Citations

Abstract Background Obesity is an established risk factor for colorectal cancer (CRC), but the evidence for the association is inconsistent across molecular subtypes of the disease. Methods We pooled data on body mass index (BMI), tumor microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, and Jass classification types for 11 872 CRC cases and 11 013 controls from 11 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for covariables. Results Higher BMI was associated with increased CRC risk (OR per 5 kg/m2 = 1.18, 95% CI = 1.15 to 1.22). The positive association was stronger for men than women but similar across tumor subtypes defined by individual molecular markers. In analyses by Jass type, higher BMI was associated with elevated CRC risk for types 1-4 cases but not for type 5 CRC cases (considered familial-like/Lynch syndrome microsatellite instability-H, CpG island methylator phenotype-low or negative, BRAF-wild type, KRAS-wild type, OR = 1.04, 95% CI = 0.90 to 1.20). This pattern of associations for BMI and Jass types was consistent by sex and design of contributing studies (cohort or case-control). Conclusions In contrast to previous reports with fewer study participants, we found limited evidence of heterogeneity for the association between BMI and CRC risk according to molecular subtype, suggesting that obesity influences nearly all major pathways involved in colorectal carcinogenesis. The null association observed for the Jass type 5 suggests that BMI is not a risk factor for the development of CRC for individuals with Lynch syndrome.

AbstractTherapeutic antibodies have broad indications across diverse disease states, such as oncology, autoimmune diseases, and infectious diseases. New research continues to identify antibodies with therapeutic potential as well as methods to improve upon endogenous antibodies and to design antibodies de novo. On April 27–30, 2022, experts in antibody research across academia and industry met for the Keystone symposium “Antibodies as Drugs” to present the state‐of‐the‐art in antibody therapeutics, repertoires and deep learning, bispecific antibodies, and engineering.

Abstract Background and study aims Gastric outlet obstruction (GOO) is traditionally managed with surgical gastroenterostomy (surgical-GE) and enteral stenting (ES). Endoscopic ultrasound-guided gastroenterostomy (EUS-GE) is now a third option. Large studies assessing their relative risks and benefits with adequate follow-up are lacking. We conducted a comparative analysis of patients who underwent EUS-GE, ES, or surgical-GE for GOO. Patients and methods In this retrospective comparative cohort study, consecutive patients presenting with GOO who underwent EUS-GE, ES, or surgical-GE at two academic institutions were reviewed and independently cross-edited to ensure accurate reporting. The primary outcome was need for reintervention. Secondary outcomes were technical and clinical success, length of hospital stay (LOS), and adverse events (AEs). Results A total of 436 patients (232 EUS-GE, 131 ES, 73 surgical-GE) were included. The median duration of follow-up of the entire cohort was 185.5 days (interquartile range 55.25–454.25 days). The rate of reintervention in the EUS-GE group was lower than in the ES and surgical-GE groups (0.9 %, 12.2 %, and 13.7 %, P < 0.0001). Technical success was achieved in 98.3 %, 99.2 %, and 100 % (P = 0.58), and clinical success was achieved in 98.3 %, 91.6 %, and 90.4 % (P < 0.0001) in the EUS-GE, ES, and surgical-GE groups, respectively. The EUS-GE group had a shorter LOS (2 days vs. 3 days vs. 5 days, P < 0.0001) and a lower AE rate than the ES and surgical-GE groups (8.6 % vs. 38.9 % vs. 27.4 %, P < 0.0001). Conclusion This large cohort study demonstrates the safety and palliation durability of EUS-GE as an alternative strategy for GOO palliation in select patients.

