Recent evidence suggests that community-wide active case finding (ACF) can reduce tuberculosis (TB) incidence and prevalence. Mass-screening at the community level, supported by mobile digital chest X-ray units, is now being scaled up by programmes across high burden countries. However, there is limited evidence of case-detection yields from programmes conducting ACF at scale in low-resource settings. We retrospectively analysed aggregate data from mobile X-ray screening events (called ‘camps’) in Pakistan from Q3 2017 to Q2 2021. A total of 11 327 camps were conducted that screened 1 214 289 individuals and detected 7625 cases of All-Forms TB (AF–TB), among whom 3500 (45.9%) were bacteriologically confirmed (B+) and the remaining were treated empirically. The yield for B+ and AF-TB per 100 000 population screened nationally was 289 (95% CI: 279 to 298) and 631 (95% CI: 617 to 646), respectively. Yield of TB detected from screening was highly variable between regions of Pakistan, ranging from 70 to 678 per 100 000 B+ and 76 to 1136 per 100 000 for AF–TB. Our findings have two major lessons for TB programmes. First, there was significant geographical variation in yields of both B+ and AF-TB, supporting targeting of interventions in areas of high prevalence to maximise the intervention’s effectiveness. Second, more than half of TB cases were treated empirically, and approaches to improve sample collection, linkage to diagnostics, non-sputum based tests and standardisation of treatment for bacteriologically unconfirmed TB need to be concurrently prioritised by programmes considering scale-up of mobile X-ray-based ACF.

Abstract Background: Lineage plasticity enables prostate cancer cells to bypass androgen receptor (AR) dependence, contributing to metastasis, treatment resistance, and lethality. The developmental transcription factor PROX1 was recently identified as an early driver of lineage plasticity. The TMPRSS2-ERG fusion, a common genomic event in prostate cancer, induces ERG overexpression and aggressive tumor behavior. We investigated the relationship between PROX1 expression and ERG expression in the context of TMPRSS2-ERG fusion in prostate cancer. Methods: We analyzed data from The Cancer Genome Atlas (TCGA) Prostate Adenocarcinoma (PRAD) dataset (n = 492 samples). The UCSC Xena Browser was used to visualize and integrate gene expression, copy number alterations, and fusion status. Complementary analyses were performed using cBioPortal. Genomic instability was assessed using both fraction of the genome altered (FGA) and mutation count. The correlation between PROX1 and ERG expression was evaluated in fusion-positive and fusion-negative tumors. Results: PROX1 expression showed a strong positive correlation with ERG expression in TMPRSS2-ERG fusion-positive tumors (r = 0.4, p = 3.2 X 10⁻¹⁶). Fusion-positive samples exhibited elevated PROX1 expression, whereas fusion-negative samples had lower expression. This pattern suggests that PROX1 induction is associated with ERG-driven transcriptional reprogramming linked to the TMPRSS2-ERG fusion. Conclusion: PROX1 expression is significantly associated with ERG expression and TMPRSS2-ERG fusion status in prostate cancer. These findings reinforce the role of PROX1 as an early marker and potential mediator of lineage plasticity. Targeting PROX1 or its regulatory pathways may offer a novel therapeutic strategy to mitigate plasticity-driven progression and treatment resistance in TMPRSS2-ERG fusion-positive prostate cancer.

