Real-world experience with caplacizumab in the management of acute TTP.

The cornerstone of life-saving therapy in immune-mediated thrombotic thrombocytopenic purpura (iTTP) has been plasma exchange (PEX) combined with immunomodulatory strategies. Caplacizumab, a novel anti-von Willebrand factor nanobody trialed in 2 multicenter randomized controlled trials (RCTs) leading to European Union and US Food and Drug Administration approval, has been available in the United Kingdom (UK) through a patient access scheme. Data were collected retrospectively from 2018 to 2020 for 85 patients (4 children) receiving caplacizumab from 22 UK hospitals. Patient characteristics and outcomes in the real-world clinical setting were compared with caplacizumab trial end points and historical outcomes in the precaplacizumab era. Eighty-four of 85 patients received steroid and rituximab alongside PEX; 26% required intubation. Median time to platelet count normalization (3 days), duration of PEX (7 days), and hospital stay (12 days) were comparable with RCT data. Median duration of PEX and time from PEX initiation to platelet count normalization were favorable compared with historical outcomes (P < .05). Thrombotic thrombocytopenic purpura (TTP) recurred in 5 of 85 patients; all had persistent ADAMTS13 activity < 5 IU/dL. Of 31 adverse events in 26 patients, 17 of 31 (55%) were bleeding episodes, and 5 of 31 (16%) were thrombotic events (2 unrelated to caplacizumab); mortality was 6% (5/85), with no deaths attributed to caplacizumab. In 4 of 5 deaths, caplacizumab was introduced >48 hours after PEX initiation (3-21 days). This real-world evidence represents the first and largest series of TTP patients, including pediatric patients, receiving caplacizumab outside of clinical trials. Representative of true clinical practice, the findings provide valuable information for clinicians treating TTP globally.

Caught in motion: human NTHL1 undergoes interdomain rearrangement necessary for catalysis.

Base excision repair (BER) is the main pathway protecting cells from the continuous damage to DNA inflicted by reactive oxygen species. BER is initiated by DNA glycosylases, each of which repairs a particular class of base damage. NTHL1, a bifunctional DNA glycosylase, possesses both glycolytic and ß-lytic activities with a preference for oxidized pyrimidine substrates. Defects in human NTHL1 drive a class of polyposis colorectal cancer. We report the first X-ray crystal structure of hNTHL1, revealing an open conformation not previously observed in the bacterial orthologs. In this conformation, the six-helical barrel domain comprising the helix-hairpin-helix (HhH) DNA binding motif is tipped away from the iron sulphur cluster-containing domain, requiring a conformational change to assemble a catalytic site upon DNA binding. We found that the flexibility of hNTHL1 and its ability to adopt an open configuration can be attributed to an interdomain linker. Swapping the human linker sequence for that of Escherichia coli yielded a protein chimera that crystallized in a closed conformation and had a reduced activity on lesion-containing DNA. This large scale interdomain rearrangement during catalysis is unprecedented for a HhH superfamily DNA glycosylase and provides important insight into the molecular mechanism of hNTHL1.

Interventions for preventing thrombosis in solid organ transplant recipients.

