Feasibility, safety, efficacy and potential scaling-up of sofosbuvir-based HCV treatment in Central and West Africa: (TAC ANRS 12311 trial).

Access to Hepatis C treatment in Sub-Saharan Africa is a clinical, public health and ethical concern. The multi-country open-label trial TAC ANRS 12311 allowed assessing the feasibility, safety, efficacy of a specific care model of HCV treatment and retreatment in patients with hepatitis C in Sub Saharan Africa. Between November 2015 and March 2017, with follow-up until mid 2019, treatment-naïve patients with HCV without decompensated cirrhosis or liver cancer were recruited to receive 12 week-treatment with either sofosbuvir + ribavirin (HCV genotype 2) or sofosbuvir + ledipasvir (genotype 1 or 4) and retreatment with sofosbuvir + velpatasvir + voxilaprevir in case of virological failure. The primary outcome was sustained virological response at 12 weeks after end of treatment (SVR12). Secondary outcomes included treatment adherence, safety and SVR12 in patients who were retreated due to non-response to first-line treatment. The model of care relied on both viral load assessment and educational sessions to increase patient awareness, adherence and health literacy. The study recruited 120 participants, 36 HIV-co-infected, and 14 cirrhotic. Only one patient discontinued treatment because of return to home country. Neither death nor severe adverse event occurred. SVR12 was reached in 107 patients (89%): (90%) in genotype 1 or 2, and 88% in GT-4. All retreated patients (n = 13) reached SVR12. HCV treatment is highly acceptable, safe and effective under this model of care. Implementation research is now needed to scale up point-of-care HCV testing and SVR assessment, along with community involvement in patient education, to achieve HCV elimination in Sub-Saharan Africa.

Cardiac Adverse Events and Remdesivir in Hospitalized Patients with Coronavirus Disease 2019 (COVID-19): A Post Hoc Safety Analysis of the Randomized DisCoVeRy Trial.

BACKGROUND: We aimed to evaluate the cardiac adverse events (AEs) in hospitalized patients with Coronavirus Disease 2019 (COVID-19) receiving remdesivir plus standard of care (SoC) compared to SoC alone (control), as an association was noted in some cohort studies and disproportionality analyses of safety databases. METHODS: This post-hoc safety analysis is based on data from the multicenter, randomized, open-label, controlled DisCoVeRy trial in hospitalized patients with COVID-19 (NCT04315948). Any first AE occurring between randomization and day 29 in the modified intention-to-treat (mITT) population randomized to either remdesivir or control group was considered. Analysis was performed using Kaplan-Meier survival curves and Kaplan-Meier estimates were calculated for event rates. RESULTS: Cardiac AEs were reported in 46 (11.2%) of 410 and 48 (11.3%) of 423 patients in the mITT population (n = 833) enrolled in the remdesivir and control groups, respectively. The difference between both groups was not significant (HR 1.0, 95% CI 0.7-1.5, p = 0.98), even when evaluating serious and non-serious cardiac AEs separately. The majority of reports in both groups were of arrhythmic nature (remdesivir, 84.8%; control, 83.3%) and were associated with a favorable outcome. There was no significant difference between remdesivir and control groups in the occurrence of different cardiac AE subclasses, including arrhythmic events (HR 1.1, 95% CI: 0.7-1.7, p = 0.68). CONCLUSIONS: Remdesivir treatment was not associated with an increased risk of cardiac AEs, whether serious or not, and regardless of AE severity, compared to control, in patients hospitalized with moderate or severe COVID-19. This is consistent with the results of other randomized controlled trials and meta-analyses.

Multiple cardiovascular risk factor care in 55 low- and middle-income countries: A cross-sectional analysis of nationally-representative, individual-level data from 280,783 adults.

