Histological Phenotyping in Eosinophilic Esophagitis: Localized Proximal Disease Is Infrequent but Associated with Less Severe Disease and Better Disease Outcome.

INTRODUCTION: It is still unknown whether eosinophilic esophagitis (EoE) patients with localized disease are different from those with extended disease. METHODS: We evaluated prospectively included patients in the Swiss EoE cohort. Data on all patients with active disease at baseline, no concomitant gastroesophageal reflux disease, no strictures at baseline, and at least one follow-up visit were analyzed. We compared patients with histologically localized proximal versus distal versus extended (=proximal and distal) disease with regard to patient, disease characteristics, disease presentation, and development of complications. RESULTS: We included 124 patients with a median of 2.5 years of follow-up (73.4% males, median age 35.0 years). Ten patients had proximal (8.1%), 46 patients had distal (37.1%), and 68 patients had extended disease (54.8%). Patients with proximal disease were significantly more often females (80%) compared with patients with distal (26.1%, p = 0.002) or extended disease (19.1%, p < 0.001) and reported less severe symptoms (VAS 0 vs. VAS 1, p = 0.001). Endoscopic and histological disease was less pronounced in the proximal esophagus of proximal EoE compared to extended disease (EREFS 1.0 vs. 3.0, p = 0.001; 27.0 eos/hpf vs. 52.5 eos/hpf, p = 0.008). Patients with proximal disease were less likely to undergo dilation compared to patients with distal disease in the follow-up (3.3% vs. 23.3%, p = 0.010). In a multivariate Cox regression model, proximal eosinophilia was less likely to be associated with treatment failure compared to distal eosinophilia. CONCLUSION: Although isolated proximal EoE is infrequent, it is associated with less severe disease and better disease outcome. Proximal disease appears to present a unique EoE phenotype.

Non-pulmonary complications of intrathecal morphine administration: a systematic review and meta-analysis with meta-regression.

BACKGROUND: Intrathecal morphine provides effective analgesia for a range of operations. However, widespread implementation into clinical practice is hampered by concerns for potential side-effects. We undertook a systematic review, meta-analysis, and meta-regression with the primary objective of determining whether a threshold dose for non-pulmonary complications could be defined and whether an association could be established between dose and complication rates when intrathecal morphine is administered for perioperative or obstetric analgesia. METHODS: We systematically searched the literature for randomised controlled trials comparing intrathecal morphine vs control in patients undergoing any type of surgery under general or spinal anaesthesia, or women in labour. Primary outcomes were rates of postoperative nausea and vomiting, pruritus, and urinary retention within the first 24 postoperative hours, analysed according to doses (1-100 µg; 101-200 µg; 201-500 µg; >500 µg), type of surgery, and anaesthetic strategy. Trials were excluded if doses were not specified. RESULTS: Our analysis included 168 trials with 9917 patients. The rates of postoperative nausea and vomiting, pruritus, and urinary retention were significantly increased in the intrathecal morphine group, with an odds ratio (95% confidence interval) of 1.52 (1.29-1.79), P<0.0001; 6.11 (5.25-7.10), P<0.0001; and 1.73 (1.17-2.56), P=0.005, respectively. Meta-regression could not establish an association between dose and rates of non-pulmonary complications. There was no subgroup difference according to surgery for any outcome. The quality of evidence was low (Grading of Recommendations Assessment, Development, and Evaluation [GRADE] system). CONCLUSIONS: Intrathecal morphine significantly increased postoperative nausea and vomiting, pruritus, and urinary retention after surgery or labour in a dose-independent manner. SYSTEMATIC REVIEW PROTOCOL: PROSPERO (CRD42023387838).

Impact of spinal versus general anaesthesia on perioperative obstructive sleep apnoea severity in patients undergoing hip arthroplasty: a post hoc analysis of two randomised controlled trials.

BACKGROUND: Recommendations suggest favouring regional over general anaesthesia to reduce impact on postoperative sleep apnoea severity, but there is currently no evidence to support this. We compared the impact of general vs spinal anaesthesia on postoperative sleep apnoea severity and assessed the evolution of sleep apnoea severity up to the third postoperative night. METHODS: This post hoc analysis used pooled data from two previous randomised controlled trials in patients undergoing total hip arthroplasty under general or spinal anaesthesia (n=96), without performing a preliminary power analysis. All participants underwent respiratory polygraphy before surgery and on the first and third postoperative nights. The primary outcomes were the supine apnoea-hypopnea index on the first postoperative night and the evolution of the supine apnoea-hypopnea index up to the third postoperative night. Secondary outcomes included the oxygen desaturation index on the first and third postoperative nights. RESULTS: In the general and spinal anaesthesia groups, mean (95% confidence interval) values for the supine apnoea-hypopnoea index on the first postoperative night were 20 (16-25) and 21 (16-26) events h-1 (P=0.82), respectively; corresponding values on the third postoperative night were 34 (22-45) and 35 (20-49) events h-1 (P=0.91). The generalised estimating equations model showed a significant time effect. Secondary outcomes were similar in the two groups. CONCLUSIONS: Use of spinal anaesthesia compared with general anaesthesia was not associated with a reduction in postoperative sleep apnoea severity, which was worse on the third postoperative night. CLINICAL TRIAL REGISTRATION: NCT02717780 and NCT02566226.

