Classification Accuracy and Description of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in an Integrated Health Care System, 2006-2017.

INTRODUCTION: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic illness characterized by marked functional limitations and fatigue. Electronic health records can be used to estimate incidence of ME/CFS but may have limitations. METHODS: The authors used International Classification of Diseases (ICD) diagnosis codes to identify all presumptive cases of ME/CFS among 9- to 39-year-olds from 2006 to 2017. The authors randomly selected 200 cases for medical record review to classify cases as confirmed, probable, or possible, based on which and how many current clinical criteria they met, and to further characterize their illness. The authors calculated crude annual rates of ME/CFS coding stratified by age and sex using only those ICD codes that had identified confirmed, probable, or possible ME/CFS cases in the medical record review. RESULTS: The authors identified 522 individuals with presumptive ME/CFS based on having ≥ 1 ICD codes for ME/CFS in their electronic medical record. Of the 200 cases selected, records were available and reviewed for 188. Thirty (15%) were confirmed or probable ME/CFS cases, 39 (19%) were possible cases, 119 (60%) were not cases, and 12 (6%) had no medical record available. Confirmed/probable cases commonly had chronic pain (80%) or anxiety/depression (70%), and only 13 (43%) had completed a sleep study. Overall, 37 per 100,000 had ICD codes that identified confirmed, probable, or possible ME/CFS. Rates increased between 2006 and 2017, with the largest absolute increase among those 30-39 years old. CONCLUSIONS: Using ICD diagnosis codes alone inaccurately estimates ME/CFS incidence.

Obesity-associated inflammation countered by a Mediterranean diet: the role of gut-derived metabolites.

The prevalence of obesity has increased dramatically worldwide and has become a critical public health priority. Obesity is associated with many co-morbid conditions, including hypertension, diabetes, and cardiovascular disease. Although the physiology of obesity is complex, a healthy diet and sufficient exercise are two elements known to be critical to combating this condition. Years of research on the Mediterranean diet, which is high in fresh fruits and vegetables, nuts, fish, and olive oil, have demonstrated a reduction in numerous non-communicable chronic diseases associated with this diet. There is strong evidence to support an anti-inflammatory effect of the diet, and inflammation is a key driver of obesity. Changes in diet alter the gut microbiota which are intricately intertwined with human physiology, as gut microbiota-derived metabolites play a key role in biological pathways throughout the body. This review will summarize recent published studies that examine the potential role of gut metabolites, including short-chain fatty acids, bile acids, trimethylamine-N-oxide, and lipopolysaccharide, in modulating inflammation after consumption of a Mediterranean-like diet. These metabolites modulate pathways of inflammation through the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, toll-like receptor 4 signaling, and macrophage driven effects in adipocytes, among other mechanisms.

Novel Loci (EIF4A2, ADIPOQ, TPRG1) for Triglyceride / High-density Lipoprotein Cholesterol Ratio Longitudinal Change (ΔTHR) among Subjects without Type 2 Diabetes: Evidence from the Long Life Family Study (LLFS) and the Framingham Heart Study (FHS) Offspring Cohort (OS).