The prevalence of multiple age-related cardiovascular disease (CVD) risk factors is high among individuals living in low- and middle-income countries. We described receipt of healthcare services for and management of hypertension and diabetes among individuals living with these conditions using individual-level data from 55 nationally representative population-based surveys (2009-2019) with measured blood pressure (BP) and diabetes biomarker. We restricted our analysis to non-pregnant individuals aged 40-69 years and defined three mutually exclusive groups (i.e., hypertension only, diabetes only, and both hypertension-diabetes) to compare individuals living with concurrent hypertension and diabetes to individuals with each condition separately. We included 90,086 individuals who lived with hypertension only, 11,975 with diabetes only, and 16,228 with hypertension-diabetes. We estimated the percentage of individuals who were aware of their diagnosis, used pharmacological therapy, or achieved appropriate hypertension and diabetes management. A greater percentage of individuals with hypertension-diabetes were fully diagnosed (64.1% [95% CI: 61.8-66.4]) than those with hypertension only (47.4% [45.3-49.6]) or diabetes only (46.7% [44.1-49.2]). Among the hypertension-diabetes group, pharmacological treatment was higher for individual conditions (38.3% [95% CI: 34.8-41.8] using antihypertensive and 42.3% [95% CI: 39.4-45.2] using glucose-lowering medications) than for both conditions jointly (24.6% [95% CI: 22.1-27.2]).The percentage of individuals achieving appropriate management was highest in the hypertension group (17.6% [16.4-18.8]), followed by diabetes (13.3% [10.7-15.8]) and hypertension-diabetes (6.6% [5.4-7.8]) groups. Although health systems in LMICs are reaching a larger share of individuals living with both hypertension and diabetes than those living with just one of these conditions, only seven percent achieved both BP and blood glucose treatment targets. Implementation of cost-effective population-level interventions that shift clinical care paradigm from disease-specific to comprehensive CVD care are urgently needed for all three groups, especially for those with multiple CVD risk factors.

Comparative evolutionary analyses of peste des petits ruminants virus genetic lineages.

Peste des petits ruminants virus (PPRV) causes a highly infectious disease affecting mainly goats and sheep in large parts of Africa, Asia, and the Middle East and has an important impact on the global economy and food security. Full genome sequencing of PPRV strains has proved to be critical to increasing our understanding of PPR epidemiology and to inform the ongoing global efforts for its eradication. However, the number of full PPRV genomes published is still limited and with a heavy bias towards recent samples and genetic Lineage IV (LIV), which is only one of the four existing PPRV lineages. Here, we generated genome sequences for twenty-five recent (2010-6) and seven historical (1972-99) PPRV samples, focusing mainly on Lineage II (LII) in West Africa. This provided the first opportunity to compare the evolutionary pressures and history between the globally dominant PPRV genetic LIV and LII, which is endemic in West Africa. Phylogenomic analysis showed that the relationship between PPRV LII strains was complex and supported the extensive transboundary circulation of the virus within West Africa. In contrast, LIV sequences were clearly separated per region, with strains from West and Central Africa branched as a sister clade to all other LIV sequences, suggesting that this lineage also has an African origin. Estimates of the time to the most recent common ancestor place the divergence of modern LII and LIV strains in the 1960s-80s, suggesting that this period was particularly important for the diversification and spread of PPRV globally. Phylogenetic relationships among historical samples from LI, LII, and LIII and with more recent samples point towards a high genetic diversity for all these lineages in Africa until the 1970s-80s and possible bottleneck events shaping PPRV's evolution during this period. Molecular evolution analyses show that strains belonging to LII and LIV have evolved under different selection pressures. Differences in codon usage and adaptative selection pressures were observed in all viral genes between the two lineages. Our results confirm that comparative genomic analyses can provide new insights into PPRV's evolutionary history and molecular epidemiology. However, PPRV genome sequencing efforts must be ramped up to increase the resolution of such studies for their use in the development of efficient PPR control and surveillance strategies.

Predictors of severity and prolonged hospital stay of viral acute respiratory infections (ARI) among children under five years in Burkina Faso, 2016-2019.

