Risk of Dementia in Korean Vietnam War Veterans.

BACKGROUND: The number of cases of all types of dementia is increasing, and a significant increase in prevalence has been noted among veterans. Evidence of an association between dementia and exposure to chemicals such as Agent Orange from the Vietnam War is still limited, and there is a reported lack of awareness. OBJECTIVE: This study aimed to investigate the risk of dementia among Vietnam War veterans in Korea. DESIGN: This retrospective longitudinal study compared the incidence of dementia between Vietnam War veterans and the general population. SETTING: This study used data from the nationally representative Korean Vietnam War Veterans' Health Study Cohort, a combined dataset sourced from the Ministry of Patriots and Veterans Affairs in Korea and the National Health Insurance Sharing Service database. PARTICIPANTS: There were 191,272 Vietnam War veterans and 1,000,320 people of different ages, sexes, and residences. matched control in 2002. The total number of person-years were 18,543,181. MEASUREMENTS: The dementia group included participants who had visited a medical facility with any of the following ICD-10 codes in the follow-up periods: "F00 Dementia in Alzheimer's disease," "F01 Vascular dementia," "F02 Dementia in other diseases classified elsewhere," or "F03 Unspecified dementia." RESULTS: The incidence rate ratio for all types of dementia was 1.16, with higher ratios observed for vascular and unspecified dementia, particularly in the younger age groups. There was a significant increase in the risk of dementia, Alzheimer's disease, vascular dementia, and unspecified dementia. CONCLUSION: Vietnam War veterans showed an increased risk for all types of dementia. These findings are hypothesized to be due to the effects of the chemicals used during the Vietnam War, which can cause a variety of neurodegenerative diseases. Further studies are warranted to investigate the potential health determinants related to the Vietnam War, focusing on the neurodegenerative effects.

Multi-center external validation of an automated method segmenting and differentiating atypical lipomatous tumors from lipomas using radiomics and deep-learning on MRI.

Background: As differentiating between lipomas and atypical lipomatous tumors (ALTs) based on imaging is challenging and requires biopsies, radiomics has been proposed to aid the diagnosis. This study aimed to externally and prospectively validate a radiomics model differentiating between lipomas and ALTs on MRI in three large, multi-center cohorts, and extend it with automatic and minimally interactive segmentation methods to increase clinical feasibility. Methods: Three study cohorts were formed, two for external validation containing data from medical centers in the United States (US) collected from 2008 until 2018 and the United Kingdom (UK) collected from 2011 until 2017, and one for prospective validation consisting of data collected from 2020 until 2021 in the Netherlands. Patient characteristics, MDM2 amplification status, and MRI scans were collected. An automatic segmentation method was developed to segment all tumors on T1-weighted MRI scans of the validation cohorts. Segmentations were subsequently quality scored. In case of insufficient quality, an interactive segmentation method was used. Radiomics performance was evaluated for all cohorts and compared to two radiologists. Findings: The validation cohorts included 150 (54% ALT), 208 (37% ALT), and 86 patients (28% ALT) from the US, UK and NL. Of the 444 cases, 78% were automatically segmented. For 22%, interactive segmentation was necessary due to insufficient quality, with only 3% of all patients requiring manual adjustment. External validation resulted in an AUC of 0.74 (95% CI: 0.66, 0.82) in US data and 0.86 (0.80, 0.92) in UK data. Prospective validation resulted in an AUC of 0.89 (0.83, 0.96). The radiomics model performed similar to the two radiologists (US: 0.79 and 0.76, UK: 0.86 and 0.86, NL: 0.82 and 0.85). Interpretation: The radiomics model extended with automatic and minimally interactive segmentation methods accurately differentiated between lipomas and ALTs in two large, multi-center external cohorts, and in prospective validation, performing similar to expert radiologists, possibly limiting the need for invasive diagnostics. Funding: Hanarth fonds.

Metabolic Functions of the Infrapatellar Fat Pad: Implications for Knee Health and Pathology.

