AGA Clinical Practice Update on Diet and Nutritional Therapies in Patients With Inflammatory Bowel Disease: Expert Review.

DESCRIPTION: Diet plays a critical role in human health, but especially for patients with inflammatory bowel disease (IBD). Guidance about diet for patients with IBD are often controversial and a source of uncertainty for many physicians and patients. The role of diet has been investigated as a risk factor for IBD etiopathogenesis and as a therapy for active disease. Dietary restrictions, along with the clinical complications of IBD, can result in malnutrition, an underrecognized condition among this patient population. The aim of this American Gastroenterological Association (AGA) Clinical Practice Update (CPU) is to provide best practice advice statements, primarily to clinical gastroenterologists, covering the topics of diet and nutritional therapies in the management of IBD, while emphasizing identification and treatment of malnutrition in these patients. We provide guidance for tailored dietary approaches during IBD remission, active disease, and intestinal failure. A healthy Mediterranean diet will benefit patients with IBD, but may require accommodations for food texture in the setting of intestinal strictures or obstructions. New data in Crohn's disease supports the use of enteral liquid nutrition to help induce remission and correct malnutrition in patients heading for surgery. Parenteral nutrition plays a critical role in patients with IBD facing acute and/or chronic intestinal failure. Registered dietitians are an essential part of the interdisciplinary team approach for optimal nutrition assessment and management in the patient population with IBD. METHODS: This expert review was commissioned and approved by the AGA Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the CPU Committee and external peer review through standard procedures of Gastroenterology. The best practice advice statements were drawn from reviewing existing literature combined with expert opinion to provide practical advice on the role of diet and nutritional therapies in patients with IBD. Because this was not a systematic review, formal rating of the quality of evidence or strength of the presented considerations was not performed. Best Practice Advice Statements BEST PRACTICE ADVICE 1: Unless there is a contraindication, all patients with IBD should be advised to follow a Mediterranean diet rich in a variety of fresh fruits and vegetables, monounsaturated fats, complex carbohydrates, and lean proteins and low in ultraprocessed foods, added sugar, and salt for their overall health and general well-being. No diet has consistently been found to decrease the rate of flares in adults with IBD. A diet low in red and processed meat may reduce ulcerative colitis flares, but has not been found to reduce relapse in Crohn's disease. BEST PRACTICE ADVICE 2: Patients with IBD who have symptomatic intestinal strictures may not tolerate fibrous, plant-based foods (ie, raw fruits and vegetables) due to their texture. An emphasis on careful chewing and cooking and processing of fruits and vegetables to a soft, less fibrinous consistency may help patients with IBD who have concomitant intestinal strictures incorporate a wider variety of plant-based foods and fiber in their diets. BEST PRACTICE ADVICE 3: Exclusive enteral nutrition using liquid nutrition formulations is an effective therapy for induction of clinical remission and endoscopic response in Crohn's disease, with stronger evidence in children than adults. Exclusive enteral nutrition may be considered as a steroid-sparing bridge therapy for patients with Crohn's disease. BEST PRACTICE ADVICE 4: Crohn's disease exclusion diet, a type of partial enteral nutrition therapy, may be an effective therapy for induction of clinical remission and endoscopic response in mild to moderate Crohn's disease of relatively short duration. BEST PRACTICE ADVICE 5: Exclusive enteral nutrition may be an effective therapy in malnourished patients before undergoing elective surgery for Crohn's disease to optimize nutritional status and reduce postoperative complications. BEST PRACTICE ADVICE 6: In patients with IBD who have an intra-abdominal abscess and/or phlegmonous inflammation that limits ability to achieve optimal nutrition via the digestive tract, short-term parenteral nutrition may be used to provide bowel rest in the preoperative phase to decrease infection and inflammation as a bridge to definitive surgical management and to optimize surgical outcomes. BEST PRACTICE ADVICE 7: We suggest the use of parenteral nutrition for high-output gastrointestinal fistula, prolonged ileus, short bowel syndrome, and for patients with IBD with severe malnutrition when oral and enteral nutrition has been trialed and failed or when enteral access is not feasible or contraindicated. BEST PRACTICE ADVICE 8: In patients with IBD and short bowel syndrome, long-term parenteral nutrition should be transitioned to customized hydration management (ie, intravenous electrolyte support and/or oral rehydration solutions) and oral intake whenever possible to decrease the risk of developing long-term complications. Treatment with glucagon-like peptide-2 agonists can facilitate this transition. BEST PRACTICE ADVICE 9: All patients with IBD warrant regular screening for malnutrition by their provider by means of assessing signs and symptoms, including unintended weight loss, edema and fluid retention, and fat and muscle mass loss. When observed, more complete evaluation for malnutrition by a registered dietitian is indicated. Serum proteins are no longer recommended for the identification and diagnosis of malnutrition due to their lack of specificity for nutritional status and high sensitivity to inflammation. BEST PRACTICE ADVICE 10: All patients with IBD should be monitored for vitamin D and iron deficiency. Patients with extensive ileal disease or prior ileal surgery (resection or ileal pouch) should be monitored for vitamin B12 deficiency. BEST PRACTICE ADVICE 11: All outpatients and inpatients with complicated IBD warrant co-management with a registered dietitian, especially those who have malnutrition, short bowel syndrome, enterocutaneous fistula, and/or are requiring more complex nutrition therapies (eg, parenteral nutrition, enteral nutrition, or exclusive enteral nutrition), or those on a Crohn's disease exclusion diet. We suggest that all newly diagnosed patients with IBD have access to a registered dietitian. BEST PRACTICE ADVICE 12: Breastfeeding is associated with a lower risk for diagnosis of IBD during childhood. A healthy, balanced, Mediterranean diet rich in a variety of fruits and vegetables and decreased intake of ultraprocessed foods have been associated with a lower risk of developing IBD.

