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Hypervolemia and vitamin D deficiency occur frequently in patients receiving peritoneal dialysis and may contribute to left ventricular (LV) hypertrophy. The effect of bioelectrical impedance analysis (BIA)-guided volume management or vitamin D supplementation on LV mass among those receiving peritoneal dialysis is uncertain.Two-by-two factorial randomized controlled trial.Sixty-five patients receiving maintenance peritoneal dialysis.BIA-guided volume management versus usual care and oral cholecalciferol 50,000 U weekly for 8 weeks followed by 10,000 U weekly for 44 weeks or matching placebo.Change in LV mass at 1 year measured by cardiac magnetic resonance imaging.Total body water decreased by 0.9 + 2.4 (SD) L in the BIA group compared with a 1.5 ± 3.4 L increase in the usual care group (adjusted between-group difference: -2.4 [95% CI, -4.1 to -0.68] L, P = 0.01). LV mass increased by 1.3 ± 14.3 g in the BIA group and decreased by 2.4 ± 37.7 g in the usual care group (between-group difference: +2.2 [95% CI, -13.9 to 18.3] g, P = 0.8). Serum 25-hydroxyvitamin D concentration increased by a mean of 17.2 ± 30.8 nmol/L in the cholecalciferol group and declined by 8.2 ± 24.3 nmol/L in the placebo group (between-group difference: 28.3 [95% CI, 17.2-39.4] nmol/L, P 0.001). LV mass decreased by 3.0 ± 28.1 g in the cholecalciferol group and increased by 2.0 ± 31.2 g in the placebo group (between-group difference: -4.5 [95% CI, -20.4 to 11.5] g, P = 0.6).Relatively small sample size with larger than expected variation in change in LV mass.BIA-guided volume management had a modest impact on volume status with no effect on the change in LV mass. Vitamin D supplementation increased serum vitamin D concentration but had no effect on LV mass.Unrestricted Baxter International extramural grant and the Kidney Foundation of Canada.Registered at ClinicalTrials.gov with study number NCT01045980.

OBJECTIVESThe goal of this study was to characterize the complications and morbidity related to the surgical management of pediatric fourth ventricle tumors.METHODSAll patients referred to the authors’ institution with posterior fossa tumors from 2002 to 2018 inclusive were screened to include only true fourth ventricle tumors. Preoperative imaging and clinical notes were reviewed to extract data on presenting symptoms; surgical episodes, techniques, and adjuncts; tumor histology; and postoperative complications.RESULTSThree hundred fifty-four children with posterior fossa tumors were treated during the study period; of these, 185 tumors were in the fourth ventricle, and 167 fourth ventricle tumors with full data sets were included in this analysis. One hundred patients were male (mean age ± SD, 5.98 ± 4.12 years). The most common presenting symptom was vomiting (63.5%). The most common tumor types, in order, were medulloblastoma (94 cases) > pilocytic astrocytoma (30 cases) > ependymoma (30 cases) > choroid plexus neoplasms (5 cases) > atypical teratoid/rhabdoid tumor (4 cases), with 4 miscellaneous lesions. Of the 67.1% of patients who presented with hydrocephalus, 45.5% had an external ventricular drain inserted (66.7% of these prior to tumor surgery, 56.9% frontal); these patients were more likely to undergo ventriculoperitoneal shunt (VPS) placement at a later date (p = 0.00673). Twenty-two had an endoscopic third ventriculostomy, of whom 8 later underwent VPS placement. Overall, 19.7% of patients had a VPS sited during treatment.Across the whole series, the transvermian approach was more frequent than the telovelar approach (64.1% vs 33.0%); however, the telovelar approach was significantly more common in the latter half of the series (p < 0.001). Gross-total resection was achieved in 70.7%. The most common postoperative deficit was cerebellar mutism syndrome (CMS; 28.7%), followed by new weakness (24.0%), cranial neuropathy (18.0%), and new gait abnormality/ataxia (12.6%). Use of intraoperative ultrasonography significantly reduced the incidence of CMS (p = 0.0365). There was no significant difference in the rate of CMS between telovelar or transvermian approaches (p = 0.745), and multivariate logistic regression modeling did not reveal any statistically significant relationships between CMS and surgical approach.CONCLUSIONSSurgical management of pediatric fourth ventricle tumors continues to evolve, and resection is increasingly performed through the telovelar route. CMS is enduringly the major postoperative complication in this patient population.

Animals must quickly adapt food-seeking strategies to locate nutrient sources in dy-namically changing environments. Learned associations between food and environ-mental cues that predict its availability promote food-seeking behaviors. However,when such cues cease to predict food availability, animals undergo “extinction” learn-ing, resulting in the inhibition of food-seeking responses. Repeatedly activated setsof neurons, or “neuronal ensembles,” in the dorsal medial prefrontal cortex (dmPFC)are recruited following appetitive conditioning and undergo physiological adapta-tions thought to encode cue-reward associations. However, little is known about howthe recruitment and intrinsic excitability of such dmPFC ensembles are modulated byextinction learning. Here, we used in vivo 2-Photon imaging in male Fos-GFP micethat express green fluorescent protein (GFP) in recently behaviorally activated neu-rons to determine the recruitment of activated pyramidal and GABAergic interneu-ron dmPFC ensembles during extinction. During extinction, we revealed a persistentactivation of a subset of interneurons which emerged from a wider population of in-terneurons activated during the initial extinction session. This activation pattern wasnot observed in pyramidal cells, and extinction learning did not modulate the excit-ability properties of activated pyramidal cells. Moreover, extinction learning reducedthe likelihood of reactivation of pyramidal cells activated during the initial extinction ession. Our findings illuminate novel neuronal activation patterns in the dmPFCunderlying extinction of food-seeking, and in particular, highlight an important rolefor interneuron ensembles in this inhibitory form of learning.

Myoelectric prosthetic arms have primarily focused on adults, despite evidence showing the benefits of early adoption. This work presents SIMPA, a low-cost 3D-printed prosthetic arm with soft grippers. The arm has been designed using CAD and 3D-scanning, and manufactured using predominantly 3D-printing techniques. A voluntary opening control system utilizing an armband-based sEMG has been developed concurrently. Grasp tests have resulted in an average effectiveness of 87%, with objects in excess of 400g being securely grasped. The results highlight the effectiveness of soft grippers as an end device in prosthetics, as well as the viability of toddler scale myoelectric devices.

