Scoring donor lungs for graft failure risk: The Lung Donor Risk Index (LDRI).

Lung transplantation lags behind other solid organ transplants in donor lung utilization due, in part, to uncertainty regarding donor quality. We sought to develop an easy-to-use donor risk metric that, unlike existing metrics, accounts for a rich set of donor factors. Our study population consisted of n = 26 549 adult lung transplant recipients abstracted from the United Network for Organ Sharing Standard Transplant Analysis and Research file. We used Cox regression to model graft failure (GF; earliest of death or retransplant) risk based on donor and transplant factors, adjusting for recipient factors. We then derived and validated a Lung Donor Risk Index (LDRI) and developed a pertinent online application (https://shiny.pmacs.upenn.edu/LDRI_Calculator/). We found 12 donor/transplant factors that were independently predictive of GF: age, race, insulin-dependent diabetes, the difference between donor and recipient height, smoking, cocaine use, cytomegalovirus seropositivity, creatinine, human leukocyte antigen (HLA) mismatch, ischemia time, and donation after circulatory death. Validation showed the LDRI to have GF risk discrimination that was reasonable (C = 0.61) and higher than any of its predecessors. The LDRI is intended for use by transplant centers, organ procurement organizations, and regulatory agencies and to benefit patients in decision-making. Unlike its predecessors, the proposed LDRI could gain wide acceptance because of its granularity and similarity to the Kidney Donor Risk Index.

Adolescent Depression Symptom Trajectories Detected Via Universal Screening in Pediatric Primary Care.

Unique trajectories of adolescent depression symptoms have been identified, yet less is known about whether such patterns translate to real-world clinical settings. Because annual adolescent depression screening is becoming more prevalent in primary care, we examined whether longitudinal patterns of depression symptoms documented in the developmental psychopathology literature can also be detected via routine screening in primary care and explored how membership in the identified trajectories varied based on concurrent suicide risk and sociodemographic factors. A total of 1,359 adolescents aged 12-16 years old at the first timepoint were included in the current analyses. These adolescents completed three depression screeners during their well-visits in a large pediatric primary care network between November 15, 2017 and February 1, 2020. Retrospective electronic health record data were extracted, including sociodemographic variables and depression screening results. Dynamic functional time series clustering results indicated the optimal number of clusters was five. The five depression symptom trajectories were: (1) A-Shaped (i.e., relatively low depression symptoms at Time 1, a substantial increase in symptoms at Time 2, and a return to low symptoms at Time 3), (2) Increasing, (3) Low-Stable, (4) High-Decreasing, and (5) Low-Decreasing. Cluster differences in suicide risk largely mapped onto depression symptom levels at each assessment. We found cluster differences based on practice location, insurance type, and adolescent race. The symptom trajectories observed in this study resemble those found in the developmental psychopathology literature, though some key differences were noted. Findings can inform future research and symptom monitoring in primary care.

Preservation of ß-cell Function in Pancreatic Insufficient Cystic Fibrosis With Highly Effective CFTR Modulator Therapy.

CONTEXT: Elexacaftor/tezacaftor/ivacaftor (ETI; Trikafta) enhances aberrant cystic fibrosis transmembrane conductance regulator function and may improve the insulin secretory defects associated with a deterioration in clinical outcomes in pancreatic insufficient cystic fibrosis (PI-CF). OBJECTIVE: This longitudinal case-control study assessed changes in ß-cell function and secretory capacity measures over 2 visits in individuals with PI-CF who were initiated on ETI after the baseline visit (2012-2018) and (1) restudied between 2019 and 2021 (ETI group) vs (2) those restudied between 2015 and 2018 and not yet treated with cystic fibrosis transmembrane conductance regulator modulator therapy (controls). METHODS: Nine ETI participants (mean ± SD age, 25 ± 5 years) and 8 matched controls were followed up after a median (interquartile range) 5 (4-7) and 3 (2-3) years, respectively (P < .01), with ETI initiation a median of 1 year before follow-up. Clinical outcomes, glucose-potentiated arginine, and mixed-meal tolerance test measures were assessed with comparisons of within- and between-group change by nonparametric testing. RESULTS: Glucose-potentiated insulin and C-peptide responses to glucose-potentiated arginine deteriorated in controls but not in the ETI group, with C-peptide changes different between groups (P < .05). Deterioration in basal proinsulin secretory ratio was observed in controls but improved, as did the maximal arginine-induced proinsulin secretory ratio, in the ETI group (P < .05 for all comparisons). During mixed-meal tolerance testing, early insulin secretion improved as evidenced by more rapid insulin secretory rate kinetics. CONCLUSION: ETI preserves ß-cell function in CF through effects on glucose-dependent insulin secretion, proinsulin processing, and meal-related insulin secretion. Further work should determine whether early intervention with ETI can prevent deterioration of glucose tolerance in PI-CF.

