Differential pairing of transmembrane domain GxxxG dimerization motifs defines two HLA-DR MHC class II conformers.

MHC class II molecules function to present exogenous antigen-derived peptides to CD4 T cells to both drive T cell activation and to provide signals back into the class II antigen-presenting cell. Previous work established the presence of multiple GxxxG dimerization motifs within the transmembrane domains of MHC class II α and ß chains across a wide range of species and revealed a role for differential GxxxG motif pairing in the formation of two discrete mouse class II conformers with distinct functional properties (i.e., M1-and M2-paired I-Ak class II). Biochemical and mutagenesis studies detailed herein extend this model to human class II by identifying an anti-HLA-DR mAb (Tü36) that selectively binds M1-paired HLA-DR molecules. Analysis of the HLA-DR allele reactivity of the Tü36 mAb helped define other HLA-DR residues involved in mAb binding. In silico modeling of both TM domain interactions and whole protein structure is consistent with the outcome of biochemical/mutagenesis studies and provides insight into the possible structural differences between the two HLA-DR conformers. Cholesterol depletion studies indicate a role for cholesterol-rich membrane domains in the formation/maintenance of Tü36 mAb reactive DR molecules. Finally, phylogenetic analysis of the amino acid sequences of Tü36-reactive HLA-DR ß chains reveals a unique pattern of both Tü36 mAb reactivity and key amino acid polymorphisms. In total, these studies bring the paradigm M1/M2-paired MHC class II molecules to the human HLA-DR molecule and suggest that the functional differences between these conformers defined in mouse class II extend to the human immune system.

Associations among enacted weight stigma, weight self-stigma, and multiple physical health outcomes, healthcare utilization, and selected health behaviors.

BACKGROUND: This study examined the relationship among enacted weight stigma, weight self-stigma, and multiple health outcomes. Weight stigma, a stressor experienced across all body sizes, may contribute to poorer physical health outcomes by activating the nervous and endocrine system or by triggering counterproductive health behaviors like lower physical activity, maladaptive eating patterns, and delayed health care, as well as provider bias that may cause a medical concern to be discounted. While associations of weight stigma with mental health issues are well documented, less is known about its association with physical health. METHODS: We enrolled 3821 adults who completed an online survey assessing enacted weight stigma, weight self-stigma, multiple self-reported physical health outcomes, healthcare utilization, and selected health behaviors. RESULTS: After controlling for BMI, health care delay or avoidance, sedentary behavior, and selected demographic characteristics, enacted weight stigma, significantly increased the odds of six physical health problems including hypertension (OR 1.36; CI 1.08, 1.72), hyperglycemia (OR 1.73; CI 1.29, 2.31), thyroid disorder, (OR 1.65; CI 1.27, 2.13), any arthritis (OR 1.70; CI 1.27, 2.26), non-arthritic chronic pain (OR 1.76; CI 1.4, 2.29), and infertility (OR 1.53; CI 1.14, 2.05). Weight self-stigma significantly increased the odds for three physical health problems including hypertension (OR 1.43; CI 1.16, 1.76), hyperglycemia (OR 1.37; CI 1.03, 1.81), and non-arthritic chronic pain (OR 1.5; CI 1.2,1.87). Enacted stigma was associated with more than a four-fold increase in odds of believing that a medical concern was disregarded by a health care provider. CONCLUSIONS: In this study, enacted stigma and weight self-stigma were independently associated with heightened risk for multiple physical health problems, as well as, believing health concerns were discounted by providers. Reducing weight stigma may be an important component of managing multiple physical health conditions.

Narcolepsy genetic marker HLA DQB1*06:02 and excessive daytime sleepiness in Parkinson disease patients treated with dopaminergic agents.

