Early Treatment with Pegylated Interferon Lambda for Covid-19.

BACKGROUND: The efficacy of a single dose of pegylated interferon lambda in preventing clinical events among outpatients with acute symptomatic coronavirus disease 2019 (Covid-19) is unclear. METHODS: We conducted a randomized, controlled, adaptive platform trial involving predominantly vaccinated adults with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Brazil and Canada. Outpatients who presented with an acute clinical condition consistent with Covid-19 within 7 days after the onset of symptoms received either pegylated interferon lambda (single subcutaneous injection, 180 µg) or placebo (single injection or oral). The primary composite outcome was hospitalization (or transfer to a tertiary hospital) or an emergency department visit (observation for >6 hours) due to Covid-19 within 28 days after randomization. RESULTS: A total of 933 patients were assigned to receive pegylated interferon lambda (2 were subsequently excluded owing to protocol deviations) and 1018 were assigned to receive placebo. Overall, 83% of the patients had been vaccinated, and during the trial, multiple SARS-CoV-2 variants had emerged. A total of 25 of 931 patients (2.7%) in the interferon group had a primary-outcome event, as compared with 57 of 1018 (5.6%) in the placebo group, a difference of 51% (relative risk, 0.49; 95% Bayesian credible interval, 0.30 to 0.76; posterior probability of superiority to placebo, >99.9%). Results were generally consistent in analyses of secondary outcomes, including time to hospitalization for Covid-19 (hazard ratio, 0.57; 95% Bayesian credible interval, 0.33 to 0.95) and Covid-19-related hospitalization or death (hazard ratio, 0.59; 95% Bayesian credible interval, 0.35 to 0.97). The effects were consistent across dominant variants and independent of vaccination status. Among patients with a high viral load at baseline, those who received pegylated interferon lambda had lower viral loads by day 7 than those who received placebo. The incidence of adverse events was similar in the two groups. CONCLUSIONS: Among predominantly vaccinated outpatients with Covid-19, the incidence of hospitalization or an emergency department visit (observation for >6 hours) was significantly lower among those who received a single dose of pegylated interferon lambda than among those who received placebo. (Funded by FastGrants and others; TOGETHER ClinicalTrials.gov number, NCT04727424.).

Neuromuscular disease genetics in under-represented populations: increasing data diversity.

Neuromuscular diseases (NMDs) affect ∼15 million people globally. In high income settings DNA-based diagnosis has transformed care pathways and led to gene-specific therapies. However, most affected families are in low-to-middle income countries (LMICs) with limited access to DNA-based diagnosis. Most (86%) published genetic data is derived from European ancestry. This marked genetic data inequality hampers understanding of genetic diversity and hinders accurate genetic diagnosis in all income settings. We developed a cloud-based transcontinental partnership to build diverse, deeply-phenotyped and genetically characterized cohorts to improve genetic architecture knowledge, and potentially advance diagnosis and clinical management. We connected 18 centres in Brazil, India, South Africa, Turkey, Zambia, Netherlands and the UK. We co-developed a cloud-based data solution and trained 17 international neurology fellows in clinical genomic data interpretation. Single gene and whole exome data were analysed via a bespoke bioinformatics pipeline and reviewed alongside clinical and phenotypic data in global webinars to inform genetic outcome decisions. We recruited 6001 participants in the first 43 months. Initial genetic analyses 'solved' or 'possibly solved' ∼56% probands overall. In-depth genetic data review of the four commonest clinical categories (limb girdle muscular dystrophy, inherited peripheral neuropathies, congenital myopathy/muscular dystrophies and Duchenne/Becker muscular dystrophy) delivered a ∼59% 'solved' and ∼13% 'possibly solved' outcome. Almost 29% of disease causing variants were novel, increasing diverse pathogenic variant knowledge. Unsolved participants represent a new discovery cohort. The dataset provides a large resource from under-represented populations for genetic and translational research. In conclusion, we established a remote transcontinental partnership to assess genetic architecture of NMDs across diverse populations. It supported DNA-based diagnosis, potentially enabling genetic counselling, care pathways and eligibility for gene-specific trials. Similar virtual partnerships could be adopted by other areas of global genomic neurological practice to reduce genetic data inequality and benefit patients globally.

