Systematic literature review of treatments used for refractory or unexplained chronic cough in adults.

BACKGROUND: Refractory or unexplained chronic cough (RCC or UCC) is difficult to manage and is usually treated by the off-label use of drugs approved for other indications. OBJECTIVE: The objectives of this systematic literature review (SLR) were to identify and characterize the current published body of evidence for the efficacy and safety of treatments for RCC or UCC. METHODS: The SLR was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The SLRs pre-defined population included patients ≥18 years of age who were diagnosed with chronic cough. The review was not restricted to any intervention type or study comparator, nor by timeframe. RESULTS: A total of 20 eligible publications from 19 unique trials were included. Seventeen of these trials were randomized controlled trials and most (14/17) were placebo-controlled. There was considerable variability between trials in the definition of RCC or UCC, participant exclusion and inclusion criteria, outcome measurement timepoints, and the safety and efficacy outcomes assessed. Several trials identified significant improvements in cough frequency, severity, or health-related quality of life measures while participants were on treatment, although these improvements did not persist in any of the studies that included a post-treatment follow-up timepoint. CONCLUSIONS: In the absence of an approved therapy, placebo remains the most common comparator in trials of potential RCC or UCC treatments. The between-study comparability of the published evidence is limited by heterogeneity of study design, study populations, and outcomes measures, as well as by concerns regarding study size and risk of bias.

Indirect treatment comparison of lurbinectedin versus other second-line treatments for small-cell lung cancer.

Aim: Compare lurbinectedin versus other second-line (2L) small-cell lung cancer (SCLC) treatments. Methods: An unanchored matching-adjusted indirect comparison connected the platinum-sensitive SCLC cohort of a single-arm lurbinectedin trial to a network of three randomized controlled trials (oral and intravenous [IV] topotecan, and platinum re-challenge) identified by systematic literature review. Network meta-analysis methods estimated relative treatment effects. Results: In platinum-sensitive patients, lurbinectedin demonstrated a survival benefit and favorable safety profile versus oral and IV topotecan and platinum re-challenge (overall survival, hazard ratio [HR]: 0.43; 95% credible interval [CrI]: 0.27, 0.67; HR: 0.43; 95% CrI: 0.26, 0.70; HR: 0.42; 95% CrI: 0.30, 0.58 respectively). Conclusion: Lurbinectedin showed a robust survival benefit and favorable safety versus other SCLC treatments in 2L platinum-sensitive SCLC.

CERT1 mutations perturb human development by disrupting sphingolipid homeostasis.

Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome.