Tepotinib plus osimertinib in patients with EGFR-mutated non-small-cell lung cancer with MET amplification following progression on first-line osimertinib (INSIGHT 2): a multicentre, open-label, phase 2 trial.

BACKGROUND: Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) and MET amplification as a mechanism of resistance to first-line osimertinib have few treatment options. Here, we report the primary analysis of the phase 2 INSIGHT 2 study evaluating tepotinib, a highly selective MET inhibitor, combined with osimertinib in this population. METHODS: This open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703 (enrolment complete). FINDINGS: Between Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9-20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7-60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3%]). Serious treatment-related adverse events were reported in 16 (13%) patients. Deaths of four (3%) patients were assessed as potentially related to either trial drug by the investigator due to pneumonitis (two [2%] patients), decreased platelet count (one [1%]), respiratory failure (one [1%]), and dyspnoea (one [1%]); one death was attributed to both pneumonitis and dyspnoea. INTERPRETATION: Tepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated. FUNDING: Merck (CrossRef Funder ID: 10.13039/100009945).

Correction of a severe post-surgical iatrogenic class II anterior open bite with lingual appliances and mini-screws: a case report.

An iatrogenic open bite after orthognathic surgery is an uncommon malocclusion, with only one documented case reported in the literature. However, the open bite in this case report was not a true open bite, as it resulted from the interferences between the maxillary second molars and mandibular retromolar bones. This case report aims to present the management of a true iatrogenic open bite with posterior teeth in centric occlusion, occurring after mandibular setback surgery. The anterior open bite accompanied a severe class II malocclusion and increased lower anterior facial height. The patient was treated with fixed lingual appliances and mini-screws to distalize the entire maxillary arch and close the open bite. After treatment, a positive overbite and dental class I relationship was achieved. The treatment outcomes were stable at the 2-year follow-up. Lingual appliances combined with mini-screws may offer effective non-surgical management of iatrogenic open bite after orthognathic surgery. Clinical and Surgical Implications: Iatrogenic open bites can develop from various causes that include surgical options such as orthognathic surgery or in patients treated with occlusal splint therapy. These may be treated with the help of skeletal anchorage options such as orthodontic mini-screws.

A Hyper-Transformer model for Controllable Pareto Front Learning with Split Feasibility Constraints.

Controllable Pareto front learning (CPFL) approximates the Pareto optimal solution set and then locates a non-dominated point with respect to a given reference vector. However, decision-maker objectives were limited to a constraint region in practice, so instead of training on the entire decision space, we only trained on the constraint region. Controllable Pareto front learning with Split Feasibility Constraints (SFC) is a way to find the best Pareto solutions to a split multi-objective optimization problem that meets certain constraints. In the previous study, CPFL used a Hypernetwork model comprising multi-layer perceptron (Hyper-MLP) blocks. Transformer can be more effective than previous architectures on numerous modern deep learning tasks in certain situations due to their distinctive advantages. Therefore, we have developed a hyper-transformer (Hyper-Trans) model for CPFL with SFC. We use the theory of universal approximation for the sequence-to-sequence function to show that the Hyper-Trans model makes MED errors smaller in computational experiments than the Hyper-MLP model.

Comparison of the Marginal and Internal Fit of Ceramic Laminate Veneers Fabricated with Four Different Computer-Aided Manufacturing Techniques.

Purpose: The improvement of computer-aided design and computer-aided manufacturing (CAD/CAM) has changed the methods of fabricating laminate veneers. The objectives of this study were to evaluate the marginal and internal fit of ceramic veneers manufactured with different CAD/CAM techniques. Materials and methods: A metal die was made by copying a prepared plastic maxillary central right incisor and scanned for designing a laminate veneer. One hundred laminate veneers were made with four different CAD/CAM techniques (n=25), including milled lithium disilicate (MLD), heat-pressed lithium disilicate with 3-dimensional (3D) printed wax patterns (PLD), milled zirconia (MZ), and 3Dprinted zirconia (PZ). The virtual marginal and internal fit of fabricated veneers was evaluated with digital crown fitting software. The actual marginal and internal fit was measured with the silicone replica method under a digital microscope. The measured data were analyzed using the one-way analysis of variance and the Turkey test. Results: There were significant differences in marginal and internal fit (P < 0.001) among manufacturing techniques. Both the virtual and actual marginal and internal gaps were higher in the PLD and PZ groups compared to the MLD and MZ groups. Conclusion: All four CAD/CAM techniques of manufacturing veneers, that is, milled lithium disilicate, heat-pressed lithium disilicate with 3D-printed wax patterns, milled zirconia, and 3D-printed zirconia, have clinically acceptable marginal and internal fit. Milled zirconia and lithium disilicate veneers demonstrated superior marginal and internal fit compared to 3D-printed zirconia and heat-pressed lithium disilicate veneers with 3D-printed wax patterns.