Aims/hypothesis: Triglyceride (TG) /High density lipoprotein cholesterol (HDL-C) ratio (THR) represents a single surrogate predictor of hyperinsulinemia or insulin resistance that is associated with premature aging processes, risk of diabetes and increased mortality. To identify novel genetic loci for THR change over time (ΔTHR), we conducted genome-wide association study (GWAS) and genome-wide linkage scan (GWLS) among subjects of European ancestry who had complete data from two exams collected about seven years apart from the Long Life Family Study (LLFS, n=1384), a study with familial clustering of exceptional longevity in the US and Denmark. Methods: Subjects with diabetes or using medications for dyslipidemia were excluded from this analysis. ΔTHR was derived using growth curve modeling, and adjusted for age, sex, field centers, and principal components (PCs). GWAS was conducted using a linear mixed model accounted for familial relatedness. Our linkage scan was built on haplotype-based IBD estimation with 0.5 cM average spacing. Results: Heritability of ΔTHR was moderate (46%). Our GWAS identified a significant locus at the LPL (p=1.58e-9) for ΔTHR; this gene locus has been reported before influencing baseline THR levels. Our GWLS found evidence for a significant linkage with a logarithm of the odds (LODs) exceeding 3 on 3q28 (LODs=4.1). Using a subset of 25 linkage enriched families (pedigree-specific LODs>0.1), we assessed sequence elements under 3q28 and identified two novel variants (EIF4A2/ADIPOQ-rs114108468, p=5e-6, MAF=1.8%; TPRG1-rs16864075, p=3e-6, MAF=8%; accounted for ~28% and ~29% of the linkage, respectively, and 57% jointly). While the former variant was associated with EIF4A2 (p=7e-5) / ADIPOQ (p=3.49e-2) RNA transcriptional levels, the latter variant was not associated with TPRG1 (p=0.23) RNA transcriptional levels. Replication in FHS OS observed modest effect of these loci on ΔTHR. Of 188 metabolites from 13 compound classes assayed in LLFS, we observed multiple metabolites (e.g., DG.38.5, PE.36.4, TG.58.3) that were significantly associated with the variants (p<3e-4). Conclusions: our linkage-guided sequence analysis approach permitted our discovery of two novel gene variants EIF4A2/ADIPOQ-rs114108468 and TPRG1-rs16864075 on 3q28 for ΔTHR among subjects without diabetes selected for exceptional survival and healthy aging.

Applying a User-Centered Design Framework to Develop a Remote Research Assessment Protocol for a Randomized Clinical Trial for Toddlers with Early Autism Characteristics.

COVID-19 required many research teams to shift from in-person to remote assessments, which posed both procedural and theoretical challenges. While research has explored the utility of remote assessments for autism diagnosis from the perspective of families and clinicians, less is known about their application in clinical trials. This paper describes the development of a remote research assessment protocol for a randomized clinical trial focusing on the implementation of reciprocal imitation teaching (RIT) with toddlers in Part C early intervention. This project spans two phases. For Phase 1, our team developed and documented a series of steps utilizing user-centered design (UCD) strategies (e.g., recruiting potential users, creating a prototype, engaging in iterative development) for the purpose of redesigning an assessment protocol for a remote environment. For Phase 2, we examined preliminary outcomes of the redesign process. Primary end users (assessors) rated post-redesign usability and acceptability, while acceptability was examined using attrition data from secondary end users (family participants). Preliminary fidelity of implementation was also examined. The iterative redesign process allowed the research team to refine aspects of the assessment that ultimately led to promising preliminary ratings of usability, acceptability, and feasibility, as well as high fidelity. Preliminary data suggest that the redesigned assessment appears to be an acceptable, feasible, and usable tool for autism clinical trial research and that assessors can use it with fidelity. Further research is needed to examine the reliability and validity of the assessment, as well as implementation characteristics on a larger scale.

Consensus recommendations for use of long-acting antiretroviral medications in the treatment and prevention of HIV-1: Endorsed by the American Academy of HIV Medicine, American College of Clinical Pharmacy, Canadian HIV and Viral Hepatitis Pharmacists Network, European AIDS Clinical Society, and Society of Infectious Diseases Pharmacists: An executive summary.

Five long-acting (LA) antiretrovirals (ARVs) are currently available in a limited number of countries worldwide for HIV-1 prevention or treatment - cabotegravir, rilpivirine, lenacapavir, ibalizumab, and dapivirine. Implementing use of LA ARVs in routine clinical practice requires significant changes to the current framework of HIV-1 prevention, treatment, and service provision. Given the novelty, complexity, and interdisciplinary requirements of safe and optimal use of LA ARVs, consensus recommendations on the use of LA ARVs will assist clinicians in optimizing use of these agents. The purpose of these recommendations is to provide guidance for the clinical use of LA ARVs for HIV-1 treatment and prevention. In addition, future areas of research are identified and discussed.

Consensus recommendations for use of long-acting antiretroviral medications in the treatment and prevention of HIV-1: Endorsed by the American Academy of HIV Medicine, American College of Clinical Pharmacy, Canadian HIV and Viral Hepatitis Pharmacists Network, European AIDS Clinical Society, and Society of Infectious Diseases Pharmacists.