Stimulated whole-blood cytokine/chemokine responses are associated with interstitial cystitis/bladder pain syndrome phenotypes and features of nociplastic pain: a multidisciplinary approach to the study of chronic pelvic pain research network study.

ABSTRACT: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a common and debilitating disease with poor treatment outcomes. Studies from the multidisciplinary approach to the study of chronic pelvic pain research network established that IC/BPS patients with chronic overlapping pain conditions (COPCs) experience poorer quality of life and more severe symptoms, yet the neurobiological correlates of this subtype are largely unknown. We previously showed that ex vivo toll-like receptor 4 (TLR4) cytokine/chemokine release is associated with the presence of COPCs, as well as widespread pain and experimental pain sensitivity women with IC/BPS. Here, we attempt to confirm these findings in the multisite multidisciplinary approach to the study of chronic pelvic pain Symptom Patterns Study using TLR4-stimulated whole blood (female IC/BPS patients with COPC n = 99; without n = 36). Samples were collected in tubes preloaded with TLR4 agonist, incubated for 24 hours, and resulting supernatant assayed for 7 cytokines/chemokines. These were subject to a principal components analysis and the resulting components used as dependent variables in general linear models. Controlling for patient age, body mass index, and site of collection, we found that greater ex vivo TLR4-stimulated cytokine/chemokine release was associated with the presence of COPCs ( P < 0.01), extent of widespread pain ( P < 0.05), but not experimental pain sensitivity ( P > 0.05). However, a second component of anti-inflammatory, regulatory, and chemotactic activity was associated with reduced pain sensitivity ( P < 0.01). These results confirm that the IC/BPS + COPCs subtype show higher levels of ex vivo TLR4 cytokine/chemokine release and support a link between immune priming and nociplastic pain in IC/BPS.

Long-Term Symptom Trajectories in Urologic Chronic Pelvic Pain Syndrome: A MAPP Research Network Study.

OBJECTIVE: To characterize Urologic Chronic Pelvic Pain Syndrome (UCPPS) pain and urinary symptom trajectories with up to 9 years of follow-up and evaluate whether initial 1-year trajectories are associated with longer-term changes. MATERIALS AND METHODS: Data were analyzed from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Network's prospective observational protocols including the Epidemiology and Phenotyping Study (EPS; baseline to Year 1), EPS Extension (EXT; Years 1-5), and Symptom Patterns Study (SPS: 3-year study; Years 3-9). Adults with Interstitial Cystitis/Bladder Pain Syndrome or Chronic Prostatitis/Chronic Pelvic Pain Syndrome provided patient-reported assessments biweekly (EPS), every 4 months (EXT), or quarterly (SPS). Primary outcomes were composite pain (0-28) and urinary (0-25) severity scores. Multi-phase mixed effects models estimated outcomes over time, adjusted for baseline severity and stratified by EPS symptom trajectory. RESULTS: 163 participants (52% women; mean ± SD age 46.4 ± 16.1 years) completed EPS and enrolled in EXT; 67 also enrolled in SPS. Median follow-up was 4.6 years (range 1.3-9.0). After 1 year: 27.6%, 44.8% and 27.6% and 27.0%, 38.0% and 35.0% were improved, stable or worse in pain and urinary symptom severity, respectively. On average, pain and urinary symptom scores did not change further during EXT and SPS periods. CONCLUSIONS: Women and men with UCPPS showed remarkable stability in pain and urinary symptom severity for up to 9 years, irrespective of their initial symptom trajectory, suggesting UCPPS is a chronic condition with stable symptoms over multiple years of follow-up.

