A tissue-like neurotransmitter sensor for the brain and gut.

Neurotransmitters play essential roles in regulating neural circuit dynamics both in the central nervous system as well as at the peripheral, including the gastrointestinal tract1-3. Their real-time monitoring will offer critical information for understanding neural function and diagnosing disease1-3. However, bioelectronic tools to monitor the dynamics of neurotransmitters in vivo, especially in the enteric nervous systems, are underdeveloped. This is mainly owing to the limited availability of biosensing tools that are capable of examining soft, complex and actively moving organs. Here we introduce a tissue-mimicking, stretchable, neurochemical biological interface termed NeuroString, which is prepared by laser patterning of a metal-complexed polyimide into an interconnected graphene/nanoparticle network embedded in an elastomer. NeuroString sensors allow chronic in vivo real-time, multichannel and multiplexed monoamine sensing in the brain of behaving mouse, as well as measuring serotonin dynamics in the gut without undesired stimulations and perturbing peristaltic movements. The described elastic and conformable biosensing interface has broad potential for studying the impact of neurotransmitters on gut microbes, brain-gut communication and may ultimately be extended to biomolecular sensing in other soft organs across the body.

Proactive home-based malaria management in rural communities of Bassar Health District in northern Togo from 2014 to 2017: PECADOM + , a pilot experiment.

BACKGROUND: Togo's National Malaria Control Programme has initiated an active home-based malaria management model for all age groups in rural areas of Bassar Health District. This report describes the model, reports its main results, and determines the factors associated with positive rapid diagnostic test results. METHODS: From 2014 to 2017, in three peripheral care units of Bassar Health District (Binaparba, Nangbani, and Baghan), community health workers visited residents' homes weekly to identify patients with malaria symptoms, perform rapid diagnostic tests in symptomatic patients, and give medication to positive cases. Univariate and multivariate logistic regression models were used to determine the factors associated with positive tests. RESULTS: The study covered 11,337 people (817 in 2014, 1804 in 2015, 2638 in 2016, and 6078 in 2017). The overall mean age was 18 years (95% CI 5-29; min-max: 0-112 years). The median age was 10 years (SD: 16.9). The proportions of people tested positive were 75.3% in Binaparba, 77.4% in Nangbani, and 56.6% in Baghan. The 5-10 age group was the most affected category (24.2% positive tests). Positive tests were more frequent during the rainy than during the dry season (62 vs. 38%) and the probability of positive test was 1.76 times higher during the rainy than during the dry season (adjusted OR = 1.74; 95% CI 1.60-1.90). A fever (37.5 °C or higher) increased significantly the probability of positive test (adjusted OR = 2.19; 95% CI 1.89-2.54). The risk of positive test was 1.89 times higher in passive than in active malaria detection (adjusted OR = 1.89; 95% CI 1.73-2.0). CONCLUSIONS: This novel experimental community and home-based malaria management in Togo suggested that active detection of malaria cases is feasible within 24 h, which allows rapid treatments before progression to often-fatal complications. This PECADOM + program will help Togo's National Malaria Control Programme reduce malaria morbidity and mortality in remote and hard-to-reach communities.

The utility of ctDNA in detecting minimal residual disease following curative surgery in colorectal cancer: a systematic review and meta-analysis.

INTRODUCTION: Colorectal cancer is the fourth most common cancer in the UK. There remains a need for improved risk stratification following curative resection. Circulating-tumour DNA (ctDNA) has gained particular interest as a cancer biomarker in recent years. We performed a systematic review to assess the utility of ctDNA in identifying minimal residual disease in colorectal cancer. METHODS: Studies were included if ctDNA was measured following curative surgery and long-term outcomes were assessed. Studies were excluded if the manuscript could not be obtained from the British Library or were not available in English. RESULTS: Thirty-seven studies met the inclusion criteria, involving 3002 patients. Hazard ratios (HRs) for progression-free survival (PFS) were available in 21 studies. A meta-analysis using a random effects model demonstrated poorer PFS associated with ctDNA detection at the first liquid biopsy post-surgery [HR: 6.92 CI: 4.49-10.64 p < 0.00001]. This effect was also seen in subgroup analysis by disease extent, adjuvant chemotherapy and assay type. DISCUSSION: Here we demonstrate that ctDNA detection post-surgery is associated with a greater propensity to disease relapse and is an independent indicator of poor prognosis. Prior to incorporation into clinical practice, consensus around timing of measurements and assay methodology are critical. PROTOCOL REGISTRATION: The protocol for this review is registered on PROSPERO (CRD42021261569).

