Targeted Systemic Therapies for Adults with Atopic Dermatitis: Selecting from Biologics and JAK Inhibitors.

Therapeutic options for people with moderate or severe atopic dermatitis refractory to topical therapy have rapidly expanded in recent years. These new targeted immunomodulatory agents-biologics and Janus kinase (JAK) inhibitors-have each demonstrated high levels of efficacy and acceptable safety in mostly placebo-controlled clinical trials for atopic dermatitis, but there is no universally applicable algorithm to help choose between them for a given patient. Hence, patients and physicians should utilize shared decision making, discussing efficacy, safety, mode of delivery, monitoring, costs, speed of onset, and other factors to reach individualized treatment decisions. In this review, we try to aid shared decision making by summarizing the efficacy, safety, and monitoring of biologics and oral JAK inhibitors for adults with atopic dermatitis. Network meta-analyses suggest that higher doses of abrocitinib and upadacitinib are more effective than biologics. They also show that, among biologics, dupilumab is likely more effective than tralokinumab and lebrikizumab. Biologics are generally considered safer than JAK inhibitors, although concerns about JAK inhibitors are mainly extrapolated from older generation JAK inhibitors used in higher-risk populations. We also outline evidence and considerations for choosing and using systemic immunomodulatory treatments for special populations including pregnant individuals, those with human immunodeficiency virus (HIV), hepatitis B and C, end stage kidney disease, and older adults.

Predisposing, enabling and reinforcing factors associated with opioid addiction helping behaviour in tri-state Appalachian counties: application of the PRECEDE-PROCEED model-cross-sectional analysis.

OBJECTIVES: The overdose epidemic was designated a 'Public Health Emergency' in the USA on 26 October 2017, bringing attention to the severity of this public health problem. The Appalachian region remains substantially impacted by the effects from years of overprescription of opioids, and subsequently opioid non-medical use and addiction. This study aims to examine the utility of the PRECEDE-PROCEED model constructs (ie, predisposing, reinforcing and enabling factors) to explain opioid addiction helping behaviour (ie, helping someone who has an opioid addiction) among members of the public living in tri-state Appalachian counties. DESIGN: Cross-sectional study. SETTING: Rural county in the Appalachian region of the USA. PARTICIPANTS: A total of 213 participants from a retail mall in a rural Appalachian Kentucky county completed the survey. Most participants were between the ages of 18 and 30 years (n=68; 31.9%) and identified as men (n=139; 65.3%). PRIMARY OUTCOME MEASURE: Opioid addiction helping behaviour. RESULTS: The regression model was significant (F (6, 180)=26.191, p<0.001) and explained 44.8% of the variance in opioid addiction helping behaviour (R2=0.448). Attitude towards helping someone with opioid addiction (B=0.335; p<0.001), behavioural skills (B=0.208; p=0.003), reinforcing factors (B=0.190; p=0.015) and enabling factors (B=0.195; p=0.009) were all significantly associated with opioid addiction helping behaviour. CONCLUSIONS: PRECEDE-PROCEED model constructs have utility to explain opioid addiction helping behaviour among individuals in a region greatly impacted by the overdose epidemic. This study provides an empirically tested framework for future programmes addressing helping behaviour related to opioid non-medical use.

Evidence-Based Assessment of Congenital Heart Disease Genes to Enable Returning Results in a Genomic Study.

BACKGROUND: Congenital heart disease (CHD) is the most common major congenital anomaly and causes significant morbidity and mortality. Epidemiologic evidence supports a role of genetics in the development of CHD. Genetic diagnoses can inform prognosis and clinical management. However, genetic testing is not standardized among individuals with CHD. We sought to develop a list of validated CHD genes using established methods and to evaluate the process of returning genetic results to research participants in a large genomic study. METHODS: Two-hundred ninety-five candidate CHD genes were evaluated using a ClinGen framework. Sequence and copy number variants involving genes in the CHD gene list were analyzed in Pediatric Cardiac Genomics Consortium participants. Pathogenic/likely pathogenic results were confirmed on a new sample in a clinical laboratory improvement amendments-certified laboratory and disclosed to eligible participants. Adult probands and parents of probands who received results were asked to complete a post-disclosure survey. RESULTS: A total of 99 genes had a strong or definitive clinical validity classification. Diagnostic yields for copy number variants and exome sequencing were 1.8% and 3.8%, respectively. Thirty-one probands completed clinical laboratory improvement amendments-confirmation and received results. Participants who completed postdisclosure surveys reported high personal utility and no decision regret after receiving genetic results. CONCLUSIONS: The application of ClinGen criteria to CHD candidate genes yielded a list that can be used to interpret clinical genetic testing for CHD. Applying this gene list to one of the largest research cohorts of CHD participants provides a lower bound for the yield of genetic testing in CHD.

Ross Procedure in Children: The Society of Thoracic Surgeons Congenital Heart Surgery Database Analysis.

