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Primaquine can be used to prevent the transmission of falciparum malaria from human to mosquito. Bob Taylor and colleagues at the Mahidol Oxford Research Unit (MORU) developped an age-based regimen for single low-dose primaquine to block the transmission of malaria in sub-Saharan Africa.
An adaptive multiarm randomised trial of biomedical and psychosocial interventions to improve convalescence following severe acute malnutrition in sub-Saharan Africa: Co-SAM trial protocol.
INTRODUCTION: Children discharged from hospital following management of complicated severe acute malnutrition (SAM) have a high risk of mortality, readmission and failed nutritional recovery. Current management approaches fail to sufficiently promote convalescence after inpatient nutritional rehabilitation. Novel interventions during the post-discharge period could enhance convalescence to help children survive and thrive. METHODS AND ANALYSIS: The Co-SAM trial is an adaptive, multicountry, phase III, individually randomised clinical trial, based on the principles that (i) interacting biological and social factors drive multimorbidity in children with SAM, and (ii) both medical and psychosocial interventions may therefore ameliorate underlying causal pathways to reduce morbidity and mortality and improve recovery. Children aged 6-59 months with complicated SAM, who have stabilised and started the transition to ready-to-use therapeutic food (RUTF), will be enrolled and randomised to one of five trial arms (standard-of-care alone; antimicrobials; reformulated RUTF; psychosocial support; or a combination of all strategies). Standard-of-care, which is provided in all trial arms, includes RUTF until nutritional recovery (defined as weight-for-height Z-score >-2, mid-upper arm circumference >12.5 cm and oedema-free since the last study visit), and other management recommended in WHO guidelines. The 12-week antimicrobial package provides daily co-formulated rifampicin and isoniazid (with pyridoxine) and 3 days of azithromycin monthly. The reformulated RUTF, which incorporates medium-chain triglycerides and hydrolysed protein to increase nutrient bioavailability and reduce metabolic stress, is provided at the same dose and duration as standard RUTF. The 12-week psychosocial package includes caregiver problem-solving therapy, educational modules, peer support groups and child play. The combined arm includes all interventions. Children start their intervention package prior to hospital discharge, with follow-up data collection in study clinics at 2, 4, 6, 8, 12 and 24 weeks. The primary composite outcome is death, hospitalisation or failed nutritional recovery within 24 weeks post-randomisation. An interim analysis will allow unpromising arms to be dropped, while the final analysis will be conducted when 1266 children have completed the study. Embedded process evaluation and laboratory substudies will explore the mechanisms of action of the interventions. ETHICS AND DISSEMINATION: The trial has been approved by ethics committees in Zimbabwe, Zambia, Kenya and UK. Dissemination will be via community advisory boards in each country; Ministries of Health; and dialogue with policymakers including UNICEF. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov: NCT05994742; Pan African Clinical Trials Registry: PACTR202311478928378.
Methodological opportunities in genomic data analysis to advance health equity.
The causes and consequences of inequities in genomic research and medicine are complex and widespread. However, it is widely acknowledged that underrepresentation of diverse populations in human genetics research risks exacerbating existing health disparities. Efforts to improve diversity are ongoing, but an often-overlooked source of inequity is the choice of analytical methods used to process, analyse and interpret genomic data. This choice can influence all areas of genomic research, from genome-wide association studies and polygenic score development to variant prioritization and functional genomics. New statistical and machine learning techniques to understand, quantify and correct for the impact of biases in genomic data are emerging within the wider genomic research and genomic medicine ecosystems. At this crucial time point, it is important to clarify where improvements in methods and practices can, or cannot, have a role in improving equity in genomics. Here, we review existing approaches to promote equity and fairness in statistical analysis for genomics, and propose future methodological developments that are likely to yield the most impact for equity.
Detection of mpox and other orthopoxviruses using a lateral flow device as a point-of-care diagnostic.
