An epigenetic candidate-gene association study of parental styles in suicide attempters with substance use disorders.

Suicide attempts (SA) are prevalent in substance use disorders (SUD). Epigenetic mechanisms may play a pivotal role in the molecular mechanisms of environmental effects eliciting suicidal behaviour in this population. Hypothalamic-pituitary-adrenal axis (HPA), oxytocin and neurotrophin pathways have been consistently involved in SA, yet , their interplay with childhood adversity remains unclear, particularly in SUD. In 24 outpatients with SUDs, we examined the relation between three parental dysfunctional styles and history of SA with methylation of 32 genes from these pathways, eventually analysing 823 methylation sites. Extensive phenotypic characterization was obtained using a semi-structured interview. Parental style was patient-reported using the Measure of Parental Style (MOPS) questionnaire, analysed with and without imputation of missing items. Linear regressions were performed to adjust for possible confounders, followed by multiple testing correction. We describe both differentially methylated probes (DMPs) and regions (DMRs) for each set of analyses (with and without imputation of MOPS items). Without imputation, five DMRs in OXTR, CRH and NTF3 significantly interacted with MOPS father abuse to increase the risk for lifetime SA, thus covering the three pathways. After imputation of missing MOPS items, two other DMPs from FKBP5 and SOCS3 significantly interacted with each of the three father styles to increase the risk for SA. Although our findings must be interpreted with caution due to small sample size, they suggest implications of stress reactivity genes in the suicidal risk of SUD patients and highlight the significance of father dysfunction as a potential marker of childhood adversity in SUD patients.

Drug-Drug Interactions Involving Dexamethasone in Clinical Practice: Myth or Reality?

Concomitant administration of multiple drugs frequently causes severe pharmacokinetic or pharmacodynamic drug-drug interactions (DDIs) resulting in the possibility of enhanced toxicity and/or treatment failure. The activity of cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp), a drug efflux pump sharing localization and substrate affinities with CYP3A4, is a critical determinant of drug clearance, interindividual variability in drug disposition and clinical efficacy, and appears to be involved in the mechanism of numerous clinically relevant DDIs, including those involving dexamethasone. The recent increase in the use of high doses of dexamethasone during the COVID-19 pandemic have emphasized the need for better knowledge of the clinical significance of drug-drug interactions involving dexamethasone in the clinical setting. We therefore aimed to review the already published evidence for various DDIs involving dexamethasone in vitro in cell culture systems and in vivo in animal models and humans.

Infliximab for the Treatment of Inflammatory Labyrinthitis: A Retrospective Cohort Study.

Inflammatory labyrinthitis is defined as a fluctuant vestibulo-cochlear syndrome associated with an impairment of the blood-labyrinthine barrier (BLB) on delayed FLAIR MRI sequences. Systemic and intratympanic corticosteroids are the gold standard treatment but their effect is frequently insufficient. The objective is here to determine whether infliximab could be of value in the treatment of bilateral inflammatory labyrinthitis. A retrospective monocentric study was conducted between January 2013 and December 2021. All patients included in the study were affected with a bilateral vestibulo-cochlear syndrome associated with bilateral blood-labyrinthine barrier impairment. Patients were administered infliximab at the dose of 5 mg/kg every 6 weeks for 6 months. Audiometry, MRI with delayed FLAIR sequences on the labyrinth, and corticosteroid doses still required were assessed both before and after treatment with infliximab was completed. Pure-tone average (PTA) was the primary outcome. The secondary outcomes were the speech recognition threshold (SRT), the Dizziness Handicap Inventory (DHI) score, and the corticosteroid (CS) dose. A total of nine patients including five men and four women were enrolled in the study. Thirteen ears were analyzed. After a 6-month period of treatment, the mean PTA (54 ± 24 db versus 66 ± 22 db; p = 0.027), SRT (54 ± 37 db versus 66 ± 32 db; p = 0.041) and DHI score (27 ± 15 versus 9 ± 2; p = 0.032) significantly improved. After the 6-month treatment period, the mean CS dose decreased from 38 ± 33 to 6 ± 5 mg/day (p = 0.003). We conclude that infliximab substantially improves the vestibulo-cochlear function in patients with bilateral inflammatory labyrinthitis and could be of value in corticosteroid-dependent cases.

Pachymeningitis associated with IgG4-related disease and ANCA positivity: Case report and review of the literature.

