Cardiovascular events reported in patients with B-cell malignancies treated with zanubrutinib.

First-generation Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, has been associated with an increased risk of cardiovascular toxicities. Zanubrutinib is a more selective, next-generation BTK inhibitor. In this analysis, incidence rates of atrial fibrillation, symptomatic (grade ≥2) ventricular arrhythmia, and hypertension were evaluated in a pooled analysis of 10 clinical studies with zanubrutinib monotherapy in patients (N = 1550) with B-cell malignancies and a pooled analysis of head-to-head studies comparing zanubrutinib with ibrutinib (ASPEN cohort 1; ALPINE). Among the 10 studies, most patients (median age, 67 years) were male (66.3%) and had CLL/SLL (60.5%). Overall incidence and exposure-adjusted incidence rates (EAIR) for atrial fibrillation, symptomatic ventricular arrhythmia, and hypertension were lower with zanubrutinib than ibrutinib. Despite a similar prevalence of preexisting cardiovascular events in ASPEN and ALPINE, atrial fibrillation/flutter incidence rates (6.1% vs 15.6%) and EAIR (0.2 vs 0.64 persons per 100 person-months; P < .0001) were lower with zanubrutinib than with ibrutinib. Symptomatic ventricular arrhythmia incidence was low for both zanubrutinib (0.7%) and ibrutinib (1.7%) with numerically lower EAIR (0.02 vs 0.06 persons per 100 person-months, respectively) for zanubrutinib. The hypertension EAIR was lower with zanubrutinib than ibrutinib in ASPEN but similar between treatment arms in ALPINE. The higher hypertension EAIR in ALPINE was inconsistent with other zanubrutinib studies. However, fewer discontinuations (1 vs 14) and deaths (0 vs 6) due to cardiac disorders occurred with zanubrutinib versus ibrutinib in ALPINE. These data support zanubrutinib as a treatment option with improved cardiovascular tolerability compared with ibrutinib for patients with B-cell malignancies in need of BTK inhibitors. These trials were registered at www.ClinicalTrials.gov as # NCT03053440, NCT03336333, NCT03734016, NCT04170283, NCT03206918, NCT03206970, NCT03332173, NCT03846427, NCT02343120, and NCT03189524

Inactive matrix gla protein plasma levels are associated with peripheral neuropathy in Type 2 diabetes.

AIMS/HYPOTHESIS Diabetic peripheral neuropathy is a frequent and severe complication of diabetes. As Matrix-gla-protein (MGP) is expressed in several components of the nervous system and is involved in some neurological disease, MGP could play a role in peripheral nervous system homeostasis. The aim of this study was to evaluate factors associated with sensitive diabetic neuropathy in Type 2 Diabetes, and, in particular, dephospho-uncarboxylated MGP (dp-ucMGP), the inactive form of MGP. METHODS 198 patients with Type 2 Diabetes were included. Presence of sensitive diabetic neuropathy was defined by a neuropathy disability score (NDS) ≥6. Plasma levels of dp-ucMGP were measured by ELISA. RESULTS In this cohort, the mean age was 64+/-8.4 years old, and 80% of patients were men. Peripheral neuropathy was present in 15.7% of the patients and was significantly associated (r = 0.51, p<0.0001) with dp-ucMGP levels (β = -0.26, p = 0.045) after integrating effects of height (β = -0.38, p = 0.01), insulin treatment (β = 0.42, p = 0.002), retinopathy treated by laser (β = 0.26, p = 0.02), and total cholesterol levels (β = 0.3, p = 0.03) by multivariable analysis. CONCLUSIONS The association between diabetic neuropathy and the inactive form of MGP suggests the existence of new pathophysiological pathways to explore. Further studies are needed to determine if dp-ucMGP may be used as a biomarker of sensitive neuropathy. Since dp-ucMGP is a marker of poor vitamin K status, clinical studies are warranted to explore the potential protective effect of high vitamin K intake on diabetic peripheral neuropathy

Clinical spectrum and evolution of immune-checkpoint inhibitors toxicities over a decade-a worldwide perspective.

