First-Line Sugemalimab Plus Chemotherapy for Advanced Gastric Cancer: The GEMSTONE-303 Randomized Clinical Trial.

Importance: Gastric cancer, including gastroesophageal junction cancer, is one of the most commonly diagnosed cancers worldwide, with high mortality. Sugemalimab is a fully human anti-programmed death-ligand 1 (PD-L1) antibody. The combination of sugemalimab and chemotherapy showed promising antitumor activity and safety in a phase 1b study among patients with treatment-naive, unresectable, locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma.

Crossed paths: a systematic review unveiling patterns in crossed testicular ectopia.

Purpose: Crossed Testicular Ectopia (CTE) is a rare congenital anomaly where both testes descend on one side of the body. Although previously believed to be exceedingly uncommon, the number of published cases has grown, suggesting it may be more prevalent than initially believed. CTE is associated with various abnormalities, of which the most cited anomaly is persistent mullerian duct syndrome (PMDS) which has its own implications regarding infertility.

SLC25A38 is required for mitochondrial pyridoxal 5'-phosphate (PLP) accumulation.

Many essential proteins require pyridoxal 5'-phosphate, the active form of vitamin B6, as a cofactor for their activity. These include enzymes important for amino acid metabolism, one-carbon metabolism, polyamine synthesis, erythropoiesis, and neurotransmitter metabolism. A third of all mammalian pyridoxal 5'-phosphate-dependent enzymes are localized in the mitochondria; however, the molecular machinery involved in the regulation of mitochondrial pyridoxal 5'-phosphate levels in mammals remains unknown.

Active learning-assisted directed evolution.

Directed evolution (DE) is a powerful tool to optimize protein fitness for a specific application. However, DE can be inefficient when mutations exhibit non-additive, or epistatic, behavior. Here, we present Active Learning-assisted Directed Evolution (ALDE), an iterative machine learning-assisted DE workflow that leverages uncertainty quantification to explore the search space of proteins more efficiently than current DE methods.

Neurovascular Complications Following Clavicle Fracture Fixation: Timing, Mechanisms, and Clinical Implications.

This review addresses the neurovascular complications associated with the surgical treatment of clavicle fractures through open reduction and internal fixation (ORIF). Despite being a generally safe procedure, it can lead to severe complications including brachial plexopathy, pseudoaneurysm, arteriovenous fistulas (AVF), deep vein thrombosis (DVTs), and thoracic outlet syndrome (TOS). One significant observation, not often highlighted in previous literature, is that neurovascular complications are more common in cases involving delayed fixation, nonunion, or malunion, compared to those treated acutely.

Identification of an antibiotic from an HTS targeting EF-Tu:tRNA interaction: a prospective topical treatment for MRSA skin infections.

Because of the urgent need for new antibiotics to treat drug-resistant bacterial pathogens, we employed an assay that rapidly screens large quantities of compounds for their ability to interfere with bacterial protein synthesis, in particular, the delivery of amino acids to the ribosome via tRNA and elongation factor Tu (EF-Tu). We have identified a drug lead, named MGC-10, which kills Gram-positive bacteria, including methicillin-resistant (MRSA), with a MIC of 6 µM, while being harmless to mammalian cells in that concentration range. The antibacterial activity of MGC-10 was broad against over 50 strains of antibiotic-resistant samples obtained from hospital infections, where MGC-10 inhibited all tested strains of MRSA.

Catalase activity deficiency sensitizes multidrug-resistant Mycobacterium tuberculosis to the ATP synthase inhibitor bedaquiline.

Multidrug-resistant tuberculosis (MDR-TB), defined as resistance to the first-line drugs isoniazid and rifampin, is a growing source of global mortality and threatens global control of tuberculosis disease. The diarylquinoline bedaquiline has recently emerged as a highly efficacious drug against MDR-TB and kills Mycobacterium tuberculosis by inhibiting mycobacterial ATP synthase. However, the mechanisms underlying bedaquiline's efficacy against MDR-TB remain unknown.

Predicting bacterial fitness in Mycobacterium tuberculosis with transcriptional regulatory network-informed interpretable machine learning.

(Mtb) is the causative agent of tuberculosis disease, the greatest source of global mortality by a bacterial pathogen. Mtb adapts and responds to diverse stresses such as antibiotics by inducing transcriptional stress-response regulatory programs. Understanding how and when these mycobacterial regulatory programs are activated could enable novel treatment strategies for potentiating the efficacy of new and existing drugs.

