We generated human iPS derived neural stem cells and differentiated cells from healthy control individuals and an individual with autism spectrum disorder carrying bi-allelic NRXN1-alpha deletion. We ...investigated the expression of NRXN1-alpha during neural induction and neural differentiation and observed a pivotal role for NRXN1-alpha during early neural induction and neuronal differentiation. Single cell RNA-seq pinpointed neural stem cells carrying NRXN1-alpha deletion shifting towards radial glia-like cell identity and revealed higher proportion of differentiated astroglia. Furthermore, neuronal cells carrying NRXN1-alpha deletion were identified as immature by single cell RNA-seq analysis, displayed significant depression in calcium signaling activity and presented impaired maturation action potential profile in neurons investigated with electrophysiology. Our observations propose NRXN1-alpha plays an important role for the efficient establishment of neural stem cells, in neuronal differentiation and in maturation of functional excitatory neuronal cells.
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•Disease modeling of autism in iPS derived neural stem cells carrying bi-allelic NRXN1-alpha deletion.•Single cell analysis accurately resolves genes and cell identities.•Deletion of NRXN1-alpha skews neural stem cells towards radial glia-like cells with preference for generating astroglia.•Deletion of NRXN1-alpha depresses calcium-signaling activity and impairs maturation in excitatory neurons.
Abstract Opioid addiction and HIV disease frequently co-occur. Adverse drug interactions have been reported between methadone and some HIV medications, but less is known about interactions between ...buprenorphine, an opioid partial agonist used to treat opioid dependence, and HIV therapeutics. This study examined drug interactions between buprenorphine and the protease inhibitors atazanavir and atazanavir/ritonavir. Opioid-dependent, buprenorphine/naloxone-maintained, HIV-negative volunteers ( n = 10 per protease inhibitor) participated in two 24-h sessions to determine pharmacokinetics of (1) buprenorphine and (2) buprenorphine and atazanavir (400 mg daily) or atazanavir/ritonavir (300/100 mg daily) following administration for 5 days. Objective opiate withdrawal scale scores and mini-mental state examination were determined prior to and following antiretroviral administration to examine pharmacodynamic effects. Pharmacokinetics of atazanavir and atazanavir/ritonavir were compared in subjects and matched, healthy controls ( n = 10 per protease inhibitor) to determine effects of buprenorphine. With atazanavir and atazanavir/ritonavir, respectively concentrations of buprenorphine ( p < 0.001, p < 0.001), norbuprenorphine ( p = 0.026, p = 0.006), buprenorphine glucuronide ( p = 0.002, p < 0.001), and norbuprenorphine glucuronide (NS, p = 0.037) increased. Buprenorphine treatment did not significantly alter atazanavir or ritonavir concentrations. Three buprenorphine/naloxone-maintained participants reported increased sedation with atazanavir/ritonavir. Atazanavir or atazanavir/ritonavir may increase buprenorphine and buprenorphine metabolite concentrations and might require a decreased buprenorphine dose.
Clinical trials of venetoclax reported negligible rates of clinical tumor lysis syndrome (TLS) in patients with chronic lymphocytic leukemia (CLL) when using an extended dose escalation schedule. We ...aimed to understand TLS prophylaxis, rates of select adverse events (AE), and impact of dosing modifications in routine clinical practice.
This retrospective cohort study included 297 CLL venetoclax-treated patients outside of clinical trials in academic and community centers. Demographics, baseline disease characteristics, venetoclax dosing, TLS risk and prophylaxis, and AEs were collected.
The group was 69% male, 96% had relapsed/refractory CLL, 45% had deletion chromosome 17p, 84% had unmutated
, 80% received venetoclax monotherapy, and median age was 67. TLS risk was categorized as low (40%), intermediate (32%), or high (28%), and 62% had imaging prior to venetoclax initiation. Clinical TLS occurred in 2.7% of patients and laboratory TLS occurred in 5.7%. Pre-venetoclax TLS risk group and creatinine clearance independently predict TLS development in multivariable analysis. Grade 3/4 AEs included neutropenia (39.6%), thrombocytopenia (29.2%), infection (25%), neutropenic fever (7.9%), and diarrhea (6.9%). Twenty-two patients (7.4%) discontinued venetoclax due to an AE. Progression-free survival was similar regardless of number of dose interruptions, length of dose interruption, and stable venetoclax dose.
These data provide insights into current use of venetoclax in clinical practice, including TLS rates observed in clinical practice. We identified opportunities for improved adherence to TLS risk stratification and prophylaxis, which may improve safety.