Effects of GLP-1 and GIP on Islet Function in Glucose-Intolerant, Pancreatic-Insufficient Cystic Fibrosis.

Impaired insulin and incretin secretion underlie abnormal glucose tolerance (AGT) in pancreatic insufficient cystic fibrosis (PI-CF). Whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can enhance pancreatic islet function in cystic fibrosis (CF) is not known. We studied 32 adults with PI-CF and AGT randomized to receive either GLP-1 (n = 16) or GIP (n = 16) during glucose-potentiated arginine (GPA) testing of islet function on two occasions, with either incretin or placebo infused, in a randomized, double-blind, cross-over fashion. Another four adults with PI-CF and normal glucose tolerance (NGT) and four matched control participants without CF underwent similar assessment with GIP. In PI-CF with AGT, GLP-1 substantially augmented second-phase insulin secretion but without effect on the acute insulin response to GPA or the proinsulin secretory ratio (PISR), while GIP infusion did not enhance second-phase or GPA-induced insulin secretion but increased the PISR. GIP also did not enhance second-phase insulin in PI-CF with NGT but did so markedly in control participants without CF controls. These data indicate that GLP-1, but not GIP, augments glucose-dependent insulin secretion in PI-CF, supporting the likelihood that GLP-1 agonists could have therapeutic benefit in this population. Understanding loss of GIP's insulinotropic action in PI-CF may lead to novel insights into diabetes pathogenesis.

Clinical Phenotyping for Pain Mechanisms in Urologic Chronic Pelvic Pain Syndromes: A MAPP Research Network Study.

Three categories of pain mechanisms are recognized as contributing to pain perception: nociceptive, neuropathic, and nociplastic (ie, central nervous system augmented pain processing). We use validated questionnaires to identify pain mechanisms in Urologic Chronic Pelvic Pain Syndrome (UCCPS) patients (n = 568, female = 378, male = 190) taking part in the Symptom Patterns Study of the Multidisciplinary Approach to the study of chronic Pelvic Pain Research Network. A cutoff score of 12 on the painDETECT questionnaire (-1 to 38) was used to classify patients into the neuropathic category while the median score of 7 on the fibromyalgia survey criteria (0-31) was used to classify patients into the nociplastic category. Categories were compared on demographic, clinical, psychosocial, psychophysical and medication variables. At baseline, 43% of UCPPS patients were classified as nociceptive-only, 8% as neuropathic only, 27% as nociceptive+nociplastic, and 22% as neuropathic+nociplastic. Across outcomes nociceptive-only patients had the least severe symptoms and neuropathic+nociplastic patients the most severe. Neuropathic pain was associated with genital pain and/or sensitivity on pelvic exam, while nociplastic pain was associated with comorbid pain conditions, psychosocial difficulties, and increased pressure pain sensitivity outside the pelvis. A self-report method classifying individuals on pain mechanisms reveals clinical differences that could inform clinical trials and novel targets for treatment. PERSPECTIVE: This article presents differences in clinical characteristics based on a simple self-report method of classifying pain mechanisms for Urologic Chronic Pelvic Pain Syndrome patients. This method can be easily applied to other chronic pain conditions and may be useful for exploring pathophysiology in pain subtypes.

Is Pelvic Floor Muscle Tenderness a Distinct Urologic Chronic Pelvic Pain Syndrome Phenotype? Findings from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Symptom Pattern Study.

