A randomised Trial of Autologous Blood products, leukocyte and platelet-rich fibrin (L-PRF), to promote ulcer healing in LEprosy: The TABLE trial.

INTRODUCTION: Autologous blood products like Platelet Rich Plasma (PRP) and Leukocyte and Platelets Rich Fibrin (L-PRF) have been used for many years across many types of skin ulcers. However, the effectiveness of autologous blood products on wound healing is not well established. METHODS: We evaluated the 'second generation' autologous product- Leukocyte and Platelet- Rich Fibrin (L-PRF). Our trial was undertaken on patients suffering from neuropathic leprosy ulcers at the Anandaban hospital which serves the entire country of Nepal. We conducted a 1:1 (n = 130) individually randomised trial of L-PRF (intervention) vs. normal saline dressing (control) to compare rate of healing and time to complete healing. Rate of healing was estimated using blind assessments of ulcer areas based on three different measurement methods. Time to complete healing was measured by the local unblinded clinicians and by blind assessment of ulcer images. RESULTS: The point estimates for both outcomes were favourable to L-PRF but the effect sizes were small. Unadjusted mean differences (intervention vs control) in mean daily healing rates (cm2) were respectively 0.012 (95% confidence interval 0.001 to 0.023, p = 0.027); 0.016 (0.004 to 0.027, p = 0.008) and 0.005 (-0.005 to 0.016, p = 0.313) across the three measurement methods. Time to complete healing at 42 days yielded Hazard Ratios (unadjusted) of 1.3 (0.8 to 2.1, p = 0.300) assessed by unblinded local clinicians and 1.2 (0.7 to 2.0, p = 0.462) on blind assessment. CONCLUSION: Any benefit from L-PRF appears insufficient to justify routine use in care of neuropathic ulcers in leprosy. TRIAL REGISTRATION: ISRCTN14933421. Date of trial registration: 16 June 2020.

Insights into microorganisms, associated factors, and the oral microbiome in infective endocarditis patients.

Introduction: Infective Endocarditis (IE) is a rare, life-threatening infection of the endocardium with multisystem effects. Culprit microorganisms derived from different niches circulate through the bloodstream and attach to the endocardium, particularly the heart valves. This study aimed to investigate culprit microorganisms among a cross-sectional cohort of IE patients, their associated factors, and to explore the potential relationship to the oral microbiome. Methods: In this observational study, we undertook a cross-sectional analysis of 392 medical records from patients diagnosed with IE. The primary outcome of this study was to analyse the association between the IE culprit microorganisms and the underlying anatomical types of IE (native valve (NVE), prosthetic valve (PVE), or cardiac device-related (CDE)). Secondary outcomes encompassed a comparative analysis of additional factors, including: the treatment approaches for IE, and the categorisation of blood cultures, extending to both genus and species levels. Additionally, we cross-referenced and compared the species-level identification of IE bacteraemia outcome measures with data from the expanded Human Oral Microbiome Database (eHOMD). Results: A culprit microorganism was identified in 299 (76.28%) case participants. Staphylococcal infections were the most common (p < 0.001), responsible for 130 (33.16%) hospitalisations. There were 277 (70.66%) cases of NVE, 104 (26.53%) cases of PVE, and 11 (2.81%) cases of CDE. The majority of PVE occurred on prosthetic aortic valves (78/104, 75%), of which 72 (93.5%) were surgical aortic valve replacements (SAVR), 6 (7.8%) were transcatheter aortic valve implants, and one transcatheter pulmonary valve implant. Overall, underlying anatomy (p = 0.042) as well as the treatment approaches for IE (p < 0.001) were significantly associated with IE culprit microorganisms. Cross-reference between IE bacteraemia outcomes with the eHOMD was observed in 267/392 (68.11%) cases. Conclusions: This study demonstrated that IE patients with a history of stroke, smoking, intravenous drug use, or dialysis were more likely to be infected with Staphylococcus aureus. CDE case participants and patients who had previous SAVR were most associated with Staphylococcus epidermidis. IE patients aged 78+ were more likely to develop enterococci IE than other age groups. Oral microorganisms indicated by the eHOMD are significantly observed in the IE population. Further research, through enhanced dental and medical collaboration, is required to correlate the presence of oral microbiota as causative factor for IE.