BACKGROUND: Viruses are the leading etiology of acute respiratory infections (ARI) in children. However, there is limited knowledge on drivers of severe acute respiratory infection (SARI) cases involving viruses. We aimed to identify factors associated with severity and prolonged hospitalization of viral SARI among children < 5 years in Burkina Faso. METHODS: Data were collected from four SARI sentinel surveillance sites during October 2016 through April 2019. A SARI case was a child < 5 years with an acute respiratory infection with history of fever or measured fever ≥ 38 °C and cough with onset within the last ten days, requiring hospitalization. Very severe ARI cases required intensive care or had at least one danger sign. Oropharyngeal/nasopharyngeal specimens were collected and analyzed by multiplex real-time reverse-transcription polymerase chain reaction (rRT-PCR) using FTD-33 Kit. For this analysis, we included only SARI cases with rRT-PCR positive test results for at least one respiratory virus. We used simple and multilevel logistic regression models to assess factors associated with very severe viral ARI and viral SARI with prolonged hospitalization. RESULTS: Overall, 1159 viral SARI cases were included in the analysis after excluding exclusively bacterial SARI cases (n = 273)very severe viral ARI cases were common among children living in urban areas (AdjOR = 1.3; 95% CI: 1.1-1.6), those < 3 months old (AdjOR = 1.5; 95% CI: 1.1-2.3), and those coinfected with Klebsiella pneumoniae (AdjOR = 1.9; 95% CI: 1.2-2.2). Malnutrition (AdjOR = 2.2; 95% CI: 1.1-4.2), hospitalization during the rainy season (AdjOR = 1.71; 95% CI: 1.2-2.5), and infection with human CoronavirusOC43 (AdjOR = 3; 95% CI: 1.2-8) were significantly associated with prolonged length of hospital stay (> 7 days). CONCLUSION: Younger age, malnutrition, codetection of Klebsiella pneumoniae, and illness during the rainy season were associated with very severe cases and prolonged hospitalization of SARI involving viruses in children under five years. These findings emphasize the need for preventive actions targeting these factors in young children.

Prophylactic Intravenous Acetaminophen in Extremely Premature Infants: Minimum Effective Dose Research by Bayesian Approach.

BACKGROUND: Patent ductus arteriosus (PDA) in preterm infants is associated with increased morbidities and mortality. Prophylactic treatment with cyclooxygenase inhibitors, as indomethacin or ibuprofen, failed to demonstrate significant clinical benefits. Acetaminophen may represent an alternative treatment option. OBJECTIVE: This study evaluated the minimum effective dose of prophylactic acetaminophen to close the ductus and assessed the safety and tolerability profile in extremely preterm infants at 23-26 weeks of gestation. METHODS: A dose finding trial with Bayesian continual reassessment method was performed in a multicenter study with premature infants hospitalized in neonatal intensive care unit. Infants of 23-26 weeks of gestation and post-natal age ≤ 12 h were enrolled. Four intravenous acetaminophen dose levels were predefined. The primary outcome was the ductus arteriosus closing at two consecutive echocardiographies or at day 7. The main secondary objectives included the safety of acetaminophen on hemodynamics and biological hepatic function. RESULTS: A total of 29 patients were analyzed sequentially for the primary analysis with 20 infants assigned to the first dose level followed by 9 infants to the second dose level. No further dose level increase was necessary. The posterior probabilities of success, estimated from the Bayesian logistic model, were 46.1% [95% probability interval (PI), 24.9-63.9] and 67.6% (95% PI, 51.5-77.9) for dose level 1 and 2, respectively. A closing or closed pattern was observed among 19 patients at the end of treatment [65.5% (95% confidence interval (CI), 45.7-82.0)]. No change in alanine aminotransferase values was observed during treatment. A significant decrease in aspartate aminotransferase values was observed with postnatal age. No change in systolic and diastolic blood pressures was observed during treatment. CONCLUSIONS: Minimum effective dose to close the ductus was 25 mg/kg loading dose then 10 mg/kg/6 h for 5 days in extremely preterm infants. Acetaminophen was well tolerated in this study following these doses. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04459117.

MOSAIC: A cohort study of human mpox virus disease.

Background: Human mpox is a viral disease caused by an Orthopoxvirus, human mpox virus (hMPXV), typically causing fever and a rash. Mpox has historically been endemic to parts of Central and West Africa, with small numbers of imported cases reported elsewhere, but starting May 2022 an unprecedented global outbreak caused by clade IIb hMPXV was reported outside traditionally endemic countries. This prompted the initiation of MOSAIC, a cohort study implemented in Europe and Asia that aims to describe clinical and virologic outcomes of PCR-confirmed hMPXV disease, including those who receive antiviral therapy. The focus of this article, however, is on describing the study protocol itself with implementation process and operational challenges. Methods: MOSAIC recruits participants of any age with laboratory-confirmed mpox disease who provide informed consent. Participants enrol in the cohort for a total of six months. Blood, lesion and throat samples are collected at several timepoints from the day of diagnosis or the first day of treatment (Day 1) until Day 28 for PCR detection of hMPXV. Clinical data are collected by clinicians and participants (via a self-completion questionnaire) for six months to characterize the signs and symptoms associated with the illness, as well as short- and more long-term outcomes. Discussion: The design and prompt implementation of clinical research response is key in addressing emerging outbreaks. MOSAIC began enrolment within two months of the start of the international mpox epidemic. Enrolment has been stopped and the last follow-up visits are expected in January 2024. ICTRP registration: EU CT number: 2022-501132-42-00 (22/06/2022).

