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Objective Variants in the SLCO1B1 gene, encoding a hepatic methotrexate (MTX) transporter, affect clearance of high‐dose MTX. We tested whether in the *14 and *15 alleles of SLCO1B1 influenced the response to low‐dose MTX in juvenile idiopathic arthritis (JIA) patients. Methods The study included 310 JIA patients genotyped for three single nucleotide polymorphisms (SNPs) in SLCO1B1 (rs4149056, rs2306283, and rs11045819). A patient's SLCO1B1 diplotype was determined by combining the SNPs into the *1a, *1b, *4, *5, *14, and *15 alleles. Number of active joints at follow‐up (visit closest to 6 months of treatment and prior to starting a tumor necrosis factor inhibitor) was used as the dependent variable in a negative binomial regression model that included active joint count at baseline as a covariate. Results The SLCO1B1*14 allele was associated with less response to MTX (P = 0.024) and the *15 allele was not associated with response to MTX (P = 0.392). Conclusion SLCO1B1 alleles may be associated with poor response to MTX in JIA patients. The *14 allele has been associated with fast clearance (low exposure) after high‐dose MTX in patients with leukemia. Thus, the SLCO1B1 gene may be informative for precision dosing of MTX in JIA patients. Patients carrying the *14 allele may require a higher dose than noncarriers to achieve a similar response to MTX.

Electronic cigarettes (ECs) are marketed as nicotine delivery devices. Two studies with EC-naïve participants suggest that ECs deliver little or no nicotine. In those studies, standard-sized ECs were used, though experienced EC users often use larger devices that house higher voltage and/or longer lasting batteries. Whether user experience and device characteristics influence EC nicotine delivery is uncertain. The purpose of the present study was to examine the effects of ECs in experienced users who were using their preferred devices. Eight EC users (3 women) who had been using ECs for at least 3 months, completed one 5-hr session using devices they provided and the flavor/strength nicotine cartridges they selected. Sessions consisted of 4 phases: baseline, 10 puffs (30-s interpuff interval) from the device, 1-hr ad lib puffing period, and a 2-hr rest period (no puffing). Outcome measures in each phase included plasma nicotine concentration, heart rate, and subjective ratings of nicotine/product effects and abstinence symptoms. Relative to baseline, plasma nicotine and heart rate increased significantly within 5 min of the first puff and remained elevated throughout the ad lib puffing period. Increases in ratings of direct effects of nicotine and product were observed as well as decreases in abstinence symptoms. User experience and/or device characteristics likely influence EC nicotine delivery and other effects. Systematic manipulation of these and other variables could elucidate conditions that produce intended effects.

Objective This study uses time diaries to examine how parents' work arrangements shaped their time use at home and work during the COVID‐19 pandemic. Background The pandemic transformed home and work life for parents, disrupting employment and childcare. The shift to work from home offered more flexibility to manage increased care burdens, but the lack of separation between work and family also likely contributed to more challenging work environments, especially among mothers. Method This study relies on the 2017–2020 American Time Use Survey and matching to estimate changes in time use among parents working from home and on site in the pandemic relative to comparable parents prior to the pandemic. Results Data showed no overall increases in primary childcare time among working parents. Parents working from home during the pandemic, however, spent more time in the presence of children and supervising children, much in combination with paid work. Mothers working from home increased their supervisory parenting while working for pay more than fathers, and they more often changed their paid work schedules. The study's main findings were robust to gendered unemployment and labor force exits. Conclusion Parents, especially mothers, working from home responded to childcare demands through multitasking and schedule changes with potential negative effects on work quality and stress. Parents working on site during the pandemic experienced smaller changes in time use. Implications The pandemic has generated new inequalities between those with and without the flexibility to work from home, and exacerbated gender inequalities among those working from home.