Patients on peritoneal dialysis are at risk of developing peritoneal fibrosis and angiogenesis, which can lead to dysfunction of the peritoneal membrane. Recent evidence has identified cross‐talk between transforming growth factor beta (TGFB) and the WNT/β‐catenin pathway to induce fibrosis and angiogenesis. Limited evidence exists describing the role of non‐canonical WNT signalling in peritoneal membrane injury. Non‐canonical WNT5A is suggested to have different effects depending on the receptor environment. WNT5A has been implicated in antagonizing canonical WNT/β‐catenin signalling in the presence of receptor tyrosine kinase‐like orphan receptor (Ror2). We co‐expressed TGFB and WNT5A using adenovirus and examined its role in the development of peritoneal fibrosis and angiogenesis. Treatment of mouse peritoneum with AdWNT5A decreased the submesothelial thickening and angiogenesis induced by AdTGFB. WNT5A appeared to block WNT/β‐catenin signalling by inhibiting phosphorylation of glycogen synthase kinase 3 beta (GSK3B) and reducing levels of total β‐catenin and target proteins. To examine the function of Ror2, we silenced Ror2 in a human mesothelial cell line. We treated cells with AdWNT5A and observed a significant increase in fibronectin compared with AdWNT5A alone. We also analysed fibronectin and vascular endothelial growth factor (VEGF) in a TGFB model of mesothelial cell injury. Both fibronectin and VEGF were significantly increased in response to Ror2 silencing when cells were exposed to TGFB. Our results suggest that WNT5A inhibits peritoneal injury and this is associated with a decrease in WNT/β‐catenin signalling. In human mesothelial cells, Ror2 is involved in regulating levels of fibronectin and VEGF.

Background: Stenosis of cerebral aqueduct (CA) is featured in many studies related to elevated intracranial cerebral pressures (ICP). It also presents a challenging situation to clinicians. Compressive forces play a lead role in pathological situations like tumor presence and hence can cause obstruction to the flow of cerebrospinal fluid (CSF). Due to this barrier, excessive retention of CSF in ventricles can occur. This in turn could contribute to increased pressure gradients inside the cranium. In literature, most of the numerical models are restricted to modeling the CSF flow by considering ventricle walls as rigid material unlike its behavior a deformable character. This paper, therefore, addresses the same from a holistic perspective by taking into consideration the dynamics of the flexible character of the ventricular wall. This adds to the novelty of this work by reconstructing an anatomically realistic ventricular wall behavior. To do this, the authors aim to develop a computational model of stenosis of CA due to brain tumor by invoking a fluid-structure interaction (FSI) method. The proposed 3D FSI model is simulated under two cases. First, simulation of pre-stenosis case with no interaction of tumor forces and secondly, a stenosis condition together-with dynamic interaction of tumor forces. Results: Comparing the forces with and without tumor reveals a marked obstruction of CSF outflow post third ventricle and the cerebral aqueduct. Not only this but a drastic rise of CSF velocity from 21.2 mm/s in pre-stenosis case to 54.1 mm/s stenosis case is also observed along with a net deformation increase of 0.144 mm on walls of ventricle. Conclusions: This is a significant contribution to brain simulation studies for pressure calculations, wherein the presence of tumors is a major concern.

Glomerulonephritis (GN) is a common cause of end-stage kidney disease and is characterized by glomerular inflammation, hematuria, proteinuria, and progressive renal dysfunction. Transforming growth factor (TGF)-β is involved in glomerulosclerosis and interstitial fibrosis. TGF-β activates multiple signaling pathways, including the canonical SMAD pathway. We evaluated the role of SMAD signaling in renal injury and proteinuria in a murine model of GN. SMAD3+/+ or SMAD3−/− mice received anti-glomerular basement membrane antibodies to induce GN. We confirmed previous reports that demonstrated that SMAD3 is an important mediator of glomerulosclerosis and renal interstitial fibrosis. Proteinuria was highly SMAD3 dependent. We found differential effects of SMAD3 deletion on podocytes and glomerular endothelial cells. GN led to podocyte injury, including foot process effacement and loss of podocyte-specific markers. Interestingly, these changes were not SMAD3 dependent. Furthermore, there were significant changes to glomerular endothelial cells, including loss of fenestrations, swelling, and basement membrane reduplication, which were SMAD3 dependent. Despite ongoing markers of podocyte injury in SMAD3−/− mice, proteinuria was transient. Renal injury in the setting of GN involves TGF-β and SMAD3 signaling. Cell populations within the glomerulus respond differently to SMAD3 deletion. Proteinuria correlated more with endothelial cell changes as opposed to podocyte injury in this model.

Introduction Discordance in kidney disease severity between affected relatives is a recognized feature of autosomal dominant polycystic kidney disease (ADPKD). Here, we report a systematic study of a large cohort of families to define the prevalence and clinical features of intrafamilial discordance in ADPKD. Methods The extended Toronto Genetic Epidemiology Study of Polycystic Kidney Disease (eTGESP) cohort includes 1390 patients from 612 unrelated families with ADPKD ascertained in a regional polycystic kidney disease center. All probands underwent comprehensive PKD1 and PKD2 mutation screening. Total kidney volume by magnetic resonance imaging (MRI) was available in 500 study patients. Results Based on (i) rate of estimated glomerular filtration rate (eGFR) decline, (ii) age at onset of end-stage renal disease (ESRD), and (iii) Mayo Clinic Imaging Classification (MCIC), 20% of patients were classified as having mild disease, and 33% as having severe disease. Intrafamilial ADPKD discordance with at least 1 mild and 1 severe case was observed in 43 of 371 (12%) families, at a similar frequency regardless of the responsible gene (PKD1/PKD2/no mutation detected) or mutation type (protein-truncating versus nontruncating). Intrafamilial discordance was more common in larger families and was present in 30% of families with more than 5 affected members. The heritability of age at onset of ESRD was similar between different mutation types. Conclusion Extreme kidney disease discordance is present in at least 12% of families with ADPKD, regardless of the underlying mutated gene or mutation class. Delineating genetic and environmental modifiers underlying the observed intrafamilial ADPKD variability will provide novel insights into the mechanisms of progression in ADPKD., Graphical abstract

Medical professionals and students often feel as if they do not have enough understanding of the human papillomavirus (HPV) vaccine in order to recommend or obtain vaccination themselves. A 25-question online survey regarding knowledge and attitudes about the HPV vaccine was distributed among professional students, including all classes of medical students, at a Nevada university. First- and second-year medical students were administered the same survey 1 week after a new vaccine workshop. One third of respondents were aware of the link between HPV and oropharyngeal cancer, and 63% believed that the HPV vaccine should be mandatory. Reported full vaccination status (OR = 2.63 compared with no vaccination, 95% CI = 1.53, 4.53), awareness of the link to oropharyngeal cancer (OR = 1.85, 95% CI = 1.04, 3.29), and female sex (OR = 1.64, 95% CI = 1.00, 2.70) positively predicted whether a student believed the HPV vaccine should be mandatory. After an interactive workshop, first- and second-year medical students improved on HPV knowledge questions, comfort in HPV vaccine counseling, and having enough information to counsel on the HPV vaccine. Post-test knowledge scores surpassed those of current third- and fourth-year medical students, who never underwent such curriculum. Medical, physician assistant, graduate, and undergraduate students lack HPV knowledge, with a low percentage aware of oropharyngeal cancer as a result of HPV infection. An interactive curriculum implemented for first- and second-year medical students improved knowledge and comfort in counseling on HPV vaccination.

