Re-resection Rates and Disease Recurrence in Crohn's Disease - A Population-Based Study Using Individual-Level Patient Data.

BACKGROUND AND AIMS: Despite advances in the medical treatment of Crohn's disease (CD), many patients will still need bowel resections and face the subsequent risk of recurrence and re-resection. We describe contemporary re-resection rates and identify disease-modifying factors and risk factors for re-resection. METHODS: We conducted a retrospective, population-based, individual patient data cohort study covering 47.4% of the Danish population, including all CD patients who underwent a primary resection between 2010 and 2020. RESULTS: Among 631 primary resected patients, 24.5% underwent a second resection, and 5.3% a third. Re-resection rates after one, five, and 10 years were 12.6%, 22.4%, and 32.2%, respectively. Reasons for additional resections were mainly disease activity (57%) and stoma reversal (40%). Disease activity-driven re-resection rates after one, five, and 10 years were 3.6%, 10.1%, and 14.1%, respectively. Most stoma reversals occurred within one year (80%). The median time to recurrence was 11.0 months. Biologics started within one year of the first resection revealed protective effect against re-resection for stenotic and penetrating phenotypes. Prophylactic biologic therapy at primary ileocecal resection reduced disease recurrence and re-resection risk (HR 0.58, 95% CI (0.34-0.99), p=0.047). Risk factors for re-resection were location of resected bowel segments at the primary resection, disease location, disease behavior, smoking, and perianal disease. CONCLUSION: Re-resection rates, categorized by disease activity, are lower than those reported in other studies and are closely associated with disease phenotype and localization. Biological therapy may be disease-modifying for certain subgroups when initiated within one year of resection.

Clinical and Metabolic Characterization of Women With Gestational Diabetes Mellitus Within the First Year Postpartum.

Context: Women with gestational diabetes mellitus (GDM) have an increased risk of long-term complications, including impaired glucose metabolism, type 2 diabetes (T2DM), cardiovascular disease, and obesity. In current clinical practice, a 1 size fits all approach to GDM is applied, although heterogeneity among women with GDM has been recognized. Objective: To give the most adequate preventive care and postpartum (PP) guidance, we aimed to make a metabolic characterization and identify subgroups of women with previous GDM within the first year PP. Methods: In this prospective cohort study, we collected data in gestational week 34-38, at 3 months, and 1 year PP on women with GDM who participated in a PP follow-up program in Central Region Denmark from April 2019 to December 2022. Results: In total, 1270 women were included in the program in late pregnancy. Of the 768 women participating in either the oral glucose tolerance test 3 months PP (n = 545) or the 1-year follow-up (n = 493) or both (n = 261), 608 (79.2%) were normoglycemic, 137 (17.8%) had prediabetes, 20 (2.6%) had T2DM, and 3 (.4%) had developed T1DM. More than 40% of the women gained weight in the first year PP compared with their pregestational weight. Conclusion: Our study shows that 20.8% of women with GDM who volunteered to participate in a clinical follow-up program developed prediabetes or diabetes (T1DM and T2DM) within the first year PP. The GDM diagnosis encompasses a heterogenetic group of women and a deeper characterization may provide an opportunity for a more personalized risk assessment to prevent the progression to T2DM.

Prevalence and prognostic implications of hypertensive response to exercise in patients with hypertrophic cardiomyopathy.

Objective: Hypertensive response to exercise (HRE) is observed in patients with hypertrophic cardiomyopathy (HCM) with normal resting blood pressure (BP). However, the prevalence or prognostic implications of HRE in HCM remain unclear. Methods: In this study, normotensive HCM subjects were enrolled. HRE was defined as systolic BP > 210 mmHg in men or >190 mmHg in women, or diastolic BP > 90 mmHg, or an increase in diastolic BP > 10 mmHg during treadmill exercise. All participants were followed for subsequent development of hypertension, atrial fibrillation (AF), heart failure (HF), sustained ventricular tachycardia/fibrillation (VT/VF), and all-cause death. Six hundred and eighty HCM patients were screened. Results: 347 patients had baseline hypertension, and 333 patients were baseline normotensive. 132 (40%) of the 333 patients had HRE. HRE was associated with female sex, lower body mass index and milder left ventricular outflow tract obstruction. Exercise duration and metabolic equivalents were similar between patients with or without HRE, but the HRE group had higher peak heart rate (HR), better chronotropic response and more rapid HR recovery. Conversely, non-HRE patients were more likely to exhibit chronotropic incompetence and hypotensive response to exercise. After a mean follow-up of 3.4 years, patients with and without HRE had similar risks of progression to hypertension, AF, HF, sustained VT/VF or death. Conclusion: HRE is common in normotensive HCM patients during exercise. HRE did not carry higher risks of future hypertension or cardiovascular adverse outcomes. Conversely, the absence of HRE was associated with chronotropic incompetence and hypotensive response to exercise.