Five long-acting (LA) antiretrovirals (ARVs) are currently available in a limited number of countries worldwide for HIV-1 prevention or treatment-cabotegravir, rilpivirine, lenacapavir, ibalizumab, and dapivirine. Implementing use of LA ARVs into routine clinical practice requires significant changes to the current framework of HIV-1 prevention, treatment, and service provision. Given the novelty, complexity, and interdisciplinary requirements needed to safely and optimally utilize LA ARVs, consensus recommendations on the use of LA ARVs will assist clinicians in optimizing use of these agents. The purpose of these recommendations is to provide guidance for the clinical use of LA ARVs for HIV-1 treatment and prevention. In addition, future areas of research are also identified and discussed.

The BMP2 prodomain promotes dimerization and cleavage of BMP6 homodimers and BMP2/6 heterodimers in vivo.

Bone morphogenetic protein 2 (BMP2) and BMP6 are key regulators of systemic iron homeostasis. All BMPs are generated as inactive precursor proteins that dimerize and are cleaved to generate the bioactive ligand and inactive prodomain fragments, but nothing is known about how BMP2 or BMP6 homodimeric or heterodimeric precursor proteins are proteolytically activated. Here, we conducted in vitro cleavage assays, which revealed that BMP2 is sequentially cleaved by furin at two sites, initially at a site upstream of the mature ligand, and then at a site adjacent to the ligand domain, while BMP6 is cleaved at a single furin motif. Cleavage of both sites of BMP2 is required to generate fully active BMP2 homodimers when expressed in Xenopus embryos or liver endothelial cells, and fully active BMP2/6 heterodimers in Xenopus . We analyzed BMP activity in Xenopus embryos expressing chimeric proteins consisting of the BMP2 prodomain and BMP6 ligand domain, or vice versa. We show that the prodomain of BMP2 is necessary and sufficient to generate active BMP6 homodimers and BMP2/6 heterodimers, whereas the BMP6 prodomain cannot generate active BMP2 homodimers or BMP2/6 heterodimers. We examined BMP2 and BMP6 homodimeric and heterodimeric ligands generated from native and chimeric precursor proteins expressed in Xenopus embryos. Whereas native BMP6 is not cleaved when expressed alone, it is cleaved to generate BMP2/6 heterodimers when co-expressed with BMP2. Furthermore, BMP2-6 chimeras are cleaved to generate BMP6 homodimers. Our findings reveal an important role for the BMP2 prodomain in dimerization and proteolytic activation of BMP6.

Infant and adult human intestinal enteroids are morphologically and functionally distinct.

Human intestinal enteroids (HIEs) are gaining recognition as physiologically relevant models of the intestinal epithelium. While HIEs from adults are used extensively in biomedical research, few studies have used HIEs from infants. Considering the dramatic developmental changes that occur during infancy, it is important to establish models that represent infant intestinal characteristics and physiological responses. We established jejunal HIEs from infant surgical samples and performed comparisons to jejunal HIEs from adults using RNA sequencing (RNA-Seq) and morphologic analyses. We then validated differences in key pathways through functional studies and determined whether these cultures recapitulate known features of the infant intestinal epithelium. RNA-Seq analysis showed significant differences in the transcriptome of infant and adult HIEs, including differences in genes and pathways associated with cell differentiation and proliferation, tissue development, lipid metabolism, innate immunity, and biological adhesion. Validating these results, we observed a higher abundance of cells expressing specific enterocyte, goblet cell, and enteroendocrine cell markers in differentiated infant HIE monolayers, and greater numbers of proliferative cells in undifferentiated 3D cultures. Compared to adult HIEs, infant HIEs portray characteristics of an immature gastrointestinal epithelium including significantly shorter cell height, lower epithelial barrier integrity, and lower innate immune responses to infection with an oral poliovirus vaccine. HIEs established from infant intestinal tissues reflect characteristics of the infant gut and are distinct from adult cultures. Our data support the use of infant HIEs as an ex vivo model to advance studies of infant-specific diseases and drug discovery for this population. IMPORTANCE: Tissue or biopsy stem cell-derived human intestinal enteroids are increasingly recognized as physiologically relevant models of the human gastrointestinal epithelium. While enteroids from adults and fetal tissues have been extensively used for studying many infectious and non-infectious diseases, there are few reports on enteroids from infants. We show that infant enteroids exhibit both transcriptomic and morphological differences compared to adult cultures. They also differ in functional responses to barrier disruption and innate immune responses to infection, suggesting that infant and adult enteroids are distinct model systems. Considering the dramatic changes in body composition and physiology that begin during infancy, tools that appropriately reflect intestinal development and diseases are critical. Infant enteroids exhibit key features of the infant gastrointestinal epithelium. This study is significant in establishing infant enteroids as age-appropriate models for infant intestinal physiology, infant-specific diseases, and responses to pathogens.