A butterfly pan-genome reveals that a large amount of structural variation underlies the evolution of chromatin accessibility.

Despite insertions and deletions being the most common structural variants (SVs) found across genomes, not much is known about how much these SVs vary within populations and between closely related species, nor their significance in evolution. To address these questions, we characterized the evolution of indel SVs using genome assemblies of three closely related Heliconius butterfly species. Over the relatively short evolutionary timescales investigated, up to 18.0% of the genome was composed of indels between two haplotypes of an individual Heliconius charithonia butterfly and up to 62.7% included lineage-specific SVs between the genomes of the most distant species (11 Mya). Lineage-specific sequences were mostly characterized as transposable elements (TEs) inserted at random throughout the genome and their overall distribution was similarly affected by linked selection as single nucleotide substitutions. Using chromatin accessibility profiles (i.e., ATAC-seq) of head tissue in caterpillars to identify sequences with potential cis-regulatory function, we found that out of the 31,066 identified differences in chromatin accessibility between species, 30.4% were within lineage-specific SVs and 9.4% were characterized as TE insertions. These TE insertions were localized closer to gene transcription start sites than expected at random and were enriched for sites with significant resemblance to several transcription factor binding sites with known function in neuron development in Drosophila We also identified 24 TE insertions with head-specific chromatin accessibility. Our results show high rates of structural genome evolution that were previously overlooked in comparative genomic studies and suggest a high potential for structural variation to serve as raw material for adaptive evolution.

Real-world evidence for factors associated with maintenance treatment practices among U.S. adults with autoimmune hepatitis.

BACKGROUND AIMS: While avoidance of long-term corticosteroids is a common objective in the management of autoimmune hepatitis (AIH), prolonged immunosuppression is usually required to prevent disease progression. This study investigates the patient and provider factors associated with treatment patterns in U.S. patients with AIH. APPROACH RESULTS: A retrospective cohort of adults with incident and prevalent AIH was identified from Optum's de-identified Clinformatics® Data Mart Database. All patients were followed for at least 2 years, with exposures assessed during the first year and treatment patterns during the second. Patient and provider factors associated with corticosteroid-sparing monotherapy and cumulative prednisone use were identified using multivariable logistic and linear regression, respectively.The cohort was 81.2% female, 66.3% White, 11.3% Black, 11.2% Hispanic and with median age 61 years. Among 2,203 patients with ≥1 AIH prescription fill, 83.1% received a single regimen for >6 months of the observation year, which included 52.2% azathioprine monotherapy, 16.9% azathioprine/prednisone and 13.3% prednisone monotherapy. Budesonide use was uncommon (2.1% combination, 1.9% monotherapy). Hispanic ethnicity (aOR 0.56; p=0.006), cirrhosis (aOR 0.73; p=0.019), osteoporosis (aOR 0.54; p=0.001) and top quintile of provider AIH experience (aOR 0.66; p=0.005) were independently associated with lower use of corticosteroid-sparing monotherapy. Cumulative prednisone use was greater with diabetes (+441 mg/year; p=0.004), osteoporosis (+749 mg/year; p<0.001) and highly experienced providers (+556 mg/year; p<0.001). CONCLUSIONS: Long-term prednisone therapy remains common, and unexpectedly higher among patients with comorbidities potentially aggravated by corticosteroids. The greater use of corticosteroid-based therapy with highly experienced providers may reflect more treatment-refractory disease.

