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Background Missing data are ubiquitous in randomised controlled trials. Although sensitivity analyses for different missing data mechanisms (missing at random vs. missing not at random) are widely recommended, they are rarely conducted in practice. The aim of the present study was to demonstrate sensitivity analyses for different assumptions regarding the missing data mechanism for randomised controlled trials using latent growth modelling (LGM). Methods Data from a randomised controlled brief alcohol intervention trial was used. The sample included 1646 adults (56% female; mean age = 31.0 years) from the general population who had received up to three individualized alcohol feedback letters or assessment-only. Follow-up interviews were conducted after 12 and 36 months via telephone. The main outcome for the analysis was change in alcohol use over time. A three-step LGM approach was used. First, evidence about the process that generated the missing data was accumulated by analysing the extent of missing values in both study conditions, missing data patterns, and baseline variables that predicted participation in the two follow-up assessments using logistic regression. Second, growth models were calculated to analyse intervention effects over time. These models assumed that data were missing at random and applied full-information maximum likelihood estimation. Third, the findings were safeguarded by incorporating model components to account for the possibility that data were missing not at random. For that purpose, Diggle-Kenward selection, Wu-Carroll shared parameter and pattern mixture models were implemented. Results Although the true data generating process remained unknown, the evidence was unequivocal: both the intervention and control group reduced their alcohol use over time, but no significant group differences emerged. There was no clear evidence for intervention efficacy, neither in the growth models that assumed the missing data to be at random nor those that assumed the missing data to be not at random. Conclusion The illustrated approach allows the assessment of how sensitive conclusions about the efficacy of an intervention are to different assumptions regarding the missing data mechanism. For researchers familiar with LGM, it is a valuable statistical supplement to safeguard their findings against the possibility of nonignorable missingness. Trial registration The PRINT trial was prospectively registered at the German Clinical Trials Register (DRKS00014274, date of registration: 12th March 2018).

Aims Catheter ablation (CA) is recommended for patients with atrial fibrillation (AF) after failure of antiarrhythmic drugs (AADs). The role of CA as ‘initial therapy’ for AF is to be determined. Methods and results Following PRISMA guideline an up-to-date pooled analysis of randomized data comparing ablation vs. AADs as first-line therapy for symptomatic AF was performed. The primary outcome was recurrence of atrial tachyarrhythmia. The secondary outcomes were improvement in quality-of-life (QoL) and major adverse events. A total of 997 patients from five randomized trials were enrolled (mean age 57.4 years, 68.6% male patients, 98% paroxysmal AF, mean follow-up 1.4 years). The baseline characteristics were similar between the ablation and AADs group. Overall pooled analysis showed that, as compared with AADs, CA as first-line therapy was associated with significantly higher freedom from arrhythmia recurrence (69% vs. 48%, odds ratio: 0.36, 95% confidence interval: 0.27–0.48, P Conclusions Catheter ablation as ‘initial therapy’ was superior to AADs in maintenance of sinus rhythm and improving QoL for patients with symptomatic paroxysmal AF, without increasing risk of serious adverse events.

Purpose To test the value of preoperative and postoperative cystatin C (CysC) as a predictor on kidney function after partial (PN) or radical nephrectomy (RN) in renal cell carcinoma (RCC) patients with normal preoperative renal function. Methods From 01/2011 to 12/2014, 195 consecutive RCC patients with a preoperative estimated glomerular filtration rate (eGFR) > 60 ml/min/1.73m2 underwent surgical RCC treatment with either PN or RN. Logistic and linear regression models tested for the effect of CysC as a predictor of new-onset chronic kidney disease in follow-up (eGFR 2). Moreover, postoperative CysC and creatinine values were compared for kidney function estimation. Results Of 195 patients, 129 (66.2%) underwent PN. In postoperative and in follow-up setting (median 14 months, IQR 10–20), rates of eGFR 2 were 55.9 and 30.2%. In multivariable logistic regression models, preoperative CysC [odds ratio (OR): 18.3] and RN (OR: 13.5) were independent predictors for a reduced eGFR 2 in follow-up (both p 2. Finally, we observed a plateau of postoperative creatinine values in the range of 1.2–1.3 mg/dl, when graphically depicted vs. postoperative CysC values (‘creatinine blind area’). Conclusion Preoperative CysC predicts renal function impairment following RCC surgery. Furthermore, CysC might be superior to creatinine for renal function monitoring in the early postoperative setting.

Background Hybrid activation mapping is a novel tool to correct for spatial displacement of the mapping catheter due to asymmetrical contraction of myocardium during premature ventricular contractions (PVC). The aim of this study is to describe and improve our understanding of spatial displacement during PVC mapping as well as options for correction using hybrid activation mapping. Methods and results We analyzed 5798 hybrid mapping points in 40 acquired hybrid maps of 22 consecutive patients (age 63 ± 16 years, 45% female) treated for premature ventricular contractions (PVCs). Median PVC-coupling interval was 552 ms (IQR 83 ms). Spatial displacement was determined by measuring the dislocation of the catheter tip during PVC compared to the preceding sinus beat. Mean spatial displacement was 3.8 ± 1.5 mm for all maps. The displacement was 1.3 ± 0.4 mm larger for PVCs with non-outflow-tract origin compared to PVCs originating from the ventricular outflow tracts (RVOT/LVOT; p = 0.045). Demographic parameters, PVC-coupling-interval and chamber of origin had no significant influence on the extent of spatial displacement. Conclusion Ectopic activation of the ventricular myocardium during PVCs results in spatial displacement of mapping points that is significantly larger for PVCs with non-outflow-tract origin. The correction for spatial displacement may improve accuracy of radiofrequency current (RFC)-application in catheter ablation of PVCs.

Background Vaccination against SARS-CoV-2 has been the main tool to contain the pandemic. The rush development of the 3 vaccines and their expedited approval have led to inoculation of millions of patients around the world, leading to a containment of the disease. Despite continuous viral mutations and the identification of weaker variants, the severity of the infections has been mild, with many patients being either asymptomatic or recovering at home. Currently the focus has shifted from the host of organ damage related to the infection to potential side effects of the vaccine. Myocarditis has been reported as one of the potential side effects from the mRNA vaccine, affecting young healthy individuals. Up to September 30, 2021, 1.243 cases of myocarditis after vaccination with BNT162b2 Comirnaty© were registered in young adults by the Paul-Ehrlich-Institute in Germany alone. The exact pathophysiology and the risk factors for myocarditis following vaccination remain unclear. We present a case series of eight patients with cardiac symptom shortly after SARS-CoV-2 mRNA vaccination (BNT162b6, Biontech, Comirnaty© or mRNA-1237 Moderna, Spikevax©). Patients and methods Eight patients between 13 and 56 years of age, vaccinated with either BNT162b2 or mRNA-1273 mRNA vaccine between January and August 2021 developed cardiac side effects shortly after either their first or second dose of the vaccine. Clinical data were retrieved from the clinical information system and analyzed. To support diagnosis of myocarditis or pericarditis, cardiac magnetic resonance imaging (MRI) was performed shortly after the onset of symptoms, with further investigations in severe cases. Symptoms were defined as dyspnea, chest pain and cardiac arrhythmia as determined by electrocardiography. Results Eight patients (5 males and 3 females) developed cardiac symptoms compatible with myocarditis, according to the CDC criteria, shortly after SARS-CoV-2 mRNA vaccination. Three patients (2 males, 1 female) required hospitalization due to severe chest pain and elevated troponin levels. All patients recovered fully within 7 days from the symptom onset. Conclusions Our data suggest that cardiac adverse events such as myocarditis or pericarditis shortly after SARS-CoV-2 mRNA vaccination are rare but possible and occur particularly in male patients.