BACKGROUND: Graft thrombosis is a well-recognised complication of solid organ transplantation and is one of the leading causes of graft failure. Currently there are no standardised protocols for thromboprophylaxis. Many transplant units use unfractionated heparin (UFH) and fractionated heparins (low molecular weight heparin; LMWH) as prophylaxis for thrombosis. Antiplatelet agents such as aspirin are routinely used as prophylaxis of other thrombotic conditions and may have a role in preventing graft thrombosis. However, any pharmacological thromboprophylaxis comes with the theoretical risk of increasing the risk of major blood loss following transplant. This review looks at benefits and harms of thromboprophylaxis in patients undergoing solid organ transplantation. OBJECTIVES: To assess the benefits and harms of instituting thromboprophylaxis to patients undergoing solid organ transplantation. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 10 November 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) and quasi-RCTs designed to examine interventions to prevent thrombosis in solid organ transplant recipients. All donor types were included (donor after circulatory (DCD) and brainstem death (DBD) and live transplantation). There was no upper age limit for recipients in our search. DATA COLLECTION AND ANALYSIS: The results of the literature search were screened and data collected by two independent authors. Dichotomous outcome results were expressed as risk ratio (RR) with 95% confidence intervals (CI). Random effects models were used for data analysis. Risk of bias was independently assessed by two authors using the risk of bias assessment tool. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: We identified nine studies (712 participants). Seven studies (544 participants) included kidney transplant recipients, and studies included liver transplant recipients. We did not identify any study enrolling heart, lung, pancreas, bowel, or any other solid organ transplant recipient. Selection bias was high or unclear in eight of the nine studies; five studies were at high risk of bias for performance and/or detection bias; while attrition and reporting biases were in general low or unclear. Three studies (180 participants) primarily investigated heparinisation in kidney transplantation. Only two studies reported on graft vessel thrombosis in kidney transplantation (144 participants). These small studies were at high risk of bias in several domains and reported only two graft thromboses between them; it therefore remains unclear whether heparin decreases the risk of early graft thrombosis or non-graft thrombosis (very low certainty). UFH may make little or no difference versus placebo to the rate of major bleeding events in kidney transplantation (3 studies, 155 participants: RR 2.92, 95% CI 0.89 to 9.56; I² = 0%; low certainty evidence). Sensitivity analysis using a fixed-effect model suggested that UFH may increase the risk of haemorrhagic events compared to placebo (RR 3.33, 95% CI 1.04 to 10.67, P = 0.04). Compared to control, any heparin (including LMWH) may make little or no difference to the number of major bleeding events (3 studies, 180 participants: RR 2.70, 95% CI 0.89 to 8.19; I² = 0%; low certainty evidence) and had an unclear effect on risk of readmission to intensive care (3 studies, 180 participants: RR 0.68, 95% CI 0.12 to 3.90, I² = 45%; very low certainty evidence). The effect of heparin on our other outcomes (including death, patient and graft survival, transfusion requirements) remains unclear (very low certainty evidence). Three studies (144 participants) investigated antiplatelet interventions in kidney transplantation: aspirin versus dipyridamole (1), and Lipo-PGE1 plus low-dose heparin to "control" in patients who had a diagnosis of acute rejection (2). None of these reported on early graft thromboses. The effect of aspirin, dipyridamole and Lipo PGE1 plus low-dose heparin on any outcomes is unclear (very low certainty evidence). Two studies (168 participants) assessed interventions in liver transplants. One compared warfarin versus aspirin in patients with pre-existing portal vein thrombosis and the other investigated plasmapheresis plus anticoagulation. Both studies were abstract-only publications, had high risk of bias in several domains, and no outcomes could be meta-analysed. Overall, the effect of any of these interventions on any of our outcomes remains unclear with no evidence to guide anti-thrombotic therapy in standard liver transplant recipients (very low certainty evidence). AUTHORS' CONCLUSIONS: Overall, there is a paucity of research in the field of graft thrombosis prevention. Due to a lack of high quality evidence, it remains unclear whether any therapy is able to reduce the rate of early graft thrombosis in any type of solid organ transplant. UFH may increase the risk of major bleeding in kidney transplant recipients, however this is based on low certainty evidence. There is no evidence from RCTs to guide anti-thrombotic strategies in liver, heart, lung, or other solid organ transplants. Further studies are required in comparing anticoagulants, antiplatelets to placebo in solid organ transplantation. These should focus on outcomes such as early graft thrombosis, major haemorrhagic complications, return to theatre, and patient/graft survival.

Therapeutic metamorphosis: Findings from a grounded theory study of the impact of low-dose prophylaxis in children living with haemophilia in India.

