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Competing interests | The authors declare no competing interests. | PMC10122388 |
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References | PMC10122388 |
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Background | reperfusion injury | PRIMARY GRAFT DYSFUNCTION, HAND ISCHEMIA | Primary graft dysfunction (PGD) after lung transplantation (LuTx) contributes substantially to early postoperative morbidity. Both intraoperative transfusion of a large amount of blood products during the surgery and ischemia–reperfusion injury after allograft implantation play an important role in subsequent PGD development. | PMC9996868 |
Methods | reduction of blood loss, coagulopathy | SECONDARY, COAGULOPATHY | We have previously reported a randomized clinical trial of 67 patients where point of care (POC) targeted coagulopathy management and intraoperative administration of 5% albumin led to significant reduction of blood loss and blood product consumption during the lung transplantation surgery. A secondary analysis of the randomized clinical trial evaluating the effect of targeted coagulopathy management and intraoperative administration of 5% albumin on early lung allograft function after LuTx and 1-year survival was performed. | PMC9996868 |
Results | Compared to the patients in the control (non-POC) group, those in study (POC) group showed significantly superior graft function, represented by the Horowitz index (at 72 h after transplantation 402.87 vs 308.03 with | PMC9996868 |
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Conclusions | coagulopathy | COAGULOPATHY | Utilization of a POC targeted coagulopathy management combined with Albumin 5% as primary resuscitative fluid may improve early lung allograft function, provide better circulatory stability during the early post-operative period, and have potential to decrease the incidence of PGD without negative effect on 1-year survival. | PMC9996868 |
Trial registration | This clinical trial was registered at ClinicalTrials.gov (NCT03598907). | PMC9996868 |
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Keywords | PMC9996868 |
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Background | pulmonary opacities, end-stage lung disease, blood loss, ARDS, hypoxemia, bleeding/coagulopathy, coagulopathy, normovolemia | LUNG, BLOOD LOSS, COMPLICATION, CHRONIC LUNG ALLOGRAFT DYSFUNCTION, SECONDARY, COAGULOPATHY, ARDS | Lung transplantation (LuTx) remains the ultimate treatment for end-stage lung disease refractory to optimized medical therapy. Post-implantation, long-term outcomes are impaired by ongoing medical factors including chronic lung allograft dysfunction (CLAD). CLAD (and its phenotypes) represents a major complication that limits the 5-year survival to approximately 55% [PGD is defined by the presence of diffuse pulmonary opacities on thoracic imaging and various levels of hypoxemia without other identifiable causes developing in the first 72 h after lung allograft reperfusion [A reduction in blood loss during surgery and corresponding decrease in intraoperative transfusion of blood products can be achieved by utilizing intraoperative point of care (POC) targeted bleeding/coagulopathy management strategies such as rotational thromboelastometry (ROTEM), platelet function analyzer (PFA) or multiple electrode platelet aggregometry [Despite the abovementioned reduction in blood product transfusion, ongoing fluid resuscitation is necessary to maintain normovolemia during LuTx surgery. A few studies have described the potential benefits of 5% albumin solution administration for the treatment of patients with ARDS and during cardiac surgery [We present a secondary analysis of our randomized clinical trial evaluating the effect of POC coagulopathy management and intraoperative administration of 5% albumin as primary resuscitative fluid during LuTx surgery on early lung allograft function, incidence of PGD, and 1-year survival. | PMC9996868 |
Methods | PMC9996868 |
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Study design overview, surgical strategy and outcomes | blood loss, bleeding, coagulopathy, Coagulopathy | BLEEDING, LUNG, CLOT, COAGULOPATHY, BLOOD LOSS, LYSIS, SECONDARY, COAGULOPATHY, HEART | A secondary analysis of the Point of Care Management of Coagulopathy in Lung Transplantation trial (NCT03598907) was performed. This study was a single-site, prospective randomized controlled trial that examined the utilization of perioperative POC-targeted coagulopathy management in conjunction with 5% albumin solution and their effect on perioperative blood loss and consumption of blood products during LuTx. This study was approved by the institutional ethics committee (reference number EK-1402/17) and was registered in the clinical trial database at ClinicalTrials.gov (identifier number NCT03598907) prior to patient enrollment. All patients provided written informed consent for participation in the study before the LuTx procedure.As this was a pilot study, the projected number of patients to be recruited was estimated at 120 (planned for 4 years), and an a priori power analysis was not performed in this case. An interim analysis was planned after evaluation of approximately 60 patients (after 2 years). Patients were primarily randomized to two study groups – POC group and non-POC group. The perioperative anesthesia management strategy used for both the non-POC group and POC group has been described previously [Intravascular volume in this group was replaced with balanced crystalloid, non-albumin colloidal solutions such as 6% hydroxyethyl starch or 4% succinylated gelatin, and FFP. Median volume of balanced crystalloid solution and non-albumin colloidal solutions was 1000 ml (IQR 512.5; 987.5 – 1500) and 775 ml (IQR 500; 500 – 1000), respectively. Triggers to volume replacement in both POC and non-POC groups included circulatory stability expressed by dose of norepinephrine (µg/kg/min) and transesophageal echocardiography (TEE) assessment of decreased cardiac preload by left ventricular fractional area change in transgastric mid-papillary short axis view at 50% calculated veno-arterial extracorporeal membrane oxygenation (VA ECMO) flow. However, due to the limitations described of TEE as a sole intraoperative monitor of systemic volume during VA ECMO, monitors aiding in the assessment of ongoing resuscitation also included urine output and maintenance of pulsatility within systemic and pulmonary arterial waveforms [In the POC group, perioperative bleeding and coagulopathy were managed according to the POC methods performed at the beginning of the surgery, after reperfusion of the first implanted lung and at the end of the surgical procedure (Fig. ROTEM protocol for the diagnosis of coagulopathy and goal-directed therapy using EXTEM, FIBTEM, and APTEM. Abbreviations: A10: Amplitude at 10 min; CT: clotting time; IU: international unit; LI30, LI60: lysis index at 30 and 60 min, MCF: maximum clot firmness; ML: maximum lysis. Previously published in Durila M, Vajter J, Garaj M, Pollert L, Berousek J, Vachtenheim J, Jr., et al. Rotational thromboelastometry reduces blood loss and blood product usage after lung transplantation. J Heart Lung Transplant. 2021;40(7):631–41.Primary outcome for this secondary analysis was PGD development and grading during the first 72 h after lung transplantation. Measures of Horowitz index (P/F ratio; defined as arterial oxygen pressure (P | PMC9996868 |
Patient selection and enrollment | Coagulopathy | SECONDARY, LUNG, COAGULOPATHY | Patient selection and eligibility criteria for the current secondary analysis mirrored that of the Point of Care Management of Coagulopathy in Lung Transplantation trial and included patients who underwent LuTx at the University Hospital Motol between January 2018 and June 2020 [Randomization and detailed description of two randomized groups were described previously [Flow chart of the study population | PMC9996868 |
PGD definition | HEART, LUNG | The definition of PGD was based on the latest International Society for Heart and Lung Transplantation (ISHLT) recommendation and was recorded 2 h after ICU admission (time 0) and then 24 h (time 24), 48 h (time 48) and 72 h (time 72) after LuTx [ | PMC9996868 |
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Statistical analysis | Statistical analyses were performed with R statistical software, version 3.4.4 (available online at The Horowitz index was calculated at each tracked time point (0, 24, 48, 72 h), and the measured values were evaluated with Welch’s two-sample t-test. The maximum level of norepinephrine (µg/kg/min) during the first 24 h after LuTx was compared in both groups using Welch’s two-sample t-test. Postoperative ICU stay and mechanical ventilation duration was recorded and analyzed by Wilcoxon tests. Moreover, 1-year survival in both study groups was followed and survival rates were compared using log-rank tests. | PMC9996868 |