Abstract Background: The APOΕ3 Christchurch (APOΕ3Ch) variant, characterized by an R136S substitution, confers protection against Alzheimer’s disease (AD) by reducing Apolipoprotein E (ApoE) binding to heparan sulfate proteoglycans (HSPGs), thereby limiting tau propagation. While antibody-based strategies mimicking this variant have shown promise, small-molecule approaches to disrupt the ApoE–HSPG interaction remain underexplored. Methods: We conducted a structure-guided molecular docking study targeting the ApoE HSPG-binding domain centered on Arg146, using AutoDock Vina within the SAMSON platform. The ligand benzene-1,3-disulfonic acid, a small, anionic molecule with structural similarity to sulfated glycosaminoglycans, was docked to the cationic surface of ApoΕ3. Binding affinity, interaction pose, and root-mean-square deviation (RMSD) were assessed. Pharmacokinetic and toxicity predictions were performed using the pkCSM web server. Results: Benzene-1,3-disulfonic acid exhibited strong binding to the Arg146-containing pocket with a top docking score of –5.93 kcal/mol and an estimated inhibition constant (Ki) of 44.6 µmol. The top-ranked pose revealed stabilizing electrostatic interactions and hydrogen bonds with Arg146 and neighboring basic residues. pkCSM profiling predicted poor oral absorption and limited blood-brain barrier permeability, but a favorable safety profile, including no predicted hepatotoxicity, hERG inhibition (cardiac toxicity), or mutagenicity. Conclusion: These findings establish the feasibility of targeting the ApoE–HSPG interface with small molecules and identify benzene-1,3-disulfonic acid as a candidate Christchurch mimetic. While pharmacokinetic limitations preclude systemic use, intranasal delivery or ligand optimization may overcome brain access barriers. This study provides a foundation for developing novel small-molecule therapeutics to disrupt ApoE-mediated tau pathology in AD.

Abstract Background The PELO–HBS1L complex is a critical mediator of ribosome-associated quality control, responsible for resolving stalled ribosomes and maintaining translational fidelity. Recent CRISPR-based synthetic lethality screens have identified PELO and HBS1L as selective vulnerabilities in cancers with 9p21.3 deletion or microsatellite instability-high (MSI-H) phenotypes. These cancers exhibit dependency on the PELO–HBS1L complex due to coexisting destabilization of the superkiller complex (SKIc), presenting a unique opportunity for targeted therapeutic intervention. However, no small-molecule inhibitors of this complex have been reported. Methods We employed AlphaFold2-multimer modeling to generate high-confidence structural models of the PELO–HBS1L heterodimer. Structural evaluation included predicted aligned error (PAE), per-residue confidence (pLDDT), and MSA coverage. Fragment-based pocket mapping identified a candidate binding pocket, selected for docking based on accessibility and proximity to inter-chain contacts. A fragment-guided design strategy was implemented using apogossypol scaffolds bearing hydroxyamide linkers and terminal polar groups. Ligands were prepared via Open Babel and docked into the interface pocket using AutoDock Vina. Binding energy, interaction geometry, and contact distances were used to rank binding poses. Results AlphaFold2 models revealed a rigid PELO core and a flexible HBS1L tail, with PAE and pLDDT scores indicating moderate interface confidence and ligand-accessible surface features. Indole-2-carboxylic acid with guanidine substitution formed key polar contacts in the candidate binding pocket. Among apogossypol analogs, methylamine and guanidine-tailed derivatives displayed strong polar interactions at the pocket interface, including engagement with GLU215, ASN, and THR. A methylated guanidine analog further enhanced interaction density, while piperidine substitutions were poorly tolerated. Conclusion A therapeutic small molecule docked in a binding pocket at the interface of two interacting proteins can disrupt a protein-protein complex. This approach, known as protein-protein interaction (PPI) inhibition, is a well-established strategy in drug discovery. The PELO–HBS1L interface contains a druggable surface pocket that can be targeted by small molecules. Apogossypol-derived ligands with flexible, cationic extensions demonstrate promising interaction profiles and provide a foundation for further hit-to-lead optimization. These findings support development of interface-directed inhibitors to exploit synthetic lethality in PELO-dependent cancers.