Computed tomography-derived structural analysis for the likelihood of pathologic fracture in canine antebrachial osteosarcoma.

Determining the risk of pathologic fracture in dogs with a primary bone tumor would aid in case selection for in-situ treatment options. Prior research found strong relationships between in vitro strength of canine antebrachii with primary bone tumors and CT-derived metrics. This study assesses the prognosis for pathologic fracture in dogs with distal radial bone tumors using CT-derived structural analysis metrics. CT images of the antebrachium in dogs with aggressive osseous lesions of the radius were used to calculate structural rigidity and failure forces, including axial rigidity (AR), craniocaudal bending rigidity (BR), torsional rigidity (TR), and failure forces for a slightly-curved/asymmetric beam (Fs) or a curved beam (Fc). Metrics were compared with the clinical outcome of radial fracture. Eight of 19 dogs with CT-derived metrics developed a radial fracture. The prognostic potential of the metrics to discriminate fractured and nonfractured bones was analyzed using receiver operating characteristic curves (area under the curve), stepwise logistic regression, and classification regression (CART) analyses. Fc was the most sensitive and specific metric for prognosing fracture occurrence (AUC = 0.864). When dog body weight (BW) was included, all five metrics had AUC > 0.705. Fc was the best predictor of fracture using stepwise logistic regression and CART analysis, followed by BR. An indication of fracture probability can be determined by normalizing Fc or BR with dog BW or by using the logistic regression equation of either metric with dog BW. Results warrant further analysis of a larger cohort to evaluate fracture likelihood in dogs with antebrachial bone neoplasia.

3D Printed O2-Generating Scaffolds Enhance Osteoprogenitor- and Type H Vessel Recruitment During Bone Healing.

Oxygen (O2)-delivering tissue substitutes have shown tremendous potential for enhancing tissue regeneration, maturation, and healing. As O2 is both a metabolite and powerful signaling molecule, providing controlled delivery is crucial for optimizing its beneficial effects in the treatment of critical-sized injuries. Here, we report the design and fabrication of 3D-printed, biodegradable, O2-generating bone scaffold comprising calcium peroxide (CPO) that once hydrolytically activated, provides long-term generation of oxygen at a controlled, concentration-dependent manner, and polycaprolactone (PCL), a hydrophobic polymer that regulate the interaction of CPO with water, preventing burst release of O2 at early time points. When anoxic conditions were simulated in vitro, CPO-PCL scaffolds maintained the survival and proliferation of human adipose-derived stem/stromal cells (hASCs) relative to PCL-only controls. We assessed the in vivo osteogenic efficacy of hASC-seeded CPO-PCL scaffolds implanted in a non-healing critical-sized 4-mm calvarial defects in nude mice for 8 weeks. Even without exogenous osteoinductive factors, CPO-PCL scaffolds demonstrated increased new bone volume compared to PCL-only scaffolds as verified by both microcomputed tomography analysis and histological assessments. Lastly, we employed a quantitative 3D lightsheet microscopy platform to determine that O2-generating scaffolds had similar vascular volumes with slightly higher presence of CD31hiEmcnhi pro-osteogenic, type H vessels and increased number of Osterix+ skeletal progenitor cells relative to PCL-only scaffolds. In summary, 3D-printed O2 generating CPO-PCL scaffolds with tunable O2 release rates provide a facile, customizable strategy for effectively treating, craniofacial bone defects. STATEMENT OF SIGNIFICANCE: Oxygen(O2)-delivering bone substitutes show promise in defect repair applications by supplying O2 to the cells within or around the graft, improving cell survivability and enhancing bone matrix mineralization. A novel O2-generating bone scaffold has been 3D printed for the first-time which ensures patient and defect specificity. 3D printed calcium peroxide-polycaprolactone (CPO-PCL) bone scaffold provides uninterrupted O2 supply for 22 days allowing cell survival in deprived O2 and nutrient conditions. For the first time, O2-driven bone regenerative environment in mice calvaria has been captured by light-sheet imaging which illuminates abundance of Osterix+ cells, angiogenesis at a single cell resolution indicating active site of bone remodeling and growth in the presence of O2.