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Results | PMC9996868 |
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Study patients and study flow | blood loss | BLOOD LOSS | Patients were recruited during the period from January 2018 to June 2020, and based on the exclusion criteria, a total of 33/100 patients were excluded from the study. The non-POC group and POC group ultimately consisted of 36 and 31 patients, respectively. At this point, interim statistical analysis was performed, and the study was preliminarily terminated by the institutional review board because the results were significantly in favor of the POC approach, as significant decrease in perioperative blood loss and related decrease in blood products consumption was observed among the POC study group [Patients in the non-POC group were significantly older than patients in POC group (56.22 ± 9.05 vs 45.69 ± 16.54 years, Recipient and donor characteristics
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Primary graft dysfunction evaluation | Primary graft dysfunction, primary graft dysfunction | PRIMARY GRAFT DYSFUNCTION | The incidence of PGD development based on ISHLT criteria at each time point in the non-POC and POC groups is displayed in Table Primary graft dysfunction development in both groups in four tracked time periods. Data are presented as n (%)
Incidence of primary graft dysfunction after lung transplantation at 0, 24, 48 and 72 h after surgery. Abbreviations: PGD: primary graft dysfunction; POC: point of careIn both patient groups, PGD grades were dichotomized and analyzed into two categories according to their clinical relevance (PGD grade 0 – 1 vs PGD grade 2 – 3). Data are presented as n (%)
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Horowitz index evaluation | Table Horowitz index and its differences between the non-POC and POC group at each tracked time. The Horowitz index is defined as arterial oxygen pressure (P
Horowitz index at each time point (0, 24, 48, 72 h) after lung transplant surgery. Values are presented as the mean and 95% CI. Abbreviations: HI: Horowitz index; CI: confidence interval; POC: point of care | PMC9996868 |
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Norepinephrine dosage and albumin serum levels evaluation | The maximum single dose of norepinephrine (µg/kg/min) administered to every patient in both groups during the first 24 h was recorded. In the non-POC group and POC group, the maximum doses of norepinephrine were 0.379 and 0.193, respectively ( | PMC9996868 |
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Postoperative mechanical ventilation duration and length of ICU stay and 1-year survival | Duration of mechanical ventilation and length of ICU stay after LuTx surgery were decreased in POC group. However, this difference did not cross the boundary for statistical significance as shown in Table Duration of mechanical ventilation and length of intensive care unit stay after LuTx surgery in non-POC vs POC group
Kaplan Meier survival curve for patients in non-POC group (green line) vs POC group (red line). Abbreviations: POC: point of care | PMC9996868 |
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Discussion | bleeding, SIRS, intraoperative blood loss, blood loss, reperfusion injury, coagulopathy, Ischemia, TRALI | TRANSFUSION-RELATED ACUTE LUNG INJURY, BLEEDING, BLOOD LOSS, CYSTIC FIBROSIS, INTRAOPERATIVE BLOOD LOSS, COAGULOPATHY, ISCHEMIA | PGD negatively contributes to increased short-term and long-term morbidity and mortality after LuTx [Ischemia–reperfusion injury after lung allograft implantation has been shown to lead to PGD development [Transfusion of a large amount of blood products, especially FFP, to manage intraoperative blood loss during LuTx is an independent risk factor for PGD through transfusion-related acute lung injury (TRALI) [In our study, 5% albumin solution was used solely as volume replacement therapy in the POC group. Albumin is a medium-sized molecule with a molecular weight of 66–69 kDa and is the most abundant protein in human plasma (40 g/l out of a total of 70 g/l). Albumin is synthesized exclusively in the liver and plays an important role in numerous processes. For example, it serves as a major extracellular antioxidant and a major transporter in plasma, responsible for 75% of oncotic plasma pressure. Therefore, albumin solution is considered to be the standard colloidal resuscitation fluid [Fluid management during all types of surgical procedures affects postoperative outcomes [In our study, targeted coagulopathy management and 5% albumin solution administered exclusively as volume replacement therapy during LuTx surgery resulted in significant improvement in lung allograft function in the first postoperative 72 h in the POC study group compared to the non-POC study group measured by Horowitz index. This intervention also resulted in significant decrease of PGD grade 2–3 at time point 72 in POC group. This is of particular interest, as most studies examine the incidence of PGD grade 3 at 72 h. However, in our study there was no statistically significant difference in occurrence of PGD grade 3 between the non-POC and POC group at all tracked time points. Additionally, the mean value of the maximum norepinephrine level during the first 24 h after LuTx was found to be significantly decreased in the POC group. This finding supports the theory that albumin as volume replacement therapy during LuTx surgery may provide greater hemodynamic circulatory stability in the POC group during the first 24 h after surgery through both volume replacement and its hypothesized anti-inflammatory effect on the reduction in SIRS [Our study has several limitations that require rigorous and transparent discussion. First, a major limitation is that our study design contained two interventions in one study protocol (targeted coagulopathy management and 5% albumin in POC study group). As targeted coagulopathy management led to decrease of blood loss and blood products transfusion, the study was preliminarily terminated by the institutional review board due to positive results in favor of the POC approach. This preliminary termination resulted in a relatively small cohort size in each group, precluding further evaluation of effect of the second intervention in the study (5% albumin administration). Moreover, two interventions in one study protocol limits our ability to identify the precise extent of how either the first or second intervention contributed to the study results.Heterogeneity in the patient age distribution between the non-POC group, where patients were older, versus the POC group that contained a greater proportion of younger patients with cystic fibrosis was another limitation. This population difference is important to highlight, as a variety of etiology-based comorbidities can impact intraoperative management and outcomes [To the best of our knowledge, despite abovementioned limitations, the research presented herein represents the first clinical trial attempting to investigate the effect of the perioperative use of targeted bleeding and coagulopathy management combined with 5% albumin administration on lung allograft function after LuTx. Furthermore, our data provide a level of evidence suggesting albumin as an optimal choice for intraoperative resuscitation in lung transplantation that to date has been based on expert opinion in the literature. However, further investigation in this area is highly needed to provide deeper insight into potential beneficial effect of perioperative use of 5% albumin solely as volume replacement therapy during LuTx on PGD incidence. The authors suggest design future trial with 5% albumin solution administrated intraoperatively as the only intervention in study group. | PMC9996868 |
Conclusions | coagulopathy | COAGULOPATHY | The results of this study indicate that targeted coagulopathy management and 5% albumin solution solely used as volume replacement therapy during LuTx surgery may improve early lung allograft function, provide better circulatory stability during the early post-operative period, and have potential to decrease the incidence of PGD without negative effect on 1-year survival. However, further investigation is highly needed to provide deeper insight into mechanisms of potential beneficial effect of perioperative use of 5% albumin solely as volume replacement therapy during LuTx on PGD incidence, CLAD development, and long-term outcomes. | PMC9996868 |
