Prospective phase II trial of preoperative hypofractionated proton therapy for extremity and truncal soft tissue sarcoma: the PRONTO study rationale and design.

BACKGROUND: Oncologic surgical resection is the standard of care for extremity and truncal soft tissue sarcoma (STS), often accompanied by the addition of pre- or postoperative radiation therapy (RT). Preoperative RT may decrease the risk of joint stiffness and fibrosis at the cost of higher rates of wound complications. Hypofractionated, preoperative RT has been shown to provide acceptable outcomes in prospective trials. Proton beam therapy (PBT) provides the means to decrease dose to surrounding organs at risk, such as the skin, bone, soft tissues, and adjacent joint(s), and has not yet been studied in patients with extremity and truncal sarcoma. METHODS: Our study titled "PROspective phase II trial of preoperative hypofractionated protoN therapy for extremity and Truncal soft tissue sarcOma (PRONTO)" is a non-randomized, prospective phase II trial evaluating the safety and efficacy of preoperative, hypofractionated PBT for patients with STS of the extremity and trunk planned for surgical resection. Adult patients with Eastern Cooperative Group Performance Status ≤ 2 with resectable extremity and truncal STS will be included, with the aim to accrue 40 patients. Treatment will consist of 30 Gy radiobiological equivalent of PBT in 5 fractions delivered every other day, followed by surgical resection 2-12 weeks later. The primary outcome is rate of major wound complications as defined according to the National Cancer Institute of Canada Sarcoma2 (NCIC-SR2) Multicenter Trial. Secondary objectives include rate of late grade ≥ 2 toxicity, local recurrence-free survival and distant metastasis-free survival at 1- and 2-years, functional outcomes, quality of life, and pathologic response. DISCUSSION: PRONTO represents the first trial evaluating the use of hypofractionated PBT for STS. We aim to prove the safety and efficacy of this approach and to compare our results to historical outcomes established by previous trials. Given the low number of proton centers and limited availability, the short course of PBT may provide the opportunity to treat patients who would otherwise be limited when treating with daily RT over several weeks. We hope that this trial will lead to increased referral patterns, offer benefits towards patient convenience and clinic workflow efficiency, and provide evidence supporting the use of PBT in this setting. TRIAL REGISTRATION: NCT05917301 (registered 23/6/2023).

Armed actor interventions in humanitarian and public health crises: examining perspectives of crisis-affected community members.

BACKGROUND: Despite frequently providing non-military services in times of crisis, little systematic research has examined the perspectives of crisis-affected community members on the role of armed actors responding to humanitarian crises and public health emergencies. METHODS: To address this research gap, 175 interviews were conducted (2020-2021) amongst humanitarian and public health practitioners; armed actors; and crisis-affected community members across three country and four crisis contexts. Specifically, this effort included an Ebola outbreak in the Democratic Republic of the Congo; a refugee crisis on the Jordanian-Syrian border; and a volcanic eruption and COVID-19 outbreak in the Philippines. Data was analysed using grounded theory principles. RESULTS: Crisis-affected community members held diverse views. Non-state armed groups (NSAGs) and government armed actors were characterised as antagonists by some but supportive by others; gender issues were central to perceptions of armed actors, in ways that were both prejudicing and favourable. Overall perception was most closely linked to armed actor roles rather than the relative amount of conflict in a given area. CONCLUSIONS: Findings nuance the relevant literature characterizing NSAGs as disruptive agents, and also the relevant literature that does not fully consider the nuances of gender and armed actor roles as deeply relevant to crisis-affected community perspectives on armed actors. These findings have important implications for both policy and academic discourse on militarization and localization.

Outpatient COVID-19 convalescent plasma recipient antibody thresholds correlated to reduced hospitalizations within a randomized trial.

