severe impacts on the global economy due to the lack of energy source supplies. By the same time, the so called “green revolution,” promoted the mechanization of crops and agricultural production, increasing fossil fuel energy and other natural resources consumption. Therefore, the search for alternative sources of energy, together with reduction of water and emissions became an important issue. The production of energy by recovering agricultural and industrial wastes is portrayed as an important and viable alternative [42, 43]. Also, an expressive part of the academic community defend the substitution of the extensive agricultural, practised by large corporations, with great consumption of natural resources, by agro-ecological practices [44]. Among the positive aspects of recycling materials are the reduce of used resources inside the chain but also generation of jobs and increasing in other economic sectors such as energy and chemical industry [41]. Paperboard (46.9%) and yard trimmings (25.9%) are the main components recycled in USA, followed by metal, plastic, glass, wood and textile, along with food residues. The food chain contributes to a great part of the paperboard, plastic and glass residues. For this reason, regulatory agencies worldwide had been introducing specific rules for mitigating the impact of such food chain residues. For example, single-used plastic products have been restricted in European Union [45] with reduction of its consumption mainly through awareness campaigns, and introduction of labeling to instruct the consumers regarding plastic content, disposal options, and plastic harm to environment, including regulatory texts on composition and types of recycled bags. In Latin America and Caribbean countries, for mitigation of marine litter and plastic, waste governmental model guidelines for reference values, indicators and specific actions for plastic disposal was launched [46]. In Brazil, the Ministry of Environment in a partnership with the UN Environmental Program implemented a Sustainable Consumption and Production Project focused on recycling and development of innovation technologies for responsible waste reuse [46]. The work of Edwards et al. [47] exemplifies the environmental benefits of well managed urban solid wastes. The authors performed a LCA of a municipal waste management service for organic wastes, accessing its pathways (collection, pre-treatment, treatment, and end-use/disposal) for the production of high valued products or simple disposal. Classical scenarios were evaluated: disposal in landfills, composting a central facility for fertilizer production, domestic composting, and digestion for biogas and electricity production being the efficiencies inside the recycling or recovery system evaluated. The authors concluded that the bio-energy generation from digestion in landfills, from sewage waste management and from bio-solids composting had higher energy generation net value in comparison with the scenario without waste treatment techniques. The ReSOLVE Framework on Food Production Despite the great focus given by literature for food waste treatment or their valorisation, as the main alternatives for applying the CE principles in the food production, several other challenges in the food chain demands evaluation. These demands are highlighted in the three main CE principles: (i) preserving, restoring and enhancing natural capital; (ii) optimizing the yields of the productive systems by (re)circulating the products, materials and components; and (iii) design productive systems considering the mitigation of their negative externalities, i.e. negative social, economic and environmental impacts [8]. According to literature [15], industrial and other business practices could reach these principles by performing “actions” within a framework called as ReSOLVE. ReSOLVE is an anagram of “six actions,” namely Regenerate, Share, Optimize, Loop, Virtualise and Exchange. This framework is particularly assertive in proposing the introduction of new technologies or business systems for improvement of the circularity of a productive chain. Through the bibliographical research performed, the literature works were evaluated, and their scopes classified as being in one of the six ReSOLVE actions. Exemplary works are separated and presented in Table 1. In sequence, the six actions will be detailed explained with the examples proposed by those selected literature. Table 1 Some examples of more recent articles published regarding application of the ReSOLVE framework in the food chain in the period of 2017–2022 ReSOLVE action Examples References Regenerate • Food production associating plantation or cattle raising with agro forestry [48] • Integration of carbon capture and food/biomass production [49] • Use of alternative proteins in food formulation [50] Share • Shared food manufacturing facilities [51] • Food-sharing platforms to share surplus food [52] • Shared practices in food waste management [53] Optimize • Energetic optimization in food processes [54, 55] • Food production optimization with minimization of food losses [56] • Technologies to increase traceability and decrease food losses [57] Loop • Returnable packages technologies and management [58, 59] • Reutilization of food residues for production of other non-food materials, including biofuels [35, 60–63] • Extraction of bioactive compounds from food residues [64] • Extraction of macronutrients from food residues [65] Virtualise • Online food shopping technologies [66] • Food formulation using virtual reality [67] • Use of GIS (Geographical Information System), big data, and other 4.0 Industry technologies to monitor food chain, avoiding losses and increasing quality [68–73] Exchange • Replacement of non-renewable solvents or other feedstock by renewable/more sustainable chemicals for food production [74] • Food formulation by 3D printing [75] • Replacement of non-renewable energy sources by renewable ones in food processes [76] Regenerate The development of alternative productive systems to restore the biological resources of the ecosystems is point out by the ReSOLVE framework as one of the six actions for reaching the circularity of a productive chain. An interesting example in the food production chain is animal farming and monocultures. Animal farming, especially the extensive cattle raising, and large monocultures, such as soybean and corn croplands, have been associated to high environmental impacts due to land and water use, soil spoilage, greenhouse emissions among others. In this case, Miccolis et al. [48] states the impacts of both could be decreased by changing the productive system through the implementation of the agro forestry model, which could aid the regeneration of the biome. In the context of the environmental impacts of cattle raising, Grossmann and Weiss [50] suggest that regeneration could be potentially achieved by the replacement of animal protein in food formulation with the use of alternative sources of protein. This is the case of the so-called plant-based products, highly popular due to the costumer adoption of vegetarian or vegan diets increase. The authors explore the technological challenges for substitution of animal protein in food formulation, as well as how to adapt it to the customer acceptance. Another quite interesting alternative for restoring of ecosystems are the use of technologies for carbon capture and sequestration. The CO2 capture can be achieved by several technologies such as solvents, membranes, or adsorbents, but Sillman et al. [49] describes the use of a H2-oxidizing bacterium as a feasible alternative for both carbon sequestration from productive systems, conversion into protein that could be used for food or feed production. This is also pointed out by the authors as in line with the global food security problem, by increasing protein production in a more efficient and sustainable way, considering the limited land and water resources. Share This action is more commonly related to products and services consumed or shared by more than one person or used by more than one goal. Examples of such practice are sharing rides, accommodation, cars or bicycles, actually promoted by mobile apps, including the use of second-hand products. In the food chain context, Lino de Araújo et al. [51] described how shared food production plants, in the context of small-scale productions, could represent benefits in economic and environmental point of view. In case of small-scale producers, capital costs are relevant bottlenecks, avoiding business and income generation growth. However, considering that several food products could use the same equipment or technologies to be processed, shared facilities could allow small producers in scaling up their production. However, this concept can go beyond only physical goods and be transported to shared actions towards environmental benefit. Frey et al. [52] investigated the use of food-sharing computational platforms for food sharing and reduction of food loss. This sharing platform enable the users (both individuals and businesses such as producers or retailers) to share their surplus food in a “peer-to-peer” or “business-to-peer” relationships, with a profit- or non-profit-based market. This study could observe that the existence of these social or corporate-social sharing platforms, also described as social-eating platforms proved to be quite significant not only for food waste management and decreasing but also as a food security practice. This sharing practice was also evaluated in the study of Dora [53]. The author discusses the positive and collaborative contribution of shared sustainable practices of farmers and stakeholders in the food supply chain for efficient management of the food waste within the CE concept. This was achieved by sharing knowledge on more sustainable management in their farms but also sharing food surplus between themselves. The author also found that geographical distance is a very relevant factor for the success of this collaborative framework and, therefore, a robust local food supply chain facilitates the implementation of this CE practice. Optimize The enhancement of actions inside the productive chain for optimisation of energy, time, resources, reducing waste production and increasing yields is a powerful premise of the CE. An example of such action is the “Lean philosophy,” created by the Toyota industry. The reorganization of the productive system and the supply chain is a necessary practice to avoid unnecessary wastes, transport, inventory, over production and over processing, but also to mitigate “non-value” activities, and increase the real product value to the costumers [77, 78]. Several “Lean” methods, such as sustainable value stream mapping, green value stream mapping, inventory reduction, lean product flow, pre-production planning has been applied in areas of waste, energy, emission, water and chemical management concerning sustainable business [79]. Examples of the Optimize action in food industry can be exemplified by the works of Biasi et al. [54] and Meirelles et al. [55]. The authors proposed structural modifications in classical distillation and absorption/desorption columns for some food productive systems, such as ethanol production or deacidification of vegetable oils, decreasing capital and operational costs, energetic demands, and promoting the same or higher product yields. In the same way, Garre, Ruiz and Hontoria [56] evaluates the application of machine learning methods in food production to increase the efficiency of the production using less resources. This because, according to authors, some non-controlled variables in food production such as raw materials and ingredients variability, seasonality, atmospheric conditions, and a grade of randomness in products yield and market demand, can results in differences between planned and real productions, leading to unnecessary economical (and food) wastes and increases in the carbon footprint. Machine learning algorithms can be used to predict the food production variability by evaluation of the input data (types and quality of ingredients, process conditions, attributes of the raw materials, among others), mitigating wastes. Bouzembrak [57] also evaluated the use of computational techniques for food waste mitigation. In this case, “Internet of Things” platforms were used to manage the food chain and improve food safety. The authors showed the growing number of studies on technologies for monitoring food throughout the food chain for traceability, reduction of food losses, and improvement of food safety. Studies considered food production, transportation, food processing and shelf-life, the use of sensors for measurement of temperature, humidity, pH, viscosity, density, color, etc., as well as real-time communication platforms with Internet, radio frequency, and wireless sensor networks. Loop Development of “loops” within a productive chain is probably the most known action for achieving circularity within the CE framework. Loops could be comprehended as “recycling” or “reprocessing” the outputs of a production chain. Raw natural resources, chemicals, renewable or non-renewable materials, industrialized products, or energy are used inside the chain. Through the processes several outputs are generated: the final product is classically the most valued output. However, other co-products (or residues) not used in the processes itself are also produced. Those outputs can become inputs inside the same production chain or be introduced in others, creating “loops.” In the context of creating loops by using outputs of the food production, Pontes et al. [64], and Sampaio Neto et al. [65] among many others authors found in literature, evaluated the development of methods for elaboration of new products with food residues. Those authors used solvent extraction (using solvents with lower environmental impacts, such as alcohols or other natural chemicals) for separation of antioxidants extracts, rich in polyphenols and vegetable oils from leaves and bagasse of oilseeds. These valued products can be produced in the same industry or the same productive chain, with the design of what CE call as “closed-loop,” but also designated to other productive chains, what CE call as an “open-loop.” Production of renewable energy and high-valued bio-products from food waste have been also largely evaluated in literature considering designing of new destinations of residues for reduction of their impacts and nature contamination. Some examples are the extraction of organic particles from food’s processing waste, removal of inorganic contaminants in drinkable water [80] and the production of bio-energy by fermentation, aerobic or anaerobic digestion, and pyrolysis [35, 61]. Other highlight is the use of cooking-oil for manufacturing of other non-food products. Thushari and Babel [63] evaluated the environmental impacts of destining cooking-oil for production of soaps, bio-fuels and polymers. The impacts of each scenario showed that the high generation of solid and liquid wastes for production of soaps and polymers were not recommended over the utilization of the oil for biodiesel production. This is quite significant considering that production of bio-energy has been largely discussed nowadays in the context of bio-refinery, for improvement of the energy generation efficiency, but also for improvement of the CE character of the food chain and productive chains interlinked. Some studies in literature have been also evaluating how implement these new intra or inter-chain loops, but also if they are viable in the social and environmental point of view. In the first case, Huang et al. [60] proposed a framework for evaluation of the alternatives for the reutilization of food residues. The method was based in evaluating and classifying the matrix of wastes generated in the process followed by product development using the matrix of wastes as raw material. In the second case, studies evaluate if the creation of new processes within a productive cycle could lead to more impacts than benefits. They mainly use LCA as the main tool to validate their findings: some of them evaluate the entire chain and others only parts of them [59, 81, 82]. Virtualise Use of virtual platforms can reduce production costs by replacing physical facilities that are cost consuming and environment impacting. Share, optimize and virtualise strategies were used combined in several studies, with the use of big data [70], machine learning [71], Internet of Things (IoT) [72], and other technologies within the 4.0 Industry concept [73]. Aiming the virtualization of retailing in the food chain, Chang and Meyerhoefer [66] studied the increase of mobile apps in the food e-commerce as well as the consumer perceptions in this kind of retailing. The authors showed that the increase of the e-commerce importance and image was clearly observed in this study during past years, particularly due to Covid-19 pandemic situation (2020/2021). By virtualization of laboratory experiments for food products and development, Gouton [67] explored the digitalization of food senses as an alternative to decrease experimental essays in food formulation, mitigating time and cost aspects of it. The use of artificial intelligence for integration production and supply chain was one of the main technologies used and evaluated. Artificial intelligence accomplished with the use of big data, Sensors or GIS (Geographic Information Systems) technologies are presented as interesting alternatives to help retailers, industry, and the supply chain in the reduction of food wastes and losses [68]. big data could have been used for the organization of market data, prices, number of sales, purchases and operations with management of their dynamics. Sensors, such as image, thermal or moisture detectors, could verify conditions to avoid spoilage of fruits, vegetables, meats and processed foods on the market shelves as well as along the supply chain. GIS technologies could promote traceability, reducing wastes, losses and improving food security [69]. Exchange In this business action, non-renewable material, technologies, and services are replaced by renewable, advanced, and more efficient technologies and services. Some examples are as follows: the adaptation of processes to reduce waste or use of resources; replacement of non-renewable resources, such as fossil fuels or organic solvents to renewable ones in food processing in order to generate less waste and reduce environmental impacts [74]; use of 3D food printing for food formulation [75] that could save resources and decrease losses and environmental footprints; conversion of organic wastes into bio-energy, development of organic digestors tanks, and use of solar energy–based processes, replacing electric- or fossil fuel–based energy sources [76]. Final Remarks and Conclusions Global initiatives to implement changes in the way goods are produced and commercialized dates from the last century. The food industry is one of the major sources of negative environmental footprints, due to high use of water, fossil fuel–based resources and non-renewable energy, generating great amount of waste. Due to international pressure and governmental incentive, great efforts to change the food industry have been made, with investment in research and development of new technologies. Indeed, they were encouraged since last century by several environmental agreements, including the well-known SDG framework, proposed in the UN Conference COP 21 [83]. However, there are still some bottlenecks regarding implementation and adaptation costs for new technologies and public adaptation. This highlights the great importance of public policies towards a more sustainable way of production. Throughout the last decades, several theories on how to implement such changes in business, political, and social context such as “Industrial Ecology,” “Buen Vivir,” and the “Food-Energy-Water” Nexus shed light to important changes in the classical relationship among industry, community, and environment, proposing different ways human could better face the use of nature resources in their life. However, CE has been seen as the most known and esteemed in literature to be able to reach such targets among academic work in diverse spheres of knowledge. EU countries, for example, built directives regarding environmental welfare and sustainable production tackling diverse topics, such as the use of petroleum-based inputs, such as polymers in food packaging, politics for waste disposal, or environmental conservation. In March 2020, they launched a new “Circular Economy Action Plan,” based on the “Green Deal,” aiming to reduce 55% of greenhouse gas (GHG) emissions by 2030 and ensure less waste, focusing efforts to enforce circularity on sectors with large production of waste and consumption of resources, including food production [84]. Using the Ellen Macarthur’s ReSOLVE framework [14], this work could categorize some bibliographic findings according to practical approaches towards a food production within the CE context. In doing so, food waste was observed as the main target in several works. Examples are as follows: processing of bio-products using biotechnology or other chemical processes; energy generation using technologies of composting, digestion, or pyrolysis; use of 4.0 Industry technologies such as IoT, AI, or GIS as well as sensors to detect and avoid generation of waste, improvement in market or production strategies using shared systems. However, one could observe that along with the food waste problem, one of the main targets in literature, other actions have been explored to promote a more circular food production. Examples in this case are as follows: the use of extraction techniques to explore the production of nutraceutical compounds from co-products along food production chain; techniques to increase efficiency within production stages, using methods such as the “Lean concept” and optimization by simulation techniques as a way of reducing cost and disposal of natural resources; use of big data science to organize information on sales and stocks among food supply chain; use of market sharing food platforms; practice of sharing knowledge between farmers and retailers regarding sustainable methods of production; exchange methods of production or energy sources by introducing new technologies more environmental friendly. Implementation of new food production methods and retailing sustainable alternatives defy the “status-quo” or the “business as usual” way of thinking, which is the common practice for most of the food companies that rules the food market structure worldwide. Indeed, structural and adaptation costs need for implementation of circular economy practices in goods production are not instantly perceived as beneficial to most of enterprises [8, 14]. In this case, notably, modifications will only be implemented through incentives towards this structural adaptation. For such, public policies and directives are paramount to ensure the success of CE in long term. Acknowledgements The authors wish to acknowledge the national funding agencies: The São Paulo Research Foundation (FAPESP) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). Author Contribution Validation, formal analysis, investigation, writing—original draft preparation: M.L.M.B.B.G.; visualization, supervision, project administration, funding acquisition, writing—review and editing, resources: G.J.M.; conceptualization, methodology, data curation: M.L.M.B.B.G. and G.J.M. Funding This research was funded by the São Paulo Research Foundation (FAPESP), Brazil, Grant No. 2014/21252-0. This study was also financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brasil (CAPES) - Finance Code 001. Data Availability Not applicable Declarations Ethics Approval and Consent to Participate Not applicable Consent for Publication All authors have read and agreed to the published version of the manuscript. Conflict of Interest The authors declare no competing interests. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ==== Refs References 1. Food and Agriculture Organization (2019) FAOSTAT Database 2019 2. Food and Agriculture Organization (2020) FAOSTAT Database 2020 3. United Nations (2015) Transforming our world: the 2030 Agenda for Sustainable Development. https://sdgs.un.org/2030agenda. Accessed 10 Dec 2022 4. 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Accessed 15 June 2022	0	PMC9747261	NO-CC CODE	2022-12-15 23:21:59	no	Circ Econ Sustain. 2022 Dec 14;:1-19	utf-8	Circ Econ Sustain	2,022	10.1007/s43615-022-00243-0	oa_other
==== Front J Clin Virol J Clin Virol Journal of Clinical Virology 1386-6532 1873-5967 Elsevier B.V. S1386-6532(22)00286-4 10.1016/j.jcv.2022.105354 105354 Article Epidemiological and genetic characteristics of respiratory syncytial virus infection in children from Hangzhou after the peak of COVID-19 Guo Ya-jun a Wang Bing-han b Li Lin a Li Ya-ling c Chu Xiao-li a Li Wei a⁎ a Department of Clinical Laboratory, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health. Hangzhou 310052, PR China b School of Public Health, Zhejiang University School of Medicine, Hangzhou 310052, PR China c Zhejiang LAB. Hangzhou 310052, PR China ⁎ Corresponding author at: The Children's Hospital of Zhejiang University School of Medicine, 3333 Binsheng road, Hangzhou 310052, China. 10 12 2022 1 2023 10 12 2022 158 105354105354 30 9 2022 4 12 2022 © 2022 Elsevier B.V. All rights reserved. 2022 Elsevier B.V. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Background Respiratory syncytial virus (RSV) is one of the main pathogens that causes acute lower respiratory tract infection (ARTI) in infants. During the Coronavirus Disease 2019 (COVID-19) pandemic, although strict interventions have been implemented, RSV infection has not decreased. Objectives To study the epidemiological and genetic characteristics of RSV circulating in Hangzhou after the peak of COVID-19. Methods A total of 1225 nasopharyngeal swabs were collected from outpatients with ARTIs from July 2021 to January 2022 in The Children's Hospital, Zhejiang University School of Medicine. Results A total of 267 (21.79%) of the 1225 samples were RSV positive. There was no gender bias. However, an obvious age preference for infection was observed, and children aged 3-6 years were more susceptible, which was very different from previous RSV pandemic seasons. Phylogenetic analysis of 115 sequenced RSV isolates showed that all the RSV-A viruses belong to the ON1 subtype, which could be clustered into three clusters. While all the RSV-B viruses belong to BA9. Further analysis of the mutations highlights the fixation of ten mutations, which should be given extra attention regarding their biological properties. Conclusion The incidence of RSV infection in preschool children reported in this study is high. Phylogenetic analysis showed that the subtype A ON1 genotype was the dominant strain in Hangzhou from July 2021 to January 2022. Keywords Respiratory syncytial virus COVID-19 Children Genotype Abbreviations RSV, Respiratory syncytial virus ARTI, Acute lower respiratory tract infection NCBI, National Center for Biotechnology Information ==== Body pmc1 Introduction Respiratory syncytial virus belongs to the family Pneumoviridae and the genus Orthopneumovirus [1]. RSV is a non-segmented negative-stranded RNA virus with a genomic length of approximately 15.2 kilobases. Its virion's diameter ranges from 100 to 300 nm. As one of the most common pathogens that cause acute lower respiratory tract infection in infants, RSV usually infects children under 2 years of age and causes severe cases that require hospitalization or even death [2], [3], [4], [5], [6], [7], [8]. Like other viruses, RSV does not have any specific clinical manifestations ranging from fever to chest pain. As a result, RSV infection presents a diagnostic challenge, as it can be confused with infections caused by other viruses or bacteria. RSV has ten genes that encode eleven proteins named NS1, NS2, N, P, M, SH, G, F, M2-1, M2-2 and L [9]. Among these proteins, adhesion protein G and fusion protein F glycoproteins are the main surface antigens that induce neutralizing antibodies and are usually designed as the targets of vaccines and therapeutic drugs. Additionally, the two antigenic subtypes of RSV (serotype A and serotype B) were divided based on the reactivity of the F and G surface proteins to monoclonal antibodies. Of these two important proteins, the G protein is the most variable protein of RSV. Two hyper-variable regions, which have a close relationship with viral antigenic variation, are located in the G protein. Thus, monitoring the mutations in hyper-variable region of the G protein could provide timely information on viral antigenic drift and help the development of related vaccines. In this study, we collected over 1225 nasopharyngeal swabs from outpatients with ARTIs from July 2021 to January 2022 in The Children's Hospital, Zhejiang University School of Medicine. In the 1225 swab samples, 107 were identified as RSV-A positive, and 8 were RSV-B positive. Epidemiological analysis revealed that the age of the most susceptible population ranged from 3 years to 6 years (85.8% of all infections). In contrast to other reports in China, the dominant RSV virus in Hangzhou is RSV-A rather than RSV-B. Phylogenetic analysis showed that all of the detected RSV-A viruses belonged to the ON1 subtype, which could be clustered into three clusters. All of the detected RSV-B viruses belonged to BA9. Further analysis of the mutations highlights the fixation of ten mutations, which should be given extra attention regarding their biological properties. 2 Materials and methods 2.1 Patients and samples Nasopharyngeal swabs were collected from pediatric patients with ARTIs in The Children's Hospital, Zhejiang University School of Medicine (Hangzhou, Zhejiang), from July 2021 to January 2022. The inclusion criteria were as follows: fever (body temperature≥37.5°C), accompanied by one or more symptoms of ARTIs including cough, runny nose, sputum, and sore throat. Information including demographic data, case history, symptoms, and clinical results of each patient was collected. The throat swabs were stored in 2.5 ml of viral transport medium (KaiBiLi, Hangzhou, China). RSV and five common respiratory viruses were screened: influenza virus-A, influenza virus-B, human parainfluenza virus-1, human parainfluenza virus-3 and human adenovirus. 2.2 Nucleic acid extraction and screening for respiratory viruses Viral RNA and DNA were extracted from 300 µL nasopharyngeal swab using a Nucleic Acid Extraction Kit (Catalog Z-ME-0044, Shanghai Zhijiang biotechnology Ltd. Co, China) according to the manufacturer's instructions. Common respiratory viruses and RSV were screened by real-time PCR with the Applied Biosystems 7500 real-time PCR system (Applied Biosystems, Foster City, CA, USA). The thermocycling protocol was reverse transcription and included 10 min at 45 °C, 5 min at 95 °C and 45 cycles of denaturation at 95 °C for 15 s and annealing at 60 °C for 45 s. All experimental operations were strictly performed in accordance with the manufacturer's instructions. 2.3 Nested PCR for G gene Amplification of RSV-A and RSV-B The RSV-positive samples were selected and reverse transcription of the extracted viral RNA was performed by using the MonScript RTIII Super Mix with dsDNase (Monad Biotech Co..Lid, China). The second hypervariable region of the G protein gene was the target for the external and seminested PCRs [10]. First, external PCR was carried out with the forward primer ABG490 and the reverse primer F164. Four microliters of cDNA were added to 21 μl PCR reagents (2 × Taq MasterMix, CWBio Co., Ltd, China). Amplification was carried out at 94 °C for 2 min, followed by 35 cycles of 94 °C for 30 s, 55 °C for 30 s, and 72 °C for 30 s, with a final extension at 72 °C for 4 min. Four microliters of the external PCR products were used for the seminested PCRs. Second, AG655 for group A (450bp) and BG517 for group B (585bp) were used as forward primers, and F164 was used as the reverse primer for the seminested PCR (primers are listed in Table 1 ). Amplification was carried out at 94 °C for 2 min,followed by 35 cycles of 94 °C for 30 s, 55 °C for 30 s, and 72 °C for 30 s, with a final extension at 72 °C for 4 min. Finally, the PCR products were sent to TSingKe Biological Technology Co., Ltd. (Hangzhou, China) for sequencing.Table 1 Primers used for RSV G gene amplification. Table 1Primers Sequence(5’-3’) ABG490 5’-ATGATTWYCAYTTTGAAGTGTTC-3′ AG655 5’-GATCYCAAACCTCAAACCAC-3’ BG517 5’-TTYGTTCCCTGTAGTATATGTG-3’ F164 5’-GTTATGACACTGGTATACCAACC-3’ 2.4 Statistical analysis SPSS 22.0 was used for statistical analysis. The Chi-square test was used to compare the detection rates of RSV among different groups, and P<0.05 indicated statistically significant differences. 2.5 Phylogenetic analysis The nucleotide sequences obtained from within the second hyper-variable region of the G gene of subgroups A and B were compared to the available RSV sequences from GenBank. All sequences were aligned by using MAFFT v7.4.1 [11]. Phylogenetic trees were constructed by using the IQTREE v2.1.3 [12] and visualized with R package ggtree [13]. Analysis of complete gap deletion or missing data was also performed. Genetic distances were calculated using the Kimura 2‐Parameter method in MEGA-X [14]. 2.6 Nucleotide sequence accession numbers Representative nucleotide sequences of RSV group A and B genotypes were submitted to GenBank and given accession numbers OP310836-OP310942 and OP310945-OP310952. 3 Results 3.1 Epidemiological characteristics of RSV-positive cases As was shown in Table 2 , 267 (21.79%, 267/1225) among the 1225 samples were found to be RSV positive. Among the 267 positive patients, 130 (10.61%, 130/1225) were male, and 137 (11.18%, 137/1225) were female; the difference was insignificant (χ 2= 2.242, P = 0.134). There were 2 cases aged from 0 to 6 months old (0.16%, 2 / 1225), 20 cases aged from 6 months to 1 year old (1.63%, 20/1225), 104 cases aged from 1 to 3 years old (8.49%, 104/1225), 125 cases aged from 3 to 6 years old (10.21%, 125/1225), and 16 cases aged from 6 years to 18 years old (1.3%, 16/1225). The positive detection rates from the age of 1 to 3 years age group (χ2 = 9.599, P = 0.002) and 3 to 6 years age group (χ2 = 26.586, P<0.001) were significant higher compared with the other groups, while there was no difference between the two age groups (χ2 = 0.907, P = 0.341). Adenovirus was the most common co-infecting virus in RSV-positive cases (7.49%, 20/267).Table 2 Epidemiologic characteristics of 267 children with RSV infection. Table 2Age Gender ≤6m ≤1y ≤3y ≤6y >6y Totle positive case χ2 P Male 1(0.08%) 13(1.06%) 47(3.84%) 61(4.98%) 8(0.65%) 130(10.61%) 2.242 0.134 Female 1(0.08%) 7(0.57%) 57(4.65%) 64(5.23%) 8(0.65%) 137(11.18%) Totle positive case 2(0.16%) 20(1.63%) 104(8.49%) 125(10.21%) 16(1.3%) 267(21.79%) χ2 0.363 1.8 9.599 26.586 2.798 P 0.547 0.18 0.002* <0.001* 0.094 The chi-square (χ༒) test was performed using SPSS.A P-value<0.05 is indicated by * and is considered statistically significant. 3.2 Phylogenetic analysis of genotype For the 267 RSV-positive samples, 115 were successfully sequenced. Of these 115 sequences, 107 were identified to be the RSV-A genotype, and 8 were detected to be the RSV-B genotype using genotype-specific primers. To show their evolutionary history, phylogenetic analysis was used to analyze all the sequenced RSV-A and RSV-B. Forty-four representative RSV-A sequences, and 24 RSV-B sequences were selected by clustering all the RSV-A sequences and RSV-B sequences in the National Center for Biotechnology Information (NCBI) with CD-HIT [15]. Phylogenetic trees of the second hyper-variable region of G gene in RSV-A and RSV-B were built with both sequenced sequences and related representative sequences, respectively (Figs. 1 and 2 ). All the sequenced RSV-A viruses belonged to the genotype ON1 and could be clustered into 3 clusters. For the phylogenetic analysis with 8 sequenced RSV-B viruses and 24 representative sequences (Fig. 2), all these 8 sequences were classified as the BA9 genotype. For children with ON1 or BA9 RSV infection, Fever, Cough and Coarse breath sound were most common clinical symptoms with the proportion above 85% (Table 3 ).Fig. 1 G gene phylogenetic trees of RSV A strains. The phylogenetic trees of RSV A strains (A) derived in the study during 2021-2022 based on the G gene. The phylogenetic trees were constructed using the maximum likelihood method with 1,000 bootstraps. Reference genotypes downloaded from the GenBank are labeled with red dots. Fig 1 Fig. 2 G gene phylogenetic trees of RSV B strains. The phylogenetic trees of RSV B strains (B) derived in the study during 2021-2022 based on the G gene. The phylogenetic trees were constructed using the maximum likelihood method with 1,000 bootstraps. Reference genotypes downloaded from the GenBank are labeled with blue dots. Fig 2 Table 3 Clinical symptoms of children with RSV infection. Table 3Characteristics Overall (n = 115) Group P-value ON1 (n = 107) BA9 (n = 8) Age, mean (SD) 3.1 (1.5) 3.2 (1.5) 2.5 (1.1) 0.200 Female, N (%) 67 (58.3) 63 (58.9) 4 (50.0) 0.905 Fever, N (%) 114 (99.1) 106 (99.1) 8 (100.0) 1.000 Cough, N (%) 104 (90.4) 97 (90.7) 7 (87.5) 1.000 Expectoration, N (%) 63 (54.8) 57 (53.3) 6 (75.0) 0.411 Pharyngeal congestion or pharyngalgia, N (%) 99 (86.1) 93 (86.9) 6 (75.0) 0.682 Coarse breath sound, N (%) 104 (90.4) 99 (92.5) 5 (62.5) 0.031 Abdominal pain, N (%) 2 (1.7) 2 (1.9) 0 (0.0) 1.000 Diarrhea, N (%) 1 (0.9) 1 (0.9) 0 (0.0) 1.000 Vomit, N (%) 6 (5.2) 4 (3.7) 2 (25.0) 0.074 Pant, N (%) 2 (1.7) 1 (0.9) 1 (12.5) 0.312 Anhelation, N (%) 1 (0.9) 1 (0.9) 0 (0.0) 1.000 Otalgia, N (%) 2 (1.7) 2 (1.9) 0 (0.0) 1.000 According to the phylogenetic analysis of the partial G gene fragment to the RSV strain, the A strains isolated in the present study was similar to the strain (MZ515854) found in United Kingdom, the percentage identity at nucleotide and amino acid(aa) levels between them were 97.93% and 95.71%. 107 ON1 strains were classified into 3 clusters. Cluster 1 consisted of 42 strains and cluster 2 include 62 strains which were similar to the strains from the United Kingdom (MZ515854, MZ516096). Whereas 3 ON1 strains were similar to the strains from Beijing, China (OM256491 and OM256490). The BA9 strains isolated in the study were similar to the strain (MZ516135) found in Netherlands, the percentage identity at the nucleotide and amino acid (AA) levels between them were 98.65% and 97.03%, respectively. 3.3 Amino acid analysis All amino acid mutations of RSV-A were shown in Table S1. Compared with the reference strain MZ515854, we identified the specific amino acid substitution in cluster 1 of the ON1 strain of RSV-A: P230T, E232G, T241P, G284S, S299N; specific amino acid substitution in cluster 2 of the folLlowing virus strains: V225A (23 strains), E232G/R, Y273H (28 strains), L274P (57 strains), L298P (36 strains), Y304H (10 strains), L310P (19 strains); and specific amino acid substitutions in cluster 3: E224A, V225A, E232G, L247P, Q258H, L266H, L274P, T282I, G296S, L298P, Y304H, L310P, S311P, L314P and T320A. All three clusters had an amino acid substitution at position 232, and there were the same or different amino acid substitutions but the same mutation site among the three clusters. For example, cluster 2 had the same amino acid substitution as cluster 1 at sites 284 (2 strains) and 299 (2 strains). The difference is that although both clusters had mutations at sites 230 and 300, 4 strains of cluster 2 were P230H, and 6 strains were P300Q. The same situation occurred at site 258, and there were 2 strains of Q258R in cluster 1, but the substituted amino acids in cluster 3 were different. Other mutations found in this study include T239A, E286K, T245A, L248F, P256Q, E257K, T264I, E271K, L289I, T293S, S294T and S313Y (Fig. 3 ).Fig. 3 Deduced amino acid alignments of the G genes from Hangzhou RSV-A strains and reference strains (MZ515854). Fig 3 All amino acid mutations of RSV-B were shown in Table S2. In comparison with the reference strain MZ516135, we found that there were different degrees of amino acid mutations in the BA9 type of RSV-B (Fig. 4 ). The same amino acid substitutions at the same site included I252T (2 strains), V269A and A274T (3 strains), and 2 strains (E290D and E290K) with different amino acid substitutions at the same site. The amino acid substitutions of the BA9 type found in this study were T198P, K199Q, T201H, N202I, K203Q, K211R, T226I, N228G, K231E, K232E, T238A, D251N, T253A, K256E, I268T, S275P, T292I, N294Y, T296K, T300I and A301V.Fig. 4 Deduced amino acid alignments of the G genes from Hangzhou RSV-B strains and reference strains (MZ516135). Fig 4 4 Discussion RSV is an important pathogen responsible for the development of ARTIs and has attracted the attention of pediatricians. [16,17]. In 2021, although strict interventions were implemented to prevent the transmission of COVID-19, the infection of other respiratory syncytial viruses including RSV did not decrease. In the present study, 1225 throat swabs were collected from the ARTIs of pediatric patients from July 2021 to January 2022, when represented a typical time period after the peak of COVID-19. The positive rate of RSV was 21.79%. This is lower than the infection rate reported in Hangzhou from 2011 to 2013 (34.5%) [18] but higher than the rate in Zhongshan from 2018 to 2020(12.67%) [19]. The focus of our research is the molecular epidemiology, evolution and transmission of RSV to identify epidemic viruses and clinical features, which is important for future epidemiological studies and possible evaluation of future anti-RSV therapy [20]. No gender bias was found in the present study. However, in contrast to previous studies showing that the highest incidence of RSV occurs in children under 1 year old [21,22], we found that the infection rate of children aged 3-6 years old was significantly higher than that of other age groups. A possible explanation might be that adults are required to wear masks in public and wash their hands more frequently due to the outbreak of COVID-19 during the study period, which reduces the risk of respiratory tract infection in adults. As a result, infants and young children under 3 years of age also have a corresponding reduction in the risk of infection. When the outbreak of COVID-19 has been effectively controlled, primary and secondary school children are more active and effective in implementing measures to prevent COVID-19 infection; in contrast, preschool children aged 3-6 years old are slightly weaker in this regard, resulting in an increased risk of infection. RSV is often co-infected with other respiratory viruses, and adenovirus co-infection was dominant in this study, which is consistent with the research report in Guangzhou [23]. According to reports, the G protein of RSV is highly variable; the extracellular domain of G protein contains two mucin-like regions, which are rich in serine, threonine and proline, as well as N-linked oligosaccharides and O-linked oligosaccharides [24]. These two regions are called hyper variable regions HVR1 and HVR2, HVR1 and HVR2 are separated by a highly conserved region of 13 amino acids [25]. The hypervariable region is a high incidence area of gene mutation and an important area that stimulates the body to produce neutralizing antibodies [26]. From 2009 to 2014, the dominant subtype transformation pattern of RSV in southern Zhejiang was BAABB [27], in which the NA1 genotype was the most common subtype A, followed by the ON1 genotype. The main subtype of RSV transmission in children with ARTIs in Shanghai from 2019 to 2021 was subtype B, and all of them were of the BA9 genotype [28]. While this study shows that subtype A is mainly prevalent in Hangzhou, all of them are ON1 genotype although the BA9 genotype of RSV-B was co-circulation in Hangzhou as well. The diversity of RSV strains and the continuous change in circulating strains in a region make it particularly important to determine the cycle pattern of strains and to understand the relationship between strains and RSV diseases. According to the amino acid sequence alignment of G gene, it was found that there were different amino acid mutations at different sites between the same genotyped strains of RSV-A and RSV-B, which indicated that there were great differences among different genotypes of different subtypes in the evolution of RSV. The previous study has illustrated that the children who infected with genotype A/NA1 were more easily diagnosed lower respiratory tract infections and were required hospitalization more often than those who infected with genotype A/ON1 [29]. In addition, the clinical severity of RSV-A ON1 was higher in PICU-treated children [30]. In this study, all children were from outpatients who showed mild clinical symptoms. In summary, our findings describe the epidemiological and genetic changes in RSV infection after the outbreak of COVID-19, and further emphasize the importance of continuous surveillance of RSV in the shadow of COVID-19 locally and globally. It is indispensable to study the relationship between the subtypes of RSV and the caused diseases, to calculate the correlation between the subtypes of RSV and the severity of the disease and clinical symptoms, and to establish preventive diagnosis and treatment programs for specific subtypes, which will also provide ideas for the development of follow-up vaccines. 5 Conclusion The present study investigated the epidemiological and genetic characteristics of respiratory syncytial virus infection in children in Hangzhou after the epidemic peak of COVID-19. Although some prevention and control measures have been implemented in China, the incidence of RSV was high during this survey period. The incidence rate of preschool children reported in this study was higher, which is different from that described in previous studies. Phylogenetic analysis showed that the subtype A ON1 genotype was the dominant strain in Hangzhou from July 2021 to January 2022. Declaration of Competing Interest The authors declare that they have no conflict of interest. Appendix Supplementary materials Image, application 1 Image, application 2 Image, application 3 Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.jcv.2022.105354. ==== Refs References 1 Amarasinghe Gaya K Ceballos Nidia G Aréchiga Banyar Ashley C Taxonomy of the order Mononegavirales: update 2018 Arch. Virol. 163 8 2018 2283 2294 29637429 2 Pangesti KNA Abd El Ghany M Walsh MG Kesson AM Hill-Cawthorne GA Molecular epidemiology of respiratory syncytial virus Rev. Medic. Virol. 28 2 2018 3 Liu WK Chen DH Tan WP Xu D Qiu SY Zeng ZQ Li X Zhou R. 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==== Front J Spec Educ J Spec Educ SED spsed The Journal of Special Education 0022-4669 1538-4764 SAGE Publications Sage CA: Los Angeles, CA 10.1177/00224669221140568 10.1177_00224669221140568 Empirical Research Adaptation of Universal Behavioral Supports Within an Alternative Education Setting https://orcid.org/0000-0002-5818-969X Minkos Marlena L. PhD, NCSP, BCBA 1 Winter Emily L. PhD, NCSP 1 Trudel Sierra M. MS, NCSP 1 1 University of Connecticut, Storrs, USA Marlena L. Minkos, Neag School of Education, University of Connecticut, 249 Glenbrook Road, Unit 3064, Storrs, CT 06269, USA. E-mail: [email protected] 10 12 2022 10 12 2022 00224669221140568© Hammill Institute on Disabilities 2022 2022 Hammill Institute on Disabilities This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections. Alternative education (AE) settings support students with significant social–emotional and behavioral needs. Such settings often implement individualized programming; however, this presents challenges with staffing resources and training. Application of systems to address behavior on a schoolwide level could simplify training, increase staffing flexibility, and decrease use of crisis response procedures. This 2-year, descriptive case study provides an implementation example of universal behavioral supports based on a Positive Behavioral Interventions and Supports (PBIS) framework within an AE setting. Over the course of the study, a reduction in staff use of restraint and seclusion procedures was observed. Additionally, staff perceived the framework favorably. Implementation steps are described, along with differentiation of the framework to meet the needs of a heterogeneous student population within the context of the COVID-19 pandemic. Tier 1 universal behavioral supports PBIS alternative education autism EBD restraint seclusion COVID-19 edited-statecorrected-proof typesetterts1 ==== Body pmcPositive Behavioral Interventions and Supports (PBIS) is a multi-tiered prevention and intervention framework designed to support students’ social, emotional, and behavioral functioning and academic performance. It is not a manualized program or curriculum, but rather a collection of evidence-based practices that can be adapted within a variety of educational settings. In 2020, over 29,000 schools across the world had adopted PBIS to improve student outcomes (George & Martinez, 2020). PBIS involves implementing a continuum of evidence-based practices to address student needs, using data to monitor progress, and relying on teams to guide implementation. Practices and interventions are organized within three tiers where all students are provided with Tier 1 supports, at-risk students are provided with targeted interventions through Tier 2, and high-risk students are provided with individualized interventions through Tier 3. Core features of Tier 1 include (a) defining three to five positively stated expectations that apply to all students and staff across settings, (b) explicitly teaching expectations across settings, (c) implementing a system for acknowledging prosocial behaviors, (d) responding to problem behaviors using a consistent continuum of responses that matches the severity of the behavior, and (e) frequently reviewing behavioral data to guide decision-making. Interventions provided at Tiers 2 and 3 build upon and intensify Tier 1 practices, resulting in a comprehensive and cohesive framework. When students do not respond adequately to Tier 3 supports, they may be referred for an evaluation to determine eligibility for special education services under the Individuals with Disabilities Education Act (IDEA, 2004). Within general education settings, implementation of Tier 1 practices has been associated with positive behavioral and academic outcomes, including decreased disciplinary incidents and suspensions, increased students meeting state testing benchmarks, and improvements in school climate (Bradshaw et al., 2009, 2010; Childs et al., 2016; Gage et al., 2017, 2019). Alternative Education Settings Despite the positive effects of PBIS, students with significant emotional and behavioral difficulties are often best supported within more specialized and restrictive settings. According to the National Center for Education Statistics (U.S. Department of Education, National Center for Education Statistics, 2021), over 20,000 students with disabilities were placed in separate schools, residential facilities, or correctional facilities during the 2019 to 2020 school year, representing 2.9% of the student population in the United States. These facilities are often referred to as alternative education (AE) settings, as students are typically placed in them following removal from general education settings as a result of significant behavioral difficulties which precipitate the need for more individualized support. Although AE settings can vary widely from state to state, they often serve as transitional educational placements, with students potentially moving to more or less restrictive settings at any point in the school year (Kumm et al., 2020). Behind students with deaf-blindness and multiple disabilities, students with emotional and behavioral disabilities (EBD) were the third most common group placed in AE settings. Students with hearing impairment and autism represent the fourth and fifth most commonly referred groups, respectively (U.S. Department of Education, National Center for Education Statistics, 2021). Overall, AE settings are tasked with providing evidence-based programming to students with varied and intense behavioral needs. Alternative education settings face additional, unique challenges in supporting students with a range of significant disabilities. Challenges include high rates of staff turnover, providing adequate supports for staff who are inexperienced in working with students with behavioral difficulties, short-term educational placements leading to frequent turnover of students within the setting, students requiring different levels of support at any given time during placements, as well as the need for staff to be able to work with a variety of students (Baker et al., 2008; Connor et al., 2003; Lehr et al., 2009). As such, there is a need for evidence-based practices to facilitate the provision of high-quality behavioral supports in an efficient and effective way within complex AE settings. Integration of universal, Tier 1 practices within AE settings could potentially reduce the need for more complex, individualized systems, thus maximizing efficiency of both training provided to staff as well as support provided to students. In addition, use of universal practices could increase opportunities for flexible staffing options, as some elements of support would remain similar across students. A growing body of research suggests that PBIS can be adapted within AE settings to effectively support the social–emotional and behavioral needs of students with significant disabilities. More specifically, implementation of Tier 1 PBIS within AE settings has been associated with increases in on-task and prosocial behaviors, along with decreases in problem behaviors such as defiance and physical aggression (Farkas et al., 2012; Griffiths et al., 2019; Simonsen et al., 2010). Results of a recent systematic review of 19 studies conducted by Grasley-Boy and colleagues (2021) indicated that use of restraint and seclusion procedures following implementation of PBIS within AE settings almost always decreased and continued on a decreasing trend over multiple years when evaluated over time. These results are particularly meaningful for practitioners working with students with significant behavioral needs, as such restrictive crisis procedures involve removing students from the classroom setting and can increase the likelihood of aggressive behaviors (Magee & Ellis, 2001). In addition, physical restraints can result in lasting psychological effects and even death in rare instances (Couvillon et al., 2010; Mohr et al., 2003). Although physical restraints may be necessary to maintain safety in certain situations, it is important that such procedures are used sparingly. These results suggest that implementation of Tier 1 PBIS may provide a set of practices to decrease use of physical restraints in AE settings through a focus on prevention of behavioral escalation. Results of the review also indicated a reduction in inappropriate behaviors across studies. Because students supported within AE settings have complex and varied learning and behavioral needs, implementation of PBIS practices within such settings warrants special consideration and adaptation. Clemens and colleagues (2021) suggest that typical Tier 1 practices should be intensified within AE settings. For example, such settings may require more explicit and frequent instruction in expectations and prosocial behaviors that are embedded in routines throughout the day and across settings. This instruction will also need to be differentiated to meet the needs of a heterogeneous student population. Intensification of Tier 1 strategies should also include more frequent acknowledgment and reinforcement of adaptive skills which, again, are differentiated according to student needs. In addition, implementation of PBIS systems within AE settings requires special consideration with respect to staff support. In their focus group study, McDaniel and colleagues (2014) found that integrating PBIS with existing, more individualized systems within AE settings can present challenges with staff buy-in. In such situations, the researchers recommend simplifying the systems to ensure feasibility. The researchers also note that job responsibilities within AE settings are particularly demanding and complex in comparison to more traditional settings, thus continuing to highlight the importance of efficiency. According to Simonsen and colleagues (2010), ongoing coaching and professional development is needed to support implementation within complex AE settings. Although a growing body of evidence provides support for the adoption of PBIS within AE settings, there is a need for more specific guidance and examples regarding adaptation of the framework. The purpose of this paper is to share the results of a 2-year, descriptive case study in which Tier 1 universal behavioral supports based on a PBIS framework were implemented within an AE setting in the Northeast. Implementation steps are described along with how the framework was differentiated to meet the needs of a heterogeneous student population. Outcome measures are discussed with respect to staff use of restraint and seclusion procedures and feasibility and acceptability. Method Setting Universal behavioral supports were implemented in a publicly funded, AE setting in the Northeast for students in Pre–K through age 21. The school provided comprehensive special education services to students with a variety of developmental disabilities, including autism, EBD, and complex medical backgrounds. Students presented with a wide range of cognitive abilities and communication modalities, ranging from intellectual disability to superior cognitive functioning and non-verbal to typical verbal communication. Most students in the school received 1:1 adult support throughout the day. The school supported roughly 60 students. Long-term options and short-term diagnostic support were provided. The school was diverse with respect to race, ethnicity, and socioeconomic status. During the 2020 through 2021 school year, 20% of students in the school identified as Hispanic or Latino, 15% as Black or African American, 45% as White, 15% as two or more races, and 5% as Asian. Fifty-seven percent of students were eligible for free and reduced price meals (PowerSchool, 2021). Implementation Steps The school provided high-quality, specialized support rooted in behavior analytic principles. Families, educators, and regional administrators have been noted to value the highly individualized programming the school has to offer. However, developing and implementing solely individualized programming has presented challenges with respect to staff resources and training. The application of systems and processes to address behavior on a schoolwide level was initiated to potentially simplify staff training, enable greater flexibility with staffing resources, and improve the quality of instruction. To lead efforts in systematizing select aspects of teaching, reinforcing, and responding to behavior, a School-Wide Behavior Support Team (SWBST) was created at the beginning of the 2019 to 2020 school year. The team included the school principal, two intensive program coordinators, a school psychologist, a school psychology advanced practicum student, and a social work intern. The team met monthly to guide implementation of key components of a schoolwide behavioral framework over the course of the 2019 to 2020 and 2020 to 2021 school years. It is important to note that much of this work took place within the context of the COVID-19 pandemic. Therefore, adaptations were made to the framework to maximize student learning within a unique, hybrid instructional environment and to promote safe, health-related behaviors during in-person learning. Schoolwide Expectations and Matrix Prior to the start of the 2019 through 2020 school year, schoolwide behavioral expectations were developed by the school principal and intensive program coordinators and included: Take Care of Ourselves, Take Care of Others, and Take Care of Our Environment. In the fall of 2019, a behavioral expectations matrix was developed that defined specific behaviors associated with each expectation across settings within the school. Members of the SWBST, including the school psychology advanced practicum student and the social work intern, assisted in the creation of the matrix. First, they created a blank matrix, identifying critical areas in the school requiring specifically defined expectations. Then, they toured the building, identifying any existing signage with rules listed. Next, staff responsible for the locations were interviewed about expectations and asked to review previously identified expectations (i.e., from signage) for accuracy. Feedback was used to refine the matrix, and language was reviewed to ensure that it was consistent and positively stated. Although the matrix was initially drafted in the fall of 2019, it was updated in the fall of 2020 to include social distancing, hand sanitizing, and mask-wearing expectations, which became pertinent as students returned to school buildings in the midst of the COVID-19 pandemic. The matrix was intended to be a resource for educators to access and refer to when teaching behavioral expectations to students. For example, when teaching students to “Take Care of Ourselves,” teachers referred to the matrix to ensure that they taught students what it “looks like” in the classroom: complete all work, do your best work, ask for help when needed, raise your hand, follow directions the first time, and stay focused. Posters were created and displayed in common areas across the school to remind students of the expectations. They included both pictures and words to increase accessibility for a wide range of learners. Behavioral Expectations Instruction Lesson plans were created for each schoolwide expectation (i.e., Take Care of Ourselves, Take Care of Others, Take Care of Our Environment). The lesson plans were designed to provide an overarching framework for lessons following a Model, Lead, Test progression in which skills are first modeled for students, then students have the opportunity to practice skills with adult assistance, and finally students engage in skills independently and receive feedback on their performance. The lesson plans included a bank of resources to facilitate instruction that teachers could adapt to meet the needs of their specific student population. The SWBST felt that this approach would be more feasible than creating scripted lesson plans due