Enzalutamide: Understanding and Managing Drug Interactions to Improve Patient Safety and Drug Efficacy.

Enzalutamide is an oral androgen receptor signaling inhibitor utilized in the treatment of men with prostate cancer. It is a moderate inducer of the cytochrome P450 (CYP) enzymes CYP2C9 and CYP2C19, and a strong inducer of CYP3A4. It was also shown to be a mild inhibitor of the efflux transporter P-glycoprotein in patients with prostate cancer. Enzalutamide is primarily metabolized by CYP3A4 and CYP2C8. The risk of enzalutamide drug interactions arises primarily when it is coadministered with other drugs that interact with these CYPs, including CYP3A4. In this review, we begin by providing an overview of enzalutamide including its dosing, use in special populations, pharmacokinetics, changes to its prescribing information, and potential for interaction with coadministered drugs. Enzalutamide interactions with drugs from a wide range of medication classes commonly prescribed to patients with prostate cancer are described, including oral androgen deprivation therapy, agents used to treat a range of cardiovascular diseases, antidiabetic drugs, antidepressants, anti-seizure medications, common urology medications, analgesics, proton pump inhibitors, immunosuppressants, and antigout drugs. Enzalutamide interactions with common vitamins and supplements are also briefly discussed. This review provides a resource for healthcare practitioners and patients that will help provide a basis for the understanding and management of enzalutamide drug-drug interactions to inform decision making, improve patient safety, and optimize drug efficacy.

Enzalutamide is a drug that is used to treat various stages of advanced prostate cancer, a type of cancer that begins in the prostate and may spread beyond the prostate. Enzalutamide stops testosterone from stimulating prostate cancer growth. Like other drugs, enzalutamide enters the bloodstream, and then is processed and removed from the body. Sometimes, when a person takes multiple drugs, one drug can make it difficult for the body to process and remove one or more of the other drugs. This is referred to as a drug interaction. Enzalutamide drug interactions can cause the level of other drugs in the body to increase or decrease in an abnormal way. It is also possible for certain other drugs to alter the levels of enzalutamide. Drug interactions that cause the level of a drug to get too low can prevent that drug from working effectively, whereas drug interactions that cause the level of a drug to get too high can lead to side effects of that drug. People with prostate cancer are mostly aged 65 years or older and often take medications to treat a variety of diseases. Examples include medications to treat heart conditions, diabetes, high cholesterol, high blood pressure, and many other conditions. Here, we describe enzalutamide drug interactions with these types of medications. Our goal is to provide a resource to help healthcare providers and patients better understand enzalutamide drug interactions and how to manage them to improve patient safety and drug effectiveness.

A Murine Model of Hyperlipidemia-Induced Heart Failure with Preserved Ejection Fraction.

The pathophysiology of heart failure with preserved ejection fraction (HFpEF) driven by lipotoxicity is incompletely understood. Given the urgent need for animal models that accurately mimic cardio-metabolic HFpEF, a hyperlipidemia-induced murine model was developed by reverse engineering phenotypes seen in HFpEF patients. This model aimed to investigate HFpEF, focusing on the interplay between lipotoxicity and metabolic syndrome. Hyperlipidemia was induced in wild-type (WT) mice on a 129J strain background through bi-weekly intraperitoneal injections of poloxamer-407 (P-407), a block co-polymer that blocks lipoprotein lipase, combined with a single intravenous injection of adeno-associated virus 9-cardiac troponin T-low-density lipoprotein receptor (AAV9-cTnT-LDLR). Extensive assessments were conducted between 4 and 8 weeks post-treatment, including echocardiography, blood pressure recording, whole-body plethysmography, echocardiography (ECG) telemetry, activity wheel monitoring (AWM), and biochemical and histological analyses. The LDLR/P-407 mice exhibited distinctive features at four weeks, including diastolic dysfunction, preserved ejection fraction, and increased left ventricular wall thickness. Notably, blood pressure and renal function remained within normal ranges. Additionally, ECG and AWM revealed heart blocks and reduced activity, respectively. Diastolic function deteriorated at eight weeks, accompanied by a significant decline in respiratory rates. Further investigation into the double treatment model revealed elevated fibrosis, wet/dry lung ratios, and heart weight/body weight ratios. The LDLR/P-407 mice exhibited xanthelasmas, ascites, and cardiac ischemia. Interestingly, sudden deaths occurred between 6 and 12 weeks post-treatment. The murine HFpEF model offers a valuable and promising experimental resource for elucidating the intricacies of metabolic syndrome contributing to diastolic dysfunction within the context of lipotoxicity-mediated HFpEF.