BACKGROUNDCOVID-19 convalescent plasma (CCP) virus-specific antibody levels that translate into recipient posttransfusion antibody levels sufficient to prevent disease progression are not defined.METHODSThis secondary analysis correlated donor and recipient antibody levels to hospitalization risk among unvaccinated, seronegative CCP recipients within the outpatient, double-blind, randomized clinical trial that compared CCP to control plasma. The majority of COVID-19 CCP arm hospitalizations (15/17, 88%) occurred in this unvaccinated, seronegative subgroup. A functional cutoff to delineate recipient high versus low posttransfusion antibody levels was established by 2 methods: (i) analyzing virus neutralization-equivalent anti-Spike receptor-binding domain immunoglobulin G (anti-S-RBD IgG) responses in donors or (ii) receiver operating characteristic (ROC) curve analysis.RESULTSSARS-CoV-2 anti-S-RBD IgG antibody was volume diluted 21.3-fold into posttransfusion seronegative recipients from matched donor units. Virus-specific antibody delivered was approximately 1.2 mg. The high-antibody recipients transfused early (symptom onset within 5 days) had no hospitalizations. A CCP-recipient analysis for antibody thresholds correlated to reduced hospitalizations found a statistical significant association between early transfusion and high antibodies versus all other CCP recipients (or control plasma), with antibody cutoffs established by both methods-donor-based virus neutralization cutoffs in posttransfusion recipients (0/85 [0%] versus 15/276 [5.6%]; P = 0.03) or ROC-based cutoff (0/94 [0%] versus 15/267 [5.4%]; P = 0.01).CONCLUSIONIn unvaccinated, seronegative CCP recipients, early transfusion of plasma units in the upper 30% of study donors' antibody levels reduced outpatient hospitalizations. High antibody level plasma units, given early, should be reserved for therapeutic use.TRIAL REGISTRATIONClinicalTrials.gov NCT04373460.FUNDINGDepartment of Defense (W911QY2090012); Defense Health Agency; Bloomberg Philanthropies; the State of Maryland; NIH (3R01AI152078-01S1, U24TR001609-S3, 1K23HL151826NIH); the Mental Wellness Foundation; the Moriah Fund; Octapharma; the Healthnetwork Foundation; the Shear Family Foundation; the NorthShore Research Institute; and the Rice Foundation.

Derivation and Internal Validation of a Mortality Prognostication Machine Learning Model in Ebola Virus Disease Based on Iterative Point-of-Care Biomarkers.

Background: Although multiple prognostic models exist for Ebola virus disease mortality, few incorporate biomarkers, and none has used longitudinal point-of-care serum testing throughout Ebola treatment center care. Methods: This retrospective study evaluated adult patients with Ebola virus disease during the 10th outbreak in the Democratic Republic of Congo. Ebola virus cycle threshold (Ct; based on reverse transcriptase polymerase chain reaction) and point-of-care serum biomarker values were collected throughout Ebola treatment center care. Four iterative machine learning models were created for prognosis of mortality. The base model used age and admission Ct as predictors. Ct and biomarkers from treatment days 1 and 2, days 3 and 4, and days 5 and 6 associated with mortality were iteratively added to the model to yield mortality risk estimates. Receiver operating characteristic curves for each iteration provided period-specific areas under curve with 95% CIs. Results: Of 310 cases positive for Ebola virus disease, mortality occurred in 46.5%. Biomarkers predictive of mortality were elevated creatinine kinase, aspartate aminotransferase, blood urea nitrogen (BUN), alanine aminotransferase, and potassium; low albumin during days 1 and 2; elevated C-reactive protein, BUN, and potassium during days 3 and 4; and elevated C-reactive protein and BUN during days 5 and 6. The area under curve substantially improved with each iteration: base model, 0.74 (95% CI, .69-.80); days 1 and 2, 0.84 (95% CI, .73-.94); days 3 and 4, 0.94 (95% CI, .88-1.0); and days 5 and 6, 0.96 (95% CI, .90-1.0). Conclusions: This is the first study to utilize iterative point-of-care biomarkers to derive dynamic prognostic mortality models. This novel approach demonstrates that utilizing biomarkers drastically improved prognostication up to 6 days into patient care.

Perceptions toward Ebola vaccination and correlates of vaccine uptake among high-risk community members in North Kivu, Democratic Republic of the Congo.