to the wide range of developmental levels served by the program. Lesson plans included links to a variety of online resources, including videos, music, short stories, and books. Developmentally appropriate resources were selected to appeal to student learning through storytelling and guided practice for younger students and reflection on personal experiences and relevant topics such as social media, relationships, and mental health for older students. Each lesson included the following components: setting where lesson would occur; lesson objective; materials required; positive teaching examples; and sample activities that could be used to Model, Lead, and Test students’ understanding of the skills. A variety of activities were described to provide options for facilitating instruction with a range of age levels (e.g., elementary, middle, high school). Lesson plans also included guidance on how to acknowledge students for engaging in expectations, as well as suggestions regarding potential modifications for students with unique needs. The SWBST created a Behavioral Expectations Lesson Plan Guidelines document to ensure that lessons were taught consistently across the school setting. The guidelines described staff expectations regarding implementation and included a calendar for lesson planning. Teachers were encouraged to adapt the calendar, including the duration of lessons, to meet the needs of their students. However, daily instruction was expected to remain constant. As previously mentioned, instruction varied based on the needs of the classroom. As such, lesson plans offered potential modifications for teachers to consider based on the needs of their students. For students who are nonverbal, potential modifications included minimizing verbal instructions, increasing the use of visuals, and placing a strong emphasis on explicit modeling and repetition. For higher functioning students with stronger cognitive abilities and verbal communication, potential modifications included increased emphasis on critical thinking and self-reflection. For example, students might be asked to write down personally relevant examples of what it means to “Take Care of Ourselves,” prior to staff sharing examples. Another sample activity for higher functioning students included watching a video about the importance of hard work when learning about the behavioral expectation of Take Care of Ourselves and then participating in a facilitated discussion on the tangible rewards of hard work. To promote generalization of skills throughout the school, teachers were encouraged to have students practice skills in various locations throughout the building by taking “field trips” to other parts of the school. Within those settings, staff members modeled expected behaviors, led students through activities where they could practice expected behaviors with assistance, and then had students engage in behaviors independently and receive feedback. Positive Reinforcement System Beginning at the start of the 2019 to 2020 school year, students were awarded with a Sand Dollar ticket paired with specific praise when they demonstrated one of the schoolwide expectations. The principal selected the Sand Dollar theme to align with the school’s location along the shoreline. When a student demonstrated an expectation, a paper ticket was provided in the moment by the classroom teacher or support staff, and the staff member told the student specifically why they were being awarded the Sand Dollar while also noting the expectation followed. For example, the staff member would say, “I noticed that you asked your friend what was wrong when you saw that he was upset. Great job taking care of others!” The student’s name, date, and specific behavior being acknowledged was written on the ticket. In addition, a box was checked to indicate which schoolwide behavior expectation was met. The student was able to enter the ticket into a fishbowl in the main office for a weekly prize drawing. At the end of each week, two Sand Dollar tickets were drawn from the fishbowl, one for an elementary student and one for a secondary student. This was done to increase opportunities for students across grade levels to win. Also, when the reinforcement system was initially introduced, it was noted that secondary teachers were awarding Sand Dollars at lower rates than elementary teachers. Subsequent to ensuring that a secondary student was a Sand Dollar winner each week, rates of Sand Dollars awarded to secondary students increased. When students won the Sand Dollar drawing, they could pick a reward of their choice from a menu of options. A variety of choices were offered to meet a range of preferences and included such things as lunch with the principal, extra time to play outside with friends, and a variety of gift cards in small denominations. Student feedback was sought and utilized when creating the menu and informed ongoing updates. Copies of winning Sand Dollar tickets were also posted on an announcement board in a central location within one of the hallways, and a special note was sent home to the family. Winners were announced over the school intercom, and this quickly became a much anticipated event. Higher functioning students were given the opportunity to announce the winners, which became a preferred activity. During the 2020 to 2021 school year, the SWBST added an additional schoolwide incentive to the reinforcement system. During monthly meetings, the team set a goal number of Sand Dollars to be awarded schoolwide for the upcoming month based on the number of tickets awarded the previous month. Weekly progress updates were posted on the announcement board, and a schoolwide reward was provided when the predetermined goal was achieved. Students were given the opportunity to vote on schoolwide rewards. Examples of rewards included: movie and popcorn, pajama day and hot chocolate, new recess item and extra time outside, and an ice cream social. In addition to providing students with reinforcement for displaying expectations, the reinforcement system also involved acknowledging staff for engaging in behaviors consistent with Take Care of Ourselves, Take Care of Others, and Take Care of Our Environment. Any staff member could award another staff member with a Sand Dollar, which was put into a monthly prize drawing with the opportunity to win a gift card of their choice. To support teacher implementation of the reinforcement system, a Positive Reinforcement System Guidelines document was developed. The document provided teachers and staff with explicit guidance on how to deliver and maintain the system, along with a description of primary components (e.g., student and staff Sand Dollars, weekly drawings, schoolwide rewards, etc.). Classroom teachers were encouraged to collaborate with support staff who worked with their students (e.g., Board Certified Behavior Analysts, social workers) to determine how to best utilize Sand Dollars to meet individual student needs. During the 2020 to 2021 school year, instruction was provided in a hybrid format for the majority of the year where students engaged in a combination of remote and in-person learning. Staff continued to award students with Sand Dollars during remote instruction, filling out an electronic version of the ticket and posting a picture of the ticket on the online learning platform for the student and family to view. When awarding Sand Dollars during remote instruction, staff also filled out a paper version of the ticket to enter into the weekly drawing. The SWBST noted that low numbers of Sand Dollars were awarded during periods of prolonged remote instruction. To address this, they created a teacher incentive that used a BINGO-style board that could be customized to meet the needs of each individual classroom. Teachers were asked to fill in the blocks on the BINGO board with behaviors that they might award Sand Dollars for during remote instruction. Each time they awarded a Sand Dollar, they filled in the block on the BINGO board that corresponded with the behavior. Teachers who completed their BINGO board received a gift card. Ongoing Training and Coaching Initially, at the start of the 2019 through 2020 school year, the schoolwide expectations and reinforcement system were introduced to staff by members of the SWBST during a staff meeting. The team recognized a need for more explicit and ongoing training for staff at the start of the 2020 through 2021 school year, when students and staff returned to school buildings after a prolonged period of closure due to the COVID-19 pandemic. In early fall 2020, the SWBST led two short trainings to introduce Behavioral Expectations Lesson Plans to teachers and to re-familiarize staff with the Behavioral Expectations Matrix and School-wide Positive Reinforcement System. Check-ins also occurred with the full staff in October, January, and March to support implementation, gather feedback, answer questions, brainstorm solutions, and share data. In addition, individual consultation sessions were conducted with teachers to gather feedback on perceptions of the framework and to identify additional supports needed. Teachers were provided with strategies to support differentiation of the framework for a variety of learners, and feedback from these individual meetings shaped future professional development. Communication With Staff and Families Home–school and schoolwide communication regarding the framework was essential. A Sand Dollar certificate was created and sent home with drawing winners to support home-school communication. In addition, a Sand Dollar Digest was disseminated to teachers to communicate monthly Sand Dollar goals and rewards, as well as to highlight implementation examples and to share data updates. Student progress toward Sand Dollar goals was tracked visually on an announcement board in a community space in the hallway. The most current Sand Dollar Digest was also posted on the announcement board, along with Sand Dollar certificates of drawing winners. Implementation Fidelity The Benchmarks of Quality (BoQ) is a fidelity measure and progress monitoring tool that was utilized by the SWBST to inform ongoing implementation of universal behavioral supports. The BoQ is a 53-item, rubric-style measure designed to systematically assess core features of Tier 1 PBIS across 10 key domains (Kincaid et al., 2010). It was chosen as a progress monitoring measure because of its narrow focus on Tier 1 features, which was consistent with the focus of this case study. The BoQ has demonstrated evidence of reliability and validity (Cohen et al., 2007) and can be used to inform both initial and ongoing implementation. A total score of 70% or above on the BoQ indicates that Tier 1 supports are currently in place to a degree that can impact students positively (Kincaid et al., 2010). The SWBST completed the BoQ collaboratively in the summer of 2019 to provide a pre-implementation measure. The team met as a group to complete the measure, coming to a consensus on each item through discussion. The BoQ was completed by the SWBST again in May 2020 and May 2021 as progress monitoring measures. According to the BoQ, the total implementation score rose significantly from 38% in the summer of 2019 to 71% in May 2020. The most significant growth was seen in the areas of Expectations & Rules Developed, Reward/Recognition Program, and Lesson Plans for Teaching Expectations. Areas of relative weakness included Faculty Commitment, Procedures for Dealing with Discipline, Data Entry & Analysis Plan, PBIS Team, and Evaluation. Post-implementation results of this measure were just above 70% in May 2020, indicating that Tier 1 supports were in place to a degree that could impact students positively at the time. However, the team recognized the importance of ongoing efforts needed to maintain the fidelity of the framework. Action steps for the following school year were developed based on the results of the BoQ and included the following: (a) establish a process for the SWBST to regularly review outcome data (i.e., staff use of restraints and seclusions, number of Sand Dollars awarded), (b) introduce newly developed lesson plans and guidelines for behavioral expectations instruction and reinforcement system, (c) add regular schoolwide rewards along with goal-setting to the reinforcement system, (d) increase opportunities for student and staff involvement in the framework, (e) develop and implement a systematic process for sharing schoolwide data regularly with staff, and (f) provide staff with ongoing training and coaching through regular check-ins and consultation. The total implementation score rose again from 71% in May 2020 to 76% in May 2021. The most significant growth was seen in the areas of Evaluation, PBIS Team, and Expectations & Rules Developed. Areas of relative weakness included Faculty Commitment, Procedures for Dealing with Discipline, and Data Entry & Analysis Plan. Reward/Recognition Program decreased slightly due to inconsistency in implementation of the staff reward system. Data Entry & Analysis Plan also decreased slightly due to re-conceptualizing these data from a purely schoolwide perspective versus individual student data collection systems. These results were also utilized to develop action steps and recommendations for future work. An area identified for particular focus moving forward pertained to Data Entry & Analysis. Within this AE setting, all students had individualized behavior plans coupled with individualized data systems. Although the staff collected a great deal of individual student data, there were no systems in place to analyze student behavior data on a schoolwide level, which posed challenges in evaluating the effectiveness of the framework. Results of the BoQ are summarized in Figure 1. Figure 1. Results of Benchmarks of Quality. Design and Data Analysis This descriptive case study was conducted to assess potential impacts of universal behavioral supports within an AE setting. Data on implementation fidelity were also collected at multiple points to guide intervention planning. Pre–post data on staff use of restraint and seclusion procedures were collected, along with qualitative and quantitative data on feasibility and acceptability. Results Staff Use of Restraint and Seclusion Procedures Data on staff use of restraint and seclusion procedures were collected and documented according to procedures specified by state law. These data were then analyzed monthly during scheduled SWBST meetings. The team identified average restraints and seclusions per student per month as an appropriate progress monitoring measure, as it would account for variations in student attendance over time. Average restraints and seclusions per student over the course of the 2018 to 2019, 2019 to 2020, and 2020 to 2021 school years are summarized in Figure 2. Figure 2. Average Restraints and Seclusions Per Student 2018 through 2021. Analysis of data indicate that average restraints and seclusions per student were lower over the course of the 2019 through 2020 school year (first year of implementation) in comparison to the 2018 through 2019 school year (pre-implementation). Data were not analyzed for the month of March 2020 because school was closed from 16 March as a result of the COVID-19 pandemic, thus a valid comparison to previous months was not possible. Data were not available for the months of April through June 2020 due to the prolonged school building closure as a result of the pandemic. Decreases in average restraints and seclusions per student continued to be observed throughout the 2020 through 2021 school year. More specifically, staff used restraint and/or seclusion procedures with each student on average 3.25 times per month (SD = 1.36) pre-implementation during the 2018 through 2019 school year. Subsequent to implementation of the universal behavioral framework, use of restraint and/or seclusion procedures decreased to an average of 2.09 times per month (SD = 1.21) per student during the first year of implementation (2019 to 2020) and 0.67 times per month (SD = 0.55) during the second year of implementation (2020 to 2021). Overall, a 79% decrease in staff use of restraint and seclusion procedures was observed over the course of this case study. Feasibility and Acceptability Usage Rating Profile–Intervention Revised (URP-IR) To assess the feasibility and acceptability of the universal behavioral framework from the perspective of implementers, teachers were asked to complete the Usage Rating Profile–Intervention Revised (URP-IR) at the end of the 2020 through 2021 school year. The URP-IR is a self-report measure designed to assess factors believed to influence the probability that someone would consider an intervention and subsequently use it over time (Chafouleas et al., 2011). The 29-item questionnaire produces subscale scores related to the areas of acceptability, understanding, family-school collaboration, feasibility, system climate, and system support (Chafouleas et al., 2011). Teachers rated their overall satisfaction with the universal behavioral framework regarding each factor noted above. Scoring for each scale ranges from 1 (Strongly Disagree) to 6 (Strongly Agree). For each scale, apart from System Support and Home School Collaboration, higher scores are desirable. Lower scores on System Support indicate confidence in independently implementing the framework, and lower scores on Home School Collaboration indicate that a home–school relationship is not imperative to the success of implementing the intervention. Overall, as noted by the Feasibility (M = 4.50; SD = 0.87) and Acceptability (M = 4.77; SD = 0.73) scales, teachers agreed that the universal behavioral framework could be easily implemented and addressed the behavioral needs of students. In addition, they communicated interest in implementing the framework. Teachers agreed that the framework aligns with the school’s mission and system and that the school environment was conducive to implementation, as noted by the System Climate scale (M = 5.03; SD = 0.45). In addition, teachers agreed that they understood the purpose and how to implement the framework, as noted by the Understanding scale (M = 5.25; SD = 0.68). According to the System Support scale (M = 3.60; SD = 1.00), teachers indicated that additional assistance (e.g., resources, consultation, training) would be beneficial to support implementation of the framework. Teacher Survey Classroom teachers were also asked to complete a survey shared via Google Forms to gain a better understanding of their perception of the framework within the context of the COVID-19 pandemic. Feedback provided was as follows: Question 1: How did the schoolwide behavior support program fit within the context of the COVID-19 pandemic? What were the challenges? What were the benefits? Staff generally felt that the schoolwide behavior support program fit within the context of the pandemic and that the expectations, specifically Take Care of Self and Take Care of Others, connected well to safety precautions that were necessary. Teachers noted that the program created continuity between remote and in-person learning environments. Challenges were noted with the implementation of the reinforcement system within a remote learning environment, as well as with the integration of multiple reinforcement systems within the classroom. Question 2: Do you feel that the schoolwide behavior support program cultivated community, inclusion, and/or connectedness at the school? Please explain. All staff who completed the survey indicated that they felt that the schoolwide behavior support program helped to cultivate a sense of community and connectedness at school. Specific examples provided included students within classrooms working together to earn Sand Dollars, opportunities to congratulate peers when they won the weekly drawing, and bringing together separate classrooms to work toward a common goal. In addition, one teacher noted that the program provided a foundation for classroom lessons to discuss positive behavior. Another teacher noted that their students sometimes struggled to maintain safety and positivity when Sand Dollar drawing winners were announced, and the schoolwide rewards were confusing for some students who had difficulty drawing connections between remote and in-person learning environments. Question 3: Do you have any suggestions to make the schoolwide behavior support program more inclusive for our diverse group of learners? Teachers suggested the need for more individualization of the Behavioral Expectations Matrix to address the wide variety of student needs. Next, teachers suggested that pairing Sand Dollars with highly preferred items may help to increase student motivation and reinforce behavioral expectations for some students. Another suggestion to make the program more inclusive was to increase opportunities for students with limited communication or functional skills to win the Sand Dollar drawing. Finally, teachers reported a need to utilize strategies to increase “buy in” from higher functioning, secondary students. Discussion Alternative education settings provide support to students with a wide range of significant disabilities coupled with intensive social–emotional and behavioral needs. Such settings also face unique challenges including high rates of staff and student turnover, providing adequate training for staff with limited experience supporting students with behavioral difficulties, and the need for staff to be able to work with a variety of students (Baker et al., 2008; Connor et al., 2003; Lehr et al., 2009). Integration of universal, Tier 1 practices within AE settings could potentially improve the efficiency and effectiveness of behavioral supports while also increasing opportunities for flexible staffing options. Implementation of Tier 1 PBIS in AE settings has been shown to increase on-task and prosocial behaviors, decrease problem behaviors, and decrease staff use of restraint and seclusion procedures (Farkas et al., 2012; Grasley-Boy et al., 2021; Griffiths et al., 2019; Simonsen et al., 2010). Over the course of this 2-year, descriptive case study, aspects of Tier 1 PBIS were integrated with individualized behavioral systems within an AE setting in the Northeast. Adaptations were made to the system to support a student population with a wide variety of needs within the context of the COVID-19 pandemic. Based on recommendations from the literature, explicit and frequent instruction in expectations was embedded across settings, an intensified reinforcement system was implemented that included both individual and schoolwide rewards along with staff incentives, and both instruction and reinforcement were differentiated to meet the needs of a heterogeneous student population. In addition, ongoing coaching and professional development were provided to staff to support implementation. Progress monitoring measures indicated that overall implementation fidelity of key components of Tier 1 PBIS rose from 38% pre-implementation in the summer of 2019 to 76% after 2 years of implementation in May 2021. According to the BoQ, by the end of the first year of implementation, the school had achieved a total score above 70%, indicating that a universal behavioral framework was implemented to a degree that could achieve positive student outcomes. Over the course of the case study, a 79% reduction in staff use of restraint and seclusion procedures was observed. Results of a social validity measure indicated that teachers found the framework to be feasible and acceptable. Qualitative information provided through teacher surveys suggested that staff felt that the framework increased a feeling of connectedness within the school throughout the pandemic. Challenges noted included differentiation of the framework to meet the needs of diverse learners, as well as maintaining consistency between remote and in-person learning environments. Limitations These results should be interpreted in light of relevant limitations. First, this case study was conducted within an AE setting in the Northeast that supports students with a range of disabilities, including autism, EBD, and intellectual disability. Some conclusions gathered from the study may not be as directly relevant to AE settings that support students with significantly different developmental disabilities (i.e., deafness, blindness). Second, this case study utilized a combination of quantitative and qualitative data to draw conclusions about implementation of a universal behavioral framework within an AE setting. Although the descriptive methodology used provides important information pertaining to practical application, integration of this information with results of studies using more rigorous empirical methodology will be important in examining specific aspects of implementation that contribute to outcomes. In addition, implementation fidelity data were focused solely on system-level aspects of the framework. Thus, information on classroom-level quality of instruction (e.g., frequency, duration, and differentiation of lessons) was not gathered. It will be important for future researchers to examine both systems- and classroom-level implementation fidelity to strengthen conclusions drawn about the framework and outcome variables. Finally, the results of this case study should be interpreted in light of the fact that the school operated in a hybrid instructional model much of the 2020 through 2021 school year, from September through the end of April. Within this model, all students engaged in remote instruction on Wednesdays, and therefore were not in school buildings. Most students attended school in person 4 days per week during that time period, whereas some families chose to have their child attend school in person fewer days per week or engage only in remote learning. Therefore, there were fewer students attending school than in previous years, and there were also fewer days of in-person learning over the course of the school year. These factors may have contributed to a calmer school environment with a higher staff to student ratio than in other years, thus presenting limitations to interpreting the data. Still, data indicated a reduction in staff use of restraints and seclusions the previous year as well when typical in-person instruction was occurring, thus providing promising evidence for the framework. Implications for Research and Practice Results of this case study provide important implications for both research and practice. It will be important for researchers to continue to conduct empirical investigations of PBIS implementation in AE settings to further refine recommendations regarding adaptation of the framework that led to positive outcomes. In addition to including measures of implementation fidelity, social validity, and staff outcomes as this case study did, studies should also include socially important student outcome variables, such as measures of disruptive or unsafe behavior to comprehensively assess efficacy of the framework. Researchers might also examine whether implementation of such frameworks within AE settings could potentially decrease staff turnover. It will also be important for practitioners to consider how to best aggregate and analyze student data on a schoolwide level in AE settings where many programs utilize individual student data to drive decision-making. One possible option is to identify a small number of behaviors to track schoolwide that would be most impactful on the overall school climate, such as behaviors related to safety (e.g., physical aggression, property destruction, elopement). These behaviors could be easily tracked within an online system, such as the School-Wide Information System (SWIS; see www.pbisapps.org), so that staff could more directly assess whether implementation of a universal behavioral framework impacted student behavior by reviewing schoolwide trends over time. Although efforts were made to differentiate the framework to meet the needs of diverse learners, the process continued to be noted as a challenge over the course of the study. Differentiation of instruction and reinforcement will likely look different depending upon the unique AE setting and should be an ongoing process involving frequent reflection and modification. Some potential options for strengthening differentiation include asking teachers to adapt behavioral expectations matrices for individual students in their classrooms to promote thinking about how the expectations and reinforcement system can be modified to meet the needs of specific students. It may also be beneficial to consider student representation during leadership team meetings to provide high-functioning students the opportunity to share their voice and cultivate leadership skills. Regardless of specific practices and strategies utilized to differentiate instruction and reinforcement, ongoing coaching and training were noted to be important aspects of this case study that contributed to the success of the framework. In addition, both researchers and practitioners should continue to explore how to best integrate a universal framework for instruction and reinforcement with individualized systems in a way that is both feasible and effective. Finally, this case study focused on implementation of behavioral expectation instruction and reinforcement. One key component of PBIS, responding to problem behavior using a consistent continuum of responses, was not addressed. Future work should address which aspects of responding to behavior could be feasibly systematized within a school that provides highly individualized supports. Conclusion The purpose of this 2-year, descriptive case study was to provide an implementation example of universal behavioral supports within an AE setting and to explore outcomes related to staff use of restraint and seclusion procedures. Overall, results of the case study contribute to a growing evidence base providing promising support for the adoption of universal behavioral supports within AE settings. Consistent with previous research, implementation of Tier 1 behavioral supports based on a PBIS framework with fidelity over the course of 2 years resulted in a reduction in staff use of restraint and seclusion procedures. In addition, staff reported that the framework was feasible and acceptable to implement and strengthened a sense of community within the context of the COVID-19 pandemic. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. ORCID iD: Marlena L. Minkos https://orcid.org/0000-0002-5818-969X ==== Refs References Baker A. J. L. Fulmore D. Collins J. (2008). 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School-wide benchmarks of quality (Revised). University of South Florida. Kumm S. Wilkinson S. McDaniel S. (2020). Alternative education settings in the United States. Intervention in School and Clinic, 56 (2 ), 123–126. 10.1177/1053451220914895 Lehr C. A. Tan C. S. Ysseldyke J. (2009). Alternative schools: A synthesis of state-level policy and research. Remedial and Special Education, 30 (1 ), 19–32. 10.1177/0741932508315645 Magee S. K. Ellis J. (2001). The detrimental effects of physical restraint as a consequence for inappropriate classroom behavior. Journal of Applied Behavior Analysis, 34 (4 ), 501–504. 10.1901/jaba.2001.34-501 11800190 McDaniel S. C. Jolivette K. Ennis R. P. (2014). Barriers and facilitators to integrating SWPBIS in alternative education settings with existing behavior management systems. Journal of Disability Policy Studies, 24 (4 ), 247–256. 10.1177/1044207312465471 Mohr W. K. Petti T. A. Mohr B. D. (2003). Adverse effects associated with physical restraint. Canadian Journal of Psychiatry, 48 (5 ), 330–337. 10.1177/070674370304800509 12866339 PowerSchool. (2021). PowerSchool [Software]. https://www.powerschool.com Simonsen B. Britton L. Young D. (2010). School-wide positive behavior support in an alternative school setting: A case study. Journal of Positive Behavior Interventions, 12 (3 ), 180–191. 10.1177/1098300708330495 U.S. Department of Education, National Center for Education Statistics. (2021). Digest of education statistics. https://nces.ed.gov/programs/digest/current_tables.asp	0	PMC9747359	NO-CC CODE	2022-12-15 00:04:03	no	J Spec Educ. 2022 Dec 10;:00224669221140568	utf-8	J Spec Educ	2,022	10.1177/00224669221140568	oa_other
==== Front Am J Health Promot Am J Health Promot spahp AHP American Journal of Health Promotion 0890-1171 2168-6602 SAGE Publications Sage CA: Los Angeles, CA 36494184 10.1177_08901171221141974 10.1177/08901171221141974 Qualitative Research Characterizing Responses to COVID-19 Vaccine Promotion on TikTok https://orcid.org/0000-0001-5290-9759 Southwick Lauren MPH 12 Francisco Ashley 3 https://orcid.org/0000-0002-8287-3934 Bradley Megan 12 Klinger Elissa SM 12 Chandra Guntuku Sharath PhD 134 1 Penn Medicine Center for Digital Health, 6572 University of Pennsylvania , Philadelphia, PA, USA 2 Penn Medicine Center for Health Care Innovation, 6572 University of Pennsylvania , Philadelphia, PA, USA 3 Department of Computer and Information Science, 6572 University of Pennsylvania , Philadelphia, PA, USA 4 Perelman School of Medicine, 6572 University of Pennsylvania , Philadelphia, PA, USA Lauren Southwick, Center for Digital Health, University of Pennsylvania/University of Pennsylvania Health System, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA. Email: [email protected] 9 12 2022 9 12 2022 08901171221141974© The Author(s) 2022 2022 SAGE Publications This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections. Purpose The Alabama Department of Public Health (ADPH) sponsored a TikTok contest to improve vaccination rates among young people. This analysis sought to advance understanding of COVID-19 vaccine perceptions among ADPH contestants and TikTok commenters. Approach This exploratory content analysis characterized sentiment and imagery in the TikTok videos and comments. Videos were coded by two reviewers and engagement metrics were collected for each video. Setting Publicly available TikTok videos entered into ADPH’s contest with the hashtags #getvaccinatedAL and #ADPH between July 16 – August 6, 2021. Participants ADPH contestants (n = 44) and TikTok comments (n = 502). Method A content analysis was conducted; videos were coded by two reviewers and engagement metrics was collected for each video (e.g., reason for vaccination, content, type of vaccination received). Video comments were analyzed using VADER, a lexicon and rule-based sentiment analysis tool). Results Of 44 videos tagged with #getvaccinatedAL and #ADPH, 37 were related to the contest. Of the 37 videos, most cited family/friends and civic duty as their reason to get the COVID-19 vaccine. Videos were shared an average of 9 times and viewed 977 times. 70% of videos had comments, ranging from 0-61 (mean 44). Words used most in positively coded comments included, “beautiful,” “smiling face emoji with 3 hearts,” “masks,” and “good.;” whereas words used most in negatively coded comments included “baby,” “me,” “chips,” and “cold.” Conclusion Understanding COVID-19 vaccine sentiment expressed on social media platforms like TikTok can be a powerful tool and resource for public health messaging. COVID-19 social media awareness strategies digital data TikTok, vaccine COVID-19 vaccine community specific settings adolescents age specific specific populations edited-statecorrected-proof typesetterts10 ==== Body pmcPurpose Vaccines against the severe acute respiratory syndrome coronavirus (SARS-CoV-2) that causes COVID-19 are essential for population-level health and safety.1 Since December 2020, four COVID-19 vaccines have received U.S. Food and Drug Administration (FDA) emergency use authorization to prevent COVID-19 transmission.2 Despite these major advancements, twenty percent of eligible U.S. adults remain unvaccinated and rates among minors is higher. Approximately 25% of children ≥ 12 years of age and 30% of children n ≥ 5 years of age remain unvaccinated.3,4 Alabama, a southeastern U.S. state, has one of the lowest rates of vaccinated eligible individuals. Only 52% of the state’s population receiving at least one dose of the COVID-19 vaccine, as of August 2022.5 Approximately, 36.3% of 12–17-year-olds and 45.4% of 18–24-year-olds report having received the COVID-19 vaccine.6 These rates are lower to comparable to other states like Louisiana, Georgia, Florida, and Mississippi, which have overall vaccination rates of 54%, 56%, 69%, and 53%, respectively.3 A 2020 Alabama community health study surveyed 3700 individuals between the ages of 18 and > 60 on their perceptions of COVID-19 information, testing, and vaccination. Only 39% of the survey respondents indicated that they would receive a COVID-19 vaccine.7 Whereas one-third of the survey respondents expressed distrust in government agencies like the Center for Disease Control and Prevention (CDC) and other health agencies.7 Budhwani and colleagues (2021) interviewed 28 African American or Black adolescents aged 15–17-year-old in rural Alabama in May 20218 to elucidate sentiments toward the COVID-19 vaccine. They found varying levels of vaccine acceptance.8 Participants referenced both the positive and negative sides of each reason, reciting protection of and advice from older family members as reasons to get vaccinated, and rumored misinformation, such as the presence of microchips in the vaccines, as reasons to not receive the COVID-19 vaccine.8 These levels of vaccine acceptance are critical to understand since Alabama lags behind of other U.S.’ vaccination rates which puts Alabamians at greater risk7 especially with new variants, such as Delta, Omicron, or BA.5.9 Especially during highly infectious public health emergencies, more researchers are using social media platforms such as Facebook, Instagram, Twitter, and TikTok to capture prevailing attitudes and norms.10,11 Analyzing content on social media platforms is quite pertinent since more Americans receive information and especially health information from social media platforms, like Facebook, Instagram, and TikTok.12 In response to this new trend, the CDC recommends health departments to use social media platforms and challenges13 to disseminate public health messaging quickly and effectively. On the CDC’s website, “Ways Health Departments Can Help Increase COVID-19 Vaccinations,” they showcase health department’s social media outreach strategies. For example, in California, the Pasadena Public Health Department created a #VaccinatePasadena challenge for students aged 4-24 to submit artwork or share a TikTok or Instagram video on the “benefits of choosing vaccination, counter harmful myths, and promote an open dialogue about COVID-19 and vaccines,”.14 In the summer of 2021, the Alabama Department of Public Health (ADPH) sponsored a TikTok video contest to promote getting the COVID-19 vaccine among Alabama’s young people (aged 13 and 29). All contestants were asked to submit a TikTok video showing themselves getting vaccinated or include a creative message explaining, “This is why I got vaccinated.” Contestants entered their video by tagging ADPH (@alcovidvaccine) and using the hashtags of #getvaccinatedAL and #ADPH. A panel of judges (i.e., marketing/advertising professionals and ADPH personnel) selected four winners based on creativity, originality, and popularity (such as the number of likes and shares) and each winner received a $250 Visa gift card. Our analysis sought to advance our understanding of the COVID-19 vaccine perception among Alabama’s Department of Public Health contestants and viewers. The purpose of this exploratory content analysis was to describe the content of TikTok videos entered in the ADPH contest and the videos’ associated comments. Methods Search Srategy We conducted a retrospective review of publicly accessible TikTok videos posted with #getvaccinatedAL and #ADPH on the platform during the period of July 16 – August 6, 2021. All videos and comments were extracted on August 7th, 2021, for a total sample of 44 videos. We extracted videos to capture the content, public sentiment, and rationale on why they received the COVID-19 vaccine (Table 1: Codebook). We also captured how TikTok users engaged with the content (i.e., comments) by extracting the first 100 comments per video.Table 1. Codebook and Descriptive Analysis. Note: 37 of the 44 videos posted were related to the contest. Theme Theme Operational Definition Sub-themes Sub-theme Operational Definition Percentage n (%) Reason for vaccination Contestant explicitly mentioned why they received the COVID-19 vaccine Societal / Civic duty Quality of responsibility of a citizen and social participation 18 49 Friends/Family Individual(s) with mutual affection or ancestral relation 19 51 Returning to pre-COVID-19 Desire to return to pre-pandemic lifestyle 11 30 Prevent COVID-19 cases Desire to not get COVID-19 oneself or pass it on to others 8 22 Immune-compromised Having an impaired immune system 8 22 Sentiment Video’s prevailing mood or attitude Humor/Parody Quality of being amusing or comic 8 22 Fear Quality of using unpleasant emotions to motivate behavior or change beliefs 5 14 Informative Providing useful or entertaining or information 7 19 Empathy Quality of relating or sharing the feelings of another 15 41 Against the COVID-19 vaccine Opposed to getting the COVID-19 vaccination 1 3 Neutral Does not evoke emotions 4 11 Content Objects featured Vaccination Card CDC COVID-19 vaccination card 9 24 Friends/Family Individual(s) with mutual affection or ancestral relation 12 32 Media Featuring a news clip, social media posts and videos 8 22 Dancing Featuring individual(s) dancing 7 19 Adhesive bandage Featuring adhesive bandage on arm 9 24 Sports Featuring physical activities such as football, baseball, etc. 5 14 Health care workers Featuring individuals dressed in scrubs, white coats and those who explicitly note their medical credentials 8 22 Not applicable 3 8 COVID-19 vaccine If contestant mentions the COVID-19 vaccine 7 19 Does the video mention specific COVID-19 vaccine type Moderna 4 57 Pfizer 1 14 Johnson & johnson 2 28 Astra zeneca 0 0 CDC banner Video displays CDC banner 8 22 Not related Providing content other than vaccine 7 16 Coding Approach We used a coding approach previously described.10,11,15 In brief, an initial 20 videos on July 27th, 2021, were coded to identify themes (e.g., reason(s) for vaccination, sentiment, content featured in video, type of COVID-19 vaccine received) for the codebook. We then iterated on this approach and re-coded an additional 20 videos to build and refine the codebook. Our codebook consisted of reasons for vaccination, sentiment, video production, sound, content, mention of COVID-19 vaccine, if the CDC banner was featured, and not related (Table 1: Codebook). Using Microsoft Excel (Version 16.51), the 44 videos were coded (Table 1). The final code for each video was decided by the agreement between two reviewers (LS and AW). Descriptive Analysis We performed descriptive statistics to quantify the proportion of themes. We analyzed the comments using VADER, a lexicon and rule-based sentiment analysis tool specifically attuned to sentiments expressed on social media. VADER estimates sentiment in three categories: positive, negative, and neutral. We calculated the mean percentage of positive, negative, and neutral comments of each of the videos per category (Table 2). For each category, we also obtained top 10 words among all comments posted on all videos annotated in the category (Table 3). We removed stop words by dropping the top 50 most frequent words across all comments. This dropped uninformative words such as (a, the, #fyp, vaccine, tiktok etc.). The #fyp is a common hashtag used to promote TikTok content. We consulted with our University'’ Institutional Review Board who verified that this study does not need an IRB approval as we did not interact with any individuals and the data is public. However, we have exercised caution to redact any personally identifying information and have paraphrased all illustrative posts used in the paper.Table 2. Distribution of positive, negative, and neutral comments on TikTok videos per theme in our dataset Theme Sub-themes n (videos) n (comments) Percentage of Comments Mean/Std Dev. Positive Negative Neutral Reason for vaccination Societal / Civic duty 10 307 48.48 (13.27) 13.81 (14.18) 37.71 (14.76) Friends/Family 12 139 54.3 (21.06) 7.0 (9.91) 38.7 (20.37) Returning to pre-COVID-19 5 74 46.82 (10.07) 18.84 (16.64) 34.34 (12.33) Prevent COVID-19 cases 3 21 54.69 (11.91) 6.06 (10.5) 39.25 (15.79) Immune-compromised 5 51 58.41 (23.94) 6.19 (8.52) 35.4 (23.26) Sentiment Humor/Parody 4 44 33.73 (23.91) 14.98 (18.19) 51.29 (35.1) Fear — — — — — Informative 8 287 45.46 (17.99) 10.03 (11.58) 44.51 (20.03) Empathy 5 55 61.74 (23.64) 6.19 (8.52) 32.07 (21.79) Against the COVID-19 vaccine — — — — — Neutral — — — — — Content Vaccination Card 8 78 48.97 (18.7) 4.43 (6.72) 46.61 (19.29) Friends/Family 12 139 54.3 (21.06) 7.0 (9.91) 38.7 (20.37) Media 3 50 54.05 (24.18) 9.52 (16.5) 36.43 (15.2) Dancing 2 21 38.12 (25.63) 3.12 (4.42) 58.75 (30.05) Adhesive bandage 6 54 52.48 (14.77) 7.89 (8.84) 39.62 (14.83) Sports 4 69 41.77 (10.34) 22.12 (15.8) 36.11 (13.49) Health care workers 3 21 43.45 (6.27) 9.72 (8.67) 46.83 (12.22) COVID-19 vaccine 2 14 60.61 (8.57) 9.09 (12.86) 30.3 (4.29) Table 3. Top words and emojisa based on frequency of occurrence in the comments of videos per sub-theme. Theme Sub-themes Top Words (all Comments) Reason for vaccination Societal / Civic duty For, good, your, my, choice, smiling face emoji with 3 hearts, do, me, shot, with, what, on, up, own, be, luck, god Friends/Family For, good, your, smiling face emoji with 3 hearts, my, choice, are, what, do, with, me, shot, on, up, own, luck, be, all Returning to pre-COVID-19 my, me, on, u, good, are, your, i'm, great, as, for, covid, ppl, make, clapping hands emoji, job, still Prevent COVID-19 cases my, your, so, me, loudly crying emoji, at, are, doing, story, on, getting, flexed bicep emoji, immunity, all, animations, aa, like, as Immune-compromised Smiling face emoji with 3 hearts”, my, beautiful, she, for, your, what, with, so, red heart emoji, vaccinated, her, baby, daughter, been, everyone, love, has Sentiment Humor/Parody rock on emoji, smiling face emoji with 3 hearts, thanks, vaccinated, masks, flushed face emoji, how, getting, me, on, sorry, 2, jabs, your, thoughts, bring, southern Fear — Informative Good, for, your, my, choice, are, do, so, shot, smiling face emoji with 3 hearts me, what, with, own, up, be, on, luck, god Empathy Smiling face emoji with 3 hearts, my, beautiful, she, for, so, your, what, with, red heart emoji vaccinated, her, all, baby, love, four leaf clover emoji, daughter, purple heart emoji Against the COVID-19 vaccine — Neutral — Content Vaccination Card Smiling face emoji with 3 hearts, love, rock on emoji, for, thanks, are, amazing, your, thank, awesome, red heart emoji news, doing, story, on, vaccinated, let, do Friends/Family Smiling face emoji with 3 hearts, my, for, so, love, your, she, are, beautiful, great, with, red heart emoji all, good, job, what, baby, vaccinated Media Smiling face emoji with 3 hearts, love, are, my, for, great, amazing, job, u, me, be, good, think, your, grinning emoji, so, up, live Dancing Love, yessss, amazing, gahhh, best, as, should, queen, 100, thank, creative, great, job, challenge, an, email, monocle emoji, emoji with tears of laughter, second Adhesive bandage Smiling face emoji with 3 hearts, rock on emoji, thanks, your, for, love, my, me, red heart emoji are, good, all, amazing, so, loudly crying emoji, let, been Sports rock on emoji, my, smiling face emoji with 3 hearts, clapping hands emoji, u, me, on, great, your, so, for, are, ppl, job, still, do Health care workers Smiling face emoji with 3 hearts, rock on emoji, sharing, thanks, has, been, with, your, flexed bicep emoji, immunity, red heart emoji their for, let, do, #Alabama COVID-19 vaccine my, your, me, loudly crying emoji, are, doing, story, on, so, animations, aa, like, as, well, covid, glowing star emoji aEmoji description informed by https://emojipedia.org/ Results Overall, of 44 videos tagged with #getvaccinatedAL and #ADPH; 37 were related to the contest. Of the 37 videos, most videos’ sentiment (e.g., prevailing mood or attitude) was coded as empathetic (n = 15, 41%) and half of contestants cited ‘friends/family’ (n = 18, 49%) and ‘societal and civic duties’ (n = 19, 51%) as their reason(s) to get the COVID-19 vaccine (Table 1). One in three videos featured photos or videos of ‘friends and family’ in their submission (n = 12, 32%). Other objects featured were vaccination cards (n = 9, 24%), adhesive bandages (n = 9, 24%), media (e.g., news clip, social media posts and videos) (n = 8, 22%), health care works (n = 8, 22%), and individuals dancing (n = 7, 19%). Whereas only 19% (n = 7) of videos explicitly mention that they received a COVID-19 vaccine. Of which, most contestants received the Moderna vaccine (n = 4) (Table 1). The TikTok platform labeled one in five (n = 8) videos with the CDC banner, “Learn More about the COVID-19 banner,” and provided a link to the CDC website. Videos entered in the ADPH contest were shared an average of 9 times (min: 0 and max: 164) and played an average of 977 times (min: 37 and max: 5,988). Most videos, 70% (n = 26) received comments from other TikTok users. The number of comments per video ranged from 0 to 611. Average number of comments were 44 per video (median = 42). Few videos (19%, n = 5) had more than 50 comments. Three videos in our sample were outliers in which they had 611, 291, and 117 comments. Using VADER, most comments (n = 502) were coded as positive (Table 2). Table 2. shows percentage of positive, neutral, and negative comments on videos annotated as different themes. Videos with ‘friends/family’, ‘society/civic duty’, ‘prevent COVID-19 cases’, ‘immune compromised’ as their reason(s) for getting the COVID-19 vaccination had a higher number of positive comments (Table 2). Whereas videos coded as ‘empathy’ for the theme sentiment, and featured objects like ‘media’, ‘band-aid’, ‘sports’ also had a higher number of positive comments (Table 2) compared to videos coded as ‘informative’ for the theme sentiment and featured objects like ‘vaccination card’, and ‘HCWs.’ had similar mean percentages of positive and neutral comments per video. Furthermore, the most frequently used words and emojis in comments were, “smiling face emoji with 3 hearts”, “your”, “amazing”, “masks”, “beautiful”, and “good,” (Table 3). Most used words in the negative categorized comments, included, “baby”, “shot”, “cold”, “me”, “my”, “chip”, and “covid.” (Table 3). Emojis are described by using https://emojipedia.org/. Table 4. Includes illustrative comments per VADER estimated sentiment category (e.g., positive, neutral, and negative). Positive comments endorse and validate the contestant vaccination status; one commenter said, “What a lovely baby. I’ve been fully vaccinated for a while and have been encouraging everyone to do the same [double heart emoji]” (Table 4). Most negative comments prominently included views against getting the COVID-19 vaccine such as allergic reactions, government tracking, and misinformation about COVID-19 contagion and spread. One commenter posted, “i think it’s probably the vaccinated that'spreading covid, not the unvaccinated. i don’t understand how people can be this clueless!”Table 4. Illustrative commentsa per estimated sentiment categories: positive, neutral, and negative. Estimated Sentiment Illustrative Comments Positive “Awesome video! Congrats on being recognized”“Love you so much [name]. Everyone get the vaccine [syringe emoji] even if you think you don’t you do” “What a lovely baby. I’ve been fully vaccinated for awhile and have been encouraging everyone to do the same [double heart emoji] Neutral “hey that’s my house in your video” “your video is on my fyp” “Omg, she looks just like you” Negative “please tell me more about the vaccine. I'’e scared of getting it because my stupid parents says we'’e allergic to it and decided to never vaccinate us”“Thank you! People think the government tracks us with chips. that'’ stupid.”“i think it’s probably the vaccinated that'’ spreading covid, not the unvaccinated. i don’t understand how people can be this clueless!” aAll comments paraphrased to preserve anonymity and emoji description informed by https://emojipedia.org/ Discussion Our descriptive analysis captures the ADPH contestants’ rationale and imagery used to convey why they received the COVID-19 vaccine. Approximately, one-third of videos included actual footage (i.e., photos or videos) of their friends and family in their submission and cited ‘friends/family’ as a reason to get the COVID-19 vaccine (n = 19, 51%) (Table 1). Since the COVID-19 pandemic drastically changed the ways we interact with one another,16 most contestants urge others to get vaccinated to be able to safely spend time with their loved ones. Additionally, most videos evoked ‘empathy’(n = 15, 41%) and videos featured objects such as a ‘vaccination card’ (n = 9, 24%) and ‘adhesive bandages’ (n = 9, 24%) to demonstrate the process of receiving the vaccine. Featuring a vaccination card was illuminating since most states and counties, vaccination cards grant individuals’ access to social activities, like restaurants and concerts in summer 2021. Interestingly, few videos mentioned which type of COVID-19 vaccine they received and were tagged by the TikTok platform with the CDC banner noting “Learn More about the COVID-19 banner.” TikTok reports using a vaccine tag to detect and tag videos with words and hashtags related to the COVID-19 vaccine.17 Analyzing video comments revealed both positive and negative responses to promoting the COVID-19 vaccine (Table 2). Most individuals who entered the ADPH contest received positive feedback and enforcement from their TikTok followers. Videos with ‘friends/family’ (54%), ‘society/civic duty’ (48%), ‘prevent COVID-19 cases’ (55%), ‘immune compromised’ (58%) as their reason(s) for getting the COVID-19 vaccination had a higher percent of positive comments as compared to neutral and negative comments (Table 2). However not all videos received endorsement. Some comments in our sample were similar to Budhwani and colleagues (2021) findings, where young Alabamians cited misinformation, side effects, and institutional mistrust, contributing to their acceptance of the COVID-19 vaccine.8 For example, one commenter said, “You are being lied too!!!” and ““i think it’s probably the vaccinated that'’s spreading covid, not the unvaccinated. i don’t understand how people can be this clueless!” Of note, negative comments included more first-person singular words such as “me, my” Previous research found that first person singular words suggest a sense of fear or uncertainty.18 In addition, emojis were used frequently in the comments. Emojis are pictograms, logograms, ideograms and smileys. Emojis have become widespread and increasingly used in digital communication. Prior research found that emojis convey semantic information and support reading comprehension;19 Oxford Dictionary even named emoji face with tears of laughter the Word of the Year in 2015. It is noteworthy to underscore the widespread use of emojis in the comments among this study sample. ADPH used TikTok for their contest. TikTok’s use has dramatically increased during the COVID-19 pandemic, it gained over 300 million users in one year.20 TikTok videos are short format and uniquely captures users’ attention in ways that other social platforms such as YouTube videos cannot.21,22 Similarly, engaging individuals aged 13-29 is a unique population. Since TikTok is primarily used by young people; 63.5% are younger than 29 years of age.20 Young people, especially minors are a unique population as they have some ability to consent to vaccination, however in the majority of states, the ultimate decision lies with their parent(s) or legal guardian(s).23 Because of this, vaccination rates for young people may lag behind that of adults and their opinions of the vaccine may mimic that of influential figures in their lives. Table 4. includes a comment from a young person under 18 years of age states, “Please tell me more about the vaccine. I've scared of getting it because my stupid parents says we're allergic to it and decided to never vaccinate us,” (Table 4). Despite these complex challenges, teens are mobilizing together to provide timely, relevant health information. For instance, Vaxteen.org was started by a high school senior who wanted to provide reliable and easy-to-understand information to her peers. Vaxteen.org provides helpful tools like, ‘how to talk to your parents about vaccination,’ ‘common myths busted’ and recent press on how teens are banding together on TikTok and Reddit, another prominent social media platform, for vaccination resources and stories.24 Furthermore, social media challenges and contests draw upon important psychological and behavioral economic principles such as ‘norm setting’ and utilize direct, personal experience, both of which are powerful heuristics in the health-related decision-making process. James and colleagues (2021) found that messaging that is focused on “pro-social COVID-19 vaccination and social image concerns” were the most effective at increasing intended vaccine uptake and impacted respondents’ intended willingness to persuade others to get vaccinated against COVID-19.25 They highlight the power of prosocial behavior to impact young people's decision-making process, who especially strive for social acceptance.26 The collaboration between Vietnamese young people and Vietnam's National Institute of Occupational and Environmental Health, represents a real-world example of leveraging social media and pro-social, norm setting messaging to impact health-behaviors and health-related decisions. Early in the COVID-19 pandemic, there was a TikTok handwashing dance challenge (e.g., #GhenCoVyChallenge) intended to motivate individuals, especially young people, to properly wash their hands. The PSA responded to the World Health Organization’s recommendation that regular handwashing is a “simple and effective method to protect the community from diseases,” The challenge went viral in May 2020, it received over 44.1 million views on TikTok and over 8 million views on YouTube. It represents a successful global social media and public health campaign. The portrayal of “challenges'' on popular social media platforms has the ability to introduce public health topics earlier to younger individuals and can reach distant audiences, leading to the promotion and acquisition of pro-social health behaviors.27 Strengths There are several strengths to our analysis. Our study sample uniquely captures contestants and their viewer’s comments. Previous research primarily captures the video content and not TikTok users’ reactions to it.17 Second, our codebook captured both video themes and production variables. Our analysis provides an ecological lens into the motivations and concerns towards the COVID-19 vaccine especially among ADPH contestants, individuals aged 13-29 and viewers, which is the majority demographic of TikTok.13 Limitations There are limitations to our sample and analysis. First, we only identified videos using #getvaccinatedAL and #ADPH during the Alabama Department of Public Health’s contest, July 16 – August 6, 2021, and additional hashtags or might yield subsets of videos with differing content, sentiment, and levels of incorrect content and misinformation. Second, we used VADER to characterize comment sentiment, which has limitations to coding compound sentences. Third we captured the first 100 comments per video. Anecdotally, highly commented videos included a lively conversation endorsing and discrediting the COVID-19 vaccine’s efficacy, thus captured comments reflect a limited and perhaps positive-leaning perspective. Despite these limitations, capturing prevailing imagery and sentiment towards the COVID-19 vaccine is essential for public health messaging.8,15 Future research should analyze all video comments in order to characterize the entire comment population rather than just a sample (i.e., first 100 comments). This analysis did not capture the extent to which the campaign was successful in reaching and converting unvaccinated individuals to receive the COVID-19 vaccines. Rather, we classified the type of content and sentiment used in TikTok videos created to motivate Alabamians to get vaccinated. Considering the importance of booster shots, additional insight into why individuals get vaccinated or not is especially pertinent. Future research is also needed on TikTok users to better understand how TikTok videos influence their understanding of the COVID-19 vaccine. Additionally, pilot studies are needed to test and evaluate the ‘success’, may it be debunking COVID-19 vaccine misinformation or increasing the number of fully vaccinated and boosted individuals, of social media contests and campaigns. Conclusion As we continue to combat COVID-19 infections and illness, promoting the COVID-19 vaccine is paramount. Our findings demonstrate that a public health department sponsored contest garnered ‘empathic’ content to promote younge people to get vaccinated. Furthermore, analyzing TikTok videos provides real-time insights into public discourse and could be used to inform public health messaging.So WHAT? What is already known about the topic? COVID-19 vaccination rates are a key public health concern. What does this article add? We conducted an exploratory analysis of Alabama Department of Public Health (ADPH) video entries with #getvaccinatedAL and #ADPH to capture rationale and imagery used to why Alabamians received the COVID-19 vaccine. We found most videos were coded as empathetic and cited family, friends, and civic duty as reasons to get the COVID-19 vaccine. Most videos were shared 9 times and received over 900 views. Comments were mostly positive and most used words were “beautiful,” “smiling face emoji with 3 hearts,” “masks,” and “good.” What are the implications for health promotion practice or research? Understanding COVID-19 vaccine sentiment expressed online through social media platforms and crowdsourced communication can be a powerful tool and resource to tailor public health messaging. ORCID iDs Lauren Southwick https://orcid.org/0000-0001-5290-9759 Megan Bradley https://orcid.org/0000-0002-8287-3934 Author Contributions: Lauren Southwick: Design of experiment, writing of the article, revising of text and/or figures Ashley Francisco: Data analysis and interpretation, writing of the article Megan Bradley: Data analysis and interpretation, writing of the article Elissa Klinger: Writing of the article, revising of text and/or figures Sharath Guntuku: Design of experiment, revising of text and/or figures The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. ==== Refs References 1 Castells MC Phillips EJ . Maintaining Safety with SARS-CoV-2 Vaccines. N Engl J Med. 2021;384 :643-649.33378605 2 Center for Disease Control and Prevention. Different COVID-19 Vaccines, https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines.html. (2021, Accessed August 31, 2021). 3 Kaiser Family Foundation. Latest Data on COVID-19 Vaccinations by Race/Ethnicity, https://www.kff.org/coronavirus-covid-19/issue-brief/latest-data-on-covid-19-vaccinations-race-ethnicity/ (2021, Accessed August 25, 2021). 4 American Academy of Pediatrics , Analysis of Data Posted by the Centers for Disease Children and COVID-19 Vaccinations Trends, https://www.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/children-and-covid-19-vaccination-trends/ (2021, Accessed August 20, 2021). 5 Available COVID-19 data by U.S. state, https://github.com/owid/covid-19-data/blob/master/public/data/vaccinations/us_state_vaccinations.csv August 15, 2022). 6 Alabama Public Health. Department COVID-19 Vaccine Distribution 2022, January;11 :2022. https://alpublichealth.maps.arcgis.com/apps/dashboards/e4a232feb1344ce0afd9ac162f3ac4ba. 7 Crozier J Christensen N Li P , et al. Rural, Underserved, and Minority Populations’ Perceptions of COVID-19 Information, Testing, and Vaccination: Report from a Southern State. Https://HomeLiebertpubCom/Pop2021 8 Budhwani H Maycock T Murrell W , et al. COVID-19 Vaccine Sentiments Among African American or Black Adolescents in Rural Alabama. J Adolesc Heal. 2021;69 :1041. 9 Forni G Mantovani A Forni G , et al. COVID-19 vaccines: where we stand and challenges ahead. Cell Death Differ. 2021;28 :626-639.33479399 10 Seltzer EK Horst-Martz E Lu M , et al. Public sentiment and discourse about Zika virus on Instagram. Publ Health 2017;150 :170-517. 11 Seltzer EK Jean NS Kramer-Golinkoff E , et al. The content of social media’s shared images about Ebola: A retrospective study. PPubl Health 2015;129 :1273-1277. 12 Pew Research Center About half of Americans use social media to follow COVID-19 vaccine news, https://www.pewresearch.org/fact-tank/2021/08/24/about-four-in-ten-americans-say-social-media-is-an-important-way-of-following-covid-19-vaccine-news/. (2022, August 15, 2022). 13 Ways Health Departments. Can Help Increase COVID-19 Vaccinations, CDC. Available at: https://www.cdc.gov/vaccines/covid-19/health-departments/generate-vaccinations.html https://www.cdc.gov/vaccines/covid-19/health-departments/generate-vaccinations.html Accessed August 15, 2022. 14 VaccinatePasadena Video Contest - Public Health Department. Available at: https://www.cityofpasadena.net/public-health/2022-vaccinatepasadena-video-contest/. Accessed August 9, 2022. 15 Southwick L Guntuku SC Klinger E V. , et al Characterizing COVID-19 Content Posted to TikTok: Public Sentiment and Response During the First Phase of the COVID-19 Pandemic. J Adolesc Health 2021;1 :11 16 Included Everyone. Social Impact of COVID-19 \| DISD. Available at: https://www.un.org/development/desa/dspd/everyone-included-covid-19.html https://www.un.org/development/desa/dspd/everyone-included-covid-19.html Accessed March 21, 2022. 17 TikTok , Taking action against COVID-19 vaccine misinformation \| TikTok Newsroom, https://newsroom.tiktok.com/en-gb/taking-action-against-covid-19-vaccine-misinformation. (2022, August 15, 2022) 18 Ward A Lyubomirsky S Sousa L , et al. Can’t quite commit: rumination and uncertainty. Pers Soc Psychol Bull. 2003;29 :96-107.15272963 19 Barach E Feldman LB Sheridan H . Are emojis processed like words?: Eye movements reveal the time course of semantic processing for emojified text. Psychon Bull Rev. 2021;28 :978-991.33511541 20 Olvera C Stebbins GT Goetz CG , et al. TikTok Tics: A Pandemic Within a Pandemic. Mov Disord Clin Pract. 2021;8 :1200-1205.34765687 21 Anderson KE . Getting acquainted with social networks and apps: it is time to talk about TikTok. Libr Hi Tech News. 2020;37 :7-12. 22 Comp G Dyer S Gottlieb M . Is TikTok The Next Social Media Frontier for Medicine? AEM Educ Train. 2020;5 :11. 23 Morgan L Schwartz JL Sisti DA . COVID-19 Vaccination of Minors Without Parental Consent: Respecting Emerging Autonomy and Advancing Public Health. JAMA Pediatr. 2021;175 :995-996.34251411 24 VaxTeen , https://www.vaxteen.org/. (2022, January 14 , 2022). 25 James EK Bokemper SE Gerber AS Omer SB Huber GA , Persuasive messaging to increase COVID-19 vaccine uptake intentions. Vaccine. 2021;39 :7158PMC8531257 34774363 26 McElhaney KB Antonishak J Allen JP , They like me, they like me not": popularity and adolescents' perceptions of acceptance predicting social functioning over time. Child Dev. 2008;79 :720PMC3073367.18489423 27 Tan RY Pua AE Wong LL , et al. Assessing the quality of COVID-19 vaccine videos on video- 50 sharing platforms. Explor Res Clin Soc Pharm. 2021;2 :100035.34568867	36494184	PMC9747361	NO-CC CODE	2022-12-15 00:04:04	no	Am J Health Promot. 2022 Dec 9;:08901171221141974	utf-8	Am J Health Promot	2,022	10.1177/08901171221141974	oa_other
