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BackgroundHistologically normal appendices resected for right iliac fossa pain in children demonstrate immunohistochemical markers of inflammation. We aimed to establish if subclinical inflammation was present in histologically normal appendices resected from adults with right iliac fossa pain.MethodsImmunohistochemistry was performed on formalin-fixed paraffin-embedded appendices for tumour necrosis factor (TNF)-α, interleukin (IL)-6, IL-2R and serotonin in four groups: Group I (n = 120): uncomplicated appendicitis, Group II (n = 118): complicated appendicitis (perforation or gangrene), Group III (n = 104): histologically normal appendices resected for right iliac fossa pain and Group IV (n = 106) appendices resected at elective colectomy. Expression was quantified using the H-scoring system.ResultsMedian, interquartile range expression of TNF-α was increased in Groups I (5.9, 3.1–9.8), II (6.8, 3.6–12.1) and III (9.8, 6.2–15.2) when compared with Group IV (3.0, 1.4–4.7,p p p p ConclusionHistologically normal appendices resected from symptomatic patients exhibited increased proinflammatory cytokine expression on immunohistochemistry suggesting the presence of an inflammatory process not detected on conventional microscopy.

BackgroundDeaths from COVID-19 have exceeded 1.8 million globally (January 2020). We examined trends in markers of neonatal care before and during the pandemic at two tertiary neonatal units in Zimbabwe and Malawi.MethodsWe analysed data collected prospectively via the NeoTree app at Sally Mugabe Central Hospital (SMCH), Zimbabwe, and Kamuzu Central Hospital (KCH), Malawi. Neonates admitted from 1 June 2019 to 25 September 2020 were included. We modelled the impact of the first cases of COVID-19 (Zimbabwe: 20 March 2020; Malawi: 3 April 2020) on number of admissions, gestational age and birth weight, source of admission referrals, prevalence of neonatal encephalopathy, and overall mortality.FindingsThe study included 3,450 neonates at SMCH and 3,350 neonates at KCH. Admission numbers at SMCH did not initially change after the first case of COVID-19 but fell by 48% during a nurses’ strike (Relative risk (RR) 0·52, 95%CI 0·40-0·68, p < 0·002). At KCH, admissions dropped by 42% (RR 0·58; 95%CI 0·48-0·70; p < 0·001) soon after the first case of COVID-19. At KCH, gestational age and birth weight decreased slightly (1 week, 300 grams), outside referrals dropped by 28%, and there was a slight weekly increase in mortality. No changes in these outcomes were found at SMCH.InterpretationThe indirect impacts of COVID-19 are context-specific. While this study provides vital evidence to inform health providers and policy makers, national data are required to ascertain the true impacts of the pandemic on newborn health.FundingInternational Child Health Group, Wellcome Trust.RESEARCH IN CONTEXTEvidence before this studyWe searched PubMed for evidence of the indirect impact of the COVID-19 pandemic on neonatal care in low-income settings using the search terms neonat*ornewborn, andCOVID-19orSARS-CoV 2orcoronavirus, and the Cochrane low and middle income country (LMIC) filters, with no language limits between 01.10.2019 and 21.11.20. While there has been a decrease in global neonatal mortality rates, the smaller improvements seen in low-income settings are threatened by the direct and indirect impact of the COVID-19 pandemic. A modelling study of this threat predicted between 250000-1.1 million extra neonatal deaths as a result of decreased service provision and access in LMICs. A webinar and survey of frontline maternal/newborn healthcare workers in >60 countries reported a decline in both service attendance and in quality of service across the ante-, peri- and post-natal journey. Reporting fear of attending services, and difficulty in access, and a decrease in service quality due to exacerbation of existing service weaknesses, confusion over guidelines and understaffing. Similar findings were reported in a survey of healthcare workers providing childhood and maternal vaccines in LMICs. One study to date has reported data from Nepal describing an increase in stillbirths and neonatal deaths, with institutional deliveries nearly halved during lockdown.Added value of this studyTo our knowledge, this is the first and only study in Sub-Saharan Africa describing the impact of COVID-19 pandemic on health service access and outcomes for newborns in two countries. We analysed data from the digital quality improvement and data collection tool, the NeoTree, to carry out an interrupted time series analysis of newborn admission rates, gestational age, birth weight, diagnosis of hypoxic ischaemic encephalopathy and mortality from two large hospitals in Malawi and Zimbabwe (n∼7000 babies). We found that the indirect impacts of COVID-19 were context-specific. In Sally Mugabe Central Hospital, Zimbabwe, initial resilience was demonstrated in that there was no evidence of change in mortality, birth weight or gestational age. In comparison, at Kamuzu Central Hospital, Malawi, soon after the first case of COVID-19, the data revealed a fall in admissions (by 42%), gestational age (1 week), birth weight (300 grams), and outside referrals (by 28%), and there was a slight weekly increase in mortality (2%). In the Zimbabwean hospital, admission numbers did not initially change after the first case of COVID-19 but fell by 48% during a nurses’ strike, which in itself was in response to challenges exacerbated by the pandemic.Implications of all the available evidenceOur data confirms the reports from frontline healthcare workers of a perceived decline in neonatal service access and provision in LMICs. Digital routine healthcare data capture enabled rapid profiling of indirect impacts of COVID-19 on newborn care and outcomes in two tertiary referral hospitals, Malawi and Zimbabwe. While a decrease in service access was seen in both countries, the impacts on care provided and outcome differed by national context. Health systems strengthening, for example digital data capture, may assist in planning context-specific mitigation efforts.

A Pregnant Woman with Ventricular Tachycardia and Shock A 26-year-old pregnant woman presented at 32 weeks of gestation with cardiogenic shock after cardiac arrest. The troponin T level was markedl...

The leading cause of central vision loss, age‐related macular degeneration (AMD), is a degenerative disorder characterized by atrophy of retinal pigment epithelium (RPE) and photoreceptors. For 15% of cases, neovascularization occurs, leading to acute vision loss if left untreated. For the remaining patients, there are currently no treatment options and preventing progressive RPE atrophy remains the main therapeutic goal. Previously, we have shown treatment with interleukin‐33 can reduce choroidal neovascularization and attenuate tissue remodelling. Here, we investigate IL‐33 delivery in aged, high‐fat diet (HFD) fed mice on a wildtype and complement factor H heterozygous knockout background. We characterize the non‐toxic effect following intravitreal injection of IL‐33 and further demonstrate protective effects against RPE cell death with evidence of maintaining metabolic retinal homeostasis of Cfh+/−~HFD mice. Our results further support the potential utility of IL‐33 to prevent AMD progression.

Patients with more than one chronic condition often receive care from several providers and facilities, which may lead to fragmentation of care. Poor care coordination in dual health care system use has been associated with increased emergency department visits, hospitalizations, and costs.Dual health care system use is increasing among veterans, and we sought to evaluate the effect of dual health care system use on statin treatment in veterans with type 2 diabetes at high risk of cardiovascular events, using varying degrees of Centers for MedicareMedicaid Services (CMS) services.This was a 10-year retrospective longitudinal cohort study of national clinical and administrative data that included 689,138 veterans with type 2 diabetes who were aged 65 years or older on January 1, 2006. Patients were followed from January 1, 2007, until December 31, 2016. Administrative and clinical data from the Veterans Health Administration's (VHA) Corporate Data Warehouse were merged with CMS inpatient, outpatient, and pharmacy data. Statin use was defined as any therapy and subcategorized as high versus low or moderate intensity per the American College of Cardiology/American Heart Association guidelines. Marginal generalized estimating equation-type models for longitudinal data were used to model the association between dual health care utilization status (50%, 50%-80%, and80% VHA utilization, with the first group serving as the reference group) and statin use after adjusting for measured covariates.The mean ages at baseline for each group were similar and ranged between 75.4 and 76.9 years. For the outcome of any statin use, the group with50% VHA utilization was significantly less likely to receive statin therapy compared with the group with80% VHA utilization (OR = 0.26, 95% CI = 0.26-0.26), while the group with 50%-80% VHA utilization was slightly more likely (OR = 1.05, 95% CI = 1.04-1.07). Similarly, for the high-intensity versus low-/moderate-intensity or no statins outcome, the group with50% VHA utilization was significantly less likely to receive a high-intensity statin compared with the group with80% VHA utilization (OR = 0.56, 95% CI = 0.55-0.57), while the group with 50%-80% VHA utilization was only slightly less likely (OR = 0.95, 95% CI =0.94-0.96).Among veterans with diabetes at high risk of cardiovascular events, dual health care system utilization status appeared to affect statin use. We observed lower odds for any statin use and high-intensity statin therapy among the cohort with the lowest degree of VHA utilization (i.e.,50%). Interventions to increase statin use among veterans at high risk of cardiovascular events with lower degrees of VHA utilization should be explored.This study was supported by a grant funded by the Department of Veterans Affairs' Health Services Research and Development Service and was undertaken at the Health Equity and Rural Outreach Center (HEROIC) at Ralph H. Johnson Veteran Affairs Medical Center, Charleston, SC. The authors report no potential conflicts of interest relevant to this article. This article represents the views of the authors and not those of the Medical University of South Carolina or Veteran Health Administration.