Odynophagia and Retrosternal Pain Are Common in Eosinophilic Esophagitis and Associated with an Increased Overall Symptom Severity.

BACKGROUND AND AIMS: Dysphagia is the hallmark symptom in eosinophilic esophagitis (EoE). However, data are limited regarding the overall prevalence and potential implications of atypical symptoms like odynophagia and retrosternal pain. METHODS: Patients enrolled into the Swiss EoE cohort study (SEECS) were analyzed regarding the presence of odynophagia and retrosternal pain. Demographics, other EoE-related symptoms, histologic and endoscopic activity were compared between EoE-patients with vs. without odynophagia and/or retrosternal pain. RESULTS: 474 patients (75.2% male) were analyzed. In their individual course of disease 110 (23.2%) patients stated to have ever experienced odynophagia and 64 (13.5%) retrosternal pain independent of food intake, 24 (5%) patients complained about both symptoms. Patients with odynophagia consistently scored higher in symptom severity (p < 0.001), EREFS score (median 3.0 vs. 2.0, p = 0.006), histologic activity and a lower quality of life (p = 0.001) compared to patients without odynophagia. Sex, age at diagnosis, EoE-specific treatment, complications such as candida or viral esophagitis and disease duration were similar in patients with vs. without odynophagia. Also patients with retrosternal pain scored higher in symptom severity (2.0 vs. 1.0, p = 0.001 and 2.0 vs. 1.0, p < 0.001 in physician and patient questionnaire assessment, respectively). However, there was neither a difference in endoscopic/histologic disease activity nor in quality of life according to presence or absence of retrosternal pain. Due to logistic reasons, a stratification regarding the presence of concomitant dysphagia was not possible. CONCLUSION: Odynophagia and swallowing-independent retrosternal pain are common symptoms in patients with EoE, associate with an overall higher EoE-related symptom severity and for the case of odynophagia lower quality of life. However, the influence of concomitant dysphagia and its severity remains unclear and needs to be included in future analyses.

Duration of analgesia after forefoot surgery compared between an ankle and a sciatic nerve block at the popliteal crease: A randomised controlled single-blinded trial.

BACKGROUND: Forefoot surgery is associated with severe postoperative pain. Ankle and sciatic nerve blocks provide satisfactory postoperative analgesia after forefoot surgery, but little is known on their respective duration of analgesia. OBJECTIVE: This randomised controlled, single-blinded trial tested the hypothesis that after forefoot surgery in the setting of multimodal analgesia, an ankle block provides analgesia superior to that of a sciatic nerve block at the popliteal crease. DESIGN: A randomised controlled study. SETTING: A single centre study in a university hospital in Switzerland, from September 2018 to November 2022. PATIENTS: From 91 patients scheduled for forefoot surgery, 60 met the inclusion criteria of which 56 completed the protocol and their data were available for analysis. Exclusion criteria were existing sciatic nerve deficit, pre-existing peripheral neuropathy, chronic pain diagnosis, pregnancy, or identified contraindications to peripheral nerve block. INTERVENTION: Patients undergoing forefoot surgery were randomly allocated to either a multi-injection ankle block (partly under ultrasound guidance) or a sciatic nerve block at the popliteal crease (under ultrasound guidance) combined with a saphenous nerve block at the ankle. Patients in each group received a total of 30 ml of ropivacaine 0.5% and a multimodal analgesic regimen inclusive of dexamethasone, paracetamol, ketorolac then ibuprofen. MAIN OUTCOME MEASURE: The primary outcome was duration of analgesia, defined as time to first morphine request. RESULTS: Mean ±â€ŠSD duration of analgesia was 15.4 ±â€Š8.0 h in the ankle block group and 20.0 ±â€Š10.3 h in the sciatic nerve block group ( P  = 0.32). Of note, 15 of 26 (58%) and 24 of 30 (80%) patients of the ankle and sciatic nerve block groups did not request any morphine ( P  = 0.09). Other secondary outcomes were similar between groups. CONCLUSION: Compared with the ankle block, the sciatic nerve block at the popliteal crease does not provide a longer duration of analgesia in patients undergoing forefoot surgery in the setting of multimodal analgesia. TRIAL REGISTRATION: Clinicaltrials.com identifier: NCT03683342.