Effectiveness of Trachomatous Trichiasis Case-identification Approaches in Ethiopia.

BACKGROUND: Trachoma control programs use multiple approaches to identify individuals with trachomatous trichiasis (TT). Evidence is limited regarding which approaches are most effective and cost-efficient. METHODS: We evaluated the effectiveness of two TT case-identification approaches in Ethiopia: community mobilization to encourage self-referral for centralized screening and house-to-house screenings conducted by case finders. We compared the number of true cases found per 1000 population and costs associated with case identification under each approach, stratified by villages that received one or multiple screening visits. RESULTS: We conducted screenings in 396 villages. In villages receiving one house-to-house visit, case finders identified 14,229 suspected cases, of whom 10,513 (73.9%) presented for TT confirmation. A median of 17.2% (interquartile range [IQR]: 9.1%-27.8%) of those presenting truly had TT (positive predictive value). In single-visit villages, the community mobilization approach yielded higher rates of confirmed cases than the house-to-house approach (1.5 [IQR: 1.1, 2.6] vs. 1.1 [IQR: 0.5, 1.9] cases per 1000 population), and the median cost of identifying a TT case was less ($5.59 vs. $31.18) using community mobilization than house-to-house. In multiple-visit villages, additional screening visits increased the median rate of confirmed cases to 2.5 per 1000 population in community mobilization villages, but the rate remained unchanged in house-to-house villages. CONCLUSIONS: Community mobilization-based TT case finding had a higher yield than house-to-house, at a substantially lower cost. Future research should examine whether additional tools to aid case finders in their diagnosis increases case-finding efficiency and accuracy and whether TT prevalence and surgical program duration impact case-finding success.

Diabetes risk and provision of diabetes prevention activities in 44 low-income and middle-income countries: a cross-sectional analysis of nationally representative, individual-level survey data.

BACKGROUND: The global burden of diabetes is rising rapidly, yet there is little evidence on individual-level diabetes prevention activities undertaken by health systems in low-income and middle-income countries (LMICs). Here we describe the population at high risk of developing diabetes, estimate diabetes prevention activities, and explore sociodemographic variation in these activities across LMICs. METHODS: We performed a pooled, cross-sectional analysis of individual-level data from nationally representative, population-based surveys conducted in 44 LMICs between October, 2009, and May, 2019. Our sample included all participants older than 25 years who did not have diabetes and were not pregnant. We defined the population at high risk of diabetes on the basis of either the presence of impaired fasting glucose (or prediabetes in countries with a haemoglobin A1c available) or overweight or obesity, consistent with the WHO Package of Essential Noncommunicable Disease Guidelines for type 2 diabetes management. We estimated the proportion of survey participants that were at high risk of developing diabetes based on this definition. We also estimated the proportion of the population at high risk that reported each of four fundamental diabetes prevention activities: physical activity counselling, weight loss counselling, dietary counselling, and blood glucose screening, overall and stratified by World Bank income group. Finally, we used multivariable Poisson regression models to evaluate associations between sociodemographic characteristics and these activities. FINDINGS: The final pooled sample included 145 739 adults (86 269 [59·2%] of whom were female and 59 468 [40·4%] of whom were male) across 44 LMICs, of whom 59 308 (40·6% [95% CI 38·5-42·8]) were considered at high risk of diabetes (20·6% [19·8-21·5] in low-income countries, 38·0% [37·2-38·9] in lower-middle-income countries, and 57·5% [54·3-60·6] in upper-middle-income countries). Overall, the reach of diabetes prevention activities was low at 40·0% (38·6-41·4) for physical activity counselling, 37·1% (35·9-38·4) for weight loss counselling, 42·7% (41·6-43·7) for dietary counselling, and 37·1% (34·7-39·6) for blood glucose screening. Diabetes prevention varied widely by national-level wealth: 68·1% (64·6-71·4) of people at high risk of diabetes in low-income countries reported none of these activities, whereas 49·0% (47·4-50·7) at high risk in upper-middle-income countries reported at least three activities. Educational attainment was associated with diabetes prevention, with estimated increases in the predicted probability of receipt ranging between 6·5 (3·6-9·4) percentage points for dietary fruit and vegetable counselling and 21·3 (19·5-23·2) percentage points for blood glucose screening, among people with some secondary schooling compared with people with no formal education. INTERPRETATION: A large proportion of individuals across LMICs are at high risk of diabetes but less than half reported receiving fundamental prevention activities overall, with the lowest receipt of these activities among people in low-income countries and with no formal education. These findings offer foundational evidence to inform future global targets for diabetes prevention and to strengthen policies and programmes to prevent continued increases in diabetes worldwide. FUNDING: Harvard T H Chan School of Public Health McLennan Fund: Dean's Challenge Grant Program and the EU's Research and Innovation programme Horizon 2020.