A recent surge in human mastadenovirus (HAdV) cases, including five deaths, amongst a haematopoietic stem cell transplant population led us to use whole genome sequencing (WGS) to investigate. We compared sequences from 37 patients collected over a 20-month period with sequences from GenBank and our own database of HAdVs. Maximum likelihood trees and pairwise differences were used to evaluate genotypic relationships, paired with the epidemiological data from routine infection prevention and control (IPC) records and hospital activity data. During this time period, two formal outbreaks had been declared by IPC, while WGS detected nine monophyletic clusters, seven were corroborated by epidemiological evidence and by comparison of single-nucleotide polymorphisms. One of the formal outbreaks was confirmed, and the other was not. Of the five HAdV-associated deaths, three were unlinked and the remaining two considered the source of transmission. Mixed infection was frequent (10%), providing a sentinel source of recombination and superinfection. Immunosuppressed patients harboring a high rate of HAdV positivity require comprehensive surveillance. As a consequence of these findings, HAdV WGS is being incorporated routinely into clinical practice to influence IPC policy contemporaneously.

It is intriguing that, unlike adults with HIV-1, children with HIV-1 reach a greater CD4+ T cell recovery following planned treatment cessation. The reasons for the better outcomes in children remain unknown but may be related to increased thymic output and diversity of T cell receptor repertoires. HIV-1 infected children from the PENTA 11 trial tolerated planned treatment interruption without adverse long-term clinical, virological, or immunological consequences, once antiretroviral therapy was re-introduced. This contrasts to treatment interruption trials of HIV-1 infected adults, who had rapid changes in T cells and slow recovery when antiretroviral therapy was restarted. How children can develop such effective immune responses to planned treatment interruption may be critical for future studies. PENTA 11 was a randomized, phase II trial of planned treatment interruptions in HIV-1-infected children (ISRCTN 36694210). In this sub-study, eight patients in long-term follow-up were chosen with CD4+ count>500/ml, viral load + and naïve CD4+ T cell receptors according to diversity, clonal expansions, sequence sharing, antigen specificity, and T cell receptor similarities following treatment interruption compared to continuous treatment. We observed an increase in thymic output following treatment interruption compared to continuous treatment. This was accompanied by an increase in T cell receptor clonal expansions, increased T cell receptor sharing, and higher sequence similarities between patients, suggesting a more focused T cell receptor repertoire. The low numbers of patients included is a limitation and the data should be interpreted with caution. Nonetheless, the high levels of thymic output and the high diversity of the T cell receptor repertoire in children may be sufficient to reconstitute the T cell immune repertoire and reverse the impact of interruption of antiretroviral therapy. Importantly, the effective T cell receptor repertoires following treatment interruption may inform novel therapeutic strategies in children infected with HIV-1.

One of the main features of Alzheimer’s disease is the progressive loss of memory, likely due to pathological changes within brain regions such as the hippocampus and entorhinal cortex. These structures are embedded within the extended memory circuit, an interconnected set of brain regions that are essential for episodic memory. The anterior thalamic nuclei (ATN) and thalamic nucleus reuniens (NRe) are both extensively and reciprocally connected with these important memory regions, so we sought to test the hypothesis that chemogenetically-enhancing neurotransmission through NRe and ATN would ameliorate memory deficits in two mechanistically-distinct mouse models of Alzheimer’s disease. Using the hAPP-J20 mouse model of amyloidopathy and the Tg4510 mouse model of tauopathy, we carried out stereotaxic injections of viral vectors to transduce hM3Dq (Gq)_mCherry into NRe or the anterio-dorsal/anterio-ventral nuclei of ATN, using mCherry as a control. At nine months (hAPP-J20) or six months (Tg4510) of age, mice underwent a behaviour battery of open field (OF), novel object recognition (NOR) and radial arm maze (RAM), with DREADD agonist 21 administered 30min prior to each behaviour test. Tissue was collected post-behaviour to confirm injection site and virus expression. Both Tg4510 and hAPP-J20 mice show marked hyperactivity in the OF, significant deficits in recognition memory, and a significant impairment in spatial reference and spatial working memory. Unexpectedly, chemogenetic activation of ATN or NRe did not significantly improve spatial memory impairments or reduce the observed hyperactivity, although NRe activation did modestly rescue recognition memory in J20 mice. This may be due to compensation elsewhere within the memory circuit, or that the pathological changes are too far advanced for behaviour reversal.

Funder: The University of Sussex Strategic Development Funds, Funder: Sussex Neuroscience 4‐year PhD programme, Exposure to environmental enrichment can modify the impact of motivationally relevant stimuli. For instance, previous studies in rats have found that even a brief, acute (~1 day), but not chronic, exposure to environmentally enriched (EE) housing attenuates instrumental lever pressing for sucrose-associated cues in a conditioned reinforcement setup. Moreover, acute EE reduces corticoaccumbens activity, as measured by decreases in expression of the neuronal activity marker "Fos." Currently, it is not known whether acute EE also reduces sucrose seeking and corticoaccumbens activity elicited by non-contingent or "forced" exposure to sucrose cues, which more closely resembles cue exposure encountered in daily life. We therefore measured the effects of acute/intermittent (1 day or 6 day of EE prior to test day) versus chronic (EE throughout conditioning lasting until test day) EE on the ability of a Pavlovian sucrose cue to elicit sucrose seeking (conditioned approach) and Fos expression in the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), and nucleus accumbens (NAc) in mice. One day, but not 6 day or chronic EE , reduced sucrose seeking and Fos in the deep layers of the dorsal mPFC. By contrast, 1 day, 6 day, and chronic EE all reduced Fos in the shallow layers of the OFC. None of the EE manipulations modulated NAc Fos expression. We reveal how EE reduces behavioral reactivity to sucrose cues by reducing activity in select prefrontal cortical brain areas. Our work further demonstrates the robustness of EE in its ability to modulate various forms of reward-seeking across species.

Brain is an actuator for control and coordination. When a pathology arises in cranium, it may leave a degenerative, disfiguring and destabilizing impact on brain physiology. However, the leading consequences of the same may vary from case to case. Tumour, in this context, is a special type of pathology which deforms brain parenchyma permanently. From translational perspective, deformation mechanics and pressures, specifically the intracranial cerebral pressure (ICP) in a tumour-housed brain, have not been addressed holistically in literature. This is an important area to investigate in neuropathy prognosis. To address this, we aim to solve the pressure mystery in a tumour-based brain in this study and present a fairly workable methodology. Using image-based finite-element modelling, we reconstruct a tumour-based brain and probe resulting deformations and pressures (ICP). Tumour is grown by dilating the voxel region by 16 and 30 mm uniformly. Cumulatively three cases are studied including an existing stage of the tumour. Pressures of cerebrospinal fluid due to its flow inside the ventricle region are also provided to make the model anatomically realistic. Comparison of obtained results unequivocally shows that as the tumour region increases its area and size, deformation pattern changes extensively and spreads throughout the brain volume with a greater concentration in tumour vicinity. Second, we conclude that ICP pressures inside the cranium do increase substantially; however, they still remain under the normal values (15 mmHg). In the end, a correlation relationship of ICP mechanics and tumour is addressed. From a diagnostic purpose, this result also explains why generally a tumour in its initial stage does not show symptoms because the required ICP threshold has not been crossed. We finally conclude that even at low ICP values, substantial deformation progression inside the cranium is possible. This may result in plastic deformation, midline shift etc. in the brain.