Autologous blood products: Leucocyte and Platelets Rich Fibrin (L-PRF) and Platelets Rich Plasma (PRP) gel to promote cutaneous ulcer healing - a systematic review.

OBJECTIVE: To summarise evidence on the effectiveness of Platelet-Rich Plasma (PRP) gel and Leucocyte and Platelet Rich Fibrin (L-PRF) gel as agents promoting ulcer healing compared with the standard wound dressing techniques alone. DESIGN: Systematic review. ELIGIBILITY CRITERIA: Individual patient randomised controlled trials on skin ulcers of all types excluding traumatic lesions.Intervention group: treatment with topical application of L-PRF gel or PRP gel to the wound surface. CONTROL GROUP: treatment with standard skin ulcer care using normal saline, normgel or hydrogel dressings. INFORMATION SOURCES: Medline (Ovid), Excerpta Medica Database (EMBASE), Scopus, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Web of Science and manual search of studies from previous systematic reviews and meta-analyses. The papers published from 1946 to 2022 with no restriction on geography and language were included. The last date of the search was performed on 29 August 2022. DATA EXTRACTION AND SYNTHESIS: Independent reviewers identified eligible studies, extracted data, assessed risk of bias using V.2 of the Cochrane risk-of-bias tool for randomised trials tool and assessed certainty of evidence by using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. MAIN OUTCOME MEASURES: Time to complete healing, proportion healed at a given time and rate of healing. RESULTS: Seven studies met the inclusion criteria, five using PRP gel and two using L-PRF gel. One study showed a better proportion of complete healing, three reported reduced meantime to complete healing and five showed improved rate of healing per unit of time in the intervention group. The risk of bias was high across all studies with one exception and the GRADE showed very low certainty of evidence. CONCLUSION: The findings show potential for better outcomes in the intervention; however, the evidence remains inconclusive highlighting a large research gap in ulcer treatment and warrant better-designed clinical trials. PROSPERO REGISTRATION NUMBER: CRD42022352418.

Prevalence of plantar ulcer and its risk factors in leprosy: a systematic review and meta-analysis.

BACKGROUND: Plantar ulcers are a leading complication of leprosy that requires frequent visits to hospital and is associated with stigma. The extent of burden of ulcers in leprosy and its risk factors are scant impeding the development of targeted interventions to prevent and promote healing of ulcers. The aim of this review is to generate evidence on the prevalence of plantar ulcer and its risk factors in leprosy. METHODS: Databases (Medline, Embase, Web of Science, CINAHL, BVS), conference abstracts and reference lists were searched for eligible studies. Studies were included that reported a point prevalence of plantar ulcer and/or its "risk factors" associated with development of ulcers (either causatively or predictively), including individual level, disease related and bio-mechanical factors. We followed PRISMA guidelines for this review. Random-effects meta-analysis was undertaken to estimate the pooled point prevalence of ulcers. Reported risk factors in included studies were narratively synthesised. This review is registered in PROSPERO: CRD42022316726. RESULTS: Overall, 15 studies (8 for prevalence of ulcer and 7 for risk factors) met the inclusion criteria. The pooled point prevalence of ulcer was 34% (95% CIs: 21%, 46%) and 7% (95% CIs: 4%, 11%) among those with foot anaesthesia and among all people affected by leprosy, respectively. Risk factors for developing ulcers included: unable to feel 10 g of monofilament on sensory testing, pronated/hyper-pronated foot, foot with peak plantar pressure, foot with severe deformities, and those with lower education and the unemployed. CONCLUSIONS: The prevalence of plantar ulceration in leprosy is as high as 34% among those with loss of sensation in the feet. However, the incidence and recurrence rates of ulceration are least reported. The inability to feel 10 g of monofilament appears to be a strong predictor of those at risk of developing ulcers. However, there is a paucity of evidence on identifying those at risk of developing plantar ulcers in leprosy. Prospective studies are needed to estimate the incidence of ulcers. Identifying individuals at risk of ulcers will help design targeted interventions to minimize risk factors, prevent ulcers and promote ulcer healing.

An evaluation protocol of 'Replicability Model' project for detection and treatment of leprosy and related disability in Chhattisgarh, India.