OBJECTIVE: To determine whether narcolepsy Human Leukocyte Antigen (HLA) risk allele DQB1*0602 is associated with excessive daytime sleepiness (EDS) and inappropriate sleep in patients with Parkinson disease (PD). BACKGROUND: EDS is a common and disabling non-motor manifestation of PD, affecting quality of life and driving performance. DQB1*0602 is an HLA risk allele for narcolepsy. It is present in 12-30% of the general population. We hypothesize that DQB1*0602 is associated with an increased risk of EDS and inappropriate sleep in PD patients. METHODS: This was a cross-sectional observational study of 150 PD individuals on dopaminergic agents. Main outcome measures were DQB1*0602 status and the modified Epworth Sleepiness Scale. Individuals with dementia, loss of independence, narcolepsy and untreated sleep apnea were excluded. Confounding variables for EDS were assessed using Parkinson Disease Sleep Scale, Mayo Sleep Questionnaire, Unified PD Rating Scale, Hoehn and Yahr scale. RESULTS: DQB1*06:02 positive PD patients were approximately three times more likely to experience EDS and fall asleep inappropriately during activities that required sustained alertness (e.g. driving, eating, attending work etc.). Exploratory post hoc analysis showed a dopaminergic drug dose- and type- dependent effect on daytime sleepiness in DQB1*06:02 positive individuals. No significant differences were found in confounding variables. CONCLUSION: PD individuals are more likely to experience EDS and fall asleep inappropriately during activities if DQB1*0602 positive. Genetic vulnerability may explain EDS risk in PD.

Male sex, ostomy, infection, and intravenous fluids are associated with increased risk of postoperative ileus in elective colorectal surgery.

BACKGROUND: Postoperative ileus is a common and costly complication after elective colorectal surgery. Effects of intravenous fluid administration remain controversial, and the effect of ostomy construction has not been fully evaluated. Various restrictive intravenous fluid protocols may adversely affect renal function. We aimed to investigate the impact of intestinal reconstruction and intravenous fluid on ileus and renal function after colorectal resection under an enhanced recovery protocol. METHODS: A retrospective study of a prospectively maintained institutional database for a tertiary academic medical center following National Surgical Quality Improvement Program standards was reviewed, analyzing elective colorectal resections performed under enhanced recovery protocol from 2015 to 2018. Postoperative ileus was defined as nasogastric decompression, nil per os >3 days postoperatively, or nasogastric tube insertion. Patients with and without ileus were compared. Intravenous fluid and different anastomoses and ostomies were investigated. Acute kidney injury was a secondary outcome, due to the potential of renal damage with restriction of intravenous fluid volume during and after surgery and controversy in current literature in this matter. RESULTS: Postoperative ileus occurred in 18.5% of patients (n = 464). Male sex (odds ratio 1.97, 95% confidence interval 1.12-3.52) and postoperative infection (odds ratio 2.13, 95% confidence interval 1.03-4.35) were associated with ileus. Compared to colorectal anastomosis, ileostomy/ileorectal anastomosis had the highest risk of ileus (odds ratio 4.9, 95% confidence interval 2.33-11.3), colostomy second highest (odds ratio 3.3, 95% confidence interval 1.35-8.39), while ileocolic anastomosis did not significantly differ (odds ratio 2.06, 95% confidence interval 0.69-5.85) on multivariate analysis. Each liter of intravenous fluid within the first 72 hours significantly correlated with postoperative ileus (odds ratio 1.41, 95% confidence interval 1.27-1.59). Rates of acute kidney injury did not differ (P = .18). CONCLUSION: Each additional liter of intravenous fluid given in the first 72 hours increased the risk of postoperative ileus 1.4-fold. There is substantially higher risk of ileus with male sex, infection, ileostomy/ileorectal anastomosis, and colostomy. Judicious use of intravenous fluid, as described in our enhanced recovery protocol, is not detrimental for renal function in the setting of normal baseline.

A Mobile Phone Application for Assessing Daily Variation in Pain Location and Pain Intensity in Patients with Urologic Chronic Pelvic Pain Syndrome: A MAPP Network Study.

