Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts.

The true prevalence and penetrance of monogenic disease variants are often not known because of clinical-referral ascertainment bias. We comprehensively assess the penetrance and prevalence of pathogenic variants in HNF1A, HNF4A, and GCK that account for >80% of monogenic diabetes. We analyzed clinical and genetic data from 1,742 clinically referred probands, 2,194 family members, clinically unselected individuals from a US health system-based cohort (n = 132,194), and a UK population-based cohort (n = 198,748). We show that one in 1,500 individuals harbor a pathogenic variant in one of these genes. The penetrance of diabetes for HNF1A and HNF4A pathogenic variants was substantially lower in the clinically unselected individuals compared to clinically referred probands and was dependent on the setting (32% in the population, 49% in the health system cohort, 86% in a family member, and 98% in probands for HNF1A). The relative risk of diabetes was similar across the clinically unselected cohorts highlighting the role of environment/other genetic factors. Surprisingly, the penetrance of pathogenic GCK variants was similar across all cohorts (89%-97%). We highlight that pathogenic variants in HNF1A, HNF4A, and GCK are not ultra-rare in the population. For HNF1A and HNF4A, we need to tailor genetic interpretation and counseling based on the setting in which a pathogenic monogenic variant was identified. GCK is an exception with near-complete penetrance in all settings. This along with the clinical implication of diagnosis makes it an excellent candidate for the American College of Medical Genetics secondary gene list.

Racial Disparity in Length of Stay Following Implementation of a Bariatric Enhanced Recovery Program.

INTRODUCTION: Enhanced Recovery Programs (ERPs) mitigate racial disparities in postoperative length of stay (LOS) for colorectal populations. It is unclear, however, if these effects exist in the bariatric surgery population. Therefore, this study aimed to evaluate the racial disparities in LOS before and after implementation of bariatric surgery ERP. METHODS: A retrospective cohort study was performed using data from a single institution. Patients undergoing minimally invasive sleeve gastrectomy or Roux-en-Y gastric bypass from 2017 to 2019 (pre-ERP) or 2020-2022 (ERP) were included. Chi-square, Kruskal-Wallis, and analysis of variance were used to compare groups, and estimated LOS (eLOS) was assessed via multivariable regression. RESULTS: Seven hundred sixty four patients were identified, including 363 pre-ERPs and 401 ERPs. Pre-ERP and ERP cohorts were similar in age (median 44.3 years versus 43.8 years, P = 0.80), race (53.4% Black versus 56.4% Black, P = 0.42), and preoperative body mass index (median 48.3 versus 49.4, P = 0.14). Overall median LOS following bariatric surgery decreased from 2 days pre-ERP to 1 day following ERP (P < 0.001). Average LOS for Black and White patients decreased by 0.5 and 0.48 days, respectively. However, overall eLOS remained greater for Black patients compared with White patients despite ERP implementation (eLOS 0.21 days, P = 0.01). CONCLUSIONS: Implementation of a bariatric surgery ERP was associated with decreased LOS for both Black and White patients. However, Black patients did have slightly longer LOS than White patients in both pre-ERP and ERP eras. More work is needed to understand the driving mechanism(s) of these disparities to eliminate them.

Early postoperative outcomes following bariatric surgery in the United States: Are racial disparities improving?

BACKGROUND: Bariatric surgery offers effective treatment for morbid obesity and associated medical comorbidities, with excellent short- and long-term outcomes. Although it has been well documented that racial minority bariatric patients have worse outcomes than White patients, it remains unclear whether this recognition has led to improvement. Herein, we assess recent trends in bariatric surgery among Black and White patients and compare early postoperative outcomes by race. METHODS: Primary sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) patients from 2015 to 2021 reported to the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program were studied. Bariatric patients were stratified by race (Black and White) and perioperative outcomes were compared between matched Black and White patients. Primary outcome was 30-day mortality. Secondary outcomes included hospital readmissions, hospital length of stay (LOS), reoperation, and postoperative complications. RESULTS: Overall, there were 193,071 Black and 645,224 White primary bariatric patients, with a higher volume of SG and RGYB performed among White patients. A total of 219,566 Black and White bariatric patients were matched and included in the case-control. Black patients were found to have higher rates of 30-day mortality (0.02% vs. 0.01%; p = 0.03) and readmissions (3.68% vs. 2.65%; p < 0.001). There were no significant differences in LOS, reoperations, or overall postoperative complications. However, there was a higher postoperative pulmonary thromboembolism rate (0.16% vs 0.08%; p < 0.001).). The differences in perioperative outcomes stratified by race persisted over the study period (Fig. 1). CONCLUSION: Black bariatric surgery patients continue to have worse perioperative outcomes compared with their White counterparts. Further work must be done to determine contributing factors in order to effect improvement in outcomes in bariatric surgical care for racial minority patients.