INTRODUCTION: People affected by leprosy are at increased risk of impairments and deformities from peripheral nerve damage. This mostly occurs if diagnosis and treatment is delayed and contributes to continued transmission within the community. Champa district of Chhattisgarh state in India is an endemic area with the highest national annual case detection and disability rates for leprosy. The Replicability Model is a system strengthening intervention implemented by the Leprosy Mission Trust India in Champa that aims to promote early diagnosis and treatment of leprosy, improve on-going management of the effects of leprosy and improve welfare for the people affected by leprosy. This protocol presents a plan to describe the overall implementation of the Replicability Model and describe the barriers and facilitators encountered in the process. We will also quantify the effect of the program on one of its key aims- early leprosy diagnosis. METHODS: The replicability model will be implemented over four years, and the work described in this protocol will be conducted in the same timeframe. We have two Work Packages (WPs). In WP1, we will conduct a process evaluation. This will include three methods i) observations of replicability model implementation teams' monthly meetings ii) key informant interviews (n = 10) and interviews with stakeholders (n = 30) iii) observations of key actors (n = 15). Our purpose is to describe the implementation process and identify barriers and facilitators to successful implementation. WP2 will be a quantitative study to track existing and new cases of leprosy using routinely collected data. If the intervention is successful, we expect to see an increase in cases (with a higher proportion detected at an early clinical stage) followed by a decrease in total cases. CONCLUSION: This study will enable us to improve and disseminate the Replicability Model by identifying factors that promote success. It will also identify its effectiveness in fulfilling one of its aims: reducing the incidence of leprosy by finding and tracking cases at an earlier stage in the disease.

Safety and upscaling of remote consulting for long-term conditions in primary health care in Nigeria and Tanzania (REaCH trials): stepped-wedge trials of training, mobile data allowance, and implementation.

BACKGROUND: In-person health care poses risks to health workers and patients during pandemics. Remote consultations can mitigate these risks. The REaCH intervention comprised training and mobile data allowance provision for mobile phones to support remotely delivered primary care in Africa compared with no training and mobile data allowance. The aim of this study was to estimate the effects of REaCH among adults with non-communicable diseases on remote and face-to-face consultation rates, patient safety, and trustworthiness of consultations. METHODS: In these two independent stepped-wedge cluster randomised controlled trials, we enrolled 20 primary care clusters in each of two settings (Oyo State, Nigeria, and Morogoro Region, Tanzania). Eligible clusters had 100 or more patients with diabetes, hypertension, and cardiovascular or pulmonary disease employing five health workers. Clusters were computer-randomised to one of ten (Nigeria) or one of seven (Tanzania) sequences to receive the REaCH intervention. Only outcome assessors were masked. Primary outcomes were consultation, prescription, and investigation rates, and trustworthiness collected monthly for 12 months (Nigeria) and 9 months (Tanzania) from open cohorts. Ten randomly sampled consulting patients per cluster-month completed patient reported outcome measures. This trial was registered with ISRCTN, ISRCTN17941313. FINDINGS: Overall, 40 clusters comprising 8776 (Nigeria) and 3246 (Tanzania) patients' open cohort data were analysed (6377 [72·7%] of 8776 females in Nigeria, and 2235 [68·9%] of 3246 females in Tanzania). The mean age of the participants was 55·3 years (SD 13·9) in Nigeria and 59·2 years (14·2) in Tanzania. In Nigeria, no evidence of change in face-to-face consulting rate was observed (rate ratio [RR] 1·06, 95% CI 0·98 to 1·09; p=0·16); however, remote consultations increased four-fold (4·44, 1·34 to >10; p=0·01). In Tanzania, face-to-face (0·94, 0·61 to 1·67; p=0·99) and remote consulting rates (1·17, 0·56 to 5·57; p=0·39) were unchanged. There was no evidence of difference in prescribing rates (Nigeria: 1·05, 0·60 to 1·14; p=0·23; Tanzania: 0·92, 0·60 to 1·67; p=0·97), investigation rates (Nigeria: 1·06, 0·23 to 2·12; p=0·49; Tanzania: 1·15, 0·35 to 1·64; 0·58) or trustworthiness scores (Nigeria: mean difference 0·05, 95% CI -0·45 to 0·42; p=0·89; Tanzania: 0·07, -0·15 to 0·76; p=0·70). INTERPRETATION: REaCH can be implemented and could improve intervention versus control health-care access. Remote consultations appear safe and trustworthy, supporting universal health coverage. FUNDING: The UK Research and Innovation Collective Fund. TRANSLATIONS: For the Swahili and Yoruba translations of the abstract see Supplementary Materials section.