==== Front BCQ spbcq Business and Professional Communication Quarterly 2329-4906 2329-4922 SAGE Publications Sage CA: Los Angeles, CA 10.1177/23294906221137860 10.1177_23294906221137860 Original Research Article Managing in Writing: Recommendations from Textual Patterns in Managers’ Email Communication Molek-Kozakowska Katarzyna 1 https://orcid.org/0000-0001-8554-6771 Molek-Winiarska Dorota 2 1 Univerity of Opole, Institute of Linguistics, Poland 2 Wroclaw University of Economics and Business, Poland Dorota Molek-Winiarska, Wroclaw University of Economics and Business, Komandorska, 118/120, Wroclaw, 53-345, Poland. Email: [email protected] 10 12 2022 10 12 2022 23294906221137860© 2022 by the Association for Business Communication 2022 Association for Business Communication This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections. This study draws from personality psychology and linguistics of written communication to explore the characteristics of self-selected well-written email communications (N=273) solicited from Polish managers who organized and supervised the (remote) work of their units during the COVID-19 period. The focus is on the writing of managers with above-average levels of conscientiousness and agreeableness, as these personality factors are predictors of efficacy in the completion of two work-related goals, Achievement and Communion, according to the Theory of Purposeful Work Behavior. The linguistic patterns responsible for effective email communication are identified through both automated and qualitative textual analyses of the email sample. The study has implications for management training via the assumption that linguistic patterns that a reflexive manager uses in writing are subjected to monitoring and can be modeled and adapted to. Specific recommendations for managerial writing styles concern informational, instructional, explanatory, feedback, and query messages. management communication written communication personality traits ICT COVID Purposeful Work Behavior Wroclaw University of Economics and Business, Faculty of Management edited-statecorrected-proof typesetterts1 ==== Body pmcIntroduction This study offers input for management training programs by highlighting the increasing importance of written communication that has complemented face-to-face managerial interactions during the COVID-19 pandemic. While research demonstrates that managerial writing styles are influenced by managers’ personality, they also vary enormously depending on the context of the organization, the communicative goal of the text (e.g., information, instruction, and feedback) and the composition of the working team. Textual patterns that a manager uses while addressing coworkers and subordinates in writing are subjected to monitoring and can be modeled or trained. Even though recent scholarship highlights the value of such features as leader’s “supportiveness,” “preciseness,” and “assuredness” in addressing subordinates (Dirani et al., 2020; Kempster & Jackson, 2021; Kirchner et al., 2021), few studies offer specific advice how to construct texts that bear those features or how to reflect on one’s writing style to channel it better to such desirable communicative goals. This study investigates the ways Polish managers communicated through emails with the people whose work they managed during the COVID-19 period. The managers whose writing is examined here are heads of units, departments, or offices of either public or private organizations, with between 3 and 30+ subordinates. Because they are institutionally appointed heads of working teams, we have chosen to refer to them as “managers” and to the communications they engage in as “managing in writing” of work-related tasks and relations in the respective organizations. This is a terminological choice, since what we study here overlaps to a substantial degree with research on leadership practices and teamwork mechanisms (Dinh et al., 2014; Hoch & Kozlowski, 2014; Judge & Bono, 2000). We acknowledge the priorities given to communication in leadership studies, but keep our terminology of management because of relatively formalized work relationships, which, as our study assumes, tend to be reproduced through writing styles. The object of analysis in this study is written communication. The linguistic patterns that are responsible for specific writing styles that could be recommended are identified through both automated and qualitative textual analyses of emails. However, to identify such patterns we needed a consistent sample of well-written, rather than random, texts given the infinite variety of writing styles. To obtain such a sample, we subjected the managers whose emails we solicited to “Big Five” personality questionnaire measuring neuroticism, extraversion, openness to experience, conscientiousness, and agreeableness. As it is the latter two traits that are considered to be the most likely to influence writing styles in ways that were worth pursuing from the point of view of recommendations for managing, we focused on analyzing the texts of conscientious and agreeable managers only. In this study, we perceive written communication as a goal-driven action that is influenced by managers’ personality on the one hand, and constrained by institutional norms, conventions and affordances of written mode, and emailing on the other. This complex dialectic makes it hard to present “management through writing” as a closed set of fixed and deterministic factors. Rather than to assume a fit-for-all best practice approach to managerial writing, we aim to promote managerial reflexivity with regard to writing styles, in tune with research which indicates that the more reflexivity there is, the more apt team management strategies and higher performance can be noticed (Konradt, 2015). Reflexivity, in the context of managerial writing, would be “the ambition to carefully and systematically take a critical view of one’s own assumptions, ideas and vocabulary and to consider if alternative ones make sense” (Alvesson et al., 2017, p. 14, emphasis ours). Even though we narrow the scope of the study to how personality traits of conscientiousness and agreeableness are reflected in managers’ communications, it would be reductive to claim that personality is a determiner of one’s writing style, especially in view of the broad literature that challenges this. Therefore, we draw on the Theory of Purposeful Work Behavior (Barrick et al., 2013) and represent managerial email texts as actions channeled toward achieving certain work-related goals: getting things done (Achievement), controlling the work of the unit (Autonomy), being recognized as in charge (Status), and fostering work-related relationships (Communion). While agreeable managers devote more effort to fostering communion, and conscientious people stress achievement, good management will call for a contextually calibrated mix of various written patterns and vocabulary choices that we aim to describe here. The objective of this study is thus to identify the linguistic patterns in well-written email communication that conscientious and agreeable Polish managers use to effectively deal with work management, and to explain how these patterns help to realize work-related goals (mainly Achievement and Communion) in ways that could be recommended to reflexive managers. Even though our raw textual data are in Polish, we believe that the analytic insights and interpretations are not language-specific and the recommendations can be applicable in various work settings. We translate all Polish key words and phrases into English using literal translation, sometimes giving more than one equivalent for precision. Literature Review There are many strands of research at the intersection of management and leadership on the one hand, and communication styles on the other, often with a view to improving the efficiency of management and teamwork. One strand of this research focuses on personal qualities and trust in managerial communication (Bakker-Pieper & de Vries, 2013; de Vries, Bakker-Pieper, & Oostenveld, 2010; Yang et al., 2020). Another strand of scholarship identifies effective communication patterns in various sectors and recommends best practices with respect to, for example, motivating workers, preventing conflict or limiting free-riding (de Vries, Bakker-Pieper, Konings, & Schouten, 2013; Boulu-Reshef et al., 2020; Thapa et al., 2022). This study considers this literature, but refocuses from studying managers’ personalities to studying managers’ communications, particularly emails. The latest strand of studies traces the processes related to reconfiguring managerial communication given the ongoing COVID-19 pandemic that normalized remote work with less direct control over employees and with a growing prevalence of computer-mediated communication channels (Kirchner et al., 2021; Thapa et al., 2022). (Written) communication is shown as an even more essential competence for managers at the time of pandemic, as they become chief informational officers in many organizations (Dirani et al., 2020). Oberländer and Bipp (2022) point to the growing role of digital communication during the ongoing pandemic in the context of facilitating work engagement and providing social support. However, even though computer-mediated communication technologies have been available for some time, some research suggests that employees perceive face-to-face communication to be of “higher quality” than telephone and email communication (Braun et al., 2019; Brown et al., 2014; Turnage & Goodboy, 2016). This finding inspires our study in aiming to explore textual patterns of effective email communication in which managers delegate tasks without compromising their subordinates’ sense of autonomy and belonging to a team (Barrick et al., 2013). Recent perspectives on processual, relational, and shared leadership (Endres & Weibler, 2017; Gadelshina, 2020) draw more attention to how communication is performed—not as a transfer of information but as a complex process of meaning and relationship building, which is iterative and socially constructed. As a result, successful management should no longer be theorized as attributed to the competencies and actions of the person in charge but to the emergent practices of interacting often through communicating, negotiating, and coordinating (Uhl-Bien, 2006). As a result, in this study we make use of personality tests only to identify managers with the traits that are likely to be reproduced in writing styles—particularly conscientiousness and agreeableness—in order to attend to linguistic patterning in their email communications. Computer-Mediated Written Communication: Affordances of the Mode and Technology According to Braun et al. (2019), the written mode, as opposed to the spoken mode, is characterized by comparatively low synchronicity and utilization of contextual cues. Emails do not usually require immediate feedback (which would be useful in the case of the need for clarification), but they can be returned to by employees, reread and reprocessed on demand. In addition, recent studies conducted under the circumstances of the pandemic indicate that email communication is perceived to be less time-consuming, more reliable, and more efficient than telephone communication or even face-to-face meetings. It is also the main channel of instruction distribution and feedback, and a possible vehicle to foster trust within the organization (Haesevoets et al., 2021). Having said this, we are also aware of the life-work balance movements that advocate cutting down on excessive emailing, especially beyond work hours (Russell & Woods, 2020). On the sender’s side, email communication allows for rehearsing and tailoring the messages to the needs of the recipients, provided that managers chose to take time to do this. The choice of the written mode of communication is also related to such factors as decrease in personalization (loss of tonality of voice, intonation prosody, mitigating fillers) and in language variety, mainly due to formulaic conventions required in emails. Even though it takes more time to write/read written messages, the processing of information is on average more efficient in the work context (see Table 1 for an extensive comparison of three forms of office communication). Table 1. Comparison of forms of communication. Channel characteristics Face-to-face communication Email communication Telephone communication Utilization of information cues High Low Low Extent of personalization High Medium Medium Capacity of feedback High Medium High Degree of language variety High Medium High Channel richness High Medium-low Medium Transmission velocity High Medium-low High Parallelism Medium High Low Symbol sets Few-many Few-medium Few Rehearsability Low High Low Reprocessability Low High Low Information transmission Fast Slow Fast Information processing Low Medium Low Overall synchronicity High Low Medium Source: Braun, S., Hernandez Bark, A., Kirchner, A., Stegmann, S., & Van Dick, R. (2019). Emails from the boss—curse or blessing? Relations between communication channels, leader evaluation, and employees’ attitudes. International Journal of Business Communication, 56(1), 50-81. DOI: 10.1177/2329488415597516. A line of research shows that emails are a primary and pervasive form of communication in organizations today (D’Urso & Pierce, 2009; Haesevoets et al., 2021; Turnage & Goodboy, 2016). Positive aspects of email communication underlined in studies (that date back to the 1980s) include mainly reprocessability, rehearsability, and convenience. Negative aspects of email communication center on the lack of clarity, lack of reliability due to delays in answering, and their “impersonal” character, which is counterproductive to team-building. Although email communication provides users with response flexibility by normalizing a time lag between message reception and reply (Cambier & Vlerick, 2020), business norms regarding email responsiveness have been evolving systematically and involve pressure to respond to a message within 24 hours (Barber & Santuzzi, 2015; Grawitch et al., 2018). It has also been determined that some types of information in the organizational environment are better suited to email mode than other forms. Employees point out that project-related and “core business” issues are likely to be transmitted via email (with information archived and evidenced), as are security and safety announcements. Meanwhile praise, annual assessments, promotion, or disciplinary messages are preferred to be delivered in the face-to-face mode (Brown et al., 2014). Another aspect is the “shielding effect” of discussing negative issues via email (Riordan & Kreuz, 2010) as well as the written mode being better for expressing dissent to a supervisor (Turnage & Goodboy, 2016). In this vein, email communication is also a way to get around stressful confrontation. Regarding the changes due to COVID-19, the informational and supportive role of email communication in the area of health and safety is being recognized (Clarke, 2013; Dirani et al., 2020; Mullen & Kelloway, 2009; Vera et al., 2021). In terms of using email for work feedback, Derks and Bakker analyze the mechanisms of positive and negative feedback via email. Positive feedback is easy to deliver because it makes the recipient happier and the sender anticipates possible positive emotions of the receiver, which facilitates sending the message without delay. However, with negative feedback the manager may experience a natural feeling of reluctance in communicating something unpleasant. All in all, emails constitute a relatively safer environment and might be easier for a manager to use because of a decrease in the psychological discomfort related to giving feedback (Derks & Bakker, 2010). The ongoing debate whether email communication is economical (Kupritz & Cowell, 2011), or whether it decreases productivity because of massive flow of information, persistent interruptions, and distractions (de Lange et al., 2002) has not yielded clear answers. Caron et al., for example, find that, on the whole, managers are very task-oriented in their email communication, but “they are fairly reflexive about the role of email writing practices in the co-construction of the professional identities and relationships” (2013, p. 20). To enhance this reflexivity, the present study does not focus on whether it is advisable to write another email or not but on how to compose it to maximize the likelihood of achieving the desired work-related goals: to make information be assimilated, instructions followed, questions answered, explanations understood, positive feedback found motivating, negative feedback accepted without resentment, and work relationships maintained. Both social theorists (Giddens, 1984) and management gurus (Schön, 2017) advocate reflexivity as a means to observe how routines are generated in order to control the social practice and, when needed, to challenge them. Writing routines and formulaic language patterns may save time, but when they are failing managers, it might be time to destabilize communication modes and reorganize practice following critical reflection (Cunliffe, 2004). Personality and Managerial Communication Some studies that focus on management and communication at the workplace try to establish links between personality types and effective management/leadership (Agbi, 2018; Parr et al., 2016; Ruiller et al., 2019). The most recognized approach is to operationalize personality differences on the basis of the five personality factor model (Big Five) (Costa & McCrae, 1992) and validated questionnaires measuring neuroticism (reverse of emotional stability), extraversion (motivation to seek interaction with others), openness to experience (willingness to explore new experiences), conscientiousness (tendency to act in a disciplined, deliberate manner), and agreeableness (being friendly and accommodating). Agreeableness is related to personal characteristics like compliance, sympathy, warmth, and modesty (Costa & McCrae, 1992; John & Srivastava, 1999). In research studies, Big Five personality traits tend to be used to explore any correlations with many different variables that facilitate management. Personality dimensions were repeatedly investigated in conjunction with communication skills (McCrae & Allik, 2002; Mount & Barrick, 1995), communication styles (Bakker-Pieper & de Vries, 2013; de Vries, Bakker-Pieper, Konings, & Schouten, 2013), communication reticence (Hazel et al., 2014), active listening (Pence & Vickery, 2012), assertiveness (Sims, 2016), blogging (Guadagno et al., 2008), and social network behavior (Amichai-Hamburger & Vinitzky, 2010; Huang, 2019), leadership styles (de Vries, Bakker-Pieper, & Oostenveld, 2010), or transformational leadership (Judge & Bono, 2000). It has been demonstrated that extroversion is closely related to “expressive” (verbal) communication and that conscientiousness links with “precise” communication style (Bakker-Pieper & de Vries, 2013). In other studies, personality features have been treated as predictors in goal-striving actions with work-emails (Russell & Woods, 2020). It was found that conscientiousness was associated with achievement goals, while extraversion with autonomy goals and agreeableness with communion goals. Conscientiousness was strongly related to goal-striving in a work-email context. In a related manner, highly conscientious leaders show high performance on defining and implementing strategies while extrovert leaders tend to be better at building partnership and engaging in creative communication (Parr et al., 2016). Following this line of argument, it is worth exploring how managers characterized by above-average scores on conscientiousness and agreeableness could be compared in their email writing styles (choices of words and structures) to general usage. Given the existing gaps in literature on managerial writing styles and personality, we base this decision on the description of the two traits by psychologists and their possible realizations in textual data. Theory of Purposeful Work Behavior: Email Communication as a Goal-Driven Action Personality differences tend to influence individuals’ work-related goals, according to the Theory of Purposeful Work Behavior (Barrick et al., 2013). Goals are internal representations of desired end states that can be achieved through various actions (DeShon & Gillespie, 2005). There are four overarching work-related goals: Achievement (being competent), Autonomy (being in control), Status (being recognized), and Communion (feeling of belonging). The four goals are broadly conceptualized and widely shared, but personality factors are relatively good predictors of one’s priority of goals (Russell & Woods, 2020). For example, conscientious people are oriented toward Achievement goals because they are interested in producing results and accomplishing tasks. Meanwhile, agreeable people tend to prioritize Communion goals, because they are interested in “getting along” with coworkers (Barrick et al., 2013). In the context of this theory, we place managers’ email communication as a specific and purposeful action to achieve their preferred work-goals. That is why we aim to explore linguistic patterns across texts that serve different communicative goals—sharing information, giving instruction, explaining a work-related problem, giving feedback, keeping rapport through interaction, questions, and small talk. Research Questions In this study we are primarily interested in the following: What are the linguistic patterns in well-written email communication that certain types of managers (identified by personality traits of conscientiousness and agreeableness) tend to use for work management? How do these patterns serve to realize work-related goals (Achievement and Communion) in ways that could be recommended? Study Design Purpose and Context The aim of this project is to map the communicative patterns of managers who need to manage and control the work of their subordinates in the new circumstances of the remote work induced by the restrictions on gatherings during the COVID-19 pandemic. Special attention is to be paid to how managers inform about tasks to be done, explain them, and encourage subordinates to be efficient and timely with their duties, as well as control their outputs and give feedback in writing rather than the usual office face-to-face interactions. Obviously, the use of online platforms and communication applications is widespread for video calls, video conferencing, and other collaborative environments in both the private and public sector in Poland. However, the design is based on the assumption that study participants consider written interaction to play an important role in the management of their units, despite the fact they have other modes and forms of communication at their disposal. Procedures and Methods The prospective participants—middle level managers—were approached with an invitation letter sent through an institution operating EMBA studies that they had taken part in. The invitation letter (in Polish) specified the aims of the study, offered the chance for the participants to complete a survey and a personality questionnaire, and asked them to provide a sample of self-selected emails, memos, or newsletters in which they were communicating work tasks. The texts solicited were supposed to be written within at least a 6-month-long period of the pandemic. The letter also specified which sensitive information to remove from the sample, what types and minimal parameters of texts were required, and where to send the materials. The participants were ensured that the data were anonymized and safe, the information remained confidential, and the study results would be shared on request. The intermediary contact person was hired to answer any further questions on research ethics, and to ensure data sets and psychological questionnaires were appropriately anonymized. The study design was cleared by the University of Economics and Business in Wroclaw Personal Data Security office and approved by ethical committee prior to commencement. For personality testing, a 60-item Personality Inventory, the NEO-FFI (Costa & McCrae, 1992), was used in order to assess individual differences in personality factors. NEO-FFI provides a concise measure of the five personality traits, with 12 items for each factor, for example, neuroticism (N), extraversion (E), openness to experience (O), agreeableness (A), and conscientiousness (C). Each of the items is measured on a Likert-based scale ranging from 0 (strongly disagree) to 4 (strongly agree). Nearly half (28 of 60) of the items are reverse-worded. The Polish version of the NEO-FFI was administered (Zawadzki et al., 1998), and the reliability of NEO-FFI questionnaire results in our sample was α Cr = 0.77, which is sufficiently high to proceed. Participant and Textual Sampling Nineteen managers responded to the invitation letter with complete data sets (personality tests and samples of emails). Eleven of them represented private enterprises (large or medium) in such sectors as agricultural production, specialist analytic services, quality in manufacturing, business consulting, HR, and training. The other eight represented public organizations and worked within HR and project management, academic publishing, research management, recruitment, and client services. Ten managers were female and nine were male (age M = 41.5, SD = 7.3; job tenure M = 15.5, SD = 6.5). In addition, we found that 5 managers coordinated the work of fewer than 5 subordinates, while the other 14 managers were in charge of more than 5 subordinates (one of them even more than 30). Four managers work in a multilingual environment, sometimes sending messages in English (not sampled here), but the majority of participants work only with Polish-speaking coworkers. To ensure representativeness and balance, 49% of the emails sampled were authored by men and 51% texts by women. However, this does not imply any correlations, as the participants themselves could decide how many texts to share with researchers, which varied from 11 (one female public organization department manager) to 40 (one male private enterprise director), with most participants sharing 16-20 texts. Regarding the corpus of texts included in the study, after manually screening the material solicited from conscientious and agreeable managers, we were able to include 273 texts in the data set. The overall word size of the sample is approximately 24,608 words, which makes the average length of the email to be about 90 words. However, the length of the emails varied enormously in size—ranging from simple acknowledgements of the work received of 14 words to detailed instructions for complex tasks or procedures amounting to 540 words. A vast majority (95%) were emails from managers to their coworkers—approximately half were addressed collectively to the team(s) they manage; others were addressed to specific individuals (based on the salutation/greeting included in the email). The remaining texts read as memos with minutes taken after meetings or newsletters directed to the whole unit. Because of the significant individual variety of communication styles within age groups and genders, as well as contextual constraints on communication across sectors, institutions, or working groups, we eschew correlating linguistic patterns with demographic or institutional characteristics, so as not to give rise to stereotyping or false generalizations. It is assumed that patterns in linguistic data become visible and identifiable when samples are placed against each other or against a reference corpus of standard usage. Given that this analysis is of exploratory nature, we decided to cluster textual samples around “types of personality”—conscientious and agreeable, not around individual or institutional criteria. Textual Analysis Protocols To map the characteristics of written style of the data set, we used automated text processing tool—Korpusomat (Kieraś et al., 2018). Corpus linguistics offers specific algorithms and tools to obtain information about language patterns based on frequency of occurrences and co-occurrences of individual words (segments) and their quantification. This allows researchers to offer an accurate description, which, in turn, leads to a deeper understanding of the relationship between recurrent linguistic forms and their communicative goals and serves as a departure point for further in-depth qualitative analyses and interpretations (Sinclair & Carter, 2004). Korpusomat is a web-based application that allows one to create and process self-made corpuses of textual material. The application bases on Multi-Tier Annotation Search tool for the Polish language that provides quick and reliable searchers and quantifications of huge amounts of plain text and metadata. Korpusomat can apply various operations to the textual input based on the online grammatical dictionary of the Polish language (an online database of grammatical descriptions of over 450,000 Polish lexemes, http://sgjp.pl). In this study, Korpusomat has been used to generate frequency lists as well as to identify keywords and strong collocations. Keywords are terms that the algorithm singles out as much more frequent in the given sample in comparison to their typical frequency in reference corpus of standard Polish usage. The measure of keyness is numerical—the higher the number, the more salient a given term is in the sample. Strong collocations that characterize our sample were calculated according to metrics of conditional co-occurrence and are listed basing on likelihood. However, even the best metrics of frequency and keyness and strong collocations do not give a full picture of the writing style that contributes to effective performance of managerial actions. In order to capture any emerging patterns, we used open coding for goal orientation and interactional patterns in the emails. Following multiple close readings of all the 273 texts of conscientious and agreeable managers, we inductively assigned such codes as the dominant communicative goal or action performed by writing, as well as stylistic variations, length of paragraphs and sentences, word choice in expressions of feedback, special signs, etc. Results This section starts by presenting the results of Big Five questionnaires administered to the participants and identifies the types of managers in our study, with special attention to conscientious and agreeable types. This is followed by multilevel textual analyses. First, the results of inductive coding reveal the makeup of the textual sample according to the identified dominant communicative goals (information, instruction, explanation, feedback, or query). Then, rankings of lexical items are revealed through an automated retrieval of keywords by Korpusomat, and an analysis of semantic fields, that is, salient verbs and nouns. Finally, a qualitative analysis of specific patterns that emerge in subsets of emails by conscientious and agreeable managers respectively is provided. The characteristics of managerial writing styles are captured vis-à-vis the communicative goals of the texts in which they appear. Personality Types in Participant Sample The analysis of the Big Five personality scale results (see Table 2) showed that none of the participants is highly neurotic; most are emotionally stable and resilient, which indicates that they are not very prone to anxiety and impulsive reactions. Fourteen of 19 participants are characterized by average levels of extraversion (from medium low to medium high), which indicates a balanced need for active socializing on the one hand and privacy on the other. Regarding the trait of openness to experience, three participants score relatively low and can be considered rather conservative, nine individuals are average or medium high, and another seven are highly open to new challenges. These managers might be acting in unconventional ways, deciding independently and may even question authority. Table 2 presents the results of NEO-FFI scale for all participants (in STEN scale and interpretation). As already mentioned, however, it is the two remaining Big Five traits—conscientiousness and agreeableness—that are of particular interest here. Basing on these traits’ descriptions (John & Srivastava, 1999), they are most likely to be reflected in writing styles, so also in managers’ email communications. Table 2. NEO-FFI Results of 19 Participating Managers, With Individuals Scoring From Medium High (7) to Extremely High (10) on Agreeableness and/or Conscientiousness. Participants STEN Scale Interpretation N E O A C 1 4 4 3 5 7 1 = extremely low 2-3 = low 4 = medium low 5-6 = medium 7 = medium high 8-9 = high 10 = extremely high 2 3 6 7 9 5 3 4 4 6 9 6 4 1 8 2 3 10 5 1 7 8 5 8 6 1 5 5 6 4 7 3 5 8 7 7 8 2 6 6 8 9 9 2 6 6 6 5 10 3 6 7 4 7 11 3 4 8 3 6 12 2 4 8 9 7 13 5 9 5 6 4 14 6 2 3 2 4 15 5 7 8 4 7 16 4 7 7 4 5 17 4 6 7 3 4 18 2 3 8 7 7 19 2 3 8 7 7 Note. A = agreeableness; C = conscientiousness; E = extroversion; N = neuroticism; O = openness to experience; STEN = Standard TEN Scoring. Following the results of the personality questionnaire, we were able to identify participants who scored high on conscientiousness. It is expected that none of the participants would hold their positions were they not sufficiently conscientious, but there were 9 persons with low or medium scores and 10 persons with medium high, high, or even extreme score on conscientiousness. Such people tend to be very well-organized, scrupulous and reliable, and strong-willed and persevering. This can sometimes border on perfectionism, which, in the office context, would involve high demands and expectations concerning coworkers and their outputs. We claim that such expectations would transpire in written communication and in the wording of feedback given. Obviously, institutional work regulations, employee rights, and the fact that written communication can be saved and returned to (cf. reprocessability in Braun et al., 2019) shield office coworkers from the manager’s extreme demands, but not from, for example, micromanagement. In a similar vein, we selected to look at how agreeableness (the ability to act in a friendly way, to avoid conflict, and negotiate and mediate among coworkers) could be reflected in specific patterns of managers’ written communication. We found participants who scored medium high and high on agreeableness (7 persons) and those who scored low or medium (12 persons). The persons who are lower than average on agreeableness tend to be skeptical of others and may show their dissatisfaction, or put emphasis on acting in practical ways without too much regard for others’ feelings. By contrast, agreeable people manifest concerns for others’ well-being in their writing through politeness and indirectness. Obviously, the well-defined institutional context, office etiquette, and good team dynamics, as well as the fact that written mode is less situationally bound (low synchronicity and informational cues; Braun et al., 2019), act as mitigating factors for less agreeable managers to abstain from expressing themselves in ways that would make interactions awkward or hurtful. Text Types According to Communicative Goal Through a close reading and open coding of emails by the conscientious and agreeable managers, we inductively assigned all the texts to six types basing on the dominant communicative goal or action performed while or by writing. Obviously, several longer texts contained a few different communicative actions (e.g., greeting, evaluating, explaining, and thanking). In such cases, we disregarded the formulaic expressions and looked at what was emphasized: stated at the beginning, covered in the most of words, highlighted by bolded font, marked as number one in a list, etc. Table 3 presents the categorization of the sample texts into the six types, together with details on subtypes of feedback. Table 3. Categorization of the Sample Texts Into the Six Types. Type Number Percentage Informational 93 34.1 Instructional 56 20.5 Explanatory 44 16.1 Feedback 44 16.1 Positive feedback 27 Negative feedback 17 Query 29 10.6 Ceremonial 7 2.6 Total 273 100.0 Through closer reading, we could further nuance the characteristics of the above text types:Informational texts were the ones where information or decision was announced, or where command was issued regarding the day-to-day management of units’ work. These emails were usually shorter and sometimes used question forms for requests or orders “Would you/Can you please send/complete/prepare . . . ?” Instructional texts offered more specific guidance as to what needs to be done, when to do it, and sometimes explicitly mentioning who from the unit should do it. These emails were usually longer, sometimes with bullet points or time frames / deadlines. Explanatory texts provided further information on how to do something and/or why it needs to be done (reference to regulation, earlier decision, policy, project schedule), sometimes at length and in detail. Some of these emails could strike as follow-ups to tasks that had been done improperly, or as justifications of decisions taken by the manager. Feedback texts included evaluation on tasks completed or in progress. The proportion of positive to negative feedback was traced as well, with many emails including various shades of appraisal, thanks and appreciation, and encouragement to improve some details of the output and to consult further. Query texts were the ones where genuine questions were asked of coworkers regarding their resources, expertise, and availability. Alternatively, this type also involved suggestions to comanage work, or proposals to meet, volunteer, or contribute posed in a tone that allowed negotiating or opting out. These types of texts also characterized working relationships that were official, external to the core working team, or involved superiors in hierarchical (public) organizations. Ceremonial texts were routine emails with best wishes, thanks, or confirmations of receipt of materials. Results of Keyword Analysis The salient lexical units in texts authored by highly conscientious and agreeable managers were revealed by Korpusomat in the course of automated keyness analysis. Tables 4 and 5 present the most salient verbs and nouns in the emails (the higher the keyness metric, the more characteristic the word is in the context of managerial emails). Table 4. Characteristic Verbs in the Sample (Baseline for Keyness = 3.0). Verb in Polish (Base Form) English Equivalent(s) Keyness prosić to ask for 11.76 pozdrawiać to send greetings (regards) 9.26 przesłać to send 6.81 przesyłać to be sending 6.80 dziękować to thank 6.02 pzdr to send greetings (rgds) 5.51 wysłać to have sent 5.22 ustalić to settle/arrange 4.78 czekać to wait 4.33 dotyczyć to concern, relate to 4.23 potrzebować to require/ need 4.15 przekazać to forward 3.93 zaproponować to propose 3.87 przygotować to prepare 3.85 zgłaszać to report, announce 3.76 zapraszać to invite 3.67 zrobić to do, make 3.59 poprawiać to improve 3.50 zaplanować to plan 3.44 uzupełniać to complete 3.37 zapoznać to familiarize 3.34 dodać to add 3.25 zgłosić to propose 3.24 płacić to pay 3.39 omawiać to discuss 3.23 wybrać to choose 3.15 potwierdzić to confirm 3.13 wypełniać to fill in 3.01 Table 5. Characteristic Nouns in the Sample (Baseline for Keyness = 3.0). Noun in Polish English Equivalent(s) Keyness spotkanie meeting 9.74 informacja information 9.57 email email 7.34 temat topic 6.95 termin term, date, deadline 6.82 pracownik employee 6.55 jutro tomorrow 5.24 zespół team, group 5.02 strona page, webpage 4.95 plik file 4.87 prośba request 4.83 zebranie pooling, gathering, meeting 4.78 propozycja proposal 4.62 szkolenie training 4.57 pytanie question 4.50 zmiana change, amendment 4.47 zaproszenie invitation 4.41 zajęcia activities, actions, tasks 4.39 link link 4.01 procedura procedure 3.87 program program 3.82 wsparcie support 3.79 dana data 3.61 prezentacja presentation 3.60 opcja option 3.58 koordynator coordinator 3.48 harmonogram plan, timetable 3.52 projekt project 3.51 praca work, job 3.47 wersja version 3.37 system system 3.33 rekomendacja recommendation 3.25 ankieta survey 3.23 materiał material 3.22 dział unit, department 3.16 zadanie task, assignment 3.15 oferta offer 3.12 lista list 3.10 potrzeba need 3.05 As can be observed, this sample is characterized by many specific verbs that belong to the semantic field of “managing work,” especially in its office capacity (planning, preparing, arranging, reporting, sending), as well as “organizing the workflow” (dates, schedules, timetables) and “inputs/outputs” (data, meetings, presentations, offers, contracts). A notable part of the key terminology is oriented toward making communication smooth and instructions clear. Also the very act of managing is rather tentative and such words as “ask for,” “request,” “proposal,” “need,” ‘invite,” “option,” “possibility” outnumber high-pressure, authoritarian, or obligation-laden commands and circumstances (“deadline,” “assignment”). Also, there is relatively much meta-talk (turning attention to the quality and completeness of information transmission), or ensuring that messages are received and information is accessible (“send,” “forward,” “discuss”). Such words typically occur in modes that allow low “utilization of information cues” and “channel richness” (cf. Table 1), but that may be especially popular with agreeable and conscientious writers who use them to ensure a smooth flow of information and a sufficient level of cooperativeness in the team. With a few exceptions (“procedure,” “survey”), the top nouns are sourced from casual usage and are fairly neutral or polite (with sending “regards” topping the list of verbs). Given such word statistics, it can be interpreted that managerial writing in general is direct and precise as well as interactive, casual when appropriate, and supportive throughout, especially when it comes to making coworkers acquainted with tasks in order to proceed with the assigned work. The keyness lists suggest that being demanding in the way directives are issued to subordinates is not common in the cases of conscientious and agreeable managers and that consensual and negotiated outcomes are preferred (evidenced by “discuss,” “option,” “invitation”). This way of addressing the coworkers is also confirmed by the strongest collocations identified by Korpusomat’s algorithm, with top phrases being “dear colleagues,” “next weeks,” “this term,” “meeting of,” “today’s meeting,” “new schedule,” and “upcoming tasks.” This indicates the managers’ willingness to plan work in such a way that their subordinates are properly informed about timelines, developments, and status. Results of Qualitative Comparative Analysis The results of qualitative analysis based on the open coding of email texts reveal some additional patterning, as well as differences between conscientious and agreeable managers’ communications. For example, based on this sample, conscientious managers’ writing styles indicate that these people tend to prefer working and interacting within relatively small and tightly knit teams with quite well-defined areas of responsibility, chains of command, and established work relationships. The emails indicate a preference for traditional greetings and salutations, and for rather direct and technical language, which may read rather curt or obscure to an outsider. The informational and instructional emails feature many instances of sectoral jargon and work-related abbreviations. In explanatory emails, the authors are careful to refer to external documents (either in attachments or as hyperlinks) that provide rationales for the tasks to be completed in the office, and they like to summarize previous (face-to-face) interactions or remind of the decisions taken. The instructional and explanatory emails read professional and practical, with well composed clauses and high clarity of complex message reasoning. As a result, they prove the managers caring to organize work efficiently, to avoid chaos and a waste of time. This is sometimes done through listing (numbers, bullet points, and specific paragraphs) in longer emails. These texts tend to feature reminders and arrangements for meetings. They also establish deadlines and assign tasks to people (without seemingly consulting their availability). When feedback is provided, it is rather meticulous and attends to the features of the output that need improving. As could be expected, in the case of conscientious managers, most texts are informational and explanatory and focus on “getting the job done.” This does not mean that they are rude because the authors follow the appropriate stylized patterns of address (e.g., Dear . . . ) and use the required politeness features for requests (e.g., Can you please . . . ). Importantly, many emails conclude with a phrase that reiterates the manager’s availability to answer follow-up questions individually or to consult before submitting the work output (Do not hesitate to contact me, if . . . ; In case of questions, call me . . . ). If meeting agendas are included in emails, they tend to have “other business” or “feedback” listed. This can be interpreted as the managers’ need to ensure the quality of the output first (perfectionism), even at the cost of spending more time consulting and reviewing the more challenging parts. One of these managers is actually fond of asking their team to contribute and to express their views on how things should be done. Such “query emails” may indicate an actual understanding that things “get done” better if there are more people putting an effort into shaping them. Alternatively, this could also indicate the need for maintaining a sense of collaboration and teamwork that characterizes a conscientious manager who also happens to be agreeable. The conscientious managers present themselves to be “in charge” as coordinators and to some extent evaluators of the work of others, but the style does not carry indications of authoritarianism. Agreeableness is manifested in writing style through a variety of stylistic and compositional choices. The participants who scored highest on agreeableness on average submitted larger samples, which may indicate that they are open to sending more emails to set up, organize, negotiate, or consult the issues around the workplace (or that they were more open to taking part in the research study and sharing more material). In a slight contrast to the type of conscientious manager described above, here we can trace more variety in writing patterns, as if the authors were more eager to accommodate in their writing style to the particular recipient(s) of particular emails, rather than trying to maintain a matter-of-fact managerial writing persona at most times. There also are striking stylistic differences between emails directed to the coworkers (with informal, lexically diverse, and personalized elements) and externals (rather conventional and emotionally neutral), as well as superiors in the organization whom they may sometimes have to include in an email round. Also this subset of emails contains more examples of giving feedback, queries, explanations, and well-wishing than the one by conscientious managers. The emails tend to be enriched with the expression of emotion as well, for example, featuring apologies for delay/absence, excuses and justifications, positive sentiments (enthusiastic address “My team!,” “My colleagues!”), and even colloquialisms and jocular shortcuts/emojis (e.g., smiley, @, hi/rgds). There is also less stress on well-rounded clauses and flawless spelling/punctuation. Actually, some emails seem to have been sent in a hurry from a phone, which indicates that it was important for the manager to respond as quickly as possible to a coworker with explanation or clarification. When a bigger workload or a radical change of organizational routine is explained, some managers acknowledge this with “I realize . . . this is not comfortable . . . this is unusual/new . . . ” and some sort of formulaic apology may be included, for example, “sorry to bother you.” The “query” emails in this sample are characterized by question forms that are not formulaic requests, but actual dilemmas and points to reflect on and share. Opinions are elicited, and space for discussion is opened. Meanwhile informational or instructional emails sometimes feature instances of “please” and serve a confirmatory function, with double-checking and/or requests for contributions. They sometimes illustrate what can be labeled as “thinking out loud,” but also deal with divergent opinions and contribute to settling debates in a comfortable manner without compromising workplace Communion (e.g., one manager called a debate “our mini-argument,” thus diminishing the significance of an interpersonal division). Regarding feedback, many cases of negative feedback are couched in ambivalence (“well done, but how about . . . ”, “fine, fine . . . ”) and include “helpful” suggestions for adding some detail or rereading the instructions later. Politeness also helps to mitigate uncomfortable situations of dealing with coworkers’ negligence or ignorance, often in an indirect manner, by reminding them of the regulations and obligations, calendarizing events by first inquiring with them, or seeking to excuse failures with external factors rather than ill-will. The style in informational and explanatory emails, especially when decision making is involved, is sometimes rife with hedges and passives (“it seems we will have to postpone . . ., ” “this should best be done by . . . ”). The commands and deadlines tend to be presented as things to be done earlier “for one’s own benefit” and “the sooner, the better.” Sometimes approval is sought before finalizing decisions by “opening them to further negotiations.” Discussion and Recommendations The rationale for self-selected, rather than random, textual sampling in this study was underpinned by its focus on tracing communication patterns that the participants—managers and organizers of the work of others—considered to be “good practice,” or at least routine, rather than an example of communication failures or breakdowns. Because of the enormous stylistic variety in managerial writing contexts, we were not interested in all possible ways of addressing coworkers or subordinates, but rather in restricting this variability to emails of conscientious and agreeable managers, in order to be able to map effective communication patterns that could be seen as worth reproducing. Also the context of transiting from mostly spoken instruction, supervision, and interaction to the written mode of managing was within the horizon of our inquiry. Given that managing is largely about planning, organizing, motivating, and controlling, the managers’ written communications, for example, emails, should be devised in ways that effectively realize these functions through tailored informational, instructional, explanatory, feedback, and query texts, which were analyzed in this study. Based on extant studies, also from the times of the COVID-19 pandemic, suggestions for managers related to their email communication involve precision and clarity, as well as support and positive reinforcement. Our findings confirm the claims made by many researchers (Dirani et al., 2020; Kirchner et al., 2021; Oberländer & Bipp, 2022) that specifically crafted writing styles help managers in their roles as supporters and facilitators of remote collaborative work. Conscientious managers’ writing style, with its carefulness, rationality, as well as its summarizing and well-structured exposition, assists their subordinates in being efficient in completing tasks (Achievement, according to Purposeful Work Behavior theory). On the other hand, agreeable managers’ writing style shows the managers’ being more supportive and open to negotiations (Communion, according to Purposeful Work Behavior theory). Both purposes are served by offering frequent feedback and by taking interest in the degree of subordinates’ task engagement (cf. Oberländer & Bipp, 2022) to monitor effectiveness. In our sample of written managerial communication, there was a prevalence of informational and instructional texts, which are likely to increase the efficacy of remote work in the pandemic with clear and precise managerial massages. This is especially important to acknowledge in the context of the pandemic, where internal regulations and sectoral circumstances are likely to change more often, and where employees should be able to rely on managers as primary information sources. Such reliance increases the sense of support and the feeling of safety on the part of the subordinates, but puts additional demands on the communicative competences and writing styles of managers (Dirani et al., 2020; Oberländer & Bipp, 2022). In addition, psychologists confirm that in stressful situations, clarity and preciseness are appreciated. In that respect, conscientious managers have an advantage, and other personality types should remember to consider the directness and readability of their instructions (Aronson & Aronson, 2018). In its practical dimension, this study also aims to offer input for reflexivity in managerial writing or even managerial training programs by attending to the nuances of written communication during such crises as the COVID-19 pandemic. Although writing styles are influenced by managers’ personality, the textual choices that a manager makes while addressing coworkers and subordinates can be modeled or trained (de Vries, Bakker-Pieper, & Oostenveld, 2010; Kirchner et al., 2021). In our results, we have described linguistic patterns identified in authentic well-written emails to offer specific advice how to construct texts that “get things done” while being supportive. This specific advice on lexical choices, stylistic variants, and compositional patterns can be subsumed under a more general recommendation that all managers could profit from adopting writing styles exemplified by conscientious and agreeable types, even if that is not usually how they tend to write. By trying out certain textual patterns, and developing a writing style that puts premium on preciseness, clarity, as well as support and communion, as exemplified in the analysis, a manager can self-monitor and experiment to better address the challenges of remote work. On the basis of this study, we could suggest the following reflection-inspiring questions Why have you chosen the written mode? Why is this information important to be communicated in this way? What is the main aim of your message—to inform, instruct, explain, give feedback, ask? Which words would be appropriate to signal the aim(s) up front? Which work-related goal do you plan to foreground—getting the work done or sustaining smooth work relationships? What is your current work relationship with the message recipient and how you plan to change/reinforce it? How can the structure and working of your message influence the realization of work-related goals and your relationships with the recipient(s)? How direct, explicit, and open do you intend to be about your goals? Which politeness strategies and phraseological combinations would best suit your goals? The training of reflexive managers—who can analyze their personal habits and traits, and who can adjust to technological and workplace conditions—is recommended, in line with previous research synthesized in our literature review (Caron et al., 2013). In this sense, the findings of this study do not come as a surprise because its design was aimed to increase the granularity of managerial studies and nuance and deepen the understanding of managing through writing on the example of emails of Polish managers. Our results resonate with previous work on organizational contexts where workers are considered to be autonomous and self-disciplined while being guided and led rather than managed (Hoch & Kozlowski, 2014; Russell & Woods, 2020). They also offer insights into a post-COVID work environment where remote work and mental health or work-life balance become increasingly important factors in management (Dirani et al., 2020). Conclusion The embrace of the evolution of computer and Internet technologies offers managers a variety of channels and modes of interacting with subordinates and coworkers. Efficient virtual teams thrive on chat or email communications, which is why the written mode is now considered almost as important as face-to-face communication (Arvedsen & Hassert, 2020; Liao, 2017). For example, recent studies show significant but not very strong relation between email communication and perceived leaders’ effectiveness. This relation was only slightly weaker than the relation between face-to-face communication and effectiveness (Braun et al., 2019). At the same time, the basic rules of workplace communication—a two-way exchange, which is rich with information and high on synchronicity—guarantee sustainable and mutually rewarding manager-employee relationships (Yukl, 2006). In this study, we assume that workplace emails are but one example of actions that realize specific goals in accordance with the Theory of Purposeful Work-Behavior: Achievement, Autonomy, Prestige and Communion. While not suggesting that there is one-to-one correspondence between an individual email and a goal, we have described typical patterns, salient terms, and communicative moves that characterize writing styles channeled toward Achievement and Communion, which are becoming especially significant in the context of remote work, and which are best reflected in writing styles of conscientious and agreeable managers. We also suggest specific recommendations based on the results of the conducted analyses, which have implications for fostering reflexivity and enriching managerial training with respect to broader repertoires of writing styles. However, the recommendations are not aimed at invalidating managers’ preferred personality and style of communication but to reflect on the possible amendments they could introduce to the way they use the written mode and the email in addressing coworkers and subordinates to perform effective management/leadership. This is compatible with recent trends in developing managerial reflexivity training, where emphasis is put on exploring new pathways to effectiveness because of the need for constant changes and adaptations (Crevani et al., 2021). According to Dirani et al. (2020), in times of crisis, new types of communications are needed and should be embraced by managing staff, to ensure that the objectives of the organization are met without compromising its human capital, namely, the safety and well-being of the employees. Limitations and Implications for Future Research This study design is not devoid of limitations, given its specific cross-disciplinary character that involves resorting to personality psychology, linguistic research, and written communication in the study of and recommendations for management training. Our analysis of writing styles was correlated only with two personality factors out of the Big Five, which were selected on the basis of literature as influencing written communication. However, other psychological variables, including temperamental types of leadership styles, could also be used to reveal important writing patterns that lend themselves to reflexivity-fostering recommendations. Needless to say, the sample of texts and people who authored them was relatively limited and disparate. Stronger implications could have been derived for specific sectors or types of managed organizations, had we used a different sampling procedure. Also, we focused on the emails sent by managers without controlling how these texts were received, and thus we could not say much about how efficient interactions over email should proceed. If office computer-based communication is relatively established and more formal, then smartphone emailing has recently widened the repertoires in which leaders manage work-related tasks and, above all, workplace relationships (Caron et al., 2013). This study has not tackled the evolving styles that these new mobile digital affordances enable. The study on the convergence of linguistic patterns sourced from mobile text-messaging and business emailing would be another contribution in this line of inquiry. Author Biographies Katarzyna Molek-Kozakowska, is associate professor and head of Department of English at the Institute of Linguistics of University of Opole and Senior Research Fellow at Vilnius Gediminas Technical University. She specializes in discourse analysis and communication studies. Dorota Molek-Winiarska is associate professor in Human Resources Management Department, Wroclaw University of Economics and Business. She is an occupational psychologist and HR consultant. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The project has been financed by the Faculty of Management, Wroclaw University of Economics and Business (Internal grant no. MPK B702046). ORCID iD: Dorota Molek-Winiarska https://orcid.org/0000-0001-8554-6771 ==== Refs References Agbi R. O. (2018). Leadership communications strategies for enhancing virtual team performance. Walden Dissertations and Doctoral Studies. https://scholarworks.waldenu.edu/dissertations. Alvesson M. Blom M. Sveningsson S. (2017). Reflexive leadership: Organising in an imperfect world. SAGE. Amichai-Hamburger Y. Vinitzky G. (2010). Social network use and personality. Computers in Human Behavior, 26 (6 ), 1289-1295. 10.1016/j.chb.2010.03.018. Aronson E. Aronson J. (2018). 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==== Front Int J Artif Organs Int J Artif Organs JAO spjao The International Journal of Artificial Organs 0391-3988 1724-6040 SAGE Publications Sage UK: London, England 36495090 10.1177/03913988221142904 10.1177_03913988221142904 Original Research Article The ProtekDuo in ECMO configuration for ARDS secondary to COVID-19: A systematic review https://orcid.org/0000-0003-2406-655X Maybauer Marc O 1234 Capoccia Massimo 5 Maybauer Dirk M 23 Lorusso Roberto 6 Swol Justyna 7 Brewer Joseph M 1 1 Nazih Zuhdi Transplant Institute, Advanced Cardiac and Specialty Critical Care, Oklahoma City, OK, USA 2 Department of Anaesthesiology and Intensive Care Medicine, Philipps University, Marburg, Germany 3 Critical Care Research Group, Prince Charles Hospital, University of Queensland, Brisbane, QLD, Australia 4 Department of Anesthesiology, Division of Critical Care Medicine, University of Florida College of Medicine, Gainesville, FL, USA 5 Department of Cardiac Surgery, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, UK 6 ECLS Centrum, Cardio -Thoracic Surgery Department, Heart & Vascular Center, Maastricht University Medical Center, Maastricht (MUMC), The Netherlands; and Cardiovascular Research Institute (CARIM), Maastricht, The Netherlands 7 Department of Pneumology, Allergology and Sleep Medicine, Paracelsus Medical University, Nuremberg, Germany Marc O Maybauer, Department of Anesthesiology, Division of Critical Care Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA. Email: [email protected] 10 12 2022 10 12 2022 039139882211429043 9 2022 14 11 2022 © The Author(s) 2022 2022 SAGE Publications This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections. Objective: Assessment of the results of the ProtekDuo cannula applied for dedicated right ventricular support with oxygenator in ARDS secondary to COVID-19. Methods: Systematic literature search in NHS library, Medline (Pubmed) and EMBASE using appropriate keywords as well as PICOS and PRISMA approach. Results: Out of 285 publications found, 5 publications met the search criteria and were included in this review. A total of 194 patients with ARDS secondary to COVID-19 underwent ProtekDuo placement to establish a combination of respiratory [veno-venous extracorporeal membrane oxygenation (V-V ECMO)] and right ventricular support. Patients treated using the ProtekDuo cannula had survival rates between 59% and 89% throughout the five studies, and a significant survival benefit when compared to an invasive ventilation group or compared to dual site V-V ECMO or other double lumen ECMO cannulas. One study focused on extubation and discontinuation of ventilator support, which could be achieved in 100% of ProtekDuo patients. An association for reduced incidence of acute kidney injury (AKI) and use of continuous renal replacement therapy (CRRT) could be shown when the ProtekDuo was used. Conclusion: Only limited literature is available for the ProtekDuo in V-P ECMO configuration in the setting of COVID-19 ARDS and should be interpreted with caution. Data on the ProtekDuo is suggestive for lower rates of mortality, AKI and CRRT as compared to other respiratory support modalities. ECLS extracorporeal life support extracorporeal membrane oxygenation percutaneous RVAD right ventricular assist device ProtekDuo edited-statecorrected-proof typesetterts1 ==== Body pmcIntroduction The ProtekDuo (LivaNova PLC, London, UK) is a single-site, double-lumen cannula that is inserted percutaneously into the right internal jugular vein (RIJV) and advanced through the right heart until the distal tip of the cannula rests in the main pulmonary artery (PA). When in proper position, the cannula’s proximal fenestrations in the right atrium (RA) drain venous blood toward the extracorporeal membrane oxygenation (ECMO) system which is reinfused, after proper blood-related gas exchange, through distal fenestrations in the main PA downstream the pulmonic valve. The site of inflow and outflow, therefore, allow bypassing of the right ventricle (RV), making the cannula an effective percutaneous right ventricular assist device (RVAD). The ProtekDuo comes in two sizes, 29 and 31 French (Fr) and approximates a blood flow of 4–5 liters per minute (LPM), utilizing a centrifugal pump.1 For cannula placement, an 8 French (Fr) introducer sheath is first inserted into the RIJV and then a pulmonary artery catheter (PAC) or pulmonary wedge pressure catheter is floated through the sheath into the right PA. Thereafter, a Lunderquist® Extra-Stiff (Cook, Bloomington, USA) or Amplatz Super Stiff™ (Boston Scientific, Malborough, MA, USA) exchange guidewire (both 0.035″ × 260 cm) is inserted through the PAC which is removed while keeping the wire in the PA position. Serial dilators may be used and the ProtekDuo cannula then inserted over the wire under fluoroscopy into its position in the main PA. The implanted double-lumen cannula can then be connected with an extracorporeal circuit which provides only blood drainage and reinfusion, therefore unloading the right atrium and RV, thereby supporting the right heart-related circulation (RVAD configuration) or combining RV and respiratory support by introducing an oxygenator in the same circuit (OxyRVAD or V-P ECMO configuration). Any commercially available and approved extracorporeal circuit, oxygenator, and pump may be sufficient for use. It should be secured like any other large bore cannula.1 If fluoroscopy is not available, a transesophageal echocardiogram may be a useful tool for an ECMO retrieval team that cannulates in remote small hospitals without catheter laboratory or other technical capacity. During the COVID-19 pandemic, use of the ProtekDuo as RVAD was broadened by adding an oxygenator to the circuit to provide venovenous extracorporeal membrane oxygenation (OxyRVAD) for patients suffering from acute respiratory distress syndrome (ARDS). When considering the position paper of the Extracorporeal Life Support Organization (ELSO), the so called “ELSO Maastricht Treaty for ECLS Nomenclature: Abbreviations for cannulation configuration in extracorporeal life support,” this ECMO configuration is named venopulmonary (V-P) ECMO.2 Based on our own previous experience with the ProtekDuo as RVAD and V-P ECMO/OxyRVAD we were interested in further investigating the actual ProtekDuo-related results in COVID-19 patients. Presently, the number of patients who require ECMO for COVID-19 infection went down to zero at our institution. Widely organized vaccination programs may be responsible for this development, and even though not yet conclusive, we do not anticipate many patients or studies to come up in the near future. Therefore, we aimed to conduct a systematic review of the available literature to determine the present level of evidence for its function as V-P ECMO/OxyRVAD in patients with ARDS secondary to COVID-19 infection. Materials and methods The PICOS approach (Participants, Intervention, Comparison, Outcome and Study Design) for selection of clinical studies has been used for our systematic literature search as recently described (Table 1).3 The PRISMA system (Preferred Reporting Items for Systematic Review and Meta-Analyses) has been used throughout the screening process to ensure clarity and transparency (Figure 1).4 The systematic literature search was performed in Medline (PubMed), EMBASE, and through the NHS (National Health Service) Library in the United Kingdom. The search strategy was developed and carried out supported by the NHS Library. The search included controlled vocabulary and free text terms such as: ProtekDuo or Protek Duo or percutaneous right ventricular assist device and oxygenator or ECMO or Extracorporeal Membrane Oxygenation or ECLS or Extra Corporeal Life Support and RVAD or RVAD/OXY or OxyRVAD. The literature was screened for any publication on the ProtekDuo, and a redundancy check was performed. The search strategy included all clinical studies. All authors participated in the study selection and determination of eligibility for inclusion in this systematic review. Discordances were addressed by consensus. Clinical guidelines, reviews, book chapters, editorials and letters to the editor were excluded as displayed in Figure 1. All publications relevant to the subject, however, were reviewed and contextually integrated in the discussion of this systematic review. Table 1. PICOS approach for the selection of studies in the systematic search process. Participants Patients with ARDS secondary to COVID-19 Intervention ECMO with Protek Duo cannula Comparison With control group if available Outcomes Effectiveness of treatment in terms of survival rate and complications Study design Prospective and retrospective clinical studies, case series Figure 1. PRISMA flow diagram of the systematic search. Adjusted from Page et al. BMJ 2021.15 Results We identified a total of 285 publications, of which 175 were found in EMBASE, 36 in Medline (PubMed) and 74 through the NHS library. A total of 100 duplicates and 64 conference abstracts were discarded, while 12 records were marked as ineligible by automation tools. A total of 176 papers were eliminated and 109 remaining records were screened. In the screening phase, 16 publications were excluded for being editorials or letters to the editor and 14 publications were deemed irrelevant to the subject, leaving 79 articles to be assessed for eligibility. Further exclusion criteria were applied for case reports with less than 5 subjects, review articles, articles that did not provide sufficient details about the devices used, articles in which the ProtekDuo was used for RVAD only or for non-COVID-19 related respiratory support, and articles with data spread over multiple publications. In total, an additional 77 articles were excluded. Lastly, reviews of reference lists and availability of articles in press resulted in the addition of two articles. The final review included five articles, one was a large case series of 40 patients and the others were retrospective studies. In the five selected studies, a total of 194 patients underwent ProtekDuo placement in combination with an oxygenator (V-P ECMO/OxyRVAD configuration) for the treatment of ARDS due to COVID-19. The ProtekDuo showed survival rates between 59 and 89% throughout the five studies and was suggestive for a survival benefit when compared to an invasive ventilation group9 or compared to dual site V-V ECMO or other double-lumen ECMO cannulas.10 One study focused on extubation and discontinuation of ventilator support, which could be achieved in 100% of ProtekDuo patients.8 In addition, an association of reduced incidence of acute kidney injury (AKI) and consecutive use of continuous renal replacement therapy (CRRT) could be demonstrated when the ProtekDuo was used (Table 2). Table 2. Protek Duo for RVAD+ECMO. First author, study design Use of Protek Duo Comparison Patients included Important outcomes Cain et al.,9 Retrospective cohort RVAD+ECMO for COVID-19 ARDS Protek Duo for RVAD+ECMO compared to invasive mechanical ventilation alone 39 adult patients 18 with Protek Duo for RVAD+ECMO 21 with IMV alone In-hospital mortality: Total 13(33%), IMV = 11 (52.4%), RVAD+ECMO = 2 (11.1%), p = 0.008 30-day mortality: Total 10 (25.6%), IMV = 9(42.9%%), RVAD+ECMO = 1 (5.6%), p = 0.011 ICU LOS: 13 (6–27), IMV = 11.5(6–22.5), RVAD+ECMO = 21 (9–36), p = 0.067 AKI:15 (38.5%), IMV = 15 (71.4%), RVAD+ECMO = 0 (0%), p ⩽ 0.001 Duration of IMV:7.5 (1–22), IMV = 10 (5–20), RVAD+ECMO = 5(1–34), p = 0.44 Mustafa et al.,8 Case series RVAD+ECMO for COVID-19 ARDS None 40 adult patients Ventilator discontinuation: 40 (100%) ECMO initiation to extubation: 13 ± 2.6 days Weaned from ECMO: 32 (80%) Hospital discharge: 29 (73%) Mortality: 6 (15%) Saeed et al.,10 Multicenter retrospective study RVAD+ECMO for COVID-19 ARDS Compared dual-site (femoral vein-femoral vein or femoral vein-internal jugular vein) to single, dual-lumen cannula in internal jugular vein with tip positioned in the pulmonary artery (Protek Duo), and (3) single, dual-lumen cannula in internal jugular vein advanced through the SVC into the right atrium with tip positioned in the IVC (Crescent or Avalon cannulas) 435 adult patients 99 (23%) had Protek Duo cannulation, 247 (57%) had dual site cannulation, 89 (20%) had single site IVC cannulation 90-day in hospital mortality for entire cohort: 55% Unadjusted 90-day in hospital mortality: dual site = 60%, single site to PA = 41%, single site IVC = 61%, p = 0.06 Adjusted (clinical and center factors) 90-day in hospital mortality was lower in single site PA (HR 0.52, p = 0.029) and similar in single site IVC (HR 0.98, p = 0.86) compared to dual site Single site PA cannulation had longer duration of ECMO compared to other modes Single site PA had shorter mechanical ventilation and more commonly discharged home Smith et al.,11 Retrospective cohort RVAD+ECMO for COVID-19 ARDS Protek Duo for RVAD+ECMO compared to other V-V ECMO configuration and different eras of Protek use N = 54 38 (70.4%) had Protek Duo and 16 (29.6%) had VV ECMO Compared 2 eras of Protek pts: ERA 1 = Mar 1–Jul 6, 2020 ERA 2 = Jul 7, 2020–Mar 1, 2021 Pts treated with Protek: ERA 1 = 18 ERA 2 = 20 The total in-hospital mortality was 42.6% (39.5% V-P ECMO, 50.0% V-V ECMO). Cumulative mortality 120-days post-cannulation was 45.7% (V-V ECMO 60.8%, V-P ECMO 40.0%) Era 2 patients experienced a longer intubation duration (3.0 vs 24.0 days, p = 0.026), higher incidences of reintubation (27.8 vs 60.0%, p = 0.046), in-hospital mortality (16.7% vs 60.0%, p = 0.006), RRT (0.0% vs 50.0%, p < 0.001), and infection (61.1% vs 95.0%, p = 0.016) due to increased rate of secondary bacterial pneumonia (22.2% vs 85.0%, p < 0.001). Era 2 patients were significantly less likely to be discharged home (72.2% vs 5.6%, p < 0.001). Era 2 patients suffered significantly more cannula-associated complications (25.0% vs 0.0%, p = 0.048) Era 2 patients experienced significantly more “major” bleeding events (22.2% vs 60.0%, p = 0.025). Era 2 patients had a much higher cumulative incidence of mortality (60.4%) compared to Era 1 patients (16.2%) El Banayosy et al.,12 Retrospective cohort RVAD+ECMO for COVID-19 ARDS None 9 adult patients (initial configuration: 2 V-P, 6 V-V, 1 V-A; mode for Protek: 4 V-P, 1 V-VP, 4 both Survival: 67% ECMO duration: 55 ± 29 days The ProtekDuo was placed in a late stage after V-V ECMO when either right heart failure or oxygenation problems occurred. Discussion The group of Zwischenberger first described the placement of a single-site, percutaneous, double-lumen cannula for RVAD in an ovine model in 2015.5 Over the following years, numerous authors have reported cases in which the ProtekDuo has been utilized in multiple configurations including its original configuration as RVAD, RVAD with oxygenator for ECMO (V-P ECMO/OxyRVAD), left ventricular assist device (LVAD), biventricular assist device (BiVAD) or ECPELLA 2.0 when either combined with a durable LVAD or any of the multiple available Impella® devices. It had also been used as double-lumen drainage cannula for cardiopulmonary bypass (CPB), and in other ECMO configurations, such as veno-pulmonary (V-P), venovenous-pulmonary (VV-P), and in veno-venopulmonary (V-VP) ECMO. These configurations and technical aspects have been described by our group elsewhere in detail.6,7 The focus of this systematic review is to explore the results related to the use of the ProtekDuo, as part of V-P ECMO configuration circuit, since several publications have recently been published supporting this extracorporeal cardio-respiratory support modality during the COVID-19 pandemic for ARDS. The ProtekDuo with oxygenator may be beneficial in ARDS due to its default V-P ECMO position with drainage of venous blood from the RA and return of arterialized blood into the PA. Considering its average blood flow of 4.5 LPM, it mostly achieves sufficient flow and oxygenation, especially since two cardiac valves are in between both cannula openings and prevent recirculation. For the rare cases of high body mass index with increased need for blood flow and oxygenation, reconfiguration to V-VP ECMO as developed and described by Maybauer et al. has been shown to be effective in providing up to 7 LPM of oxygenated blood flow, with approximately 40% of the blood flow bypassing the RV.6 In 2020, Mustafa et al. presented the first experience with V-P ECMO for patients with ARDS secondary to COVID-19. The group presented a case series of 40 patients in which they reported an average duration of mechanical ventilation of 13 days, 80% (32 patients) rate of ECMO weaning, and 73% (29 patients) survival rate.8 Similarly, good results were reported by Cain et al.9 who compared 39 patients in two groups: V-P ECMO (18 patients) and invasive mechanical ventilation (IMV, 21 patients). Their group reported a significant reduction of in-hospital (52.4% vs 11.1%, p = 0.0008) and 30-day mortality rates (42.9% vs 5.6%, p = 0.011) in favor of the V-P ECMO group without any device related complications. In addition, while the occurrence of acute kidney injury (AKI) was not evident in the V-P ECMO group at all, the IMV group had 15 cases of AKI (71.4%, p < 0.001). In 2022, a large multicenter retrospective study including 435 adult patients was published by Saeed et al.10 This group compared the dual-site versus single-site cannulation approach. For dual site they used femoral vein to femoral vein or femoral vein to internal jugular vein access. For single site they used the ProtekDuo with its tip in the pulmonary artery, or Crescent/Avalon cannulas with their tip positioned in the inferior vena cava (IVC). Of 435 adult patients, 99 (23%) had Protek Duo cannulation, 247 (57%) had dual site cannulation, and 89 (20%) had single site IVC cannulation. The 90-day in hospital mortality for the entire cohort was 55% with an unadjusted 90-day in hospital mortality of 60% for dual site, 41% for ProtekDuo, and 61% IVC. After adjusting for clinical and center factors, the 90-day in-hospital mortality was significantly lower for ProtekDuo (HR 0.52, p = 0.029) and similar in single site IVC (HR 0.98, p = 0.86) compared to dual site. However, the ProtekDuo cannulation had longer duration of ECMO compared to other modes, but had shorter mechanical ventilation and patients were more commonly discharged home. Smith et al.11 investigated a cohort of 54 patients, comparing the ProtekDuo with V-V ECMO through 1 year of the pandemic. Sixteen (29.6%) of their patients received V-V ECMO and 38 (70.4%) V-P ECMO after a median time of 7 days from admission to cannulation. Their median ECMO support time was 30.5 days (V-V ECMO 35.0 days vs V-P ECMO 26.0 days). In this study, the total in-hospital mortality was 42.6% with 39.5% for V-P ECMO and 50.0% for V-V ECMO. The total cumulative mortality after 120-days post-cannulation was 45.7%, with 60.8% for V-V ECMO and 40.0% for V-P ECMO. The authors concluded ECMO support for COVID-19 was beneficial and that V-P ECMO support demonstrated consistent advantages in survival compared to V-V ECMO. In contrast to the above-mentioned studies where V-P ECMO was the initial configuration, the most recent study by the group of Maybauer showed that V-P or V-VP ECMO configuration was established weeks after the onset of ARDS and ECMO initiation. This selected group of patients still displayed good outcomes with a survival rate of 67%12 and the ProtekDuo has been shown to be a game changer when used in patients with ARDS secondary to COVID-19.13 However, the available data is scarce and may have institutional bias. It should therefore be considered with caution. The use of this cannula is also not without risk. The bend in the cannula could potentially lead to cannula fracture and even though extremely rare, it could lead to right coronary artery obstruction depending on the position in the RV, as described by Unger et al.14 Conclusion It should be borne in mind that the amount of published literature and evidence for use of the ProtekDuo cannula in patients with ARDS secondary to COVID-19 is limited. However, the number of patients requiring ECMO support for COVID-19 ARDS has now decreased to zero. This may be due to herd immunity through infection or widespread vaccination programs and/or decrease in virulence. Future large cohort studies on COVID-19 and ECMO cannot be predicted at this time. Therefore, we aimed to summarize and present the available data. The ProtekDuo contributed to reduced mortality, reduced acute kidney injury, and consecutively reduced need for continuous renal replacement therapy. Therefore, many authors of the above-mentioned papers suggest using the ProtekDuo as first line cannula in the setting of COVID-19 ARDS. Investigations of the ProtekDuo in other causes of ARDS are warranted to compare its use in different etiologies of ARDS. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. ORCID iD: Marc O Maybauer https://orcid.org/0000-0003-2406-655X ==== Refs References 1 Maybauer MO Koerner MM Swol J , et al . The novel ProtekDuo ventricular assist device: configurations, technical aspects, and present evidence. Perfusion. Epub ahead of print 26 May 2022. DOI: 10.1177/02676591221090607 2 Broman LM Taccone FS Lorusso R , et al . The ELSO Maastricht Treaty for ECLS nomenclature: abbreviations for cannulation configuration in extracorporeal life support - a position paper of the Extracorporeal Life Support Organization. Crit Care 2019; 23 (1 ): 36.30736845 3 Geli J Capoccia M Maybauer DM , et al . Argatroban anticoagulation for adult Extracorporeal Membrane Oxygenation: A systematic review. J Intensive Care Med 2022; 37 (4 ): 459–471.33653194 4 Moher D Liberati A Tetzlaff J , et al .; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6 (7 ): e1000097. 5 Wang D Jones C Ballard-Croft C , et al . Development of a double-lumen cannula for a percutaneous RVAD. ASAIO J 2015; 61 (4 ): 397–402.25851314 6 Maybauer MO Koerner MM Mihu MR , et al . The ProtekDuo as double lumen return cannula in V-VP ECMO configuration: A first-in-man method description. Ann Card Anaesth 2022; 25 (2 ): 217–219.35417975 7 Maybauer MO Koerner MM Harper MD , et al . The ProtekDuo as double lumen arterial return cannula in extracorporeal membrane oxygenation. Int J Artif Organs 2021; 44 (9 ): 623. 8 Mustafa AK Alexander PJ Joshi DJ , et al . Extracorporeal membrane oxygenation for patients with COVID-19 in severe respiratory failure. JAMA Surg 2020; 155 (10 ): 990–992.32780089 9 Cain MT Smith NJ Barash M , et al . Extracorporeal membrane oxygenation with right ventricular assist device for COVID-19 ARDS. J Surg Res 2021; 264 : 81–89.33789179 10 Saeed O Stein LH Cavarocchi N , et al . Outcomes by cannulation methods for venovenous extracorporeal membrane oxygenation during COVID-19: a multicenter retrospective study. Artif Organs 2022; 46 (8 ): 1659–1668.35191553 11 Smith NJ Park S Zundel MT , et al . Extracorporeal membrane oxygenation for COVID-19: an evolving experience through multiple waves. Artif Organs 2022; 46 : 2257–2265.35957490 12 El Banayosy AM El Banayosy A Brewer JM , et al . The ProtekDuo for percutaneous V-P and V-VP ECMO in patients with COVID-19 ARDS. Int J Artif Organs 2022; 45 : 1006–1012.36085584 13 Maybauer MO Lorusso R Swol J. The ProtekDuo cannula for extracorporeal membrane oxygenation: A game changer in COVID-19! Artif Organs 2022; 46 : 2107–2108.35929444 14 Unger ED Sweis RN Bharat A. Unusual complication of a right ventricular support-extracorporeal membrane oxygenation Cannula. JAMA Cardiol 2021; 6 (6 ): 723–724.33729424 15 Page MJ McKenzie JE Bossuyt PM , et al . The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 74 : 790–799.	36495090	PMC9747364	NO-CC CODE	2022-12-15 00:04:04	no	Int J Artif Organs. 2022 Dec 10;:03913988221142904	utf-8	Int J Artif Organs	2,022	10.1177/03913988221142904	oa_other
==== Front Clin Pediatr (Phila) Clin Pediatr (Phila) CPJ spcpj Clinical Pediatrics 0009-9228 1938-2707 SAGE Publications Sage CA: Los Angeles, CA 36495165 10.1177/00099228221141534 10.1177_00099228221141534 Brief Report SARS-CoV-2 Infection Mitigation Strategies Concomitantly Reduce Group A Streptococcus Pharyngitis https://orcid.org/0000-0002-5665-7357 Boyanton Bobby L. Jr MD 12 https://orcid.org/0000-0002-0715-151X Snowden Jessica N. MD 3456 https://orcid.org/0000-0002-6347-9675 Frenner Rachel A. BS 1 Rosenbaum Eric R. MD 12 Young Heather L. MD 56 Kennedy Joshua L. MD 78 1 Department of Pathology, Arkansas Children’s Hospital, Little Rock, AR, USA 2 Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA 3 Departments of Pediatrics and Biostatistics, Arkansas Children’s Hospital, Little Rock, AR, USA 4 Departments of Pediatrics and Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR, USA 5 Department of Infectious Diseases, Arkansas Children’s Hospital, Little Rock, AR, USA 6 Department of Infectious Diseases, University of Arkansas for Medical Sciences, Little Rock, AR, USA 7 Departments of Pediatrics and Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA 8 Arkansas Children’s Research Institute, Little Rock, AR, USA Bobby L. Boyanton Jr, M.D., Department of Pathology, Arkansas Children’s Hospital, Slot #820, Little Rock, AR 72202, USA. Email: [email protected] Joshua L. Kennedy, M.D., Departments of Pediatrics and Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. Email: [email protected] All authors contributed equally to this body of work. 10 12 2022 10 12 2022 00099228221141534© The Author(s) 2022 2022 SAGE Publications This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections. edited-statecorrected-proof typesetterts1 ==== Body pmcIntroduction Group A streptococcus (GAS) is the most common cause of pediatric bacterial pharyngitis.1,2 Children are the primary reservoir for GAS and represent the pool from which children and adults acquire infection. The bacteria are spread person-to-person by contacting secretions or articles/surfaces contaminated by infected individuals.1,2 Thus, eliminating these transmission sources should reduce the burden of GAS pharyngitis (GAS-P). Implementation of infection mitigation strategies (IMS) to combat the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic provided an opportunity to study the impact of such measures on the GAS-P burden. The goal of this study was to characterize the impact of SARS-CoV-2 IMS on pediatric cases of GAS-P and determine whether the pandemic caused inequalities in how patients used our health care system. Methods This retrospective case-series chart review study was approved by the Institutional Review Board of the University of Arkansas for Medical Sciences (No. 274080). Arkansas Children’s Hospital is a tertiary care facility in Little Rock, Arkansas, and includes a level 1 emergency department (ED) and 7 outpatient (OP) clinics. All patients tested for GAS-P from April 1, 2018, to December 31, 2019, and from April 1, 2020, to December 31, 2021, were identified from our integrated electronic health record (Epic Systems, Verona, Wisconsin). Patient-specific information (age at the time of testing, date/location of testing [ED or OP], sex, race/ethnicity) was obtained. All testing used the Sofia Strep A FIA (Quidel, San Diego, California) point-of-care rapid antigen test (RAT); all negative RATs were confirmed by nucleic acid amplification (Solana GAS Assay [Quidel] or GeneXpert Xpress Strep A [Cepheid, Sunnyvale, California]). A patient was considered GAS-positive if RAT was positive or if RAT was negative and confirmation testing was positive. A patient was considered GAS-negative if both RAT and confirmation testing were negative. To avoid counting multiple test results for the same episode of GAS-P, repeat test results within 14 days, if encountered, were excluded. In Arkansas, SARS-CoV-2 IMS began late March 2020 and included universal masking, physical distancing, restricted access to public activities, and temporary cessation of in-person school and extracurricular activities, including daycare facilities. Frequent hand hygiene and cleansing of high-contact surfaces were highly recommended. In August 2021, students opted to learn virtually or in-person, the latter requiring continued use of universal masking and physical distancing. Data were sorted into SARS-CoV-2 pre-mitigation (April 2018-December 2019) and mitigation (April 2020-December 2021) periods. Subgroup stratification included patient location (ED vs. OP) (emergency department vs outpatient) and patient age groups: 0-5 years, 6-10 years, 11-13 years, 14-18 years. Descriptive statistics were used to tabulate the test positivity rate and the interval change in the positivity rate (pre-mitigation period minus mitigation period). Chi-square (χ2-independence) analysis was used to determine the statistical difference of the interval change in the positivity rate. All statistical analyses were performed with Microsoft Excel 365 (Microsoft Corp., Redmond, Washington); P values <.05 were considered significant. Results During the two 21-month periods, 17 979 tests for GAS-P were performed on 14 675 patients (≤18 years; 54% female). There were no instances of repeat test results within 14 days for any patient evaluated for GAS-P. During the pre-mitigation time period, the incidence of GAS-P was 181.8 cases per 1000 visits (19 316 visits for pharyngitis, 3512 cases of GAS-P). During the mitigation time period, the incidence of GAS-P was 33.5 cases per 1000 visits (11 421 visits for pharyngitis, 1013 cases of GAS-P). After the implementation of IMS, the incidence of GAS-P dropped by 81.6% (P < .0001). The temporal relationship of the total number of tests performed and the overall GAS-P test positivity rate is depicted in Figure 1A. Table 1 summarizes patient demographic information, the GAS-P test positivity rates for the pre-mitigation and mitigation periods, and the interval reduction in the GAS-P test positivity rate after IMS implementation. In addition, these data are presented in aggregate, as well as stratified by patient location (ED vs. OP). In the pre-mitigation period, 12 135 tests were performed with a positivity rate of 28.9%. In the mitigation period, 5844 tests were performed with a positivity rate of 17.3%. The 40.1% reduction in the overall positivity rate observed after implementing IMS was statistically significant (P < .001). For patients evaluated in the ED, 6160 (pre-mitigation) and 4217 (mitigation) tests were performed with a positivity rate of 27.1% and 16.0%, respectively. For patients evaluated in the OP setting, 5975 (pre-mitigation) and 1627 (mitigation) tests were performed with a positivity rate of 30.9% and 20.8%, respectively. The positivity rate reductions for ED (40.9%) and OP (32.7%) were statistically significant (P < .001). Age subgroups (0-5, 6-10, 11-13, 14-18 years) were chosen to correlate with education level (preschool, elementary, middle, high school), respectively. Implementing IMS led to statistically significant reductions in positivity rates (range, 19.6%-46.2%) for each age group, regardless of where patients were evaluated. Specifically, the reduction in the positivity rate was most prominent in the younger age groups (Figure 1B). There was an approximately 6% incremental reduction in the positivity rate for each successively younger age group (preschool, 42.1%; elementary school, 40.1%; middle school, 35.5%; high school, 23.9%). Racial/ethnic distribution of patients evaluated in the ED and OP setting is depicted in Figure 1C. For ED, racial/ethnic distribution was equivalent in both the pre-mitigation and mitigation periods, respectively: black (51%, 50.7%), white (34.3%, 32.4%), Hispanic (11.7%, 12.9%), other (3.1, 3.9%). For OP, racial/ethnic distribution ranged from equivalent to slightly variable (nonstatistically significant) in the pre-mitigation and mitigation periods: black (36.6%, 36.5%), white (33.6%, 25.9%), Hispanic (26.3%, 34%), other (3.5%, 3.5%). Figure 1. (A) Summary of GAS-P tests results from April 1, 2018, to December 31, 2019 (pre-SARS-CoV-2 period) and April 1, 2020, to December 31, 2021 (SARS-CoV-2 period). Q1, January-March; Q2, April-June; Q3, July-September; Q4, October-December. Black vertical broken line indicates implementation of IMS. Number of tests performed per quarter (columns) and GAS-P test positivity rates (curvilinear lines) for emergency department (black) and outpatient (gray) settings. (B) Linear relationship of age group and magnitude of percent reduction in the GAS-P positivity rate with implementation of IMS. (C) Racial/ethnic distribution of patients evaluated in the emergency department (black) or outpatient (gray) settings. Pre-IMS, period before implementing infection mitigation strategies (IMS); IMS, period with implementation of IMS. Table 1. Summary of Patient Demographics, GAS-P Test Positivity Rates, and Interval Change (Percent Change in GAS-P Positivity Rate After Implementing IMS). Demographic information Pre-mitigation period (April 2018-December 2019) Mitigation period (April 2020-December 2021) Interval change χ2 Location Age, y Unique patients Positive tests Total tests % Positive Positive tests Total tests % Positive (%) P value All All 14 675 3512 12 135 28.9 1013 5844 17.3 −40.1 <.001 0-5 5348 1233 4287 28.8 328 1969 16.7 −42.1 <.001 6-10 5104 1556 4275 36.4 412 1889 21.8 −40.1 <.001 11-13 2098 426 1636 26.0 135 804 16.8 −35.5 <.001 14-18 2642 297 1937 15.3 138 1182 11.7 −23.9 <.001 ED All 8788 1668 6160 27.1 675 4217 16.0 −40.9 <.001 0-5 3488 660 2439 27.1 221 1518 14.6 −46.2 <.001 6-10 2903 693 2071 33.5 276 1321 20.9 −37.6 <.001 11-13 1127 173 725 23.9 83 545 15.2 −36.2 <.001 14-18 1523 142 925 15.4 95 833 11.4 −25.7 <.05 OP All 5887 1844 5975 30.9 338 1627 20.8 −32.7 <.001 0-5 1860 573 1848 31.0 107 451 23.7 −23.5 <.05 6-10 2201 863 2204 39.2 136 568 23.9 −38.9 <.001 11-13 971 253 911 27.8 52 259 20.1 −27.7 <.05 14-18 1119 155 1012 15.3 43 349 12.3 −19.6 .17 Abbreviations: ED, emergency department; OP, outpatient. Discussion To attenuate the SARS-CoV-2 pandemic, various IMS were implemented, including universal masking, physical distancing, restricted access to public activities, cessation of in-person school and extracurricular activities, heightened hand hygiene, and frequent cleansing of high-contact surfaces. Such IMS have demonstrated statistically significant reductions in the incidence of numerous pediatric infections, including acute otitis media, common cold, croup, gastroenteritis, pneumococcal pneumonia, pharyngitis (GAS and nonstreptococcal), pneumonia, otorrhea, and sinusitis.3-10 Collectively, reductions in the incidence of the following bacterial and viral infectious agents were observed: adenovirus, bocavirus, coronaviruses (HKU1, OC43, NL63, 229E), enterovirus/rhinovirus, human metapneumovirus, influenza, methicillin-resistant Staphylococcus aureus, parainfluenza virus types 1-4, respiratory syncytial virus, and Streptococcus pneumoniae.3-10 With respect to GAS-P, reduced incidence or prevalence of pediatric cases has been documented in the North Central and Northeastern United States.4,8 Similarly, we demonstrated a significant reduction in pediatric GAS-P after implementing IMS in the South Central United States. To the best of our knowledge, we are first to perform age-based subgroup analyses of the pediatric population and report the inverse relationship between children age groups and the magnitude of the percent reduction in the GAS-P positivity rate after implementing IMS. In short, we observed an approximate 6% incremental reduction in the GAS-P positivity rate for each successively younger age group (preschool [0-5 years], 42.1%; elementary school [6-10 years], 40.1%; middle school [11-13 years], 35.5%; high school [14-18 years], 23.9%). This finding supports the conclusion that SARS-CoV-2 IMS had the greatest benefit in the youngest patients. This observation was unexpected considering the inherent challenges parents/custodians faced when trying to enforce IMS in preschool (0-5 years), and to a lesser extent, elementary school (6-10 years) children. This finding is likely due to the closure of daycare facilities and schools, essentially eliminating the comingling of children in this age group. In addition, any degree of compliance with IMS from middle school (11-13 years), high school (14-18 years), and adults (>19 years) would incrementally decrease the overall burden of GAS-P within a population, possibly even reducing the “carrier state” as previously described.2 The racial/ethnic distribution of patients using our health care system, either the ED or OP setting, for evaluation of GAS-P remained essentially unchanged in the pre-IMS and IMS periods. If present, any bias in how patients of varying races/ethnicities accessed our health care system was independent of the SARS-CoV-2 pandemic. There are limitations to our study which are accordingly acknowledged. First, we were unable to determine the number of children in this study with viral pharyngitis. A significant proportion of these children may also have been tested and determined to be negative for GAS, thereby lowering the observed GAS-P positivity rate. It is well established that upper respiratory tract viruses are the single most common cause of pharyngitis in the pediatric population, accounting for 25% to 45% of cases.11 These include adenovirus, bocavirus, coronaviruses (229E, HKU1, NL63, OC43), enterovirus/rhinovirus, human metapneumovirus, influenza A/B, parainfluenza (types 1-4), and respiratory syncytial virus.11 Prior to the SARS-CoV-2 pandemic, these viruses readily circulated. Of note, the frequency of these viruses was reduced to 1% or less during the SARS-CoV-2 pandemic.3 However, 2 recently published meta-analyses demonstrated that pharyngitis was only observed in 5% to 22% of children with SARS-CoV-2 infection.12,13 Any impact that circulating respiratory viruses may have had on GAS-P positivity rates would have been more pronounced prior to the SARS-CoV-2 pandemic. Therefore, our observed reduction in the GAS-P positivity rate is likely independent of the number of children with viral pharyngitis. Second, our results were generated from a single pediatric hospital network that essentially represented the metropolitan area of Little Rock, AR, and may not be reflective of other urban and rural pediatric populations. Finally, we highlight a temporal association between IMS implementation and the reduction in pediatric GAS-P. Although a causal relationship cannot be definitively established, our data are in alignment with others and collectively provide additional evidence for such a relationship. Conclusions The SARS-CoV-2 IMS effectively reduced the burden of GAS-P in our pediatric population. The magnitude was most pronounced in the youngest age group (<10 years of age). Any bias in how patients of varying races/ethnicities accessed our health care system was independent of the SARS-CoV-2 pandemic. Author Contribution BLB: Contributed to conception and design; contributed to acquisition, analysis, or interpretation; drafted the manuscript; critically revised the manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. JNS: Contributed to conception and design; contributed to analysis or interpretation; critically revised the manuscript, gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. RAF: Contributed to conception and design; contributed to acquisition, analysis, or interpretation; drafted the manuscript; critically revised the manuscript; gave final approval, agrees to be accountable for all aspects of work ensuring integrity and accuracy. ERR: Contributed to conception and design; contributed to analysis or interpretation; drafted the manuscript, critically revised the manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. HLY: Contributed to conception and design; contributed to analysis or interpretation; drafted the manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. JLK: Contributed to conception and design; contributed to analysis or interpretation; drafted the manuscript; critically revised the manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accurary. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. ORCID iDs: Bobby L. Boyanton Jr https://orcid.org/0000-0002-5665-7357 Jessica N. Snowden https://orcid.org/0000-0002-0715-151X Rachel A. Frenner https://orcid.org/0000-0002-6347-9675 ==== Refs References 1 Cherry JD . Pharyngitis (pharyngitis, tonsillitis, tonsillopharyngitis, and nasopharyngitis). In: RD Feigin, JD Cherry, GJ Demmler-Harrison, & SL Kaplan eds. Feigin & Cherry’s Textbook of Pediatric Infectious Diseases. 6th ed. Philadelphia, PA: Saunders Elsevier; 2009 :160-169. 2 Martin JM Green M Barbadora KA Wald ER . Group A streptococci among school-aged children: clinical characteristics and the carrier state. Pediatrics 2004;114 (5 ):1212-1219.15520098 3 Olsen SJ Winn AK Budd AP , et al . Changes in influenza and other respiratory virus activity during the COVID-19 pandemic—United States, 2020-2021. MMWR Morb Mortal Wkly Rep. 2021;70 :1013-1019.34292924 4 McBride JA Eickhoff J Wald ER . Impact of COVID-19 quarantine and school cancelation on other common infectious diseases. Pediatr Infect Dis J. 2020;39 (12 ):e449-e452. 5 Torretta S Capaccio P Coro I , et al . Incidental lowering of otitis-media complaints in otitis-prone children during COVID-19 pandemic: not all evil comes to hurt. Eur J Pediatr. 2021;180 :649-652.32691131 6 McNeil JC Flores AR Kaplan SL Hulten KG . The indirect impact of the SARS-CoV-2 pandemic on invasive group a Streptococcus, Streptococcus pneumoniae and Staphylococcus aureus infections in Houston area children. Pediatr Infect Dis J. 2021;40 :e313-e316. 7 Dalabih A Young HL Frenner RA Stroud MH Boyanton BL Jr. SARS-CoV-2 prevention measures concomitantly attenuate methicillin-resistant Staphylococcus aureus infection rates. Clin Pediatr. 2022;61 :137-140. 8 Hatoun J Correa ET Donahue SMA Vernacchio L . Social distancing for COVID-19 and diagnoses of other infectious diseases in children. Pediatrics. 2020;146 (4 ):e2020006460. doi:10.1542/peds.2020-006460. 9 Sakamoto H Ishikane M Ueda P . Seasonal influenza activity during the SARS-CoV-2 outbreak in Japan. JAMA. 2020;323 :1969-1971.32275293 10 Sullivan SG Carlson S Cheng AC , et al . Where has all the influenza gone? The impact of COVID-19 on the circulation of influenza and other respiratory viruses, Australia, March to September 2020. Euro Surveill. 2020;25 (47 ):2001847.33243355 11 Caserta MT Flores AR . Pharyngitis. In: Mandell GL Douglas RG Jr Bennett JE eds. Principles and Practice of Infectious Diseases. 7th ed. Philadelphia, PA: Churchill Livingstone; 2010 :815-821. 12 Mansourian M Ghandi Y Habibi D Mehrabi S . COVID-19 infection in children: a systemic review and meta-analysis of clinical features and laboratory findings. Arch Pediatr. 2021;28 (3 ):242-248.33483192 13 Assaker R Colas AE Julien-Marsollier F , et al . Presenting symptoms of COVID-19 in children: a meta-analysis of published studies. Br J Anaesth. 2020;125 (3 ):e330-e332.	36495165	PMC9747366	NO-CC CODE	2022-12-15 00:04:04	no	Clin Pediatr (Phila). 2022 Dec 10;:00099228221141534	utf-8	Clin Pediatr (Phila)	2,022	10.1177/00099228221141534	oa_other
==== Front Int J Artif Organs Int J Artif Organs JAO spjao The International Journal of Artificial Organs 0391-3988 1724-6040 SAGE Publications Sage UK: London, England 36495032 10.1177/03913988221141719 10.1177_03913988221141719 Original Research Article CoronaVac, BNT162b2 and heterologous COVID-19 vaccine outcomes in patients with ventricular assist device https://orcid.org/0000-0003-1705-4999 Karahan Mehmet 1 https://orcid.org/0000-0001-7198-069X Kervan Umit 1 Kocabeyoglu Sinan Sabit 1 Sert Dogan Emre 1 Tekce Yasemin Tezer 2 Yavuz Omer Abdullah 1 Kucuker Seref Alp 1 Ozatik Mehmet Ali 1 Catav Zeki 1 Sener Erol 1 1 Cardiovascular Surgery, Ankara City Hospital, Cankaya, Ankara, Turkiye 2 Infectious Diseases, Ankara City Hospital, Cankaya, Ankara, Turkiye Mehmet Karahan, Cardiovascular Surgery, Ankara City Hospital, Universiteler Mah., 1604 Street, No: 9, Cankaya/Ankara 06800, Turkiye. Email: [email protected] 9 12 2022 9 12 2022 0391398822114171912 7 2022 10 11 2022 © The Author(s) 2022 2022 SAGE Publications This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections. Background: A consensus has not yet been reached regarding which COVID-19 vaccine program should be applied in patients with ventricular assist device (VAD). Our aim was to assess the clinical outcome of inactivated, mRNA and heterologous vaccine program in patient with VAD. Methods: In this retrospective and cross-sectional study; adult patients who underwent VAD implantation between January 2012 and September 2021 and received any vaccine that were used in Republic of Türkiye for COVID-19, were included. The patients were divided into three groups according to the type of vaccine; “inactivated,” “mRNA” and “heterologous.” Clinical outcomes were analyzed. Results: Eighteen patients were in each group in the “inactivated,” “mRNA” and “heterologous” groups. Mean age was 51.6 ± 12 years in “inactivated” group, 42.5 ± 15.5 years in “mRNA” group and 41.1 ± 15.4 years in “heterologous” group. There was no significant difference between the groups in age, gender, body surface area, body mass index and etiology (p > 0.05). After last dose of vaccines, the number of patients had COVID-19 positive test were three (16.7%), one (5.6%), and two (11.1%) in “inactivated,” “mRNA” and “heterologous” groups, respectively. Pump thrombosis was seen in two patients in “mRNA” group and one patient in “heterologous” group. No pump thrombosis was seen in “inactivated” group. COVID-19-related death or intubation was not observed. Conclusion: All vaccine that used for COVID-19 are safe and effective in patients with VAD. In countries that give priority to inactivated vaccines, mRNA vaccines may then be made as boosters. COVID-19 vaccine ventricular assist device edited-statecorrected-proof typesetterts1 ==== Body pmcVisual abstract. Distribution of patients according to their vaccine status Introduction Ventricular assist devices (VAD) are the treatment option in advanced heart failure, which is one of the most important causes of detrimental complications due to coronavirus disease 2019 (COVID-19).1,2 Although the reasons remain unclear, patients with VAD have impaired immune systems and are susceptible to infection.3 Presence of infection in patients with VAD is associated with serious morbidity such as pump thrombosis, and mortality.4 Currently, inactivated and messenger-RNA (mRNA) vaccines are used in Republic of Türkiye. Although the safety and efficacy of these vaccines are high, its relation with thromboembolic events is controversial.5 Limited information is available on the outcomes of vaccination in VAD patients who are on long-term anticoagulants and are at risk for pump thrombosis. Moreover, there is no consensus yet on which vaccination program should be used in VAD patients. In this study, 6-month outcomes of the use of COVID-19 vaccines (inactivated, mRNA, and heterologous) in VAD patients are reported. Material and methods In our retrospective and cross-sectional study; adult patients who underwent VAD implantation between January 2012 and September 2021 and received any vaccine that were used in Republic of Türkiye for COVID-19, were included. Patients who had COVID-19 before or during being vaccinated, have not completed at least two dose of vaccinations, under 18 years old, and refused to be participant in the study were excluded from the study. In the COVID-19 pandemic, the two groups of vaccines most widely used in Republic of Türkiye were administered to our patients. The emergency use approval in Republic of Türkiye for CoronaVac (Sinovac Biotech Co., Ltd., Beijing, China) was issued in January 2021, and for BNT162b2 (Pfizer-BioNTech, Mainz, Germany) in March 2021. Within these dates, vaccinations started in the order determined by the government. Since our patients were one of the first groups to be vaccinated, vaccinations have started as of these dates. The patients were divided into three groups according to their vaccination status. The patients vaccinated with only the inactivated vaccine (CoronaVac) (two or three doses) were classified as “inactivated,” those with only BNT162b2 (two or three doses) were classified as “mRNA,” and those with a single or double dose of mRNA vaccine after at least double dose inactivated vaccine were classified as “heterologous.” Age, body mass index, body surface area, gender, etiology, device type, follow-up time, history of COVID-19, cerebrovascular event, pump thrombosis, driveline infections were analyzed. At least 14 days after last dose of vaccine, patients with positive SARS-CoV-2 reverse transcription-polymerase chain reaction test from respiratory tract samples were accepted as COVID-19 positive. The density of diagnosis of patients with COVID-19 and the fluctuations in COVID-19 trends in Republic of Türkiye were also analyzed.6 The study was approved by the local ethical committee (ACH E1/2551/2022 20.04.2022). Statistics Statistical analyzes were performed using the SPSS version 23 (IBM Corp., Armonk, NY, USA). For normal distribution, the Levene test was used for continuous variables and one-way ANOVA was used to determine if there was a difference between independent groups. For non-normal distribution, Kruskal-Wallis test was used. Cox-regression analysis was used to assess the effect of vaccine types. Arithmetic mean and standard deviation for numerical variables with normal distribution as the descriptive statistics; median, minimum and maximum values for the data with non-normal distribution; number and percentage values for the attribute variables are given. p < 0.05 was considered statistically significant. Results Fifty-four patients with VAD who received any COVID-19 vaccine were included in our study. Eighteen were in “inactivated” group (seven of the patients received two doses, 11 received three doses); 18 in “mRNA” group (10 patients received two doses, eight received three doses); 18 patients in the “heterologous” group (12 patients with two doses of inactivated and a single dose of mRNA as a booster; 6 patients with two doses of inactivated and two doses of mRNA as a booster). The baseline characteristics of the patients are summarized in Table 1. Mean age was 51.6 ± 12 years in “inactivated” group, 42.5 ± 15.5 years in “mRNA” group and 41.1 ± 15.4 years in “heterologous” group. There was no significant difference between the groups in age, gender, body surface area, body mass index and etiology (p > 0.05). The VADs used in this study were HeartWare HVAD (Medtronic Inc., Minneapolis, Minnesota, USA) and Heartmate III (Abbott Inc., Chicago, Illinois, USA). As biventricular assist device (BiVAD); one patient had Heartware in the “inactivated” group, while one patient had Heartware and two patients had Heartmate three in the “mRNA” group. All other patients had left-sided VAD (LVAD). Follow-up periods after the last dose of vaccine were 189 ± 80 days in the “inactivated” group, 155 ± 96 days in the “mRNA” group, and 169 ± 60 days in the “heterologous” group. There was no difference in the follow-up times between the groups (p > 0.05). Table 1. Demographics of the patients. Inactivated (n = 18) mRNA (n = 18) Heterologous (n = 18) Age (years) 51.6 ± 12 (22–67) 42.5 ± 15.5 (18–65) 41.1 ± 15.4 (18–66) p > 0.05 Body mass index (kg/m2) 26.9 ± 4.5 24.4 ± 5 25.3 ± 3.5 p > 0.05 Body surface are (m2) 1.8 ± 0.1 1.8 ± 0.1 1.8 ± 0.2 p > 0.05 Male gender (%) 13 (72.2%) 16 (88.9%) 13 (72.2%) p > 0.05 Etiology p > 0.05 Dilated CMP 9 (50%) 10 (55.6%) 14 (77.8%) Ischemic CMP 8 (44.4%) 7 (38.9%) 6 (16.7%) Hypertrophic CMP 1 (5.6%) 0 0 Postpartum CMP 0 1 (5.6%) 1 (5.6%) Device type p > 0.05 Heartware 4 (22.2%) 7 (38.9%) 5 (27.8%) Heartmate 3 13 (72.2%) 8 (44.4%) 13 (72.2%) BiVAD Heartware 0 1 (5.6%) 0 BiVAD Heartmate 3 1 (5.6%) 2 (11.1%) 0 Follow-up after last dose of vaccine (days) 189 ± 80 (55–331) 155 ± 96 (35–300) 169 ± 60 (61–239) p > 0.05 CMP: cardiomyopathy; BiVAD: biventricular assist device. The number of patients had COVID-19 positive test were three (16.7%), one (5.6%), and two (11.1%) in the “inactivated,” “mRNA”, and “heterologous” groups, respectively (p > 0.05) and none of them were hospitalized (Table 2). The type of vaccine did not make any difference in patients in terms of getting COVID-19 after vaccine application (p = 0.769) (Figure 1). The left hemiplegic-cerebrovascular event was observed in one patient in “mRNA” group. Pump thrombosis was seen in two patients in “mRNA” group and one patient in “heterologous” group. No pump thrombosis was seen in “inactivated” group. Driveline infections (DLI) were seen in four patients in the “inactivated” group, one patient in the “mRNA” group, and five patients in the “heterologous group. While drivelines with infection in all groups were rerouted, only two (10.2%) of the patients in the “heterologous” group were rerouted (Table 2). Table 2. Presence of COVID-19 and post-vaccination adverse events in patients with VAD. Inactivated (n = 18) mRNA (n = 18) Heterologous (n = 18) COVID-19 after last dose of vaccine Negative 15 (83.3%) 17 (94.4%) 16 (88.9%) p > 0.05* Positive at home 3 (16.7%) 1 (5.6%) 2 (11.1%) p > 0.05* CVE after vaccine 0 (0%) 1 (5.6%) 0 (0%) p > 0.05 Pump thrombosis after vaccine 0 (0%) 2 (11.1%) 1 (5.6%) p > 0.05 Driveline infection Exit site drainage 0 (0%) 0 (0%) 3 (16.7%) p > 0.05 Rerouting 4 (22.2%) 1 (5.6%) 2 (11.1) p > 0.05 CVE: cerebrovascular events; VAD: ventricular assist device. * One-way ANOVA. **Kruskal Wallis Test Figure 1. Freedom from COVID-19 after last dose of vaccine. Although death due to right heart failure was observed in one patient during the follow-up period in “inactivated” group, COVID-19-related death or intubation was not observed. One patient with LVAD and one patient with BiVAD (both of them had no vaccine) underwent heart transplantation and no adverse events related to COVID-19 were encountered in the follow-up. Booster doses were not administrated before or after transplant. After the start administration of “inactivated” vaccine in January 2021 and “mRNA” vaccinations in March 2021, three peak points were seen in Republic of Türkiye; in April and September/October of 2021 and in January/February of 2022. An overlap was seen between these periods of infection and COVID-19 positive test of patients with VAD (Figure 2). Figure 2. COVID-19 positive patients with VAD and in Republic of Türkiye. Discussion In this study, patients had inactivated vaccine or mRNA vaccine or prime booster vaccination using two dose of inactivated vaccine and one dose of mRNA vaccine booster (heterologous) were analyzed. In “mRNA” group, number of patients with COVID-19 positive test was lower than the other groups but statistical significance could not be reached. Besides, with all vaccine regimen, the disease was not severe enough to require hospitalization. Our study design proceeded from two main branches after administration of different types of vaccines in patient with VAD. The first was the vaccine effect (protection from COVID-19). We waited for the vaccination program to be completed so that we could reach the theoretically effective dose of the vaccine.7 Thus, while it has been reported in the literature that the protective effect of the first dose vaccines was low, we wanted to show the level of protection with booster doses. The second arm was vaccine side effects (pump thrombosis, cerebrovascular event, etc.). In this respect, it was important to collect the data from the first dose in order to show the side effects that may occur even after the first dose. To our knowledge, this is the first study to show the outcomes of inactivated, mRNA and heterologous vaccines in patients with VAD. Different vaccine regimens are applied in every country in the world. Some countries use inactivated and some use mRNA vaccines, while others have both vaccines. In Republic of Türkiye, in accordance to the government policy, primarily inactivated vaccines were provided and applied. Subsequently, mRNA vaccines were also used and heterologous vaccine programs were formed. Vaccine data in particularly vulnerable populations are valuable, as inactivated vaccines and mRNA vaccines are used together, as COVID-19 protection is provided by two different pathways. All vaccines against COVID-19 in market are safe and effective to prevent the disease and mortality.8–10 In a study assessing the immunogenicity of BNT162b2 vaccine in patients with VAD, anti-spike IgG were positive in 83% of patients 6 months after last dose of vaccine.7 This result was also supported by a study in which IgG seropositivity was higher in the BNT162b2 group than in the CoronaVac group.11 In a large-scale population study using BNT161b2 as a booster dose after two doses of CoronaVac vaccine; it has been found that only after CoronaVac vaccine, the protection can be reduced, and the vaccine effect can be strengthened with a booster dose of BNT162b2. It has been found that the use of heterologous vaccines, especially in elderly patients, will help prevent both infection and serious adverse effects of disease.12 In another study from Chile that used homologous and heterologous booster vaccines, both vaccination methods gave better results than the no vaccine population and the heterologous booster method was found to be more effective than the homologous method.13 In a study that compared two mRNA vaccines; mRNA1273 vaccine may be more effective than BNT162b2.14 It has been shown that both mRNA vaccines were effective, especially in the immunosuppressed and male population, which were in the high-risk group for breakthrough infection. In the literature, to our knowledge, there is no study yet on the CoronaVac vaccine used in patients with VAD. In our study, while the rates of patients who did not have COVID-19 positive test in the “inactivated” and “mRNA” groups were around 75%, this rate approached 90% in the “heterologous” group. Although there is no statistical significance due to the small number of patients, the patients who were severely ill enough to require hospitalization among the patients had COVID-19 positive test were not seen in the “heterologous” group. In the early days of the pandemic, we informed our patients that they should pay particular attention to primary protection. Moreover, possible high seropositivity was achieved with the initiation of vaccination programs, and high mortality rates may have decreased in other studies conducted before vaccination programs.15 The patients with VAD have impaired cellular immunity and are susceptible to infections.3 Before the vaccination programs, in VAD patients, hospitalization and mortality of COVID-19 were high as 60% and 20%, respectively.15 The biggest advantage of the vaccination program is undoubtedly that it has ensured the protection of such patients. No mortality was observed in any of our vaccine groups. The fact that no mortality in vaccinated patients indicates that it is important to be vaccinated regardless of the type of vaccine in VAD patients who are prone to infection and the undesirable effects of infection; it also prevents these patients, who are also transplant candidates, from being frail during their preparation for transplantation. Thrombosis cases associated with COVID-19 are common, it has been reported that thrombosis can also be seen in some series, albeit rarely, after COVID-19 vaccine. Although the underlying mechanism of post-vaccine thrombosis has not yet been fully elucidated, it is thought to be related to pathways that promote platelet and coagulation pathway.16 We encountered pump thrombosis in our two different vaccine groups. The international normalized ratio (INR) of all patients were within therapy limits (2.5–3.5) at the time of post-vaccine pump thrombosis, and tissue plasminogen activator (tPA) was administrated to all of them after hospitalization. Thrombosis of all patients resolved after tPA and they were discharged without any problem. Whether this situation was related to the vaccine or not, needs to be investigated in larger series. We have noticed that the need for driveline translocation (rerouting) has increased in the patients with VAD since the vaccination program started (however, this data is not available in the article). After COVID-19 vaccine, especially mRNA vaccine, skin lesions such as angioedema urticaria and pruritus can occur.17,18 Especially considering the rate of driveline infection in the “combine” group; we can speculate whether COVID-19 vaccines could cause a late-term hypersensitivity reaction and increase the need for translocation by causing the progression of driveline infections that were previously observed in mild form. We have used telemedicine to follow-up our patients during the pandemic. The mechanical circulatory support system coordinators have contacted with our patients periodically by phone and e-mail. In these interviews, in addition to lockdown the country, we have called them to stay home and given information about prevention. We have followed-up our patients’ COVID-19 status, INR levels, pump information via telemedicine. This helped us to update our data and to maintain close surveillance. In addition to vaccine shield, we think that basic protective cautions such as maintaining social distance, wearing a mask, staying away from crowded areas are also important to protect from disease. Because, by looking at the trend of the number of the patients had COVID-19 positive test in Republic of Türkiye, there was a similarity in the number of patients with VAD who admitted to our center as COVID-19 during the relaxation of the restrictions corresponding to those periods. Moreover, these precautions could help to decrease the rate of Covid-19-positive patients in our cohort. Limitations First, this study is a single center design and has small group of patients. More information may be obtained with future multicenter studies involving such patients, which are a small group in number. Second, the immunogenicity provided by the vaccine has not been demonstrated in plasma. Conclusion Inactivated and mRNA vaccines used in the COVID-19 pandemic are safe and effective for VAD patients. In cases where the first two doses are given as inactivated vaccines, mRNA vaccines can be considered as a booster. Moreover, we think that the social isolation rules, which are at least as effective as the vaccine, should continue in special patient groups during the pandemic period. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. ORCID iDs: Mehmet Karahan https://orcid.org/0000-0003-1705-4999 Umit Kervan https://orcid.org/0000-0001-7198-069X ==== Refs References 1 Birati EY Jessup M. Left ventricular assist devices in the management of heart failure. Card Fail Rev 2015; 1 (1 ): 25–30.28785427 2 Nishiga M Wang DW Han Y , et al . COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives. Nat Rev Cardiol 2020; 17 (9 ): 543–558.32690910 3 Kimball PM Flattery M McDougan F , et al . Cellular immunity impaired among patients on left ventricular assist device for 6 months. Ann Thorac Surg 2008; 85 (5 ): 1656–1661.18442560 4 O’Horo JC Abu Saleh OM Stulak JM , et al . Left ventricular assist device infections: a systematic review. ASAIO J 2018; 64 (3 ): 287–294.29095732 5 Uaprasert N Panrong K Rojnuckarin P , et al . Thromboembolic and hemorrhagic risks after vaccination against SARS-CoV-2: a systematic review and meta-analysis of randomized controlled trials. Thromb J 2021; 19 (1 ): 86.34774069 6 COVID-19 information platform: Ministry of Health of Turkey, https://covid19.saglik.gov.tr/TR-66935/genel-koronavirus-tablosu.html (1 March 2022) 7 Itzhaki Ben Zadok O Shaul AA Ben-Avraham B , et al . Six-months immunogenicity of BNT162b2 mRNA vaccine in heart transplanted and ventricle assist device-supported patients. ESC Heart Fail 2022; 9 (2 ): 905–911.34981657 8 Benjamanukul S Traiyan S Yorsaeng R , et al . Safety and immunogenicity of inactivated COVID-19 vaccine in health care workers. J Med Virol 2022; 94 (4 ): 1442–1449.34783049 9 Botton J Semenzato L Jabagi MJ , et al . Effectiveness of Ad26.COV2.S vaccine vs BNT162b2 vaccine for COVID-19 hospitalizations. JAMA Netw Open 2022; 5 (3 ): e220868. 10 Tanriover MD Doğanay HL Akova M , et al . Efficacy and safety of an inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac): interim results of a double-blind, randomised, placebo-controlled, phase 3 trial in Turkey. Lancet 2021; 398 (10296 ): 213–222.34246358 11 Sauré D O’Ryan M Torres JP , et al . Dynamic IgG seropositivity after rollout of CoronaVac and BNT162b2 COVID-19 vaccines in Chile: a sentinel surveillance study. Lancet Infect Dis 2022; 22 (1 ): 56–63.34509185 12 Cerqueira-Silva T Katikireddi SV de Araujo Oliveira V , et al . Vaccine effectiveness of heterologous CoronaVac plus BNT162b2 in Brazil. Nat Med 2022; 28 (4 ): 838–843.35140406 13 Jara A Undurraga EA Zubizarreta JR , et al . Effectiveness of homologous and heterologous booster doses for an inactivated SARS-CoV-2 vaccine: a large-scale prospective cohort study. Lancet Glob Health 2022; 10 (6 ): e798–e806. 14 Liu C Lee J Ta C , et al . Risk factors associated with SARS-CoV-2 breakthrough infections in fully mRNA-vaccinated individuals: retrospective analysis. JMIR Public Health Surveill 2022; 8 (5 ): e35311. 15 Birati EY Najjar SS Tedford RJ , et al . Characteristics and outcomes of COVID-19 in patients on left ventricular assist device support. Circ Heart Fail 2021; 14 (4 ): e007957. 16 Violi F Cammisotto V Pastori D , et al . Thrombosis in pre- and post-vaccination phase of COVID-19. Eur Heart J Suppl 2021; 23 (Suppl E ): E184–E8. 17 Robinson LB Fu X Hashimoto D , et al . Incidence of cutaneous reactions after messenger RNA COVID-19 vaccines. JAMA Dermatol 2021; 157 (8 ): 1000–1002.34160555 18 Hoff NP Freise NF Schmidt AG , et al . Delayed skin reaction after mRNA-1273 vaccine against SARS-CoV-2: a rare clinical reaction. Eur J Med Res 2021; 26 (1 ): 98.34433495	36495032	PMC9747367	NO-CC CODE	2022-12-15 00:04:04	no	Int J Artif Organs. 2022 Dec 9;:03913988221141719	utf-8	Int J Artif Organs	2,023	10.1177/03913988221141719	oa_other