One-step laparoscopic cholecystectomy with common bile duct exploration and stone extraction versus two-step endoscopic retrograde cholangiography with stone extraction plus laparoscopic cholecystectomy for patients with common bile duct stones: a randomised feasibility and pilot clinical trial-the preGallStep trial.

BACKGROUND: Endoscopic retrograde cholangiography (ERC) with stone extraction and papillotomy with subsequent laparoscopic cholecystectomy-the two-step approach-is the standard treatment of common bile duct stones in many countries. However, ERC is associated with a high risk of complications and more than half of patients require multiple ERCs. Meta-analyses of randomised clinical trials find no major differences of the two-step approach in comparison with laparoscopic cholecystectomy with intraoperative laparoscopic stone clearance-the one-step approach. Currently, there are insufficient data to ascertain superiority. METHODS: The preGallstep trial is an investigator-initiated, multicentre randomised feasibility and pilot clinical trial with blinded outcome assessment. Eligible patients are patients with common bile duct stones (identified by magnetic resonance cholagiopancreatography), age 18 years or above with the possibility to perform both interventions within a reasonable time. We intent to randomise 150 participants allocated 1:1. The experimental intervention is the one-step approach. This consists of laparoscopic common bile duct exploration plus laparoscopic cholecystectomy. The control intervention is the two-step approach which consists of ERC plus sphincterotomy (first step) and subsequent laparoscopic cholecystectomy (second step). Feasibility outcomes include the proportion of eligible patients not wanting to participate, reasons for rejection to participate, difficulties during the informed consent procedure, difficulties with randomisation, difficulties with data management, difficulties with blinding patient charts and forms and difficulties with maintaining blinding for the outcome assessors. The primary pilot outcome is the proportion of participants with at least one postoperative complication according to the Clavien-Dindo score grade II and above until 90 days after randomisation. This outcome will be used for a future sample size calculation of a larger pragmatic trial. Further, a range of clinical explorative outcomes will be assessed. DISCUSSION: As no sample size is estimated in this trial, there is a risk of wrongly assessing the effect on the patient-related outcome. The surgical procedures cannot be blinded. However, blinding will be employed in all other aspects of the trial, including the establishment of a blinded outcome adjudication committee with three independent assessors. Heterogeneity in screening, randomisation, diagnostics, treatment procedures, interventions and follow-up across trial sites may cause challenges in conducting a larger pragmatic trial. To monitor inter-site differences, we have implemented a central data monitoring scheme. TRIAL REGISTRATION: ClinicalTrials.gov identification: NCT04801238 , Registered on 16 March 2021.

Lipid Modulation of a Class B GPCR: Elucidating the Modulatory Role of PI(4,5)P2 Lipids.

Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) lipids have been shown to stabilize an active conformation of class A G-protein coupled receptors (GPCRs) through a conserved binding site, not present in class B GPCRs. For class B GPCRs, previous molecular dynamics (MD) simulation studies have shown PI(4,5)P2 interacting with the Glucagon receptor (GCGR), which constitutes an important target for diabetes and obesity therapeutics. In this work, we applied MD simulations supported by native mass spectrometry (nMS) to study lipid interactions with GCGR. We demonstrate how tail composition plays a role in modulating the binding of PI(4,5)P2 lipids to GCGR. Specifically, we find the PI(4,5)P2 lipids to have a higher affinity toward the inactive conformation of GCGR. Interestingly, we find that in contrast to class A GPCRs, PI(4,5)P2 appear to stabilize the inactive conformation of GCGR through a binding site conserved across class B GPCRs but absent in class A GPCRs. This suggests differences in the regulatory function of PI(4,5)P2 between class A and class B GPCRs.

National clinical practice guidelines for the treatment of symptomatic gallstone disease: 2021 recommendations from the Danish Surgical Society.

