Barttin is the accessory subunit of the human ClC-K chloride channels, which are expressed in both the kidney and inner ear. Barttin promotes trafficking of the complex it forms with ClC-K to the plasma membrane and is involved in activating this channel. Barttin undergoes post-translational palmitoylation that is essential for its functions, but the enzyme(s) catalyzing this post-translational modification is unknown. Here, we identified zinc finger DHHC-type containing 7 (DHHC7) protein as an important barttin palmitoyl acyltransferase, whose depletion affected barttin palmitoylation and ClC-K-barttin channel activation. We investigated the functional role of barttin palmitoylation in vivo in Zdhhc7−/− mice. Although palmitoylation of barttin in kidneys of Zdhhc7−/− animals was significantly decreased, it did not pathologically alter kidney structure and functions under physiological conditions. However, when Zdhhc7−/− mice were fed a low-salt diet, they developed hyponatremia and mild metabolic alkalosis, symptoms characteristic of human Bartter syndrome (BS) type IV. Of note, we also observed decreased palmitoylation of the disease-causing R8L barttin variant associated with human BS type IV. Our results indicate that dysregulated DHHC7-mediated barttin palmitoylation appears to play an important role in chloride channel dysfunction in certain BS variants, suggesting that targeting DHHC7 activity may offer a potential therapeutic strategy for reducing hypertension.

Type 1 diabetes is an autoimmune-mediated disease that culminates in the targeted destruction of insulin-producing β-cells. CD4 responses in NOD mice are dominated by insulin epitope B:9-23 (InsB_9-23) specificity, and mutation of the key T-cell receptor (TCR) contact residue within the epitope prevents diabetes development. However, it is not clear how insulin self-antigen controls the selection of autoimmune and regulatory T cells (Tregs). Here we demonstrate that mutation of insulin epitope results in escape of highly pathogenic T cells. We observe an increase in antigen reactivity, clonality, and pathogenicity of insulin-specific T cells that develop in the absence of cognate antigen. Using a single TCR system, we demonstrate that Treg development is greatly diminished in mice with the Y16A mutant epitope. Collectively, these results suggest that the tyrosine residue at position 16 is necessary to constrain TCR reactivity for InsB_9-23 by both limiting the development of pathogenic T cells and supporting the selection of Tregs.

As the U.S. health-care system sags under the strain of the COVID-19 pandemic, health-care workers are not only on the frontlines fighting the virus, they are also some of the most at-risk individuals, making it more essential than ever to have sufficient numbers of qualified health professionals. While 1.5 million immigrants and refugees are already working in the U.S. health-care system, an additional 263,000 immigrants and refugees in the U.S. with health-related college degrees are working in low-skilled jobs or are out of work.

OBJECTIVE

In patients with type 2 diabetes (T2D) and critical limb ischemia (CLI), migration of circulating CD34⁺ cells predicted cardiovascular mortality at 18 months after revascularization. This study aimed to provide long-term validation and mechanistic understanding of the biomarker.

In a time of critical shortages of U.S. health-care workers during the COVID-19 pandemic, retired doctors are being called back to work and medical students are graduating on a fast track. There is another important pool that could be tapped: Immigrants and refugees who have college degrees in health fields but are working in low-skilled jobs or out of work. MPI estimates 263,000 immigrants are experiencing skill underutilization and could be a valuable resource.

Two articles in the most recent issue of Theory & Psychology may interest AHP readers. Full details below. “How lost and accomplished revolutions shaped psychology: Early Critical Theory (Frankfurt School), Wilhelm Reich, and Vygotsky,” by Gordana Jovanovi?. Abstract: On the occasion of recent centenaries of revolutions in Europe (1917, 1918–19), this article examines, within a … Continue reading New Theory & Psychology: Early Critical Theory and Beck’s Cognitive Theory →

Concerns about local school systems can pose recruitment and retention hurdles for the armed services as they seek to meet the needs of military families.

Graphic novels -- History and criticism.

Matthias Löwe, Kristina Schubert.

Source: Electronic Journal of Statistics, Volume 14, Number 1, 1796--1815.

Abstract:
We show how to exactly reconstruct the block structure at the critical line in the so-called Ising block model. This model was recently re-introduced by Berthet, Rigollet and Srivastava in [2]. There the authors show how to exactly reconstruct blocks away from the critical line and they give an upper and a lower bound on the number of observations one needs; thereby they establish a minimax optimal rate (up to constants). Our technique relies on a combination of their methods with fluctuation results obtained in [20]. The latter are extended to the full critical regime. We find that the number of necessary observations depends on whether the interaction parameter between two blocks is positive or negative: In the first case, there are about $Nlog N$ observations required to exactly recover the block structure, while in the latter case $sqrt{N}log N$ observations suffice.