¼ Despite being historically viewed as a vestigial structure, the infrapatellar fat pad (IPFP) is now recognized as a metabolically active structure, influencing knee health through cytokine production and metabolic pathways.¼ With distinct anatomical regions, the IPFP contains diverse cell types including adipocytes, fibroblasts, and immune cells, influencing its functional roles, pathology, and contributions to knee disorders.¼ The IPFP acts as an endocrine organ by releasing adipokines such as adiponectin, leptin, and tumor necrosis factor α, regulating energy balance, immune responses, and tissue remodelling, with implications for knee joint health.¼ The IPFP's metabolic interactions with neighboring tissues influence joint health, clinical conditions such as knee pain, osteoarthritis, postoperative complications, and ganglion cysts, highlighting its therapeutic potential and clinical relevance.¼ Understanding the multifaceted metabolic role of the IPFP opens avenues for collaborative approaches that integrate orthopaedics, endocrinology, and immunology to develop innovative therapeutic strategies targeting the intricate connections between adipokines, joint health, and immune responses.

Endpoints and Design for Clinical Trials in USH2A-Related Retinal Degeneration: Results and Recommendations From the RUSH2A Natural History Study.

Purpose: To evaluate functional and structural assessments as endpoints for clinical trials for USH2A-related retinal degeneration. Methods: People with biallelic disease-causing variants in USH2A, visual acuity ≥ 20/80, and visual field ≥ 10° diameter were enrolled in a 4-year, natural history study. Participants underwent static perimetry, microperimetry, visual acuity, fullfield stimulus testing (FST), and optical coherence tomography annually. Rates of change estimated from mixed-effects linear models and percentages of eyes with changes exceeding the coefficient of repeatability (CoR) or thresholds conforming with U.S. Food and Drug Administration (FDA) guidelines were evaluated. Results: Rates of change were generally more sensitive to change than proportions of eyes exceeding a threshold such as the CoR. Baseline ellipsoid zone area ≥ 3 mm2 was necessary to detect change. Mean sensitivity and volumetric hill of vision measures on static perimetry had similar properties and were the most sensitive to changes of the continuous measures. The highest 4-year proportions of eyes exceeding the CoR were from FST testing (47%) and microperimetry (32%). Specification of loci as functional transition points (FTPs) resulted in 45% (static perimetry) and 46% (microperimetry) at 4 years, meeting FDA guidelines for progression. Conclusions: Rate of change of mean sensitivity on static perimetry was a sensitive perimetric continuous measure. Percentages of within-eye change were largest with FST testing and microperimetry. FTPs appear to be particularly sensitive to change. These results affect clinical trial design for USH2A-related retinal degeneration. Translational Relevance: Analyses of natural history data from the Rate of Progression in USH2A-Related Retinal Degeneration (RUSH2A) study can inform eligibility criteria and endpoints for clinical trials.

Efficacy and safety of a diffusion-based extended-release fluticasone propionate intra-articular injection (EP-104IAR) in knee osteoarthritis (SPRINGBOARD): a 24-week, multicentre, randomised, double-blind, vehicle-controlled, phase 2 trial.

