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Abstract Background Optimal treatment for resectable gastric and gastroesophageal junction (GEJ) adenocarcinoma remains unclear due to limited head-to-head comparisons among chemotherapy and chemoradiation regimens. This network meta-analysis aimed to determine the relative efficacy of available multimodality treatment regimens in these patients. Methods MEDLINE, EMBASE, Scopus, Web of Science, and CENTRAL were searched till September 20, 2024. Phase 3 randomized trials evaluating perioperative/neoadjuvant systemic therapy ± radiation in resectable gastric/GEJ adenocarcinoma were included. Primary outcomes were disease-free survival (DFS) and overall survival (OS). Frequentist network meta-analysis was conducted to compare hazard ratios (HRs) and 95% confidence intervals (CIs). Results Fifteen trials (8072 patients) were analyzed. pFLOT (perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel) ranked highest for DFS in the overall population (P-score 91%), achieving significant improvements compared to surgery alone (HR 0.48, 95% CI, 0.38-0.60) and nCROSS (neoadjuvant paclitaxel, carboplatin, and radiotherapy) (0.67, 0.56-0.81). For OS, nPLF + nCRT(EP) (neoadjuvant cisplatin, leucovorin, and fluorouracil for induction, followed by etoposide, cisplatin, and radiotherapy) (P-score 90%) and pFLOT (P-score 87%) were the top regimens. pFLOT significantly outperformed surgery alone (0.57, 0.45-0.72) and nCROSS (0.73, 0.60-0.89). Based on the limited data available, adding neoadjuvant chemoradiation to pFLOT provided no additional OS (1.14, 0.76-1.72) or DFS (1.22, 0.83-1.82) benefit. Similarly, adding pembrolizumab to perioperative chemotherapy (cisplatin and fluorouracil/capecitabine) was not superior to pFLOT (DFS: 1.10, 0.71-1.69; OS: 1.09, 0.69-1.72). Conclusions pFLOT demonstrated superior efficacy in resectable gastric/GEJ adenocarcinoma, outperforming surgery alone, nCROSS, and alternative perioperative regimens. The additive role of immunotherapy requires further investigation to optimize patient selection and outcomes.

Background Right ventricular (RV) maladaptation to elevated pulmonary afterload is the primary determinant of outcomes in pulmonary artery (PA) hypertension; however, the pathobiological mechanisms underlying RV decompensation remain poorly understood. Methods We performed global untargeted metabolomics on plasma from 55 patients who underwent gold‐standard RV‐PA coupling measurements using multibeat pressure volume loop assessment in a single‐center cohort and from 1027 patients with coupling surrogate measurements in a larger multicenter cohort, the PVDOMICS (Pulmonary Vascular Disease Phenomics) study. Age and sex‐adjusted linear regression was performed to identify associations between metabolites and coupling metrics. Additionally, we performed a metabolic flux analysis using gene expression data from RV tissue in an independent cohort of 32 patients. Partial least squares–discriminant analysis was used to identify metabolites and reactions characteristic of the decompensated RV. Results RV‐PA coupling was negatively associated with tricarboxylic acid (TCA) cycle intermediate levels. Specifically, plasma α‐ketoglutarate and fumarate were significantly associated with all coupling metrics in both cohorts. Metabolic flux analysis indicated that decompensated RVs exhibited aberrant TCA cycle activity, including reduced acetyl coenzyme A entry and increased lactate elimination, suggesting a shift from the TCA cycle toward glycolysis at the RV tissue level. Conclusions We identify an association between circulating TCA cycle intermediate levels and RV‐PA uncoupling in 2 independent cohorts, and dysregulated TCA cycle metabolism in decompensated PA hypertension RVs, suggesting that aberrant TCA cycle metabolism could represent a hallmark of RV maladaptation in PA hypertension. Further study of this pathway is warranted to develop novel biomarkers of RV function or RV‐targeted therapies.