==== Front Int J Artif Organs Int J Artif Organs JAO spjao The International Journal of Artificial Organs 0391-3988 1724-6040 SAGE Publications Sage UK: London, England 36495032 10.1177/03913988221141719 10.1177_03913988221141719 Original Research Article CoronaVac, BNT162b2 and heterologous COVID-19 vaccine outcomes in patients with ventricular assist device https://orcid.org/0000-0003-1705-4999 Karahan Mehmet 1 https://orcid.org/0000-0001-7198-069X Kervan Umit 1 Kocabeyoglu Sinan Sabit 1 Sert Dogan Emre 1 Tekce Yasemin Tezer 2 Yavuz Omer Abdullah 1 Kucuker Seref Alp 1 Ozatik Mehmet Ali 1 Catav Zeki 1 Sener Erol 1 1 Cardiovascular Surgery, Ankara City Hospital, Cankaya, Ankara, Turkiye 2 Infectious Diseases, Ankara City Hospital, Cankaya, Ankara, Turkiye Mehmet Karahan, Cardiovascular Surgery, Ankara City Hospital, Universiteler Mah., 1604 Street, No: 9, Cankaya/Ankara 06800, Turkiye. Email: [email protected] 9 12 2022 9 12 2022 0391398822114171912 7 2022 10 11 2022 © The Author(s) 2022 2022 SAGE Publications This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections. Background: A consensus has not yet been reached regarding which COVID-19 vaccine program should be applied in patients with ventricular assist device (VAD). Our aim was to assess the clinical outcome of inactivated, mRNA and heterologous vaccine program in patient with VAD. Methods: In this retrospective and cross-sectional study; adult patients who underwent VAD implantation between January 2012 and September 2021 and received any vaccine that were used in Republic of Türkiye for COVID-19, were included. The patients were divided into three groups according to the type of vaccine; “inactivated,” “mRNA” and “heterologous.” Clinical outcomes were analyzed. Results: Eighteen patients were in each group in the “inactivated,” “mRNA” and “heterologous” groups. Mean age was 51.6 ± 12 years in “inactivated” group, 42.5 ± 15.5 years in “mRNA” group and 41.1 ± 15.4 years in “heterologous” group. There was no significant difference between the groups in age, gender, body surface area, body mass index and etiology (p > 0.05). After last dose of vaccines, the number of patients had COVID-19 positive test were three (16.7%), one (5.6%), and two (11.1%) in “inactivated,” “mRNA” and “heterologous” groups, respectively. Pump thrombosis was seen in two patients in “mRNA” group and one patient in “heterologous” group. No pump thrombosis was seen in “inactivated” group. COVID-19-related death or intubation was not observed. Conclusion: All vaccine that used for COVID-19 are safe and effective in patients with VAD. In countries that give priority to inactivated vaccines, mRNA vaccines may then be made as boosters. COVID-19 vaccine ventricular assist device edited-statecorrected-proof typesetterts1 ==== Body pmcVisual abstract. Distribution of patients according to their vaccine status Introduction Ventricular assist devices (VAD) are the treatment option in advanced heart failure, which is one of the most important causes of detrimental complications due to coronavirus disease 2019 (COVID-19).1,2 Although the reasons remain unclear, patients with VAD have impaired immune systems and are susceptible to infection.3 Presence of infection in patients with VAD is associated with serious morbidity such as pump thrombosis, and mortality.4 Currently, inactivated and messenger-RNA (mRNA) vaccines are used in Republic of Türkiye. Although the safety and efficacy of these vaccines are high, its relation with thromboembolic events is controversial.5 Limited information is available on the outcomes of vaccination in VAD patients who are on long-term anticoagulants and are at risk for pump thrombosis. Moreover, there is no consensus yet on which vaccination program should be used in VAD patients. In this study, 6-month outcomes of the use of COVID-19 vaccines (inactivated, mRNA, and heterologous) in VAD patients are reported. Material and methods In our retrospective and cross-sectional study; adult patients who underwent VAD implantation between January 2012 and September 2021 and received any vaccine that were used in Republic of Türkiye for COVID-19, were included. Patients who had COVID-19 before or during being vaccinated, have not completed at least two dose of vaccinations, under 18 years old, and refused to be participant in the study were excluded from the study. In the COVID-19 pandemic, the two groups of vaccines most widely used in Republic of Türkiye were administered to our patients. The emergency use approval in Republic of Türkiye for CoronaVac (Sinovac Biotech Co., Ltd., Beijing, China) was issued in January 2021, and for BNT162b2 (Pfizer-BioNTech, Mainz, Germany) in March 2021. Within these dates, vaccinations started in the order determined by the government. Since our patients were one of the first groups to be vaccinated, vaccinations have started as of these dates. The patients were divided into three groups according to their vaccination status. The patients vaccinated with only the inactivated vaccine (CoronaVac) (two or three doses) were classified as “inactivated,” those with only BNT162b2 (two or three doses) were classified as “mRNA,” and those with a single or double dose of mRNA vaccine after at least double dose inactivated vaccine were classified as “heterologous.” Age, body mass index, body surface area, gender, etiology, device type, follow-up time, history of COVID-19, cerebrovascular event, pump thrombosis, driveline infections were analyzed. At least 14 days after last dose of vaccine, patients with positive SARS-CoV-2 reverse transcription-polymerase chain reaction test from respiratory tract samples were accepted as COVID-19 positive. The density of diagnosis of patients with COVID-19 and the fluctuations in COVID-19 trends in Republic of Türkiye were also analyzed.6 The study was approved by the local ethical committee (ACH E1/2551/2022 20.04.2022). Statistics Statistical analyzes were performed using the SPSS version 23 (IBM Corp., Armonk, NY, USA). For normal distribution, the Levene test was used for continuous variables and one-way ANOVA was used to determine if there was a difference between independent groups. For non-normal distribution, Kruskal-Wallis test was used. Cox-regression analysis was used to assess the effect of vaccine types. Arithmetic mean and standard deviation for numerical variables with normal distribution as the descriptive statistics; median, minimum and maximum values for the data with non-normal distribution; number and percentage values for the attribute variables are given. p < 0.05 was considered statistically significant. Results Fifty-four patients with VAD who received any COVID-19 vaccine were included in our study. Eighteen were in “inactivated” group (seven of the patients received two doses, 11 received three doses); 18 in “mRNA” group (10 patients received two doses, eight received three doses); 18 patients in the “heterologous” group (12 patients with two doses of inactivated and a single dose of mRNA as a booster; 6 patients with two doses of inactivated and two doses of mRNA as a booster). The baseline characteristics of the patients are summarized in Table 1. Mean age was 51.6 ± 12 years in “inactivated” group, 42.5 ± 15.5 years in “mRNA” group and 41.1 ± 15.4 years in “heterologous” group. There was no significant difference between the groups in age, gender, body surface area, body mass index and etiology (p > 0.05). The VADs used in this study were HeartWare HVAD (Medtronic Inc., Minneapolis, Minnesota, USA) and Heartmate III (Abbott Inc., Chicago, Illinois, USA). As biventricular assist device (BiVAD); one patient had Heartware in the “inactivated” group, while one patient had Heartware and two patients had Heartmate three in the “mRNA” group. All other patients had left-sided VAD (LVAD). Follow-up periods after the last dose of vaccine were 189 ± 80 days in the “inactivated” group, 155 ± 96 days in the “mRNA” group, and 169 ± 60 days in the “heterologous” group. There was no difference in the follow-up times between the groups (p > 0.05). Table 1. Demographics of the patients. Inactivated (n = 18) mRNA (n = 18) Heterologous (n = 18) Age (years) 51.6 ± 12 (22–67) 42.5 ± 15.5 (18–65) 41.1 ± 15.4 (18–66) p > 0.05 Body mass index (kg/m2) 26.9 ± 4.5 24.4 ± 5 25.3 ± 3.5 p > 0.05 Body surface are (m2) 1.8 ± 0.1 1.8 ± 0.1 1.8 ± 0.2 p > 0.05 Male gender (%) 13 (72.2%) 16 (88.9%) 13 (72.2%) p > 0.05 Etiology p > 0.05 Dilated CMP 9 (50%) 10 (55.6%) 14 (77.8%) Ischemic CMP 8 (44.4%) 7 (38.9%) 6 (16.7%) Hypertrophic CMP 1 (5.6%) 0 0 Postpartum CMP 0 1 (5.6%) 1 (5.6%) Device type p > 0.05 Heartware 4 (22.2%) 7 (38.9%) 5 (27.8%) Heartmate 3 13 (72.2%) 8 (44.4%) 13 (72.2%) BiVAD Heartware 0 1 (5.6%) 0 BiVAD Heartmate 3 1 (5.6%) 2 (11.1%) 0 Follow-up after last dose of vaccine (days) 189 ± 80 (55–331) 155 ± 96 (35–300) 169 ± 60 (61–239) p > 0.05 CMP: cardiomyopathy; BiVAD: biventricular assist device. The number of patients had COVID-19 positive test were three (16.7%), one (5.6%), and two (11.1%) in the “inactivated,” “mRNA”, and “heterologous” groups, respectively (p > 0.05) and none of them were hospitalized (Table 2). The type of vaccine did not make any difference in patients in terms of getting COVID-19 after vaccine application (p = 0.769) (Figure 1). The left hemiplegic-cerebrovascular event was observed in one patient in “mRNA” group. Pump thrombosis was seen in two patients in “mRNA” group and one patient in “heterologous” group. No pump thrombosis was seen in “inactivated” group. Driveline infections (DLI) were seen in four patients in the “inactivated” group, one patient in the “mRNA” group, and five patients in the “heterologous group. While drivelines with infection in all groups were rerouted, only two (10.2%) of the patients in the “heterologous” group were rerouted (Table 2). Table 2. Presence of COVID-19 and post-vaccination adverse events in patients with VAD. Inactivated (n = 18) mRNA (n = 18) Heterologous (n = 18) COVID-19 after last dose of vaccine Negative 15 (83.3%) 17 (94.4%) 16 (88.9%) p > 0.05* Positive at home 3 (16.7%) 1 (5.6%) 2 (11.1%) p > 0.05* CVE after vaccine 0 (0%) 1 (5.6%) 0 (0%) p > 0.05 Pump thrombosis after vaccine 0 (0%) 2 (11.1%) 1 (5.6%) p > 0.05 Driveline infection Exit site drainage 0 (0%) 0 (0%) 3 (16.7%) p > 0.05 Rerouting 4 (22.2%) 1 (5.6%) 2 (11.1) p > 0.05 CVE: cerebrovascular events; VAD: ventricular assist device. * One-way ANOVA. **Kruskal Wallis Test Figure 1. Freedom from COVID-19 after last dose of vaccine. Although death due to right heart failure was observed in one patient during the follow-up period in “inactivated” group, COVID-19-related death or intubation was not observed. One patient with LVAD and one patient with BiVAD (both of them had no vaccine) underwent heart transplantation and no adverse events related to COVID-19 were encountered in the follow-up. Booster doses were not administrated before or after transplant. After the start administration of “inactivated” vaccine in January 2021 and “mRNA” vaccinations in March 2021, three peak points were seen in Republic of Türkiye; in April and September/October of 2021 and in January/February of 2022. An overlap was seen between these periods of infection and COVID-19 positive test of patients with VAD (Figure 2). Figure 2. COVID-19 positive patients with VAD and in Republic of Türkiye. Discussion In this study, patients had inactivated vaccine or mRNA vaccine or prime booster vaccination using two dose of inactivated vaccine and one dose of mRNA vaccine booster (heterologous) were analyzed. In “mRNA” group, number of patients with COVID-19 positive test was lower than the other groups but statistical significance could not be reached. Besides, with all vaccine regimen, the disease was not severe enough to require hospitalization. Our study design proceeded from two main branches after administration of different types of vaccines in patient with VAD. The first was the vaccine effect (protection from COVID-19). We waited for the vaccination program to be completed so that we could reach the theoretically effective dose of the vaccine.7 Thus, while it has been reported in the literature that the protective effect of the first dose vaccines was low, we wanted to show the level of protection with booster doses. The second arm was vaccine side effects (pump thrombosis, cerebrovascular event, etc.). In this respect, it was important to collect the data from the first dose in order to show the side effects that may occur even after the first dose. To our knowledge, this is the first study to show the outcomes of inactivated, mRNA and heterologous vaccines in patients with VAD. Different vaccine regimens are applied in every country in the world. Some countries use inactivated and some use mRNA vaccines, while others have both vaccines. In Republic of Türkiye, in accordance to the government policy, primarily inactivated vaccines were provided and applied. Subsequently, mRNA vaccines were also used and heterologous vaccine programs were formed. Vaccine data in particularly vulnerable populations are valuable, as inactivated vaccines and mRNA vaccines are used together, as COVID-19 protection is provided by two different pathways. All vaccines against COVID-19 in market are safe and effective to prevent the disease and mortality.8–10 In a study assessing the immunogenicity of BNT162b2 vaccine in patients with VAD, anti-spike IgG were positive in 83% of patients 6 months after last dose of vaccine.7 This result was also supported by a study in which IgG seropositivity was higher in the BNT162b2 group than in the CoronaVac group.11 In a large-scale population study using BNT161b2 as a booster dose after two doses of CoronaVac vaccine; it has been found that only after CoronaVac vaccine, the protection can be reduced, and the vaccine effect can be strengthened with a booster dose of BNT162b2. It has been found that the use of heterologous vaccines, especially in elderly patients, will help prevent both infection and serious adverse effects of disease.12 In another study from Chile that used homologous and heterologous booster vaccines, both vaccination methods gave better results than the no vaccine population and the heterologous booster method was found to be more effective than the homologous method.13 In a study that compared two mRNA vaccines; mRNA1273 vaccine may be more effective than BNT162b2.14 It has been shown that both mRNA vaccines were effective, especially in the immunosuppressed and male population, which were in the high-risk group for breakthrough infection. In the literature, to our knowledge, there is no study yet on the CoronaVac vaccine used in patients with VAD. In our study, while the rates of patients who did not have COVID-19 positive test in the “inactivated” and “mRNA” groups were around 75%, this rate approached 90% in the “heterologous” group. Although there is no statistical significance due to the small number of patients, the patients who were severely ill enough to require hospitalization among the patients had COVID-19 positive test were not seen in the “heterologous” group. In the early days of the pandemic, we informed our patients that they should pay particular attention to primary protection. Moreover, possible high seropositivity was achieved with the initiation of vaccination programs, and high mortality rates may have decreased in other studies conducted before vaccination programs.15 The patients with VAD have impaired cellular immunity and are susceptible to infections.3 Before the vaccination programs, in VAD patients, hospitalization and mortality of COVID-19 were high as 60% and 20%, respectively.15 The biggest advantage of the vaccination program is undoubtedly that it has ensured the protection of such patients. No mortality was observed in any of our vaccine groups. The fact that no mortality in vaccinated patients indicates that it is important to be vaccinated regardless of the type of vaccine in VAD patients who are prone to infection and the undesirable effects of infection; it also prevents these patients, who are also transplant candidates, from being frail during their preparation for transplantation. Thrombosis cases associated with COVID-19 are common, it has been reported that thrombosis can also be seen in some series, albeit rarely, after COVID-19 vaccine. Although the underlying mechanism of post-vaccine thrombosis has not yet been fully elucidated, it is thought to be related to pathways that promote platelet and coagulation pathway.16 We encountered pump thrombosis in our two different vaccine groups. The international normalized ratio (INR) of all patients were within therapy limits (2.5–3.5) at the time of post-vaccine pump thrombosis, and tissue plasminogen activator (tPA) was administrated to all of them after hospitalization. Thrombosis of all patients resolved after tPA and they were discharged without any problem. Whether this situation was related to the vaccine or not, needs to be investigated in larger series. We have noticed that the need for driveline translocation (rerouting) has increased in the patients with VAD since the vaccination program started (however, this data is not available in the article). After COVID-19 vaccine, especially mRNA vaccine, skin lesions such as angioedema urticaria and pruritus can occur.17,18 Especially considering the rate of driveline infection in the “combine” group; we can speculate whether COVID-19 vaccines could cause a late-term hypersensitivity reaction and increase the need for translocation by causing the progression of driveline infections that were previously observed in mild form. We have used telemedicine to follow-up our patients during the pandemic. The mechanical circulatory support system coordinators have contacted with our patients periodically by phone and e-mail. In these interviews, in addition to lockdown the country, we have called them to stay home and given information about prevention. We have followed-up our patients’ COVID-19 status, INR levels, pump information via telemedicine. This helped us to update our data and to maintain close surveillance. In addition to vaccine shield, we think that basic protective cautions such as maintaining social distance, wearing a mask, staying away from crowded areas are also important to protect from disease. Because, by looking at the trend of the number of the patients had COVID-19 positive test in Republic of Türkiye, there was a similarity in the number of patients with VAD who admitted to our center as COVID-19 during the relaxation of the restrictions corresponding to those periods. Moreover, these precautions could help to decrease the rate of Covid-19-positive patients in our cohort. Limitations First, this study is a single center design and has small group of patients. More information may be obtained with future multicenter studies involving such patients, which are a small group in number. Second, the immunogenicity provided by the vaccine has not been demonstrated in plasma. Conclusion Inactivated and mRNA vaccines used in the COVID-19 pandemic are safe and effective for VAD patients. In cases where the first two doses are given as inactivated vaccines, mRNA vaccines can be considered as a booster. Moreover, we think that the social isolation rules, which are at least as effective as the vaccine, should continue in special patient groups during the pandemic period. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. ORCID iDs: Mehmet Karahan https://orcid.org/0000-0003-1705-4999 Umit Kervan https://orcid.org/0000-0001-7198-069X ==== Refs References 1 Birati EY Jessup M. Left ventricular assist devices in the management of heart failure. Card Fail Rev 2015; 1 (1 ): 25–30.28785427 2 Nishiga M Wang DW Han Y , et al . COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives. Nat Rev Cardiol 2020; 17 (9 ): 543–558.32690910 3 Kimball PM Flattery M McDougan F , et al . Cellular immunity impaired among patients on left ventricular assist device for 6 months. Ann Thorac Surg 2008; 85 (5 ): 1656–1661.18442560 4 O’Horo JC Abu Saleh OM Stulak JM , et al . Left ventricular assist device infections: a systematic review. ASAIO J 2018; 64 (3 ): 287–294.29095732 5 Uaprasert N Panrong K Rojnuckarin P , et al . 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==== Front Bus Soc Bus Soc BAS spbas Business and Society 0007-6503 1552-4205 SAGE Publications Sage CA: Los Angeles, CA 10.1177/00076503221141880 10.1177_00076503221141880 Original Manuscript - Full Length Grand Challenges and Female Leaders: An Exploration of Relational Leadership During the COVID-19 Pandemic https://orcid.org/0000-0002-2689-9988 Oliver Abbie Griffith 1 https://orcid.org/0000-0001-5921-9646 Pfarrer Michael D. 2 https://orcid.org/0000-0002-5759-0502 Neville François 3 1 University of Virginia, Charlottesville, USA 2 University of Georgia, Athens, USA 3 McMaster University, Hamilton, Ontario, Canada Abbie Griffith Oliver, McIntire School of Commerce, University of Virginia, Rouss & Robertson Halls, East Lawn, PO Box 400173, Charlottesville, VA 22904, USA. Email: [email protected] 10 12 2022 10 12 2022 00076503221141880© The Author(s) 2022 2022 SAGE Publications This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections. Managing grand challenges demands a relational leader who encourages collaboration, coordination, and trust with various stakeholders. Although leaders appear to play a critical role in addressing grand challenges, relatively little research exists about the factors that inform stakeholder perceptions of leaders during a grand challenge. To address this limitation, we integrate implicit leadership theory and gender role theory to consider stakeholders’ gender prescriptive expectations when evaluating leader effectiveness during the COVID-19 pandemic. We theorize that stakeholders advantage female leaders based on mental schemas of what is required in a pandemic—relational leadership—and stakeholders’ prescriptive expectations of female leaders as more relational. Using a laboratory experiment, we find that female leaders are perceived as more relational, and hence, more effective than their male counterparts. Our findings advance scholars’ and practitioners’ understanding of strategic leadership, stakeholder management, and grand challenges. grand challenges relational leadership gender stereotypes female leaders COVID-19 edited-statecorrected-proof typesetterts1 ==== Body pmcManagement scholars have become increasingly interested in societal grand challenges (George et al., 2016; Howard-Grenville, 2021). A grand challenge constitutes a “specific critical barrier that, if removed, would help solve an important societal problem with a high likelihood of global impact through widespread implementation” (George et al., 2016, p. 1881). Examples of grand challenges include climate change, societal aging, natural resource management, gender inequality, and health and well-being—for example, the United Nations Sustainable Development Goals (2021). Grand challenges are complex and uncertain, with no agreed-upon solution (Ferraro et al., 2015). The global COVID-19 pandemic fits the definition of a grand challenge facing society. The social, economic, and health consequences of COVID-19 affect numerous stakeholders, and a collaborative effort among them is required to address the pandemic (George et al., 2016; Howard-Grenville, 2021; Pinkse & Kolk, 2012). Given the complexities associated with this effort, and when the path to success is often unknown, prior research has suggested the need for organizational, political, and community leaders (henceforth, “societal leaders” or “leaders”) who can coordinate and collaborate with diverse stakeholders (e.g., business, health, and public policy) while communicating with the public effectively (Howard-Grenville, 2021; Schad & Smith, 2019). Such leaders must often take a relational approach, emphasizing collaboration, open communication, and trust (Carmeli et al., 2009). Although societal leaders appear to play a critical role in addressing grand challenges, we still know little about the factors that inform stakeholder perceptions of leader effectiveness during a grand challenge. We believe this is a critical omission because prior work across a variety of management disciplines (e.g., leadership, stakeholder management, upper echelons) suggests that stakeholder perceptions of leader effectiveness influence a leader’s ability to lead (Lord et al., 2020; Offermann & Coats, 2018; Shondrick et al., 2010). For instance, examining the role of narcissistic CEOs during the COVID-19 pandemic, Kim and colleagues (2021) explained that stakeholders “pay close attention to CEOs’ personal characteristics and adjust their behaviors accordingly” (p. 1283). Therefore, by gaining a better understanding of stakeholder perceptions of leader effectiveness during a grand challenge, we can deepen our understanding of the factors that impact our ability as a society to address grand challenges. As such, we ask, “Are certain types of leaders perceived as more relational and hence more effective at addressing grand challenges such as COVID-19?” To answer this question, we recognize that inferences regarding leader effectiveness can be difficult for stakeholders because they are often at arm’s length from leaders (Boivie et al., 2016; Fanelli & Misangyi, 2006). This difficulty is further exacerbated in situations with elevated levels of uncertainty, such as with managing grand challenges. In such contexts, stakeholders rely on heuristics or stereotypes to form judgments (Fiske & Taylor, 1991). Given these circumstances, the strength of unambiguous demographic signals may be especially relevant to perceptions of leader effectiveness. When considering which of a leader’s demographic signals might inform stakeholder perceptions of effectiveness, we focus on gender for two principal reasons. First, psychology research contends that gender provides the most robust basis for stereotyping people (Stangor et al., 1992). Gender stereotypes are widely held (Heilman et al., 1995), automatically activated (Devin, 1989), and influential (Banaji & Hardin, 1996). As such, gender has “a remarkable ability to dominate in impression formation” (Heilman & Parks-Stamm, 2007, p. 49). Thus, unlike other attributes (e.g., education, experience), gender represents a clear and easy-to-observe signal likely to shape stakeholders’ perceptions of leaders’ approaches and—ultimately—effectiveness. Second, scholarly and popular media accounts present a tension regarding how female leaders may be perceived during a grand challenge. In general, female leaders are often victims of a “think leader—think male” mindset that leads others to perceive female leaders as ineffective in, or unfit for, leadership roles (Koenig et al., 2011; Schein, 1973). This mindset is one reason the media are often accused of being overly critical of female leaders such as Hillary Clinton and Theresa May as they tried to tackle grand challenges (Campus, 2013; Chamorro-Premuzic, 2019). Conversely, female leaders have also been viewed as having a more relational approach than their male counterparts during COVID-19, which may influence perceptions of their effectiveness in addressing grand challenges. For example, Germany’s Angela Merkel has been praised for creating a calm, reasoned message that “hit home” (Rising & Moulson, 2020). Similarly, New Zealand’s Jacinda Ardern has been noted for her “clarity and compassion” (Marks, 2020). The contrast between the “think leader—think male” and “think female—think relational” mindsets that color perceptions of female leaders further highlights the need to establish whether female leaders are genuinely perceived as more effective at addressing grand challenges, such as COVID-19. With our investigation, we draw on implicit leadership theory (Lord et al., 2020) and integrate it with gender role theory (Eagly & Wood, 2012) to theorize that when facing a grand challenge, stakeholders will seek a relational leader—an open communicator—who encourages collaboration, coordination, and trust (Carmeli et al., 2009; Mazzei et al., 2012). These perceptions align with society’s prescriptive stereotypical view of female leaders as the more communal gender. While not all female leaders will reflect this stereotype, female leaders are often perceived to be—and also socialized to be—more relationship-oriented (Eagly et al., 2000; Heilman, 2012; Prentice & Carranza, 2002). As such, we argue that stakeholders facing a grand challenge, such as COVID-19, will break from the traditional “think leader—think male” mindset and prefer female leaders based on the relational skills stakeholders demand during these periods (a “think female—think relational” mindset; Kahn et al., 2013; Mishra, 1996). In turn, we theorize that stakeholder preferences for a relational leader and stereotypical views of female leaders lead to enhanced perceptions of female leaders’ effectiveness during the COVID-19 pandemic. We test our arguments with a laboratory experiment. We find that stakeholders’ gender prescriptive expectations of leaders result in female leaders being perceived as 12% more relational in their leadership approach than their male counterparts, all things being equal. We also find that in the context of managing COVID-19, there is a significant and direct link between relational leadership and perceptions of leader effectiveness. Together, these results yield a significant, fully mediated model that links female leaders to increased perceptions of leader effectiveness through relational leadership. In doing so, we provide several contributions. First, we inform the increasingly important stream of management research focused on societal grand challenges. Yet, this stream remains nascent, consisting mainly of conceptual and editorial articles (Eisenhardt et al., 2016; George et al., 2016) focused on understanding the general effects of grand challenges on businesses (Kulik et al., 2016; Olsen et al., 2016). We build on these efforts and recognize that grand challenges involve intersecting issues related to strategic leadership, stakeholder management, and societal norms. To this end, we integrate key streams of literature on implicit leadership theory and gender role theory to highlight stakeholders’ gender prescriptive expectations of leaders in addressing grand challenges such as COVID-19. Focusing on gender offers evidence that stakeholders naturally advantage certain types of leaders based on mental schemas of what is required in the context and their perceptions of a specific leader. Ultimately, we move the conversation on grand challenges in management research forward by unpacking the complex relational processes between societal leaders and stakeholders involved in addressing these challenges. Second, as the debate continues around when female leaders benefit or suffer from gender bias (Jeong & Harrison, 2016), we contribute by theoretically and empirically isolating how perceptions of relational leadership are a critical mechanism to explain how stakeholders might favorably evaluate female leaders. Ultimately, contrary to the general “think leader—think male” mindset at the core of gender role theory, we demonstrate that female leaders have a “think female—think relational” advantage in contexts where stakeholders are naturally more predisposed to relational leadership approaches, such as grand challenges (Eagly & Carli, 2003; Post et al., 2019; Rosette & Tost, 2010). In doing so, we answer the recent call “to better understand how women leaders are perceived” (Jeong & Harrison, 2016, p. 37). Finally, by investigating perceptions of leader effectiveness during COVID-19, we shed light on the crisis management aspect of grand challenges. While prior work demonstrates that leaders can influence stakeholder perceptions (Bundy et al., 2017; Neville, 2020), it has primarily focused on stylistic elements of leaders’ communication strategies and not on perceptions of their attributes (Jun & Wu, 2021). As the relationship between business and society becomes more intertwined (Krause & Miller, 2020), our need to understand who a leader is—as the “face” of an organization or country—seems just as important as what they say. Theoretical Framework As defined above, a grand challenge refers to a significant obstacle that, if addressed, would help advance society on social, environmental, and economic dimensions (George et al., 2016). Grand challenges are considered “seemingly intractable” puzzles (Ferraro et al., 2015, p. 367) that do not offer straightforward solutions or consistent assumptions. The 17 Sustainable Development Goals (SDGs) of the United Nations (UN) are commonly viewed as the most comprehensive list of ongoing grand challenges. Some examples include ensuring water and sanitation availability and sustainable management, full and productive employment and decent work, and inclusive, safe, resilient, and sustainable living environments (United Nations, 2021). Recently, an event that fits the definition of a grand challenge—ensuring health and well-being—is the COVID-19 pandemic. Addressing a grand challenge is complicated; it requires coordinated and collaborative action toward a clearly articulated problem and goal (George et al., 2016; Longhofer et al., 2019; Pinkse & Kolk, 2012). This situation necessitates that societal leaders and stakeholders “coordinate their efforts to secure a common goal that none could obtain without the efforts of others” (Flanagin et al., 2006, p. 30). However, because societal actors’ and other entities’ (e.g., corporations) interests may not always align, consensus related to goals and potential solutions may be hard to achieve, making the type of coordinated and collaborative action needed to address a grand challenge a difficult objective. Given these complications, a grand challenge places a premium on leaders who can articulate a vision and bring diverse stakeholders together. As stakeholders look toward leaders to guide them under challenging circumstances, their perceptions of leader effectiveness become critical determinants of whether these stakeholders will buy into a leader’s vision and proposed strategies (Hambrick & Lovelace, 2018; Kim et al., 2021). In times of uncertainty, individuals often make quick, heuristic causal attributions to assign responsibility to an individual for the actions of a group or an organization (Bingham & Eisenhardt, 2011; Fiske & Taylor, 1991). This phenomenon is perhaps best known as the romance of leadership (Meindl, 1995; Waldman et al., 2001). For example, in a corporate context, the CEO is a psychologically easy and attractive option for stakeholders to blame or reward when considering the uncertainty and causal ambiguity associated with corporate events. Leaders that achieve public prominence or generate positive media coverage receive disproportionate praise for firm performance (Hammond et al., 2021). At the same time, research has established that the leader takes the brunt of the blame for adverse events such as financial restatements (Gomulya & Boeker, 2014), performance shortfalls (Sanders, 2001), and fraud (Cowen & Marcel, 2011). The same phenomenon also exists in politics, where voters reward and punish politicians for economic conditions often created before the leaders took office (Nye, 2008). Given that stakeholders overweight the responsibility of leaders in general and assessing leader quality is hampered by the uncertain and complex nature of grand challenges such as COVID-19, it is essential to consider stakeholder perceptions of leader effectiveness in such situations. Adopting a follower-centric approach, implicit leadership theory asserts that followers’ perceptions of leadership are based on their “schemas of an ideal leader” (Hechanova et al., 2018, p. 917). These schemas are often used to identify the attributes and behaviors that distinguish effective leaders from ineffective ones (Caringal-Go et al., 2021; Holmberg & Åkerblom, 2006). Also, the theory states that the congruence of followers’ mental representations of a leader and the leader’s actual characteristics will influence how they act toward leaders. Surprisingly, however, the literature has not considered the factors that inform stakeholder perceptions of leaders in highly uncertain and complex contexts, such as a grand challenge. Below, we articulate theory explaining why gender may play an outsized role in influencing stakeholders’ reactions to leaders during COVID-19. Grand Challenges and the Relational Leadership Advantage When facing grand challenges, scholars advocate for a relational leadership approach based on collaboration, communication, and trust (Gittell, 2006; Maak & Pless, 2006; Schad & Smith, 2019; Williams et al., 2017). As such, relational leadership embodies skills critical to effectively managing grand challenges in several ways. First, grand challenges can significantly alter how individuals, families, and the public relate to one another (Kahn et al., 2013). Relational leaders are better equipped to handle the anxiety, panic, and distress that can arise from these events (König et al., 2020). Second, crisis management practitioners and scholars advocate for leaders to connect emotionally and psychologically with stakeholders, suggesting that relational leaders’ focus on open communication and trust is effective when facing a grand challenge (Wooten & James, 2008). Medical studies supporting this approach have found that patients receive terrible news better when physicians use an empathetic, other-focused communication style (e.g., more approachable, compassionate) in a non-dominant fashion (e.g., less assertive, less intimidating)—all descriptors of relational leadership (Mast et al., 2005). Even in nonverbal encounters, Griffith and colleagues (2003) showed that patient satisfaction was higher when doctors engaged relationally—smiling, maintaining eye contact, and gesturing more. Finally, a relational leader can better coordinate the myriad of interdependent tasks and actors (e.g., health providers, government entities, and the public) needed to address a grand challenge that hinges on accurate, frequent, timely, and solution-oriented communications bolstered by “shared goals, shared knowledge, and mutual respect” (Gittell, 2006, p. 74; Hoffer Gittell, 2002). In line with coordination, relational leaders are more likely to seek input from various sources and be more adaptable in evolving situations (Cunliffe & Eriksen, 2011) that are critical to addressing a grand challenge. For instance, relational leadership is linked to generating new ideas and innovation among followers (Peng & Wei, 2018; Schaubroeck et al., 2011); critical inputs in addressing the often-novel issues brought forth by grand challenges. Overall, the preceding discussion suggests that relational leaders are more successful in addressing grand challenges such as COVID-19 and that stakeholders’ perceptions of how relational these leaders are will help ensure this success. Thus, the question arises: Which leader characteristics influence stakeholder perceptions of relational leadership? “Think Female—Think Relational” As we have highlighted, gender has a remarkable ability to influence the perceptions of leaders. Of course, perceptions of gender are also highly prone to stereotyping (Eagly & Mladinic, 1989; Heilman, 2012). Stereotypes are widely held but oversimplified beliefs, expectations, and assumptions of a particular type of person based on their group membership (e.g., males vs. females; Heilman & Parks-Stamm, 2007). Stereotypical judgments are automatic, immediate, and pervasive in daily life. An individual may implicitly hold a stereotype about another person without necessarily endorsing it personally (Macrae & Bodenhausen, 2000). Gender stereotypes, in particular, have been validated across time, cultures, and diverse leadership settings (Heilman, 2012; Williams & Best, 1990). For example, in the context of corporate boards of directors, Zhu and Westphal (2014) demonstrated that even among this supposedly sophisticated group, gender is a more salient attribute than age, education, functional background, or leadership experience when evaluating others. Furthermore, it has been demonstrated that situational uncertainty and complexity allow for more bias in evaluation (Botelho & Abraham, 2017; Davison & Burke, 2000). The more uncertainty and complexity involved, the less evidence for an accurate assessment, and the more weight is necessarily placed on inference. Token or minority status, as is the case for female leaders, leads to more stereotyped characterizations because observers use gender stereotypes to fill in the missing information in such contexts (Kanter, 1977). Gender role theory (Eagly & Wood, 2012) suggests that women are stereotyped as having communal qualities associated with their traditional role of homemaker. These descriptions stand in stark contrast to agentic qualities attributed to males—powerful, commanding, and assertive—related to the role of breadwinner. These stereotypes reflect how observers believe the genders are and help set observers’ expectations of how each gender should act. Vital to our investigation is that prescriptive stereotypes establish social rules for how each gender should act and are used to rationalize a social system that has historically been successful (Heilman & Chen, 2005; Heilman & Parks-Stamm, 2007). Prescriptive stereotypes for gender carry more weight in social interactions than other group stereotypes and are often more pervasive than observers realize. For example, Rudman and Glick (2008) argued that it is more socially acceptable to tell a woman she “ought” to be more nurturing or a man he “should” be more aggressive than to tell an Asian- or African American that they are not conforming to racial or ethnic stereotypes. Prescriptive stereotypes about women specify that women should behave more communally and demonstrate social sensitivity and concern for others’ welfare, such as being kind, sympathetic, and understanding (Heilman & Parks-Stamm, 2007). These normative shoulds also come with reciprocal should-nots. For example, the desirable attributes for males, agentic achievement-oriented behaviors, are deemed inappropriate for women. Conversely, males should not display communal service-oriented behaviors (Eagly & Karau, 2002). Interestingly, these prescriptive stereotypes are so strong in impression formation that they exist for female leaders, even though studies show that some female leaders are potentially no more communal or relational than their male counterparts. For example, Adams and Funk (2012) found that female directors were more agentic and risk-loving than their male counterparts, suggesting that women in leadership positions do not satisfy many of these traditional gender stereotypes seen in the general population. More recently, Gallus and colleagues (2020) demonstrated that gender differences diminish or become nearly nonexistent as one moves higher up in organizational hierarchies, reinforcing that female leaders may not be different. Despite this evidence, female leaders are stereotypically perceived as more relational than their male counterparts (e.g., more compassionate, attentive, and sensitive to stakeholder needs; Dennis & Kunkel, 2004; Ibrahim et al., 2009). For example, Ryan et al. (2007, p. 190) highlighted that when participants perceived a match between women’s abilities and the communal skills necessary in managing an underperforming company, they assumed females possessed “special” relational attributes such as “women always want to help the underdog.” Similarly, Oliver and colleagues (2018) demonstrated that even among knowledgeable board chairpersons, CEO gender influenced perceptions of the CEO as a communal steward or an agentic-risk taker. These findings translate into political settings as well. Lammers and colleagues (2009) found that female candidates are preferred when issues that demand relational and pro-social skills (such as health care) are deemed most important. Female leaders are viewed more favorably when they can negotiate on behalf of the “general welfare” or the “common good” (Anderson, 2020), critical components of battling a grand challenge. Constituents also view female leaders as better equipped to handle social issues, such as education, civil rights, poverty, and homelessness (Falk & Kenski, 2006; Huddy & Terkildsen, 1993), reinforcing that female leaders should be better equipped as relational leaders than males. Some female leaders even reinforce these stereotypes through their words and actions. The first female CEO of a Big Four accounting firm, Lynne Doughtie of KPMG, stated, “I have found that women are really in their element in a very collaborative approach” (King, 2017). Specific to COVID-19, when Angela Merkel addressed the German public at the onset of the pandemic, she was flanked by multiple public health officials, and she took pains to say that the information she was sharing was collaborative and had come from experts (Bennhold & Eddy, 2020). This image stood in stark contrast to the top-down, autocratic leadership approaches taken by such leaders as the United States’ Donald Trump and Brazil’s Jair Bolsonaro (Dewan, 2020). Finally, a recent qualitative study of U.S. Governors’ remarks following the onset of COVID-19 also suggests that female governors used more empathetic language than male governors in addressing constituents (Sergent & Stajkovic, 2020). Building on these considerations, we theorize that stakeholders’ evaluations of leader effectiveness during grand challenges will hinge on relational leadership attributes—being open, demonstrating trustworthiness, and collaborating well with others—that align with the prescriptive stereotypes female leaders are assumed to possess. Given the natural preference for a relational leader during a grand challenge, we argue that the “think female—think relational” mindset wins out in impression formation when evaluating female leadership as opposed to the prevailing negative “think leader—think male” mindset that may dominate in more general settings. Taken together, when assessing a female’s leadership in managing a grand challenge such as COVID-19, stakeholders adopt a “think female—think relational” mindset aligned with prescriptive gender stereotypes. These stereotypes are often reinforced by society and even some current female leaders’ actions, as well as the uncertainty present in tackling a grand challenge and assessing leader effectiveness. Stakeholders expect a female leader to behave more relationally and demonstrate social sensitivity and concern for others’ welfare. As such, these stereotypes lead stakeholders to view female leaders as more relational and hence more effective at managing a grand challenge. Hypothesis: By engendering increased perceptions of relational leadership, stakeholders will perceive female leaders as more effective than male leaders at addressing grand challenges such as COVID-19. Method This study examines stakeholders’ perceptions of female leadership during a grand challenge, the COVID-19 pandemic. We tested our hypothesis in a way that allowed us to identify and isolate the influence of gender and perceptions of relational leadership on stakeholders’ perceptions of leaders’ effectiveness at managing COVID-19. To this end, an experiment was an ideal study design (Cook et al., 2002).1 An important advantage of an experimental design is that it allows for higher levels of internal validity than cross-sectional and longitudinal studies by enabling researchers to make clearer inferences about the causal processes involved between the variables (Cook et al., 2002). Furthermore, many confounding factors that could influence stakeholder perceptions of leader effectiveness in the context of COVID-19, such as attribution of blame, severity, or communication style (Bundy et al., 2017), can be held constant to focus on the variables of interest. The principal drawback to this method is that external validity may be limited. However, as we describe below, we believe we have struck the right balance between internal and external validity by (a) carefully selecting an appropriate sample of participants and (b) building our experimental scenario based on realistic instances of leader announcements and communications in the context of a grand challenge. Research Design and Procedures Development, Validation, and Pretest of the Experimental Material To develop the experimental material, we followed recommendations to adhere closely to real-life cases (Aguinis & Bradley, 2014; Highhouse, 2009). Knowing stakeholders turn to media coverage for information during grand challenges and similarly uncertain and complex events (Graf-Vlachy et al., 2020), we worked to establish experimental realism by presenting a scenario based on actual news coverage of COVID-19 (Aguinis & Bradley, 2014). Specifically, the scenario was adapted from a major news article discussing a leader’s response to COVID-19 in April 2020 (Fifield, 2020). The scenario describes the leader’s televised address, presents direct quotes from the leader to the public, and shares accounts of the leader’s conversation with influential stakeholders. To test the strength of our manipulations and the reliability of our chosen scales, we conducted a pretest on an online sample of adults (U.S.-based participants) recruited through the online platform Lucid, a market research firm (Coppock & McClellan, 2019).2 Of the 41 participants, 27 were male, and 14 were female, with a mean age of 46.41 (SD = 18.03) years. Our pretest demonstrated that our manipulation check was successful and that our scales were reliable. During the pretest, we also wanted to understand whether other characteristics of our scenario could be driving perceptions outside of the leader’s gender. Following prior research, participants were also asked to rate grand challenge severity, their state negative affect (Watson & Clark, 1999), and their feelings of hostile sexism to determine whether the scenarios generated any negative feelings that might influence their perceptions of the leader’s gender (Glick & Fiske, 1997). To assess the severity of the grand challenge, the participants answered the following on a 5-point scale (strongly disagree to strongly agree)—“The crisis is (1) a major problem, (2) significant, (3) severe.” The coefficient alpha was .88. We measured participants’ state negative affect following instructions outlined in the PANAS–X Manual (Watson & Clark, 1999). Example emotions included upset, distressed, irritable, hostile, disgusted, and contempt. The coefficient alpha was .97. We utilized the hostile sexism scale developed by Glick and Fiske (1997) to assess whether any aspect of the scenario generated intense gendered feelings toward the target. The coefficient alpha was .89. No significant differences were found across these three measures (severity, negative affect, hostile sexism) between the male and female scenarios in the pretest. Based on these findings, we made minor changes to the scenarios in the experiment before conducting the main study (see the appendix for scenario). Main Study Participants Using the G*Power software, we conducted an a priori power analysis. We specified an effect size of 0.4, a conventional value indicative of a medium effect size (Cohen, 1988; Murphy et al., 2014). Following prior recommendations, we ensured that our chosen effect size was “the smallest effect that would be meaningful in some practical sense” (Fritz et al., 2012, p. 18), given that large effect sizes are not common in behavioral science (Cohen, 1988, p. 284). In addition, we specified a desired α = .05 and power (1 − β) = 0.8. The power analysis revealed a desired sample size of at least 52 participants for the experiment. We recruited U.S.-based participants via Lucid, an online platform. The sample was restricted via preselection to participants 18 years or older who passed a consciousness check in which they were asked to briefly describe the scenario in their own words briefly. Given that our theory is not stakeholder specific, and our scenario relates to perceptions of country leaders, we deemed individuals that met the U.S. minimum voting age to be an appropriate sample. One hundred six participants accessed the survey instrument through Lucid. A portion of those participants was not included in the final sample because they either did not meet the age requirement, did not sign the informed consent, or did not pass the consciousness check. The final sample included 82 participants, age (M = 46.41, SD = 16.83), 49.00% female. Regarding education, 35.36% had a high school diploma or equivalent, 31.70% had an associate’s or bachelor’s degree, 31.70% had a master’s degree, and 1.22% had a doctoral or professional degree. In terms of employment, 50.00% were employed full-time, 9.76% were employed part-time, 1.22% were employed seasonally, 24.39% were not employed, and specific to the ramifications of COVID-19, 14.63% were furloughed. In terms of political affiliation, 12.26% identified as independent, 41.46% as Republican, and 46.34% as Democrat. Data Collection We collected data to test our Hypothesis using a 2 × 1 factorial between-subjects design with the independent variable being leader gender (female vs. male). We randomly assigned participants to the two conditions, with the manipulated variable being leader gender (female vs. male). In Part I of the study, all participants read media coverage of a leader following the onset of COVID-19. The coverage was partnered with a gendered graphic of the leader behind a podium. We designed the scenario to provide enough background information on the leader, COVID-19, and the leader’s statement for participants to make informed judgments, yet also distract participants from the leader’s gender as the topic of the investigation. Following the presentation of the leader’s statement, we then asked a series of questions to measure participants’ perceptions of relational leadership and leader effectiveness. These questions represented our mediator and dependent variable. In Part II, participants answered a series of questions related to their demographic and socio-cognitive attributes that were used in supplemental analyses to rule out alternative explanations. Manipulated Independent Variables We manipulated the leader’s gender by name and gender-relevant pronouns used in the media coverage. The headline and graphic were used to support the manipulation further. Participants indicated if the leader was male or female. An analysis of variance (ANOVA) revealed a significant main effect based on leader gender, F(1,39) = 26.90, p = .000, M = 0.85 versus −0.71, ensuring the manipulation’s effectiveness. Dependent Variables Leader Effectiveness To assess leader effectiveness, we adapted measures based on perceived leader self-efficacy (Chen et al., 2001; Fast et al., 2014). We presented the items as leader-referent as opposed to self-referent. The participants answered the following on 5-point scales (strongly disagree to strongly agree)— “(1) Compared to others, this leader will do most tasks very well; (2) This leader will be able to achieve most of the goals that have been set; (3) This leader will be able to successfully overcome many challenges; (4) Even when things are tough, this leader will perform quite well.” The coefficient alpha was .90. Relational Leadership Adapting measures from Carmeli et al. (2009), we presented the participants with the following on 5-point scales (strongly disagree to strongly agree)—“In my view, this leader . . . (1) encourages collaboration; (2) cultivates a trustful environment; (3) encourages open conversation.’’ The coefficient alpha was .84. We also performed a factor analysis with the combined items from relational leadership and leader effectiveness, which confirmed a two-factor structure with discriminant validity. Analysis In our analysis, we conducted univariate ANOVAs and intercell contrasts to test our hypothesis directly. We tested all intercell contrasts (the cell mean differences in each information condition) using Fischer’s least significant test. To further test mediation, we used sgmediation in STATA 16 to perform the Preacher and Hayes (2004) bootstrapped test of mediation (1,000 replications; Edwards & Lambert, 2007; Hayes, 2013). Results An analysis of variance (ANOVA) revealed a significant main effect based on gender, F(1,80) = 29.96, p = .000, M = 0.53 versus −0.74, ensuring the manipulation’s effectiveness. We, therefore, did not drop any cases based on manipulation failure. Table 1 presents the relevant means and standard deviations for each dependent variable. Table 1. Means, Standard Deviations, and Correlations Among Variables. Dependent variables M SD 1 Relational leadership 4.02 0.97 Leader effectiveness 3.86 0.97 0.75 Dependent Variables An ANOVA of participants’ ratings on the relational leadership scale revealed a significant main effect for gender, F(1, 80) = 4.45, p = .038. Intercell contrasts provided support that females were viewed as more relational leaders. As displayed in Table 2, female leaders were rated as 12% more relational (4.26 vs. 3.81, 95% confidence interval = [0.025, 0.864]). An ANOVA of participants’ ratings on leader effectiveness did not reveal a significant main effect of gender on leader effectiveness. Given our primary interest lies in understanding the mechanism driving leader effectiveness, a significant test of the direct effect is not a prerequisite for a test of the indirect effect in our hypothesis (Hayes, 2013; MacKinnon et al., 2002; Zhao et al., 2010). Table 2. Means and Standard Deviations. Condition Relational leadership Leader effectiveness Male 3.81a (1.01) 3.76c (1.02) Female 4.26b (0.88) 3.98c (0.91) Note. Means within a column with different subscripts differ significantly (p = .038) as indicated by Fisher’s least significant difference procedure. Mediation Given the significant direct effect of gender on relational leadership and the significant correlation between relational leadership and leader effectiveness (r = .75, p =.000) in Table 1, we estimated the path estimates of the indirect, direct, and total effects of leader gender on leader effectiveness. In Table 3, the path coefficient from female leader to relational leadership (a = 0.46; 95% confidence interval = [0.042, 0.887]) was significant, as was the path coefficient from relational leadership to leader effectiveness (b = 0.76; 95% confidence interval = [0.608, 0.913]). Likewise, the positive indirect effect of female leadership on leader effectiveness through relational leadership (a × b = 0.35; 95% bias-corrected bootstrap confidence interval = [0.014, 0.692]) estimated with 1,000 replications was also significant. These findings provide support for our hypothesis—leader gender has an indirect and significant effect (fully mediated) on perceptions of leader effectiveness in managing COVID-19, given that participants perceive females as more relational leaders. Table 3. Path Estimates of Indirect, Direct, and Total Effects for Gender Predicting Leader Effectiveness. Female → Mediator Mediator → Leader effectiveness Indirect Direct Total Relational leadership 0.46 (p = .032) 0.76 (p = .000) 0.35 (p = .041) −0.13 0.22 Note. Significance tests for the indirect and total effects are based on the bias-corrected confidence intervals derived from bootstrapping estimates with 1000 samples. Supplemental Analyses and Robustness Checks Given that stakeholders—and their perceptions—are heterogeneous, we were interested to see whether our outcomes differed based on specific stakeholder characteristics. Via a series of ANOVAs, we also tested whether outcomes differed based on participants’ gender, political affiliation (0 = independent, 1 = conservative, 2 = liberal), age, or education level (coded 1 if participants completed at least 4 years of college). We found no significant differences in terms of relational leadership among each of the four variables while controlling for leader gender. Also, none of the four controls had a significant effect on leader effectiveness or weakened the influence of relational leadership on leader effectiveness when included in the model. Furthermore, we ran our mediation analysis with participant gender, political affiliation, age, and education level as controls, and our indirect effect was consistent and significant across each model. The fact that participants’ characteristics did not influence stereotypical perceptions that females are more relational is not surprising, given that gender provides the strongest basis for stereotyping and categorizing people (Haslam & Fiske, 1992; Stangor et al., 1992). We were also curious about participants’ knowledge of COVID-19 and whether it influenced their leadership perceptions. As such, we created a COVID-19 knowledge measure based on facts listed on the Centers for Disease Control and Prevention’s website. Example items included “(1) The virus is thought to spread between people who are in close contact with one another (within about 6 feet); (2) Symptoms may appear 2–14 days after exposure to the virus; (3) The virus is thought to spread through respiratory droplets produced when an infected person coughs, sneezes, or talks.” Participants responded on 5-point scales (strongly disagree to strongly agree) with a mean answer of 4.51 and coefficient alpha of .80, indicating participants were aware of the pandemic. There were no significant differences in knowledge across the two conditions and no significant relationship between COVID-19 knowledge and leader effectiveness when controlling for leader gender and relational leadership. We also estimated our main indirect effect using Imai and colleagues’ causal mediation method (Imai et al., 2011) via the medeff command in STATA 16 (Hicks & Tingley, 2011). The estimate of the average causal mediation effect was similar and significant (b = 0.36, 95% confidence interval = [0.021, 0.698]). We also used the medsens command (Cox et al., 2013) to calculate sensitivity analyses for our mediation effect due to the non-random assignment of relational leadership. We found that a confounding variable would have to be correlated with our predictor and outcome variables at (r = .74) to bias our results, providing further confidence in our analyses. If successful leadership is associated with stereotypically male or agentic qualities, it may not be associated with stereotypically female or relational qualities. This lack-of-fit argument is often referred to as the “think leader—think male” association (Heilman & Haynes, 2005; Koenig et al., 2011; Schein, 1973). A host of studies argue that this mentality results in less favorable assessments of female employees’ and executives’ competence (Eagly & Makhijani, 1992; Lyness & Heilman, 2006). As such, we tested how perceptions of leader agency influenced our relationships. Example items included self-confident, determined, decisive, assertive, and does not get dominated by one’s feelings (Kulich et al., 2018). The coefficient alpha was .91. We also performed a factor analysis to ensure that the leader agency and leadership effectiveness measures loaded onto separate dimensions. Leader gender was not significantly correlated with leader agency. Furthermore, the relationship between relational leadership and leader effectiveness remained significant while controlling for leader agency and leader gender. These findings further support our claims that the benefits females receive via positive stereotypes of their relational skills offset any penalties they may receive via negative stereotypes of their (lack of) agency. Finally, to ensure that our results were indeed driven by gender and not the stimulus name in our scenario (Michele/Michael), we conducted a posttest to ascertain whether our chosen names conveyed different meanings to respondents (N = 81, 29% female, Mage = 38.40, Amazon mTurk). Participants rated a selection of names (Michele/Michael/Deborah/David) on the extent to which they were wealthy, attractive, or intelligent. We chose these characteristics as prior research suggests certain stimulus names may introduce bias based on these criteria in experiments (Kasof, 1993). Our results yielded no significant differences (p > .05) in ratings for Michele versus Michael, suggesting that both names convey similar meanings for respondents. These posttest findings, as well as our careful use of gendered headlines, graphics, and pronouns, increase our confidence that the results of our main study are not attributable to an effect of a leader’s name but, indeed, are driven by the leader’s gender. Discussion We set out to investigate stakeholder perceptions of leaders’ effectiveness at addressing a grand challenge—“formulations of global problems that can be plausibly addressed through coordinated and collaborative effort” (George et al., 2016, p. 1889). Given the strength of gender stereotypes in external impression formation and the role of uncertainty and complexity in biasing judgments, we theorized that female leaders were more likely to signal the desired relational attributes that stakeholders seek during a grand challenge. Specifically, we found that stakeholders do “think female, think relational”—resulting in increased perceptions of female leaders’ effectiveness in the context of managing the COVID-19 pandemic. Our work makes several contributions to both research and practice. First, practitioners and management scholars recognize the “emerging trend of strategic leaders becoming—in both their own and stakeholders’ perceptions—societal leaders” (Krause & Miller, 2020, p. 1315). At the same time, management scholars are beginning to recognize the necessity of investigating the role of organizations and their leaders in understanding the influence of, and their influence on, the grand challenges facing society. To date, the literature on grand challenges has remained mostly silent on how specific leader characteristics influence stakeholder reactions. Given the importance of understanding stakeholder perceptions in terms of leader effectiveness, and that the cognitive processes through which stakeholders evaluate leaders can be seen as “strongly influenced by human judgment, perceptions, and emotions” rather than hyper-rational (Zadeh, 1975, p. 200), this is a surprising omission. By integrating key insights from implicit leadership theory, gender role theory, and the literature on grand challenges, we advocate for a stakeholder-focused approach to understanding how stakeholders’ gender prescriptive expectations influence perceptions of leader effectiveness during a grand challenge. We hope our work will spur interest in stakeholder-centered theory development when investigating grand challenges and other uncertain and complex contexts. This need is essential as stakeholder perceptions of leader effectiveness can significantly affect a leader’s ability to lead under challenging circumstances. As such, we contribute by considering stakeholder perceptions during a grand challenge to gain a deeper understanding of grand challenges, strategic leadership, and stakeholder responses (Caringal-Go et al., 2021). Second, we isolated a context and theoretical rationale that illuminates a potential female leadership advantage. In doing so, we contribute to the practitioner and scholarly debate about whether female leaders and female-led organizations benefit or suffer from stereotypical bias (Jeong & Harrison, 2016). By focusing on reactions to female leadership during COVID-19, we also move the conversation past the appointment or election of female leaders (Dixon-Fowler et al., 2013; Lee & James, 2007) and focus on the management of a specific context that provides a female leadership advantage with stakeholders—a grand challenge. Our experimental design also allowed us to isolate the psychological mechanism—relational leadership—driving the female leader advantage during a grand challenge. In doing so, we answer calls to theoretically and empirically “open the black box of women’s leadership” (Hoobler et al., 2018, p. 2488) in a controlled lab setting to understand how prescriptive expectations of gender translate into differential outcomes for female leaders. Third, we contribute to the crisis management literature. Much of the literature on crisis management is focused on issues in which attributions of responsibility and solutions are mostly clear, including fraud, product recalls, and environmental wrongdoing (Bundy et al., 2017). In contrast, the types of crises associated with grand challenges have garnered little attention from crisis management scholars. We contribute by highlighting the necessity to understand perceptions of leadership in a context in which the root causes and solutions are often uncertain and complex. Finally, our work has implications for practitioners tasked with navigating a grand challenge. Our findings offer some evidence that leadership style—namely, a relational approach—can critically influence stakeholders’ perceptions during challenging times. Moving forward, leaders must recognize the need to appear relational in contexts requiring collaboration and trust to navigate. More personally for said leaders, stakeholders’ perceptions may have costly career consequences for leaders regardless of whether said perceptions of relational leadership and effectiveness rooted in stakeholders’ mental schemas are accurate. While we focused on female leaders, we believe our findings may be particularly important for male leaders to understand, given they seem to start at a “relational deficit” in the eyes of stakeholders. We believe this insight may potentially translate across numerous contexts (political, organizational, or civic associations). Organizations, governmental, and public relations agencies may wish to train leaders to demonstrate relational attributes when engaging with diverse and multiple stakeholder groups. Concretely, the literature on crisis communication provides a variety of ways a leader can signal a more relational approach through their impression management and organizational response strategies (Bundy et al., 2017). While our work focused on how stakeholders generally perceived leaders due to the strength of gender stereotypes, it would be beneficial for leaders to also consider whether their actions and messages relaying relational leadership are received similarly across a heterogeneous set of stakeholders. It may be necessary for leaders to tailor their messaging to build trust and collaboration with disparate stakeholder groups. One can imagine a scenario where the mechanisms for interpreting relational leadership might be quite different based on the worldviews and utility functions of different stakeholders (Bridoux & Stoelhorst, 2014; Harrison et al., 2010; Lange et al., 2022). Future Research Directions and Limitations Future research should investigate whether our findings depend on a specific leadership role. For example, did stakeholders respond differently to Dr. Deborah Birx, the White House Coronavirus Task Force coordinator, because her role was more technical and expertise-driven than executive-level leaders, whose expertise is often more empathetic in nature? Do stereotypical views of female leaders as less competent and less likable than their male peers manifest themselves more in lower-level and technical roles where competence is not just assumed (Rudman & Glick, 2008)? Also, future research should unpack if the desire for relational leadership is isolated to the onset of grand challenges or if these preferences change as the challenge enters various stages (Bundy et al., 2017). Are there residual benefits for being a relational leader who has handled a grand challenge well, or do observers hold a relational leader to a higher standard once the initial challenge is mitigated or underway? Also, while we focused on the stereotypical views of female leaders as relational leaders, future work should investigate the implications of leaders violating stereotypical expectations while managing a grand challenge (e.g., female leaders demonstrating low levels and male leaders displaying high levels of relational leadership). For example, a recent article on BBC.com highlighting CEOs’ responses to COVID-19 suggested that “what many [men] have done is borrow from the female playbook, which involves being incredibly caring of their stakeholders, and upping their communication skills” (Goswami, 2020). Understanding how leaders move between different leadership styles and the ramifications of such moves in terms of stakeholders’ perceptions of both male and female leaders would also be fruitful. Future research should also investigate whether our theory and findings translate to other grand challenges and national contexts where relational leadership might be less desired. For example, examining what leadership styles are preferred during the Black Lives Matter movement in the United States is ripe for investigation. Keisha Lance Bottoms, the former mayor of Atlanta, received praise for her response to the unrest in her city following the killing of George Floyd in Minneapolis in 2020. She evoked her relational nature in her statement,I am a mother to four black children in America, one of whom is 18 years old. And when I saw the murder of George Floyd, I hurt like a mother would hurt. . .So, you’re not going to out-concern me and out-care about where we are in America. (Krieg & LeBlanc, 2020) Like Angela Merkel’s press conference at the onset of COVID-19, Bottoms surrounded herself with a cadre of support that included the police chief, social activists, and local artists to reinforce her message. However, would we expect similar praise from stakeholders in other countries for their leaders under such circumstances? Given that gender stereotypes are pervasive across many stakeholders, we chose not to theorize that differences could potentially exist across individual participants. Future research might explore how the individual stakeholder attributes (age, political orientation, regulatory focus, and so forth) influence the mental schemas of appropriate leadership deployed by the individual stakeholder. In tandem with these insights, future research could investigate how these individual stakeholder attributes influence their perception of leader characteristics that are not as powerful in impression formation as surface-level characteristics such as gender. Given the rarity of the COVID-19 context and the limited number of female leaders, we used a scenario-based methodology in our controlled lab experiment to test our arguments. Because of the documented influence of news coverage on public perceptions (Graf-Vlachy et al., 2020), we worked to establish experimental realism by presenting news coverage similar to what the public consumed during the onset of COVID-19 (Aguinis & Bradley, 2014). Future research should work to support our causal link further and measure stakeholders’ reactions to COVID-19 leadership directly or via other nonexperimental means, such as polling data or social media posts. We are also at a critical point to begin investigating the ramifications of female appointments and elections amid social and economic unrest (two global challenges). Amid the #TimesUp and #MeToo movements, 11 CEOs stepped down in 2017, six of whom were replaced by women, well above the average replacement rate of 18%. In the U.S. midterm elections in 2018, women set records regarding candidates and electoral victories (Cooney, 2018). Motivated by these data, scholars should work to theoretically and empirically unpack the antecedents of increased female representation as organizational and political leaders during unrest, as well as the aftermath of such decisions on stakeholders’ perceptions and the leaders’ careers. Similarly, organizations and institutions could consider the strategic implications of deploying a female leader during an organizational scandal or crisis. Do stakeholders prefer relational leadership in contexts different from a grand challenge? This logic could be why Sheryl Sandberg, Facebook’s former Chief Operating Officer, often accompanied Mark Zuckerberg as the public face of Facebook’s apology tour following the Cambridge Analytica scandal. “We know that we did not do enough to protect people’s data,” Sandberg said. “I’m really sorry for that. Mark is really sorry for that, and what we’re doing now is taking really firm action” (Sydell, 2018). Similarly, does the National Rifle Association (NRA) strategically deploy a female spokesperson, Dana Loesch, because she “softens” the image of a stigmatized organization (Creitz, 2020)? Finally, as our research shows, stakeholders do not find a female leader more effective solely because of her gender but rather through perceptions of her relational leadership. For example, initial evidence shows that female-led countries are not experiencing statistically lower death rates from COVID-19 (Elsesser, 2020). Thus, female leaders need to be aware of the power associated with being viewed as female and as relational leaders in managing a grand challenge. Future research should investigate whether relational leaders, male or female, are more effective in their messaging and whether their impact on public perceptions goes beyond a grand challenge context. Conclusion To date, scholars have focused on how gender norms (Eagly & Karau, 2002), coupled with the pervasiveness of the stereotypical “think leader—think male” mindset, have limited females’ access to top leadership positions in business and government and often disadvantaged female leaders in terms of evaluations (Dixon-Fowler et al., 2013; Ryan & Haslam, 2007). However, this grand challenge—the COVID-19 pandemic—allowed us to investigate whether there are contexts in which there is a perceived female leadership advantage (Dezsö & Ross, 2012; Eagly & Carli, 2003; Rosette & Tost, 2010). Through our investigation, we disentangled gender differences in perceptions and evaluations of leaders during a grand challenge. Specifically, we provided theoretical grounding and empirical support to substantiate the claim that females’ perceived communality can be an asset during a grand challenge due to the public’s preference for relational leadership. As such, we documented that differences in perceptions of relational leadership based on leader gender can indeed influence evaluations of leaders. We are grateful to Associate Editor Collins Ntim and the anonymous reviewers for their helpful guidance throughout the review process. We would also like to acknowledge the insights received at the 2021 Strategic Management Society annual meeting, as well as the inspiration provided by the founding of the RADC at the 2019 Academy of Management annual meeting in Boston. Author Biographies Abbie Griffith Oliver (PhD, University of Georgia) is an assistant professor at the University of Virginia, McIntire School of Commerce. Her research explores the intersection of corporate governance and social evaluations. She focuses on the socio-cognitive mechanisms that shape strategic decision making and external perceptions of firms. She also explores how diversity influences these relationships in the upper echelons. Her articles have appeared in Academy of Management Journal, Journal of Management, and Strategic Management Journal. Michael D. Pfarrer (PhD, University of Maryland) is the C. Herman and Mary Virginia Terry Distinguished Chair of Business Administration and Associate Dean for Research and Executive Programs in the Terry College of Business at the University of Georgia. His research focuses on organizational reputation and celebrity, impression and crisis management; media and corporate communications; and the role of business in society. François Neville (PhD, Georgia State University) is an Associate Professor of Strategic Management at McMaster University, DeGroote School of Business (Hamilton, Ontario, Canada). His research interests focus on strategic leadership and corporate governance with a current focus on the role that strategic leaders play in shaping a firm’s stakeholder strategy. His articles have appeared in Business & Society, Journal of Business Venturing, Journal of Management, Journal of Management Studies, and Strategic Management Journal. Appendix A Experimental Procedure. Greeting (identical for all participants) We are interested in your perceptions of leaders. Today, we are going to provide you with various information about a leader, such as information on the leader, the leader’s background, and recent press coverage of the leader. Afterward, you will be asked a series of questions relative to your perceptions and reactions about this leader. Please read the information we provide you as carefully as possible so that you can answer the questions that follow as honestly and truthfully as possible. Description of the initial scenario (identical for all participants) The following information provides recent news coverage of the coronavirus disease 2019 (COVID-19) crisis. The names of the country and its leader are disguised for privacy reasons. You will be asked to answer questions about what you read. When you are finished reading, you may continue to the next page. Manipulated content (each participant was randomly assigned a condition) Female Leader Male Leader News coverage from The Wall Street Journal: News coverage from The Wall Street Journal: Country X shut its borders to foreigners March 19. Two days later, Michele Jones delivered a televised address from her office—the first time since 1982 that an Oval Office-style speech had been given—announcing a coronavirus response alert plan involving four stages, with a full lockdown being Level 4. Country X shut its borders to foreigners March 19. Two days later, Michael Jones delivered a televised address from his office—the first time since 1982 that an Oval Office-style speech had been given—announcing a coronavirus response alert plan involving four stages, with a full lockdown being Level 4. A group of influential leaders got on the phone with her the following day to urge moving to Level 4. “We were hugely worried about what was happening in Italy and Spain,” said one of them, CEO Tindell, founder of the Warehouse, Country’s X largest retailer. “If we didn’t shut down quickly enough, the pain was going to go on for a very long time,” he said in a phone interview. “It’s inevitable that we will have to shut down anyway, so we would rather it be sharp and short.” A group of influential leaders got on the phone with him the following day to urge moving to Level 4. “We were hugely worried about what was happening in Italy and Spain,” said one of them, CEO Tindell, founder of the Warehouse, Country’s X largest retailer. “If we didn’t shut down quickly enough, the pain was going to go on for a very long time,” he said in a phone interview. “It’s inevitable that we will have to shut down anyway, so we would rather it be sharp and short.” On March 23, a Monday, Jones delivered another statement and gave the country 48 hours to prepare for a Level 4 lockdown. “We currently have 102 cases,” she said. “But so did Italy once.” From that Wednesday night, everyone had to stay at home for 4 weeks unless they worked in an essential job, such as health care, or were going to the supermarket or exercising near their home. On March 23, a Monday, Jones delivered another statement and gave the country 48 hours to prepare for a Level 4 lockdown. “We currently have 102 cases,” he said. “But so did Italy once.” From that Wednesday night, everyone had to stay at home for 4 weeks unless they worked in an essential job, such as health care, or were going to the supermarket or exercising near their home. A few hours before midnight, my phone sounded a siren as it delivered a text alert: “Act as if you have COVID-19. This will save lives,” it said, referring to the disease caused by the novel coronavirus. “Let’s all do our bit to unite against COVID-19.” A few hours before midnight, my phone sounded a siren as it delivered a text alert: “Act as if you have COVID-19. This will save lives,” it said, referring to the disease caused by the novel coronavirus. “Let’s all do our bit to unite against COVID-19.” From the earliest stages, Jones and her team have spoken in simple language: Stay home. Don’t have contact with anyone outside your household “bubble.” Be kind. We’re all in this together. She has usually done this from the podium of news conferences, where she has discussed everything from the price of potatoes to unemployment checks. But she also regularly gives updates and answers questions on Facebook, including one done while sitting at home—possibly on her couch — in a sweatshirt. From the earliest stages, Jones and his team have spoken in simple language: Stay home. Don’t have contact with anyone outside your household “bubble.” Be kind. We’re all in this together. He has usually done this from the podium of news conferences, where he has discussed everything from the price of potatoes to unemployment checks. But he also regularly gives updates and answers questions on Facebook, including one done while sitting at home — possibly on his couch — in a sweatshirt. The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding: The authors received no financial support for the research, authorship, and/or publication of this article. ORCID iDs: Abbie Griffith Oliver https://orcid.org/0000-0002-2689-9988 Michael D. Pfarrer https://orcid.org/0000-0001-5921-9646 François Neville https://orcid.org/0000-0002-5759-0502 1. These studies were approved by our University’s Human Research Protection Program (Institutional Review Board). 2. Coppock and McClellan (2019) demonstrated that the demographic and political profiles of Lucid subjects are highly similar to U.S. national probability samples in terms of respondent characteristics and treatment effect estimates. 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Academy of Management Journal, 57 (3 ), 791–813.	0	PMC9747369	NO-CC CODE	2022-12-15 00:04:04	no	Bus Soc. 2022 Dec 10;:00076503221141880	utf-8	Bus Soc	2,022	10.1177/00076503221141880	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)02371-3 10.1016/j.jval.2022.09.167 Article CO88 The Impact of COVID-19 Pandemic on Health-Related Quality of Life Outcomes: Evidence From a Longitudinal Study on Children With Rare Disorders Bolbocean C 1 Holder J 2 1University of Oxford, Oxford, , UK 2Bridge the Gap SYNGAP, Cypress, TX, USA 14 12 2022 12 2022 14 12 2022 25 12 S35S35 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives To estimate the impact of the COVID-19 pandemic on health-related quality of life (HQoL) outcomes in children with rare disorders. To explore mechanisms which explain how families buffered COVID-19 induced stress. Methods During 2018 and 2021 a total of 691 families of children with Phelan–McDermid syndrome (PMD), Rett Syndrome (RTT) and SYNGAP1-related intellectual disability (SYNGAP1-ID) completed PedQL (V.4) questionnaire to measure proxy-assessed HRQoL outcomes. HRQoL data on 120 identical children collected during 2018 and during the first year of the pandemic was analysed using parametric and nonparametric pairwise comparisons adjusted for socio-economic covariates. Results The overall evidence shows that PedQL scores increased on average by 14 points during the COVID-19 pandemic compared to 2018; results show significant heterogeneity across diagnoses. Emotional functioning and social functioning scores recorded highest gains during the COVID-19 pandemic. Increasing time watching TV and time spent with digital devices during the pandemic were negatively associated with HRQoL. Conclusions Contrary to studies conducted on overall healthy children, our findings provide evidence that COVID-19 had an overall positive impact on HRQoL in children diagnosed with PMD, RTT and SYNGAP1-ID. Further longitudinal studies are needed to understand the magnitude, trajectory and underpinning mechanisms of HRQoL outcomes in children with severe abnormalities and developmental delay.	0	PMC9747371	NO-CC CODE	2022-12-15 23:21:59	no	Value Health. 2022 Dec 14; 25(12):S35	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.167	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03313-7 10.1016/j.jval.2022.09.1108 Article EPH187 Effects of Non-Pharmaceutical Interventions (NPIS) Aimed at Limiting the Spread of SARS-COV-2 Pentz R 1 Felder-Puig R 2 Soede I 2 Stürzlinger H 2 Teufl L 2 Winkler R 2 1Gesundheit Österreich GmbH (Austrian Public Health Institute), Wien, 9, Austria 2Gesundheit Österreich GmbH (Austrian Public Health Institute), Vienna, Austria 14 12 2022 12 2022 14 12 2022 25 12 S227S227 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives The aim of this overview of reviews is to produce an up-to-date evidence map of systematic reviews (SRs) on the effects – both, intended and unintended – of NPIs that were applied to limit the spread of SARS-CoV-2. The evidence map should enable production of rapid evidence summaries to support decision makers, contribute to a retrospective assessment of the appropriateness of NPIs and identify evidence gaps. Methods We performed systematic literature searches in the COVID L.OVE repository. Title and abstract screening was performed independently by two reviewers, full-text screening was performed by one reviewer and checked by another. We used AMSTAR 2 for quality assessment of selected SRs. Results The first round of literature searches was performed on 10 March 2022 and yielded 1724 hits. During title and abstract screening, we categorised publications according to studied NPIs and outcomes to enable a stepwise full-text screening. Of the 324 potentially relevant publications, we first screened those that investigated masks and effectiveness outcomes in full-text and included 26 SRs. We selected 7 SRs for evidence summary based on recency and study overlap (i.e., SRs that included at least 2 primary studies that are not included in a more recent SR). All SRs were rated critically low quality by AMSTAR 2 assessment. All SRs reported an association between mask wearing and reduced transmission of SARS-CoV-2, but certainty of evidence was mostly deemed low. Evidence for the effect of mask wearing on mortality is sparse. Full-text screening is still ongoing and evidence summaries for other NPIs, as well as for unintended effects will be produced. Conclusions The most recent and comprehensive SRs on mask wearing all report reduced transmission of SARS-CoV-2 but certainty of evidence is deemed low. Quality of the SRs was deemed critically low by AMSTAR 2 assessment.	0	PMC9747372	NO-CC CODE	2022-12-15 23:21:59	no	Value Health. 2022 Dec 14; 25(12):S227	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.1108	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03313-7 10.1016/j.jval.2022.09.1108 Article EPH187 Effects of Non-Pharmaceutical Interventions (NPIS) Aimed at Limiting the Spread of SARS-COV-2 Pentz R 1 Felder-Puig R 2 Soede I 2 Stürzlinger H 2 Teufl L 2 Winkler R 2 1Gesundheit Österreich GmbH (Austrian Public Health Institute), Wien, 9, Austria 2Gesundheit Österreich GmbH (Austrian Public Health Institute), Vienna, Austria 14 12 2022 12 2022 14 12 2022 25 12 S227S227 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives The aim of this overview of reviews is to produce an up-to-date evidence map of systematic reviews (SRs) on the effects – both, intended and unintended – of NPIs that were applied to limit the spread of SARS-CoV-2. The evidence map should enable production of rapid evidence summaries to support decision makers, contribute to a retrospective assessment of the appropriateness of NPIs and identify evidence gaps. Methods We performed systematic literature searches in the COVID L.OVE repository. Title and abstract screening was performed independently by two reviewers, full-text screening was performed by one reviewer and checked by another. We used AMSTAR 2 for quality assessment of selected SRs. Results The first round of literature searches was performed on 10 March 2022 and yielded 1724 hits. During title and abstract screening, we categorised publications according to studied NPIs and outcomes to enable a stepwise full-text screening. Of the 324 potentially relevant publications, we first screened those that investigated masks and effectiveness outcomes in full-text and included 26 SRs. We selected 7 SRs for evidence summary based on recency and study overlap (i.e., SRs that included at least 2 primary studies that are not included in a more recent SR). All SRs were rated critically low quality by AMSTAR 2 assessment. All SRs reported an association between mask wearing and reduced transmission of SARS-CoV-2, but certainty of evidence was mostly deemed low. Evidence for the effect of mask wearing on mortality is sparse. Full-text screening is still ongoing and evidence summaries for other NPIs, as well as for unintended effects will be produced. Conclusions The most recent and comprehensive SRs on mask wearing all report reduced transmission of SARS-CoV-2 but certainty of evidence is deemed low. Quality of the SRs was deemed critically low by AMSTAR 2 assessment.	0	PMC9747373	NO-CC CODE	2022-12-15 23:21:59	no	Value Health. 2022 Dec 14; 25(12):S283	latin-1	Value Health	2,022	10.1016/j.jval.2022.09.1396	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03243-0 10.1016/j.jval.2022.09.1038 Article EPH117 Coinfections in COVID-19 Patients in India: A Systematic Review Khambholja K 1 Patel D 1 Chhaya V 1 Sekhar S M 2 1Genpro Research, Vadodara, GJ, India 2Manipal College of Pharmaceutical Sciences, Manipal, India 14 12 2022 12 2022 14 12 2022 25 12 S213S213 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives To determine the rate of coinfections and its subsequent impact on hospitalization and mortality rate in Indian COVID-19 patients. Methods A systematic literature search was performed on PubMed, Cochrane, WHO COVID-19 database, Google Scholar and assisted by MaiA tool at various steps. The studies were retrieved and included based on JBI’s CoCoPop framework. Meta-analysis was not performed due to a limited number of studies and high heterogeneity. Descriptive statistics were summarized based on the retrieved coinfections data. The protocol was registered with PROSPERO – CRD42021275644. Results A total of 2418 patients were included from eight studies. The prevalence of coinfections ranged from 4% - 46%. Pathogen-specific data showed highest prevalence of bacterial (57.3%), followed by parasitic (21.1.%), viral (14.6%), and fungal coinfections (6.9%). About 60% - 80% of the patients with coinfections required ICU admissions. Among coinfected COVID-19 patients, the average length of hospital stay was 13.67±3.51 days. The mortality rate of COVID-19 patients with coinfections ranged from 9%-65%. Conclusions Bacterial coinfections have the highest prevalence among COVID-19 patients. A causal relationship between coinfections and mortality rate in COVID-19 patients remains unexplored. This brings up the need for comprehensive data recording practices and meticulous reporting. Further, large-scale epidemiologic studies are the need of the hour to determine the nationwide burden of coinfections in the COVID-19 pandemic.	0	PMC9747374	NO-CC CODE	2022-12-15 23:21:59	no	Value Health. 2022 Dec 14; 25(12):S213	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.1038	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03243-0 10.1016/j.jval.2022.09.1038 Article EPH117 Coinfections in COVID-19 Patients in India: A Systematic Review Khambholja K 1 Patel D 1 Chhaya V 1 Sekhar S M 2 1Genpro Research, Vadodara, GJ, India 2Manipal College of Pharmaceutical Sciences, Manipal, India 14 12 2022 12 2022 14 12 2022 25 12 S213S213 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives To determine the rate of coinfections and its subsequent impact on hospitalization and mortality rate in Indian COVID-19 patients. Methods A systematic literature search was performed on PubMed, Cochrane, WHO COVID-19 database, Google Scholar and assisted by MaiA tool at various steps. The studies were retrieved and included based on JBI’s CoCoPop framework. Meta-analysis was not performed due to a limited number of studies and high heterogeneity. Descriptive statistics were summarized based on the retrieved coinfections data. The protocol was registered with PROSPERO – CRD42021275644. Results A total of 2418 patients were included from eight studies. The prevalence of coinfections ranged from 4% - 46%. Pathogen-specific data showed highest prevalence of bacterial (57.3%), followed by parasitic (21.1.%), viral (14.6%), and fungal coinfections (6.9%). About 60% - 80% of the patients with coinfections required ICU admissions. Among coinfected COVID-19 patients, the average length of hospital stay was 13.67±3.51 days. The mortality rate of COVID-19 patients with coinfections ranged from 9%-65%. Conclusions Bacterial coinfections have the highest prevalence among COVID-19 patients. A causal relationship between coinfections and mortality rate in COVID-19 patients remains unexplored. This brings up the need for comprehensive data recording practices and meticulous reporting. Further, large-scale epidemiologic studies are the need of the hour to determine the nationwide burden of coinfections in the COVID-19 pandemic.	0	PMC9747375	NO-CC CODE	2022-12-15 23:21:59	no	Value Health. 2022 Dec 14; 25(12):S279	latin-1	Value Health	2,022	10.1016/j.jval.2022.09.1374	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)02215-X 10.1016/j.jval.2022.09.013 COVIDnomics P1 Cost-Utility Analysis of COVID-19 Vaccines in the Basque Country in the First Semester of 2021 Mar J. 1 Ibarrondo O. 2 Larrañaga I. 2 Aguiar M. 3 Stollenverk N. 3 Bidaurrazaga J. 4 Estadillo C. 3 Blasco R. 3 1 Alto Deba Hospital, Mondragon, Spain 2 Integrated Health Organisation Alto Deba - Osakidetza, Arrasate, Spain 3 Basque Center for Applied Mathematics, Bilbao, Spain 4 Basque Government, Vitoria-Gasteiz, Spain 14 12 2022 12 2022 14 12 2022 25 12 S1S1 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives To measure the epidemiological impact of the vaccination program for COVID-19 in the Basque Country according to severity and deaths of COVID-19 cases in the scenarios with and without the vaccination program. The final objective was to carry out an economic evaluation through a cost-utility analysis estimating quality-adjusted life years (QALY) and costs from the perspective of the Health Service. Methods A dynamic model representing the epidemiology of COVID-19 in the Basque population (SHARUC) already validated provided the total number of cases, hospitalizations, ICU admissions and deaths in two scenarios: with and without vaccines. A nation-wide cohort study (2.2 million inhabitants) was carried out using the Basque Health Service Database in September-December 2020 and January-June 2021 to ascertain the determinants of outcomes associated to COVID-19 (age, sex and Charlson Comorbidity Index (CCI)). Changes in life expectancy and quality-adjusted life years were estimated according to those determinants. Unit costs for healthcare outcomes were obtained from the Basque Health Service. Official and actual vaccines prices were used as sensitivity analysis. Results The figures of avoided outcomes were 31,085 infections, 1,457 hospitalizations, 309 ICU admissions and 482 deaths. According to the age, CCI and sex the life expectancy rose from 34.5594 years to 34.5832 years from the scenario without vaccines to the scenario with vaccines. The incremental utility was 36,000 QALYs for the whole population. Vaccines costs were 35,2 (official prices) and 24.85 (real prices) €millions. The saved cost was 28,9 €millions which rendered an incremental cost-effectiveness ratio from €173/QALY to dominant. Conclusions This is a preliminary result, showing that only the measurement of the direct costs of COVID-19-associated outcomes during the first semester of vaccination rollout made the intervention cost-effective and near dominant. Ongoing phase is aimed to measuring the cost effectiveness of vaccines for the whole 2021 year.	0	PMC9747376	NO-CC CODE	2022-12-15 23:21:59	no	Value Health. 2022 Dec 14; 25(12):S1	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.013	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)02215-X 10.1016/j.jval.2022.09.013 COVIDnomics P1 Cost-Utility Analysis of COVID-19 Vaccines in the Basque Country in the First Semester of 2021 Mar J. 1 Ibarrondo O. 2 Larrañaga I. 2 Aguiar M. 3 Stollenverk N. 3 Bidaurrazaga J. 4 Estadillo C. 3 Blasco R. 3 1 Alto Deba Hospital, Mondragon, Spain 2 Integrated Health Organisation Alto Deba - Osakidetza, Arrasate, Spain 3 Basque Center for Applied Mathematics, Bilbao, Spain 4 Basque Government, Vitoria-Gasteiz, Spain 14 12 2022 12 2022 14 12 2022 25 12 S1S1 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives To measure the epidemiological impact of the vaccination program for COVID-19 in the Basque Country according to severity and deaths of COVID-19 cases in the scenarios with and without the vaccination program. The final objective was to carry out an economic evaluation through a cost-utility analysis estimating quality-adjusted life years (QALY) and costs from the perspective of the Health Service. Methods A dynamic model representing the epidemiology of COVID-19 in the Basque population (SHARUC) already validated provided the total number of cases, hospitalizations, ICU admissions and deaths in two scenarios: with and without vaccines. A nation-wide cohort study (2.2 million inhabitants) was carried out using the Basque Health Service Database in September-December 2020 and January-June 2021 to ascertain the determinants of outcomes associated to COVID-19 (age, sex and Charlson Comorbidity Index (CCI)). Changes in life expectancy and quality-adjusted life years were estimated according to those determinants. Unit costs for healthcare outcomes were obtained from the Basque Health Service. Official and actual vaccines prices were used as sensitivity analysis. Results The figures of avoided outcomes were 31,085 infections, 1,457 hospitalizations, 309 ICU admissions and 482 deaths. According to the age, CCI and sex the life expectancy rose from 34.5594 years to 34.5832 years from the scenario without vaccines to the scenario with vaccines. The incremental utility was 36,000 QALYs for the whole population. Vaccines costs were 35,2 (official prices) and 24.85 (real prices) €millions. The saved cost was 28,9 €millions which rendered an incremental cost-effectiveness ratio from €173/QALY to dominant. Conclusions This is a preliminary result, showing that only the measurement of the direct costs of COVID-19-associated outcomes during the first semester of vaccination rollout made the intervention cost-effective and near dominant. Ongoing phase is aimed to measuring the cost effectiveness of vaccines for the whole 2021 year.	0	PMC9747377	NO-CC CODE	2022-12-15 23:21:59	no	Value Health. 2022 Dec 14; 25(12):S180	latin-1	Value Health	2,022	10.1016/j.jval.2022.09.871	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)02215-X 10.1016/j.jval.2022.09.013 COVIDnomics P1 Cost-Utility Analysis of COVID-19 Vaccines in the Basque Country in the First Semester of 2021 Mar J. 1 Ibarrondo O. 2 Larrañaga I. 2 Aguiar M. 3 Stollenverk N. 3 Bidaurrazaga J. 4 Estadillo C. 3 Blasco R. 3 1 Alto Deba Hospital, Mondragon, Spain 2 Integrated Health Organisation Alto Deba - Osakidetza, Arrasate, Spain 3 Basque Center for Applied Mathematics, Bilbao, Spain 4 Basque Government, Vitoria-Gasteiz, Spain 14 12 2022 12 2022 14 12 2022 25 12 S1S1 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives To measure the epidemiological impact of the vaccination program for COVID-19 in the Basque Country according to severity and deaths of COVID-19 cases in the scenarios with and without the vaccination program. The final objective was to carry out an economic evaluation through a cost-utility analysis estimating quality-adjusted life years (QALY) and costs from the perspective of the Health Service. Methods A dynamic model representing the epidemiology of COVID-19 in the Basque population (SHARUC) already validated provided the total number of cases, hospitalizations, ICU admissions and deaths in two scenarios: with and without vaccines. A nation-wide cohort study (2.2 million inhabitants) was carried out using the Basque Health Service Database in September-December 2020 and January-June 2021 to ascertain the determinants of outcomes associated to COVID-19 (age, sex and Charlson Comorbidity Index (CCI)). Changes in life expectancy and quality-adjusted life years were estimated according to those determinants. Unit costs for healthcare outcomes were obtained from the Basque Health Service. Official and actual vaccines prices were used as sensitivity analysis. Results The figures of avoided outcomes were 31,085 infections, 1,457 hospitalizations, 309 ICU admissions and 482 deaths. According to the age, CCI and sex the life expectancy rose from 34.5594 years to 34.5832 years from the scenario without vaccines to the scenario with vaccines. The incremental utility was 36,000 QALYs for the whole population. Vaccines costs were 35,2 (official prices) and 24.85 (real prices) €millions. The saved cost was 28,9 €millions which rendered an incremental cost-effectiveness ratio from €173/QALY to dominant. Conclusions This is a preliminary result, showing that only the measurement of the direct costs of COVID-19-associated outcomes during the first semester of vaccination rollout made the intervention cost-effective and near dominant. Ongoing phase is aimed to measuring the cost effectiveness of vaccines for the whole 2021 year.	0	PMC9747378	NO-CC CODE	2022-12-15 23:21:59	no	Value Health. 2022 Dec 14; 25(12):S140	latin-1	Value Health	2,022	10.1016/j.jval.2022.09.677	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)02215-X 10.1016/j.jval.2022.09.013 COVIDnomics P1 Cost-Utility Analysis of COVID-19 Vaccines in the Basque Country in the First Semester of 2021 Mar J. 1 Ibarrondo O. 2 Larrañaga I. 2 Aguiar M. 3 Stollenverk N. 3 Bidaurrazaga J. 4 Estadillo C. 3 Blasco R. 3 1 Alto Deba Hospital, Mondragon, Spain 2 Integrated Health Organisation Alto Deba - Osakidetza, Arrasate, Spain 3 Basque Center for Applied Mathematics, Bilbao, Spain 4 Basque Government, Vitoria-Gasteiz, Spain 14 12 2022 12 2022 14 12 2022 25 12 S1S1 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives To measure the epidemiological impact of the vaccination program for COVID-19 in the Basque Country according to severity and deaths of COVID-19 cases in the scenarios with and without the vaccination program. The final objective was to carry out an economic evaluation through a cost-utility analysis estimating quality-adjusted life years (QALY) and costs from the perspective of the Health Service. Methods A dynamic model representing the epidemiology of COVID-19 in the Basque population (SHARUC) already validated provided the total number of cases, hospitalizations, ICU admissions and deaths in two scenarios: with and without vaccines. A nation-wide cohort study (2.2 million inhabitants) was carried out using the Basque Health Service Database in September-December 2020 and January-June 2021 to ascertain the determinants of outcomes associated to COVID-19 (age, sex and Charlson Comorbidity Index (CCI)). Changes in life expectancy and quality-adjusted life years were estimated according to those determinants. Unit costs for healthcare outcomes were obtained from the Basque Health Service. Official and actual vaccines prices were used as sensitivity analysis. Results The figures of avoided outcomes were 31,085 infections, 1,457 hospitalizations, 309 ICU admissions and 482 deaths. According to the age, CCI and sex the life expectancy rose from 34.5594 years to 34.5832 years from the scenario without vaccines to the scenario with vaccines. The incremental utility was 36,000 QALYs for the whole population. Vaccines costs were 35,2 (official prices) and 24.85 (real prices) €millions. The saved cost was 28,9 €millions which rendered an incremental cost-effectiveness ratio from €173/QALY to dominant. Conclusions This is a preliminary result, showing that only the measurement of the direct costs of COVID-19-associated outcomes during the first semester of vaccination rollout made the intervention cost-effective and near dominant. Ongoing phase is aimed to measuring the cost effectiveness of vaccines for the whole 2021 year.	0	PMC9747379	NO-CC CODE	2022-12-15 23:21:59	no	Value Health. 2022 Dec 14; 25(12):S309	latin-1	Value Health	2,022	10.1016/j.jval.2022.09.1525	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)02215-X 10.1016/j.jval.2022.09.013 COVIDnomics P1 Cost-Utility Analysis of COVID-19 Vaccines in the Basque Country in the First Semester of 2021 Mar J. 1 Ibarrondo O. 2 Larrañaga I. 2 Aguiar M. 3 Stollenverk N. 3 Bidaurrazaga J. 4 Estadillo C. 3 Blasco R. 3 1 Alto Deba Hospital, Mondragon, Spain 2 Integrated Health Organisation Alto Deba - Osakidetza, Arrasate, Spain 3 Basque Center for Applied Mathematics, Bilbao, Spain 4 Basque Government, Vitoria-Gasteiz, Spain 14 12 2022 12 2022 14 12 2022 25 12 S1S1 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives To measure the epidemiological impact of the vaccination program for COVID-19 in the Basque Country according to severity and deaths of COVID-19 cases in the scenarios with and without the vaccination program. The final objective was to carry out an economic evaluation through a cost-utility analysis estimating quality-adjusted life years (QALY) and costs from the perspective of the Health Service. Methods A dynamic model representing the epidemiology of COVID-19 in the Basque population (SHARUC) already validated provided the total number of cases, hospitalizations, ICU admissions and deaths in two scenarios: with and without vaccines. A nation-wide cohort study (2.2 million inhabitants) was carried out using the Basque Health Service Database in September-December 2020 and January-June 2021 to ascertain the determinants of outcomes associated to COVID-19 (age, sex and Charlson Comorbidity Index (CCI)). Changes in life expectancy and quality-adjusted life years were estimated according to those determinants. Unit costs for healthcare outcomes were obtained from the Basque Health Service. Official and actual vaccines prices were used as sensitivity analysis. Results The figures of avoided outcomes were 31,085 infections, 1,457 hospitalizations, 309 ICU admissions and 482 deaths. According to the age, CCI and sex the life expectancy rose from 34.5594 years to 34.5832 years from the scenario without vaccines to the scenario with vaccines. The incremental utility was 36,000 QALYs for the whole population. Vaccines costs were 35,2 (official prices) and 24.85 (real prices) €millions. The saved cost was 28,9 €millions which rendered an incremental cost-effectiveness ratio from €173/QALY to dominant. Conclusions This is a preliminary result, showing that only the measurement of the direct costs of COVID-19-associated outcomes during the first semester of vaccination rollout made the intervention cost-effective and near dominant. Ongoing phase is aimed to measuring the cost effectiveness of vaccines for the whole 2021 year.	0	PMC9747380	NO-CC CODE	2022-12-15 23:21:59	no	Value Health. 2022 Dec 14; 25(12):S219	latin-1	Value Health	2,022	10.1016/j.jval.2022.09.1071	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03283-1 10.1016/j.jval.2022.09.1078 Article EPH157 Physical Activity Level in Association with Mental Health Before and During the Restrictions of the First Three Waves of COVID-19 Pandemic Among Hungarian Adults Ács P Boncz I Molics B Prémusz V Paár D Morvay-Sey K Pálvölgyi Á Laczkó T Makai A University of Pécs, Pécs, Hungary 14 12 2022 12 2022 14 12 2022 25 12 S221S221 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives Physically active lifestyle has beneficial effects on physical and mental health too. The consequences of the first three waves of the COVID-19 pandemic also significantly affected the everyday life of the Hungarian population, as well as the leisure time and the amount of time spent physically active. The aim of our research is to assess the physical activity and mental health of Hungarian adult population during the first three waves of the pandemic. Methods The longitudinal study based on questionnaire data during the first three waves of the COVID-19 pandemic in Hungary (2020-2021). The representative stratified sample consisted of 3600 people (18–69-year-old adults in Hungary). The International Physical Activity Questionnaire (IPAQ-SF) was used to examine physical activity patterns. To test the research hypotheses Spearman's rank correlation analysis and Wilcoxon test were calculated using SPSS 28.0 software and our results were considered significant at p <0.05. Results The mean age of the sample was 43.49 (15.13) years, the ratio of gender was representative for the Hungarian population (48.14% of females and 51.86% of males). The median (interquartile range, IQR) physical activity level of the adults (min/week) was decreased from 480.00 (230.00-1000.00) minutes / week to 310.00 (135.00-840.00) minutes/week during the restrictions (p<0.001) however during the third wave of pandemic we measured significantly higher physical activity level than the beginning of the pandemic (180 (75.00-420.00), 520 (180.00-1128.75); p<0.001). The total weekly physical activity (min) during the restrictions significantly associated with the mental health status (p<0.001). Conclusions During the first wave of the pandemic, the living and working conditions of the Hungarian population changed mostly. The results of the third waves of the pandemic indicate the adaptation of individuals to the new circumstances. Our results were showed that the physically active lifestyle has a beneficial effect on mental health status.	0	PMC9747381	NO-CC CODE	2022-12-15 23:21:59	no	Value Health. 2022 Dec 14; 25(12):S221	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.1078	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)02838-8 10.1016/j.jval.2022.09.634 Article EE388 Cost Effectiveness of Novel Antibiotic Ceftolozane/Tazobactam in Patients With Hospital-Acquired Bacterial Pneumonia or Ventilator-Associated Bacterial Pneumonia in Greece Yfantopoulos N 1 Bafaloukos I 2 Yang J 3 Mintzia E 2 Ntontsi P 2 Skroumpelos A 2 Karokis A 2 1MSD Greece, Alimos, A1, Greece 2MSD Greece, Alimos, Greece 3Merck & Co., Rahway, NJ, USA 14 12 2022 12 2022 14 12 2022 25 12 S131S131 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives Antimicrobial resistance is a critical public health issue in Greece, which has worsened during COVID-19 pandemic due to antibiotic overuse. The present study assesses the cost-effectiveness of ceftolozane/tazobactam(C/T) in ICU-admitted ventilated hospital-acquired bacterial pneumonia (vHABP) and ventilator-associated bacterial pneumonia (VABP) due to Multiple Drug Resistant Pseudomonas Aeruginosa in Greece. Methods The model is based on data from ASPECT-NP Phase-3 study and PACTS surveillance data from Italy. The model consists of two parts: a decision-tree, depicting the period from vHABP/VABP diagnosis to hospital discharge and a Markov model, projecting long-term outcomes following hospital discharge. The model calculates costs and outcomes within a 40 years’ time-horizon. Costs and QALYs are discounted at an annual rate of 3.0%. Outcomes included Incremental Cost Effectiveness Ratio(ICER), Quality Adjusted Life Years (QALY’s) and Life Years (LY’s) for each comparator as well as hospital resource use and mortality (for each comparator).The comparator used in the base case analysis was Meropenem. A deterministic sensitivity analysis (DSA) was performed to test the parameters with the greatest impact on the ICER and a Probabilistic Sensitivity Analysis (PSA) was run to test the robustness of the results. Results Patients who received C/T spent 1.97 days less (17.99 days) with mechanical ventilator support compared to Meropenem 19.97 days with mechanical ventilator support. Patients in the treatment arm with Meropenem are expected to have 8.66 LY’s and 7.11 QALY’s with a cost of 33,896€. Whereas patients in the C/T arm are expected to have 10.18 LY’s and 8.34 QALY’s at a cost of 35,135€. The ICER for C/T was 994€ per QALY compared to Meropenem. C/T showed a 99.94% probability of being cost effective at a threshold of 52,770 per QALY € (3x Greek- GDP per capita). Conclusions The present study suggests that Ceftolozane/Tazobactam is a cost-effective treatment for Greek vHABP/VABP patients.	0	PMC9747382	NO-CC CODE	2022-12-15 23:21:59	no	Value Health. 