Acknowledgements | Tomas | The authors thank all the anesthesiologists and intensivists involved in this study, especially Jaroslav Hylmar, Stanislav Novotny, Michaela Sekerasova, Tereza Krskova, Milan Grund, Jana Polaskova, Silvie Binterova, Vladimir Bicek, Martin Malosek, Jiri Roith, Vojtech Simecek, Jan Sindelar, Jiri Bures, Zdenek Havelka and Vlasta Vlasakova. The authors also thank all the surgeons involved in this study, especially Jan Simonek, Jiri Pozniak, Jan Kolarik and Monika Svorcova. The authors also thank all the perfusionists involved in this study, especially Tomas Smetak, Michal Hlavacek, Vojtech Veverka, Pavel Hedvicak, Pavol Kovac and Adam Necesany. The authors thank Irena Al Masani and Monika Peckova for help with the statistical analysis. | PMC9996868 |
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Authors’ contributions | JV and MD designed the study and collected the study data, JV, MD, JV Jr analyzed the data and wrote major part of the manuscript, JV, JV Jr, ZP, JB, TV, RL, AKM and MD participated in the performance of the research and/or substantially contributed to the writing of the manuscript. All authors edited the final manuscript. All authors read and approved the final manuscript. | PMC9996868 |
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Funding | This study was supported by the Ministry of Health, Czech Republic – Conceptual Development of Research Organization, Motol University Hospital, Prague, Czech Republic (No. 64203 and No. 6028). This work was supported by the institutional project Cooperatio Program, research area SURG. These funding agencies played no role in the analysis of the data or the preparation of this article. | PMC9996868 |
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Availability of data and materials | All data generated or analyzed in the current article are available from the corresponding author on reasonable request. | PMC9996868 |
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Declarations | PMC9996868 |
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Ethics approval and consent to participate | The study was approved by the ethical committee of University Hospital Motol with approval number EK-1402/17. Written informed consent was obtained from all included patients. The study was carried out in accordance with the declaration of Helsinki. | PMC9996868 |
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Consent for publication | Not applicable. | PMC9996868 |
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Competing interests | The authors declare that they have no competing interests. | PMC9996868 |
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References | PMC9996868 |
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Background | AF, heart disease | HEART DISEASE | AF is a widespread heart disease affecting the well-being of patients and their family members physically and psychologically. Supporting patients and their family members could potentially facilitate regaining family strength and improve HRQoL. | PMC10019651 |
Methods | Anxiety, Depression, Atrial Fibrillation | HEART, ATRIAL FIBRILLATION | Patients with newly diagnosed AF were randomised to standard care or additional family-focused intervention with change in global score of the Atrial Fibrillation Quality of Life Questionnaire (AFEQT) as primary outcome after six months’ follow-up. Secondary outcomes included the Hospital Anxiety and Depression Score, the European Heart Rhythm Association score, the Ice Expressive Family Functioning Questionnaire, and the Ice Family-Perceived Support Questionnaire (ICE-FPSQ). | PMC10019651 |
Results | SECONDARY | Sixty-eight patients received standard care (n = 35) or family focused intervention (n = 33). The median change at the six-month follow-up on the global AFEQT score was 4.17 (-1.46–9.17) in the control group and 5.83 (-2.5–30) in the intervention group, yielding a median difference of -1.67 (p = 0.500). Change in ICE-FPSQ showed significant positive scores in favour of intervention (p < 0.001); other secondary outcome changes were non-significant. | PMC10019651 |
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Conclusion | depression, anxiety | The family-focused intervention had a small positive but non-significant effect on HRQoL compared to standard care. To address the impact of AF on the patients and family members seems to improve anxiety and depression scores and perceived family support. | PMC10019651 |
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Data Availability | Data cannot be shared publicly because data contain potentially identifying or sensitive patient information. Agreggated data values are avaliable upon request from the first author. This is in accordance with "ethical and legal restrictions". It is in accordance with Danish legislation, here the Data Protection Act § 10, subsection 3, No. 3. If data is to be passed on, this must be approved by the data controller and the Danish Data Protection Authority (national supervisory authority in the area). Such a request for data access must be sent to the data controller (here it will be the project responsible for the research project), who may will be responsible for obtaining the necessary permits. Any other recuest regarding data can also be directed to this non-author contact. Rigshospitalet Forskningsjura Afsnit 11.41 Blegdamsvej 9 2100 København Ø Denmark. Tel:+45 29 35 67 99 Email: | PMC10019651 |
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Introduction | cardiac arrhythmia | ATRIAL FIBRILLATION (AF), CARDIAC ARRHYTHMIA | Atrial fibrillation (AF) is a widespread cardiac arrhythmia estimated to affect more than 20.9 million men and 12.6 million women worldwide [The European Society of Cardiology (ESC) guidelines recommend integrated AF care involving the family as a resource to ensure treatment compliance. Even so, the guidelines provide no instructions about how family involvement may be organised or facilitated in clinical practice [To our knowledge, no prior studies have examined the effect of a family-focused nursing intervention in patients with AF. Earlier intervention studies have focused on optimising treatment and adherence without focusing on the family [ | PMC10019651 |
Methods | PMC10019651 |
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Trial design | The study was designed as a non-pharmacological, prospective, randomised trial with parallel groups in which patients were followed and assigned to either usual care or usual care plus a family-focused intervention. Intervention patients received a two-hour family group session and from one to three sessions of family-focused conversations with nurses. The trial followed the CONSORT (Consolidated Standards of Reporting Trials) guidelines for non-pharmacological interventions [ | PMC10019651 |
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Setting and data collection | RECRUITMENT | Patients from two Danish university hospital out-patient clinics in the Capital Region of Denmark were screened consecutively for eligibility. Nurses from the clinics recruited patients and their family members when having a consultation with the patient in the outpatient clinic. The recruitment period was highly affected by the COVID-19 pandemic, which interrupted the study period due to the many lockdowns forcing the intervention to be paused repeatedly. The COVID-19 pandemic also challenged delivery of any interventions and care because patients and their families were allowed to visit the hospital only in acute cases from mid-March 2020 to mid-May 2020 and from December 2020 to January 2021. Furthermore, during the last six months of the intervention, patients and family members had to carry a face mask and comply with the distancing requirements of national COVID-19 guidelines. Because of COVID-19, many patients were afraid to visit the hospital, and several patients preferred telephone consultations or postponed their appointments. Therefore, the actual number of patients with AF and appointments in the out-patient clinic was lower than expected before COVID-19. Nevertheless, we found that patients and their families did not decline to participate in this study due to COVID-19; they were simply more careful when deciding when and how to receive care at the hospital.The inclusion criterion was recently diagnosed AF (< 6 months) according to the ESC guidelines [All patients were encouraged to identify a family member who would take part in the intervention. The concept of family was defined as Study data were collected and managed using Research Electronic Data Capture (REDCap) electronic data capture tools hosted in the Capital Region of Denmark [ | PMC10019651 |