BACKGROUND: Corticosteroids are among the few effective treatments for knee osteoarthritis, but short duration of action limits their utility. EP-104IAR, a long-acting formulation of fluticasone propionate for intra-articular injection, optimises the action of fluticasone propionate through novel diffusion-based extended-release technology. The SPRINGBOARD trial assessed the efficacy, safety, and pharmacokinetics of EP-104IAR in people with knee osteoarthritis. METHODS: SPRINGBOARD was a randomised, vehicle-controlled, double-blind, phase 2 trial done at 12 research sites in Denmark, Poland, and Czech Republic. We recruited adults aged 40 years or older with primary knee osteoarthritis (Kellgren-Lawrence grade 2-3) who reported Western Ontario and McMaster Universities Osteoarthritis Arthritis Index (WOMAC) pain scores of at least 4 and no more than 9 out of 10. Participants were randomly assigned (1:1) to receive one intra-articular dose of 25 mg EP-104IAR or vehicle control. Randomisation was done via interactive web-based access to a central predefined computer-generated list with block size of six (allocated by clinical site). Participants and assessors were masked to treatment allocation. Participants were followed up for 24 weeks. The primary outcome was the difference between groups in change in WOMAC pain score from baseline to week 12, analysed in all participants who were randomly assigned and received treatment. Safety, including laboratory analyses, and pharmacokinetics from quantification of fluticasone propionate in peripheral blood were assessed in all participants who received a dose of randomly assigned treatment. A person with lived experience of knee osteoarthritis was involved in study interpretation and writing of the report. This trial is registered with ClinicalTrials.gov, NCT04120402, and the EU Clinical Trials Register, EudraCT 2021-000859-39, and is complete. FINDINGS: Between Sept 10, 2021, and Nov 16, 2022, 1294 people were screened for eligibility, and 319 were randomly assigned to EP-104IAR (n=164) or vehicle control (n=155). One participant in the EP-104IAR group was excluded from all analyses because treatment was not administered due to an adverse event. 318 participants (135 [42%] male and 183 [58%] female, 315 [99%] White) received randomly assigned treatment and were included in the primary analysis and safety analysis (EP-104IAR, n=163; vehicle control, n=155). At week 12, least squares mean change in WOMAC pain score from baseline was -2·89 (95% CI -3·22 to -2·56) in the EP-104IAR group and -2·23 (-2·56 to -1·89) in the vehicle control group, with a between-group difference of -0·66 (-1·11 to -0·21; p=0·0044); a significant between-group difference persisted to week 14. 106 (65%) of 163 participants in the EP-104IAR group had one or more treatment-emergent adverse event compared with 89 (57%) of 155 participants in the vehicle control group. Effects on serum glucose and cortisol concentrations were minimal and transient. There were no treatment-emergent deaths or treatment-related serious adverse events. Plasma concentrations of fluticasone propionate showed a blunted initial peak with terminal half-life of approximately 18-20 weeks. INTERPRETATION: These phase 2 results suggest that EP-104IAR has the potential to offer clinically meaningful pain relief in knee osteoarthritis for an extended period of up to 14 weeks, longer than published data for currently marketed corticosteroids. There were minimal effects on glucose and cortisol, and stable fluticasone propionate concentrations in plasma. The safety and efficacy of EP-104IAR will be further evaluated in phase 3 trials, including the possibility of bilateral and repeat dosing with EP-104IAR. FUNDING: Eupraxia Pharmaceuticals. TRANSLATION: For the Danish translation of the abstract see Supplementary Materials section.

Robotic thoracic surgery: lessons learned from the first 1,000 procedures.

Introduction: The aim of this study was to evaluate the impact of the thoracic robotic approach in a high-volume center regarding procedures and clinical outcomes after 1,000 procedures. Methods: In a single-center subset of the Epithor® database, a prospective cohort database of French thoracic surgery, we analyzed procedural characteristics and clinical outcomes from February 2014 to April 2023. A surgical technique for lung surgery was conducted with a four-arm closed chest with the port access approach and vascular sewing and knotting were preferred over stapling. Statistical analysis was performed using the Chi-2 test for discontinuous variables and the Mann-Whitney-Wilcoxon test for continuous variables. Tests were considered significant for a p-value <0.05. Results: Robotic thoracic surgery was used in anatomical lung resection in 85% of the cases. Over the study period, 1,067 patients underwent robotic surgery, of which 509 had lobectomies and 391 segmentectomies. In the segmentectomy group vs. lobectomy group we observed a shorter length of stay (9 ± 7 vs. 7 ± 5.6 days, p < 0.001), a shorter surgery time (99 ± 24 vs. 116 ± 38 min, p < 0.001) a lower conversion rate (n = 2 vs. n = 17, p = 0.004), and a lower complication rate (28% vs. 40%, p = 0.009, mainly Clavien-Dindo II, 18% and 28%, respectively). For cancer treatment surgery, we found more previous cancer in the segmentectomy group (48% vs. 26%, p < 0.001). We also observed a progressive change of lobectomy vs. segmentectomy from 80%/20% to 30%/70% over the 9 years. Discussion: A robotic platform is an appropriate tool to perform anatomical lung resection and especially to develop a safe and systematic approach to lung-sparing sub-lobar resection.