Biportal Endoscopic Transforaminal Lumbar Interbody Fusion: How to Improve Fusion Rate?

Background: Biportal endoscopic transforaminal lumbar interbody fusion (BE-TLIF) is a minimally invasive surgical technique for treating degenerative lumbar spine conditions. It offers advantages such as reduced soft tissue trauma and lower infection rates, but certain technical aspects may be challenging. The current study aims to identify strategies to enhance the fusion rate in BE-TLIF by addressing these specific challenges.

A combinatorially complete epistatic fitness landscape in an enzyme active site.

Protein engineering often targets binding pockets or active sites which are enriched in epistasis-nonadditive interactions between amino acid substitutions-and where the combined effects of multiple single substitutions are difficult to predict. Few existing sequence-fitness datasets capture epistasis at large scale, especially for enzyme catalysis, limiting the development and assessment of model-guided enzyme engineering approaches. We present here a combinatorially complete, 160,000-variant fitness landscape across four residues in the active site of an enzyme.

Waitlist Time, Age, and Social Vulnerability: Impact on the Survival Benefit of Deceased Donor Kidney Transplantation Versus Long-term Dialysis Among Patients With End-stage Renal Disease.

Background: We sought to define the survival benefit of kidney transplantation versus long-term dialysis relative to waitlist time on dialysis, social vulnerability, and age among end-stage renal transplant candidates.

Methods: End-stage renal disease patients who were candidates for their first deceased donor kidney transplantation between 2008 and 2020 were identified using the US Renal Data System. Survival probabilities for patient survival were compared using the restricted mean survival times (RMSTs) across different age and social vulnerability index (SVI) ranges.

Targeted inhibition of kisspeptin neurons reverses hyperandrogenemia and abnormal hyperactive LH secretion in a preclinical mouse model of polycystic ovary syndrome.

Study Question: Do hyperactive kisspeptin neurons contribute to abnormally high LH secretion and downstream hyperandrogenemia in polycystic ovary syndrome (PCOS)-like conditions and can inhibition of kisspeptin neurons rescue such endocrine impairments?

Summary Answer: Targeted inhibition of endogenous kisspeptin neuron activity in a mouse model of PCOS reduced the abnormally hyperactive LH pulse secretion and hyperandrogenemia to healthy control levels.

What Is Known Already: PCOS is a reproductive disorder characterized by hyperandrogenemia, anovulation, and/or polycystic ovaries, along with a hallmark feature of abnormal LH hyper-pulsatility, but the mechanisms underlying the endocrine impairments remain unclear. A chronic letrozole (LET; aromatase inhibitor) mouse model recapitulates PCOS phenotypes, including polycystic ovaries, anovulation, high testosterone, and hyperactive LH pulses.

Chronological and Geographical Variations in the Incidence and Acceptance of COVID-19-Positive Donors and Outcomes Among Abdominal Transplant Patients.

Introduction: Given the importance of understanding COVID-19-positive donor incidence and acceptance, we characterize chronological and geographic variations in COVID-19 incidence relative to COVID-19-positive donor acceptance.

Methods: Data on deceased donors and recipients of liver and kidney transplants were obtained from the UNOS database between 2020 and 2023. Hierarchical cluster analysis was used to assess trends in COVID-19-positive donor incidence.

Natriuretic Peptides to Classify Risk of Atrial Fibrillation Detection After Stroke: Analysis of the BIOSIGNAL and PRECISE Cohort Studies.

Background And Objectives: Prolonged cardiac monitoring (PCM) increases atrial fibrillation (AF) detection after ischemic stroke, but access is limited, and it is burdensome for patients. Our objective was to assess whether midregional proatrial natriuretic peptide (MR-proANP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) could classify people who are unlikely to have AF after ischemic stroke and allow better targeting of PCM.

Methods: We analyzed people from the Biomarker Signature of Stroke Aetiology (BIOSIGNAL) study with ischemic stroke, no known AF, and ≥3 days cardiac monitoring.

Ivosidenib in Chinese patients with relapsed or refractory isocitrate dehydrogenase 1 mutated acute myeloid leukemia: a registry study.

