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Variation in the expression level and activity of genes involved in drug disposition and action ('pharmacogenes') can affect drug response and toxicity, especially when in tissues of pharmacological importance. Previous studies have relied primarily on microarrays to understand gene expression differences, or have focused on a single tissue or small number of samples. The goal of this study was to use RNA-sequencing (RNA-seq) to determine the expression levels and alternative splicing of 389 Pharmacogenomics Research Network pharmacogenes across four tissues (liver, kidney, heart and adipose) and lymphoblastoid cell lines, which are used widely in pharmacogenomics studies. Analysis of RNA-seq data from 139 different individuals across the 5 tissues (20-45 individuals per tissue type) revealed substantial variation in both expression levels and splicing across samples and tissue types. Comparison with GTEx data yielded a consistent picture. This in-depth exploration also revealed 183 splicing events in pharmacogenes that were previously not annotated. Overall, this study serves as a rich resource for the research community to inform biomarker and drug discovery and use.

Nutrition-related health disparities plague prisons in the United States. Unregulated and inadequate prison menus may contribute to noncommunicable chronic health conditions in this vulnerable population. The purpose of this research was to assess nutrition offerings provided by prison menus. Researchers requested the most current version of all master menus and associated nutrition analyses for gendered and age-centric (pediatric vs geriatric) menus. Menu and nutrient data were extracted and entered into a spreadsheet for analysis. Prisons serve gendered or nongendered menus to the general population, and 52.9% of prisons offer nongendered menus where males and females receive the same meals. This approach provides excess calories and saturated fat to females. Sodium was served in excess to both males and females. Fruit and vegetable servings on all gendered menus fell short of recommendations. The average prison menu inappropriately offers calories, sodium, and fruit and vegetable servings in a one-size-fits-all menu development method without considering gender, age, and physical activity. Interpretation and application of Dietary Guidelines for Americans are inconsistent. Nutrition guidelines recommending appropriate nutrients and food groups should be developed and available to corrections systems and dietitians. Current prison menu development practices yield inappropriate nutrition for prison populations. [ABSTRACT FROM AUTHOR]

Objectives: Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) is a rare CD-30 positive, Anaplastic Lymphoma Kinase Negative Non-Hodgkins lymphoma. The current estimated incidence is one to three cases per million implanted women. However, this is likely to rise with the increasing popularity of breast augmentation. This article contains a brief literature review and describes the Caribbean response to BIAALCL. Methods: A literature search was done on the PUBMED Database. Keywords included 'breast implant-associated anaplastic large cell lymphoma', 'brentuximab vedotin', 'breast implant', 'texturized implants'. The Caribbean Association of Plastic and Reconstructive Surgeons (CAPRS) formulated a regional response to BIA-ALCL during their meeting in August 2019. Results: The Food and Drug Administration (FDA) has received 573 unique medical device reports of BIA-ALCL worldwide. The time from implantation to diagnosis, ranges from 7.5 to 10 years and the median age at diagnosis ranges from 47 to 58 years. The pathophysiology of BIA-ALCL is likely multifactorial and involves chronic inflammation in response to textured implants and chronic biofilm, in a genetically susceptible person. Early presentation has a good prognosis with treatment (5-year survival rate of 70-90%). Conclusion: Recommendations included development of a regional breast implant registry, which will facilitate study on implant use and its complications. They also concluded that texturized devices should be avoided and utilization of smooth alternatives or autologous reconstruction be performed. Additionally, if requested by asymptomatic women, explant of textured implants and total capsulectomy is not unreasonable. However, these patients must be appropriately counselled. [ABSTRACT FROM AUTHOR]

The skeletal system derives from multiple embryonic sources whose derivatives must develop in coordination to produce an integrated whole. In particular, interactions across the lateral somitic frontier, where derivatives of the somites and lateral plate mesoderm come into contact, are important for proper development. Many questions remain about genetic control of this coordination, and embryological information is incomplete for some structures that incorporate the frontier, including the sternum. Hox genes act in both tissues as regulators of skeletal pattern. Here, we used conditional deletion to characterize the tissue-specific contributions of Hoxa5 to skeletal patterning. We found that most aspects of the Hoxa5 skeletal phenotype are attributable to its activity in one or the other tissue, indicating largely additive roles. However, multiple roles are identified at the junction of the T1 ribs and the anterior portion of the sternum, or presternum. The embryology of the presternum has not been well described in mouse. We present a model for presternum development, and show that it arises from multiple, paired LPM-derived primordia. We show evidence that HOXA5 expression marks the embryonic precursor of a recently identified lateral presternum structure that is variably present in therians., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mitchel, Bergmann, Brent, Finkelstein, Schindler, Holzman, Jeannotte and Mansfield.)

