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Methods | In this double-blind, double-dummy, parallel group study, glucose-6-phosphate dehydrogenase-normal Indonesian soldiers with microscopically confirmed | PMC10533414 |
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Findings | ADVERSE EVENTS, ADVERSE EVENT | Between April 8, 2018, and Feb 4, 2019, of 164 patients screened for eligibility, 150 were randomly assigned (50 per treatment group). 6-month Kaplan-Meier relapse-free efficacy (microbiological intention to treat) was 11% (95% CI 4–22) in patients treated with dihydroartemisinin–piperaquine alone versus 21% (11–34) in patients treated with tafenoquine plus dihydroartemisinin–piperaquine (hazard ratio 0·44; 95% CI [0·29–0·69]) and 52% (37–65) in the primaquine plus dihydroartemisinin-piperaquine group. Adverse events over the first 28 days were reported in 27 (54%) of 50 patients treated with dihydroartemisinin–piperaquine alone, 29 (58%) of 50 patients treated with tafenoquine plus dihydroartemisinin–piperaquine, and 22 (44%) of 50 patients treated with primaquine plus dihydroartemisinin–piperaquine. Serious adverse events were reported in one (2%) of 50, two (4%) of 50, and two (4%) of 50 of patients, respectively. | PMC10533414 |
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Interpretation | Although tafenoquine plus dihydroartemisinin–piperaquine was statistically superior to dihydroartemisinin–piperaquine alone for the radical cure of | PMC10533414 |
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Funding | MALARIA | ExxonMobil, Bill & Melinda Gates Foundation, Newcrest Mining, UK Government all through Medicines for Malaria Venture; and GSK. | PMC10533414 |
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Translation | For the Indonesian translation of the abstract see Supplementary Materials section. | PMC10533414 |
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Research in context | RELAPSE |
The efficacy of a single 300-mg dose of tafenoquine co-administered with chloroquine for the radical cure of
This is the first clinical study to evaluate the efficacy and safety of a single 300-mg dose of tafenoquine co-administered with dihydroartemisinin–piperaquine for the radical cure of
This study does not support co-administration of a single 300-mg dose tafenoquine with dihydroartemisinin–piperaquine for the radical cure of The emergence of chloroquine resistanceThe INSPECTOR study (Indonesian Study Proving Efficacy of Combination Therapy on Relapse) is the first study to evaluate co-administration of tafenoquine with dihydroartemisinin–piperaquine for the radical cure of | PMC10533414 |
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Methods | PMC10533414 |
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Study design and participants | infection | INFECTION, SECONDARY | This double-blind, double-dummy, randomised, parallel group study enrolled soldiers from two battalions based in East Java (battalion 1 at Malang; battalion 2 at Madiun; Patients were eligible for enrolment if they were male, aged at least 18 years, had microscopically confirmed The main exclusion criteria were severe The trial was designed to support the use of tafenoquine 300 mg with dihydroartemisinin–piperaquine. The underlying relapse rate following a course of dihydroartemisinin–piperaquine cannot be assumed from historical data owing to the natural variation in both infection rates and relapse rates among infected subjects. The dihydroartemisinin–piperaquine alone group was included as a relapse-prevention placebo control to provide an efficacy benchmark in the same setting and at the same time as the study treatment groups. The inclusion of the primaquine group provided a context against which to interpret the observed tafenoquine efficacy rate. A statistical comparison for non-inferiority between tafenoquine and primaquine was not done; such a comparison would require a considerably larger sample size and was not the main objective of the study, which was to estimate the efficacy of tafenoquine.The study complied with Good Clinical Practice, the Declaration of Helsinki, and relevant regulatory requirements. Ethics approval was obtained from the Oxford Tropical Research Ethics Committee (Project 9-16) and the Faculty of Medicine Universitas Indonesia Ethics Committee (FKUI 593/UNs.F1/ETIK/2016 dated July 18, 2016). Written informed consent was obtained individually from study patients and affirmed by an independent peer witness. Army rank superiors were not permitted to witness or participate in the consenting process to avoid any perception of coercion. The protocol was amended once on April 20, 2017 (before study start) to include an additional secondary objective requested by the Indonesian regulatory agency: comparison of dihydroartemisinin–piperaquine plus primaquine (as per national treatment guidelines) with dihydroartemisinin–piperaquine alone. The full protocol is available online (NCT 02802501). | PMC10533414 |
Randomisation and masking | Eligible patients were randomly assigned in a 1:1:1 ratio to dihydroartemisinin–piperaquine alone, dihydroartemisinin–piperaquine plus tafenoquine, or dihydroartemisinin–piperaquine plus primaquine. All patients received open-label dihydroartemisinin–piperaquine for 3 days plus masked treatment as follows: tafenoquine 300-mg single dose on day 1 and placebo for primaquine on days 1–14; primaquine 15 mg on days 1–14 and placebo for tafenoquine on day 1; or placebo for tafenoquine on day 1 and placebo for primaquine on days 1–14. The study sponsor provided a computer-generated randomisation schedule to the site. Visually matched tafenoquine and primaquine placebos were used to maintain masking of site staff, patients, and sponsor personnel.As methaemoglobin increases are associated with use of 8-aminoquinolines such as primaquine and tafenoquine, methaemoglobin assessments were done by an independent site assessor to avoid unmasking. Additionally, independent sponsor staff processed the methaemoglobin data. The independent methaemoglobin site and sponsor staff did not have access to other study data. | PMC10533414 |
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Procedures | malaria | MALARIA, BLOOD, RELAPSE | Study treatments were supplied by the sponsor as eurartesim tablets containing dihydroartemisinin 40 mg and piperaquine 320 mg (Alfasigma, Bologna, Italy), tafenoquine 150-mg tablets (GSK, London, UK), and primaquine formulated as over-encapsulated 15-mg tablets (Sanofi-Aventis, Bridgewater, NJ, USA). All patients received open-label, oral dihydroartemisinin–piperaquine daily over 3 consecutive days (days 1–3), according to weight (three tablets <75 kg or four tablets ≥75 kg). Tafenoquine (or matched placebo) was given as a single oral 300-mg dose (two × 150-mg tablets) on either day 1 or day 2. Primaquine (or matched primaquine placebo) was administered as a single oral 15-mg daily dose for 14 consecutive days starting on day 1 or day 2. All study medications were administered under direct supervision by study staff in the clinic.Following informed consent, screening assessments were done and all patients who were eligible to receive dihydroartemisinin–piperaquine on the basis of labelling received their first dose of dihydroartemisinin–piperaquine at least 3 h after their last meal. Once laboratory results confirmed continued eligibility, patients were randomly assigned to masked study medication, with the first dose given, with food, at least 3 h after dihydroartemisinin–piperaquine, on day 1 or day 2. Blood smears for parasite assessment were done twice daily until two consecutive negative smears were obtained. After completion of the dosing period, patients attended a further seven follow-up visits (on days 21, 28, 60, 90, 120, 150, and 180).Patients were evaluated by clinical assessments and laboratory investigations including Giemsa-stained blood smears for parasitology, 12-lead electrocardiograms, haematology and clinical chemistry tests, and methaemoglobin measurement by means of a non-invasive pulse oximeter (Masimo, Irvine, CA, USA) at screening and selected visits throughout the study. After their initial in-patient treatments, patients were instructed to promptly return to the clinic (open 24 h) if they had malaria symptoms. Patients who returned with Blood samples were taken for tafenoquine pharmacokinetic analysis, cytochrome P-450 2D6 (CYP2D6) genotyping and parasite microsatellite DNA analysis (to establish the proportion of heterologous and homologous relapses). Relapse was defined as genetically homologous when All patients who were relapse free at 6 months received high-dose open-label primaquine (ie, 0·5 mg/kg daily) for 14 days at the end of the study to minimise the likelihood of relapse. | PMC10533414 |