BACKGROUND AND OBJECTIVE: Gallstones are highly prevalent, and more than 9000 cholecystectomies are performed annually in Denmark. The aim of this guideline was to improve the clinical course of patients with gallstone disease including a subgroup of high-risk patients. Outcomes included reduction of complications, readmissions, and need for additional interventions in patients with uncomplicated gallstone disease, acute cholecystitis, and common bile duct stones (CBDS). METHODS: An interdisciplinary group of clinicians developed the guideline according to the GRADE methodology. Randomized controlled trials (RCTs) were primarily included. Non-RCTs were included if RCTs could not answer the clinical questions. Recommendations were strong or weak depending on effect estimates, quality of evidence, and patient preferences. RESULTS: For patients with acute cholecystitis, acute laparoscopic cholecystectomy is recommended (16 RCTs, strong recommendation). Gallbladder drainage may be used as an interval procedure before a delayed laparoscopic cholecystectomy in patients with temporary contraindications to surgery and severe acute cholecystitis (1 RCT and 1 non-RCT, weak recommendation). High-risk patients are suggested to undergo acute laparoscopic cholecystectomy instead of drainage (1 RCT and 1 non-RCT, weak recommendation). For patients with CBDS, a one-step procedure with simultaneous laparoscopic cholecystectomy and CBDS removal by laparoscopy or endoscopy is recommended (22 RCTs, strong recommendation). In high-risk patients with CBDS, laparoscopic cholecystectomy is suggested to be included in the treatment (6 RCTs, weak recommendation). For diagnosis of CBDS, the use of magnetic resonance imaging or endoscopic ultrasound prior to surgical treatment is recommended (8 RCTs, strong recommendation). For patients with uncomplicated symptomatic gallstone disease, observation is suggested as an alternative to laparoscopic cholecystectomy (2 RCTs, weak recommendation). CONCLUSIONS: Seven recommendations, four weak and three strong, for treating patients with symptomatic gallstone disease were developed. Studies for treatment of high-risk patients are few and more are needed. ENDORSEMENT: The Danish Surgical Society.

Development of upper gastrointestinal cancer in patients with symptomatic gallstones, cholecystectomy, and sphincterotomy: A nationwide cohort study.

BACKGROUND AND OBJECTIVE: Exposures of gallstones and treatments thereof in relation to development of cancer have not been explored before in long-term follow-up studies. Our objective was to determine whether symptomatic gallstones, cholecystectomy, or sphincterotomy were associated with development of upper gastrointestinal cancers. METHODS: This is a nationwide cohort study of persons born in Denmark 1930-1984 included from age 30 years with long-term follow-up (1977-2014). Exposures were hospital admissions with gallstones, cholecystectomy, and sphincterotomy. Time-varying covariates were included in analyses to allow the impact of exposures to change with time. Follow-up periods were 2-5 and > 5 years. Hazard ratios (HR) with 95% confidence intervals (CI) were reported. RESULTS: A total of 4,465,962 persons were followed. We found positive associations between sphincterotomy and biliary (>5 years HR 4.34, CI [2.17-8.70]), gallbladder (2-5 years HR 20.7, CI [8.55-50.1]), and pancreatic cancer (2-5 years HR 3.68, CI [2.09-6.49]). Cholecystectomy was positively associated with duodenal (2-5 years HR 2.94, CI [1.31-6.58]) and small bowel cancer (2-5 years HR 2.75, CI [1.56-4.87]). Inverse associations were seen for cholecystectomy and biliary (>5 years HR 0.60, CI [0.41-0.87]), pancreatic (>5 years HR 0.45 CI [0.35-0.57]), esophageal (>5 years HR 0.57, CI [0.43-0.74]), and gastric cancer (>5 years HR 0.68, CI [0.55-0.86]) and for gallstones and pancreatic cancer (>5 years HR 0.66, CI [0.47-0.93]). Gallstones were positively associated with gallbladder (>5 years HR 3.51, CI [2.02-6.10]) and small bowel cancer (2-5 years HR 3.21, CI [1.60-6.45]). CONCLUSIONS: A positive association between sphincterotomy and biliary cancer was identified. Cholecystectomy seems to be inversely associated with biliary, pancreatic, esophageal, and gastric cancer. Associations should be explored in similar large cohorts.

The Effects of Sodium Ions on Ligand Binding and Conformational States of G Protein-Coupled Receptors-Insights from Mass Spectrometry.