OBJECTIVEGeographic and racial/ethnic disparities related to diabetes control and treatment have not previously been examined at the national level.RESEARCH DESIGN AND METHODSA retrospective cohort study was conducted in a national cohort of 1,140,634 veterans with diabetes, defined as two or more diabetes ICD-9 codes (250.xx) across inpatient and outpatient records. Main exposures of interest included 125 Veterans Administration Medical Center (VAMC) catchment areas as well as racial/ethnic group. The main outcome measure was HbA1c level dichotomized at ≥8.0% (≥64 mmol/mol).RESULTSAfter adjustment for age, sex, racial/ethnic group, service-connected disability, marital status, and the van Walraven Elixhauser comorbidity score, the prevalence of uncontrolled diabetes varied by VAMC catchment area, with values ranging from 19.1% to 29.2%. Moreover, these differences largely persisted after further adjusting for medication use and adherence as well as utilization and access metrics. Racial/ethnic differences in diabetes control were also noted. In our final models, compared with non-Hispanic Whites, non-Hispanic Blacks (odds ratio 1.11 [95% credible interval 1.09–1.14]) and Hispanics (1.36 [1.09–1.14]) had a higher odds of uncontrolled HBA1c level.CONCLUSIONSIn a national cohort of veterans with diabetes, we found geographic as well as racial/ethnic differences in diabetes control rates that were not explained by adjustment for demographics, comorbidity burden, use or type of diabetes medication, health care utilization, access metrics, or medication adherence. Moreover, disparities in suboptimal control appeared consistent across most, but not all, VAMC catchment areas, with non-Hispanic Black and Hispanic veterans having a higher odds of suboptimal diabetes control than non-Hispanic White veterans.

Methamphetamine (MA) use during pregnancy is a significant public health concern in the United States and affects long-term brain and behavioral development in children. We hypothesized that prenatal MA exposure would be related to greater DNA methylation of HSD11B2 and postnatal environmental stress.The Infant Development, Environment, and Lifestyle Study (IDEAL), a longitudinal study of prenatal MA exposure enrolled mother-infant dyads in California, Hawaii, Iowa, and Oklahoma. Prenatal exposure was defined by maternal self-report and/or meconium toxicology screening. At ages 10-11 years, 100 children were assessed for drug exposure and DNA methylation of HSD11B2. Hierarchical linear models were used to determine the association between prenatal MA exposure and methylation of HSD11B2 at four CpG sites.Prenatal MA exposure (1.4% vs 0.31%, P 0.01) and early childhood adversity (3.0 vs 2.0, P 0.01) were associated with greater DNA methylation of HSD11B2 at the CpG2 site. The statistically significant effects of early childhood adversity (B = 0.11, P 0.01) and prenatal MA exposure (B = 0.32, P = 0.03) on DNA methylation remained after adjusting for covariates.Prenatal MA exposure is related to postnatal childhood adversity and epigenetic alterations in HSD11B2, an important gene along the stress response pathway suggesting prenatal and postnatal programming effects.Prenatal methamphetamine exposure has been associated with developmental issues in newborns, yet little is known about the stress pathophysiology of methamphetamine on neurobehavior. This is the first evidence that prenatal methamphetamine exposure acts as a stressor, confirming the third pathophysiology of methamphetamine exposure.

Significance Neuropeptide Y (NPY) is implicated in many pathological conditions including obesity, diabetes, and insulin resistance. However, a pathogenic role of NPY in kidney disease has not been described. We found that NPY is produced by the podocyte in the glomerulus, and this production decreases in renal disease, in contrast to an increase in circulating NPY levels. In the glomerulus, NPY signals via the NPY receptor 2 (NPY2R) and modulates PI3K, MAPK, and NFAT signaling, along with RNA processing and cell migration and, if prolonged, predicted nephrotoxicity. The pharmacological inhibition of NPY-NPY2R signaling also protected against albuminuria and kidney disease in a mouse model of glomerulosclerosis, suggesting that inhibiting this pathway may be therapeutically beneficial in the prevention of kidney disease., Albuminuria is an independent risk factor for the progression to end-stage kidney failure, cardiovascular morbidity, and premature death. As such, discovering signaling pathways that modulate albuminuria is desirable. Here, we studied the transcriptomes of podocytes, key cells in the prevention of albuminuria, under diabetic conditions. We found that Neuropeptide Y (NPY) was significantly down-regulated in insulin-resistant vs. insulin-sensitive mouse podocytes and in human glomeruli of patients with early and late-stage diabetic nephropathy, as well as other nondiabetic glomerular diseases. This contrasts with the increased plasma and urinary levels of NPY that are observed in such conditions. Studying NPY-knockout mice, we found that NPY deficiency in vivo surprisingly reduced the level of albuminuria and podocyte injury in models of both diabetic and nondiabetic kidney disease. In vitro, podocyte NPY signaling occurred via the NPY2 receptor (NPY2R), stimulating PI3K, MAPK, and NFAT activation. Additional unbiased proteomic analysis revealed that glomerular NPY-NPY2R signaling predicted nephrotoxicity, modulated RNA processing, and inhibited cell migration. Furthermore, pharmacologically inhibiting the NPY2R in vivo significantly reduced albuminuria in adriamycin-treated glomerulosclerotic mice. Our findings suggest a pathogenic role of excessive NPY-NPY2R signaling in the glomerulus and that inhibiting NPY-NPY2R signaling in albuminuric kidney disease has therapeutic potential.

The endothelial glycocalyx is a key component of the glomerular filtration barrier. We have shown that matrix metalloproteinase (MMP)-mediated syndecan 4 shedding is a mechanism of glomerular endothelial glycocalyx damage in vitro, resulting in increased albumin permeability. Here we sought to determine whether this mechanism is important in early diabetic kidney disease, by studying streptozotocin-induced type 1 diabetes in DBA2/J mice. Diabetic mice were albuminuric, had increased glomerular albumin permeability and endothelial glycocalyx damage. Syndecan 4 mRNA expression was found to be upregulated in isolated glomeruli and in flow cytometry-sorted glomerular endothelial cells. In contrast, glomerular endothelial luminal surface syndecan 4 and Marasmium oreades agglutinin lectin labelling measurements were reduced in the diabetic mice. Similarly, syndecan 4 protein expression was significantly decreased in isolated glomeruli but increased in plasma and urine, suggesting syndecan 4 shedding. Mmp-2, 9 and 14 mRNA expression were upregulated in isolated glomeruli, suggesting a possible mechanism of glycocalyx damage and albuminuria. We therefore characterised in detail the activity of MMP-2 and 9 and found significant increases in kidney cortex, plasma and urine. Treatment with MMP-2/9 inhibitor I for 21 days, started six weeks after diabetes induction, restored endothelial glycocalyx depth and coverage and attenuated diabetes-induced albuminuria and reduced glomerular albumin permeability. MMP inhibitor treatment significantly attenuated glomerular endothelial and plasma syndecan 4 shedding and inhibited plasma MMP activity. Thus, our studies confirm the importance of MMPs in endothelial glycocalyx damage and albuminuria in early diabetes and demonstrate that this pathway is amenable to therapeutic intervention. Hence, treatments targeted at glycocalyx protection by MMP inhibition may be of benefit in diabetic kidney disease.