3Rs implementation in veterinary vaccine batch-release testing: Current state-of-the-art and future opportunities. A webinar and workshop report.

Regulatory authorities require veterinary batch-release testing to confirm vaccine potency and safety, but these tests have traditionally relied on large numbers of laboratory animals. Advances in vaccine research and development offer increasing opportunities to replace in vivo testing, and some stakeholders have made significant progress in incorporating 3Rs elements in quality control strategies. A three-part event series entitled "3Rs Implementation in Veterinary Vaccine Batch-Release Testing: Current state-of-the-art and future opportunities" was jointly organized by the Animal-Free Safety Assessment Collaboration, HealthforAnimals, and the International Alliance of Biological Standardization. Two webinars and a workshop aimed to outline the state-of-the-art non-animal approaches for veterinary batch-release testing. The events included information on the state of the deletion of obsolete safety testing and the current initiatives implemented by European, North American, and Asian-Pacific stakeholders on 3Rs implementation and regulatory acceptance. The events contributed to a better understanding of the barriers to 3Rs implementation. Participants highlighted the need for open communication, continued collaboration between stakeholders, and international harmonization of regulatory requirements to help accelerate acceptance. Despite the challenges, the countries represented at this three-part event have shared their commitments to advancing the acceptance of alternative methods.

Stem cell activation during distraction enterogenesis in the murine colon.

PURPOSE: Short bowel syndrome (SBS) is a devastating disease. We have proposed spring-mediated distraction enterogenesis for intestinal lengthening. Colonic lengthening is a potential treatment option for SBS to enhance fluid absorption capacity. We hypothesized that intraluminal spring-mediated colonic lengthening is associated with stem cell proliferation. METHODS: C57BL/6 mice underwent placement of a gelatin-encapsulated compressed or uncompressed nitinol spring in a cecal segment. Animals were given clear liquid diet until postoperative day (POD) 7, followed by regular diet until POD 14. Cecal lengths were measured at euthanasia, and tissue was formalin fixed for histological processing. For Lgr5-GFP mice, immunohistochemistry against GFP was performed to localize Lgr5+ cells within crypts. RESULTS: Significant cecal lengthening with compressed springs and shortening with uncompressed springs were observed on POD 7 and 14. Mucosa of the compressed spring group was significantly thicker on POD 14. The density of Lgr5+ cells within the crypts in the compressed spring groups was higher than that in the uncompressed spring groups on both POD 7 and 14. CONCLUSION: Expandable springs can be used to lengthen the colon in the mouse model. Colonic lengthening was associated with gradual mucosal thickening and correlated with an increased density of stem cells within the crypts.

E-nursing homes: transforming access to nurses in nursing homes in response to the staffing crisis.

The UK is facing a nationwide staffing crisis within adult social care, due to difficulties in recruiting and retaining registered nurses. Current interpretation of legislation means nursing homes must always have the physical presence of a registered nurse on duty within the home. With the shortage of registered nurses increasing, reliance on agency workers is commonplace, a practice impacting service cost and continuity of care. Lack of innovation to tackle this issue means the question of how to transform service delivery to combat staffing shortages is open for debate. The potential for technology to augment the provision of care was highlighted during the COVID-19 pandemic. In this article the authors present one possible solution focused on the provision of digital nursing care within nursing homes. Anticipated benefits include enhanced accessibility of nursing roles, reduced risk of viral spread and opportunities for upskilling staff. However, challenges include the current interpretation of legislation.

Abemaciclib in patients with p16ink4A-deficient mesothelioma (MiST2): a single-arm, open-label, phase 2 trial.