Associations between maternal preconception and pregnancy adiposity and neuropsychiatric and behavioral outcomes in the offspring: A systematic review and meta-analysis.

Maternal adiposity (overweight or obesity) has been associated with adverse perinatal outcomes, although the potential risks of long-term neuropsychiatric and behavioral outcomes in the offspring remain unclear. Using the PRISMA guidelines, we searched PubMed, EMBASE, Scopus, and Web of Science to identify studies on maternal adiposity and offspring neuropsychiatric outcomes. Inverse variance-weighted random-effects meta-analyses were used to pool effect estimates with 95 % confidence intervals (95 % CIs) from adjusted odds ratios (OR) and hazard ratios (HR). Estimates were computed separately for preconception and pregnancy maternal overweight and obesity, with outcomes stratified by the type of neuropsychiatric outcome. In our meta-analyses of 42 epidemiological studies involving 3,680,937 mother-offspring pairs, we found increased risks of ADHD [OR=1.57, 95 % CI: 1.42-1.74], autism spectrum disorder [OR=1.42, 95 % CI: 1.22-1.65], conduct disorder [OR=1.16, 95 % CI: 1.00-1.35], Psychotic disorder [HR=1.61, 95 % CI: 1.41-1.83], externalizing behaviors [OR=1.30, 95 % CI: 1.07-1.56] and peer relationship problems [OR=1.25, 95 % CI: 1.04-1.27] in the offspring of preconception obese mothers. Similar increased risks were found in the offspring of preconception overweight mothers and those exposed to maternal adiposity during pregnancy. However, no association was found with offspring mood, anxiety, personality, eating, sleep disorders or prosocial problems. Preconception weight management may mitigate such adverse effects in the offspring.

THE IMPACT OF BIRTH WEIGHT ON INFANT MORTALITY IN KAZAKHSTAN.

INTRODUCTION: Recognizing the importance of birth weight is fundamental to addressing public health challenges associated with maternal and child health. Birth weight serves as a critical indicator, offering insights into mortality, stunting, and the development of chronic diseases later in life. This study delves into fertility and infant mortality trends in Kazakhstan, with a specific focus on understanding urban-rural disparities and gender variations in mortality rates. OBJECTIVES: The primary objective of this study is to evaluate the influence of birth weight on infant mortality in Kazakhstan, considering demographic and regional nuances. Through comprehensive analysis, we aim to discern patterns and factors contributing to infant mortality, thereby informing targeted interventions and policies aimed at improving maternal and child health outcomes across the country. MATERIALS AND METHODS: The analysis was conducted using the data provided by the Republican State Enterprise on the PCV of the "Republican Centre for Electronic Health Care" of the Ministry of Health of Kazakhstan. RESULTS: In Kazakhstan, birth rates reached their zenith in 2021 (total 446,491 births). However, this figure experienced a downturn in 2022, declining to 403,893 births. Notably, urban regions consistently reported higher birth rates compared to rural areas. The year 2022 witnessed a decline in birth rates across both urban and rural populations, with decreases of 9.5% and 11.7%, respectively, compared to the previous year. Analysis using linear regression techniques on infant mortality rates spanning from 2017 to 2022 revealed no statistically significant time trend (slope=51.29, correlation coefficient=0.42, p=0.41). Gender-specific disparities in mortality rates were starkly evident, with boys exhibiting higher mortality rates compared to girls across all population subsets. Geographical analysis conducted in 2022 exposed significant divergences in mortality rates across various regions. CONCLUSIONS: The study highlights significant urban-rural disparities and gender differences in birth rates and infant mortality within Kazakhstan. It also confirms the protective effect of higher birth weight on infant mortality. Regional disparities suggest targeted public health interventions are necessary to address these variations effectively.