The use of mass spectrometry to investigate proteins is now well established and provides invaluable information for both soluble and membrane protein assemblies. Maintaining transient noncovalent interactions under physiological conditions, however, remains challenging. Here, using nanoscale electrospray ionization emitters, we establish conditions that enable mass spectrometry of two G protein-coupled receptors (GPCR) from buffers containing high concentrations of sodium ions. For the Class A GPCR, the adenosine 2A receptor, we observe ligand-induced changes to sodium binding of the receptor at the level of individual sodium ions. We find that antagonists promote sodium binding while agonists attenuate sodium binding. These findings are in line with high-resolution X-ray crystallography wherein only inactive conformations retain sodium ions in allosteric binding pockets. For the glucagon receptor (a Class B GPCR) we observed enhanced ligand binding in electrospray buffers containing high concentrations of sodium, as opposed to ammonium acetate buffers. A combination of native and -omics mass spectrometry revealed the presence of a lipophilic negative allosteric modulator. These experiments highlight the advantages of implementing native mass spectrometry, from electrospray buffers containing high concentrations of physiologically relevant salts, to inform on allosteric ions or ligands with the potential to define their roles on GPCR function.

Macroscopic hematuria as a risk factor for hypertension in ageing people with hemophilia and a family history of hypertension.

Ageing people with hemophilia (PWH) have a higher prevalence of hypertension than the general population. This study aimed to determine whether macroscopic hematuria was associated with hypertension in PWH in a post hoc analysis using data from a cross-sectional study conducted by the ADVANCE Working Group (the H3 study), which included PWH ≥ 40 years of age. Data from 16 contributing centers, located in 13 European countries and Israel, were analyzed using logistic regression models. Of 532 recruited PWH in the H3 study, 117 had hypertension and a positive family history of hypertension (hypertension FH+), 75 had hypertension and a negative family history of hypertension (hypertension FH-), 290 had no diagnosis of hypertension, and the remaining 50 had missing hypertension data. Logistic regressions showed that macroscopic hematuria was associated with hypertension FH+, both in the univariate (OR = 1.84 [1.17-2.90], P = .01) and in the multivariate model (OR = 1.80 [1.03-3.16], P = .04). Macroscopic hematuria was not associated with hypertension FH-. Moreover, in a multivariate logistic regression the odds of hypertension FH+ were increased with the number of macroscopic hematuria episodes. The association between macroscopic hematuria and hypertension was significant for PWH with a family history of hypertension.

The clinical course of common bile duct stone clearance with endoscopic retrograde cholangio-pancreaticography.

Objectives: Two-stage treatment of common bile duct stones by Endoscopic Retrograde Cholangio-Pancreatography and subsequent laparoscopic cholecystectomy is well established. In many cases multiple procedures are needed before clearance of the common bile duct is obtained. This study aimed to describe the clinical course from common bile duct stone diagnosis to successful clearance. Materials and Methods: A prospective observational study from 2011 to 2014 of consecutive patients diagnosed with common bile duct stones undergoing Endoscopic Retrograde Cholangio-Pancreatography at a public university hospital. Results: In this study 297 patients with common bile duct stones were identified. More than one Endoscopic Retrograde Cholangio-Pancreatography was performed in 174 (59%) patients and more than two in 51(17%) before clearance. A sphincterotomy was performed in 269 (91%) patients and 189 (64%) had a stent inserted. Bleeding occurred in 17 (6%) requiring injection treatment and post procedure complications occurred in 38 (13%). Subsequent laparoscopic cholecystectomy was performed in 180 (61%) patients. Overall, the patients were hospitalized for 11 (8.5) days and the length of treatment from diagnose to stone clearance was 49 (84.5) days. Overweight, pancreatitis at admission, universal anesthesia, and expert level endoscopist inversely determined common bile duct clearance failure. Conclusions: Common bile duct clearance by Endoscopic Retrograde Cholangio-Pancreatography requires multiple procedures and complications are frequent leading to prolonged treatment and hospitalization suggesting a limited efficacy.

Venous thromboembolic complications following surgical treatment for degenerative spinal disease.