Two New Steroidal Saponins with Potential Anti-Inflammatory Effects from the Aerial Parts of Gnetum formosum Markgr.

Gnetum formosum Markgr., a member of the Gnetaceae family, is distributed in Vietnam. This plant remains a botanical enigma with an unexplored diversity of chemical constituents and pharmacological effects. In this study, two new steroidal saponins, namely gnetumosides A (1) and B (2), were isolated from the aerial parts of G. formosum. Their chemical structures were elucidated using spectroscopic techniques, including high-resolution electrospray ionization mass spectrometry (HR-ESI-MS) and NMR, along with chemical hydrolysis and comparison with the reported literature. The potential anti-inflammatory effects of the isolated compounds were evaluated by measuring lipopolysaccharide-stimulated nitric oxide (NO) production in murine macrophage cells. Notably, compound 1 exhibited the most potent inhibitory activity (IC50 = 14.10 ± 0.75 µM), comparable to dexamethasone. Additionally, the mechanisms underlying the observed anti-inflammatory effects were investigated through molecular docking and molecular dynamics simulations on inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins. This study is the first to investigate the chemical constituents and pharmacological effects of G. formosum.

The anconeus-triceps lateral flap approach in terrible triad of the elbow: good outcome in a series of ten cases.

Introduction: Standard surgical management for the terrible triad of the elbow (TTE) has been established since 2004, yet postoperative complications are common and consensus on optimal management is absent. Different surgical algorithms for treating TTE and their efficacy have been reported worldwide, yet evidence from Vietnam remains limited. Methods: Ten cases diagnosed with TTE admitted to the Hospital of Traumatology and Orthopedics, a tertiary orthopedic center in Ho Chi Minh City, were presented to demonstrate the effectiveness and rate of postoperative complications following our stepwise surgical procedures using the anconeus-triceps lateral flap approach. The intraoperative "drop sign", quantitative assessment of pain and level of upper arm disability (via VAS and QuickDASH score) was mentioned to assess the algorithm's benefit. All patients' information was retrieved from medical records from August 2022 to January 2024. Results: All 10 cases required repair of the lateral ligament complex and underwent surgery within 2 days of hospitalization. Immediate postoperative imaging revealed no drop sign, and none of the patients experienced elbow dislocation nor the need for repeated surgery, and a full range of elbow motion was demonstrated at 3-6 months follow-up. Conclusion: TTE is a challenging injury that almost always obligates surgical correction. The anconeus-triceps lateral flap approach, with its advantages of better visualization and preservation of certain essential stabilizing muscles of the elbow, was demonstrated to yield a high success rate and low postoperative complication rate.

Genomic investigations of diverse corbiculate bee gut-associated Gilliamella reveal conserved pathways for energy metabolism, with diverse and variable energy sources.