Purpose To evaluate the interplay of stricture recurrence, sexual function, and treatment satisfaction after substitution urethroplasty. Methods Observational study of men undergoing 1-stage buccal mucosal graft urethroplasty for anterior urethral stricture between 2009 and 2016. Patients were dichotomized by self-reported treatment satisfaction. Sexual function was assessed by validated and non-validated patient-reported outcome measures. Functional recurrence was defined as symptomatic need of re-intervention. Bivariate analyses, Kaplan–Meier estimates, qualitative and quantitative analyses by uni- and multivariable regression were employed to evaluate the interplay of sexual function, functional recurrence, and treatment satisfaction. Results Of 534 men with bulbar (82%), penobulbar (11%), and penile strictures (7.3%), 451 (84%) were satisfied with the surgery. There were no differences in stricture location, previous treatment, graft length, or surgical technique between satisfied and unsatisfied patients (all p ≥ 0.2). Recurrence-free survival was 85% at a median follow-up of 33 mo and decreased significantly with each Likert item towards increasing dissatisfaction (p < 0.001). Dissatisfied patients more often reported postoperative loss of rigidity, tumescence, reduced ejaculatory volume, ejaculatory pain, and reduced penile length (all p ≤ 0.042). In 83 dissatisfied men, functional recurrence (28%) and oral morbidity (20%) were the main drivers of dissatisfaction in qualitative analysis. Multivariable analyses revealed functional recurrence and impaired postoperative ejaculatory function as independent predictors of treatment dissatisfaction (all p ≤ 0.029) after adjusting for confounders. Conclusion We found an association of both functional success and sexual function with patient-reported treatment satisfaction after substitution urethroplasty. Such findings validate the clinical significance of defining the symptomatic need for re-intervention as an endpoint and underline the importance of further research evaluating sexual function before and after open urethral reconstruction.

Self-reported physical activity differs from activity levels measured by device. We tested the effect of a video that visualizes the intensity levels of physical activity to increase the agreement between self-reported and accelerometer-based moderate-to-vigorous physical activity (MVPA) within a single-blinded, randomized study. Participants (N = 378, 40-75 years) wore an accelerometer for seven days. Prior to the collection of self-reported data by the IPAQ-SF, participants were randomly assigned (1:1) to a control group (CG) or a video group (VG). The outcome was the absolute difference between self-reported and accelerometer-based time spent in MVPA (Δ MVPAIPAQ-Accelerometry ). To examine the agreement, we used Spearman correlation coefficients and Bland-Altman analysis. To test the video effect, we used Wilcoxon signed-rank test, Bayes factor, and simultaneous-quantile regression. In total, 302 participants fulfilled the accelerometer wear time criteria (≥10 hours/day; ≥6 days) and completed self-reports within three days after the wearing period. The median of Δ MVPAIPAQ-Accelerometry was -9.0 min/day (IQR: -32.0 to 66.6) for CG and -11.5 min/day (IQR: -29.9 to 14.3) for VG. Wilcoxon signed-rank test revealed no differences in Δ MVPAIPAQ-Accelerometry between study groups whereas Bayes factor indicated insensitivity of the data. Simultaneous-quantile regression revealed no relationship between video presentation and Δ MVPAIPAQ-Accelerometry in the 25th percentile. In the 50th (b = -12.4 [95% CI = -23.2 to -1.5] and 75th percentile (b = -45.7 [95% CI = -70.5 to -20.9]), Δ MVPAIPAQ-Accelerometry was negatively associated with video presentation. To conclude, video-supported assessment may increase the accuracy of self-reported MVPA among individuals who slightly underestimated and those who overestimated their MVPA.

Background and aims Existing evidence suggests that text message interventions can help people to reduce their alcohol consumption. However, studies with alcohol-dependent patients are lacking. In this study a 1-year automatic mobile phone-based short messaging service (SMS) intervention on alcohol consumption in patients after alcohol detoxification in hospital was compared with treatment as usual. Design Multi-center, randomized, controlled, two parallel-group, observer-blinded trial. Setting and participants Primary and secondary care: four hospitals and community (1 million residents, 7600 km2 area in Germany). A total of 462 patients with alcohol dependence (ICD-10) were included during inpatient detoxification treatment. Patients were randomly assigned (1 : 1) to an SMS intervention and treatment as usual (SMS + TAU; n = 230; mean age: 45.4 years; 22.6% women) or TAU alone (n = 232 mean age: 44.5 years; 22.8% women). Planned, automated messages were sent to patients over 1 year to record assistance needs. A 'yes' or missing response triggered a telephone call from a hospital therapist. Outcome was assessed by an independent survey center. Measurements The primary end-point was a three-category alcohol consumption measure covering months 10-12 after discharge: abstinence, non-heavy drinking, heavy drinking [men > 60 g/day; women > 40 g/day equal to World Health Organization (WHO) criteria: high risk and very high risk, mean consumption]. Secondary end-points were number of abstinent days over 12 months and frequency of abstinence. Results The arms differed primarily in the heavy drinking category (intervention group 22.2%, TAU-only group 32.3%) in months 9-12. This is reflected by an odds ratio (OR) = 1.68, 95% confidence interval (CI) = 1.11-2.54, P = 0.015 for heavy drinking versus non-heavy drinking/abstinence. No difference between treatments was found with respect to any drinking versus abstinence (OR = 1.13). These results were confirmed by models adjusting for randomization strata. Conclusions In Germany, a 12-month mobile phone short messaging service-based intervention enhanced the reduction in heavy drinking for 1 year in routine care among adults with alcohol dependence discharged from inpatient alcohol detoxification.

The aim of the present study was to analyze copy number variations (CNV) of multiple oncogenes and tumor suppressor genes in genomic DNA from primary tumor tissue, lymph node metastasis and cell-free DNA (cfDNA) from serum of 72 urothelial carcinoma of bladder (UCB) patients treated with radical cystectomy (RC), using multiplex ligation-dependent probe amplification (MLPA). We hypothesized that primary tumor and lymph node metastasis show similar CNV profiles, and CNV are more present in lymph node metastasis compared to primary tumor tissue. Samples from 43 (59.7%) patients could be analyzed. In total, 35 (83%), 26 (68%) and 8 (42%) patients had CNV in primary tumor, serum and lymph node metastasis, respectively. MYC, CCND1, ERBB2 and CCNE1 displayed the most frequent amplifications. In particular, CNV in ERBB2 was associated with aggressive tumor characteristics. CNV in both ERBB2 and TOP2A were risk factors for disease recurrence. The current findings show that CNV are present in various oncogenes and tumor suppressor genes in genomic DNA from primary tumor, lymph node metastasis and cfDNA from serum. CNV were more present in genomic DNA from primary tumor tissue compared to cfDNA from serum and genomic DNA from lymph node metastasis. Patients with CNV in ERBB2 and TOP2A are at increased risk for disease recurrence following RC. Further studies are necessary to validate, whether these genes may represent promising candidates for targeted-therapy.

Background The aim was to investigate the suitability of a municipal registry office for alcohol screening and brief intervention. We analyzed whether trial participation and retention differ by alcohol- and health-related, demographic and socio-economic participant characteristics. Methods Over 3 months, all 18- to 64-year-old visitors of a registry office were systematically screened. Persons with alcohol consumption in the past 12 months (N = 1646) were randomized to brief alcohol intervention (BAI) or assessment only. BAI was delivered by computer-generated individualized feedback letters at baseline, 3 and 6 months. Logistic and ordered logistic regression models were used to investigate whether the odds of trial participation and retention depended on participant characteristics. Models were rerun separately for low-risk and at-risk drinkers with Alcohol Use Disorder Identification Test-Consumption scores ≥4/≥5 for women/men indicating at-risk drinking. Results The trial participation rate was 67% with higher odds of participation in younger adults (P Conclusion Our data suggest that registry offices could be a suitable setting to reach people from the general population for BAI. Especially the understudied group of low-risk drinkers was well reached through BAI and showed high adherence. BAI that addresses alcohol consumers beyond those at risk may be well accepted in proactively recruited people from the general population.

Aims S100B, a well-known damage-associated molecular pattern protein is released acutely by central and peripheral nerves and upon concomitant denervation in pulmonary vein isolation (PVI). We aimed to investigate whether the ablation technique used for PVI impacts S100B release in patients with paroxysmal atrial fibrillation (AF). Methods and results The study population consisted of 73 consecutive patients (age: 62.7 ± 10.9 years, 54.8% males) undergoing first-time PVI with either radiofrequency (RF; n = 30) or cryoballoon (CB; n = 43) for paroxysmal AF. S100B determined from venous plasma samples taken immediately before and after PVI increased from 33.5 ± 1.8 to 91.1 ± 5.3 pg/mL (P Conclusion The ablation technique used for PVI has an impact on the release of S100B, a well-established biomarker for neural damage.