Statins are the most commonly prescribed cardiovascular disease drug, but their inter-individual efficacy varies considerably. Genetic factors uncovered to date have only explained a small proportion of variation in low-density lipoprotein cholesterol (LDLC) lowering. To identify novel markers and determinants of statin response, we used whole transcriptome sequence data collected from simvastatin and control incubated lymphoblastoid cell lines (LCLs) established from participants of the Cholesterol and Pharmacogenetics (CAP) simvastatin clinical trial. We looked for genes whose statin-induced expression changes were most different between LCLs derived from individuals with high versus low plasma LDLC statin response during the CAP trial. We created a classification model of 82 "signature" gene expression changes that distinguished high versus low LDLC statin response. One of the most differentially changing genes was zinc finger protein 542 pseudogene (ZNF542P), the signature gene with changes most correlated with statin-induced change in cellular cholesterol ester, an in vitro marker of statin response. ZNF542P knock-down in a human hepatoma cell line increased intracellular cholesterol ester levels upon simvastatin treatment. Together, these findings imply a role for ZNF542P in LDLC response to simvastatin and, importantly, highlight the potential significance of noncoding RNAs as a contributing factor to variation in drug response.

Background: Numerous genetic contributors to cardiovascular disease risk have been identified through genome-wide association studies; however, identifying the molecular mechanism underlying these associations is not straightforward. The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial of rosuvastatin users identified a sub-genome-wide association of rs6924995, a single-nucleotide polymorphism ≈10 kb downstream of myosin regulatory light chain interacting protein (MYLIP, aka IDOL and inducible degrader of low-density lipoprotein receptor [LDLR]), with LDL cholesterol statin response. Interestingly, although this signal was initially attributed to MYLIP, rs6924995 lies within RP1-13D10.2, an uncharacterized long noncoding RNA., Methods and Results: Using simvastatin and sham incubated lymphoblastoid cell lines from participants of the Cholesterol and Pharmacogenetics (CAP) simvastatin clinical trial, we found that statin-induced change in RP1-13D10.2 levels differed between cell lines from the tails of the white and black low-density lipoprotein cholesterol response distributions, whereas no difference in MYLIP was observed. RP1-13D10.2 overexpression in Huh7 and HepG2 increased LDLR transcript levels, increased LDL uptake, and decreased media levels of apolipoprotein B. In addition, we found a trend of slight differences in the effects of RP1-13D10.2 overexpression on LDLR transcript levels between hepatoma cells transfected with the rs6924995 A versus G allele and a suggestion of an association between rs6924995 and RP1-10D13.2 expression levels in the CAP lymphoblastoid cell lines. Finally, RP1-13D10.2 expression levels seem to be sterol regulated, consistent with its potential role as a novel lipid regulator., Conclusions: RP1-13D10.2 is a long noncoding RNA that regulates LDLR and may contribute to low-density lipoprotein cholesterol response to statin treatment. These findings highlight the potential role of noncoding RNAs as determinants of interindividual variation in drug response., (© 2016 American Heart Association, Inc.)

Disengagement can be observed, measured, and,most of all, understood. A bad attitude does not have to be permanent or terminal. While the individual who is an RTW Grump may never become“Mr. Sunshine,” he can be realigned toward a more healthy skepticism to incremental or selective change. The RTW Grump can be approached in a manner that invites incremental engagement at strategic points. Disengagement represents an unnecessary disconnect from previously valued relationships. Making the leading contributors to disengagement (i.e., morale, changing value of work,patience, self-esteem) the foundation for the RTW plan increases the likelihood that a person, who for no apparent good reason should be able to return to work, actually becomes reengaged.

The contributions of the Sgs1, Mph1, and Srs2 DNA helicases during mitotic double-strand break (DSB) repair in yeast were investigated using a gap-repair assay. A diverged chromosomal substrate was used as a repair template for the gapped plasmid, allowing mismatch-containing heteroduplex DNA (hDNA) formed during recombination to be monitored. Overall DSB repair efficiencies and the proportions of crossovers (COs) versus noncrossovers (NCOs) were determined in wild-type and helicase-defective strains, allowing the efficiency of CO and NCO production in each background to be calculated. In addition, the products of individual NCO events were sequenced to determine the location of hDNA. Because hDNA position is expected to differ depending on whether a NCO is produced by synthesis-dependent-strand-annealing (SDSA) or through a Holliday junction (HJ)-containing intermediate, its position allows the underlying molecular mechanism to be inferred. Results demonstrate that each helicase reduces the proportion of CO recombinants, but that each does so in a fundamentally different way. Mph1 does not affect the overall efficiency of gap repair, and its loss alters the CO-NCO by promoting SDSA at the expense of HJ-containing intermediates. By contrast, Sgs1 and Srs2 are each required for efficient gap repair, strongly promoting NCO formation and having little effect on CO efficiency. hDNA analyses suggest that all three helicases promote SDSA, and that Sgs1 and Srs2 additionally dismantle HJ-containing intermediates. The hDNA data are consistent with the proposed role of Sgs1 in the dissolution of double HJs, and we propose that Srs2 dismantles nicked HJs., Competing Interests: SJ-R is currently an associate editor for PLOS Genetics.

