J Clin Med. 2021 Oct 29;10(21):5086. doi: 10.3390/jcm10215086.

ABSTRACT

In our previous study, we showed that sildenafil citrate (SC), a selective PDE5A blocker, modulated NK cell activity in patients with recurrent pregnancy loss, which correlated with positive pregnancy outcomes. It was found that NK cells had a pivotal role in decidualization, angiogenesis, spiral artery remodeling, and the regulation of trophoblast invasion. Thus, in the current study, we determined the effects of SC on angiogenic factor expression and production, as well as idNK cell activity in the presence of nitric synthase blocker L-NMMA. Methods: NK cells (CD56+) were isolated from the peripheral blood of 15 patients and 15 fertile women on MACS columns and cultured in transformation media containing IL-15, TGF-β, and AZA-a methylation agent-for 7 days in hypoxia (94% N2, 1% O2, 5% CO2). Cultures were set up in four variants: (1) with SC, (2) without SC, (3) with NO, a synthase blocker, and (4) with SC and NO synthase blocker. NK cell activity was determined after 7 days of culturing as CD107a expression after an additional 4h of stimulation with K562 erythroleukemia cells. The expression of the PDE5A, VEGF-A, PIGF, IL-8, and RENBP genes was determined with quantitative real-time PCR (qRT-PCR) using TaqMan probes and ELISA was used to measure the concentrations of VEGF-A, PLGF, IL-8, Ang-I, Ang-II, IFN-γ proteins in culture supernatants after SC supplementation. Results: SC downregulated PDE5A expression and had no effect on other studied angiogenic factors. VEGF-A expression was increased in RPL patients compared with fertile women. Similarly, VEGF production was enhanced in RPL patients' supernatants and SC increased the concentration of PIGF in culture supernatants. SC did not affect the expression or concentration of other studied factors, nor idNK cell activity, regardless of NO synthase blockade.

PMID:34768607 | DOI:10.3390/jcm10215086

J Clin Med. 2021 Oct 22;10(21):4875. doi: 10.3390/jcm10214875.

ABSTRACT

The early diagnosis of malignant mesothelioma (MM) could improve the prognosis of MM patients. To confirm an MM diagnosis, an immunohistochemical analysis of several tumor tissue markers, including calretinin, is currently required. Our aim is to evaluate serum calretinin as a potential biomarker in asbestos-related diseases, especially in MM. Our study includes 549 subjects: 164 MM patients, 117 subjects with asbestosis, 195 subjects with pleural plaques and 73 occupationally asbestos-exposed subjects without asbestos-related diseases. The serum calretinin concentration was determined with a commercially available enzyme immunoassay. Data on the soluble mesothelin-related peptides (SMRP) concentration are available from previous studies. MM patients had a significantly higher calretinin concentration than subjects without disease, subjects with pleural plaques or subjects with asbestosis (all p < 0.001). The histological type was significantly associated with serum calretinin: patients with sarcomatoid MM had lower calretinin than patients with the epithelioid type (p = 0.001). In a ROC curve analysis, the area under the curve for calretinin concentration predicting MM was 0.826 (95% CI = 0.782-0.869; p < 0.001). At the cutoff value of 0.32 ng/mL, sensitivity was 0.683, while specificity was 0.886. The combination of calretinin and SMRP had the highest predictive value. Calretinin is a useful biomarker that can distinguish MM from other asbestos-related diseases and could, therefore, contribute to an earlier non-invasive diagnosis of MM.

PMID:34768395 | DOI:10.3390/jcm10214875

J Am Acad Child Adolesc Psychiatry. 2021 Nov 9:S0890-8567(21)01938-9. doi: 10.1016/j.jaac.2021.11.001. Online ahead of print.

NO ABSTRACT

PMID:34767918 | DOI:10.1016/j.jaac.2021.11.001

J Cachexia Sarcopenia Muscle. 2021 Nov 11. doi: 10.1002/jcsm.12849. Online ahead of print.