Gilliamella is a genus of bacteria commonly found as symbionts of corbiculate bees. Research into energy metabolism by this genus has predominantly been done through in vivo and in vitro experiments focused on the type species Gilliamella apicola. This study examined 95 publicly available genomes representing at least 18 Gilliamella species isolated predominantly from the hindgut of corbiculate bees. Energy metabolism pathways were found to be highly conserved across not only the Gilliamella but also other members of the family Orbaceae. Evidence suggests Gilliamella are capable of fermentation of both fumarate and pyruvate. Fermentation of the former produces succinate. Fermentation of the latter can produce acetate, ethanol, formate, and both isoforms of lactate for all Gilliamella and acetoin for some G. apicola strains. According to genomic evidence examined, all Gilliamella are only capable of respiration under microoxic conditions, while higher oxygen conditions likely inhibits respiration. Evidence suggests that the glycolysis and pentose phosphate pathways are essential mechanisms for the metabolism of energy sources, with the TCA cycle playing little to no role in energy metabolism for all Gilliamella species. Uptake of energy sources, i.e. sugars and derivatives, likely relies predominantly on the phosphoenol-pyruvate-dependent phosphotransferase system. Differences in the utilized energy sources may confer fitness advantages associated with specific host species.

Multimodal pretraining for unsupervised protein representation learning.

Proteins are complex biomolecules essential for numerous biological processes, making them crucial targets for advancements in molecular biology, medical research, and drug design. Understanding their intricate, hierarchical structures, and functions is vital for progress in these fields. To capture this complexity, we introduce Multimodal Protein Representation Learning (MPRL), a novel framework for symmetry-preserving multimodal pretraining that learns unified, unsupervised protein representations by integrating primary and tertiary structures. MPRL employs Evolutionary Scale Modeling (ESM-2) for sequence analysis, Variational Graph Auto-Encoders (VGAE) for residue-level graphs, and PointNet Autoencoder (PAE) for 3D point clouds of atoms, each designed to capture the spatial and evolutionary intricacies of proteins while preserving critical symmetries. By leveraging Auto-Fusion to synthesize joint representations from these pretrained models, MPRL ensures robust and comprehensive protein representations. Our extensive evaluation demonstrates that MPRL significantly enhances performance in various tasks such as protein-ligand binding affinity prediction, protein fold classification, enzyme activity identification, and mutation stability prediction. This framework advances the understanding of protein dynamics and facilitates future research in the field. Our source code is publicly available at https://github.com/HySonLab/Protein_Pretrain.

Risk factors of postoperative complications and their effect on survival after laparoscopic gastrectomy for gastric cancer.

Background: The association between postoperative complications and long-term survival after laparoscopic gastrectomy (LG) for gastric cancer (GC) remains uncertain. This study aimed to determine the incidence and risk factors of postoperative complications and evaluate their impact on survival outcomes in patients undergoing LG. Methods: A retrospective study was conducted on 621 patients who underwent LG for gastric adenocarcinoma between March 2015 and December 2021. Postoperative complications were classified according to the Clavien-Dindo classification, with major complications defined as Grade III or higher. Logistic regression models with stepwise backward procedure were used to identify risk factors for complications. To assess the impact of postoperative complications on survival, uni- and multi-variable Cox proportional hazard models were used for overall survival (OS) and disease-free survival (DFS). Results: Overall rate of postoperative complications was 17.6% (109 patients); 33 patients (5.3%) had major complications. Independent risk factors for major complications were Charlson comorbidities index (OR [95% CI], 1.87 [1.09-3.12], p-value = 0.018 for each one score increase), and type of anastomosis (OR [95% CI], 0.28 [0.09-0.91], p-value = 0.029 when comparing Billroth II with Billroth I). Multivariable analysis identified major complications as an independent prognostic factor to reduce OS (HR [95% CI], 2.32 [1.02-5.30], p-value = 0.045) and DFS (HR [95% CI], 2.63 [1.37-5.06], p-value = 0.004). Other prognostic factors for decreased survival outcomes were tumor size, presence of invasive lymph nodes, and T4a stage. Conclusions: Major complications rate of LG for GC was approximately 5.3%. Charlson comorbidities index and type of anastomosis were identified as risk factors for major postoperative complications. Major complications were demonstrated to pose adverse impact on survival outcomes.

High Prevalence of Highly Pathogenic Avian Influenza: A Virus in Vietnam's Live Bird Markets.