Malignant hypercalcemia revealing a diffuse large B-cell lymphoma in a patient with a previous diagnosis of chronic myelomonocytic leukemia: An uncommon hematological coexistence.

A 76-year-old patient previously admitted to the cardiology department for replacement of a right ventricular lead on a double-chamber pacemaker was admitted to the internal medicine department 15 days after for bronchopneumopathy. His past medical history was relevant for Type 2 diabetes mellitus, heart failure due to dilated hypokinetic heart disease, transcatheter aortic valve implantation (TAVI), and chronic myelomonocytic leukemia (CMML-0) diagnosed in 2021. Twenty-four hours after admission, the patient's general condition deteriorated abruptly, with the onset of drowsiness and psychomotor retardation. Laboratory exams revealed hypercalcemia at 4.18 mmol/L. Intensive hydration, calcitonin, and zoledronic acid were initiated and the patient was transferred to the nephrology intensive care unit where he underwent two sessions of hemodialysis to normalize serum calcium levels before readmission to internal medicine. Laboratory exams revealed low parathyroid hormone, normal 1-25-OH vitamin D, and increased parathyroid hormone-related peptide. Thoracoabdominal and positron emission tomography (PET) scan showed diffuse abdominopelvic peritoneal carcinosis associated with low-grade pleural effusion and multiple supra- and sub-diaphragmatic adenopathies, leading to a search for a solid tumor. The patient's clinical condition worsened leading to a transfer to the intensive care unit. The biopsy of a peritoneal carcinosis nodule confirmed the diagnosis of diffuse large B-cell lymphoma. Specific treatments were unsuccessful and the patient expired.

Impact of malaria diagnostic choice on monitoring of Plasmodium falciparum prevalence estimates in the Democratic Republic of the Congo and relevance to control programs in high-burden countries.

Malaria programs rely upon a variety of diagnostic assays, including rapid diagnostic tests (RDTs), microscopy, polymerase chain reaction (PCR), and bead-based immunoassays (BBA), to monitor malaria prevalence and support control and elimination efforts. Data comparing these assays are limited, especially from high-burden countries like the Democratic Republic of the Congo (DRC). Using cross-sectional and routine data, we compared diagnostic performance and Plasmodium falciparum prevalence estimates across health areas of varying transmission intensity to illustrate the relevance of assay performance to malaria control programs. Data and samples were collected between March-June 2018 during a cross-sectional household survey across three health areas with low, moderate, and high transmission intensities within Kinshasa Province, DRC. Samples from 1,431 participants were evaluated using RDT, microscopy, PCR, and BBA. P. falciparum parasite prevalence varied between diagnostic methods across all health areas, with the highest prevalence estimates observed in Bu (57.4-72.4% across assays), followed by Kimpoko (32.6-53.2%), and Voix du Peuple (3.1-8.4%). Using latent class analysis to compare these diagnostic methods against an "alloyed gold standard," the most sensitive diagnostic method was BBA in Bu (high prevalence) and Voix du Peuple (low prevalence), while PCR diagnosis was most sensitive in Kimpoko (moderate prevalence). RDTs were consistently the most specific diagnostic method in all health areas. Among 9.0 million people residing in Kinshasa Province in 2018, the estimated P. falciparum prevalence by microscopy, PCR, and BBA were nearly double that of RDT. Comparison of malaria RDT, microscopy, PCR, and BBA results confirmed differences in sensitivity and specificity that varied by endemicity, with PCR and BBA performing best for detecting any P. falciparum infection. Prevalence estimates varied widely depending on assay type for parasite detection. Inherent differences in assay performance should be carefully considered when using community survey and surveillance data to guide policy decisions.