Direct measurements of neurosteroid binding to specific sites on GABAA receptors.

BACKGROUND AND PURPOSE: Neurosteroids are allosteric modulators of GABAA currents, acting through several functional binding sites although their affinity and specificity for each site are unknown. The goal of this study was to measure steady-state binding affinities of various neurosteroids for specific sites on the GABAA receptor. EXPERIMENTAL APPROACH: Two methods were developed to measure neurosteroid binding affinity: (1) quenching of specific tryptophan residues in neurosteroid binding sites by the neurosteroid 17-methylketone group, and (2) FRET between MQ290 (an intrinsically fluorescent neurosteroid) and tryptophan residues in the binding sites. The assays were developed using ELIC-α1GABAAR, a chimeric receptor containing transmembrane domains of the α1-GABAA receptor. Tryptophan mutagenesis was used to identify specific interactions. KEY RESULTS: Allopregnanolone (3α-OH neurosteroid) was shown to bind at intersubunit and intrasubunit sites with equal affinity, whereas epi-allopregnanolone (3ß-OH neurosteroid) binds at the intrasubunit site. MQ290 formed a strong FRET pair with W246, acting as a site-specific probe for the intersubunit site. The affinity and site-specificity of several neurosteroid agonists and inverse agonists was measured using the MQ290 binding assay. The FRET assay distinguishes between competitive and allosteric inhibition of MQ290 binding and demonstrated an allosteric interaction between the two neurosteroid binding sites. CONCLUSIONS AND IMPLICATIONS: The affinity and specificity of neurosteroid binding to two sites in the ELIC-α1GABAAR were directly measured and an allosteric interaction between the sites was revealed. Adaptation of the MQ290 FRET assay to a plate-reader format will enable screening for high affinity agonists and antagonists for neurosteroid binding sites.

Complementary food exposure and children's early understanding of food words: the approaching eating through language (APPEAL) study.

Introduction: Language skills, such as the ability to understand words (receptive language), develop during infancy and are built through interactions with the environment, including eating. Exposure to complementary foods also begins in infancy and may play a significant role in language development, especially in understanding of food-related words. However, the relationship between the complementary foods to which a child is exposed and early language acquisition has not been previously studied. We hypothesized that young children's food-related receptive language (FRL) would reflect the complementary foods to which they were frequently offered by caregivers. Methods: Caregivers of young children (4-26 months; n = 408) in the Approaching Eating through Language (APPEAL) Study in the US were surveyed via Qualtrics. FRL was assessed by caregiver-report via a modified MacArthur-Bates Communicative Development Inventory. Complementary foods offered (CFO) by caregivers were assessed using a modified Food Frequency Questionnaire. Latent Class Analysis (LCA) was implemented to identify, 1) groupings of foods frequently offered (>1x/week) and 2) groupings of food-related words understood by the young children. Results: A 5-class best fit LCA model was identified for CFO (-log likelihood [-llik]=-8727) and for FRL (-llik=-5476). Cross-classification of the CFO and FRL derived classes revealed that children with higher exposure to complementary foods were perceived by caregivers to be most likely to also understand a greater number of food-related words (Probability=0.48). As expected, children having been offered a greater number of complementary foods and who understood a greater number of food-related words were older, compared to those with less complementary food exposure and food-related language acquisition (p < 0.001). Discussion: These findings support the potential role of introduction to complementary foods in development of food-related language.

Type 2 Diabetes.

Type 2 diabetes (T2D) is a prevalent disease that increases risk for vascular, renal, and neurologic complications. Prevention and treatment of T2D and its complications are paramount. Many advancements in T2D care have emerged over the past 5 years, including increased understanding of the importance of early intensive glycemic control, mental health, social determinants of health, healthy eating patterns, continuous glucose monitoring, and the benefits of some drugs for preventing cardiorenal disease. This review summarizes the evidence supporting T2D prevention and treatment, focusing on aspects that are commonly in the purview of primary care physicians.

Sensitivity of ocean circulation to warming during the Early Eocene greenhouse.