The tenth Ebola Virus Disease (EVD) outbreak (2018-2020, North Kivu, Ituri, South Kivu) in the Democratic Republic of the Congo (DRC) was the second-largest EVD outbreak in history. During this outbreak, Ebola vaccination was an integral part of the EVD response. We evaluated community perceptions toward Ebola vaccination and identified correlates of Ebola vaccine uptake among high-risk community members in North Kivu, DRC. In March 2021, a cross-sectional survey among adults was implemented in three health zones. We employed a sampling approach mimicking ring vaccination, targeting EVD survivors, their household members, and their neighbors. Outbreak experiences and perceptions toward the Ebola vaccine were assessed, and modified Poisson regression was used to identify correlates of Ebola vaccine uptake among those offered vaccination. Among the 631 individuals surveyed, most (90.2%) reported a high perceived risk of EVD and 71.6% believed that the vaccine could reduce EVD severity; however, 63.7% believed the vaccine had serious side effects. Among the 474 individuals who had been offered vaccination, 397 (83.8%) received the vaccine, 180 (45.3%) of those vaccinated received the vaccine after two or more offers. Correlates positively associated with vaccine uptake included having heard positive information about the vaccine (RR 1.30, 95% CI 1.06-1.60), the belief that the vaccine could prevent EVD (RR 1.23, 95% CI 1.09-1.39), and reporting that religion influenced all decisions (RR 1.13, 95% CI 1.02-1.25). Ebola vaccine uptake was high in this population, although mixed attitudes and vaccine delays were common. Communicating positive vaccine information, emphasizing the efficacy of the Ebola vaccine, and engaging religious leaders to promote vaccination may aid in increasing Ebola vaccine uptake during future outbreaks.

COVID-19 convalescent plasma therapy decreases inflammatory cytokines: a randomized controlled trial.

IMPORTANCE: This study examined the role that cytokines may have played in the beneficial outcomes found when outpatient individuals infected with SARS-CoV-2 were transfused with COVID-19 convalescent plasma (CCP) early in their infection. We found that the pro-inflammatory cytokine IL-6 decreased significantly faster in patients treated early with CCP. Participants with COVID-19 treated with CCP later in the infection did not have the same effect. This decrease in IL-6 levels after early CCP treatment suggests a possible role of inflammation in COVID-19 progression. The evidence of IL-6 involvement brings insight into the possible mechanisms involved in CCP treatment mitigating SARS-CoV-2 severity.

Human dissection for anesthesiology resident training augments anatomical knowledge and clinical skills.

Anatomy is an essential component of clinical anesthesiology. The use of simulated patients and alternative materials, including embalmed human bodies, have become increasingly common during resident physician training due to the deemphasis on anatomical education during undergraduate medical training. In this report, the need for a more extensive review of relevant anatomy for the practice of anesthesiology was addressed by the design, evaluation, and dissemination of a human dissection course for procedural training of anesthesiology residents. The course utilized "freedom art" embalmed human bodies that allowed trainees to perform ultrasound-based regional and neuraxial techniques followed by detailed dissections of critical anatomy. One hundred and four residents participated in workshops and small group discussions and were evaluated using pre- and post-course assessments. A variety of clinical techniques were performed on the bodies, including regional blocks and neuraxial catheter placement. Insertion of peripheral/neuraxial catheters was successful, with dissections demonstrating the expected placement. Assessment scores improved following the course (pre-course mean 52.7%, standard deviation (σ) 13.1%; post-course mean 72.2%, σ 11.6%; t-test p < 0.0001) and feedback highlighted the usefulness and clinical relevance of course content. The ability to correlate ultrasound imaging with subsequent dissections of the "blocked" area and visualization of dye staining was extremely relevant for spatial understanding of the anatomy relevant for the clinical practice of these techniques. This manuscript demonstrates successful implementation of a comprehensive course for anesthesiology resident physicians to address gaps in undergraduate anatomical education and suggests that broader adoption of dissection courses may be beneficial for training anesthesiologists.

Autosomal dominant ApoA4 mutations present as tubulointerstitial kidney disease with medullary amyloidosis.

Sporadic cases of apolipoprotein A-IV medullary amyloidosis have been reported. Here we describe five families found to have autosomal dominant medullary amyloidosis due to two different pathogenic APOA4 variants. A large family with autosomal dominant chronic kidney disease (CKD) and bland urinary sediment underwent whole genome sequencing with identification of a chr11:116692578 G>C (hg19) variant encoding the missense mutation p.L66V of the ApoA4 protein. We identified two other distantly related families from our registry with the same variant and two other distantly related families with a chr11:116693454 C>T (hg19) variant encoding the missense mutation p.D33N. Both mutations are unique to affected families, evolutionarily conserved and predicted to expand the amyloidogenic hotspot in the ApoA4 structure. Clinically affected individuals suffered from CKD with a bland urinary sediment and a mean age for kidney failure of 64.5 years. Genotyping identified 48 genetically affected individuals; 44 individuals had an estimated glomerular filtration rate (eGFR) under 60 ml/min/1.73 m2, including all 25 individuals with kidney failure. Significantly, 11 of 14 genetically unaffected individuals had an eGFR over 60 ml/min/1.73 m2. Fifteen genetically affected individuals presented with higher plasma ApoA4 concentrations. Kidney pathologic specimens from four individuals revealed amyloid deposits limited to the medulla, with the mutated ApoA4 identified by mass-spectrometry as the predominant amyloid constituent in all three available biopsies. Thus, ApoA4 mutations can cause autosomal dominant medullary amyloidosis, with marked amyloid deposition limited to the kidney medulla and presenting with autosomal dominant CKD with a bland urinary sediment. Diagnosis relies on a careful family history, APOA4 sequencing and pathologic studies.