Cooperation between different data owners may lead to an improvement in forecast quality - for instance by benefiting from spatial-temporal dependencies in geographically distributed time series. Due to business competitive factors and personal data protection questions, said data owners might be unwilling to share their data, which increases the interest in collaborative privacy-preserving forecasting. This paper analyses the state-of-the-art and unveils several shortcomings of existing methods in guaranteeing data privacy when employing Vector Autoregressive (VAR) models. The paper also provides mathematical proofs and numerical analysis to evaluate existing privacy-preserving methods, dividing them into three groups: data transformation, secure multi-party computations, and decomposition methods. The analysis shows that state-of-the-art techniques have limitations in preserving data privacy, such as a trade-off between privacy and forecasting accuracy, while the original data in iterative model fitting processes, in which intermediate results are shared, can be inferred after some iterations.

Nicotine addiction, through smoking, is the principal cause of preventable mortality worldwide. Human genome-wide association studies have linked polymorphisms in the CHRNA5-CHRNA3-CHRNB4 gene cluster, coding for the α5, α3, and β4 nicotinic acetylcholine receptor (nAChR) subunits, to nicotine addiction. β4*nAChRs have been implicated in nicotine withdrawal, aversion, and reinforcement. Here we show that β4*nAChRs also are involved in non-nicotine-mediated responses that may predispose to addiction-related behaviors. β4 knock-out (KO) male mice show increased novelty-induced locomotor activity, lower baseline anxiety, and motivational deficits in operant conditioning for palatable food rewards and in reward-based Go/No-go tasks. To further explore reward deficits we used intracranial self-administration (ICSA) by directly injecting nicotine into the ventral tegmental area (VTA) in mice. We found that, at low nicotine doses, β4KO self-administer less than wild-type (WT) mice. Conversely, at high nicotine doses, this was reversed and β4KO self-administered more than WT mice, whereas β4-overexpressing mice avoided nicotine injections. Viral expression of β4 subunits in medial habenula (MHb), interpeduncular nucleus (IPN), and VTA of β4KO mice revealed dose- and region-dependent differences: β4*nAChRs in the VTA potentiated nicotine-mediated rewarding effects at all doses, whereas β4*nAChRs in the MHb-IPN pathway, limited VTA-ICSA at high nicotine doses. Together, our findings indicate that the lack of functional β4*nAChRs result in deficits in reward sensitivity including increased ICSA at high doses of nicotine that is restored by re-expression of β4*nAChRs in the MHb-IPN. These data indicate that β4 is a critical modulator of reward-related behaviors.

SIGNIFICANCE STATEMENT Human genetic studies have provided strong evidence for a relationship between variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster and nicotine addiction. Yet, little is known about the role of β4 nicotinic acetylcholine receptor (nAChR) subunit encoded by this cluster. We investigated the implication of β4*nAChRs in anxiety-, food reward- and nicotine reward-related behaviors. Deletion of the β4 subunit gene resulted in an addiction-related phenotype characterized by low anxiety, high novelty-induced response, lack of sensitivity to palatable food rewards and increased intracranial nicotine self-administration at high doses. Lentiviral vector-induced re-expression of the β4 subunit into either the MHb or IPN restored a "stop" signal on nicotine self-administration. These results suggest that β4*nAChRs provide a promising novel drug target for smoking cessation.

Today leading international experts on climate change, the IPCC, presented their latest report on the impacts of climate change on humanity, and what we can do about it. It’s a lengthy report, so we’ve shrunk it down to Oxfam's five key takeaways on climate change and hunger. 1. Climate change: the impacts on crops are worse than we thought Climate change has [...]

The positive outcomes won’t be immediately apparent, but will help reduce the strain on our healthcare system

Legal experts and leading scientists have teamed up with Creative Commons to create the Open COVID Pledge to help speed up the battle against the coronavirus pandemic. The Pledge gives broad permission to anyone to use intellectual property not otherwise accessible to the public, and generally replaces the need for any other license or royalty agreement.

Students who were chronically absent or at risk of dropping out before the coronavirus outbreak are even more at risk now that schools are closed, experts say.

The association of retinal hemorrhages (RHs) with abusive head trauma (AHT) is robust; 46% to 100% RHs are reported in AHT. There is potential selection bias with risk of circular reasoning because the majority of studies describing RH focus on AHT.