ADAMTSL2 mutations determine the phenotypic severity in geleophysic dysplasia.

Geleophysic dysplasia-1 (GD1) is an autosomal recessive disorder caused by ADAMTS-like 2 (ADAMTSL2) variants. It is characterized by distinctive facial features, limited joint mobility, short stature, brachydactyly, and life-threatening cardiorespiratory complications. The clinical spectrum spans from perinatal lethality to milder adult phenotypes. We developed and characterized cellular and mouse models, to replicate the genetic profile of a patient who is compound heterozygous for 2 ADAMTSL2 variants, namely p.R61H and p.A165T. The impairment of ADAMTSL2 secretion was observed in both variants, but p.A165T exhibited a more severe impact. Mice carrying different allelic combinations revealed a spectrum of phenotypic severity, from lethality in knockout homozygotes to mild growth impairment observed in adult p.R61H homozygotes. Homozygous and hemizygous p.A165T mice survived but displayed severe respiratory and cardiac dysfunction. The respiratory dysfunction mainly affected the expiration phase, and some of these animals had microscopic post-obstructive pneumonia. Echocardiograms and MRI studies revealed a significant systolic dysfunction, accompanied by a reduction of the aortic root size. Histology verified the presence of hypertrophic cardiomyopathy with myocyte hypertrophy, chondroid metaplasia, and mild interstitial fibrosis. This study revealed a substantial correlation between the degree of impaired ADAMTSL2 secretion and the severity of the observed phenotype in GD1.

Psychological and attentional outcomes following acute mindfulness induction among high anxiety individuals: A systematic review and meta-analysis.

BACKGROUND: Training outcomes of mindfulness interventions for anxiety have been extensively researched. Less is known about the acute effects of mindfulness induction and associated mechanisms. This systematic review aimed to identify 1) the effect of mindfulness induction on pre-post measures of state anxiety and attention among adults experiencing high levels of anxiety; and 2) the impact of predictors, mediators and moderators on post-induction changes in anxiety and attention. State distress and mindfulness were included as secondary outcomes. METHODS: A systematic search was conducted in November 2021 in electronic databases using relevant search terms. Five studies (four randomised controlled trials and one non-randomised controlled trial) were included, comprising a total of 277 participants with elevated trait/generalised anxiety. Each study used a brief audio-based mindfulness induction exercise. RESULTS: The meta-analysis indicated mindfulness induction had medium and large effects on state anxiety (k = 3, n = 100, g = -0.60, 95%CI [-1.04, -0.16]; p = .008) and state mindfulness (k = 2, n = 110, g = 0.91, 95%CI [0.52, 1.30], p < .001), respectively, when compared with non-therapeutic control conditions. Furthermore, two studies showed small and moderate effects of mindfulness on state anxiety when compared to therapeutic active controls, but were not pooled in a meta-analysis. While results could not be pooled for attention, there was limited evidence of behavioural improvements on tasks measuring aspects of attention following mindfulness induction. However, one study found an increase in Low Beta to High Beta ratio and a reduction in Beta activity in the Anterior Cingulate Cortex following mindfulness induction. Moreover, another study found aspects of state mindfulness mediated reductions in state anxiety. LIMITATIONS: A small number of studies were included in the review, with high risk of bias and low certainty of evidence present. CONCLUSION: The findings support the use of mindfulness induction to reduce state anxiety in anxious individuals but suggest gains in state mindfulness may be a more realistic expected outcome. Further controlled trials are needed to delineate the relative effects of objectively assessed anxiety outcomes from mindfulness induction in clinically defined samples.