Identification of Novel Genetic Risk Variants Associated with Hidradenitis Suppurativa in an Exome Sequencing Cohort of 92,455 Individuals.

INTRODUCTION: Hidradenitis suppurativa (HS) is a prevalent and persistent inflammatory skin disorder, lacking a known cure or effective biomarkers for early diagnosis at present. The genetic determinants of HS have not been fully documented, but it is believed to result from a combination of genetic and environmental factors. METHODS: To identify relevant HS gene variants in sporadic HS patients, this study utilized longitudinal electronic health records (EHRs) and whole-exome sequencing. DNA exome sequencing data from 92,455 participant samples in the MyCode biobank, linked to Geisinger's EHR, were analyzed. This cohort included 1,092 HS cases and 91,363 healthy controls. The MyCode EHR has a median longitudinal follow-up of 15 years per participant, with an average of 87 clinical encounters, 687 laboratory tests, and 7 procedures. RESULTS: There were 1,092 (901 females and 191 males) participants aged 14-89 years (median 47 years) with HS (L73.2), indicating a 1.18% prevalence and accounting for a 4.7:1 female-to-male ratio among the individuals presenting for clinical care. γ-secretase complex, syndromic, and autoinflammatory gene variants were assessed. Potential pathogenic variants were identified among 66 individuals in the HS genes studied. Molecularly, the estimated HS variant prevalence was 1:1,400 in the cohort, 12.3% of variant carriers had HS diagnosis in EHR. CONCLUSIONS: Using longitudinal EHR data, genomic screening identified HS-associated gene variants in a defined group of sporadic HS patients to augment the clinical diagnosis, particularly in cases of ambiguity. Based on this study, the field of skin disorders can benefit from a personalized approach to HS diagnosis using large-scale sequencing.

Readability of patient education materials for bariatric surgery.

INTRODUCTION: Bariatric surgery is a successful treatment for obesity, but barriers to surgery exist, including low health literacy. National organizations recommend patient education materials (PEM) not exceed a sixth-grade reading level. Difficult to comprehend PEM can exacerbate barriers to bariatric surgery, especially in the Deep South where high obesity and low literacy rates exist. This study aimed to assess and compare the readability of webpages and electronic medical record (EMR) bariatric surgery PEM from one institution. METHODS: Readability of online bariatric surgery and standardized perioperative EMR PEM were analyzed and compared. Text readability was assessed by validated instruments: Flesch Reading Ease Formula (FRE), Flesch Kincaid Grade Level (FKGL), Gunning Fog (GF), Coleman-Liau Index (CL), Simple Measure of Gobbledygook (SMOG), Automated Readability Index (ARI), and Linsear Write Formula (LWF). Mean readability scores were calculated with standard deviations and compared using unpaired t-tests. RESULTS: 32 webpages and seven EMR education documents were analyzed. Webpages were overall "difficult to read" compared to "standard/average" readability EMR materials (mean FRE 50.5 ± 18.3 vs. 67.4 ± 4.2, p = 0.023). All webpages were at or above high school reading level: mean FKGL 11.8 ± 4.4, GF 14.0 ± 3.9, CL 9.5 ± 3.2, SMOG 11.0 ± 3.2, ARI 11.7 ± 5.1, and LWF 14.9 ± 6.6. Webpages with highest reading levels were nutrition information and lowest were patient testimonials. EMR materials were sixth to ninth grade reading level: FKGL 6.2 ± 0.8, GF 9.3 ± 1.4, CL 9.7 ± 0.9, SMOG 7.1 ± 0.8, ARI 6.1 ± 1.0, and LWF 5.9 ± 0.8. CONCLUSION: Surgeon curated bariatric surgery webpages have advanced reading levels above recommended thresholds compared to standardized PEM from an EMR. This readability gap may unintentionally contribute to barriers to surgery and affect postoperative outcomes. Streamlined efforts are needed to create materials that are easier to read and comply with recommendations.