Abstract As the prevalence of hip arthroscopy increases, management of capsular defects as well as capsulotomy closure has increasingly been recognized for their impact on recurrent symptoms in the young athletic hip. Several recent studies have shown that capsular closure at the time of primary hip arthroscopy improves both short‐ and long‐term patient‐reported outcomes, revision rates, and conversion to arthroplasty. Specifically, capsular insufficiency is a source of recurrent pain and microinstability. In this context, far medial labral tears pose a challenge for suture fixation, given the historic need of extending the interportal capsulotomy to obtain adequate trajectory for suture anchors and subsequent passage. Given the suboptimal stability consequences of extending the capsulotomy medially, here we present a novel approach for suture fixation of the medial labrum. This technique provides an effective method for suture fixation of the medial labrum, without necessitating extension of the interportal capsulotomy. Technique Video video See video under supplementary data.

Abstract Objective The aim of this study was to evaluate the efficacy and safety of a 60‐day peripheral nerve stimulation (PNS) treatment targeting the occipital nerves for reducing pain and improving function in individuals diagnosed with cervicogenic headache or occipital neuralgia. Background Headache conditions are prevalent and commonly disabling, and conventional therapeutic strategies are often insufficient. Development of a percutaneous 60‐day PNS treatment has created new opportunities to evaluate PNS of the occipital nerves. Methods This study was an institutional review board‐approved, multicenter, prospective, single‐arm study that enrolled participants from October 2022 to March 2024. Participants with cervicogenic headache or occipital neuralgia received a 60‐day PNS treatment targeting the occipital nerves. The primary endpoint was the proportion reporting clinically significant (≥30%) reductions in average pain and/or pain interference at end of treatment (EOT). Additional analysis included the proportion of participants with ≥50% reduction in average pain intensity and/or pain interference and additional outcomes including Patient Global Impression of Change, six‐item Headache Impact Test, and Neck Disability Index. Results At EOT, 90% of participants (18/20) met the primary endpoint. Further, 85% (17/20) and 83% (15/18) reported ≥50% reductions in pain and/or pain interference at EOT and 3 months, respectively. Clinically meaningful improvements were observed in functional and headache‐related disability and quality‐of‐life measures. All study‐related adverse events were non‐serious. Conclusion Most participants reported significant reductions in pain and/or pain interference following 60‐day PNS targeting the occipital nerves. Outcomes through 3 months demonstrate how 60‐day PNS offers an effective approach for the treatment of headache.

Background: Currently, biomarkers do not have a role in diagnosis or outcome prediction models for patients with recurrent anterior shoulder instability. Purpose/Hypothesis: The purpose of this study was to compare gene expression differences in the blood and tissue of patients with anterior shoulder instability with and without significant glenoid bone loss (GBL). The hypothesis was that the severity of GBL would be associated with the expression level of genes in the blood and capsular tissue of patients with anterior shoulder instability. Study Design: Descriptive laboratory study. Methods: Consecutive patients with anterior shoulder instability undergoing arthroscopic and open shoulder stabilization were prospectively enrolled. Blood and anterior capsular tissue specimens obtained during surgery were compared between patients with significant GBL (≥10%) and patients without significant GBL (<10%). RNA was extracted, and a panel of 277 inflammatory genes was utilized to quantify gene expression at the RNA level using a probe-based RNA quantification platform. Differential expression analysis was performed to identify genes expressed at different levels between patients with and without significant GBL. The expression levels of the subset of genes identified were used to generate a ridge regression model to predict the severity of GBL. Quantitative polymerase chain reaction was performed to confirm probe-based RNA findings. Results: A total of 17 patients were included, with a mean age of 26 years. Overall, 7 patients had <10% GBL (mean, 2.3%), and 10 patients had ≥10% GBL (mean, 16.4%). There were 9 genes that were identified as significantly differentially expressed in the blood, and 5 of these ( IFIT1 , IFIT3 , IFI44 , PRKCB , and OAS2 with P values of 1 × 10 −5 , 1 × 10 −4 , 1 × 10 −4 , 1 × 10 −4 , and 6 × 10 −4 , respectively) were confirmed using nonparametric tests. The authors developed a model using the 5 genes to predict the severity of GBL, and this had an accuracy of 88% (95% CI, 64%-99%). By quantitative polymerase chain reaction, IFIT3 was confirmed to be significantly differentially expressed ( P = .012). Conclusion: There were significant gene expression differences in the blood of patients with (≥10%) and without (<10%) significant GBL. The differential expression of 5 genes allowed for the development of an accurate predictive model and transcriptomic biomarker to predict the severity of GBL. Clinical Relevance: The addition of a blood biomarker to current outcome prediction models may provide increased accuracy in identifying those at risk of failure from arthroscopic Bankart repair.