BACKGROUND: Genetically stratified therapy for malignant mesothelioma is unavailable. Mesotheliomas frequently harbour loss of the chromosome 9p21.3 locus (CDKN2A-MTAP), which is associated with shorter overall survival due to loss of the tumour suppressor p16ink4A, an endogenous suppressor of cyclin-dependent kinase (CDK)4 and CDK6. Genetic restoration of p16ink4A suppresses mesothelioma in preclinical models, underpinning the rationale for targeting CDK4 and CDK6 in p16ink4A-negative mesothelioma. We developed a multicentre, stratified, phase 2 trial to test this hypothesis. METHODS: The MiST2 study was a single-arm, open-label, phase 2 clinical trial done two UK centres. Patients older than 18 years with any histologically confirmed subtype of mesothelioma (pleural or peritoneal) with radiological progression after at least one course of platinum-based chemotherapy were molecularly screened by immunohistochemistry for p16ink4A. Patients with p16ink4A-negative mesothelioma were eligible for inclusion in the study. Patients were required to have measurable disease by modified Response Evaluation Criteria in Solid Tumours version 1.1 for malignant mesothelioma, a predicted life expectancy of at least 12 weeks, and an Eastern Cooperative Oncology Group performance status score of 0-1. Patients received oral abemaciclib 200 mg twice daily, administered in 28-day cycles for 24 weeks. The primary endpoint was the disease control rate (patients with complete responses, partial responses, or stable disease) at 12 weeks. The null hypothesis could be rejected if at least 11 patients had disease control. The efficacy and safety populations were defined as all patients who received at least one dose of the study drug. The study is registered with ClinicalTrials.gov, NCT03654833, and is ongoing (but MiST2 is now closed). FINDINGS: Between Sept 31, 2019, and March 2, 2020, 27 eligible patients consented to molecular screening. The median follow-up was 18·4 weeks (IQR 6·7-23·9). One patient was excluded before treatment because of a serious adverse event before study drug allocation. 26 (100%) of 26 treated patients were p16ink4A deficient and received at least one dose of abemaciclib. Disease control at 12 weeks was reported in 14 (54%) of 26 patients (95% CI 36-71). Grade 3 or worse treatment-related adverse events (of any cause) occurred in eight (27%) of 26 patients (diarrhoea, dyspnoea, thrombocytopenia, vomiting, urinary tract infection, increased alanine aminotransferase, ascites, chest infection or suspected chest infection, neutropenic sepsis, alopecia, blood clot left calf, fall [broken neck and collar bone], haemoptysis, lower respiratory tract infection, and pulmonary embolism). Grade 3 or worse treatment-related adverse events occurred in three (12%) of 26 patients (diarrhoea, thrombocytopenia, vomiting, increased alanine aminotransferase, and pulmonary embolism). Serious adverse events occurred in six (23%) of 26 patients, leading to treatment discontinuation in one (4%) patient (diarrhoea, urinary tract infection, chest infection, neutropenic sepsis, fall [broken neck and collar bone], haemoptysis, lower respiratory tract infection, and pulmonary embolism). One patient had a serious adverse event related to abemaciclib (diarrhoea). One (4%) of 26 patients died from an adverse event (neutropenic sepsis). INTERPRETATION: This study met its primary endpoint, showing promising clinical activity of abemaciclib in patients with p16ink4A-negative mesothelioma who were previously treated with chemotherapy, and warrants its further investigation in a randomised study as a targeted stratified therapy. FUNDING: University of Leicester, Asthma UK and British Lung Foundation Partnership, and the Victor Dahdaleh Foundation.

Effects of COVID-19 Pandemic on Voluntary Medical Male Circumcision Services for HIV Prevention, Sub-Saharan Africa, 2020.

Beginning in March 2020, to reduce COVID-19 transmission, the US President's Emergency Plan for AIDS Relief supporting voluntary medical male circumcision (VMMC) services was delayed in 15 sub-Saharan African countries. We reviewed performance indicators to compare the number of VMMCs performed in 2020 with those performed in previous years. In all countries, the annual number of VMMCs performed decreased 32.5% (from 3,898,960 in 2019 to 2,631,951 in 2020). That reduction is largely attributed to national and local COVID-19 mitigation measures instituted by ministries of health. Overall, 66.7% of the VMMC global annual target was met in 2020, compared with 102.0% in 2019. Countries were not uniformly affected; South Africa achieved only 30.7% of its annual target in 2020, but Rwanda achieved 123.0%. Continued disruption to the VMMC program may lead to reduced circumcision coverage and potentially increased HIV-susceptible populations. Strategies for modifying VMMC services provide lessons for adapting healthcare systems during a global pandemic.

Ex vivo explant model of adenoma and colorectal cancer to explore mechanisms of action and patient response to cancer prevention therapies.