Genomics-First Evaluation of Heart Disease Associated With Titin-Truncating Variants.

BACKGROUND: Truncating variants in the Titin gene (TTNtvs) are common in individuals with idiopathic dilated cardiomyopathy (DCM). However, a comprehensive genomics-first evaluation of the impact of TTNtvs in different clinical contexts, and the evaluation of modifiers such as genetic ancestry, has not been performed. METHODS: We reviewed whole exome sequence data for >71 000 individuals (61 040 from the Geisinger MyCode Community Health Initiative (2007 to present) and 10 273 from the PennMedicine BioBank (2013 to present) to identify anyone with TTNtvs. We further selected individuals with TTNtvs in exons highly expressed in the heart (proportion spliced in [PSI] >0.9). Using linked electronic health records, we evaluated associations of TTNtvs with diagnoses and quantitative echocardiographic measures, including subanalyses for individuals with and without DCM diagnoses. We also reviewed data from the Jackson Heart Study to validate specific analyses for individuals of African ancestry. RESULTS: Identified with a TTNtv in a highly expressed exon (hiPSI) were 1.2% individuals in PennMedicine BioBank and 0.6% at Geisinger. The presence of a hiPSI TTNtv was associated with increased odds of DCM in individuals of European ancestry (odds ratio [95% CI]: 18.7 [9.1-39.4] {PennMedicine BioBank} and 10.8 [7.0-16.0] {Geisinger}). hiPSI TTNtvs were not associated with DCM in individuals of African ancestry, despite a high DCM prevalence (odds ratio, 1.8 [0.2-13.7]; P=0.57). Among 244 individuals of European ancestry with DCM in PennMedicine BioBank, hiPSI TTNtv carriers had lower left ventricular ejection fraction (ß=-12%, P=3×10-7), and increased left ventricular diameter (ß=0.65 cm, P=9×10-3). In the Geisinger cohort, hiPSI TTNtv carriers without a cardiomyopathy diagnosis had more atrial fibrillation (odds ratio, 2.4 [1.6-3.6]) and heart failure (odds ratio, 3.8 [2.4-6.0]), and lower left ventricular ejection fraction (ß=-3.4%, P=1×10-7). CONCLUSIONS: Individuals of European ancestry with hiPSI TTNtv have an abnormal cardiac phenotype characterized by lower left ventricular ejection fraction, irrespective of the clinical manifestation of cardiomyopathy. Associations with arrhythmias, including atrial fibrillation, were observed even when controlling for cardiomyopathy diagnosis. In contrast, no association between hiPSI TTNtvs and DCM was discerned among individuals of African ancestry. Given these findings, clinical identification of hiPSI TTNtv carriers may alter clinical management strategies.

Color lens-free imaging using multi-wavelength illumination based phase retrieval.

Accurate image reconstruction in color lens-free imaging has proven challenging. The color image reconstruction of a sample is impacted not only by how strongly the illumination intensity is absorbed at a given spectral range, but also by the lack of phase information recorded on the image sensor. We present a compact and cost-effective approach of addressing the need for phase retrieval to enable robust color image reconstruction in lens-free imaging. The amplitude images obtained at transparent wavelength bands are used to estimate the phase in highly absorbed wavelength bands. The accurate phase information, obtained through our iterative algorithm, removes the color artefacts due to twin-image noise in the reconstructed image and improves image reconstruction quality to allow accurate color reconstruction. This could enable the technique to be applied for imaging of stained pathology slides, an important tool in medical diagnostics.

