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Listing and transplanting patients with acute liver failure (ALF) is challenging, requiring rapid assessment of the likelihood of recovery. The availability of a large number of ALF liver explants, along with their clinical data, afforded an opportunity to retrospectively evaluate liver transplantation (LT) decision-making. We hypothesized that, with the benefit of hindsight, a small number of patients might have recovered without LT. Three hundred liver explants from ALF patients of varying etiologies who had undergone LT over 22 years in the Acute Liver Failure Study Group registry were reviewed for histopathological features and degree of necrosis by a committee of 8 hepatopathologists. A second committee of 8 experienced transplant hepatologists independently reviewed clinical data on these same 300 patients and retrospectively scored the likelihood that each patient required transplantation. Only 3 (1%) of those reviewed by the Clinical Committee were considered to “Definitely” not require liver grafting, while an additional 10 (3.3%) were deemed to “Possibly” not require transplantation (Not Likely Group, N=13). There was no difference in the degree of necrosis in explants in these groups, when compared to the remaining Likely Group, N=287 (95.6%), except in acetaminophen (APAP)-associated ALF, where the degree of necrosis was more uniformly graded as severe, correlating with the need for transplantation. Virtually every patient undergoing LT for ALF retrospectively appeared to need their transplant, based on expert clinical consensus review. Overall, there was poor correlation between clinical severity and apparent degree of necrosis seen in the 300 liver explants, except perhaps for APAP subjects.

Abstract Objective Rare large B-cell lymphomas (LBCLs) present with concurrent or subsequent lymphomatous effusion (solid-effusion LBCL, SE-LBCL), which may have an inferior prognosis compared with their noneffusion counterpart. In addition, the relationship between SE-LBCL and human herpesvirus 8–negative effusion-based LBCL (EB-LBCL) remains unclear. Methods We collected 141 cases of SE-LBCL and a control cohort of 101 cases of stage IV solid-only LBCL. The clinicopathologic features were analyzed and compared between SE-LBCL and solid-only LBCL. Results Patients with SE-LBCL had a median age of 67 years with a male-to-female ratio of 1.3:1. Eighty-six patients had concurrent solid lymphoma and lymphomatous effusion, whereas 55 developed lymphomatous effusion subsequently. Most cases involved the pleural cavities (79%, 112/141), followed by the peritoneal (21%, 29/141) and pericardial (11%, 16/141) cavities. BCL6, CD10, and MUM1 were expressed in 77% (90/117), 46% (60/130), and 61% (58/95) of cases, respectively, and 58% (71/123) were subclassified into the germinal center B-cell (GCB) subtype. Rearrangements of BCL2, BCL6, and MYC were detected in 42% (31/73), 35% (22/63), and 40% (35/88), respectively, and 22% (19/87) had both MYC and BCL2 rearrangements. The patients with SE-LBCL had a dismal prognosis, with a median survival of 5.7 months, which was significantly worse than solid-only LBCL (147.5 months; P < .0001). Conclusions The pathologic features of SE-LBCL were similar to those of solid-only LBCL but distinct from those of EB-LBCL; in particular, lymphomatous effusion was an independently adverse prognostic factor in LBCL. Our study underscores the need for surveillance of lymphomatous effusion during LBCL staging and development of effective therapeutic regimens for SE-LBCL.

AbstractA diverse workforce in emergency medicine (EM) aims to improve patient care by addressing racism in health care, increasing representation in medicine, and improving the quality of training for all residents. Many EM residency programs have launched recruitment efforts to attract residents from diverse backgrounds. However, recruitment efforts only represent the first step in building a culturally responsible workforce. Trainees who are underrepresented in medicine must be welcomed into an inclusive training environment that has been thoughtfully constructed before they arrive. This type of supportive environment can be achieved by shifting away from majority‐serving ideals and building an informed infrastructure that functions to help all trainees succeed. We expand upon challenges and areas of opportunity at the individual, departmental, and institutional levels and describe common pitfalls when trying to create inclusive spaces for residents including lack of vision alignment, inadequate financial investment, and performative allyship. We also propose strategies that focus specifically on actionable changes that residency program, departmental, and institutional leadership can implement to mitigate these challenges.

Gastric cancer is the fifth leading cause of cancer-related deaths worldwide. Over 95% of gastric cancers are adenocarcinomas, which are typically classified based on anatomic location and histologic type. Gastric cancer generally carries a poor prognosis because it is often diagnosed at an advanced stage. Systemic therapy can provide palliation, improve survival, and enhance the quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing has had a significant impact on clinical practice and patient care. Targeted therapies have demonstrated encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. This selection from the NCCN Clinical Practice Guidelines in Oncology for Gastric Cancer highlights recommendations for biomarker testing and discusses updates for the treatment of advanced disease, including peritoneal carcinoma as only disease and unresectable locally advanced, recurrent, or metastatic disease.