Oral Fluvoxamine With Inhaled Budesonide for Treatment of Early-Onset COVID-19 : A Randomized Platform Trial.

BACKGROUND: Previous trials have demonstrated the effects of fluvoxamine alone and inhaled budesonide alone for prevention of disease progression among outpatients with COVID-19. OBJECTIVE: To determine whether the combination of fluvoxamine and inhaled budesonide would increase treatment effects in a highly vaccinated population. DESIGN: Randomized, placebo-controlled, adaptive platform trial. (ClinicalTrials.gov: NCT04727424). SETTING: 12 clinical sites in Brazil. PARTICIPANTS: Symptomatic adults with confirmed SARS-CoV-2 infection and a known risk factor for progression to severe disease. INTERVENTION: Patients were randomly assigned to either fluvoxamine (100 mg twice daily for 10 days) plus inhaled budesonide (800 mcg twice daily for 10 days) or matching placebos. MEASUREMENTS: The primary outcome was a composite of emergency setting retention for COVID-19 for more than 6 hours, hospitalization, and/or suspected complications due to clinical progression of COVID-19 within 28 days of randomization. Secondary outcomes included health care attendance (defined as hospitalization for any cause or emergency department visit lasting >6 hours), time to hospitalization, mortality, patient-reported outcomes, and adverse drug reactions. RESULTS: Randomization occurred from 15 January to 6 July 2022. A total of 738 participants were allocated to oral fluvoxamine plus inhaled budesonide, and 738 received placebo. The proportion of patients observed in an emergency setting for COVID-19 for more than 6 hours or hospitalized due to COVID-19 was lower in the treatment group than the placebo group (1.8% [95% credible interval {CrI}, 1.1% to 3.0%] vs. 3.7% [95% CrI, 2.5% to 5.3%]; relative risk, 0.50 [95% CrI, 0.25 to 0.92]), with a probability of superiority of 98.7%. No relative effects were found between groups for any of the secondary outcomes. More adverse events occurred in the intervention group than the placebo group, but no important differences between the groups were detected. LIMITATION: Low event rate overall, consistent with contemporary trials in vaccinated populations. CONCLUSION: Treatment with oral fluvoxamine plus inhaled budesonide among high-risk outpatients with early COVID-19 reduced the incidence of severe disease requiring advanced care. PRIMARY FUNDING SOURCE: Latona Foundation, FastGrants, and Rainwater Charitable Foundation.

A common polymorphism in the 5' UTR of ERCC5 creates an upstream ORF that confers resistance to platinum-based chemotherapy.

We show that a common polymorphic variant in the ERCC5 5' untranslated region (UTR) generates an upstream ORF (uORF) that affects both the background expression of this protein and its ability to be synthesized following exposure to agents that cause bulky adduct DNA damage. Individuals that harbor uORF1 have a marked resistance to platinum-based agents, illustrated by the significantly reduced progression-free survival of pediatric ependymoma patients treated with such compounds. Importantly, inhibition of DNA-PKcs restores sensitivity to platinum-based compounds by preventing uORF1-dependent ERCC5 expression. Our data support a model in which a heritable 5' noncoding mRNA element influences individuals' responses to platinum-based chemotherapy.

Newcomer knowledge, attitudes, and beliefs about human papillomavirus (HPV) vaccination.

BACKGROUND: Human Papillomavirus (HPV) is the most common sexually transmitted infection in Canada and around the world. Vaccination is an effective prevention strategy, but uptake is low, especially among newcomers to Canada. We sought to understand newcomers' knowledge, attitudes, and beliefs (KAB) on HPV and HPV vaccination and their role in HPV vaccine acceptance. METHODS: Newcomers were defined as individuals born outside Canada, (i.e., individuals born in a different country, the majority of whom are immigrants or refugees, but also includes students and undocumented migrants). Eligible participants were newcomers, aged 16 or older and who could read or write in English, French or Arabic. Surveys were administered in two community health centres in Ottawa, Canada that primarily engage with newcomer populations. Follow-up interviews were conducted either at the community health centre or over the phone, depending on participants' preferences. RESULTS: Fifty participants completed the survey, the majority of whom were women (74%) and spoke Arabic as their first language (54%). Seven participants completed supplemental interviews to complement their survey responses. The majority (70%) of participants had not previously heard of HPV. Less than half (46%) knew that the vaccine is effective in preventing certain types of cancer; nearly 40% incorrectly believed the vaccine could cure HPV. Qualitative interviews supported the survey findings. CONCLUSIONS: Despite a lack of HPV knowledge due to cultural and language barriers, there is still a strong desire among newcomers to receive the vaccine, especially when accompanied by a physician recommendation. Cultural and language-appropriate resources are needed to help newcomers make informed vaccination decisions and promote HPV vaccine uptake.

