Citations

INTRODUCTION: Chronic idiopathic constipation (CIC) is a common disorder associated with significant impairment in quality of life. This clinical practice guideline, jointly developed by the American Gastroenterological Association and the American College of Gastroenterology, aims to inform clinicians and patients by providing evidence-based practice recommendations for the pharmacological treatment of CIC in adults. METHODS: The American Gastroenterological Association and the American College of Gastroenterology formed a multidisciplinary guideline panel that conducted systematic reviews of the following agents: fiber, osmotic laxatives (polyethylene glycol, magnesium oxide, lactulose), stimulant laxatives (bisacodyl, sodium picosulfate, senna), secretagogues (lubiprostone, linaclotide, plecanatide), and serotonin type 4 agonist (prucalopride). The panel prioritized clinical questions and outcomes and used the Grading of Recommendations Assessment, Development, and Evaluation framework to assess the certainty of evidence for each intervention. The Evidence to Decision framework was used to develop clinical recommendations based on the balance between the desirable and undesirable effects, patient values, costs, and health equity considerations. RESULTS: The panel agreed on 10 recommendations for the pharmacological management of CIC in adults. Based on available evidence, the panel made strong recommendations for the use of polyethylene glycol, sodium picosulfate, linaclotide, plecanatide, and prucalopride for CIC in adults. Conditional recommendations were made for the use of fiber, lactulose, senna, magnesium oxide, and lubiprostone. DISCUSSION: This document provides a comprehensive outline of the various over-the-counter and prescription pharmacological agents available for the treatment of CIC. The guidelines are meant to provide a framework for approaching the management of CIC; clinical providers should engage in shared decision making based on patient preferences as well as medication cost and availability. Limitations and gaps in the evidence are highlighted to help guide future research opportunities and enhance the care of patients with chronic constipation.

AbstractGlucagon‐like peptide 1 receptor agonists (GLP‐1 RAs) reduce elevated blood glucose levels and induce weight loss. Multiple GLP‐1 RAs and one combined GLP‐1/glucose‐dependent insulinotropic polypeptide agonist are currently available. This review was conducted with the aim of summarising direct comparisons between subcutaneous semaglutide and other GLP‐1 RAs in individuals with type 2 diabetes (T2D), particularly with respect to efficacy for inducing weight loss and improving other markers of metabolic health. This systematic review of PubMed and Embase from inception to early 2022 was registered on PROSPERO and was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses and Meta‐Analysis of Observational Studies in Epidemiology guidelines. Of the 740 records identified in the search, five studies fulfilled the inclusion criteria. Comparators included liraglutide, exenatide, dulaglutide and tirzepatide. In the identified studies, multiple dosing regimens were utilised for semaglutide. Randomised trials support the superior efficacy of semaglutide over other GLP‐1 RAs with respect to weight loss in T2D, but tirzepatide is more effective than semaglutide.

Abstract In this multi-institutional retrospective study, we examined the characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS)—a rare category defined by high-grade morphologic features and lack of MYC rearrangements with BCL2 and/or BCL6 rearrangements ("double hit"). Our results show that HGBL-NOS tumors are heterogeneous: 83% of patients had a germinal center B-cell immunophenotype, 37% a dual-expressor immunophenotype (MYC and BCL2 expression), 28% MYC rearrangement, 13% BCL2 rearrangement, and 11% BCL6 rearrangement. Most patients presented with stage IV disease, a high serum lactate dehydrogenase, and other high-risk clinical factors. Most frequent first-line regimens included dose-adjusted cyclophosphamide, doxorubicin, vincristine, and etoposide, with rituximab and prednisone (DA-EPOCH-R; 43%); rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 33%); or other intensive chemotherapy programs. We found no significant differences in the rates of complete response (CR), progression-free survival (PFS), or overall survival (OS) between these chemotherapy regimens. CR was attained by 69% of patients. PFS at 2 years was 55.2% and OS was 68.1%. In a multivariable model, the main prognostic factors for PFS and OS were poor performance status, lactate dehydrogenase >3 × upper limit of normal, and a dual-expressor immunophenotype. Age >60 years or presence of MYC rearrangement were not prognostic, but patients with TP53 alterations had a dismal PFS. Presence of MYC rearrangement was not predictive of better PFS in patients treated with DA-EPOCH-R vs R-CHOP. Improvements in the diagnostic criteria and therapeutic approaches beyond dose-intense chemotherapy are needed to overcome the unfavorable prognosis of patients with HGBL-NOS.