Movement of solutes across the peritoneum allows for the use of peritoneal dialysis to treat kidney failure. However, there is a large inter-individual variability in the peritoneal solute transfer rate (PSTR). Here, we tested the hypothesis that common genetic variants are associated with variability in PSTR. Of the 3561 participants from 69 centers in six countries, 2850 with complete data were included in a genome-wide association study. PSTR was defined as the four-hour dialysate/plasma creatinine ratio from the first peritoneal equilibration test after starting PD. Heritability of PSTR was estimated using genomic-restricted maximum-likelihood analysis, and the association of PSTR with a genome-wide polygenic risk score was also tested. The mean four-hour dialysate/plasma creatinine ratio in participants was 0.70. In 2212 participants of European ancestry, no signal reached genome-wide significance but 23 single nucleotide variants at four loci demonstrated suggestive associations with PSTR. Meta-analysis of ancestry-stratified regressions in 2850 participants revealed five single-nucleotide variants at four loci with suggestive correlations with PSTR. Association across ancestry strata was consistent for rs28644184 at the KDM2B locus. The estimated heritability of PSTR was 19%, and a permuted model polygenic risk score was significantly associated with PSTR. Thus, this genome-wide association study of patients receiving peritoneal dialysis bolsters evidence for a genetic contribution to inter-individual variability in PSTR.

ETHNOPHARMACOLOGICAL RELEVANCE Salvia officinalis L. (sage), and Chamaemelum nobile (L.) (chamomile) have been used traditionally to treat various inflammatory conditions. AIMS Our study aims to investigate the anti-inflammatory properties of both plant extracts in IL-1β-stimulated neuroblastoma cells (SK-N-SH) and human subcutaneous mature adipocytes, as well as their potential protective effects against mature adipocytes conditioned media (ACM)-induced neuro-inflammation. MATERIALS AND METHODS Human subcutaneous mature adipocytes and neuroblastoma cells were treated with 5 μg/ml (low dose: LD) and 50 μg/ml (high dose: HD) of each extract, with or without 0.5 ng/ml of human recombinant IL-1β. To understand the cross talk between fat tissue and neuronal cells, SK-N-SH cell line was incubated with ACM 10%, in presence or absence of both extracts LD and HD. Following 4, and 24 h incubation, the released MCP-1, IL-6, IL-8, TNF-α, ICAM-1, VCAM-1 and SAA levels were measured using MSD Cytokines and Chemokines assay kits, and the cells were used for gene expression. RNA was quantified using Qubit™ RNA HS Assay. RNA aliquots were shipped to Eurofins Genomics (Aarhus, Denmark) for expression analysis on the human Clariom™ GO Screen Assay (952,361; ThermoFisher). RESULTS Chamomile showed stronger effects compared to sage in both cell lines, at 4 and 24 h. Adipocytes acute treatment with sage decreased MCP-1, IL-6, IL-8 (p

The extent of prescription and illicit drug abuse in geographically isolated rural and micropolitan communities in the intermountain western United States (US) has not been well tracked. The goal of this pilot study was to accurately measure drug dose consumption rates (DCR) between two select populations, normalize the data and compare the DCRs to similar communities. To learn about patterns of drug abuse between the two disparate communities, we used the emergent field of wastewater-based epidemiology (WBE). A rapid, quantitative and systematic process for the determination of multiple classes of prescribed and illicit drugs was applied to influent wastewater samples. Influent samples were collected over the course of three months (April to June 2019) at two wastewater treatment plants representing a small urban and a rural community. Collection of sewage influent included 24-h composite samples and the use of polar organic chemical integrative samplers (POCIS), time-weighted samplers. Using the results from the composite sampling data, DCRs per 1000 population could be calculated from the concentration data and the use of excretion correction factors. The following 18 compounds: amphetamine, methamphetamine, MDA, MDMA, morphine, 6-acetylmorphine, methadone, EDDP, codeine, benzoylecgonine, hydrocodone, hydromorphone, oxycodone, noroxycodone, ketamine, fluoxetine, tramadol, and ritalinic acid; represent a subset of the targeted analytes that were consistently measured at detectable concentration levels, and present at both sites. Following normalization of the drug measurements to influent flow rates and per capita, the small urban community demonstrated greater collective excretion rates (CER) than the rural community, with the exceptions of amphetamine and methamphetamine., Graphical abstract Unlabelled Image, Highlights • Drug use assessed using wastewater-based epidemiology in western United States • Comparison of rural community drug consumption rates with urban areas • Highlighting the need for standardization in WBE testing

Introduction: Sudden unexpected death in infancy (SUDI) represents the commonest presentation of postneonatal death, yet despite full postmortem examination (autopsy), the cause of death is only determined in around 45% of cases, the majority remaining unexplained. In order to aid counselling and understand how to improve the investigation, we explored whether machine learning could be used to derive data driven insights for prediction of infant autopsy outcome. Methods: A paediatric autopsy database containing >7,000 cases in total with >300 variables per case, was analysed with cases categorised both by stage of examination (external, internal and internal with histology), and autopsy outcome classified as explained-(medical cause of death identified) or unexplained. For the purposes of this study only cases from infant and child deaths aged ≤ 2 years were included (N=3100). Following this, decision tree, random forest, and gradient boosting models were iteratively trained and evaluated for each stage of the post-mortem examination and compared using predictive accuracy metrics. Results: Data from 3,100 infant and young child autopsies were included. The naive decision tree model using initial external examination data had a predictive performance of 68% for determining whether a medical cause of death could be identified. Model performance increased when internal examination data was included and a core set of data items were identified using model feature importance as key variables for determining autopsy outcome. The most effective model was the XG Boost, with overall predictive performance of 80%, demonstrating age at death, and cardiovascular or respiratory histological findings as the most important variables associated with determining cause of death. Conclusion: This study demonstrates the feasibility of using machine learning models to objectively determine component importance of complex medical procedures, in this case infant autopsy, to inform clinical practice. It further highlights the value of collecting routine clinical procedural data according to defined standards. This approach can be applied to a wide range of clinical and operational healthcare scenarios providing objective, evidence-based information for uses such counselling, decision making and policy development.