Objective Continuous antipsychotic treatment is fundamental to successful management of schizophrenia. However, many oral antipsychotics are associated with adverse effects (AEs). While prior research has shown antipsychotic AEs to negatively impact patient adherence, no study has examined the incremental costs associated with AEs, especially among Medicare beneficiaries who constitute approximately half of all patients with schizophrenia in the U.S. This study aimed to compare incremental healthcare costs among Medicare beneficiaries with schizophrenia treated with oral antipsychotics who did and did not experience adverse events (AEs). Methods All fee-for-service Medicare beneficiaries with schizophrenia who initiated a new OAP between 01/01/2017 and 12/31/2019 were included in the sample (index date = date of new OAP prescription). All-cause and schizophrenia-related costs were measured while a patient was receiving treatment and were converted into monthly measures given differential follow-up periods. Generalized linear models were used to generate adjusted cost estimates. Results In our final sample of 46,452 Medicare beneficiaries with schizophrenia, movement disorders such as tardive dyskinesia and extrapyramidal symptoms were observed in 10.0% of beneficiaries. Metabolic side effects included hyperlipidemia (33.6%), diabetes (33.1%), and hypotension (6.8%). Patients who experienced adverse events consistently had significantly higher all-cause monthly healthcare costs compared to patients who did not experience adverse events. This was true for beneficiaries experiencing movement disorders ($5,281 vs. $4,851, Δ = $430, p = 0.0766), hyperlipidemia ($5,123 vs. $4,768, Δ = $355, p = 0.0179), diabetes ($5,249 vs. $4,698, Δ = $551, p = 0.0049), and hypotension ($6,631 vs. $4,685, Δ = $1,946, p < 0.001). A similar pattern was observed for monthly schizophrenia-related costs. Conclusions Our findings underscore the additional healthcare cost burden associated with adverse events in patients receiving oral antipsychotic treatment. Efforts should be directed towards selecting agents that minimize side effects and/or developing new therapeutic alternatives with improved tolerability profiles.

BackgroundHand-arm vibration syndrome (HAVS) is an occupational disease associated with long-term exposure to power tools leading to hand-transmitted vibration exposure. Prior research has focussed on physical manifestations with little known about the psychological impacts of HAVS.AimsTo examine if HAVS severity and/or functional impairment is associated with psychological outcomes.MethodsWe conducted a cross-sectional study collecting data through a survey and retrospective chart review of workers being assessed for HAVS at an occupational medicine clinic. We collected information on demographics, work conditions, disease characteristics and physical and psychological outcomes as measured through validated instruments (SF-12, QuickDASH, GAD-2, PHQ-2). Descriptive statistics and bivariate analyses were followed by multivariable models to explore associations between mental health outcomes and predictor variables.ResultsParticipants (N = 94; 56% response rate) were male with a mean age of 48.2 years. The majority (62%) worked in the mining sector, and 27% of participants reported feeling depressed and 35% reported showing little interest in or pleasure in doing things, while 28% reported clinically significant anxiety symptoms. In multivariable models, the QuickDASH, a measure of upper-extremity function and disability, was the only significant predictor of psychological outcomes.ConclusionsWorkers with HAVS have poorer mental health and physical functioning outcomes in comparison to the general population. Employers should consider tailored policies and interventions to address the mental health of workers with HAVS.

Abstract Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with limited therapeutic options. The interaction between Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), a critical microglial receptor, and Apolipoprotein E (ApoE), the strongest genetic risk factor for late-onset AD, plays a pivotal role in modulating immune responses in the brain. However, the structural and functional dynamics of TREM2-ApoE isoform interactions (ε2, ε3, and ε4) remain incompletely understood. Methods: Protein-protein docking using ClusPro was employed to model the interactions between wild-type TREM2 and the three ApoE isoforms (ε2, ε3, ε4) using crystallographic structures. Stability and structural dynamics of these complexes were analyzed using molecular dynamics simulations performed in GROMACS. Key parameters assessed included Root Mean Square Deviation (RMSD) for structural stability and Radius of Gyration for compactness. Results: Docking results indicated that ApoE ε3 had the lowest energy-weighted score, suggesting the most stable docking conformation. However, molecular dynamics simulations revealed that ApoE ε4 exhibited greater interaction robustness despite lower compactness. ApoE ε2 demonstrated the least stable interaction, characterized by significant variability in structural compactness. These findings highlight isoform-specific differences in TREM2-ApoE interactions, with ApoE ε4 exhibiting unique binding characteristics consistent with its strong association with AD risk. Conclusion: The therapeutic potential of modulating TREM2-ApoE interactions warrants exploration. Small molecules or biologics that selectively enhance or inhibit these interactions could represent novel strategies for mitigating AD risk or progression, particularly in individuals carrying the ApoE ε4 allele.