INTRODUCTION: The clinical benefits of administering low-dose prophylaxis in children with haemophilia are well established. Qualitative research describing the impact of prophylaxis on quality of life is comparatively rare in this area. AIM: The aim of this study was to investigate in children the experiences of living and becoming adjusted to haemophilia before prophylaxis, by collecting information directly from children and their parents or guardians. A further goal was to evaluate whether and how the use of low-dose prophylaxis impacts the disease experience. METHODS: A grounded theory design according to Strauss and Corbin was chosen for this study. The study was conducted in the Haemophilia Treatment Centre at Aluva, Kerala, India and involved nineteen participants (children, mothers, father and grandmothers) who were selected by theoretical sampling. Data were collected through audiotaped interviews, which included demographic and semi-structured interview questions. Data were coded and evolved into concepts and categories that lead to the emergence of theory. RESULTS: The study resulted in the construction of 'Theory of Therapeutic Metamorphosis'. It comprised two stages: stage of bondage (enduring hardships), experienced during the absence of prophylaxis or on-demand treatment and stage of freedom (deliverance/reductions, energized life/improvements and behaviour to seek prophylaxis) experienced during low-dose prophylaxis. CONCLUSION: This study illustrates the challenges faced by children with haemophilia and their families and the positive impact of low-dose prophylaxis. Further prospective research studies are required to add to the growing knowledge in this area.

Modeling the impact of school reopening on SARS-CoV-2 transmission using contact structure data from Shanghai.

BACKGROUND: Mathematical modeling studies have suggested that pre-emptive school closures alone have little overall impact on SARS-CoV-2 transmission, but reopening schools in the background of community contact reduction presents a unique scenario that has not been fully assessed. METHODS: We adapted a previously published model using contact information from Shanghai to model school reopening under various conditions. We investigated different strategies by combining the contact patterns observed between different age groups during both baseline and "lockdown" periods. We also tested the robustness of our strategy to the assumption of lower susceptibility to infection in children under age 15 years. RESULTS: We find that reopening schools for all children would maintain a post-intervention R0 < 1 up to a baseline R0 of approximately 3.3 provided that daily contacts among children 10-19 years are reduced to 33% of baseline. This finding was robust to various estimates of susceptibility to infection in children relative to adults (up to 50%) and to estimates of various levels of concomitant reopening in the rest of the community (up to 40%). However, full school reopening without any degree of contact reduction in the school setting returned R0 virtually back to baseline, highlighting the importance of mitigation measures. CONCLUSIONS: These results, based on contact structure data from Shanghai, suggest that schools can reopen with proper precautions during conditions of extreme contact reduction and during conditions of reasonable levels of reopening in the rest of the community.

A Tandem Evolutionary Algorithm for Identifying Causal Rules from Complex Data.

We propose a new evolutionary approach for discovering causal rules in complex classification problems from batch data. Key aspects include (a) the use of a hypergeometric probability mass function as a principled statistic for assessing fitness that quantifies the probability that the observed association between a given clause and target class is due to chance, taking into account the size of the dataset, the amount of missing data, and the distribution of outcome categories, (b) tandem age-layered evolutionary algorithms for evolving parsimonious archives of conjunctive clauses, and disjunctions of these conjunctions, each of which have probabilistically significant associations with outcome classes, and (c) separate archive bins for clauses of different orders, with dynamically adjusted order-specific thresholds. The method is validated on majority-on and multiplexer benchmark problems exhibiting various combinations of heterogeneity, epistasis, overlap, noise in class associations, missing data, extraneous features, and imbalanced classes. We also validate on a more realistic synthetic genome dataset with heterogeneity, epistasis, extraneous features, and noise. In all synthetic epistatic benchmarks, we consistently recover the true causal rule sets used to generate the data. Finally, we discuss an application to a complex real-world survey dataset designed to inform possible ecohealth interventions for Chagas disease.

Assessment of the efficacy of a novel tailored vitamin K dosing regimen in lowering the International Normalised Ratio in over-anticoagulated patients: a randomised clinical trial.