Introduction The aim of this study was to investigate electrophysiological findings in patients with arrhythmia recurrence undergoing a repeat ablation procedure using ultra-high-density (UHDx) mapping following an index procedure using either contact-force (CF)-guided radiofrequency current (RFC) pulmonary vein isolation (PVI) or second-generation cryoballoon (CB) PVI for treatment of atrial fibrillation (AF). Methods and results Fifty consecutive patients with recurrence of AF and/or atrial tachycardia (AT) following index CF-RFC PVI (n = 21) or CB PVI (n = 29) were included. A 64-pole mini-basket mapping catheter in combination with an UHDx-mapping system-guided ablation was used. RFC was applied using a catheter tip with three incorporated mini-electrodes. PV reconnection rates were higher after CF-RFC PVI (CF-RFC: 2.5 ± 1.3 PVs vs CB: 1.4 ± 0.9 PVs; P = .0025) and left PVs were more frequently reconnected (CF-RFC: 64% PVs vs CB: 35% PVs; P = .0077). Fractionated signals along the antral index ablation line (FS) were found in 30% of CB-PVI patients (CF-RFC: 9.5% vs CB:30%; P = .098) targeted for ablation. In five cases, FS were a critical part of maintaining consecutive AT. The main AT mechanism found during reablation (n = 45 ATs) was macroreentry (80% [36/45], CF-RFC: 78.9% vs CB: 80.8%; P = 1.0) with a variety of circuits throughout both atria. Conclusion UHDx mapping is sensitive in detecting conduction gaps along the index ablation line. Left PVs are more frequently reconnected after initial CF-RFC PVI. FS are a common finding after CB PVI and can maintain certain forms of ATs. ATs after index PVI are mostly macroreentries with a broad spectrum of entities.

Background: ISGylation is the conjugation of ISG15 with target proteins. ISGylation occurs through an enzymatic cascade, which is similar to that of ubiquitination. Through ISGylation, ISG15 can bind to proteins involved in cell proliferation and differentiation, thus promoting genesis and progression of malignancies. The present study aims to investigate expression of genes involved in ISGylation and ubiquitination in patients with hepatocellular carcinoma and to correlate gene expression with clinical laboratory parameters of these patients. Methods: mRNA expression of genes encoding enzymes involved in the ISGylation process (EFP, HERC5, UBA1, UBC and USP18) was evaluated by quantitative real-time PCR in 38 pairs of tumour and adjacent non-tumour tissues from patients with hepatocellular carcinoma and correlated with distinct clinical laboratory parameters. Results: Relative mRNA expression of EFP, HERC5, UBA1 and USP18 was significantly higher in tumour tissues compared to adjacent non-tumour tissues (P=0.006; 0.012; 0.02 and 0.039, respectively). The correlation pattern of mRNA expression between genes in the tumours differed from the pattern in adjacent non-tumour tissues. Relative expression of EFP, HERC5 and UBA1 in adjacent non-tumour tissues was positively associated with direct bilirubin levels (Spearman's rho=0.31, 0.33 and 0.45; P=0.06, 0.05 and 0.01, respectively) and relative expression of USP18 in adjacent non-tumour tissues correlated negatively with ALT levels (Spearman's rho= -0.33, P=0.03). Conclusions: EFP, HERC5, UBA1, and USP18 genes are upregulated in tumour tissues of patients with HCC and, thus, may be associated with the pathogenesis of hepatocellular carcinoma.

Patients with type 2 diabetes mellitus (T2DM) have a greater risk of developing life-threatening cardiac arrhythmias. Because the underlying mechanisms and potential influence of diabetic autonomic neuropathy are not well understood, we aimed to assess the relevance of a dysregulation in cardiac autonomic tone. Ventricular arrhythmia susceptibility was increased in Langendorff-perfused hearts isolated from mice with T2DM ( db/db). Membrane properties and synaptic transmission were similar at cardiac postganglionic parasympathetic neurons from diabetic and control mice; however, a greater asynchronous neurotransmitter release was present at sympathetic postganglionic neurons from the stellate ganglia of db/db mice. Western blot analysis showed a reduction of tyrosine hydroxylase (TH) from the ventricles of db/db mice, which was confirmed with confocal imaging as a heterogeneous loss of TH-immunoreactivity from the left ventricular wall but not the apex. In vivo stimulation of cardiac parasympathetic (vagus) or cardiac sympathetic (stellate ganglion) nerves induced similar changes in heart rate in control and db/db mice, and the kinetics of pacing-induced Ca2+transients (recorded from isolated cardiomyocytes) were similar in control and db/db cells. Antagonism of cardiac muscarinic receptors did not affect the frequency or severity of arrhythmias in db/db mice, but sympathetic blockade with propranolol completely inhibited arrhythmogenicity. Collectively, these findings suggest that the increased ventricular arrhythmia susceptibility of type 2 diabetic mouse hearts is due to dysregulation of the sympathetic ventricular control.NEW & NOTEWORTHY Patients with type 2 diabetes mellitus have greater risk of suffering from sudden cardiac death. We found that the increased ventricular arrhythmia susceptibility in type 2 diabetic mouse hearts is due to cardiac sympathetic dysfunction. Sympathetic dysregulation is indicated by an increased asynchronous release at stellate ganglia, a heterogeneous loss of tyrosine hydroxylase from the ventricular wall but not apex, and inhibition of ventricular arrhythmias in db/db mice after β-sympathetic blockade.

Background Evidence suggests that people who abstain from alcohol have a higher mortality rate than those who drink low to moderate amounts. However, little is known about factors that might be causal for this finding. The objective was to analyze former alcohol or drug use disorders, risky drinking, tobacco smoking, and fair to poor health among persons who reported abstinence from alcohol drinking in the last 12 months before baseline in relation to total, cardiovascular, and cancer mortality 20 years later. Methods and findings A sample of residents aged 18 to 64 years had been drawn at random among the general population in northern Germany and a standardized interview conducted in the years 1996 to 1997. The baseline assessment included 4,093 persons (70.2% of those who had been eligible). Vital status and death certificate data were retrieved in the years 2017 and 2018. We found that among the alcohol-abstinent study participants at baseline (447), there were 405 (90.60%) former alcohol consumers. Of the abstainers, 322 (72.04%) had met one or more criteria for former alcohol or drug dependence or abuse, alcohol risky drinking, or had tried to cut down or to stop drinking, were daily smokers, or self-rated their health as fair to poor. Among the abstainers with one or more of these risk factors, 114 (35.40%) had an alcohol use disorder or risky alcohol consumption in their history. Another 161 (50.00%) did not have such an alcohol-related risk but were daily smokers. The 322 alcohol-abstinent study participants with one or more of the risk factors had a shorter time to death than those with low to moderate alcohol consumption. The Cox proportional hazard ratio (HR) was 2.44 (95% confidence interval (CI), 1.68 to 3.56) for persons who had one or more criteria for an alcohol or drug use disorder fulfilled in their history and after adjustment for age and sex. The 125 alcohol-abstinent persons without these risk factors (27.96% of the abstainers) did not show a statistically significant difference from low to moderate alcohol consumers in total, cardiovascular, and cancer mortality. Those who had stayed alcohol abstinent throughout their life before (42; 9.40% of the alcohol-abstinent study participants at baseline) had an HR 1.64 (CI 0.72 to 3.77) compared to low to moderate alcohol consumers after adjustment for age, sex, and tobacco smoking. Main limitations of this study include its reliance on self-reported data at baseline and the fact that only tobacco smoking was analyzed as a risky behavior alongside alcohol consumption. Conclusions The majority of the alcohol abstainers at baseline were former alcohol consumers and had risk factors that increased the likelihood of early death. Former alcohol use disorders, risky alcohol drinking, ever having smoked tobacco daily, and fair to poor health were associated with early death among alcohol abstainers. Those without an obvious history of these risk factors had a life expectancy similar to that of low to moderate alcohol consumers. The findings speak against recommendations to drink alcohol for health reasons., In this cohort study conducted over 20 years, Ulrich John and colleagues examine the relationship between alcohol abstinence and mortality in a German adult population., Author summary Why was this study done? According to evidence, alcohol abstinence seems to be associated with a lower life expectancy than low to moderate alcohol consumption. Individuals who abstain from alcohol might include those who have risk factors that can be reasons for the shorter life expectancy compared to low to moderate alcohol consumers. What did the researchers do and find? A random adult general population sample had been drawn and the study participants been inquired about their consumption of or abstinence from alcohol in a first contact. Twenty years later, proportions of deceased and time to death were determined and compared between former alcohol abstainers and low to moderate alcohol consumers among the 4,028 study participants. The findings show that 91% of the alcohol abstainers at first contact had consumed alcohol in life before and 72% had a history of one or more criteria of a former alcohol or drug use disorder, former risky alcohol consumption, efforts to cut down or to stop drinking, daily tobacco smoking, or fair to poor health. In terms of mortality rate, no statistically significant difference was apparent between alcohol abstinent persons without these risk factors and who had self-rated their health as good to excellent and persons who consumed low to moderate amounts of alcohol. What do these findings mean? Former alcohol use disorders, risky consumption, efforts to cut down on drinking, ever daily tobacco smoking, and fair to poor health may predict early death among alcohol abstainers. Healthy alcohol abstainers who have no alcohol- or tobacco-related risk factors may not have a higher mortality than low to moderate alcohol consumers. The findings speak against recommendations to drink alcohol for health reasons.