2022 Dec 14; 25(12):S131	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.634	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03505-7 10.1016/j.jval.2022.09.1300 Article HPR171 COVID 19 Vaccination - How to Support Decisions on Vaccination Prioritization for New Variants of Concern? Jahn B 1 Sroczynski G 1 Bicher M 2 Rippinger C 3 Mühlberger N 1 Santamaria J 1 Urach C 3 Popper N 4 Siebert U 5 1UMIT - University for Health Sciences, Medical Informatics and Technology, Institute of Public Health, Medical Decision Making and Health Technology Assessment, Hall i.T., Austria 2dwh GmbH, dwh simulation-services; TU Wien, Institute for Information Systems Engineering, Vienna, Austria 3dwh GmbH, dwh simulation services, Vienna, Austria 4dwh GmbH, dwh simluation services; TU Wien, Institute for Information Systems and Engineering; DEXHELPP, Association for Decision Support Health Policy and Planning, Vienna, Austria 5UMIT - University for Health Sciences, Medical Informatics and Technology, Hall i.T., Austria; Massachussetts General Hospital, Harvard Medical School, Boston, USA; Harvard T.H. Chan School of Public Health, Boston, USA, Boston, MA, USA 14 12 2022 12 2022 14 12 2022 25 12 S263S263 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives Since the SARS-CoV-2 outbreak, new virus variants have developed. Variants of concerns (VoC) may require adaptations of current vaccines. We aim to identify optimal vaccination strategies for a COVID-19 vaccine adapted to a hypothetical (VoC) focusing on age-specific prioritization of a partially vaccinated population and initially limited vaccination doses. Methods A dynamic agent-based population model for Austria was extended to capture the impact of different variants. A hypothetical, new VoC affects the current pandemic. The parameters for the variant’s infectivity, virulence, susceptibility to the current vaccine and initial vaccination coverage when the VoC is detected were varied in 81 scenarios. Evaluated vaccination strategies are: 1) revaccination of the elderly with the VoC-vaccine, 2) vaccination of the unvaccinated with the VoC-vaccine, 3) VoC-vaccine and the current vaccine provided to the unvaccinated, and 4) VoC-vaccine to elderly and current vaccine to unvaccinated compared to 5) continuing with the current vaccine, only to minimize COVID-19-related hospitalizations and deaths. A time horizon of ten months was considered. Results Prioritization of vaccination depends strongly on combination of effectiveness of the current vaccine for the VoC, vaccination coverage and VoC infectivity, less on additional information on VoC severity. For example, at a 75% reduced effectiveness of the current vaccine for the VoC: Minimizing hospitalizations are achieved by selecting strategy 1 followed by 3 (1 followed by 2) considering increased VoC-infectivity of 0% or 33% (66%) independent of vaccination coverage. Assuming a 50% relative reduction of the effectiveness of the current vaccine for VoC, for example for 33% and 66% increased infectivity of the VoC, we would prefer strategy 1 followed by 2, strategies considering revaccinations with VoC vaccine would not be a preferred option focusing on hospitalizations. Conclusions Our study provides a flexible vaccination-decision basis. The current analysis identified no generally preferred strategy for VoC-adapted vaccines.	0	PMC9747383	NO-CC CODE	2022-12-15 23:21:59	no	Value Health. 2022 Dec 14; 25(12):S263	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.1300	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03180-1 10.1016/j.jval.2022.09.975 Article EPH53 The Role of Incentives- Parents’ Intention to Vaccinate Their 5- to 11-Year-Old Children with the COVID-19 Vaccine in Israel Shmueli L Bar Ilan University, Tel-Aviv, TA, Israel 14 12 2022 12 2022 14 12 2022 25 12 S201S201 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives Immediately after Pfizer announced encouraging effectiveness and safety results from their COVID-19 vaccine clinical trials in 5- to 11-year-old children, we aimed to assess parents’ perceptions and intention to vaccinate their 5-11-year-old children and to determine the role of incentives beyond socio-demographic, health-related and behavioral factors, in predicting this intention. Methods A cross-sectional representative online survey among parents of children between 5-11 years of age in Israel (n=1,012). The survey was carried out between September 23 and October 4, 2021, at a critical time, immediately after Pfizer’s announcement. Two multivariate regressions were performed to determine predictors of parents’ intention to vaccinate their 5-11-year-old children against COVID-19. Results Overall, 57% of the participants reported that they intend to vaccinate their 5-11-year-old children against COVID-19 in the coming winter. 27% noted that they would vaccinate their 5-11-year-old children immediately; 26% within three months; and 24% within more than three months. Perceived susceptibility, benefits, barriers and cues to action, as well as two incentives - vaccine availability and receiving a “Green Pass” - were all significant predictors. However, Incentives such as monetary rewards or monetary penalties did not increase the probability of parents’ intention to vaccinate their children. Parental concerns centered around the safety of the vaccine, fear of severe side effects, and fear that clinical trials and the authorization process were carried out too quickly. Conclusions Providing up-to-data on the role of incentives in vaccinating 5-11-year-old children, is essential for health policy makers and healthcare providers. Our findings underscore the importance of COVID-19 vaccine accessibility. Monetary incentives did not increase the intention to get vaccinated against COVID-19, mainly since a monetary payment for vaccination is likely to be small and is unlikely to compensate for the risk of vaccination but only for the inconvenience.	0	PMC9747384	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S201	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.975	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)04658-7 10.1016/j.jval.2022.09.2453 Article SA59 Is There Life for Pre-Prints After COVID-19? Wittkopf P 1 Raorane R 2 Casañas i Comabella C 2 Iheanacho I 2 1Evidera, Glasgow, GLG, UK 2Evidera, London, LON, UK 14 12 2022 12 2022 14 12 2022 25 12 S494S495 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives During the COVID-19 pandemic, pre-prints were widely used to accelerate data dissemination. Advantages of using such material in a crisis are compelling but should still be balanced against potential limitations (e.g., the lack of peer-review and possible unexplained data discrepancies between pre-prints and corresponding journal publications). We aimed to assess recently published pre-prints on non-COVID-19 treatments, for insights into the utility of such material in the absence of related peer-reviewed publications. Methods The pre-print databases SSRN and MedRXiv were systematically searched for records posted in 2021 and reporting randomised trials of any pharmacological or surgical interventions for non-COVID-19 indications. MEDLINE and Embase were also searched for corresponding peer-reviewed articles published by May 2022. Data gathered and analysed included posting/publication date, sample size and any differences in definition/reporting of primary outcomes between pre-pint and peer-reviewed publication. Results Overall, 41 (of 688 screened) pre-prints were included, with 22 having a corresponding peer-reviewed publication. The median time from pre-print posting to journal publication was 4.35 months (range: 1–13.4 months), over a median follow-up (i.e., time from pre-print posting to database search) of 9.9 months (range: 1.8–15.5 months). For the 19 pre-prints without a peer-reviewed publication, the median follow-up was 7.4 months (range: 4.6–14.9 months). There were no discrepancies in the reporting of primary outcomes in 18 out of the 19 pre-print/peer-reviewed-publication dyads. In one of the dyads, the pre-print reported only the per-protocol results, while the peer-reviewed publication reported only the intention-to-treat analysis. Nevertheless, the overall conclusions were similar in both publications. Conclusions Our study suggests that pre-prints can be a reliable source of evidence, often accessible several months before any corresponding peer-reviewed publication. While the findings need confirmation in further research, they raise questions about whether pre-prints should be considered routinely in settings where early availability of data may be crucial, such as reimbursement decision-making.	0	PMC9747385	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S494-S495	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.2453	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)04394-7 10.1016/j.jval.2022.09.2189 Article PCR256 Humanistic Burden and Prevalence of Mental Conditions Among COVID-19 Patients in Japan and China Tan WH 1 Chen Y 1 Lin HC 2 Grillo V 1 Woo A 1 1Cerner Enviza, Singapore, Singapore 2Cerner Enviza, Taipei, Taiwan 14 12 2022 12 2022 14 12 2022 25 12 S439S440 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives The COVID-19 pandemic results in widespread health, economic, and social disruptions. It is therefore important to understand the multifaceted effects of COVID-19, including the humanistic burden and impact on mental conditions. This study aims to assess the humanistic burden and prevalence of mental conditions among COVID-19 patients in Asian countries. Methods This study utilized the Internet-based National Health and Wellness Survey (NHWS) conducted in Japan and China. We included respondents in surveys conducted after the COVID-19 outbreak: the 2021 Japan NHWS (n=30,015) and the 2020 China NHWS (n=20,051). COVID-19 patients were identified based on self-reported physician diagnosis. A subset of non-COVID respondents was selected using 1:4 propensity score matching. For each country, demographic characteristics, Health-related Quality of Life (HRQoL), work productivity and activity impairment (WPAI), and prevalence of emotional and mental conditions were compared between COVID-19 patients and selected controls using bivariate analyses. Results In both countries, COVID-19 patients had statistically significantly lower HRQoL and higher WPAI compared to selected controls on all measures we examined (P<0.01). A higher proportion of COVID-19 patients exhibited symptoms of depression (Patient Health Questionnaire-9 [PHQ-9] ≥10: Japan: 24.3% vs. 12.4%; China: 66.4% vs 18.2%) or anxiety (General Anxiety Disorder-7 [GAD-7] ≥10: Japan: 17.5% vs. 9.4%; China: 40.1% vs 8.2%)) in both countries. COVID-19 patients reported significantly higher total work productivity impairment compared to non-COVID respondents (Japan: 37.3% vs. 20.4%; China: 63.9% vs. 27.5%, p<0.001). Increased rates of emotional and mental conditions (e.g., bipolar disorder, depression, and schizophrenia) were also observed in COVID-19 patients in both countries (P<0.05). Conclusions This study demonstrated a substantial impact of COVID-19 on HRQoL, WPAI, and mental conditions in both Japan and China. COVID-19 patients experienced significantly worse HRQoL and WPAI, as well as an elevated rate of mental conditions than the non-COVID population.	0	PMC9747386	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S439-S440	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.2189	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03132-1 10.1016/j.jval.2022.09.927 Article EPH4 Burden and Characteristics of COVID-19 in France During 2020 Based on National Hospital Database Leboucher C 1 Blein C 1 Machuron V 2 Le Lay K 2 Benyounes K 2 Millier A 3 Raffi F 4 1Creativ-Ceutical, Lyon, 69, France 2Roche, Boulogne-Billancourt, France 3Creativ-Ceutical, Paris, France 4CHU Nantes, Nantes, France 14 12 2022 12 2022 14 12 2022 25 12 S191S191 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives The objectives of the study were to describe the characteristics of Covid-19 patients hospitalised, the level of intensity of care that was required for their management and in particular the ventilation status, and to estimate the direct medical costs of these hospitalisations to the French national health insurance. Methods The study included all patients hospitalised with an ICD-10 diagnostic code for Covid-19 between 1st January 2020 and 31st December 2020 and stratified into 4 ventilations: status without and with oxygen support (O2), with non-invasive ventilation (NIV), with mechanical ventilation (MV) based on medical procedure. Due to underreporting of procedures related to oxygen support, status “without O2” was combined to O2 status. Risk factors for complications were identified based on the list defined by the French National Health Authority. Cost estimation of hospitalisation was determined from the DRG. Results 199,455 patients were included for 238,582 stays. 1% of stays were in NIV status, 8% in MV. Median age was 69 years and 54% of patients were men. Men were overrepresented in NIV and MV. 10% of people over 80 had MV. 34% of patients had no risk factor (11% of MV, 6% of NIV and 36% of O2). 16% of patients died (14% of O2, 25% of NIV, 36% of MV). The mortality rate increased with the age, between 1 and 5% for patients younger than 60 years to 33% for patients older than 80 years old. The mean cost of Covid-19 hospitalisation was €5,510 (€+/- 7,142) and the median €3,800. It increased with ventilation support intensity from €3,990 (€+/- 3,021) for O2, €10, 600 (€+/- 5,534) for NIV, €21,100 (€+/- 15,343) for MV. Conclusions Age, sex and risk factor increased the severity of ventilation support, cost and mortality rates. Elderly people had less MV support, shorter length of stay and lower cost.	0	PMC9747387	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S191	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.927	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)02282-3 10.1016/j.jval.2022.09.080 Article P68 Investing in the Prevention of Infectious Disease Outbreaks: Fiscal Health Modelling for Assessing the Public Investment Case Schöttler M 1 van der Schans S 2 Connolly M 3 Van der Schans J 4 Boersma C 5 Postma M 6 1Health-Ecore B.V., Zeist, UT, Netherlands 2University Medical Center Groningen, University of Groningen, Groningen, GR, Netherlands 3Global Market Access Solutions LLC, Mooresville, NC, USA 4University of Groningen, Faculty of Economics and Business, Unit of Economics, Econometrics and Finance, Groningen, Netherlands 5University of Groningen, University Medical Center Groningen, Zeist, UT, Netherlands 6Health-Ecore, Zeist, UT, Netherlands 14 12 2022 12 2022 14 12 2022 25 12 S16S16 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives National strategies for preparedness on future outbreaks of COVID-19 often include the timely preparedness with available vaccines. Fiscal health modelling (FHM) has recently been brought forward as an additional analysis by defining the fiscal impact of a health condition from a governmental perspective. As governments are the main decision-makers on preparedness, this study assesses a FHM framework for a communicable disease. Methods Using data of the Dutch COVID-19 pandemic, two approaches for identifying the fiscal impact of COVID-19 were assessed: 1. modelling of future fiscal impact based on publicly available population counts; and 2. assessment of the extrapolated tax and benefit income and gross domestic product (GDP) in a particular time period with the respective realized values. The appropriateness of different modelling approaches was in line with the ISPOR FHM guidelines and extensively validated in an expert meeting. Results Dutch publicly available data was the basis for the analysis performed, showing total counts of 2.36 million infections, 52,678 hospitalisations, 9,805 ICU admissions and 9,493 deaths in a period of 24 months following the start of COVID-19 in 2020. Consequences which can be causally linked to these counts influencing income tax collected and social benefits paid (approach 1) amounted to a fiscal loss of €158 million over 2 years. The total losses in terms of the fiscal income and GDP (approach 2), were estimated at respectively €13,582 million and €96.3 billion over 24 months. Conclusions This study is a full integrated fiscal macro-economic orientation to analyse different aspects of an infectious disease outbreak and its influence on government public accounts. The suitability of the two presented approaches depends on the perspective of the analysis, time horizon of the analysis and availability of data. The consequence-linking approach is more suited to a prospective estimation and the extrapolating approach more to a retrospective one.	0	PMC9747388	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S16	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.080	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03281-8 10.1016/j.jval.2022.09.1076 Article EPH155 A Systematic Review of the Impact of Vaccination on Long COVID Thompson JY 1 Nnate DA 2 Mussad M 3 Carroll S 3 Buck P 3 Strain WD 4 Banerjee A 5 Van de Velde N 3 1University of Birmingham, Birmingham, UK 2Countess of Chester NHS Foundation Trust, Chester, UK 3Moderna, Inc., Cambridge, MA, USA 4University of Exeter, Exeter, UK 5University College London, London, UK 14 12 2022 12 2022 14 12 2022 25 12 S220S220 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives Coronavirus disease 2019 (COVID-19) has multisystem effects, with a myriad of symptoms that may persist beyond four weeks (i.e., “long COVID”) but may be amenable to vaccination. This review systematically synthesised evidence to evaluate the health and economic burden of long COVID, specifically its relationship to vaccines. Methods Relevant databases were searched for experimental randomized controlled trials (RCTs) and non-interventional studies. No language restrictions were applied. Estimates from 29 studies were narratively synthesised from Canada (2), United States (6), Australia (1), United Kingdom (9), France (2), India (2), Europe (1), Indonesia (1), Israel (1), Egypt (1), and international (3). Of the 29 studies identified, only 11 studies considered fully vaccinated vs partially vaccinated or unvaccinated groups before they were infected. Most studies were conducted among community-dwelling individuals (n=20), four among hospitalized patients, and five in either setting. Seven studies considered participants that were vaccinated post-infection. In comparison, eleven studies did not provide adequate information about vaccination status. Results Of the 29 studies, 17 explored the relationship between vaccination and symptoms of long-COVID; 1 study reported worsening of symptoms, 11 studies reported improvement of symptoms, and 5 reported no difference in symptom profile following vaccination. Only two studies provided information on the economic benefit of vaccination strategies. Conclusions The COVID-19 and long COVID evidence base is evolving, and additional data may be presented at the conference. Data collected to date suggest that the prevalence of long COVID is a crude approximation, which underestimates the burden of the disease and the impact of vaccines and findings may also be limited by the reporting and quality of eligible studies. Furthermore, we would not be able to evaluate the impact of risk aversion via adherence to public health guidelines or non-pharmacological interventions due to measurement error, thereby increasing the possibility of bias.	0	PMC9747389	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S220	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.1076	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)04186-9 10.1016/j.jval.2022.09.1981 Article PCR46 Assessing the Mental Health of Secondary School Students in the Light of COVID-19 Vajda R 1 Karamán E 2 Csákvári T 1 Fusz K 1 Khatatbeh H 3 Miszory E 1 Boncz I 1 Pakai A 4 1University of Pécs, Pécs, Hungary 2Zrínyi Miklós High School, Zalaegerszeg, Hungary 3University of Pécs, pecs, Hungary 4University of Pécs, Pécs, ZA, Hungary 14 12 2022 12 2022 14 12 2022 25 12 S398S399 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives The COVID-19 pandemic has had a significant impact on the lives of high school students as well. Prolonged confinement, social isolation, fear of the disease, or the loss of a close family member are all experiences that students may have endured. Our aim was to assess students’ health and risk behaviours, relationships, and mental health after the fifth wave of COVID-19. Methods A quantitative, cross-sectional study was carried out between 2022.03.01. and 2022. 04.15. We selected Hungarian secondary school students between 15-20 years of age (N=150). Our self-administered questionnaire consisted of questions about socio-demographic factors, perceived health status, peer relationships, satisfaction with life and the Perceived Stress Scale (PSS). Results The majority of our sample are girls, vocational students and were living in villages. The mean age is 16.85±1.51 years. Most of them spend two hours a day in front of the TV, and an additional three hours with other electronic tools in their free time. 20.8% of students have four, 19.8% have three, 18.8% have five close friends. 52.1% rate their health as “good”, 31.3% as “appropriate”. The mean score of their life satisfaction is 6.34±1.85. Average score of PSS was 31.74± 9.13. The mean PSS score of girls (33.07±9.07) are significantly higher than the boys’ (25.88±6.96; p=0.001). There is no relation between age and PSS score (p=0.161), or the type of school (p=0.412). Conclusions The study showed significant stress and symptoms of mental problems, especially among girls. The information revealed allows for a better understanding of the health indicators and psychological characteristics of adolescents. Our results provide information for the development of prevention programs, thereby contributing to the reduction of adolescents’ behavioural disorders.	0	PMC9747390	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S398-S399	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.1981	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)02566-9 10.1016/j.jval.2022.09.362 Article EE110 Psychological Impact of COVID-19 and the Economic Burden of Rheumatic and Musculoskeletal Diseases Lorenzoni V 1 Palla I 1 Andreozzi G 1 Fulvio G 2 Tani C 2 Trentin F 2 Pedrinelli V 3 Carmassi C 3 Mosca M 2 Turchetti G 1 1Scuola Superiore Sant'Anna, Pisa, Italy 2Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy 3University of Pisa, Section of Psychiatry, Department of Clinical and Experimental Medicine, Pisa, Italy 14 12 2022 12 2022 14 12 2022 25 12 S74S75 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives The COVID-19 pandemic significantly impacted on mental health both in the general population and in specific vulnerable subgroups. In particular, patients with rheumatic and musculoskeletal diseases (RMDs) have been shown to be more vulnerable, as they experienced difficulties in the management of disease, and might have severe psychological consequences that might impact on the economic burden of disease. The present study aims to explore the impact of post-traumatic stress disorders (PTSD) on the economic burden of RMDs during the COVID-19 pandemic in Italy. Methods As part of the activities of the PERMAS prospective observational project information about resources used related to direct (i.e., direct health costs, out-of-pocket expenses and other direct non-health costs) and indirect costs were collected from RMDs patients enrolled from May 2021 to April 2022. Direct costs were estimated based on national tariffs while costs for informal assistance and productivity losses were estimated respectively using the proxy-good method and the human capital approach and referred to 2021.We analysed the impact of PTSD (assessed using Trauma and Loss Spectrum- Self Report scale) on costs with a two-part model using a probit model for the first part and a gamma distribution and log link in the second part and adjusting for age, gender, type of RM disease and education level. Results Out of 237 patients considered in the analysis, 126 (53.2%) reported a PTSD. Overall, total costs related to disease were 2583€(0;40,529) per patient/year and costs were about 29% higher in patients with PTSD. Indeed results from the two-part model showed that the amount of costs related to the disease significantly increased in patients with PTSD (β=0.448(0.162), p-value<0.001) independently of age, gender, type of RM disease, education level. Conclusions The impact COVID-19 has had on mental health of RMDs patients has the potential to impact also on the economic burden of disease.	0	PMC9747391	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S74-S75	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.362	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)04094-3 10.1016/j.jval.2022.09.1889 Article MT15 Obvio-19 App Ease of Use of Cancer Patients for Reporting COVID-19 Symptomology (ONCOVID Study) Heidman M 1 Culbreth-Notaro M 2 Dallabrida S 3 Raymond E 4 Bartels C 5 1SPRIM US LLC, Orlando, FL, USA 2ObvioHealth, New York, NY, USA 3SPRIM US LLC, Boston, MA, USA 4Saint-Joseph Hospital, Paris, France 5SPRIM US LLC, Stuttgart, Germany 14 12 2022 12 2022 14 12 2022 25 12 S380S381 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives Due to being immunocompromised, cancer patients are at higher risk of contracting COVID-19, as well as severe complications as a result. The means to report COVID-19 symptoms quickly and accurately to a clinician is critical so they can receive immediate care to reduce long term impacts and reduce risk of potential death. The Obvio-19 app was developed to issue users a series of once daily questions regarding their health, symptomology, and COVID-19 exposure opportunities such that potential COVID-19 infection could be quickly identified. In the ONCOVID Study, patients’ sentiment regarding ease of use of the app is assessed. Methods Thirty-three (n=33) cancer patients were recruited from Saint Joseph Hospital in Paris and asked to utilize the Obvio-19 app over a six-month period, no patients with blood cancers were included. The purpose of this study was to evaluate cancer patient user experience with Obvio-19 application including ease of use and sentiments regarding its use for reporting. Of thirty-three patients, none contracted COVID-19 and sixteen (n=16) were able to complete the OBVIONCO survey after 6 months of use regarding their experience. Results When asked to rate “Ease of use of the Obvio-19 app” from 1 to 5 with 5 being “very easy” and 1 being “very difficult”, 88% (n=14) selected “5 – very easy” and the remaining 12% (n=2) selected “4”. Additionally, 82% (n=13) communicated that they felt completing the questionnaire in an electronic application is easier that a paper form. 88% (n=14) felt the there was an appropriate number of questions asked each day and all patients (n=16) were able to complete the daily process in less than 2 minutes. Conclusions This study demonstrates how electronic application-based monitoring provides less burden on cancer patients monitored and treated from home and reduces need for clinic visits and potential unnecessary exposure to COVID-19.	0	PMC9747392	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S380-S381	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.1889	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)04094-3 10.1016/j.jval.2022.09.1889 Article MT15 Obvio-19 App Ease of Use of Cancer Patients for Reporting COVID-19 Symptomology (ONCOVID Study) Heidman M 1 Culbreth-Notaro M 2 Dallabrida S 3 Raymond E 4 Bartels C 5 1SPRIM US LLC, Orlando, FL, USA 2ObvioHealth, New York, NY, USA 3SPRIM US LLC, Boston, MA, USA 4Saint-Joseph Hospital, Paris, France 5SPRIM US LLC, Stuttgart, Germany 14 12 2022 12 2022 14 12 2022 25 12 S380S381 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives Due to being immunocompromised, cancer patients are at higher risk of contracting COVID-19, as well as severe complications as a result. The means to report COVID-19 symptoms quickly and accurately to a clinician is critical so they can receive immediate care to reduce long term impacts and reduce risk of potential death. The Obvio-19 app was developed to issue users a series of once daily questions regarding their health, symptomology, and COVID-19 exposure opportunities such that potential COVID-19 infection could be quickly identified. In the ONCOVID Study, patients’ sentiment regarding ease of use of the app is assessed. Methods Thirty-three (n=33) cancer patients were recruited from Saint Joseph Hospital in Paris and asked to utilize the Obvio-19 app over a six-month period, no patients with blood cancers were included. The purpose of this study was to evaluate cancer patient user experience with Obvio-19 application including ease of use and sentiments regarding its use for reporting. Of thirty-three patients, none contracted COVID-19 and sixteen (n=16) were able to complete the OBVIONCO survey after 6 months of use regarding their experience. Results When asked to rate “Ease of use of the Obvio-19 app” from 1 to 5 with 5 being “very easy” and 1 being “very difficult”, 88% (n=14) selected “5 – very easy” and the remaining 12% (n=2) selected “4”. Additionally, 82% (n=13) communicated that they felt completing the questionnaire in an electronic application is easier that a paper form. 88% (n=14) felt the there was an appropriate number of questions asked each day and all patients (n=16) were able to complete the daily process in less than 2 minutes. Conclusions This study demonstrates how electronic application-based monitoring provides less burden on cancer patients monitored and treated from home and reduces need for clinic visits and potential unnecessary exposure to COVID-19.	0	PMC9747393	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S192	latin-1	Value Health	2,022	10.1016/j.jval.2022.09.930	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)04094-3 10.1016/j.jval.2022.09.1889 Article MT15 Obvio-19 App Ease of Use of Cancer Patients for Reporting COVID-19 Symptomology (ONCOVID Study) Heidman M 1 Culbreth-Notaro M 2 Dallabrida S 3 Raymond E 4 Bartels C 5 1SPRIM US LLC, Orlando, FL, USA 2ObvioHealth, New York, NY, USA 3SPRIM US LLC, Boston, MA, USA 4Saint-Joseph Hospital, Paris, France 5SPRIM US LLC, Stuttgart, Germany 14 12 2022 12 2022 14 12 2022 25 12 S380S381 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives Due to being immunocompromised, cancer patients are at higher risk of contracting COVID-19, as well as severe complications as a result. The means to report COVID-19 symptoms quickly and accurately to a clinician is critical so they can receive immediate care to reduce long term impacts and reduce risk of potential death. The Obvio-19 app was developed to issue users a series of once daily questions regarding their health, symptomology, and COVID-19 exposure opportunities such that potential COVID-19 infection could be quickly identified. In the ONCOVID Study, patients’ sentiment regarding ease of use of the app is assessed. Methods Thirty-three (n=33) cancer patients were recruited from Saint Joseph Hospital in Paris and asked to utilize the Obvio-19 app over a six-month period, no patients with blood cancers were included. The purpose of this study was to evaluate cancer patient user experience with Obvio-19 application including ease of use and sentiments regarding its use for reporting. Of thirty-three patients, none contracted COVID-19 and sixteen (n=16) were able to complete the OBVIONCO survey after 6 months of use regarding their experience. Results When asked to rate “Ease of use of the Obvio-19 app” from 1 to 5 with 5 being “very easy” and 1 being “very difficult”, 88% (n=14) selected “5 – very easy” and the remaining 12% (n=2) selected “4”. Additionally, 82% (n=13) communicated that they felt completing the questionnaire in an electronic application is easier that a paper form. 88% (n=14) felt the there was an appropriate number of questions asked each day and all patients (n=16) were able to complete the daily process in less than 2 minutes. Conclusions This study demonstrates how electronic application-based monitoring provides less burden on cancer patients monitored and treated from home and reduces need for clinic visits and potential unnecessary exposure to COVID-19.	0	PMC9747394	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S243	latin-1	Value Health	2,022	10.1016/j.jval.2022.09.1192	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03162-X 10.1016/j.jval.2022.09.957 Article EPH35 Post-COVID Conditions in Hospitalized COVID-19 Patients in Germany Pacis S 1 Maywald U 2 Wilke T 3 Ghiani M 3 1Cytel Inc, Berlin, BE, Germany 2AOK PLUS, Dresden, Germany 3IPAM - Institut für Pharmakoökonomie und Arzneimittellogistik e.V., Wismar, Germany 14 12 2022 12 2022 14 12 2022 25 12 S197S198 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives “Post-COVID” conditions include a wide range of new health problems following COVID-19 infection. The ICD-10-GM code for post-COVID (U09.9!) became effective on 01/01/2021, but may not identify all post-COVID symptoms. We used claims data from AOK PLUS, a large regional sickness fund covering ≈3.7 million inhabitants in Saxony and Thuringia, to describe incident diagnoses following COVID-19 hospitalization. Methods Inpatient cases of confirmed COVID-19 (ICD-10-GM code U07.1) between 01/01/2020—30/06/2021 with minimum 60 days follow-up were included. Long-COVID conditions were identified as incident ICD-10-GM inpatient or outpatient diagnoses occurring in the 31-180 days after COVID-19 discharge date that did not occur in the 1-year baseline period before COVID-19 hospitalization, excluding diagnoses due to pregnancy and external causes of morbidity. Results There were 18,251 inpatient COVID-19 patients, of which 12,162 (66.6%) had incident post-COVID conditions (65.2% outpatient only, 7.8% inpatient only, 27.0% inpatient and outpatient). Of patients diagnosed with COVID-19 in 2021, only 2245 (21.5%) were diagnosed with post-COVID condition (U09.9!). Respiratory symptoms were most common (J00-J99, 20.7%), with 6.7% experiencing respiratory failure (J96). Heart disease (I20-I52) and urinary complications (N30-N39, R30-R39) were also frequent (18.3% and 18.1%, respectively), most commonly heart failure (I50, 5.7%) and urinary incontinence (R32, 7.0%). Symptoms affecting the nervous or musculoskeletal systems (R25-R29) were diagnosed in 10.9% of patients, including gait/mobility disorders (R26, 6.6%). Renal complications (N17-N19) were found in 7.4% of patients, with 5.2% newly diagnosed with chronic kidney disease. Patients who were intubated or in the ICU (7.7%) were more likely to have post-COVID conditions compared to those with less severe hospitalizations (p=0.003). Patients with post-COVID conditions were also more likely to be older (mean age 70.0 vs. 65.0, p<0.001) and female (p<0.001). Conclusions Claims data can be used to identify incident post-COVID symptoms, although may overestimate number of conditions directly related to COVID-19.	0	PMC9747395	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S197-S198	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.957	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03162-X 10.1016/j.jval.2022.09.957 Article EPH35 Post-COVID Conditions in Hospitalized COVID-19 Patients in Germany Pacis S 1 Maywald U 2 Wilke T 3 Ghiani M 3 1Cytel Inc, Berlin, BE, Germany 2AOK PLUS, Dresden, Germany 3IPAM - Institut für Pharmakoökonomie und Arzneimittellogistik e.V., Wismar, Germany 14 12 2022 12 2022 14 12 2022 25 12 S197S198 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives “Post-COVID” conditions include a wide range of new health problems following COVID-19 infection. The ICD-10-GM code for post-COVID (U09.9!) became effective on 01/01/2021, but may not identify all post-COVID symptoms. We used claims data from AOK PLUS, a large regional sickness fund covering ≈3.7 million inhabitants in Saxony and Thuringia, to describe incident diagnoses following COVID-19 hospitalization. Methods Inpatient cases of confirmed COVID-19 (ICD-10-GM code U07.1) between 01/01/2020—30/06/2021 with minimum 60 days follow-up were included. Long-COVID conditions were identified as incident ICD-10-GM inpatient or outpatient diagnoses occurring in the 31-180 days after COVID-19 discharge date that did not occur in the 1-year baseline period before COVID-19 hospitalization, excluding diagnoses due to pregnancy and external causes of morbidity. Results There were 18,251 inpatient COVID-19 patients, of which 12,162 (66.6%) had incident post-COVID conditions (65.2% outpatient only, 7.8% inpatient only, 27.0% inpatient and outpatient). Of patients diagnosed with COVID-19 in 2021, only 2245 (21.5%) were diagnosed with post-COVID condition (U09.9!). Respiratory symptoms were most common (J00-J99, 20.7%), with 6.7% experiencing respiratory failure (J96). Heart disease (I20-I52) and urinary complications (N30-N39, R30-R39) were also frequent (18.3% and 18.1%, respectively), most commonly heart failure (I50, 5.7%) and urinary incontinence (R32, 7.0%). Symptoms affecting the nervous or musculoskeletal systems (R25-R29) were diagnosed in 10.9% of patients, including gait/mobility disorders (R26, 6.6%). Renal complications (N17-N19) were found in 7.4% of patients, with 5.2% newly diagnosed with chronic kidney disease. Patients who were intubated or in the ICU (7.7%) were more likely to have post-COVID conditions compared to those with less severe hospitalizations (p=0.003). Patients with post-COVID conditions were also more likely to be older (mean age 70.0 vs. 65.0, p<0.001) and female (p<0.001). Conclusions Claims data can be used to identify incident post-COVID symptoms, although may overestimate number of conditions directly related to COVID-19.	0	PMC9747396	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S175-S176	latin-1	Value Health	2,022	10.1016/j.jval.2022.09.849	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03162-X 10.1016/j.jval.2022.09.957 Article EPH35 Post-COVID Conditions in Hospitalized COVID-19 Patients in Germany Pacis S 1 Maywald U 2 Wilke T 3 Ghiani M 3 1Cytel Inc, Berlin, BE, Germany 2AOK PLUS, Dresden, Germany 3IPAM - Institut für Pharmakoökonomie und Arzneimittellogistik e.V., Wismar, Germany 14 12 2022 12 2022 14 12 2022 25 12 S197S198 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives “Post-COVID” conditions include a wide range of new health problems following COVID-19 infection. The ICD-10-GM code for post-COVID (U09.9!) became effective on 01/01/2021, but may not identify all post-COVID symptoms. We used claims data from AOK PLUS, a large regional sickness fund covering ≈3.7 million inhabitants in Saxony and Thuringia, to describe incident diagnoses following COVID-19 hospitalization. Methods Inpatient cases of confirmed COVID-19 (ICD-10-GM code U07.1) between 01/01/2020—30/06/2021 with minimum 60 days follow-up were included. Long-COVID conditions were identified as incident ICD-10-GM inpatient or outpatient diagnoses occurring in the 31-180 days after COVID-19 discharge date that did not occur in the 1-year baseline period before COVID-19 hospitalization, excluding diagnoses due to pregnancy and external causes of morbidity. Results There were 18,251 inpatient COVID-19 patients, of which 12,162 (66.6%) had incident post-COVID conditions (65.2% outpatient only, 7.8% inpatient only, 27.0% inpatient and outpatient). Of patients diagnosed with COVID-19 in 2021, only 2245 (21.5%) were diagnosed with post-COVID condition (U09.9!). Respiratory symptoms were most common (J00-J99, 20.7%), with 6.7% experiencing respiratory failure (J96). Heart disease (I20-I52) and urinary complications (N30-N39, R30-R39) were also frequent (18.3% and 18.1%, respectively), most commonly heart failure (I50, 5.7%) and urinary incontinence (R32, 7.0%). Symptoms affecting the nervous or musculoskeletal systems (R25-R29) were diagnosed in 10.9% of patients, including gait/mobility disorders (R26, 6.6%). Renal complications (N17-N19) were found in 7.4% of patients, with 5.2% newly diagnosed with chronic kidney disease. Patients who were intubated or in the ICU (7.7%) were more likely to have post-COVID conditions compared to those with less severe hospitalizations (p=0.003). Patients with post-COVID conditions were also more likely to be older (mean age 70.0 vs. 65.0, p<0.001) and female (p<0.001). Conclusions Claims data can be used to identify incident post-COVID symptoms, although may overestimate number of conditions directly related to COVID-19.	0	PMC9747397	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S213	latin-1	Value Health	2,022	10.1016/j.jval.2022.09.1039	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03654-3 10.1016/j.jval.2022.09.1449 Article HSD106 Analysis of Diagnostic and Medical Delay Data Among Lung Cancer Patients in 2019 and 2020 Varga JK 1 Boncz I 2 Grmela G 1 Pápai-Székely Z 1 Mátyus M 1 Zsoldos G 1 Kiss P 1 Grassalkovich A 1 Kívés Z 3 1Saint George University Hospital of County Fejér, Székesfehérvár, Hungary 2University of Pécs, Pécs, Hungary 3University of Pécs, PÉCS, BA, Hungary 14 12 2022 12 2022 14 12 2022 25 12 S293S293 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives This study aims to investigate the diagnosis and medical delay among lung cancer patients, furthermore, the involvement of the SARS-CoV-2 pandemic in diagnostic delay. Methods The retrospective study was performed in Pulmonology Department at Fejer County University Teaching Hospital in Hungary, between January 1, 2019 and December 31, 2020. We analysed the data of patients with primary lung cancer and changes in the diagnostic and medical delay time (n=102). Descriptive statistical analyses were applied (mean, standard deviation, absolute and relative frequency). Results The average age is 68 years. 44.1% of patients were admitted to the institution from lung care, 12.7% from the emergency department and 43.1% from other providers. The mean diagnostic delay was 89.8±47.9 days in the two years. The time from first appointment to the chest CT was 21.42±28.08 days. On average, 21.93±25.1 days elapsed from CT to bronchoscopy. On average 35.79±29.2 days elapsed between oncoteam consultation and initiation of treatment. For those requiring PET/CT, the total diagnostic time increased from 69.7 days to 119.6 days (p<0.001). The total diagnostic time of patients receiving chemotherapy (22.9 days) was significantly lower compared to both patients receiving surgery (50.9 days) and those receiving radiotherapy (101.3 days) (p<0.001). In 2020, the number of primary lung care appointments decreased significantly, from 58% to 31% of all primary care visits, while the proportion of primary appointments in other care settings increased significantly from 2019 to 2020, from 28% to 58% (p=0.008). No significant difference was observed in the mean of the total diagnostic delay times (p=0.273), it was 83.8±47.9 days in 2019 and then 94.7± 47.8 days. Conclusions Reducing the therapeutic delay – which constitutes a substantial part of the total diagnostic period, is a realistic goal and should be targeted.	0	PMC9747398	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S293	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.1449	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)02869-8 10.1016/j.jval.2022.09.665 Article EE419 Economic Evaluation of Extracorporeal Membrane Oxygenation (ECMO) vs Invasive Ventilation for COVID-19 Patients with Severe Acute Respiratory Distress Syndrome (ARDS) R.M. K 1 Gopalan G 2 Kachroo K 3 Pudi N 4 Sharma J 5 1Kalam Institute of Health Technology, AMTZ- A JBI Affiliated Group, Visakhapatnam, India 2Kalam Institute of Health Technology, AMTZ - A JBI Affiliated group, Visakhapatnam, AP, India 3Kalam Institute of Health Technology, Visakhapatnam, India 4Kalam Institute of Health Technology, AMTZ- A JBI Affiliated group, Visakhapatnam, AP, India 5Kalam Institute of Health Technology- A JBI Affiliated group, Vishakhapatnam, AP, India 14 12 2022 12 2022 14 12 2022 25 12 S138S138 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives Most of the clinicians use invasive mechanical ventilation in COVID- 19 patients with moderate or severe Acute Respiratory Distress Syndrome and in those who have substantial gas exchange anomalies in the setting of possibly reversible acute respiratory failure may benefit from Extracorporeal Membrane Oxygenation (ECMO) as a salvage therapy. This research aims to assess the cost- effectiveness of use of VV- ECMO when compared to that of invasive mechanical ventilation, in COVID- 19 patients with ARDS. Methods In individuals infected with Covid-19, a cost-effectiveness analysis was performed comparing Venovenous Extracorporeal Membrane Oxygenation (VV- ECMO) to that of invasive mechanical ventilation. A decision tree was constructed using data from previously published studies and other government websites comparing the use of VV- ECMO to that of invasive mechanical ventilation in COVID- 19 patients with severe ARDS. Results VV- ECMO when used in COVID-19 ARDS patients gains 1.89 QALY, in the time horizon of one month whereas invasive mechanical ventilation mode gains only 0.48 QALY with an ICER value of ₹ 3,35,311.78 per QALY gained. When the WTP is greater than ₹ 4,00,000, VV- ECMO is almost 85% cost effective. One- way sensitivity analysis reveals that the uncertainty in the probability of patients alive after receiving VV- ECMO, probability of patients having no adverse reaction after receiving VV- ECMO and cost of VV- ECMO, have the greatest impact on the ICER. Conclusions Although managing COVID- 19 patients with ARDS with VV- ECMO is comparatively costlier than that of managing with invasive mechanical ventilation in monetary terms, the QALY gained is fairly higher in case of VV- ECMO and is cost effective. It was also observed from the studies that there is reduced length of stay in patients under VV- ECMO compared to the alternative.	0	PMC9747399	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S138	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.665	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03279-X 10.1016/j.jval.2022.09.1074 Article EPH153 Increased Prevalence of Post-Traumatic Stress Syndrome Among Healthcare Workers During the Coronavirus Epidemic Bogdán P 1 Szabó L 1 Verzár Z 1 Khatatbeh H 2 Zrínyi M 3 Kozmann K 1 Boncz I 1 Pakai A 3 1University of Pécs, Pécs, Hungary 2University of Pécs, pecs, Hungary 3University of Pécs, Pécs, ZA, Hungary 14 12 2022 12 2022 14 12 2022 25 12 S220S220 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives The coronavirus pandemic has placed a huge physical and psychological burden on health workers. Prolonged exposure to stress has been shown to increase the risk of developing post-traumatic stress disorder (PTSD). Our study aims to objectify the negative psychological and physical effects suffered, their extent and severity, among nurses working in Covid-19 wards. Methods A descriptive, quantitative, cross-sectional study was conducted between June 2022 and August 2022 at the University of Pécs Clinical Centre - Regional Coronavirus Care Centre. Non-random, purposive expert sampling was used to select nurses who had been involved in covid care for at least 6 months. We excluded professionals involved in covid care for less than 6 months. Data were collected online using two standard questionnaires, the Impact of Event Scale - Revised and the Expanded Nursing Stress Scale, and sociodemographic data were collected on gender, age, weight, BMI, job title, years of education, years of work, type of residence, marital status, number of children, underlying medical conditions, smoking, alcohol consumption. Data were processed in SPSSv2.5, descriptive statistics, correlation, χ2 test, ANOVA and t-test were calculated (p<0.05). Results On the "IES-R" scale, at least 10% of the respondents were classified as severely exposed to PTSD (p<0.05). Nurses over 40 years of age had higher mean scores on the "ENSS" scale than those under 40 years of age (p<0.05). We measured significantly higher scores on the "ENSS" scale in the category "death and dying" (p<0.05). Conclusions We consider it important to detect the negative effects of stress early to intervene at the appropriate level in vulnerable groups, either by involving a psychologist or by teaching emotional coping. APNs can and should play a prominent role in preventing and assessing the onset of PTSD and then providing support.	0	PMC9747400	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S220	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.1074	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03279-X 10.1016/j.jval.2022.09.1074 Article EPH153 Increased Prevalence of Post-Traumatic Stress Syndrome Among Healthcare Workers During the Coronavirus Epidemic Bogdán P 1 Szabó L 1 Verzár Z 1 Khatatbeh H 2 Zrínyi M 3 Kozmann K 1 Boncz I 1 Pakai A 3 1University of Pécs, Pécs, Hungary 2University of Pécs, pecs, Hungary 3University of Pécs, Pécs, ZA, Hungary 14 12 2022 12 2022 14 12 2022 25 12 S220S220 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives The coronavirus pandemic has placed a huge physical and psychological burden on health workers. Prolonged exposure to stress has been shown to increase the risk of developing post-traumatic stress disorder (PTSD). Our study aims to objectify the negative psychological and physical effects suffered, their extent and severity, among nurses working in Covid-19 wards. Methods A descriptive, quantitative, cross-sectional study was conducted between June 2022 and August 2022 at the University of Pécs Clinical Centre - Regional Coronavirus Care Centre. Non-random, purposive expert sampling was used to select nurses who had been involved in covid care for at least 6 months. We excluded professionals involved in covid care for less than 6 months. Data were collected online using two standard questionnaires, the Impact of Event Scale - Revised and the Expanded Nursing Stress Scale, and sociodemographic data were collected on gender, age, weight, BMI, job title, years of education, years of work, type of residence, marital status, number of children, underlying medical conditions, smoking, alcohol consumption. Data were processed in SPSSv2.5, descriptive statistics, correlation, χ2 test, ANOVA and t-test were calculated (p<0.05). Results On the "IES-R" scale, at least 10% of the respondents were classified as severely exposed to PTSD (p<0.05). Nurses over 40 years of age had higher mean scores on the "ENSS" scale than those under 40 years of age (p<0.05). We measured significantly higher scores on the "ENSS" scale in the category "death and dying" (p<0.05). Conclusions We consider it important to detect the negative effects of stress early to intervene at the appropriate level in vulnerable groups, either by involving a psychologist or by teaching emotional coping. APNs can and should play a prominent role in preventing and assessing the onset of PTSD and then providing support.	0	PMC9747401	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S106	latin-1	Value Health	2,022	10.1016/j.jval.2022.09.515	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03580-X 10.1016/j.jval.2022.09.1375 Article HSD31 Analysis of the Balanced Scorecard's Managerial Subdimensions in Health Care Organizations During the COVID-19 Pandemic Amer F 1 Hammoud S 1 Khatatbeh H 2 Lohner S 2 Boncz I 2 Endrei D 2 1University of Pécs, Pécs, BA, Hungary 2University of Pécs, Pécs, Hungary 14 12 2022 12 2022 14 12 2022 25 12 S279S279 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives We intended to review all the managerial subdimensions used in balanced scorecard (BSC) implementations and then to assess the impact of the pandemic on the managerial subdimensions of health care organizations (HCOs). Methods We performed a systematic review in accordance with PRISMA guidelines to find all internal key performance indicators (KPIs) used in BSC implementations from the time of inception until October 2020 in PubMed, Embase, Cochrane, Google Scholar databases, and Google's search engine. Second, we searched for independent studies using the resulting managerial subdimensions with the COVID-19 keyword in Google engine and Google Scholar until June 2021. Results Out of 4031 studies, 36 implementations remained. From these, 72 managerial KPIs were extracted. Categorizing KPIs resulted in 4 subdimensions: planning and targets, standards and regulations, internal assessment, and external assessment. Hospitals utilized some of these subdimensions’ KPIs to perform planning and internal assessment of their performance. The CDC developed a checklist to help hospitals assess and improve their preparedness for responding to COVID-19. However, insufficient standardization of quality measurement approaches in the COVID-19 era was perceived, which disrupted the comparison and understanding of health systems’ optimal performance. The lack of standardization and conflicting or irrational managerial decisions were deemed dissatisfactory factors for health care workers in the pandemic. Moreover, few studies have examined centralized governance's impact on HCOs during the pandemic, which positively affected reactive strategies. Learning from past pandemics was suggested to may positively influences proactive and reactive strategies. However, the role of internal assessment, such as BSC and total quality management tools, or external assessments, such as Joint Commission International accreditations, certification, auditing, or peer review on HCOs during the pandemic, still requires more investigation. Conclusions Future research to improve the performance of the managerial subdimensions during the pandemic, as well as a comprehensive assessment for HCOs is still needed.	0	PMC9747402	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S279	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.1375	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03969-9 10.1016/j.jval.2022.09.1764 Article MSR32 COVID-19 Beds’ Occupancy and Hospital Complaints: A Predictive Model Foglia E 1 Ferrario LB 1 Bellavia D 2 Schettini F 1 Falletti E 1 Gallese C 1 Nobile MS 3 Riva SG 4 1LIUC University, Castellanza, Italy 2LIUC University, Limbiate, MI, Italy 3Ca’ Foscari University of Venice, Venezia, Italy 4University of Oxford, Oxford, UK 14 12 2022 12 2022 14 12 2022 25 12 S356S356 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives COVID-19 pandemic limited the number of patients that could be promptly and adequately taken in charge. The proposed research aims at predicting the number of patients requiring any type of hospitalizations, considering not only patients affected by COVID-19, but also other severe viral diseases, including untreated chronic and frail patients, and also oncological ones, to estimate potential hospital lawsuits and complaints. Methods An unsupervised learning approach of artificial neural network’s called Self-Organizing Maps (SOM), grounding on the prediction of the existence of specific clusters and useful to predict hospital behavioral changes, has been designed to forecast the hospital beds’ occupancy, using pre and post COVID-19 time-series, and supporting the prompt prediction of litigations and potential lawsuits, so that hospital managers and public institutions could perform an impacts’ analysis to decide whether to invest resources to increase or allocate differentially hospital beds and humans capacity. Data came from the UK National Health Service (NHS) statistic and digital portals, concerning a 4-year time horizon, related to 2 pre and 2 post COVID-19 years. Results Clusters revealed two principal behaviors in selecting the resources allocation. In case of increase of non-COVID hospitalized patients, a reduction in the number of complaints (-55%) emerged. A higher number of complaints was registered (+17%) against a considerable reduction in the number of beds occupied (-26%). Based on the above, the management of hospital beds is a crucial factor which can influence the complaints trend. Conclusions The model could significantly support in the management of hospital capacity, helping decision-makers in taking rational decisions under conditions of uncertainty. In addition, this model is highly replicable also in the estimation of current hospital beds, healthcare professionals, equipment, and other resources, extremely scarce during emergency or pandemic crises, being able to be adapted for different local and national settings.	0	PMC9747403	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S356	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.1764	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03969-9 10.1016/j.jval.2022.09.1764 Article MSR32 COVID-19 Beds’ Occupancy and Hospital Complaints: A Predictive Model Foglia E 1 Ferrario LB 1 Bellavia D 2 Schettini F 1 Falletti E 1 Gallese C 1 Nobile MS 3 Riva SG 4 1LIUC University, Castellanza, Italy 2LIUC University, Limbiate, MI, Italy 3Ca’ Foscari University of Venice, Venezia, Italy 4University of Oxford, Oxford, UK 14 12 2022 12 2022 14 12 2022 25 12 S356S356 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives COVID-19 pandemic limited the number of patients that could be promptly and adequately taken in charge. The proposed research aims at predicting the number of patients requiring any type of hospitalizations, considering not only patients affected by COVID-19, but also other severe viral diseases, including untreated chronic and frail patients, and also oncological ones, to estimate potential hospital lawsuits and complaints. Methods An unsupervised learning approach of artificial neural network’s called Self-Organizing Maps (SOM), grounding on the prediction of the existence of specific clusters and useful to predict hospital behavioral changes, has been designed to forecast the hospital beds’ occupancy, using pre and post COVID-19 time-series, and supporting the prompt prediction of litigations and potential lawsuits, so that hospital managers and public institutions could perform an impacts’ analysis to decide whether to invest resources to increase or allocate differentially hospital beds and humans capacity. Data came from the UK National Health Service (NHS) statistic and digital portals, concerning a 4-year time horizon, related to 2 pre and 2 post COVID-19 years. Results Clusters revealed two principal behaviors in selecting the resources allocation. In case of increase of non-COVID hospitalized patients, a reduction in the number of complaints (-55%) emerged. A higher number of complaints was registered (+17%) against a considerable reduction in the number of beds occupied (-26%). Based on the above, the management of hospital beds is a crucial factor which can influence the complaints trend. Conclusions The model could significantly support in the management of hospital capacity, helping decision-makers in taking rational decisions under conditions of uncertainty. In addition, this model is highly replicable also in the estimation of current hospital beds, healthcare professionals, equipment, and other resources, extremely scarce during emergency or pandemic crises, being able to be adapted for different local and national settings.	0	PMC9747404	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S244	latin-1	Value Health	2,022	10.1016/j.jval.2022.09.1195	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)04594-6 10.1016/j.jval.2022.09.2389 Article RWD164 The Impact of the COVID-19 Pandemic on Patients With Type 2 Diabetes in Greece: Results From a Real-World Study Daflla L- 1 Poulia K-A 2 Doupis J 3 Kotsopoulos N 4 Yfantopoulos I 5 1National and Kapodistrian University, Athens, Greece 2Agricultural University of Athens, Laboratory on Dietetics and Quality of Life, Athens, Greece 3Diabetes Department and Clinical Research Center, Iatriko Palaiou Falirou Medical Center, Athens, Greece 4Health Policy Institute, Athens, Greece 5University of Athens MBA, Athens, Greece 14 12 2022 12 2022 14 12 2022 25 12 S481S482 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives Diabetes Mellitus (DM) is a non-communicable chronic disease of increasing prevalence and positively associated with physical inactivity and obesity. The aim was to investigate the magnitude of regional health inequalities in the prevalence of T2 DM in the Greek population, before and during the pandemic using geospatial data. Methods Data from the DM registry of the National Health Insurance Organization, Unique National Insurance Numbers for the years 2019 and 2020, were correlated with counties’ geospatial data, leveraging Geographical Information Systems (GIS). Subsequently, thematic maps were developed using gender and age-specific DM2 data. Results The prevalence of DM in the Greek population in 2019 was 499,2 patients per 10.000 people (5,38% of the total population). In 2020 the corresponding prevalence increased by 20% and was estimated at 606 patients/10.000 people i.e. (6.06% of the total population). The prevalence of DM2 increased by 21.46% and by 19.13% in men and women, respectively. A substantial increase was observed in young of 15-24 years of age (from 1.98/10.000 population in 2019 to 3.16/10.000 population). Considering the effects of the economic crisis on the prevalence of DM in Greece we found the highest increase in the islandic regions (Dodecanese 30%, Zakinthos 28.8%, Samos 25.9%, Corfu 25.7%, Kyklades 25.2%). When hotspot analysis was applied a significant clustering of high prevalence in women in Northern Greece was identified. Conclusions COVID-19 pandemic appears to have a catalytic negative effect on the population of Greece with increased prevalence of DM, especially among the youth. The lockdown, the increased unemployment rates of the young population, the closure of many diabetic clinics, the limitation of appointments in certified diabetic clinics as well as the transformation of hospitals into COVID-19 clinics disrupted significantly the function of health services. The results reveal the significant deterioration of diabetes health status in Greece due to COVID-19 pandemic.	0	PMC9747405	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S481-S482	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.2389	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03311-3 10.1016/j.jval.2022.09.1106 Article EPH185 Increased Influenza Vaccine Coverage Rate Following COVID-19: Durable Trend or Epiphenomenon? Ngami A 1 Christie T 2 Guelfucci F 1 Bianic F 1 Net P 1 1Syneos Health, Montrouge, France 2Syneos health, Singapore, Singapore 14 12 2022 12 2022 14 12 2022 25 12 S226S226 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives The 2021/22 influenza season was still marked by the circulation of the Sars-CoV-2 responsible for the COVID-19 pandemic. Leveraging past research, we aimed at comparing pre and post-COVID-19 periods influenza vaccine coverage rate (VCR). We also explored the evolution of influenza VCR between the last two seasons. Methods We conducted secondary desk research to collect annual influenza VCR from the seasons 2010/11 to 2021/22 in France, Italy, Spain, UK, Canada and US. Government and public health agency websites were consulted and VCR were extracted for all populations eligible to influenza vaccination. We used non-parametric Wilcoxon signed-rank tests to investigate significant variations in VCR for the pooled 2020/22 seasons compared to previous seasons (overall and by age-group). We also looked at VCR evolution between the 2020/21 and 2021/22 seasons. Results Overall VCR in France increased by 12.26% in 2020/22 compared to previous seasons (p=0.001). Significant increases in VCR in both adults aged 65+ years and below 65 years at-risk were observed in France, UK and the US with +12.56% / +12.43% and +8.98% respectively (all p=0.001). Significant results were also observed in at-risk adults <65y with +7.17% (UK) and +23.58% (US). No significant changes were observed in any eligible groups in Canada, and VCR for Italy and Spain were not available at the time of the study. However, decreases in VCR were observed in 2021/22 compared to 2020/21, with -3.20% in overall VCR in France and -16.10% and -7.50% in the US for the ≥18y and ≥65y age groups respectively. Conclusions Significant augmentations in influenza VCR were observed during the 2020/22 seasons compared to the pre-COVID-19. However, drops in VCR were observed in multiple age groups and countries in 2021/22 compared to the previous season, potentially demonstrating early signs of vaccine fatigue across populations.	