Long-Term Outcome of Surgery for Perianal Crohn's Fistula.

Background and Objectives: Patients with perianal Crohn's (CD) fistula often need repetitive surgeries and none of the established techniques was shown to be superior or preferable. Furthermore, the long-term outcome of fistula Seton drainage is not well described. The aims of this study were to analyze the long-term healing and recurrence rate of CD perianal fistulas in a large patient cohort. Materials and Methods: Database analysis of the Swiss IBD (Inflammatory Bowel Disease) cohort study. Results: 365 perianal fistula patients with 576 surgical interventions and a median follow-up of 7.5 years (0-12.6) were analyzed. 39.7% of patients required more than one procedure. The first surgical interventions were fistulectomies ± mucosal sliding flap (59.2%), Seton drainage (29.6%), fistula plugs or fibrin glue installations (2.5%) and combined procedures (8.8%). Fistulectomy patients required no more surgery in 69%, one additional surgery in 25% and more than one additional surgery in 6%, with closure rates at 7.5 years follow-up of 77.1%, 74.1% and 66.7%, respectively. In patients with Seton drainage as index surgery, 52% required no more surgery, and over 75% achieved fistula closure after 10 years. Conclusions: First-line fistulectomies, when feasible, achieved the highest healing rates, but one-third of patients required additional surgeries, and one-fourth of patients will remain with a fistula at 10 years. Initial Seton drainage and concurrent medical therapy can achieve fistula closure in 75%. However, in 50% of patients, more surgeries are needed, and fistula closure is achieved in only two-thirds of patients.

Barrett's Esophagus in Eosinophilic Esophagitis in Swiss Eosinophilic Esophagitis Cohort Study (SEECS).

INTRODUCTION: There is a complex interrelationship between gastroesophageal reflux disease (GERD) and eosinophilic esophagitis (EoE) potentially promoting the occurrence and modulating severity of each other reciprocally. Presence of Barrett's esophagus (BE) is a defining factor for the diagnosis of GERD. While several studies investigated the potential impact of concomitant GERD on the presentation and course of EoE, little was known with regards to BE in EoE patients. METHODS: We analyzed prospectively collected clinical, endoscopic, and histological data from patients enrolled in the Swiss Eosinophilic Esophagitis Cohort Study (SEECS) regarding differences between EoE patients with (EoE/BE+) versus without BE (EoE/BE-) and determined the prevalence of BE in EoE patients. RESULTS: Among a total of 509 EoE patients included in our analysis, 24 (4.7%) had concomitant BE with a high male preponderance (EoE/BE+ 83.3% vs. EoE/BE- 74.4%). While there were no differences in dysphagia, odynophagia was significantly (12.5 vs. 3.1%, p = 0.047) more common in EoE/BE+ versus EoE/BE-. General well-being at last follow-up was significantly lower in EoE/BE+. Endoscopically, we observed an increased incidence of fixed rings in the proximal esophagus in EoE/BE+ (70.8 vs. 46.3% in EoE/BE-, p = 0.019) and a higher fraction of patients with a severe fibrosis in the proximal histological specimen (8.7 vs. 1.6% in EoE/BE, p = 0.017). CONCLUSION: Our study reveals that BE is twice as frequent in EoE patients compared to general population. Despite many similarities between EoE patients with and without BE, the finding of a more pronounced remodeling in EoE patients with Barrett is noteworthy.

Sensory block duration after spinal anaesthesia supplemented with intravenous dexamethasone: a randomised controlled double-blinded trial.