Multiple abrupt warming events ("hyperthermals") punctuated the Early Eocene and were associated with deep-sea temperature increases of 2 to 4 °C, seafloor carbonate dissolution, and negative carbon isotope (δ13C) excursions. Whether hyperthermals were associated with changes in the global ocean overturning circulation is important for understanding their driving mechanisms and feedbacks and for gaining insight into the circulation's sensitivity to climatic warming. Here, we present high-resolution benthic foraminiferal stable isotope records (δ13C and δ18O) throughout the Early Eocene Climate Optimum (~53.26 to 49.14 Ma) from the deep equatorial and North Atlantic. Combined with existing records from the South Atlantic and Pacific, these indicate consistently amplified δ13C excursion sizes during hyperthermals in the deep equatorial Atlantic. We compare these observations with results from an intermediate complexity Earth system model to demonstrate that this spatial pattern of δ13C excursion size is a predictable consequence of global warming-induced changes in ocean overturning circulation. In our model, transient warming drives the weakening of Southern Ocean-sourced overturning circulation, strengthens Atlantic meridional water mass aging gradients, and amplifies the magnitude of negative δ13C excursions in the equatorial to North Atlantic. Based on model-data consistency, we conclude that Eocene hyperthermals coincided with repeated weakening of the global overturning circulation. Not accounting for ocean circulation impacts on δ13C excursions will lead to incorrect estimates of the magnitude of carbon release driving hyperthermals. Our finding of weakening overturning in response to past transient climatic warming is consistent with predictions of declining Atlantic Ocean overturning strength in our warm future.

Discovery of genomic and transcriptomic pleiotropy between kidney function and soluble receptor for advanced glycation end products using correlated meta-analyses: The Long Life Family Study.

Patients with chronic kidney disease (CKD) have increased oxidative stress and chronic inflammation, which may escalate the production of advanced glycation end-products (AGEs). High soluble receptor for AGE (sRAGE) and low estimated glomerular filtration rate (eGFR) levels are associated with CKD and aging. We evaluated whether eGFR calculated from creatinine and cystatin C share pleiotropic genetic factors with sRAGE. We employed whole-genome sequencing and correlated meta-analyses on combined genome-wide association study (GWAS) p-values in 4182 individuals (age range: 24-110) from the Long Life Family Study (LLFS). We also conducted transcriptome-wide association studies (TWAS) on whole blood in a subset of 1209 individuals. We identified 59 pleiotropic GWAS loci (p < 5 × 10-8) and 17 TWAS genes (Bonferroni-p < 2.73 × 10-6) for eGFR traits and sRAGE. TWAS genes, LSP1 and MIR23AHG, were associated with eGFR and sRAGE located within GWAS loci, lncRNA-KCNQ1OT1 and CACNA1A/CCDC130, respectively. GWAS variants were eQTLs in the kidney glomeruli and tubules, and GWAS genes predicted kidney carcinoma. TWAS genes harbored eQTLs in the kidney, predicted kidney carcinoma, and connected enhancer-promoter variants with kidney function-related phenotypes at p < 5 × 10-8. Additionally, higher allele frequencies of protective variants for eGFR traits were detected in LLFS than in ALFA-Europeans and TOPMed, suggesting better kidney function in healthy-aging LLFS than in general populations. Integrating genomic annotation and transcriptional gene activity revealed the enrichment of genetic elements in kidney function and aging-related processes. The identified pleiotropic loci and gene expressions for eGFR and sRAGE suggest their underlying shared genetic effects and highlight their roles in kidney- and aging-related signaling pathways.

Exceptional Response to Trastuzumab Deruxtecan in a Patient With Recurrent Ovarian Clear Cell Carcinoma With Human Epidermal Growth Factor Receptor 2 Expression.

Case report of a HER2-expressed ovarian clear cell carcinoma with exceptional response to trastuzumab deruxtecan.

Non-kinase off-target inhibitory activities of clinically-relevant kinase inhibitors.