Optimal study designs for cluster randomised trials: An overview of methods and results.

There are multiple possible cluster randomised trial designs that vary in when the clusters cross between control and intervention states, when observations are made within clusters, and how many observations are made at each time point. Identifying the most efficient study design is complex though, owing to the correlation between observations within clusters and over time. In this article, we present a review of statistical and computational methods for identifying optimal cluster randomised trial designs. We also adapt methods from the experimental design literature for experimental designs with correlated observations to the cluster trial context. We identify three broad classes of methods: using exact formulae for the treatment effect estimator variance for specific models to derive algorithms or weights for cluster sequences; generalised methods for estimating weights for experimental units; and, combinatorial optimisation algorithms to select an optimal subset of experimental units. We also discuss methods for rounding experimental weights, extensions to non-Gaussian models, and robust optimality. We present results from multiple cluster trial examples that compare the different methods, including determination of the optimal allocation of clusters across a set of cluster sequences and selecting the optimal number of single observations to make in each cluster-period for both Gaussian and non-Gaussian models, and including exchangeable and exponential decay covariance structures.

Evaluation of combinatorial optimisation algorithms for c-optimal experimental designs with correlated observations.

We show how combinatorial optimisation algorithms can be applied to the problem of identifying c-optimal experimental designs when there may be correlation between and within experimental units and evaluate the performance of relevant algorithms. We assume the data generating process is a generalised linear mixed model and show that the c-optimal design criterion is a monotone supermodular function amenable to a set of simple minimisation algorithms. We evaluate the performance of three relevant algorithms: the local search, the greedy search, and the reverse greedy search. We show that the local and reverse greedy searches provide comparable performance with the worst design outputs having variance <10% greater than the best design, across a range of covariance structures. We show that these algorithms perform as well or better than multiplicative methods that generate weights to place on experimental units. We extend these algorithms to identifying modle-robust c-optimal designs. Supplementary Information: The online version contains supplementary material available at 10.1007/s11222-023-10280-w.

Efficacy of the spatial repellent product Mosquito Shield™ against wild pyrethroid-resistant Anopheles arabiensis in south-eastern Tanzania.

BACKGROUND: Spatial repellents that create airborne concentrations of an active ingredient (AI) within a space offer a scalable solution to further reduce transmission of malaria, by disrupting mosquito behaviours in ways that ultimately lead to reduced human-vector contact. Passive emanator spatial repellents can protect multiple people within the treated space and can last for multiple weeks without the need for daily user touchpoints, making them less intrusive interventions. They may be particularly advantageous in certain use cases where implementation of core tools may be constrained, such as in humanitarian emergencies and among mobile at-risk populations. The purpose of this study was to assess the efficacy of Mosquito Shield™ deployed in experimental huts against wild, free-flying, pyrethroid-resistant Anopheles arabiensis mosquitoes in Tanzania over 1 month. METHODS: The efficacy of Mosquito Shield™ transfluthrin spatial repellent in reducing mosquito lands and blood-feeding was evaluated using 24 huts: sixteen huts were allocated to Human Landing Catch (HLC) collections and eight huts to estimating blood-feeding. In both experiments, half of the huts received no intervention (control) while the remaining received the intervention randomly allocated to huts and remained fixed for the study duration. Outcomes measured were mosquito landings, blood-fed, resting and dead mosquitoes. Data were analysed by multilevel mixed effects regression with appropriate dispersion and link function accounting for volunteer, hut and day. RESULTS: Landing inhibition was estimated to be 70% (57-78%) [IRR 0.30 (95% CI 0.22-0.43); p < 0.0001] and blood-feeding inhibition was estimated to be 69% (56-79%) [IRR 0.31 (95% CI 0.21-0.44; p < 0.0001] There was no difference in the protective efficacy estimates of landing and blood-feeding inhibition [IRR 0.98 (95% CI 0.53-1.82; p = 0.958]. CONCLUSIONS: This study demonstrated that Mosquito Shield™ was efficacious against a wild pyrethroid-resistant strain of An. arabiensis mosquitoes in Tanzania for up to 1 month and could be used as a complementary or stand-alone tool where gaps in protection offered by core malaria vector control tools exist. HLC is a suitable technique for estimating bite reductions conferred by spatial repellents especially where direct blood-feeding measurements are not practical or are ethically limited.