BACKGROUND: Intravenous dexamethasone prolongs duration of analgesia or sensory block after injection of local anaesthetics close to peripheral nerves by an average of 8 h. Uncertainty remains on the potential increase in the duration of sensory block after spinal anaesthesia. The objective of this randomised controlled double-blinded trial was to investigate whether dexamethasone i.v. prolongs the sensory block of spinal anaesthesia with bupivacaine when compared with a control group. METHODS: Of 50 patients undergoing lower limb osteoarticular surgery under spinal anaesthesia with isobaric bupivacaine 15 mg i.t. with morphine 100 µg i.t. were randomised to receive either dexamethasone 0.15 mg kg-1 i.v. or normal saline 3 ml i.v. The primary outcome was duration of sensory block defined as the time elapsed between injection of the local anaesthetic in the intrathecal space and the regression of sensory block by two dermatomes compared with the highest dermatome blocked. Secondary outcomes included intravenous morphine consumption, pain scores at rest and on movement, postoperative nausea and vomiting, and blood glucose at 2, 24, and 48 h. RESULTS: Median duration of sensory block was 135 (105-225) min in the dexamethasone group and 158 (135-240 min) in the control group (P=0.19). Patients in the dexamethasone group received less morphine at 24 h, had significantly less postoperative nausea and vomiting at 2 h and 24 h, and had increased blood glucose at 24 h. Other secondary outcomes were similar between groups. CONCLUSION: Intravenous dexamethasone did not prolong the sensory block of spinal anaesthesia with isobaric bupivacaine. However, it reduced morphine consumption and rate of postoperative nausea and vomiting at 24 h, at the expense of an increased blood glucose. CLINICAL TRIAL REGISTRATION: NCT03527576 (Clinicaltrials.gov).

Sex Impacts Disease Activity But Not Symptoms or Quality of Life in Adults With Eosinophilic Esophagitis.

BACKGROUND: Eosinophilic esophagitis has a strong male predominance that appears at least partially due to genetic susceptibility. However, data regarding sex-related differences in patients with EoE are scarce. METHODS: We analyzed prospectively collected data from adults enrolled into the Swiss Eosinophilic Esophagitis Cohort Study. Patients with and without dilation in the past 12 months completed patient-reported Eosinophilic Esophagitis Activity Index (EEsAI) and EoE-specific quality of life in adults (EoE-QoL-A) and underwent endoscopy with biopsies. We used linear regression with EEsAI or EoE-QoL-A as the outcome, eosinophils per high power field, rings and strictures, current therapy use, and disease duration as predictors. RESULTS: A total of 266 patients (77% male, median age at diagnosis 35.8 years, median disease duration 10.4 years) were seen during 408 visits. Men had a longer diagnostic delay (62 months vs 36 months; P = .022), higher endoscopic disease activity (median endoscopic reference score 3.0 [interquartile range, 1.0-6.0] vs 2.0 [interquartile range, 0.0-4.0]; P = .010), more microabscesses (25% vs 13%; P = .025), and more often fibrosis of the lamina propria (mild/moderate 74.7% vs 61.5%, severe 9.1% vs 5.8%; P = .047) than women. When adjusting for objective measures of disease activity, disease duration, and current therapy use, we did not observe differences in EEsAI or EoE-QoL-A between women and men. CONCLUSIONS: Male EoE patients had higher endoscopic and histologic disease activity than female patients. When adjusting for biologic activity and therapy use, we did not identify differences in symptom severity or EoE-QoL between male and female eosinophilic esophagitis patients.

Sex-dependent influence of maternal predictors on fetal anthropometry in pregnancies with gestational diabetes mellitus.

BACKGROUND: Third trimester fetal anthropometric parameters are known to predict neonatal complications. A better understanding of predictors of adverse fetal parameters might help to personalize the use and frequency of fetal ultrasound. The objectives of this study were: (a) to evaluate the utility of maternal sociodemographic, anthropometric and metabolic predictors to predict 3rd trimester fetal anthropometric parameters in women with gestational diabetes mellitus (GDM), (b) to assess whether the impact of these maternal predictors is fetal sex-dependent, and (c) to provide a risk stratification for markers of fetal overgrowth (fetal weight centile (FWC) and fetal abdominal circumference centile (FACC) depending on prepregnancy BMI and gestational weight gain (GWG) until the 1st GDM visit. METHODS: This prospective study included 189 women with GDM. Maternal predictors were age, ethnicity, prepregnancy BMI, GWG and excessive weight gain until the 1st GDM visit, fasting, 1-hour and 2-hour blood glucose oral glucose tolerance test values, HbA1c at the 1st visit and medical treatment requirement. Fetal outcomes included FWC, FWC >90% and <10%, FACC, FACC >90% and <10%, at 29 0/7 to 35 6/7 weeks of gestational age. We performed univariate and multivariate regression analyses and probability analyses. RESULTS: In multivariate analyses, prepregnancy BMI was associated with FWC, FWC > 90% and FACC. GWG until the 1st GDM visit was associated with FWC, FACC and FACC > 90% (all p ≤ 0.045). Other maternal parameters were not significantly associated with fetal anthropometry in multivariate analyses (all p ≥ 0.054). In female fetuses, only GWG was associated with FACC (p= 0.044). However, in male fetuses, prepregnancy BMI was associated with FWC, FWC > 90% and FACC and GWG with FWC in multivariate analyses (all p ≤ 0.030). In women with a prepregnancy BMI of ≥ 25 kg/m2 and a GWG until the 1st GDM visit ≥ 10.3 kg (mean GWG), the risk for FWC > 90% and FACC > 90% was 5.3 and 4 times higher than in their counterparts. CONCLUSIONS: A personalized fetal ultrasound surveillance guided by fetal sex, prepregnancy BMI and GWG may be beneficial in reducing adverse fetal and neonatal outcomes.

