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Based on results from preclinical and clinical studies, a five-drug combination of isoniazid, rifapentine, pyrazinamide, ethambutol, and clofazimine was identified with treatment shortening potential for drug-susceptible tuberculosis; the Clo-Fast trial aimed to determine the efficacy and safety of this regimen. We compared 3 months of isoniazid, rifapentine, pyrazinamide, ethambutol, and clofazimine, administered with a clofazimine loading dose, to the standard 6 month regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol in drug-susceptible tuberculosis. Clo-Fast was a phase 2c open-label trial recruiting participants at six sites in five countries. Participants aged 18 years or older with pulmonary tuberculosis who were sputum smear positive for acid-fast bacilli or molecular tuberculosis assay positive (with Mycobacterium tuberculosis with sensitivity to rifampicin and isoniazid) were eligible for enrolment. Individuals with HIV infection with a CD4+ cell count ≥100 cells per mm3 could participate. Participants were randomly assigned in a 2:1 ratio (group 1: group 2) or a 2:1:1 ratio (group 1: group 2: group 3), depending on consent to participate in the intensive pharmacokinetic visits required in group 3, using a central web-based system with permuted blocks. The group 1 regimen included 8 weeks of rifapentine–isoniazid–pyrazinamide–ethambutol–clofazimine, with a 2-week 300 mg clofazimine loading dose, followed by 5 weeks of rifapentine–isoniazid–pyrazinamide–clofazimine (13 weeks total). The group 2 control regimen included 8 weeks of isoniazid–rifampicin–pyrazinamide–ethambutol followed by 18 weeks of rifampicin–isoniazid. Group 3 was identical to group 1 over the first 4 weeks of treatment, except that the regimen was administered without a clofazimine loading dose (100 mg daily); after 4 weeks of group 3 treatment, participants transitioned to local standard of care to complete treatment. Group 3 was designed to assess the effect of a 2-week loading dose on clofazimine pharmacokinetics. Randomisation was stratified by HIV status and advanced disease on chest radiograph. The primary efficacy endpoint was time to sputum culture-negative status by 12 weeks. The primary safety endpoint was the proportion of participants experiencing any grade 3 or worse adverse event over 65 weeks. The key secondary endpoint was unfavourable clinical or bacteriological outcomes by week 65. The efficacy analysis population contained participants assigned to groups 1 and 2 who were not late exclusions (no positive culture at screening, entry, or week 1, or if rifampicin resistance or isoniazid resistance was detected at screening or entry); the safety analysis population contained all randomly assigned participants who took at least one dose of treatment. The trial was registered with ClinicalTrials.gov ID: NCT04311502. 104 participants were randomly assigned to group 1 (n=58), group 2 (n=31), and group 3 (n=15). 82 (79%) were male and 74 (71%) had radiographically advanced disease; 30 (29%) were people with HIV. The trial was stopped early for lack of clinical efficacy. For the primary efficacy outcome, 49 (89%) of 55 group 1 participants and 28 (90%) of 31 group 2 participants had stable sputum culture conversion by week 12 (adjusted hazard ratio 1·21 [90% CI 0·82–1·79]; p=0·2089). Adverse events grade 3 or worse occurred in 26 (45%) of 58 group 1 participants and five (16%) of 31 group 2 participants (difference 30%, 90% CI 14–45; p=0·002). The cumulative probability of a week 65 unfavourable outcome was 52% (95% CI 37–69) in group 1 versus 27% (14–50) in group 2 (p=0·049). Although the trial was stopped early, we found that a 3-month regimen containing clofazimine and rifapentine had 12-week culture conversion rates that did not differ statistically from the standard of care. The regimen was associated with an unacceptably high proportion of participants with unfavourable composite clinical outcomes and grade 3 or worse adverse events. US National Institutes of Health Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG) and the National Institute of Allergy and Infectious Diseases.

Riociguat, a soluble guanylate cyclase stimulator, is approved for treatment of adults with pulmonary arterial hypertension (PAH). The safety, tolerability, and pharmacokinetics (PK) of oral riociguat in a pediatric population with PAH was assessed in PATENT–CHILD (NCT02562235), a multicenter, single‐arm, 24‐week, open‐label, Phase 3 study. Patients aged 6–17 years in World Health Organization functional class (WHO‐FC) I–III treated with stable endothelin receptor antagonists and/or prostacyclin analogs received riociguat equivalent to 0.5–2.5 mg three times daily in adults, as either oral pediatric suspension or tablets, based on bodyweight. Primary outcomes were safety, tolerability, and PK of riociguat. Twenty‐four patients (mean age 12.8 years), 18 of whom were in WHO‐FC II, were enrolled. Adverse events (AEs), mostly mild or moderate, were reported in 20 patients (83%). Four patients (17%) experienced a serious AE; all resolved by study end and two (8%) were considered study‐drug related. Hypotension was reported in three patients and hemoptysis in one (all mild/moderate intensity). Riociguat plasma concentrations in pediatric patients were consistent with those published in adult patients. From baseline to Week 24, mean ± standard deviation increase in 6‐minute walking distance was 23 ± 69 m (n = 19), and mean decrease in NT‐proBNP was –66 ± 585 pg/ml (n = 14). There was no change in WHO‐FC. Two patients experienced clinical worsening events of hospitalization for right heart failure. PK results confirmed a suitable riociguat dosing strategy for pediatric patients with PAH. The data suggest an acceptable safety profile with potential efficacy signals.