Interaction of the tumor suppressor SMAD4 and WNT signaling in progression to oral squamous cell carcinoma.

SMAD4 is a tumor suppressor mutated or silenced in multiple cancers, including oral cavity squamous cell carcinoma (OSCC). Human clinical samples and cell lines, mouse models and organoid culture were used to investigate the role that SMAD4 plays in progression from benign disease to invasive OSCC. Human OSCC lost detectable SMAD4 protein within tumor epithelium in 24% of cases, and this loss correlated with worse progression-free survival independent of other major clinical and pathological features. A mouse model engineered for KrasG12D expression in the adult oral epithelium induced benign papillomas, however the combination of KrasG12D with loss of epithelial Smad4 expression resulted in rapid development of invasive carcinoma with features of human OSCC. Examination of regulatory pathways in 3D organoid cultures of SMAD4+ and SMAD4- mouse tumors with Kras mutation found that either loss of SMAD4 or inhibition of TGFß signaling upregulated the WNT pathway and altered the extracellular matrix. The gene signature of the mouse tumor organoids lacking SMAD4 was highly similar to the gene signature of human head and neck squamous cell carcinoma. In summary, this work has uncovered novel mechanisms by which SMAD4 acts as a tumor suppressor in OSCC. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Fungal Endocarditis: Pathophysiology, Epidemiology, Clinical Presentation, Diagnosis, and Management.

Fungal endocarditis accounts for 1% to 3% of all infective endocarditis cases, is associated with high morbidity and mortality (>70%), and presents numerous challenges during clinical care. Candida spp. are the most common causes of fungal endocarditis, implicated in over 50% of cases, followed by Aspergillus and Histoplasma spp. Important risk factors for fungal endocarditis include prosthetic valves, prior heart surgery, and injection drug use. The signs and symptoms of fungal endocarditis are nonspecific, and a high degree of clinical suspicion coupled with the judicious use of diagnostic tests is required for diagnosis. In addition to microbiological diagnostics (e.g., blood culture for Candida spp. or galactomannan testing and PCR for Aspergillus spp.), echocardiography remains critical for evaluation of potential infective endocarditis, although radionuclide imaging modalities such as 18F-fluorodeoxyglucose positron emission tomography/computed tomography are increasingly being used. A multimodal treatment approach is necessary: surgery is usually required and should be accompanied by long-term systemic antifungal therapy, such as echinocandin therapy for Candida endocarditis or voriconazole therapy for Aspergillus endocarditis.

Provider Specialization in Inflammatory Bowel Diseases: Quality of Care and Outcomes.

BACKGROUND & AIMS: Management of inflammatory bowel diseases (IBD) is complex and variation in care has been well-documented. However, the drivers of practice variation remain unexplored. We examined variation based on the treating gastroenterologist's IBD focus (proportion of outpatient visits for IBD). METHODS: We conducted a retrospective cohort of newly diagnosed patients with IBD using data from Optum's deidentified Clinformatics Data Mart Database (2000-2020). The exposure variable was whether the treating gastroenterologist had an IBD focus (>90th percentile of IBD visits/total outpatient visits). We used adjusted regression models to evaluate associations between provider IBD focus and process measures (use of mesalamine, corticosteroid, biologic, and narcotic medications and endoscopic or radiographic imaging) and clinical outcomes (time to IBD-related hospitalization and bowel resection surgery). We tested for change in treatment patterns over time by including an interaction term for study era (2004-2012 vs 2013-2020). RESULTS: The study included 772 children treated by 493 providers and 2864 adults treated by 2076 providers. In children, none of the associations between provider focus and process or outcome measures were significant. In adults, care from an IBD-focused provider was associated with more use of biologics, combination therapy, and imaging and endoscopy, and less mesalamine use for Crohn's disease (P < .05 for all comparisons) but not with other process measures. Biologics were prescribed more frequently and narcotics less frequently during the later era (P < .05 for both). Hospitalization and surgery rates were not associated with IBD focus or era. CONCLUSIONS: IBD care for adults varies by provider specialization. Given the evolving complexity, novel methods may be needed to standardize care.

Incidence, Prevalence, and Racial and Ethnic Distribution of Inflammatory Bowel Disease in the United States.