Aims To investigate latent patterns of alcohol use and bingeing by gender and their association with depressive symptom severity and individual depressive symptoms. Design Cross-sectional data were collected from January 2017 to March 2018 as part of a joint screening recruiting for different intervention studies. Setting Ambulatory practices and general hospitals from three sites in Germany. Participants A total of 5208 male and 5469 female proactively recruited alcohol users aged 18-64 years. Measurements Frequency and typical quantity of alcohol use, frequency of bingeing, alcohol-related problems (assessed by the Alcohol Use Disorder Identification Test); depressive symptom severity, individual depressive symptoms (assessed with the Patient Health Questionnaire-8); and socio-demographics and health-related variables. Findings Latent categorical analysis identified six patterns of alcohol use, with the majority of patients engaging in 'light use plus no or occasional bingeing' (males: 41.85%; females: 64.04%), followed by 'regular use plus occasional bingeing' (males: 34.03%; females: 16.17%). Multinomial logistic regression analyses (three-step approach with correction for classification uncertainty, as implemented in the Mplus R3STEP command) controlling for socio-demographics and health-related variables revealed that severity of depressive symptoms was positively associated with 'frequent use plus frequent bingeing' when compared with 'light use plus no or occasional bingeing' [relative risk ratio (RRR)male = 1.07, 95% confidence interval (CI) = 1.03-1.11; RRRfemale = 1.09, 95% CI = 1.04-1.14]. Severity of depressive symptoms was negatively associated with 'regular use plus occasional bingeing' for males (RRRmale = 0.98, 95% CI = 0.95-1.00) and positively with 'occasional use plus occasional bingeing' for females (RRRfemale = 1.03, 95% CI = 1.01-1.05) when compared with 'light use plus no or occasional bingeing'. Individual depressive symptoms were differentially associated with alcohol use patterns, with depressed mood, poor appetite or overeating, feelings of worthlessness or guilt and psychomotor agitation or retardation, being especially pronounced in the 'frequent use plus frequent bingeing' class (RRRsmale = 1.72-2.36; RRRsfemale = 1.99-2.17). Conclusions Patterns of 'frequent alcohol use plus frequent bingeing' and 'occasional alcohol use plus occasional bingeing' appear to have positive associations with depression when compared with 'light alcohol use plus no or occasional bingeing'.

The importance of peripheral chemoreceptors for cardiorespiratory neural control is known for decades. Pure oxygen inhalation deactivates chemoreceptors and increases parasympathetic outflow. However, the relationship between autonomic nervous system (ANS) activation and resulting respiratory as well as heart rate (HR) dynamics is still not fully understood.In young adults the impact of (1) 100 % pure oxygen inhalation (hyperoxic cardiac chemoreflex sensitivity (CHRS) testing), (2) the cold face test (CFT) and (3) the cold pressor test (CPT) on heart rate variability (HRV), hemodynamics and respiratory rate was investigated in randomized order. Baseline ANS outflow was determined assessing respiratory sinus arrhythmia via deep breathing, baroreflex sensitivity and HRV.Baseline ANS outflow was normal in all participants (23 ± 1 years, 7 females, 3 males). Hyperoxic CHRS testing decreased HR (after 60 ± 3 vs before 63 ± 3 minChanges in HR characteristics during deactivation of peripheral chemoreceptors but not during the CFT and CPT are related with a decrease in respiratory rate. This highlights the need of respiratory rate assessment when evaluating adaptations of cardiorespiratory chemoreceptor control.

Background Ultra‐high‐density mapping enables detailed mechanistic analysis of atrial reentrant tachycardia but has yet to be used to assess circuit conduction velocity (CV) patterns in adults with congenital heart disease. Methods and Results Circuit pathways and central isthmus CVs were calculated from consecutive ultra‐high‐density isochronal maps at 2 tertiary centers over a 3‐year period. Circuits using anatomic versus surgical obstacles were considered separately and pathway length P P =0.016), faster non‐isthmus CV (0.52 m/s; IQR, 0.33–0.71 versus 0.38 m/s; IQR, 0.27–0.46; P =0.009), and fewer slow isochrones (4; IQR, 2.3–6.8 versus 6; IQR 5–7; P =0.008). Both central isthmus ( R 2 =0.45; P R 2 =0.71; P R 2 =0.94; P 85% predicted isthmus block in all cases. Over >1 year of follow‐up, arrhythmia‐free survival was better for homogeneous CV patterns (90% versus 57%; P =0.04). Conclusions Ultra‐high‐density mapping‐guided CV analysis distinguishes atrial reentrant patterns in adults with congenital heart disease with surgical obstacles producing slower and smaller circuits. Very slow central isthmus CV may be essential for atrial tachycardia maintenance in small circuits, and non‐isthmus conduction time in tachycardia appears to be useful for rapid assessment of postablation conduction block.

AIMS Catheter contact and local tissue characteristics are relevant information for successful radiofrequency current (RFC)-ablation. Local impedance (LI) has been shown to reflect tissue characteristics and lesion formation during RFC-ablation. Using a novel ablation catheter incorporating three mini-electrodes, we investigated LI in relation to generator impedance (GI) in patients with ventricular tachycardia (VT) and its applicability as an indicator of effective RFC-ablation. METHODS AND RESULTS Baseline impedance, Δimpedance during ablation and drop rate (Δimpedance/time) were analyzed for 625 RFC-applications in 28 patients with recurrent VT undergoing RFC-ablation. LI was lower in scarred (87.0 Ω [79.0-95.0]) compared to healthy myocardium (97.5 Ω ([82.75-111.50]; P = .03) while GI did not differ between scarred and healthy myocardium. ΔLI was higher (18 Ω [9.4-26.0]) for VT-terminating as compared to non-terminating RFC-ablation (ΔLI 13 Ω [8.85-18.0]; P = .03), but did not differ for ΔGI between terminating vs nonterminating RFC-ablation. Correspondingly, LI drop rate was higher for RFC-ablation terminating the VT compared with RFC-ablation not terminating the VT (0.63 Ω/s [0.52-0.76] vs 0.32 Ω [0.20-0.58]; P = .008) while there was no difference for GI drop rate. ΔLI was higher in patients with nonischemic cardiomyopathy vs patients with ischemic cardiomyopathy (16 Ω [11.0-20.0] vs 11.0 Ω [7.85-17.00]; P = .003). CONCLUSION Our findings suggest that LI is a sensitive parameter to guide RFC-ablation in patients with VT. LI indicates differences in tissue characteristics and generally is higher in patients with nonischemic cardiomyopathy. Hence, the etiology of the underlying cardiomyopathy needs to be considered when adopting LI for monitoring catheter ablation of VT.

Objective To analyze functional outcomes and complication rates of distal double cuffs (DC) or transcorporal cuffs (TC) as salvage approaches in high-risk patients, since there is an ongoing debate about optimal cuff-placement in a salvage setting (SV). Existing studies analyzing DC or TC are controversial with respect to functional outcomes and complication rates. Studies directly comparing both approaches in SV are scarce. Methods and Patients Prospective data collection was performed since 2009. DC/TC were applied according to a standardized protocol in SV. Salvage DC was chosen in case of a membranous single cuff explantation due to erosion or infection. TC were implanted after bulbar urethroplasty or DC explantation. Activation was performed 6 weeks postoperatively. Further follow-up was scheduled 6/24 months postoperatively and every 2 years thereafter. Primary/secondary endpoints were continence/complication rates. Results In total, 71 high-risk patients were available for analysis (58 DC, 13 TC). Median age was 70 years. Median follow-up was 24 months. Objective/social continence were 88%/94% in the DC and 72%/100% in the TC cohort, respectively (P = .37/P = 1). Overall, there were no significant differences with respect to infections, erosions, mechanical failure, and explantation rates. The times of explantation-free survival were similar in Kaplan-Meier analysis (Log-rank 0.399). Conclusion Complication and continence rates were not significantly different between both cohorts. Hence, a DC in SV can be considered as equally safe and effective. A sequential implantation (first DC, second TC) may be a viable approach to extend overall AUS incontinence therapy.