A comparison of statistical methods for allocating disease costs in the presence of interactions.

We consider the non-trivial problem of estimating a health cost repartition among diseases from patients' hospital stays' global costs in the presence of multimorbidity, that is, when the patients may suffer from more than one disease. The problem is even harder in the presence of interactions among the disease costs, that is, when the costs of having, for example, two diseases simultaneously do not match the sum of the basic costs of having each disease alone, generating an extra cost which might be either positive or negative. In such a situation, there might be no "true solution" and the choice of the method to be used to solve the problem will depend on how one wishes to allocate the extra costs among the diseases. In this article, we study mathematically how different methods proceed in this regard, namely ordinary least squares (OLS), generalized linear models (GLM), and an iterative proportional repartition (IPR) algorithm, in a simple case with only two diseases. It turned out that only IPR allowed to retrieve the total costs and the unambiguous solution that one would have in a setting without interaction, that is, when no extra cost has to be allocated, while OLS and GLM may produce some negative health costs. Also, contrary to OLS, IPR is taking into account the basic costs of the diseases for the allocation of the extra cost. We conclude that IPR seems to be the most natural method to solve the problem, at least among those considered.

Genotype-phenotype associations of polymorphisms within the gene locus of NOD-like receptor pyrin domain containing 3 in Swiss inflammatory bowel disease patients.

BACKGROUND: Genetic variations within the regulatory region of the gene encoding NOD-like receptor pyrin domain containing 3 (NLRP3) have been associated with Crohn's Disease (CD). NLRP3 is part of the NLRP3-inflammasome that mediates the maturation of IL-1ß and IL-18. Carrying the major allele of the single nucleotide polymorphisms (SNPs) rs10733113, rs4353135 and rs55646866 is associated with an increased risk for CD. We here studied the impact of these polymorphisms on clinical characteristics in patients of the Swiss IBD Cohort Study (SIBDCS). METHODS: We included 981 Crohn's disease (CD) patients and 690 ulcerative colitis (UC) patients of the SIBDCS. We analyzed whether three CD-associated NLRP3 polymorphisms have an impact on the clinical disease course in these patients. RESULTS: In CD patients presence of the major allele (G) of rs10733113 was associated with less surgeries and lower maximal CDAI and a similar trend was observed for rs55646866 and rs4353135. Presence of the major allele of all three SNPs was negatively correlated to maximal CDAI. In UC patients homozygous genotype for the major allele (CC) for rs55646866 was associated with a higher age at diagnosis and a higher MTWAI index. Homozygous genotype for the major allele of all three polymorphisms was associated with a higher number of ambulatory visits and longer hospital stays. CONCLUSIONS: In CD patients presence of the major allele of all three polymorphisms was associated with markers of a less severe disease course, while in UC the homozygous genotype for all major alleles suggested a more severe disease activity.

Higher educational level in patients with eosinophilic esophagitis: a comparative analysis.

BACKGROUND: Eosinophilic esophagitis is a chronic inflammatory gastrointestinal disease with a high prevalence in younger, atopic males. In our clinical practice, we observed a striking preponderance of patients having a high educational background. The purposes of this study were first to assess the level of education of eosinophilic esophagitis patients and second to compare the findings to patients with inflammatory bowel disease, another chronic immune-mediated condition of the gastrointestinal tract, and with the Swiss general population. METHODS: Using a questionnaire, we assessed the educational level of adult patients who have attended Swiss Eosinophilic Esophagitis Clinics in the past. In addition, the educational level of the parents was assessed as well. We calculated the proportions of patients and parents who have obtained a higher educational level. Data from the Swiss Inflammatory Bowel Disease Cohort Study and from the Swiss general population served as confirmation and as comparison, respectively. RESULTS: A total of 277 successfully contacted patients (response rate 69.1%; mean age 51.1 years, 73% male) participated. A significantly higher proportion of surveyed eosinophilic esophagitis patients had a high International Standard Classification of Education level (66.8%, P < 0.001) compared with inflammatory bowel disease patients (n = 2534; 34.2%, P < 0.001) and to the Swiss general population (n = 6,066,907; 30.5% P < 0.001). CONCLUSION: Our analysis confirms the clinical observation that eosinophilic esophagitis patients have a significantly higher educational level compared with the general population and to patients with other chronic inflammatory diseases of the gastrointestinal tract. As a limitation, this impressive finding remains on a purely descriptive level.