Management of pharmacovigilance during the COVID-19 pandemic crisis by the safety department of an academic sponsor: Lessons learnt and challenges from the EU DisCoVeRy clinical trial.

The current COVID-19 pandemic was an exceptional health situation, including for drug use. As there was no known effective drug for COVID-19 at the beginning of the pandemic, different drug candidates were proposed. In this article, we present the challenges for an academic Safety Department to manage the global safety of a European trial during the pandemic. The National Institute for Health and Medical Research (Inserm) conducted a European multicenter, open-label, randomized, controlled trial involving three repurposed and one-in development drugs (lopinavir/ritonavir, IFN-ß1a, hydroxychloroquine, and remdesivir) in adults hospitalized with COVID-19. From 25 March 2020 to 29 May 2020, the Inserm Safety Department had to manage 585 Serious Adverse Events (SAEs) initial notification and 396 follow-up reports. The Inserm Safety Department's staff was mobilized to manage these SAEs and to report Expedited safety reports to the competent authorities within the legal timeframes. More than 500 queries were sent to the investigators due to a lack of or incoherent information on SAE forms. At the same time, the investigators were overwhelmed by the management of patients suffering from COVID-19 infection. These particular conditions of missing data and lack of accurate description of adverse events made evaluation of the SAEs very difficult, particularly the assessment of the causal role of each investigational medicinal product. In parallel, working difficulties were accentuated by the national lockdown, frequent IT tool dysfunctions, delayed implementation of monitoring and the absence of automatic alerts for SAE form modification. Although COVID-19 is a confounding factor per se, the delay in and quality of SAE form completion and the real-time medical analysis by the Inserm Safety Department were major issues in the quick identification of potential safety signals. To conduct a high-quality clinical trial and ensure patient safety, all stakeholders must take their roles and responsibilities.

Ensuring quality control in a COVID-19 clinical trial during the pandemic: The experience of the Inserm C20-15 DisCoVeRy study.

SETTING: Health measures taken during the pandemic deeply modified the clinical research practices. At the same time, the demand for the results of the COVID-19 trials was urgent. Thus, the objective of this article is to share Inserm's experience in ensuring quality control in clinical trials in this challenging context. OBJECTIVES: DisCoVeRy is a phase III randomized study that aimed at evaluating the safety and efficacy of 4 therapeutic strategies in hospitalized COVID-19 adult patients. Between March, 22nd 2020 and January, 20th 2021, 1309 patients were included. In order to guarantee the best quality of data, the Sponsor had to adapt to the current sanitary measures and to their impact on clinical research activity, notably by adapting Monitoring Plan objectives, involving the research departments of the participating hospitals and a network of clinical research assistants (CRAs). RESULTS: Overall, 97 CRAs were involved and performed 909 monitoring visits. The monitoring of 100% of critical data for all patients included in the analysis was achieved, and despite of the pandemic context, a conform consent was recovered for more than 99% of patients. Results of the study were published in May and September 2021. DISCUSSION/CONCLUSION: The main monitoring objective was met thanks to the mobilization of considerable personnel resources, within a very tight time frame and external hurdles. There is a need for further reflection to adapt the lessons learned from this experience to the context of routine practice and to improve the response of French academic research during a future epidemic.

Estimated Effectiveness of JYNNEOS Vaccine in Preventing Mpox: A Multijurisdictional Case-Control Study - United States, August 19, 2022-March 31, 2023.

