Did the COVID-19 pandemic affect levels of burnout, anxiety and depression among doctors and nurses in Bangladesh? A cross-sectional survey study.

INTRODUCTION: COVID-19 has caused severe disruption to clinical services in Bangladesh but the extent of this, and the impact on healthcare professionals is unclear. We aimed to assess the perceived levels of anxiety, depression and burnout among doctors and nurses during COVID-19 pandemic. METHODS: We undertook an online survey using RedCap, directed at doctors and nurses across four institutions in Bangladesh (The Sheikh Russel Gastro Liver Institute & Hospital (SRNGIH), Dhaka Medical College Hospital (DMCH), Mugda Medical College Hospital (MMCH) and M Abdur Rahim Medical College (MARMC) Hospital). We collected information on demographics, awareness of well-being services, COVID-19-related workload, as well as anxiety, depression and burnout using two validated questionnaires: the Hospital Anxiety and Depression Scale (HADS) and the Maslach Burnout Inventory (MBI). RESULTS: Of the 3000 participants approached, we received responses from 2705 (90.2%). There was a statistically significant difference in anxiety, depression and burnout scores across institutions (p<0.01). Anxiety, depression and burnout scores were statistically worse in COVID-19 active staff compared with those not working on COVID-19 activities (p<0.01 for HADS anxiety and depression and MBI emotional exhaustion (EE), depersonalisation (DP) and personal accomplishment (PA)). Over half of the participants exhibited some level of anxiety (SRNGIH: 52.2%; DMCH: 53.9%; MMCH: 61.3%; MARMC: 68%) with a high proportion experiencing depression (SRNGIH: 39.5%; DMCH: 38.7%; MMCH: 53.7%; MARMC: 41.1%). Although mean burnout scores were within the normal range for each institution, a high proportion of staff (almost 20% in some instances) were shown to be classified as experiencing burnout by their EE, DP and PA scores. CONCLUSION: We identified a high prevalence of perceived anxiety, depression and burnout among doctors and nurses during the COVID-19 pandemic. This was worse in staff engaged in COVID-19-related activities. These findings could help healthcare organisations to plan for future similar events.

A simulation study of extrapolation uncertainty in exposure assessment - Use of pilot study results for site investigation.

Accurate characterization of soil contaminant concentrations is often crucial for assessing risks to human and ecological health. However, fine-scale assessments of large tracts of land can be cost prohibitive due to the number of samples needed. One solution to this problem is to extrapolate sampling results from one area to another unsampled area. In the absence of a validated extrapolation methodology, regulatory agencies have employed policy-based techniques for large sites, but the likelihood of decision errors resulting from these extrapolations is largely unexplored. This study describes the results of a simulation study aimed at guiding environmental sampling for sites where extrapolation concepts are of interest. The objective of this study is to provide practical recommendations to regulatory agencies for extrapolating sampling results on large tracts of land while minimizing errors that are detrimental to human health. A variety of site investigation scenarios representative of environmental conditions and sampling schemes were tested using adaptive sampling when collecting discrete samples or applying incremental sampling methodology (ISM). These simulations address extrapolation uncertainty in cases where a Pilot Study might result in either false noncompliance or false compliance conclusions. A wide range of plausible scenarios were used that reflect the variety of heterogeneity seen at large sites. This simulation study demonstrates that ISM can be reliably applied in a Pilot Study for purposes of extrapolating the outcome to a large area site because it decreases the likelihood of false non-compliance errors while also providing reliable estimates of true compliance across unsampled areas. The results demonstrate how errors depend on the magnitude of the 95% upper confidence limit for the mean concentration (95UCL) relative to the applicable action level, and that error rates are highest when the 95UCL is within 10%-40% of the action level. The false compliance rate can be reduced to less than 5% when 30% or more of the site is characterized with ISM. False compliance error rates using ISM are insensitive to the fraction of the decision units (DUs) that are characterized with three replicates (with a minimum of 10 percent), so long as 95UCLs are calculated for the DUs with one replicate using the average coefficient of variation from the three replicate DUs.

Human iPSC modeling recapitulates in vivo sympathoadrenal development and reveals an aberrant developmental subpopulation in familial neuroblastoma.