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Conventional treatment | arrhythmia | CONCOMITANT DISEASE, ARRHYTHMIA | The two recruiting outpatient clinics had similar standard care programs for AF patients. According to existing guidelines, the intervention group and the control group both received standard medical treatment for patients with AF [The standard care and treatment program comprised at least one cardiologist consultation followed by at least one nurse consultation during which disease-specific information on AF was disseminated. The communication effort focused on informing the patient of the medication and treatment plans. All patients received information about anticoagulation treatment, other medical treatment of the arrhythmia and any relevant concomitant diseases, scheduled cardioversion and invasive catheter treatment, if needed. Patients were also offered attendance at the standard information program comprising a two-hour disease-specific group session for 8–10 AF patients during which an AF-specialised cardiology nurse informed about common elements of AF and treatments developed based on the ESC guidelines, and answered patients’ questions. The two-hour session focused on AF and its treatment. | PMC10019651 |
Family-focused intervention | The family-focused intervention was given in addition to the conventional treatment and care provided for patients with AF. The intervention was delivered based on the theoretical framework of family nursing, the Calgary Models and the Illness Belief Model [Patients and family members were offered the family-focused intervention according to their needs during a period of one to two months. Because the components in the intervention were tailored individually it was not possible to standardise the dose of the intervention. We did not exclude patients if they could not attend with a family member because the framework implicates a family perspective on how illness impacts the patients and the family, whether or not a family member is present [The family-focused intervention comprised of a two-hour group education and 1–3 family nursing therapeutic conversations (FNTCs) delivered within two months. The intervention was considered delivered when patients and family members had participated in minimum one element of the intervention components (two-hour group session and or minimum one FNTCs).Instead of a standard two-hour group education for patients with AF, intervention group families were first offered a two-hour educational family group session adapted to the theoretical framework of family nursing [ | PMC10019651 |
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The themes for the two-hour family educational group sessions. | AF: atrial fibrillationEach family was invited to participate in up to one to three 60-minute FNTC sessions depending on their needs. The FNTCs were based on the Calgary Family Assessment Models (CFAM) and the Calgary Family Intervention Models (CFIM) in which the whole family is considered the unit of assessment and intervention [ | PMC10019651 |
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Contents of FNTCs based on: | PMC10019651 |
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Adherence to the intervention | All FNTCs were digitally recorded, allowing the research team to evaluate if the family-focused intervention had been delivered as intended. In practice, this was done by the first author who revised 19 randomly selected recordings to establish if the components in | PMC10019651 |
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Outcomes | Anxiety Depression, Atrial Fibrillation | HEART, ATRIAL FIBRILLATION | The patients completed a set of self-reported questionnaires, tapping answers directly into the data management program REDCap using an Ipad before receiving the intervention and at a six-month follow-up visit. The baseline and follow-up visits were conducted in the out-patient clinic and facilitated by the first author who was available if patients and family members had any questions or experienced technical problems with the Ipad.The primary outcome was defined as a clinically relevant change of 11 points on the global score measured on the Atrial Fibrillation Effect on Quality of Life Questionnaire (AFEQT). Secondary outcomes were changes in the Hospital Anxiety Depression Scale (HADS), the European Heart Rhythm Association Scale (EHRA), the Ice Expressive Family Functioning (ICE-EFFQ), and the Ice Family Perceived Support (ICE-FPSQ). Additionally, we registered adherence to the intervention by counting how many family sessions the patients and their families attended. | PMC10019651 |
Measurements | depression, anxiety | CHRONIC ILLNESS | The AFEQT questionnaire is a self-administered disease-specific licensed and validated questionnaire sensitive to clinical changes in patients with AF [A high score, close to 100, indicates a high (good) HRQoL and a low score close to 0 a low HRQoL. Treatment satisfaction is not calculated in the overall global AFEQT score in the survey. Furthermore, for each domain (Symptoms, Daily activities, Treatment concerns and Treatment satisfaction) there is a corresponding subscale score, which also ranges from 0–100 (0 = worst and100 = best).The original questionnaire was generated with input from patients and was found to be feasible, reliable, valid and responsive to treatment [The HADS is licensed and validated in Danish to measure the level of depression and anxiety [The EHRA score is a well-known and validated practical semi-quantitative tool to measure relevant change in patients’ AF-related symptoms and perceptions of general state of health from the perspective of the patient [The ICE-EFFQ and the ICE-FPSQ are questionnaires that measure family functioning in families experiencing acute or chronic illness and patients and family members perceived support when offered family-focused in the healthcare system [ | PMC10019651 |
Sample size | A sample size of 50 patients in two arms (a total of 100 patients) was deemed sufficient for detection of an 11-point difference on the AFEQT with an expected standard deviation of 20, a power of 80% and a significance level of 0.05. Calculation was based on a two-sided independent two-sample t-test. When measuring HRQoL from a patient perspective an 6–19 point increase has been deemed to reflect a meaningful improvement in HRQoL measured by the AFEQT [ | PMC10019651 |
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Statistical analysis | Continuous variables are presented as mean with standard deviation (SD) or median with interquartile range (IQR) depending on distribution of the variable. Categorical variables are presented as counts and percentiles. The within group change was calculated as follow-up minus baseline and presented as median. The change difference was calculated as control minus intervention. Changes from baseline to follow-up between intervention and standard care group were tested using the Wilcoxon rank-sum test because the normality assumption of the distribution could not be satisfied. The normality assumption was evaluated using QQ plots and histograms.Given that the intervention is offered to the patients depending on their needs in order to mirror clinical practice, the analysis is considered intention to treat (ITT).To account for possible differences in baseline values between groups (see the Missing data were considered missing at random. No further imputation of missing values was made. Statistical significance was defined as a p-value below 0.05. All analyses were conducted using R version 3.6.1 [ | PMC10019651 |
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Ethical considerations | All patients and family members received written and oral information about the trial and gave written consent before participating [ | PMC10019651 |
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Results | The original plan was to recruit ten patients with a family member per month during a 12-month period from November 2019 (first patient recruited 28 | PMC10019651 |
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Consolidated standards of reporting trials (Consort) flowchart. | The mean age of the patients was 68 years in both groups. The intervention group (n = 33) counted 22 male patients and 11 female patients; the control group (n = 35), 22 male patients and 13 female patients. Patients’ AF symptoms varied considerably; from almost no symptoms to symptoms disabling their everyday life. Twenty-two of the enrolled intervention patients were accompanied by their spouses; four patients, by adult son or daughter; three patients, by a friend; and four patients attended alone because they had no family member who could accompany them. The groups were considered similar at baseline as no clinical difference was observed between the groups for the baseline variables, all patient characteristic at baseline are presented in | PMC10019651 |