ABSTRACT

BACKGROUND: Age-related muscle dysfunctions are common disorders resulting in poor quality of life in the elderly. Probiotic supplementation is a potential strategy for preventing age-related sarcopenia as evidence suggests that probiotics can enhance muscle function via the gut-muscle axis. However, the effects and mechanisms of probiotics in age-related sarcopenia are currently unknown. In this study, we examined the effects of Lactobacillus casei Shirota (LcS), a probiotic previously reported to improve muscle function in young adult mice.

METHODS: We administered LcS (1 × 108 or 1 × 109 CFU/mouse/day) by oral gavage to senescence-accelerated mouse prone-8 mice for 12 weeks (16- to 28-week-old). Sixteen-week-old and 28-week-old SMAP8 mice were included as non-aged and aged controls, respectively. Muscle condition was evaluated using dual-energy X-ray absorptiometry for muscle mass, holding impulse and grip strength tests for muscle strength, and oxygen consumption rate, gene expressions of mitochondrial biogenesis, and mitochondrial number assays for mitochondria function. Inflammatory cytokines were determined using enzyme-linked immunosorbent assay. Gas chromatography-mass spectrometry was utilized to measure the short-chain fatty acid levels. The gut microbiota was analysed based on the data of 16S rRNA gene sequencing of mouse stool.

RESULTS: The LcS supplementation reduced age-related declines in muscle mass (>94.6%, P < 0.04), strength (>66% in holding impulse and >96.3% in grip strength, P < 0.05), and mitochondrial function (P < 0.05). The concentration of short-chain fatty acids (acetic, isobutyric, butyric, penic, and hexanoic acid) was recovered by LcS (>65.9% in the mice given high dose of LcS, P < 0.05) in the aged mice, and LcS attenuated age-related increases in inflammation (P < 0.05) and reactive oxygen species (>89.4%, P < 0.001). The high dose of LcS supplementation was also associated with distinct microbiota composition as indicated by the separation of groups in the beta-diversity analysis (P = 0.027). LcS supplementation altered predicted bacterial functions based on the gut microbiota. Apoptosis (P = 0.026), p53 signalling (P = 0.017), and non-homologous end-joining (P = 0.031) were significantly reduced, whereas DNA repair and recombination proteins (P = 0.043), RNA polymerase (P = 0.008), and aminoacyl-tRNA biosynthesis (P = 0.003) were increased. Finally, the genera enriched by high-dose LcS [linear discriminant analysis (LDA) score > 2.0] were positively correlated with healthy muscle and physiological condition (P < 0.05), while the genera enriched in aged control mice (LDA score > 2.0) were negatively associated with healthy muscle and physiological condition (P < 0.05).

CONCLUSIONS: Lactobacillus casei Shirota represents an active modulator that regulates the onset and progression of age-related muscle impairment potentially via the gut-muscle axis.

PMID:34766473 | DOI:10.1002/jcsm.12849

Front Pharmacol. 2021 Oct 26;12:733285. doi: 10.3389/fphar.2021.733285. eCollection 2021.

ABSTRACT

Tacrolimus is an essential immunosuppressant for the prevention of rejection in solid organ transplantation. Its low therapeutic index and high pharmacokinetic variability necessitates therapeutic drug monitoring (TDM) to individualise dose. However, rejection and toxicity still occur in transplant recipients with blood tacrolimus trough concentrations (C0) within the target ranges. Peripheral blood mononuclear cells (PBMC) have been investigated as surrogates for tacrolimus's site of action (lymphocytes) and measuring allograft tacrolimus concentrations has also been explored for predicting rejection or nephrotoxicity. There are relatively weak correlations between blood and PBMC or graft tacrolimus concentrations. Haematocrit is the only consistent significant (albeit weak) determinant of tacrolimus distribution between blood and PBMC in both liver and renal transplant recipients. In contrast, the role of ABCB1 pharmacogenetics is contradictory. With respect to distribution into allograft tissue, studies report no, or poor, correlations between blood and graft tacrolimus concentrations. Two studies observed no effect of donor ABCB1 or CYP3A5 pharmacogenetics on the relationship between blood and renal graft tacrolimus concentrations and only one group has reported an association between donor ABCB1 polymorphisms and hepatic graft tacrolimus concentrations. Several studies describe significant correlations between in vivo PBMC tacrolimus concentrations and ex vivo T-cell activation or calcineurin activity. Older studies provide evidence of a strong predictive value of PBMC C0 and allograft tacrolimus C0 (but not blood C0) with respect to rejection in liver transplant recipients administered tacrolimus with/without a steroid. However, these results have not been independently replicated in liver or other transplants using current triple maintenance immunosuppression. Only one study has reported a possible association between renal graft tacrolimus concentrations and acute tacrolimus nephrotoxicity. Thus, well-designed and powered prospective clinical studies are still required to determine whether measuring tacrolimus PBMC or graft concentrations offers a significant benefit compared to current TDM.