Colorectal cancer (CRC) is the second leading cause of cancer death in the UK. Novel therapeutic prevention strategies to inhibit the development and progression of CRC would be invaluable. Potential contenders include low toxicity agents such as dietary-derived agents or repurposed drugs. However, in vitro and in vivo models used in drug development often do not take into account the heterogeneity of tumours or the tumour microenvironment. This limits translation to a clinical setting. Our objectives were to develop an ex vivo method utilizing CRC and adenoma patient-derived explants (PDEs) which facilitates screening of drugs, assessment of toxicity, and efficacy. Our aims were to use a multiplexed immunofluorescence approach to demonstrate the viability of colorectal tissue PDEs, and the ability to assess immune cell composition and interactions. Using clinically achievable concentrations of curcumin, we show a correlation between curcumin-induced tumour and stromal apoptosis (P < .001) in adenomas and cancers; higher stromal content is associated with poorer outcomes. B cell (CD20+ve) and T cell (CD3+ve) density of immune cells within tumour regions in control samples correlated with curcumin-induced tumour apoptosis (P < .001 and P < .05, respectively), suggesting curcumin-induced apoptosis is potentially predicted by baseline measures of immune cells. A decrease in distance between T cells (CD3+ve) and cytokeratin+ve cells was observed, indicating movement of T cells (CD3+ve) towards the tumour margin (P < .001); this change is consistent with an immune environment associated with improved outcomes. Concurrently, an increase in distance between T cells (CD3+ve) and B cells (CD20+ve) was detected following curcumin treatment (P < .001), which may result in a less immunosuppressive tumour milieu. The colorectal tissue PDE model offers significant potential for simultaneously assessing multiple biomarkers in response to drug exposure allowing a greater understanding of mechanisms of action and efficacy in relevant target tissues, that maintain both their structural integrity and immune cell compartments.

Consolidated Overview of Notifiable Adverse Events in the U.S. President's Emergency Plan for AIDS Relief's Voluntary Medical Male Circumcision Program Through 2020.

PURPOSE OF REVIEW: Through December 2020, the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) supported more than 25 million voluntary medical male circumcisions (VMMC) as part of the combined HIV prevention strategy in 15 African countries. PEPFAR monitors defined adverse events (AEs) occurring within 30 days of VMMC through its notifiable adverse event reporting system (NAERS). All NAERS reports through December 2020 were reviewed to quantify AE type, severity, and relation to the VMMC procedure. Interventions to improve client safety based on NAERS findings are described. RECENT FINDINGS: Fourteen countries reported 446 clients with notifiable adverse events (NAEs); 394/446 (88%) were determined VMMC-related, representing approximately 18 NAE reports per million circumcisions. Fatalities comprised 56/446 (13%) with 24/56 (43%) of fatalities determined VMMC-related, representing 0.96 VMMC-related fatalities per million circumcisions. The remaining 390 NAEs were non-fatal with 370/390 (95%) VMMC-related. Multiple programmatic changes have been made based on NAERS data to improve client safety. Client safety is paramount in this surgical program designed for individual and population-level benefit. Surveillance of rare but severe complications following circumcision has identified pre-existing or new safety concerns and guided continuous programmatic improvement.

Defining the Global Research and Programmatic Agenda and Priority Actions for Voluntary Medical Male Circumcision for HIV Prevention.

PURPOSE OF REVIEW: Since 2007, voluntary medical male circumcision (VMMC) programs have been associated with substantially reduced HIV incidence across 15 prioritized countries in Eastern and Southern Africa. Drawing on the programmatic experience of global VMMC leaders, this report reviews progress made in the first 15 years of the program, describes programmatic and research gaps, and presents considerations to maximize the impact of VMMC. RECENT FINDINGS: Overall, key programmatic and research gaps include a lack of robust male circumcision coverage estimates due to limitations to the data and a lack of standardized approaches across programs; challenges enhancing VMMC uptake include difficulties reaching populations at higher risk for HIV infection and men 30 years and older; limitations to program and procedural quality and safety including variations in approaches used by programs; and lastly, sustainability with limited evidence-based practices. Considerations to address these gaps include the need for global guidance on estimating coverage, conducting additional research on specific sub-populations to improve VMMC uptake, implementation of responsive and comprehensive approaches to adverse event surveillance, and diversifying financing streams to progress towards sustainability. This report's findings may help establish a global VMMC research and programmatic agenda to inform policy, research, and capacity-building activities at the national and global levels.