Studies defining normal and disrupted human neural crest cell development have been challenging given its early timing and intricacy of development. Consequently, insight into the early disruptive events causing a neural crest related disease such as pediatric cancer neuroblastoma is limited. To overcome this problem, we developed an in vitro differentiation model to recapitulate the normal in vivo developmental process of the sympathoadrenal lineage which gives rise to neuroblastoma. We used human in vitro pluripotent stem cells and single-cell RNA sequencing to recapitulate the molecular events during sympathoadrenal development. We provide a detailed map of dynamically regulated transcriptomes during sympathoblast formation and illustrate the power of this model to study early events of the development of human neuroblastoma, identifying a distinct subpopulation of cell marked by SOX2 expression in developing sympathoblast obtained from patient derived iPSC cells harboring a germline activating mutation in the anaplastic lymphoma kinase (ALK) gene.

Suicide rates in the UK Armed Forces, compared with the general workforce and merchant shipping during peacetime years since 1900.

INTRODUCTION: The main objective was to compare suicide rates and their trends across the three UK Armed forces (Royal Navy, Army and Royal Air Force) from 1900 to 2020. Further objectives were to compare suicide rates with those in the corresponding general population and in UK merchant shipping and to discuss preventative measures. METHODS: Examination of annual mortality reports and returns, death inquiry files and official statistics. The main outcome measure was the suicide rate per 100 000 population employed. RESULTS: Since 1990, there have been significant reductions in suicide rates in each of the Armed Forces, although a non-significant increase in the Army since 2010. Compared with the corresponding general population, during the most recent decade from 2010 up to 2020, suicide rates were 73% lower in the Royal Air Force, 56% lower in the Royal Navy and 43% lower in the Army. Suicide rates have been significantly decreased in the Royal Air Force since the 1950s, in the Royal Navy since the 1970s and in the Army since the 1980s (comparisons for the Royal Navy and the Army were not available from the late 1940s to the 1960s).During the earliest decades from 1900 to the 1930s, suicide rates in the Armed Forces were mostly quite similar or moderately increased compared with the general population, but far lower than in merchant shipping. Following legislative changes in the last 30 years, suicide rates through poisoning by gases and through firearms or explosives have fallen sharply. CONCLUSIONS: The study shows that suicide rates in the Armed Forces have been lower than in the general population over many decades. The sharp reductions in suicide rates over the last 30 years suggest the effectiveness of recent preventative measures, including reductions in access to a method of suicide and well-being initiatives.

The Improved Kidney Risk Score in ANCA-Associated Vasculitis for Clinical Practice and Trials.

SIGNIFICANCE STATEMENT: Reliable prediction tools are needed to personalize treatment in ANCA-associated GN. More than 1500 patients were collated in an international longitudinal study to revise the ANCA kidney risk score. The score showed satisfactory performance, mimicking the original study (Harrell's C=0.779). In the development cohort of 959 patients, no additional parameters aiding the tool were detected, but replacing the GFR with creatinine identified an additional cutoff. The parameter interstitial fibrosis and tubular atrophy was modified to allow wider access, risk points were reweighted, and a fourth risk group was created, improving predictive ability (C=0.831). In the validation, the new model performed similarly well with excellent calibration and discrimination ( n =480, C=0.821). The revised score optimizes prognostication for clinical practice and trials. BACKGROUND: Reliable prediction tools are needed to personalize treatment in ANCA-associated GN. A retrospective international longitudinal cohort was collated to revise the ANCA renal risk score. METHODS: The primary end point was ESKD with patients censored at last follow-up. Cox proportional hazards were used to reweight risk factors. Kaplan-Meier curves, Harrell's C statistic, receiver operating characteristics, and calibration plots were used to assess model performance. RESULTS: Of 1591 patients, 1439 were included in the final analyses, 2:1 randomly allocated per center to development and validation cohorts (52% male, median age 64 years). In the development cohort ( n =959), the ANCA renal risk score was validated and calibrated, and parameters were reinvestigated modifying interstitial fibrosis and tubular atrophy allowing semiquantitative reporting. An additional cutoff for kidney function (K) was identified, and serum creatinine replaced GFR (K0: <250 µ mol/L=0, K1: 250-450 µ mol/L=4, K2: >450 µ mol/L=11 points). The risk points for the percentage of normal glomeruli (N) and interstitial fibrosis and tubular atrophy (T) were reweighted (N0: >25%=0, N1: 10%-25%=4, N2: <10%=7, T0: none/mild or <25%=0, T1: ≥ mild-moderate or ≥25%=3 points), and four risk groups created: low (0-4 points), moderate (5-11), high (12-18), and very high (21). Discrimination was C=0.831, and the 3-year kidney survival was 96%, 79%, 54%, and 19%, respectively. The revised score performed similarly well in the validation cohort with excellent calibration and discrimination ( n =480, C=0.821). CONCLUSIONS: The updated score optimizes clinicopathologic prognostication for clinical practice and trials.