PMID:34764868 | PMC:PMC8576179 | DOI:10.3389/fphar.2021.733285

Sci Rep. 2021 Nov 11;11(1):22452. doi: 10.1038/s41598-021-01417-w.

NO ABSTRACT

PMID:34764341 | DOI:10.1038/s41598-021-01417-w

Lancet Child Adolesc Health. 2021 Nov 8:S2352-4642(21)00268-6. doi: 10.1016/S2352-4642(21)00268-6. Online ahead of print.

ABSTRACT

BACKGROUND: Pharmacogenetic studies in asthma cohorts, primarily made up of White people of European descent, have identified loci associated with response to inhaled beta agonists and corticosteroids (ICSs). Differences exist in how individuals from different ancestral backgrounds respond to long-acting beta agonist (LABA) and ICSs. Therefore, we sought to understand the pharmacogenetic mechanisms regulating therapeutic responsiveness in individuals of African descent.

METHODS: We did ancestry-based pharmacogenetic studies of children (aged 5-11 years) and adolescents and adults (aged 12-69 years) from the Best African Response to Drug (BARD) trials, in which participants with asthma uncontrolled with low-dose ICS (fluticasone propionate 50 μg in children, 100 μg in adolescents and adults) received different step-up combination therapies. The hierarchal composite outcome of pairwise superior responsiveness in BARD was based on asthma exacerbations, a 31-day difference in annualised asthma-control days, or a 5% difference in percentage predicted FEV1. We did whole-genome admixture mapping of 15 159 ancestral segments within 312 independent regions, stratified by the two age groups. The two co-primary outcome comparisons were the step up from low-dose ICS to the quintuple dose of ICS (5 × ICS: 250 μg twice daily in children and 500 μg twice daily in adolescents and adults) versus double dose (2-2·5 × ICS: 100 μg twice daily in children, 250 μg twice daily in adolescents and adults), and 5 × ICS versus 100 μg fluticasone plus a LABA (salmeterol 50 μg twice daily). We used a genome-wide significance threshold of p<1·6 × 10-4, and tested for replication using independent cohorts of individuals of African descent with asthma.

FINDINGS: We included 249 unrelated children and 267 unrelated adolescents and adults in the BARD pharmacogenetic analysis. In children, we identified a significant admixture mapping peak for superior responsiveness to 5 × ICS versus 100 μg fluticasone plus salmeterol on chromosome 12 (odds ratio [ORlocal African] 3·95, 95% CI 2·02-7·72, p=6·1 × 10-5) fine mapped to a locus adjacent to RNFT2 and NOS1 (rs73399224, ORallele dose 0·17, 95% CI 0·07-0·42, p=8·4 × 10-5). In adolescents and adults, we identified a peak for superior responsiveness to 5 × ICS versus 2·5 × ICS on chromosome 22 (ORlocal African 3·35, 1·98-5·67, p=6·8 × 10-6) containing a locus adjacent to TPST2 (rs5752429, ORallele dose 0·21, 0·09-0·52, p=5·7 × 10-4). We replicated rs5752429 and nominally replicated rs73399224 in independent African American cohorts.

INTERPRETATION: BARD is the first genome-wide pharmacogenetic study of LABA and ICS response in clinical trials of individuals of African descent to detect and replicate genome-wide significant loci. Admixture mapping of the composite BARD trial outcome enabled the identification of novel pharmacogenetic variation accounting for differential therapeutic responses in people of African descent with asthma.

FUNDING: National Institutes of Health, National Heart, Lung, and Blood Institute.