Outcomes | infection, recrudescence, infections, fever | RECURRENCE, ADVERSE EVENTS, INFECTIONS, INFECTION, CYP2D6 POLYMORPHISM | The primary outcome was relapse-free efficacy over 6 months, defined as clearance of initial infection without subsequent microscopically confirmed recurrence or receipt of other antimalarial treatment. Secondary outcomes were relapse-free efficacy over 4 months, time to fever clearance, time to parasite clearance, and percentage of patients with recrudescence (genetically homologous recurrence within 14 days) to ensure the blood stage efficacy of dihydroartemisinin–piperaquine. Safety assessments included frequency and severity of adverse events and review of 12-lead electrocardiograms, vital signs, and laboratory values. Tafenoquine pharmacokinetic assessments were also planned.The incidence of genetically homologous infections was established by five microsatellite markers. Additionally, the influence of human CYP2D6 polymorphisms on relapse was explored post-hoc by means of a CYP2D6 activity score system (see | PMC10533414 |
Statistical methods | The primary comparison of interest was relapse-free efficacy over 6 months for tafenoquine plus dihydroartemisinin–piperaquine versus dihydroartemisinin–piperaquine alone. By means of the log-rank test for the primary comparison to detect a clinically meaningful difference of 35% in relapse-free survival rates over 6 months, and assuming a 50% rate on dihydroartemisinin–piperaquine alone,All randomly assigned patients who received at least one dose of masked treatment and had microscopically confirmed The primary endpoint, time to relapse over 6 months, was summarised by means of Kaplan-Meier estimates and analysed by means of a Cox's proportional-hazards model, adjusting for battalion, for the microbiological intention-to-treat (primary) and per-protocol (sensitivity) populations. Of note, the protocol described a log-rank test, but this was amended in the study analysis plan (finalised before the unmasking of the study) to Cox's proportional hazards. Patients were censored if they did not show initial clearance of | PMC10533414 |
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Role of the funding source | The study sponsor (GSK) was responsible for study monitoring, data management, data analysis, and writing of the clinical report. | PMC10533414 |
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Results | REGRESSION, DRUG-INDUCED LIVER INJURY, ADVERSE EVENT, ADVERSE EVENTS | Between April 8, 2018, and Feb 4, 2019, of 164 patients screened for eligibility, 150 were randomly assigned to masked study treatment; 50 per treatment group (battalion 1 n=69; battalion 2 n=81; Trial profileALT=alanine aminotransferase. DP=dihydroartemisinin–piperaquine. mITT=microbiological intention-to-treat. PP=per-protocol. PQ=primaquine. *Participants can be excluded for more than one reason. †The patient discontinued treatment, but continued and completed the study. The safety population included all patients who were randomly assigned and received at least one dose of masked study medication. The mITT population was a subgroup of the safety population who had microscopically confirmed Baseline characteristics for safety populationData are mean (SD), n (%), and median (range). IU=international units.Glucose-6-phosphate dehydrogenase activity ≥5·1 IU/gHb was considered normal based on ≥70% of the site median 7·29 (range 5·77–11·92) IU/gHb established from the first 33 recruited patients who were G6PD normal by the fluorescent spot test.There were no discordant G6PD results between the qualitative fluorescent spot test and the quantitative spectrophotometric assay in any randomly assigned patient.Poor activity score 0; intermediate=activity score=0·25 to 1; normal activity score=1·25–2·25; ultra activity score >2·25 (see In the microbiological intention-to-treat population, 44 patients (88%) in the dihydroartemisinin–piperaquine alone group, 39 patients (78%) in the tafenoquine plus dihydroartemisinin–piperaquine group and 24 patients (48%) in the primaquine plus dihydroartemisinin–piperaquine group had microscopically confirmed Kaplan-Meier survival curves for 6-month relapse-free efficacy for the microbiological intention-to-treat populationDP=dihydroartemisinin–piperaquine. PQ=primaquine. TQ=tafenoquine. *Estimated from Cox's proportional-hazards analysis adjusting for battalion. A hazard ratio of <1 indicates a lower chance of relapse compared with the reference treatment. No patients met the criteria for censoring.Logistic regression analysis of relapse-free efficacy at 6 months (modified intention to treat population)Data are n (%) unless stated otherwise. DP=dihydroartemisinin-piperaquine. Model includes terms for battalion and treatment. Patients who did not show initial clearance of An odds ratio <1 represents a smaller chance of relapse compared with DP alone.An odds ratio <1 represents a smaller chance of relapse compared with primaquine plus DP.Primaquine plus dihydroartemisinin–piperaquine reduced the risk of relapse over 6 months by 74·2% versus dihydroartemisinin–piperaquine alone (HR 0·26; 95% CI 0·16–0·43; The percentage of relapse-free patients in all treatment groups over 6 months was higher in battalion 1 than battalion 2 (battalion 1 dihydroartemisinin–piperaquine alone five [22%] of 23; tafenoquine plus dihydroartemisinin–piperaquine seven [32%] of 22; primaquine plus dihydroartemisinin–piperaquine 19 [79%] of 24; battalion 2 dihydroartemisinin–piperaquine alone one [4%] of 27; tafenoquine plus dihydroartemisinin–piperaquine four [14%] of 28; primaquine plus dihydroartemisinin–piperaquine seven [27%] of 26). The reduction in the 6-month relapse risk for tafenoquine plus dihydroartemisinin–piperaquine versus dihydroartemisinin–piperaquine alone was greater for battalion 2 (battalion 1 HR 0·70; 95% CI 0·35–1·39; battalion 2: HR 0·38; 0·21–0·67; see Relapse-free efficacy trends over 4 months were similar to the 6-month results (Treatment groups were well matched for CYP2D6 metaboliser class with 67 (45%) of 150 being categorised as poor or intermediate metabolisers (categorised post-hoc according to Clinical Pharmacogenetics Implementation Consortium guidelines). Logistic regression analyses showed no significant effect of CYP2D6 activity score (Overall, 88 (83%) of 106 of all first relapses were genetically heterologous by microsatellite genotyping and the proportion of heterologous to homologous relapses was not influenced by treatment (The adverse event profile was similar across treatment groups, although the proportion of patients in the primaquine plus dihydroartemisinin–piperaquine group reporting any adverse event was lower than for other groups (Most frequent adverse events and serious adverse events during the double-blind treatment phase (safety population)Data are n (%). DP=dihydroartemisinin–piperaquine.Only adverse events with an onset up to day 29 are presented. The interpretation of the incidence of adverse events after day 29 is likely to be confounded by medication administered to treat relapses (primaquine plus DP).One patient was diagnosed with grade 1 drug-induced liver injury at the time of their first Five serious adverse events were reported during the 6-month follow-up of which two were considered possibly related to treatment by the investigator (A higher percentage of patients in the tafenoquine plus dihydroartemisinin–piperaquine group (12 [24%] of 50) had a clinically significant QTcF prolongation (defined as ≥60 msec change from baseline) on the 12-lead electrocardiogram (dihydroartemisinin–piperaquine alone group seven [14%] of 50; primaquine plus dihydroartemisinin–piperaquine group five [10%] of 50). In all cases, QTcF prolongation was asymptomatic and returned to normal within 1 week without intervention (Haemoglobin values were similar between treatment groups (Box plot of haemoglobin and methaemoglobin values over time (safety population)DP=dihydroartemisinin-piperaquine. PQ=primaquine. RLP=relapse visit. TQ=tafenoquine.Owing to various logistical factors including the global response to the COVID-19 pandemic, it has not, to date, been possible to transport samples for pharmacokinetic analyses to a validated laboratory outside of Indonesia. Pharmacokinetic data from study patients cannot therefore be included in this publication. | PMC10533414 |