Background Olfactory dysfunction (OD) is a common symptom in patients with coronavirus disease 2019 (COVID-19) with limited treatment options. Objective This pilot study aimed to investigate an acupuncture protocol in patients with COVID-19 related OD. Methods Thirty patients were randomized into 2 groups. The standard group was treated with budesonide nasal irrigation and olfactory training. The acupuncture group received ten sessions of acupuncture therapy in addition to the standard group treatment. Olfaction was assessed using the University of Pennsylvania Smell Identification Test, 10-point visual analog scale, and Sino-Nasal Outcome Test at baseline and after 3 months of treatment. Differences between study arms were compared using Fisher’s exact and Wilcoxon rank sum tests. Results Eighteen of the 30 (60%) enrolled patients completed the study, including 11 (73%) in the standard and 7 (47%) in the acupuncture group. Reasons for participant drop-out included cost of travel and time constraints. There were no acupuncture complications. Conclusions Acupuncture as an adjunct therapy for COVID-19 related OD is well tolerated. Subsequent studies with larger sample sizes are needed to assess the effect of acupuncture on OD.

Abstract Rationale: SARS-CoV-2 infection may be associated with new or worsening respiratory symptoms that, if persistent, may contribute to “Long COVID.” Research is needed on the prevalence and risk determinants of Long COVID and related respiratory symptoms in adults with and without pre-existing obstructive lung disease or smoking history. Methods: C4R is a prospective, observational study that collected information on SARS-CoV-2 infection using standardized methods across 14 NIH-funded cohorts. The third wave of C4R questionnaires, administered June 2023 to January 2025, assessed self-reported Long COVID via the question, “Do you think that you are experiencing, or have ever experienced, what has been called “long COVID,” or symptoms related to COVID at least a month after your infection?” Questionnaires also assessed the presence (vs absence) of 22 symptoms that have been linked to Long COVID, including cough, shortness of breath, and post-exertional malaise. Pre-pandemic obstructive lung disease (COPD or asthma) and smoking status (ever/never) were harmonized from self-reported data collected at the most recent pre-pandemic cohort exam. Poisson regression was used to assess prevalence ratios (PRs) adjusting for age, sex, BMI, education, and pre-pandemic hypertension, diabetes, cardiovascular disease, and depressive symptoms. PRs for respiratory symptoms were tested according to self-reported Long COVID and history of non-hospitalized or hospitalized infection; effect modification by pre-pandemic lung disease and smoking was assessed by multiplicative interaction terms and in fully stratified models. Results: Among 23,434 questionnaire respondents, 1,484 (6.3%) self-reported Long COVID, including 246/1,262 (19.5%) with pre-pandemic lung disease and 664/4,018 (16.5%) with smoking history. The adjusted PR for Long COVID was 1.17 (95%CI:0.99-1.39;P=0.06) comparing participants with/without lung disease and 1.17 (95%CI:1.04-1.32;P=0.01) comparing participants with/without smoking history. Respiratory symptoms were more prevalent in those with self-reported Long COVID, as well as in those with a history of hospitalized or non-hospitalized infection (Table). Associations were generally stronger in participants without pre-pandemic lung disease (p-interaction&lt;0.05 for all comparisons). Respiratory symptoms were also more prevalent with a history of repeated, and pre-Omicron infections, and were less prevalent among participants vaccinated prior to their first infection; findings were similar even after excluding participants with self-reported Long COVID. Conclusions: Long COVID is common, particularly in adults with pre-existing COPD or asthma or smoking history. Long COVID and history of SARS-CoV-2 infection, including non-hospitalized infections, was associated with greater respiratory symptom burden. Whether SARS-CoV-2 infection or Long COVID are associated with development or progression of obstructive lung diseases warrants future studies.