Lessons learned from COVID-19 for the post-antibiotic future.

INTRODUCTION: COVID-19 has rapidly and radically changed the face of human health and social interaction. As was the case with COVID-19, the world is similarly unprepared to respond to antimicrobial resistance (AMR) and the challenges it will produce. COVID-19 presents an opportunity to examine how the international community might better respond to the growing AMR threat. MAIN BODY: The impacts of COVID-19 have manifested in health system, economic, social, and global political implications. Increasing AMR will also present challenges in these domains. As seen with COVID-19, increasing healthcare usage and resource scarcity may lead to ethical dilemmas about prioritization of care; unemployment and economic downturn may disproportionately impact people in industries reliant on human interaction (especially women); and international cooperation may be compromised as nations strive to minimize outbreaks within their own borders. CONCLUSION: AMR represents a slow-moving disaster that offers a unique opportunity to proactively develop interventions to mitigate its impact. The world's attention is currently rightfully focused on responding to COVID-19, but there is a moral imperative to take stock of lessons learned and opportunities to prepare for the next global health emergency.

Reporting on the opioid crisis (2000-2018): role of The Globe and Mail, a Canadian English-language newspaper in influencing public opinion.

BACKGROUND: We aim to describe the general characteristics of how the Canadian newspaper The Globe and Mail reports on opioid-related news, the opioid crisis and its victims, and explore how Canadians' perceptions of the opioid crisis could have developed over time from this reporting. The Globe and Mail has the highest circulation among Canadian newspapers and is Canada's newspaper of record. METHODS: Reviewers performed independent, blinded bibliometric searches of all The Globe and Mail articles archived in the Canadian Periodicals Index Quarterly spanning an 18-year period (1 January 2000-1 June 2018) related to the keywords "opioids" or "drugs and opioids" and "opiates". Independently and in duplicate, reviewers manually extracted qualitative data from articles and identified emergent themes. Articles were screened independently by both reviewers based on the inclusion criteria. Conflicts were resolved by discussion and consensus. Social representation theory was used as a framework for describing how the opioid crisis is portrayed in Canada. RESULTS: Our search yielded 650 relevant opioid articles. The number of articles peaked in 2009, 2012, and in 2016, coinciding with major developments in the epidemic. The language used in this discourse has evolved over the years and has slowly shifted towards less stigmatizing language. Content analysis of the articles revealed common social representations attributing responsibility to pharmaceutical companies, physicians, and foreign countries. CONCLUSIONS: The Globe and Mail's coverage of the opioid crisis is focused on basic social representations and attributed responsibility for the crisis to a few collectives. A shift toward coverage of the root causes of the opioid epidemic could positively influence the general public's perception of the opioid crisis and promote deeper understanding of the issue. Journalists face several obstacles to achieve greater focus and framing of the opioid crisis; a closer working relationship between the media and the research community is needed.

Postnatal gestational age estimation via newborn screening analysis: application and potential.

Introduction: Preterm birth is a major global health concern, contributing to 35% of all neonatal deaths in 2016. Given the importance of accurately ascertaining estimates of preterm birth and in light of current limitations in postnatal gestational age (GA) estimation, novel methods of estimating GA postnatally in the absence of prenatal ultrasound are needed. Previous work has demonstrated the potential for metabolomics to estimate GA by analyzing data captured through routine newborn screening. Areas covered: Circulating analytes found in newborn blood samples vary by GA. Leveraging newborn screening and demographic data, our group developed an algorithm capable of estimating GA postnatally to within approximately 1 week of ultrasound-validated GA. Since then, we have built on the model by including additional analytes and validating the model's performance through internal and external validation studies, and through implementation of the model internationally. Expert opinion: Currently, using metabolomics to estimate GA postnatally holds considerable promise but is limited by issues of cost-effectiveness and resource access in low-income settings. Future work will focus on enhancing the precision of this approach while prioritizing point-of-care testing that is both accessible and acceptable to individuals in low-resource settings.