Current guidelines advocate using fixed-doses of oral vitamin K to reverse excessive anticoagulation in warfarinised patients who are either asymptomatic or have minor bleeds. Over-anticoagulated patients present with a wide range of International Normalised Ratio (INR) values and response to fixed doses of vitamin K varies. Consequently a significant proportion of patients remain outside their target INR after vitamin K administration, making them prone to either haemorrhage or thromboembolism. We compared the performance of a novel tailored vitamin K dosing regimen to that of a fixed-dose regimen with the primary measure being the proportion of over-anticoagulated patients returning to their target INR within 24 h. One hundred and eighty-one patients with an index INR > 6·0 (asymptomatic or with minor bleeding) were randomly allocated to receive oral administration of either a tailored dose (based upon index INR and body surface area) or a fixed-dose (1 or 2 mg) of vitamin K. A greater proportion of patients treated with the tailored dose returned to within target INR range compared to the fixed-dose regimen (68·9% vs. 52·8%; P = 0·026), whilst a smaller proportion of patients remained above target INR range (12·2% vs. 34·0%; P < 0·001). Individualised vitamin K dosing is more accurate than fixed-dose regimen in lowering INR to within target range in excessively anticoagulated patients.

VKORC1 and CYP2C9 genotype and patient characteristics explain a large proportion of the variability in warfarin dose requirement among children.

Although genetic and environmental factors explain approximately half of the interindividual variability in warfarin dose requirement in adults, there is limited information available in children. In a cross-sectional study of anticoagulated children from 5 tertiary care centers, 120 children with a stable warfarin dose were genotyped for VKORC1 (-1639G > A; rs9923231), CYP2C9 (*2 and *3 alleles; rs1799853 and rs1057910), and CYP4F2 (V433M; rs2108622) polymorphisms. Clinical and demographic features were recorded. Multiple regression analysis of the data showed that, although CYP4F2 made no contribution to the dose model, 72.4% of the variability in warfarin dose requirement is attributed to by patient height, genetic polymorphisms in VKORC1 and CYP2C9, and indication for warfarin. The recently published International Warfarin Pharmacogenetics Consortium pharmacogenetic-based warfarin dosing algorithm (based on data derived from anticoagulated adults) consistently overestimated warfarin dose for our cohort of children. A similar proportion of the interindividual variability in warfarin dose is explained by genetic factors in children compared with adult patients, although height is a greater predictor in children. A pharmacogenomic approach to warfarin dosing has the potential to improve the efficacy and safety of warfarin therapy in children. However, algorithms should be derived from data in children if their potential benefit is to be realized.

Global report on COVID-19 vaccination and reasons not to vaccinate among adults with intellectual disabilities: Results from secondary analyses of Special Olympics' program planning.

The COVID-19 pandemic has disproportionately affected people with intellectual disabilities worldwide. The objective of this study was to identify global rates of COVID-19 vaccination and reasons not to vaccinate among adults with intellectual disabilities (ID) associated with country economic income levels. The Special Olympics COVID-19 online survey was administered in January-February 2022 to adults with ID from 138 countries. Descriptive analyses of survey responses include 95% margins of error. Logistic regression and Pearson Chi-squared tests were calculated to assess associations with predictive variables for vaccination using R 4.1.2 software. Participants (n = 3560) represented 18 low (n = 410), 35 lower-middle (n = 1182), 41 upper-middle (n = 837), and 44 high (n = 1131) income countries. Globally, 76% (74.8-77.6%) received a COVID-19 vaccination while 49.5% (47.9-51.2%) received a COVID-19 booster. Upper-middle (93% (91.2-94.7%)) and high-income country (94% (92.1-95.0%)) participants had the highest rates of vaccination while low-income countries had the lowest rates (38% (33.3-42.7%)). In multivariate regression models, country economic income level (OR = 3.12, 95% CI [2.81, 3.48]), age (OR = 1.04, 95% CI [1.03, 1.05]), and living with family (OR = 0.70, 95% CI [0.53, 0.92]) were associated with vaccination. Among LLMICs, the major reason for not vaccinating was lack of access (41.2% (29.5-52.9%)). Globally, concerns about side effects (42%, (36.5-48.1%)) and parent/guardian not wanting the adult with ID to vaccinate (32% (26.1-37.0%)) were the most common reasons for not vaccinating. Adults with ID from low and low-middle income countries reported fewer COVID-19 vaccinations, suggesting reduced access and availability of resources in these countries. Globally, COVID-19 vaccination levels among adults with ID were higher than the general population. Interventions should address the increased risk of infection for those in congregate living situations and family caregiver apprehension to vaccinate this high-risk population.