In 2022, the World Health Organization declared the worldwide outbreak of mpox to be a public health emergency of international concern. The causative monkeypox virus (MPXV) belonged to clade IIb and is transmitted through sexual contact with a low case fatality rate (0.1%), which, together with under-detection, all contributed to a rapid global spread particularly within the MSM (men who have sex with men) community. As MPXV clade II remains circulating worldwide, a new outbreak of the more fatal clade I disease has been declared in Central and East Africa, and remains uncontrolled in part due to the lack of point-of-care (POC) diagnostics for rapid decisions on treatment and self-isolation. To address the lack of POC solutions for mpox, we have designed and evaluated an orthopoxvirus-specific lateral flow device (LFD) that could be used for the diagnosis of mpox. Using an LFD comprising four monoclonal antibodies against the A27 protein, we demonstrate sensitivity to 3 × 105 pfu/mL. This sensitivity is expected to be sufficient for the detection of MPXV from lesion sites and may also be sufficient for other sample types such as saliva and urine. We found that the presence of guanidinium thiocyanate, a common ingredient in inactivating viral transport media, masked the LFD antigen, resulting in false negatives. POC diagnosis of mpox may be possible using an LFD to reduce delays arising from sample shipment to centralized laboratory testing facilities. In order to achieve this, our work demonstrates that an LFD-optimized buffer is required, as the sample collection buffer may have a detrimental impact on sensitivity for clinical material.IMPORTANCEMpox cases have dramatically increased both in traditionally monkeypox virus endemic countries and also worldwide. This increase comes at a time when immunity derived from smallpox vaccination is no longer available. Diagnosis of mpox is complicated due to both disease presentation and the availability of local diagnostic laboratories. The availability of a point-of-care diagnostic tool such as an lateral flow device (LFD) would play an important role to both diagnose and prevent onward transmission. This manuscript provides developers and assessors with key data for defining true sensitivity and specificity of a successful LFD in addition to buffer conditions for sample collection.
An RBD-Fc mucosal vaccine provides variant-proof protection against SARS-CoV-2 in mice and hamsters.
Current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are effective against severe disease and death, but do not prevent viral infections, probably due to the limited mucosal immunity induced by intramuscular administration of the vaccine. Fusion of SARS-CoV-2 subunit immunogens with a human IgG Fc backbone can be used as a mucosal vaccine but its effectiveness in delivery in animal models, and its immunogenicity and the vaccine-induced protection against viral infections requires further studies. Here we investigate a bivalent RBD-Fc vaccine that includes the spike receptor-binding domains (RBDs) of the ancestral and BQ.1.1 variant of SARS-CoV-2. Ex vivo fluorescent imaging demonstrates that this vaccine can be effectively delivered to the lungs of mice through intranasal administration, with enhancement of retention in the nasal cavity and lung parenchyma. In mice, the vaccine elicited potent and broad-spectrum antibody responses against different variants including KP.3 which could persist for at least 3 months after booster. Importantly, it was able to induce RBD-specific mucosal IgA responses. Further, heterologous intranasal immunisation with adeno-vectored Chadv1 and RBD-Fc elicited both potent neutralising antibody and T cell responses. Immunised BALB/c and K18-hACE2-transgenic mice were also protected against viral challenge of XBB.1 and viral transmission was effectively limited in hamsters through intranasal immunisation. This work thus demonstrates the potential of RBD-Fc antigens as mucosal vaccines for prevention of breakthrough infections and onward transmission. Moreover, Fc-fusion proteins can be used as an effective mucosal vaccine strategy which can be used either alone or in combination with other vaccine technology to constitute heterologous immunisations, enabling strong protection against SARS-CoV-2 and other respiratory viruses.
Magnetic resonance enterography to predict subsequent disabling Crohn's disease in newly diagnosed patients (METRIC-EF)-multivariable prediction model, multicentre diagnostic inception cohort.
ObjectivesMagnetic resonance enterography (MRE) is a first-line investigation to diagnose Crohn's disease (CD), but its role for prognostication is unknown. Accordingly, we assessed the predictive ability of prognostic models including MRE scores (MRE Global Score (MEGS), simplified MR Index of Activity (sMARIA), and Lémann index (LI)) against models using clinical predictors alone for the development of modified Beaugerie disabling CD (MBDD) within 5 years of diagnosis.MethodsThis was a multicentre, diagnostic inception cohort of patients with newly diagnosed CD across 9 UK hospitals, followed for 4 years or more. We censored development of MBDD ≤ 90 days from diagnosis, and used time-to-event models using Royston-Parmer flexible parametric models.ResultsWe included 194 patients, median age 29, IQR 22-44 years, 52% female. Within 5 years of diagnosis, 42% (81/194) developed MBDD. In univariable analysis, initial steroid requirement was associated with increased risk of developing MBDD (HR 2.11 (95% CI 1.36, 3.26). The baseline clinical model had 49% (39, 60) sensitivity and 66% (57, 74) specificity for predicting the top 40% of patients with the greatest risk of developing MBDD, and 86% (77, 92) sensitivity and 35% (27, 45) specificity for predicting the development of MBDD in patients with an absolute risk of ≥ 10%. There was no significant difference in sensitivity when the MEGS, sMARIA, or LI were added to the baseline clinical model.ConclusionsAddition of MRE scores at diagnosis to a multivariable model comprising clinical predictors did not improve prediction of MBDD within 5 years of diagnosis.Key pointsQuestion Magnetic resonance enterography (MRE) is important for diagnosing and monitoring Crohn's disease (CD), but primary research evaluating its prognostic role is lacking. Findings Adding MRE findings at diagnosis to a multivariable model comprising clinical predictors did not improve the prediction of disabling CD within 5 years of diagnosis. Clinical relevance When tested in a prospective, multicentre trial, current MRE activity and damage scores at diagnosis did not reliably predict whether patients would subsequently develop disabling CD. Notwithstanding this finding, MRE remains an essential tool for diagnosis and monitoring.