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Baseline characteristics of randomised patients. | ATRIAL FIBRILLATION | *Baseline data are self-reported **Other antiarrhythmic drugs, e.g,. amiodarone.*AF: atrial fibrillation. BMI = Body Mass Index. *NOAC = Novel oral anticoagulation.All categorical variables are presented as frequencies with percentages.All continuous variables are presented as median with interquartile range. | PMC10019651 |
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Patient adherence to two- educational group session and number of FNTC´s. | *FNTC: family nursing therapeutic conversation*Adherence was calculated as how many elements each patient attended during the intervention period | PMC10019651 |
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Intervention effect on the primary outcome and secondary outcomes | At baseline, a difference was observed between the groups’ self-reported HRQoL measured on the global AFEQT score with a median score of 76.67 (61.67–80.83) in the control group versus 63.75 (47.50–78.54) in the intervention group. The median change at the six-month follow-up on the Global AFEQT score was 4.17 (-1.46–9.17) in the control group compared with 5.83 (-2.5–30) in the intervention group, yielding a median difference of -1.67 (CI = -9.77–2.27, p = 0.500). We did not find any significant changes within the subscales; however, we did observe a large variation within the intervention group compared to the control group based on interquartile ranges and CI’s (symptoms, daily activities, treatment concerns. See | PMC10019651 |
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Primary outcomes on AFEQT. | atrial fibrillation, depression, anxiety | ATRIAL FIBRILLATION | All estimates except change difference are presented as median with interquartile range, change difference presented as difference in median change with 95% confidence interval. AFEQT: atrial fibrillation Quality of life.*p values are based on Wilcoxon sum-rank test comparing control and intervention changeOutcomes on anxiety and depression showed decreased levels at follow-up for both groups, but the intervention group recorded a larger, but non-significant, decline in their scores (HADS-A: median change -3: -5.00 - -1.00) and (HADS-D: median change -1: -5.00–0.00). EHRA scores also decreased in both groups from 3 to 2 during the six-month follow-up. The ICE-EFFEQ showed positive, but non-significant, changes in all domains, except for communication with a difference in median change of -1.00 (CI = -2.94 –-1.00, p = 0.027). The ICE-FPSQ-total showed significant positive scores in all domains in favour of the intervention (all p < 0.001). See | PMC10019651 |
Secondary outcomes on the HADS, EHRA, ICE-EFFQ and ICE-FPSQ. | Depression, Anxiety | HEART, SENSITIVITY | All estimates except change difference are presented as median with interquartile range, change difference presented as difference in median change with 95% confidence interval.HADS: Hospital Anxiety and Depression Scale. EHRA score: European Heart Rhythm Association score. ICE-EFFQ: Ice Expressive Family Functioning. ICE-FPSQ: Ice Family Perceived Support questionnaire.Sensitivity analysis adjusting for baseline values showed a larger estimated difference on Global AFEQT score -4.21 (CI = -9.33–9.01, p = 0.910). The only estimate leading to a different interpretation of the result was for ICE-EFFEQ communication having a non-significant difference in median change -0.86 (CI = -1.80 –-0.021, p = 0.149). All estimates and p-values for adjusted analysis are presented in | PMC10019651 |
Discussion | depression, heart failure, insecurity, anxiety | HEART FAILURE, SECONDARY | No statistically significant improvement from the intervention was found for the six months change on Global AFEQT score, compared to standard care. Additionally, confidence intervals for the estimates were wide, giving a large uncertainty and making interpretation about the size of the difference hard. Adjustments for baseline values did result in a larger estimated difference, however the uncertainty for this estimate was even larger than the uncertainty for the unadjusted estimate and thereby not making interpretation of the result any easier. Because of this large uncertainty a possible relevant effect may be present, but it is not possible to answer from the data in this study.For secondary outcomes only ICE-FPSQ Cognitive, emotional and total score showed a significant difference and reasonable thin confidence intervals, indicating a possible difference might be present. This would have to be confirmed in another study. However, there is no consensus in literature og what constitutes a relevant change [Supportive of the possible future use of family-focused nursing as an integrated part of AF care and treatment, this intervention was shown to be feasible in an out-patient clinical setting even during the COVID-19 pandemic. Notably, approximately half of the eligible and approached patients and their families accepted participation in the study.According to Dorian et al., 18.9 increase in the global AFEQT score is considered a moderate improvement and 27.8 a large improvement [Results similar results to ours were observed in a randomised controlled study investigating the effect of nursing interventions targeting patients with heart failure and their family members; due to lack of power, this study detected no significant effect on HRQOL, anxiety or depression [Even though none of the patient in the control or intervention group had high scores on the HADS at baseline, we observed a decrease in anxiety and depression scores in both groups though the intervention group experienced more positive (50%) changes reflected in the AFEQT scores, which could be a clinical relevant change on HADS [Whether our results should pave the way for a more systematic use of family-focused intervention may be discussed with a focus on the evaluation method and the study context. The present study can be categorised as a complex intervention within the context of the healthcare system where multiple factors may influence outcomes, actions and behaviour of patients, families and health professionals [Other interventions targeting HRQoL in AF patients have used AFEQT to measure quality of life [Another relevant aspect to consider is that the family-focused intervention may potentially have affected other patient-reported outcomes than those we chose, e.g., emotional wellbeing and self-efficacy, which is the individual’s belief in his or her capacity to manage specific tasks and feeling self-confident [Nevertheless, we provided reflective space for expressing illness beliefs and insecurity among patients and their family members. The present study focused on patient-related outcomes. However, it could also have been designed to measure family member outcomes as well. Petursdottir et al. showed that a family therapeutic intervention yielded increased perceived support, decreased stress and reduced caregiving demands among the family members [ | PMC10019651 |
Strengths and limitations | SECONDARY, BLIND | The methodology of the study using an intervention group vs. a control group in a RCT design is a strength in order to avoid systematic errors and the intervention and the control group were not clinically different from each other in the descriptive baseline characteristics, possible differences were present for outcomes measures at baseline, however the sensitivity analysis showed this only impacted the result of a single secondary outcome. Due to COVID-19, the inclusion period was disrupted, and the patient inclusion rate was lower than expected. Thus, the study ended up being underpowered (control group n = 35; intervention group n = 33) for assessing the effect of the family-focused intervention on the AFEQT score. Furthermore the 11 point change on the AFEQT used in the sample size calculation could have been reduced to 5 [The generalisability of the study findings is limited due to the COVID-19 pandemic, resulting in patient receiving. intervention/standard care as early as intended, thereby impacting the effect of the intervention. Additionally, the pandemic probably affected the mental and physical well-being of the participating patients and their families. However, we expect that the negative effects of COVID- 19 have equally affected the intervention and control group. Because the intervention potentially allowed participants to only undergo one session in total there is a possibility that different participants received different amount of the intervention, which could introduce bias in the results. Furthermore, the intervention was delivered in the course of a year. The nurses might have improved their family-focused nursing skills during the trial, reducing the effect at the beginning of the trial, checked during the intervention