Background: In recent years, Vietnam has suffered multiple epizootics of influenza in poultry. Methods: From 10 January 2019 to 26 April 2021, we employed a One Health influenza surveillance approach at live bird markets (LBMs) and swine farms in Northern Vietnam. When the COVID-19 pandemic permitted, each month, field teams collected oral secretion samples from poultry and pigs, animal facility bioaerosol and fecal samples, and animal worker nasal washes at 4 LBMs and 5 swine farms across 5 sites. Initially samples were screened with molecular assays followed by culture in embryonated eggs (poultry swabs) or Madin-Darby canine kidney cells (human or swine swabs). Results: Many of the 3493 samples collected had either molecular or culture evidence for influenza A virus, including 314 (37.5%) of the 837 poultry oropharyngeal swabs, 144 (25.1%) of the 574 bioaerosol samples, 438 (34.9%) of the 1257 poultry fecal swab samples, and 16 (1.9%) of the 828 human nasal washes. Culturing poultry samples yielded 454 influenza A isolates, 83 of which were H5, and 70 (84.3%) of these were highly pathogenic. Additionally, a positive human sample had a H9N2 avian-like PB1 gene. In contrast, the prevalence of influenza A in the swine farms was much lower with only 6 (0.4%) of the 1700 total swine farm samples studied, having molecular evidence for influenza A virus. Conclusions: This study suggests that Vietnam's LBMs continue to harbor high prevalences of avian influenza A viruses, including many highly pathogenic H5N6 strains, which will continue to threaten poultry and humans.

Assessing the Efficacy of Acanthoic Acid Isolated from Acanthopanax koreanum Nakai in Male Infertility: An In Vivo and In Silico Approach.

Acanthoic acid, a diterpene isolated from the root bark of Acanthopanax koreanum Nakai, possesses diverse pharmacological activities, including anti-inflammatory, anti-diabetic, gastrointestinal protection, and cardiovascular protection. This study is the first to investigate the egg-hatching rates of Drosophila melanogaster affected by acanthoic acid. Notably, male flies supplemented with 10 µM acanthoic acid exhibited a strong increase in hatching rates compared with controls under adverse temperature conditions, suggesting a potential protective effect against environmental stressors. Molecular docking simulations revealed the binding affinities and specific interactions between acanthoic acid and proteins related to male infertility, including SHBG, ADAM17, and DNase I, with binding affinity values of -10.2, -6.8, and -5.8 kcal/mol, respectively. Following the docking studies, molecular dynamic simulations were conducted for a duration of 100 ns to examine the stability of these interactions. Additionally, a total binding energy analysis and decomposition analysis offered insights into the underlying energetic components and identified key contributing residues.

An independent, multi-country head-to-head accuracy comparison of automated chest x-ray algorithms for the triage of pulmonary tuberculosis.

Background: Computer-aided detection (CAD) algorithms for automated chest X-ray (CXR) reading have been endorsed by the World Health Organization for tuberculosis (TB) triage, but independent, multi-country assessment and comparison of current products are needed to guide implementation. Methods: We conducted a head-to-head evaluation of five CAD algorithms for TB triage across seven countries. We included CXRs from adults who presented to outpatient facilities with at least two weeks of cough in India, Madagascar, the Philippines, South Africa, Tanzania, Uganda, and Vietnam. The participants completed a standard evaluation for pulmonary TB, including sputum collection for Xpert MTB/RIF Ultra and culture. Against a microbiological reference standard, we calculated and compared the accuracy overall, by country and key groups for five CAD algorithms: CAD4TB (Delft Imaging), INSIGHT CXR (Lunit), DrAid (Vinbrain), Genki (Deeptek), and qXR (qure.AI). We determined the area under the ROC curve (AUC) and if any CAD product could achieve the minimum target accuracy for a TB triage test (≥90% sensitivity and ≥70% specificity). We then applied country- and population-specific thresholds and recalculated accuracy to assess any improvement in performance. Results: Of 3,927 individuals included, the median age was 41 years (IQR 29-54), 12.9% were people living with HIV (PLWH), 8.2% living with diabetes, and 21.2% had a prior history of TB. The overall AUC ranged from 0.774-0.819, and specificity ranged from 64.8-73.8% at 90% sensitivity. CAD4TB had the highest overall accuracy (73.8% specific, 95% CI 72.2-75.4, at 90% sensitivity), although qXR and INSIGHT CXR also achieved the target 70% specificity. There was heterogeneity in accuracy by country, and females and PLWH had lower sensitivity while males and people with a history of TB had lower specificity. The performance remained stable regardless of diabetes status. When country- and population-specific thresholds were applied, at least one CAD product could achieve or approach the target accuracy for each country and sub-group, except for PLWH and those with a history of TB. Conclusions: Multiple CAD algorithms can achieve or exceed the minimum target accuracy for a TB triage test, with improvement when using setting- or population-specific thresholds. Further efforts are needed to integrate CAD into routine TB case detection programs in high-burden communities.