US and European Patient and Health Care Professional Perspectives on Fatigue in Ulcerative Colitis and Crohn's Disease: Results From the Communicating Needs and Features of Inflammatory Bowel Disease Experiences Survey.
BACKGROUND: Fatigue is a burdensome symptom of Crohn's disease (CD) and ulcerative colitis (UC). The Communicating Needs and Features of Inflammatory Bowel Disease Experiences (CONFIDE) study investigated how patients and health care professionals (HCPs) in the United States (US) and Europe (France, Germany, Italy, Spain, and the United Kingdom) perceived the experiences and impact of CD/UC-related symptoms. METHODS: Online, quantitative, cross-sectional surveys were conducted separately among patients with moderate-to-severe CD/UC (defined based on previous treatment, steroid use, and/or hospitalization) and HCPs who treated patients with CD/UC. US and Europe data are presented as descriptive statistics. RESULTS: Surveys were completed by 215 US and 547 European patients with CD, 200 US and 556 European patients with UC, and 200 US and 503 European HCPs. Overall, 35.8% US and 34.2% European patients with CD and 27.5% US and 20.9% European patients with UC reported currently experiencing fatigue (in past month). Most of these patients reported severe fatigue and indicated that CD/UC negatively affected their sleep, energy levels, and quality of life (QoL). The majority of patients currently experiencing but not discussing fatigue with their HCPs at every appointment wished they discussed it more frequently. However, most HCPs reported proactively discussing fatigue at routine appointments. Approximately 20% patients with CD/UC reported declining participation in work/school, social activities, and sports/physical exercise, and avoiding sexual activities due to fatigue. CONCLUSIONS: US and European patients with CD/UC experienced severe burden of fatigue, which negatively affected their QoL. Assessing and discussing fatigue in routine appointments is critical for effectively managing this debilitating symptom.
Identification of undetected SARS-CoV-2 infections by clustering of Nucleocapsid antibody trajectories.
During the COVID-19 pandemic, numerous SARS-CoV-2 infections remained undetected. We combined results from routine monthly nose and throat swabs, and self-reported positive swab tests, from a UK household survey, linked to national swab testing programme data from England and Wales, together with Nucleocapsid (N-)antibody trajectories clustered using a longitudinal variation of K-means (N = 185,646) to estimate the number of infections undetected by either approach. Using N-antibody (hypothetical) infections and swab-positivity, we estimated that 7.4% (95%CI: 7.0-7.8%) of all true infections (detected and undetected) were undetected by both approaches, 25.8% (25.5-26.1%) by swab-positivity-only and 28.6% (28.4-28.9%) by trajectory-based N-antibody-classifications-only. Congruence with swab-positivity was respectively much poorer and slightly better with N-antibody classifications based on fixed thresholds or fourfold increases. Using multivariable logistic regression N-antibody seroconversion was more likely as age increased between 30-60 years, in non-white participants, those less (recently/frequently) vaccinated, for lower cycle threshold values in the range above 30, and in symptomatic and Delta (vs. BA.1) infections. Comparing swab-positivity data sources showed that routine monthly swabs were insufficient to detect infections and incorporating national testing programme/self-reported data substantially increased detection. Overall, whilst N-antibody serosurveillance can identify infections undetected by swab-positivity, optimal use requires fourfold-increase-based or trajectory-based analysis.
Differential effectiveness of low-intensity exercise in young and old rats.
Low-intensity exercise increases strength and function in old adults, but it is unclear if change occurs secondary to "neural adaptation" or to intrinsic muscle adaptation. Whether function and strength change concomitantly is also unclear. We examined effects of a modest intensity, 10-session exercise program on muscle mass, contractile force, and function (gait) in 6-month-old and 30-month-old rats. Animals underwent 45 minutes of activity (e.g., ramp walking, balancing) 5 days/week. In old animals, a significant increase in muscle mass and peak contractile force occurred with exercise in soleus, plantaris, extensor digitorum longus, and peroneus longus compared with controls, but did not restore values to those for young controls. The increase in muscle force in old rats was accompanied by a significant lengthening of stride (90 +/- 9 to 103 +/- 15 mm), which was still 23% less than stride values for young rats. Changes in muscle function and gait with exercise were not apparent in young rats. Results suggest that (a). rapid and significant changes in muscle mass and strength in an aged organism can occur with a modest activity program, (b). the threshold for muscle adaptation may differ in young versus old rats, and (c). changes in strength and function in old rats may occur concomitantly.