Amid increasing rates of electronic cigarette (e-cigarette) use in the United States, there is an urgent need to monitor patterns of use at the population level in order to inform practice, policy and regulation. This article examines how patterns of e-cigarette use among adults differ between users and nonusers of cigarettes using the most current national data. We analyzed data from the 2014 National Health Interview Survey. We estimated prevalence of ever, current, and daily e-cigarette use and examined how use patterns differed by demographic subgroups and measures of cigarette smoking status that accounted for the recent availability of e-cigarettes in the US marketplace. Current e-cigarette use is extremely low among never cigarette smokers (0.4%) and former smokers who quit cigarettes 4 or more years ago (0.8%). Although e-cigarette experimentation is most common among current cigarette smokers and young adults, daily use is highest among former smokers who quit in the past year (13.0%) and older adults. Compared to daily cigarette smokers, recently quit smokers were more than four times as likely to be daily users of e-cigarettes (AOR: 4.33 [95% CI: 3.08-6.09]). Extremely low e-cigarette use among never-smokers and longer term former smokers suggest that e-cigarettes neither promote widespread initiation nor relapse among adults. Recognition of the heterogeneity of smokers, including the time since quitting, is critical to draw accurate conclusions about patterns of e-cigarette use at the population level and its potential for public health benefit or harm. Data from 2014 National Health Interview Survey indicate that e-cigarettes have not been attracting adult non-smokers or promoting relapse in longer term former smokers. Moreover, the data are suggestive that some recent quitters may have done so with the assistance of e-cigarettes. Creating measures of smoking status that treat former smokers as a homogenous group is insufficient to assess the epidemiology of e-cigarette use and the potential impact on public health.

Although an increasing number of copy-number variations are being identified as susceptibility loci for a variety of pediatric diseases, the penetrance of these copy-number variations remains mostly unknown. This poses challenges for counseling, both for recurrence risks and prenatal diagnosis. We sought to provide empiric estimates for penetrance for some of these recurrent, disease-susceptibility loci. We conducted a Bayesian analysis, based on the copy-number variation frequencies in control populations (n = 22,246) and in our database of >48,000 postnatal microarray-based comparative genomic hybridization samples. The background risk for congenital anomalies/developmental delay/intellectual disability was assumed to be ~5%. Copy-number variations studied were 1q21.1 proximal duplications, 1q21.1 distal deletions and duplications, 15q11.2 deletions, 16p13.11 deletions, 16p12.1 deletions, 16p11.2 proximal and distal deletions and duplications, 17q12 deletions and duplications, and 22q11.21 duplications. Estimates for the risk of an abnormal phenotype ranged from 10.4% for 15q11.2 deletions to 62.4% for distal 16p11.2 deletions. This model can be used to provide more precise estimates for the chance of an abnormal phenotype for many copy-number variations encountered in the prenatal setting. By providing the penetrance, additional, critical information can be given to prospective parents in the genetic counseling session. Genet Med 2013:15(6):478–481

Objectives The study investigated the links between workplace measures implemented in response to COVID‐19 with mental health and work performance of employees in Japan. Methods This was a cross‐sectional study of a sample from a cohort study of full‐time employees. Participants (n = 1448) completed an online self‐report questionnaire on March 19‐22, 2020. Multiple linear regression was conducted to ascertain their fear of and worry associated with COVID‐19, psychological distress, and work performance. Results The number of workplace measures correlated positively with respondents' fear of and worry associated with COVID‐19 (adjusted standardized β = 0.123, P < .001), negatively with psychological distress and positively with work performance (adjusted standardized β = −0.068, P = .032; adjusted standardized β = 0.101, P = .002; respectively). Conclusions Workplace measures may promote and maintain the mental health and work performance of employees during the COVID‐19 epidemic. The positive association between the number of measures and fear and worry about COVID‐19 may reflect increased awareness about COVID‐19 among employees resulted from taking the measures.

A multicenter, retrospective study of patients infected with carbapenem-resistant Pseudomonas aeruginosa who were treated with ceftolozane/tazobactam was performed. Among 35 patients, pneumonia was the most common indication and treatment was successful in 26 (74%). Treatment failure was observed in all cases where isolates demonstrated ceftolozane-tazobactam minimum inhibitory concentrations ≥8 μg/mL.