The international meeting on reconstructive Urology (IMORU) is a live surgery event (LSE) where expert surgeons perform various reconstructive surgeries. To evaluate patient safety, an extended follow-up of the complications of two subsequent IMORU meetings were gathered. Also, a detailed survey concerning the participant’s assessment of the educational benefit was performed. All patients that were operated during the IMORU V and VI were included. Primary endpoint was the analysis of complications. Outcome was reviewed 36 months postoperatively via telephone survey and clinical database assessment, registrating any complications. At IMORU VII all participants were able to participate in a survey using a standardized, not-validated questionnaire concerning the learning effect and the quality of the surgeries. 57 operations by 32 different surgeons were reviewed. The total number of any complications (peri- or postoperative) was n = 9 (15.8%) with three major complications. Four (7%) perioperative complications and five (8.8%) postoperative complications were noted. The Charlson score proved to be the only significant recorded predictor of the incidence of any complication (p = 0.019; univariate logistic regression analysis). Participant survey showed that the surgeons, surgical technique, and surgical presentation were perceived as excellent. Improvement of knowledge and of the surgical armamentarium both received positive ratings. This is to our knowledge the first follow-up of LSE in the field of reconstructive urology. Rate of complications in general was acceptable. The performed survey showed participants value the quality and the educational benefit. Further studies are needed to improve learning possibilities.

INTRODUCTION Disturbance of sympathetic and vagal nervous system participates in the pathogenesis of hypertension and atrial fibrillation (AF). Renal denervation (RDN) can modulate autonomic nervous activity and reduce blood pressure (BP) in hypertensive patients. We aimed to evaluate the effect of RDN combined with pulmonary vein isolation (PVI) in patients with AF and hypertension. METHODS Clinical trials including randomized data comparing PVI plus RDN vs PVI alone were enrolled. Primary outcome was incidence of AF recurrence after procedure. RESULTS A total of 387 patients, of them 252 were randomized and were enrolled. Mean age was 57 ± 10 years, 71% were male, and mean left ventricular ejection fraction was 57.4% ± 6.9%. Follow-up for randomized data was 12 months. Overall comparison for primary outcome showed that PVI + RDN was associated with significantly lower AF recurrence as compared with PVI alone (35.8% vs 55.4%, P

Aims To test the effect of the dipeptidyl peptidase-4 inhibitor saxagliptin on adipose tissue inflammation and microvascular function, and whole-body postprandial endothelial function. Methods A randomized, double-blind, placebo-controlled, parallel study was conducted between June 2013 and November 2016 in 44 overweight or obese people without diabetes (saxagliptin, n=28; placebo, n=16). Subcutaneous abdominal adipose tissue biopsies, a 4-h fat-enriched meal test and peripheral arterial tonometry for measurement of endothelial function were performed at baseline and after 6 weeks of treatment with saxagliptin (5 mg/day) or matching placebo. Results Forty participants were analysed (saxagliptin, n=26; placebo, n=14). Secretion of interleukin-8 from adipose tissue explants was reduced after saxagliptin (median fold-change from baseline: 0.8 saxagliptin vs 3.3 placebo; P=0.02). Adipose tissue expression of thioredoxin-inhibitory protein (TxNIP) was lower after saxagliptin (0.75 vs 1.0; P=0.02), while there were no significant differences in adipose tissue secretion of interleukin-1b, interleukin-6 or macrophage chemoattractant protein 1 (MCP-1), adipose tissue macrophage content, adipose tissue mRNA levels of mcp1, cd36, cd68, il6, il8, txnip and adpq, and activation of adipose tissue inflammatory pathways [extracellular signal-regulated kinase, c-Jun N-terminal kinase (JNK) and nuclear factor-κB (NF- κB)] or insulin-induced vasodilation of adipose tissue arterioles. Postprandial plasma glucose was slightly lower (by an estimated 0.3 mmol/l; P=0.01), while postprandial insulin, triglyceride levels and endothelial function were unchanged after saxagliptin. Conclusions The effect of saxagliptin on adipose tissue inflammation was relatively modest, with many inflammatory markers unchanged. We also found no evidence that saxagliptin therapy improved adipose tissue arteriole vasodilation or postprandial endothelial function.

Background: A pre-post pilot study was conducted to test the feasibility, acceptability, and potential effectiveness of a fully automatized computer-based intervention targeting hazardous drinking and depressiveness in proactively recruited health care patients (HCPs). To address the importance of the sample selection when testing interventions, HCPs were compared to media recruited volunteers (MVs). Method: In a multicenter screening program 2,773 HCPs were screened for hazardous drinking and depressive symptoms. MVs were recruited via media solicitation. Over a period of 6 months, study participants received 6 individualized counseling letters and weekly short messages. Pre-post data were analyzed for 30 participants (15 HCPs, 15 MVs). Intervention acceptability was assessed in post-intervention interviews conducted with 32 study participants. Results: MVs showed higher problem severity and motivation to change than HCPs. Over the course of the intervention both subsamples reduced regular binge drinking (HCPs: p = 0.016; MVs: p = 0.031) and depressiveness (HCPs: p = 0.020; MVs: p < 0.001). MVs further reduced average daily alcohol consumption (p = 0.034). The intervention received positive ratings from both subsamples, the alcohol module was rated more favorably by MVs than by HCPs (p = 0.012). Subsamples further differed in terms of intervention usage (p = 0.013). Conclusion: The intervention was technically and logistically feasible, well accepted, and may have the potential to reduce hazardous drinking and depressive symptoms in different populations. Subsamples differed in terms of problem severity, motivation to change, intervention usage, pre-post changes, and attitudes toward the intervention, showing that intervention development should involve the intended target populations to avoid biased conclusions on intervention effectiveness and acceptability.

AIMS A novel measure of local impedance (LI) has been found to predict lesion formation during radiofrequency current (RFC) catheter ablation. The aim of this study was to investigate the utility of this novel approach, while comparing LI to the well-established generator impedance (GI). METHODS AND RESULTS In 25 consecutive patients with a history of atrial fibrillation, catheter ablation was guided by a 3D-mapping system measuring LI in addition to GI via an ablation catheter tip with three incorporated mini-electrodes. Local impedance and GI before and during RFC applications were studied. In total, 381 RFC applications were analysed. The baseline LI was higher in high-voltage areas (>0.5 mV; LI: 110.5 ± 13.7 Ω) when compared with intermediate-voltage sites (0.1-0.5 mV; 90.9 ± 10.1 Ω, P < 0.001), low-voltage areas (

Background and aims Internet Addiction (IA) has consistently been related to comorbid psychiatric disorders and lowered self-esteem. However, most studies relied on self-report questionnaires using non-representative samples. This study aims to analyze the relative impact of self-esteem and comorbid psychopathology with lifetime IA in a population-based sample of excessive Internet users using clinical diagnoses assessed in a personal interview. Methods The sample of this study is based on a general population survey. Using the Compulsive Internet Use Scale, all participants with elevated Internet use scores were selected and invited to a follow-up interview. Current DSM-5 criteria for Internet gaming disorder were rephrased to apply to all Internet activities. Out of 196 participants, 82 fulfilled the criteria for IA. Self-esteem was measured with the Rosenberg’s Self-Esteem Scale. Results Self-esteem is significantly associated with IA. For every unit increase in self-esteem, the chance of having IA decreased by 11%. By comparison, comorbidities such as substance-use disorder (excluding tobacco), mood disorder, and eating disorder were significantly more likely among Internet-addicted than in the non-addicted group. This could not be reported for anxiety disorders. A logistic regression showed that by adding self-esteem and psychopathology into the same model, self-esteem maintains its strong influence on IA. Discussion and conclusions Self-esteem was associated with IA, even after adjustment for substance-use disorders, mood disorder, and eating disorder. Self-esteem and psychopathology should be considered in prevention, intervention measures, as well as in the conception of etiological models.