Incidence and prevalence of eosinophilic oesophagitis across Europe: A systematic review and meta-analysis.

BACKGROUND: Several studies have reported large increases in the incidence of eosinophilic oesophagitis (EoE) in the last 20 years. We aimed to systematically review the incidence and prevalence of EoE, focused on all European countries. METHODS: Systematic review and meta-analysis up to 31 December 2022, based on PubMed, CINAHL and extensive hand searching of reference lists. Twenty-five eligible studies were identified and included. RESULTS: For both adults and children, the highest EoE incidence and prevalence have been reported from regional studies in Spain. EoE incidence for both adults and children was significantly lower (p < 0.001) in nationwide studies (meta-analysis = 3.64 per 100,000 person-years overall) compared with regional or centre-based studies (7.16). EoE incidence and prevalence were significantly higher (p < 0.001) in adults than children. All studies that reported on longitudinal trends in EoE incidence showed increases over time, more markedly during more recent years. Larger increases in incidence tend to refer to regional rather than nationwide studies; from Spain, Switzerland and Denmark, both for paediatric and adult age groups. Increases in EoE incidence 100,000 person-years were larger than for incidence per number of diagnostic endoscopies. The most frequently reported co-morbidities in adults were rhinitis, followed by asthma, food allergy and gastroesophageal reflux disease, and in children, erosive oesophagitis, asthma, food allergy and rhinitis. CONCLUSIONS: The incidence of EoE has increased in Europe over the last 30 years, exceeding increases in the volume of oesophago-gastro-duodenoscopies performed. The patchy and low incidence and prevalence of EoE generally in Europe and compared with North America, may reflect a lack of clinical awareness and research focus rather than a genuinely low incidence of EoE. A co-ordinated Europe-wide study that uses standardised methodology is urgently needed to provide a comprehensive picture of EoE incidence and prevalence across Europe.

Symptomatic benefits of testosterone treatment in patient subgroups: a systematic review, individual participant data meta-analysis, and aggregate data meta-analysis.

BACKGROUND: Testosterone replacement therapy is known to improve sexual function in men younger than 40 years with pathological hypogonadism. However, the extent to which testosterone alleviates sexual dysfunction in older men and men with obesity is unclear, despite the fact that testosterone is being increasingly prescribed to these patient populations. We aimed to evaluate whether subgroups of men with low testosterone derive any symptomatic benefit from testosterone treatment. METHODS: We did a systematic review and meta-analysis to evaluate characteristics associated with symptomatic benefit of testosterone treatment versus placebo in men aged 18 years and older with a baseline serum total testosterone concentration of less than 12 nmol/L. We searched major electronic databases (MEDLINE, Embase, Science Citation Index, and the Cochrane Central Register of Controlled Trials) and clinical trial registries for reports published in English between Jan 1, 1992, and Aug 27, 2018. Anonymised individual participant data were requested from the investigators of all identified trials. Primary (cardiovascular) outcomes from this analysis have been published previously. In this report, we present the secondary outcomes of sexual function, quality of life, and psychological outcomes at 12 months. We did a one-stage individual participant data meta-analysis with a random-effects linear regression model, and a two-stage meta-analysis integrating individual participant data with aggregated data from studies that did not provide individual participant data. This study is registered with PROSPERO, CRD42018111005. FINDINGS: 9871 citations were identified through database searches. After exclusion of duplicates and publications not meeting inclusion criteria, 225 full texts were assessed for inclusion, of which 109 publications reporting 35 primary studies (with a total 5601 participants) were included. Of these, 17 trials provided individual participant data (3431 participants; median age 67 years [IQR 60-72]; 3281 [97%] of 3380 aged ≥40 years) Compared with placebo, testosterone treatment increased 15-item International Index of Erectile Function (IIEF-15) total score (mean difference 5·52 [95% CI 3·95-7·10]; τ2=1·17; n=1412) and IIEF-15 erectile function subscore (2·14 [1·40-2·89]; τ2=0·64; n=1436), reaching the minimal clinically important difference for mild erectile dysfunction. These effects were not found to be dependent on participant age, obesity, presence of diabetes, or baseline serum total testosterone. However, absolute IIEF-15 scores reached during testosterone treatment were subject to thresholds in patient age and baseline serum total testosterone. Testosterone significantly improved Aging Males' Symptoms score, and some 12-item or 36-item Short Form Survey quality of life subscores compared with placebo, but it did not significantly improve psychological symptoms (measured by Beck Depression Inventory). INTERPRETATION: In men aged 40 years or older with baseline serum testosterone of less than 12 nmol/L, short-to-medium-term testosterone treatment could provide clinically meaningful treatment for mild erectile dysfunction, irrespective of patient age, obesity, or degree of low testosterone. However, due to more severe baseline symptoms, the absolute level of sexual function reached during testosterone treatment might be lower in older men and men with obesity. FUNDING: National Institute for Health and Care Research Health Technology Assessment Programme.