Malignancies in Inflammatory Bowel Disease: Frequency, Incidence and Risk Factors-Results from the Swiss IBD Cohort Study.

BACKGROUND: Malignancy may occur as long-term complication of inflammatory bowel disease (IBD) due to different risk factors. We assessed prevalence and incidence of malignancy, and predictive factors in the Swiss IBD Cohort Study (SIBDCS). METHODS: All IBD patients in the SIBDCS were analyzed from a cross-sectional and longitudinal perspective. Patients with malignancies were compared to controls. Standardized incidence ratios (SIR) were calculated based on age-specific and sex-specific background rates. RESULTS: Malignancies were identified in 122 of 3119 patients (3.9%). In a logistic regression model, age (OR 1.04 per year), intestinal surgery (OR 3.34), and treatment with steroids (OR 2.10) were the main predictors for the presence of malignancy, while treatment with 5-ASA (OR 0.57) and biologics (OR 0.38) were protective. From a longitudinal perspective, 67 out of 2580 patients (2.6%) were newly diagnosed with malignancy during a follow-up of 12,420.8 years (median 4.9 years). While there was no increased risk for malignancy overall (SIR 0.93, 95% CI 0.72-1.18) and colorectal cancer (SIR 1.55, 95% CI 0.71-2.95), IBD patients had an increased risk for lymphoma (SIR 2.98, 95% CI 1.36-5.66) and biliary cancer (SIR 6.3, 95% CI 1.27-18.41). In a Cox regression model, age and recent use of immunomodulators were the main predictors for development of malignancies, while 5-ASA, biologics were protective. CONCLUSIONS: IBD patients showed increased risk for lymphoma and biliary cancer, but not colorectal cancer and cancer overall. Age and recent use of immunomodulators were the main risk factors for malignancy, while aminosalicylates and biologics appear to be protective.

The impact of the rs8005161 polymorphism on G protein-coupled receptor GPR65 (TDAG8) pH-associated activation in intestinal inflammation.

BACKGROUND: Tissue inflammation in inflammatory bowel diseases (IBD) is associated with a decrease in local pH. The gene encoding G-protein-coupled receptor 65 (GPR65) has recently been reported to be a genetic risk factor for IBD. In response to extracellular acidification, proton activation of GPR65 stimulates cAMP and Rho signalling pathways. We aimed to analyse the clinical and functional relevance of the GPR65 associated single nucleotide polymorphism (SNP) rs8005161. METHODS: 1138 individuals from a mixed cohort of IBD patients and healthy volunteers were genotyped for SNPs associated with GPR65 (rs8005161, rs3742704) and galactosylceramidase (rs1805078) by Taqman SNP assays. 2300 patients from the Swiss IBD Cohort Study (SIBDC) were genotyped for rs8005161 by mass spectrometry based SNP genotyping. IBD patients from the SIBDC carrying rs8005161 TT, CT, CC and non-IBD controls (CC) were recruited for functional studies. Human CD14+ cells were isolated from blood samples and subjected to an extracellular acidic pH shift, cAMP accumulation and RhoA activation were measured. RESULTS: In our mixed cohort, but not in SIBDC patients, the minor variant rs8005161 was significantly associated with UC. In SIBDC patients, we observed a consistent trend in increased disease severity in patients carrying the rs8005161-TT and rs8005161-CT alleles. No significant differences were observed in the pH associated activation of cAMP production between IBD (TT, CT, WT/CC) and non-IBD (WT/CC) genotype carriers upon an acidic extracellular pH shift. However, we observed significantly impaired RhoA activation after an extracellular acidic pH shift in IBD patients, irrespective of the rs8005161 allele. CONCLUSIONS: The T allele of rs8005161 might confer a more severe disease course in IBD patients. Human monocytes from IBD patients showed impaired pH associated RhoA activation upon an acidic pH shift.

Potentially modifiable predictors of adverse neonatal and maternal outcomes in pregnancies with gestational diabetes mellitus: can they help for future risk stratification and risk-adapted patient care?