Survey of awareness, attitudes, and compliance with COVID-19 measures among Vermont residents.

The objective of this research was to examine residents' awareness, attitudes, and compliance with COVID-19 public health guidelines in Vermont, which emerged as an early leader in national pandemic response. Our methods included conducting an online survey of adult Vermont residents between January and April 2021. We analyzed demographics associated with awareness and compliance, and identified features associated with non-compliance. Our results show that of the 2,208 adult Vermont residents who completed the survey, 90% were extremely aware of the state's COVID-19 guidelines, and 95% reported knowing exactly what to do to follow recommended actions. Political affiliation emerged as a primary factor related to attitudes and compliance. Self-identified Republicans were less likely to agree that public health measures keep people safe or help businesses stay open, and were less likely to follow masking, quarantine, social distancing, and vaccine guidance than Independents, Progressives, and Democrats. The large differences in COVID-19 infection and death rates across the country, and recent shift toward a "pandemic of the unvaccinated," underscore the need for identifying public health strategies that work in some areas in order to adapt and apply them to areas that have struggled with controlling the virus. Consistent with national surveys, our results show that resistance to public health guidance is a partisan challenge even in states with high compliance. Identifying populations that are less supportive or hesitant to follow guidelines while understanding factors that motivate compliance can help inform strategies for developing targeted programs to encourage collective action on pandemic response. Developing communication strategies that reach people who do not believe COVID-19 guidelines keep them safe is necessary to reach universal compliance.

Identifying neuroanatomical and behavioral features for autism spectrum disorder diagnosis in children using machine learning.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that can cause significant social, communication, and behavioral challenges. Diagnosis of ASD is complicated and there is an urgent need to identify ASD-associated biomarkers and features to help automate diagnostics and develop predictive ASD models. The present study adopts a novel evolutionary algorithm, the conjunctive clause evolutionary algorithm (CCEA), to select features most significant for distinguishing individuals with and without ASD, and is able to accommodate datasets having a small number of samples with a large number of feature measurements. The dataset is unique and comprises both behavioral and neuroimaging measurements from a total of 28 children from 7 to 14 years old. Potential biomarker candidates identified include brain volume, area, cortical thickness, and mean curvature in specific regions around the cingulate cortex, frontal cortex, and temporal-parietal junction, as well as behavioral features associated with theory of mind. A separate machine learning classifier (i.e., k-nearest neighbors algorithm) was used to validate the CCEA feature selection and for ASD prediction. Study findings demonstrate how machine learning tools might help move the needle on improving diagnostic and predictive models of ASD.

Immunotranscriptomic profiling the acute and clearance phases of a human challenge dengue virus serotype 2 infection model.

About 20-25% of dengue virus (DENV) infections become symptomatic ranging from self-limiting fever to shock. Immune gene expression changes during progression to severe dengue have been documented in hospitalized patients; however, baseline or kinetic information is difficult to standardize in natural infection. Here we profile the host immunotranscriptome response in humans before, during, and after infection with a partially attenuated rDEN2Δ30 challenge virus (ClinicalTrials.gov NCT02021968). Inflammatory genes including type I interferon and viral restriction pathways are induced during DENV2 viremia and return to baseline after viral clearance, while others including myeloid, migratory, humoral, and growth factor immune regulation factors pathways are found at non-baseline levels post-viremia. Furthermore, pre-infection baseline gene expression is useful to predict rDEN2Δ30-induced immune responses and the development of rash. Our results suggest a distinct immunological profile for mild rDEN2Δ30 infection and offer new potential biomarkers for characterizing primary DENV infection.

A United Kingdom Haemophilia Centre Doctors' Organization guideline approved by the British Committee for Standards in Haematology: guideline on the use of prophylactic factor VIII concentrate in children and adults with severe haemophilia A.