0	PMC9747406	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S226	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.1106	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03311-3 10.1016/j.jval.2022.09.1106 Article EPH185 Increased Influenza Vaccine Coverage Rate Following COVID-19: Durable Trend or Epiphenomenon? Ngami A 1 Christie T 2 Guelfucci F 1 Bianic F 1 Net P 1 1Syneos Health, Montrouge, France 2Syneos health, Singapore, Singapore 14 12 2022 12 2022 14 12 2022 25 12 S226S226 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives The 2021/22 influenza season was still marked by the circulation of the Sars-CoV-2 responsible for the COVID-19 pandemic. Leveraging past research, we aimed at comparing pre and post-COVID-19 periods influenza vaccine coverage rate (VCR). We also explored the evolution of influenza VCR between the last two seasons. Methods We conducted secondary desk research to collect annual influenza VCR from the seasons 2010/11 to 2021/22 in France, Italy, Spain, UK, Canada and US. Government and public health agency websites were consulted and VCR were extracted for all populations eligible to influenza vaccination. We used non-parametric Wilcoxon signed-rank tests to investigate significant variations in VCR for the pooled 2020/22 seasons compared to previous seasons (overall and by age-group). We also looked at VCR evolution between the 2020/21 and 2021/22 seasons. Results Overall VCR in France increased by 12.26% in 2020/22 compared to previous seasons (p=0.001). Significant increases in VCR in both adults aged 65+ years and below 65 years at-risk were observed in France, UK and the US with +12.56% / +12.43% and +8.98% respectively (all p=0.001). Significant results were also observed in at-risk adults <65y with +7.17% (UK) and +23.58% (US). No significant changes were observed in any eligible groups in Canada, and VCR for Italy and Spain were not available at the time of the study. However, decreases in VCR were observed in 2021/22 compared to 2020/21, with -3.20% in overall VCR in France and -16.10% and -7.50% in the US for the ≥18y and ≥65y age groups respectively. Conclusions Significant augmentations in influenza VCR were observed during the 2020/22 seasons compared to the pre-COVID-19. However, drops in VCR were observed in multiple age groups and countries in 2021/22 compared to the previous season, potentially demonstrating early signs of vaccine fatigue across populations.	0	PMC9747407	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S218	latin-1	Value Health	2,022	10.1016/j.jval.2022.09.1065	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03311-3 10.1016/j.jval.2022.09.1106 Article EPH185 Increased Influenza Vaccine Coverage Rate Following COVID-19: Durable Trend or Epiphenomenon? Ngami A 1 Christie T 2 Guelfucci F 1 Bianic F 1 Net P 1 1Syneos Health, Montrouge, France 2Syneos health, Singapore, Singapore 14 12 2022 12 2022 14 12 2022 25 12 S226S226 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives The 2021/22 influenza season was still marked by the circulation of the Sars-CoV-2 responsible for the COVID-19 pandemic. Leveraging past research, we aimed at comparing pre and post-COVID-19 periods influenza vaccine coverage rate (VCR). We also explored the evolution of influenza VCR between the last two seasons. Methods We conducted secondary desk research to collect annual influenza VCR from the seasons 2010/11 to 2021/22 in France, Italy, Spain, UK, Canada and US. Government and public health agency websites were consulted and VCR were extracted for all populations eligible to influenza vaccination. We used non-parametric Wilcoxon signed-rank tests to investigate significant variations in VCR for the pooled 2020/22 seasons compared to previous seasons (overall and by age-group). We also looked at VCR evolution between the 2020/21 and 2021/22 seasons. Results Overall VCR in France increased by 12.26% in 2020/22 compared to previous seasons (p=0.001). Significant increases in VCR in both adults aged 65+ years and below 65 years at-risk were observed in France, UK and the US with +12.56% / +12.43% and +8.98% respectively (all p=0.001). Significant results were also observed in at-risk adults <65y with +7.17% (UK) and +23.58% (US). No significant changes were observed in any eligible groups in Canada, and VCR for Italy and Spain were not available at the time of the study. However, decreases in VCR were observed in 2021/22 compared to 2020/21, with -3.20% in overall VCR in France and -16.10% and -7.50% in the US for the ≥18y and ≥65y age groups respectively. Conclusions Significant augmentations in influenza VCR were observed during the 2020/22 seasons compared to the pre-COVID-19. However, drops in VCR were observed in multiple age groups and countries in 2021/22 compared to the previous season, potentially demonstrating early signs of vaccine fatigue across populations.	0	PMC9747408	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S168	latin-1	Value Health	2,022	10.1016/j.jval.2022.09.812	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)02326-9 10.1016/j.jval.2022.09.122 Article CO43 The Role of Different Biomarkers in the Prognosis of COVID-19 Infection Horváthné Galántai B 1 Ujszászi Z 1 Tímea S 2 Takács K 3 Boncz I 3 Varga B 2 Pakai A 4 József T 5 1Karolina Hospital-RI, Mosonmagyaróvár, Hungary 2University of Pécs, Kaposvár, Hungary 3University of Pécs, Pécs, Hungary 4University of Pécs, Pécs, ZA, Hungary 5University of Pécs, Kaposvár, SO, Hungary 14 12 2022 12 2022 14 12 2022 25 12 S25S25 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives To assess whether ferritin, D-dimer, and MDW results of COVID-19-positive patients are effective in judging the severity of the infection. Methods Our retrospective, quantitative, laboratory-based study was performed between February 18 and June 8, 2021, at Karolina Hospital of Mosonmagyaróvár, Hungary. Ferritin and D-dimer results were obtained from 464 patients 119 of them had MDW results in the database. Descriptive statistics, Kruskal-Wallis test with Post-hoc Bonferroni correction and one-sample Wilcoxon test (p<0.05) were calculated with Microsoft® Excel® and SPSS 23.0 software. Results Ferritin results’ median for discharged patients (n=177) was 364 ng/ml (IQR: 167-684), 755 ng/ml (IQR: 372-1261) for hospitalized ones (n=182), 755 ng/ml (IQR: 425-1506) for patients requiring intensive care or those who died (n=105) (p<0.001). Median MDW of the discharged (n=43) was 23.55 (IQR: 21.45-24.81), 26.16 (IQR: 24.28-27.32) for hospitalized (n=50), and 27.45 (IQR: 24.55-29.47) for patients in need of intensive care or died (n=26) (p<0.001). Median D-dimer for discharged was 696 ng/ml (IQR: 494-1026), 865 ng/ml (IQR: 672-1263), for the hospitalized, and 1,455 ng/ml (IQR: 1.191-3.049) for patients requiring intensive care or died. The discharged (p=0.005) and ITO (p<0.001) groups differed significantly. Ferritin results were grouped according to deviation from the reference value. Patients with normal ferritin level (n=58) spent 4.4 days in hospital, those with slightly elevated values (n=151) spent 4.61, patients with 3-5 times higher than the reference value (n=103) stayed 7.52 and patients with extra high ferritin levels (n=152) stayed 8.79 days (p<0.001). Average length of stay in the ICU were: 0.4 for patients with normal ferritin results, 0.8 for those who had it 1-3 times higher, 1.4 for those with 3-5 times higher, 1.6 for patients with the highest ferritin score (p<0.001). Conclusions D-dimer did not show significant differences, however, ferritin and MDW levels did among patients admitted to hospitals.	0	PMC9747409	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S25	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.122	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)02326-9 10.1016/j.jval.2022.09.122 Article CO43 The Role of Different Biomarkers in the Prognosis of COVID-19 Infection Horváthné Galántai B 1 Ujszászi Z 1 Tímea S 2 Takács K 3 Boncz I 3 Varga B 2 Pakai A 4 József T 5 1Karolina Hospital-RI, Mosonmagyaróvár, Hungary 2University of Pécs, Kaposvár, Hungary 3University of Pécs, Pécs, Hungary 4University of Pécs, Pécs, ZA, Hungary 5University of Pécs, Kaposvár, SO, Hungary 14 12 2022 12 2022 14 12 2022 25 12 S25S25 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives To assess whether ferritin, D-dimer, and MDW results of COVID-19-positive patients are effective in judging the severity of the infection. Methods Our retrospective, quantitative, laboratory-based study was performed between February 18 and June 8, 2021, at Karolina Hospital of Mosonmagyaróvár, Hungary. Ferritin and D-dimer results were obtained from 464 patients 119 of them had MDW results in the database. Descriptive statistics, Kruskal-Wallis test with Post-hoc Bonferroni correction and one-sample Wilcoxon test (p<0.05) were calculated with Microsoft® Excel® and SPSS 23.0 software. Results Ferritin results’ median for discharged patients (n=177) was 364 ng/ml (IQR: 167-684), 755 ng/ml (IQR: 372-1261) for hospitalized ones (n=182), 755 ng/ml (IQR: 425-1506) for patients requiring intensive care or those who died (n=105) (p<0.001). Median MDW of the discharged (n=43) was 23.55 (IQR: 21.45-24.81), 26.16 (IQR: 24.28-27.32) for hospitalized (n=50), and 27.45 (IQR: 24.55-29.47) for patients in need of intensive care or died (n=26) (p<0.001). Median D-dimer for discharged was 696 ng/ml (IQR: 494-1026), 865 ng/ml (IQR: 672-1263), for the hospitalized, and 1,455 ng/ml (IQR: 1.191-3.049) for patients requiring intensive care or died. The discharged (p=0.005) and ITO (p<0.001) groups differed significantly. Ferritin results were grouped according to deviation from the reference value. Patients with normal ferritin level (n=58) spent 4.4 days in hospital, those with slightly elevated values (n=151) spent 4.61, patients with 3-5 times higher than the reference value (n=103) stayed 7.52 and patients with extra high ferritin levels (n=152) stayed 8.79 days (p<0.001). Average length of stay in the ICU were: 0.4 for patients with normal ferritin results, 0.8 for those who had it 1-3 times higher, 1.4 for those with 3-5 times higher, 1.6 for patients with the highest ferritin score (p<0.001). Conclusions D-dimer did not show significant differences, however, ferritin and MDW levels did among patients admitted to hospitals.	0	PMC9747410	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S327-S328	latin-1	Value Health	2,022	10.1016/j.jval.2022.09.1618	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)02326-9 10.1016/j.jval.2022.09.122 Article CO43 The Role of Different Biomarkers in the Prognosis of COVID-19 Infection Horváthné Galántai B 1 Ujszászi Z 1 Tímea S 2 Takács K 3 Boncz I 3 Varga B 2 Pakai A 4 József T 5 1Karolina Hospital-RI, Mosonmagyaróvár, Hungary 2University of Pécs, Kaposvár, Hungary 3University of Pécs, Pécs, Hungary 4University of Pécs, Pécs, ZA, Hungary 5University of Pécs, Kaposvár, SO, Hungary 14 12 2022 12 2022 14 12 2022 25 12 S25S25 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives To assess whether ferritin, D-dimer, and MDW results of COVID-19-positive patients are effective in judging the severity of the infection. Methods Our retrospective, quantitative, laboratory-based study was performed between February 18 and June 8, 2021, at Karolina Hospital of Mosonmagyaróvár, Hungary. Ferritin and D-dimer results were obtained from 464 patients 119 of them had MDW results in the database. Descriptive statistics, Kruskal-Wallis test with Post-hoc Bonferroni correction and one-sample Wilcoxon test (p<0.05) were calculated with Microsoft® Excel® and SPSS 23.0 software. Results Ferritin results’ median for discharged patients (n=177) was 364 ng/ml (IQR: 167-684), 755 ng/ml (IQR: 372-1261) for hospitalized ones (n=182), 755 ng/ml (IQR: 425-1506) for patients requiring intensive care or those who died (n=105) (p<0.001). Median MDW of the discharged (n=43) was 23.55 (IQR: 21.45-24.81), 26.16 (IQR: 24.28-27.32) for hospitalized (n=50), and 27.45 (IQR: 24.55-29.47) for patients in need of intensive care or died (n=26) (p<0.001). Median D-dimer for discharged was 696 ng/ml (IQR: 494-1026), 865 ng/ml (IQR: 672-1263), for the hospitalized, and 1,455 ng/ml (IQR: 1.191-3.049) for patients requiring intensive care or died. The discharged (p=0.005) and ITO (p<0.001) groups differed significantly. Ferritin results were grouped according to deviation from the reference value. Patients with normal ferritin level (n=58) spent 4.4 days in hospital, those with slightly elevated values (n=151) spent 4.61, patients with 3-5 times higher than the reference value (n=103) stayed 7.52 and patients with extra high ferritin levels (n=152) stayed 8.79 days (p<0.001). Average length of stay in the ICU were: 0.4 for patients with normal ferritin results, 0.8 for those who had it 1-3 times higher, 1.4 for those with 3-5 times higher, 1.6 for patients with the highest ferritin score (p<0.001). Conclusions D-dimer did not show significant differences, however, ferritin and MDW levels did among patients admitted to hospitals.	0	PMC9747411	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S212	latin-1	Value Health	2,022	10.1016/j.jval.2022.09.1030	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03225-9 10.1016/j.jval.2022.09.1020 Article EPH99 Determinants of COVID-19 Vaccination in Hungary, Results of a Large Cross-Sectional Online Survey Beretzky Z 1 Xu FF 2 Brodszky V 1 1Corvinus University of Budapest, Department of Health Economics, Budapest, Hungary 2Corvinus University, Budapest, Hungary 14 12 2022 12 2022 14 12 2022 25 12 S210S210 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives Several different coronavirus (COVID-19) vaccines have already been authorized and distributed all over the world, including Hungary since December 2020, but vaccination rates and acceptance of the vaccines vary. We aimed to assess the factors influencing the acceptance of COVID-19 vaccinations. Methods We conducted a cross-sectional online questionnaire survey exploring the determinants of vaccination in May 2021. The survey included question on demographic and socio-demographics (such as age, gender, education, marital status, employment status, household size, monthly net household income, place of residence) factors, and respondents’ experience with COVID-19 infections and vaccination (registration was required in order to receive vaccination in Hungary). Results Altogether 2,000 respondents filled out our survey, with the average age of 49.1 (SD=15.3), out of whom 370 respondents (18.5%) stated that they already had a COVID-19 infection. Altogether 1374 (67.4%) respondents received at least the first dose of vaccine, while 106 (5.3%) have registered to be vaccinated, and 547 respondents (27.4%) did not get the vaccine nor register to be vaccinated. We found that higher income and residence in the capital or county seats were associated with a higher probability of vaccination. The rate of vaccination was higher in the group aged above 65 years (85.6% vs. 63.7%) and male respondents had a higher rate of vaccination (73.3% vs. 63.7%), suggesting that they might be more willing to accept the vaccine. We found that education also has significant impact on vaccine acceptance (58.2% vaccinated in primary education. 79.2% in the tertiary education group). Conclusions Sociodemographic factors, such as age, gender, level of education and income might have significantly influenced respondent’s probability of vaccination in Hungary.	0	PMC9747412	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S210	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.1020	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)04531-4 10.1016/j.jval.2022.09.2326 Article RWD101 Impact of COVID-19 Vaccination in Reducing Standard Hospitalization Cost Among COVID-19 Patients in the US – A Retrospective Study Roy A 1 Gupta A 1 Rastogi M 1 Sharma A 1 Verma V 2 Kukreja I 3 Gaur A 1 Chopra A 1 Nayyar A 1 Daral S 1 Pandey S 1 Mohanty P 1 Khandelwal H 1 1Optum, Gurugram, HR, India 2Optum, Gurgaon, HR, India 3Optum, New Delhi, DL, India 14 12 2022 12 2022 14 12 2022 25 12 S468S468 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives Hospitalization due to COVID-19 has huge implications for the patients and the government as it causes huge financial stress. The objective of this study is to analyze the impact of COVID-19 vaccination in reducing standard hospitalization costs among COVID-19 patients in the US. Methods In this retrospective study, Optum’s de-identified Clinformatics® Data Mart database was used to identify all the patients above 18 years who underwent treatment for COVID-19 in the US between 1 Jan 2021 to 30 Sep 2021. The occurrence of the ICD-10 code for COVID-19 infection in the claims database was defined as the index event. These patients were then checked for hospitalization for the treatment of COVID-19. The average length of stay and standard costs were compared between unvaccinated patients, and fully vaccinated patients (who had COVID-19 after 28 days of the second dose of the COVID-19 vaccine). Wilcoxon Whitney U test was applied to analyze the level of significance. Results Out of 277,319 COVID-19 patients, 274,165 (98.9%) were unvaccinated while 3,154 (1.1%) were fully vaccinated patients. The average length of stay among the unvaccinated (7.7 days) was statistically higher (p<.0001) as compared to fully vaccinated patients (7.2 days). Also, the mean standard costs among the unvaccinated ($39,328 for 120,727 patients) was statistically higher (p = .0009) as compared to fully vaccinated patients ($35,410 for 496 patients). Conclusions COVID-19 vaccines significantly reduced the average length of stay and standard hospitalization cost among the COVID-19 patients. Thus COVID-19 vaccines can reduce the burden on the healthcare system.	0	PMC9747413	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S468	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.2326	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)04531-4 10.1016/j.jval.2022.09.2326 Article RWD101 Impact of COVID-19 Vaccination in Reducing Standard Hospitalization Cost Among COVID-19 Patients in the US – A Retrospective Study Roy A 1 Gupta A 1 Rastogi M 1 Sharma A 1 Verma V 2 Kukreja I 3 Gaur A 1 Chopra A 1 Nayyar A 1 Daral S 1 Pandey S 1 Mohanty P 1 Khandelwal H 1 1Optum, Gurugram, HR, India 2Optum, Gurgaon, HR, India 3Optum, New Delhi, DL, India 14 12 2022 12 2022 14 12 2022 25 12 S468S468 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives Hospitalization due to COVID-19 has huge implications for the patients and the government as it causes huge financial stress. The objective of this study is to analyze the impact of COVID-19 vaccination in reducing standard hospitalization costs among COVID-19 patients in the US. Methods In this retrospective study, Optum’s de-identified Clinformatics® Data Mart database was used to identify all the patients above 18 years who underwent treatment for COVID-19 in the US between 1 Jan 2021 to 30 Sep 2021. The occurrence of the ICD-10 code for COVID-19 infection in the claims database was defined as the index event. These patients were then checked for hospitalization for the treatment of COVID-19. The average length of stay and standard costs were compared between unvaccinated patients, and fully vaccinated patients (who had COVID-19 after 28 days of the second dose of the COVID-19 vaccine). Wilcoxon Whitney U test was applied to analyze the level of significance. Results Out of 277,319 COVID-19 patients, 274,165 (98.9%) were unvaccinated while 3,154 (1.1%) were fully vaccinated patients. The average length of stay among the unvaccinated (7.7 days) was statistically higher (p<.0001) as compared to fully vaccinated patients (7.2 days). Also, the mean standard costs among the unvaccinated ($39,328 for 120,727 patients) was statistically higher (p = .0009) as compared to fully vaccinated patients ($35,410 for 496 patients). Conclusions COVID-19 vaccines significantly reduced the average length of stay and standard hospitalization cost among the COVID-19 patients. Thus COVID-19 vaccines can reduce the burden on the healthcare system.	0	PMC9747414	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S225	latin-1	Value Health	2,022	10.1016/j.jval.2022.09.1099	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03647-6 10.1016/j.jval.2022.09.1442 Article HSD99 Analysis of the Balanced Scorecard's Customer Subdimensions in Health Care Organizations During the COVID-19 Pandemic Amer F 1 Hammoud S 1 Khatatbeh H 2 Lohner S 2 Boncz I 2 Endrei D 2 1University of Pécs, Pécs, BA, Hungary 2University of Pécs, Pécs, Hungary 14 12 2022 12 2022 14 12 2022 25 12 S292S292 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives Customers in health include patients and health care workers (HCWs). We intended to review all the customer subdimensions used in balanced scorecard (BSC) implementations and then to assess the impact of the pandemic on the customer subdimensions at health care organizations (HCOs). Methods First, we performed a systematic review in accordance with PRISMA guidelines to find all customer key performance indicators (KPIs) used in BSC implementations from the time of inception until October 2020 in PubMed, Embase, Cochrane, Google Scholar databases, and Google's search engine. Second, we performed a search for independent studies using the resulting customer subdimensions with the COVID-19 keyword in Google engine and Google Scholar until June 2021. Results 161 customer KPIs were extracted from 36 implementations. Categorizing KPIs resulted into 3 major-dimensions and 12 subdimensions. In the next step, the patient centeredness major-dimension, patient satisfaction was not affected or was found to remain positive. Few studies have focused on assessing the psychological effects on patients. Patient complaints, loyalty assessment, and the psychological impact on non-COVID-19 patients still need more investigation. In the response to patients and communication major-dimension, physician–patient communication positively affected the patient's psychological status. However, using protective equipment during the pandemic could have imposed a barrier to effective communication. More research is still needed to improve and evaluate patient education programs, patient guidelines, counseling and consultation services, and communication between HCWs and patients during the pandemic. In HCWs’ centeredness major-dimension, HCWs’ satisfaction, burnout, stress, psychological support and motivation were found to be improved. Studies have suggested strategies to facilitate recruitment. Nevertheless, the HCW vaccination, engagement, motivation, teamwork, and loyalty subdimensions and their impact are still not well investigated during the pandemic. Conclusions Researchers are encouraged to analyze the pandemic impact on customer subdimensions, and to better focus on them in the future performance evaluations of HCOs.	0	PMC9747415	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S292	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.1442	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03194-1 10.1016/j.jval.2022.09.989 Article EPH67 Sleep Disorders, Depression, Anxiety, and Stress During the COVID-19 Pandemic Kovács L 1 Boncz I 2 Csákvári T 2 Kívés Z 3 1Veszprém County Government Office Balatonfüred, Tapolca, Hungary 2University of Pécs, Pécs, Hungary 3University of Pécs, PÉCS, BA, Hungary 14 12 2022 12 2022 14 12 2022 25 12 S204S204 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives The aim of our research is to define sleep disorders, depression, anxiety, and stress that can be associated with the coronavirus during the COVID-19 pandemic. Methods A cross-sectional analysis was carried out in 2021, by non-random sampling (n=222) in Hungary. We applied a questionnaire survey. Group of questions: socio-demographic variables, economic activity during the pandemic and quarantine, health behaviour. Validated questionnaires: Zung self-rating anxiety scale, COVID Stress Scale, Patient health questionnaire, Groningen Sleep Quality questionnaire. In addition to the descriptive statistical analysis χ2-test, Independent t-test, ANOVA were applied (p<0.05) with SPSS software. Results 18% of patients had moderate to severe depression and 5% had severe depression. Women (66.1%) have a significantly higher rate of depression (p=0.028) than men (33.9%). Physically active (14.3%) p=0.021) and non- or low-smokers had a lower rate of moderate to severe depression than those with no change in physical activity (63.4%) and less exercise (22%). 82.4% of respondents had normal and 17.6% had mild anxiety levels. 58.6% of respondents had sleep disorders. Among those without depression, there was a significantly (p<0.001) lower rate of sleep disorder (30% vs. 37.7%). According to the COVID-19 stress scale, the highest score is observed on the sub-scales for fear of danger (9.5) and related compulsion (7.8). Men (11.29) reported significantly (p<0.001) higher values on the coronavirus fear subscale (7.5) and the xenophobia subscale (3.8). On the subscale of compulsive checks, the stress score of women (7.39) was also significantly (p=0.009) lower than that of men (9.29). Conclusions Insomnia, anxiety, and depression were very common during the COVID-19 pandemic. Public health prevention programs are needed to prevent chronicity and reduce adverse outcomes.	0	PMC9747416	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S204	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.989	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03912-2 10.1016/j.jval.2022.09.1707 Article HTA250 Health Technology Assessment Policy and Guideline Changes in the EU-5 During the COVID-19 Pandemic Era: An Insight Into Trends and Drivers Ghosh S 1 Chatterjee M 2 1IQVIA, New Delhi, DL, India 2IQVIA, Gurgaon, India 14 12 2022 12 2022 14 12 2022 25 12 S345S345 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives Health technology assessment (HTA) bodies underwent policy and guideline rehaul during the recent COVID-19 pandemic with prioritised access being in the foreground. This research aimed to understand the trends in these updates adopted by the EU-5 HTA bodies. Methods A review of recent HTA agency guideline and policy decisions in the EU-5 [namely UK , France, Italy, Spain and Germany] was done using IQVIA™ ’s proprietary platform ‘HTA Accelerator’ from 01/Jan/2020 to 06/Jun/2022. Thorough hand-searching of these updates were made to understand the patterns of HTA guideline changes. Results 24 guidelines and policy updates were made during the above timeframe: 11 (France [HAS]); 2 (Spain [AEMPS, AETSA]) ; 2 (Italy [AIFA]); 4 (Germany [G-BA]) and 5 (UK [NICE, SMC]). In France, the guideline updates were mostly around performing economic evaluation, pricing rules and health benefits. While in Germany they were around adopting evaluation methods (assessments service quantity and quality; treatment durations in trial arms; and a concrete definition of clinical relevance). Also, G-BA clarified the procedure for collecting RWE for European medicines agency (EMA) approved orphan products under conditional marketing authorization or exceptional circumstances when the data is insufficient for a benefit assessment. A delayed dossier submission to facilitate "rolling review procedure" was initiated for all COVID-19 therapies. In the UK, a framework for RWE in HTA to encourage use of available data for informing NICE guidance. Also, EMA and the European Network for Health Technology Assessment (EUnetHTA) 21 consortium have published a joint work plan to implement the European HTA Regulation in January 2025. While changes by the Italian and Spanish HTA bodies mainly concerned with creating HTA network, pricing and reimbursement decree. Conclusions Emphasis on dissemination of RWE data remained mainstay for the updates. Pertaining to the pandemic, specialized delayed dossier submission policy for COVID-19 targeted therapies was also noteworthy.	0	PMC9747417	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S345	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.1707	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03912-2 10.1016/j.jval.2022.09.1707 Article HTA250 Health Technology Assessment Policy and Guideline Changes in the EU-5 During the COVID-19 Pandemic Era: An Insight Into Trends and Drivers Ghosh S 1 Chatterjee M 2 1IQVIA, New Delhi, DL, India 2IQVIA, Gurgaon, India 14 12 2022 12 2022 14 12 2022 25 12 S345S345 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives Health technology assessment (HTA) bodies underwent policy and guideline rehaul during the recent COVID-19 pandemic with prioritised access being in the foreground. This research aimed to understand the trends in these updates adopted by the EU-5 HTA bodies. Methods A review of recent HTA agency guideline and policy decisions in the EU-5 [namely UK , France, Italy, Spain and Germany] was done using IQVIA™ ’s proprietary platform ‘HTA Accelerator’ from 01/Jan/2020 to 06/Jun/2022. Thorough hand-searching of these updates were made to understand the patterns of HTA guideline changes. Results 24 guidelines and policy updates were made during the above timeframe: 11 (France [HAS]); 2 (Spain [AEMPS, AETSA]) ; 2 (Italy [AIFA]); 4 (Germany [G-BA]) and 5 (UK [NICE, SMC]). In France, the guideline updates were mostly around performing economic evaluation, pricing rules and health benefits. While in Germany they were around adopting evaluation methods (assessments service quantity and quality; treatment durations in trial arms; and a concrete definition of clinical relevance). Also, G-BA clarified the procedure for collecting RWE for European medicines agency (EMA) approved orphan products under conditional marketing authorization or exceptional circumstances when the data is insufficient for a benefit assessment. A delayed dossier submission to facilitate "rolling review procedure" was initiated for all COVID-19 therapies. In the UK, a framework for RWE in HTA to encourage use of available data for informing NICE guidance. Also, EMA and the European Network for Health Technology Assessment (EUnetHTA) 21 consortium have published a joint work plan to implement the European HTA Regulation in January 2025. While changes by the Italian and Spanish HTA bodies mainly concerned with creating HTA network, pricing and reimbursement decree. Conclusions Emphasis on dissemination of RWE data remained mainstay for the updates. Pertaining to the pandemic, specialized delayed dossier submission policy for COVID-19 targeted therapies was also noteworthy.	0	PMC9747418	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S204	latin-1	Value Health	2,022	10.1016/j.jval.2022.09.990	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03915-8 10.1016/j.jval.2022.09.1710 Article HTA253 Payer Perspectives on the Impact of the COVID-19 Pandemic on Health Technology Assessments (HTA) in Europe Hutcheson R Agrawal M Singh S Vishwakarma R Chaupin A Market Access Transformation, Fleet, UK 14 12 2022 12 2022 14 12 2022 25 12 S346S346 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives The COVID-19 pandemic has had a tremendous impact on healthcare systems, economies, and many aspects of everyday life. The core objectives of this research were to assess the impact that the pandemic has had on HTA assessments in Europe, outline key issues faced by payers, and determine payers’ outlook on future implications. Methods A qualitative, web-based survey was fielded via the Rapid Payer ResponseTM online portal (RPR®) to 15 current payers with experience in market access and reimbursement from the UK (NICE, NHS, CCG), Germany (G-BA, KV), France (CNEDiMTS, CT), Italy (AIFA, regional), and Spain (AEMPS, CIPM, MSSSI/MoH). Results 9/15 (60%) payers expressed that the pandemic resulted in delays in HTA assessments, with an average delay of 6 to 12 months. German payers did not experience delays, noting that timelines are regulated by law. Delays in the other countries resulted in fewer completed HTA assessments per year compared to pre-pandemic years for 7/15 (47%) payers, with 6/15 (40%) feeling that access to medicines during the pandemic was impacted. Key challenges expressed by payers included clinical trial delays, de-prioritisation of non-COVID diagnoses or care, tighter healthcare budgets, and lack of staff due to COVID-related leave or re-allocations. 7/15 (47%) payers have already experienced or anticipate a quick return to pre-pandemic conditions, whereas the other 8/15 (53%) expect long-lasting effects on HTA and access in the coming years. Payers noted that pharmaceutical manufacturers could better support the HTA process by increasing preparedness and transparency, prioritising agents for review, and meeting more rigorous clinical trial design and evidence expectations. Conclusions Payers across all scope countries except Germany conveyed that the COVID-19 pandemic has had a significant impact on HTA assessments, which may have longer-lasting implications. Close collaboration and alignment between pharmaceutical manufacturers and HTA bodies may allow for a more efficient recovery.	0	PMC9747419	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S346	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.1710	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)04497-7 10.1016/j.jval.2022.09.2292 Article RWD67 Association of COVID-19 With Venous Thrombosis and Arterial Thrombosis Pandey S 1 Markan R 1 Kumar S 1 Sharma A 1 Roy A 1 Verma V 2 Kukreja I 3 Gaur A 1 Chopra A 1 Nayyar A 1 Daral S 1 1Optum, Gurugram, HR, India 2Optum, Gurgaon, HR, India 3Optum, New Delhi, DL, India 14 12 2022 12 2022 14 12 2022 25 12 S461S461 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives Management of COVID-19 infection is evolving with the understanding of the disease. There is well-established literature pointing towards the increased coagulation risk associated with COVID-19. This study compares the relative coagulation risk between the COVID-19 and influenza patients. This study aims to analyze the risk of venous thrombosis and arterial thrombosis because of COVID-19 as compared with influenza. Methods In this retrospective study, Optum’s de-identified Market Clarity dataset was used to identify two cohorts of adult (>18 years) patients: 1. diagnosed with COVID-19 (index) between 1 April 2020 to 31 March 2021; 2. influenza patients diagnosed (index) between 1 April 2019 to 31 March 2020 based on the ICD-10-CM codes. The patients should have continuous enrollment for 12 months post- and 3 months pre-index. In the post-index period, outcomes of arterial thrombosis and venous thrombosis were assessed. Propensity scores matching (PSM) were calculated using age, gender, and clinical conditions. Odds ratios at 95% CI were calculated and Z test was used to calculate statistical significance. Results There were 201,568 patients with COVID-19 and 257,431 patients with influenza. COVID-19 patients had a higher risk of both venous thromboembolic risk (OR 1.44, 95% CI 1.35-1.53; P < 0.0001) and arterial thromboembolic risk (OR 1.04, 95% CI 1.01-1.08; p = 0.0067) as compared with the influenza patients. Conclusions The study shows that COVID-19 is associated with a higher risk for both venous thrombosis and arterial thrombosis as compared to influenza. This study may help to better understand the risk for both venous thrombosis and arterial thrombosis associated with COVID-19.	0	PMC9747420	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S461	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.2292	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03217-X 10.1016/j.jval.2022.09.1012 Article EPH91 Association Between Mental Disorders and COVID-19 Outcomes in Hospitalized Patients in France: A Retrospective Nationwide Population-Based Study Descamps A 1 Frenkiel J 2 Zarca K 2 Laïdi C 3 Godin O 3 Launay O 4 Leboyer M 3 Durand-Zaleski I 5 1Université de Paris, Inserm CIC 1417, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, CIC Cochin Pasteur, Paris, 75, France 2DRCI-URC Eco Ile-de-France (AP-HP), Assistance Publique-Hôpitaux de Paris, Paris, France 3Université Paris Est Créteil, Inserm U955, IMRB, Translational Neuro-Psychiatry, Créteil, France 4Université de Paris, Inserm CIC 1417, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, CIC Cochin Pasteur, Paris, France 5DRCI-URC Eco Ile-de-France (AP-HP), Assistance Publique-Hôpitaux de Paris, Paris, 75, France 14 12 2022 12 2022 14 12 2022 25 12 S208S208 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives Mental disorders are at-risk of severe COVID-19 outcomes. There is limited and heterogeneous national data in hospital settings evaluating the risks associated with any pre-existing mental disorder, and susceptible subgroups. Our study aimed to investigate the association between pre-existing psychiatric disorders and outcomes of adults hospitalised for COVID-19. Methods We used data obtained from the French national hospital database linked to the state-level psychiatric registry. The primary outcome was 30-days in-hospital mortality. Secondary outcomes were to compare the length of hospital stay, Intensive Care Unit (ICU) admission and ICU length. Propensity score matching analysis was used to control for COVID-19 confounding factors between patients with or without mental disorder and stratified by psychiatric subgroups. Results Among 97,302 adults hospitalised for COVID-19 from March to September 2020, 10,083 (10.3%) had a pre-existing mental disorder, mainly dementia (3,581 [3.7%]), mood disorders (1,298 [1.3%]), anxiety disorders (995 [1.0%]), psychoactive substance use disorders (960 [1.0%]), and psychotic disorders (866 [0.9%]). In propensity-matched analysis, 30-days in-hospital mortality was increased among those with at least one pre-existing mental disorder (hazard ratio (HR) 1.15, 95% CI 1.08–1.23), psychotic disorder (1.90, 1.24–2.90), mood disorder (1.19, 1.00–1.42) and psychoactive substance disorders (1.53, 1.10–2.14). The odds of ICU admission were consistently decreased for patients with any pre-existing mental disorder (OR 0.83, 95% CI 0.76–0.92) and for those with dementia (0.64, 0.53–0.76). Conclusions Pre-existing mental disorders were independently associated with in-hospital mortality. These findings underscore the important need for adequate care and targeted interventions for at-risk individuals with severe mental illness.	0	PMC9747421	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S208	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.1012	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03641-5 10.1016/j.jval.2022.09.1436 Article HSD93 Investigating the Impact of COVID-19 on Haemodialysis Rice CT 1 Unal GA 1 João Carvalho S 1 Davidson J 2 1Corevitas, London, UK 2Corevitas, London, LON, UK 14 12 2022 12 2022 14 12 2022 25 12 S291S291 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives COVID-19 impacted the provision of routine healthcare services, including life-extending measures such as haemodialysis provision among people with chronic kidney disease (CKD). We aimed to assess changes in haemodialysis provision before and after the emergence of COVID-19. We considered whether COVID-19 impacted haemodialysis access procedures specifically surgical creation of an arteriovenous fistula, as is best practice for delivery of haemodialysis, or insertion of a temporary or tunnelled dialysis access catheter. Methods Using an England-wide reimbursement secondary care dataset, the Hospital Episodes Statistics, we identified all patients with CKD stage 5 or kidney failure, and a record of haemodialysis. We excluded patients who received a kidney transplant. We then used a binary classification of before (01/01/2018 – 31/12/2021) and after (01/01/2020 – 31/12/2021) the emergence of COVID-19 to classify when patients commenced dialysis. We compared number of patients whose treatment was initiated via a fistula or a dialysis access catheter using ꭕ2 testing. Results We found a 40% reduction in the number of patients with CKD5 or kidney failure receiving haemodialysis after the emergence of COVID-19 compared with before (8,595 vs 14,406, respectively). We observed a corresponding 42% decrease in the number of recorded dialysis sessions before and after COVID-19. However, there was no statistical difference in the proportion of new patients receiving their initial dialysis by dialysis access catheter compared with fistula, 2.5% of new patients with a record of access procedure had initial dialysis via a dialysis access catheter before the COVID-19 pandemic, compared with 1.8% after (p=0.42). Conclusions The number of dialysis access procedures did not fall following COVID-19 onset. However, the number of patients receiving dialysis was proportionally reduced. Further investigation is necessary to determine the reason, such as excess deaths of those with kidney failure or changes in patient risk attitudes to in facility treatments.	0	PMC9747422	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S291	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.1436	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)04613-7 10.1016/j.jval.2022.09.2408 Article SA14 Clinical Evidence on Corticosteroid Treatment Reported in the First Year of the COVID-19 Pandemic – Comparison of Clinical Trial Publications and Treatment Recommendation Wüstner S 1 Hogger S 2 Gartner-Freyer D 3 Friederich A 4 Schley K 5 Leverkus F 6 1AMS Advanced Medical Services GmbH, Munich, Germany 2AMS Advanced Medical Services GmbH, Mannheim, Germany 3Novartis Pharma GmbH, Nuernberg, Germany 4Amgen GmbH, Munich, Germany 5Pfizer Deutschland GmbH, Berlin, BE, Germany 6Pfizer Deutschland GmbH, Berlin, Germany 14 12 2022 12 2022 14 12 2022 25 12 S485S485 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives In the beginning of the COVID-19 pandemic, health care systems were under tremendous pressure, and unprecedented efforts were made to generate evidence on effective and safe treatment options. At that time, mainly repurposed drugs such as corticosteroids were available. We aimed to analyze factors that characterize successful evidence generation and to identify study types that had the greatest impact on treatment recommendations. Methods A systematic literature search was conducted to identify clinical study publications with hospitalized COVID-19 patients treated with corticosteroids. To infer the impact of clinical data from different types of studies on patient care, we analyzed their inclusion in the form of direct and indirect references in treatment guidelines over time. Results We found that initially a large number observational studies were initiated, most of them retrospective cohort studies based on real word data. The majority of observational studies used statistical methods to control confounding, such as multivariate models or propensity score methods. Then large adaptive platform trials or coordinated meta-analyses of RCTs provided the best available clinical evidence to support treatment recommendations in a timely manner. With respect to sample size, patients enrolled in RCTs and especially in platform trials contributed disproportionately more to evidence based decision-making than patients observed in observational studies. Conclusions From our analysis, we derived factors characterizing studies and analyses that contributed most to inform treatment guidelines, which can support pre-planning and streamlining future approaches. Using real world data as a basis for observational studies allows to gain sufficiently large sample size and provide fast data collection and analysis. With respect to RCT, multi-arm platform trials with master protocols and coordinated meta-analyses proved particularly successful. This was best achieved when networks and structures were already in place. Part of the analysis from this abstract was published in Front. Public Health on 18 February 2022 (https://doi.org/10.3389/fpubh.2022.804404).	0	PMC9747423	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S485	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.2408	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)04464-3 10.1016/j.jval.2022.09.2259 Article RWD34 Comparison of ICU/Ventilator Usage Among Vaccinated and Unvaccinated COVID-19 Patients Roy A 1 Gupta A 1 Rastogi M 1 Verma V 2 Kukreja I 3 Gaur A 1 Chopra A 1 Nayyar A 1 Daral S 1 Pandey S 1 Mohanty P 1 Anand S 1 Dwivedi P 1 1Optum, Gurugram, HR, India 2Optum, Gurgaon, HR, India 3Optum, New Delhi, DL, India 14 12 2022 12 2022 14 12 2022 25 12 S454S454 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives The objective of this study is to analyze the impact of COVID-19 vaccination in reducing standard hospitalization costs among COVID-19 patients in the US who required admission to the ICU or usage of ventilators. Methods In this retrospective study, Optum’s de-identified Clinformatics® Data Mart database was used to identify all the patients above 18 years who underwent treatment for COVID-19 in the US between 1 Jan 2021 to 30 Sep 2021. The occurrence of the ICD-10 code for COVID-19 infection in the claims database was defined as the index event. These patients were then checked for admission to the ICU or usage of ventilators. The average length of stay and standard costs were compared between unvaccinated patients, and fully vaccinated patients (who had COVID-19 after 28 days of the second dose of the COVID-19 vaccine). Wilcoxon Whitney U test was applied to analyze the level of significance. Results Out of 76,320 COVID-19 patients who required admission to the ICU or usage of ventilators, 75,839 (99.4%) were unvaccinated while 481 (0.4%) were fully vaccinated patients. The average length of stay among the unvaccinated (11.2 days) was significantly higher (p<.0001) as compared to fully vaccinated patients (8.8 days). Also, the mean standard costs among the unvaccinated ($30,025 for 49,724 patients) was significantly higher (p = .03) as compared to fully vaccinated patients ($23,170 for 205 patients). Conclusions COVID-19 vaccines significantly reduced the average length of stay and standard hospitalization cost among the COVID-19 patients who required admission to the ICU or usage of ventilators.	0	PMC9747424	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S454	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.2259	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)02638-9 10.1016/j.jval.2022.09.434 Article EE184 Assessing the Cost-Effectiveness of the Novavax COVID-19 Vaccine as a Potential Booster Vaccine Option for Adults in the United States Paret K 1 Beyhaghi H 2 Herring W 3 Rousculp M 4 Toback S 5 Mauskopf J 1 1RTI Health Solutions, Research Triangle Park, NC, USA 2Novavax, Inc., Durham, NC, USA 3RTI Health Solutions, Durham, NC, USA 4Novavax, Inc., Cary, NC, USA 5Novavax, Inc., Gaithersburg, MD, USA 14 12 2022 12 2022 14 12 2022 25 12 S89S89 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives The introduction of the Novavax vaccine to the coronavirus disease 2019 (COVID-19) vaccine market has the potential to increase vaccine coverage in the United States (US), where coverage has lagged compared with other high-income countries. This modeling study estimated the cost-effectiveness of including the Novavax vaccine as a potential booster vaccine option for previously vaccinated adults in the US. Methods A Markov model was developed to estimate COVID-19–related cases, hospitalizations, and deaths with and without the Novavax vaccine as a booster vaccine option. The model population included those boosted and those not boosted and was stratified by age, with health states including susceptible, detected infection, long COVID-19, and recovered. The severity of COVID-19 outcomes among detected infections was based on the highest level of care required. Booster vaccine efficacy was assumed to equal primary vaccine efficacy, sourced from published phase 3 clinical trials based primarily on the prototype variant. Efficacy was assumed to wane equally for all vaccines. Costs per dose were assumed to be equal for all booster vaccines. Other model parameters were sourced from published literature. We estimated the cost-effectiveness from a payer perspective (direct medical costs only) over a 1-year time horizon. Scenario analyses were conducted to investigate the impact of age, coverage assumptions, and analysis perspective on model outcomes. Results A 5% increase in booster vaccine coverage among a cohort of 100,000 adults eligible for booster vaccination, allocated to the Novavax vaccine market share, resulted in 20.00 quality-adjusted life-years (QALY) gained at an incremental cost of $2,082. The incremental cost-effectiveness ratio of adding the Novavax vaccine as a booster option was $104/QALY gained. Conclusions Our results suggest that including the Novavax vaccine as a potential COVID-19 booster option for adults in the US has the potential to be cost-effective across a variety of coverage and market share scenarios.	0	PMC9747425	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S89	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.434	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)02638-9 10.1016/j.jval.2022.09.434 Article EE184 Assessing the Cost-Effectiveness of the Novavax COVID-19 Vaccine as a Potential Booster Vaccine Option for Adults in the United States Paret K 1 Beyhaghi H 2 Herring W 3 Rousculp M 4 Toback S 5 Mauskopf J 1 1RTI Health Solutions, Research Triangle Park, NC, USA 2Novavax, Inc., Durham, NC, USA 3RTI Health Solutions, Durham, NC, USA 4Novavax, Inc., Cary, NC, USA 5Novavax, Inc., Gaithersburg, MD, USA 14 12 2022 12 2022 14 12 2022 25 12 S89S89 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives The introduction of the Novavax vaccine to the coronavirus disease 2019 (COVID-19) vaccine market has the potential to increase vaccine coverage in the United States (US), where coverage has lagged compared with other high-income countries. This modeling study estimated the cost-effectiveness of including the Novavax vaccine as a potential booster vaccine option for previously vaccinated adults in the US. Methods A Markov model was developed to estimate COVID-19–related cases, hospitalizations, and deaths with and without the Novavax vaccine as a booster vaccine option. The model population included those boosted and those not boosted and was stratified by age, with health states including susceptible, detected infection, long COVID-19, and recovered. The severity of COVID-19 outcomes among detected infections was based on the highest level of care required. Booster vaccine efficacy was assumed to equal primary vaccine efficacy, sourced from published phase 3 clinical trials based primarily on the prototype variant. Efficacy was assumed to wane equally for all vaccines. Costs per dose were assumed to be equal for all booster vaccines. Other model parameters were sourced from published literature. We estimated the cost-effectiveness from a payer perspective (direct medical costs only) over a 1-year time horizon. Scenario analyses were conducted to investigate the impact of age, coverage assumptions, and analysis perspective on model outcomes. Results A 5% increase in booster vaccine coverage among a cohort of 100,000 adults eligible for booster vaccination, allocated to the Novavax vaccine market share, resulted in 20.00 quality-adjusted life-years (QALY) gained at an incremental cost of $2,082. The incremental cost-effectiveness ratio of adding the Novavax vaccine as a booster option was $104/QALY gained. Conclusions Our results suggest that including the Novavax vaccine as a potential COVID-19 booster option for adults in the US has the potential to be cost-effective across a variety of coverage and market share scenarios.	0	PMC9747426	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S195	latin-1	Value Health	2,022	10.1016/j.jval.2022.09.946	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03547-1 10.1016/j.jval.2022.09.1342 Article HPR214 Challenges of Measuring Healthcare System Resilience Araja D Berkis U Riga Stradins University, Riga, Latvia 14 12 2022 12 2022 14 12 2022 25 12 S272S272 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives The term ‘healthcare system resilience’ becomes topical in strategies and policy planning documents around the world, particularly in the scope of the COVID-19 pandemic. United Nations General Assembly has defined resilience as ‘the ability of a system, community or society exposed to hazards to resist, absorb, accommodate, adapt to, transform and recover from the effects of a hazard in a timely and efficient manner, including through the preservation and restoration of its essential basic structures and functions through risk management.’ The aim of this conceptual paper was to highlight the contextual framework and principal indicators of the healthcare system resistance. Methods The literature review was performed, using PubMed, Web of Science, and Scopus databases. Results The results demonstrated that the concept of resilience was introduced to the health systems literature from the ecological sciences through an increased understanding of healthcare systems as complex adaptive systems. In this context, the idea of resilience can act as a useful tool to understand healthcare system dynamics. The ecological idea that strategies to enhance resilience can be based on absorptive, adaptive, or transformative domains depending on the impact and intensity of the crisis has been particularly impactful in the healthcare system resilience discourse. Previous research proposed to define the healthcare system resilience indicators within each of the World Health Organization’s six building blocks of the healthcare system. Conclusions The results of this study identified the research gap between theoretical framework and empirical experience in measuring the healthcare system resilience indicators and therefore provide suggestions for further research. Simultaneously, the question arises about the healthcare ecosystem as an expected future model of healthcare and its comparative level of readiness for resilience, considering issues - to strengthen the resilience of the existing model or transform it into a new, possibly more resilient perspective model.	0	PMC9747427	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S272	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.1342	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)03597-5 10.1016/j.jval.2022.09.1392 Article HSD49 Improving Influenza Vaccination Rates: Evaluation of Pharmacy Vaccination Model Project During COVID-19 Pandemic in Germany May U 1 Bauer C 2 Giulini-Limbach C 1 Pham TK 2 Schneider-Ziebe A 2 1Fresenius University of Applied Sciences, Wiesbaden, Germany 2May und Bauer – Konzepte im Gesundheitsmarkt GbR, Rheinbreitbach, Germany 14 12 2022 12 2022 14 12 2022 25 12 S283S283 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives COVID-19 has reinforced the need for pharmacist involvement to improve vaccination accessibility and rates in Germany. New legislation in March 2020 enabled model projects for influenza vaccination in German pharmacies, serving as a gateway for pharmacist-administration of other vaccines (e.g. COVID-19). The legislation demands a scientific evaluation of the model projects to decide on their inclusion in standard care. The first model project was initiated between the Pharmacists’ Association North Rhine and the health insurance company AOK Rhineland Hamburg in 2020. The authors were entrusted with the scientific evaluation to assess safety aspects and patient experience of influenza vaccination services in German pharmacies. Methods A patient questionnaire was developed. Patient survey results were collected and evaluated for the 2020/21 and 2021/22 influenza vaccination seasons. Results 420 patients from 33 pharmacies (2020/21) and 1,371 patients from 127 pharmacies (2021/22) across North Rhine-Westphalia participated in this model project. The vaccination service convinced 12% (2020/21) and 14% (2021/22) of patients who would not have been vaccinated without the pharmacy-led service and a further 13% (2020/21) and 16% (2021/22) were unsure. In 2020/21, no adverse reactions occurred. Three mild incidents were recorded and professionally handled without consequences in 2021/22. Patient satisfaction with pharmacy-led vaccinations was high (99%, 2020/21; 100%, 2021/22). Almost all patients would get vaccinated again at the pharmacy (98%, 2020/21; 99%, 2021/22) and many would get vaccinated against other illnesses (78%, 2020/21; 98%, 2021/22). Conclusions The model project evaluation demonstrates that pharmacy-led influenza vaccinations increase the vaccination rate and expand vaccination coverage to people who otherwise would not have been vaccinated. This is due to low-threshold access, high level of trust in pharmacists’ competence and high levels of safety. These positive findings supported the decision to allow pharmacists to vaccinate against COVID-19 and include pharmacy vaccinations in German standard care.	0	PMC9747428	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S283	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.1392	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)04410-2 10.1016/j.jval.2022.09.2205 Article PCR272 Attitudes Towards Coronavirus Vaccination Among the Hungarian Population Bernáth B 1 Szabó L 1 Zrínyi M 2 Ábrahám R 1 Kelemen G 1 Khatatbeh H 3 Boncz I 1 Pakai A 2 1University of Pécs, Pécs, Hungary 2University of Pécs, Pécs, ZA, Hungary 3University of Pécs, pecs, Hungary 14 12 2022 12 2022 14 12 2022 25 12 S443S443 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives A vaccine to combat pandemic COVID-19 is available and its widespread adoption is key to fighting the pandemic. The aim of our study is to assess the willingness of the Hungarian population to receive the COVID-19 vaccine. Methods Quantitative, descriptive, cross-sectional research was conducted between October and November 2021. The target group of the non-random convenience sampling was Hungarian residents. We excluded questionnaires that were filled in incorrectly. The data collection instrument was an online questionnaire designed to assess socio-demographic data, knowledge about coronavirus, and willingness to vaccinate. In addition to descriptive statistical analysis, a two-sample T-test and χ2-test were performed using SPSS software (p<0.05). Results Of the 1415 participants, 1193 were female, with an average age of 43.27±12.92 years. 79.9% of the respondents had requested the vaccination. Females (p<0.001), those living in the capital (p<0.001), those with 8 years of primary education or less (p<0.001) were more likely to have received the vaccine. There was a significant association between willingness to vaccinate and knowledge score about coronavirus (p<0.001). However, age did not influence vaccine uptake (p>0.05). Conclusions There was a generally positive attitude towards COVID-19 vaccination. We need to focus on messages about the safety of the vaccine and to ensure reliable professionals to provide information. Vaccination is our main form of protection against the pandemic, and we must make its promotion a priority. We can use our results and knowledge to spread the vaccine as a solution more widely.	0	PMC9747429	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S443	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.2205	oa_other
==== Front Value Health Value Health Value in Health 1098-3015 1524-4733 Published by Elsevier Inc. S1098-3015(22)04661-7 10.1016/j.jval.2022.09.2456 Article SA62 Impact of the COVID-19 Pandemic on Health Care Resource Utilisation and Costs in Asthma in England: A Population-Based Study Rothnie KJ 1 Tritton T 2 Han X 3 Holbrook T 2 Numbere B 1 Ford AF 2 Massey L 2 Fu Q 3 Hutchinson FM 4 Birch HJ 1 Leather D 5 Sharma R 1 Compton C 1 Ismaila AS 3 1Value Evidence and Outcomes, R&D Global Medical, GlaxoSmithKline, Brentford, Middlesex, UK 2Adelphi Real World, Bollington, Cheshire, UK 3Value Evidence and Outcomes, R&D Global Medical, GlaxoSmithKline, Collegeville, PA, USA 4Country Medical Office – United Kingdom and Ireland GlaxoSmithKline, Brentford, Middlesex, UK 5Global Medical Affairs, GlaxoSmithKline, London, UK 14 12 2022 12 2022 14 12 2022 25 12 S495S495 Copyright © 2022 Published by Elsevier Inc. 2022 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcObjectives Delivery of medical care for chronic diseases has been disrupted by the COVID-19 pandemic. We describe all-cause and asthma-related healthcare resource utilisation (HCRU) and costs among patients with asthma during the initial period of the COVID-19 pandemic in England. Methods This was a retrospective dynamic cohort study of English asthma patients aged ≥18 years, for the period from Mar 2019 until Aug 2020 using primary care and linked hospital data. We assessed monthly all-cause and asthma-related HCRU and total direct healthcare costs over the study period and compared the months of the early pandemic (April–Aug 2020) to prior years. Results In total, 823,645 asthma patients were included (mean [SD] age: 51.4 [17.7] years, 58.1% females). Mean monthly all-cause face-to-face primary care, secondary care outpatient, and inpatient admissions were lower in April 2020 compared with April 2019, with reductions of 70.2%, 38.5%, and 50.0%, respectively. Mean monthly all-cause telephone primary care consultations increased 270% between April 2019 and April 2020. Mean total all-cause healthcare costs were 35.9% lower in April 2020 compared with April 2019. Mean monthly asthma-related face to face primary care and inpatient admissions were lower in April 2020 compared with April 2019, with reductions of 66.7% and 50.0%, respectively. There was no difference in asthma-related outpatient attendances. Mean monthly asthma-related telephone primary care consultations increased 800% between April 2019 and April 2020. Mean total asthma-related healthcare costs were 45.7% lower in April 2020 compared with April 2019. The levels of healthcare interactions following April 2020 did not return to pre-pandemic levels by the end of the observation period. Conclusions All-cause and asthma-related primary care and inpatient admissions decreased among patients with asthma during the COVID-19 pandemic. Telemedicine became a more frequently used channel for accessing healthcare during the early pandemic for asthma patients. Funding GSK (214629).	0	PMC9747430	NO-CC CODE	2022-12-15 23:22:00	no	Value Health. 2022 Dec 14; 25(12):S495	utf-8	Value Health	2,022	10.1016/j.jval.2022.09.2456	oa_other

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