The 22q11.2 locus contains genes critical for brain development. Reciprocal Copy Number Variations (CNVs) at this locus impact risk for neurodevelopmental and psychiatric disorders. Both 22q11.2 ...deletions (22qDel) and duplications (22qDup) are associated with autism, but 22qDel uniquely elevates schizophrenia risk. Understanding brain phenotypes associated with these highly penetrant CNVs can provide insights into genetic pathways underlying neuropsychiatric disorders. Human neuroimaging and animal models indicate subcortical brain alterations in 22qDel, yet little is known about developmental differences across specific nuclei between reciprocal 22q11.2 CNV carriers and typically developing (TD) controls. We conducted a longitudinal MRI study in a total of 385 scans from 22qDel (n = 96, scans = 191, 53.1% female), 22qDup (n = 37, scans = 64, 45.9% female), and TD controls (n = 80, scans = 130, 51.2% female), across a wide age range (5.5-49.5 years). Volumes of the thalamus, hippocampus, amygdala, and anatomical subregions were estimated using FreeSurfer, and the linear effects of 22q11.2 gene dosage and non-linear effects of age were characterized with generalized additive mixed models (GAMMs). Positive gene dosage effects (volume increasing with copy number) were observed for total intracranial and whole hippocampus volumes, but not whole thalamus or amygdala volumes. Several amygdala subregions exhibited similar positive effects, with bi-directional effects found across thalamic nuclei. Distinct age-related trajectories were observed across the three groups. Notably, both 22qDel and 22qDup carriers exhibited flattened development of hippocampal CA2/3 subfields relative to TD controls. This study provides novel insights into the impact of 22q11.2 CNVs on subcortical brain structures and their developmental trajectories.
Introduction:
The clinical features and increased mortality associated with Cushing's syndrome result from a chronic excess of circulating cortisol. As LCI699 potently inhibits 11β-hydroxylase, which ...catalyzes the final step of cortisol synthesis, it is a potential new treatment for Cushing's disease, the most common cause of endogenous Cushing's syndrome.
Methods:
Adult patients with moderate-to-severe Cushing's disease (urinary free cortisol UFC levels >1.5 × ULN upper limit of normal) received oral LCI699 for 10 weeks in this proof-of-concept study. LCI699 was initiated at 4 mg/d in two equal doses; the dose was escalated every 14 days to 10, 20, 40, and 100 mg/d until UFC normalized, whereupon the dose was maintained until treatment ended (day 70). The primary endpoint was UFC ≤ ULN or a ≥50% decrease from baseline at day 70.
Results:
Twelve patients were enrolled and completed the study. Baseline UFC ranged over 1.6–17.0 × ULN. All 12 patients achieved UFC ≤ ULN or a ≥50% decrease from baseline at day 70; 11 (92%) had normal UFC levels at that time. After treatment discontinuation (day 84), UFC was >ULN in 10 patients with available measurements. Mean 11-deoxycortisol, 11-deoxycorticosterone, and adrenocorticotropic hormone levels increased during treatment and declined after discontinuation. Mean systolic and diastolic blood pressure decreased from baseline by 10.0 and 6.0 mmHg, respectively. LCI699 was generally well tolerated; most adverse events (AEs) were mild or moderate. The most common AEs included fatigue (7/12), nausea (5/12), and headache (3/12). No serious drug-related AEs were reported.
Conclusions:
LCI699 was efficacious and well tolerated in patients with Cushing's disease enrolled in this proof-of-concept study.
In 2010, the Veterans Health Administration Office of Nursing Services (VHA ONS) issued a Staffing Methodology (SM) Directive, standardizing the method of determining appropriate nurse staffing for ...VHA facilities.
To assess associations between the Directive, nurse staffing trends, and healthcare-associated infections.
We conducted multi-level interrupted time series analyses of nurse staffing trends and the rates of two healthcare-associated infections before and after implementation of the Directive, October 1, 2008 - June 30, 2014.
Acute care, critical care, mental health acute care, and longterm care nursing units (called Community Living Centers, CLC in VHA) among 285 VHA facilities were included in nurse staffing trends analyses, while acute and critical care units in 123 facilities were used in the analysis of infection rates.
Monthly rates were calculated at the facility unit level and included nursing hours per patient day (NHPPD) for all nursing personnel and number of catheter-associated urinary tract infections (CAUTI) and central line-associated bloodstream infections (CLABSI) per 1000 device days.
Nursing hours per patient day increased in both time periods. However, the differential change in rate of nursing hours per patient day following implementation of the Directive was not statistically significant. On average, we found a statistically significant decrease of 0.05 unit in the post-Directive central line-associated bloodstream infection rates associated with a unit increase in nursing hours per patient day.
System-wide implementation of Staffing Methodology may be one contributing factor impacting patient outcomes.
Women now dominate student enrollment in colleges of veterinary medicine in the USA, as well as in other countries. Projections indicate that this will remain a constant. The implications for ...teaching, learning, mentoring, leadership, professional development, student and faculty diversity, and curriculum structure are enormous. This article provides the groundwork for examining gender diversity in veterinary medical education. Women's development and ways of knowing are identified as paramount for understanding and benefiting students and faculty in their higher education experiences and in their professional lives. Seminal research focusing on women's development and ways of knowing is introduced, summarized, and contrasted to male-centered models, and implications for teaching practice are considered. Our underlying premise is that research about women's moral and intellectual development is relevant to veterinary education and supports the adoption of student-centered approaches to teaching and learning.