A comparison of the NIRUDAK models and WHO algorithm for dehydration assessment in older children and adults with acute diarrhoea: a prospective, observational study.

BACKGROUND: Despite the importance of accurate and rapid assessment of hydration status in patients with acute diarrhoea, no validated tools exist to help clinicians assess dehydration severity in older children and adults. The aim of this study is to validate a clinical decision support tool (CDST) and a simplified score for dehydration severity in older children and adults with acute diarrhoea (both developed during the NIRUDAK study) and compare their accuracy and reliability with current WHO guidelines. METHODS: A random sample of patients aged 5 years or older presenting with diarrhoea to the icddr,b Dhaka Hospital in Bangladesh between Jan 30 and Dec 13, 2022 were included in this prospective cohort study. Patients with fewer than three loose stools per day, more than 7 days of symptoms, previous enrolment in the study, or a diagnosis other than acute gastroenteritis were excluded. Patients were weighed on arrival and assessed separately by two nurses using both our novel clinical tools and WHO guidelines. Patients were weighed every 4 h to determine their percent weight change with rehydration, our criterion standard for dehydration. Accuracy for the diagnosis of dehydration category (none, some, or severe) was assessed using the ordinal c-index (ORC). Reliability was assessed by comparing the prediction of severe dehydration from each nurse's independent assessment using the intraclass correlation coefficient (ICC). FINDINGS: 1580 patients were included in our primary analysis, of whom 921 (58·3%) were female and 659 (41·7%) male. The ORC was 0·74 (95% CI 0·71-0·77) for the CDST, 0·75 (0·71-0·78) for the simplified score, and 0·64 (0·61-0·67) for the WHO guidelines. The ICC was 0·98 (95% CI 0·97-0·98) for the CDST, 0·94 (0·93-0·95) for the simplified score, and 0·56 (0·52-0·60) for the WHO guidelines. INTERPRETATION: Use of our CDST or simplified score by clinicians could reduce undertreatment and overtreatment of older children and adults with acute diarrhoea, potentially reducing morbidity and mortality for this common disease. FUNDING: US National Institutes of Health. TRANSLATION: For the Bangla translation of the abstract see Supplementary Materials section.

Early antibody treatment, inflammation, and risk of post-COVID conditions.

IMPORTANCE: Approximately 20% of individuals infected with SARS-CoV-2 experienced long-term health effects, as defined PCC. However, it is unknown if there are any early biomarkers associated with PCC or whether early intervention treatments may decrease the risk of PCC. In a secondary analysis of a randomized clinical trial, this study demonstrates that among outpatients with SARS-CoV-2, increased IL-6 at time of infection is associated with increased odds of PCC. In addition, among individuals treated early, within 5 days of symptom onset, with COVID-19 convalescent plasma, there was a trend for decreased odds of PCC after adjusting for other demographic and clinical characteristics. Future treatment studies should be considered to evaluate the effect of early treatment and anti-IL-6 therapies on PCC development.

Maternal, fetal, and perinatal outcomes among pregnant women admitted to an Ebola treatment center in the Democratic Republic of Congo, 2018-2020.