Consensus-based guidelines supported by the literature are presented on the role of prophylactic administration of factor VIII concentrate in children and adults with severe haemophilia A. The timing of initiation of prophylaxis, the choice of prophylactic regimen, monitoring, management of breakthrough bleeding and education of the patient and family are discussed.

The management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab.

In Paroxysmal nocturnal haemoglobinuria (PNH), pregnancy is associated with increased maternal and foetal complications to such an extent that the condition has been considered relatively contra-indicated in PNH. Eculizumab has revolutionized the treatment of PNH. We evaluate its use in pregnancy to date. We report on seven patients exposed to eculizumab at different stages of pregnancy including the first two patients to receive the drug from conception to delivery. There was no evidence of complement blockade from cord blood samples taken at delivery. Eculizumab appears safe to use in this setting and is likely to prevent many of the complications usually observed.

Novel Evolutionary Algorithm Identifies Interactions Driving Infestation of Triatoma dimidiata, a Chagas Disease Vector.

Chagas disease is a lethal, neglected tropical disease. Unfortunately, aggressive insecticide-spraying campaigns have not been able to eliminate domestic infestation of Triatoma dimidiata, the native vector in Guatemala. To target interventions toward houses most at risk of infestation, comprehensive socioeconomic and entomologic surveys were conducted in two towns in Jutiapa, Guatemala. Given the exhaustively large search space associated with combinations of risk factors, traditional statistics are limited in their ability to discover risk factor interactions. Two recently developed statistical evolutionary algorithms, specifically designed to accommodate risk factor interactions and heterogeneity, were applied to this large combinatorial search space and used in tandem to identify sets of risk factor combinations associated with infestation. The optimal model includes 10 risk factors in what is known as a third-order disjunctive normal form (i.e., infested households have chicken coops AND deteriorated bedroom walls OR an accumulation of objects AND dirt floors AND total number of occupants ≥ 5 AND years of electricity ≥ 5 OR poor hygienic condition ratings AND adobe walls AND deteriorated walls AND dogs). Houses with dirt floors and deteriorated walls have been reported previously as risk factors and align well with factors currently targeted by Ecohealth interventions to minimize infestation. However, the tandem evolutionary algorithms also identified two new socioeconomic risk factors (i.e., households having many occupants and years of electricity ≥ 5). Identifying key risk factors may help with the development of new Ecohealth interventions and/or reduce the survey time needed to identify houses most at risk.

Residual survival and local dispersal drive reinfestation by Triatoma dimidiata following insecticide application in Guatemala.

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and transmitted by triatomine insect vectors. In Guatemala, insecticide spraying is an integral part of management of the main vector, Triatoma dimidiata. Spraying typically has low efficacy, which may be due to incomplete elimination from infested houses, within-village dispersal, or influx from other villages or sylvan environments. To evaluate how these mechanisms contribute to reinfestation, we conducted a time-course analysis of T. dimidiata infestation, abundance and household genetic structure in two nearby villages in Jutiapa, Guatemala; houses in the first village were surveyed, treated with insecticide if infested and then re-surveyed at eight and 22 months following spraying, while the second village served as an untreated control to quantify changes associated with seasonal dispersal. Insects were genotyped at 2-3000 SNP loci for kinship and population genetic analyses. Insecticide application reduced overall infestation and abundance, while the untreated village was stable over time. Nevertheless, within two years 35.5% of treated houses were reinfested and genetic diversity had largely recovered. Insects collected from reinfested houses post-spraying were most closely related to pre-spray collections from the same house, suggesting that infestations had not been fully eliminated. Immigration by unrelated insects was also detected within a year of spraying; when it occurred, dispersal was primarily local from neighboring houses. Similar dispersal patterns were observed following the annual dispersal season in the untreated village, with high-infestation houses serving as sources for neighboring homes. Our findings suggest that the efficacy of pyrethroid application is rapidly diminished by both within-house breeding by survivors and annual cycles of among-house movement. Given these patterns, we conclude that house structural improvements, an integral part of the Ecohealth approach that makes houses refractory to vector colonization and persistence, are critical for long-term reduction of T. dimidiata infestation.