BACKGROUND: Immune-checkpoint inhibitors (ICI) have revolutionized cancer treatment by harnessing the immune system but ICI can induce life-threatening immune-related adverse events (irAE) affecting every organ. METHODS: We extracted irAE from VigiBase, the international pharmacovigilance database, first reported in 2008 until 01/2023 to characterize irAE reporting trends, clinical features, risk factors and outcomes. FINDINGS: We distinguished 25 types of irAE (n&nbsp;=&nbsp;50,347cases, single irAE/case in 84.9%). Cases mainly involved anti-PD1 (programmed-death-1) monotherapy (62.4%) in male (61.7%) aged 64.3&nbsp;±&nbsp;12.6 years. After 2020 vs. prior to 2016, proportion of anti-CTLA4 (Cytotoxic-T-Lymphocyte-Antigen-4) monotherapy prescription almost vanished (1.6% vs. 47%, respectively) contrasting with increased use of anti-PDL1 (PD1-ligand) monotherapy (18% vs. 0.9%) and anti-CTLA4+anti-PD(L)1 combination (20% vs. 8.9%). Anti-LAG3 (Lymphocyte-Activation-Gene-3) prescription was limited (&lt;1%) in the studied timeframe. After 2020, over 14 different cancer types were treated vs. almost exclusively melanoma and lung cancers before 2016. Overall, the most reported irAE were skin reactions (22.9%), pneumonitis (18.5%), enterocolitis (14.4%) and thyroiditis (12.1%). ICI-myotoxicities (6.6%) included myositis, myocarditis and myasthenia-gravis like syndrome and were the most overlapping irAE (up to 30% overlap, vs. &lt;3% in general for other inter-irAE overlap). The top factors associated with specific irAE (odds-ratio&gt;5) were presence of thymic cancer for ICI-myotoxicities or hepatitis; presence of melanoma for vitiligo, uveitis or sarcoidosis; specific types of ICI regimen (anti-LAG3 for meningitis, anti-CTLA4 for hypophysitis); and specific reporting regions (eastern Asia for cholangitis). Median time-to-onset ranged from 31 to 273 days, being shortest for myotoxicities and most delayed for skin-bullous auto-immune reactions. Overall fatality was highest for myocarditis&nbsp;=&nbsp;27.6%, myasthenia&nbsp;=&nbsp;23.1%, severe cutaneous adverse reactions (SCAR)&nbsp;=&nbsp;22.1%, myositis&nbsp;=&nbsp;21.9%, pneumonitis&nbsp;=&nbsp;21%, and encephalomyelitis&nbsp;=&nbsp;18%; generally decreasing after 2020, except for myasthenia and SCAR. When reported, irAE recurrence rate after rechallenge was 28.9% (n&nbsp;=&nbsp;275/951). INTERPRETATION: This up-to-date comprehensive worldwide pharmacovigilance study defines the spectrum, characteristics, and evolution of irAE reporting summarizing over a decade of use. Multiple risk factors and clinical peculiarities for specific irAE have been identified as signals to guide clinical practice and future research. FUNDING: Paul Gougis was supported by the academic program: Contrats ED: Programme blanc Institut Curie PSL for the conduct of his PhD. Baptiste Abbar was supported by the Fondation ARC Pour le Rechercher Sur le Cancer. The RT2L research group (Institut Curie) was supported by the academic program SHS INCa, Sanofi iTech award, and by Monoprix∗

Association between metformin use and below-the-knee arterial calcification score in type 2 diabetic patients.