BACKGROUND Psychosocial adversity escalates medical risk for poor outcomes in infants born

Mitochondrial supercomplexes form around a conserved core of monomeric complex I and dimeric complex III; wherein a subunit of the former, NDUFA11, is conspicuously situated at the interface. We identified nduf-11 (B0491.5) as encoding the Caenorhabditis elegans homologue of NDUFA11. Animals homozygous for a CRISPR-Cas9-generated knockout allele of nduf-11 arrested at the second larval (L2) development stage. Reducing (but not eliminating) expression using RNAi allowed development to adulthood, enabling characterisation of the consequences: destabilisation of complex I and its supercomplexes and perturbation of respiratory function. The loss of NADH dehydrogenase activity was compensated by enhanced complex II activity, with the potential for detrimental reactive oxygen species (ROS) production. Cryo-electron tomography highlighted aberrant morphology of cristae and widening of both cristae junctions and the intermembrane space. The requirement of NDUF-11 for balanced respiration, mitochondrial morphology and development presumably arises due to its involvement in complex I and supercomplex maintenance. This highlights the importance of respiratory complex integrity for health and the potential for its perturbation to cause mitochondrial disease. This article has an associated First Person interview with Amber Knapp-Wilson, joint first author of the paper., Summary: Destabilisation of complex I and its supercomplexes by removal of the assembly factor NDUF-11 severely affects balanced respiration, mitochondrial morphology and, ultimately, whole animal physiology.

BackgroundInterstitial fibrosis, tubular atrophy, and inflammation are major contributors to renal allograft failure. Here we seek an objective, quantitative pathological assessment of these lesions to improve predictive utility.MethodsWe constructed a deep-learning-based pipeline recognizing normal vs. abnormal kidney tissue compartments and mononuclear leukocyte (MNL) infiltrates from Periodic acid-Schiff (PAS) stained slides of transplant biopsies (training: n=60, testing: n=33) that quantified pathological lesions specific for interstitium, tubules and MNL infiltration. The pipeline was applied to 789 whole slide images (WSI) from baseline (n=478, pre-implantation) and 12-month post-transplant (n=311) protocol biopsies in two independent cohorts (GoCAR: 404 patients, AUSCAD: 212 patients) of transplant recipients to correlate composite lesion features with graft loss.ResultsOur model accurately recognized kidney tissue compartments and MNLs. The digital features significantly correlated with Banff scores, but were more sensitive to subtle pathological changes below the thresholds in Banff scores. The Interstitial and Tubular Abnormality Score (ITAS) in baseline samples was highly predictive of 1-year graft loss (p=2.8e-05), while a Composite Damage Score (CDS) in 12-month post-transplant protocol biopsies predicted later graft loss (p=7.3e-05). ITAS and CDS outperformed Banff scores or clinical predictors with superior graft loss prediction accuracy. High/intermediate risk groups stratified by ITAS or CDS also demonstrated significantly higher incidence of eGFR decline and subsequent graft damage.ConclusionsThis deep-learning approach accurately detected and quantified pathological lesions from baseline or post-transplant biopsies, and demonstrated superior ability for prediction of posttransplant graft loss with potential application as a prevention, risk stratification or monitoring tool.

There are 2. 4 million annual neonatal deaths worldwide. Simple, evidence-based interventions such as temperature control could prevent approximately two-thirds of these deaths. However, key problems in implementing these interventions are a lack of newborn-trained healthcare workers and a lack of data collection systems. NeoTree is a digital platform aiming to improve newborn care in low-resource settings through real-time data capture and feedback alongside education and data linkage. This project demonstrates proof of concept of the NeoTree as a real-time data capture tool replacing handwritten clinical paper notes over a 9-month period in a tertiary neonatal unit at Harare Central Hospital, Zimbabwe. We aimed to deliver robust data for monthly mortality and morbidity meetings and to improve turnaround time for blood culture results among other quality improvement indicators. There were 3222 admissions and discharges entered using the NeoTree software with 41 junior doctors and 9 laboratory staff trained over the 9-month period. The NeoTree app was fully integrated into the department for all admission and discharge documentation and the monthly presentations became routine, informing local practice. An essential factor for this success was local buy-in and ownership at each stage of the project development, as was monthly data analysis and presentations allowing us to rapidly troubleshoot emerging issues. However, the laboratory arm of the project was negatively affected by nationwide economic upheaval. Our successes and challenges piloting this digital tool have provided key insights for effective future roll-out in Zimbabwe and other low-income healthcare settings.

The role of dietary calcium in cardiovascular disease prevention is unclear. We aimed to determine the association between calcium intake and incident cardiovascular disease and mortality. Data were extracted from the European Prospective Investigation of Cancer, Norfolk (EPIC-Norfolk). Multivariable Cox regressions analysed associations between calcium intake (dietary and supplemental) and cardiovascular disease (myocardial infarction, stroke, heart failure, aortic stenosis, peripheral vascular disease) and mortality (cardiovascular and all-cause). The results of this study were pooled with those from published prospective cohort studies in a meta-analsyis, stratifying by average calcium intake using a 700 mg/day threshold. A total of 17,968 participants aged 40–79 years were followed up for a median of 20.36 years (20.32–20.38). Compared to the first quintile of calcium intake (

Background Infants born very preterm are more likely to experience neonatal morbidities compared to their term peers. Variations in DNA methylation (DNAm) associated with these morbidities may yield novel information about the processes impacted by these morbidities. Methods This study included 532 infants born Results We identified ten differentially methylated CpGs (α Bonferroni-adjusted for 706,278 tests) that were associated with increasing neonatal morbidity risk scores at three intergenic regions and at HPS4, SRRD, FGFR1OP, TNS3, TMEM266, LRRC3B, ZNF780A, and TENM2. These mostly followed dose–response patterns, for 8 CpGs increasing DNAm associated with increased numbers of morbidities, while for 2 CpGs the risk score was associated with decreasing DNAm. BPD was the most substantial contributor to differential methylation. We also identified seven potential DMRs and over-representation of genes involved in Wnt signaling; however, these results were not significant after Bonferroni adjustment for multiple testing. Conclusions Neonatal DNAm, within genes involved in fibroblast growth factor activities, cellular invasion and migration, and neuronal signaling and development, are sensitive to the neonatal health complications of prematurity. We hypothesize that these epigenetic features may be representative of an integrated marker of neonatal health and development and are promising candidates to integrate with clinical information for studying developmental impairments in childhood.