Insertable, dual-density dielectric barrier for acoustic pressure level reduction in a high-performance human head-only MRI system.

We report use of a dual-density dielectric barrier surrounding a detachable high-pass radiofrequency (RF) birdcage coil to achieve an order-of-magnitude reduction of acoustic noise in a high-performance head gradient system. The barrier consisted of a 4.5 mm-thick mass-loaded vinyl and a 6 mm-thick polyurethane foam. It was inserted into the radial gap between the birdcage coil and the RF shield in a prototype head-only gradient system at 3 T. More than 9 dBA reduction of sound pressure level was achieved on the average with representative, high acoustic-noise imaging sequences. Increased acoustic damping was apparent from acoustic impulse response functions. High dielectric constant of the mass-loaded vinyl effectively added distributed capacitance to the birdcage coil, lowering the resonance frequency, but not seriously degrading the RF transmission performance. The barrier occupied the radial space normally used for air cooling of the RF coil and the RF shield. The resulting omission of air cooling was found to be acceptable with efficient gradient thermal management and use of a high-resistivity RF shield for eddy current reduction. The proposed method can improve patient experience while preserving image quality in a high-power head-only gradient system.

Nationwide precision oncology pilot study: KOrean Precision Medicine Networking Group Study of MOlecular profiling-guided therapy based on genomic alterations in advanced solid tumors (KOSMOS) KCSG AL-20-05.

BACKGROUND: Next-generation sequencing (NGS) has become widely available but molecular profiling-guided therapy (MGT) had not been well established in the real world due to lack of available therapies and expertise to match treatment. Our study was designed to test the feasibility of a nationwide platform of NGS-guided MGT recommended by a central molecular tumor board (cMTB) for metastatic solid tumors. PATIENTS AND METHODS: Patients with advanced or metastatic solid tumors with available NGS results and without standard treatment were enrolled. The cMTB interpreted the patients' NGS reports and recommended the following: (i) investigational medicinal products (IMPs) approved in other indications; (ii) alternative treatments; (iii) clinical trials. The primary variables were the proportion of patients with actionable genomic alterations and those receiving MGT as per cMTB recommendations. Others included treatment duration (TD), overall response rate (ORR), disease control rate (DCR), and safety. RESULTS: From February 2021 to February 2022, 193 cases [99 (51.3%) men; median age 58 years (range 24-88 years); median line of previous treatment 3 (range 0-9)] from 29 sites were enrolled for 60 cMTB sessions. The median time from case submission to cMTB discussion was 7 days (range 2-20 days), and to IMP treatment initiation was 28 days (range 14-90 days). Actionable genetic alterations were found in 145 patients (75.1%). A total of 89 (46.1%) patients received actual dosing of IMPs, and 10 (5.2%) were enrolled in cMTB-recommended clinical trials, achieving an MGT rate of 51.3%. ORR and DCR of IMPs were 10.1% and 72.5%, respectively. The median TD was 3.5 months [95% confidence interval (CI) 2.8-5.5 months], and the 4-month TD rate was 44.9%. The median overall survival of patients who received IMPs was 6.9 months (95% CI 5.2-10.0 months). CONCLUSION: KOSMOS confirmed the feasibility of MGT recommended by the cMTB, achieving a high MGT match rate and promising effectiveness in heavily pretreated advanced cancer patients.

Evaluation of maternal bromoform supplementation in late gestation on blood parameters of cows and their progeny.