As of March 31, 2023, more than 30,000 monkeypox (mpox) cases had been reported in the United States in an outbreak that has disproportionately affected gay, bisexual, and other men who have sex with men (MSM) and transgender persons (1). JYNNEOS vaccine (Modified Vaccinia Ankara vaccine, Bavarian Nordic) was approved by the Food and Drug Administration (FDA) in 2019 for the prevention of smallpox and mpox via subcutaneous injection as a 2-dose series (0.5 mL per dose, administered 4 weeks apart) (2). To expand vaccine access, an Emergency Use Authorization was issued by FDA on August 9, 2022, for dose-sparing intradermal injection of JYNNEOS as a 2-dose series (0.1 mL per dose, administered 4 weeks apart) (3). Vaccination was available to persons with known or presumed exposure to a person with mpox (postexposure prophylaxis [PEP]), as well as persons at increased risk for mpox or who might benefit from vaccination (preexposure mpox prophylaxis [PrEP]) (4). Because information on JYNNEOS vaccine effectiveness (VE) is limited, a matched case-control study was conducted in 12 U.S. jurisdictions,† including nine Emerging Infections Program sites and three Epidemiology and Laboratory Capacity sites,§ to evaluate VE against mpox among MSM and transgender adults aged 18-49 years. During August 19, 2022-March 31, 2023, a total of 309 case-patients were matched to 608 control patients. Adjusted VE was 75.2% (95% CI = 61.2% to 84.2%) for partial vaccination (1 dose) and 85.9% (95% CI = 73.8% to 92.4%) for full vaccination (2 doses). Adjusted VE for full vaccination by subcutaneous, intradermal, and heterologous routes of administration was 88.9% (95% CI = 56.0% to 97.2%), 80.3% (95% CI = 22.9% to 95.0%), and 86.9% (95% CI = 69.1% to 94.5%), respectively. Adjusted VE for full vaccination among immunocompromised participants was 70.2% (95% CI = -37.9% to 93.6%) and among immunocompetent participants was 87.8% (95% CI = 57.5% to 96.5%). JYNNEOS is effective at reducing the risk for mpox. Because duration of protection of 1 versus 2 doses remains unknown, persons at increased risk for mpox exposure should receive the 2-dose series as recommended by the Advisory Committee on Immunization Practices (ACIP),¶ regardless of administration route or immunocompromise status.

Aid when 'there is nothing left to offer': Experiences of palliative care and palliative care needs in humanitarian crises.

Access to palliative care, and more specifically the alleviation of avoidable physical and psychosocial suffering is increasingly recognized as a necessary component of humanitarian response. Palliative approaches to care can meet the needs of patients for whom curative treatment may not be the aim, not just at the very end of life but alleviation of suffering more broadly. In the past several years many organizations and sectoral initiatives have taken steps to develop guidance and policies to support integration of palliative care. However, it is still regarded by many as unfeasible or aspirational in crisis contexts; particularly where care for persons with life threatening conditions or injuries is logistically, legally, and ethically challenging. This article presents a synthesis of findings from five qualitative sub-studies within a research program on palliative care provision in humanitarian crises that sought to better understand the ethical and practical dimensions of humanitarian organizations integrating palliative care into emergency responses. Our multi-disciplinary, multi-national team held 98 in-depth semi-structured interviews with people with experiences in natural disasters, refugee camps in Rwanda and Jordan, and in Ebola Treatment Centers in Guinea. Participants included patients, family members, health care workers, and other staff of humanitarian agencies. We identified four themes from descriptions of the struggles and successes of applying palliative care in humanitarian settings: justification and integration of palliative care into humanitarian response, contextualizing palliative care approaches to crisis settings, the importance of being attentive to the 'situatedness of dying', and the need for retaining a holistic approach to care. We discuss these findings in relation to the ideals embraced in palliative care and corresponding humanitarian values, concluding that palliative care in humanitarian response is essential for responding to avoidable pain and suffering in humanitarian settings.

Implementation of a centralized pharmacovigilance system in academic pan-European clinical trials: Experience from EU-Response and conect4children consortia.

Setting-up a high quality, compliant and efficient pharmacovigilance (PV) system in multi-country clinical trials can be more challenging for academic sponsors than for companies. To ensure the safety of all participants in academic studies and that the PV system fulfils all regulations, we set up a centralized PV system that allows sponsors to delegate work on PV. This initiative was put in practice by our Inserm-ANRS MIE PV department in two distinct multinational European consortia with 19 participating countries: conect4children (c4c) for paediatrics research and EU-Response for Covid-19 platform trials. The centralized PV system consists of some key procedures to harmonize the complex safety processes, creation of a local safety officer (LSO) network and centralization of all safety activities. The key procedures described the safety management plan for each trial and how tasks were shared and delegated between all stakeholders. Processing of serious adverse events (SAEs) in a unique database guaranteed the full control of the safety data and continuous evaluation of the risk-benefit ratio. The LSO network participated in efficient regulatory compliance across multiple countries. In total, there were 1312 SAEs in EU-Response and 83 SAEs in c4c in the four trials. We present here the lessons learnt from our experience in four clinical trials. We managed heterogeneous European local requirements and implemented efficient communication with all trial teams. Our approach builds capacity for PV that can be used by multiple academic sponsors.