Protein kinases are responsible for a myriad of cellular functions, such as cell cycle, apoptosis, and proliferation. Because of this, kinases make excellent targets for therapeutics. During the process to identify clinical kinase inhibitor candidates, kinase selectivity profiles of lead inhibitors are typically obtained. Such kinome selectivity screening could identify crucial kinase anti-targets that might contribute to drug toxicity and/or reveal additional kinase targets that potentially contribute to the efficacy of the compound via kinase polypharmacology. In addition to kinome panel screening, practitioners also obtain the inhibition profiles of a few non-kinase targets, such as ion-channels and select GPCR targets to identify compounds that might possess potential liabilities. Often ignored is the possibility that identified kinase inhibitors might also inhibit or bind to the other proteins (greater than 20,000) in the cell that are not kinases, which may be relevant to toxicity or even additional mode of drug action. This review highlights various inhibitors, which have been approved by the FDA or are currently undergoing clinical trials, that also inhibit other non-kinase targets. The binding poses of the drugs in the binding sites of the target kinases and off-targets are analyzed to understand if the same features of the compounds are critical for the polypharmacology.

Prevalence, Determinants, and Trends in the Experience and Perpetration of Intimate Partner Violence Among a Cohort of Gay, Bisexual, and Other Men Who Have Sex with Men in Montréal, Toronto, and Vancouver, Canada (2017-2022).

Purpose: Longitudinal data on the experience and perpetration of intimate partner violence (IPV) among gay, bisexual, and other men who have sex with men (GBM) are limited. We estimated the prevalence of past 6-month (P6M) physical and/or sexual IPV (hereafter IPV) experience and perpetration, identified their determinants, and assessed temporal trends, including the impact of the coronavirus disease (COVID)-19 pandemic. Methods: We used data from the Engage Cohort Study (2017-2022) of GBM recruited using respondent-driven sampling in Montréal, Toronto, and Vancouver. Adjusted prevalence ratios (aPRs) for determinants and self-reported P6M IPV were estimated using generalized estimating equations, accounting for attrition (inverse probability of censoring weights) and relevant covariates. Longitudinal trends of IPV were also assessed. Results: Between 2017 and 2022, 1455 partnered GBM (median age 32 years, 82% gay, and 71% White) had at least one follow-up visit. At baseline, 31% of participants experienced IPV in their lifetime and 17% reported ever perpetrating IPV. During follow-up, IPV experience was more common (6%, 95% confidence interval [CI]: 5%-7%) than perpetration (4%, 95% CI: 3%-5%). Factors associated with P6M IPV experience included prior IPV experience (aPR: 2.68, 95% CI: 1.76-4.08), lower education (aPR: 2.31, 95% CI: 1.32-4.04), and substance use (injection aPR: 5.05, 95% CI: 2.54-10.05, non-injection aPR: 1.68, 95% CI: 1.00-2.82). Similar factors were associated with IPV perpetration. IPV was stable over time; periods of COVID-19 restrictions were not associated with IPV changes in this cohort. Conclusion: Prevalence of IPV was high among GBM. Determinants related to marginalization were associated with an increased risk of IPV. Interventions should address these determinants to reduce IPV and improve health.

Be the Qualitative Researcher: A Team-Based, Active Learning Strategy Using Popular Music Lyrics.

ABSTRACT: A team-based, active learning activity was created to facilitate undergraduate nursing students' understanding of qualitative research concepts. Working in small groups, students utilized the full-text lyrics of albums by recording artist Taylor Swift to analyze phrasing, create a qualitative coding scheme, code the data, and create a content and thematic analysis. The students then collaboratively created a Google Slide to present their findings for the class. An anonymous postactivity survey indicated greater student satisfaction with this activity than with traditional didactic lectures.

Ultra-Processed Foods: A Narrative Review of the Impact on the Human Gut Microbiome and Variations in Classification Methods.

Ultra-processed foods (UPFs) are foods that are industrially processed and are often pre-packaged, convenient, energy-dense, and nutrient-poor. UPFs are widespread in the current Western diet and their proposed contribution to non-communicable diseases such as obesity and cardiovascular disease is supported by numerous studies. UPFs are hypothesized to affect the body in multiple ways, including by inducing changes in the gut microbiome. This review summarizes the available research on the effect of UPFs on the gut microbiome. We also review current usage of the NOVA food classification system in randomized controlled trials and observational studies and how its implementation effects UPF research. Despite some differences in methodology between studies, results often associate UPF consumption with a number of negative health consequences. There are attempts to standardize a UPF classification system; however, reaching and implementing a consensus is difficult. Future studies focusing on the mechanisms by which UPFs effect the body, including through the microbiome and metabolome, will be essential to refine our understanding of the effects of UPFs on human health.