Purpose Recently, a novel cardiac imaging system based on a wide-band dielectric technology (KODEX-EPD) was introduced to guide catheter ablation. The aim of the study was to evaluate this 3D wide-band dielectric imaging system (WDIS) during cryoballoon (CB)-based atrial fibrillation (AF) ablation focusing on accuracy of pulmonary vein (PV)-anatomy. Methods In consecutive patients with symptomatic AF, CB-based ablation was performed in conjunction with the 3D WDIS. Selective PV-angiographies were performed, and 3D anatomy of the left atrium (LA) and PVs using the 3D WDIS was created. The ostial diameters of the ipsilateral right-sided and left-sided PVs and ostial diameters of the right-/left-sided upper/lower PVs demonstrated by selective angiographies were analyzed and compared to 3D WDIS-based PV visualization. Results In 65 patients (42/65 (65%) male, age 65 ± 9 years, 29/65 (45%) paroxysmal AF) a total of 260 PVs were identified. Median ostial PV-diameters for the ipsilateral left- and right-sided PVs were 38 [34; 43] and 37 [34; 40.3] mm when assessed fluoroscopically and 40 [35.7; 43] and 39 [35.0; 43] mm as demonstrated by 3D WDIS. There was no statistically significant difference between both methods regarding PV-diameter measurements. KODEX-EPD overestimated fluoroscopy measurements by 1.08 mm (95% limits of agreement of -1.93 mm and 4.1 mm). Conclusion The novel wide-band dielectric 3D-imaging system is feasible to create high-resolution images of cardiac structures during CB ablation procedures and accurately visualizes PV-anatomy.

[Figure: see text].

OBJECTIVE The aim of this study was to determine the effects of prolonged (72 hours) glucagon administration at a low dose (LD) (12.5 ng/kg/min) and high dose (HD) (25 ng/kg/min) on energy expenditure (EE) in healthy individuals with overweight or obesity. METHODS Thirty-one healthy participants with overweight or obesity (BMI of 27-45 kg/m2 , 26-55 years old, 23 females) were randomized into LD, HD, or placebo groups and underwent 72-hour intravenous infusion of glucagon. Whole-room calorimetry was used to assess EE and substrate use during five overnight stays (2 days at baseline, 3 days of infusion) and during two 24-hour stays (baseline vs. day 3). Blood was sampled at regular intervals throughout the inpatient stay and analyzed for glucagon and biomarkers of metabolism. RESULTS HD infusion elevated plasma glucagon levels compared with the placebo and LD infusion (P

Background Atrial fibrillation (AF) is common in patients with hypertrophic cardiomyopathy (HCM) and is associated with a deterioration of clinical status. Ablation of symptomatic AF is an established therapy, but in HCM, the characteristics of recurrent atrial arrhythmias and the long‐term outcome are uncertain. Methods and Results Sixty‐five patients with HCM (aged 64.5±9.9 years, 42 [64.6%] men) underwent AF ablation. The ablation strategy included pulmonary vein isolation in all patients and ablation of complex fractionated atrial electrograms or subsequent atrial tachycardias (AT) if appropriate. Paroxysmal, persistent AF, and a primary AT was present in 13 (20.0%), 51 (78.5%), and 1 (1.5%) patients, respectively. Twenty‐five (38.4%) patients developed AT with a total number of 54 ATs. Stable AT was observed in 15 (23.1%) and unstable AT in 10 (15.3%) patients. The mechanism was characterized as a macroreentry in 37 (68.5%), as a localized reentry in 12 (22.2%), a focal mechanism in 1 (1.9%), and not classified in 4 (7.4%) ATs. After 1.9±1.2 ablation procedures and a follow‐up of 48.1±32.5 months, freedom of AF/AT recurrences was demonstrated in 60.0% of patients. No recurrences occurred in 84.6% and 52.9% of patients with paroxysmal and persistent AF, respectively ( P Conclusions AF ablation in patients with HCM is effective for long‐term rhythm control, and especially patients with paroxysmal AF undergoing pulmonary vein isolation have a good clinical outcome. ATs after AF ablation are frequently observed in HCM. Freedom of atrial arrhythmia is achieved by persistent AF ablation in a reasonable number of patients even though the use of antiarrhythmic drug therapy remains high.

The autonomic nervous system is a substantial driver of cardiac electrophysiology. Especially the role of its sympathetic branch is an ongoing matter of investigation in the pathophysiology of ventricular arrhythmias (VA). Neurons in the stellate ganglia (SG) – bilateral star-shaped structures of the sympathetic chain – are an important component of the sympathetic infrastructure. The SG are a recognized target for treatment via cardiac sympathetic denervation in patients with therapy-refractory VA. While neuronal remodeling and glial activation in the SG have been described in patients with VA, the underlying cellular and molecular processes that potentially precede the onset of arrhythmia are only insufficiently understood and should be elucidated to improve autonomic modulation. Mouse models allow us to study sympathetic neuronal remodeling, but identification of the murine SG is challenging for the inexperienced investigator. Thus, in-depth cellular and molecular biological studies of the murine SG are lacking for many common cardiac diseases. Here, we describe a basic repertoire for dissecting and studying the SG in adult mice for analyses at RNA level (RNA isolation for gene expression analyses, in situ hybridization), protein level (immunofluorescent whole mount staining), and cellular level (basic morphology, cell size measurement). We present potential solutions to overcome challenges in the preparation technique, and how to improve staining via quenching of autofluorescence. This allows for the visualization of neurons as well as glial cells via established markers in order to determine cell composition and remodeling processes. The methods presented here allow characterizing the SG to gain further information on autonomic dysfunction in mice prone to VA and can be complemented by additional techniques investigating neuronal and glial components of the autonomic nervous system in the heart.

BACKGROUND: The efficacy and safety of benralizumab, an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody, for the prevention of exacerbations in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) are not known.METHODS: In the GALATHEA and TERRANOVA trials, we enrolled patients with COPD (at a ratio of approximately 2:1 on the basis of eosinophil count [≥220 per cubic millimeter vs. RESULTS: In GALATHEA, the estimates of the annualized exacerbation rate were 1.19 per year (95% confidence interval [CI], 1.04 to 1.36) in the 30-mg benralizumab group, 1.03 per year (95% CI, 0.90 to 1.19) in the 100-mg benralizumab group, and 1.24 per year (95% CI, 1.08 to 1.42) in the placebo group; the rate ratio as compared with placebo was 0.96 for 30 mg of benralizumab (P = 0.65) and 0.83 for 100 mg of benralizumab (P = 0.05). In TERRANOVA, the estimates of the annualized exacerbation rate for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year (95% CI, 0.87 to 1.13), 1.21 per year (95% CI, 1.08 to 1.37), 1.09 per year (95% CI, 0.96 to 1.23), and 1.17 per year (95% CI, 1.04 to 1.32), respectively; the corresponding rate ratios were 0.85 (P = 0.06), 1.04 (P = 0.66), and 0.93 (P = 0.40). At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial. Types and frequencies of adverse events were similar with benralizumab and placebo.CONCLUSIONS: Add-on benralizumab was not associated with a lower annualized rate of COPD exacerbations than placebo among patients with moderate to very severe COPD, a history of frequent moderate or severe exacerbations, and blood eosinophil counts of 220 per cubic millimeter or greater (Funded by AstraZeneca [GALATHEA and TERRANOVA] and Kyowa Hakko Kirin [GALATHEA]; GALATHEA and TERRANOVA ClinicalTrials.gov numbers, NCT02138916 and NCT02155660.).

A reliable diagnosis of adult Attention Deficit/Hyperactivity Disorder (ADHD) is challenging as many of the symptoms of ADHD resemble symptoms of other disorders. ADHD is associated with gambling disorder and obesity, showing overlaps of about 20% with each diagnosis. It is important for clinical practice to differentiate between conditions displaying similar symptoms via established diagnostic instruments. Applying the LightGBM algorithm in machine learning, we were able to differentiate subjects with ADHD, obesity, problematic gambling, and a control group using all 26 items of the Conners’ Adult ADHD Rating Scales (CAARS-S: S) with a global accuracy of .80; precision (positive predictive value) ranged between .78 (gambling) and .92 (obesity), recall (sensitivity) between .58 for obesity and .87 for ADHD. Models with the best 5 and best 10 items resulted in less satisfactory fits. The CAARS-S seems to be a promising instrument to be applied in clinical practice also for multiclassifying disorders displaying symptoms resembling ADHD.

Purpose: To assess perioperative outcomes of holmium laser enucleation of the prostate (HoLEP) in a real-world scenario and with a focus on demanding patient factors, such as large prostate size, a...