Target regimen profiles for tuberculosis treatment.

Simpler, shorter, safer and more effective treatments for tuberculosis that are easily accessible to all people with tuberculosis are desperately needed. In 2016, the World Health Organization (WHO) developed target regimen profiles for the treatment of tuberculosis to make drug developers aware of both the important features of treatment regimens, and patient and programmatic needs at the country level. In view of recent ground-breaking advances in tuberculosis treatment, WHO has revised and updated these regimen profiles. We used a similar process as for the 2016 profiles, including a baseline treatment landscape analysis, an initial stakeholder survey, modelling studies estimating the impact and cost-effectiveness of novel tuberculosis treatment regimens, and an extensive stakeholder consultation. We developed target regimen profiles for the treatment of rifampicin-susceptible and rifampicin-resistant tuberculosis, as well as a pan-tuberculosis regimen that would be appropriate for patients with any type of tuberculosis. We describe the revised target regimen profile characteristics, with specific minimal and optimal targets to be met, rationale and justification, and aspects relevant to all target regimen profiles (drug susceptibility testing, adherence and forgiveness, treatment strategies, post-tuberculosis lung disease, and cost and access considerations). We discuss the trade-offs of proposed characteristics for decision-making at developmental or operational levels. We expect that, following these target regimen profile revisions, tuberculosis treatment developers will produce regimens that are quality-assured, affordable and widely available, and that meet the needs of affected populations.

Des traitements de la tuberculose plus simples, plus courts, plus sûrs et plus efficaces, facilement accessibles à toutes les personnes atteintes de tuberculose, font cruellement défaut. En 2016, l'Organisation mondiale de la santé (OMS) a élaboré des profils de schéma thérapeutique cible pour le traitement de la tuberculose, afin de sensibiliser les concepteurs de médicaments aux caractéristiques importantes des schémas thérapeutiques et aux besoins des patients et des programmes au niveau national. Compte tenu des avancées récentes dans le traitement de la tuberculose, l'OMS a révisé et mis à jour ces profils de schéma thérapeutique. Nous avons appliqué un processus similaire à celui des profils de 2016, y compris une analyse de base des différentes possibilités thérapeutiques, une enquête initiale auprès des parties prenantes, des études de modélisation estimant l'impact et le rapport coût-efficacité des nouveaux schémas thérapeutiques pour la tuberculose, ainsi qu'une vaste consultation des parties prenantes. Nous avons élaboré des profils de schéma thérapeutique cible pour le traitement de la tuberculose sensible à la rifampicine ou résistant à la rifampicine, ainsi qu'un schéma multiforme qui conviendrait aux patients atteints de n'importe quel type de tuberculose. Nous décrivons les caractéristiques du profil révisé de schéma thérapeutique cible, avec les objectifs minimaux et optimaux spécifiques à atteindre, le raisonnement et les aspects pertinents pour tous les profils de schéma thérapeutique cible (tests de sensibilité aux médicaments, observance thérapeutique et manque d'observance («forgiveness¼), stratégies de traitement, maladie pulmonaire post-tuberculeuse et considérations de coût et d'accès). Nous discutons des compromis des caractéristiques proposées pour la prise de décisions au niveau du développement ou au niveau opérationnel. Nous espérons qu'à la suite de ces révisions du profil de schéma thérapeutique cible, les concepteurs de traitements antituberculeux produiront des schémas dont la qualité est assurée, qui sont abordables et largement disponibles et qui répondent aux besoins des populations touchées.