BACKGROUND Vascular calcification (VC) is common in type 2 diabetes, and is associated with cardiovascular complications. Recent preclinical data suggest that metformin inhibits VC both in vitro and in animal models. However, metformin's effects in patients with diabetic VC have not previously been characterized. The present study investigated the association between metformin use and lower-limb arterial calcification in patients with type 2 diabetes and high cardiovascular risk. METHODS The DIACART cross-sectional cohort study included 198 patients with type 2 diabetes but without severe chronic kidney disease. Below-the-knee calcification scores were assessed by computed tomography and supplemented by colour duplex ultrasonography. Data on anti-diabetic drugs were carefully collected from the patients' medical records and during patient interviews. Biochemical and clinical data were studied as potential confounding factors. RESULTS Metformin-treated patients had a significantly lower calcification score than metformin-free patients (mean ± standard deviation: 2033 ± 4514 and 4684 ± 9291, respectively; p = 0.01). A univariate analysis showed that metformin was associated with a significantly lower prevalence of severe below-the-knee arterial calcification (p = 0.02). VC was not significantly associated with the use of other antidiabetic drugs, including sulfonylureas, insulin, gliptin, and glucagon like peptide-1 analogues. A multivariate logistic regression analysis indicated that the association between metformin use and calcification score (odds ratio [95% confidence interval] = 0.33 [0.11-0.98]; p = 0.045) was independent of age, gender, tobacco use, renal function, previous cardiovascular disease, diabetes duration, neuropathy, retinopathy, HbA1c levels, and inflammation. CONCLUSIONS In patients with type 2 diabetes, metformin use was independently associated with a lower below-the-knee arterial calcification score. This association may contribute to metformin's well-known vascular protective effect. Further prospective investigations of metformin's potential ability to inhibit VC in patients with and without type 2 diabetes are now needed to confirm these results

High Sensitivity Troponin T and NT-proBNP in Patients Receiving Chimeric Antigen Receptor (CAR) T-Cell Therapy

Retrospective studies suggest that chimeric antigen receptor T-cell (CAR T) therapy may lead to cardiac injury, but this has not been assessed systematically or prospectively. In this prospective study of 40 patients who received CAR T, we systematically measured high-sensitivity troponin T (hsTropT) and N-terminal pro-B natriuretic peptide (NTproBNP) at baseline and on day 1, days 7, and 21 after CAR T. Biomarker elevations with respect to timepoint and cytokine release syndrome (CRS) status were examined using repeated measure analysis of variance. hsTropT did not differ with time or with the presence of grade 2 CRS. Median hsTropT was 12.1 ng/L [interquartile range (IQR): 9.2, 20.1] at baseline, 13.1 ng/L (IQR: 9.6, 24.2) at day 1, 11.9 ng/L (IQR: 9.6, 18.0) at day 7, and 15.3 ng/L (10.8, 20.2) at day 21. In contrast, NTproBNP rose on day 1 (PWilcox = 0.0002) and day 7 (PWilcox = 2.7 × 10−5), and the degree of elevation differed by the presence of grade 2 CRS (Pinteraction = 0.002). Median NTproBNP was 179 pg/mL (IQR: 116, 325) at baseline, 357 pg/mL (IQR: 98, 813) at day 1, 420 pg/mL (IQR: 239, 1242) at day 7, and 177 pg/mL (IQR: 80, 278) at day 21. In conclusion, hsTropT l did not differ across timepoints after CAR T therapy, but NTproBNP rose at day 7, the prognostic implications of which should be the target of future research, as the indications for this therapy expand

Comparative safety of mRNA COVID-19 vaccines to influenza vaccines: A pharmacovigilance analysis using WHO international database.