Bromoform supplementation has been successful in reducing enteric methanogenesis in ruminants; however, the impacts on the health of these animals are still limited. The current study evaluates the impact of maternal bromoform supplementation on the health of late-gestation cows and their progeny. Pregnant Angus cows (n = 42) were allocated into a control or bromoform group (n = 21 cows per treatment). Bromoform extracted from Asparagopsis armata (7,372 mg/kg) was supplemented once daily. Blood samples were collected from cows before supplementation (baseline). Within 24 h of parturition, blood and colostrum samples were collected from each cow and blood from neonates. Colostrum brix was measured to indicate immunoglobulin content. All data was analysed using the MIXED procedure in SAS. Supplementation of cows with bromoform resulted in increased blood urea to creatinine ratio (P = 0.048), base excess (P = 0.049), total carbon dioxide (TCO2; P = 0.048) and a decrease in blood glutamate dehydrogenase (GLDH; P = 0.031) compared to the control group. For cows in the bromoform group, a trend was observed for higher levels of partial pressure of carbon dioxide (pCO2; P = 0.070) and bicarbonate (HCO3-; P = 0.052), and lower levels of partial pressure of oxygen (pO2; P = 0.058) compared to the control group. Blood gamma-glutamyl transferase (GGT) was elevated in offspring of cows fed bromoform (P = 0.050). The lower blood pO2 of pregnant cows fed bromoform and elevated blood GGT levels in offspring are not well understood and highlight the need for further investigation. Additionally, the low-dose bromoform supplementation affected various blood gas parameters of cows and calves, demonstrating the importance of monitoring these parameters when using different doses of halogenated compounds in livestock.

Acceleration of HDL-Mediated Cholesterol Efflux Alleviates Periodontitis.

Periodontitis (PD) is a common inflammatory disease known to be closely associated with metabolic disorders, particularly hyperlipidemia. In the current study, we demonstrated that hypercholesterolemia is a predisposing factor in the development of PD. Logistic regression analysis revealed a strong positive correlation between PD and dyslipidemia. Data from in vivo (PD mouse model subjected to a high cholesterol diet) and in vitro (cholesterol treatment of gingival fibroblasts [GFs]) experiments showed that excess cholesterol influx into GFs potentially contributes to periodontal inflammation and, subsequently, alveolar bone erosion. Additionally, we compared the protective efficacies of cholesterol-lowering drugs with their different modes of action against PD pathogenesis in mice. Among the cholesterol-lowering drugs we tested, fenofibrate exerted the most protective effect against PD pathogenesis due to an increased level of high-density lipoprotein cholesterol, a lipoprotein involved in cholesterol efflux from cells and reverse cholesterol transport. Indeed, cholesterol efflux was suppressed during PD progression by downregulation of the apoA-I binding protein (APOA1BP) expression in inflamed GFs. We also demonstrated that the overexpression of APOA1BP efficiently regulated periodontal inflammation and the subsequent alveolar bone loss by inducing cholesterol efflux. Our collective findings highlight the potential utility of currently available cholesterol-lowering medications for the mitigation of PD pathogenesis. By targeting the acceleration of high-density lipoprotein-mediated cellular cholesterol efflux, a new therapeutic approach for PD may become possible.

Work-related injuries and illnesses (WRII) presenting to Illinois hospitals, 2017-2021: The importance of emergency department (ED) data.

OBJECTIVES: Research characterizing work-related injuries and illnesses (WRII) has predominantly focused on inpatients and deaths, despite evidence that 4% of WRII are admitted as inpatients and deaths are less than 0.2% of acute WRII. Our aim is to determine the usefulness of incorporating emergency department (ED) hospital data into current occupational health surveillance systems. METHODS: Data on ED and admitted WRII treated in Illinois hospitals from 2017 to 2021 were analyzed. Demographic characteristics, primary diagnosis, procedures undertaken, and unique patient estimates are described. Multivariable logistic regression models were developed to evaluate predictors of treatment in the ED and multivariable median regression models determined associations of total hospital charges. RESULTS: Between 2017 and 2021 there were 488,033 hospital presentations (95.9% nonadmissions) for WRII in Illinois, equating to a crude annual population rate of 1502.1/100,000. Non-Hispanic Whites (NHW) were disproportionately treated for illnesses, while Hispanic or Latino workers were disproportionately treated for injuries. African-Americans had the highest rate of ED emergent presentations (incident rate ratio [IRR] = 1.3, ref = NHW) and were less likely to be admitted for emergent presentations (IRR = 0.7, ref = NHW). ED presentations were more likely to be female, present with an injury, and at a rural, versus urban, hospital. Radiological investigations compromised the majority of procedures for nonadmitted patients (n = 403,317), and 94.8% were coded for a body region CONCLUSION: Between 2017 and 2021 in Illinois, there were nearly 500,000 hospital visits charged to workers' compensation totaling over US$ four billion. ED data provide additional insights into work-related chronic conditions, health disparities, and the usage of diagnostic and therapeutic procedures for WRII.