Introduction: We created and tested a mobile app that facilitates the ecological momentary assessment of pain intensity and pain location and identifies heterogeneous patient pain phenotypes. Methods: A mobile app was created with patient, clinician and researcher input. A sample of 20 participants with urologic chronic pelvic pain syndrome were then asked to complete a 14-day pain assessment using the app. Data were analyzed to assess compliance, usability and the ability for the app to capture variation in pain intensity and pain location. Ecological momentary assessment pain data were then compared to end-of-week pain summary questions to determine construct validity. Results: Mean compliance was 70±8%, higher earlier in the study period (p <0.0005) and better in older individuals (p <0.0001). During the 14-day assessment, 90% of participants reported daily variation in pelvic pain intensity (SD 0.64-3.02; out of 10), 95% reported variation in their nonpelvic pain (SD 0.17-3.63; out of 10) and 100% reported variations in number of sites with pain (SD 0.22-1.44; out of 7). Pelvic pain and nonpelvic pain intensity, as determined by cumulative app scores, were associated with patient reported end-of-week scores; worst pain (r pelvic =0.67; r nonpelvic =0.53) and average pain (r pelvic =0.78; r nonpelvic =0.73). Conclusions: The easy-to-use app captured unique patterns of pain not fully captured by traditional end-of-day/week summary questions or by traditional in-office assessments. Mobile apps for assessing chronic conditions will become increasingly important as telehealth becomes more commonplace.

Enacted weight stigma and weight self stigma prevalence among 3821 adults.

BACKGROUND: Weight stigma is associated with several negative health issues such as anxiety, depression, maladaptive eating, and metabolic and cardiovascular disease, independent of weight and problematic for individuals of all ages and body sizes. To reduce harmful effects of weight stigma, it is imperative we accurately capture the prevalence of weight stigma in the population to better understand the magnitude of the problem. The purpose of this study was to describe the prevalence of both enacted weight stigma and weight-self stigma and include important contextual factors such as demographic characteristics and the belief about personal controllability of body weight. METHODS: This cross-sectional study included over 3800 adults who completed an online survey that captured their experiences with weight-based discrimination, teasing and beliefs about obesity. Using multivariate logistic regression, we predicted the odds of weight stigma across demographic characteristics and beliefs about obesity. RESULTS: The prevalence of weight stigma in this sample was 57%. We found that the odds of weight discrimination and teasing are higher across BMI categories and that the odds of weight self-stigma are highest among those who are categorized as overweight or obese. Additionally, the odds of weight self-stigma are higher for those who believe individuals are personally responsible for body weight. CONCLUSIONS: Our findings are comprehensive and offer new information crucial to our overall understanding of weight-based stigma and discrimination. Most people have weight stigma and it is prevalent in individuals of all body sizes. This study has significant implications for research and clinical practice.

Development and Validation of A Male Anterior Urethral Stricture Classification System.

OBJECTIVE: To develop and validate a clinical classification system for urethral stricture disease (USD) based on the retrograde urethrogram (RUG), physical exam, and stricture-specific patient history. MATERIALS AND METHODS: Three elements were chosen to be included in the classification system: 1) Length of urethral stricture (L); 2) Stricture segment/location (S); 3) Stricture Etiology (E) (LSE classification system). Each element was divided into clinically relevant sub-categories. A three-step development and validation process then ensued, culminating in an in-person Trauma and Urologic Reconstruction Network of Surgeons (TURNS) meeting, at which the final classification system was unanimously agreed upon by attendees based on interrater reliability data obtained from the classifying of 22 clinical vignettes. A final validation step involved retrospectively classifying cases in the TURNS database to determine if classification influenced surgical technique and was associated with presumed stricture etiology. RESULTS: The final LSE classification system was found to have an interrater reliability of 0.79 (individual components 0.76, 0.70 and 0.93 respectfully). Retrospective classification of the 2162 TURNS strictures revealed the segment (S) to be strongly associated with urethroplasty type (p = 0.0005) and stricture etiology (E) (p = 0.0005). CONCLUSION: We developed and validated a novel, easy to use, urethral stricture classification system. The system's ability to aid in directing treatments, predict treatment outcomes, and facilitate collaborative research efforts will require further study.