The outbreak of COVID-19 has transformed societies across the world as governments tackle the health, economic and social costs of the pandemic. It has also raised concerns about the spread of hateful language and prejudice online, especially hostility directed against East Asia. In this paper we report on the creation of a classifier that detects and categorizes social media posts from Twitter into four classes: Hostility against East Asia, Criticism of East Asia, Meta-discussions of East Asian prejudice and a neutral class. The classifier achieves an F1 score of 0.83 across all four classes. We provide our final model (coded in Python), as well as a new 20,000 tweet training dataset used to make the classifier, two analyses of hashtags associated with East Asian prejudice and the annotation codebook. The classifier can be implemented by other researchers, assisting with both online content moderation processes and further research into the dynamics, prevalence and impact of East Asian prejudice online during this global pandemic., 12 pages

Opioid misuse takes an enormous toll on the health and economy of the U.S., costing 130 lives per day, and an estimated 157 billion dollars per year. Mitigating the epidemic requires better information on the mix of drugs being used in a community and when and where drug use concentrates. Many widely used data sources, such as national population surveys, have a two-year lag before the data are available, and underestimate the prevalence of drug use because they rely on self-reported information about a stigmatized behavior. For rural populations, the data gap is compounded by privacy policies that suppress key information (for example, opioid-related death rates) in small populations. Municipal wastewater testing is an innovative approach to assessing community-level drug use that can provide near real-time, cost-effective, and unbiased measures of drug use. Importantly, wastewater-based data cannot reveal who is using a particular drug, mitigating privacy concerns. The methodology is routinely used across Europe and Australia as part of a holistic multi-indicator monitoring and alert system. When combined with geospatial mapping and advanced analytics, wastewater-based data can help locate geographic hotspots of use and provide an early warning for new substances entering into a community. We conducted a pilot study to compare temporal trends in estimates of per-capita drug use between wastewater-based data and other local data sources in two municipalities (one urban, one rural) in Montana. In the first phase of our study (Bishop et al, 2020, manuscript is in submission to Sci Total Environ), we optimized testing to estimate per-capita drug use in wastewater in an urban and rural municipality. Here, we report the value of these data for public health officials to predict rather than react to changes in drug use patterns. We also illustrate how rural populations can use the methodology to assess the impacts of local law enforcement efforts and evaluate the effectiveness of programs, such as the prescription take-back program, to improve public health and safety.

Understanding the structural biology of the insulin receptor and how it signals is of key importance in the development of insulin analogs to treat diabetes. We report here a cryo-electron microscopy structure of a single insulin bound to a physiologically relevant, high-affinity version of the receptor ectodomain, the latter generated through attachment of C-terminal leucine zipper elements to overcome the conformational flexibility associated with ectodomain truncation. The resolution of the cryo-electron microscopy maps is 3.2 Å in the insulin-binding region and 4.2 Å in the membrane-proximal region. The structure reveals how the membrane proximal domains of the receptor come together to effect signalling and how insulin’s negative cooperativity of binding likely arises. Our structure further provides insight into the high affinity of certain super-mitogenic insulins. Together, these findings provide a new platform for insulin analog investigation and design., The insulin receptor plays a key role in many physiological processes, yet how insulin effects receptor signaling at the structural level remains incomplete. Here the authors present a high-resolution cryo-EM structure of a high-affinity form of the insulin-bound insulin receptor ectodomain that sheds light on the mechanism of signal transduction.

Background Adenoviruses are significant pathogens for the immunocompromised, arising from primary infection or reinfection. Serotyping is insufficient to support nosocomial transmission investigations. We investigate whether whole-genome sequencing (WGS) provides clinically relevant information on transmission among patients in a pediatric tertiary hospital. Methods We developed a target-enriched adenovirus WGS technique for clinical samples and retrospectively sequenced 107 adenovirus-positive residual diagnostic samples, including viremias (>5 × 104 copies/mL), from 37 patients collected January 2011-March 2016. Whole-genome sequencing was used to determine genotype and for phylogenetic analysis. Results Adenovirus sequences were recovered from 105 of 107 samples. Full genome sequences were recovered from all 20 nonspecies C samples and from 36 of 85 species C viruses, with partial genome sequences recovered from the rest. Whole-genome phylogenetic analysis suggested linkage of 3 genotype A31 cases and uncovered an unsuspected epidemiological link to an A31 infection first detected on the same ward 4 years earlier. In 9 samples from 1 patient who died, we identified a mixed genotype adenovirus infection. Conclusions Adenovirus WGS from clinical samples is possible and useful for genotyping and molecular epidemiology. Whole-genome sequencing identified likely nosocomial transmission with greater resolution than conventional genotyping and distinguished between adenovirus disease due to single or multiple genotypes.

Objective: To identify the level of public support for a Human Rights Act for Queensland (HRAQ) and for inclusion of the right to health by participants in a public inquiry process. Methods: We reviewed the 492 written submissions to the Legal Affairs and Community Safety Committee's Inquiry into a potential HRAQ and the transcripts documenting the public hearings held by the Committee in 2016. Results: A total of 465 written submissions were analysed; 419 (90%) were for a HRAQ. More than 80% of the ‘for’ submissions advocated the right to health's inclusion. At the seven public hearings, 72 persons made verbal submissions and most supported a HRAQ. Five major themes were identified in our synthesis of the public hearing transcripts. Three related specifically to health and human rights: 1) the need to consider the holistic health and human rights of Indigenous Queenslanders and Indigenous Queensland communities; 2) instilling a human rights culture in Queensland; and 3) access to health care and the underlying determinants of health. The other two themes related to the conduct of the Inquiry: 4) the importance of community participation in developing a HRAQ; and 5) concerns about the public consultation processes. Conclusion: This study found strong support in the majority of submissions for the Queensland Parliament to draft and enact a HRAQ, and for the inclusion of the right to health in such legislation. Implications for public health: The Queensland Parliament's enactment of a HRAQ that expressly included the right to health would increase the accountability and transparency of government health (and related) decision making and resource allocation, and would better identify and address health inequities across the state. This Act is imperative for improving the health and wellbeing of all Queenslanders, particularly rural and remote and Aboriginal and Torres Strait Islander Queenslanders.

Human type 1 insulin-like growth factor receptor is a homodimeric receptor tyrosine kinase that signals into pathways directing normal cellular growth, differentiation and proliferation, with aberrant signalling implicated in cancer. Insulin-like growth factor binding is understood to relax conformational restraints within the homodimer, initiating transphosphorylation of the tyrosine kinase domains. However, no three-dimensional structures exist for the receptor ectodomain to inform atomic-level understanding of these events. Here, we present crystal structures of the ectodomain in apo form and in complex with insulin-like growth factor I, the latter obtained by crystal soaking. These structures not only provide a wealth of detail of the growth factor interaction with the receptor’s primary ligand-binding site but also indicate that ligand binding separates receptor domains by a mechanism of induced fit. Our findings are of importance to the design of agents targeting IGF-1R and its partner protein, the human insulin receptor., The human type 1 insulin-like growth factor receptor (IGF-1R) is important for normal human growth and development. Here, the authors present the crystal structures of the IGF-1R ectodomain both in its apo form and in complex with its ligand insulin-like growth factor I and discuss the receptor activation mechanism.

