Adeno-associated virus (AAV)–based gene therapy is an emerging treatment for hemophilia A (HA) and hemophilia B (HB). In this systematic review and meta-analysis, we searched for studies of adult males with severe or moderately severe HA or HB who received AAV-based gene therapy. Annualized bleeding rate (ABR), annualized infusion rate (AIR), total factor use, factor levels, and adverse events (AEs) were extracted. Eight HA trials representing 7 gene therapies and 211 patients and 12 HB trials representing 9 gene therapies and 184 patients were included. For HA, gene therapy resulted in an annualized decrease of 7.58 bleeding events (95% confidence interval [CI], −11.50 to −3.67) and 117.2 factor infusions (95% CI, −151.86 to −82.53) compared with before gene therapy. Factor VIII level at 12 months ranged from 10.4 to 70.31 IU/mL by 1-stage assay. HB gene therapies were associated with an annualized decrease of 5.64 bleeding events (95% CI, −8.61 to −2.68) and 58.92 factor infusions (95% CI, −68.19 to −49.65). Mean factor IX level at 12 months was 28.72 IU/mL (95% CI, 18.78-38.66). Factor expression was more durable for HB than HA; factor IX levels remained at 95.7% of their peak whereas factor VIII levels fell to 55.8% of their peak at 24 months. The pooled percentage of patients experiencing a serious AE was 19% (10%-31%) and 21% (10%-37%) for HA and HB gene therapies, respectively. No thrombosis or inhibitor formation was reported. AAV-based gene therapies for both HA and HB demonstrated significant reductions in ABR, AIR, and factor use.

PURPOSE: The proportion of gastroesophageal junction adenocarcinoma is increasing. This study evaluated trends in early-onset gastric and esophageal cancers and compared socioeconomic and clinical characteristics between early-onset versus late-onset disease.MATERIALS AND METHODS: We included all patients with gastric and esophageal cancer from 2004 to 2015 from the National Cancer Database. Patients were categorized by age < 50, 50-69, and ≥ 70 years. Differences in pathologic and socioeconomic factors between early-onset and late-onset cancers were assessed by using chi-square test. The effects of demographic and socioeconomic factors on overall survival (OS) were assessed using Cox models.RESULTS: The proportion of patients with early-onset gastric cancer increased from 23.9% in 2004-2006 to 26.2% in 2013-2015, whereas the proportion of early-onset esophageal cancer decreased from 27.3% in 2004-2006 to 23.1% in 2013-2015. For both malignancies, the early-onset group was more likely to be Black or Hispanic and more likely to be diagnosed with stage IV cancer. Black patients had the worst median OS in both malignancies. In gastric cancer, within the Black patient group, patients experienced worse OS if they had government insurance versus private insurance (hazard ratio 1.2; 95% CI, 1.1 to 1.3; P value < .0001) or if they were in the lowest community median income category versus the highest category (hazard ratio 1.2; 95% CI, 1.1 to 1.3; P value < .0001).CONCLUSION: Early-onset gastric cancer is increasing, whereas early-onset esophageal cancer is declining. Early-onset gastric cancer disproportionately affects non-White patients, particularly Hispanic patients. Black patients have worse outcomes compared with other races for both gastric and esophageal cancer.

Aims: The flipped classroom (FC) model utilizes pre-class foundational learning with in-class higher-order application exercises. FC approaches have reported positive perceptions and mixed academic performance outcomes in medical education; however, little evidence exists on their impact in the 56-week didactic curriculum of Physician Assistant (PA) education. Methods: A 4-week FC curriculum was piloted in a PA behavioral medicine course (n = 34). Before class, students completed online video modules. During class, students completed a pre-class quiz and answered clinical case-based questions in a think-pair-share format. Results: Students rated in-class time higher than a lecture-based segment of the same course (p = 0.028). Assessment of achievement emotions demonstrated increased enjoyment (p = 0.028) and decreased boredom (p < 0.001) in the FC curriculum with no difference in anxiety. The FC curriculum produced a 57.2 min increase in pre-class preparation time with no change in post-class studying time. Compared to historical lecture-based controls (n = 35), students in the FC curriculum scored significantly higher on clinical vignette questions (p = 0.019) with equivalent performance on other question formats. Conclusions: This study offers the first positive outcomes of an FC approach in PA education and provides a framework for improving academic performance while scaling back in-class time.

Thrombotic thrombocytopenic purpura (TTP) is a rare, potentially fatal thrombotic microangiopathy caused by severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motif 13) deficiency. Prompt treatment improves survival; however, reference standard enzyme-linked immunosorbent assay and FRETS-VWF73 ADAMTS13 activity assays have long turnaround times (TATs) that necessitate empiric treatment of many patients who ultimately are found not to have TTP. Rapid assays with analytical TATs <1 hour have recently become available. We conducted a systematic review and meta-analysis of the performance characteristics of rapid assays relative to reference standard assays for ADAMTS13 activity for patients with suspected or confirmed TTP. Nineteen studies representing 3 rapid ADAMTS13 assays and 4207 patient samples were included. The HemosIL AcuStar chemiluminescence immunoassay (CLIA) demonstrated high sensitivity (0.98; 95% confidence interval [CI], 0.94-1.00), specificity (0.99; 95% CI, 0.97-1.00), and positive (PPV) (0.96; 95% CI, 0.90-0.98) and negative predictive values (NPV) (0.99; 95% CI, 0.99-1.00). The Technofluor fluorescence resonance energy transfer (FRET) and Technoscreen assays had sensitivity of 0.93 (95% CI, 0.86-0.96) and 0.98 (95% CI, 0.42-1.00), specificity of 0.98 (95% CI, 0.95-0.99) and 0.87 (95% CI, 0.76-0.94), PPV of 0.97 (95% CI, 0.85-1.00) and 0.71 (95% CI, 0.59-0.80), and NPV of 0.96 (95% CI, 0.93-0.98) and 0.99 (95% CI, 0.72-1.00), respectively. The proportion of discrepant results (relative to reference standard assays) was 0.04 (95% CI, 0.03-0.05) for HemosIL AcuStar, 0.04 (95% CI, 0.02-0.06) for Technofluor FRET, and 0.11 (95% CI, 0.07-0.16) for the Technoscreen assay. With rapid TAT and high sensitivity, the HemosIL AcuStar CLIA seems able to reliably avert empiric plasma exchange, corticosteroids, and caplacizumab in patients without TTP.

Purpose: Letters of recommendations (LORs) are key components of academic medicine applications. Given that bias against students and trainees underrepresented in medicine (UIM) has been demonstrated across assessment, achievement, and advancement domains, the authors reviewed studies on LORs to assess racial, ethnic, and UIM differences in LORs. Standardized LORs (SLORs), an increasingly common form of LORs, were also assessed for racial and ethnic differences. Method: A systematic review was conducted for English-language studies that assessed racial or ethnic differences in LORs in academic medicine published from database inception to July 16, 2023. Studies evaluating SLORs underwent data abstraction to evaluate their impact on the given race or ethnicity comparison and outcome variables. Results: Twenty-three studies describing 19,012 applicants and 41,925 LORs were included. Nineteen studies (82.6%) assessed LORs for residency, 4 (17.4%) assessed LORs for fellowship, and none evaluated employment or promotion. Fifteen of 17 studies (88.2%) assessing linguistic differences reported a significant difference in a particular race or ethnicity comparison. Of the 7 studies assessing agentic language (e.g., “strong,” “confident”), 1 study found fewer agentic terms used for Black and Latinx applicants, and 1 study reported higher agency scores for Asian applicants and applicants of races other than White. There were mixed results for the use of communal and grindstone language in UIM and non-UIM comparisons. Among 6 studies, 4 (66.7%) reported that standout language (e.g., “exceptional,” “outstanding”) was less likely to be ascribed to UIM applicants. Doubt-raising language was more frequently used for UIM trainees. When SLORs and unstructured LORs were compared, fewer linguistic differences were found in SLORs. Conclusions: There is a moderate bias against UIM candidates in the domains of linguistic differences, doubt-raising language, and topics discussed in LORs, which has implications for perceptions of competence and ability in the high-stakes residency and fellowship application process.

Anti-PD-1 based therapies and brentuximab vedotin (BV) have significantly improved survival in patients with classic Hodgkin lymphoma (cHL) and have been incorporated into earlier lines of therapy. However, there is insufficient data regarding the clinical outcomes in patients who develop refractory disease or who become intolerant of BV and anti-PD-1 therapies (double refractory/intolerant; DR/INT). Here, we evaluated outcomes in patients with DR/INT cHL from 15 US academic medical centers. A total of 173 patients were identified as DR/INT. The median overall survival from the time of cHL diagnosis (OS-1) was 14.8 years (95% CI: 10.9–20.9 years) and the 10-year OS-1 estimate was 62% (95% CI: 52–70%). After accounting for differences in age, patients who underwent autologous stem cell transplant prior to developing DR/INT had significantly longer OS-1 (HR 0.53, 95% CI: 0.29–0.96, p = 0.04). Median OS from time of DR/INT (OS-2) was 7.4 years (95% CI: 4.3-NR) and the 5-year OS-2 estimate was 57% (95% CI: 48-66%). Both anti-PD-1 and BV based therapy rechallenge were effective with median PFS of 237 days (95% CI: 155-357 days) and 183 days (95% CI: 108–273 days), respectively. Finally, advanced therapy options such as CD30 directed chimeric antigen receptor T-cell therapy and allogeneic stem cell transplant after DR/INT were associated with improved OS-2 (p < 0.001). To our knowledge, this represents the largest cohort of patients with DR/INT cHL. OS-2 will serve as a benchmark for future studies aiming to improve survival in DR/INT cHL.