Abstract RATIONALE: Chronic kidney disease (CKD) is common in the general population and is associated with inflammation and compromised immune function. Since these mechanisms are hypothesized to promote severe COVID-19, we tested associations of pre-pandemic CKD with incident COVID-19 hospitalization or death in a large, multi-ethnic, US general population-based meta-cohort of adults. METHODS: Data were harmonized and pooled from 9 NIH-funded longitudinal cohorts participating in the Collaborative Cohort of Cohorts for COVID-19 Research (C4R). CKD was classified by KDIGO 2024 CKD guideline (Low Risk, Moderately Increased Risk, High Risk, Very High Risk) using pre-pandemic urinary albumin-to-creatinine ratio (uACR) and estimated glomerular filtration rate using creatinine (eGFRcr). Incident COVID-19 hospitalization or death was ascertained over 2020−2023 via self-report and active surveillance, with medical record adjudication in a subset. In our primary analysis, we assessed associations between CKD stages and incident COVID-19 hospitalization or death. A secondary analysis examined joint association of CKD stages and the number of comorbidities (obesity, hypertension, diabetes, and cardiovascular disease) with the severe COVID-19. Multivariable hazard ratios (HRs) were estimated by cause-specific Cox regression, adjusting for socio-demographics and smoking. RESULTS: Among 26,039 multi-ethnic adult participants (mean age 66.1±14.8, 60.6 % female, 28.6% Whites, 3.2% Asians, 20.6% Blacks, 41.3% Hispanics, 6.3% American Indians) with a median follow-up of 550 days since the onset of the pandemic (baseline: March 1, 2020), there were 734 incident COVID-19 hospitalizations or deaths. The mean time since CKD markers were measured before the baseline was 6.5 years. The cumulative incidence of severe COVID-19 was 2.3, 3.5, 6.5, and 7.3% across CKD risk stages, and similar patterns were observed within variant types (Figure 1). Compared to participants with Low Risk of CKD, there was a graded increased hazards of severe COVID-19 across CKD stages, with HRs (95% CIs) of 1.27 (1.03−1.55) for Moderately Increased Risk, 2.33 (1.77−3.06) for High Risk, and 2.72 (1.89−3.92) for Very High Risk. In a joint analysis, both increased CKD risk and a higher number of comorbidities were associated with a higher risk of severe COVID-19, showing the highest HR of 12.29 (5.75−26.27) in Very High Risk individuals with four comorbidities compared to Low Risk individuals with none. CONCLUSIONS: Higher CKD stages were associated with a greater risk of COVID-19 hospitalization or death and the risk is substantially heightened with additional comorbidities. These results suggest that adults with CKD and related comorbidities may merit enhanced COVID-19 risk mitigation.

Abstract Rationale: Prior studies report association between pulmonary artery (PA) dilation on computed tomography (CT) imaging and pulmonary hypertension (PH). These studies predate expansion of PH hemodynamic diagnostic criteria and do not report patient mortality. As such, little is known about the presence of vascular changes in mild PH or their association with survival. We sought to investigate these relationships in individuals without significant parenchymal lung disease. Methods: We obtained CT images for subjects with group 1 or 2 PH, disease comparators, and healthy controls enrolled in the Pulmonary Vascular Disease Phenomics (PVDOMICS) study. We used Osirix imaging software to measure the main, left, and right PA (MPA, LPA, and RPA) and MPA:aorta (PA:Ao) ratio by diameter and cross-sectional area at locations consistent with prior studies. We evaluated associations with mortality and mean PA pressure (mPAP) using multivariable Cox and linear regression models adjusting for age, sex, and BMI. Descriptive statistics are presented as mean ± SD. Results: We identified 558 subjects (59 controls, 138 comparators, and 361 PH [267 group 1, 94 group 2]). 79 subjects had mPAP &lt; 21 mmHg, 39 had mPAP 21-24 mmHg, and 371 had mPAP ≥ 25 mmHg. Increased MPA, LPA, and RPA diameter and area, PA:Aodia, and PA:Aoarea were associated with decreased survival (all p &lt; 0.001) after multivariable adjustment. First versus third quantiles of all measurements were associated with mortality, with adjusted hazard ratio of 2.99 [95% CI 1.77, 5.05] for MPA diameter (2.84 vs 3.82 cm), 3.74 [2.07, 6.74] for MPA area (7.26 vs 12.74 cm2) and 5.24 [2.58, 10.66] for LPA area (4.55 vs 7.03 cm2). All measures significantly increased alongside PH severity from mPAP &lt; 20 to 21-24 to ≥ 25 mmHg (see figure 1 for MPA diameter). All measures positively correlated with mPAP, including MPA diameter (ρspearman = 0.55) and PA:Aodia (ρ = 0.56). After multivariable adjustment, Q1 to Q3 increments in MPA diameter and PA:Aodia were associated with mPAP increase of 12.5 [10.7, 14.4] and 13.9 [11.9, 15.8] mmHg, respectively. BMI showed no correlation with PA size (ρ = 0.076 for MPA area, -0.051 for PA:Aodia). Conclusions: PA size increases alongside PH severity using updated hemodynamic criteria and is associated with incremental increases in PA pressure and mortality. LPA dilation demonstrates particularly strong association with mortality. PA size does not correlate with BMI. These novel findings enhance our understanding of vascular changes across the PH disease spectrum.