Site-directed mutagenesis of Mycobacterium tuberculosis and functional validation to investigate potential bedaquiline resistance-causing mutations.

Molecular detection of bedaquiline resistant tuberculosis is challenging as only a small proportion of mutations in candidate bedaquiline resistance genes have been statistically associated with phenotypic resistance. We introduced two mutations, atpE Ile66Val and Rv0678 Thr33Ala, in the Mycobacterium tuberculosis H37Rv reference strain using homologous recombineering or recombination to investigate the phenotypic effect of these mutations. The genotype of the resulting strains was confirmed by Sanger- and whole genome sequencing, and bedaquiline susceptibility was assessed by minimal inhibitory concentration (MIC) assays. The impact of the mutations on protein stability and interactions was predicted using mutation Cutoff Scanning Matrix (mCSM) tools. The atpE Ile66Val mutation did not elevate the MIC above the critical concentration (MIC 0.25-0.5 µg/ml), while the MIC of the Rv0678 Thr33Ala mutant strains (> 1.0 µg/ml) classifies the strain as resistant, confirming clinical findings. In silico analyses confirmed that the atpE Ile66Val mutation minimally disrupts the bedaquiline-ATP synthase interaction, while the Rv0678 Thr33Ala mutation substantially affects the DNA binding affinity of the MmpR transcriptional repressor. Based on a combination of wet-lab and computational methods, our results suggest that the Rv0678 Thr33Ala mutation confers resistance to BDQ, while the atpE Ile66Val mutation does not, but definite proof can only be provided by complementation studies given the presence of secondary mutations.

The impact of genotype on the phenotype of Mycobacterium tuberculosis ΔsufR mutants.

Iron-sulphur (FeS) cluster biogenesis is a tightly regulated process in vivo. In Mycobacterium tuberculosis (Mtb), SufR functions as a transcriptional repressor of the operon encoding the primary FeS cluster biogenesis system. Previously, three independently isolated mutants (ΔRv1460stop_1.19, ΔRv1460stop _5.19 and ΔRv1460stop _5.20) harbouring the same deletion in sufR, displayed different growth kinetics in OADC supplemented 7H9 media. To investigate this discrepancy, we performed whole genome sequencing of the 3 mutants and the wild-type progenitor. Single nucleotide polymorphisms (SNPs) were identified in 3 genes in the ΔRv1460stop_1.19 mutant and one gene in the ΔRv1460stop_5.20 mutant. Phenotyping of the ΔRv1460stop_5.19 mutant, which had no additional SNPs, revealed increased susceptibility to clofazimine, DMNQ and menadione, while uptake and survival in THP-1 cells were not significantly different from the wild-type strain. Given that these results differ from those reported for other sufR deletion mutants (ΔSufRMTB and MtbΔSufR), they suggest that the position of the sufR deletion and the genotype of the progenitor strain impact the resulting phenotype.

Gaps in clinical research in frontotemporal dementia: A call for diversity and disparities-focused research.

Frontotemporal dementia (FTD) is one of the leading causes of dementia before age 65 and often manifests as abnormal behavior (in behavioral variant FTD) or language impairment (in primary progressive aphasia). FTD's exact clinical presentation varies by culture, language, education, social norms, and other socioeconomic factors; current research and clinical practice, however, is mainly based on studies conducted in North America and Western Europe. Changes in diagnostic criteria and procedures as well as new or adapted cognitive tests are likely needed to take into consideration global diversity. This perspective paper by two professional interest areas of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment examines how increasing global diversity impacts the clinical presentation, screening, assessment, and diagnosis of FTD and its treatment and care. It subsequently provides recommendations to address immediate needs to advance global FTD research and clinical practice.