BACKGROUND: Gestational diabetes mellitus (GDM) exposes mothers and their offspring to short and long-term complications. The objective of this study was to identify the importance of potentially modifiable predictors of adverse outcomes in pregnancies with GDM. We also aimed to assess the relationship between maternal predictors and pregnancy outcomes depending on HbA1c values and to provide a risk stratification for adverse pregnancy outcomes according to the prepregnancy BMI (Body mass index) and HbA1c at the 1st booking. METHODS: This prospective study included 576 patients with GDM. Predictors were prepregnancy BMI, gestational weight gain (GWG), excessive weight gain, fasting, 1 and 2-h glucose values after the 75 g oral glucose challenge test (oGTT), HbA1c at the 1st GDM booking and at the end of pregnancy and maternal treatment requirement. Maternal and neonatal outcomes such as cesarean section, macrosomia, large and small for gestational age (LGA, SGA), neonatal hypoglycemia, prematurity, hospitalization in the neonatal unit and Apgar score at 5 min < 7 were evaluated. Univariate and multivariate regression analyses and probability analyses were performed. RESULTS: One-hour glucose after oGTT and prepregnancy BMI were correlated with cesarean section. GWG and HbA1c at the end pregnancy were associated with macrosomia and LGA, while prepregnancy BMI was inversely associated with SGA. The requirement for maternal treatment was correlated with neonatal hypoglycemia, and HbA1c at the end of pregnancy with prematurity (all p < 0.05). The correlations between predictors and pregnancy complications were exclusively observed when HbA1c was ≥5.5% (37 mmol/mol). In women with prepregnancy BMI ≥ 25 kg/m2 and HbA1c ≥ 5.5% (37 mmol/mol) at the 1st booking, the risk for cesarean section and LGA was nearly doubled compared to women with BMI with < 25 kg/m2 and HbA1c <  5.5% (37 mmol/mol). CONCLUSIONS: Prepregnancy BMI, GWG, maternal treatment requirement and HbA1c at the end of pregnancy can predict adverse pregnancy outcomes in women with GDM, particularly when HbA1c is ≥5.5% (37 mmol/mol). Stratification based on prepregnancy BMI and HbA1c at the 1st booking may allow for future risk-adapted care in these patients.

Symptoms of Depression and Anxiety Are Independently Associated With Clinical Recurrence of Inflammatory Bowel Disease.

BACKGROUND & AIMS: We examined the relationship between symptoms of depression and anxiety and clinical recurrence of inflammatory bowel disease (IBD) in a large patient cohort. We considered the progression of depression and anxiety over time. METHODS: We collected clinical and treatment data on 2007 adult participants of the Swiss IBD study (56% with Crohn's disease [CD], 48% male) performed in Switzerland from 2006 through 2015. Depression and anxiety symptoms were quantified by using the Hospital Anxiety and Depression Scale. The relationship between depression and anxiety scores and clinical recurrence was analyzed by using survival-time techniques. RESULTS: We found a significant association between symptoms of depression and clinical recurrence over time (for all patients with IBD, P = .000001; for subjects with CD, P = .0007; for subjects with ulcerative colitis, P = .005). There was also a significant relationship between symptoms of anxiety and clinical recurrence over time in all subjects with IBD (P = .0014) and in subjects with CD (P = .031) but not ulcerative colitis (P = .066). CONCLUSIONS: In an analysis of a large cohort of subjects with IBD, we found a significant association between symptoms of depression or anxiety and clinical recurrence. Patients with IBD should therefore be screened for clinically relevant levels of depression and anxiety and referred to psychologists or psychiatrists for further evaluation and treatment.

The Clinical Relevance of the IBD-Associated Variation within the Risk Gene Locus Encoding Protein Tyrosine Phosphatase Non-Receptor Type 2 in Patients of the Swiss IBD Cohort.

BACKGROUND/AIMS: The single nucleotide polymorphism (SNP) rs1893217 within the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) results in a dysfunctional PTPN2 protein is associated with Crohn's disease (CD) and exists in perfect linkage disequilibrium with the CD- and ulcerative colitis (UC)-associated PTPN2 SNP rs2542151. We investigated associations of PTPN2 SNP rs1893217 and clinical characteristics of inflammatory bowel disease (IBD) patients. METHODS: One thousand seventy three patients with CD and 734 patients with UC from the Swiss IBD Cohort Study (SIBDCS) were included. Epidemiologic, disease and treatment characteristics were analysed for an association with the presence of one of the rs1893217 genotypes 'homozygous wild-type' (TT), 'heterozygous' (CT) and 'homozygous variant' (CC). RESULTS: About 2.88% of IBD patients were identified with CC, 26.8% with CT and 70.4% with TT genotype. The CC-genotype was associated with the existence of gallstones in CD and pancolitis in UC patients. The presence of the C-allele (i.e. either CC or CT genotype) was associated with the onset of uveitis, but protected from aphthous oral ulcers in CD patients. UC patients carrying a C-allele were diagnosed at an older age but required intestinal surgery more often. The presence of the C-allele was associated with a successful treatment with anti-TNF antibodies in both CD and UC patients. CONCLUSION: IBD patients carrying the C-allele of PTPN2 SNP rs1893217 are at greater risk for developing a severe disease course but are more likely to respond to treatment with anti-TNF antibodies. These findings demonstrate a clinical relevance of this PTPN2 risk variant in IBD patients.