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Discussion | malaria, deaths | MALARIA, ADVERSE EVENT | This is the first study to evaluate the efficacy and safety of a single 300-mg dose of tafenoquine co-administered with an artemisinin-based combination therapy for the radical cure of The reasons for the lack of clinically relevant efficacy with tafenoquine plus dihydroartemisinin–piperaquine are unknown. Although no pharmacokinetic data are yet available, a pharmacokinetic interaction is considered unlikely given that there was no clinically significant pharmacokinetic interaction between tafenoquine and dihydroartemisinin–piperaquine in a previous healthy volunteer study.Previous studies of primaquine plus chloroquine indicate that diminished primaquine efficacy might be associated with impaired CYP2D6 activity.The soldiers' battalion had a significant effect on estimates of efficacy, whereas other covariates (weight and baseline parasite counts) exerted no significant influence on the primary endpoint. Although these observations did not change the overall interpretation of the study (treatment differences were in the same direction in both battalions), there was a notably higher relapse rate across all treatment groups in the second battalion compared with the first battalion, which could not be explained by differences in study conduct or drug supplies. Despite both battalions having similar baseline characteristics and being deployed to the same region of Indonesian Papua for similar durations, sharp differences in transmission intensity within that region are believed to have occurred. Battalion 1 had been working in a sparsely populated and forested sector, whereas battalion 2 had been operating in a relatively settled (cleared forest) and populated area—conditions conducive to relatively light and heavy malaria transmission, respectively—on the basis of the dominant anopheline vectors in New Guinea, which prefer open sunlight to shady forests.Consideration has been given to whether the 300-mg dose of tafenoquine used in this study might be suboptimal.Patients in this study were infected with The adverse event profile for tafenoquine plus dihydroartemisinin–piperaquine was consistent with the known adverse event profiles for the individual drugs and there were no new safety signals. There were no deaths, and no patients withdrew from the study. Two patients had a serious adverse event, which the investigator considered related to study treatment, but neither received tafenoquine. QTc prolongation is a known risk with dihydroartemisinin–piperaquine.The current study has several limitations. It was only done in patients who had been infected with The study design in which patients were infected in a highly malarious region and returned to an area free of malaria transmission meant that In conclusion, the results of this study do not support co-administration of single 300-mg dose tafenoquine with dihydroartemisinin–piperaquine for the radical cure of
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Data sharing | Within 6 months of this publication, anonymised individual patient data, the annotated case report form, protocol, reporting and analysis plan, dataset specifications, raw dataset, analysis-ready dataset, and clinical study report will be available for research proposals approved by an independent review committee. Proposals should be submitted to | PMC10533414 |
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Declaration of interests | IS reports grants or contracts from Menzies School of Health Research, Darwin and the National Health and Medical Research Council | PMC10533414 |
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References | PMC10533414 |
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Supplementary Materials | PMC10533414 |
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Indonesian translation of the abstract | PMC10533414 |
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Supplementary appendix 2 | PMC10533414 |
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Acknowledgments | The trial was designed and funded by MMV and supported by the sponsor GSK. The protocol was drafted by GSK with input from MMV and the Indonesian study team. MMV was funded by various donors for this trial including ExxonMobil and the Bill & Melinda Gates Foundation (grant number INV-007155/19-BMGF-006), Newcrest Mining, and the UK Government. GSK funded the costs associated with the development of the present publication. Editorial support after initial draft was provided by Allyson Lehrman and Sarah Hummasti of AOIC (revising the document based on author input, assembling drafts, tables and figures, collating co-author comments, and researching references) and AOIC assisted with graphics; both were funded by the study sponsor, GSK. We express sincere gratitude to the soldiers, officers, and commanders of the Army of the Republic of Indonesia for their support and participation in this clinical trial. We are grateful to all members of the clinical research team at the Eijkman-Oxford Clinical Research Unit, the Eijkman Institute of Molecular Biology, the Faculty of Medicine, University of Indonesia, as well as the Alert Asia Foundation (all in Jakarta). We also thank the entire GSK study team for their contributions to this study. | PMC10533414 |
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Contributors | SD | IS was the principal investigator and JKB was responsible for study conceptualisation. JKB, IS, AS, LLE, RN, AWS, WB, SL, IE, JAG, J-PK, SD, EC, SJ, MT, and NG contributed to the study design and protocol development. SD and LKT were responsible for funding acquisition. LKT, SD, HS, AM, and EC were responsible for the project administration. IS, JKB, AS, KC, LLE, YWS, DS, AWS, WB, CBP, SL, EC, KF, AB, DF, SD, JAG, and LKT contributed to the implementation of the study or data collection. DS, AWS, RN, and CC-D were responsible for laboratory analyses. KR was responsible for statistical analysis. HS and AM led discussion related to the pharmacokinetic data analysis, absence of pharmacokinetic samples and effect on the manuscript, regulatory study activities, and reporting. II, MT, and NG were responsible for the pharmacokinetic data acquisition. HS and AM were responsible for the pharmacokinetic data management activities. JKB, IS, LLE, RN, AWS, LKT, J-PK, DF, SJ, EC, KR, NG, HS, AM, MT, and SD contributed to data interpretation. EC and LKT wrote the first draft of the manuscript and suggested the visual presentation of the data. LKT, JKB, and EC had full access to all the analysed data received to date and verified all data. All authors had access to the available analysed data, contributed to manuscript revision, take responsibility for the content of the manuscript, and had final responsibility for the decision to submit for publication. | PMC10533414 |
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Background | HAT | AFRICAN TRYPANOSOMIASIS | Passive diagnosis of human African trypanosomiasis (HAT) at the health facility level is a major component of HAT control in Guinea. We examined which clinical signs and symptoms are associated with HAT, and assessed the performance of selected clinical presentations, of rapid diagnostic tests (RDT), and of reference laboratory tests on dried blood spots (DBS) for diagnosing HAT in Guinea. | PMC10026442 |
Method | The study took place in 14 health facilities in Guinea, where 2345 clinical suspects were tested with RDTs (HAT Sero- | PMC10026442 |
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Results | The HAT prevalence, as confirmed parasitologically, was 2.0% (48/2345, 95% | PMC10026442 |
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Graphical Abstract | PMC10026442 |
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Keywords | PMC10026442 |
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Background | Infection | EBOLA, INFECTION | Infection with the parasite Despite considerable challenges, Guinea implements an efficacious HAT control program based on medical interventions supplemented with vector control. Even during the Ebola epidemic outbreak in 2014–2016, the national HAT control program managed to deploy insecticide impregnated targets in Boffa, and limited parasite transmission to humans by reducing the tsetse fly vector density [While the most sensitive parasite detection techniques are routinely applied in Guinea [Within the framework of a multi-country diagnostic trial, the diagnostic performance of clinical signs and symptoms, of 3 RDTs and of serological and molecular reference laboratory tests on DBS was evaluated prospectively for diagnosis of HAT, in the context of passive screening in HAT endemic areas in Guinea. | PMC10026442 |
Methods | PMC10026442 |
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Study setting | AFRICAN TRYPANOSOMIASIS | In Guinea, clinical suspects were prospectively recruited for the Diagnostic tools for human African trypanosomiasis elimination and clinical trials work package 2 (DiTECT-HAT-WP2) study between January 2017 and January 2020 in 14 hospitals and health posts in the prefectures of Boffa, Dubreka and Forecariah. In these 3 prefectures, the HAT prevalence expressed as number of HAT cases per 10,000 inhabitants in 2017 was respectively 2.92, 0.53 and 1.51, and decreased to 0.97, 0.33 and 0.99 in 2019 [The initial sample size estimation was based on 13 health structures, performing RDTs on 15 clinical suspects each month, for 27 months, which would have resulted in 5265 inclusions. We estimated that in about 10% of the clinical suspects tested, at least one RDT would be positive. The HAT prevalence among clinical suspects was estimated at 1%, which would result in inclusion of 53 HAT patients. | PMC10026442 |