OBJECTIVE: Hypertrophic pachymeningitis is a rare clinical disorder involving localized or diffuse thickening of the dura mater. Considering pachymeningitis is both in the clinical spectrum of IgG4-RD and ANCA vasculitis (specifically granulomatosis with polyangiitis), an overlap syndrome is discussed. METHODS: We report a case of hypertrophic pachymeningitis revealed by headache and cranial nerve dysfunction, and coexistence of biopsy-proven IgG4-RD pachymeningitis and MPO-ANCA positivity. Furthermore, all cases previously reported in the literature of pachymeningitis with IgG4-RD and presence of ANCA were analyzed. RESULTS: Thirteen patients with pachymeningitis, IgG4-RD and ANCA were analyzed. Patients with HP-related IgG4 and ANCA are mainly male (8, 62%). Median age at diagnosis was 64 years. Main clinical manifestations at diagnosis were localized to the head and neck with headaches (10, 77%), cranial nerve dysfunction (7, 54%), hearing impairment (6, 46%) and vertigo (4, 31%). Except 1 patient with diffuse aortitis, no other systemic manifestation was observed at diagnosis and during follow-up. Serum IgG4 was often elevated (11, 85%) and ANCA was mainly with myeloperoxidase specificity (11, 85%). Seven patients had cerebrospinal fluid analyse with lymphocytic pleocytosis in 5 cases (71%), elevated proteins in 4 cases (57%), positive oligoclonal bands in 3 cases (42%) and decreased glucose in one case (14%). On the MRI, the thickening of the dura mater concerned most often the posterior fossa, in 7 cases (54%). Among 10 cases with histological findings, all showed increased IgG4-positivity of plasma cells, 50% lymphocytic infiltrate but none presented the three major histological criteria of IgG4-related disease. Three (30%) showed histological signs of vasculitis with vascular wall damage and/or giant cells. Among the 12 patients treated with steroid therapy, a clinical improvement was noted in 11 cases (92%). Relapse occurred during tapering in 4 patients (33%). An immunosuppressive drug was added in 2nd line for 7 cases (54%), with a clinical improvement in all. CONCLUSION: Pachymeningitis with IgG4 and ANCA seems a localized disease to the head and neck. Leptomeningeal biopsy commonly found IgG4 criteria and no vasculitis. All patients responded well to steroid therapy and immunosuppressive drugs, especially rituximab, with clinical and radiological improvement but relapse and/or sequelae are not uncommon.

18-Fluorodeoxyglucose positron emission tomography/computed tomography for large vessel vasculitis in clinical practice.

Diagnosis, prognostic assessment, and monitoring disease activity in patients with large vessel vasculitis (LVV) can be challenging. Early recognition of LVV and treatment adaptation is essential because vascular complications (aneurysm, dilatations, ischemic complications) or treatment related side effects can occur frequently in these patients. 18-fluorodeoxyglucose positron emission tomography/computed tomography (2-[18F]FDG-PET/CT) is increasingly used to diagnose, follow, and evaluate treatment response in LVV. In this review, we aimed to summarize the current evidence on the value of 2-[18F]FDG-PET/CT for diagnosis, follow, and treatment monitoring in LVV.

Pharmacokinetics and Clinical Implications of Two Non-Tablet Oral Formulations of L-Thyroxine in Patients with Hypothyroidism.

BACKGROUND: Increased knowledge of the pharmacokinetic characteristics of orally administered levothyroxine (L-T4) has improved individualization of dosing regimens. However, up to 40-45% of patients, depending on the leading cause of hypothyroidism, are still over- or, more often, undertreated. Unintentional non-adherence to L-T4 replacement therapy includes all situations of unintended drug-drug and drug-food interactions as well as fasting conditions that are not necessarily respected by patients. RESULTS: In this specific context, the overall information concerning those factors with the potential to affect L-T4 absorption refers only to tablet formulation. Indeed, this is the reason why new non-tablet formulations of L-T4 were introduced some years ago. In this regard, the current literature review was designed to summarize pharmacokinetic, drug and food interactions and clinical data focusing on two new oral L-T4 formulations, i.e., liquid and soft-gel capsule in healthy volunteers and patients with primary hypothyroidism. The non-tablet L-T4 soft-gel capsules and solution have proven bioequivalence with the usual L-T4 tablet Princeps and generic formulations. Clinical studies have suggested higher performance of non-tablet formulations than tablet in those patients with suboptimal adherence. The impact of gastrointestinal conditions and variation of gastric pH was lower with either soft gel/solution than with tablets. In addition, the extent of drug-drug and drug-food interactions remains low and of uncertain clinical relevance. CONCLUSIONS: Pending further studies allowing one to extend the use of soft-gel/solution preparations in unselected patients, non-tablet L-T4 formulations should be considered as a first-line choice, especially in those patients with moderate-to-high potential of suboptimal tablet performance.