PMID:34762840 | DOI:10.1016/S2352-4642(21)00268-6

Lancet Child Adolesc Health. 2021 Nov 8:S2352-4642(21)00330-8. doi: 10.1016/S2352-4642(21)00330-8. Online ahead of print.

NO ABSTRACT

PMID:34762839 | DOI:10.1016/S2352-4642(21)00330-8

J Oncol Pharm Pract. 2021 Nov 11:10781552211057486. doi: 10.1177/10781552211057486. Online ahead of print.

ABSTRACT

INTRODUCTION: Sacituzumab govitecan-hziy, approved in 2020 for treatment of metastatic triple-negative breast cancer, provides a new option for a population with a historically poor prognosis with standard chemotherapy. Uridine diphosphate glucuronosyltransferase family 1 member A1 poor metabolizers are at increased risk for profound neutropenia. This case discusses clinical implications of the uridine diphosphate glucuronosyltransferase family 1 member A1*28/*28 genotype in patients receiving sacituzumab govitecan-hziy.

CASE REPORT: A 38-year-old otherwise healthy pre-menopausal female of South Asian descent was diagnosed with non-metastatic, hormone receptor-positive, and human epidermal growth factor receptor 2-negative breast cancer. This was treated with neoadjuvant chemotherapy and multiple lines of subsequent therapies. Upon finding bone metastasis, an additional six lines of therapy ensued. In total, 3.5 years post-diagnosis, sacituzumab govitecan-hziy was started for disease transformation to triple-negative status.

MANAGEMENT AND OUTCOME: Sacituzumab govitecan-hziy was initiated at the Food and Drug Administration-approved 10 mg/kg/dose on days 1 and 8 of a 21-day cycle. Grade 4 neutropenia occurred after one dose. Pharmacogenomics testing identified the patient as a uridine diphosphate glucuronosyltransferase family 1 member A1*28 homozygous expressor. Sacituzumab govitecan-hziy was dose-reduced, and granulocyte colony-stimulating factor was administered due to the severity of neutropenia. The patient continued on sacituzumab govitecan-hziy until disease progression.

DISCUSSION: Sacituzumab govitecan-hziy's propensity to cause neutropenia is multifactorial. Although incidence of all-grade neutropenia from sacituzumab govitecan-hziy is elevated for uridine diphosphate glucuronosyltransferase family 1 member A1*28 homozygous expressors, this does not translate to increased risk for febrile neutropenia. Detailed guidance is lacking regarding empiric dose adjustments or prophylactic granulocyte colony-stimulating factor for these patients.1 Currently, pre-sacituzumab govitecan-hziy pharmacogenomics testing to identify uridine diphosphate glucuronosyltransferase family 1 member A1 poor metabolizers is not recommended, and the cost-effectiveness of this approach is unclear.

PMID:34761708 | DOI:10.1177/10781552211057486

Pharmacogenomics. 2021 Nov 11. doi: 10.2217/pgs-2021-0134. Online ahead of print.

NO ABSTRACT

PMID:34761695 | DOI:10.2217/pgs-2021-0134

Clin Transl Sci. 2021 Nov 10. doi: 10.1111/cts.13185. Online ahead of print.

ABSTRACT

The purpose of this study was to investigate the potential clinical relevance of estimating the apparent clearance (CL/F) of atorvastatin through population pharmacokinetics (popPK) modeling with samples collected in a real-life setting in a cohort of ambulatory patients at risk of cardiovascular disease by using an opportunistic sampling strategy easily accessible in clinical routine. A total of 132 PK samples at a maximum of 3 visits were collected in the 70 included patients. The effects of demographic, genetic and clinical covariates were also considered. With the collected data, we developed a two-compartments PopPK model that allowed estimating atorvastatin CL/F relatively precisely and considering the genotype of the patient for SLCO1B1 c.521T>C SNP. Our results indicate that the estimation of the apparent clearance of atorvastatin through our PopPK model might help in identifying patients at risk of myalgia. Indeed, we showed that a patient presenting a CL/F lower than 414.67 L.h-1 is at risk of suffering from muscle discomfort. We also observed that the CL/F was correlated with the efficacy outcomes, suggesting that a higher CL/F is associated with a better drug efficacy (i.e. a greater decrease in total and LDL-cholesterol levels). In conclusion, our study demonstrates that PopPK modeling can be useful in daily clinics to estimate a patient' atorvastatin clearance. Notifying the clinician with this information can help in identifying patients at risk of myalgia and gives indication about the potential responsiveness to atorvastatin therapy.