Evaluation of an organisational-level monetary incentive to promote the health and wellbeing of workers in small and medium-sized enterprises: A mixed-methods cluster randomised controlled trial.

We conducted an independent evaluation on the effectiveness of an organisational-level monetary incentive to encourage small and medium-sized enterprises (SMEs) to improve employees' health and wellbeing. This was A mixed-methods cluster randomised trial with four arms: high monetary incentive, low monetary incentive, and two no monetary incentive controls (with or without baseline measurements to examine 'reactivity' The consequence of particpant awareness of being studied, and potential impact on participant behavior effects). SMEs with 10-250 staff based in West Midlands, England were eligible. We randomly selected up to 15 employees at baseline and 11 months post-intervention. We elicited employee perceptions of employers' actions to improve health and wellbeing; and employees' self-reported health behaviours and wellbeing. We also interviewed employers and obtained qualitative data. One hundred and fifty-two SMEs were recruited. Baseline assessments were conducted in 85 SMEs in three arms, and endline assessments in 100 SMEs across all four arms. The percentage of employees perceiving "positive action" by their employer increased after intervention (5 percentage points, pp [95% Credible Interval -3, 21] and 3pp [-9, 17], in models for high and low incentive groups). Across six secondary questions about specific issues the results were strongly and consistently positive, especially for the high incentive. This was consistent with qualitative data and quantitative employer interviews. However, there was no evidence of any impact on employee health behaviour or wellbeing outcomes, nor evidence of 'reactivity'. An organisational intervention (a monetary incentive) changed employee perceptions of employer behaviour but did not translate into changes in employees' self-reports of their own health behaviours or wellbeing. Trial registration: AEARCTR-0003420, registration date: 17.10.2018, retrospectively registered (delays in contracts and identfying a suitable trial registry). The authors confirm that there are no ongoing and related trials for this intervention.

Management of a complex acetabular fracture following defibrillation for ventricular fibrillation cardiac arrest.

In this case report, we describe the first case of a patient who sustained a complex acetabular fracture following defibrillation for ventricular fibrillation cardiac arrest in the context of acute myocardial infarction. The patient was unable to undergo definitive open reduction internal fixation surgery due to the need to continue dual antiplatelet therapy following coronary stenting of his occluded left anterior descending artery. Following multidisciplinary discussions, a staged approach was opted for, with percutaneous closed reduction screw fixation of the fracture performed while the patient was maintained on dual antiplatelet therapy. The patient was discharged with a plan to perform definitive surgical management when safe to discontinue dual antiplatelets. This is the first confirmed case of defibrillation causing an acetabular fracture. We discuss the various aspects that need to be considered when patients are being worked up for surgery while on dual antiplatelet therapy.

Community and facility-level barriers to achieving UHC in Kono District, Sierra Leone and Maryland County, Liberia.

Universal Health Coverage (UHC) is achieved when individuals and communities receive the health services they need without suffering financial hardship. However, many countries face barriers to building health systems that enable the availability of affordable, accessible care. The goal of this study was to present a model of local monitoring of barriers and to provide a roadmap for designing interventions that improve access to and use of healthcare delivery systems. We conducted household, individual, and health facility surveys in seven catchment areas in Sierra Leone and Liberia between December 2019 and March 2020. A two-stage cluster sampling method was used to sample households and individuals, and all health facilities were included. We divide access barriers into demand (patient-side care seeking behavior), supply (availability of facilities and services), and their intersection (affordability, spending, and use rates). Among the 2,576 respondents within our 1,051 surveyed households, the propensity to seek care when ill was reported at 90% in Sierra Leone (n = 1,283) and 70% in Liberia (n = 806). We estimated that 31% of households spent greater than 10% of their total expenditure on healthcare in a month, and that 14.5% of households spent greater than 25%. Overall, the general service readiness index mean score for all health centers was around 70%. The greatest hindrance to service readiness was the availability of essential medicines, with facilities reporting an average score of 32% in Sierra Leone and 63% in Liberia. Our evidence suggests that the cost of care is both a barrier to care-seeking and a persisting problem among care-seeking patients. Lack of service availability (essential equipment and medicines), poses a risk to high-quality care. The research team recommends deploying interventions (visit cost subsidies, supply chain improvements) targeted at resolving these issues in order to advance the goal of achieving UHC.