The NLRP3-inflammasome, implicated in the pathogenesis of several inflammatory disorders, has been analysed in rheumatoid arthritis (RA).
Relative gene expression of NLRP3-inflammasome components was ...characterised in PBMCs of 29 patients receiving infliximab. A total of 1278 Caucasian patients with RA from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) cohort receiving tumour necrosis factor (TNF) antagonists (infliximab, adalimumab and etanercept) were genotyped for 34 single nucleotide polymorphisms (SNPs), spanning the genes NLRP3, MEFV and CARD8. Regression analyses were performed to test for association between genotype and susceptibility and treatment response (disease activity score across 28 joints (DAS28) and EULAR improvement criteria) at 6 months, with secondary expression quantitative trait loci (eQTL) analyses.
At baseline, gene expression of ASC, MEFV, NLRP3-FL, NLRP3-SL and CASP1 were significantly higher compared with controls whereas CARD8 was lower in the patients. Caspase-1 and interleukin-18 levels were significantly raised in patients with RA. SNPs in NLRP3 showed association with RA susceptibility and EULAR response to anti-TNF in the BRAGGSS cohort, and in monocytes but not B cells, in eQTL analysis of 283 healthy controls. CARD8 SNPs were associated with RA susceptibility and DAS28 improvement in response to anti-TNF and eQTL effects in monocytes and B cells.
This study found evidence of modulation of the NLRP3-inflammasome in patients with RA prior to receiving infliximab and some evidence of association for SNPs at NLRP3 and CARD8 loci with RA susceptibility and response to anti-TNF. The SNPs associated with susceptibility/response are not the main eQTL variants for either locus, and the associations with treatment response require replication in an independent cohort.
Aim
Gut microbial dysbiosis is implicated in the pathogenesis of non‐alcoholic steatohepatitis (NASH). We investigated downstream effects of gut microbiota modulation on markers of hepatic ...inflammation, steatosis, and hepatic and peripheral insulin sensitivity in patients with NASH using rifaximin therapy.
Methods
Patients with biopsy‐proven NASH and elevated aminotransferase values were included in this open‐label pilot study, all receiving 6 weeks rifaximin 400 mg twice daily, followed by a 6‐week observation period. The primary endpoint was change in alanine aminotransferase (ALT) after 6 weeks of rifaximin. Secondary endpoints were change in hepatic lipid content and insulin sensitivity measured with a hyperinsulinemic–euglycemic clamp.
Results
Fifteen patients (13 men and 2 women) with a median (range) age of 46 (32–63) years were included. Seven had diabetes on oral hypoglycemic medications and 8 had no diabetes. After 6 weeks of therapy, no differences were seen in ALT (55 33–191 vs. 63 41–218 IU/L, P = 0.41), peripheral glucose uptake (28.9 19.4–48.3 to 25.5 17.7–47.9 μmol/kg/min, P = 0.30), hepatic insulin sensitivity (35.2 15.3–51.7% vs. 30.0 10.8–50.5%, P = 0.47), or hepatic lipid content (21.6 2.2–46.2% vs. 24.8 1.7–59.3%, P = 0.59) before and after rifaximin treatment. After 12 weeks from baseline, serum ALT increased to 83 (30–217) IU/L, P = 0.02. There was a significant increase in the homeostasis model assessment–estimated insulin resistance index (P = 0.05). The urinary metabolic profile indicated a significant reduction in urinary hippurate with treatment, which reverted to baseline after cessation of rifaximin, although there was no consistent difference in relative abundance of fecal microbiota with treatment.
Conclusion
These data do not indicate a beneficial effect of rifaximin in patients with NASH.
Adverse events from intrapartum antibiotic prophylaxis (IAP) are poorly documented yet essential to inform clinical practice for neonatal group B Streptococcus (GBS) disease prevention. In this ...systematic review, we appraised and synthesised the evidence on the adverse events of IAP in the mother and/or her child.
We searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Cochrane, and Science Citation Index from date of inception until October 16th 2016. Reference lists of included studies and relevant systematic reviews were hand-searched. We included primary studies in English that reported any adverse events from intrapartum antibiotics for any prophylactic purpose compared to controls. The search was not restricted to prophylaxis for GBS but excluded women with symptoms of infection or undergoing caesarean section. Two reviewers assessed the methodological quality of studies, using the Cochrane Risk of Bias tool, and the Risk of Bias Assessment Tool for Nonrandomised Studies. Results were synthesised narratively and displayed in text and tables.
From 2364 unique records, 30 studies were included. Despite a wide range of adverse events reported in 17 observational studies and 13 randomised controlled trials (RCTs), the evidence was inconsistent and at high risk of bias. Only one RCT investigated the long-term effects of IAP reporting potentially serious outcomes such as cerebral palsy; however, it had limited applicability and unclear biological plausibility. Seven observational studies showed that IAP for maternal GBS colonisation alters the infant microbiome. However, study populations were not followed through to clinical outcomes, therefore clinical significance is unknown. There was also observational evidence for increased antimicrobial resistance, however studies were at high or unclear risk of bias.
The evidence base to determine the frequency of adverse events from intrapartum antibiotic prophylaxis for neonatal GBS disease prevention is limited. As RCTs may not be possible, large, better quality, and longitudinal observational studies across countries with widespread IAP could fill this gap.
CRD42016037195 .
Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, ...including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.
The James Webb Space Telescope Mission Acton, Scott; Adams, Cynthia K.; Aguilar, Jonathan Albert ...
Publications of the Astronomical Society of the Pacific,
06/2023, Letnik:
135, Številka:
1048
Journal Article
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