Adjustment to the first year of university involves engaging with the university culture and developing a sense of belonging or attachment. Difficulty making the transition to university can result in students deferring or withdrawing from their courses. While mature-age students experience many of the challenges of all first-year students such as social dislocation, academic anxiety, and unrealistic expectations, they are more likely than school-leaver students to have family responsibilities and time constraints. The ability to manage competing demands on their time can affect their participation in campus-based activities and negatively impact their sense of belonging to the university. This paper reports on the adjustment to the first year of university of 40 mature-age students, measured through an analysis of their responses on a 55-item survey questionnaire. The findings suggest that the mature-age students adjusted well, academically; however, they had lower measures of adjustment in their social and personal adjustment. The challenge for universities is to identify and respond to the needs of mature-age students during their transition to university.

BackgroundTislelizumab, an anti-PD-1 monoclonal antibody, demonstrated clinical activity and was well-tolerated in patients with previously treated advanced hepatocellular carcinoma (HCC) in the Phase 2 RATIONALE-208 study (NCT03419897). We explored whether baseline neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) or their post-treatment change correlated with clinical efficacy of tislelizumab treatment.MethodsEligible patients (>18 years) who had received ≥1 prior line of systemic therapy for advanced HCC were administered open-label tislelizumab (200 mg) intravenously every 3 weeks until no further clinical benefit was observed. NLR and PLR were assessed using peripheral blood samples collected at baseline, Cycle 2 Day 1 (C2D1), C3D1, and C4D1. Survival analysis (progression free survival [PFS] and overall survival [OS]) was conducted by Kaplan-Meier method and survival rate at risk was compared by log rank test. Logistic regression was used to analyze association of post-treatment change of NLR or PLR with objective response rate (ORR). In the baseline analysis, median NLR or PLR in this study was used as a cut-off. All statistical analysis results are post-hoc exploratory and thereby p values are descriptive.ResultsOverall, 249 patients were enrolled, of which 249, 234, 203, and 186 patients had evaluable NLR and PLR data at baseline, C2D1, C3D1, and C4D1, respectively. Analysis of NLR at baseline, using median NLR (3.2) as cut-off, demonstrated higher OS (p=0.0024) and PFS (p=0.071) in NLR-low versus NLR-high groups (median OS [mOS]:17.4 versus 9.9 months; median PFS [mPFS]: 2.8 versus 1.5 months). Analysis of PLR at baseline, using median PLR (141.4) as cut-off, showed higher OS (p=0.0085) and PFS (pAbstract 362 Table 1Post-treatment decreases in NLR or PLR were associated with response to tislelizumab monotherapyAbstract 362 Figure 1Post-treatment decreases in NLR or PLR were associated with improved OS following tislelizumab monotherapyConclusionsIn patients with previously treated advanced HCC that received tislelizumab monotherapy, lower baseline NLR or PLR was associated with longer OS and PFS, and post-treatment decreases of NLR or PLR were associated with higher ORR and longer OS. These observations support NLR and PLR as potential prognostic biomarkers in patients with advanced HCC treated with tislelizumab and will be further investigated in an on-going Phase 3 study (NCT03412773).AcknowledgementsThis study is sponsored by BeiGene Ltd. Medical writing support for the development of this abstract, under direction of the authors, was provided by Claire White, PhD, and Kirsty Millar, MSc, of Ashfield MedComms, an Ashfield Health company, and was funded by BeiGene Ltd.Trial RegistrationNCT03419897Ethics ApprovalThis study was conducted according to the ethical principles of the Declaration of Helsinki, Good Clinical Practice guidelines, the principles of informed consent and the requirements of the public registration of clinical trials. Written informed consent was obtained from each patient prior to screening. The protocol was approved by the institutional ethics committee and was monitored by the investigators and study sponsor.

Background: Irrespective of the underlying aetiology, 90% of hepatocellular carcinomas arise and progress on a background of chronic inflammation. We have explored the independent prognostic value of circulating inflammatory cells. Methods: Peripheral blood count data sets from 583 consecutive patients presenting to a single UK centre (2000–2010) were analysed for associations with tumour stage, liver function, performance status (PST) and survival. Validation was in an independent Hong Kong cohort (585 patients; 2007–2013). Results: In both UK and Hong Kong cohorts, neutrophils, platelets, lymphocytes, the neutrophil/lymphocyte ratio (NLR) and the Systemic Immune-Inflammation Index (SII) correlated stepwise, either increasing or decreasing (lymphocytes), with tumour node metastasis (TNM) and Childs–Pugh stage, PST and consequently with the combined Barcelona Clinic for Liver Cancer stage. Survival analyses confirmed the NLR and SII as highly significant prognostic biomarkers. Focused on individual cell types, only the neutrophil count was independently associated with both TNM stage and PST, as well as being significantly and independently associated with poorer survival. Conclusions: In this study of 1168 patients, neutrophils alone, rather than lymphocytes or platelets, were independently associated with outcome. These data support further characterisation of a potentially distinctive role for neutrophils as facilitators of tumour progression and deteriorating performance.

CITATION: Delisle, H. et al. 2017. Capacity-building for a strong public health nutrition workforce in low-resource countries. Bulletin of the World Health Organization, 95:385-388. doi:10.2471/BLT.16.174912

Background Combined MD/PhD programs provide a structured path for physician-scientist training, but assessment of their success within Canada is limited by a lack of quantitative data. We collected outcomes data for graduates of Canadian MD/PhD programs. Methods We developed and implemented a Web-based survey consisting of 41 questions designed to collect outcomes data for Canadian MD/PhD program alumni from 8 Canadian universities who had graduated before September 2015. Respondents were categorized into 2 groups according to whether they had or had not completed all training. Results Of the 186 eligible alumni of MD/PhD programs, 139 (74.7%) completed the survey. A total of 136/138 respondents (98.6%) had completed or were currently completing residency training, and 66/80 (82%) had completed at least 1 postgraduate fellowship. Most (58 [83%]) of the 70 respondents who had completed all training were appointed as faculty at academic institutions, and 37 (53%) had been principal investigators on at least 1 recent funded project. Among the 58 respondents appointed at academic institutions, 44/57 (77%) dedicated at least 20% of their time to research, and 25/57 (44%) dedicated at least 50% to research. During their combined degree, 102/136 respondents (75.0%) published 3 or more first-author papers, and 133/136 (97.8%) matched with their first choice of specialty. The median length of physician-scientist training was 13.5 years. Most respondents graduated with debt despite having been supported by Canadian Institutes of Health Research MD/PhD studentships. Interpretation Most Canadian MD/PhD program alumni pursued careers consistent with their physician-scientist training, which indicates that these programs are meeting their primary objective. Nevertheless, our findings highlight that a minority of these positions are research intensive; this finding warrants further study. Our data provide a baseline for future monitoring of the output of Canadian MD/PhD programs.