BACKGROUND & AIMS: We sought to estimate the incidence, prevalence, and racial-ethnic distribution of physician-diagnosed inflammatory bowel disease (IBD) in the United States. METHODS: The study used 4 administrative claims data sets: a 20% random sample of national fee-for-service Medicare data (2007 to 2017); Medicaid data from Florida, New York, Pennsylvania, Ohio, and California (1999 to 2012); and commercial health insurance data from Anthem beneficiaries (2006 to 2018) and Optum's deidentified Clinformatics Data Mart (2000 to 2017). We used validated combinations of medical diagnoses, diagnostic procedures, and prescription medications to identify incident and prevalent diagnoses. We computed pooled age-, sex-, and race/ethnicity-specific insurance-weighted estimates and pooled estimates standardized to 2018 United States Census estimates with 95% confidence intervals (CIs). RESULTS: The age- and sex-standardized incidence of IBD per 100,000 person-years was 10.9 (95% CI, 10.6-11.2). The incidence of IBD peaked in the third decade of life, decreased to a relatively stable level across the fourth to eighth decades, and declined further. The age-, sex- and insurance-standardized prevalence of IBD was 721 per 100,000 population (95% CI, 717-726). Extrapolated to the 2020 United States Census, an estimated 2.39 million Americans are diagnosed with IBD. The prevalence of IBD per 100,000 population was 812 (95% CI, 802-823) in White, 504 (95% CI, 482-526) in Black, 403 (95% CI, 373-433) in Asian, and 458 (95% CI, 440-476) in Hispanic Americans. CONCLUSIONS: IBD is diagnosed in >0.7% of Americans. The incidence peaks in early adulthood and then plateaus at a lower rate. The disease is less commonly diagnosed in Black, Asian, and Hispanic Americans.

The Role of Hospital Characteristics in Clinical and Quality Outcomes for Gastrointestinal Bleeding in a National Cohort.

INTRODUCTION: There is substantial variability in patient outcomes for gastrointestinal bleeding (GIB) across hospitals. This study aimed to identify hospital factors associated with GIB outcomes. METHODS: This was a retrospective cohort study of Medicare fee-for-service beneficiaries hospitalized for GIB from 2016 to 2018. These data were merged with the American Hospital Association Annual Survey data to incorporate hospital characteristics. We used generalized linear mixed-effect models to estimate the effect of hospital-level characteristics on patient outcomes after adjusting for patient risk factors including anticoagulant and antiplatelet use, recent GIB, and comorbidities. The primary outcome was 30-day mortality, and secondary outcomes included length of stay and a composite outcome of 30-day readmission or mortality. RESULTS: Factors associated with improved GIB 30-day mortality included large hospital size (defined as beds >400, odds ratio [OR] 0.93, 95% confidence interval [CI] 0.90-0.97), greater case volume (OR 0.97, 95% CI 0.96-0.98), increased resident and nurse staffing (OR 0.88, 95% CI 0.83-0.94), and blood donor center designation (OR 0.93, 95% CI 0.88-0.99). Patients treated at a hospital with multiple advanced capabilities, such as availability of advanced endoscopy, advanced intensive care unit (ICU) capabilities (both a medical-surgical ICU and cardiac ICU), blood donor center, and liver transplant center, had a 22% reduction in 30-day mortality risk, compared with those hospitalized in a hospital with none of these services (OR 0.78, 95% CI 0.68-0.91). However, length of stay increased with additional services. DISCUSSION: Patients hospitalized for GIB at hospitals with multiple advanced specialized capabilities have lower mortality but longer lengths of stay. Further research should examine the processes of care linked to these services that contribute to improved mortality in GIB.

Recurrent Wnt Pathway and ARID1A Alterations in Sinonasal Olfactory Carcinoma.