PMID:34761521 | DOI:10.1111/cts.13185

Endocrine. 2021 Nov 10. doi: 10.1007/s12020-021-02934-4. Online ahead of print.

ABSTRACT

PURPOSE: Metformin induces GLUT-4 mRNA expression in insulin target tissues in PCOS. It is unclear how long this impact is sustained after withdrawal of metformin. We aimed to compare the effect of metformin withdrawal on GLUT-4 mRNA expression in subcutaneous adipose tissue after prior short (ST, 1 year, N = 11) and long term (LT, at least 3 years, N = 13) treatment in obese PCOS women.

METHODS: At baseline and 6 months after withdrawal, biopsy of subcutaneous adipose tissue followed by quantitative PCR analysis was performed to determine GLUT-4 mRNA expression.

RESULTS: We found no time/effect differences in GLUT-4 mRNA expression in ST (2-dCt at baseline 0.42 (0.16-0.48) vs 2-dCt after 6 months 0.31 (0.22-0.56), p = 0.594) and no time/effect difference in LT group (2-dCt at baseline 0.24 (0.14-0.39) vs 2-dCt after 6 months 0.25 (0.20-0.38), p = 0.382). There was also no difference in GLUT-4 mRNA expression between both groups at baseline and after 6 months.

CONCLUSIONS: In summary, 6 months after metformin withdrawal, GLUT-4 mRNA expression in subcutaneous adipose tissue remained stable, regardless of the prior treatment duration.

PMID:34761355 | DOI:10.1007/s12020-021-02934-4

Biomed Rep. 2021 Dec;15(6):105. doi: 10.3892/br.2021.1481. Epub 2021 Oct 22.

ABSTRACT

Immune system dysregulation plays a role in the pathogenesis of complex human diseases, including psychiatric disorders. In addition, elevated levels of pro-inflammatory cytokines, including tumor necrosis factor α (TNF-α) may be conditioned by the presence of specific polymorphic variants. The present case-controlled preliminary study evaluated the prevalence of TNFA gene single nucleotide polymorphisms (SNPs) G-308A (rs1800629) and T-1031C (rs1799964) in 83 Polish patients with depression by restriction fragment length polymorphism analysis. The results were compared with the frequencies of genotypes in a geographically- and ethnically-matched group of individuals without depression. No statistically significant difference in genotype/allele frequency was observed for either SNP between the two groups. No association was found between the particular genotypes and selected demographic/clinical features, including sex, age at diagnosis or severity of depressive symptoms before/after pharmacotherapy. Thus, there does not appear to be any connection between the studied SNPs and the development and progression of depression; however, further studies are required with larger cohorts to better understand this aspect of depression.

PMID:34760278 | PMC:PMC8567462 | DOI:10.3892/br.2021.1481

Neuropsychol Rev. 2021 Nov 10. doi: 10.1007/s11065-021-09527-y. Online ahead of print.