PURPOSE: Of women with interstitial cystitis/bladder pain syndrome and men with chronic prostatitis/chronic pelvic pain syndrome 85% have concomitant pelvic floor muscle tenderness (PFT). The significance of this finding is incompletely understood. This study examines PFT among participants in the MAPP (Multidisciplinary Approach to the Study of Chronic Pelvic Pain) Research Network and its relationship with urologic chronic pelvic pain syndrome (UCPPS) symptom severity in order to determine whether this is a phenotypic predictor in UCPPS. MATERIALS AND METHODS: Participants in the MAPP Network Symptom Patterns Study underwent a standardized pelvic examination (PEX). Trained examiners palpated 6 locations evaluating the pelvic musculature for PFT. Participants were assigned a 0 to 6 PEX score based on the number of areas with tenderness on PEX. Using regression tree models, PEX scores were divided into low (0, 1), mid (2, 3, 4, 5) and high (6). The relationship between PFT and UCPPS symptoms was examined using several validated questionnaires. RESULTS: The study cohort consisted of 562 UCCPS participants (375 females and 187 males) and 69 controls. Diagnoses included interstitial cystitis/bladder pain syndrome (397), chronic prostatitis/chronic pelvic pain syndrome (122), both (34) or no diagnosis (9). Of UCPPS participants 81% had PFT on PEX compared to 9% of controls: 107 (19%) low, 312 (56%) mid and 143 (25%) high. Participants with higher PFT scores had more severe disease burden (worse pelvic pain and urinary symptoms), worse quality of life and more widespread distribution of nonpelvic pain. CONCLUSIONS: UCPPS patients with more widespread PFT have severe pain and urinary symptoms, worse quality of life and a more centralized pain phenotype.

Higher Incidence of Metabolic Syndrome in Black Women With Polycystic Ovary Syndrome: A Longitudinal Study.

CONTEXT: Cross-sectional studies have identified an increased risk of metabolic syndrome (MetSyn) in women with polycystic ovary syndrome (PCOS), but longitudinal data are limited and primarily include White and European cohorts. OBJECTIVE: To compare the longitudinal risk of MetSyn in Black and White women with PCOS and to identify potential factors mediating the risk of MetSyn. METHODS: Longitudinal cohort study with a follow-up of 5.3 years at an academic medical center. OF: 247 adult women with hyperandrogenic PCOS phenotype with 2 or more visits at least 3 years apart. The main outcome measure was incidence of MetSyn in Black and White women with PCOS. RESULTS: Using a mixed-effects model over time, the incidence of MetSyn was higher in Black women (45.9 ±â€…4.74 per 100 person-years) than in White women (31.3 ±â€…3.03 per 100 person-years) (P < .01) after adjusting for age and medication status. This difference persisted among women under age 30. Among Black women who did not have MetSyn at their prior visit, 28.0% had MetSyn at the next visit, compared with 12.1% of White women after adjusting for age and medication status (P < .01). In both races, the model-based estimated rates of MetSyn increased significantly with increase in body mass index and free testosterone. CONCLUSION: We describe a persistent higher incidence of MetSyn in Black than in White women with PCOS. In addition to early cardiometabolic screening at the time of diagnosis, our findings highlight the need for ongoing and frequent screening in this population.

Effect of Sitagliptin on Islet Function in Pancreatic Insufficient Cystic Fibrosis With Abnormal Glucose Tolerance.

PURPOSE: Impaired incretin secretion may contribute to the defective insulin secretion and abnormal glucose tolerance (AGT) that associate with worse clinical outcomes in pancreatic insufficient cystic fibrosis (PI-CF). The study objective was to test the hypothesis that dipeptidyl peptidase-4 (DPP-4) inhibitor-induced increases in intact incretin hormone [glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)] concentrations augment insulin secretion and glucagon suppression and lower postprandial glycemia in PI-CF with AGT. METHODS: 26 adults from Children's Hospital of Philadelphia and University of Pennsylvania CF Center with PI-CF and AGT [defined by oral glucose tolerance test glucose (mg/dL): early glucose intolerance (1-h ≥ 155 and 2-h < 140), impaired glucose tolerance (2-h ≥ 140 and < 200 mg/dL), or diabetes (2-h ≥ 200)] were randomized to a 6-month double-blind trial of DPP-4 inhibitor sitagliptin 100 mg daily or matched placebo; 24 completed the trial (n = 12 sitagliptin; n = 12 placebo). Main outcome measures were mixed-meal tolerance test (MMTT) responses for intact GLP-1 and GIP, insulin secretory rates (ISRs), glucagon suppression, and glycemia and glucose-potentiated arginine (GPA) test-derived measures of ß- and α-cell function. RESULTS: Following 6-months of sitagliptin vs placebo, MMTT intact GLP-1 and GIP responses increased (P < 0.001), ISR dynamics improved (P < 0.05), and glucagon suppression was modestly enhanced (P < 0.05) while GPA test responses for glucagon were lower. No improvements in glucose tolerance or ß-cell sensitivity to glucose, including for second-phase insulin response, were found. CONCLUSIONS: In glucose intolerant PI-CF, sitagliptin intervention augmented meal-related incretin responses with improved early insulin secretion and glucagon suppression without affecting postprandial glycemia.