Permutation-based multiple testing corrections for P $$ P $$ -values and confidence intervals for cluster randomized trials.

In this article, we derive and compare methods to derive P-values and sets of confidence intervals with strong control of the family-wise error rates and coverage for estimates of treatment effects in cluster randomized trials with multiple outcomes. There are few methods for P-value corrections and deriving confidence intervals, limiting their application in this setting. We discuss the methods of Bonferroni, Holm, and Romano and Wolf and adapt them to cluster randomized trial inference using permutation-based methods with different test statistics. We develop a novel search procedure for confidence set limits using permutation tests to produce a set of confidence intervals under each method of correction. We conduct a simulation-based study to compare family-wise error rates, coverage of confidence sets, and the efficiency of each procedure in comparison to no correction using both model-based standard errors and permutation tests. We show that the Romano-Wolf type procedure has nominal error rates and coverage under non-independent correlation structures and is more efficient than the other methods in a simulation-based study. We also compare results from the analysis of a real-world trial.

Spoilage Pseudomonas survive common thermal processing schedules and grow in emulsified meat during extended vacuum storage.

Some Pseudomonas species are common meat spoilage bacteria that are often associated with the spoilage of fresh meat. The recently reported ability of these bacteria to also spoil cooked and vacuum packaged meat products has created the need to investigate all potential routes of spoilage they may be able to utilize. The objective of this experiment was to determine if spoilage Pseudomonas spp. survive thermal processing and grow during refrigerated storage under vacuum. Pseudomonas spp. isolates collected from spoiled turkey products were inoculated into a salted and seasoned meat emulsion that was vacuum sealed and thermally treated to final temperatures of 54.4 and 71.1°C to mimic thermal processes commonly used in the meat industry. Samples were stored for a total of 294 days at 4 and 10°C and plated using Pseudomonas spp. specific agar plates. Pseudomonas spp. concentrations were below the detection limit (0.18 log10 CFU/g) immediately after thermal processing and were first recovered from thermally processed samples after 14 days of storage. The final concentration was greater than 2 log10 CFU/g (p < 0.05 compared to post-thermal processing) in thermally processed treatment groups at the end of storage, indicating that these Pseudomonas spp. isolates were able to survive thermal processing and grow during extended vacuum storage. This raises concerns about the ability of spoilage bacteria to survive the thermal processing schedules commonly used in the meat industry and confirms that some Pseudomonas spp. are capable of thriving in products other than aerobically stored fresh meat. Practical Application: Spoilage Pseudomonas spp. can survive traditional thermal processing schedules. Heat resistance should be evaluated for commensal and spoilage bacteria to better understand possible ways spoilage of food products may occur.

CDC light traps underestimate the protective efficacy of an indoor spatial repellent against bites from wild Anopheles arabiensis mosquitoes in Tanzania.