Se necesitan con urgencia tratamientos más sencillos, breves, seguros y eficaces contra la tuberculosis que sean fácilmente accesibles para todas las personas con tuberculosis. En 2016, la Organización Mundial de la Salud (OMS) elaboró perfiles objetivo de esquemas terapéuticos para el tratamiento de la tuberculosis con el fin de que los fabricantes de medicamentos conocieran tanto las características importantes de estos esquemas como las necesidades programáticas y de los pacientes en cada país. Teniendo en cuenta los recientes avances pioneros en el tratamiento de la tuberculosis, la OMS ha revisado y actualizado estos perfiles de esquemas terapéuticos. Se ha seguido un proceso similar al de los perfiles de 2016, que incluye un análisis de referencia del panorama terapéutico, una encuesta inicial a las partes interesadas, estudios de modelización para estimar el impacto y la rentabilidad de los nuevos esquemas terapéuticos para el tratamiento de la tuberculosis, y una amplia consulta a las partes interesadas. Se desarrollaron perfiles objetivo de esquemas terapéuticos para el tratamiento de la tuberculosis sensibles a la rifampicina y resistente a la rifampicina, así como un esquema farmacológico capaz de tratar todas las formas de tuberculosis que sería apropiado para pacientes con cualquier tipo de tuberculosis. Se describieron las características revisadas de los perfiles objetivo de los esquemas terapéuticos, con los objetivos mínimos y óptimos específicos que deben alcanzarse, los fundamentos y la justificación, y los aspectos relevantes para todos los perfiles objetivo de los esquemas terapéuticos (pruebas de sensibilidad a los fármacos, adherencia y olvido, estrategias de tratamiento, enfermedad pulmonar postuberculosa, y consideraciones de coste y acceso). Se discutieron las ventajas y desventajas de las características propuestas para la toma de decisiones a nivel de desarrollo u operativo. Se espera que, tras estas revisiones de los perfiles objetivo de los esquemas terapéuticos, las personas encargadas del desarrollo de tratamientos para la tuberculosis elaboren esquemas terapéuticos de calidad garantizada, asequibles y ampliamente disponibles, y que respondan a las necesidades de las poblaciones afectadas.

Head-to-head comparison of diagnostic accuracy of TB screening tests: Chest-X-ray, Xpert TB host response, and C-reactive protein.

Background: Accessible, accurate screening tests are necessary to advance tuberculosis (TB) case finding and early detection in high-burden countries. We compared the diagnostic accuracy of available TB triage tests. Methods: We prospectively screened consecutive adults with ≥2 weeks of cough presenting to primary health centers in the Philippines, Vietnam, South Africa, Uganda, and India. All participants received the index tests: chest-X-ray (CXR), venous or capillary Cepheid Xpert TB Host Response (HR) testing, and point-of-care C-reactive protein (CRP) testing (Boditech iChroma II). CXR images were processed using computer-aided detection (CAD) algorithms. We assessed diagnostic accuracy against a microbiologic reference standard (sputum Xpert Ultra, culture). Optimal cut-points were chosen to achieve sensitivity ≥90% and maximize specificity. Two-test screening algorithms were considered, using two approaches: 1) sequential negative serial screening in which the second screening test is conducted only if the first is negative and positive is defined as positive on either test and 2) sequential positive serial screening, in which the second screening test is conducted only if the first is positive and positive is defined as positive on both tests. Results: Between July 2021 and August 2022, 1,392 participants with presumptive TB had valid results on index tests and the reference standard, and 303 (22%) had confirmed TB. In head-to-head comparisons, CAD4TB v7 showed the highest specificity when using a cut-point that achieves 90% sensitivity (70.3% vs. 65.1% for Xpert HR, difference 95% CI 1.6 to 8.9; 49.7% for CRP, difference 95% CI 17.0 to 24.3). Among the possible two-test screening algorithms, three met WHO target product profile (TPP) minimum accuracy thresholds and had higher accuracy than any test alone. At 90% sensitivity, the specificity was 79.6% for Xpert HR-CAD4TB [sequential negative], 75.9% for CRP-CAD4TB [sequential negative], and 73.7% for Xpert HR-CAD4TB [sequential positive]. Conclusions: CAD4TB achieves TPP targets and outperforms Xpert HR and CRP. Combining screening tests further increased accuracy. Cost and feasibility of two-test screening algorithms should be explored. Registration: NCT04923958.