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Study protocol | The study protocol is summarized in Fig. DiTECT-HAT-WP2 study conduct and test results in Guinea. | PMC10026442 |
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Inclusion criteria | confusion, itching, convulsions, aggressiveness, abnormal movements, amenorrhea, motor disorders, psychiatric, coma, insomnia, headache, abortion, weight loss, apathy | STERILITY, SPEECH DISORDERS, MOTOR DISORDERS, RECURRENT FEVER, COMA | Individuals consulting the study SSS or CDT could be consecutively included if they had visited or resided in a HAT endemic area and presented with clinical suspicion for HAT. Clinical suspicion was defined as presence of at least one of the following clinical signs or symptoms: Recurrent fever not responding to anti-malarial medication; headache for a long duration (> 14 days); presence of enlarged lymph nodes in the neck; important weight loss; weakness; severe itching; amenorrhea, abortion, or sterility; coma; psychiatric problems (e.g., aggressiveness, apathy, mental confusion, increasing unusual hilarity, etc.); sleep disruption (nocturnal insomnia and/or excessive diurnal sleeping); motor disorders (abnormal movements, shaking, walking difficulties); convulsions; or speech disorders. Individuals were excluded from participation if they had already been treated for HAT, did not give their written informed consent or were less than 4 years old. | PMC10026442 |
Serological screening and parasitological confirmation | Finger prick blood was tested with 3 RDTs, HAT Sero- | PMC10026442 |
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Dried blood spot preparation | LYSED, ALDRICH | For every serological suspect two types of DBS were prepared. On a Whatman grade 4 filter paper, 16 drops of 30 µl of heparinized blood were deposited and left to dry. In parallel, 180 µl of heparinized blood were lysed for 5 min with 20 µl of 5% SDS solution (Sigma Aldrich, Saint Louis, MO, USA), and 2 drops of 40 µl of lysed blood were deposited on a Whatman grade 1001 filter paper. Filter papers were dried, packed in separate envelopes, which in turn were packed in hermetic plastic bags containing silica gel. | PMC10026442 |
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Patient management | A lumbar puncture was carried out on parasitologically confirmed HAT patients, or if the clinician considered it appropriate, based on strong clinical suspicion. The cerebrospinal fluid (CSF) was examined for the number of white blood cells, and for presence of trypanosomes using the modified single centrifugation [ | PMC10026442 |
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Study participants with missing data | sleeping sickness | SLEEPING SICKNESS | Serological suspects that could not be confirmed at the first microscopic examination, were invited for re-examination at the CDT or were re-examined by the national program. A number of RDT seropositives detected at SSS level and who did not show up at CDT were offered microscopic examination through the national sleeping sickness program (PNLTHA). | PMC10026442 |
Reference laboratory tests | The DBS were sent to the Centre International de Recherche-Développement sur l’Elevage en zone Subhumide (Bobo-Dioulasso, Burkina Faso), where reference laboratory tests were performed. Test performers were not informed about the clinical and reference standard results. On DBS collected on Whatman grade 4 paper, trypanolysis and ELISA/ | PMC10026442 |
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Data analysis | REGRESSION, REGRESSION | Results obtained at the CDT were immediately entered in a digital case report form [Regression analysis and evaluation of the diagnostic performance were based on the participants HAT status (Fig. Regression analysis using Stata Statistical Software (Release 14, College Station, TX: StataCorp LP) was performed to assess for associations with the HAT status and thus identify which demographic features and clinical presentations could be used as criteria to target future testing for HAT. Continuous variables were assessed for normal distribution, and the correlation between the thirteen clinical signs and symptoms was determined. Unconditional associations between HAT status and the explanatory variables (gender, age, and clinical signs and symptoms) were investigated. Subsequently, mixed logistic regression models were developed for the HAT status, with prefecture included as a random effect to account for spatial clustering within each prefecture. Backward elimination was then used to screen variables, and only statistically significant variables (The diagnostic performance of the clinical presentation (only those that were retained in mixed logistic regression), the three RDTs (individually, in parallel, and in series), and of the four reference laboratory tests was determined. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy for diagnosis of HAT were calculated with 95% Clopper Pearson confidence intervals (GraphPad Prism 9). The Kappa agreement for combinations of RDTs and reference laboratory tests was also determined, and interpreted as poor (< 0.00), slight (0.00–0.20), fair (0.21–0.40), moderate (0.41–0.60), substantial (0.61–0.80), or almost perfect (0.81–1.00) [ | PMC10026442 |
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Results | PMC10026442 |
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Descriptive statistics of field results | HAT, headache | RECURRENT FEVER, REGRESSION, AFRICAN TRYPANOSOMIASIS | In total, 2353 clinical suspects were included: 707 in the prefecture of Boffa, 705 in Dubreka, and 941 in Forecariah. Of these clinical suspects, 1320 (56.1%) were female and 1033 (43.9%) male. Their median age was 30 years (range: 4–89). The most frequently observed clinical presentations were recurrent fever not responding to anti-malarial medication (96%) and headache for a long duration (80.3%), followed by weakness (21.1%) (Table Frequency of clinical presentations in study participants and HAT patients, and association to HAT positivityThis table shows gender, age and the frequency of clinical symptoms and signs in clinical suspects and in HAT patients. The association to HAT positivity was first assessed in univariable analysis and after using multi-variable mixed logistic regression. HAT: Human African trypanosomiasis; | PMC10026442 |
HAT status of study participants | For further analysis of the results, study participants were considered as true HAT positives if they were confirmed as HAT patients based on trypanosome observation during microscopy performed on blood, lymph, or CSF specimens ( | PMC10026442 |
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Clinical symptoms and signs associated with HAT, regression analysis | motor disorders, HAT, coma, Coma | MOTOR DISORDERS, AFRICAN TRYPANOSOMIASIS, COMA, COMA | The frequency of the different inclusion clinical symptoms and signs, in HAT (Frequency of 13 clinical symptoms and signs in human African trypanosomiasis (HAT) and non-HAT affected study participants. The figure contains data for 48 HAT and 2297 non-HAT participants with the exception of * only 19 HAT and 1294 non-HAT female participantsConvulsions were highly correlated with coma (Spearman's rho ρ = 0.87) and motor disorders (ρ = 0.63). Coma was also correlated with motor disorders (ρ = 0.70) and enlarged lymph nodes in the neck (ρ = 0.61). The results of the unconditional associations between the explanatory variables gender, age and clinical parameters, and the dependent variable HAT positivity, are presented in Table | PMC10026442 |
Diagnostic performance of clinical presentation | HAT, itching, weight loss, weight loss and motor disorders | MOTOR DISORDERS, AFRICAN TRYPANOSOMIASIS | The diagnostic performance of (co-)occurrence of the 4 clinical symptoms and signs that were associated singly or in combination with HAT, namely enlarged lymph nodes in the neck, severe itching, important weight loss and motor disorders, was studied in function of the HAT status in 48 HAT and 2297 non-HAT affected study participants (Table The diagnostic performance of occurrence of 4 key clinical presentations for human African trypanosomiasis (HAT) diagnosisSensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of occurrence of presence of enlarged lymph nodes in the neck and/or important weight loss and/or severe itching, and/or motor disorders were determined for identification of HAT patients. The occurrence of at least one symptom or sign (≥ 1/4) and co-occurrence (≥ 2/4; ≥ 3/4 or all 4/4) of the 4 selected clinical presentations was counted in 48 HAT patients and 2297 non-HAT affected study participants, and proportions ( | PMC10026442 |