AbstractPulmonary arterial hypertension (PAH) is a progressive, devastating disease, and its main histological manifestation is an occlusive pulmonary arteriopathy. One important functional component of PAH is aberrant endothelial cell (EC) function including apoptosis‐resistance, unchecked proliferation, and impaired migration. The mechanisms leading to and maintaining physiologic and aberrant EC function are not fully understood. Here, we tested the hypothesis that in PAH, ECs have increased expression of the transmembrane protein integrin‐β5, which contributes to migration and survival under physiologic and pathological conditions, but also to endothelial‐to‐mesenchymal transition (EnMT). We found that elevated integrin‐β5 expression in pulmonary artery lesions and lung tissue from PAH patients and rats with PH induced by chronic hypoxia and injection of CD117+ rat lung EC clones. These EC clones exhibited elevated expression of integrin‐β5 and its heterodimerization partner integrin‐αν and showed accelerated barrier formation. Inhibition of integrin‐ανβ5 in vitro partially blocked transforming growth factor (TGF)‐β1‐induced EnMT gene expression in rat lung control ECs and less in rat lung EC clones and human lung microvascular ECs. Inhibition of integrin‐ανβ5 promoted endothelial dysfunction as shown by reduced migration in a scratch assay and increased apoptosis in synergism with TGF‐β1. In vivo, blocking of integrin‐ανβ5 exaggerated PH induced by chronic hypoxia and CD117+ EC clones in rats. In summary, we found a role for integrin‐ανβ5 in lung endothelial survival and migration, but also a partial contribution to TGF‐β1‐induced EnMT gene expression. Our results suggest that integrin‐ανβ5 is required for physiologic function of ECs and lung vascular homeostasis.

AbstractObjectiveTo characterize normative adult ranges for cochlear promontory thickness relevant to the development of subendosteal and transpromontory electrodes to rehabilitate various neurotologic disorders.PatientsAdults (≥18 years).InterventionIn vivo radiologic assessment using a 192‐slice CT scanner (Force‐192; Siemens Healthcare) with ultrahigh‐resolution scan mode combined and iterative reconstruction.Main Outcome MeasureCochlear promontory thickness.ResultsAmong 48 included patients (96 ears), the mean (SD) age was 56 (18) years (range 25–94) and included 25 (52%) women. Of that 12 patients (25%) had osteopenia (n = 6) or osteoporosis (n = 6). The mean (SD) body mass index was 28 (5) kg/m2. The mean (SD) promontory thickness for the 96 temporal bones under study was 1.22 (0.24) mm (range 0.55–1.85). There was not a statistically significant association between age and promontory thickness (correlation coefficient .08; p = .44). Promontory thickness was significantly greater for men than women (mean 1.28 vs. 1.17 mm; p = .03) and increased with increasing body mass index (correlation coefficient .30; p = .004). Last, promontory thickness was significantly less for patients with osteopenia or osteoporosis compared with those without these conditions (mean 1.09 vs. 1.27 mm; p = .002).ConclusionsCochlear promontory thickness can vary by almost 1.5 mm across patients and is significantly associated with patient sex, body mass index, and comorbid osteopenia/osteoporosis. Subendosteal and transpromontory electrode placement techniques must account for this degree of variability.Level of EvidenceIV

Nicotine from cigarette smoke is a biologically active molecule that has pleiotropic effects in the airway, which could play a role in smoking-induced lung disease. However, whether nicotine and its metabolites reach sustained, physiologically relevant concentrations on airway surfaces of smokers is not well defined. To address these issues, concentrations of nicotine, cotinine, and hydroxycotinine were measured by mass spectrometry (MS) in supernatants of induced sputum obtained from participants in the subpopulations and intermediate outcome measures in COPD study (SPIROMICS), an ongoing observational study that included never smokers, former smokers, and current smokers with and without chronic obstructive pulmonary disease (COPD). A total of 980 sputum supernatants were analyzed from 77 healthy never smokers, 494 former smokers (233 with COPD), and 396 active smokers (151 with COPD). Sputum nicotine, cotinine, and hydroxycotinine concentrations corresponded to self-reported smoking status and were strongly correlated to urine measures. A cutoff of ∼8–10 ng/mL of sputum cotinine distinguished never smokers from active smokers. Accounting for sample dilution during processing, active smokers had airway nicotine concentrations in the 70–850 ng/mL (∼0.5–5 µM) range, and concentrations remained elevated even in current smokers who had not smoked within 24 h. This study demonstrates that airway nicotine and its metabolites are readily measured in sputum supernatants and can serve as biological markers of smoke exposure. In current smokers, nicotine is present at physiologically relevant concentrations for prolonged periods, supporting a contribution to cigarette-induced airway disease.

