The Cytokine Release Inhibitory Drug CRID3 Targets ASC Oligomerisation in the NLRP3 and AIM2 Inflammasomes

Background: The Inflammasomes are multi-protein complexes that regulate caspase-1 activation and the production of the pro-inflammatory cytokine IL-1 beta. Previous studies identified a class of diarylsulfonylurea containing compounds called Cytokine Release Inhibitory Drugs (CRIDs) that inhibited the post-translational processing of IL-1 beta. Further work identified Glutathione S-Transferase Omega 1 (GSTO1) as a possible target of these CRIDs. This study aimed to investigate the mechanism of the inhibitory activity of the CRID CP-456,773 (termed CRID3) in light of recent advances in the area of inflammasome activation, and to clarify the potential role of GSTO1 in the regulation of IL-1 beta production

TPH2 polymorphisms and expression in Prader-Willi syndrome subjects with differing genetic subtypes

Prader-Willi syndrome (PWS) is a genetic imprinting disease that causes developmental and behavioral disturbances resulting from loss of expression of genes from the paternal chromosome 15q11-q13 region. In about 70% of subjects, this portion of the paternal chromosome is deleted, while 25% have two copies of the maternal chromosome 15, or uniparental maternal disomy (UPD; the remaining subjects have imprinting center defects. There are several documented physical and behavioral differences between the two major PWS genetic subtypes (deletion and UPD) indicating the genetic subtype plays a role in clinical presentation. Serotonin is known to be disturbed in PWS and affects both eating behavior and compulsion, which are reported to be abnormal in PWS. We investigated the tryptophan hydroxylase gene (TPH2), the rate-limiting enzyme in the production of brain serotonin, by analyzing three different TPH2 gene polymorphisms, transcript expression, and correlation with PWS genetic subtype. DNA and RNA from lymphoblastoid cell lines derived from 12 PWS and 12 comparison subjects were used for the determination of genetic subtype, TPH2 polymorphisms and quantitative RT-PCR analysis. A similar frequency of TPH2 polymorphisms was seen in the PWS and comparison subjects with PWS deletion subjects showing increased expression with one or more TPH2 polymorphism. Both PWS deletion and PWS UPD subjects had significantly lower TPH2 expression than control subjects and PWS deletion subjects had significantly lower TPH2 expression compared with PWS UPD subjects. PWS subjects with 15q11-q13 deletions had lower TPH2 expression compared with PWS UPD or control subjects, requiring replication and further studies to identify the cause including identification of disturbed gene interactions resulting from the deletion process

Attributable costs of enterococcal bloodstream infections in a nonsurgical hospital cohort

BACKGROUND: Vancomycin-resistant enterococcal (VRE) bloodstream infections (BSI) are associated with increased morbidity and mortality. OBJECTIVE: To determine the attributable costs of vancomycin-sensitive (VSE) and VRE BSI and the independent impact of vancomycin-resistance on hospital costs. METHODS: A retrospective cohort study was conducted of 21,154 non-surgical patients admitted to an academic medical center between 2002 and 2003. Using administrative data, attributable hospital costs (inflation adjusted to $2007) and length of stay were estimated with multivariate generalized least squares (GLS) models and propensity score matched-pairs. RESULTS: The cohort included 182 VSE and 94 VRE BSI cases. After adjustment for demographics, comorbidities, procedures, non-enterococcal BSI, and early mortality, the attributable costs of VSE BSI were$2,250 (95% confidence interval [CI], $1,758–$2,880) in the standard GLS model and $2,023 (95$1,588–$2,575) in the propensity-score weighted GLS model and the attributable costs of VRE BSI were$4,479 (95% CI, $3,500–$5,732) in the standard GLS model and $4,036 (95$3,170–$5,140) in the propensity-score weighted GLS model. The median of the difference in costs between matched-pairs was$5,282 ($2,042–$8,043) for VSE BSI and $9,949 (95$1,579–$24,693) for VRE BSI. The attributable costs of vancomycin-resistance were$1,713 (95% CI, $1,338–$2,192) in the standard GLS model and $1,546 (95$1,214–$1,968) in the propensity-score weighted GLS model. Attributable length of stay ranged from 1.1–2.2 days for VSE BSI and 2.2–3.5 days for VRE BSI cases. CONCLUSIONS: VSE and VRE BSI were independently associated with hospital costs and length of stay. Vancomycin-resistance was associated with increased costs

Further evidence for the involvement of EFL1 in a Shwachman-Diamond-like syndrome and expansion of the phenotypic features.