INTRODUCTION: A venous thromboembolism (VTE), i.e. deep vein thrombosis (DVT) or pulmonary embolism (PE), is a potentially lethal complication to surgical procedures. The aim of this study was to evaluate the incidence of symptomatic VTEs in a large consecutive Danish cohort treated surgically for degenerative spinal disease. METHODS: This was a retrospective, consecutive, one-centre cohort study of patients treated surgically for either cervical or lumbar degenerative disease. According to the local treatment protocol, patients with an increased risk of VTE received rivaroxaban as thrombosis prophylaxis. VTE events within six months from the surgical procedure were identified via the Danish National Patient Register and confirmed by patient chart review. RESULTS: A total of 6,145 surgical procedures were included - 808 cervical and 5,337 lumbar procedures. Twelve patients (0.2%) were examined on suspicion of symptomatic VTE, ten for DVT and two for PE. VTE was confirmed in eight patients (0.1%), seven DVT and one PE. One patient died within six months, producing a mortality rate of 0.01%. CONCLUSIONS: VTEs are an uncommon but potentially lethal complication in patients who undergo surgery for a degenerative spinal disease. Incidence and mortality were low in a consecutive cohort where rivaroxaban was used as thrombosis prophylaxis in patients with an increased preoperative risk of VTE. FUNDING: none. TRIAL REGISTRATION: not relevant.

Evolution of ventricular hypertrophy and myocardial mechanics in physiological and pathological hypertrophy.

Left ventricular hypertrophy (LVH) is an adaptive response to physiological or pathological stimuli, and distinguishing between the two has obvious clinical implications. However, asymmetric septal hypertrophy and preserved cardiac function are noted in early stages in both cases. We characterized the early anatomic and functional changes in a mouse model of physiological and pathological stress using serial echocardiography-based morphometry and tissue velocity imaging. Weight-matched CF-1 male mice were separated into Controls ( n = 10), treadmill Exercise 1 h daily for 5 days/wk ( n = 7), and transverse aortic constriction (TAC, n = 7). Hypertrophy was noted first in the left ventricle basal septum compared with other segments in Exercise (0.84 ± 0.02 vs. 0.79 ± 0.03 mm, P = 0.03) and TAC (0.86 ± 0.05 vs. 0.77 ± 0.04 mm, P = 0.02) at 4 and 3 wk, respectively. At 8 wk, eccentric LVH was noted in Exercise and concentric LVH in TAC. Septal E/E' ratio increased in TAC (32.6 ± 3.7 vs. 37 ± 6.2, P = 0.002) compared with the Controls and Exercise (32.3 ± 5.2 vs. 32.8 ± 3.8 and 31.2 ± 4.9 vs. 28.2 ± 5.0, respectively, nonsignificant for both). Septal s' decreased in TAC (21 ± 3.6 vs. 17 ± 4.2 mm/s, P = 0.04) but increased in Exercise (19.6 ± 4.1 vs. 29.2 ± 2.3 mm/s, P = 0.001) and was unchanged in Controls (20.1 ± 4.2 vs. 20.9 ± 5.1 mm/s, nonsignificant). With similar asymmetric septal hypertrophy and normal global function during the first 4-8 wk of pathological and physiological stress, there is an early marginal increase with subsequent decrease in systolic tissue velocity in pathological but early and progressive increase in physiological hypertrophy. Tissue velocities may help adjudicate between these two states when there are no overt anatomic or functional differences. NEW & NOTEWORTHY Pathological and physiological stress-induced ventricular hypertrophy have different clinical connotations but present with asymmetric septal hypertrophy and normal global function in their early stages. We observed a marginal but statistically significant decrease in systolic tissue velocity in pathological but progressive increase in velocity in physiological hypertrophy. Tissue velocity imaging could be an important tool in the management of asymmetric septal hypertrophy by adjudicating between these two etiologies when there are no overt anatomic or functional differences.

Percutaneous Cholecystostomy Versus Conservative Treatment for Acute Cholecystitis: a Cohort Study.