It is unknown whether loading of the lower limbs through additional storage of fat mass as evident in obesity would promote muscular adaptations similar to those seen with resistance exercise. It is ...also unclear whether ageing modulates any such adjustments. This study aimed to examine the relationships between adiposity, ageing and skeletal muscle size and architecture. A total of 100 untrained healthy women were categorised by age into young (Y) (mean ± SD: 26.7 ± 9.4 years) vs. old (O) (65.1 ± 7.2 years) and body mass index (BMI) classification (underweight, normal weight, overweight and obese). Participants were assessed for body fat using dual energy x‐ray absorptiometry, and for gastrocnemius medialis (GM) muscle architecture (skeletal muscle fascicle pennation angle and length) and size GM muscle volume and physiological cross‐sectional area (PCSA) using B‐mode ultrasonography. GM fascicle pennation angle (FPA) in the obese Y females was 25% greater than underweight (P = 0.001) and 25% greater than normal weight (P = 0.001) individuals, while O females had 32 and 22% greater FPA than their underweight (P = 0.008) and normal weight (P = 0.003) counterparts. Furthermore, FPA correlated with body mass in both Y and O females (Y r = 0.303; P < 0.001; O r = 0.223; P = 0.001), yet no age‐related differences in the slope or r‐values were observed (P > 0.05). Both GM muscle volume (P = 0.003) and PCSA (P = 0.004) exhibited significant age × BMI interactions. In addition, muscle volume and PCSA correlated with BMI, body mass and fat mass. Interestingly, ageing reduced both the degree of association in these correlations (P < 0.05) and the slope of the regressions (P < 0.05). Our findings partly support our hypotheses in that obesity‐associated changes in GM PCSA and volume differed between the young and old. The younger GM muscle adapted to the loading induced by high levels of body mass, adiposity and BMI by increasing its volume and increasing its pennation angle, ultimately enabling it to produce higher maximum torque. Such an adaptation to increased loading did not occur in the older GM muscle. Nonetheless, the older GM muscle FPA increased to a similar extent to that seen in young GM muscle, an effect which partly explains the relatively enhanced absolute maximum torque observed in obese older females.
•The PEMS was tested in undergraduate students and weight-loss seeking patients.•Eating tasty food for Coping motives predicted higher binge scores and BMI.•Reward Enhancement and Conformity motives ...in students may indicate binge risk.•Identifying one's main motive to eat tasty food may help prevent binge disorders.•Knowing one's primary PEMS motive can help tailor treatments for better outcomes.
The aim of this study was to use the Palatable Eating Motives Scale (PEMS) to determine if and what motives for eating tasty foods (e.g., junk food, fast food, and desserts) are associated with binge-eating in two diverse populations. BMI and scores on the PEMS, Yale Food Addiction Scale (YFAS), and Binge-eating Scale (BES) were obtained from 247 undergraduates at the University of Alabama at Birmingham (UAB) and 249 weight-loss seeking patients at the UAB EatRight program. Regression analyses revealed that eating tasty foods to forget worries and problems and help alleviate negative feelings (i.e., the 4-item Coping motive) was associated with binge-eating independently of any variance in BES scores due to sex, age, ethnicity, BMI, other PEMS motives, and YFAS scores in both students (R2 = .57) and patients (R2 = .55). Coping also was associated with higher BMI in students (p < 0.01), and in patients despite their truncated BMI range (p < 0.05). Among students, the motives Conformity and Reward Enhancement were also independently associated with binge-eating. For this younger sample with a greater range of BES scores, eating for these motives, but not for Social ones, may indicate early maladaptive eating habits that could later develop into disorders characterized by binge-eating if predisposing factors are present. Thus, identifying one's tasty food motive or motives can potentially be used to thwart the development of BED and obesity, especially if the motive is Coping. Identifying one's PEMS motives should also help personalize conventional treatments for binge-eating and obesity toward improved outcomes.
Excited-state spectroscopy from the first experiment at the Facility for Rare Isotope Beams (FRIB) is reported. A 24(2)-μs isomer was observed with the FRIB Decay Station initiator (FDSi) through a ...cascade of 224- and 401-keV γ rays in coincidence with ^{32}Na nuclei. This is the only known microsecond isomer (1 μs≤T_{1/2}<1 ms) in the region. This nucleus is at the heart of the N=20 island of shape inversion and is at the crossroads of the spherical shell-model, deformed shell-model, and ab initio theories. It can be represented as the coupling of a proton hole and neutron particle to ^{32}Mg, ^{32}Mg+π^{-1}+ν^{+1}. This odd-odd coupling and isomer formation provides a sensitive measure of the underlying shape degrees of freedom of ^{32}Mg, where the onset of spherical-to-deformed shape inversion begins with a low-lying deformed 2^{+} state at 885 keV and a low-lying shape-coexisting 0_{2}^{+} state at 1058 keV. We suggest two possible explanations for the 625-keV isomer in ^{32}Na: a 6^{-} spherical shape isomer that decays by E2 or a 0^{+} deformed spin isomer that decays by M2. The present results and calculations are most consistent with the latter, indicating that the low-lying states are dominated by deformation.