A phase II study of tepotinib in patients with advanced solid cancers harboring MET exon 14 skipping mutations or amplification (KCSG AL19-17).

BACKGROUND: We evaluated the efficacy and safety of tepotinib in patients with various solid cancers harboring MET exon 14 skipping mutation (METex14) or MET gene amplification. PATIENTS AND METHODS: A phase II, multicenter study was conducted in patients with advanced or metastatic solid cancers who progressed after standard treatment, harboring either METex14 or MET amplification detected in tissue-based next-generation sequencing (NGS). The primary endpoint was objective response rate (ORR). For exploratory analyses, we analyzed the gene profiles using plasma NGS test. RESULTS: Thirty-five patients were enrolled. The ORR was 57.6% for all patients, 52.2% for those with METex14, and 70% for those with MET amplification. Median progression-free survival (PFS) was 8 months [95% confidence interval (CI) 4.5-11.5 months] and median overall survival (OS) was 14 months (95% CI 7.8-20.2 months) in all patients. For patients with non-small-cell lung cancer with METex14, the median PFS was 9 months (95% CI 4.7-13.4 months) and the median OS was 17 months [95% CI not applicable (NA)-NA]. For patients with MET amplification, the median PFS was 7 months (95% CI 1.5-12.5 months) and the median OS was 10 months (95% CI 5.8-14.2 months). The ORR of patients with MET dysregulation detected by plasma NGS was 72.2%, whereas the ORR was 30% in those without detection. The most common adverse events were peripheral edema, asthenia, transaminase elevation, and anorexia, mostly grade 1 or 2. CONCLUSIONS: Tepotinib demonstrated consistent antitumor activity in patients with METex14, and promising antitumor activity in various cancers with MET amplification. Detection of MET dysregulation by plasma NGS may predict the response to tepotinib.

Quality control efforts of medical institutions: the impacts of a value-based payment system on medical staff and healthcare-associated infections.

BACKGROUND: In South Korea, various quality assessments have been introduced to improve the quality of care; as such, the overall level of quality of medical institutions has improved. However, gaps still exist between institutions. AIM: To evaluate the impact of quality management efforts of medical institutions on securing medical staff and healthcare-associated infections in intensive care units (ICUs). METHODS: This study used data from the second and third ICU quality assessments conducted by the Health Insurance Review and Assessment Service, which included 265 hospitals and 39,096 inpatients. The continuous quality improvement efforts of medical institutions were measured according to changes in their grade based on quality assessment results. In addition, healthcare-associated infection rates were measured, including rates for ventilator-associated pneumonia and catheter-associated infections. The incidence rate ratio (IRR) was calculated using generalized estimating equation Poisson regression models that included hospital and patient characteristics. RESULTS: Healthcare-associated infections occurred in approximately 2% of patients using ventilators or catheters. Ventilator-associated pneumonia increased significantly in institutions with a decline in grade [IRR 2.038, 95% confidence interval (CI) 1.426-2.915]. In institutions with an improvement in grade, infections associated with central venous catheters (IRR 0.484, 95% CI 0.330-0.711) and urinary catheters (IRR 0.587, 95% CI 0.398-0.866) decreased. CONCLUSIONS: Although quality assessment has been introduced in ICUs in South Korea, some gaps remain between medical institutions. Differences in securing medical resources through the quality management efforts of medical institutions were observed, and the infection rate was low in hospitals with high-quality management and high in hospitals with low-quality management.