Investigating Mycobacterium tuberculosis sufR (rv1460) in vitro and ex vivo expression and immunogenicity.

Iron is vital metal for Mycobacterium tuberculosis infection, survival, and persistence within its human host. The mobilization of sulphur (SUF) operon encodes the primary iron-sulphur (Fe-S) biogenesis system in M. tuberculosis and is induced during iron limitation and intracellular growth of M. tuberculosis, pointing to its importance during infection. To study sufR expression at single cell level during intracellular growth of M. tuberculosis a fluorescent reporter was generated by cloning a 123 bp sufR promoter region upstream of a promotorless mcherry gene in an integrating vector. Expression analysis and fluorescence measurements during in vitro culture revealed that the reporter was useful for measuring induction of the promoter but was unable to detect subsequent repression due to the stability of mCherry. During intracellular growth in THP-1 macrophages, increased fluorescence was observed in the strain harbouring the reporter relative to the control strain, however this induction was only observed in a small sub-set of the population. Since SufR levels are predicted to be elevated during infection we hypothesize that it is immunogenic and may induce an immune response in M. tuberculosis infected individuals. The immune response elicited by SufR for both whole blood assay (WBA, a short term 12-hr stimulation to characterise the production of cytokines/growth factors suggestive of an effector response) and lymphocyte proliferation assay (LPA, a longer term 7-day stimulation to see if SufR induces a memory type immune response) were low and did not show a strong immune response for the selected Luminex analytes (MCP-1, RANTES, IL-1b, IL-8, MIP-1b, IFN-g, IL-6 and MMP-9) measured in three clinical groups, namely active TB, QuantiFERON positive (QFN pos) and QFN negative (QFN neg) individuals.

The Mycobacterium smegmatis HesB Protein, MSMEG_4272, Is Required for In Vitro Growth and Iron Homeostasis.

A-type carrier (ATC) proteins are proposed to function in the biogenesis of Fe-S clusters, although their exact role remains controversial. The genome of Mycobacterium smegmatis encodes a single ATC protein, MSMEG_4272, which belongs to the HesB/YadR/YfhF family of proteins. Attempts to generate an MSMEG_4272 deletion mutant by two-step allelic exchange were unsuccessful, suggesting that the gene is essential for in vitro growth. CRISPRi-mediated transcriptional knock-down of MSMEG_4272 resulted in a growth defect under standard culture conditions, which was exacerbated in mineral-defined media. The knockdown strain displayed reduced intracellular iron levels under iron-replete conditions and increased susceptibility to clofazimine, 2,3-dimethoxy-1,4-naphthoquinone (DMNQ), and isoniazid, while the activity of the Fe-S containing enzymes, succinate dehydrogenase, and aconitase were not affected. This study suggests that MSMEG_4272 plays a role in the regulation of intracellular iron levels and is required for in vitro growth of M. smegmatis, particularly during exponential growth.

Psychological Outcomes and Mechanisms of Mindfulness-Based Training for Generalised Anxiety Disorder: A Systematic Review and Meta-Analysis.