Sinonasal tumors with neuroepithelial differentiation, defined by neuroectodermal elements reminiscent of olfactory neuroblastoma (ONB) and epithelial features such as keratin expression or gland formation, are a diagnostically challenging group that has never been formally included in sinonasal tumor classifications. Recently, we documented that most of these neuroepithelial neoplasms have distinctive histologic and immunohistochemical findings and proposed the term "olfactory carcinoma" to describe these tumors. However, the molecular characteristics of olfactory carcinoma have not yet been evaluated. In this study, we performed targeted molecular profiling of 23 sinonasal olfactory carcinomas to further clarify their pathogenesis and classification. All tumors included in this study were composed of high-grade neuroectodermal cells that were positive for pankeratin and at least 1 specific neuroendocrine marker. A significant subset of cases also displayed rosettes and neurofibrillary matrix, intermixed glands with variable cilia, peripheral p63/p40 expression, and S100 protein-positive sustentacular cells. Recurrent oncogenic molecular alterations were identified in 20 tumors, including Wnt pathway alterations affecting CTNNB1 (n = 8) and PPP2R1A (n = 2), ARID1A inactivation (n = 5), RUNX1 mutations (n = 3), and IDH2 hotspot mutations (n = 2). Overall, these findings do demonstrate the presence of recurrent molecular alterations in olfactory carcinoma, although this group of tumors does not appear to be defined by any single mutation. Minimal overlap with alterations previously reported in ONB also adds to histologic and immunohistochemical separation between ONB and olfactory carcinoma. Conversely, these molecular findings enhance the overlap between olfactory carcinoma and sinonasal neuroendocrine carcinomas. A small subset of neuroepithelial tumors might better fit into the superseding molecular category of IDH2-mutant sinonasal carcinoma. At this point, sinonasal neuroendocrine and neuroepithelial tumors may best be regarded as a histologic and molecular spectrum that includes core groups of ONB, olfactory carcinoma, neuroendocrine carcinoma, and IDH2-mutant sinonasal carcinoma.

Sociodemographic and geographic differences in the US epidemiology of autoimmune hepatitis with and without cirrhosis.

BACKGROUND AND AIMS: Data on the epidemiology of autoimmune hepatitis (AIH) in the United States are limited. This study investigated the sociodemographic and geographic factors associated with AIH incidence and prevalence with and without cirrhosis. APPROACH AND RESULTS: In a retrospective cohort of adults in the Optum Clinformatics Data Mart (2009-2018), we identified AIH cases using a validated claims-based algorithm. Incidence and prevalence were compared between sociodemographic subgroups. Logistic regression evaluated the association of US Census Division with AIH incidence and the factors associated with incident AIH with cirrhosis. From 2009 to 2018, the age- and sex-standardized prevalence of AIH in the Optum cohort was 26.6 per 100,000 persons with an incidence of 4.0 per 100,000 person-years. AIH incidence increased earlier among Hispanics (age 50-59 years) and later among Asians (≥80 years). Adjusted AIH incidence was higher in the Mountain Division (odds ratio [OR] 1.17) and lower in the Pacific (OR 0.68), Middle Atlantic (OR 0.81), and West North Central Divisions (OR 0.86 vs. East North Central; p < 0.001). Male sex (OR 1.31, p = 0.003), Black race (OR 1.32, p = 0.022), and Hispanic ethnicity (OR 1.37 vs. non-Hispanic White, p = 0.009) were associated with incident AIH with cirrhosis. Incident AIH with cirrhosis was greater in the West South Central Division (OR 1.30 vs. South Atlantic; p = 0.008). CONCLUSIONS: AIH epidemiology differs according to sociodemographic and geographic factors in the United States. Studies are needed to determine the genetic, epigenetic, and environmental factors underlying the heterogeneity in AIH risk and outcomes.

Penn Healthy Diet survey: pilot validation and scoring.

Though diet quality is widely recognised as linked to risk of chronic disease, health systems have been challenged to find a user-friendly, efficient way to obtain information about diet. The Penn Healthy Diet (PHD) survey was designed to fill this void. The purposes of this pilot project were to assess the patient experience with the PHD, to validate the accuracy of the PHD against related items in a diet recall and to explore scoring algorithms with relationship to the Healthy Eating Index (HEI)-2015 computed from the recall data. A convenience sample of participants in the Penn Health BioBank was surveyed with the PHD, the Automated Self-Administered 24-hour recall (ASA24) and experience questions. Kappa scores and Spearman correlations were used to compare related questions in the PHD to the ASA24. Numerical scoring, regression tree and weighted regressions were computed for scoring. Participants assessed the PHD as easy to use and were willing to repeat the survey at least annually. The three scoring algorithms were strongly associated with HEI-2015 scores using National Health and Nutrition Examination Survey 2017-2018 data from which the PHD was developed and moderately associated with the pilot replication data. The PHD is acceptable to participants and at least moderately correlated with the HEI-2015. Further validation in a larger sample will enable the selection of the strongest scoring approach.

Changes in Adherence and Viral Load Suppression Among People with HIV in Manila: Outcomes of the Philippines Connect for Life Study.