BACKGROUND: Single-center studies have demonstrated excellent results for the Ross procedure in children. We aimed to evaluate national variation in clinical outcomes using The Society of Thoracic Surgeons Congenital Heart Surgery Database. METHODS: The database was used to identify 2805 children undergoing the Ross procedure from 2000 through 2018, comprising 163 neonates (<30 days, 5.8%), 448 infants (30-365 days, 16.0%), 1444 children (1-12 years, 51.5%), and 750 teenagers (13-17 years, 26.7%). Centers were divided into terciles by procedural volume. Multivariable logistic regression was used to identify predictors of a composite outcome of operative mortality, neurologic deficit, or renal failure requiring dialysis. RESULTS: Neonates and infants were more likely to present with aortic stenosis than children and teenagers (61.7% [n = 377] vs 34.6% [n = 760]; P < .01) and have risk factors including preoperative shock (9.2% [n = 56] vs 0.4% [n = 8]; P < .01). Operative mortality was 24.1% (n = 39) in neonates, 11.2% (n = 50) in infants, 1.5% (n = 21) in children , and 0.8% (n = 6) in teenagers (P < .01). Independent predictors of the composite outcome in children aged <1 year included neonatal age (odds ratio [OR], 3.0; 95% CI, 1.9-4.8), low-volume center (OR, 2.1; 95% CI, 1.1-3.9), and procedure year (OR, 0.7; 95% CI, 0.5-0.9 per 5 years). In children aged ≥1 year, no association was found between center volume, procedure year, and outcome. CONCLUSIONS: The Ross procedure is being performed with low mortality in children aged ≥1 year throughout North America. High-volume centers have improved outcomes in children aged <1 year, who have different anatomic characteristics and risk profiles.

Genome-Wide De Novo Variants in Congenital Heart Disease Are Not Associated With Maternal Diabetes or Obesity.

BACKGROUND: Congenital heart disease (CHD) is the most common anomaly at birth, with a prevalence of ≈1%. While infants born to mothers with diabetes or obesity have a 2- to 3-fold increased incidence of CHD, the cause of the increase is unknown. Damaging de novo variants (DNV) in coding regions are more common among patients with CHD, but genome-wide rates of coding and noncoding DNVs associated with these prenatal exposures have not been studied in patients with CHD. METHODS: DNV frequencies were determined for 1812 patients with CHD who had whole-genome sequencing and prenatal history data available from the Pediatric Cardiac Genomics Consortium's CHD GENES study (Genetic Network). The frequency of DNVs was compared between subgroups using t test or linear model. RESULTS: Among 1812 patients with CHD, the number of DNVs per patient was higher with maternal diabetes (76.5 versus 72.1, t test P=3.03×10-11), but the difference was no longer significant after including parental ages in a linear model (paternal and maternal correction P=0.42). No interaction was observed between diabetes risk and parental age (paternal and maternal interaction P=0.80 and 0.68, respectively). No difference was seen in DNV count per patient based on maternal obesity (72.0 versus 72.2 for maternal body mass index <25 versus maternal body mass index >30, t test P=0.86). CONCLUSIONS: After accounting for parental age, the offspring of diabetic or obese mothers have no increase in DNVs compared with other children with CHD. These results emphasize the role for other mechanisms in the cause of CHD associated with these prenatal exposures. REGISTRATION: URL: https://clinicaltrials.gov; NCT01196182.

Cerebral aggregate g-ratio mapping using magnetic resonance relaxometry and diffusion tensor imaging to investigate sex and age-related differences in white matter microstructure.

Axonal demyelination is a cardinal feature of aging and age-related diseases. The g-ratio, mathematically defined as the inner-to-outer diameter of a myelinated axon, is used as a structural index of optimal axonal myelination and has been shown to represent a sensitive imaging biomarker of microstructural integrity. Several magnetic resonance imaging (MRI) methods for whole-brain mapping of aggregate g-ratio have been introduced. Computation of the aggerate g-ratio requires estimates of the myelin volume fraction (MVF) and the axonal volume fraction (AVF). While accurate determinations of MVF and AVF can be obtained through multicomponent relaxometry or diffusion analyses, respectively, these methods require lengthy acquisition times making their implementation challenging in a clinical context. Therefore, any attempt to overcome this drawback is needed. Expanding on our previous work, we introduced a new MRI method for whole-brain mapping of aggregate g-ratio. This new approach is based on the use of a single-shell diffusion for AVF determination, reducing the acquisition time by approximately ~10 min from our recently introduced approach, while offering the possibility to investigate g-ratio differences in previous studies with existing data for MVF mapping and single-shell diffusion data for AVF mapping. Our comparison analysis indicates that our newly derived aggregate g-ratio values were similar to those derived from our previous method, which requires a longer acquisition time. Further, in agreement with our previous observations, we found quadratic U-shaped relationships between aggregate g-ratio and age in this much larger study cohort. However, our results show that sexual dimorphism in g-ratio was not significant in any brain region investigated.