Junior doctor teaching delivered by near peers.

BACKGROUND: Near-peer teaching - trainees teaching more junior trainee colleagues - has been widely described in undergraduate medical education. Several benefits have been reported, including a more comfortable learning environment for learners and the development of tutors' teaching skills. Near-peer teaching programmes in postgraduate training are less commonly described in the existing literature, however. This article outlines a pilot study of a postgraduate near-peer teaching programme implemented at the Royal Victoria Infirmary, Newcastle, UK. METHODS: A 16-week teaching programme was developed in which core medical trainees delivered teaching sessions to their more junior Foundation Year-2 colleagues. The teaching was based on cases that the Foundation Year-2 doctors frequently manage during clinical practice. Evaluation questionnaires were completed and learners were asked to rate their confidence in managing the cases before and after each session. Furthermore, each tutor underwent a standardised teaching assessment during their first and final sessions. RESULTS: Fifteen sessions were delivered by four tutors. All sessions received positive feedback from learners with nine sessions receiving a five out of five rating. In addition, the confidence ratings of the learners increased following each session. The tutors improved in all items of the teaching assessments and the overall rating of their teaching. Near-peer teaching could enhance the training of junior doctors DISCUSSION: The results of this pilot study suggest that the benefits described in undergraduate near-peer teaching programmes may also be seen in postgraduate medical education. Thus near-peer teaching could enhance the training of junior doctors, and we encourage the proliferation of such programmes to further evaluate their benefits in this setting.

Uncovering vector, parasite, blood meal and microbiome patterns from mixed-DNA specimens of the Chagas disease vector Triatoma dimidiata.

Chagas disease, considered a neglected disease by the World Health Organization, is caused by the protozoan parasite Trypanosoma cruzi, and transmitted by >140 triatomine species across the Americas. In Central America, the main vector is Triatoma dimidiata, an opportunistic blood meal feeder inhabiting both domestic and sylvatic ecotopes. Given the diversity of interacting biological agents involved in the epidemiology of Chagas disease, having simultaneous information on the dynamics of the parasite, vector, the gut microbiome of the vector, and the blood meal source would facilitate identifying key biotic factors associated with the risk of T. cruzi transmission. In this study, we developed a RADseq-based analysis pipeline to study mixed-species DNA extracted from T. dimidiata abdomens. To evaluate the efficacy of the method across spatial scales, we used a nested spatial sampling design that spanned from individual villages within Guatemala to major biogeographic regions of Central America. Information from each biotic source was distinguished with bioinformatics tools and used to evaluate the prevalence of T. cruzi infection and predominant Discrete Typing Units (DTUs) in the region, the population genetic structure of T. dimidiata, gut microbial diversity, and the blood meal history. An average of 3.25 million reads per specimen were obtained, with approximately 1% assigned to the parasite, 20% to the vector, 11% to bacteria, and 4% to putative blood meals. Using a total of 6,405 T. cruzi SNPs, we detected nine infected vectors harboring two distinct DTUs: TcI and a second unidentified strain, possibly TcIV. Vector specimens were sufficiently variable for population genomic analyses, with a total of 25,710 T. dimidiata SNPs across all samples that were sufficient to detect geographic genetic structure at both local and regional scales. We observed a diverse microbiotic community, with significantly higher bacterial species richness in infected T. dimidiata abdomens than those that were not infected. Unifrac analysis suggests a common assemblage of bacteria associated with infection, which co-occurs with the typical gut microbial community derived from the local environment. We identified vertebrate blood meals from five T. dimidiata abdomens, including chicken, dog, duck and human; however, additional detection methods would be necessary to confidently identify blood meal sources from most specimens. Overall, our study shows this method is effective for simultaneously generating genetic data on vectors and their associated parasites, along with ecological information on feeding patterns and microbial interactions that may be followed up with complementary approaches such as PCR-based parasite detection, 18S eukaryotic and 16S bacterial barcoding.