Global health security and the health-security nexus: principles, politics and praxis.

The past four decades have seen a steady rise of references to 'security' by health academics, policy-makers and practitioners, particularly in relation to threats posed by infectious disease pandemics. Yet, despite an increasingly dominant health security discourse, the many different ways in which health and security issues and actors intersect have remained largely unassessed and unpacked in current critical global health scholarship. This paper discusses the emerging and growing health-security nexus in the wake of COVID-19 and the international focus on global health security. In recognising the contested and fluid concept of health security, this paper presents two contrasting approaches to health security: neocolonial health security and universal health security. Building from this analysis, we present a novel heuristic that delineates the multiple intersections and entanglements between health and security actors and agendas to broaden our conceptualisation of global health security configurations and practices and to highlight the potential for harmful unintended consequences, the erosion of global health norms and values, and the risk of health actors being co-opted by the security sector.

Stage 4N neuroblastoma before and during the era of anti-GD2 immunotherapy.

Patients with stage 4N neuroblastoma (distant metastases limited to lymph nodes) stand out as virtually the only survivors of high-risk neuroblastoma (HR-NB) before myeloablative therapy (MAT) and immunotherapy with anti-GD2 monoclonal antibodies (mAbs) became standard. Because no report presents more recent results with 4N, we analyzed our large 4N experience. All 51 pediatric 4N patients (<18 years old) diagnosed 1985 to 2021 were reviewed. HR-NB included MYCN-nonamplified 4N diagnosed at age ≥18 months and MYCN-amplified 4N. Among 34 MYCN-nonamplified high-risk patients, 20 are relapse-free 1.5+ to 37.5+ (median 12.5+) years post-diagnosis, including 13 without prior MAT and 5 treated with little (1 cycle; n = 2) or no mAb (n = 3), while 14 patients (7 post-MAT, 8 post-mAbs) relapsed (all soft tissue). Of 15 MYCN-amplified 4N patients, 7 are relapse-free 2.1+ to 26.4+ (median 11.6+) years from the start of chemotherapy (all received mAbs; 3 underwent MAT) and 4 are in second remission 4.2+ to 21.8+ years postrelapse (all soft tissue). Statistical analyses showed no significant association of survival with either MAT or mAbs for MYCN-nonamplified HR-NB; small numbers prevented these analyses for MYCN-amplified patients. The two patients with intermediate-risk 4N (14-months-old) are relapse-free 7+ years postresection of primary tumors; distant disease spontaneously regressed. The natural history of 4N is marked by NB confined to soft tissue without early relapse in bones or bone marrow, where mAbs have proven efficacy. These findings plus curability without MAT, as seen elsewhere and at our center, support consideration of treatment reduction for MYCN-nonamplified 4N.

Governing digital health for infectious disease outbreaks.

ABSTRACTHow can governing digital health for infectious disease outbreaks be enhanced? In many ways, the COVID-19 pandemic has simultaneously represented both the potential and marked limitations of digital health practices for infectious disease outbreaks. During the pandemic's initial stages, states along with Big Data and Big Tech actors unleashed a scope of both established and experimental digital technologies for tracking infections, hospitalisations, and deaths from COVID-19 - and sometimes exposure to the virus SARS-CoV-2. Despite the proliferation of these technologies at the global level, transnational and cross-border integration, and cooperation within digital health responses to COVID-19 often faltered, while digital health regulations were fragmented, contested, and uncoordinated. This article presents a critiquing reflection of approaches to conceptualising, understanding, and implementing digital health for infectious disease outbreaks, observed from COVID-19 and previous examples. In assessing the strengths and limitations of existing practices of governing digital health for infectious disease outbreaks, this article particularly examines 'informal' digital health to build upon and consider how digitised responses to addressing and governing infectious disease outbreaks may be reconceptualised, revisited, or revised.

Anaplastic Lymphoma Kinase Inhibitors for Therapy of Neuroblastoma in Adults.