The Philippines HIV epidemic is among the fastest growing globally. Infections among men who have sex with men are rising at an alarming rate, necessitating targeted evidence-based interventions to retain people living with HIV in care, support adherence, and reach viral suppression. We conducted a 48-week prospective cohort study of 462 participants in which we provided a mobile health (mHealth) adherence support intervention using the Connect for Life platform. We observed an improvement in adherence, with the proportion of participants taking more than 95% of their antiretroviral therapy (ART) doses increasing from 78.6% at baseline to 90.3% at 48 weeks. Among treatment experienced participants, adherence improved significantly (McNemar's test = 21.88, P < 0.001). Viral load suppression did not change, with 92.6% suppression at baseline and 92.0% at 48 weeks. Illicit drug use was associated with reduced adherence (aOR = 0.56, 95%CI 0.31-1.00, P = 0.05) and being on second-line therapy was associated with poor viral load suppression (aOR = 0.33, 95%CI 0.14-0.78, P = 0.01). Quality of life improved following ART initiation, from a mean of 84.6 points (of a possible 120) at baseline to 91.01 at 48 weeks. Due to technical issues, fidelity to the intended intervention was low, with 22.1% (102/462) of participants receiving any voice calls and most others receiving a scaled-back SMS intervention. The mHealth intervention did not have any observed effect on adherence or on viral load suppression. While evidence of effectiveness of mHealth adherence interventions is mixed, these platforms should continue to be explored as part of differentiated treatment support services.

Hospitalizations for opportunistic infections following transplantation and associated risk factors: A national cohort study of Medicare beneficiaries.

BACKGROUND: Opportunistic infections (OIs) are a significant cause of morbidity and mortality after organ transplantation, though data in the liver transplant (LT) population are limited. METHODS: We performed a retrospective cohort study of LT recipients between January 1, 2007 and Deceber 31, 2016 using Medicare claims data linked to the Organ Procurement and Transplantation Network database. Multivariable Cox regression models evaluated factors independently associated with hospitalizations for early (≤1 year post transplant) and late (>1 year) OIs, with a particular focus on immunosuppression. RESULTS: There were 11 320 LT recipients included in the study, of which 13.2% had at least one OI hospitalization during follow-up. Of the 2638 OI hospitalizations, 61.9% were early post-LT. Cytomegalovirus was the most common OI (45.4% overall), although relative frequency decreased after the first year (25.3%). Neither induction or maintenance immunosuppression were associated with early OI hospitalization (all p > .05). The highest risk of early OI was seen with primary sclerosing cholangitis (aHR 1.74; p = .003 overall). Steroid-based and mechanistic target of rapamycin inhibitor-based immunosuppression at 1 year post LT were independently associated with increased late OI (p < .001 overall). CONCLUSION: This study found OI hospitalizations to be relatively common among LT recipients and frequently occur later than previously reported. Immunosuppression regimen may be an important modifiable risk factor for late OIs.

E-Protein Inhibition in ILC2 Development Shapes the Function of Mature ILC2s during Allergic Airway Inflammation.

E-protein transcription factors limit group 2 innate lymphoid cell (ILC2) development while promoting T cell differentiation from common lymphoid progenitors. Inhibitors of DNA binding (ID) proteins block E-protein DNA binding in common lymphoid progenitors to allow ILC2 development. However, whether E-proteins influence ILC2 function upon maturity and activation remains unclear. Mice that overexpress ID1 under control of the thymus-restricted proximal Lck promoter (ID1tg/WT) have a large pool of primarily thymus-derived ILC2s in the periphery that develop in the absence of E-protein activity. We used these mice to investigate how the absence of E-protein activity affects ILC2 function and the genomic landscape in response to house dust mite (HDM) allergens. ID1tg/WT mice had increased KLRG1- ILC2s in the lung compared with wild-type (WT; ID1WT/WT) mice in response to HDM, but ID1tg/WT ILC2s had an impaired capacity to produce type 2 cytokines. Analysis of WT ILC2 accessible chromatin suggested that AP-1 and C/EBP transcription factors but not E-proteins were associated with ILC2 inflammatory gene programs. Instead, E-protein binding sites were enriched at functional genes in ILC2s during development that were later dynamically regulated in allergic lung inflammation, including genes that control ILC2 response to cytokines and interactions with T cells. Finally, ILC2s from ID1tg/WT compared with WT mice had fewer regions of open chromatin near functional genes that were enriched for AP-1 factor binding sites following HDM treatment. These data show that E-proteins shape the chromatin landscape during ILC2 development to dictate the functional capacity of mature ILC2s during allergic inflammation in the lung.