Developing molecular classifiers to detect environmental stressors, smolt stages and morbidity in coho salmon, Oncorhynchus kisutch.

Aquatic species are increasingly confronted with environmental stressors because of climate change. Although molecular technologies have advanced our understanding of how organisms respond to stressors in laboratory settings, the ability to detect physiological responses to specific stressors under complex field conditions remains underdeveloped. This research applied multi-stressor challenge trials on coho salmon, employing the "Salmon Fit-Chips" genomic tool and a random forest-based classification model to develop classifiers predictive for chronic thermal and hypoxic stress, as well as salinity acclimation, smolt stage and morbidity status. The study also examined how smolts and de-smolts (smolts not having entered SW during the smolt window) responded transcriptionally to exposure to saltwater. Using RF classifiers optimized with 4 to 12 biomarkers, we identified transcriptional signatures that accurately predicted the presence of each stressor and physiological state, achieving prediction accuracy rates between 86.8 % and 100 %, regardless of other background stressors present. Stressor recovery time was established by placing fish back into non-stressor conditions after stress exposure, providing important context to stressor detections in field applications. Recovery from thermal and hypoxic stress requires about 3 and 2 days, respectively, with >3 days needed for re-acclimation to freshwater for seawater acclimated fish. The study also found non-additive (synergistic) effects of multiple stressors on mortality risk. Importantly, osmotic stress associated with de-smolts was the most important predictor of mortality. In saltwater, de-smolts exposed to salinity, high temperature, and hypoxia experienced a 9-fold increase in mortality compared to those only exposed to saltwater, suggesting a synergistic response to multiple stressors. These findings suggest that delays in hatchery releases to support release of larger fish need to be carefully scrutinized to ensure fish are not being released as de-smolts, which are highly susceptible to additional climate-induced stressors like rising temperatures and reduced dissolved oxygen levels in the marine environment.

A longitudinal assessment of heat exposure and biomarkers of kidney function on heat shock protein 70 and antibodies among agricultural workers.

BACKGROUND: Exposure to extreme heat impacts millions of people worldwide and outdoor workers are among the populations most affected by hot temperatures. Heat stress induces several biological responses in humans, including the production of heat shock proteins (HSP) and antibodies against HSP (anti-HSP) which may play a central role in the body's cellular response to a hot environment. OBJECTIVE: This longitudinal study investigated the impact of elevated temperatures and humidity on the presence of HSP70 and anti-HSP70 and examined relationships with markers of kidney function in an at-risk workforce under conditions of extreme heat and exertion in Guatemala. METHODS: We collected ambient temperature and relative humidity data as well as biomarkers and clinical data from 40 sugarcane workers at the start and the end of a 6-month harvest. We used generalized mixed-effects models to estimate temperature effects on HSP70 and anti-HSP70 levels. In addition, we examined trends between HSP70 and anti-HSP70 levels and markers of kidney function across the harvest. RESULTS: At the end of the harvest, temperatures were higher, and workers had, on average, higher levels of HSP70 and anti-HSP70 compared to the beginning of the season. We observed significant increasing trends with temperature indices, heat index, and HSP70 levels. Maximum temperature was associated with HSP70 increments after controlling for age, systolic and diastolic blood pressure (ß: 0.21, 95% Confidence Interval: 0.09, 0.33). Kidney function decline across the harvest was associated with both higher levels of anti-HSP70 levels at the end of the harvest as well as greater increases in anti-HSP70 levels across the harvest. CONCLUSIONS: These results suggest that workplace heat exposure may increase the production of HSP70 and anti-HSP70 levels and that there may be a relationship between increasing anti-HSP70 antibodies and the development of renal injury. HSP70 holds promise as a biomarker of heat stress in exposed populations.