OBJECTIVE: This study aims to investigate maternal, fetal, and perinatal outcomes during the 2018-2020 Ebola outbreak in Democratic Republic of Congo (DRC). METHODS: Mortality between pregnant and non-pregnant women of reproductive age admitted to DRC's Mangina Ebola treatment center (ETC) were compared using propensity score matching. Propensity scores were calculated using age, initial Ebola viral load, Ebola vaccination status, and investigational therapeutic. Additionally, fetal and perinatal outcomes of pregnancies were also described. RESULTS: Twenty-seven pregnant women were admitted to the Mangina ETC during December 2018-January 2020 among 162 women of childbearing age. We found no evidence of increase mortality among pregnant women compared to non-pregnant women (relative risk:1.0, 95%CI: 0.58-1.72). Among surviving mothers, pregnancy outcomes were poor with at least 58% (11/19) experiencing loss of pregnancy while 16% (3/19) were discharged with viable pregnancy. Two mothers with viable pregnancies were vaccinated, and all received investigational therapeutics. Two live births occurred, with one infant surviving after the infant and mother received an investigational post-exposure prophylaxis and Ebola therapeutic respectively. CONCLUSIONS: Pregnancy was not associated with increased mortality among women with EVD in the Mangina ETC. Fetal and perinatal outcomes remained poor in pregnancies complicated by EVD, though novel therapeutics may have potential for improving these outcomes.

Dynamics of inflammatory responses after SARS-CoV-2 infection by vaccination status in the USA: a prospective cohort study.

BACKGROUND: Cytokines and chemokines play a critical role in the response to infection and vaccination. We aimed to assess the longitudinal association of COVID-19 vaccination with cytokine and chemokine concentrations and trajectories among people with SARS-CoV-2 infection. METHODS: In this longitudinal, prospective cohort study, blood samples were used from participants enrolled in a multi-centre randomised trial assessing the efficacy of convalescent plasma therapy for ambulatory COVID-19. The trial was conducted in 23 outpatient sites in the USA. In this study, participants (aged ≥18 years) were restricted to those with COVID-19 before vaccination or with breakthrough infections who had blood samples and symptom data collected at screening (pre-transfusion), day 14, and day 90 visits. Associations between COVID-19 vaccination status and concentrations of 21 cytokines and chemokines (measured using multiplexed sandwich immunoassays) were examined using multivariate linear mixed-effects regression models, adjusted for age, sex, BMI, hypertension, diabetes, trial group, and COVID-19 waves (pre-alpha or alpha and delta). FINDINGS: Between June 29, 2020, and Sept 30, 2021, 882 participants recently infected with SARS-CoV-2 were enrolled, of whom 506 (57%) were female and 376 (43%) were male. 688 (78%) of 882 participants were unvaccinated, 55 (6%) were partly vaccinated, and 139 (16%) were fully vaccinated at baseline. After adjusting for confounders, geometric mean concentrations of interleukin (IL)-2RA, IL-7, IL-8, IL-15, IL-29 (interferon-λ), inducible protein-10, monocyte chemoattractant protein-1, and tumour necrosis factor-α were significantly lower among the fully vaccinated group than in the unvaccinated group at screening. On day 90, fully vaccinated participants had approximately 20% lower geometric mean concentrations of IL-7, IL-8, and vascular endothelial growth factor-A than unvaccinated participants. Cytokine and chemokine concentrations decreased over time in the fully and partly vaccinated groups and unvaccinated group. Log10 cytokine and chemokine concentrations decreased faster among participants in the unvaccinated group than in other groups, but their geometric mean concentrations were generally higher than fully vaccinated participants at 90 days. Days since full vaccination and type of vaccine received were not correlated with cytokine and chemokine concentrations. INTERPRETATION: Initially and during recovery from symptomatic COVID-19, fully vaccinated participants had lower concentrations of inflammatory markers than unvaccinated participants suggesting vaccination is associated with short-term and long-term reduction in inflammation, which could in part explain the reduced disease severity and mortality in vaccinated individuals. FUNDING: US Department of Defense, National Institutes of Health, Bloomberg Philanthropies, State of Maryland, Mental Wellness Foundation, Moriah Fund, Octapharma, HealthNetwork Foundation, and the Shear Family Foundation.

The role of civil society organizations (CSOs) in the COVID-19 response across the Global South: A multinational, qualitative study.