Shape-controlled synthesis of micro-/nanosized Cu particles with spherical and polyhedral shapes using the polyol process.

This study reports the synthesis of Cu micro-/nanosized particles through the polyol process. Cu particles were synthesized by reducing copper(ii) chloride in ethylene glycol (EG), polyvinylpyrrolidone (PVP), and potassium bromide (KBr) at low temperatures with or without the use of sodium borohydride (NaBH4).

Adsorbents for hydrogen-bond accepting hazardous chemicals by post-synthetic modification of UiO-66-NH2.

Adsorbents for hydrogen-bond accepting chemicals such as organophosphates are developed by post-synthetically modifying UiO-66-NH2 through two analogous condensation reactions to incorporate hydrogen-bond donating adsorbent groups. When benzaldehydes are employed as coupling partners, the resulting imine-functionalized MOFs show improvements in uptake capacity with increasingly electron-deficient adsorbent groups. By contrast, when the coupling partners are benzoic acids, the resulting amide-functionalized MOFs exhibit improvements in uptake capacity with increasingly electron-rich adsorbent groups. Both modification approaches also increase binding affinity for organophosphates relative to unmodified UiO-66-NH2, demonstrating successful modification of the MOF scaffold to create adsorbents for hazardous chemicals.

Pyrazinamide Safety, Efficacy, and Dosing for Treating Drug-Susceptible Pulmonary Tuberculosis: A Phase 3, Randomized, Controlled Clinical Trial.

RATIONALE: Optimizing pyrazinamide dosing is critical to improve treatment efficacy while minimizing toxicity during tuberculosis treatment. Study 31/ACTG A5349 represents the largest Phase 3 randomized controlled therapeutic trial to date for such investigation. OBJECTIVES: We sought to report pyrazinamide pharmacokinetic parameters, risk factors for lower pyrazinamide exposure, and relationships between pyrazinamide exposure with efficacy and safety outcomes. We aimed to determine pyrazinamide dosing strategies that optimize risks and benefits. METHODS: We analyzed pyrazinamide steady-state pharmacokinetic data using population nonlinear mixed-effects models. We evaluated the contribution of pyrazinamide exposure to long-term efficacy using parametric time-to-event models and safety outcomes using logistic regression. We evaluated optimal dosing with therapeutic windows targeting ≥95% durable cure and safety within the observed proportion of the primary safety outcome. MEASUREMENTS AND MAIN RESULTS: Among 2255 participants with 6978 plasma samples, pyrazinamide displayed 7-fold exposure variability (151-1053 mg·h/L). Body weight was not a clinically relevant predictor of drug clearance and thus did not justify the need for weight-banded dosing. Both clinical and safety outcomes were associated with pyrazinamide exposure, resulting in a therapeutic window of 231-355 mg·h/L for the control and 226-349 mg·h/L for the rifapentine-moxifloxacin regimen. Flat dosing of pyrazinamide at 1000 mg would have permitted an additional 13.1% (n=96) participants allocated to the control and 9.2% (n=70) to the rifapentine-moxifloxacin regimen dosed within the therapeutic window, compared to the current weight-banded dosing. CONCLUSIONS: Flat dosing of pyrazinamide at 1000 mg daily would be readily implementable and could optimize treatment outcomes in drug-susceptible tuberculosis. Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT02410772. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Expression of SUMO and NF-κB genes in hepatitis B virus-associated hepatocellular carcinoma patients: An observational study.