Fast compressive lens-free tomography for 3D biological cell culture imaging.

We present a compressive lens-free technique that performs tomographic imaging across a cubic millimeter-scale volume from highly sparse data. Compared with existing lens-free 3D microscopy systems, our method requires an order of magnitude fewer multi-angle illuminations for tomographic reconstruction, leading to a compact, cost-effective and scanning-free setup with a reduced data acquisition time to enable high-throughput 3D imaging of dynamic biological processes. We apply a fast proximal gradient algorithm with composite regularization to address the ill-posed tomographic inverse problem. Using simulated data, we show that the proposed method can achieve a reconstruction speed ∼10× faster than the state-of-the-art inverse problem approach in 3D lens-free microscopy. We experimentally validate the effectiveness of our method by imaging a resolution test chart and polystyrene beads, demonstrating its capability to resolve micron-size features in both lateral and axial directions. Furthermore, tomographic reconstruction results of neuronspheres and intestinal organoids reveal the potential of this 3D imaging technique for high-resolution and high-throughput biological applications.

Pixel super-resolution for lens-free holographic microscopy using deep learning neural networks.

Lens-free holographic microscopy (LFHM) provides a cost-effective tool for large field-of-view imaging in various biomedical applications. However, due to the unit optical magnification, its spatial resolution is limited by the pixel size of the imager. Pixel super-resolution (PSR) technique tackles this problem by using a series of sub-pixel shifted low-resolution (LR) lens-free holograms to form the high-resolution (HR) hologram. Conventional iterative PSR methods require a large number of measurements and a time-consuming reconstruction process, limiting the throughput of LFHM in practice. Here we report a deep learning-based PSR approach to enhance the resolution of LFHM. Compared with the existing PSR methods, our neural network-based approach outputs the HR hologram in an end-to-end fashion and maintains consistency in resolution improvement with a reduced number of LR holograms. Moreover, by exploiting the resolution degradation model in the imaging process, the network can be trained with a data set synthesized from the LR hologram itself without resorting to the HR ground truth. We validated the effectiveness and the robustness of our method by imaging various types of samples using a single network trained on an entirely different data set. This deep learning-based PSR approach can significantly accelerate both the data acquisition and the HR hologram reconstruction processes, therefore providing a practical solution to fast, lens-free, super-resolution imaging.

Predictive factors of weight regain following laparoscopic Roux-en-Y gastric bypass.

BACKGROUND: Strategies to address weight recidivism following Roux-en-Y gastric bypass (RYGB) could be developed if patients at risk were identified in advance. This study aimed to determine factors that predict weight regain. METHODS: Retrospective review was performed of patients who underwent laparoscopic RYGB at a single institution over 10 years. Group-based modeling was used to estimate trajectories of weight regain after nadir and stratify patients based on percent weight change (%WC). RESULTS: Three trajectories were identified from 586 patients: 121 had ongoing weight loss, 343 were weight stable, and 122 regained weight. Male sex (p = 0.020) and white race (p < 0.001) were associated with stable weight or weight regain. Being from a neighborhood of socioeconomic advantage (p = 0.035) was associated with weight regain. Patients with weight regain experienced improved percent weight loss (%WL) at nadir (p < 0.001) and ΔBMI (p = 0.002), yet they had higher weight and BMI and lower %WL and ΔBMI than the other two groups during long-term follow-up. On multivariate analyses, those who regained weight were more likely from socioeconomically advantaged neighborhoods (OR 1.82, CI 1.18-2.79). CONCLUSIONS: Several patient-related characteristics predicted an increased likelihood of weight regain. Further studies are needed to elucidate how these factors contribute to weight recidivism following bariatric surgery.

Outcomes associated with preoperative weight loss after laparoscopic Roux-en-Y gastric bypass.

BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGB) is an effective treatment for achieving and maintaining weight loss and for improving obesity-related comorbidities. As part of the approval process for bariatric surgery, many insurance companies require patients to have documented recent participation in a supervised weight loss program. The goal of this study was to evaluate the relationship of preoperative weight changes with outcomes following LRYGB. METHODS: A retrospective review was conducted of adult patients undergoing LRYGB between 2008 and 2012 at a single institution. Patients were stratified into quartiles based on % excess weight gain (0-4.99 % and ≥5 % EWG) and % excess weight loss (0-4.99 % and ≥5 % EWL). Generalized linear models were used to examine differences in postoperative weight outcomes at 6, 12, and 24 months. Covariates included in the final adjusted models were determined using backwards stepwise selection. RESULTS: Of the 300 patients included in the study, there were no significant demographic differences among the quartiles. However, there was an increased time to operation for patients who gained or lost ≥5 % excess body weight (p < 0.001). Although there was no statistical significance in postoperative complications, there was a higher rate of complications in patients with ≥5 % EWG compared to those with ≥5 % EWL (12.5 vs. 4.8 %, respectively; p = 0.29). Unadjusted and adjusted generalized linear models showed no statistically significant association between preoperative % excess weight change and weight loss outcomes at 24 months. CONCLUSION: Patients with the greatest % preoperative excess weight change had the longest intervals from initial visit to operation. No significant differences were seen in perioperative and postoperative outcomes. This study suggests preoperative weight loss requirements may delay the time to operation without improving postoperative outcomes or weight loss.

Conformational transitions of the cross-linking domains of elastin during self-assembly.

Elastin is the intrinsically disordered polymeric protein imparting the exceptional properties of extension and elastic recoil to the extracellular matrix of most vertebrates. The monomeric precursor of elastin, tropoelastin, as well as polypeptides containing smaller subsets of the tropoelastin sequence, can self-assemble through a colloidal phase separation process called coacervation. Present understanding suggests that self-assembly is promoted by association of hydrophobic domains contained within the tropoelastin sequence, whereas polymerization is achieved by covalent joining of lysine side chains within distinct alanine-rich, α-helical cross-linking domains. In this study, model elastin polypeptides were used to determine the structure of cross-linking domains during the assembly process and the effect of sequence alterations in these domains on assembly and structure. CD temperature melts indicated that partial α-helical structure in cross-linking domains at lower temperatures was absent at physiological temperature. Solid-state NMR demonstrated that ß-strand structure of the cross-linking domains dominated in the coacervate state, although α-helix was predominant after subsequent cross-linking of lysine side chains with genipin. Mutation of lysine residues to hydrophobic amino acids, tyrosine or alanine, leads to increased propensity for ß-structure and the formation of amyloid-like fibrils, characterized by thioflavin-T binding and transmission electron microscopy. These findings indicate that cross-linking domains are structurally labile during assembly, adapting to changes in their environment and aggregated state. Furthermore, the sequence of cross-linking domains has a dramatic effect on self-assembly properties of elastin-like polypeptides, and the presence of lysine residues in these domains may serve to prevent inappropriate ordered aggregation.

Helicobacter pylori infection inhibits phagocyte clearance of apoptotic gastric epithelial cells.

Increased apoptotic death of gastric epithelial cells is a hallmark of Helicobacter pylori infection, and altered epithelial cell turnover is an important contributor to gastric carcinogenesis. To address the fate of apoptotic gastric epithelial cells and their role in H. pylori mucosal disease, we investigated phagocyte clearance of apoptotic gastric epithelial cells in H. pylori infection. Human gastric mononuclear phagocytes were analyzed for their ability to take up apoptotic epithelial cells (AECs) in vivo using immunofluorescence analysis. We then used primary human gastric epithelial cells induced to undergo apoptosis by exposure to live H. pylori to study apoptotic cell uptake by autologous monocyte-derived macrophages. We show that HLA-DR(+) mononuclear phagocytes in human gastric mucosa contain cytokeratin-positive and TUNEL-positive AEC material, indicating that gastric phagocytes are involved in AEC clearance. We further show that H. pylori both increased apoptosis in primary gastric epithelial cells and decreased phagocytosis of the AECs by autologous monocyte-derived macrophages. Reduced macrophage clearance of apoptotic cells was mediated in part by H. pylori-induced macrophage TNF-α, which was expressed at higher levels in H. pylori-infected, compared with uninfected, gastric mucosa. Importantly, we show that H. pylori-infected gastric mucosa contained significantly higher numbers of AECs and higher levels of nonphagocytosed TUNEL-positive apoptotic material, consistent with a defect in apoptotic cell clearance. Thus, as shown in other autoimmune and chronic inflammatory diseases, insufficient phagocyte clearance may contribute to the chronic and self-perpetuating inflammation in human H. pylori infection.