Abstract RATIONALE: Endothelial-to-mesenchymal transition (EndMT) is a cellular process in which endothelial cells (ECs) transition into mesenchymal cells, a mechanism recently linked to pulmonary vascular remodeling in pulmonary hypertension (PH). However, the regulatory mechanisms driving EndMT in PH remain largely undefined. MicroRNA-153 (miR-153), a small non-coding RNA, regulates gene expression by targeting the 3'-untranslated region (3'-UTR) of mRNA, affecting mRNA translation and stability. This study investigates miR-153's role in modulating EndMT in PH. METHODS: Human lung vascular endothelial cells (LVECs) were isolated from healthy individuals and patients with idiopathic pulmonary arterial hypertension (IPAH). In vitro, normal LVECs were exposed to hypoxia (3% O₂) for 72 hours or treated with TGF-β1 (10 ng/mL) for 7 days to induce EndMT. Levels of miR-153 and EndMT markers were quantified by qPCR, Western blotting, or immunostaining. Proliferation and apoptosis of ECs were assessed using EdU and TUNEL assays, respectively. LVECs were transfected with miR-153 inhibitor or mimic, then exposed to normoxic or hypoxic conditions, respectively for 72 hours. In vivo, mice were subjected to either hypoxia (10% O₂ for 6 weeks, Hx-PH) or Sugen5416/hypoxia (20 mg/kg i.p. plus 10% O₂ for 6 weeks, SuHx-PH) to induce PH. The PH phenotype in mice was evaluated by hemodynamic measurements and histological analysis of H&E-stained lung tissues. RESULTS:In silico analysis identified miR-153 as a direct regulator of human SNAI1 and SNAI2 genes via binding to their 3'-UTR. Downregulation of miR-153 in IPAH LVECs was correlated with elevated SNAI1/2 expression, increased EndMT, and higher proliferation compared to normal LVECs. Hypoxia or TGF-β1 treatment reduced miR-153 expression, increased EndMT transcription factors (SNAI1/2), mesenchymal markers (SM-22, vimentin), and reduced EC markers (CD31, VE-cadherin). In normoxic LVECs, miR-153 inhibition significantly upregulated SNAI1/2, increased EndMT and EC proliferation, and reduced apoptosis. Conversely, miR-153 mimic abolished hypoxia- and TGF-β1-induced EndMT. Overexpression of miR-153 attenuated hypoxia-induced EC survival. In PH mouse models, reduced miR-153 levels were associated with activated SNAI1/2, EndMT, and pulmonary vascular remodeling. CONCLUSIONS: Downregulation of miR-153 drives phenotypic transition of LVECs to proliferative mesenchymal cells via SNAI-mediated EndMT, contributing to pulmonary vascular remodeling and PH. Therefore, miR-153 could be a potential therapeutic target for PH treatment.