This systematic review aimed to identify 1) the effect of mindfulness training on pre-post measures of anxiety and attention among adults experiencing high levels of generalised anxiety; and 2) the impact of predictors, mediators and moderators on post-intervention changes in anxiety or attention. Trait mindfulness and distress measures were included as secondary outcomes. A systematic search was conducted in November 2021 in electronic databases using relevant search terms. Eight articles comprising four independent studies were included (N = 334). All studies included participants diagnosed with generalised anxiety disorder (GAD) who participated in an 8-week manualised program. The meta-analysis indicated that mindfulness training had a large effect on anxiety symptoms (g = -1.92, 95%CI[-3.44, -0.40]) when compared to inactive (i.e., care as usual, waitlist) or non-specified (i.e., condition not defined) controls. However, a significant effect was not found when compared to active controls. Effects for depression, worry and trait mindfulness did not reach statistical significance, despite small-large effect sizes favouring mindfulness compared to inactive/non-specified controls. Our narrative review found evidence that changes in aspects of trait mindfulness mediate anxiety reduction following mindfulness training. However, a small number of studies were available for inclusion in the review, with high risk of bias and low certainty of evidence present. Overall, the findings support the use of mindfulness training programs for GAD and indicate mechanisms that may differ from those involved in other cognitive therapy approaches. Further RCTs with evidence-based controls are needed to clarify techniques most beneficial for generalised anxiety to support individually tailored treatment. Supplementary Information: The online version contains supplementary material available at 10.1007/s12144-023-04695-x.

Web-accessible application for identifying pathogenic transcripts with RNA-seq: Increased sensitivity in diagnosis of neurodevelopmental disorders.

For neurodevelopmental disorders (NDDs), a molecular diagnosis is key for management, predicting outcome, and counseling. Often, routine DNA-based tests fail to establish a genetic diagnosis in NDDs. Transcriptome analysis (RNA sequencing [RNA-seq]) promises to improve the diagnostic yield but has not been applied to NDDs in routine diagnostics. Here, we explored the diagnostic potential of RNA-seq in 96 individuals including 67 undiagnosed subjects with NDDs. We performed RNA-seq on single individuals' cultured skin fibroblasts, with and without cycloheximide treatment, and used modified OUTRIDER Z scores to detect gene expression outliers and mis-splicing by exonic and intronic outliers. Analysis was performed by a user-friendly web application, and candidate pathogenic transcriptional events were confirmed by secondary assays. We identified intragenic deletions, monoallelic expression, and pseudoexonic insertions but also synonymous and non-synonymous variants with deleterious effects on transcription, increasing the diagnostic yield for NDDs by 13%. We found that cycloheximide treatment and exonic/intronic Z score analysis increased detection and resolution of aberrant splicing. Importantly, in one individual mis-splicing was found in a candidate gene nearly matching the individual's specific phenotype. However, pathogenic splicing occurred in another neuronal-expressed gene and provided a molecular diagnosis, stressing the need to customize RNA-seq. Lastly, our web browser application allowed custom analysis settings that facilitate diagnostic application and ranked pathogenic transcripts as top candidates. Our results demonstrate that RNA-seq is a complementary method in the genomic diagnosis of NDDs and, by providing accessible analysis with improved sensitivity, our transcriptome analysis approach facilitates wider implementation of RNA-seq in routine genome diagnostics.

Recommendations for diagnosing and managing individuals with glutaric aciduria type 1: Third revision.

Glutaric aciduria type 1 is a rare inherited neurometabolic disorder of lysine metabolism caused by pathogenic gene variations in GCDH (cytogenic location: 19p13.13), resulting in deficiency of mitochondrial glutaryl-CoA dehydrogenase (GCDH) and, consequently, accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid and glutarylcarnitine detectable by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Depending on residual GCDH activity, biochemical high and low excreting phenotypes have been defined. Most untreated individuals present with acute onset of striatal damage before age 3 (to 6) years, precipitated by infectious diseases, fever or surgery, resulting in irreversible, mostly dystonic movement disorder with limited life expectancy. In some patients, striatal damage develops insidiously. In recent years, the clinical phenotype has been extended by the finding of extrastriatal abnormalities and cognitive dysfunction, preferably in the high excreter group, as well as chronic kidney failure. Newborn screening is the prerequisite for pre-symptomatic start of metabolic treatment with low lysine diet, carnitine supplementation and intensified emergency treatment during catabolic episodes, which, in combination, have substantially improved neurologic outcome. In contrast, start of treatment after onset of symptoms cannot reverse existing motor dysfunction caused by striatal damage. Dietary treatment can be relaxed after the vulnerable period for striatal damage, that is, age 6 years. However, impact of dietary relaxation on long-term outcomes is still unclear. This third revision of evidence-based recommendations aims to re-evaluate previous recommendations (Boy et al., J Inherit Metab Dis, 2017;40(1):75-101; Kolker et al., J Inherit Metab Dis 2011;34(3):677-694; Kolker et al., J Inherit Metab Dis, 2007;30(1):5-22) and to implement new research findings on the evolving phenotypic diversity as well as the impact of non-interventional variables and treatment quality on clinical outcomes.