Postpartum weight retention in women with polycystic ovary syndrome.

BACKGROUND: Compared with women without polycystic ovary syndrome, women with polycystic ovary syndrome have a higher prevalence of cardiometabolic risk factors. Postpartum weight retention has been shown to contribute to these risks in the general population, but little is known about postpartum weight retention among women with polycystic ovary syndrome. OBJECTIVE: This study aimed to compare postpartum weight retention and peripartum weight trends between women with polycystic ovary syndrome and controls. STUDY DESIGN: Data on live, full-term singleton deliveries from January 1, 2014, to January 1, 2019, in women with and without polycystic ovary syndrome were abstracted from the electronic medical record. Weights during the pregestational period, pregnancy, and up to 12 months postpartum were collected. The primary outcome was likelihood of high postpartum weight retention of ≥5 kg above pregestational weight at 12 months after delivery. Secondary outcomes included the prevalence of high weight retention at other postpartum time points (6 weeks, 3 months, 6 months), absolute postpartum weight retention, gestational weight gain, and excess weight gain above the Institute of Medicine guidelines for weight gain in pregnancy. RESULTS: A total of 6333 women had the requisite weight information (pregestational, peak pregnancy, and at least 1 postpartum weight), including 429 (6.8%) with polycystic ovary syndrome. After adjusting for age, pregestational body mass index, race, gestational diabetes mellitus, and parity, women with polycystic ovary syndrome were less likely to be high weight retainers at 6 weeks after delivery (adjusted odds ratio, 0.71; P=.02). There was no difference in postpartum weight retention between groups at 3, 6, and 12 months after delivery. Overall, the prevalence of high weight retainers at 12 months after delivery was high in both groups (22.7% in polycystic ovary syndrome vs 29.2% in controls; P=.13), and there was no difference in absolute weight retention (1.69 kg in polycystic ovary syndrome vs 2.05 kg in controls; P=.25). Although women with polycystic ovary syndrome had a higher pregestational body mass index, they had lower gestational weight gain (median, 12.7 kg) than controls (median, 13.5 kg) (P=.01). These findings were driven by the group with obesity. The percentage of women who surpassed the Institute of Medicine guidelines for gestational weight gain based on the body mass index category was similar between groups (43.4% in polycystic ovary syndrome vs 47.3% in controls; P=.12). Overall, 18.5% of women with polycystic ovary syndrome and 23.4% of controls had a higher body mass index category at 12 months after delivery than before pregnancy. CONCLUSION: Women with polycystic ovary syndrome had lower gestational weight gain and lower likelihood of high weight retention at 6 weeks after delivery but similar weight retention at 12 months after delivery compared with controls. Overall, the large proportion of women with high postpartum weight retention highlights the importance of the peripartum time period for weight management, particularly in this high-risk group predisposed to obesity and cardiometabolic disease.

Identification and Management of Adolescent Depression in a Large Pediatric Care Network.