Despite receiving less attention than high-income countries, low- and middle-income countries (LMICs) experienced more than 85% of global excess deaths during the first two years of the COVID-19 pandemic. Due to the unprecedented speed and scale of the COVID-19 pandemic, which placed large demands on government capacity, many LMICs relied on civil society organizations (CSOs) to assist in implementing COVID-19 response programs. Yet few studies have examined the critical role CSOs played in mitigating the effects of the COVID-19 pandemic in low resource settings. This study explored the CSO response to COVID-19 in five of the most heavily impacted LMICs in the Global South. Interviews were conducted from May to August 2021 with a purposive sample of CSO key informants within each of the five countries. A total of 52 CSOs were selected from which 53 key informants were interviewed either via Zoom or by phone. Interviews were coded and analyzed using NVivo or MAXQDA2020. Out of the 52 CSOs selected, 24 were national organizations, 8 were regional, and 20 were local. CSOs fell into six categories: community-based organizations, non-governmental organizations, unions/professional organizations, campaigns/social movements, research organizations/think tanks, and networks/coalitions. CSOs across all five countries adapted their missions, stretched their resources, and performed a wide range of activities that fit into five programmatic areas: food security and livelihood support, public health and medical care, cash transfer programs, risk communication and community education, and needs assessment. This qualitative analysis demonstrates the critical role CSOs played in supplementing government emergency aid response by delivering necessary resources and supporting highly vulnerable populations during the COVID-19 pandemic, as well as the primary challenges they faced in doing so. Given the generally weak state of public capacity in the LMICs studied, this role was vital to responding to the pandemic.

Ebola vaccine uptake and attitudes among healthcare workers in North Kivu, Democratic Republic of the Congo, 2021.

Introduction: During the 2018-2020 Ebola virus disease (EVD) outbreak in the eastern part of the Democratic Republic of the Congo (DRC), prevention and control measures, such as Ebola vaccination were challenging by community mistrust. We aimed to understand perceptions regarding Ebola vaccination and identify determinants of Ebola vaccine uptake among HCWs. Methods: In March 2021, we conducted a cross-sectional survey among 438 HCWs from 100 randomly selected health facilities in three health zones (Butembo, Beni, Mabalako) affected by the 10th EVD outbreak in North Kivu, DRC. HCWs were eligible if they were ≥ 18 years and were working in a health facility during the outbreak. We used survey logistic regression to assess correlates of first-offer uptake (i.e., having received the vaccine the first time it was offered vs. after subsequent offers). Results: Of the 438 HCWs enrolled in the study, 420 (95.8%) reported that they were eligible and offered an Ebola vaccine. Among those offered vaccination, self-reported uptake of the Ebola vaccine was 99.0% (95% confidence interval (CI) [98.5-99.4]), but first-offer uptake was 70.2% (95% CI [67.1, 73.5]). Nearly all HCWs (94.3%; 95% CI [92.7-95.5]) perceived themselves to be at risk of contracting EVD. The most common concern was that the vaccine would cause side effects (65.7%; 95% CI [61.4-69.7]). In the multivariable analysis, mistrust of the vaccine source or how the vaccine was produced decreased the odds of first-time uptake. Discussion: Overall uptake of the Ebola vaccine was high among HCWs, but uptake at the first offer was substantially lower, which was associated with mistrust of the vaccine source. Future Ebola vaccination efforts should plan to make repeated vaccination offers to HCWs and address their underlying mistrust in the vaccines, which can, in turn, improve community uptake.

Common Risk Variants in AHI1 Are Associated With Childhood Steroid Sensitive Nephrotic Syndrome.

Introduction: Steroid-sensitive nephrotic syndrome (SSNS) is the most common form of kidney disease in children worldwide. Genome-wide association studies (GWAS) have demonstrated the association of SSNS with genetic variation at HLA-DQ/DR and have identified several non-HLA loci that aid in further understanding of disease pathophysiology. We sought to identify additional genetic loci associated with SSNS in children of Sri Lankan and European ancestry. Methods: We conducted a GWAS in a cohort of Sri Lankan individuals comprising 420 pediatric patients with SSNS and 2339 genetic ancestry matched controls obtained from the UK Biobank. We then performed a transethnic meta-analysis with a previously reported European cohort of 422 pediatric patients and 5642 controls. Results: Our GWAS confirmed the previously reported association of SSNS with HLA-DR/DQ (rs9271602, P = 1.12 × 10-27, odds ratio [OR] = 2.75). Transethnic meta-analysis replicated these findings and identified a novel association at AHI1 (rs2746432, P = 2.79 × 10-8, OR = 1.37), which was also replicated in an independent South Asian cohort. AHI1 is implicated in ciliary protein transport and immune dysregulation, with rare variation in this gene contributing to Joubert syndrome type 3. Conclusions: Common variation in AHI1 confers risk of the development of SSNS in both Sri Lankan and European populations. The association with common variation in AHI1 further supports the role of immune dysregulation in the pathogenesis of SSNS and demonstrates that variation across the allele frequency spectrum in a gene can contribute to disparate monogenic and polygenic diseases.