BACKGROUND: Percutaneous cholecystostomy is frequently used as a treatment option for acute calculous cholecystitis in patients unfit for surgery. There is sparse evidence on the long-term impact of cholecystostomy on gallstone-related morbidity and mortality in patients with acute calculous cholecystitis. This study describes the long-term outcome of acute calculous cholecystitis following percutaneous cholecystostomy compared to conservative treatment. METHODS: This was a cohort study of patients admitted at our institution from 2006 to 2015 with acute calculous cholecystitis without early or delayed cholecystectomy. Endpoints were gallstone-related readmissions, recurrent cholecystitis, and overall mortality. RESULTS: The investigation included 201 patients of whom 97 (48.2%) underwent percutaneous cholecystostomy. Patients in the cholecystostomy group had significantly higher age, comorbidity level, and inflammatory response at admission. The median duration of catheter placement in the cholecystostomy group was 6 days. The complication rate of cholecystostomy was 3.1% and the mortality during the index admission was 3.5%. The median follow-up was 1.6 years. The rate of gallstone-related readmissions was 38.6%, and 25.3% had recurrence of cholecystitis. Cox regression analyses revealed no significant differences in gallstone-related readmissions, recurrence of acute calculous cholecystitis, and overall mortality in the two groups. CONCLUSIONS: Percutaneous cholecystostomy in the treatment of acute calculous cholecystitis was neither associated with long-term benefits nor complications. Based on the high gallstone-related readmission rates of this study population and todays perioperative improvements, we suggest rethinking the indications for non-operative management including percutaneous cholecystostomy in acute calculous cholecystitis.

Optimized Workflow for Selecting Peptides for HDX-MS Data Analyses.

Hydrogen deuterium exchange measured by mass spectrometry (HDX-MS) is a commonly used technique for studying the structural dynamics of proteins in solution. The first part of any bottom-up HDX-MS experiment is to identify the peptides generated from a digestion step. This requires manual inspection of the identified peptides to determine their use for HDX-MS analysis, which is a time-consuming task. Throughout the literature, there have been different approaches for removing peptides that do not yield quantifiable HDX information. This includes using validity scores from the software used in the generation of the peptide map and that the peptide should be found in two out of three technical replicate experiments. Here, we analyze the previously available methods for filtering the identified peptides in regard to their ability to predict whether a peptide will provide quantifiable HDX-MS data or not. We also present a new score-based system relying on a combination of MS/MS parameters that offers an improved method for separating quantifiable peptides from the nonquantifiable. Using this score-based method reduces the number of peptide spectra that needs to be manually inspected and thereby the time spent curating HDX-MS data. Graphical Abstract ᅟ.

Two-dimensional global longitudinal strain is superior to left ventricular ejection fraction in prediction of outcome in patients with left-sided infective endocarditis.

BACKGROUND: Impaired cardiac function is the main predictor of poor outcome in infective endocarditis (IE). Global longitudinal strain (GLS) derived from two-dimensional strain echocardiography has proven superior in prediction of long-term outcome as compared to left ventricular ejection fraction (LVEF) in valvular disease and heart failure in general. Whether measurements of cardiac deformation can predict survival in patients with IE has not previously been investigated. METHODS: The study included consecutive patients with Duke definite IE who underwent transthoracic and transesophageal echocardiography within 7 days. Clinical and echocardiographic markers associated with 1-year survival were identified using a Cox-proportional hazards model that included propensity adjustment for surgery. Reclassification statistics including receiver operating characteristic curves and net reclassification improvement were applied to LVEF and GLS, respectively. RESULTS: A cohort of 190 patients met eligibility criteria. LVEF and GLS were both prognostic markers of mortality. Independent markers of 1-year mortality were S. aureus IE (HR:2.02; 95%CI 1.11-5.72, p = .022), diabetes (HR:2.05; 95%CI 1.12-3.75, p = .020), embolic stroke (HR:3.95; 95%CI 1.93-8.10, p < .001) and LVEF<45% (HR: 3.02; 95% CI 1.70-5.38, p < .001), GLS> -15.4% (HR:2.95; 95%CI 1.52-5.72, p < .001). Adding LVEF<45% to a model with known risk factors of IE did not significantly improve risk classification, whereas addition of GLS to the model resulted in significant increase (AUC = 0.763, p < .001). CONCLUSIONS: When treatment was taken into account, LVEF<45% and GLS > -15.4% were both associated with adverse long-term outcome in left-sided IE. GLS >-15.4 % was significantly associated with 1-year mortality in the multivariate analysis. Further, GLS was superior to LVEF in risk prediction and risk discrimination of long-term outcome in patients with left-sided IE.

Allele-specific differences in transcriptome, miRNome, and mitochondrial function in two hypertrophic cardiomyopathy mouse models.