Funder: New faculty research seed money grant of Yonsei University College of Medicine for 2021 (2021-32-0049).Two messenger RNA (mRNA) vaccines developed by Pfizer-BioNTech and Moderna are being rolled out. Despite the high volume of emerging evidence regarding adverse events (AEs) associated with the COVID-19 mRNA vaccines, previous studies have thus far been largely based on the comparison between vaccinated and unvaccinated control, possibly highlighting the AE risks with COVID-19 mRNA vaccination. Comparing the safety profile of mRNA vaccinated individuals with otherwise vaccinated individuals would enable a more relevant assessment for the safety of mRNA vaccination. We designed a comparative safety study between 18 755 and 27 895 individuals who reported to VigiBase for adverse events following immunization (AEFI) with mRNA COVID-19 and influenza vaccines, respectively, from January 1, 2020, to January 17, 2021. We employed disproportionality analysis to rapidly detect relevant safety signals and compared comparative risks of a diverse span of AEFIs for the vaccines. The safety profile of novel mRNA vaccines was divergent from that of influenza vaccines. The overall pattern suggested that systematic reactions like chill, myalgia, fatigue were more noticeable with the mRNA COVID-19 vaccine, while injection site reactogenicity events were more prevalent with the influenza vaccine. Compared to the influenza vaccine, mRNA COVID-19 vaccines demonstrated a significantly higher risk for a few manageable cardiovascular complications, such as hypertensive crisis (adjusted reporting odds ratio [ROR], 12.72; 95% confidence interval [CI], 2.47-65.54), and supraventricular tachycardia (adjusted ROR, 7.94; 95% CI, 2.62-24.00), but lower risk of neurological complications such as syncope, neuralgia, loss of consciousness, Guillain-Barre syndrome, gait disturbance, visual impairment, and dyskinesia. This study has not identified significant safety concerns regarding mRNA vaccination in real-world settings. The overall safety profile patterned a lower risk of serious AEFI following mRNA vaccines compared to influenza vaccines

Neuropsychological Adverse Drug Reactions to Remdesivir: Results from the WHO International Pharmacovigilance Database

OBJECTIVE: Although remdesivir (GS-5734) has recently demonstrated clinical benefits against the pandemic outbreak of coronavirus disease 2019 (COVID-19), neuropsychological adverse reactions (ADRs) remain to be examined in real-world settings. Therefore, we aimed to identify and characterize the neuropsychological ADRs associated with remdesivir use. MATERIALS AND METHODS: We obtained data for this international pharmacovigilance cohort study from individual case safety reports (ICSRs) in a World Health Organization database (VigiBase) from the first report on remdesivir on February 17, 2020, until August 30, 2020 (n=1,403,532). ADRs reported to be relevant to remdesivir were compared with the full database by using a Bayesian neural network method to calculate the information component (IC). RESULTS: A total of 2,107 reported cases of neuropsychological ADRs suspected to be associated with remdesivir were identified from among all ICSRs in the database during the observation period. Although 108 neuropsychological ADRs (64 neurologic events and 44 psychologic events) were reported in association with the medication, no statistically significant pharmacovigilance signal could be detected; the IC025 value was negative for all of the neuropsychological dysfunctions (anxiety [n=13, 0.62%], seizures [n=12, 0.57%], lethargy [n=6, 0.28%], agitation [n=5, 0.25%], cerebral infarction [n=3, 0.14%], ischemic stroke [n=3, 0.14%], and hemiparesis [n=3, 0.14%]). CONCLUSIONS: Our study demonstrates that remdesivir, a novel drug applied to the treatment of COVID-19, does not have a significant association with adverse neurologic or psychiatric reactions in the real-world setting

Hormonal Therapies Up-Regulate Manf and Overcome Female Susceptibility to Immune Checkpoint Inhibitor Myocarditis

