A multicenter matched-cohort analysis of gastroschisis outcomes in infants born before 32 weeks gestation.

OBJECTIVE: To examine neonatal outcomes of infants with gastroschisis born <32 weeks' gestation compared to matched infants without gastroschisis. STUDY DESIGN: Retrospective matched-cohort analysis of infants with gastroschisis born <32 weeks' gestation at Children's Hospitals Neonatal Consortium (CHNC) NICUs from 2010 to 2022 compared to gestational age-matched controls. RESULTS: The study included 119 infants with gastroschisis and 357 matched infants; 60% of infants born 29-32 weeks, 23% born 26-28 weeks, and 16% born < 25 weeks. Mortality was not significantly different between groups (11% vs. 9%, p = 0.59). Preterm co-morbidities such as IVH, BPD, ROP, and PVL were similar, as were rates of surgical NEC. Infants with gastroschisis had longer hospital stays (92 vs. 67 days), higher CLABSI and UTIs, and were more likely to need feeding support at discharge. CONCLUSION: Compared to infants without gastroschisis, infants <32 weeks' gestation with gastroschisis had similar risks for inpatient mortality, NEC, and other preterm co-morbidities.

The effect of bethanechol on tracheobronchomalacia in preterm infants with bronchopulmonary dysplasia: a retrospective cohort study.

OBJECTIVE: Bethanechol has demonstrated improvement in trachealis tone in animal models, but no trials have studied efficacy in infants. This study aimed to examine if bethanechol improves a standardized pulmonary severity score (PSS) in infants with severe bronchopulmonary dysplasia with a diagnosis of tracheobronchomalacia (TBM). STUDY DESIGN: This retrospective cohort study evaluated cases treated with bethanechol matched with controls who did not receive bethanechol. TBM was diagnosed by dynamic computography. Daily PSS was recorded for each infant from 40 to 55 weeks post-menstrual age. RESULTS: Cases' mean PSS change was 21% lower than the controls' mean PSS change pre- and post-bethanechol (95% CI -40%, -2%) by paired t-test (p = 0.03). Matched differences (controls' PSS - cases' PSS) demonstrated greater mean PSS difference post-bethanechol compared to pre-bethanechol 0.17, (95% CI 0.05, 0.29) by paired t-test (p = 0.009). CONCLUSION: Infants with TBM treated with bethanechol compared to those not treated had a lower PSS reflecting improved respiratory status.

Empyema Necessitans a Rare Complication of Methicillin-Resistant Staphylococcus Aureus Empyema in a Child.

Empyema necessitans is a rare complication of a pleural effusion that occurs when infected fluid dissects into the chest wall from the pleural space. Mycobacterium tuberculosis and Actinomyces israelii have previously been the most commonly reported etiologic agents. This case presents an empyema necessitans secondary to methicillin-resistant Staphylococcus aureus (MRSA) following an influenza A infection in a child.

Using regulatory variants to detect gene-gene interactions identifies networks of genes linked to cell immortalisation.

The extent to which the impact of regulatory genetic variants may depend on other factors, such as the expression levels of upstream transcription factors, remains poorly understood. Here we report a framework in which regulatory variants are first aggregated into sets, and using these as estimates of the total cis-genetic effects on a gene we model their non-additive interactions with the expression of other genes in the genome. Using 1220 lymphoblastoid cell lines across platforms and independent datasets we identify 74 genes where the impact of their regulatory variant-set is linked to the expression levels of networks of distal genes. We show that these networks are predominantly associated with tumourigenesis pathways, through which immortalised cells are able to rapidly proliferate. We consequently present an approach to define gene interaction networks underlying important cellular pathways such as cell immortalisation.

High-throughput discovery of organic cages and catenanes using computational screening fused with robotic synthesis.

Supramolecular synthesis is a powerful strategy for assembling complex molecules, but to do this by targeted design is challenging. This is because multicomponent assembly reactions have the potential to form a wide variety of products. High-throughput screening can explore a broad synthetic space, but this is inefficient and inelegant when applied blindly. Here we fuse computation with robotic synthesis to create a hybrid discovery workflow for discovering new organic cage molecules, and by extension, other supramolecular systems. A total of 78 precursor combinations were investigated by computation and experiment, leading to 33 cages that were formed cleanly in one-pot syntheses. Comparison of calculations with experimental outcomes across this broad library shows that computation has the power to focus experiments, for example by identifying linkers that are less likely to be reliable for cage formation. Screening also led to the unplanned discovery of a new cage topology-doubly bridged, triply interlocked cage catenanes.

A Simulation-based, cognitive assessment of resident decision making during complex urinary catheterization scenarios.