PURPOSE: Adult-onset neuroblastoma (AON) differs significantly in biology and clinical behavior from childhood-onset disease. AON poses therapeutic challenges since tolerance of intensive multimodality therapies that are standard of care for pediatric neuroblastoma (NB) is poor. AON is enriched for somatic mutations including anaplastic lymphoma kinase (ALK), deemed to be an oncogenic driver in NB. ALK inhibitors (ALKis), therefore, have the potential to be of therapeutic benefit. The purpose of this study is to report on their use in AON. METHODS: A single-center retrospective review of adults with NB receiving ALKi (2012-2022) was performed. Response was evaluated using International Neuroblastoma Response Criteria. RESULTS: Fifteen patients with ALK-mutated AON were treated with US Food and Drug Administration-approved ALKi starting at a median age of 34 (16-71) years. Initial ALKi was lorlatinib, crizotinib, and alectinib in seven, five, and three patients respectively; seven received multiple ALKis due to progressive disease/intolerability of one agent. All patients experienced ≥grade 2 adverse events (AEs): crizotinib and alectinib were associated primarily with gastrointestinal AEs, lorlatinib with neurologic AEs, weight gain, and hyperlipidemia resulting in dose reduction or discontinuation of ALKi in several patients. No responses were observed with crizotinib (n = 5 patients), ceritinib, alectinib, or brigatinib (n = 1 each). Of the 13 patients receiving lorlatinib, four, five, and four patients had a complete or partial response (major response rate 69%), and stable disease, respectively. Responses were noted in all disease compartments; complete metabolic response was seen in two L2 patients. Ten of 13 patients remain progression-free at a median of 19 (6-50) months on lorlatinib. Three (two receiving dose-reduced therapy) had progressive disease. Median survival from start of first ALKi was 43 ± 26 months. CONCLUSION: ALKis, particularly lorlatinib, are effective treatment options for AON. However, AEs necessitating dose reduction are common.

On Sequential Bayesian Inference for Continual Learning.

Sequential Bayesian inference can be used for continual learning to prevent catastrophic forgetting of past tasks and provide an informative prior when learning new tasks. We revisit sequential Bayesian inference and assess whether using the previous task's posterior as a prior for a new task can prevent catastrophic forgetting in Bayesian neural networks. Our first contribution is to perform sequential Bayesian inference using Hamiltonian Monte Carlo. We propagate the posterior as a prior for new tasks by approximating the posterior via fitting a density estimator on Hamiltonian Monte Carlo samples. We find that this approach fails to prevent catastrophic forgetting, demonstrating the difficulty in performing sequential Bayesian inference in neural networks. From there, we study simple analytical examples of sequential Bayesian inference and CL and highlight the issue of model misspecification, which can lead to sub-optimal continual learning performance despite exact inference. Furthermore, we discuss how task data imbalances can cause forgetting. From these limitations, we argue that we need probabilistic models of the continual learning generative process rather than relying on sequential Bayesian inference over Bayesian neural network weights. Our final contribution is to propose a simple baseline called Prototypical Bayesian Continual Learning, which is competitive with the best performing Bayesian continual learning methods on class incremental continual learning computer vision benchmarks.

Clonal evolution during metastatic spread in high-risk neuroblastoma.

Patients with high-risk neuroblastoma generally present with widely metastatic disease and often relapse despite intensive therapy. As most studies to date focused on diagnosis-relapse pairs, our understanding of the genetic and clonal dynamics of metastatic spread and disease progression remain limited. Here, using genomic profiling of 470 sequential and spatially separated samples from 283 patients, we characterize subtype-specific genetic evolutionary trajectories from diagnosis through progression and end-stage metastatic disease. Clonal tracing timed disease initiation to embryogenesis. Continuous acquisition of structural variants at disease-defining loci (MYCN, TERT, MDM2-CDK4) followed by convergent evolution of mutations targeting shared pathways emerged as the predominant feature of progression. At diagnosis metastatic clones were already established at distant sites where they could stay dormant, only to cause relapses years later and spread via metastasis-to-metastasis and polyclonal seeding after therapy.

What incentives encourage local communities to collect and upload mosquito sound data by using smartphones? A mixed methods study in Tanzania.