Major bleeding in patients with mediastinitis: a heartbreaking series.

Deep sternal wound infection (DSWI) is a life-threatening complication that develops in 5% of patients undergoing median sternotomy. One feared complication is major bleeding, associated with up to 50% mortality. We characterized a series of patients who experienced major bleeding following DSWI. We included eight patients with DSWI who experienced major bleeding at our institution from 1990 to 2012. The median age was 70.9 (range, 47-81) and the cohort consisted of seven male patients and one female patient. All eight patients required emergent surgical repair for the bleeding and all survived past 30 days postoperatively from the repair.

Multipurpose use of the 'bear claw' (over-the-scope-clip system) to treat endoluminal gastrointestinal disorders.

BACKGROUND AND AIM: The 'bear-claw' or over-the-scope-clip system (OTSC; Ovesco Endoscopy, Tübingen, Germany) is a new clipping device developed for closure of large luminal gastrointestinal (GI) defects. The aim of the present study was to evaluate the clinical outcomes of patients treated with the OTSC. METHODS: The present study was an observational, open-label, retrospective, single-arm case series conducted at two hospitals with tertiary care endoscopy. It involved 20 clip applications in 16 patients (median age 65.8 years [range 51-90 years], seven women) with GI defects from fistulas and anastomotic dehiscence and peptic ulcer bleeding. RESULTS: The range of indications included gastrointestinal bleeding (n=6), gastrocutaneous fistulas (n=3), esophagotracheal and/or esophagopleural fistulae (n=3), resection ofsubmucosal tumor (n=2), stent fixation (n=1), and anastomotic leak after esophagectomy (n=1). The overall success rate for the OTSC device was 75% (12 out of 16 patients). The overall per case success rate was 70% (14 of 20 applications). Mean follow up was 10 months (range 1-10). There were no complications (0%) related to endoscopy, sedation or application of the clipping device. CONCLUSIONS: The OTSC system is a useful device in a variety of clinical scenarios including the management of larger GI leaks and fistulas, GI bleeding, full-thickness resection of tumors, and stent anchoring, even in very old and frail patients.

Tetraspanins are involved in Schwann cell-axon interaction.

Many studies have shown that tetraspanins play important role in cell-cell and cell-extracellular matrix (ECM) interactions. The repertoire and functions of tetraspanins in Schwann cells, glial cells of the peripheral nervous system have remained largely uncharacterized. This study was undertaken to identify Schwann cell tetraspanins and to elucidate their possible functions. Microarray analysis revealed the expression of numerous tetraspanins in primary culture of Schwann cells. Expression of five of them, CD9, CD63, CD81, CD82, and CD151, and of tetraspanin-associated protein EWI-2 was also confirmed by immunofluorescence. Localization of CD9, CD63, CD81, and EWI-2 was largely confined to paranodes and Schmidt-Lanterman incisures, regions of noncompact myelin. Immunoprecipitation experiments showed that these four proteins form a complex in Schwann cells. siRNA silencing of individual components of the complex did not affect Schwann cell adhesion to ECM proteins or attachment to and alignment with axons. However, suppression of both CD63 and CD81 expression together significantly inhibited extension of Schwann cell processes along axons, without affecting initial attachment of the cells to the axonal surface. Adhesion, spreading, and migration of Schwann cells on ECM proteins also were not affected by double silencing of CD63 and CD81. Suppression of CD63 and CD81 expression did not affect the ability of Schwann cells to myelinate dorsal root ganglion neurons in vitro. These findings strongly suggest that CD63 and CD81 play an important role in Schwann cell spreading along axons but seem to be dispensable for Schwann cell myelination.