ABSTRACT

HIV-associated neurocognitive impairment remains a challenge even in the era of antiretroviral therapy (ART). Over 90% of people living with HIV are in low- and middle-income countries. Hence, it is not surprising that such countries bear a considerable burden of comorbidities like HIV-associated neurocognitive impairment despite an overall increase in life expectancy. The literature suggests differences in patient characteristics, clinical profile, prevalent HIV subtypes, treatment choices, pharmacogenetics, and socioeconomic factors between low- and middle-income countries compared with high-income countries. Therefore, we aimed to evaluate the effect of ART on neurocognitive outcomes in low- and middle-income countries. A comprehensive search of five databases (PubMed, CINAHL, CENTRAL, PsychInfo, Google scholar) for studies published between 1996 to 2020 was performed to identify studies that reported neurocognitive outcomes in ART-treated and ART naïve HIV positive individuals. Two independent reviewers conducted study screening, data extraction, and evaluation of the risk of bias. Pooled effect size estimates (Hedges' g) and 95% CI were computed using random-effects models. Sensitivity analysis, subgroup analysis, meta-regression, and evaluation of publication bias were also conducted. Forty studies (24 cross-sectional, 13 longitudinal studies, and two randomized controlled trials) contributed to a series of meta-analyses. We found significant small to moderate effects of antiretroviral therapy for global cognition (Hedges' g observed = 0.30; 95% CI: 0.15, 0.44; k = 25; p = 0.0003; I2 = 92.1%; tau = 0.32; Q = 305.1), executive function (Hedges' g = 0.24, 95%CI: 0.02,0.46; p-0.04; k = 8; I2 = 37.5%; tau = 0.23; Q = 11.2), and speed of information processing (Hedges' g = 0.25, 95% CI: 0.05, 0.45; k = 9; p = 0.02; I2 = 86.4%; tau = 0.21; Q = 58.9). We found no significant ART effect on attention-working memory, learning and memory, motor function, and verbal fluency. No significant effect was seen with the duration of therapy, efavirenz use, and Central Penetrating Effectiveness (CPE) of antiretroviral therapy. Subgroup analyses identified study design (between-group and within-group; cross-sectional and longitudinal) and normative scores as significant sources of heterogeneity. Meta-regression analysis indicated that nadir CD4 modified the magnitude of ART's effect on cognitive outcomes. Age, gender, and country income-group were not significant moderators. Our findings provide systematic evidence that antiretroviral therapy improves neurocognitive outcomes in the domains of global cognition, executive function and speed of information processing, of people living with HIV in low- and middle-income countries, especially those with advanced immunosuppression. However, these findings are not definitive as they are limited by the probability of publication bias, high heterogeneity, and exclusion of significant confounders. Prospero registration number: CRD42020203791.

PMID:34757490 | DOI:10.1007/s11065-021-09527-y

Prog Neuropsychopharmacol Biol Psychiatry. 2021 Oct 28:110464. doi: 10.1016/j.pnpbp.2021.110464. Online ahead of print.

ABSTRACT

BACKGROUND: Cognitive impairment is a core deficit across psychotic disorders, the causes and therapeutics of which remain unclear. Epidemiological observations have suggested associations between cognitive dysfunction in psychotic disorders and cardiovascular risk factors, but an underlying etiology has not been established.

METHODS: Neuropsychological performance using the Brief Assessment of Cognition in Schizophrenia (BACS) was assessed in 616 individuals of European ancestry (403 psychosis, 213 controls). Polygenic risk scores for coronary artery disease (PRSCAD) were quantified for each participant across 13 p-value thresholds (PT 0.5-5e-8). Cardiovascular and psychotropic medications were categorized for association analyses. Each PRSCAD was examined in relation to the BACS and the optimized PT was confirmed with five-fold cross-validation and independent validation. Functional enrichment analyses were used to identify biological mechanisms linked to PRSCAD-cognition associations. Multiple regression analyses examined PRSCAD under the optimal PT and medication burden in relation to the BACS composite and subtest scores.

RESULTS: Higher PRSCAD was associated with lower BACS composite scores (p = 0.001) in the psychosis group, primarily driven by the Verbal Memory subtest (p < 0.001). Genes linked to multiple nervous system related processes and pathways were significantly enriched in PRSCAD. After controlling for PRSCAD, a greater number of cardiovascular medications was also correlated with worse BACS performance in patients with psychotic disorders (p = 0.029).

CONCLUSIONS: Higher PRSCAD and taking more cardiovascular medications were both significantly associated with cognitive impairment in psychosis. These findings indicate that cardiovascular factors may increase the risk for cognitive dysfunction and related functional outcomes among individuals with psychotic disorders.

PMID:34756932 | DOI:10.1016/j.pnpbp.2021.110464

J Am Heart Assoc. 2021 Nov 10:e022433. doi: 10.1161/JAHA.121.022433. Online ahead of print.