Immune checkpoint inhibitors (ICIs) have been increasingly used in combination for cancer treatment but are associated with myocarditis. Here, we report that tumor-bearing mice exhibited response to treatment with combinatorial anti-programmed cell death 1 and anti-cytotoxic T lymphocyte antigen-4 antibodies but also presented with cardiovascular toxicities observed clinically with ICI therapy, including myocarditis and arrhythmia. Female mice were preferentially affected with myocarditis compared to male mice, consistent with a previously described genetic model of ICI myocarditis and emerging clinical data. Mechanistically, myocardial tissue from ICI-treated mice, the genetic mouse model, and human heart tissue from affected patients with ICI myocarditis all exhibited down-regulation of MANF (mesencephalic astrocyte-derived neurotrophic factor) and HSPA5 (heat shock 70-kDa protein 5) in the heart; this down-regulation was particularly notable in female mice. ICI myocarditis was amplified by heart-specific genetic deletion of mouse Manf and was attenuated by administration of recombinant MANF protein, suggesting a causal role. Ironically, both MANF and HSPA5 were transcriptionally induced by liganded estrogen receptor β and inhibited by androgen receptor. However, ICI treatment reduced serum estradiol concentration to a greater extent in female compared to male mice. Treatment with an estrogen receptor β-specific agonist and androgen depletion therapy attenuated ICI-associated cardiac effects. Together, our data suggest that ICI treatment inhibits estradiol-dependent expression of MANF/HSPA5 in the heart, curtailing the cardiomyocyte response to immune injury. This endocrine-cardiac-immune pathway offers new insights into the mechanisms of sex differences in cardiac disease and may offer treatment strategies for ICI myocarditis

Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism

Objectives Gut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome\u27s functional composition in healthy metabolic state and the most severe states of obesity and type 2 diabetes within the MetaCardis cohort. We focused on the role of B vitamins and B7/B8 biotin for regulation of host metabolic state, as these vitamins influence both microbial function and host metabolism and inflammation. Design We performed metagenomic analyses in 1545 subjects from the MetaCardis cohorts and different murine experiments, including germ-free and antibiotic treated animals, faecal microbiota transfer, bariatric surgery and supplementation with biotin and prebiotics in mice. Results Severe obesity is associated with an absolute deficiency in bacterial biotin producers and transporters, whose abundances correlate with host metabolic and inflammatory phenotypes. We found suboptimal circulating biotin levels in severe obesity and altered expression of biotin-associated genes in human adipose tissue. In mice, the absence or depletion of gut microbiota by antibiotics confirmed the microbial contribution to host biotin levels. Bariatric surgery, which improves metabolism and inflammation, associates with increased bacterial biotin producers and improved host systemic biotin in humans and mice. Finally, supplementing high-fat diet-fed mice with fructo-oligosaccharides and biotin improves not only the microbiome diversity, but also the potential of bacterial production of biotin and B vitamins, while limiting weight gain and glycaemic deterioration. Conclusion Strategies combining biotin and prebiotic supplementation could help prevent the deterioration of metabolic states in severe obesity

Cardiovascular events and safety outcomes associated with remdesivir using a World Health Organization international pharmacovigilance database

On October 2020, the US Food and Drug Administration (FDA) approved remdesivir as the first drug for the treatment of coronavirus disease 2019 (COVID-19), increasing remdesivir prescriptions worldwide. However, potential cardiovascular (CV) toxicities associated with remdesivir remain unknown. We aimed to characterize the CV adverse drug reactions (ADRs) associated with remdesivir using VigiBase, an individual case safety report database of the World Health Organization (WHO). Disproportionality analyses of CV-ADRs associated with remdesivir were performed using reported odds ratios and information components. We conducted in vitro experiments using cardiomyocytes derived from human pluripotent stem cell cardiomyocytes (hPSC-CMs) to confirm cardiotoxicity of remdesivir. To distinguish drug-induced CV-ADRs from COVID-19 effects, we restricted analyses to patients with COVID-19 and found that, after adjusting for multiple confounders, cardiac arrest (adjusted odds ratio [aOR]: 1.88, 95% confidence interval [CI]: 1.08–3.29), bradycardia (aOR: 2.09, 95% CI: 1.24–3.53), and hypotension (aOR: 1.67, 95% CI: 1.03–2.73) were associated with remdesivir. In vitro data demonstrated that remdesivir reduced the cell viability of hPSC-CMs in time- and dose-dependent manners. Physicians should be aware of potential CV consequences following remdesivir use and implement adequate CV monitoring to maintain a tolerable safety margin