Prioritizing health: Churches response to the COVID-19 pandemic.

Churches serve as a source of connection and support for spiritual wellbeing. More recently, church communities recognize the importance of extending support beyond spirituality and taking a holistic approach that includes mental and physical health. How each church goes about providing support varies among denominations and the needs of their communities. This exploratory study examines how churches of various denominations in the Tri-City region (Pomona, La Verne, and Claremont) of Los Angeles County perceive the seriousness of COVID-19, their responses to the pandemic, and the potential impact on their congregations. Results indicated that the majority (84%) of spiritual community participants view COVID-19 as a threat to personal health, and are taking steps to minimize the threat to their congregations' health and surrounding communities. Implications for church leadership to consider when planning continued operations and congregant support in response to COVID-19 are discussed.

Chemical Elements, Flavor Chemicals, and Nicotine in Unused and Used Electronic Cigarettes Aged 5-10 Years and Effects of pH.

The concentrations of elements/metals, nicotine, flavor chemicals and acids were compared in the e-liquids of unused and used first-generation electronic cigarettes (ECs) that were stored for 5-10 years. Metal analysis was performed using inductively coupled plasma optical emission spectroscopy; nicotine and flavor chemical analyses were performed using gas chromatography/mass spectroscopy. Of the 22 elements analyzed, 10 (aluminum, chromium, copper, iron, lead, nickel, selenium, silicon, tin, zinc) were often found in the e-liquids. Five elements had the highest average concentrations: copper (1161.6 mg/L), zinc (295.8 mg/L), tin (287.6 mg/L), nickel (71.1 mg/L), and lead (50.3 mg/L). Nicotine concentrations were always lower than label concentrations indicated. Of the 181 flavor chemicals analyzed, 11 were detected in at least one sample, with hydroxyacetone being present in all samples. In used products, some flavor chemicals appeared to be by-products of heating. E-liquids with the highest concentrations of acids and the lowest pH levels also had the highest concentrations of elements/metals. Metal concentrations in e-liquids increased after use in some products, and some metal concentrations, such as nickel, were high enough to be a health concern. Leachates from discarded ECs could contribute toxic metals/chemicals to the environment, supporting the need for better regulation of atomizer design, composition, and disposal.

Mouse Model of Heart Failure With Preserved Ejection Fraction Driven by Hyperlipidemia and Enhanced Cardiac Low-Density Lipoprotein Receptor Expression.