Parents as partners: investigating the role(s) of mothers in coordinating health and education activities for children with chronic care needs.

Interprofessional collaboration (IPC) between health professionals, and educators is an essential component of academic success and well-being for children who experience chronic illnesses. This study sought to understand parents' roles in and perceptions of IPC between their child's healthcare professionals and educators. We recruited 23 mothers to participate in our study. Data were analyzed using a combination of univariate analyses and content analysis. Overall, parents reported that they could effectively communicate their child's health and educational needs with health and educational professionals, but statistical analysis determined moderately increased challenges presenting information across professions. Most participants (n = 19) indicated that IPC between health and educational professionals could be improved. Effectively engaging parents as partners in IPC can promote more seamless collaboration and communication of a child's needs and offer a greater likelihood of achieving a child's health and educational goals.

Service-Learning in Communities of Elders (SLICE): Development and Evaluation of an Introductory Geriatrics Course for Medical Students.

PROBLEM: Medical students have limited exposure to Geriatrics in their traditional training. Service-learning offers students the opportunity to engage with older adult communities and become more comfortable interacting with this population. INTERVENTION: A preclinical elective course was developed to expand medical students' experiences in Geriatrics through service-learning. In this course, students conducted needs assessments in diverse older adult communities, created health education projects to address community-identified needs, and reflected on their experiences through written assignments and presentations. The course instructor presented lectures on special topics in Geriatrics, including ageism and health literacy. The curriculum aimed to familiarize students with older adults' needs in a variety of settings. CONTEXT: Over 3 years, 74 students participated in the service-learning course. Students were assigned to older adult community sites, where they conducted needs assessments and designed and implemented original educational projects targeting community concerns. Program evaluation methods included a validated survey assessing students' attitudes toward older adults, course evaluations, review of student assignments and projects, and feedback from older adult participants and site coordinators. OUTCOME: Students gained hands-on experience working with older adults and designing appropriate health education projects. Analysis of attitude surveys demonstrated students' increased interest in Geriatrics as a career. Both students and older adult participants described enjoyable, valuable experiences gained from service-learning activities. LESSONS LEARNED: Students appreciated the combination of community and classroom learning about Geriatrics. Service-learning was most constructive at sites with responsive coordinators, engaged older adults, and a need for health education resources. The course challenged students to assess health needs in communities that included cognitively impaired elders and to design educational projects tailored to older adults.

A cross-sectional study of medical students' knowledge of patient safety and quality improvement.

BACKGROUND: The Association of American Medical Colleges and the World Health Organization have endorsed formal patient safety and quality improvement (QI) education for medical students. We surveyed medical students to assess their current level of patient safety and QI knowledge and to identify factors associated with increased knowledge. METHODS: A literature review, focus groups with medical students, and local expert interviews were used to develop an electronic survey, which was distributed to all medical students at a single medical school in the spring of 2012. RESULTS: Fifty-seven percent of the medical school student body (N = 790) participated in the survey. A greater proportion of students reported previous exposure to patient safety education than to QI education (79% vs 47%). Students scored an average of 56% and 58% on the patient safety and QI knowledge tests, respectively. Having or pursuing an advanced degree (P = .02) and previous exposure to patient safety education (P = .02) were associated with higher knowledge scores. After adjusting for confounding variables, only previous exposure to QI education (P = .02) was associated with higher QI knowledge scores. LIMITATIONS: There is a risk of measurement bias due to the use of an unvalidated instrument. Students who have greater knowledge of patient safety or QI might recall exposure at a greater frequency, inflating the association between exposure and knowledge. Also, this is a cross-sectional study, so we cannot draw conclusions about causality. CONCLUSION: Medical students' knowledge of patient safety and QI is low. Previous formal or informal education about these topics is associated with increased knowledge.

Using Vaccine Safety Data to Demonstrate the Potential of Pooled Data Analysis.