BACKGROUND: Methods for evaluating efficacy of core malaria interventions in experimental and operational settings are well established but gaps exist for spatial repellents (SR). The objective of this study was to compare three different techniques: (1) collection of blood-fed mosquitoes (feeding), (2) human landing catch (HLC), and (3) CDC light trap (CDC-LT) collections for measuring the indoor protective efficacy (PE) of the volatile pyrethroid SR product Mosquito Shield™ METHODS: The PE of Mosquito Shield™ against a wild population of pyrethroid-resistant Anopheles arabiensis mosquitoes was determined via feeding, HLC, or CDC-LT using four simultaneous 3 by 3 Latin squares (LS) run using 12 experimental huts in Tanzania. On any given night each technique was assigned to two huts with control and two huts with treatment. The LS were run twice over 18 nights to give a sample size of 72 replicates for each technique. Data were analysed by negative binomial regression. RESULTS: The PE of Mosquito Shield™ measured as feeding inhibition was 84% (95% confidence interval (CI) 58-94% [Incidence Rate Ratio (IRR) 0.16 (0.06-0.42), p < 0.001]; landing inhibition 77% [64-86%, (IRR 0.23 (0.14-0.36) p < 0.001]; and reduction in numbers collected by CDC-LT 30% (0-56%) [IRR 0.70 (0.44-1.0) p = 0.160]. Analysis of the agreement of the PE measured by each technique relative to HLC indicated no statistical difference in PE measured by feeding inhibition and landing inhibition [IRR 0.73 (0.25-2.12) p = 0.568], but a significant difference in PE measured by CDC-LT and landing inhibition [IRR 3.13 (1.57-6.26) p = 0.001]. CONCLUSION: HLC gave a similar estimate of PE of Mosquito Shield™ against An. arabiensis mosquitoes when compared to measuring blood-feeding directly, while CDC-LT underestimated PE relative to the other techniques. The results of this study indicate that CDC-LT could not effectively estimate PE of the indoor spatial repellent in this setting. It is critical to first evaluate the use of CDC-LT (and other tools) in local settings prior to their use in entomological studies when evaluating the impact of indoor SR to ensure that they reflect the true PE of the intervention.

Inactivation of Salmonella in nonintact beef during low-temperature sous vide cooking.

Sous vide cooking is a method of food preparation in which food is vacuum sealed and cooked in a water bath that is set to a precise temperature and circulated by a sous vide device. Due to ease of use and affordability, this cooking method has grown increasingly popular in food service kitchens and domestic settings. However, low-temperature, long holding time sous vide cooking recommendations from manufacturers and chefs in popular press raise food safety concerns - specifically those for the preparation of nonintact beef products. The objective of this experiment was to address these concerns by validating a 5 log reduction of Salmonella spp. in sous vide cooked, nonintact beef steaks. Beef semitendinosus sliced into 2.54 cm steaks were internally inoculated to 7 log with Salmonella Typhimurium, Enteritidis, and Heidelberg via a needle inoculation pin pad. Steaks were individually vacuum sealed, and sous vide cooked at 46.1, 51.6, and 54.4°C. The minimum time measured for a 5 log reduction at 51.6 and 54.4°C was 150 and 64.5 min, respectively (P < 0.01). Additionally, a 7.28 log final reduction was achieved at 51.6°C after 322.5 min (P < 0.01). However, 46.1°C was only able to achieve a final reduction of 2.01 log (P < 0.01) after a holding time of 420 min. The results of this experiment validate in sous vide cooked products the time and temperature combinations provided in the USDA-FSIS Appendix A guidance for a 5 log reduction of Salmonella spp. in meat products. Moreover, more research is needed with other relevant foodborne pathogens to determine if sous vide cooking below Appendix A recommendations could lead to unsafe products.

LRRC15 mediates an accessory interaction with the SARS-CoV-2 spike protein.

The interactions between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and human host factors enable the virus to propagate infections that lead to Coronavirus Disease 2019 (COVID-19). The spike protein is the largest structural component of the virus and mediates interactions essential for infection, including with the primary angiotensin-converting enzyme 2 (ACE2) receptor. We performed two independent cell-based systematic screens to determine whether there are additional proteins by which the spike protein of SARS-CoV-2 can interact with human cells. We discovered that in addition to ACE2, expression of LRRC15 also causes spike protein binding. This interaction is distinct from other known spike attachment mechanisms such as heparan sulfates or lectin receptors. Measurements of orthologous coronavirus spike proteins implied the interaction was functionally restricted to SARS-CoV-2 by accessibility. We localized the interaction to the C-terminus of the S1 domain and showed that LRRC15 shares recognition of the ACE2 receptor binding domain. From analyzing proteomics and single-cell transcriptomics, we identify LRRC15 expression as being common in human lung vasculature cells and fibroblasts. Levels of LRRC15 were greatly elevated by inflammatory signals in the lungs of COVID-19 patients. Although infection assays demonstrated that LRRC15 alone is not sufficient to permit viral entry, we present evidence that it can modulate infection of human cells. This unexpected interaction merits further investigation to determine how SARS-CoV-2 exploits host LRRC15 and whether it could account for any of the distinctive features of COVID-19.