Effectiveness of seasonal malaria chemoprevention in three regions of Togo: a population-based longitudinal study from 2013 to 2020.

BACKGROUND: In 2012, the World Health Organization (WHO) recommended seasonal malaria chemoprevention (SMC) in areas of high seasonal transmission. Though implemented since 2013, the effectiveness of SMC in Togo was never evaluated. METHODS: This study concerned routine data from 2013 to 2020 mass SMC campaigns for children under five in all health facilities of three Regions of Togo. Treatment coverage, reasons for non-treatment, and SMC-attributable adverse reactions were analysed per year and treatment round. Random effect logistic models estimated SMC effectiveness per health district, year, and treatment round. RESULTS: The overall coverage was 98% (7,971,877 doses for 8,129,668 children). Contraindication was the main reason for non-administration. Over the study period, confirmed malaria cases decreased from 11,269 (1st round of 2016) to 1395 (4th round of 2020). Only 2,398 adverse reactions were reported (prevalence: 3/10,000), but no severe Lyell syndrome or Stevens-Johnson-type skin reaction. Compared to 2016, malaria prevalence decrease was estimated at 22.6% in 2017 (p < 0.001) and 75% in 2020 (p < 0.001). SMC effectiveness ranged from 76.6% (2nd round) to 96.2% (4th round) comparison with the 1st round. CONCLUSIONS: SMC reduced significantly malaria cases among children under five. The results reassure all actors and call for effort intensification to reach the WHO goals for 2030.

Generation of Porcine Ileum Through Spring-Mediated Mechanical Distraction.

INTRODUCTION: Short bowel syndrome is a devastating gastrointestinal disorder in which decreased bowel length results in inadequate absorption causing nutritional deficiencies. Current treatment options are accompanied by significant morbidity. We have proposed spring-mediated distraction enterogenesis as a method to lengthen bowel with success seen in porcine jejunum. We hypothesize that spring-mediated distraction enterogenesis can be demonstrated in porcine ileum with preservation of ileal structure and function. MATERIALS AND METHODS: Laparotomy was performed on juvenile female mini-Yucatan pigs and a gelatin-encapsulated compressed nitinol spring was inserted into the ileal lumen and affixed proximally and distally. A control segment distal to the spring segment was marked with sutures. Postoperatively, pigs were placed on a liquid diet and euthanized on postoperative day 7. Spring and control segments were measured and processed for immunohistochemistry to evaluate for the presence of vitamin B12-intrinsic factor cotransporter, chromogranin A-producing cells, and 5-HT producing cells. RESULTS: All seven pigs survived to postoperative day 7 with no adverse effects. On average, pigs gained 84.3 ± 66.4 g/d. Spring segments lengthened 1.5 ± 0.7 cm with a relative lengthening by 128% ± 56%, which was statistically significant when compared to control (P < 0.01). The average density of chromogranin-A cells in control compared to spring segments was not significantly changed (2.9 ± 1.1 cells/mm versus 3.2 ± 1.2 cells/mm, P = 0.17). Both vitamin B12-intrinsic factor cotransporter and 5-HT producing cells were present in both control and lengthened ileum. CONCLUSIONS: Intraluminal nitinol springs significantly lengthened porcine ileum. The increase in density of enteroendocrine cells may indicate enhanced endocrine function of the lengthened ileum.

Gastrointestinal Myoelectric Measurements via Simultaneous External and Internal Electrodes in Pigs.

INTRODUCTION: Currently, there is no accurate noninvasive measurement system to diagnose gastrointestinal (GI) motility disorders. Wireless skin patches have been introduced to provide an accurate noninvasive measurement of GI myoelectric activity which is essential for developing neuro-stimulation devices to treat GI motility disorders. The aim of this study is to compare the external and internal electrical signal measurements in ambulatory pigs. METHODS: Yucatan pigs underwent placement of internal electrodes on the stomach, small intestine, and colon. Wires were brought through the abdominal wall. Signals were collected by a wireless receptor. Four external patches were placed on the abdominal skin to record the signals simultaneously. Pigs were kept for 6 d while the sensors were continuously recording the data from both systems. RESULTS: Internal sensors detected rich signals from each organ. The stomach had a dominant frequency that ranged from 4 to 4.5 cpm, with occasional higher frequencies at 2, 3 and 4 times that. Small intestine signals had their primary energy in the 12-15 cpm range. Colon signals primarily displayed a dominant broad peak in the 4-6 cpm region. External skin patches detected a substantial fraction of the activities measured by the internal electrodes. A clear congruence in the frequency spectrum was observed between the internal and external readings. CONCLUSIONS: Internally measured myoelectrical signals confirmed different patterns of rhythmic activity of the stomach, small intestine, and colon. Skin patches provided GI myoelectric measurement with a range of frequencies that could be useful in the diagnosis and treatment of motility disorders.