Patterns of bruising in preschool children with inherited bleeding disorders: a longitudinal study.

OBJECTIVE: The extent that inherited bleeding disorders affect; number, size and location of bruises in young children <6 years. DESIGN: Prospective, longitudinal, observational study. SETTING: Community. PATIENTS: 105 children with bleeding disorders, were compared with 328 without a bleeding disorder and classified by mobility: premobile (non-rolling/rolling over/sitting), early mobile (crawling/cruising) and walking and by disease severity: severe bleeding disorder factor VIII/IX/XI <1 IU/dL or type 3 von Willebrand disease. INTERVENTIONS: Number, size and location of bruises recorded in each child weekly for up to 12 weeks. OUTCOMES: The interventions were compared between children with severe and mild/moderate bleeding disorders and those without bleeding disorders. Multiple collections for individual children were analysed by multilevel modelling. RESULTS: Children with bleeding disorders had more and larger bruises, especially when premobile. Compared with premobile children without a bleeding disorder; the modelled ratio of means (95% CI) for number of bruises/collection was 31.82 (8.39 to 65.42) for severe bleeding disorders and 5.15 (1.23 to 11.17) for mild/moderate, and was 1.81 (1.13 to 2.23) for size of bruises. Children with bleeding disorders rarely had bruises on the ears, neck, cheeks, eyes or genitalia. CONCLUSIONS: Children with bleeding disorder have more and larger bruises at all developmental stages. The differences were greatest in premobile children. In this age group for children with unexplained bruising, it is essential that coagulation studies are done early to avoid the erroneous diagnosis of physical abuse when the child actually has a serious bleeding disorder, however a blood test compatible with a mild/moderate bleeding disorder cannot be assumed to be the cause of bruising.

Geospatial and Temporal Analysis of Thyroid Cancer Incidence in a Rural Population.

BACKGROUND: The increasing incidence of thyroid cancer has resulted in the rate tripling over the past 30 years. Reasons for this increase have not been established. Geostatistics and geographic information system (GIS) tools have emerged as powerful geospatial technologies to identify disease clusters, map patterns and trends, and assess the impact of ecological and socioeconomic factors (SES) on the spatial distribution of diseases. In this study, these tools were used to analyze thyroid cancer incidence in a rural population. METHODS: Thyroid cancer incidence and socio-demographic factors in Vermont (VT), United States, between 1994 and 2007 were analyzed by logistic regression and geospatial and temporal analyses. RESULTS: The thyroid cancer age-adjusted incidence in Vermont (8.0 per 100,000) was comparable to the national level (8.4 per 100,000), as were the ratio of the incidence of females to males (3.1:1) and the mortality rate (0.5 per 100,000). However, the estimated annual percentage change was higher (8.3 VT; 5.7 U.S.). Incidence among females peaked at 30-59 years of age, reflecting a significant rise from 1994 to 2007, while incidence trends for males did not vary significantly by age. For both females and males, the distribution of tumors by size did not vary over time; ≤1.0 cm, 1.1-2.0 cm, and >2.0 cm represented 38%, 22%, and 40%, respectively. In females, papillary thyroid cancer (PTC) accounted for 89% of cases, follicular (FTC) 8%, medullary (MTC) 2%, and anaplastic (ATC) 0.6%, while in males PTC accounted for 77% of cases, FTC 15%, MTC 1%, and ATC 3%. Geospatial analysis revealed locations and spatial patterns that, when combined with multivariate incidence analyses, indicated that factors other than increased surveillance and access to healthcare (physician density or insurance) contributed to the increased thyroid cancer incidence. Nine thyroid cancer incidence hot spots, areas with very high normalized incidence, were identified based on zip code data. Those locations did not correlate with urban areas or healthcare centers. CONCLUSIONS: These data provide evidence of increased thyroid cancer incidence in a rural population likely due to environmental drivers and SES. Geospatial modeling can provide an important framework for evaluation of additional associative risk factors.