Tuberculosis treatment has undergone its most profound transformation since the launch of the standardised DOTS strategy in 1994. Since 2020, a series of pivotal randomised trials, including TB-PRACTECAL, ZeNix, Nix-TB, endTB, BEAT-TB, SHINE, and Study 31/A5349, have redefined the management of both drug-susceptible and drug-resistant tuberculosis. These studies have enabled shorter, fully oral regimens with improved efficacy and safety across adult and paediatric populations, including people with HIV, and have driven major updates to WHO treatment guidelines. Despite these advances, tuberculosis remains the leading cause of death from a single infectious agent worldwide, with substantial mortality occurring before treatment initiation due to delayed diagnosis and pretreatment loss to follow-up, and additional deaths during treatment related to advanced disease, drug resistance, comorbidities, and challenges with treatment tolerance and adherence. In 2024, an estimated 10·7 million people developed tuberculosis of whom approximately 390 000 developed multidrug-resistant (MDR) or rifampicin-resistant (RR) tuberculosis. Tuberculosis caused an estimated 1·23 million deaths globally, including approximately 150 000 deaths attributable to MDR tuberculosis or RR tuberculosis. Outcomes remain poorest among people with HIV, young children (who rarely access treatment and prevention), migrants, and displaced populations. The tuberculosis drug development pipeline in 2026 is more advanced than at any time since the introduction of rifampicin. Novel and repurposed compounds, including DprE1 inhibitors, next-generation oxazolidinones (including TBAJ-587 and TBAJ-876), cytochrome bc1 inhibitors, and long-acting formulations, are in late-stage evaluation. Host-directed therapies are also advancing as adjunctive strategies to reduce inflammation-mediated tissue damage and long-term morbidity, although they remain investigational. This Series paper synthesises advances in adult and paediatric tuberculosis therapeutics from Nov 15, 2020, to Jan 15, 2026, and highlights priorities to translate therapeutic innovation into equitable population-level effects.
Tetralogy of Fallot (TOF) patients are at risk for long-term adverse events. Electrocardiogram (ECG) abnormalities may reflect ventricular maladaptation and predict complications. We investigated whether ECG changes correlated with cardiac magnetic resonance imaging (CMR) measures of right ventricular (RV) function and their prevalence in less mature myocardium (prematurity or early repair). This retrospective study included 219 TOF patients operated between 2000-01-01 and 2018-12-31. Parameters analyzed included PQ interval, QRS duration, dispersion, fragmentation, QTc, JTc, and right bundle branch block (RBBB) at predefined time points. In patients undergoing pulmonary valve replacement (PVR) with available CMR, measures of RV size and function were compared with ECG variables. Early repair was defined as < 3 months and prematurity < 37 weeks’ gestation. Median age at follow-up was 12.3 years (IQR, 8.4;17), and 4.9 months (IQR, 3.4;6.9) at primary repair. PQ interval correlated with RV end-diastolic, stroke and regurgitant volume, whereas RBBB correlated with larger RV. Forty-five patients (21
Understanding the mechanism of action (MoA) of bioactive compounds is a central challenge in drug discovery and chemical biology. We propose a strategy for integrating morphological data with proteomics to provide deeper insights into the MoA of compounds. We combine the rich phenotypic profiles of Cell Painting (CP) with the unbiased protein target detection of Thermal Proteome Profiling (TPP), and construct protein-protein interaction networks based on potential targets identified using both assays. We validated our method with public TPP datasets for the five compounds (+)-JQ1, I-BET151, Vemurafenib, Crizotinib and Panobinostat, and public Proteome Integral Solubility Alteration (PISA) data for 49 compounds, together with CP data for 5259 drugs on U2OS cells. We show that the combined approach could accurately identify known MoAs for four out of five validation compounds and known targets for 29 out of 49 compounds. Finally, we deployed our method to characterize sinomenine, a compound with elusive knowledge of MoA. Our findings revealed novel facets of sinomenine's biological activity and highlight the value of multimodal profiling for chemical biology.
Despite improvement in treatment, rheumatoid arthritis (RA) management remains inconsistent. To evaluate the worldwide disparities in the use of biological and targeted molecules (advanced) RA therapies, focusing on differences across continents and socioeconomic strata, and to identify factors associated with their utilisation. Cross-sectional analysis of the international COVAD-2 cohort, including demographics, socioeconomic factors, disease characteristics, patient-reported outcomes, and treatments. Primary outcomes assessed treatment distribution by continent, secondary outcomes evaluated distribution by Human Development Index (HDI), with predictors analysed using multivariable logistic regression. At the time of analysis, COVAD2 included 10,739 participants; 2007 had RA, 1997 with geographical data included in this study (mean age 50.9 years, 88.1
Fibroblast activation protein (FAP)–targeted PET using [⁶⁸Ga]Ga-FAPI-46 visualizes fibroblasts abundant in pancreatic cancer (PC) but also present in pancreatitis, complicating interpretation of static images. Dynamic imaging and kinetic modeling may provide additional insight, but their diagnostic value remains unclear. This study evaluated whether kinetic parameters from dynamic [⁶⁸Ga]Ga-FAPI-46 PET can differentiate PC from pancreatitis and their relationship with standardized uptake value (SUV) and tumor-to-blood ratio (TBR). Sixty-one patients with suspected pancreaticobiliary cancer underwent a 45-min dynamic [⁶⁸Ga]Ga-FAPI-46 PET scan, followed by static scans at 60 and 180 min. Time–activity curves were generated for 51 malignant and 53 benign lesions. Compartment models and Logan analysis yielded kinetic parameters (K1, k2, k3, k4, VT, VNS, VS). SUV and TBR were correlated with VT, and group comparisons and ROC analyses assessed discriminatory performance. Reversible models best described the tracer kinetics. VT and VS were significantly higher in PC than pancreatitis, and k2 and k4 were lower, indicating higher [⁶⁸Ga]Ga-FAPI-46 binding respectively slower washout in malignant lesions. SUV correlated strongly with VT (r ≥ 0.784), and TBR showed very strong correlations (r ≥ 0.902) for the 0–60 min interval, with strong correlations observed across all models and time points. ROC analyses demonstrated comparable differentiation between VT, SUVmax, and TBRmax. Kinetic parameters showed strong correlations with simplified methods and similar ability to differentiate PC from pancreatitis. SUV and TBR measures thus represent practical alternatives to kinetic modelling for lesion characterization. ClinicalTrials.gov ID: NCT05172310