OBJECTIVE: Primary care has been promoted as a setting to identify and manage adolescent depression. This study examined primary care-based adolescent depression identification and follow-up care when elevated symptoms were identified. METHODS: Data came from a large pediatric care network with an organizational recommendation to screen for depression at age 16 well-visits using an electronic health record (EHR)-integrated standardized measure. Analyses examined rates of screening and elevated symptoms, pediatricians' initial responses to elevated scores, and types of follow-up care received over 1 year using retrospective EHR data extraction and manual chart reviews. RESULTS: Across program sites, 76.3% (n = 6981) of patients attending their age 16 well-visits were screened. About one-quarter had an elevated score (19.2% mild and 6.7% moderate-to-severe), many of whom received active follow-up on their well-visit date. Over 1 year, three-fourths of patients with scores in the moderate-to-severe range and 40.0% of patients with scores in the mild range received follow-up care (e.g., antidepressant prescriptions) as per EHR extraction. Follow-up rates were higher as per manual chart reviews. CONCLUSION: Routine adolescent depression screening is feasible across diverse primary care sites. Most patients with elevated scores were not already receiving behavioral health services, suggesting screening identified previously undetected concerns. In turn, many adolescents with elevated scores initiated treatment after screening, which indicates providing screen results at the point of care may facilitate pediatrician actions. Still, gaps in follow-up care demonstrate the need for greater investment in primary care-based behavioral health services to support high-quality treatment and ultimately decrease the burden of adolescent depression.

Plasma sTNFR1 and IL8 for prognostic enrichment in sepsis trials: a prospective cohort study.

BACKGROUND: Enrichment strategies improve therapeutic targeting and trial efficiency, but enrichment factors for sepsis trials are lacking. We determined whether concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1), interleukin-8 (IL8), and angiopoietin-2 (Ang2) could identify sepsis patients at higher mortality risk and serve as prognostic enrichment factors. METHODS: In a multicenter prospective cohort study of 400 critically ill septic patients, we derived and validated thresholds for each marker and expressed prognostic enrichment using risk differences (RD) of 30-day mortality as predictive values. We then used decision curve analysis to simulate the prognostic enrichment of each marker and compare different prognostic enrichment strategies. MEASUREMENTS AND MAIN RESULTS: An admission sTNFR1 concentration > 8861 pg/ml identified patients with increased mortality in both the derivation (RD 21.6%) and validation (RD 17.8%) populations. Among immunocompetent patients, an IL8 concentration > 94 pg/ml identified patients with increased mortality in both the derivation (RD 17.7%) and validation (RD 27.0%) populations. An Ang2 level > 9761 pg/ml identified patients at 21.3% and 12.3% increased risk of mortality in the derivation and validation populations, respectively. Using sTNFR1 or IL8 to select high-risk patients improved clinical trial power and efficiency compared to selecting patients with septic shock. Ang2 did not outperform septic shock as an enrichment factor. CONCLUSIONS: Thresholds for sTNFR1 and IL8 consistently identified sepsis patients with higher mortality risk and may have utility for prognostic enrichment in sepsis trials.

Quantitative assessment of nonpelvic pressure pain sensitivity in urologic chronic pelvic pain syndrome: a MAPP Research Network study.

Experimental pain sensitivity was assessed in individuals with urologic chronic pelvic pain syndrome (UCPPS) as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. A series of computer-controlled pressure stimuli were delivered to the thumbnail bed, an asymptomatic site distant from the area of UCPPS pain that is considered to be indicative of overall body pain threshold. Stimuli were rated according to a standardized magnitude estimation protocol. Pain sensitivity in participants with UCPPS was compared with healthy controls and a mixed pain group composed of individuals with other chronic overlapping pain conditions, including fibromyalgia, chronic fatigue, and irritable bowel syndromes. Data from 6 participating MAPP testing sites were pooled for analysis. Participants with UCPPS (n = 153) exhibited an intermediate pain sensitivity phenotype: they were less sensitive relative to the mixed pain group (n = 35) but significantly more sensitive than healthy controls (n = 100). Increased pain sensitivity in patients with UCPPS was associated with both higher levels of clinical pain severity and more painful body areas outside the pelvic region. Exploratory analyses in participants with UCPPS revealed that pain sensitivity increased during periods of urologic symptom flare and that less pressure pain sensitivity at baseline was associated with a greater likelihood of subsequent genitourinary pain improvement 1 year later. The finding that individuals with UCPPS demonstrate nonpelvic pain hypersensitivity that is related to clinical symptoms suggests that central nervous system mechanisms of pain amplification contribute to UCPPS.