In Canada, vaccine safety studies are often conducted at the provincial/territorial level where the primary data on vaccination reside. Combining health services data from multiple jurisdictions using a pooled data analytic approach would reduce the amount of time needed to detect vaccine safety signals. To determine the difference in the time it would take to identify safety signals using different proportions of the Canadian population, we conducted power and sample size calculations for a hypothetical self-controlled case series-based surveillance analysis. We used scenarios modeled after the real-world examples of myocarditis and vaccine-induced immune thrombotic thrombocytopenia (VITT) following COVID-19 vaccination as our base cases. Our calculations demonstrated that in the case of a myocarditis-type event, a pooled analysis would reduce the time needed to detect a safety signal by over 60% compared to using Ontario data alone. In the case of a VITT-type event, a pooled analysis could detect a safety signal 49 days sooner than using Ontario data alone, potentially averting as many as 30 events. Our analysis demonstrates that there is substantial value in using pan-Canadian health services data to evaluate the safety of vaccines. Efforts should be made to develop a pan-Canadian vaccine data source to allow for an earlier evaluation of suspected adverse events following immunization.

The first genetically confirmed cohort of Facioscapulohumeral Muscular Dystrophy from Northern India.

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common form of hereditary myopathy. Sixty per cent of the world's population lives in Asia, so a significant percentage of the world's FSHD participants is expected to live there. To date, most FSHD studies have involved individuals of European descent, yet small-scale studies of East-Asian populations suggest that the likelihood of developing FSHD may vary. Here, we present the first genetically confirmed FSHD cohort of Indian ancestry, which suggests a pathogenic FSHD1 allele size distribution intermediate between European and North-East Asian populations and more asymptomatic carriers of 4 unit and 5 unit FSHD1 alleles than observed in European populations. Our data provides important evidence of differences relevant to clinical diagnostics and underscores the need for global FSHD participation in research and trial-ready Indian FSHD cohorts.

Patient safety and quality improvement education: a cross-sectional study of medical students' preferences and attitudes.

BACKGROUND: Recent educational initiatives by both the World Health Organization and the American Association of Medical Colleges have endorsed integrating teaching of patient safety and quality improvement (QI) to medical students. Curriculum development should take into account learners' attitudes and preferences. We surveyed students to assess preferences and attitudes about QI and patient safety education. METHODS: An electronic survey was developed through focus groups, literature review, and local expert opinion and distributed via email to all medical students at a single medical school in the spring of 2012. RESULTS: A greater proportion of students reported previous exposure to patient safety than to quality improvement topics (79% vs. 47%). More than 80% of students thought patient safety was of the same or greater importance than basic science or clinical skills whereas quality improvement was rated as the same or more important by about 70% of students. Students rated real life examples of quality improvement projects and participation in these projects with actual patients as potentially the most helpful (mean scores 4.2/5 and 3.9/5 respectively). For learning about patient safety, real life examples of mistakes were again rated most highly (mean scores 4.5/5 for MD presented mistakes and 4.1/5 for patient presented mistakes). Students rated QI as very important to their future career regardless of intended specialty (mean score 4.5/5). CONCLUSIONS: Teaching of patient safety and quality improvement to medical students will be best received if it is integrated into clinical education rather than solely taught in pre-clinical lectures or through independent computer modules. Students recognize that these topics are important to their careers as future physicians regardless of intended specialty.

Opioid Agonist Therapies and Pregnancy Outcomes for Pregnant People With Opioid Use Disorder: Protocol for a Systematic Review.