Prehabilitation and rehabilitation for attenuating hindlimb unweighting effects on skeletal muscle and gait in adult and old rats.
ObjectiveTo compare the effectiveness of no exercise with prehabilitation (exercise before hindlimb unweighting [HLU]) versus rehabilitation (exercise given after HLU) on gait function and skeletal muscle mass and force.DesignRandomized controlled trial.SettingAnimal laboratory.AnimalsMale-specific, pathogen-free Fisher344/Brown Norway rats (N=149). Groups consisted of adult and old controls, HLU, prehabilitation, rehabilitation, natural cage recovery (reloading), and exercise without HLU.InterventionsTen days of general conditioning exercise were given to 6-month-old adult and 30-month-old old rats before or after a week of HLU.Main outcome measuresGait stride length and width; soleus, plantaris, extensor digitorum longus, and peroneus longus mass and peak contractile force; whole gastrocnemius mass; and total protein concentration for the soleus and gastrocnemius.ResultsMuscle mass (approximately 30%) and force (24%-36%) declined with age in all muscles studied. In adult rats declines in muscle mass occurred with HLU in the soleus, plantaris, and gastrocnemius. Prehabilitation did not prevent the loss of muscle mass in adult rats. Rehabilitation and natural recovery effectively restored soleus and gastrocnemius muscle mass in adult rats but not soleus peak force. Old rats had a significant 23% HLU effect only on gastrocnemius mass (control, 1670+/-129 mg; HLU, 1274+/-184 mg). Prehabilitation did not prevent the decline in gastrocnemius mass. Rehabilitation in old rats restored gastrocnemius mass to within 13% of control levels. Prehabilitation was effective for preventing and rehabilitation was effective for restoring soleus contractile force in old rats (control, 114+/-9 mg; HLU, 67+/-22 mg; prehabilitation, 106+/-31 mg; rehabilitation, 120+/-26 mg) compared with recovery without exercise (86+/-29 g). A significant reduction in stride length was observed with aging (136+/-18 mm vs 98+/-10 mm), which decreased further with HLU (78+/-14 mm). Prehabilitation attenuated HLU-related reductions in stride length, and rehabilitation was effective for stride length restoration in old rats.ConclusionsExercise, particularly rehabilitation, was more effective for old than young rats. Prehabilitation and rehabilitation diminished some of the detrimental effects of HLU on skeletal muscle mass and force and gait function in old rats.
Determining a role for Patient and Public Involvement and Engagement (PPIE) in genomic data governance for cancer care
Abstract Comprehensive collections of cancer data, including genomic data, are needed to improve cancer risk prediction and treatments. A recent government review, Better, Broader, Safer: Using health data for research and analysis, has argued for high-quality Patient and Public Involvement and Engagement (PPIE) for ethical data use. In this paper we determine a role and justification for PPIE to govern uses of genomic data in fields like cancer. First, we analyse two public attitudes studies about the role of PPIE in genomics governance. Second, we characterise two ethically-significant features of the context of governing genomic data: 1) data aggregation leading to novel group formation, and 2) the hybrid territory of genomic cancer data uses. Thirdly, we bring together these aspects to describe a fully determined role for PPIE within an approach to governing cancer genomic data, which is tailored to major areas of ethical consideration. Our account is a novel interpretation of what PPIE is for in governance, how it may foster public support and how its success in so doing depends on it being tailored to context.