Background Cardiovascular (CV) disease is the leading cause of death among United States women. Rural residence and ethnic-minority status are individually associated with increased CV mortality. Managing dyslipidemia is important in the prevention of CV mortality. However, the impact of race/ethnicity and location of residence on sex differences in dyslipidemia management is not well understood. Therefore, we sought to understand the joint effects of race/ethnicity and location of residence on lipid management differences between veteran men and women with type 2 diabetes (T2D). Methods Veterans Health Administration and Centers for Medicare and Medicaid Services data were used to perform a longitudinal cohort study of veterans with T2D (2007–2016). Mixed effects logistic regression with a random intercept was used to model the association between sex and low-density lipoprotein (LDL) > 100 mg/dL and its interaction with race/ethnicity and location of residence after adjusting for all measured covariates. Results When female sex and rural location of residence were both present, they were associated with an antagonistic harmful effect on LDL. Similar antagonistic harmful effects on LDL were observed when the joint effect of female sex and several minority race/ethnicity groups were evaluated. After adjusting for measured covariates, the odds of LDL > 100 mg/dL were higher for urban women (OR = 2.66, 95%CI 2.48–2.85) and rural women (OR = 3.26, 95%CI 2.94–3.62), compared to urban men. The odds of LDL > 100 mg/dL was the highest among non-Hispanic Black (NHB) women (OR = 5.38, 95%CI 4.45–6.51) followed by non-Hispanic White (NHW) women (OR = 2.59, 95%CI 2.44–2.77), and Hispanic women (OR = 2.56, 95%CI 1.79–3.66). Conclusion Antagonistic harmful effects on LDL were observed when both female sex and rural location of residence were present. These antagonistic effects on LDL were also present when evaluating the joint effect of female sex and several minority race/ethnicity groups. Disparities were most pronounced in NHB and rural women, who had 5.4 and 3.3 times the odds of elevated LDL versus NHW and urban men after adjusting for important covariates. These striking effect sizes in a population at high cardiovascular risk (i.e., older with T2D) suggest interventions aimed at improving lipid management are needed for individuals falling into one or more groups known to face health disparities.

There are 2.9 million annual neonatal deaths worldwide. Simple, evidence-based interventions such as temperature control could prevent approximately two-thirds of these deaths. However, key problems in implementing these interventions are a lack of newborn-trained healthcare workers and a lack of data collection systems. NeoTree is a digital platform aiming to improve newborn care in low-resource settings through real-time data capture and feedback alongside education and data linkage. This project demonstrates proof of concept of the NeoTree as a real-time data capture tool replacing hand-written clinical paper notes over a 9-month period in a tertiary neonatal unit at Harare Central hospital, Zimbabwe. We aimed to deliver robust data for monthly mortality and morbidity meetings, and to improve turn-around time for blood culture results among other quality improvement indicators.There were 3222 admissions and discharges entered using the NeoTree software with 41 junior doctors and 9 laboratory staff trained over the 9-month period. The NeoTree app was fully integrated into the department for all admission and discharge documentation and the monthly presentations became routine, informing local practice. An essential factor for this success was local buy-in and ownership at each stage of the project development, as was monthly data analysis and presentations allowing us to rapidly troubleshoot emerging issues. However, the laboratory arm of the project was negatively affected by nationwide economic upheaval. Our successes and challenges piloting this digital tool have provided key insights for effective future roll-out in Zimbabwe and other low-income healthcare settings.

BACKGROUND AND OBJECTIVES: The effects of in utero methamphetamine exposure on behavioral problems in school-aged children are unclear. Our objective for this study was to evaluate behavior problems in children at aged 3, 5, and 7.5 years who were prenatally exposed to methamphetamine. METHODS: Subjects were enrolled in the Infant Development, Environment, and Lifestyle study, a longitudinal prospective study of prenatal methamphetamine exposure and child outcomes. Exposed and comparison groups were matched on birth weight, race, education, and health insurance. At ages 3, 5, and 7.5 years, 339 children (171 exposed) were assessed for behavior problems by using the Child Behavior Checklist. Generalized estimating equations were used to determine the effects of prenatal methamphetamine exposure, age, and the interaction of exposure and age on behavior problems. Caregiver psychological symptoms were assessed by using the Brief Symptom Inventory. RESULTS: Analyses adjusted for covariates revealed that relative to age 3, children at 5 years had less externalizing and aggressive behavior and more internalizing behavior, somatic complaints, and withdrawn behavior. By age 7.5, aggressive behavior continued to decrease, attention problems increased and withdrawn behavior decreased. There were no main effects for methamphetamine exposure and no interactions of exposure and age. Caregiver psychological symptoms predicted all behavior problems and the quality of the home predicted externalizing problems and externalizing syndrome scores. CONCLUSIONS: Behavioral effects longitudinally from ages 3 to 7.5 years were not associated with prenatal methamphetamine exposure, whereas caregiver psychological symptoms and the quality of the home were predictors of behavior problems.

IntroductionNeonatal sepsis is responsible for significant morbidity and mortality worldwide. Diagnosis is often difficult due to non-specific clinical features and the unavailability of laboratory tests in many low-income and middle-income countries (LMICs). Clinical prediction models have the potential to improve diagnostic accuracy and rationalise antibiotic usage in neonatal units, which may result in reduced antimicrobial resistance and improved neonatal outcomes. In this paper, we outline our scoping review protocol to map the literature concerning clinical prediction models to diagnose neonatal sepsis. We aim to provide an overview of existing models and evidence underlying their use and compare prediction models between high-income countries and LMICs.Methods and analysisThe protocol was developed with reference to recommendations by the Joanna Briggs Institute. Searches will include six electronic databases (Ovid MEDLINE, Ovid Embase, Scopus, Web of Science, Global Index Medicus and the Cochrane Library) supplemented by hand searching of reference lists and citation analysis on included studies. No time period restrictions will be applied but only studies published in English or Spanish will be included. Screening and data extraction will be performed independently by two reviewers, with a third reviewer used to resolve conflicts. The results will be reported by narrative synthesis in line with the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews guidelines.Ethics and disseminationThe nature of the scoping review methodology means that this study does not require ethical approval. Results will be disseminated through peer-reviewed publications and conference presentations, as well as through engagement with peers and relevant stakeholders.

Background and Purpose— Fatigue is a common symptom among stroke survivors and in general practice. However, the clinical significance of fatigue and its relationship to incident stroke is unclear. The aim of this study was to examine the relationship between self-reported fatigue and the incidence of stroke in a general population. Methods— This was a prospective, population-based study. The study population was 15 654 men and women aged 39 to 79 years recruited in 1993 to 1997 and followed till March 2016. Fatigue was assessed at 18 months after baseline using the vitality domain of the Short Form 36 questionnaire. Cox proportional hazard models were constructed to describe the prospective relationship between baseline fatigue and incident stroke adjusting for age, sex, systolic blood pressure, cholesterol, physical activity, smoking status, alcohol consumption, fruit and vegetable consumption, diabetes mellitus, body mass index, vitamin supplement use, education level, Townsend deprivation index, and occupational social class. Incident stroke was ascertained using death certificates and hospital record linkage data. Results— Through 249 248 person-years of follow-up, 1509 incident strokes occurred. Participants who reported the highest level of fatigue (quartile 4) were more likely to be women, to be multimorbid, and to perceive their health as fair or poor. We observed ≈50% relative risk increase in stroke risk (hazard ratio, 1.49 [95% CI, 1.29–1.71]) in those who reported the highest level of fatigue compared with those who reported the lowest level of fatigue (Q4 versus Q1). This relationship remained unaltered regardless of anemia status, the presence or absence of chronic bronchitis, thyroid dysfunction, or depression. Conclusions— Self-report fatigue assessed by the vitality domain of the Short Form 36 questionnaire predicts the risk of future stroke at the general population level. Identifying and addressing stroke risk factors in those who report fatigue in general practice may have substantial benefit at the population level.

Gastrointestinal pneumatosis has been reported from the esophagus to the rectum, with most cases involving the small bowel, stomach, or colon. Esophageal pneumatosis is rare, with only a small number of case reports described in the literature, although it is likely underreported. Esophageal pneumatosis may be idiopathic or secondary to a specific underlying cause. Mechanisms of esophageal pneumatosis include increased intraluminal pressure, mucosal disruption, and dissection of air from an extraesophageal source. Depending on the underlying cause, esophageal pneumatosis is usually benign although it may be indicative of a life threatening condition. Esophageal pneumatosis is typically detected with CT, although it may be evident during direct visualization with endoscopy. In this article, we review the etiologies and imaging appearances of esophageal pneumatosis.