The effect of spring diameter on porcine ileal distraction enterogenesis.

PURPOSE: Spring-mediated distraction enterogenesis has proven to be successful for intestinal lengthening. We aimed to evaluate the effect of spring diameter mismatch on intestinal adaptation. METHODS: Juvenile mini-Yucatan pigs underwent placement of compressed nitinol springs with diameter of 10, 11, or 12 mm into the ileal lumen. Pigs were euthanized on postoperative day 7. The lengths, histology, total area of blood vessels, and enteric ganglia were evaluated. RESULTS: All spring groups exhibited significant ileal lengthening. Across the different diameters, spring-expanded segments were similar in terms of ileal lengthening, crypt height, muscular thickness, blood vessels, and enteric ganglia area. CONCLUSION: Spring-mediated distraction enterogenesis is successful in the porcine ileum. A smaller diameter spring is as effective as a larger diameter spring in lengthening the ileum. Springs of varying diameters result in comparable structural changes in the ileum.

Inequalities in cancer screening, prevention and service engagement between UK ethnic minority groups.

More people in the UK are living with cancer than ever before. With an increasingly ethnically diverse population, greater emphasis must be placed on understanding factors influencing cancer outcomes. This review seeks to explore UK-specific variations in engagement with cancer services in minority ethnic groups and describe successful interventions. The authors wish to highlight that, despite improvement to engagement and education strategies, inequalities still persist and work to improve cancer outcomes across our communities still needs to be prioritised. There are many reasons why cancer healthcare inequities exist for minority communities, reported on a spectrum ranging from cultural beliefs and awareness, through to racism. Strategies that successfully enhanced engagement included language support; culturally-sensitive reminders; community-based health workers and targeted outreach. Focusing on the diverse city of Leicester the authors describe how healthcare providers, researchers and community champions have worked collectively, delivering targeted community-based strategies to improve awareness and access to cancer services.

Using target sequence capture to improve the phylogenetic resolution of a rapid radiation in New Zealand Veronica.

PREMISE: Recent, rapid radiations present a challenge for phylogenetic reconstruction. Fast successive speciation events typically lead to low sequence divergence and poorly resolved relationships with standard phylogenetic markers. Target sequence capture of many independent nuclear loci has the potential to improve phylogenetic resolution for rapid radiations. METHODS: Here we applied target sequence capture with 353 protein-coding genes (Angiosperms353 bait kit) to Veronica sect. Hebe (common name hebe) to determine its utility for improving the phylogenetic resolution of rapid radiations. Veronica section Hebe originated 5-10 million years ago in New Zealand, forming a monophyletic radiation of ca 130 extant species. RESULTS: We obtained approximately 150 kbp of 353 protein-coding exons and an additional 200 kbp of flanking noncoding sequences for each of 77 hebe and two outgroup species. When comparing coding, noncoding, and combined data sets, we found that the latter provided the best overall phylogenetic resolution. While some deep nodes in the radiation remained unresolved, our phylogeny provided broad and often improved support for subclades identified by both morphology and standard markers in previous studies. Gene-tree discordance was nonetheless widespread, indicating that additional methods are needed to disentangle fully the history of the radiation. CONCLUSIONS: Phylogenomic target capture data sets both increase phylogenetic signal and deliver new insights into the complex evolutionary history of rapid radiations as compared with traditional markers. Improving methods to resolve remaining discordance among loci from target sequence capture is now important to facilitate the further study of rapid radiations.

Seasonality of confirmed malaria cases from 2008 to 2017 in Togo: a time series analysis by health district and target group.