ABSTRACT

Background The relationship between COVID-19 and ischemic stroke is poorly understood due to potential unmeasured confounding and reverse causation. We aimed to leverage genetic data to triangulate reported associations. Methods and Results Analyses primarily focused on critical COVID-19, defined as hospitalization with COVID-19 requiring respiratory support or resulting in death. Cross-trait linkage disequilibrium score regression was used to estimate genetic correlations of critical COVID-19 with ischemic stroke, other related cardiovascular outcomes, and risk factors common to both COVID-19 and cardiovascular disease (body mass index, smoking and chronic inflammation, estimated using C-reactive protein). Mendelian randomization analysis was performed to investigate whether liability to critical COVID-19 was associated with increased risk of any cardiovascular outcome for which genetic correlation was identified. There was evidence of genetic correlation between critical COVID-19 and ischemic stroke (rg=0.29, false discovery rate [FDR]=0.012), body mass index (rg=0.21, FDR=0.00002), and C-reactive protein (rg=0.20, FDR=0.00035), but no other trait investigated. In Mendelian randomization, liability to critical COVID-19 was associated with increased risk of ischemic stroke (odds ratio [OR] per logOR increase in genetically predicted critical COVID-19 liability 1.03, 95% CI 1.00-1.06, P-value=0.03). Similar estimates were obtained for ischemic stroke subtypes. Consistent estimates were also obtained when performing statistical sensitivity analyses more robust to the inclusion of pleiotropic variants, including multivariable Mendelian randomization analyses adjusting for potential genetic confounding through body mass index, smoking, and chronic inflammation. There was no evidence to suggest that genetic liability to ischemic stroke increased the risk of critical COVID-19. Conclusions These data support that liability to critical COVID-19 is associated with an increased risk of ischemic stroke. The host response predisposing to severe COVID-19 is likely to increase the risk of ischemic stroke, independent of other potentially mitigating risk factors.

PMID:34755518 | DOI:10.1161/JAHA.121.022433

Clin Transl Sci. 2021 Nov 10. doi: 10.1111/cts.13193. Online ahead of print.

ABSTRACT

As pharmacogenomic (PGx) testing increases in popularity, lay concepts of drug-gene interactions set the stage for shared decision-making in precision medicine. Few studies explore what recipients of PGx results think is happening in their bodies when a drug-gene interaction is discovered. To characterize biobank participants' understanding of PGx research results, we conducted afocus group study which took place after pharmacogenomic variants conferring increased risk of dihydropyrimidine dehydrogenase (DPD) deficiency were disclosed to biobank contributors. DPD deficiency confers an increased risk of adverse reaction to commonly used cancer chemotherapeutics. Ten focus groups were conducted, ranging from two to eight participants. 54 individuals participated in focus groups. A framework approach was used for descriptive and explanatory analysis. Descriptive themes included participants' efforts to make sense of PGx findings as they related to: (1) health implications, (2) drugs, and (3) genetics. Explanatory analysis supplied a functional framework of how participant word choices can perform different purposes in PGx communication.. Results bear three main implications for PGx research-related disclosure. First, participants' use of various terms suggest participants generally understanding their PGx results, including how positive PGx results differ from positive disease susceptibility genetic results. Second, PGx disclosure in biobanking can involve participant conflation of drug-gene interactions with allergies or other types of medical reactions. Third, the functional framework suggests a need to move beyond a deficit model of genetic literacy in PGx communication. Together, findings provide an initial evidence base for supporting bi-directional expert-recipient PGx results communication.

PMID:34755460 | DOI:10.1111/cts.13193

J Intern Med. 2021 Nov 10. doi: 10.1111/joim.13417. Online ahead of print.

ABSTRACT

BACKGROUND: Little is known about ANCA-associated vasculitis (AAV) in older patients.

OBJECTIVES: We aim to study relapse risk of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) in patients diagnosed after 75 years and compare it with those of patients aged 65-75 years.

METHODS: Data from AAV patients aged ≥65 years were extracted from the French Vasculitis Study Group (FVSG) database and from a call for observation to FVSG members. Cox and Fine-Gray models were used to assess relapse risk, taking death into account either as a censoring or a competing event, respectively.