Elevated levels of vascular endothelial growth factor (VEGF) A are thought to cause glomerular endothelial cell (GEnC) dysfunction and albuminuria in diabetic nephropathy. We hypothesized that VEGFC could counteract these effects of VEGFA to protect the glomerular filtration barrier and reduce albuminuria. Isolated glomeruli were stimulated ex vivo with VEGFC, which reduced VEGFA- and type 2 diabetes–induced glomerular albumin solute permeability (Ps’alb). VEGFC had no detrimental effect on glomerular function in vivo when overexpression was induced locally in podocytes (podVEGFC) in otherwise healthy mice. Further, these mice had reduced glomerular VEGFA mRNA expression, yet increased glomerular VEGF receptor heterodimerization, indicating differential signaling by VEGFC. In a model of type 1 diabetes, the induction of podVEGFC overexpression reduced the development of hypertrophy, albuminuria, loss of GEnC fenestrations and protected against altered VEGF receptor expression. In addition, VEGFC protected against raised Ps’alb by endothelial glycocalyx disruption in glomeruli. In summary, VEGFC reduced the development of diabetic nephropathy, prevented VEGF receptor alterations in the diabetic glomerulus, and promoted both glomerular protection and endothelial barrier function. These important findings highlight a novel pathway for future investigation in the treatment of diabetic nephropathy.

Background The profound inflammatory response associated with brain death is frequently cited as the reason organs procured from brain dead donors are associated with worse graft function. The intestine releases inflammatory mediators in other types of shock, but its role is brain death has not been well-studied. Direct peritoneal resuscitation (DPR) improves visceral organ blood flow and reduces inflammation after hemorrhagic shock. We hypothesized that use of DPR would maintain intestinal integrity and reduce circulating inflammatory mediators after brain death. Methods Brain death was induced in male Sprague-Dawley rats by inserting a 4F Fogarty catheter into the epidural space and slowly inflating it. After herniation, rats were resuscitated with normal saline to maintain a mean arterial pressure of 80 mm Hg and killed with tissue collected immediately (time 0), or 2 hours, 4 hours, or 6 hours after brain death. Randomly selected animals received DPR via an intraperitoneal injection of 30-mL commercial peritoneal dialysis solution. Results Levels of proinflammatory cytokines, including IL-1β and IL-6, as well as high-mobility group box 1 protein and heat shock protein 70, were all increased after brain death and decreased with DPR. Fatty acid binding protein and lipopolysaccharide, both markers of intestinal injury, were increased in the serum after brain death and decreased with DPR. Immunohistochemistry staining for zona occludin-1 showed decreased intestinal tight junction integrity after brain death, which improved with DPR. Conclusions Intestinal permeability increases after brain death, and this contributes to the increased inflammation seen throughout the body. Using DPR prevents intestinal ischemia and helps preserve intestinal integrity. This suggests that using this novel therapy as an adjunct to the resuscitation of brain dead donors has the potential to reduce inflammation and potentially improve the quality of transplanted organs.

Objectives This study explores perceptions of US Veterans Affairs (VA) and non-VA healthcare providers caring for Veterans with heart failure (HF) regarding Veteran knowledge and motivations for dual use, provider roles in recommending and coordinating dual use, systems barriers and facilitators, and suggestions for improving cross-system care. Methods Twenty VA and 11 non-VA providers participated in semi-structured interviews, which were analyzed using parallel qualitative content and discourse analysis. Results VA and non-VA providers described variable HF knowledge and self-management among Veterans, and both groups described the need for improved education addressing medication adherence, self-care, and management of acute symptoms. Both groups described highly limited roles for providers in shaping choices surrounding dual use. VA and non-VA providers had significantly different perceptions regarding the availability, quality, and effectiveness of VA HF services. Multiple non-VA providers expressed frustration with and difficulty in contacting VA providers, accessing records, and making referrals into the VA system. Suggestions for improved care focused on patient education and care coordination. Discussion Dual healthcare system use for Veterans is increasingly common. Similarities and contrasts in perceptions of VA and non-VA providers are instructive and should be incorporated into future policy and program initiatives.

Varicella zoster virus (VZV) infection has been implicated in multiple sclerosis (MS), but direct causal involvement has been disputed. Nevertheless, knowledge of VZV exposure is important, given the risk of serious complications of first exposure while undergoing immunosuppressive treatment, in particular with fingolimod. We distributed questionnaires to MS clinic patients, requesting information about history of chickenpox, sibling/household/occupational exposure, history of zoster (shingles), and disease-modifying treatment. A random, proportionally representative sample of 51 patients that included patients with positive, negative, and unknown chickenpox history were selected for determination of VZV IgG by ELISA. Of 1206 distributed questionnaires, 605 were returned (50% response rate). Of these, 86% reported history of chickenpox, 5.6% gave negative history, and 8.5% did not know. Of 594 who answered the zoster question, 78% gave a negative response, 4% did not know, and 104 (17%) answered yes. Of these, 83 reported 1 episode; 12 had 2; 5 had 3; and 1 each reported 5, 6, and 15 episodes. Of 51 patients tested for VZV IgG (44 "yes," 4 "no," and 3 "I don't know" answers to the question of whether they had chickenpox), 48 were seropositive; the 3 seronegative all had reported having had chickenpox. The high rate of MS patients reporting prior chickenpox infection is comparable with previous reports. A substantial proportion of MS patients, estimated to be higher than an age-matched general population, report single or multiple episodes of zoster. These data are useful for consideration of immunosuppressive treatments and/or VZV and zoster vaccination.

Chronic kidney disease (CKD) is strongly associated with a decrease in the expression of VEGF-A. However, little is known about the contribution of VEGF-A splice isoforms to kidney physiology and pathology. Previous studies suggest that the splice isoform VEGF-A165b (resulting from alternative usage of a 3’ splice site in the terminal exon) is protective for kidney function. We show here, in a quad-transgenic model, that over-expression of VEGF-A165b alone is sufficient to rescue the increase in proteinuria as well as glomerular water permeability in the context of progressive depletion of all VEGF-A isoforms from the podocytes. Ultrastructural studies show that the glomerular basement membrane is thickened, podocyte slit width is increased and sub-podocyte space coverage is reduced when VEGF-A is depleted, all of which are rescued in VEGF-A165b over-expressors. VEGF-A165b restores the expression of PECAM-1 in glomerular endothelial cells and glomerular capillary circumference. Mechanistically, it increases VEGFR2 expression both in vivo and in vitro and down-regulates genes involved in migration and proliferation of endothelial cells, otherwise up-regulated by the canonical isoform VEGF-A165. Our study indicates that manipulation of VEGF-A splice isoforms could be a novel therapeutic avenue in chronic glomerular disease.

Peritoneal resuscitation (PR) represents a unique modality of treatment for severely injured trauma patients requiring damage control surgery. These data represent the outcomes of a single institution randomized controlled trial into the efficacy of PR as a management option in these patients.From 2011 to 2015, one hundred and three patients were enrolled in a prospective randomized controlled trial evaluating the use of PR in the treatment of patients undergoing damage control surgery compared with conventional resuscitation (CR) alone. Patient demographics, clinical variables, and outcomes were collected. Univariate and multivariate analysis was performed with a priori significance at p ≤ 0.05.After initial screening, 52 patients were randomized to the PR group and 51 to the CR group. Age, sex, initial pH, and mechanism of injury were used for randomization. Method of abdominal closure was standardized across groups. Time to definitive abdominal closure was reduced in the PR group compared with the CR group (4.1 ± 2.2 days vs 5.9 ± 3.5 days; p ≤ 0.002). Volume of resuscitation and blood products transfused in the initial 24 hours was not different between the groups. Primary fascial closure rate was higher in the PR group (83% vs 66%; p ≤ 0.05). Intra-abdominal complications were lower in the PR compared with the CR group (8% vs 18%), with abscess formation rate (3% vs 14%; p 0.05) being significant. Patients in the PR group had a lower 30-day mortality rate, despite similar Injury Severity Scores (13% vs 28%; p = 0.06).Peritoneal resuscitation enhances management of damage control surgery patients by reducing time to definitive abdominal closure, intra-abdominal infections, and mortality rates.