Safety and broad immunogenicity of HIVconsvX conserved mosaic candidate T-cell vaccines vectored by ChAdOx1 and MVA in HIV-CORE 006: a double-blind, randomised, placebo-controlled phase 1 trial in healthy adults living without HIV-1 in eastern and southern Africa
Background: Even within the context of antiretroviral treatment and prevention, an HIV-1 vaccine remains the best strategy for ending the HIV/AIDS epidemic. A vaccine is particularly needed in sub-Saharan Africa, where HIV-1 greatly affects people's lives and economy. Here, we aimed to assess the safety and immunogenicity of candidate T-cell vaccines in African populations. Methods: HIV-CORE 006 was a double-blind, randomised, placebo-controlled phase 1 trial conducted across four clinical research centres in Uganda, Kenya, and Zambia. Eligible participants were not pregnant, were living without HIV-1 or HIV-2, had a low likelihood of acquiring HIV-1, were aged 18–50 years, fully comprehended the purpose and details of this study as outlined in the participant information sheet, and passed an assessment of understanding before providing written informed consent. Participants were randomly assigned (9:2) to receive either a vaccine regimen or a placebo. The vaccine was administered as ChAdOx1.tHIVconsv1 (C1) followed by MVA.tHIVconsv3 (M3) and MVA.tHIVconsv4 (M4) in regimen C1-M3M4. The first primary outcome was the vaccines’ safety assessment, assessed in all participants who received at least one vaccine or placebo dose. The second primary outcome evaluated the C1-M3M4 regimen's induction of HIVconsvX-specific T-cell responses by assessing the proportion of vaccine recipients who responded to the vaccination, assessed in all participants who received all doses of vaccine or placebo as per protocol. This study is registered with ClinicalTrials.gov, NCT04553016, and the Pan-African Clinical Trials Registry PACTR202006495409011, and is now closed. Findings: Between July 15, 2021, and Nov 2, 2022, 89 healthy adults living without HIV-1 were randomly assigned, with 88 receiving either the vaccine (n=72) or placebo (n=16). Of these 88 participants, 57 (65%) were male and 31 (35%) were female. The C1, M3, and M4 vaccine components were well tolerated and induced HIVconsvX-specific responses in 70 (99%) of the 71 participants who completed all vaccine doses. Vaccine-elicited T cells peaked at a median of 2310 (IQR 1080–4480) IFN-γ spot-forming units per 106 peripheral blood mononuclear cells and recognised a median of eight (five to ten) of ten peptide pools spanning the HIVconsvX immunogen. The total frequencies of elicited T cells decreased 4·6 times over a 40-week follow-up period compared with the peak responses. Upon antigenic re-exposure, T cells proliferated, exhibited multiple effector functions, and inhibited HIV-1 representatives from clades A, B, C, and D. Interpretation: Results from key sub-Saharan African populations supported the safety of the vaccine regimen previously shown in the first-in-human trial in the UK. The induction of T cells and their characteristics encourage vaccine integration into HIV-1 cure strategies, which could inform HIV-1 prevention efforts. Funding: The European and Developing Countries Clinical Trials Partnership.
Fatal Mycobacterium avium meningitis in an HIV-negative Vietnamese man: a case report
Background: Nontuberculous mycobacteria are environmental mycobacteria that rarely cause human disease, especially in the central nervous system. Central nervous system infection by Mycobacterium avium complex, the most common pathogen among nontuberculous mycobacteria species, is rare and seldom reported, even in those with advanced human immunodeficiency virus infection. We describe a case of Mycobacterium avium complex meningitis with cerebral hemorrhage in an human immunodeficiency virus uninfected man in Vietnam. Case presentation: A 56-year-old Vietnamese man with hypertension was hospitalized with a 5-day history of headache, dizziness, low-grade fever, and unresponsive to 5 days of oral antibiotics. A brain magnetic resonance imaging, performed on day 12, showed hydrocephalus and lacunar infarct. The patient did not improve with 8 days of empirical treatment with ceftriaxone, vancomycin, dexamethasone, and meropenem, and was transferred to a referral hospital for tropical diseases. At the second hospital admission, a cerebrospinal fluid analysis showed a white cell count of 22,518 cells/μL with 81% neutrophils, protein 1.72 g/L, and glucose 0.85 mmol/L. Acid-fast bacilli smear of the cerebrospinal fluid was positive. Molecular testing of the cerebrospinal fluid was negative on GeneXpert Ultra testing, while the line probe assay was positive for Mycobacterium avium. Blood cultures at two sites, cerebrospinal fluid cultures for bacteria and fungi, and human immunodeficiency virus Ag/Ab test were negative. The patient was continuously administered meropenem with the addition of azithromycin, rifampin, and ethambutol. Then, 1 day after nontuberculous mycobacteria treatment, he developed right-sided hemiplegia, and brain computed tomography showed a hemorrhage in the parietal area, adjacent to the left lateral ventricle, and left lateral intraventricular hemorrhage shifts the midline to the right. He was transferred to the third referral general hospital and died 22 days after the onset of symptoms. Conclusion: Nontuberculous mycobacteria-central nervous system infection might mimic unresponsive pyogenic bacterial meningitis. A rapid and accurate diagnosis is essential for initiating appropriate therapy for this deadly disease.