BACKGROUND: To detect and identify mosquitoes using their characteristic high-pitched sound, we have developed a smartphone application, known as the 'HumBug sensor', that records the acoustic signature of this sound, along with the time and location. This data is then sent remotely to a server where algorithms identify the species according to their distinctive acoustic signature. Whilst this system works well, a key question that remains is what mechanisms will lead to effective uptake and use of this mosquito survey tool? We addressed this question by working with local communities in rural Tanzania and providing three alternative incentives: money only, short message service (SMS) reminders and money, and SMS reminders only. We also had a control group with no incentive. METHODS: A multi-site, quantitative empirical study was conducted in four villages in Tanzania from April to August 2021. Consenting participants (n = 148) were recruited and placed into one of the three intervention arms: monetary incentives only; SMS reminders with monetary incentives; and SMS reminders only. There was also a control group (no intervention). To test effectiveness of the mechanisms, the number of audio uploads to the server of the four trial groups on their specific dates were compared. Qualitative focus group discussions and feedback surveys were also conducted to explore participants' perspectives on their participation in the study and to capture their experiences of using the HumBug sensor. RESULTS: Qualitative data analysis revealed that for many participants (37 out of 81), the main motivation expressed was to learn more about the types of mosquitoes present in their houses. Results from the quantitative empirical study indicate that the participants in the 'control' group switched on their HumBug sensors more over the 14-week period (8 out of 14 weeks) when compared to those belonging to the 'SMS reminders and monetary incentives' trial group. These findings are statistically significant (p < 0.05 or p > 0.95 under a two-sided z-test), revealing that the provision of monetary incentives and sending SMS reminders did not appear to encourage greater number of audio uploads when compared to the control. CONCLUSIONS: Knowledge on the presence of harmful mosquitoes was the strongest motive for local communities to collect and upload mosquito sound data via the HumBug sensor in rural Tanzania. This finding suggests that most efforts should be made to improve flow of real-time information back to the communities on types and risks associated with mosquitoes present in their houses.

Aided Cortical Auditory Evoked Potentials in Infants With Frequency-Specific Synthetic Speech Stimuli: Sensitivity, Repeatability, and Feasibility.

OBJECTIVES: The cortical auditory evoked potential (CAEP) test is a candidate for supplementing clinical practice for infant hearing aid users and others who are not developmentally ready for behavioral testing. Sensitivity of the test for given sensation levels (SLs) has been reported to some degree, but further data are needed from large numbers of infants within the target age range, including repeat data where CAEPs were not detected initially. This study aims to assess sensitivity, repeatability, acceptability, and feasibility of CAEPs as a clinical measure of aided audibility in infants. DESIGN: One hundred and three infant hearing aid users were recruited from 53 pediatric audiology centers across the UK. Infants underwent aided CAEP testing at age 3 to 7 months to a mid-frequency (MF) and (mid-)high-frequency (HF) synthetic speech stimulus. CAEP testing was repeated within 7 days. When developmentally ready (aged 7-21 months), the infants underwent aided behavioral hearing testing using the same stimuli, to estimate the decibel (dB) SL (i.e., level above threshold) of those stimuli when presented at the CAEP test sessions. Percentage of CAEP detections for different dB SLs are reported using an objective detection method (Hotellings T 2 ). Acceptability was assessed using caregiver interviews and a questionnaire, and feasibility by recording test duration and completion rate. RESULTS: The overall sensitivity for a single CAEP test when the stimuli were ≥0 dB SL (i.e., audible) was 70% for the MF stimulus and 54% for the HF stimulus. After repeat testing, this increased to 84% and 72%, respectively. For SL >10 dB, the respective MF and HF test sensitivities were 80% and 60% for a single test, increasing to 94% and 79% for the two tests combined. Clinical feasibility was demonstrated by an excellent >99% completion rate, and acceptable median test duration of 24 minutes, including preparation time. Caregivers reported overall positive experiences of the test. CONCLUSIONS: By addressing the clinical need to provide data in the target age group at different SLs, we have demonstrated that aided CAEP testing can supplement existing clinical practice when infants with hearing loss are not developmentally ready for traditional behavioral assessment. Repeat testing is valuable to increase test sensitivity. For clinical application, it is important to be aware of CAEP response variability in this age group.

Membranous nephropathy in the UK Biobank.