Background The standard of care (SOC) treatment for drug-susceptible pulmonary tuberculosis (DS-TB) consists of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE). New treatment regimen options for DS-TB are needed as HRZE is long in duration (6 months), associated with frequent adverse events, unforgiving of adherence lapses, and complicated by rifamycin-based drug-drug interactions. The recent resurgence of TB drug development, particularly in the context of drug-resistant TB, offers promise for additional regimens for persons with DS-TB, provided they are sufficiently effective and well-tolerated. We spotlight wave 1 of the RAD-TB platform trial (ACTG A5409, NCT06192160) that will investigate new chemical entities for the treatment of DS-TB. Methods In wave 1 of the RAD-TB platform, adult participants initiating treatment for DS-TB will be randomized to SOC (HRZE, Arm 1) or one of five experimental arms for the 8-week intensive phase. The experimental treatment arms will consist of a bedaquiline and pretomanid backbone (BPa) in combination with one of three oxazolidinones. Arm 2 will study linezolid (BPaL) at a dose of 600 mg daily, Arms 3A and 3B will study TBI-223 at 1200 mg and 2400 mg daily, respectively, and Arms 4A and 4B will study sutezolid at 800 mg and 1600 mg daily, respectively. The primary efficacy objective is to compare sputum culture time to positivity (TTP) slope over the first 6 weeks of treatment for each experimental treatment arm to SOC. The primary safety objective is to compare new Grade 3 or higher adverse events over the first 8 weeks of treatment for each experimental treatment arm to SOC. After the intensive phase, all participants will receive the standard isoniazid and rifampicin (HR) continuation phase for 18 weeks. Participants will be followed for 52 weeks after TB treatment initiation to assess long-term outcomes. Discussion Wave 1 of the RAD-TB platform aims to identify the optimal oxazolidinone(s), with regard to both efficacy and safety, to combine with the BPa backbone for the treatment of DS-TB. Subsequent waves of this platform trial may add a fourth drug to the regimen, study new diarylquinolines to substitute for bedaquiline, or study novel agents from other TB drug classes. Trials registration ClinicalTrials.gov NCT06192160 . Registered on January 5, 2024.

Ion mobility–mass spectrometry (IM-MS) is a powerful tool for the simultaneous analysis of mass, charge, size, and shape of ionic species. It allows the characterization of even low-abundant species in complex samples and is therefore particularly suitable for the analysis of proteins and their assemblies. In the last few years even complex and intractable species have been investigated successfully with IM-MS and the number of publications in this field is steadily growing. This trend article highlights recent advances in which IM-MS was used to study protein–ligand complexes and in particular focuses on the catch and release (CaR) strategy and collision-induced unfolding (CIU). Graphical Abstract Native mass spectrometry and ion mobility-mass spectrometry are versatile tools to follow the stoichiometry, energetics, and structural impact of protein-ligand binding.

The psychological integration of body-related attitudes (BodyRA) is a critical developmental task in adolescence. Adolescents must adapt to their changing body image and body satisfaction. For young people, BodyRA (body dissatisfaction, bulimia, and drive for thinness) are connected to insecurities, which can disturb identity integration and personality development. Our goal was to evaluate the importance of BodyRA also for other mental disorders other than anorexia nervosa (AN), and the association between BodyRA with temperament and personality traits and identity diffusion. Data for the period of 2012 to 2019 were retrospectively analyzed from a convenience sample of patients in a child and adolescent psychiatric hospital (n = 114). The patients were 13 to 17 years of age and had a BMI of 11.9–36.1 kg/m2. As expected, BodyRA were found to be more pronounced in AN, as well as in borderline personality disorder (BPD), depression (DD), and attention deficit hyperactivity disorder (ADHD). BodyRA correlated significantly with internalizing problems in patients with DD (r = 0.428–0.565, p < 0.01) and BPD (r = 0.680, p < 0.01) as well as with BMI (r = 0.404, p < 0.01) in patients with DD. Moreover, we detected significant correlations with impaired identity development in patients with DD (r = 0.482–0.565, p < 0.01) and BPD (r = 0.681–0.703, p < 0.01). BodyRA also correlated significantly with the personality traits of harm avoidance (r = 0.377–0.541, p < 0.01) and self-directedness (r = −0.537–−0.635, p < 0.01) in DD. These personality traits and bulimia were used as predictors for identity diffusion in the investigated disorders of this study. We conclude that BodyRA, harm avoidance and self-directedness are associated with identity development in adolescent females with mental disorders.

Background:Obesity in adolescents with intellectual and developmental disabilities) occurs at twice the frequency as their typically developing peers. Typically developing adolescents with obesity have abnormal cardiac function (as measured by strain echocardiography) and cardiac mass, but the effects of obesity on cardiac health in adolescents with Down syndrome or autism spectrum disorder are unknown. The purpose of this study was to evaluate the impact of body mass index on cardiac function in adolescents with Down syndrome or autism.Methods:Adolescents (age 12–21 years) with Down syndrome (n = 28), autism (n = 33), and age-/sex-matched typically developing controls (n = 15) received an echocardiogram optimised for strain analysis at a single timepoint. Measures of ventricular function, mass, and size were collected. Regression modelling evaluated the impact of body mass index and intellectual and developmental disabilities diagnosis on these cardiac measures.Results:In regression modelling, an elevated body mass index z-score was associated with diminished systolic biventricular function by global strain (left ventricular longitudinal strain β 0.87, P < 0.001; left ventricular circumferential strain β 0.57, p 0.003; right ventricular longitudinal strain β 0.63, P < 0.001). Diminished left ventricular diastolic function by early diastolic strain rate was also associated with elevated body mass index (global longitudinal end-diastolic strain rate β −0.7, P < 0.001). No association was found between traditional (non-strain) measures of systolic and diastolic ventricular function and body mass index z-score.Conclusions:Obesity in adolescents with Down syndrome or autism negatively impacts cardiac function as measured by echocardiographic strain analysis that was not detected by traditional parameters.