Diagnostic performance of rapid diagnostic tests | HAT | AFRICAN TRYPANOSOMIASIS | For estimation of the RDT diagnostic performance in 48 HAT and 2297 non-HAT clinical suspects, a few participants had partially missing RDT results (Table The diagnostic performance of 3 rapid diagnostic tests for diagnosis of human African trypanosomiasis (HAT)The individual diagnostic sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). Reference standard: Microscopic observation of trypanosomes in any body fluid. Individual RDT results of human African trypanosomiasis (HAT) patients and HAT free participants. The Venn diagram shows results in the RDTs HAT Sero-K-Set, rHAT Sero-Strip and SD Bioline HAT of 48 HAT patients and 2297 HAT free participants. | PMC10026442 |
Diagnostic performance of reference laboratory tests on dried blood spots | Among the 48 HAT patients, 34/48 had a DBS and all 4 DBS test results were available for 33/34, while 1/34 HAT patient missed a LAMP result. Among the 66 RDT positive HAT negatives (Fig. Reference laboratory test results on dried blood spots. The Venn diagram shows the results of trypanolysis, ELISA/Table The diagnostic performance of reference laboratory tests on dried blood spot for diagnosis of human African trypanosomiasisThe individual diagnostic sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of trypanolysis (TL), ELISA/The TgsGp-qPCR was carried out on 19 DBS only, 13 from HAT patients and 6 from RDT positive HAT negatives. Among the tested HAT patients, TgsGp-qPCR sensitivity was 38.5% (5/13, 95% | PMC10026442 |
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Discussion | The HAT prevalence observed among the study participants during the 3 years of passive screening was 2.0%. The overall HAT prevalence reported by the national program in passive screening in the same prefectures in 2017 and 2018 was respectively 0.98 and 0.39% [Although there may be geographical and stage specific variations, the clinical picture of HAT has been described in detail [The combined seroprevalence during this study was 5.2%, ranging from 1.9 to 4.7% for the individual RDTs. As for the HAT prevalence, this was again higher than the overall seroprevalence of 1.72% and 0.98% previously reported in 2017 and 2018 [Evaluation of the diagnostic performance of the parasitological tests was not an objective of our study and not all tests were systematically performed on all RDT positives, but our results confirm the relatively high sensitivity of lymph examination in Guinea [Unfortunately, DBS were missing for a relatively high number of RDT positives. The specificity of the 4 reference laboratory tests in this study was similar as for passive screening in Côte d’Ivoire [Some limitations of this multi-country study have already been discussed in detail elsewhere [The actual study also has important strengths. The high HAT prevalence in Guinea allowed us to assess the association between clinical symptoms and signs and HAT in Guinea and the diagnostic performance of the combination of 4 key clinical presentations, 3 RDTs, and consequent reference laboratory tests on DBS of RDT positives. A similar study in Côte d’Ivoire [ | PMC10026442 |
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Conclusions | In passive case detection, we can propose to health workers and clinicians in Guinean HAT endemic areas a relatively simple set of criteria with high sensitivity for selecting individuals to be further tested using HAT RDTs, which would result in a reduction of almost 70% of the HAT RDTs to be carried out. Performance of both HAT Sero-In the future, priority should be given to assessing the diagnostic performance of new generation RDTs and of new reference laboratory tests. Inhibition ELISA could replace trypanolysis [ | PMC10026442 |
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Abbreviations | AFRICAN TRYPANOSOMIASIS | Centre for diagnosis and treatmentCerebrospinal fluidDried blood spotDiagnostic tools for human African trypanosomiasis elimination and clinical trials work package 2, passive case detectionEnzyme-linked immunoassayHuman African trypanosomiasisLoopamp Mini anion exchange centrifugation technique on buffy coatNegative predictive valuePositive predictive valueRapid diagnostic testSerological screening sitesQuantitative polymerase chain reactionBruno Bucheton and Veerle Lejon contributed equally to this work | PMC10026442 |
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Acknowledgements | We acknowledge staff members of the Guinean HAT National Elimination Program, and the HAT team of the Centre International de Recherche-Développement sur l’Elevage en Zone Subhumide in Bobo-Dioulasso (Burkina Faso). We also acknowledge the health staff members from the health facilities involved in the study. | PMC10026442 |
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Author contributions | All authors participated in writing, reviewing and editing of the draft. VL was responsible for conceptualization, formal analysis, data curation, funding acquisition, methodology, project administration and original draft preparation. OC participated in investigation and methodology. MC was involved in conceptualization, methodology, project administration, and supervision. LCF performed formal analysis and validation. HI was involved in conceptualization and investigation. JK participated to investigation and supervision. CFAC performed investigations. EMF participated in conceptualization and methodology. PB was involved in conceptualization, data curation, funding acquisition, and methodology. BB participated in conceptualization, formal analysis, methodology, and project administration. All authors read and approved the final manuscript. | PMC10026442 |
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Funding | This study was funded by the EDCTP2 programme supported by the Horizon 2020 European Union funding for Research and Innovation (Grant Number DRIA-2014-306-DiTECT-HAT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. | PMC10026442 |
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Availability of data and materials | AFRICAN TRYPANOSOMIASIS | The public sharing of personal health data is subject to the General Data Protection Regulation. The health data underlying the findings described in the manuscript can therefore not be made public. Metadata are available via Lejon V, Camara O, Camara M, Ilboudo H, Kaboré J, Compaoré CFA, Buscher P, Bucheton B, 2022, "Passive case detection of Human African Trypanosomiasis in Guinea: symptoms and signs, rapid diagnostic test results and laboratory test results", DataSuds, | PMC10026442 |
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Declarations | PMC10026442 |
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Ethics approval and consent to participate | MINOR, AFRICAN TRYPANOSOMIASIS | The study in Guinea was part of the multi-country diagnostic clinical trial “Diagnostic tools for human African trypanosomiasis elimination and clinical trials work package 2, passive case detection” (DiTECT-HAT-WP2), registered on ClinicalTrials.Gov under identifier NCT03356665. Before initiation of the study, DiTECT-HAT-WP2 received ethical clearance from the Advisory Committee on Deontology and Ethics of the French National Institute for Research on Sustainable Development (plenary meeting of 17–20 October 2016), of the Institutional Review Board of the Institute of Tropical Medicine in Antwerp Belgium (reference 1133/16), and of the Ethics Committee of the University of Antwerp (Belgian registration number B300201730927). In Guinea, DiTECT-HAT-WP2 was approved by the Comité National d’Ethique pour la Recherche en Santé (CNERS, reference 025/CNERS/17). Potential study participants were informed how and why the study was carried out, and gave their written informed consent before inclusion in the study. For minor participants, an assent was obtained and written informed consent was provided by the parents or legal guardians. All clinical investigations were conducted according to the Declaration of Helsinki. | PMC10026442 |
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Consent for publication | Not applicable. | PMC10026442 |
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Competing interests | The authors declare that they have no competing interests. | PMC10026442 |
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References | PMC10026442 |
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Background and Purpose | hearing skills | Use of unilateral cochlear implant (UCI) is associated with limited spatial hearing skills. Evidence that training these abilities in UCI user is possible remains limited. In this study, we assessed whether a Spatial training based on hand-reaching to sounds performed in virtual reality improves spatial hearing abilities in UCI users | PMC10313844 |
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Methods | Using a crossover randomized clinical trial, we compared the effects of a Spatial training protocol with those of a Non-Spatial control training. We tested 17 UCI users in a head-pointing to sound task and in an audio-visual attention orienting task, before and after each training. <br>Study is recorded in clinicaltrials.gov (NCT04183348). | PMC10313844 |
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Results | During the Spatial VR training, sound localization errors in azimuth decreased. Moreover, when comparing head-pointing to sounds before vs. after training, localization errors decreased after the Spatial more than the control training. No training effects emerged in the audio-visual attention orienting task. | PMC10313844 |
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Conclusions | Our results showed that sound localization in UCI users improves during a Spatial training, with benefits that extend also to a non-trained sound localization task (generalization). These findings have potentials for novel rehabilitation procedures in clinical contexts. | PMC10313844 |
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Supplementary Information | The online version contains supplementary material available at 10.1007/s00405-023-07886-1. | PMC10313844 |
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Keywords | Open access funding provided by Università degli Studi di Trento within the CRUI-CARE Agreement. | PMC10313844 |
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Introduction | BILATERAL HEARING LOSS, NEUROSENSORY DEAFNESS | In case of neurosensory deafness, standard interventions often comprise the application of cochlear implants (CI). Although this surgery is indicated for people with bilateral hearing loss, many patients receive only one CI [In this context of impoverished auditory cues, can CI users improve their sound localization skills? In people with normal hearing listening with one ear plugged, sound localization abilities can be trained [In the present study, we leveraged such VR training protocol based on active interactions with the auditory scene. To test the efficacy of this training in 17 UCI users, we contrasted this Spatial training with a control procedure that did not entail processing of spatial features of the sound (i.e., the Non-Spatial training). Crucially, we compared these two VR trainings in a crossover experimental design, which allow us to test the effect of both training paradigms on each participant. Before and after each training paradigm, we tested participants in a head-pointing to sound localization task, which entails different sound positions and requires localizing sounds using a different effector (head instead of hand). In addition, to probe for training benefits when implicit sound localization is required, we tested participants in an audio-visual attention orienting task, in which they were asked to judge the elevation of a visual stimulus while listening a sudden sound. | PMC10313844 |
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Methods | PMC10313844 |
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Participants | neurological or psychiatric, HEH, vestibular deficit | Twenty UCI participants were recruited to participate in the study. Sample size was based on two previous experiments addressing a similar research question with an identical experimental design, but with different populations (normal hearing: [All participants were recruited at the ORL department of the civil hospital Edouard Herriot (HEH) in Lyon (France), and tested in a dedicated room inside the HEH premises. All had normal or corrected-to-normal vision and reported no movement or vestibular deficit, nor neurological or psychiatric history. Anamnestic and clinical data for individual UCI participants are provided in Table Anamnestic and clinical characteristics of CI participantsExtended information about participants’ cochlear implantsNote that the thresholds reported refer to PTA in the condition in which participant performed the experiment (with or without hearing aid) | PMC10313844 |
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Study design | head posture, HMD | The entire experiment was conducted inside VR environment. Participants wore a HMD (resolution: 1080 × 1200 px, Field Of View (FOV): 110°, Refresh rate: 90 Hz) that produced an immersive VR experience: participants always saw a reproduction of the room in which they were located. Importantly, the VR also allowed continuous tracking of their head posture and movements. All sounds were delivered from a real speaker, tracked in 3D space and moved by the experimenter’s hand to pre-determined positions within the VR environment (identical to the methods adopted in [Participants performed each of the two VR training (Spatial and Non-Spatial) in a within-subject crossover design, in two separate experimental sessions (washout interval was at least 15 days, training order was counterbalanced across participants; see Fig. Experimental procedure and setting. | PMC10313844 |
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Procedures | PMC10313844 |
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Testing phases | PMC10313844 |
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Head-pointing sound localization task | In each trial, a single auditory target (3 s white noise burst) was presented from 8 possible pre-determined positions (5 repetitions each, resulting in 40 trials in each testing phase). The 8 positions were placed at 55 cm from the center of the subject’s head and they varied along the azimuth dimension (± 22.5° and ± 67.5° with respect to the midsagittal plane) and vertical dimension (5° and − 15° with respect to the plane passing through the ears). The variation along the vertical dimension was introduce only to increase variability in the task, and we did not expect training-related changes in this dimension in which sound localization relies on monaural spectra cues. For this reason, we did not analyze performance along the vertical dimension or have hypothesis about participants errors along the vertical plane. While listening the sound, participants were not informed about the pre-determined target positions and were immersed in an empty virtual room (identical size to the real room, i.e., 3.6 m × 3.9 m, height 2.7 m). Participants were instructed to point with their head toward the perceived sound position, as soon as the sound finished, and validate their response using the VR controller they held in their right hand (Fig. | PMC10313844 |
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Audio-visual cueing task | This task aimed to assess to what extent lateralized sound could capture the participant’s audio-visual attention. The task was performed outside VR in the same room of the sound localization task, with participants sat at a desk in front of a computer monitor flanked by speakers. In each trial, a visual disk appeared above or below eye-level (± 1.15°), on the left or right side (128 trials overall, equiprobable across the four possible positions). Participants were instructed to discriminate the vertical position of the disk as fast and accurately as possible, using up/down arrows keys on the keyboard (Fig. | PMC10313844 |
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VR training tasks | Participants were immersed in the same virtual room as the head-pointing sound localization task, but saw 13 virtual loudspeakers spanning ± 72° in front space (see Fig. | PMC10313844 |
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Spatial VR training | Participants were instructed to reach the speaker emitting the sound using the VR controller they held in their right hand. The sound lasted until the participant reached and ‘touched’ the correct speaker. If they reached the wrong speaker, the correct loudspeaker started to display concentric red beams that expanded from the correct position to reach, and the sound continued until the correct location was finally reached (a video that illustrates the training tasks is available in 22, | PMC10313844 |
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Non-Spatial VR training | Participants were instructed to identify the amplitude modulation in the target sound, and indicate their discrimination through a reaching movement using VR controller. For fast amplitude-modulated sounds, participants reached in front of them, aiming to touch the invisible virtual button placed above the central speaker. For slow amplitude-modulated sounds, participants reached instead the invisible virtual button placed below the same central speaker. As in the Spatial Training feedback procedure, the sound stopped only when a correct response was provided. If they reached the wrong button, a visual feedback was displayed and the sound continued until the correct button was finally touched. In both trainings, the feeling of touch was induced by making the controller vibrate as soon as it collided with objects (speakers or invisible buttons). | PMC10313844 |