Emerging evidence suggest that transcription factors play multiple roles in the development of pancreatitis, a necroinflammatory condition lacking specific therapy. Estrogen-related receptor γ (ERRγ), a pleiotropic transcription factor, has been reported to play a vital role in pancreatic acinar cell (PAC) homeostasis. However, the role of ERRγ in PAC dysfunction remains hitherto unknown. Here, we demonstrated in both mice models and human cohorts that pancreatitis is associated with an increase in ERRγ gene expression via activation of STAT3. Acinar-specific ERRγ haploinsufficiency or pharmacological inhibition of ERRγ significantly impaired the progression of pancreatitis both in vitro and in vivo. Using systematic transcriptomic analysis, we identified that voltage-dependent anion channel 1 (VDAC1) acts as a molecular mediator of ERRγ. Mechanistically, we showed that induction of ERRγ in cultured acinar cells and mouse pancreata enhanced VDAC1 expression by directly binding to specific site of the Vdac1 gene promoter and resulted in VDAC1 oligomerization. Notably, VDAC1, whose expression and oligomerization were dependent on ERRγ, modulates mitochondrial Ca 2+ and ROS levels. Inhibition of the ERRγ–VDAC1 axis could alleviate mitochondrial Ca 2+ accumulation, ROS formation and inhibit progression of pancreatitis. Using two different mouse models of pancreatitis, we showed that pharmacological blockade of ERRγ–VDAC1 pathway has therapeutic benefits in mitigating progression of pancreatitis. Likewise, using PRSS1 R122H -Tg mice to mimic human hereditary pancreatitis, we demonstrated that ERRγ inhibitor also alleviated pancreatitis. Our findings highlight the importance of ERRγ in pancreatitis progression and suggests its therapeutic intervention for prevention and treatment of pancreatitis.

ObjectiveThis study describes the prevalence of pathogenic germline variants (PGVs) in head and neck cancer patients, the incremental yield compared to a guideline‐based approach to genetic evaluation, and the uptake of family variant testing.Study DesignProspective cohort study.SettingThree tertiary academic medical centers.MethodsGermline sequencing using an 84‐gene screening platform among unselected head and neck cancer patients who received care at Mayo Clinic Cancer Centers between April 2018 and March 2020.ResultsAmongst 200 patients, the median age was 62.0 years (Q1, Q3: 55, 71), 23.0% were female, 89.0% white/non‐Hispanic, 5.0% Hispanic/Latinx, 6% of another race, and 42.0% had prognostic stage IV disease. The most common subsites were the oropharyngeal (45.0%) and salivary glands (12.0%). The most common histology was squamous cell carcinoma (74.5%). Twenty‐one patients (10.5%) had a total of 22 PGVs; 20 of the 21 patients (95.2%) did not meet criteria for testing by current guidelines. Regarding penetrance of the 22 PGVs, 11 were high or moderate (most commonPMS2orHOXB13), and 11 were low or recessive (most commonMUTYH,WNR, orRECQL4). One patient had a change in care based on an identified PGV. Family variant testing was completed at a rate of 4.8%.ConclusionsUniversal gene panel testing identified a PGV in 10.5% of head and neck cancer patients; almost all would have been missed by current guideline‐based testing. One of 21 patients had a treatment change due to their PGV, indicating that head and neck cancer treatment decisions are not yet widely informed by germline alterations.Level of Evidence3Laryngoscope, 133:3378–3388, 2023

We previously identified Oxalobacter formigenes-derived secreted factors stimulating oxalate transport by human intestinal epithelial cells in vitro and reducing urinary oxalate excretion in hyperoxaluric mice by enhancing colonic oxalate secretion. We now identified Sel1-like proteins and small peptides as the major secreted factors and they have significant therapeutic potential for hyperoxalemia and hyperoxaluria, impacting the outcomes of patients suffering from kidney stones, primary and secondary hyperoxaluria, chronic kidney disease, kidney failure, and renal transplant recipients.

AbstractBackgroundQuality of life (QOL) for individuals with sinonasal malignancy (SNM) is significantly under‐studied, yet it is critical for counseling and may impact treatment. In this study we evaluated how patient, treatment, and disease factors impact sinonasal‐specific and generalized QOL using validated metrics in a large cohort over a 5‐year posttreatment time frame.MethodsPatients with SNM who underwent definitive treatment with curative intent were enrolled in a prospective, multisite, longitudinal observational study. QOL was assessed using the 22‐item Sino‐Nasal Outcome Test (SNOT‐22) and University of Washington Quality of Life Questionnaire (UWQOL) instruments at pretreatment baseline and multiple follow‐ups through 5 years posttreatment. Multivariable modeling was used to determine demographic, disease, and treatment factors associated with disease‐specific and generalized physical and social/emotional function QOL.ResultsOne hundred ninety‐four patients with SNM were analyzed. All QOL indices were impaired at pretreatment baseline and improved after treatment. SNOT‐22 scores improved 3 months and UWQOL scores improved 6 to 9 months posttreatment. Patients who underwent open compared with endoscopic tumor resection had worse generalized QOL (p < 0.001), adjusted for factors including T stage. Pterygopalatine fossa (PPF) involvement was associated with worse QOL (SNOT‐22, p < 0.001; UWQOL Physical dimension, p = 0.02). Adjuvant radiation was associated with worse disease‐specific QOL (p = 0.03). Neck dissection was associated with worse generalized physical function QOL (p = 0.01). Positive margins were associated with worse generalized social/emotional function QOL (p = 0.01).ConclusionDisease‐specific and generalized QOL is impaired at baseline in patients with SNM and improves after treatment. Endoscopic resection is associated with better QOL. PPF involvement, adjuvant radiation, neck dissection, and positive margins were associated with worse QOL posttreatment.