Trends in Urethral Stricture Disease Etiology and Urethroplasty Technique From a Multi-institutional Surgical Outcomes Research Group.

OBJECTIVE: To analyze contemporary urethroplasty trends and urethral stricture etiologies over a 7-year study period among urologists from a large multi-institutional surgical outcomes group. METHODS: Review of a multi-institutional, prospectively maintained urethroplasty database was performed on 2098 anterior urethroplasties done between 2010 and 2017 by 10 surgeons. Stricture characteristics, including etiology, length, and anatomic location were analyzed and compared to urethroplasty type over the study period using chi-squared analysis to assess for linear trends within the group and by surgeon. RESULTS: Average stricture lengths for bulbar (2.8 ± 1.8 cm), penile (3.6 ± 2.6 cm), and penile-bulbar strictures (8.7 ± 5.0) remained stable. The most common stricture etiology was idiopathic/unknown in all study years (63%). In the bulbar urethra, the group performed significantly (1) fewer excisional repairs (-31%) and more substitutional repairs (+78%); (2) of substitutional repairs, more grafts are being placed dorsally (+95%) vs ventrally (-75%) (3) of the bulbar excisional repairs, more are being performed without transection of the bulbar urethra (+430%); and in the penile urethra (4) the fasciocutaneous flap is in decline (-86%), while single-stage dorsal repairs are increasing (+280%). CONCLUSION: Anterior urethroplasty techniques continue to evolve in the absence of robust clinical data or randomized controlled trials, with a general movement in this cohort toward an initial dorsal approach for most strictures. Inter- and intrasurgeon variability in the surgical management of similar strictures was noted, and the feasibility of any future randomized controlled trials, without apparent surgical equipoise, must be questioned.

Circumcision, Buried Penis and Obesity in a Contemporary Cohort of Patients with Penile Cancer.

INTRODUCTION: We reviewed patient demographics and body morphology in a contemporary cohort of patients presenting to a tertiary care center for treatment of penile cancer. METHODS: The University of Iowa Oncology Registry was retrospectively reviewed for cases of penile cancer managed between 2006 and 2016. The database was queried for cancer specific details, followed by a chart review for body morphology data and comorbidity status. RESULTS: We treated 54 patients for penile cancer in the study period with a mean ± SD age of 64.3 ± 12.9 years and body mass index of 36.2 ± 10 kg/m2. Of these men 31.5% (17) had a clinically buried penis and 50% (27) reported prepubertal circumcision. Patients with a buried penis had a higher body mass index (46.53 ± 10.6 vs 31.48 ± 5.63 kg/m2, p <0.0001) and underwent fewer inguinal lymph node dissections (20% vs 58%, p = 0.05) than patients without a buried penis, but had similar rates of higher stage (2-4) presentation. Stage correlated with penile cancer death. Those with cancer specific mortality had a significantly higher body mass index (41.2 ± 12.4 kg/m2) vs those without penile cancer death (34.6 ± 9.1 kg/m2). CONCLUSIONS: Penile cancer remains relatively rare but contemporary cohorts suggest that circumcision may no longer be protective, especially in the setting of a clinically buried penis that may mimic an intact prepuce. How a buried penis and higher body mass index affect presentation, clinical management, surgical outcomes and disease course deserves further study.

Unscheduled Clinical Encounters in the Postoperative Period After Adult and Pediatric Urologic Surgery.