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Statistical analysis | head movements | Linear mixed-effect modeling was used for all statistical analyses. Statistical analyses were run using R (version 1.0.143). For the linear mixed-effect (LME) model, we used the R-packages emmean, lme4, lmerTest in R Studio [To study head movements, we extracted three dependent variables: number of head rotations, head-rotation extent and head-rotation bias [ | PMC10313844 |
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Results | PMC10313844 |
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VR training | PMC10313844 |
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Performance | hearing asymmetries, SD | The spatial discrepancy between the stimulated and the reached speaker (i.e., absolute localization error in azimuth, calculated as difference in absolute value between speaker and response position in azimuth in degrees) was on average 24.0 degrees (SD = 14.0), with a numerical (but not-significant) bias toward the side contralateral to the CI (− 2.6°, SD = 7.6; Sound localization performance. We analyzed the influence of hearing asymmetries in hearing thresholds (PTA) between the implanted and non-implanted ear on errors during the Spatial training. We found that the larger the asymmetry (i.e., the higher hearing thresholds in the contralateral ear), the larger the localization error (Performance in the Non-Spatial training was near ceiling for all participants (mean number of errors = 1.5%). During the Non-Spatial training, participants were also faster in completing the trial compared to the Spatial training (Non-Spatial: mean ± SD = 2.5 ± 2.1 s; Spatial training: mean ± SD = 16.1 ± 10.2 s; | PMC10313844 |
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Head movements | head movements | Head rotations were overall more frequent in the Spatial (6.51 ± 3.15) compared to the Non-Spatial VR training (1.5 ± 1.0, During the Spatial VR training, we observed that UCI users adapted their spontaneous head movements as a function of sound eccentricity as training trials progressed. Specifically, number of head rotations (Head rotation during the Spatial training. | PMC10313844 |
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Effects beyond the trained task | PMC10313844 |
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Head-pointing to sounds | PMC10313844 |
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Performance | The Spatial VR training improved performance (i.e., decreased absolute error in azimuth) more than the Non-Spatial training, irrespective of the session in which it was completed (Spatial—pre: 52.6° ± 26.2°; post: 39.3° ± 23.5°; Non-Spatial training—pre: 43.8° ± 27.4°; post: 42.0° ± 27.6°, As documented above, individual asymmetries in hearing thresholds between the implanted and non-implanted ear influenced performance: the higher the threshold in the contralateral ear, the higher the error (Trainings also influenced the response bias in sound localization (i.e., the signed error). In the pre-training session, no overall bias toward the side contralateral to the CI was measured (− 1.1°, SD = 39.2; To further examine the effect of training on head-pointing to sounds, we analyzed the direction of the first head-rotation in each trial. This measure captures the immediate orienting response toward the sound. We found that participants discriminated the side of sounds source (ipsilateral: 24.09 ± 39.42; contralateral; − 17.18 ± 47.19, | PMC10313844 |
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Head movements | head movements | In order to describe changes in head movement after training, we measured number of head rotations, head-rotation extent, head-rotation bias and direction of the first head movements during the sound (see Analysis for a description of these variables). We report here the main findings, but see Supplementary Materials for further details (Table S8).Participants changed their head-related behavior after each of the training. In the post-training session, they increased the number of movements (Pre: 1.90 ± 0.65; Post: 2.06 ± 0.52, Head-rotation bias during the Head-pointing to sounds task, as a function of training (Spatial Training and Non-Spatial training) and Phase (Before training in black and post-training in grey). Error bars represent standard errorsHead movements also changed as a function of hearing asymmetry. Participants with greater hearing asymmetry increased their head-rotation extent after the Spatial compared to Non-Spatial VR training more than participants with less hearing asymmetry ( | PMC10313844 |
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Audio-visual attention orienting task | When people with normal hearing are asked to make a visual discrimination (here on the elevation of the visual target, up vs. down), they are faster when the visual target is preceded by a sound located in the same (congruent) vs. opposite side of the space (incongruent) [ | PMC10313844 |
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Discussion | hearing threshold, head movements, head movements’ behavior, head-movement behaviors, hearing asymmetry, hearing in monaural listening conditions [ | UNILATERAL HEARING LOSS | We observed that UCI users can improve their sound localization abilities, despite the substantial impoverishment of the available auditory cues. Thus, acoustic space perception improvement is possible also for people using a single CI, at least in the experimental context we have examined. Specifically, we showed that sound localization of UCI users can improve across trials while engaged in a Spatial VR training and that error reduction extended beyond the trained task. Localization errors decreased after training, as compared to before training, and this decrement (about 13°) was greater after the Spatial compared to the Non-Spatial VR training. Further analyses revealed that hearing asymmetry (as described by PTA at the non-implanted ear) modulated training benefit. Generalization effect of Spatial training was more pronounced for participants with higher hearing asymmetry (i.e., higher hearing threshold at the contralateral ear). Finally, the Spatial VR training had no impact on the audio-visual orienting task, which involves the ability to localize sounds sources indirectly. A possible explanation for the lack of this effect is that active listening was prevented during this task as, for experimental reasons, it was performed using a chin-rest. Although this test represents a firm attempt to test the generalization effect, further studies are needed to investigate the transferability of training effects to tasks in which the ability to localize sounds is implicitly involved.A previous study by Luntz and colleagues already suggested that training UCI spatial hearing skill is possible, but this early report suffered from methodological limitations. They tested only few participants (Interestingly, our short training produced effects also in a sound localization task entailing different sound positions, a different response method (i.e., use of the head as pointer instead of reaching sound sources using the hand), and less visual cues available (i.e., potential sounds sources invisible during the test). The difference between the trained task and the test task (i.e., head-pointing to sound) is clearly evident also in the different performance achieved by the participants in the two sound localization procedures. While in the trained task, the absolute error for participants in the Spatial training group was 24° on average, in the test task, they started from an average absolute error of 52.6° to achieve a performance of 39.3° at the end of training. This difference is likely the consequence of the different priors about sound position in the two procedures: during training, all possible sound positions were visually identified, whereas during test, no visual cue helps participants to locate the sound sources.This result highlights the importance of assessing generalization effect when testing the efficacy of training protocols (see also [Given the large interindividual variability in terms of hearing experience, we investigated if hearing asymmetry influenced sound localization performance and training effects. We observed an increase in the effectiveness of the Spatial training for UCI users with higher levels of hearing asymmetry. This finding supports the idea that it is possible to improve localization of sounds even when auditory cues available are primarily monaural intensity cues, and opens the possibility to offer a similar training to people with unilateral hearing loss. Since the larger training effectiveness was documented in individuals who primarily listen monaurally using their CI, rather than individuals with bimodal experience providing binaural cues, this finding suggest that our training primarily changed the way in which participants exploited the available intensity monaural cues (but see [A further contribution of the present work concerns the study of head