BACKGROUND: This study aimed to assess the seasonality of confirmed malaria cases in Togo and to provide new indicators of malaria seasonality to the National Malaria Control Programme (NMCP). METHODS: Aggregated data of confirmed malaria cases were collected monthly from 2008 to 2017 by the Togo's NMCP and stratified by health district and according to three target groups: children < 5 years old, children ≥ 5 years old and adults, and pregnant women. Time series analysis was carried out for each target group and health district. Seasonal decomposition was used to assess the seasonality of confirmed malaria cases. Maximum and minimum seasonal indices, their corresponding months, and the ratio of maximum/minimum seasonal indices reflecting the importance of malaria transmission, were provided by health district and target group. RESULTS: From 2008 to 2017, 7,951,757 malaria cases were reported in Togo. Children < 5 years old, children ≥ 5 years old and adults, and pregnant women represented 37.1%, 57.7% and 5.2% of the confirmed malaria cases, respectively. The maximum seasonal indices were observed during or shortly after a rainy season and the minimum seasonal indices during the dry season between January and April in particular. In children < 5 years old, the ratio of maximum/minimum seasonal indices was higher in the north, suggesting a higher seasonal malaria transmission, than in the south of Togo. This is also observed in the other two groups but to a lesser extent. CONCLUSIONS: This study contributes to a better understanding of malaria seasonality in Togo. The indicators of malaria seasonality could allow for more accurate forecasting in malaria interventions and supply planning throughout the year.

Urethrocutaneous fistulas after voluntary medical male circumcision for HIV prevention-15 African Countries, 2015-2019.

BACKGROUND: Voluntary medical male circumcision (VMMC) is an HIV prevention strategy recommended to partially protect men from heterosexually acquired HIV. From 2015 to 2019, the President's Emergency Plan for AIDS Relief (PEPFAR) has supported approximately 14.9 million VMMCs in 15 African countries. Urethrocutaneous fistulas, abnormal openings between the urethra and penile skin through which urine can escape, are rare, severe adverse events (AEs) that can occur with VMMC. This analysis describes fistula cases, identifies possible risks and mechanisms of injury, and offers mitigation actions. METHODS: Demographic and clinical program data were reviewed from all reported fistula cases during 2015 to 2019, descriptive analyses were performed, and an odds ratio was calculated by patient age group. RESULTS: In total, 41 fistula cases were reported. Median patient age for fistula cases was 11 years and 40/41 (98%) occurred in patients aged < 15 years. Fistulas were more often reported among patients < 15 compared to ≥ 15 years old (0.61 vs. 0.01 fistulas per 100,000 VMMCs, odds ratio 50.9 (95% confidence interval [CI] = 8.6-2060.0)). Median time from VMMC surgery to appearance of fistula was 20 days (interquartile range (IQR) 14-27). CONCLUSIONS: Urethral fistulas were significantly more common in patients under age 15 years. Thinner tissue overlying the urethra in immature genitalia may predispose boys to injury. The delay between procedure and symptom onset of 2-3 weeks indicates partial thickness injury or suture violation of the urethral wall as more likely mechanisms of injury than intra-operative urethral transection. This analysis helped to inform PEPFAR's recent decision to change VMMC eligibility policy in 2020, raising the minimum age to 15 years.

MKLN1 splicing defect in dogs with lethal acrodermatitis.

Lethal acrodermatitis (LAD) is a genodermatosis with monogenic autosomal recessive inheritance in Bull Terriers and Miniature Bull Terriers. The LAD phenotype is characterized by poor growth, immune deficiency, and skin lesions, especially at the paws. Utilizing a combination of genome wide association study and haplotype analysis, we mapped the LAD locus to a critical interval of ~1.11 Mb on chromosome 14. Whole genome sequencing of an LAD affected dog revealed a splice region variant in the MKLN1 gene that was not present in 191 control genomes (chr14:5,731,405T>G or MKLN1:c.400+3A>C). This variant showed perfect association in a larger combined Bull Terrier/Miniature Bull Terrier cohort of 46 cases and 294 controls. The variant was absent from 462 genetically diverse control dogs of 62 other dog breeds. RT-PCR analysis of skin RNA from an affected and a control dog demonstrated skipping of exon 4 in the MKLN1 transcripts of the LAD affected dog, which leads to a shift in the MKLN1 reading frame. MKLN1 encodes the widely expressed intracellular protein muskelin 1, for which diverse functions in cell adhesion, morphology, spreading, and intracellular transport processes are discussed. While the pathogenesis of LAD remains unclear, our data facilitate genetic testing of Bull Terriers and Miniature Bull Terriers to prevent the unintentional production of LAD affected dogs. This study may provide a starting point to further clarify the elusive physiological role of muskelin 1 in vivo.