Hypertrophic cardiomyopathy (HCM) stems from mutations in sarcomeric proteins that elicit distinct biophysical sequelae, which in turn may yield radically different intracellular signaling and molecular pathologic profiles. These signaling events remain largely unaddressed by clinical trials that have selected patients based on clinical HCM diagnosis, irrespective of genotype. In this study, we determined how two mouse models of HCM differ, with respect to cellular/mitochondrial function and molecular biosignatures, at an early stage of disease. We show that hearts from young R92W-TnT and R403Q-αMyHC mutation-bearing mice differ in their transcriptome, miRNome, intracellular redox environment, mitochondrial antioxidant defense mechanisms, and susceptibility to mitochondrial permeability transition pore opening. Pathway analysis of mRNA-sequencing data and microRNA profiles indicate that R92W-TnT mutants exhibit a biosignature consistent with activation of profibrotic TGF-ß signaling. Our results suggest that the oxidative environment and mitochondrial impairment in young R92W-TnT mice promote activation of TGF-ß signaling that foreshadows a pernicious phenotype in young individuals. Of the two mutations, R92W-TnT is more likely to benefit from anti-TGF-ß signaling effects conferred by angiotensin receptor blockers and may be responsive to mitochondrial antioxidant strategies in the early stage of disease. Molecular and functional profiling may therefore serve as aids to guide precision therapy for HCM.

Screen-detected gallstone disease and autoimmune diseases - A cohort study.

BACKGROUND: Gallstone disease is highly prevalent and is associated with systemic inflammation. AIMS: To determine whether screen-detected gallstones or cholecystectomy are associated with the occurrence of autoimmune and autoinflammatory diseases and the most common subgroups thereof. METHODS: A cohort study of three randomly selected general population samples from Copenhagen was performed. Participants (n = 5928) were examined in the period 1982-1992, underwent abdominal ultrasound examination to detect gallstone disease, and followed through national registers until December 2014 (median 24.7 years) for occurrence of immunological diseases. Multivariable Cox regression analyses were performed. RESULTS: Gallstone disease was identified in 10% (591/5928) of participants, of whom 6.8% had gallstones and 3.2% had cholecystectomy at baseline. Gallstone disease was associated with incidence of autoimmune diseases (12.9% versus 7.92%; hazard ratio 1.46; 95% confidence interval [CI], [1.11;1.91]), diabetes mellitus type 1 (5.95% versus 3.67%; 1.53; [1.02;2.30]), and autoimmune thyroid disease (3.70% versus 1.59%; 2.06; [1.26;3.38]). Rheumatoid arthritis, autoinflammatory diseases, or any subgroups thereof were not associated. CONCLUSIONS: In a large general population sample, screen-detected gallstone disease was associated with the development of autoimmune diseases during long-term follow-up. Future research efforts are needed to further explore common disease mechanisms.

Clinical Outcomes in Patients With Nonobstructive, Labile, and Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disease characterized by varying degrees of left ventricular outflow tract obstruction. In a large cohort, we compare the outcomes among 3 different hemodynamic groups. METHODS AND RESULTS: We prospectively enrolled patients fulfilling standard diagnostic criteria for HCM from January 2005 to June 2015. Detailed phenotypic characterization, including peak left ventricular outflow tract pressure gradients at rest and after provocation, was measured by echocardiography. The primary outcome was a composite cardiovascular end point, which included new-onset atrial fibrillation, new sustained ventricular tachycardia/ventricular fibrillation, new or worsening heart failure, and death. The mean follow-up was 3.4±2.8 years. Among the 705 patients with HCM (mean age, 52±15 years; 62% men), 230 with obstructive HCM were older and had a higher body mass index and New York Heart Association class. The 214 patients with nonobstructive HCM were more likely to have a history of sustained ventricular tachycardia/ventricular fibrillation and implantable cardioverter defibrillator implantation. During follow-up, 121 patients experienced a composite cardiovascular end point. Atrial fibrillation occurred most frequently in the obstructive group. Patients with nonobstructive HCM had more frequent sustained ventricular tachycardia/ventricular fibrillation events. In multivariate analysis, obstructive (hazard ratio, 2.80; 95% confidence interval, 1.64-4.80) and nonobstructive (hazard ratio, 1.94; 95% confidence interval, 1.09-3.45) HCM were associated with more adverse events compared with labile HCM. CONCLUSIONS: Nonobstructive HCM carries notable morbidity, including a higher arrhythmic risk than the other HCM groups. Patients with labile HCM have a relatively benign clinical course. Our data suggest detailed sudden cardiac death risk stratification in nonobstructive HCM and monitoring with less aggressive management in labile HCM.