A longitudinal analysis of urological chronic pelvic pain syndrome flares in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network.

OBJECTIVE: To describe the frequency, intensity and duration of urological chronic pelvic pain syndrome symptom exacerbations ('flares'), as well as risk factors for these features, in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Epidemiology and Phenotyping longitudinal study. PARTICIPANTS AND METHODS: Current flare status ('urological or pelvic pain symptoms that are much worse than usual') was ascertained at each bi-weekly assessment. Flare characteristics, including start date, and current intensity of pelvic pain, urgency and frequency (scales of 0-10), were assessed for participants' first three flares and at three randomly selected times when they did not report a flare. Generalized linear and mixed effects models were used to investigate flare risk factors. RESULTS: Of the 385 eligible participants, 24.2% reported no flares, 22.9% reported one flare, 28.3% reported 2-3 flares, and 24.6% reported ≥4 flares, up to a maximum of 18 during the 11-month follow-up (median incidence rate = 0.13/bi-weekly assessment, range = 0.00-1.00). Pelvic pain (mean = 2.63-point increase) and urological symptoms (mean = 1.72) were both significantly worse during most flares (60.6%), with considerable within-participant variability (26.2-37.8%). Flare duration varied from 1 to 150 days (94.3% within-participant variability). In adjusted analyses, flares were more common, symptomatic, and/or longer-lasting in women and in those with worse non-flare symptoms, bladder hypersensitivity, and chronic overlapping pain conditions. CONCLUSION: In this foundational flare study, we found that pelvic pain and urological symptom flares were common, but variable in frequency and manifestation. We also identified subgroups of participants with more frequent, symptomatic, and/or longer-lasting flares for targeted flare management/prevention and further study.

A Case-Crossover Study of Urological Chronic Pelvic Pain Syndrome Flare Triggers in the MAPP Research Network.

PURPOSE: Although many factors have been proposed to trigger symptom exacerbations (flares) in patients with interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome, few studies have investigated these factors empirically. Therefore, we embedded a case-crossover study in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain longitudinal study to evaluate a range of patient reported triggers. MATERIALS AND METHODS: We assessed exposure to proposed triggers, including diet, physical activities, sedentary behaviors, stress, sexual activities, infection-like symptoms and allergies, by questionnaire a maximum of 3 times when participants reported flares and at 3 randomly selected times. We compared participant preflare to nonflare exposures by conditional logistic regression. RESULTS: In our full analytical sample of 292 participants only 2 factors, including recent sexual activity (OR 1.44, 95% CI 1.06-1.96) and urinary tract infection symptoms (OR 3.39, 95% CI 2.02-5.68), which may overlap with those of flares, were associated with flare onset. On subanalyses restricted to flares with specific suspected triggers additional positive associations were observed for some factors such as certain dietary factors, abdominal muscle exercises, and vaginal infection-like symptoms and fever, but not for other factors (eg stress). CONCLUSIONS: Except for sexual activity our findings suggest that patient reported triggers may be individual or group specific, or they may not contribute to flares. These findings suggest caution in following rigid, global flare prevention strategies and support additional research to develop evidence-based strategies.

Effect of exenatide, sitagliptin, or glimepiride on ß-cell secretory capacity in early type 2 diabetes.