White blood count, D-dimers, and ferritin levels as predictive factors of pulmonary embolism suspected upon admission in noncritically ill COVID-19 patients: The French multicenter CLOTVID retrospective study.

BACKGROUND: A high prevalence of pulmonary embolism (PE) has been described during COVID-19. Our aim was to identify predictive factors of PE in non-ICU hospitalized COVID-19 patients. METHODS: Data and outcomes were collected upon admission during a French multicenter retrospective study, including patients hospitalized for COVID-19, with a CT pulmonary angiography (CTPA) performed in the emergency department for suspected PE. Predictive factors significantly associated with PE were identified through a multivariate regression model. RESULTS: A total of 88 patients (median [IQR] age of 68 years [60-78]) were analyzed. Based on CTPA, 47 (53.4%) patients were diagnosed with PE, and 41 were not. D-dimer ≥3000 ng/mL (OR 8.2 [95% CI] 1.3-74.2, sensitivity (Se) 0.84, specificity (Sp) 0.78, P = .03), white blood count (WBC) ≥12.0 G/L (29.5 [2.3-1221.2], Se 0.47, Sp 0.92, P = .02), and ferritin ≥480 µg/L (17.0 [1.7-553.3], Se 0.96, Sp 0.44, P = .03) were independently associated with the PE diagnosis. The presence of the double criterion D-dimer ≥3000 ng/mL and WBC ≥12.0 G/L was greatly associated with PE (OR 21.4 [4.0-397.9], P = .004). CONCLUSION: The white blood count, the D-dimer and ferritin levels could be used as an indication for CTPA to confirm PE on admission in non-ICU COVID-19 patients.

No evidence of tocilizumab treatment efficacy for severe to critical SARS-CoV2 infected patients: Results from a retrospective controlled multicenter study.

ABSTRACT: To assess tocilizumab (TCZ) efficacy associated to standard of care (SOC) compared to SOC alone in severe coronavirus associated disease 2019 (COVID-19) patients. In a matched case-control study from 3 French Hospital COVID-19 Departments, 27 patients with severe COVID-19 treated with TCZ and SOC were matched for baseline epidemiological and clinical features and compared to 27 severe COVID-19 patients treated with SOC alone. Baseline characteristics of the study population were comparable between groups. Eleven patients (20%) died. TCZ was not associated with clinical improvement as compared to SOC regarding oxygen-free status (44% vs 63%) and death (18.5% vs 22%), despite a higher decrease of the C-reactive protein at Day 7 (10.7 vs 52 mg/L; P < 10-3). Compared to the 43 patients alive at the end-of follow-up, patients who died were older (78 vs 64 years; P < 10-3), with 82% of them older than 72 years vs only 23% of live patients (P < 10-3). Age (OR = 1.15; 95%CI = 1.04-1.3; P = .008) and age over 72 years (OR) = 14.85; 95%CI = 2.7-80; P = .002) were independently associated with mortality. TCZ in addition to SOC for severe COVID-19 patients did not reduce mortality, subsequent need for invasive mechanical ventilation nor did it shorten the time of oxygen support, despite better control of the inflammatory response. More powerful and randomized controlled trials are warranted to determine if TCZ is effective in the management of COVID-19.

D-Dimer Level and Neutrophils Count as Predictive and Prognostic Factors of Pulmonary Embolism in Severe Non-ICU COVID-19 Patients.

