A Transcriptomic Biomarker Predicting Linezolid-Associated Neuropathy During Treatment of Drug-Resistant Tuberculosis

Background: Neuropathic adverse events occur frequently in linezolid-containing regimens, some of which remain irreversible after drug discontinuation. Objective: We aimed to identify and validate a host RNA-based biomarker that can predict linezolid-associated neuropathy before multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment initiation and to identify genes and pathways that are associated with linezolid-associated neuropathy. Methods: Adult patients initiating MDR/RR-TB treatment including linezolid were prospectively enrolled in 3 independent cohorts in Germany. Clinical data and whole blood RNA for transcriptomic analysis were collected. The primary outcome was linezolid-associated optic and/or peripheral neuropathy. A random forest algorithm was used for biomarker identification. The biomarker was validated in an additional fourth cohort of patients with MDR/RR-TB from Romania. Results: A total of 52 patients from the 3 identification cohorts received linezolid treatment. Of those, 24 (46.2%) developed peripheral and/or optic neuropathies during linezolid treatment. The majority (59.3%) of the episodes were of moderate (grade 2) severity. In total, the expression of 1,479 genes differed significantly at baseline of treatment. Suprabasin (SBSN) was identified as a potential biomarker to predict linezolid-associated neuropathy. In the validation cohort, 10 of 42 (23.8%) patients developed grade ≥3 neuropathies. The area under the curve for the biomarker algorithm prediction of grade ≥3 neuropathies was 0.63 (poor; 95% confidence interval: 0.42 – 0.84). Conclusions: We identified and preliminarily validated a potential clinical biomarker to predict linezolid-associated neuropathies before the initiation of MDR/RR-TB therapy. Larger studies of the SBSN biomarker in more diverse populations are warranted

Latent Tuberculosis Infection among Health Workers in Germany—A Retrospective Study on Progression Risk and Use of Preventive Therapy

Despite the decline in tuberculosis incidence (TB) in Germany, health workers (HW) are at greater risk of becoming infected with Mycobacterium tuberculosis. To date, little is known about the risk of progression of latent tuberculosis infections (LTBI) and the use of Tuberculosis Preventive Therapy (TPT) among HW. Routine data from the German Statutory Institution for Accident Insurance and Prevention for Health and Welfare Services (BGW) were analysed and a retrospective survey was conducted. A self-administered questionnaire was sent to 1711 HW who had received recognition of an LTBI as an occupational disease between the years 2009 and 2018. The response rate was 42.3% after correcting for those with no actual address (20.4%). We included 575 HW in the data analysis of the retrospective survey. The cumulative incidence of progression, the incidence density and the associated 95% confidence interval (95% CI) were calculated. Three progressive cases were identified in the analysis of the routine data. In the survey cohort, three HW developed TB during the observation period of 5.4 years on average (standard deviation: 2.8 years; interquartile range: 5.0 years). The cumulative TB incidence was 0.52% in the survey group (95% CI: 0.14% to 1.65%). The incidence density was 0.97 cases per 1000 person years (95% CI: 0.25 to 3.10). One-third of the respondents underwent TPT. Significant differences were observed between age and activity groups in the use of TPT, but not between the genders, year of diagnosis or the reason for performing the screening. The data indicate that the risk of progression of an LTBI is low for HW. However, one-third of the HW had undergone TPT. Information about the expected progression risk is important so that it can be weighed against the risk of side effects of TPT

Prevalence of Adverse Skin Reactions in Nursing Staff Due to Personal Protective Equipment during the COVID-19 Pandemic

In order to prevent the nosocomial transmission of the SARS-CoV-2 virus, it has become necessary for health workers to increase their use of personal protective equipment (PPE). The aim of the study was to investigate the prevalence and influencing factors for adverse skin reactions (ASR) due to occupational PPE use among nursing staff in Germany during the COVID-19 pandemic. The study uses a mixed methods design. A focus group was created with experts from the field of healthcare, and an online survey was then carried out among nursing staff. Influencing factors were identified using multivariate logistic regression via odds ratios (ORs) with 95% confidence intervals (CIs). A total of 2274 nursing staff took part in the survey, with 1967 included in the analysis. The prevalence of ASR was 61%, with 94% affecting at least one area of the face. Statistically significant factors of influence were Filtering Face Peace (FFP) mask wearing duration of ≥4 h, a history of contact allergies, and being female and young. A pre-existing skin disease had a protective effect. The prevalence of PPE-related ASR underlines the necessity for targeted preventive measures for nursing staff during pandemic situation

Brain Insulin Lowers Circulating BCAA Levels by Inducing Hepatic BCAA Catabolism

SummaryCirculating branched-chain amino acid (BCAA) levels are elevated in obesity/diabetes and are a sensitive predictor for type 2 diabetes. Here we show in rats that insulin dose-dependently lowers plasma BCAA levels through induction of hepatic protein expression and activity of branched-chain α-keto acid dehydrogenase (BCKDH), the rate-limiting enzyme in the BCAA degradation pathway. Selective induction of hypothalamic insulin signaling in rats and genetic modulation of brain insulin receptors in mice demonstrate that brain insulin signaling is a major regulator of BCAA metabolism by inducing hepatic BCKDH. Short-term overfeeding impairs the ability of brain insulin to lower BCAAs in rats. High-fat feeding in nonhuman primates and obesity and/or diabetes in humans is associated with reduced BCKDH protein in liver. These findings support the concept that decreased hepatic BCKDH is a major cause of increased plasma BCAAs and that hypothalamic insulin resistance may account for impaired BCAA metabolism in obesity and diabetes