* Abbreviations: AAP — : American Academy of Pediatrics PPD — : postpartum depression In early 2019, the American Academy of Pediatrics (AAP) released a policy statement1 recognizing that “maternal depression affects the whole family” and urging pediatric providers to “incorporate recognition and management of perinatal depression into pediatric practice.” Soon after, the US Preventive Services Task Force issued new recommendations on interventions to prevent perinatal depression.2 The convergence of these 2 statements from nationally recognized bodies of experts in evidence-based medicine underscores the urgency of a heightened focus on screening and making referrals for perinatal depression in pediatric practice. The new recommendations do not go far enough and risk being out of touch with contemporary American families. The US Preventive Services Task Force evidence review and recommendations are focused exclusively on interventions to prevent maternal depression. The AAP statement acknowledged paternal postpartum depression (PPD) as an established clinical problem yet called for pediatricians to screen solely mothers at the 1-, 2-, 4-, and 6-month well-child visits and “consider screening the partner as well” at the 6-month visit. We believe it is inadequate to treat the recognition and management of paternal depression as extra or optional. To promote optimal outcomes for children, pediatric providers must assess the mental health and adjustment to parenting of all new parents, regardless of gender or marital status, and make appropriate referrals for needed care. Fathers’ time spent with children has nearly tripled since 19653; even among unmarried couples, fathers typically want to be and are involved with their children. … Address correspondence to Tova B. Walsh, PhD, School of Social Work, University of Wisconsin, 1350 University Ave, Madison, WI 53706. E-mail: tbwalsh{at}wisc.edu

Novel, all-oral interferon-free direct-acting antiviral agents have revolutionized the management of hepatitis C virus (HCV) infection by producing exceptional cure rates with minimal adverse events. While provocation or exacerbation of autoimmunity has been reported in HCV-infected patients receiving interferon, this phenomenon has not been reported in patients receiving interferon-free HCV therapy. We report the occurrence of three cases of lupus-like immune complex-mediated glomerulonephritis occurring shortly after exposure to sofosbuvir-based direct-acting antiviral therapies. In all three cases, renal function quickly improved with immunosuppression. However, two of the three patients developed infectious complications of immunosuppression and died. This is the first report of a lupus-like immune complex mediated glomerulonephritis occurring in the context of HCV eradication with all-oral direct-acting antiviral therapies.

Veterans with evidence of homelessness have high rates of mental health and substance abuse disorders, but chronic medical conditions such as diabetes are also prevalent. We aimed to determine the impact of homelessness on glycemic control in patients with type 2 diabetes mellitus. Longitudinal analysis of a retrospective cohort. A national cohort of 1,263,906 Veterans with type 2 diabetes. Subjects with evidence of homelessness were identified using a combination of diagnostic and administrative codes. Odds for poor glycemic control using hemoglobin A1C (HbA1C) cutoff values of 8 % and 9 %. Homeless defined as a score based on the number of indicator variables for homelessness within a veterans chart. Veterans with evidence of homelessness had a significantly greater annual mean HbA1C ≥ 8 (32.6 % vs. 20.43 %) and HbA1C ≥ 9 (21.4 % vs. 9.9 %), tended to be younger (58 vs. 67 years), were more likely to be non-Hispanic black (39.1 %), divorced (43 %) or never married (34 %), to be urban dwelling (88.8 %), and to have comorbid substance abuse (46.7 %), depression (42.3 %), psychoses (39.7 %), liver disease (18.8 %), and fluid/electrolyte disorders (20.4 %), relative to non-homeless veterans (all p

BACKGROUND: Among preterm infants, neurodevelopmental outcomes are influenced by both medical and sociodemographic factors. Less is known about the impact on these factors on neonatal neurobehavioral patterns. OBJECTIVE: To determine associations between demographic, psychosocial and medical risk factors and neonatal neurobehavior. METHODS: Multi-center observational study of infants born

Temporary and permanent tracheostomies are required in children to manage actual or anticipated long‐term ventilatory support, to aid secretion management or to manage fixed upper airway obstruction. Tracheostomies may be required from the first few moments of life, with the majority performed in children < 4 years of age. Although similarities with adult tracheostomies are apparent, there are key differences when managing the routine and emergency care of children with tracheostomies. The National Tracheostomy Safety Project identified the need for structured guidelines to aid multidisciplinary clinical decision making during paediatric tracheostomy emergencies. These guidelines describe the development of a bespoke emergency management algorithm and supporting resources. Our aim is to reduce the frequency, nature and severity of paediatric tracheostomy emergencies through preparation and education of staff, parents, carers and patients.

Recently, it was shown that infectious bacterial aortitis can stimulate an elevated IgG4⁺ plasma cell response in the vessel wall, which could mimic IgG4 aortitis/periaortitis. However, the factors that are associated with an elevated IgG4⁺ plasma cell response in infectious aortitis are unclear. To ascertain these factors, 17 cases of infectious aortitis and 6 cases of non-infectious severe abdominal aortic atherosclerosis were assessed for the magnitude of IgG4⁺ plasma cell response. The degree of IgG4⁺ plasma cell infiltration was determined by immunohistochemistry. Infectious cases were subcharacterized as chronic (>3 weeks duration) or acute (

Background: older adults are susceptible to dehydration due to age-related pathophysiological changes. We aimed to investigate the prevalence of hyperosmolar dehydration (HD) in hospitalised older adults, aged ≥65 years, admitted as an emergency and to assess the impact on short-term and long-term outcome. Methods: this prospective cohort study was performed on older adult participants who were admitted acutely to a large UK teaching hospital. Data collected included the Charlson comorbidity index (CCI), national early warning score (NEWS), Canadian Study of Health and Aging (CSHA) clinical frailty scale and Nutrition Risk Screening Tool (NRS) 2002. Admission bloods were used to measure serum osmolality. HD was defined as serum osmolality >300 mOsmol/kg. Participants who were still in hospital 48 h after admission were reviewed, and the same measurements were repeated. Results: a total of 200 participants were recruited at admission to hospital, 37% of whom were dehydrated. Of those dehydrated, 62% were still dehydrated when reviewed at 48 h after admission. Overall, 7% of the participants died in hospital, 79% of whom were dehydrated at admission (P = 0.001). Cox regression analysis adjusted for age, gender, CCI, NEWS, CSHA and NRS demonstrated that participants dehydrated at admission were 6 times more likely to die in hospital than those euhydrated, hazards ratio (HR) 6.04 (1.64–22.25); P = 0.007. Conclusions: HD is common in hospitalised older adults and is associated with poor outcome. Coordinated efforts are necessary to develop comprehensive hydration assessment tools to implement and monitor a real change in culture and attitude towards hydration in hospitalised older adults.

Interest in machine perfusion (MP) for donated kidneys has markedly increased in the past decade as a means to improve graft function, although the donor populations in which it should be applied have not yet been resolved. All adults undergoing de-novo isolated kidney transplantation from standard-criteria donors in the UNOS database 2005 to 2011 were reviewed with the primary endpoint of delayed graft function (DGF), defined as dialysis within seven days of transplantation, in those who received kidneys that underwent MP versus cold storage (CS) alone. Three methods were used to control for differences between groups. Multivariable logistic regression was performed, adjusting for donor and recipient characteristics significantly associated with DGF. Rates were also compared in a cohort of propensity-matched MP vs CS recipients. Finally, a paired-kidney study was performed, where one kidney underwent MP and the contralateral underwent CS. There were 36,323 patients, with unadjusted DGF rates of 18.6 per cent (n = 1830/9882) and 22.4 per cent (n = 5931/26,441; P < 0.001) in the MP vs CS groups, respectively. After multivariable analysis, the odds ratio for DGF in the MP group was 0.59 ( P < 0.001) versus CS. In the propensity-matched cohort, there were 8929 patients each in the MP and CS groups. DGF occurred in 16.8 per cent of the MP group vs 25.3 per cent with CS ( P < 0.001, OR 0.59). In the paired-kidney study, rates of DGF were 16.7 per cent vs 24.3 per cent ( P < 0.001) in the 1665 recipients each in the MP versus CS groups (OR 0.6). In conclusion, machine perfusion is beneficial in reducing DGF even when standard donors are utilized, and thus should not be limited to marginal kidneys.