The University of Alabama at Birmingham Surgery Community Network: Tackling the Challenges of Rural Surgery.

Over the past 5 years, The University of Alabama at Birmingham (UAB) Department of Surgery has taken a keen interest in the practice of surgery in rural Alabama and has established the UAB surgery community network. Our goal is to improve the delivery of surgical care in rural areas through active recruitment of rural surgeons, the development of research around rural surgery practice, and the expansion of a surgery network throughout the state. Here, we will present the challenges faced by rural surgery, our early work to address these challenges, and offer a plan for moving forward.

Stromal regulation of human gastric dendritic cells restricts the Th1 response to Helicobacter pylori.

BACKGROUND & AIMS: Mucosal dendritic cells (DCs) play a key role in initiating the T-helper (Th)1 response to Helicobacter pylori. To further elucidate the mucosal response to H pylori, we examined whether gastric stromal factors condition DCs to support tolerance to H pylori, analogous to intestinal stromal factor-driven macrophage tolerance to commensal bacteria. METHODS: To model mucosal DC development, we isolated and cultured cell-depleted human stroma/extracellular matrix from fresh gastric and intestinal mucosa to generate stroma-conditioned media. We then analyzed the capacity of stroma-conditioned media-treated monocyte-derived DCs and primary human gastric and intestinal DCs pulsed in vitro with H pylori to induce T-cell proliferation and interferon gamma secretion. RESULTS: Stromal factors in gastric mucosa suppressed H pylori-stimulated DC activation and the ability of DCs to drive a Th1 proliferative and cytokine response to H pylori. The ability of gastric stromal factors to down-regulate DC function was similar to that of intestinal stromal factors and was independent of transforming growth factor ß, prostaglandin E2, interleukin (IL)-10, and thymic stromal lymphopoietin. Stroma-conditioned media-induced reduction in DC-stimulated Th1 responses was associated with reduced DC release of IL-12. CONCLUSIONS: Gastric stromal factors down-regulate DC responsiveness to H pylori, resulting in a dampened gastric Th1 response. We speculate that stroma-induced down-regulation of DC function contributes to the permissiveness of both gastric and intestinal mucosa to colonization by persistent residential microbes.

Laparoscopic Roux-en-Y gastric bypass: long term clinical outcomes.

BACKGROUND: Bariatric surgery remains the most effective treatment for morbid obesity, and laparoscopic Roux-en-Y gastric bypass (LRYGB) continues to be the preferred operation. However, data for long-term outcomes are lacking. Our goal was to determine the long-term clinical outcomes after LRYGB. METHODS: Retrospective review of a prospectively maintained database was conducted on all patients who underwent LRYGB from 2001-2006. Only patients who had postoperative clinic visits both at ≤2 and ≥5 years were included. Data collected included patient demographics and postoperative clinical outcomes, including percent excess weight loss (%EWL), complications, and improvement or resolution of preoperative comorbidities (type 2 diabetes mellitus, hypertension, obstructive sleep apnea, and hyperlipidemia). Data were analyzed by using SAS (version 9.2) and SPSS (version 16) statistical software. RESULTS: There were 770 patients who underwent LRYGB at UAB from 2001-2006. Of these, 172 patients met inclusion criteria (148 women and 24 men) with a median age of 41 years and median body mass index of 46 kg/m(2). Median short- and long-term follow-up was 12 and 75 months, respectively. Mean %EWL was 69% for short-term and 65% for long-term follow-up (P = 0.0032). Of 172 patients, 66 experienced 81 complications at a median of 26 months after operation. The improvement or resolution of comorbidities was maintained in the long-term, and there was no statistically significant difference compared with improvement or resolution in the short-term. CONCLUSIONS: Although there was a statistically significant difference in %EWL between short- and long-term follow-up, both arms showed a clinically relevant %EWL (69 and 65%) and both were statistically significant compared with preoperative values. The improvement or resolution of comorbidities achieved with LRYGB was maintained in long-term follow-up. Thus, LRYGB resulted in significant improvement in clinical outcomes that were durable in the long term.