Background The pathways of diastolic dysfunction and heart failure with preserved ejection fraction driven by lipotoxicity with metabolic syndrome are incompletely understood. Thus, there is an urgent need for animal models that accurately mimic the metabolic and cardiovascular phenotypes of this phenogroup for mechanistic studies. Methods and Results Hyperlipidemia was induced in WT-129 mice by 4 weeks of biweekly poloxamer-407 intraperitoneal injections with or without a single intravenous injection of adeno-associatedvirus 9-cardiac troponin T-low-density lipoprotein receptor (n=31), or single intravenous injection with adeno-associatedvirus 9-cardiac troponin T-low-density lipoprotein receptor alone (n=10). Treatment groups were compared with untreated or placebo controls (n=37). Echocardiography, blood pressure, whole-body plethysmography, ECG telemetry, activity wheel monitoring, and biochemical and histological changes were assessed at 4 to 8 weeks. At 4 weeks, double treatment conferred diastolic dysfunction, preserved ejection fraction, and increased left ventricular wall thickness. Blood pressure and whole-body plethysmography results were normal, but respiration decreased at 8 weeks (P<0.01). ECG and activity wheel monitoring, respectively, indicated heart block and decreased exercise activity (P<0.001). Double treatment promoted elevated myocardial lipids including total cholesterol, fibrosis, increased wet/dry lung (P<0.001) and heart weight/body weight (P<0.05). Xanthelasma, ascites, and cardiac ischemia were evident in double and single (p407) groups. Sudden death occurred between 6 and 12 weeks in double and single (p407) treatment groups. Conclusions We present a novel model of heart failure with preserved ejection fraction driven by dyslipidemia where mice acquire diastolic dysfunction, arrhythmia, cardiac hypertrophy, fibrosis, pulmonary congestion, exercise intolerance, and preserved ejection fraction in the absence of obesity, hypertension, kidney disease, or diabetes. The model can be applied to dissect pathways of metabolic syndrome that drive diastolic dysfunction in this lipotoxicity-mediated heart failure with preserved ejection fraction phenogroup mimic.

Col4a3-/- Mice on Balb/C Background Have Less Severe Cardiorespiratory Phenotype and SGLT2 Over-Expression Compared to 129x1/SvJ and C57Bl/6 Backgrounds.

Alport syndrome (AS) is a hereditary renal disorder with no etiological therapy. In the preclinical Col4a3-/- model of AS, disease progression and severity vary depending on mouse strain. The sodium-glucose cotransporter 2 (SGLT2) is emerging as an attractive therapeutic target in cardiac/renal pathologies, but its application to AS remains untested. This study investigates cardiorespiratory function and SGLT2 renal expression in Col4a3-/- mice from three different genetic backgrounds, 129x1/SvJ, C57Bl/6 and Balb/C. male Col4a3-/- 129x1/SvJ mice displayed alterations consistent with heart failure with preserved ejection fraction (HFpEF). Female, but not male, C57Bl/6 and Balb/C Col4a3-/- mice exhibited mild changes in systolic and diastolic function of the heart by echocardiography. Male C57Bl/6 Col4a3-/- mice presented systolic dysfunction by invasive hemodynamic analysis. All strains except Balb/C males demonstrated alterations in respiratory function. SGLT2 expression was significantly increased in AS compared to WT mice from all strains. However, cardiorespiratory abnormalities and SGLT2 over-expression were significantly less in AS Balb/C mice compared to the other two strains. Systolic blood pressure was significantly elevated only in mutant 129x1/SvJ mice. The results provide further evidence for strain-dependent cardiorespiratory and hypertensive phenotype variations in mouse AS models, corroborated by renal SGLT2 expression, and support ongoing initiatives to develop SGLT2 inhibitors for the treatment of AS.

Associations between Homelessness and Alzheimer's Disease and Related Dementia: A Systematic Review.

The homeless population in the United States is rapidly aging, with a parallel increase in Alzheimer's disease and related dementia (ADRD). During an evolving pandemic that jeopardizes employment and housing, assessing the relationship between ADRD and homelessness is critical since the latter is potentially intervenable. The objective of this study is to review the literature and determine whether there is an association between homelessness and dementia risk. A systematic review of existing studies was conducted through PubMED, SCOPUS, and EMBASE among others. Of the 228 results found, nine met inclusion criteria. Homeless studies mainly centered on veteran populations (n = 6/9). There is a complex relationship suggesting homelessness as a risk for and consequence of ADRD but also co-occurrence with psychiatric disorders, substance abuse, and traumatic injuries. Future studies should employ enumeration surveys with modular longitudinal tracking and measure social determinants of health, discrimination, chronic stress, and mood disorders.