This is the first prospective observational study defining prevalence and distribution of RH in critically ill children excluding those with AHT. Severe multilayered RH were rare and observed in children with accidental fatal head injury, severe coagulopathy, severe sepsis, or a combination of these factors. (Read the full article)

Although many children are treated in general emergency departments, many such facilities have limited pediatric capabilities. Transfer to academic centers improves outcomes for critically ill patients, but transfers of noncritically ill children have not been well studied.

Although more than half of these patients are seriously ill, many transferred patients are discharged directly from the emergency department or are admitted for less than 24 hours. Orthopedic problems, gastrointestinal conditions, and traumatic head injury are the most common complaints. (Read the full article)

Vitamin D is essential for bone health and for cardiovascular and immune function. In critically ill adults, vitamin D deficiency is common and associated with sepsis and with higher critical illness severity. The influence on pediatric critical illness is unclear.

We found a high prevalence of vitamin D deficiency in critically ill children, which was associated with higher critical illness severity. Vitamin D deficiency was less common in younger patients, in non-Hispanic white patients, in patients admitted over the summer, and in children taking supplemental vitamin D, with increasing amounts being more protective. (Read the full article)

Vitamin D is a pleiotropic hormone important for proper functioning of multiple organs. Adult critical care studies have suggested vitamin D as a modifiable risk factor. No studies have investigated the prevalence, risk factors, or role in pediatric critical illness.

This study provides evidence that the majority of critically ill children have vitamin D deficiency at the time of PICU admission, and that lower levels are associated with hypocalcemia, catecholamine administration, significant fluid bolus requirements, and longer PICU admissions. (Read the full article)

Pulse oximetry testing in newborns can detect asymptomatic cases of critical congenital heart defects and has been added to the US Recommended Uniform Screening Panel. However, the impact that earlier diagnosis may have on survival in this population is unclear.

One-year survival for infants with critical congenital heart defects has been improving over time, yet mortality remains high. Survival has been greatest for those diagnosed after 1 day of age and may increase more with screening using pulse oximetry. (Read the full article)

Universal oxygen saturation screening by pulse oximetry is now recommended for early detection of critical congenital heart disease. The distribution of saturations in asymptomatic newborns in a large population has not been described.

Our study is the largest to date to establish simultaneous pre- and postductal oxygen saturation nomograms in asymptomatic newborns at ~24 hours after birth. The mean postductal saturation is higher than preductal during this time. (Read the full article)

Prenatal diagnosis and clinical examination do not identify all infants with critical congenital heart defects before hospital discharge. To improve early critical congenital heart defect detection, New Jersey was the first state to implement legislatively mandated newborn pulse oximetry screening.

This report is the first to evaluate statewide pulse oximetry screening implementation. New Jersey had a high statewide screening rate and identified 3 infants with previously unsuspected critical congenital heart defects that otherwise might have resulted in significant morbidity and mortality. (Read the full article)

Critical congenital heart disease (CCHD) was recently added to the US Recommended Uniform Screening Panel for newborns.

Routine screening could cost an estimated additional $6.28 per newborn and $40 385 per life-year gained. The incremental cost of screening might be approximately $0.50 per newborn with reusable sensors. Future analysis of newborn screening programs may help refine these projections. (Read the full article)

Newborns with critical congenital heart disease (CCHD) are at risk for cardiovascular collapse or death if discharged from the birth hospital without a diagnosis. Newborn screening aims to identify CCHD missed in prenatal and postnatal examinations.

Birth hospital nursery level and CCHD type were found to be associated with late CCHD detection. Routine newborn screening could conceivably reduce differences in the frequency of late diagnosis between birth hospital facilities. (Read the full article)

Pulse oximetry screening at 24 hours of age improves detection of critical congenital heart disease in asymptomatic newborns.

This study describes an initial experience with pulse oximetry screening for critical congenital heart disease and provides a strategy for preparing for state implementation of recent federal newborn screening recommendations. (Read the full article)

Few data on treating children hospitalized for influenza with neuraminidase inhibitors are available, contributing to uncertainty regarding the benefits of treatment.

This study of nearly 800 critically ill children suggests that treatment with neuraminidase inhibitors improves survival from influenza. This message needs additional emphasis, given that in the past 2 seasons over one-third of cases did not receive antiviral treatment. (Read the full article)

The American Academy of Pediatrics (AAP) and other organizations have recommended critical congenital heart disease (CCHD) pulse oximetry screening. Small studies have revealed lower saturations at higher altitude, but this effect on CCHD screening is unknown. The AAP requested additional studies at altitude to help clarify the dilemma.