Transfusion reactions associated with COVID-19 convalescent plasma in outpatient clinical trials.

BACKGROUND: COVID-19 convalescent plasma (CCP) is an important therapeutic option for outpatients at high risk of hospitalization from SARS-CoV-2 infection. We assessed the safety of outpatient CCP transfusions administered during clinical trials. STUDY DESIGN AND METHODS: We analyzed data pertaining to transfusion-related reactions from two randomized controlled trials in the U.S. that evaluated the efficacy of CCP versus control plasma in various ambulatory settings. Multivariable logistic regression was used to assess whether CCP was associated with transfusion reactions, after adjusting for potential confounders. RESULTS: The combined study reported 79/1351 (5.9%) adverse events during the transfusion visit, with the majority 62/1351 (4.6%) characterized by mild, allergic-type findings of urticaria, and/or pruritus consistent with minor allergic transfusion reactions; the other reported events were attributed to the patients' underlying disease, COVID-19, or vasovagal in nature. We found no difference in the likelihood of allergic transfusion reactions between those receiving CCP versus control plasma (adjusted odds ratio [AOR], 0.75; 95% CI, 0.43-1.31). Risk of urticaria and/or pruritus increased with a pre-existing diagnosis of asthma (AOR, 2.33; 95% CI, 1.16-4.67). We did not observe any CCP-attributed antibody disease enhancement in participants with COVID-19 or increased risk of infection. There were no life-threatening severe transfusion reactions and no patients required hospitalization related to transfusion-associated complications. DISCUSSION: Outpatient plasma administration was safely performed for nearly 1400 participants. CCP is a safe therapeutic option for outpatients at risk of hospitalization from COVID-19.

Moving humanitarian-military relations forward: a new typology.

This article presents a new typology for humanitarian-military relations (HMR). This typology can serve as an analytical framework for assessing, during humanitarian emergencies, how civilian responders can and should engage with armed actors. The typology considers two factors: (1) the nature of crisis-affected population's perceptions of an armed actor, and (2) the extent of alignment of civilian responders' and armed actors' interests and objectives. This typology is empirically rooted in an in-depth analysis of HMR across four humanitarian response contexts: (1) the Kivu Ebola Epidemic in the Democratic Republic of the Congo, (2) the Rukban forced displacement crisis along the Jordan-Syria border, (3) the Taal volcano eruption in the Philippines, and (4) the COVID-19 pandemic in the Philippines. The analysis presented in this article is based on 175 qualitative interviews conducted with civilian responders, armed actors, and crisis-affected individuals across these contexts.

Understanding variations in diarrhea management across healthcare facilities in Bangladesh: a formative qualitative study.

INTRODUCTION: Acute diarrhea remains a leading cause of morbidity and mortality with over 6.3 billion cases and 1.3 million deaths annually. Despite the existence of standardized guidelines for diarrhea management, wide variability in clinical practice exists, particularly in resource-limited settings. The goal of this study was to qualitatively explore how diarrhea management in Bangladesh varies according to resource availability, clinical setting, and provider roles. METHODOLOGY: This was a secondary analysis of a cross-sectional qualitative study conducted in three diverse hospital settings (district hospital, subdistrict hospital, and specialty diarrhea research hospital) in Bangladesh. A total of eight focus group discussions with nurses and physicians were conducted. Applied thematic analysis was used to identify themes regarding variations in diarrhea management. RESULTS: Of the 27 focus group participants, 14 were nurses and 13 doctors; 15 worked in a private diarrhea specialty hospital and 12 worked in government district or subdistrict hospitals. Several key themes emerged from the qualitative data analysis: 1) priorities in the clinical assessment of diarrhea 2) use of guidelines versus clinical judgment; 3) variability in clinician roles and between clinical settings influences care delivery; 4) impact of resource availability on diarrhea management; and 5) perceptions of community health workers' role in diarrhea management. CONCLUSIONS: Findings from this study may aid in informing interventions to improve and standardize diarrhea management in resource-constrained settings. Resource availability, practices regarding diarrhea assessment and treatment, provider experience, and variability in provider roles are essential considerations when developing clinical tools in low- and middle- income countries.