IMPORTANCE: Performance-measure risk adjustment is of great interest to hospital stakeholders who face substantial financial penalties from readmissions pay-for-performance (P4P) measures. Despite ...evidence of the association between social determinants of health (SDH) and individual patient readmission risk, the effect of risk adjusting for SDH on readmissions P4P penalties to hospitals is not well understood. OBJECTIVE: To determine whether risk adjustment for commonly available SDH measures affects the readmissions-based P4P penalty status of a national cohort of children’s hospitals. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of 43 free-standing children’s hospitals within the Pediatric Health Information System database in the calendar year 2013. We evaluated hospital discharges from 2013 that met criteria for 3M Health Information Systems’ potentially preventable readmissions measure for calendar year 2013. The analysis was conducted from July 2015 to August 2015. EXPOSURES: Two risk-adjustment models: a baseline model adjusted for severity of illness and an SDH-enhanced model that adjusted for severity of illness and the following 4 SDH variables: race, ethnicity, payer, and median household income for the patient’s home zip code. MAIN OUTCOMES AND MEASURES: Change in a hospital’s potentially preventable readmissions penalty status (ie, change in whether a hospital exceeded the penalty threshold) using an observed-to-expected potentially preventable readmissions ratio of 1.0 as a penalty threshold. RESULTS: For the 179 400 hospital discharges from the 43 hospitals meeting inclusion criteria, median (interquartile range IQR) hospital-level percentages for the SDH variables were 39.2% nonwhite (n = 71 300; IQR, 28.6%-54.6%), 17.9% Hispanic (n = 32 060; IQR, 6.7%-37.0%), and 58.7% publicly insured (n = 106 116; IQR, 50.4%-67.8%). The hospital median household income for the patient’s home zip code was $40 674 (IQR, $35 912-$46 190). When compared with the baseline model, adjustment for SDH resulted in a change in penalty status for 3 hospitals within the 15-day window (2 were no longer above the penalty threshold and 1 was newly penalized) and 5 hospitals within the 30-day window (3 were no longer above the penalty threshold and 2 were newly penalized). CONCLUSIONS AND RELEVANCE: Risk adjustment for SDH changed hospitals’ penalty status on a readmissions-based P4P measure. Without adjusting P4P measures for SDH, hospitals may receive penalties partially related to patient SDH factors beyond the quality of hospital care.
The drug–drug interaction profile of atorvastatin confirms that disposition is determined by cytochrome P450 (CYP) 3A4 and organic anion transporting polypeptides (OATPs). Drugs that affect gastric ...emptying, including dulaglutide, also affect atorvastatin pharmacokinetics (PK). Atorvastatin is a carboxylic acid that exists in equilibrium with a lactone form in vivo. The purpose of this work was to assess gastric acid–mediated lactone equilibration of atorvastatin and incorporate this into a physiologically‐based PK (PBPK) model to describe atorvastatin acid, lactone, and their major metabolites. In vitro acid‐to‐lactone conversion was assessed in simulated gastric fluid and included in the model. The PBPK model was verified with in vivo data including CYP3A4 and OATP inhibition studies. Altering the gastric acid–lactone equilibrium reproduced the change in atorvastatin PK observed with dulaglutide. The model emphasizes the need to include gastric acid–lactone conversion and all major atorvastatin‐related species for the prediction of atorvastatin PK.
Marine ice-sheet collapse can contribute to rapid sea-level rise. Today, the West Antarctic Ice Sheet contains an amount of ice equivalent to approximately six metres of sea-level rise, but most of ...the ice is in the slowly moving interior reservoir. A relatively small fraction of the ice sheet comprises several rapidly flowing ice streams which drain the ice to the sea. The evolution of this drainage system almost certainly governs the process of ice-sheet collapse. The thick and slow-moving interior ice reservoir is generally fixed to the underlying bedrock while the ice streams glide over lubricated beds at velocities of up to several hundred metres per year. The source of the basal lubricant - a water-saturated till, overlain by a water system - may be linked to the underlying geology. The West Antarctic Ice Sheet rests over a geologically complex region characterized by thin crust, high heat flows, active volcanism and sedimentary basins. Here we use aerogeophysical measurements to constrain the geological setting of the onset of an active West Antarctic ice stream. The onset coincides with a sediment-filled basin incised by a steep-sided valley. This observation supports the suggestion, that ice-stream dynamics - and therefore the response of the West Antarctice Ice Sheet to changes in climate - are strongly modulated by the underlying geology.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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