The AAP has endorsed higher-altitude studies of CCHD screening. This observational prospective study revealed a higher positive screen rate at moderate altitude than at sea level. These findings suggest that current national recommendations may result in increased screening failures at moderate altitude. (Read the full article)

Early referral of infants with critical congenital heart disease (CCHD) is recommended to reduce mortality. However, few population-based data have been published showing the relationship between CCHD neonatal mortality and timing of cardiac evaluation at a specialty center.

In neonates with CCHD, 35% were not evaluated at a cardiac center by 4 days of age. These cases accounted for a significant number of CCHD deaths. This information enhances the rationale for pulse oximetry screening of neonates for CCHD. (Read the full article)

Delayed diagnosis of critical congenital heart defects (CCHDs) is associated with increased morbidity and mortality.

Despite increasing prenatal diagnosis rates, delayed diagnosis of CCHDs continues to occur, with rates highest among isolated cases and those delivered at nontertiary care hospitals. Better understanding of delayed diagnosis could help to improve screening efforts. (Read the full article)

Health care–associated infections are harmful, costly, and preventable, yet there remain limited data as to their population incidence among hospitalized neonates and children in the United States.

Incidence rates of central line–associated bloodstream infections and ventilator-associated pneumonia decreased among critically ill neonates and children during a 5-year period in the United States. National efforts to improve patient safety through decreasing HAIs have been effective. (Read the full article)

The detection of critical congenital heart disease by fetal echocardiography or neonatal physical examination can have limitations. The addition of pulse oximetry screening in the newborn nursery increases the rate of diagnosis of these conditions before hospital discharge.

In a tertiary-care center with comprehensive fetal echocardiography, nearly all newborns with critical congenital heart disease are diagnosed prenatally. Pulse oximetry will identify more infants from settings with lower prenatal detection. Improving access to and training in fetal echocardiography should also improve detection of these conditions. (Read the full article)

Newborn screening for critical congenital heart defects (CCHDs) has been implemented in many hospitals, yet there is uncertainty about the number of infants with CCHDs that might be detected through universal implementation of newborn CCHD screening in the United States.

We estimated that ~875 infants with CCHDs might be detected, and ~880 missed, annually through universal CCHD screening in the United States. Increases in prenatal diagnosis are unlikely to substantially impact the number of infants detected through CCHD screening. (Read the full article)

Previous research has described important variability in the medical evaluation of suspected child physical abuse. This variability may contribute to bias and reduce reliability in the medical diagnosis of abuse.

A panel of child abuse pediatricians participated in a Delphi Process, defining critical elements for the medical evaluation of suspected physical abuse in children. Results can be used to reduce practice variability that may contribute to potential bias in evaluation. (Read the full article)

Antimicrobial peptides and proteins play critical roles in the host defense against invading pathogens. We recently discovered that recombinantly expressed human and mouse serum amyloid A1 (rhSAA1 and rmSAA1) proteins have potent antifungal activities against the major human fungal pathogen Candida albicans. At high concentrations, rhSAA1 disrupts C. albicans membrane integrity and induces rapid fungal cell death. In the current study, we find that rhSAA1 promotes cell aggregation and targets the C. albicans cell wall adhesin Als3. Inactivation of ALS3 in C. albicans leads to a striking decrease in cell aggregation and cell death upon rhSAA1 treatment, suggesting that Als3 plays a critical role in SAA1 sensing. We further demonstrate that deletion of the transcriptional regulators controlling the expression of ALS3, such as AHR1, BCR1, and EFG1 in C. albicans results in similar effects to that of the als3/als3 mutant upon rhSAA1 treatment. Global gene expression profiling indicates that rhSAA1 has a discernible impact on the expression of cell wall- and metabolism-related genes, suggesting that rhSAA1 treatment could lead to a nutrient starvation effect on C. albicans cells.