OBJECTIVE: To qualify and quantify unscheduled clinical encounters (UCEs) in postoperative urologic patients and to identify patient and procedural risk factors for UCEs. MATERIALS AND METHODS: All UCEs, including phone calls, emails, patient portal messages, clinic visits, ER visits, and hospital readmissions, were analyzed, including the reason for the interaction (eg, pain, infection, etc) were assessed retrospectively for consecutive surgical patients over a 3-month period. Demographic and perioperative data for each patient and surgery was recorded and risk factors for UCE were determined using uni- and multivariate analyses. RESULTS: Approximately 40% of adult and pediatric patients experienced a UCE, the most common being phone calls (adult-68.2%, pediatric-90.0%) for new medical concerns (adult-67.7%, pediatric-58.1%). Risk factors for UCE in the adult population included lower BMI, living closer to the surgical hospital, discharge with catheter/wound packing, higher discharge pain, and open (vs endoscopic) surgery. In the pediatric population, surgery on the urethra/ureter and discharge with catheters predicted for UCE. UCEs led to changes in clinical management (17%, 21%), unplanned clinic visits (12%, 20%), and hospital readmissions (6%, 3%) for both adult and pediatric patients, respectively. CONCLUSION: Nearly 40% of both adult and pediatric patients experienced an unplanned need for the healthcare system in the postoperative period. The effect that UCEs have on overall costs and patient satisfaction, as well as ways to decrease UCEs, require further study.

Prevalence of Post-Micturition Incontinence before and after Anterior Urethroplasty.

PURPOSE: In this study we aimed to define the prevalence of preoperative and postoperative post-micturition incontinence or post-void dribbling after anterior urethroplasty for urethral stricture disease. We also sought to determine risk factors for its presence. MATERIALS AND METHODS: We retrospectively reviewed a prospectively maintained, multi-institutional urethral stricture database to evaluate post-micturition incontinence using a single question from a validated questionnaire, "How often have you had a slight wetting of your pants a few minutes after you had finished urinating and had dressed yourself?" Possible answers were never-0 to all the time-3. The presence of post-micturition incontinence was defined as any answer greater than 0. Comparisons were made to stricture type and location, repair type and patient medical comorbidities. RESULTS: Preoperative and postoperative post-micturition incontinence questionnaires were completed by 614 and 331 patients, respectively. Patients without complete data available were excluded from study. Preoperative post-micturition incontinence was present in 73% of patients, of whom 44% stated that this symptom was present most of the time. Overall postoperative post-micturition incontinence was present in 40% of patients and again it was not predicted by stricture location or urethroplasty type. Of the 331 patients with followup questionnaires 60% reported improvement, 32% reported no change and 8% reported worsening symptoms. The overall rate of de novo post-micturition incontinence was low at 6.3%. CONCLUSIONS: The prevalence of preoperative post-micturition incontinence is high and likely under reported. In most patients post-micturition incontinence improves after urethroplasty and the prevalence of de novo post-micturition incontinence is low. The presence of post-micturition incontinence was not predicted by stricture length or location, or urethroplasty repair type.

Development of a Food Allergy Knowledge Test for Parents.

Objective: To create a measure of food allergy (FA) knowledge for parents of children with FA. Methods: The food allergy knowledge test (FAKT) was developed following rigorous test-construction guidelines. The preliminary 110-item pool content was developed in consultation with FA experts. After cognitive interviews and revisions, an 88-item preliminary version was administered to 370 parents of children with FA who were recruited online and from an allergy clinic. After item difficulty, discrimination, item-scale correlations analyses, and assessment of internal consistency, a revised 57-item version was administered to a new clinic-based sample (77 parents). Results: The revised FAKT was highly reliable (α =.86). Validity analyses revealed positive correlations ( r = .23-.57) between FAKT scores and parent age, education, insurance status, access to FA information, and auto-injector use. Conclusions: The FAKT was determined to have strong psychometrics and be appropriately reliable and valid, with clinical and research applications.

The new kidney allocation system does not equally advantage all very high cPRA candidates - A single center analysis.

The new UNOS kidney allocation system awards very high points to candidates with cPRA 99% and 100%, and allows for national sharing for cPRA 100% candidates. We sought to determine the effect of this new kidney allocation system on candidates who are very highly sensitized (90-98% cPRA) but not eligible for very high points or national sharing by examining offers to these candidates for 5months pre-implementation and two consecutive 5month periods post-implementation and comparing them to cPRA⩾99% candidates. We found that the cPRA⩾99% candidates received significantly more offers and transplants after implementation, while offers and transplants to the 90-98% candidates decreased. A slight adjustment to the allocation system may be needed to provide more equitable distribution of kidneys to all high cPRA candidates.