BACKGROUND: Despite MN being one of the most common causes of nephrotic syndrome worldwide, its biological and environmental determinants are poorly understood in large-part due to it being a rare disease. Making use of the UK Biobank, a unique resource holding a clinical dataset and stored DNA, serum and urine for ~500,000 participants, this study aims to address this gap in understanding. METHODS: The primary outcome was putative MN as defined by ICD-10 codes occurring in the UK Biobank. Univariate relative risk regression modelling was used to assess the associations between the incidence of MN and related phenotypes with sociodemographic, environmental exposures, and previously described increased-risk SNPs. RESULTS: 502,507 patients were included in the study of whom 100 were found to have a putative diagnosis of MN; 36 at baseline and 64 during the follow-up. Prevalence at baseline and last follow-up were 72 and 199 cases/million respectively. At baseline, as expected, the majority of those previously diagnosed with MN had proteinuria, and there was already evidence of proteinuria in patients diagnosed within the first 5 years of follow-up. The highest incidence rate for MN in patients was seen in those homozygous for the high-risk alleles (9.9/100,000 person-years). CONCLUSION: It is feasible to putatively identify patients with MN in the UK Biobank and cases are still accumulating. This study shows the chronicity of disease with proteinuria present years before diagnosis. Genetics plays an important role in disease pathogenesis, with the at-risk group providing a potential population for recall.

SOX11 regulates SWI/SNF complex components as member of the adrenergic neuroblastoma core regulatory circuitry.

The pediatric extra-cranial tumor neuroblastoma displays a low mutational burden while recurrent copy number alterations are present in most high-risk cases. Here, we identify SOX11 as a dependency transcription factor in adrenergic neuroblastoma based on recurrent chromosome 2p focal gains and amplifications, specific expression in the normal sympatho-adrenal lineage and adrenergic neuroblastoma, regulation by multiple adrenergic specific (super-)enhancers and strong dependency on high SOX11 expression in adrenergic neuroblastomas. SOX11 regulated direct targets include genes implicated in epigenetic control, cytoskeleton and neurodevelopment. Most notably, SOX11 controls chromatin regulatory complexes, including 10 SWI/SNF core components among which SMARCC1, SMARCA4/BRG1 and ARID1A. Additionally, the histone deacetylase HDAC2, PRC1 complex component CBX2, chromatin-modifying enzyme KDM1A/LSD1 and pioneer factor c-MYB are regulated by SOX11. Finally, SOX11 is identified as a core transcription factor of the core regulatory circuitry (CRC) in adrenergic high-risk neuroblastoma with a potential role as epigenetic master regulator upstream of the CRC.

High-precision Pb isotopes of drinking water lead pipes: Implications for human exposure to industrial Pb in the United States.

Millions of lead (Pb) pipes are still used in the drinking water distribution systems in many regions in the world. Human exposure to Pb from contaminated drinking water continues to be of concern in the United States (U.S.), as illustrated by the widely publicized "Flint Water Crisis" in 2015. The Pb isotopic composition of Pb-pipes potentially can be useful to identify human exposure to Pb from lead service lines (LSLs). In addition, as the LSLs were likely manufactured from similar industrial Pb sources as other Pb objects and materials in the USA, the Pb-pipes isotope data can provide information about the overall isotopic composition of the U.S. industrial Pb. In this work we present high-precision Pb isotope data from Pb-pipes excavated from different U.S. municipalities. The Pb-pipes show an extremely wide range of Pb isotopic compositions, with 206Pb/204Pb ranging from 17.004 to 22.010, 207Pb/204Pb from 15.460 to 15.921, and 208Pb/204Pb from 36.687 to 41.120. The wide isotope range is observed even in a single town, suggesting that no regional Pb isotope patterns can be expected within the continental USA. However, the high-precision MC-ICP-MS Pb data form a clear linear trend that, depending on the context, can be used to identify human Pb exposure. Furthermore, as the linear trend is a result of utilization of Pb ores from different domestic and international sources and secondary recycling of metallic Pb, it is likely representative of the overall isotopic composition of the U.S. industrial Pb pool. Therefore, the identified trend is the most accurate isotope representation of the U.S. anthropogenic Pb at present and can be used as first-order evaluation to determine if a person with elevated blood Pb levels was exposed to U.S. industrial Pb sources.

Growth of twins conceived using assisted reproductive treatments up to 5 years old: a national growth cohort.