PURPOSE Randomized clinical trials (RCTs) have shown progression-free survival (PFS) benefits of metastasis-directed therapy (MDT) without androgen deprivation therapy for oligometastatic castration-sensitive prostate cancer (omCSPC). Most patients with bone metastatic (BM) omCSPC recur with additional bone disease after MDT. We hypothesized the BM-targeting alpha-emitter radium-223 dichloride (Ra223) could target subclinical bone disease and delay progression. METHODS This is an investigator-initiated, multicenter, open-label phase II RCT. Eligible men with recurrent omCSPC with ≥one bone metastasis (≤three on conventional imaging and/or ≤five on molecular imaging) were randomly assigned (1:1) to stereotactic ablative radiation (SABR) MDT alone or SABR MDT with Ra223 (six cycles). Primary end point was composite PFS. RESULTS From August 9, 2019, to March 2, 2023, 64 patients were randomly assigned, 33 to SABR MDT and 31 to SABR MDT/Ra223 balancing for key covariates. Most SABR MDT/Ra223 patients (87%) received six cycles of Ra223. The median PFS was 11.8 months with SABR MDT and 10.5 months with SABR MDT/Ra223 (adjusted hazard ratio [aHR], 1.42 [95% CI, 0.79 to 2.56]; P = .24). Seven patients (11%) experienced grade 3 treatment-related adverse events (no grade 4 or 5), 2 of 33 (6%) with SABR and 5 of 30 (17%) with SABR MDT/Ra223. Patients with high-risk (HiRi) pathogenic mutations in ATM , BRCA1/2 , RB1 , or TP53 had worse PFS (HR, 5.95 [95% CI, 1.83 to 19.3]; P = .003). Greater T-cell receptor (TCR) unique productive rearrangements were prognostic for improved PFS independent of the treatment arm (aHR, 0.45 [95% CI, 0.21 to 0.96]; P = .04). CONCLUSION Adding Ra223 to SABR MDT in BM omCSPC does not delay progression of disease. We provide evidence for an HiRi mutational signature and TCR repertoire as prognostic biomarkers in omCSPC treated with SABR MDT, highlighting the importance of collecting biological correlates in RCTs for omCSPC.

OBJECTIVE Despite the use of multiple glucose-lowering medications, glycemic targets are not met in a significant fraction of people with type 2 diabetes. In this prospective, observational study we assessed the prevalence of hypercortisolism, a potential contributing factor to inadequate glucose control. RESEARCH DESIGN AND METHODS Individuals with type 2 diabetes and HbA1c 7.5%–11.5% (58–102 mmol/mol) on two or more glucose-lowering medications with or without micro-/macrovascular complications or taking multiple blood pressure–lowering medications were screened with a 1-mg dexamethasone suppression test. Common causes of false-positive DSTs were excluded. The primary end point was the prevalence of hypercortisolism, defined as post-DST cortisol >1.8 μg/dL (50 nmol/L). Characteristics associated with hypercortisolism were assessed with multiple logistic regression. The percentage and characteristics of participants with hypercortisolism and adrenal imaging abnormalities were also assessed. RESULTS Post-DST cortisol was unsuppressed in 252 of 1,057 participants (prevalence 23.8%; 95% CI 21.3, 26.5). Hypercortisolism prevalence was 33.3% among participants with cardiac disorders and 36.6% among those taking three or more blood pressure–lowering medications. Adrenal imaging abnormalities were reported in 34.7% of participants with hypercortisolism. Use of sodium–glucose cotransporter 2 inhibitors (odds ratio 1.558), maximum-dose glucagon-like peptide 1 receptor agonists (1.544), tirzepatide (1.981), or a higher number of blood pressure–lowering medications (1.390); older age (1.316); BMI <30 kg/m2 (1.639); non-Latino/Hispanic ethnicity (3.718); and use of fibrates (2.676) or analgesics (1.457) were associated with higher prevalence (all P < 0.03). CONCLUSIONS Hypercortisolism was associated with hyperglycemia in approximately one-quarter of individuals with inadequately controlled type 2 diabetes despite multiple medications.

EndMT has been reported to contribute to the pathogenesis of PAH. In this study, we aimed to determine the role of Ca 2+ signaling in the development of EndMT in human lung vascular endothelial cells. Our data suggest that TGF-β 1 requires store-operated Ca 2+ entry through STIM1/Orai channels to induce SNAI-mediated EndMT. For the first time, we demonstrated that TGF-β 1 -induced EndMT is a Ca 2+ -dependent event, whereas inhibition of STIM1/Orai interaction attenuated EndMT in response to TGF-β 1 .

Objective We aimed to assess the occurrence of carpal tunnel syndrome (CTS) before and after rheumatoid arthritis (RA) incidence and by serologic status. Methods This population‐based study included residents of a geographically defined area meeting the 1987 American College of Rheumatology classification criteria for RA in 1980 to 2019 matched 1:1 with individuals without RA. At least two diagnosis codes ≥30 days apart were used to identify CTS. Cumulative incidence of CTS adjusting for competing risk of death was assessed. Logistic regression and Cox proportional hazard models were used, adjusting for age, sex, calendar year, smoking, obesity, diabetes mellitus, and hypothyroidism. Results We included 1,335 patients with RA and 1,331 individuals without RA. The overall prevalence of CTS before or on RA incidence or index was 179 patients with RA (13%) and 85 individuals without RA (6%), respectively (odds ratio [OR] 2.23; 95% confidence interval [CI] 1.69–2.94). Most previous incidences of CTS occurred ≥2 years before the index date (112 events in patients with RA and 75 events in individuals without RA, respectively). Following RA incidence or index, individuals with RA (vs those without RA) had ~80%‐higher risk of CTS (hazard ratio [HR] 1.78; 95% CI 1.38–2.30). The risk estimates of CTS in patients with seronegative (vs seropositive) RA were OR 1.33 (95% CI 0.96–1.84) before RA incidence and HR 1.37 (95% CI 0.99–1.88) after RA incidence. In RA, obesity (HR 1.42, 95% CI 1.02–1.99) and seronegative cyclic citrullinated peptide antibody status (HR 1.79, 95% CI 1.07–2.99), but not other risk factors, were associated with increased CTS risk. Conclusion We found a more than two‐fold increase in risk of CTS in the years preceding RA and a 1.8‐fold increased risk of incident CTS following RA onset. image