movements’ behavior. First, during training, participants requiring progressively fewer head movements to perform the task and reduced the extent of their head rotation when responding to central targets. This corroborates the observation of a trial-by-trial improvement, that we described above in terms of progressive reduction of performance errors. Second, after training, head movements changed between the pre- and post-training measurements. When we focused on the first head-movement onset during the head-pointing to sounds test, we observed that the correct direction of the sound was identified faster after the Spatial compared to the Non-Spatial VR training. Third, participants also started to spontaneously implement novel head-movement behaviors after the training. Specifically, they increased the number of movements and explored a larger portion of space with the head. This was particularly evident after the Spatial VR training, hinting at the possibility that they moved the head strategically to bring their CI toward the sounds. This strategy might have favored the extraction and use of monaural intensity variation at the CI—pointing again to an advantage of the Spatial training mostly related to the use of monaural cues available at the unilateral CI. This strategy has been already documented in previous studies testing people with normal hearing in monaural listening conditions [ | PMC10313844 |
Conclusion | Using a novel VR training based on reaching to sounds, audio-visual feedback and free head movements during listening, we documented that training sound localization ability in UCI users is possible. While these observations emerged in laboratory setting, they have direct translational implications for the clinical context because the observed improvements did not result from changes in hearing settings and hearing thresholds of the participants. Instead, they were likely the result of recalibration processes and self-regulatory behavior, triggered by a combination of multisensory feedback and actions directed to sounds (with the hand and the head). In turn, these allowed participants to better exploit the residual auditory cues when processing auditory space. | PMC10313844 |
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Acknowledgements | P. | BLIND, FOUNDER | We are grateful to all the participants who accepted to participate in this study. C. V. was supported by a grant of the Università Italo-Francese/Université Franco-Italienne, the Zegna Founder’s Scholarship and Associazione Amici di Claudio Demattè. F. P. , A.F. and V.G. were supported by a grant of the Agence Nationale de la Recherche (ANR-16-CE17-0016, VIRTUALHEARING3D, France), by a prize of the Foundation Medisite (France), by the Neurodis Foundation (France) and by a grant from the Italian Ministry for Research and University (MUR, PRIN 20177894ZH). The study was supported by the IHU CaSaMe ANR-10-UBHU-0003 and ANR 2019CE37 Blind Touch. We thank J.L. Borach and S. Alouche for administrative support, E. Koun for informatics support and Giordana Torresani for graphical support (Figs. | PMC10313844 |
Author contributions | RS, FM | CV, FP, and AF conceptualized and designed the experiment and managed funding acquisition and project administration. CV, SB, SG, and FM performed the experiment. CV and FP analyzed data and wrote the paper. GV and RS worked on software. FP, AF and ET supervised the project and managed funding. LR, JG, AC, and VG helped in recruiting the patients. | PMC10313844 |
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Funding | Open access funding provided by Università degli Studi di Trento within the CRUI-CARE Agreement. | PMC10313844 |
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Data availability | Data can be retrieved osf.io/mbshq. | PMC10313844 |
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Declarations | PMC10313844 |
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Conflict of interest | The authors have no conflicts of interest to declare. | PMC10313844 |
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References | PMC10313844 |
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Abstract |
All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. | PMC10640691 |
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Background | coronavirus disease 2019 | CORONAVIRUS DISEASE 2019 | There is growing consensus that coronavirus disease 2019 booster vaccines may be coadministered with other age-appropriate vaccines. Adding to the limited available data supporting coadministration, especially with adjuvanted vaccines, could enhance vaccine coverage in adults. | PMC10640691 |
Methods | zoster | ZOSTER, SECONDARY | In this phase 3, randomized, open-label study, eligible adults aged ≥50 years were randomly assigned (1:1) to receive mRNA-1273 (50 µg) booster vaccination and a first dose of recombinant zoster vaccine (RZV1) 2 weeks apart (Seq group) or concomitantly (Coad group). The second RZV dose (RZV2) was administered 2 months post-RZV1 in both groups. Primary objectives were noninferiority of anti–glycoprotein E (gE) and anti–spike protein antibody responses in the Coad group compared to the Seq group. Safety and further immunogenicity assessments were secondary objectives. | PMC10640691 |
Results | myalgia, mild/moderate, pain | ADVERSE EVENTS | In total, 273 participants were randomized to the Seq group and 272 to the Coad group. Protocol-specified noninferiority criteria were met. The adjusted geometric mean concentration ratio (Seq/Coad) was 1.01 (95% confidence interval [CI], .89–1.13) for anti-gE antibodies 1 month post-RZV2, and 1.09 (95% CI, .90–1.32) for anti–spike antibodies 1 month post–mRNA-1273 booster. No clinically relevant differences were observed in overall frequency, intensity, or duration of adverse events between the 2 study groups. Most solicited adverse events were mild/moderate in intensity, each with median duration ≤2.5 days. Administration site pain and myalgia were the most frequently reported in both groups. | PMC10640691 |
Conclusions | zoster | ZOSTER | Coadministration of mRNA-1273 booster vaccine with RZV in adults aged ≥50 years was immunologically noninferior to sequential administration and had a safety and reactogenicity profile consistent with both vaccines administered sequentially.
When coadministered, mRNA-1273 COVID-19 booster vaccine and recombinant zoster vaccine had safety profiles and elicited immune responses consistent with when they were administered sequentially, supporting a way to improve vaccination coverage by coadministration and thereby reducing morbidity and mortality. | PMC10640691 |
Graphical Abstract | zoster, varicella zoster, coronavirus disease 2019 | ZOSTER, VARICELLA ZOSTER, VIRUS, CORONAVIRUS DISEASE 2019, DISEASE, CORONAVIRUS, DISEASE, SEVERE ACUTE RESPIRATORY SYNDROME, INFLUENZA |
Accumulating real-world data substantiate the protective benefits of messenger RNA (mRNA) coronavirus disease 2019 (COVID-19) vaccines and the need for additional doses beyond the primary series due to waning immunity and/or emergence of new variants [Numerous health agencies including the United States (US) Centers for Disease Control and Prevention (CDC) have recommended, in the absence of specific contraindications, administration of COVID-19 booster vaccines on the same day as other vaccines [When addressing coadministration of COVID-19 vaccines with other vaccines, the CDC recommends to consider the reactogenicity profile of the vaccines. The CDC notes that it is unknown whether reactogenicity of COVID-19 vaccine is increased with coadministration, particularly with vaccines known to be more reactogenic, such as adjuvanted vaccines [The adjuvanted recombinant zoster vaccine (RZV; Shingrix, GSK) is a non-live subunit vaccine that contains the varicella zoster virus glycoprotein E (gE) as the active ingredient, together with the liposome-based adjuvant system AS01Moderna's COVID-19 vaccine, mRNA-1273, is an mRNA-based vaccine encapsulated in a lipid nanoparticle. The vaccine includes a single mRNA sequence encoding the prefusion stabilized spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Wuhan strain. Two doses of 100 µg mRNA-1273, as a primary series, showed 94.1% efficacy at preventing COVID-19, including severe disease [Although coadministration with RZV is not contraindicated, no clinical trial data are available on its coadministration with COVID-19 vaccines. To address this data gap and provide evidence-based guidance for healthcare providers making decisions on such vaccine coadministrations, we conducted a clinical trial to assess the safety and immunogenicity of coadministration of a booster dose (50 µg) of mRNA-1273 with either seasonal quadrivalent influenza vaccine in adults aged ≥18 years, or RZV in adults aged ≥50 years. The results of coadministration of RZV and mRNA-1273 are reported here. | PMC10640691 |
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