Carbapenem pharmacokinetic profiles are significantly changed in critically ill patients because of the drastic variability of the patients' physiological parameters. Published population PK studies have mainly focused on specific diseases and the majority of these studies had small sample sizes. The aim of this study was to develop a population PK model of imipenem in critically ill patients that estimated the influence of various clinical and biological covariates and the use of Extracorporeal Membrane Oxygenation (ECMO) and Continuous Renal Replacement Therapy (CRRT). A two-compartment population PK model with Creatinine clearance (CrCL), body weight (WT), and ECMO as fixed effects was developed using the non-linear mixed effect model (NONMEM). A Monte Carlo simulation was performed to evaluate various dosing schemes and different levels of covariates based on the pharmacokinetic/pharmacodynamic index (f%T>MIC) for the range of clinically relevant minimum inhibitory concentrations(MICs). The results showed that there may be insufficient drug use in the clinical routine drug dose regimen, and 750mg Q6h could achieve a higher treatment success rate. The blood concentrations of imipenem in ECMO patients were lower than that of non-ECMO patients, therefore dosage may need to be increased. The dosage may need adjustment for patients with CrCL ≤ 70ml/min, but dose should be lowered carefully to avoid the insufficient drug exposure. Dose adjustment is not necessary for patients within the WT ranging from 50-80 kg. Due to the large variation in PK profile of imipenem in critically ill patients, TDM should be carried out to optimize drug regimens.

Pharmacokinetic changes are often seen in patients with severe infections. Administration by continuous infusion has been suggested to optimize antibiotic exposure and pharmacokinetic/pharmacodynamic (PK/PD) target attainment for β-lactams. In an observational study, unbound piperacillin concentrations (n=196) were assessed in 78 critically ill patients following continuous infusion of piperacillin/tazobactam (ratio 8:1). The initial dose of 8, 12 or 16 g (piperacillin component) was determined by individual creatinine clearance (CRCL). Piperacillin concentrations were compared to the EUCAST clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/L), and the following PK/PD targets were evaluated: 100% fT>1xMIC and 100% fT>4xMIC. A population pharmacokinetic model was developed using NONMEM 7.4.3 consisting of a one-compartment disposition model with linear elimination separated into non-renal and renal (linearly increasing with patient CRCL) clearances. Target attainment was predicted and visualized for all individuals based on the utilized CRCL dosing algorithm. The target of 100% fT>1xMIC was achieved for all patients based on the administered dose, but few patients achieved the target of 100% fT>4xMIC. Probability of target attainment for a simulated cohort of patients showed, that increasing the daily dose by 4 g increments (piperacillin component) did not result in substantially improved target attainment for the 100% fT>4xMIC target. To conclude, in patients with high CRCL combined with high-MIC bacterial infections, even a CI regimen with a daily dose of 24 g may be insufficient to achieve therapeutic concentrations.

Making sure the social and mental well-being of students is tended to is essential to getting young people through this period of chaos and uncertainty.

Successful intervention for inborn errors of metabolism (IEMs) is a triumph of modern medicine. For many of these conditions, medical foods are the cornerstone of therapy and the only effective interventions preventing disability or death. Medical foods are designed for patients with limited or impaired capacity to ingest, digest, absorb, or metabolize ordinary foods or nutrients, whereby dietary management cannot be achieved by modification of the normal diet alone. In the United States today, access to medical foods is not ensured for many individuals who are affected despite their proven efficacy in the treatment of IEMs, their universal use as the mainstay of IEM management, the endorsement of their use by professional medical organizations, and the obvious desire of families for effective care. Medical foods are not sufficiently covered by many health insurance plans in the United States and, without insurance coverage, many families cannot afford their high cost. In this review, we outline the history of medical foods, define their medical necessity, discuss the barriers to access and reimbursement resulting from the regulatory status of medical foods, and summarize previous efforts to improve access. The Advisory Committee on Heritable Disorders in Newborns and Children asserts that it is time to provide stable and affordable access to the effective management required for optimal outcomes through the life span of patients affected with IEMs. Medical foods as defined by the US Food and Drug Administration should be covered as required medical benefits for persons of all ages diagnosed with an IEM.

The return on Equity/Cost of Equity : This year’s table ranks 150 listed companies as creating shareholder value in 2009.

<strong>New Delhi:</strong> At least one civilian was killed while 20 people were injured on Monday in a grenade attack in Kashmir’s main city of Srinagar. The grenade attack took place in a market on Maulana Azad road of the city. People who have sustained injuries have been admitted to

DOVER, Del. – The Delaware Department of Agriculture continues to provide services to the public and industry to ensure that our food supply remains safe and plentiful for consumers during the coronavirus disease 2019 (COVID-19) outbreak. “As Delaware’s number one industry, family farms are crucial to supplying a variety of food from poultry and meats, […]

Group health insurance plus personal health insurance: Higher the number of family members, higher the insurance cover.

The scientists noted that the loss of such key stone species may lead to a rapid and dramatic change in the landscape within our lifetime.

Former Chhattisgarh chief minister Ajit Jogi, 74, was admitted in a private hospital here on Saturday after he suffered a cardiac arrest, doctors said, adding that his condition is critical.