Electronic cigarettes (ECIGs) aerosolize a liquid that usually contains propylene glycol and/or vegetable glycerin, flavorants, and the dependence-producing drug nicotine in various concentrations. This study examined the extent to which ECIG liquid nicotine concentration is related to user plasma nicotine concentration in ECIG-naïve tobacco cigarette smokers. Sixteen ECIG-naïve cigarette smokers completed four laboratory sessions that differed by the nicotine concentration of the liquid (0, 8, 18, or 36 mg/ml) that was placed into a 1.5 Ohm, dual coil \"cartomizer\" powered by a 3.3V battery. In each session, participants completed two, 10-puff ECIG use bouts with a 30-second inter-puff interval; bouts were separated by 60 minutes. Venous blood was sampled before and after bouts for later analysis of plasma nicotine concentration; puff duration, volume, and average flow rate were measured during each bout. In bout 1, relative to the 0mg/ml nicotine condition (mean = 3.8 ng/ml, SD = 3.3), plasma nicotine concentration increased significantly immediately after the bout for the 8 (mean = 8.8 ng/ml, SD = 6.3), 18 (mean = 13.2 ng/ml, SD = 13.2), and 36 mg/ml (mean = 17.0 ng/ml, SD = 17.9) liquid concentration. A similar pattern was observed after bout 2. Average puff duration in the 36 mg/ml condition was significantly shorter compared to the 0mg/ml nicotine condition. Puff volume increased during the second bout for 8 and 18 mg/ml conditions. For a given ECIG device, nicotine delivery may be directly related to liquid concentration. ECIG-naïve cigarette smokers can, from their first use bout, attain cigarette-like nicotine delivery profiles with some currently available ECIG products. Liquid nicotine concentration can influence plasma nicotine concentration in ECIG-naïve cigarette smokers, and, at some concentrations, the nicotine delivery profile of a 3.3V ECIG with a dual coil, 1.5-Ohm cartomizer approaches that of a combustible tobacco cigarette in this population. Finding a product that delivers nicotine as effectively as a tobacco cigarette, as we report here, may be essential for smokers who want to replace completely their combustible tobacco cigarettes with ECIGs.

Purpose Nonclassic 21-hydroxylase deficiency, a mild form of congenital adrenal hyperplasia (CAH), is estimated to be the most common autosomal recessive condition, with an especially high prevalence in Ashkenazi Jews (3.7% affected, 30.9% carriers), based on a 1985 HLA-B linkage study of affected families. Affected individuals, especially women, may suffer from hyperandrogenism and infertility. State-of-the-art genetic studies have not been done to confirm these remarkable rates. Methods CYP21A2 genotyping was performed in 200 unrelated healthy Ashkenazi Jewish subjects and 200 random US Caucasians who did not self-identify as a specific ethnicity using multiplex minisequencing, real-time polymerase chain reaction and junction site analysis. Results Nonclassic CAH carriership was found similarly in 15% (95% confidence interval (CI): 10.4–20.7) of Ashkenazi Jews and 9.5% (95% CI: 5.8–14.4) of Caucasians ( P =0.13). The proportion of Ashkenazi Jewish nonclassic CAH carriers (0.15 versus 0.309, P <0.0001) and disease affected (0.005 versus 0.037, P =0.009) was not as high as previously reported. The estimated prevalence of nonclassic CAH in Caucasians was 1 in 200 (0.5%, 95% CI: 0.01–2.8). Conclusion Nonclassic CAH is a common condition, regardless of ethnicity, and should be considered with preconception and infertility counseling.

Summary Pseudomonas species have become reliable platforms for bioproduction due to their capability to tolerate harsh conditions imposed by large‐scale bioprocesses and their remarkable resistance to diverse physicochemical stresses. The last few years have brought forth a variety of synthetic biology tools for the genetic manipulation of pseudomonads, but most of them are either applicable only to obtain certain types of mutations, lack efficiency, or are not easily accessible to be used in different Pseudomonas species (e.g. natural isolates). In this work, we describe a versatile, robust and user‐friendly procedure that facilitates virtually any kind of genomic manipulation in Pseudomonas species in 3–5 days. The protocol presented here is based on DNA recombination forced by double‐stranded DNA cuts (through the activity of the I‐SceI homing meganuclease from yeast) followed by highly efficient counterselection of mutants (aided by a synthetic CRISPR‐Cas9 device). The individual parts of the genome engineering toolbox, tailored for knocking genes in and out, have been standardized to enable portability and easy exchange of functional gene modules as needed. The applicability of the procedure is illustrated both by eliminating selected genomic regions in the platform strain P. putida KT2440 (including difficult‐to‐delete genes) and by integrating different reporter genes (comprising novel variants of fluorescent proteins) into a defined landing site in the target chromosome. The present protocol describes a streamlined method for precise genome engineering of Pseudomonas species. By using a combination of fluorescent markers, coupled with the activity of the I‐SceI meganuclease or CRISPR/Cas9‐mediated counterselection, virtually any genomic manipulation can be performed in 3–5 days.