Purpose The purpose of this paper is to examine patterns of drug use among a cohort of drug treatment-seeking drug-using gay men and other men who have sex with men (MSM), and whether these activities differ between, or predict, HIV status. Design/methodology/approach Cross-sectional study was conducted in a specialist club drug clinic in London covering 407 consecutive attendees who identified as MSM. Substance use, including injecting drug use (IDU), associated sexual activity and self-reported HIV status were measured by clinical interview and National Drug Treatment Monitoring System data tool. Findings Over a 45-month period, 407 MSM attended the clinic. In total, 62.1 per cent were HIV positive, 48.9 per cent had injected drugs, 14.9 per cent reported needle sharing and 73.3 per cent used drugs to facilitate sex. The most commonly reported problem drugs were GHB/GBL (54.3 per cent) methamphetamine (47.7 per cent) and mephedrone (37.8 per cent). HIV status was associated with methamphetamine, mephedrone, IDU, sharing equipment, using drugs to facilitate sex, older age and older age of drug initiation, as well as Hepatitis C virology (HCV) status. Use of methamphetamine, HCV infection, older age and IDU predicted HIV positive status in a logistic regression model. Practical implications The findings describe a constellation of risk factors including high levels of IDU, sharing of equipment and high-risk sexual activity in a population with high rates of HIV positive serology. They also provide further evidence for a link between HIV infection and use of methamphetamine. Social implications The authors suggest a need for greater awareness of HIV-related risk activities and promotion of HIV prevention strategies for MSM by both sexual health and drug treatment services. Originality/value This paper is amongst the very first studies of its nature.

Background Measuring dietary intake in children and adolescents can be challenging due to misreporting, difficulties in establishing portion size and reliance on recording dietary data via proxy reporters. The aim of this review was to present results from a recent systematic review of reviews reporting and comparing validated dietary assessment tools used in younger populations in the UK. Methods Validation data for dietary assessment tools used in younger populations (≤18 years) were extracted and summarised using results from a systematic review of reviews of validated dietary assessment tools. Mean differences and Bland-Altman limits of agreement (LOA) between the test and reference tool were extracted or calculated and compared for energy, macronutrients and micronutrients. Results Seventeen studies which reported validation of 14 dietary assessment tools (DATs) were identified with relevant nutrition information. The most commonly validated nutrients were energy, carbohydrate, protein, fat, calcium, iron, folate and vitamin C. There were no validated DATs reporting assessment of zinc, iodine or selenium intake. The most frequently used reference method was the weighed food diary, followed by doubly labelled water and 24 h recall. Summary plots were created to facilitate comparison between tools. On average, the test tools reported higher mean intakes than the reference methods with some studies consistently reporting wide LOA. Out of the 14 DATs, absolute values for LOA and mean difference were obtained for 11 DATs for EI. From the 24 validation results assessing EI, 16 (67%) reported higher mean intakes than the reference. Of the seven (29%) validation studies using doubly labelled water (DLW) as the reference, results for the test DATs were not substantially better or worse than those using other reference measures. Further information on the studies from this review is available on the www.nutritools.org website. Conclusions Validated dietary assessment tools for use with children and adolescents in the UK have been identified and compared. Whilst tools are generally validated for macronutrient intakes, micronutrients are poorly evaluated. Validation studies that include estimates of zinc, selenium, dietary fibre, sugars and sodium are needed.

Given the emphasis placed on technology by the Department of Health and the recent high profile Topol review, the role of healthcare data is set to become highly prevalent in the coming years. To bridge the gap between the traditional clinical-academic and statistician roles in translational research, the skillsets of interdisciplinary ‘clinical informaticians’ are required. This new role requires staff to be conversant in high level programming languages, such as R, python and SQL (the lingua franca of data science), whilst retaining their domain-specific knowledge and an active academic presence within their clinical specialty. To assess the feasibility of upskilling clinical staff into clinical informatician roles, we present case studies of clinicians with little-to-no formal experience of programming, statistics, and data science, who undertook this transition with the Digital Research Environment (DRE). In particular, this transition required a grounding in database extraction, data manipulation, and statistical modelling, replicating the workflow expected in a data-rich research setting. Each case study suggested that online content (tutorials, articles, open source code) provided a solid background in basic data science and functional programming. The benefits of pursuing open-source languages were most keenly observed in question and answer forums, tutorials, and open sessions, with full-text articles and books freely available. Furthermore, paid online courses were abundant, providing high-quality methodological workflows for all aspects of data science and analysis, including advanced topics such as machine learning and deep learning. We found that within 18 months, the staff were able to integrate typical data science workflows within their research programmes. The combination of clinical knowledge and data science will allow the maximum possible value to be extracted from future clinical studies and databases that host increasingly rich EPR datasets, thus further supporting evidence-based improvements to the standard of care in paediatrics.

Introduction Prior to the rollout of the GOSH EPR system, multiple hospital databases provided fragmentary data from the clinical record. To support research in GOSH and the ICH, these data will all need to be brought together with data from the EPR to provide a complete uninterrupted clinical research dataset suitable for analysis. This need will be particularly acute for research undertaken on rare diseases where accumulating a sufficient cohort of patients is often challenging. In addition, work to harmonise with external data sources would enable more ambitious multi-site research. Method The Digital Research Environment (DRE) Team bring together a core dataset of research–relevant clinical data comprising administrative data (e.g. patient demographics, ward stays) and clinical observations (e.g. lab results, vital signs, diagnoses) onto which we have mapped data from multiple legacy systems and the EPR. We have mapped these Research Data Views (RDVs) onto the FHIR standard for clinical data interoperability to allow harmonisation with data from other sources (such as other hospitals). Results We have complete extractions from multiple legacy systems to produce RDVs with data back to 1st January 2000. We are now actively extracting data from the EPR aligning with these RDVs and thus are providing a continuous clinical research dataset across EPR go-live. We have >102 million events for >400,000 patients at GOSH. These RDVs are now available via the DRE Data Selection Tool, along with complete metadata for all fields, for provision into our Research Platform for analysis. Conclusion We have implemented a resource to put all research-relevant clinical data right at the fingertips of researchers from GOSH, ICH and beyond. This will feed into research projects big and small, empowering researchers to focus on the science, rather than the manual collection of data.

Introduction Renal transplantation remains the best modality of renal replacement therapy in children with end stage kidney disease, the majority of whom have congenital anomalies of the kidneys and urinary tract (CAKUT). Febrile urinary tract infections (UTI) can cause acute kidney injury (AKI) and worsen chronic kidney disease (CKD). After renal transplantation, episodes of UTI can adversely affect renal allograft survival by causing interstitial scarring and injury, although there is a paucity of data in the literature. Management of UTI in paediatric renal transplant recipients (pRTR) is more complex compared to other healthy children. There are no current guidelines or evidence for management of this common problem. Patients and methods This was a retrospective review of pRTR at GOSH between 2010 and 2018. Data were collected from the hospital computer based systems with digital research environment and analysed using Analyxagility programme. pRTR were divided into three major groups: (a) No UTI group; (b) Infrequent UTI group (less than one UTI episode per year) and (c) Frequent UTI group (one or more UTI per year). Results 243 pRTR aged 1.3 to 17.9 (median 10.3) years), of whom 60.8% were males with 47% with primary diagnosis of CAKUT. There was a significant decline in estimated glomerular filtration rate (eGFR) in the group with UTI compared to those without UTI. In addition to the frequency of UTI in those with CAKUT, we found that the original pathology contributed to the decline in renal function (eg. recurrent FSGS). Conclusion Frequent UTI can adversely affect renal allograft function and requires prompt and effective treatment to reduce AKI and CKD. Guidelines needs to be developed to manage UTI in order to protect renal allograft function and survival (figure 1).