Introduction: Coccidioidal meningitis (CM) is the most lethal form of disseminated coccidioidomycosis. Current guidelines recommend fluconazole as initial therapy but there has been a paucity of data regarding failure of fluconazole and optimal fluconazole dosage in the treatment of CM. We conducted this study to understand risk factors for fluconazole failure. Methods: We conducted a single-center retrospective chart review of patients diagnosed with coccidioidal meningitis between 1 January 1988 and 15 May 2021. Relevant demographic and clinical variables were collected, along with outcomes including treatment failure and death at any point. Univariate tests were conducted using the chi-squared goodness of fit test and analysis of variance. Results: Among 71 patients who began treatment for CM with fluconazole, 22 (31%) developed worsening meningitis at a median time of 206 days. Longer time from symptom onset to diagnosis of CM was a risk factor for fluconazole failure. Although the absolute failure rate of fluconazole starting dose of 400 mg daily was higher than that of 800 mg daily, the differences did not achieve statistical significance (p = 0.39). Conclusion: Fluconazole failure is not uncommon in the treatment of CM. A dose of 800 mg daily was not superior to a dose of 400 mg daily. All patients on fluconazole for CM require close monitoring.

Background: Clinical and anatomical characteristics are often considered key factors in deciding between percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) in patients with complex coronary artery disease (CAD) such as left-main CAD or 3-vessel disease. However, little is known about the interaction between self-reported preprocedural physical/mental health and clinical outcomes after revascularization. Methods: This subgroup analysis of the SYNTAXES trial (SYNTAX Extended Survival), which is the extended follow-up of the randomized SYNTAX trial (Synergy Between PCI With Taxus and Cardiac Surgery) comparing PCI with CABG in patients with left-main CAD or 3-vessel disease, stratified patients by terciles of Physical (PCS) or Mental Component Summary (MCS) scores derived from the preprocedural 36-Item Short Form Health Survey, with higher PCS and MCS scores representing better physical and mental health, respectively. The primary end point was all-cause death at 10 years. Results: A total of 1656 patients with preprocedural 36-Item Short Form Health Survey data were included in the present study. Both higher PCS and MCS were independently associated with lower 10-year mortality (10-point increase in PCS adjusted hazard ratio, 0.84 [95% CI, 0.73–0.97]; P =0.021; in MCS adjusted hazard ratio, 0.85 [95% CI, 0.76–0.95]; P =0.005). A significant survival benefit with CABG over PCI was observed in the highest PCS (>45.5) and MCS (>52.3) terciles with significant treatment-by-subgroup interactions (PCS P interaction =0.033, MCS P interaction =0.015). In patients with both high PCS (>45.5) and MCS (>52.3), 10-year mortality was significantly higher with PCI compared with CABG (30.5% versus 12.2%; hazard ratio, 2.87 [95% CI, 1.55–5.30]; P =0.001), whereas among those with low PCS (≤45.5) or low MCS (≤52.3), there were no significant differences in 10-year mortality between PCI and CABG, resulting in a significant treatment-by-subgroup interaction ( P interaction =0.002). Conclusions: Among patients with left-main CAD or 3-vessel disease, patient-reported preprocedural physical and mental health status was strongly associated with long-term mortality and modified the relative treatment effects of PCI versus CABG. Patients with the best physical and mental health had better 10-year survival with CABG compared with PCI. Assessment of self-reported physical and mental health is important when selecting the optimal revascularization strategy. Registration: URL: https://www.clinicaltrials.gov ; SYNTAXES Unique identifier: NCT03417050. URL: https://www.clinicaltrials.gov ; SYNTAX Unique identifier: NCT00114972.