Protocol for a parallel group, two-arm, superiority cluster randomised trial to evaluate a community-level complementary-food safety and hygiene and nutrition intervention in Mali: the MaaCiwara study (version 1.3; 10 November 2022).

BACKGROUND: Diarrhoeal disease remains a significant cause of morbidity and mortality among the under-fives in many low- and middle-income countries. Changes to food safety practices and feeding methods around the weaning period, alongside improved nutrition, may significantly reduce the risk of disease and improve development for infants. We describe a protocol for a cluster randomised trial to evaluate the effectiveness of a multi-faceted community-based educational intervention that aims to improve food safety and hygiene behaviours and enhance child nutrition. METHODS: We describe a mixed-methods, parallel group, two-arm, superiority cluster randomised controlled trial with baseline measures. One hundred twenty clusters comprising small urban and rural communities will be recruited in equal numbers and randomly allocated in a 1:1 ratio to either treatment or control arms. The community intervention will be focussed around an ideal mother concept involving all community members during campaign days with dramatic arts and pledging, and follow-up home visits. Participants will be mother-child dyads (27 per cluster period) with children aged 6 to 36 months. Data collection will comprise a day of observation and interviews with each participating mother-child pair and will take place at baseline and 4 and 15 months post-intervention. The primary analysis will estimate the effectiveness of the intervention on changes to complementary-food safety and preparation behaviours, food and water contamination, and diarrhoea. Secondary outcomes include maternal autonomy, enteric infection, nutrition, child anthropometry, and development scores. A additional structural equation analysis will be conducted to examine the causal relationships between the different outcomes. Qualitative and health economic analyses including process evaluation will be done. CONCLUSIONS: The trial will provide evidence on the effectiveness of community-based behavioural change interventions designed to reduce the burden of diarrhoeal disease in the under-fives and how effectiveness varies across different contexts. TRIAL REGISTRATION: ISRCTN14390796. Registration date December 13, 2021.

Efficient design of geographically-defined clusters with spatial autocorrelation.

Clusters form the basis of a number of research study designs including survey and experimental studies. Cluster-based designs can be less costly but also less efficient than individual-based designs due to correlation between individuals within the same cluster. Their design typically relies on ad hoc choices of correlation parameters, and is insensitive to variations in cluster design. This article examines how to efficiently design clusters where they are geographically defined by demarcating areas incorporating individuals and households or other units. Using geostatistical models for spatial autocorrelation, we generate approximations to within cluster average covariance in order to estimate the effective sample size given particular cluster design parameters. We show how the number of enumerated locations, cluster area, proportion sampled, and sampling method affect the efficiency of the design and consider the optimization problem of choosing the most efficient design subject to budgetary constraints. We also consider how the parameters from these approximations can be interpreted simply in terms of 'real-world' quantities and used in design analysis.

Evaluations of water, sanitation and hygiene interventions should not use diarrhoea as (primary) outcome.

Water, sanitation and hygiene interventions have been the subject of cluster trials of unprecedented size, scale and cost in recent years. However, the question 'what works in water, sanitation, hygiene (WASH)?' remains poorly understood. Evaluations of community interventions to prevent infectious disease typically use lab-confirmed infection as a primary outcome; however, WASH trials mostly use reported diarrhoea. While diarrhoea is a significant source of morbidity, it is subjected to significant misclassification error with respect to enteric infection due to the existence of non-infectious diarrhoea and asymptomatic infection. We show how this may lead to bias of estimated effects of interventions from WASH trials towards no effect. The problem is further compounded by other biases in the measurement process. Alongside testing for infection of the gut, an examination of the causal assumptions underlying WASH interventions present several other reliable alternative and complementary measurements and outcomes. Contemporary guidance on the evaluation of complex interventions requires researchers to take a broad view of the causal effects of an intervention across a system. Reported diarrhoea can fail to even be a reliable measure of changes to gastrointestinal health and so should not be used as a primary outcome if we are to progress our knowledge of what works in WASH.