STUDY QUESTION: Do twins conceived through assisted reproductive treatments (ART) grow differently from naturally conceived (NC) twins in early life? SUMMARY ANSWER: Assessments at 6-8 weeks old and at school entry show that ART twins conceived from frozen embryo transfer (FET) grow faster than both NC twins and ART twins conceived from fresh embryo transfer (ET). WHAT IS KNOWN ALREADY: Singletons born from fresh ET grow more slowly in utero and in the first few weeks of life but then show postnatal catch-up growth by school age, compared to NC and FET babies. Evidence on early child growth of ART twins relative to NC twins is inconsistent; most studies are small and do not distinguish FET from fresh ET cycles. STUDY DESIGN, SIZE, DURATION: This cohort study included 13 528 live-born twin babies conceived by ART (fresh ET: 2792, FET: 556) and NC (10 180) between 1991 and 2009 in Scotland. The data were obtained by linking Human Fertilisation and Embryology Authority ART register data to the Scottish Morbidity Record (SMR02) and Scottish child health programme datasets. Outcome data were collected at birth, 6-8 weeks (first assessment), and school entry (4-7 years old) assessments. The primary outcome was growth, measured by weight at the three assessment points. Secondary outcomes were length (at birth and 6-8 weeks) or height (at school entry), BMI, occipital circumference, gestational age at birth, newborn intensive care unit admission, and growth rates (between birth and 6-8 weeks and between 6-8 weeks and school entry). PARTICIPANTS/MATERIALS, SETTING, METHODS: All twins in the linked dataset (born between 1991 and 2009) with growth data were included in the analysis. To determine outcome differences between fresh ET, FET, and NC twins, linear mixed models (or analogous logistic regression models) were used to explore the outcomes of interest. All models were adjusted for available confounders: gestational age/child age, gender, maternal age and smoking, Scottish Index of Multiple Deprivation, year of treatment, parity, ICSI, and ET stage. MAIN RESULTS AND THE ROLE OF CHANCE: In the primary birth weight models, the average birth weight of fresh ET twins was lower [-35 g; 95% CI: (-53, -16)g] than NC controls, while FET twins were heavier [71 g; 95% CI (33, 110) g] than NC controls and heavier [106 g; 95% CI (65, 146) g] than fresh ET twins. However, the difference between FET and NC twins was not significant when considering only full-term twins (≥37 weeks gestation) [26 g; 95% CI (-30, 82) g], while it was significantly higher in preterm twins [126 g; 95% CI (73, 179) g]. Growth rates did not differ significantly for the three groups from birth to 6-8 weeks. However, FET twins grew significantly faster from 6 to 8 weeks than NC (by 2.2 g/week) and fresh ET twins (by 2.1 g/week). By school entry, FET twins were 614 g [95% CI (158, 1070) g] and 581 g [95% CI (100, 1063) g] heavier than NC and fresh ET twins, respectively. Length/height and occipital frontal circumference did not differ significantly at any time point. LIMITATIONS, REASONS FOR CAUTION: Although the differences between ART and NC reflect the true ART effects, these effects are likely to be mediated partly through the different prevalence of mono/dizygotic twins in the two groups. We could not explore the mediating effect of zygosity due to the unavailability of data. The confounding variables included in the study were limited to those available in the datasets. WIDER IMPLICATIONS OF THE FINDINGS: Live-born twins from FET cycles are heavier at birth, grow faster than their fresh ET and NC counterparts, and are still heavier at school entry. This differs from that observed in singletons from the same cohort, where babies in the three conception groups had similar weights by school entry age. The results are reassuring on known differences in FET versus fresh ET and NC twin outcomes. However, FET twins grow faster and are consistently larger, and more ART twins depict catch-up growth. These may lead to an increased risk profile for non-communicable diseases in later life. As such, these twin outcomes require careful evaluation using more recent and comprehensive cohorts. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the EU H2020 Marie Sklodowska-Curie Innovative Training Networks (ITN) grant Dohartnet (H2020-MSCA-ITN-2018-812660). The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

The use of serum protein analysis in the diagnosis of fatal envenomation via Crotalus horridus (timber rattlesnake).

Deaths occurring due to rattlesnake envenomization are extremely rare and must be thoroughly investigated in the same manner as any other type of death. Our research presents the case of an adult white male who suffered a fatal timber rattlesnake (Crotalus horridus) envenomation in northwest Florida in 2018. Blood samples were taken from the decedent's heart and vasculature of the chest and sent for serum proteomic analysis. Serum proteomic analysis was utilized in order to identify proteins from timber rattlesnake (C. horridus) found within the victim's blood. The confirmation of the presence of timber rattlesnake venom within the victim's blood allows the forensic pathologist to determine the cause of death most accurately and likewise, assists with the manner of death determination. Blood samples were separated into two groups: one with the abundant endogenous proteins depleted to facilitate detection of lower abundant proteins and one undepleted. In the depleted sample, a total of 712 proteins were identified, with 47 of the proteins (6.6%) occurring originating from timber rattlesnake (C. horridus). Likewise, a total of 742 proteins were identified in the undepleted sample, with 52 of the proteins (7.0%) occurring in timber rattlesnake (C. horridus). No timber rattlesnake (C. horridus) proteins were found in control human serum.