BACKGROUND: Opioid use disorder (OUD) during pregnancy presents a significant risk to maternal, fetal, and neonatal health, increasing the likelihood of adverse events, such as maternal overdose, pregnancy loss, stillbirth, preterm birth, low birth weight, and neonatal abstinence syndrome. In order to reduce the risk of these outcomes, the standard of care for OUD during pregnancy in many jurisdictions within the United States and Canada is opioid agonist therapy (OAT). OAT refers to prescription medications that alleviate or eliminate opioid withdrawal symptoms, so that opioid use can be managed more safely. Although OAT has been recognized as a safe option for pregnant people with OUD, many jurisdictions do not have treatment guidelines regarding pharmacological options, dosing recommendations, side effect management, and individual preferences. There is currently a lack of systematic evidence on the impacts of different OAT regimens on pregnancy outcomes. OBJECTIVE: We aim to evaluate the impacts of specific OAT agents on pregnancy outcomes and inform recommendations for practitioners treating pregnant people with OUD. METHODS: The MEDLINE, Embase, CINAHL, and PsycINFO databases will be searched for published quantitative studies assessing pregnancy outcomes for individuals on OAT. Given the substantially increased risk of preterm birth, low birth weight, small for gestational age, and stillbirth among pregnant people with OUD, these four end points will comprise our primary outcomes. Database searches will not be restricted by date, and conference abstracts will be restricted to the past 2 years. Titles, abstracts, and full-text articles will be independently screened by 2 reviewers. Data will be extracted independently and in duplicate, using a data extraction form to reduce the risk of reviewer bias. The risk of bias within individual studies will be assessed by using the appropriate CASP (Critical Appraisal Skills Programme) checklists. For studies that consider the same research questions, interventions, or outcomes, meta-analyses will be conducted to synthesize the pooled effect size. In the event that studies cannot be compared directly, results will be synthesized in a narrative account. Between-study heterogeneity will be measured by using the τ2 statistic. If more than 10 studies are available for pooling, publication bias will be evaluated by using the Egger regression test. RESULTS: As of January 2023, a total of 3266 abstracts have been identified for screening. Data extraction is expected to commence in February 2023. CONCLUSIONS: The topic of OAT and its effect on pregnancy is an understudied area that has the potential to improve health outcomes, clinical practice, education, and community advocacy. The results of our review will be used to inform clinical practice guidelines and improve health outcomes for pregnant people. Findings will be disseminated to diverse groups of stakeholders, including policy makers, clinicians, community partners, and individuals with lived experience of drug use. TRIAL REGISTRATION: PROSPERO CRD42022332082; https://tinyurl.com/2p94pkx5. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/42417.

Geriatric Telehealth: A Standardized Patient Case for Medical Students.

Introduction: The COVID-19 pandemic has necessitated the rapid expansion of telemedicine. However, there has been minimal coverage of telemedicine in traditional undergraduate medicine curricula. Telemedicine presents specific challenges in the geriatric population, including unfamiliarity with technology, cognitive and sensory barriers, inclusion of family and/or caregivers, multimorbidity, and a high degree of medical complexity. Methods: We developed a workshop to allow rising third-year medical students to practice a telemedicine patient encounter while developing skills for assessing and communicating with geriatric patients. This 90-minute workshop consisted of an introductory didactic presentation and a standardized patient activity for small groups of two to five students. Students' level of comfort with telemedicine for assessment of geriatric patients was evaluated with a pre- and postsurvey. Results: Fifty-eight students participated in the workshop and completed the surveys (presurvey = 58, postsurvey = 40), with roughly half (52%) reporting prior experience with telemedicine. A 5-point Likert-type scale (1 = very uncomfortable, 5 = very comfortable) was used. Students reported statistically significant increases in comfort using telemedicine (presurvey = 3.1, postsurvey = 3.9, p < .001) and using telemedicine for patients ≥65 years (presurvey = 2.8, postsurvey = 3.9, p < .001) after completing the workshop. Discussion: Medical students' comfort levels using telemedicine and caring for patients ages 65 and older with a telehealth visit improved after participating in this workshop. To help prepare students for telehealth practice in their future careers, educators should provide them with opportunities to practice and develop this critical skill set.

Digital Immunization Tracking in Long-Term Care and Assisted Living Facilities.

A disproportionate share of the health impacts of COVID-19 has been borne by older adults, particularly those in long-term care facilities (LTCs). Vaccination has been critical to efforts to combat this issue, but as we begin to emerge from this pandemic, questions remain about how to protect the health of residents of LTC and assisted living facilities proactively in order to prevent such a disaster from occurring again. Vaccination, not just against COVID-19, but also against other vaccine-preventable illness, will be a key component of this effort. However, there are currently substantial gaps in the uptake of vaccines recommended for older adults. Technology offers an opportunity to assist in filling these vaccination gaps. Our experiences in Fredericton, New Brunswick suggest that a digital immunization solution would facilitate better uptake of adult vaccines for older adults in assisted and independent living facilities and would help policy and decision makers to identify coverage gaps and develop interventions to protect these individuals.