Femoral vs sciatic nerve block to provide analgesia after medial open wedge high tibial osteotomy in the setting of multimodal analgesia: A randomized, controlled, single-blinded trial.

STUDY OBJECTIVE: Medial open wedge high tibial osteotomy (MOW HTO) is associated with moderate to severe postoperative pain. The proximal part of the tibia is innervated by branches from the femoral nerve anteriorly and the sciatic nerve posteriorly. There is a paucity of information regarding the optimal peripheral nerve block for postoperative analgesia with minimal impact on motor function. This study tested the hypothesis that a femoral nerve block provides superior analgesia to a sciatic nerve block after MOW HTO in the setting of multimodal analgesia. DESIGN: Randomized controlled single-blind trial. SETTING: Operating room, postoperative recovery area and ward, up to 6 postoperative months. PATIENTS: Fifty patients undergoing MOW HTO. INTERVENTIONS: Interventions were femoral or sciatic nerve block under ultrasound guidance. For each intervention, a total of 100 mg of ropivacaine was injected. Postoperative pain treatment followed a pre-defined protocol with intravenous patient-controlled analgesia of morphine, paracetamol, and ibuprofen. MEASUREMENTS: The primary outcome was intravenous morphine consumption at 24 h postoperatively. Secondary outcomes included rest and dynamic pain scores (on a numeric rating scale out of 10) at 2, 24 and 48 h postoperatively. Functional outcomes included the Short Form-12, Knee injury and Osteoarthritis Outcome Score, and International Knee Documentation Committee (IKDC) scores measured at 6 months postoperatively. MAIN RESULTS: Mean [95% confidence interval] i.v. morphine consumption at 24 postoperative hours were 24 mg [15 mg,33 mg] in the femoral nerve block group and 24 mg [16 mg,32 mg] in the sciatic nerve block group (p = 0.98). There were no significant differences in the secondary outcomes between groups. CONCLUSIONS: This trial failed to demonstrate that a femoral nerve block provides superior analgesia to a sciatic nerve block after MOW HTO under general anesthesia in the setting of multimodal analgesia. There was no significant difference in quality of life and functional outcomes at 6 months postoperatively between groups. Trial registry number:Clinicaltrials.com - NCT05728294; Kofam.ch - SNCTP000003048 | BASEC2018-01774.

Association of pharmacologic thromboprophylaxis with clinically relevant bleeding and hospital-acquired anemia in medical inpatients: the risk stratification for hospital-acquired venous thromboembolism in medical patients study.

BACKGROUND: Pharmacologic thromboprophylaxis (pTPX) might exacerbate the risk of clinically relevant bleeding (CRB) and hospital-acquired anemia (HAA) in older multimorbid inpatients. OBJECTIVES: We aimed to evaluate the association of pTPX use with CRB and HAA. METHODS: We used data from a prospective cohort study conducted in 3 Swiss university hospitals. Adult patients admitted to internal medicine wards with no therapeutic anticoagulation were included. pTPX use was ascertained during hospitalization. Outcomes were in-hospital CRB and HAA. We calculated incidence rates by status of pTPX. We assessed the association of pTPX with CRB using survival analysis and with HAA using logistic regression, adjusted for infection, length of stay, and the International Medical Prevention Registry on Venous Thromboembolism bleeding risk score. RESULTS: Among 1305 patients (mean age, 63.7 years; 44% women, 90% at low risk of bleeding), 809 (62%) received pTPX. The incidence of CRB was 2.4 per 1000 patient-days and was not significantly higher in patients with pTPX than in those without. We found no significant association between pTPX and CRB. HAA was frequent (20.2%) and higher in patients with pTPX than in those without (23.2% vs 15.3%). The incidence of HAA was 21.2 per 1000 patient-days and did not significantly differ between patients with pTPX and those without. We found an association between pTPX and HAA (adjusted odds ratio, 1.4; 95% CI, 1.0-2.1). CONCLUSION: Our study confirmed the safety of pTPX in medical inpatients at low risk of bleeding but identified an association between pTPX and HAA. Adherence to guidelines that recommend administering pTPX to medical inpatients at increased venous thromboembolism risk and low bleeding risk is necessary.