Recent evidence has implicated EFL1 in a phenotype overlapping Shwachman-Diamond syndrome (SDS), with the functional interplay between EFL1 and the previously known causative gene SBDS accounting for the similarity in clinical features. Relatively little is known about the phenotypes associated with pathogenic variants in the EFL1 gene, but the initial indication was that phenotypes may be more severe, when compared with SDS. We report a pediatric patient who presented with a metaphyseal dysplasia and was found to have biallelic variants in EFL1 on reanalysis of trio whole-exome sequencing data. The variant had not been initially reported because of the research laboratory's focus on de novo variants. Subsequent phenotyping revealed variability in her manifestations. Although her metaphyseal abnormalities were more severe than in the original reported cohort with EFL1 variants, the bone marrow abnormalities were generally mild, and there was equivocal evidence for pancreatic insufficiency. Despite the limited number of reported patients, variants in EFL1 appear to cause a broader spectrum of symptoms that overlap with those seen in SDS. Our report adds to the evidence of EFL1 being associated with an SDS-like phenotype and provides information adding to our understanding of the phenotypic variability of this disorder. Our report also highlights the value of exome data reanalysis when a diagnosis is not initially apparent

Masked Bobwhite Recovery: The Need for a Multifaceted Approach

Masked bobwhite (Colinus virginianus ridgwayi) is a critically endangered quail historically found in the Sonoran grasslands of southern Arizona, USA and Sonora, Mexico. Native populations of masked bobwhite may already be extinct in the wild, but captive populations exist in the United States at G. M. Sutton Avian Research Center (Oklahoma, USA), Buenos Aires National Wildlife Refuge (Arizona, USA), and various zoos. The 47,000-hectare Buenos Aires National Wildlife Refuge, located in south-central Arizona, was established primarily for reintroduction of this bird. Recovery efforts within the refuge boundary in the 1980s and 1990s were initially successful but suffered debilitating setbacks that ultimately resulted in failure. Substantial releases were suspended in 2005. Improved habitat restoration efforts and promising conditioning and release techniques led to the belief that reintroductions could again be attempted and successful. In 2016–2017 plans were developed to increase captive propagation and reinitiate release efforts. Releases began in 2018. Over-winter survival of birds released in 2018–2019 was encouraging, and reproduction of wild birds was documented in 2019. An existing base of wild birds established from these releases could help masked bobwhite populations recover in the state. Habitat restoration, better methods of rearing, release, and conditioning, and improved production from captive facilities also inspire hope that a full recovery of the species in Arizona is possible

Prevalence and predictors of post‐traumatic stress symptoms in adolescent and young adult cancer survivors: a 1‐year follow‐up study

Objectives Post‐traumatic stress symptoms (PTSS) have been identified as a meaningful indicator of distress in cancer survivors. Distinct from young adult survivors of childhood cancer, young people diagnosed with cancer as adolescents and young adults (AYAs) face unique psychosocial issues; however, there is little published research of PTSS in the AYA population. This study examines prevalence and predictors of PTSS among AYAs with cancer. Methods As part of a longitudinal study of AYAs with cancer, 151 patients aged 15–39 years completed mailed surveys at 6 and 12 months post‐diagnosis. Severity of PTSS was estimated at 6 and 12 months post‐diagnosis. Multiple regression analyses were conducted to investigate the predictive effects of socio‐demographic and clinical characteristics on changes in PTSS over time. Results At 6 and 12 months, respectively, 39% and 44% of participants reported moderate to severe levels of PTSS; 29% had PTSS levels suggestive of post‐traumatic stress disorder. No significant differences in severity of PTSS between 6 and 12 months were observed. Regression analyses suggested that a greater number of side effects were associated with higher levels of PTSS at 6 months. Currently receiving treatment, having surgical treatment, diagnosis of a cancer type with a 90–100% survival rate, remaining unemployed/not in school, and greater PTSS at 6 months were associated with higher levels of PTSS at 12 months. Conclusions Post‐traumatic stress symptoms were observed as early as 6 months following diagnosis and remained stable at 12‐month follow‐up. The development of early interventions for reducing distress among AYA patients in treatment is recommended. Copyright © 2012 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99033/1/pon3217.pd

Associations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium

Background<p></p> Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association study (GWAS) in four prospective studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and demonstrated that sequence variants near the NINJ2 gene are associated with incident ischemic stroke. Here, we sought to fine-map functional variants in the region and evaluate the contribution of rare variants to ischemic stroke risk.<p></p> Methods and Results<p></p> We sequenced 196 kb around NINJ2 on chromosome 12p13 among 3,986 European ancestry participants, including 475 ischemic stroke cases, from the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and Framingham Heart Study. Meta-analyses of single-variant tests for 425 common variants (minor allele frequency [MAF] ≥ 1%) confirmed the original GWAS results and identified an independent intronic variant, rs34166160 (MAF = 0.012), most significantly associated with incident ischemic stroke (HR = 1.80, p = 0.0003). Aggregating 278 putatively-functional variants with MAF≤ 1% using count statistics, we observed a nominally statistically significant association, with the burden of rare NINJ2 variants contributing to decreased ischemic stroke incidence (HR = 0.81; p = 0.026).<p></p> Conclusion<p></p> Common and rare variants in the NINJ2 region were nominally associated with incident ischemic stroke among a subset of CHARGE participants. Allelic heterogeneity at this locus, caused by multiple rare, low frequency, and common variants with disparate effects on risk, may explain the difficulties in replicating the original GWAS results. Additional studies that take into account the complex allelic architecture at this locus are needed to confirm these findings

Alternative approaches to managing respiratory tract infections: a survey of public perceptions

Background Respiratory tract infections (RTIs) are a common reason for people to consult in primary care, and contribute to antibiotic overuse and antimicrobial resistance (AMR). Alternative approaches to supporting patients with RTIs may help, but it is important to understand public perceptions about these approaches before they are widely implemented. Aim To describe public perceptions regarding finger-prick testing, back-up antibiotic prescriptions (BUPs), and alternatives to traditional consultations for RTIs, and identify factors associated with favouring these approaches. Design & setting Online national survey (HealthWise Wales) with linked primary care health record data. Method Survey item response distributions were described. Associations between responses about consultation alternatives, BUP, and finger-prick point-of-care testing (POCT), and potential explanatory variables, were explored using logistic regression. Results A total of 8752 participants completed the survey between 2016 and 2018. The survey found 76.7% (n = 3807/4,966) and 71.2% (n = 3529/4,953) of responders with valid responses were in favour of being able to consult with a pharmacist or nurse in their GP surgery, or with a community pharmacist, respectively. It also showed 92.8% (n = 8034/8659) of responders indicated they would be happy to have a finger-prick test to guide antibiotic prescribing, and 31.8% (n = 2746/8646) indicated they would like to be given a BUP if their clinician thought immediate antibiotics were not required. In addition, 47.4% (n = 2342/4944) and 42.3% (n = 2095/4949) were in favour of having video and email consultations, respectively. Characteristics associated with different response options were identified. Conclusion Consulting with pharmacists, using electronic communication tools, and finger-prick testing are widely acceptable approaches. BUP was described as acceptable less often, and is likely to require greater information and support when used

Towards a Data Sharing Culture: Recommendations for Leadership from Academic Health Centers

Rebecca Crowley and colleagues propose that academic health centers can and should lead the transition towards a culture of biomedical data sharing