The complement system may be crucial during dengue virus infection and progression to severe dengue. This study investigates the role of MBL2 genetic variants and levels of MBL in serum and complement proteins in Vietnamese dengue patients. MBL2 genotypes (− 550L/H, MBL2 codon 54), MBL2 diplotypes (XA/XO, YA/XO) and MBL2 haplotypes (LXPB, HXPA, XO) were associated with dengue in the study population. The levels of complement factors C2, C5, and C5a were higher in dengue and dengue with warning signs (DWS) patients compared to those in healthy controls, while factor D levels were decreased in dengue and DWS patients compared to the levels determined in healthy controls. C2 and C5a levels were associated with the levels of AST and ALT and with WBC counts. C9 levels were negatively correlated with ALT levels and WBC counts, and factor D levels were associated with AST and ALT levels and with platelet counts. In conclusions, MBL2 polymorphisms are associated with dengue in the Vietnamese study population. The levels of the complement proteins C2, C4b, C5, C5a, C9, factor D and factor I are modulated in dengue patients during the clinical course of dengue.

Objectives: The artificial urinary sphincter (AUS) is the gold standard treatment for severe stress urinary incontinence (SUI). According to the literature, patients suffering from Parkinson’s disease (PD) or stroke (ST) show adverse continence outcomes after prostate surgery and, therefore, constitute a challenging cohort for continence surgery. However, little is known with respect to the results of AUS surgery in these patients. A retrospective analysis of our institutional, prospectively maintained AUS database aims to address this aspect with a focus on surgical and functional outcomes. Methods and Patients: All data of patients with an AUS implantation were prospectively collected in our database since 2009. The AUS was implanted according to a standardized protocol and activated at 6 weeks postoperatively at our institution. Further follow-up (FU) consisted of pad-test, uroflowmetry, residual urine, and radiography as well as a standardized questionnaire including the Incontinence Quality of Life questionnaire (I-Quol) and International Consultation on Incontinence questionnaire (ICIQ-SF) and is scheduled at 6 and 24 months and every 2 years thereafter. Patients received a preoperative urodynamic evaluation (UD). Patients with normal voiding and storage function were considered for AUS implantation. All patients performed a preoperative test for manual dexterity. Patients with a history of ST or PD were grouped and compared to nonneurological patients. Primary/secondary endpoints of the study were complications/continence. Results: 234 patients were available for analysis. The median FU was 24 months (interquartile range 7–36). Twenty-four patients (10%) had a neurological history (PD and ST). Neurological patients showed significantly worse outcomes regarding continence (objective/subjective/social continence; p = 0.04/p = 0.02/p = 0.1). Significant differences concerning explantation rates were not observed (p = 1). Kaplan-Meier analysis showed no significant difference regarding explantation-free survival (log-rank p = 0.53). Conclusion: AUS implantation shows significantly worse continence rates for neurological patients, despite the fact that all patients showed normal UD results and sufficient manual dexterity. Although neurological patients showed worse outcomes for continence, AUS implantation seems to be a safe and viable treatment for patients with a history of neurological disease.

Background Little is known about patient-reported intensity and quality of pain at the receiver site as well as postoperative complications following one-stage buccal mucosal graft urethroplasty (BMGU). Objective To evaluate perineogenital pain intensity and quality as well as short-term complications after BMGU, and to describe the impact of pain and complications on stricture recurrence. Design, setting, and participants A secondary analysis of a randomized controlled trial including 135 patients, who underwent BMGU from 2014 to 2015, was performed. Intervention One-stage BMGU. Outcome measurements and statistical analysis Patient-reported perineogenital pain was assessed by the Numeric Pain Rating Scale and the Short-form McGill Pain Questionnaire preoperatively and at 1, 5, and 21 d, and 3, 6, and 12 mo postoperatively. Complications were assessed by the Clavien-Dindo classification and the Comprehensive Complication Index. Pain and complications were compared according to stricture recurrence. Results and limitations At a mean follow-up of 21 ± 15 mo, 29 patients (21%) had stricture recurrence. Pain intensity as well as sensory and affective pain quality decreased over time, reaching a minimum at 6 mo. Postoperative complications at days 5 (95% of patients) and 21 (27% of patients) were predominantly “minor” (Clavien-Dindo classification grade ≤ IIIa). Neither patient-reported perineogenital pain nor cumulative morbidity burden was different between patients with and those without stricture recurrence (all p ≥ 0.05). Conclusions Perineogenital pain is frequent after BMGU, but pain intensity and quality decrease over time. The same holds true for postoperative complications, which are frequent but mostly present as minor events. Current findings allow for thorough preoperative patient counseling regarding the expected perineogenital pain intensity and quality over time as well as complications following BMGU. Patient summary In this study, we looked at pain intensity and pain quality as well as complications following buccal mucosal graft urethroplasty. We found that pain in the perineogenital region is frequent, but pain intensity and quality decrease over time. Similarly, postoperative complications are frequent, but mainly present as minor events.

The aim of this study was to assess whether epidemics of sexually transmitted infections caused by poorly transmittable agents corresponded to self-reported sexual activity in a distinct population. To exemplify this, a model was used to investigate whether HIV infection incidences corresponded to the extent of sexual activity as assessed by a questionnaire-based study. The model suggested between 97 and 486 sexual contacts per German individual during a sexually active lifetime based on the annual HIV incidence of 680 among the heterosexual population reported by the German National Health Authority. This is in line with the estimated 296 sexual contacts during one&rsquo, s lifetime, which was indicated by questionnaire respondents. The model confirms the correspondence of self-reported sexual activity with HIV incidence as reported by the German National Health Authority. Accordingly, HIV incidence- and prevalence-based modeling of sexual activity in a population provides crude estimations in situations where a range of uncertainty is acceptable. The model&rsquo, s veracity is limited by a number of assumptions necessitated by the paucity of data. Nevertheless, the model may be suitable in settings where severe reporting bias has to be expected for legal or socio-cultural reasons.

Locomotor recovery after incomplete spinal cord injury (iSCI) is influenced by spinal and supraspinal networks. Conventional clinical gait analysis fails to differentiate between these components. There is evidence that corticospinal control is enhanced during targeted walking, where each foot must be continuously placed on visual targets in randomized order. This study investigates the potential of targeted walking in the functional assessment of corticospinal integrity. Twenty-one controls and 16 individuals with chronic iSCI performed normal and targeted walking on a treadmill while electromyograms (EMGs) and kinematics were recorded. Precision (% of accurate foot placements) in targeted walking was significantly lower in individuals with iSCI (82.9 ± 14.7%, controls: 94.9 ± 4.0%). Although the overall kinematic pattern was comparable between walking conditions, controls showed significantly higher semitendinosus (ST) activity before heel-strike during targeted walking. This was accompanied by a shift of relative EMG intensity from 90-120 Hz to lower frequencies of 20-60 Hz, previously associated with corticospinal control of muscle activity. Targeted walking in individuals with iSCI evoked smaller EMG changes, suggesting that the switch to more corticospinal control is impaired. Accordingly, mildly impaired iSCI individuals revealed higher adaptations to the targeted walking task than more-impaired individuals. Recording of EMGs during targeted walking holds potential as a research tool to reveal further insights into the neuromuscular control of locomotion. It also complements findings of pre-clinical studies and is a promising novel surrogate marker of integrity of corticospinal control in individuals with iSCI and other neurological impairments. Future studies should investigate its potential for diagnosis or tracking recovery during rehabilitation.

Myotonic Dystrophy Type 1 (DM1) is the most frequent hereditary, adult-onset muscular dystrophy. Nevertheless, DM1-associated cognitive-motor impairments have not been fully characterized so far. This study aimed at profiling cognitive and locomotor dysfunctions in these patients. In addition, cognitive-motor interactions were assessed using a dual-task paradigm. Comprehensive cognitive-motor impairment profiles were generated for 19 patients with DM1 and 19 healthy subjects by thorough clinical, biomechanical and neuropsychological examinations. Detailed gait analysis was performed using a 3D motion capture system, whereas cognitive function was assessed using a standardized neuropsychological test battery. Patients with DM1 showed impaired functional mobility, gait velocity and endurance. DM1-related gait pathology was mainly characterized by enhanced dynamic instability, gait variability, and restricted ankle dorsiflexion. Patients' cognitive impairments particularly concerned attentional functions. Dual-task conditions induced gait deviations that slightly differed between patients and controls. DM1-associated cognitive impairments correlated with reduced functional mobility and impaired ankle dorsiflexion. Patients with DM1 revealed significant impairments of walking function, balance and cognitive performance. Differential cognitive-motor interference and significant interactions between cognitive and motor dysfunctions point towards a prominent role of cognition in gait performance of patients with DM1.