Introduction Following the publication of the GOSH digital strategy, electronic patient record (EPR) data has been recognised as an ever-growing cornerstone of the hospital infrastructure. Because EPR data remains the property of the patient and the NHS, access to it is rightly controlled by stringent governance processes which introduce a hurdle for researchers requiring the use of these data. In-short, these restrictions can make it challenging to run short-term clinical research projects, to publish reproducible results without compromising patient anonymity, and for researchers to train on complex EPR data before applying to access it. Methods The GOSH DRE team have worked with collaborators in UCL and NHS Digital to develop generative statistical and deep learning (AI) models that learn the structure and statistical properties of EPR data. These models have the capability to generate synthetic EPR data without reproducing individual patient records. To facilitate this work, de-identified EPR data from all patients treated at GOSH between January 2016 and January 2019 were extracted from the DRE data lake and modelled using the PyTorch, TensorFlow, and Scikit learn Python libraries. Results A range of privacy-preserving models were developed on admissions, ward movements, demographics, drug administrations, laboratory tests, vital signs, and microbiological isolate datasets. On inspection, each model was capable of generating realistic EPR data. A method for automatically evaluating each model’s output was developed through the use of stringent statistical similarity and disclosure control metrics that are automatically applied to generated data. Discussion Integrating the models into a programmatic interface has enabled the production of realistic, consistent EPR records that are not related to any single patient, yet generate high-quality data in the same format as the clinical data made available through the GOSH Digital Research Environment (DRE). This will enable future data-driven developments in GOSH, DRIVE, and the DRE.

Post-mortems are complex procedures that utilise a significant amount of hospital resources, yet despite this, cause of death is only determined in 45% of cases. The event itself can be very traumatic for the parents of the child yet is essential for providing further clinical understanding of the patient’s cause of death. Given this, there is an imperative to extract the greatest possible value from the data. Here, we investigated whether machine learning could be used to derive novel insights from the prediction of post-mortem outcomes. A post-mortem database containing 7000 events across 300 attributes was analysed and categorised into stage of examination (external and internal). The outcome of the examination was summarised as either ‘cause of death determined’ or ‘not determined’. From these summarised data, cases were filtered by children aged ≤ 2 years, resulting in a dataset of 3,100 events. Following this, within a GOSH Digital Research Environment (DRE) workspace, decision tree, random forest, and gradient boosting machine models were iteratively built for each stage of the post-mortem examination and compared using their accuracy metrics. The naive decision tree model using external examination data had a predictive performance of 67%. Model performance notably increased when trained on internal examination data. At each stage of the examination, a core set of data items, of which the final set included age, BMI, and heart weight were highlighted using model feature importance as key variables for determining post-mortem outcome. The use of increasingly complex modelling techniques was able to boost the predictive performance of the model by as much as 10%. This project clearly shows the value of collecting clinical procedural data which can then be modelled using machine learning techniques to inform clinical practice. With more time, further modelling, including unsupervised clustering could be undertaken to derive further insights.

Clinicians lack well-validated, non-invasive, objective tools to guide volume management in the post-resuscitative period. Bioimpedance analysis (BIA) represents a novel method for guiding fluid management. We studied the relationship of BIA vector length (VL), an indicator of volume status, to the need for mechanical ventilation in patients with sepsis. This is a multicentre prospective observational study at four Canadian ICUs. We examined adult patients admitted to the ICU within 72 hr of a sepsis diagnosis. Patients underwent daily BIA measurements for 30 days, until discharge from the ICU, or until death. Our primary outcome was the ongoing need for invasive mechanical ventilation, and we examined the association with VL using a generalized estimating equation. Our secondary analyses were targeted to determine an association between VL and other measures of volume status and acute kidney injury (AKI). We enrolled 159 patients from four centres over 27 months. The mean (standard deviation [SD]) age was 64 (15) yr with a mean (SD) APACHE (acute physiology, age, chronic health evaluation) II score of 25 (10); 57% (n = 91) were male. A 50-unit (ohm·m) increase in VL over any time period was associated with a 30% decrease in the probability of requiring invasive mechanical ventilation (P < 0.03). Volume expansion, indicated by a shorter VL, correlated with higher edema scores (r = − 0.31; P < 0.001) and higher net 24-hr fluid balance (r = − 0.27, P < 0.001). Patients with AKI had a shorter overall VL (r = − 0.23; P = 0.003). An increase in VL over time is associated with a decrease in probability of requiring invasive mechanical ventilation. Vector length correlates with other commonly used volume assessment methods in post-resuscitation patients with sepsis.

Environmental health literacy (EHL), an evolving concept, has potential for significant public health impact. However, complex skills are needed to access and use information, to study and document hazards, to link findings to health outcomes, and to understand the complexities of regulations and laws needed to take efficacious action. Because water issues are creating headlines world-wide, we draw from several water-related cases on American Indian tribal lands to examine some of the complexities associated with building needed skills, obtaining accessible information, and navigating the layers of laws and regulations that enable or inhibit efficacious action. Each case highlights the importance of partnerships, skill building, and collaborative action to redress environmental assaults. For our analysis, we draw from and expand upon Nutbeam's typology of health literacy which includes functional, interactive, and critical stages to derive lessons from each of the EHL cases. Community partnerships engaging in EHL efforts still face many challenges, including enhancing skills for community members as well as professionals, clarifying scientific processes and findings, articulating and respecting cultural practices and needs, and translating policies and laws for community accessibility and collaborative action.

Summary Human type 1 insulin-like growth factor receptor (IGF-1R) signals chiefly in response to the binding of insulin-like growth factor I. Relatively little is known about the role of insulin-like growth factor II signaling via IGF-1R, despite the affinity of insulin-like growth factor II for IGF-1R being within an order of magnitude of that of insulin-like growth factor I. Here, we describe the cryoelectron microscopy structure of insulin-like growth factor II bound to a leucine-zipper-stabilized IGF-1R ectodomain, determined in two conformations to a maximum average resolution of 3.2 Å. The two conformations differ in the relative separation of their respective points of membrane entry, and comparison with the structure of insulin-like growth factor I bound to IGF-1R reveals long-suspected differences in the way in which the critical C domain of the respective growth factors interact with IGF-1R., Graphical Abstract, Highlights • Cryo-EM structure of IGF-II bound to leucine-zippered human IGF-1R ectodomain • IGF-II C domain interacts with receptor differently to that of IGF-I, Insulin-like growth factors I and II differ in the length of their C domain, the segment that links growth factor B and A domains. Xu et al. show that the different 3D modes of C-domain engagement with type 1 insulin-like growth factor receptor align with their receptor affinity.