this was not revealed as a problem. It was not possible to blind clinicians due to the nature of the intervention. Therefore, the open-label design of the study may have biased the results in favour of the intervention because the follow-up visit was conducted by the first author who also recruited patients and their family members. It was a strength in this study that all FNTCs were recorded digitally and 19 recordings were validated by the first author to confirm that the components of the intervention were delivered as intended and that the FNTCs were individualised and met families’ needs. An additional strength is that nurses delivering the family-focused intervention received the same skills training within a theoretical and practical, certified post-graduate training programme (Linné University, Sweden) with experienced teachers and examinations to conclude the course. Furthermore, both nurses were actively involved in the planning and development of the intervention, which enhanced ownership to the intervention. Given the complex nature of this trial and the mentioned limitations, our findings should be considered preliminary and should be interpreted with caution. The fact that patients in the intervention group in this sample had lower scores at baseline could indicate a positive effect of the intervention even though the study was underpowered. Therefore, results warrant examination in a higher-powered study. Furthermore, it could be relevant to broaden a future study to also measure the effect on the family members as well as the patient, which also could support knowledge of the effect of a family-focused approach. | PMC10019651 |
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Conclusion | Family-focused intervention did not show an improvement on the global AFEQT score compared to traditional treatment. However, given the large uncertainty of the estimates it is possible that relevant effects could be present, because of this no conclusive answer about this association can be made based on this study. | PMC10019651 |
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Supporting information | PMC10019651 |
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CONSORT 2010 checklist of information to include when reporting a randomised trial*. | RECRUITMENT | (DOC)Click here for additional data file.(DOCX)Click here for additional data file.(PDF)Click here for additional data file.The authors take this opportunity to express their gratitude to all patients and family members, to project nurses Marianne Nygaard Pedersen and Jennie Schier who delivered the family-focused intervention, to the nurses in the department who contributed with recruitment of patients and family members, and to the managers of the Department of Cardiology, Amager Hvidovre Hospital for supporting this study. | PMC10019651 |
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References | PMC10019651 |
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Background | This trial aimed to evaluate the anti-obesity effects and safety of Neoagaro-oligosaccharides (NAOs) in humans in a 16 week, randomized, double-blind, placebo-controlled clinical trial. | PMC10585797 |
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Methods | overweight or obese | One hundred overweight or obese subjects with a body mass index of 23 to 34.9 kg/m | PMC10585797 |
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Results | After 16 weeks of intervention, the group administered with NAOs had statistically significant decreases in visceral fat area and visceral-subcutaneous fat area ratio compared to the placebo group. The NAOs group suppressed the increase in weight and BMI compared to the placebo group, which was significant between groups. High-density lipoprotein- cholesterol was increased in the group administered with NAOs, which showed a significant trend compared to the placebo group. Clinical changes were not observed for any safety biomarkers. | PMC10585797 |
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Conclusions | obesity | OBESITY | These results suggest that NAOs have a beneficial effect on obesity. Thus, NAOs could be used as an anti-obesity supplement without side effects. | PMC10585797 |
Trial registration | cris.nih.go.kr: (KCT0006640, 07/10/2021). | PMC10585797 |
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Keywords | PMC10585797 |
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Methods | PMC10585797 |
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Study design | MAY | This 16-week, single-center, randomized, double-blind, placebo-controlled, parallel-group, clinical study was conducted at Wonkwang University Korean Medicine Hospital in Jeonju from August 2021 to May 2022. The study protocol and informed consent form were approved by the Institutional Review Board (IRB) of Wonkwang University Korean Medicine Hospital (IRB approval No.: WUJKMH-IRB-2021-0008). This study was registered with the Clinical Research Information Service (CRIS), the Republic of Korea (Participants were recruited through several ways (banner, newspaper, Wonkwang University Korean Medicine Hospital web page, and so on). A screening visit was conducted within two weeks of the first visit to select subjects who met the inclusion & exclusion criteria. After baseline evaluation, participants were randomly assigned to test and placebo groups at a 1:1 ratio. One hundred subjects received each product at each visit every eight weeks for three visits (visit 1: week 0; visit 2: week 8; and visit 3: week 16).During the 16-week study period, subjects were asked to maintain their usual lifestyle including dietary intake and physical activity. They were asked to avoid consuming other functional foods or dietary supplements. Efficacy and safety were evaluated before and after the study period. | PMC10585797 |
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Study subjects | obesity, hypersensitivity, diabetic, medicine abuse | OBESITY, HYPERSENSITIVITY, GASTROINTESTINAL DISEASE | One hundred participants were eligible after screening tests such as questionnaires, physical examinations, and laboratory examinations. They were enrolled within two weeks after providing informed consent and before they were given supplement.Inclusion criteria were as follows: (1) those aged between 19 and 65 years old on screening test; (2) those with a body mass index (BMI) ≤ 34.9 kg/m² but ≥ 23 kg/m², percent body fat (PBF) > 25% for males and PBF > 30% for females; and (3) those who provided written consent after being thoroughly educated about the study’s aims and goals.Exclusion criteria were as follows: (1) subjects with a weight change of 10% or more within 3 months prior to the screening test; (2) those who took supplement of medicines or health functional foods that might affect body weight within 1 month prior to the screening test; (3) subjects who had an obesity surgery within 1 year; (4) those with a clinically acute disease or chronic cardiovascular, endocrine, immune, respiratory, hepatobiliary, kidney, urinary, neuropsychiatric, musculoskeletal, inflammatory, hematological, or gastrointestinal disease; (5) diabetic patients who were treated with oral hypoglycemic agents or insulin on screening tests; (6) those with a history of clinically significant hypersensitivity to seaweed or agar; (7) those who were undergoing fasting therapies; (8) those who were administered with antipsychotics within 3 months prior to the screening test; (9) those with a history of medicine abuse; (10) those who participated in other human tests within three months prior to the screening test; 11) those who had the following diagnostic and medical test results: ☞ aspartate transaminase (AST) or alanine transaminase (ALT) > 3 times the upper limit of the reference range; ☞ serum creatinine > 2.0 mg/dL; 12) those who were pregnant or nursing; 13) subjects within 6 months of childbirth; 14) those who were fertile and not taking contraceptives; and 15) those who were judged by the principal investigator to be inappropriate for participation in this study because of laboratory test results and so on. | PMC10585797 |
Study products | Test products used in this study were provided by Dyne Bio Inc.(Sungnam, Korea). As described in previous studies [
Representative chromatograms of NAOs based on high-performance liquid chromatography (HPLC) analysis of Neoagarotetraose (DP4) and Neoagarohexaose (DP6)The 3 g/day dose is based on our preclinical studies [All subjects were randomly assigned to a group administered with NAOs (3 g/day of NAOs) or a placebo group (0 g/day of NAOs). Subjects took 3 g per day (twice after breakfast and dinner, four capsules once) for 16 weeks. The placebo capsules contained corn starch with the same weight, energy, carbohydrate content and appearance as the test capsules (Table