The incidence of pulmonary embolism (PE) is high during severe Coronavirus Disease 2019 (COVID-19). We aimed to identify predictive and prognostic factors of PE in non-ICU hospitalized COVID-19 patients. In the retrospective multicenter observational CLOTVID cohort, we enrolled patients with confirmed RT-PCR COVID-19 who were hospitalized in a medicine ward and also underwent a CT pulmonary angiography for a PE suspicion. Baseline data, laboratory biomarkers, treatments, and outcomes were collected. Predictive and prognostics factors of PE were identified by using logistic multivariate and by Cox regression models, respectively. A total of 174 patients were enrolled, among whom 86 (median [IQR] age of 66 years [55-77]) had post-admission PE suspicion, with 30/86 (34.9%) PE being confirmed. PE occurrence was independently associated with the lack of long-term anticoagulation or thromboprophylaxis (OR [95%CI], 72.3 [3.6-4384.8]) D-dimers ≥ 2000 ng/mL (26.3 [4.1-537.8]) and neutrophils ≥ 7.0 G/L (5.8 [1.4-29.5]). The presence of these two biomarkers was associated with a higher risk of PE (p = 0.0002) and death or ICU transfer (HR [95%CI], 12.9 [2.5-67.8], p < 0.01). In hospitalized non-ICU severe COVID-19 patients with clinical PE suspicion, the lack of anticoagulation, D-dimers ≥ 2000 ng/mL, neutrophils ≥ 7.0 G/L, and these two biomarkers combined might be useful predictive markers of PE and prognosis, respectively.

Clustering suicidal phenotypes and genetic associations with brain-derived neurotrophic factor in patients with substance use disorders.

Suicide attempts (SA), especially recurrent SA or serious SA, are common in substance use disorders (SUD). However, the genetic component of SA in SUD samples remains unclear. Brain-derived neurotrophic factor (BDNF) alleles and levels have been repeatedly involved in stress-related psychopathology. This investigation uses a within-cases study of BDNF and associated factors in three suicidal phenotypes ('any', 'recurrent', and 'serious') of outpatients seeking treatment for opiate and/or cocaine use disorder. Phenotypic characterization was ascertained using a semi-structured interview. After thorough quality control, 98 SNPs of BDNF and associated factors (the BDNF pathway) were extracted from whole-genome data, leaving 411 patients of Caucasian ancestry, who had reliable data regarding their SA history. Binary and multinomial regression with the three suicidal phenotypes were further performed to adjust for possible confounders, along with hierarchical clustering and compared to controls (N = 2504). Bayesian analyses were conducted to detect pleiotropy across the suicidal phenotypes. Among 154 (37%) ever suicide attempters, 104 (68%) reported at least one serious SA and 96 (57%) two SA or more. The median number of non-tobacco SUDs was three. The BDNF gene remained associated with lifetime SA in SNP-based (rs7934165, rs10835210) and gene-based tests within the clinical sample. rs10835210 clustered with serious SA. Bayesian analysis identified genetic correlation between 'any' and 'serious' SA regarding rs7934165. Despite limitations, 'serious' SA was shown to share both clinical and genetic risk factors of SA-not otherwise specified, suggesting a shared BDNF-related pathophysiology of SA in this population with multiple SUDs.

COVID-19 in Older Adults: A Series of 76 Patients Aged 85 Years and Older with COVID-19.

BACKGROUND: Clinical presentation and risk factors of death in COVID-19 in oldest adults have not been well characterized. OBJECTIVES: To describe clinical features and outcome of COVID-19 in patients older than 85 years and study risk factors for mortality. DESIGN: Prospective cohort. PARTICIPANTS AND SETTING: Patients aged 85 years and older, admitted in noncritical care units at the University Hospital Lariboisière Fernand-Widal (Paris, France) for confirmed severe acute respiratory syndrome coronavirus 2 infection were included and followed up for 21 days. MEASUREMENTS: Clinical and laboratory findings were collected. Cox survival analysis was performed to explore factors associated with death. RESULTS: From March 14 to April 11, 2020, 76 patients (median age = 90 (86-92) years; women = 55.3%) were admitted for confirmed COVID-19. Of the patients, 64.5% presented with three or more comorbidities. Most common symptoms were asthenia (76.3%), fever (75.0%) and confusion and delirium (71.1%). An initial fall was reported in 25.0% of cases, and digestive symptoms were reported in 22.4% of cases. COVID-19 was severe in 51.3% of cases, moderate in 32.9%, and mild in 15.8%. Complications included acute respiratory syndrome (28.9%), cardiac decompensation (14.5%), and hypotensive shock (9.0%). Fatality at 21 days was 28.9%, after a median course of disease of 13 (8-17) days. Males were overrepresented in nonsurvivors (68.2%). In survivors, median length of stay was 12 (9-19.5) days. Independent predictive factors of death were C-reactive protein level at admission and lymphocyte count at nadir. CONCLUSION: Specific clinical features, multiorgan injury, and high case fatality rate are observed in older adults with COVID-19. However, rapid diagnosis, appropriate care, and monitoring seem to improve prognosis.