Genetic, biochemical, and clinical spectrum of patients with mitochondrial trifunctional protein deficiency identified after the introduction of newborn screening in the Netherlands.

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is included in many newborn screening (NBS) programs. Acylcarnitine-based NBS for LCHADD not only identifies LCHADD, but also the other deficiencies of the mitochondrial trifunctional protein (MTP), a multi-enzyme complex involved in long-chain fatty acid ß-oxidation. Besides LCHAD, MTP harbors two additional enzyme activities: long-chain enoyl-CoA hydratase (LCEH) and long-chain ketoacyl-CoA thiolase (LCKAT). Deficiency of one or more MTP activities causes generalized MTP deficiency (MTPD), LCHADD, LCEH deficiency (not yet reported), or LCKAT deficiency (LCKATD). To gain insight in the outcomes of MTP-deficient patients diagnosed after the introduction of NBS for LCHADD in the Netherlands, a retrospective evaluation of genetic, biochemical, and clinical characteristics of MTP-deficient patients, identified since 2007, was carried out. Thirteen patients were identified: seven with LCHADD, five with MTPD, and one with LCKATD. All LCHADD patients (one missed by NBS, clinical diagnosis) and one MTPD patient (clinical diagnosis) were alive. Four MTPD patients and one LCKATD patient developed cardiomyopathy and died within 1 month and 13 months of life, respectively. Surviving patients did not develop symptomatic hypoglycemia, but experienced reversible cardiomyopathy and rhabdomyolysis. Five LCHADD patients developed subclinical neuropathy and/or retinopathy. In conclusion, patient outcomes were highly variable, stressing the need for accurate classification of and discrimination between the MTP deficiencies to improve insight in the yield of NBS for LCHADD. NBS allowed the prevention of symptomatic hypoglycemia, but current treatment options failed to treat cardiomyopathy and prevent long-term complications. Moreover, milder patients, who might benefit from NBS, were missed due to normal acylcarnitine profiles.

The complex relationship between depression and progression to incident cognitive impairment across race and ethnicity.

INTRODUCTION: We examined baseline differences in depression and antidepressant use among cognitively normal older adults in five ethnoracial groups and assessed whether depression predicted a faster progression to incident cognitive impairment across groups. METHODS: Data from the National Alzheimer's Coordinating Center (n = 8168) were used to examine differences between non-Hispanic Whites (nHW), African Americans (AA), Hispanics, Asians, and American Indian and Alaskan Natives in cross-sectional and longitudinal models. RESULTS: AA had a lower risk of depression compared to nHW at baseline. No statistical interactions were noted between ethnoracial groups and depression. However, depression independently predicted a faster progression to incident cognitive impairment. Hispanics and Asian participants had a higher hazard for progression compared to nHW. DISCUSSION: Previously established risk factors between depression and dementia were not found among AA and nHW participants. The relationship between depression and ethnoracial groups is complex and suggests differential effects on progression from cognitive normality to impairment.

Echocardiography protocol: A tool for infrequently used parameters in mice.

Echocardiography is frequently used to evaluate cardiac function in rodent models of cardiovascular disease. Whereas methods to acquire the commonly used echocardiography parameters are well-described in published protocols or manuals, many important parameters are ill-defined and often open to subjective interpretation. Such lack of uniformity has engendered conflicting interpretations of the same parameters in published literature. In particular, parameters such as mitral regurgitation, mitral stenosis, pulmonary regurgitation, and aortic regurgitation that are required to define more esoteric etiologies in rarer mouse models often remain equivocal. The aim of this methods paper is to provide a practical guide to the acquisition and interpretation of infrequently used echocardiography parameters and set a framework for comprehensive analyses of right ventricle (RV), pulmonary artery (PA) pulmonary valve (PV), left atrium (LA), mitral valve (MV), and aortic valve (AoV) structure and function.