Effects of Tympanic Membrane Electrodes on Sound Transmission From the Ear Canal to the Middle and Inner Ears.

OBJECTIVES: The first objective of the study was to compare approaches to eardrum electrode insertion as they relate to the likelihood of introducing an acoustic leak between the ear canal and eartip. A common method for placing a tympanic membrane electrode involves securing the electrode in the canal by routing it underneath a foam eartip. This method is hypothesized to result in a slit leak between the canal and foam tip due to the added bulk of the electrode wire. An alternative approach involves creating a bore in the wall of the foam tip that the electrode can be threaded through. This method is hypothesized to reduce the likelihood of a slit leak before the electrode wire is integrated into the foam tip. The second objective of the study was to investigate how sound transmission in the ear is affected by placing an electrode on the eardrum. It was hypothesized that an electrode in contact with the eardrum increases the eardrum's mass, with the potential to reduce sound transmission at high frequencies. DESIGN: Wideband acoustic immittance and distortion product otoacoustic emissions (DPOAEs) were measured in eight human ears. Measurements were completed for five different conditions: (1) baseline with no electrode in the canal, (2) dry electrode in the canal but not touching the eardrum, secured underneath the eartip, (3) dry electrode in the canal not touching the eardrum, secured through a bore in the eartip (subsequent conditions were completed using this method), (4) hydrated electrode in the canal but not touching the eardrum, and (5) hydrated electrode touching the eardrum. To create the bore, a technique was developed in which a needle is heated and pushed through the foam eartip. The electrode is then thread through the bore and advanced slowly by hand until contacting the eardrum. Analysis included comparing absorbance, admittance phase angle, and DPOAE levels between measurement conditions. RESULTS: Comparison of the absorbance and admittance phase angle measurements between the electrode placement methods revealed significantly higher absorbance and lower admittance phase angle from 0.125 to 1 kHz when the electrode is routed under the eartip. Absorbance and admittance phase angle were minimally affected when the electrode was inserted through a bore in the eartip. DPOAE levels across the different conditions showed changes approximating test-retest variability. Upon contacting the eardrum, the absorbance tended to decrease below 1 kHz and increase above 1 kHz. However, changes were within the range of test-retest variability. There was evidence of reduced levels below 1 kHz and increased levels above 1 kHz upon the electrode contacting the eardrum. However, differences between conditions approximated test-retest variability. CONCLUSIONS: Routing the eardrum electrode through the foam tip reduces the likelihood of incurring an acoustic leak between the canal walls and eartip, compared with routing the electrode under the eartip. Changes in absorbance and DPOAE levels resulting from electrode contact with the eardrum implicate potential stiffening of eardrum; however, the magnitude of changes suggests minimal effect of the electrode on sound transmission in the ear.

Validation of new medication use algorithms as proxies for worsening disease activity in patients with juvenile idiopathic arthritis.

PURPOSE: To facilitate claims-based research on populations with juvenile idiopathic arthritis (JIA), we sought to validate an algorithm of new medication use as a proxy for worsening JIA disease activity. METHODS: Using electronic health record data from three pediatric centers, we defined new JIA medication use as (re)initiation of disease-modifying antirheumatic drugs or glucocorticoids (oral or intra-articular). Data were collected from 201 randomly selected subjects with (101) or without (100) new medication use. We assessed the positive predictive value (PPV) and negative predictive value (NPV) based on a reference standard of documented worsening of JIA disease activity. The algorithm was refined to optimize test characteristics. RESULTS: Overall, the medication-based algorithm had suboptimal performance in representing worsening JIA disease activity (PPV 69.3%, NPV 77.1%). However, algorithm performance improved for definitions specifying longer times after JIA diagnosis (≥1-year post-diagnosis: PPV 82.9%, NPV 80.0%) or after initiation of prior JIA treatment (≥1-year post-treatment: PPV 89.7%, NPV 80.0%). CONCLUSION: An algorithm for new JIA medication use appears to be a reasonable proxy for worsening JIA disease activity, particularly when specifying new use ≥1 year since initiating a prior JIA medication. This algorithm will be valuable for conducting research on JIA populations within administrative claims databases.

In older adults with frailty, virtual reality exercise training improves walking speed and balance.

SOURCE CITATION: Lee YH, Lin CH, Wu WR, et al. Virtual reality exercise programs ameliorate frailty and fall risks in older adults: a meta-analysis. J Am Geriatr Soc. 2023 May 10. [Epub ahead of print.] 37165743.