Alterations in signaling pathways and modulation of cell metabolism are associated with the pathogenesis of cancers, including hepatocellular carcinoma (HCC). Small ubiquitin-like modifier (SUMO) proteins and NF-κB family play major roles in various cellular processes. The current study aims to determine the expression profile of SUMO and NF-κB genes in HCC tumors and investigate their association with the clinical outcome of HCC. The expression of 5 genes - SUMO1, SUMO2, SUMO3, NF-κB p65, and NF-κB p50 - was quantified in tumor and adjacent non-tumor tissues of 58 HBV-related HCC patients by real-time quantitative PCR and was analyzed for the possible association with clinical parameters of HCC. The expression of SUMO2 was significantly higher in HCC tumor tissues compared to the adjacent non-tumor tissues (P = .01), while no significant difference in SUMO1, SUMO3, NF-κB p65, and NF-κB p50 expression was observed between HCC tumor and non-tumor tissues (P > .05). In HCC tissues, a strong correlation was observed between the expression of SUMO2 and NF-κB p50, between SUMO3 and NF-κB p50, between SUMO3 and NF-κB p65 (Spearman rho = 0.83; 0.82; 0.772 respectively; P < .001). The expression of SUMO1, SUMO2, SUMO3, NF-κB p65, and NF-κB p50 was decreased in grade 3 compared to grades 1 and 2 in HCC tumors according to the World Health Organization grades system. Our results highlighted that the SUMO2 gene is upregulated in tumor tissues of patients with HCC, and is related to the development of HCC, thus it may be associated with the pathogenesis of HCC.

An Effective Health System Approach to End TB: Implementing the Double X Strategy in Vietnam.

Countries that are high burden for TB must reverse the COVID-19 pandemic's devastating effects to accelerate progress toward ending TB. Vietnam's Double X (2X) strategy uses chest radiography (CXR) and GeneXpert (Xpert) rapid diagnostic testing to improve early detection of TB disease. Household contacts and vulnerable populations (e.g., individuals aged 60 years and older, smokers, diabetics, those with alcohol use disorders, and those previously treated for TB) with and without TB symptoms were screened in community campaigns using CXRs, followed by Xpert for those with a positive screen. In public non-TB district facilities, diabetics, respiratory outpatients, inpatients with lung disease, and other vulnerable populations underwent 2X evaluation. During COVID-19 restrictions in Vietnam, the 2X strategy improved access to TB services by decentralization to commune health stations, the lowest level of the health system, and enabling self-screening using a quick response mobile application. The number needed to screen (NNS) with CXRs to diagnose 1 person with TB disease was calculated for all 2X models and showed the highest yield among self-screeners (11 NNS with CXR), high yield for vulnerable populations in communities (60 NNS) and facilities (19 NNS), and moderately high yield for household contacts in community campaigns (154 NNS). Computer-aided diagnosis for CXRs was incorporated into community and facility implementation and improved physicians' CXR interpretations and Xpert referral decisions. Integration of TB infection and TB disease evaluation increased eligibility for TB preventive treatment among household contacts, a major challenge during implementation. The 2X strategy increased the rational use of Xpert, employing a health system-wide approach that reached vulnerable populations with and without TB symptoms in communities and facilities for early detection of TB disease. This strategy was effectively adapted to different levels of the health system during COVID-19 restrictions and contributed to post-pandemic TB recovery in Vietnam.

Gastrointestinal Perforation After Solid Organ Transplantation: A Case Series.

Although organ transplantation is associated with significant survival rates and cost benefits, postoperative complications still occur. Gastrointestinal complications, including those involving the stomach and intestines, account for 1-6% of posttransplant complications, with intestinal perforation specifically accounting for approximately 9%, depending on the center. In Vietnam, there are no comprehensive reports on these complications. Therefore, we report three clinical cases of gastrointestinal perforation following transplantation. Three cases of intestinal perforation are described in this case series. In 2023, a 16-year-old female patient who underwent heart transplantation for congenital heart disease was diagnosed with intestinal perforation on the 12th day. The patient required continued blood filtration support after surgery. In 2018, six days after liver transplantation, a 56-year-old male patient was diagnosed with intestinal perforation, which was subsequently repaired, and the ends of his intestines were removed. The patient was discharged in stable condition after 30 days. In 2017, five days after kidney transplantation, a 46-year-old female patient was diagnosed with intestinal perforation, which was repaired, and the perforation site was left open. The patient was discharged in stable condition after 40 days. Intestinal perforation is a relatively rare, but not uncommon, complication. Early diagnosis is challenging due to nonspecific clinical symptoms and signs. Considering the possibility of intestinal perforation and obtaining early abdominal computed tomography imaging can help prevent delayed diagnosis.