Composition of the test productsNAOs, Neoagaro-oligosaccharides | PMC10585797 |
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Efficacy outcome measurements | All subjects were subjected to efficacy evaluation before and after intake for 16 weeks during the study period. To measure abdominal fat area, subjects underwent a computed tomography (CT; WCT-200-140, Hispeed Dual) scan. Ab-dominal fat CT scans were taken with subjects lying on their backs. Total abdominal fat area (TFA), visceral fat area (VFA), and subcutaneous fat area (SFA) were measured, and the visceral-subcutaneous fat area ratio (VSR) was calculated. The same machine was used throughout the study period to evaluate changes in anthropometric parameters, including body weight, body mass index (BMI; kg/m | PMC10585797 |
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Safety Outcome measurements | ADVERSE EVENTS, BLOOD | To evaluate safety, all adverse events (AEs) were monitored. Laboratory tests, urinalysis, vital signs, and electrocardiograms were performed before and after 16 weeks of administration. Laboratory tests included hematological tests [white blood cell (WBC), red blood cell (RBC), hemoglobin, hematocrit, platelets] and blood bio-chemical tests [alkaline phosphatase (ALP), AST, ALT, total bilirubin, total protein, albumin, gamma-glutamyl transferase (gamma-GT), blood urea nitrogen (BUN), creatinine, glucose, lactate dehy-drogenase (LD), creatine kinase (CK), high sensitivity C-reactive protein (hs-CRP)]. Blood was collected after fasting for 12 h. Urinalysis measures specific gravity and pH in urine. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse were measured to evaluate vital signs. | PMC10585797 |
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Dietary intake and physical activity assessment | During the study period, subjects maintained their usual dietary intake. Changes in dietary intake were evaluated through a standardized 3-day dietary record (2 days on weekdays, 1 day on weekends). Dietary intake was analyzed by a trained dietitian. Total daily intakes of energy, carbohydrates, lipids, protein, and fiber were analyzed using a Computer-Aided Nutritional analysis program (CAN-pro, Korean Nutrition Society, Seoul).Subjects were asked to maintain their usual physical activity during the study period. Changes in physical activity were measured according to activity using a global physical activity questionnaire (GPAQ). GPAQ is a questionnaire that measures physical activity in three domains, including work (vigorous-to-moderate intensity activity for more than 10 min for daily work-related activities), transport (activities such as cycling and walking for more than 10 min for movement of place), and recreation (vigorous-to-moderate intensity activity for more than 10 min for leisure activities) [ | PMC10585797 |
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Statistical analysis | The sample size was referenced from a similar previous study [All statistical analyses were performed using SAS® (version 9.4; SAS Institute, Cary, NC, USA). Continuous variables were presented as means ± standard deviation (SD) and categorical variables were presented as frequencies. Data analysis for efficacy was performed using the full analysis set (FAS). Analysis for safety was performed using the safety set. Statistical analysis was performed for data according to protocol criteria. Significant differences in demographic characteristics at baseline were analyzed using the Chi-square test (Fisher’s exact test). Mean comparisons between the two groups were performed using an independent t-test. Statistical analysis between the two groups was performed using an independent t-test for change values before and after 16 weeks of intervention. Within each group, the comparison between before intake and 16 weeks after intake was analyzed using a paired t-test. Differences were considered statistically significant at a p-value < 0.05. | PMC10585797 |
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Results | PMC10585797 |
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Discussion | Obesity, obesity, stroke, CVD, overweight, weight loss | OBESITY, ADVERSE REACTIONS, OBESITY, OBESE, CVD, STROKE, CHRONIC DISEASES, BLIND, TYPE 2 DIABETES | We performed a 16-week, randomized, double-blind, placebo-controlled clinical trial to evaluate the anti-obesity efficacy and safety of NAOs in overweight and obese subjects. After 16 weeks of intake, VFA and VSR were significantly reduced in the NAOs group, and weight and BMI were significantly suppressed from increase compared to the placebo group. HDL-C showed a tendency to increase significantly in the NAOs group compared to the placebo group.Obesity is defined as an excess of body fat [BMI has long been recognized as a predictor of morbidity and mortality from numerous chronic diseases, including type 2 diabetes, CVD, and stroke [The mechanism of the anti-obesity effect of NAOs was confirmed in several preclinical studies, including weight loss, adipocyte size reduction, blood glucose and lipid improvement through PPAR-r and MAPK signaling pathways, adiponectin regulation, and gut microbiome modulation [This study found no differences in biomarkers except VFA, VSR, weight, and BMI. Obesity is influenced by various factors, including individual characteristics, dietary intake, and physical activity [Placebo is used to control for placebo effects in randomized clinical trials (RCTs) because it is necessary to blind researchers or subjects to prevent influence on study results. A placebo looks like a test product but contains no active ingredients. Placebos must have the same appearance, same dosage, same delivery method, and be taken at the same time at the same frequency [In preclinical studies, NAOs decreased total cholesterol, triglyceride, and LDL-C and increased HDL-C in the blood of animal models [In this clinical trial, no side effects or serious adverse reactions were observed in blood tests, electrocardiograms, or vital signs, or reported in interviews. These results confirm that daily intake of NAO for 16 weeks is safe for humans.Our study is the first human study about the anti-obesity effect of NAOs. However, a few limitations of this study should be considered. First, although the number of subjects was calculated by referring to previous similar studies, the sample size was small, limiting our findings’ generalizability. Large-scale studies are needed in the future. Second, regarding the gender of subjects, all subjects in this study were women. It is generally known that the body fat percentage and incidence of obesity are higher in women than in men [However, our study has a good design and advantages. It can provide substantial evidence for the anti-obesity effect of NAOs. | PMC10585797 |
Acknowledgements | We would like to express our gratitude to all study subjects and researchers. | PMC10585797 |
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Author contributions | Conceptualization and study design: HIB, KCH, YKP, JHL, EJK, HJK, and JCJ; Investigation: JCJ; Statistical analysis: YKP; Data interpretation: HIB, KCH, YKP, and JCJ; Manuscript preparation: HIB, KCH, YKP, and JCJ; Fund collection: JHL, EJK, and HJK. All authors have read and approved the final manuscript. | PMC10585797 |
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Funding | This research was supported by Korea Institute of Marine Science & Technology Promotion(KIMST) funded by the Ministry of Oceans and Fisheries, Korea (20200034). | PMC10585797 |
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Data availability | The datasets generated and/or analyzed during the study are not publicly available to study subject confidentiality but are available from the corresponding author on reasonable request. | PMC10585797 |
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Declarations | PMC10585797 |
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Ethics approval and consent to participate | This research included clinical trial and authors have included a statement that informed consent was obtained for experimentation with subject. All the procedures for the clinical trial were approved by the Institutional Review Board of Wonkwang University Korean Medicine Hospital (IRB approval No.: WUJKMH-IRB-2021-0008). This study was registered with the Clinical Research Information Service (CRIS), Republic of Korea (KCT0006640, 07/10/2021). | PMC10585797 |
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Consent for publication | Not applicable. | PMC10585797 |
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Competing interests | The authors declare no competing interests. | PMC10585797 |