Increased urinary albumin excretion is a key feature of glomerular disease but has limitations as a measure of glomerular permeability. Here we describe a novel assay to measure the apparent albumin permeability of single capillaries in glomeruli, isolated from perfused kidneys cleared of red blood cells. The rate of decline of the albumin concentration within the capillary lumen was quantified using confocal microscopy and used to calculate apparent permeability. The assay was extensively validated and provided robust, reproducible estimates of glomerular albumin permeability. These values were comparable with previous in vivo data, showing this assay could be applied to human as well as rodent glomeruli. To confirm this, we showed that targeted endothelial glycocalyx disruption resulted in increased glomerular albumin permeability in mice. Furthermore, incubation with plasma from patients with post-transplant recurrence of nephrotic syndrome increased albumin permeability in rat glomeruli compared to remission plasma. Finally, in glomeruli isolated from rats with early diabetes there was a significant increase in albumin permeability and loss of endothelial glycocalyx, both of which were ameliorated by angiopoietin-1. Thus, a glomerular permeability assay, producing physiologically relevant values with sufficient sensitivity to measure changes in glomerular permeability and independent of tubular function, was developed and validated. This assay significantly advances the ability to study biology and disease in rodent and human glomeruli.

Erdheim-Chester disease (ECD) is a very rare disorder with only approximately 600 cases reported in the literature. ECD has been recently reclassified as a histiocytic dendritic cell neoplasm. The clinical spectrum ranges from asymptomatic tissue accumulation of histiocytes to invasive tissue infiltration, which can cause fulminant multisystem failure. It typically presents with bone pain and constitutional symptoms. Extraosseous manifestations are not uncommon. ECD-associated interstitial lung disease has been described in 20%-35% of patients. Diagnosis is primarily by tissue biopsy and immunohistochemistry showing xanthogranulomas composed of foamy histiocytes that stain positive for CD68, CD14 and CD163 and negative for CD1a and langerin. We report a case of ECD in a young man with cardiopulmonary involvement who presented with haemoptysis and dyspnoea.

Purpose To evaluate a novel chemoradiation therapy (CRT) regimen for patients with squamous cell carcinoma of the head and neck (SCCHN) incorporating a lower intensity modulated radiation therapy dose to electively treated neck lymph nodes than is currently standard. Methods and Materials Eligible patients had locally advanced SCCHN of the oral cavity, oropharynx, larynx, or hypopharynx. The 7-week CRT course consisted of weekly cisplatin at 35 mg/m2 concurrently with sequential-boost intensity modulated radiation therapy: 36 Gy to high- and low-risk planning target volumes followed by a sequential boost to the high-risk planning target volume to 70 Gy. The primary endpoint was elective nodal failure. Secondary endpoints were survival, toxicity, feeding tube duration, and quality of life evaluated by the FACT-HN and QOL-RTI surveys. Results Between 2011 and 2014, 54 patients were enrolled, 31 (57%) of whom had human papillomavirus (HPV)–positive disease. Of the patients, 35 (65%) had stage IVa disease. The median follow-up period for survivors was 36 months (range, 12-66 months). Elective nodal failure did not develop in any patient. The actuarial 3-year survival rate for the entire cohort was 91% (95% confidence interval [CI] 0.79-0.96); for the HPV-negative group, 85% (95% CI 0.61-0.95); and for the HPV-positive group, 96% (95% CI 0.77-0.99). Common grade 3 toxicities were dysphagia (79%), mucositis and/or stomatitis (41%), nausea (20%), xerostomia (13%), vomiting (11%), and neutropenia (10%). The median feeding tube duration was 142 days. Patient FACT-HN scores were higher at 3, 6, and 12 months versus at the end of treatment (P Conclusions This CRT regimen for patients with advanced SCCHN demonstrated the potential feasibility of reducing the elective dose to the neck, a topic that requires additional study in future clinical trials.

BACKGROUND The success of damage-control surgery (DCS) for the treatment of trauma has led to its use in other surgical problems such as abdominal sepsis. Previous studies using direct peritoneal resuscitation (DPR) for the treatment of trauma have yielded promising results. We present the results of the application of this technique to patients experiencing abdominal sepsis. METHODS We enrolled 88 DCS patients during a 5 year-period (January 2008 to December 2012) into a propensity-matched study to evaluate the utility of using DPR in addition to standard resuscitation. DPR consisted of peritoneal lavage with 2.5% DELFLEX, and abdominal closure was standardized across both groups. Patients were matched using Acute Physiology and Chronic Health Evaluation II (APACHE II) variables. Univariate and multivariate analyses were performed. RESULTS There were no differences between the control and experimental groups with regard to age, sex, ethnicity, or APACHE II at 24 hours. Indications for damage control included pancreatitis, perforated hollow viscous, bowel obstruction, and ischemic enterocolitis. Patients undergoing DPR had both a higher rate of (68% vs. 43%, p < 0.03) and a shorter time to definitive fascial closure (5.9 [3.2] days vs. 7.7 [4.1] days, p < 0.02). DPR patients had a decreased APACHE II and Sequential Organ Failure Assessment (SOFA) score compared with the controls at 48 hours. In addition, DPR patients had fewer abdominal complications compared with the controls (RR, 0.57; 95% confidence interval, 0.32-1.01; p = 0.038). Ventilator days and intensive care unit length of stay were both significantly reduced in the DPR group. The DPR group showed a lower overall mortality at 30 days (16% vs. 27%, p = 0.15). CONCLUSION DPR reduces time to definitive abdominal closure, increases primary fascial closure, and reduces intra-abdominal complications following DCS. DPR may also attenuate progressive physiologic injury as demonstrated by a reduction in 48-hour intensive care unit severity scores. As a result, DPR following DCS may afford better outcomes to patients experiencing shock. LEVEL OF EVIDENCE Therapeutic study, level III.

BACKGROUND The objective was to evaluate the effects of prenatal methamphetamine exposure (PME) and postnatal drug exposures identified by child hair analysis on neurobehavioral disinhibition at 6.5 years of age. METHODS Mother-infant pairs were enrolled in the Infant Development, Environment, and Lifestyle (IDEAL) Study in Los Angeles, Honolulu, Tulsa, and Des Moines. PME was determined by maternal self-report and/or positive meconium results. At the 6.5-year follow-up visit, hair was collected and analyzed for methamphetamine, tobacco, cocaine, and cannabinoid markers. Child behavioral and executive function test scores were aggregated to evaluate child neurobehavioral disinhibition. Hierarchical linear regression models assessed the impact of PME, postnatal substances, and combined PME with postnatal drug exposures on the child's neurobehavioral disinhibition aggregate score. Past year caregiver substance use was compared with child hair results. RESULTS A total of 264 children were evaluated. Significantly more PME children (n = 133) had hair positive for methamphetamine/amphetamine (27.1% versus 8.4%) and nicotine/cotinine (38.3% versus 25.2%) than children without PME (n = 131). Overall, no significant differences in analyte hair concentrations were noted between groups. Significant differences in behavioral and executive function were observed between children with and without PME. No independent effects of postnatal methamphetamine or tobacco exposure, identified by positive hair test, were noted and no additional neurobehavioral disinhibition was observed in PME children with postnatal drug exposures, as compared with PME children without postnatal exposure. CONCLUSIONS Child hair testing offered a noninvasive means to evaluate postnatal environmental drug exposure, although no effects from postnatal drug exposure alone were seen. PME, alone and in combination with postnatal drug exposures, was associated with behavioral and executive function deficits at 6.5 years.

