Increased incidence of QT interval prolongation in a population receiving lower doses of methadone maintenance therapy.

Aims:  The aim of the study was to investigate the frequency of corrected QT interval (QTc) prolongation in a methadone maintenance therapy (MMT) population, and to examine potential associations between this QTс interval and methadone dose as well as concurrent use of opiates, cocaine, and benzodiazepines. Design:  Cross-sectional study of patients attending a specialist drug treatment clinic from July 2008 to January 2009. Setting:  Single centre inner city specialist drug treatment clinic Ireland. Participants:  180 patients on stable MMT attending for daily methadone doses, over a six month period, where a total of 376 patients were attending during the study period. Measurements:  All patients agreeing to participate in the study underwent 12-lead electrocardiograms and QTc analysis, as well as analysis of urine toxicology screen results for opiates, benzodiazepines, and cocaine. ECGs were carried out prior to methadone dose being received, regardless of time of day (trough ECG). Findings:  The average age was 32.6 ± 7.1 years, with mean (SD) methadone dose 80.4 ± 27.5mg. The mean (SD) QTc was 420.9 ± 21.1 ms, range 368-495 ms. Patients who had a positive toxicology screen for opiates were receiving significantly lower doses of methadone (77.8 ± 23.5 mg versus 85.0 ± 21.4 mg, p = 0.04). No significant association was noted between QTc-interval prolongation and presence of cocaine metabolites in the urine (p = 0.14) or methadone dose (p = 0.33). 8.8% of patients had evidence of prolonged QTc interval (8.3% male QTc ≥ 450ms and 0.5% female QTc ≥ 470 ms), with 11.1% (n = 20) having QTc intervals > 450ms. Conclusions:  Drug-induced QTc interval prolongation is evident (ranging from 8.8-11.1%, depending on definition applied) in patients receiving relatively low daily doses of methadone therapy, with no evidence of a dose-response relationships. The presence of cocaine metabolites in urine does not appear to be associated with increased QTc-interval. Increased awareness of cardiac safety guidelines, including relevant clinical and family history, baseline, and trough dose ECG monitoring, should be incorporated into methadone maintenance therapy protocols

A rare case of fournier’s gangrene

We report a rare case that highlights acute pancreatitis as the protagonist of Fournier's Gangrene. This patient was treated with a radical debridement of his perineum at presentation and subsequently reconstructed with split thickness skin grafting. This is an unusual aetiology of necrotizing fasciitis with only one other case reported in the literature. This serves to emphasize to physicians that acute pancreatitis is a potential source when investigating and treating patients with Fournier's Gangrene

A rare case of fournier’s gangrene

We report a rare case that highlights acute pancreatitis as the protagonist of Fournier\u27s Gangrene. This patient was treated with a radical debridement of his perineum at presentation and subsequently reconstructed with split thickness skin grafting. This is an unusual aetiology of necrotizing fasciitis with only one other case reported in the literature. This serves to emphasize to physicians that acute pancreatitis is a potential source when investigating and treating patients with Fournier\u27s Gangrene

A Circulating MicroRNA Signature as a Biomarker for Prostate Cancer in a High Risk Group

Introduction: Mi(cro)RNAs are small non-coding RNAs whose differential expression in tissue has been implicated in the development and progression of many malignancies, including prostate cancer. The discovery of miRNAs in the blood of patients with a variety of malignancies makes them an ideal, novel biomarker for prostate cancer diagnosis. The aim of this study was to identify a unique expression profile of circulating miRNAs in patients with prostate cancer attending a rapid access prostate assessment clinic. Methods: To conduct this study blood and tissue samples were collected from 102 patients (75 with biopsy confirmed cancer and 27 benign samples) following ethical approval and informed consent. These patients were attending a prostate assessment clinic. Samples were reverse-transcribed using stem-loop primers and expression levels of each of 12 candidate miRNAs were determined using real-time quantitative polymerase chain reaction. miRNA expression levels were then correlated with clinicopathological data and subsequently analysed using qBasePlus software and Minitab. Results: Circulating miRNAs were detected and quantified in all subjects. The analysis of miRNA mean expression levels revealed that four miRNAs were significantly dysregulated, including let-7a (p = 0.005) which has known tumour suppressor characteristics, along with miR-141 (p = 0.01) which has oncogenic characteristics. In 20 patients undergoing a radical retropubic-prostatectomy, the expression levels of miR-141 returned to normal at day 10 post-operatively. A panel of four miRNAs could be used in combination to detect prostate cancer with an area under the curve (AUC) of 0.783 and a PPV of 80%. Conclusion: These findings identify a unique expression profile of miRNA detectable in the blood of prostate cancer patients. This confirms their use as a novel, diagnostic biomarker for prostate cancer

Stratified analyses refine association between TLR7 rare variants and severe COVID-19

Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (<60 years) cases with no reported clinical risk factors (n = 378), compared to 0.24% of controls (odds ratio [OR] = 12.3, p = 1.27 × 10−10). Incorporation of the results of either functional assays or protein modeling led to a pronounced increase in effect size (ORmax = 46.5, p = 1.74 × 10−15). Association signals for the X-chromosomal gene TLR7 were also detected in the female-only subgroup, suggesting the existence of additional mechanisms beyond X-linked recessive inheritance in males. Additionally, supporting evidence was generated for a contribution to severe COVID-19 of the previously implicated genes IFNAR2, IFIH1, and TBK1. Our results refine the genetic contribution of rare TLR7 variants to severe COVID-19 and strengthen evidence for the etiological relevance of genes in the interferon signaling pathway