The biological standard of living of Korean men under Confucianism, colonialism, capitalism, and communism.

This study focuses on analysing the heights of 10,953 Korean men aged 20 to 40 years who were measured during the Joseon dynasty, the Japanese colonialisation period, and the contemporary period, the latter including both North and South Korea. This study thus provides rare long-term statistical evidence on how biological living standards have developed over several centuries, encompassing Confucianism, colonialism, capitalism, and communism. Using error bar analysis of heights for each historical sample period, this study confirms that heights rose as economic performance improved. For instance, economically poorer North Koreans were expectedly shorter, by about 6 cm, than their peers living in the developed South. Similarly, premodern inhabitants of present-day South Korea, who produced a gross domestic product (GDP) per capita below the world average, were about 4 cm shorter than contemporary South Koreans, who have a mean income above the world average. Along similar lines, North Koreans, who have a GDP per capita akin to that of the premodern Joseon dynasty, have not improved much in height. On the contrary, mean heights of North Koreans were even slightly below (by about 2.4 cm) heights of Joseon dynasty Koreans. All in all, the heights follow a U-shaped pattern across time, wherein heights were lowest during the colonial era. Heights bounced back to Joseon dynasty levels during the interwar period, a time period where South Korea benefitted from international aid, only to rise again and surpass even premodern levels under South Korea's flourishing market economy.

Salivary gland adenoid cystic carcinoma in the U.S population: Importance of grade, site of metastases, and adjuvant radiation for survival.

BACKGROUND: Adenoid cystic carcinoma (AdCC) is a rare and relatively heterogenous salivary gland malignancy, for which there is debate regarding grading, and clinical prognostic factors, including the role of adjuvant radiotherapy. METHODS: Surveillance, Epidemiology, and End Results (SEER) data were reviewed for AdCC cases from 2000 to 2018. RESULTS: A total of 1978 patients with AdCC were identified. Most patients were between 50 and 59 years of age (21.4 %), female (59.9 %), and Caucasian (76.8 %). Most tumors were localized at presentation (44.3 %), and moderately differentiated (or grade II) (43.7 %). Overall and DSS 5-year survival rates were 70.7 % (95 % CI, 69.9-78.8), and 78.6 % (95 % CI, 77.6-79.6). The best overall 5-year survival rate was observed for those treated with surgery plus radiation, 76.8 % (95 % CI, 75.5-78.1). Multivariate analysis revealed male sex, age > 65 (H.R. 2.659 (95 % CI,2.291-3.098), p < .001), grade III/IV (H.R.5.172 (95 % CI, 3.418-7.824), p < .001), nodal metastasis, distant metastasis (H.R. 2.400 (95 % CI, 2.178-2.645), p < .001), chemotherapy only, and combination therapy as negative prognostic factors, and receiving surgery plus radiation therapy (H.R.0.586 (95 % CI, 0.505-0.679), p < .001) as a positive prognostic factor. When limited just to the lungs, had much better survival than those patients with distant metastases to other sites such as the bones and liver (p < .001). CONCLUSION: This SEER study identifies grade, particularly III and IV, to be the strongest single predictor of worse survival. Patients did best when treated with surgery and postoperative radiotherapy. These results can inform future management of patients with this challenging cancer type.

Differential effects of mass-loading the eardrum and stiffening the middle ear on wideband absorbance.

The current work investigated the effects of mass-loading the eardrum on wideband absorbance in humans. A non-invasive approach to mass-loading the eardrum was utilized in which water was placed on the eardrum via ear canal access. The mass-loaded absorbance was compared to absorbance measured for two alternative middle ear states: normal and stiffened. To stiffen the ear, subjects pressurized the middle ear through either exsufflation or insufflation concurrent with Eustachian tube opening. Mass-loading the eardrum was hypothesized to reduce high-frequency absorbance, whereas pressurizing the middle ear was hypothesized to reduce low- to mid-frequency absorbance. Discriminant linear analysis classification was performed to evaluate the utility of absorbance in differentiating between conditions. Water on the eardrum reduced absorbance over the 0.7- to 6-kHz frequency range and increased absorbance at frequencies below approximately 0.5 kHz; these changes approximated the pattern of changes reported in both hearing thresholds and stapes motion upon mass-loading the eardrum. Pressurizing the middle ear reduced the absorbance over the 0.125- to 4-kHz frequency range. Several classification models based on the absorbance in two- or three-frequency bands had accuracy exceeding 88%.