BACKGROUND: This study explores general surgery residents' decision making skills in uncommon, complex urinary catheter scenarios. METHODS: 40 residents were presented with two scenarios. Scenario A was a male with traumatic urethral injury and scenario B was a male with complete urinary blockage. Residents verbalized whether they would catheterize the patient and described the workup and management of suspected pathologies. Residents' decision paths were documented and analyzed. RESULTS: In scenario A, 45% of participants chose to immediately consult Urology. 47.5% named five diagnostic tests to decide if catheterization was safe. In scenario B, 27% chose to catheterize with a 16 French Coude. When faced with catheterization failure, participants randomly upsized or downsized catheters. Chi-square analysis revealed no measurable consensus amongst participants. CONCLUSIONS: Residents need more training in complex decision making for urinary catheterization. The decision trees generated in this study provide a useful blueprint of residents' learning needs. SUMMARY: Exploration of general surgery residents' decision making skills in uncommon, complex urinary catheter scenarios revealed major deficiencies. The resulting decision trees reveal residents' learning needs.

Don't be rejected, how can we help authors, reviewers and editors?: Report of a Symposium for Editors Publishers and Others with an Interest in Scientific Publication, Held in Boston on Wednesday, 11 March 2015, during the Annual Meeting of the International Association for Dental Research.

This satellite symposium was the fifth in a series for editors, publishers, reviewers and all those with an interest in scientific publishing. It was held on Wednesday, 11 March 2015 at the IADR meeting in Boston, Massachusetts. The symposium attracted more than 210 attendees. The symposium placed an emphasis on strategies to ensure that papers are accepted by peer reviewed journals. The speaker, representing the Journal of Dental Research gave a history of peer review and explained how to access material to advise new authors. The speaker from India outlined the problems that occur when there is no culture for dental research and it is given a low priority in dental education. He outlined remedies. The speaker from SAGE publications described the help that publishers and editors can provide authors. The final speaker suggested that in developing countries it was essential to create alliances with dental researchers in developed countries and that local conferences to which external speakers were invited, stimulated research both in terms of quantity and quality. A wide ranging discussion then took place.

Exercise-induced improvements in liver fat and endothelial function are not sustained 12 months following cessation of exercise supervision in nonalcoholic fatty liver disease.

Supervised exercise reduces liver fat and improves endothelial function, a surrogate of cardiovascular disease (CVD) risk, in nonalcoholic fatty liver disease (NAFLD). We hypothesised that after a 16-week supervised exercise program, patients would maintain longer-term improvements in cardiorespiratory fitness, liver fat and endothelial function. Ten NAFLD patients (5/5 males/females, age 51±13 years, body mass index 31±3 kg m-2 (mean±s.d.)) underwent a 16-week supervised moderate-intensity exercise intervention. Biochemical markers, cardiorespiratory fitness (VO2peak), subcutaneous, visceral and liver fat (measured by magnetic resonance imaging and spectroscopy respectively) and brachial artery flow-mediated dilation (FMD) were assessed at baseline, after 16 weeks of supervised training and 12 months after ending supervision. Despite no significant change in body weight, there were significant improvements in VO2peak (6.5 ml kg-1 min-1 (95% confidence interval 2.8, 10.1); P=0.003), FMD (2.9% (1.5, 4.2); P=0.001), liver transaminases (P<0.05) and liver fat (-10.1% (-20.6, 0.5); P=0.048) immediately after the 16-week supervised training. Nevertheless, 12 months after ending supervision, VO2peak (0.9 ml kg-1 min-1 (-3.3, 5.1); P=0.65), FMD (-0.07% (-2.3, 2.2); P=0.95), liver transaminases (P>0.05) and liver fat (1.4% (-13.0, 15.9); P=0.83) were not significantly different from baseline. At 12 months following cessation of supervision, exercise-mediated improvements in liver fat and other cardiometabolic variables had reversed with cardiorespiratory fitness at baseline levels. Maintenance of high cardiorespiratory fitness and stability of body weight are critical public health considerations for the treatment of NAFLD (Clinicaltrials.gov identifier: NCT01834300).

Cumulative incidence and risk factors for limber tail in the Dogslife labrador retriever cohort.