RESULTS: The analysis included 219 patients aged ≥75 years (median 79) and 80 aged 65-75 years (median 70), of whom 155 had GPA (52%), 136 MPA (45%), with 95 (32%) anti-proteinase 3 positivity and 179 (61%) anti-myeloperoxidase. Patients aged ≥75 years had a lower relapse risk in multivariate analysis (CSHR 0.54, 95%CI 0.33-0.89, p=0.016, Cox model; SHR 0.46, 95%CI 0.29-0.74, p=0.001, Fine-Gray model) after taking into account vasculitis type. Patients aged ≥75 years had a lower probability of being treated for remission-maintenance with a combination of glucocorticoids and immunosuppressants (versus glucocorticoids alone, HR 0.28, 95%CI 0.11-0.68, p=0.005) after adjusting to Five Factor Score, although relapse-free survival was significantly longer when receiving such combination (CSHR 0.40, 95%CI 0.24-0.67, p<0.001).

CONCLUSION: AAV patients ≥75 years have a lower relapse risk than patients aged 65-75 years despite a lower probability of having received maintenance therapy with a combination of glucocorticoids and immunosuppressants, but they still benefit from such treatment regimen. This article is protected by copyright. All rights reserved.

PMID:34755398 | DOI:10.1111/joim.13417

World J Diabetes. 2021 Oct 15;12(10):1693-1703. doi: 10.4239/wjd.v12.i10.1693.

ABSTRACT

The prevalence of diabetes has increased rapidly throughout the world in recent years. Currently, approximately 463 million people are living with diabetes, and the number has tripled over the last two decades. Here, we describe the global epidemiology of diabetes in 2019 and forecast the trends to 2030 and 2045 in China, India, USA, and the globally. The gut microbiota plays a major role in metabolic diseases, especially diabetes. In this review, we describe the interaction between diabetes and gut microbiota in three aspects: probiotics, antidiabetic medication, and diet. Recent findings indicate that probiotics, antidiabetic medications, or dietary interventions treat diabetes by shifting the gut microbiome, particularly by raising beneficial bacteria and reducing harmful bacteria. We conclude that targeting the gut microbiota is becoming a novel therapeutic strategy for diabetes.

PMID:34754371 | PMC:PMC8554376 | DOI:10.4239/wjd.v12.i10.1693

J Appl Biomed. 2021;19(2):113-124. doi: 10.32725/jab.2021.013.

ABSTRACT

Oplopanax elatus (Nakai) Nakai has a long history of use as an ethnomedicine by the people living in eastern Asia. However, its bioactive constituents and cancer chemopreventive mechanisms are largely unknown. The aim of this study was to prepare O. elatus extracts, fractions, and single compounds and to investigate the herb's antiproliferative effects on colon cancer cells and the involved mechanisms of action. Two polyyne compounds were isolated from O. elatus, falcarindiol and oplopandiol. Based on our HPLC analysis, falcarindiol and oplopandiol are major constituents in the dichloromethane (CH2Cl2) fraction. For the HCT-116 cell line, the dichloromethane fraction showed significant effects. Furthermore, the IC50 for falcarindiol and oplopandiol was 1.7 μM and 15.5 μM, respectively. In the mechanistic study, after treatment with 5 μg/ml for 48 h, dichloromethane fraction induced cancer cell apoptosis by 36.5% (p < 0.01% vs. control of 3.9%). Under the same treatment condition, dichloromethane fraction caused cell cycle arrest at the G2/M phase by 32.6% (p < 0.01% vs. control of 23.4%), supported by upregulation of key cell cycle regulator cyclin A to 21.6% (p < 0.01% vs. control of 8.6%). Similar trends were observed by using cell line HT-29. Data from this study filled the gap between phytochemical components and the cancer chemoprevention of O. elatus. The dichloromethane fraction is a bioactive fraction, and falcarindiol is identified as an active constituent. The mechanisms involved in cancer chemoprevention by O. elatus were apoptosis induction and G2/M cell cycle arrest mediated by a key cell cycle regulator cyclin A.

PMID:34754259 | PMC:PMC8575125 | DOI:10.32725/jab.2021.013