OBJECTIVE: Agents that augment GLP-1 effects enhance glucose-dependent ß-cell insulin production and secretion and thus are hoped to prevent progressive impairment in insulin secretion characteristic of type 2 diabetes (T2D). The purpose of this study was to evaluate GLP-1 effects on ß-cell secretory capacity, an in vivo measure of functional ß-cell mass, early in the course of T2D. RESEARCH DESIGN AND METHODS: We conducted a randomized controlled trial in 40 subjects with early T2D who received the GLP-1 analog exenatide (n = 14), the dipeptidyl peptidase IV inhibitor sitagliptin (n = 12), or the sulfonylurea glimepiride (n = 14) as an active comparator insulin secretagogue for 6 months. Acute insulin responses to arginine (AIRarg) were measured at baseline and after 6 months of treatment with 5 days of drug washout under fasting, 230 mg/dL (glucose potentiation of arginine-induced insulin release [AIRpot]), and 340 mg/dL (maximum arginine-induced insulin release [AIRmax]) hyperglycemic clamp conditions, in which AIRmax provides the ß-cell secretory capacity. RESULTS: The change in AIRpot was significantly greater with glimepiride versus exenatide treatment (P < 0.05), and a similar trend was notable for the change in AIRmax (P = 0.1). Within each group, the primary outcome measure, AIRmax, was unchanged after 6 months of treatment with exenatide or sitagliptin compared with baseline but was increased with glimepiride (P < 0.05). α-Cell glucagon secretion (AGRmin) was also increased with glimepiride treatment (P < 0.05), and the change in AGRmin trended higher with glimepiride than with exenatide (P = 0.06). CONCLUSIONS: After 6 months of treatment, exenatide or sitagliptin had no significant effect on functional ß-cell mass as measured by ß-cell secretory capacity, whereas glimepiride appeared to enhance ß- and α-cell secretion.

The association of early transfusion with acute lung injury in patients with severe injury.

BACKGROUND: Packed red blood cell (PRBC) transfusion is associated with acute lung injury (ALI) development after trauma, but this risk may not be constant through time after trauma. We hypothesized that the relationship between PRBC delivery and ALI risk varies through time after injury. METHODS: Data were collected prospectively from 1999 to 2006. Inclusion criteria include the following: older than 13 years, surgical intensive care unit admission, and Injury Severity Score of 16 or greater. Exclusion criteria included discharge/death within 24 hours of admission. Patients were followed up prospectively for ALI development for 5 days after trauma. Discrete time models were fit to test the association of timing of PRBC delivery with the development of ALI while controlling for patient demographics, resuscitation variables, Injury Severity Score, and Acute Physiology and Chronic Health Evaluation III scores. RESULTS: At total of 602 patients were included. Median age was 33 years, 77% were male, and 50% were African American. Using a discrete time-survival model, the relation between transfusion and ALI development was found to vary by transfusion time window (p < 0.0001). The major effect of PRBC delivery on ALI risk occurred in the first 24 hours after trauma; this finding persisted in multivariable modeling (adjusted odds ratio, 1.07 per unit; 95% confidence interval, 1.02-1.11, p < 0.001). Cumulative incidence of ALI approached 50% in patients receiving 6 U of PRBC or more in the first 24 hours. CONCLUSION: The association between PRBC transfusion and ALI development in patients with trauma is time dependent, with PRBC delivery in the first 24 hours after injury driving the overall relation. Each PRBC unit during this period increases odds of subsequent ALI development by 7%. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level II.

Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia.

Recent molecular genetics studies implicate neuregulin 1 (NRG1) and its receptor erbB in the pathophysiology of schizophrenia. Among NRG1 receptors, erbB4 is of particular interest because of its crucial roles in neurodevelopment and in the modulation of N-methyl-D-aspartate (NMDA) receptor signaling. Here, using a new postmortem tissue-stimulation approach, we show a marked increase in NRG1-induced activation of erbB4 in the prefrontal cortex in schizophrenia. Levels of NRG1 and erbB4, however, did not differ between schizophrenia and control groups. To evaluate possible causes for this hyperactivation of erbB4 signaling, we examined the association of erbB4 with PSD-95 (postsynaptic density protein of 95 kDa), as this association has been shown to facilitate activation of erbB4. Schizophrenia subjects showed substantial increases in erbB4-PSD-95 interactions. We found that NRG1 stimulation suppresses NMDA receptor activation in the human prefrontal cortex, as previously reported in the rodent cortex. NRG1-induced suppression of NMDA receptor activation was more pronounced in schizophrenia subjects than in controls, consistent with enhanced NRG1-erbB4 signaling seen in this illness. Therefore, these findings suggest that enhanced NRG1 signaling may contribute to NMDA hypofunction in schizophrenia.