Large-scale chemical-genetics yields new M. tuberculosis inhibitor classes.

New antibiotics are needed to combat rising levels of resistance, with new Mycobacterium tuberculosis (Mtb) drugs having the highest priority. However, conventional whole-cell and biochemical antibiotic screens have failed. Here we develop a strategy termed PROSPECT (primary screening of strains to prioritize expanded chemistry and targets), in which we screen compounds against pools of strains depleted of essential bacterial targets. We engineered strains that target 474 essential Mtb genes and screened pools of 100-150 strains against activity-enriched and unbiased compound libraries, probing more than 8.5 million chemical-genetic interactions. Primary screens identified over tenfold more hits than screening wild-type Mtb alone, with chemical-genetic interactions providing immediate, direct target insights. We identified over 40 compounds that target DNA gyrase, the cell wall, tryptophan, folate biosynthesis and RNA polymerase, as well as inhibitors that target EfpA. Chemical optimization yielded EfpA inhibitors with potent wild-type activity, thus demonstrating the ability of PROSPECT to yield inhibitors against targets that would have eluded conventional drug discovery.

Reduced risk of de novo Barrett esophagus after bariatric surgery: a national database study.

BACKGROUND: Bariatric surgery is an effective treatment for obesity and may decrease the morbidity and mortality of obesity-associated cancers. OBJECTIVE: We investigated the risk of a new diagnosis of Barrett esophagus (BE) following bariatric surgery compared to screening colonoscopy controls. SETTING: Large national database including patients who received care in inpatient, outpatient, and specialty care services. METHODS: A national healthcare database (TriNetX, LLC) was used for this analysis. Cases included adults (aged ≥18 yr) who had undergone either sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB). Controls included adults undergoing screening colonoscopy and an esophagoduodenoscopy on the same day and had never undergone bariatric surgery. Cases and controls were propensity-matched for confounders. The risk of de novo diagnosis of BE at least 1 year after bariatric surgery was compared between cases and controls. Secondary analyses examined the effect of bariatric surgery on metabolic outcomes such as weight loss and body mass index (BMI). The risk of de novo diagnosis of BE in SG was compared with RYGB. Odds ratios (OR) and 95% CI were used to report on these associations. RESULTS: In the propensity-matched analysis, patients who had undergone a bariatric surgical procedure showed a significantly reduced risk of de novo BE when compared with screening colonoscopy controls (.67 [.48, .94]). There was substantial reduction in weight and BMI in the bariatric surgery group when compared with baseline. There was no significant difference in de novo BE diagnosis between the propensity-matched SG and RYGB groups (.77 [.5, 1.2]). CONCLUSION: Patients who underwent bariatric surgery (RYGB or SG) had a lower risk of being diagnosed with BE compared with screening colonoscopy controls who did not receive bariatric surgery. This effect appears to be largely mediated by reduction in weight and BMI.

Association between chiropractic spinal manipulative therapy and benzodiazepine prescription in patients with radicular low back pain: a retrospective cohort study using real-world data from the USA.

OBJECTIVES: Although chiropractic spinal manipulative therapy (CSMT) and prescription benzodiazepines are common treatments for radicular low back pain (rLBP), no research has examined the relationship between these interventions. We hypothesise that utilisation of CSMT for newly diagnosed rLBP is associated with reduced odds of benzodiazepine prescription through 12 months' follow-up. DESIGN: Retrospective cohort study. SETTING: National, multicentre 73-million-patient electronic health records-based network (TriNetX) in the USA, queried on 30 July 2021, yielding data from 2003 to the date of query. PARTICIPANTS: Adults aged 18-49 with an index diagnosis of rLBP were included. Serious aetiologies of low back pain, structural deformities, alternative neurological lesions and absolute benzodiazepine contraindications were excluded. Patients were assigned to cohorts according to CSMT receipt or absence. Propensity score matching was used to control for covariates that could influence the likelihood of benzodiazepine utilisation. OUTCOME MEASURES: The number, percentage and OR of patients receiving a benzodiazepine prescription over 3, 6 and 12 months' follow-up prematching and postmatching. RESULTS: After matching, there were 9206 patients (mean (SD) age, 37.6 (8.3) years, 54% male) per cohort. Odds of receiving a benzodiazepine prescription were significantly lower in the CSMT cohort over all follow-up windows prematching and postmatching (p<0.0001). After matching, the OR (95% CI) of benzodiazepine prescription at 3 months was 0.56 (0.50 to 0.64), at 6 months 0.61 (0.55 to 0.68) and 12 months 0.67 (0.62 to 0.74). Sensitivity analysis suggested a patient preference to avoid prescription medications did not explain the study findings. CONCLUSIONS: These findings suggest that receiving CSMT for newly diagnosed rLBP is associated with reduced odds of receiving a benzodiazepine prescription during follow-up. These results provide real-world evidence of practice guideline-concordance among patients entering this care pathway. Benzodiazepine prescription for rLBP should be further examined in a randomised trial including patients receiving chiropractic or usual medical care, to reduce residual confounding.