Limber tail is a condition that typically affects larger working breeds causing tail limpness and pain, resolving without veterinary intervention. It is poorly understood and the disease burden has not been well characterised. Data collected from owners of the Dogslife cohort of Labrador Retrievers have been used to describe incidents and a case-control study was undertaken to elucidate risk factors with 38 cases and 86 controls. The cumulative incidence of unexplained tail limpness was 9.7 per cent. Swimming is not a necessary precursor for limber tail, but it is a risk factor (OR=4.7) and working dogs were more susceptible than non-working dogs (OR=5.1). Higher latitudes were shown to be a risk factor for developing the condition and the case dogs were more related to each other than might be expected by chance. This suggests that dogs may have an underlying genetic predisposition to developing the condition. This study is the first, large-scale investigation of limber tail and the findings reveal an unexpectedly high illness burden. Anecdotally, accepted risk factors have been confirmed and the extent of their impact has been quantified. Identifying latitude and a potential underlying genetic predisposition suggests avenues for future work on this painful and distressing condition.

Using an Integrated -Omics Approach to Identify Key Cellular Processes That Are Disturbed in the Kidney After Brain Death.

In an era where we are becoming more reliant on vulnerable kidneys for transplantation from older donors, there is an urgent need to understand how brain death leads to kidney dysfunction and, hence, how this can be prevented. Using a rodent model of hemorrhagic stroke and next-generation proteomic and metabolomic technologies, we aimed to delineate which key cellular processes are perturbed in the kidney after brain death. Pathway analysis of the proteomic signature of kidneys from brain-dead donors revealed large-scale changes in mitochondrial proteins that were associated with altered mitochondrial activity and morphological evidence of mitochondrial injury. We identified an increase in a number of glycolytic proteins and lactate production, suggesting a shift toward anaerobic metabolism. Higher amounts of succinate were found in the brain death group, in conjunction with increased markers of oxidative stress. We characterized the responsiveness of hypoxia inducible factors and found this correlated with post-brain death mean arterial pressures. Brain death leads to metabolic disturbances in the kidney and alterations in mitochondrial function and reactive oxygen species generation. This metabolic disturbance and alteration in mitochondrial function may lead to further cellular injury. Conditioning the brain-dead organ donor by altering metabolism could be a novel approach to ameliorate this brain death-induced kidney injury.

Betti reaction enables efficient synthesis of 8-hydroxyquinoline inhibitors of 2-oxoglutarate oxygenases.

There is interest in developing potent, selective, and cell-permeable inhibitors of human ferrous iron and 2-oxoglutarate (2OG) oxygenases for use in functional and target validation studies. The 3-component Betti reaction enables efficient one-step C-7 functionalisation of modified 8-hydroxyquinolines (8HQs) to produce cell-active inhibitors of KDM4 histone demethylases and other 2OG oxygenases; the work exemplifies how a template-based metallo-enzyme inhibitor approach can be used to give biologically active compounds.

Dogslife: A cohort study of Labrador Retrievers in the UK.

Studies of animals that visit primary and secondary veterinary centres dominate companion animal epidemiology. Dogslife is a research initiative that collects data directly from owners about the health and lifestyle of Kennel Club (KC) registered Labrador Retrievers (LR) in the UK. The ultimate aim is to seek associations between canine lifestyle and health. A selection of data from Dogslife regarding the height, weight and lifestyle of 4307 LR up to four years of age is reported here. The majority of the dogs were household pets, living with at least one other pet, in families or households with more than one adult. The dogs typically ate diets of dried food and daily meal frequency decreased as the dogs aged. Working dogs spent more time exercising than pets, and dogs in Wales and Scotland were exercised more than their counterparts in England. Dogs in households with children spent less time exercising than dogs in other types of households. There was considerable variation in height and weight measurements indicative of a highly heterogeneous population. The average male height at the shoulders was 2-3cm taller than the UK breed standard. Dog weights continued to increase between one and four years of age. Those with chocolate coloured coats were heavier than their yellow and black counterparts. Greater dog weight was also associated with dogs whose owners reported restricting their dog's exercise due to where they lived. These findings highlight the utility of wide public engagement in the collation of phenotypic measures, providing a unique insight into the physical development and lifestyle of a cohort of LRs. In combination with concurrently collected data on the health of the cohort, phenotypic data from the Dogslife Project will contribute to understanding the relationship between dog lifestyle and health.

Multiple UDP-glucuronosyltransferases in human liver microsomes glucuronidate both R- and S-7-hydroxywarfarin into two metabolites.