Early Treatment with Fluvoxamine among Patients with COVID-19: A Cost-Consequence Model.

To date, two published randomized trials have indicated a clinical benefit of early treatment with fluvoxamine versus placebo for adults with symptomatic COVID-19. Using the results of the largest of these trials, the TOGETHER trial, we conducted a cost-consequence analysis to assess the health system benefits of preventing progression to severe COVID-19 in outpatient populations in the United States. A decision-analytic model in the form of a decision tree was constructed to evaluate two treatment strategies for high-risk patients with confirmed, symptomatic COVID-19 in the primary analysis: treatment with a 10-day course of fluvoxamine (100 mg twice daily) and current standard-of-care. A secondary analysis comparing a 5-day course of nirmatrelvir-ritonavir was also conducted. We used a time horizon of 28 days. Reported outcomes included cost-savings and hospitalization days avoided. The results of our analysis indicated that administration of fluvoxamine to symptomatic outpatients at high risk of progressing to severe COVID-19 was substantially cost-saving, in the amount of $232 per eligible patient and prevented an average of 0.15 hospital days per patient treated, compared with standard of care. Nirmatrelvir-ritonavir was also shown to be cost-saving despite its higher acquisition cost and provided savings to the healthcare system of $625 per patient treated. These findings suggest that fluvoxamine is likely to be a cost-effective addition to frontline COVID-19 mitigation strategies in many settings, particularly where access to nirmaltrevir-ritonavir or monoclonal antibodies is limited.

The mutational profile in a South African cohort with inherited neuropathies and spastic paraplegia.

Introduction: Limited diagnostics are available for inherited neuromuscular diseases (NMD) in South Africa and (excluding muscle disease) are mainly aimed at the most frequent genes underlying genetic neuropathy (GN) and spastic ataxias in Europeans. In this study, we used next-generation sequencing to screen 61 probands with GN, hereditary spastic paraplegia (HSP), and spastic ataxias for a genetic diagnosis. Methods: After identifying four GN probands with PMP22 duplication and one spastic ataxia proband with SCA1, the remaining probands underwent whole exome (n = 26) or genome sequencing (n = 30). The curation of coding/splice region variants using gene panels was guided by allele frequencies from internal African-ancestry control genomes (n = 537) and the Clinical Genome Resource's Sequence Variant Interpretation guidelines. Results: Of 32 GN probands, 50% had African-genetic ancestry, and 44% were solved: PMP22 (n = 4); MFN2 (n = 3); one each of MORC2, ATP1A1, ADPRHL2, GJB1, GAN, MPZ, and ATM. Of 29 HSP probands (six with predominant ataxia), 66% had African-genetic ancestry, and 48% were solved: SPG11 (n = 3); KIF1A (n = 2); and one each of SPAST, ATL1, SPG7, PCYT2, PSEN1, ATXN1, ALDH18A1, CYP7B1, and RFT1. Structural variants in SPAST, SPG11, SPG7, MFN2, MPZ, KIF5A, and GJB1 were excluded by computational prediction and manual visualisation. Discussion: In this preliminary cohort screening panel of disease genes using WES/WGS data, we solved ~50% of cases, which is similar to diagnostic yields reported for global cohorts. However, the mutational profile among South Africans with GN and HSP differs substantially from that in the Global North.

The Human Mpox Global Outbreak: Available Control Tools and the Opportunity to Break a Cycle of Neglect in Endemic Countries.

The 2022 global outbreak of human Mpox (formerly monkeypox) virus (MPXV) infection outside of the usual endemic zones in Africa challenged our understanding of the virus's natural history, transmission dynamics, and risk factors. This outbreak has highlighted the need for diagnostics, vaccines, therapeutics, and implementation research, all of which require more substantial investments in equitable collaborative partnerships. Global multidisciplinary networks need to tackle MPXV and other neglected emerging and reemerging zoonotic pathogens to address them locally and prevent or quickly control their worldwide spread. Political endorsement from individual countries and financial commitments to maintain control efforts will be essential for long-term sustainability.