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Abbreviations | diabetes | DIABETES | adverse eventsalanine transaminaseaspartate transaminasebody fat massbody mass indexblood urea nitrogencomputer-Aided Nutritional analysis programcreatine kinasecardiovascular diseaseclinical Research Information Servicecomputed tomographydiastolic blood pressuredual-energy X-ray absorptiometrygamma-glutamyl transferaseglobal physical activity questionnairehigh sensitivity C-reactive proteinhigh-density lipoprotein-cholesterolhip circumferencehealth functional foodinternational Conference on Harmonizationlean body masslactate dehy-drogenaselipopro-tein-cholesterolministry of Food and Drug Safety of Koreaneoagaro-oligosaccharidespercent body fatred blood cellsystolic blood pressuresubcutaneous fat areatotal abdominal fat areatype 2 diabetes mellitusvisceral fat areavisceral-subcutaneous fat area ratiowhite blood cellwaist circumferencewaist-hip ratioworld Health Organization | PMC10585797 |
References | PMC10585797 |
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Abstract | These authors are co‐first authors. | PMC10646994 |
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Objective | intracranial atherosclerotic stroke | This study aimed to investigate whether treatment with adjunct intravenous tirofiban is associated with improved outcomes following successful reperfusion in patients with intracranial atherosclerotic stroke. | PMC10646994 |
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Methods | artery atherosclerotic, sICH, stroke, Vessel Occlusion Stroke, Cerebral Ischemia | INTRACRANIAL HEMORRHAGE, STROKE, CEREBRAL ISCHEMIA | Patients with intracranial large artery atherosclerotic (LAA) stroke and an expanded Treatment in Cerebral Ischemia angiographic score of 2b50 to 3 from the Effect of Intravenous Tirofiban versus Placebo Before Endovascular Thrombectomy on Functional Outcomes in Large Vessel Occlusion Stroke (RESCUE BT) trial were included. The primary outcome was the difference in proportion of independent functional outcome (modified Rankin score of 0–2 at 90 days). Safety outcomes included the rates of symptomatic intracranial hemorrhage (sICH) and 90‐day mortality. | PMC10646994 |
Results | intracranial LAA stroke | Among the 382 patients with intracranial LAA stroke and successful reperfusion, 175 patients (45.8%) were treated with intravenous tirofiban and 207 (54.2%) with placebo. The proportion of patients with independent functional outcome at 90 days was 54.3% (95 out of 175) with tirofiban and 44.0% (91 out of 207) with placebo (adjusted odds ratio [aOR], 1.58; 95% CI, 1.02–2.44; | PMC10646994 |
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Interpretation | sICH, intracranial LAA stroke | Among patients with acute intracranial LAA stroke and successful reperfusion following endovascular thrombectomy, adjunct intravenous tirofiban was associated with a higher rate of independent functional outcome, without higher rates of sICH or mortality. Confirmatory randomized trials in these patients are desirable. | PMC10646994 |
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Introduction | artery atherosclerotic, stroke, vessel occlusion, microcirculatory obstructions, acute ischemic stroke | STROKE, HYPOPERFUSION, ARTERY OCCLUSION | Endovascular thrombectomy (EVT) is the standard treatment to improve functional outcomes in acute ischemic stroke patients with large vessel occlusion.Among patients with successful reperfusion with EVT, residual blood flow impairment is of two types: macrocirculatory—angiographically visible occlusions in more distal arteries; and microcirculatory—no reflow at the arteriolar–capillary level despite absence of any angiographically visible occlusion. For example, in patients with eTICI 3 outcome, no visible occlusions are present but hypoperfusion throughout the field may occur due to microcirculatory obstructions.Intracranial large artery atherosclerotic (LAA) stroke is one of the most common etiologies of large artery occlusion, especially in Asian patients. | PMC10646994 |
Methods | PMC10646994 |
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Study participants | artery atherosclerosis | ISCHEMIC STROKE | The RESCUE BT trial was a multicenter, randomized, double blinded clinical trial conducted at 55 hospitals in China from October 2018 to October 2021. Details of trial design and topline results have been described previously.For the current post hoc study, additional inclusion criteria were, (6) diagnosis of intracranial large artery atherosclerosis as the mechanism of the index ischemic stroke, and (7) achievement of successful reperfusion at the end of the mechanical thrombectomy procedure. Successful reperfusion was defined as an eTICI grade of 2b50‐3, including 2b50 (substantial reperfusion, 50–89%), 2c (excellent reperfusion, 90–99%), and 3 (completely reperfusion, 100%). | PMC10646994 |
Study treatments and interventions | The study drug was administered intravenously within 5 min after randomization. Eligible participants in the tirofiban group received intravenous bolus followed by continuous infusion of tirofiban (10 μg/kg bolus and then 0.15 μg/kg/min maintenance for up to 24 h), participants in the placebo group received saline. A rapid EVT was initiated. It was permitted to use rescue drug when reocclusion of the target artery after EVT was observed in the angiographic suite. The rescue drug was saline placebo in the tirofiban group and tirofiban in the placebo group. Patients who achieved successful reperfusion after use of rescue drug were included in this analysis in addition to those not requiring rescue drug. | PMC10646994 |
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Outcomes measures | Bleeding, sICH | BLEEDING, SECONDARY, INTRACEREBRAL HEMORRHAGE | This analysis used the same primary and all applicable secondary efficacy analyses used for the parent trial. The primary efficacy outcome measure was the proportion of patients functionally independent (modified Rankin Scale [mRS] score of 0 to 2) at 90 days. The mRS score is an ordered scale ranging from 0 (no symptoms) to 6 (death).Secondary efficacy outcomes included a shift analysis of the mRS score at 90 days; the proportion of patients disability‐free (mRS score 0 to 1); the change of the NIHSS score from baseline to 24 h and 5–7 days (or at discharge if earlier); the score of the European Quality of Life 5‐Dimension 5‐level scale (EQ‐5D‐5L; a higher score indicates a better quality of life) at 90 days. Safety outcomes included incidence of symptomatic intracerebral hemorrhage (sICH) according to Heidelberg Bleeding Classification, | PMC10646994 |
Statistical analysis | REGRESSION, SECONDARY | Continuous variables were reported as medians (interquartile ranges) and categorical variables as numbers (percentages). Baseline characteristics between patients with and without intravenous tirofiban were compared by using the Wilcoxon rank sum test or chi‐squared test as appropriate. The main efficacy outcome was estimated using a multivariable logistic regression model adjusted for age, baseline NIHSS score, baseline ASPECTS, occlusion site, time from last known well to randomization. In a sensitivity analysis, the estimated odds ratio of effect of intravenous tirofiban on independent functional outcome was performed between the tirofiban group and the placebo group only among patients who did not receive rescue drug.Among secondary clinical outcomes, the improvement in mRS score at 90 days was estimated by ordinal logistic regression model adjusted for the same variables above. The odds ratios for early neurological changes (the change of the NIHSS score from baseline to 24 h and 5–7 days) and quality of life at 90 days were analyzed using multivariable linear regression model. The risk ratio for safety outcomes was estimated by Poisson regression model. The unadjusted and adjusted value were presented with 95% confidence intervals to indicate statistical precision.Subgroup analyses were performed evaluating potential heterogeneity for efficacy effect among patients with substantial reperfusion (eTICI 2b50), excellent reperfusion (eTICI 2c), and complete reperfusion (eTICI 3), using forest plot analysis. Day 90 functional outcomes analyzed included the primary outcome (mRS 0–2), the prespecified secondary mRS outcomes (mRS 0–1). Heterogeneity was assessed by interaction Additional subgroup analyses were performed for the primary mRS 0–2 outcome stratified by the same variables as in the overall trial analysis: age, sex, baseline NIHSS score, baseline ASPECTS, occlusion site, time from last known well to randomization. All analyses were performed using SPSS version 23 (IBM Corp.) and Review Manager 5.3. For main effect analyses, | PMC10646994 |
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