The widely used anticoagulant Coumadin (R/S-warfarin) undergoes oxidation by cytochromes P450 into hydroxywarfarins that subsequently become conjugated for excretion in urine. Hydroxywarfarins may modulate warfarin metabolism transcriptionally or through direct inhibition of cytochromes P450 and thus, UGT action toward hydroxywarfarin elimination may impact levels of the parent drugs and patient responses. Nevertheless, relatively little is known about conjugation by UDP-glucuronosyltransferases in warfarin metabolism. Herein, we identified probable conjugation sites, kinetic mechanisms and hepatic UGT isoforms involved in microsomal glucuronidation of R- and S-7-hydroxywarfarin. Both compounds underwent glucuronidation at C4 and C7 hydroxyl groups based on elution properties and spectral characteristics. Their formation demonstrated regio- and enantioselectivity by UGTs and resulted in either Michaelis-Menten or substrate inhibition kinetics. Glucuronidation at the C7 hydroxyl group occurred more readily than at the C4 group, and the reaction was overall more efficient for R-7-hydroxywarfarin due to higher affinity and rates of turnover. The use of these mechanisms and parameters to model in vivo clearance demonstrated that contributions of substrate inhibition would lead to underestimation of metabolic clearance than that predicted by Michaelis-Menten kinetics. Lastly, these processes were driven by multiple UGTs indicating redundancy in glucuronidation pathways and ultimately metabolic clearance of R- and S-7-hydroxywarfarin.

Cannabis use and transition to psychosis in people at ultra-high risk.

BACKGROUND: Cannabis use is associated with an increased risk of developing a psychotic disorder but the temporal relationship between cannabis use and onset of illness is unclear. The objective of this study was to assess prospectively the influence of cannabis use on transition to psychosis in people at ultra-high risk (UHR) for the disorder. METHOD: Lifetime and continued cannabis use was assessed in a consecutively ascertained sample of 182 people (104 male, 78 female) at UHR for psychosis. Individuals were then followed clinically for 2 years to determine their clinical outcomes. RESULTS: Lifetime cannabis use was reported by 134 individuals (73.6%). However, most of these individuals had stopped using cannabis before clinical presentation (n=98, 73.1%), usually because of adverse effects. Among lifetime users, frequent use, early-onset use and continued use after presentation were all associated with an increase in transition to psychosis. Transition to psychosis was highest among those who started using cannabis before the age of 15 years and went on to use frequently (frequent early-onset use: 25%; infrequent or late-onset use: 5%; χ(2)1=10.971, p=0.001). However, within the whole sample, cannabis users were no more likely to develop psychosis than those who had never used cannabis (cannabis use: 12.7%; no use: 18.8%; χ(2)1=1.061, p=0.303). CONCLUSIONS: In people at UHR for psychosis, lifetime cannabis use was common but not related to outcome. Among cannabis users, frequent use, early-onset use and continued use after clinical presentation were associated with transition to psychosis.

The role of hypoxia-inducible factors in organ donation and transplantation: the current perspective and future opportunities.

Hypoxia-inducible factors are the universal cellular oxygen-sensitive transcription factors that activate a number of hypoxia responsive genes, some of which are responsible for protective cellular functions. During organ donation, allografts are exposed to significant periods of hypoxia and ischemia. Exploiting this pathway during donor management and organ preservation could prevent and reduce allograft injury and improve the outcomes of organ transplantation. We review the evidence on this pathway in organ preservation, drawing on experimental studies on donor management and ischemia reperfusion injury focusing on kidney, liver, cardiac and lung transplantation. We review the major technical and experimental challenges in exploring this pathway and suggest potential future avenues for research.

Non-contact video-based vital sign monitoring using ambient light and auto-regressive models.

Remote sensing of the reflectance photoplethysmogram using a video camera typically positioned 1 m away from the patient's face is a promising method for monitoring the vital signs of patients without attaching any electrodes or sensors to them. Most of the papers in the literature on non-contact vital sign monitoring report results on human volunteers in controlled environments. We have been able to obtain estimates of heart rate and respiratory rate and preliminary results on changes in oxygen saturation from double-monitored patients undergoing haemodialysis in the Oxford Kidney Unit. To achieve this, we have devised a novel method of cancelling out aliased frequency components caused by artificial light flicker, using auto-regressive (AR) modelling and pole cancellation. Secondly, we have been able to construct accurate maps of the spatial distribution of heart rate and respiratory rate information from the coefficients of the AR model. In stable sections with minimal patient motion, the mean absolute error between the camera-derived estimate of heart rate and the reference value from a pulse oximeter is similar to the mean absolute error between two pulse oximeter measurements at different sites (finger and earlobe). The activities of daily living affect the respiratory rate, but the camera-derived estimates of this parameter are at least as accurate as those derived from a thoracic expansion sensor (chest belt). During a period of obstructive sleep apnoea, we tracked changes in oxygen saturation using the ratio of normalized reflectance changes in two colour channels (red and blue), but this required calibration against the reference data from a pulse oximeter.