Rest and Stress Longitudinal Systolic Left Ventricular Mechanics in Hypertrophic Cardiomyopathy: Implications for Prognostication.

BACKGROUND: Exercise intolerance is the most common symptom in hypertrophic cardiomyopathy (HCM). We examined whether inability to augment myocardial mechanics during exercise would influence functional performance and clinical outcomes in HCM. METHODS: Ninety-five HCM patients (32 nonobstructive, 32 labile-obstructive, 31 obstructive) and 26 controls of similar age and gender distribution were recruited prospectively. They underwent rest and treadmill stress strain echocardiography, and 61 of them underwent magnetic resonance imaging. Mechanical reserve (MRES) was defined as percent change in systolic strain rate (SR) immediately postexercise. RESULTS: Global strain and SR were significantly lower in HCM patients at rest (strain: nonobstructive, -15.6 ± 3.0; labile-obstructive, -15.9 ± 3.0; obstructive, -13.8 ± 2.9; control, -17.7% ± 2.1%, P < .001; SR: nonobstructive, -0.92 ± 0.20; labile-obstructive, -0.94 ± 0.17; obstructive, -0.85 ± 0.18; control, -1.04 ± 0.14 s-1, P = .002); and immediately postexercise (strain: nonobstructive, -15.6 ± 3.0; labile-obstructive, -17.6 ± 3.6; obstructive, -15.6 ± 3.6; control, -19.2 ± 3.1%; P = .001; SR: nonobstructive, -1.41 ± 0.37; labile-obstructive, -1.64 ± 0.38; obstructive, -1.32 ± 0.29; control, -1.82 ± 0.29 s-1, P < .001). MRES was lower in nonobstructive and obstructive compared with labile-obstructive and controls (51% ± 29%, 54% ± 31%, 78% ± 38%, 77% ± 30%, P = .001, respectively). Postexercise SR and MRES were associated with exercise capacity (r = 0.47 and 0.42, P < .001 both, respectively). When adjusted for age, gender, body mass index, E/e', and resting peak instantaneous systolic gradient, postexercise SR best predicted exercise capacity (r = 0.74, P = .003). Postexercise SR was correlated with extent of late gadolinium enhancement (r = 0.34, P = .03). By Cox regression, exercise SR and MRES predicted ventricular tachycardia/ventricular fibrillation (VT/VF) even after adjustment for age, gender, family history of sudden cardiac death, septum ≥ 3 cm and abnormal blood pressure response (P = .04 and P = .046, respectively). CONCLUSIONS: Nonobstructive and obstructive patients have reduced MRES compared with labile-obstructive and controls. Postexercise SR correlates with LGE and exercise capacity. Exercise SR and MRES predict VT/VF.

Dermal uptake and percutaneous penetration of organophosphate esters in a human skin ex vivo model.

Organophosphate esters (OPEs) are used as flame retardants, plasticizers, and as hydraulic fluids. They are present in indoor environments in high concentrations compared with other flame retardants, and human exposure is ubiquitous. In this study we provide data for estimating dermal uptake for eight OPEs and ranking in OPEs risk assessment. Dermal uptake and percutaneous penetration of the OPEs were studied in a Franz diffusion cell system using human skin dosed with a mixture of OPEs in an ethanol:toluene (4:1) solution. Large variation in penetration profiles was observed between the OPEs. The chlorinated OPEs tris(2-chloroisopropyl) phosphate (TCIPP), and in particular tris(2-chloroethyl) phosphate (TCEP), penetrated the skin quite rapidly while tris(1,3-dichlor-2-propyl) phosphate (TDCIPP) and triphenyl phosphate (TPHP) tended to build up in the skin tissue and only smaller amounts permeated through the skin. For tris(isobutyl) phosphate (TIBP), tris(n-butyl) phosphate (TNBP), and tris(methylphenyl) phosphate (TMPP) the mass balance was not stable over time indicating possible degradation during the experimental period of 72 h. The rates at which OPEs permeated through the skin decreased in the order TCEP > TCIPP ≥ TBOEP > TIBP ≥ TNBP > TDCIPP > TPHP > TMPP. Generally, the permeation coefficient, kp, decreased with increasing log Kow, whereas lag time and skin deposition increased with log Kow. The present data indicate that dermal uptake is a non-negligible human exposure pathway for the majority of the studied OPEs.