The molecular structures of crossover (CO) and noncrossover (NCO) intermediates were determined by sequencing the products formed when a gapped plasmid was repaired using a diverged chromosomal template. Analyses were done in the absence of mismatch repair (MMR) to allow efficient detection of strand-transfer intermediates, and the results reveal striking differences in the extents and locations of heteroduplex DNA (hDNA) in NCO versus CO products. These data indicate that most NCOs are produced by synthesis-dependent strand annealing rather than by a canonical double-strand break repair pathway and that resolution of Holliday junctions formed as part of the latter pathway is highly constrained to generate CO products. We suggest a model in which the length of hDNA formed by the initiating strand invasion event determines susceptibility of the resulting intermediate to antirecombination and ultimately whether a CO- or a NCO-producing pathway is followed., (Copyright 2010 Elsevier Inc. All rights reserved.)

Purpose: To assess the reason for the relative high risk of local complications for women following cardiac catheterization by evaluating the associations between gender, sheath size, and local adverse outcomes following cardiac catheterization., Methods: The data used in this study were obtained from a portion of the American College of Cardiology-National Cardiovascular Data Registry (ACC-NCDR), which included 13 878 patients who underwent cardiac catheterization at one of 59 participating cardiac catheterization institutions throughout the United States during late 2003. Rates of serious local vascular adverse events were calculated by gender following cardiac catheterization, by type of vascular hemostasis used, stratified by arterial sheath size., Results: Serious local vascular events were reported in 3.54% of patients, most commonly hematoma (2.00%). The relative risk for women of any vascular complication was 1.40 [95%CI = 1.17, 1.67, p = 0.0002]. A statistically significant relative risk for woman was evident when collagen plug devices or manual compression alone were used as the first method for hemostasis. The rate of vascular complications increased progressively with increasing sheath size, more so in women than in men., Conclusions: High relative risk for women of local vascular complications following cardiac catheterization was demonstrated with use of manual compression, as well as with collagen plug devices to control femoral artery bleeding. Large sheath size is associated with both a relatively high absolute risk and a high relative risk for women. Knowledge of this information should be considered by interventional cardiologists in making decisions on how to achieve hemostasis following cardiac catheterization.

Histocompatibility in the primitive chordate, Botryllus schlosseri, is controlled by a single, highly polymorphic locus, the FuHC. By taking a forward genetic approach, we have identified a locus encoded near the FuHC, called fester, which is polymorphic, polygenic, and inherited in distinct haplotypes. Somatic diversification occurs through extensive alternative splicing, with each individual expressing a unique repertoire of splice forms, both membrane bound and potentially secreted, all expressed in tissues intimately associated with histocompatibility. Functional studies, via both siRNA-mediated knockdown and direct blocking by monoclonal antibodies raised against fester, were able to disrupt predicted histocompatibility outcomes. The genetic and somatic diversity, coupled to the expression and functional data, suggests that fester is a receptor involved in histocompatibility.

Objectives: To assess the relative risks of serious local adverse events following cardiac catheterization by type of hemostasis device (versus manual compression controls) and gender., Background: Reports to the FDA (U.S. Food and Drug Administration) of local vascular complications associated with the use of hemostasis devices following cardiac catheterization and resulting in serious injuries, raised concerns about the safety of these devices. Review of the medical literature also posed cause for concern., Methods: Data were obtained from the American College of Cardiology-National Cardiovascular Data Registry, modified to suit the needs of this research. It included information from 59 institutions and 13,878 cardiac catheterizations performed during the last quarter of 2003. Multiple logistic regression, using 10 different outcomes, was used to assess the risk associated with type of device and gender, while controlling for demographic and physiologic variables, type of procedure, and several indices of comorbidity., Results: Serious adverse events were reported in 3.37% of patients, the most common being bleeding with hematoma (2.00%). The adjusted odds ratio for women (compared to men) was 1.73 for any vascular complication. Only one hemostasis device, VasoSeal, demonstrated a high risk of any vascular complication compared to manual compression controls (OR = 2.38 [1.47-3.85; p = 0.0004]). This risk was mainly associated with diagnostic cardiac catheterization (OR = 3.36)., Conclusions: VasoSeal appears to pose a greater risk for serious local vascular complications following cardiac catheterization than either manual compression controls or other hemostasis devices. Women have almost twice the risk of men for most local complications.

Histocompatibility--the ability of an organism to distinguish its own cells and tissue from those of another--is a universal phenomenon in the Metazoa. In vertebrates, histocompatibility is a function of the immune system controlled by a highly polymorphic major histocompatibility complex (MHC), which encodes proteins that target foreign molecules for immune cell recognition. The association of the MHC and immune function suggests an evolutionary relationship between metazoan histocompatibility and the origins of vertebrate immunity. However, the MHC of vertebrates is the only functionally characterized histocompatibility system; the mechanisms underlying this process in non-vertebrates are unknown. A primitive chordate, the ascidian Botryllus schlosseri, also undergoes a histocompatibility reaction controlled by a highly polymorphic locus. Here we describe the isolation of a candidate gene encoding an immunoglobulin superfamily member that, by itself, predicts the outcome of histocompatibility reactions. This is the first non-vertebrate histocompatibility gene described, and may provide insights into the evolution of vertebrate adaptive immunity.