Ivosidenib, an isocitrate dehydrogenase 1 () inhibitor, has demonstrated clinical benefits in a pivotal study (AG120-C-001) in patients with -mutated (m) acute myeloid leukemia (AML). A registry study (CS3010-101: NCT04176393) was conducted to assess the pharmacokinetic (PK) characteristics, safety, and efficacy of ivosidenib in Chinese patients with relapsed or refractory (R/R) m AML. Patients received ivosidenib 500 mg once daily for 28-day cycles until disease progression.

The impact of county-level food access on the mortality and post-transplant survival among patients with steatotic liver disease.

Background: The impact of county-level food access on mortality associated with steatotic liver disease, as well as post-liver transplant outcomes among individuals with steatotic liver disease, have not been characterized.

Methods: Data on steatotic liver disease-related mortality and outcomes of liver transplant recipients with steatotic liver disease between 2010 and 2020 were obtained from the Centers for Disease Control Prevention mortality as well as the Scientific Registry of Transplant Recipients databases. These data were linked to the food desert score, defined as the proportion of the total population in each county characterized as having both low income and limited access to grocery stores.

Textbook outcome in liver surgery: open vs minimally invasive hepatectomy among patients with hepatocellular carcinoma.

Background: We sought to investigate whether minimally invasive hepatectomy (MIH) was superior to open hepatectomy (OH) in terms of achieving textbook outcome in liver surgery (TOLS) after resection of hepatocellular carcinoma (HCC).

Methods: Patients who underwent resection of HCC between 2000 and 2020 were identified from an international database. TOLS was defined by the absence of intraoperative grade ≥2 events, R1 resection margin, posthepatectomy liver failure, bile leakage, major complications, in-hospital mortality, and readmission.

Effect of the opioid crisis on the liver transplantation donor pool: A national analysis.

Background: Over the last decade there has been a surge in overdose deaths due to the opioid crisis. We sought to characterize the temporal change in overdose donor (OD) use in liver transplantation (LT), as well as associated post-LT outcomes, relative to the COVID-19 era.

Methods: LT candidates and donors listed between January 2016 and September 2022 were identified from the Scientific Registry of Transplant Recipients database.

Opportunities and Challenges for Machine Learning-Assisted Enzyme Engineering.

Enzymes can be engineered at the level of their amino acid sequences to optimize key properties such as expression, stability, substrate range, and catalytic efficiency-or even to unlock new catalytic activities not found in nature. Because the search space of possible proteins is vast, enzyme engineering usually involves discovering an enzyme starting point that has some level of the desired activity followed by directed evolution to improve its "fitness" for a desired application. Recently, machine learning (ML) has emerged as a powerful tool to complement this empirical process.

Comparative outcomes after treatment of peri-implant, periprosthetic, and interprosthetic femur fractures: which factors increase mortality risk?

Objectives: To compare mortality rates between patients treated surgically for periprosthetic fractures (PPF) after total hip arthroplasty (THA), total knee arthroplasty (TKA), peri-implant (PI), and interprosthetic (IP) fractures while identifying risk factors associated with mortality following PPF.

Design: Retrospective.

Setting: Single, Level II Trauma Center.

First-line sugemalimab with chemotherapy for advanced esophageal squamous cell carcinoma: a randomized phase 3 study.

Although antiprogrammed death 1 antibody plus chemotherapy has recently been approved for first-line esophageal squamous cell carcinoma (ESCC), antiprogrammed death-ligand 1 antibody may offer another combination option in this setting. In this multicenter, randomized, double-blinded phase 3 trial a total of 540 adults (aged 18-75 years) with unresectable, locally advanced, recurrent or metastatic ESCC and who had not received systemic treatment were enrolled. All patients were randomized at 2:1 to receive either sugemalimab (an anti-PD-L1 antibody; 1,200 mg) or placebo every 3 weeks for up to 24 months, plus chemotherapy (cisplatin 80 mg m on day 1 plus 5-fluorouracil 800 mg m day on days 1-4) every 3 weeks for up to six cycles.

Efficacy and safety of pralsetinib in Chinese advanced RET-mutant medullary thyroid cancer patients.

Pralsetinib has demonstrated efficacious activity in various solid tumors, including medullary thyroid cancer (MTC), as observed in the phase 1/2 global ARROW study (BLU-667-1101; NCT03037385). We evaluated the safety and efficacy of pralsetinib in Chinese patients with advanced RET-mutant MTC. In the extension cohort of ARROW, adult patients with advanced MTC, who had not received systemic therapy (except for cytotoxic chemotherapy), were treated with pralsetinib (400 mg once daily, orally).