Purpose Indomethacin, a nonselective prostaglandin inhibitor used to treat patent ductus arteriosus, is associated with intestinal perforation inducing an NEC-like illness. We sought to define the contribution of prostaglandin E 2 (PG E 2 ) and its receptor EP4 to intestinal blood flow regulation in premature neonates with NEC. Methods Newborn Sprague-Dawley rats were randomized by litter to undergo experimental NEC induction or to serve as a CONTROL. At 48hours of age, intestinal laser Doppler blood flow was assessed at baseline and after intraperitoneal administration of indomethacin, PG E 2 , EP4 antagonist, or EP4 agonist. Data were analyzed using a 2-way ANOVA with post hoc Tukey-Kramer correction. Results At baseline, NEC animals had lower intestinal blood flow than controls. Indomethacin, PG E 2 and EP4 agonist all increased ileal blood flow, but PG E 2 and EP4 agonist increased blood flow the most in NEC pups. EP4 antagonist decreased intestinal perfusion in both groups. Conclusion The above evidence suggests the importance of PG E 2 and EP4 in regulation of neonatal intestinal blood flow. Since indomethacin treatment of patent ductus arteriosus in the premature infant is associated with an increased risk of intestinal perforation owing to compromised blood flow, PG E 2 supplementation might provide intestinal protection if administered simultaneously with indomethacin.

Background Methamphetamine (MA) use among pregnant women is an increasing problem in the United States. How MA use during pregnancy affects neonatal and infant neurobehavior is unknown. Methods: The Infant Development, Environment, and Lifestyle (IDEAL) study screened 34,833 subjects at 4 clinical centers. Of the subjects, 17,961 were eligible and 3705 were consented, among which 412 were enrolled for longitudinal follow-up. Exposed subjects were identified by self-report and/or gas chromatography/mass spectroscopy (GC/MS) confirmation of amphetamine and metabolites in meconium. Comparison subjects were matched (race, birth weight, maternal education, insurance), denied amphetamine use, and had a negative meconium screen. Both groups included prenatal alcohol, tobacco, and marijuana use, but excluded use of opiates, lysergic acid diethylamide, or phencyclidine. The Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scale (NNNS) was administered within the first 5 days of life and again at 1 month to 380 enrollees (185 exposed, 195 comparison). Analysis of variance (ANOVA) tested exposure effects on NNNS summary scores at birth and 1 month. General linear model (GLM) repeated-measures analysis assessed the effect of MA exposure over time on the NNNS scores with and without covariates. Results By 1 month of age, both groups demonstrated higher quality of movement ( P = .029), less lethargy ( P = .001), and fewer asymmetric reflexes ( P = .012), with no significant differences in NNNS scores between the exposed and comparison groups. Over the first month of life, arousal increased in exposed infants but decreased in comparison infants ( P = .031) and total stress was decreased in exposed infants, with no change in comparison infants ( P = .026). Conclusions Improvement in total stress and arousal were observed in MA-exposed newborns by 1 month of age relative to the newborn period.

This study tested cognitive behavior therapy (CBT) in hypnotic-dependent, late middle-age and older adults with insomnia.Seventy volunteers age 50 and older were randomized to CBT plus drug withdrawal, placebo biofeedback (PL) plus drug withdrawal, or drug withdrawal (MED) only. The CBT and PL groups received eight, 45 min weekly treatment sessions. The drug withdrawal protocol comprised slow tapering monitored with about six biweekly, 30 min sessions. Assessment including polysomnography (PSG), sleep diaries, hypnotic consumption, daytime functioning questionnaires, and drug screens collected at baseline, posttreatment, and 1-year follow-up.Only the CBT group showed significant sleep diary improvement, sleep onset latency significantly decreased at posttreatment. For all sleep diary measures for all groups, including MED, sleep trended to improvement from baseline to follow-up. Most PSG sleep variables did not significantly change. There were no significant between group differences in medication reduction. Compared to baseline, the three groups decreased hypnotic use at posttreatment, down 84%, and follow-up, down 66%. There was no evidence of withdrawal side-effects. Daytime functioning, including anxiety and depression, improved by posttreatment. Rigorous methodological features, including documentation of strong treatment implementation and the presence of a credible placebo, elevated the confidence due these findings.Gradual drug withdrawal was associated with substantial hypnotic reduction at posttreatment and follow-up, and withdrawal side-effects were absent. When supplemented with CBT, participants accrued incremental self-reported, but not PSG, sleep benefits.

How many incorrect response options (known as distractors) to use in multiple-choice questions has been the source of considerable debate in the assessment literature, especially relative to influence on the likelihood of students’ guessing the correct answer. This study compared distractor use by second-year dental students in three successive oral and maxillofacial pathology classes that had three different examination question formats and scoring resulting in different levels of academic performance. One class was given all multiple-choice questions; the two other were given half multiple-choice questions, with and without formula scoring, and half un-cued short-answer questions. Use by at least 1 percent of the students was found to better identify functioning distractors than higher cutoffs. The average number of functioning distractors differed among the three classes and did not always correspond to differences in class scores. Increased numbers of functioning distractors were associated with higher question discrimination and greater question difficulty. Fewer functioning distractors fostered more effective student guessing and overestimation of academic achievement. Appropriate identification of functioning distractors is essential for improving examination quality and better estimating actual student knowledge through retrospective use of formula scoring, where the amount subtracted for incorrect answers is based on the harmonic mean number of functioning distractors.

Necrotizing enterocolitis (NEC) alters intestinal microvascular control mechanisms causing significant vasoconstriction. Our prior work with intraperitoneal 2.5% dextrose solution demonstrated increased intestinal perfusion in experimentally induced NEC. In the current study, we examine whether a buffered solution with lower glucose and osmolar loads similarly increases intestinal blood flow. We hypothesized that buffered 1.5% dextrose solution would increase ileal blood flow compared with baseline in NEC.We randomly assigned pregnant Sprague-Dawley rats to control (n = 103) or NEC (n = 123) groups, by litter. We induced NEC by previously published methods. Control pups were vaginally delivered and dam-fed. We used laser Doppler flowmetry to evaluate perfusion in the terminal ileum at 12, 24, 48, 72, or 96 h after delivery at baseline and after application of topical 1.5% dextrose solution. We evaluated differences between groups and time points by analysis of variance and Tukey post hoc test.Baseline blood flow in the terminal ileum increased with gestational age in both groups (P0.05). Control groups had significantly greater baseline blood flow than NEC groups (P0.05), and topical application of buffered 1.5% dextrose solution increased blood flow compared with baseline in both groups at all time points (P0.05).Topical 1.5% dextrose solution significantly enhanced blood flow in the terminal ileum to the same degree as 2.5% dextrose solution. Thus, the use of buffered 1.5% dextrose solution might be more beneficial in treating clinical NEC, because it places a lower glucose and osmotic load on NEC-injured intestine.

Until now, the functioning of the hypothalamic-pituitary-adrenal (HPA) axis in children with prenatal methamphetamine exposure (PME) had been unexamined. Previous research indicates that prenatal exposure to stimulant drugs is associated with dose-response alterations in neural growth and connectivity and consequent neurobehavioral deficits. In addition, children of drug-using parents are at an increased risk for exposure to chronic postnatal stress. In this preliminary study, we examined the associations of PME and postnatal environmental stress with cortisol stress reactivity in children with PME.Participants were 2-year-old children (N = 123; 55.3% male) with PME from a multicenter longitudinal Infant, Development, Environment, and Lifestyle Study. Saliva samples were obtained before and after a stress-inducing separation task. Hierarchical multiple regression analyses examined prenatal drug exposure, methodological and postnatal stress covariates, and interactions between levels of PME and postnatal stress.Mild to moderate potential for child physical abuse moderated increased cortisol reactivity in high exposed children with PME. Blunted cortisol reactivity was associated with caregiver's postnatal alcohol use, child's behavioral dysregulation, and the interaction between higher levels of PME and caregiver's psychopathology.Consistent with the known effects of stimulant drugs and chronically stressful environments on the HPA axis and, thus, the toxic stress and allostatic load phenomena, our results imply that elevated PME may be associated with alterations in the programming of the HPA axis reflecting hyperactivity, which under significant and chronic environmental stress then may become hypoactive.