Introduction Tailored catheter ablation of atrial tachycardias (ATs) is increasingly recommended as a potentially easy treatment strategy in the era of high-density mapping (HDM). As follow-up data are sparse, we here report outcomes after HDM-guided ablation of ATs in patients with prior catheter ablation or cardiac surgery. Methods and results In 250 consecutive patients (age 66.5 ± 0.7 years, 58% male) with ATs (98% prior catheter ablation, 13% prior cardiac surgery) an HDM-guided catheter ablation was performed with the support of a 64-electrode mini-basket catheter. A total of 354 ATs (1.4 ± 0.1 ATs per patient; mean cycle length 304 ± 4.3 ms; 64% macroreentry, 27% localized reentry, and 9% focal) with acute termination of 95% were targeted in the index procedure. A similar AT as in the index procedure recurred in five patients (2%) after a median follow-up time of 535 days (interquartile range (IQR) 25th-75th percentile: 217-841). Tailored ablation of reentry ATs with freedom from any arrhythmia was obtained in 53% after a single procedure and in 73% after 1.4 ± 0.4 ablation procedures (range: 1-4). A total of 228 patients (91%) were free from any arrhythmia recurrence after 210 days (IQR: 152-494) when including optimal usual care. Conclusions Tailored catheter ablation of ATs guided by HDM has a high acute success rate. The recurrence rate of the index AT is low. In patients with extensive atrial scaring further ablation procedures need to be considered to achieve freedom from any arrhythmia.

Introduction: We characterize trends of metastasis-directed treatments in patients with metastatic renal cell carcinoma (mRCC) in Germany in the targeted therapy era. Methods: We identified all cases with a diagnosis of renal cell carcinoma (ICD-10: C.64) and site-specific codes for secondary malignant neoplasms (C79.x) in combination with procedural codes for resection and radiation from the Institute of Hospital Remuneration and the German Federal Statistical Office (Destatis) between 2006 and 2014. We assessed site-specific temporal trends using estimated annual percent change (EAPC) linear regression. Results: Overall, 15,742 resections and 21,224 radiation treatments were recorded. These targeted lung (44.1% resections; 22.0% radiations), lymph node (14.0% resections; 12% radiations), bone (21% resections; 38% radiations), liver (9% resections; 7% radiations), adrenal (11% resections; 3% radiations), and CNS metastases (2% resections; 19% radiations). There was a significantly increasing trend for resection of lung (EAPC +1.33, p = 0.011), bone (EAPC +2.48, p = 0.014), and adrenal (EAPC +3.4, p = 0.003) metastases, while trends for resection of CNS metastases significantly decreased (EAPC –7.93, p = 0.005). Between Western and Eastern Germany linear trends of resection (EAPC +2.75, p < 0.001; EAPC –0.44, p = 0.54) and radiation (EAPC +1.08, p = 0.15; –3.41, p = 0.03) differed significantly. Conclusion: We observed an increasing trend for metastasis-directed resections and slightly declining numbers for radiation therapy in Germany for mRCC in the targeted therapy era. Treatment differed by geography. These findings suggest more aggressive treatment algorithms following the availability of targeted therapies and a yet diverging treatment landscape needing further exploration.

BACKGROUND A vast body of literature has focused on erectile function after Holmium Laser Enucleation of the Prostate (HoLEP). Interestingly, retrograde ejaculation (RE), despite its frequency has sparsely been investigated. OBJECTIVES To study patient perception and impact of RE on sexuality following HoLEP. MATERIALS AND METHODS We retrospectively analyzed 2,131 patients undergoing HoLEP 2006-2015 at our institution. Patients were followed via standardized questionnaires namely International Index of Erectile Function (IIEF) as well as Male Sexual Health Questionnaire Ejaculatory Short Form (MSHQ-EjD-SF). Exclusion criteria were missing/follow-up

Background Radiofrequency current (RFC) catheter ablation for patients with paroxysmal atrial fibrillation (AF) has been shown to be safe and effective in first-line therapy. Recent data demonstrates that RFC ablation provides better clinical outcomes compared to antiarrhythmic drug (AAD) in the treatment of early AF disease. Furthermore, studies comparing RFC and cryoballoon have established comparable efficacy and safety of pulmonary vein isolation (PVI) for patients with symptomatic paroxysmal AF. Objectives The Cryo-FIRST trial was designed to compare AAD treatment against cryoballoon PVI as a first-line therapy in treatment naive patients with AF. Efficacy and safety will be compared between the two cohorts and amongst subgroups. Methods The primary hypothesis is that cryoablation is superior to AAD therapy. To test this hypothesis, patients will be randomized in a 1:1 design. Using a 90-day blanking period, primary efficacy endpoint failure is defined as (at least) one episode of atrial arrhythmia with a duration >30 sec (documented by 7-day Holter or 12-lead ECG). Secondary endpoints (Quality-of-Life, rehospitalization, arrhythmia recurrence rate, healthcare utilization, and left atrial function) and adverse events will also be evaluated. Study enrollment will include 218 patients in up to 16 centers. Conclusions This study will be a multi-national randomized controlled trial comparing cryoablation against AAD as a first-line treatment in patients with paroxysmal AF. The results may help guide the selection of patients for early AF disease therapy via cryoballoon ablation.

Background Catheter ablation of non-reentrant, commonly termed “idiopathic” ventricular arrhythmias (VA) is highly effective in patients without structural heart disease (SHD). Meanwhile, the outcome of catheter ablation of these arrhythmias in patients with SHD remains unclear. This study sought to characterize the outcome of patients with and without SHD undergoing catheter ablation of non-reentrant VA. Methods In this single-centre study the acute and long-term outcome of 266 consecutive patients undergoing catheter ablation of non-reentrant VA was investigated. In 41.0% of patients a SHD was present (n = 109, 80.7% male, age 59.1 ± 14.7 years), 59.0% had no SHD (n = 157; 44.0% male, age 49.9 ± 16.5 years). Results Acute procedural success (absence of spontaneous or provoked VA at the end of procedure and within 48 h after the procedure) was achieved in 89.9% of patients with SHD vs. 94.3% without SHD (p = 0.238). During a mean follow-up of 34.7 ± 15.1 months a repeat catheter ablation was performed in 19.6% of patients with SHD vs. 13.0% without SHD (p = 0.179). Patients with dilated cardiomyopathy (DCM) were the most likely to require a repeat ablation procedure (32.0% of patients with DCM vs. 13.0% without SHD; p = 0.022). Periprocedural complications occurred in 5.5% of patients with SHD vs. 5.7% without SHD (p > 0.999). All complications were managed without sequelae. Conclusions The outcome of catheter ablation of non-reentrant VA in patients with SHD appears good and is comparable to patients without SHD. A slightly higher rate of repeat ablations was observed in patients with DCM.

BackgroundPhrenic nerve injury (PNI) remains one of the most frequent complications during cryoballoon-based pulmonary vein isolation (CB-PVI). Since its introduction in 2013, the use of compound motor action potential (CMAP) for the prevention of PNI during CB-PVI is increasing; however, systematic outcome data are sparse.MethodsThe CMAP technique was applied in conjunction with abdominal palpation during pacing manoeuvres (10 mV, 2 ms) from the superior vena cava for 388 consecutive patients undergoing CB-PVI between January 2015 and May 2017 at our tertiary arrhythmia centre. Cryoablation was immediately terminated when CMAP amplitude was reduced by 30%.ResultsReductions in CMAP amplitude were observed in 16 (4%) of 388 patients during isolation of the right veins. Of these, 11 (69%) patients did not manifest a reduction in diaphragmatic excursions. The drop in CMAP amplitude was observed in 10 (63%) patients during ablation of the right superior pulmonary veins (PVs) and in 7 (44%) patients during ablation of the right inferior PVs. Postprocedural persistent PNI was observed in three of four patients for a duration of 6 months, with one of these patients remaining symptomatic at the 24-month follow-up. One of the four patients was lost to long-term follow-up.ConclusionsAll PNIs occurred during right-sided CB-PVI and were preceded by a reduction in CMAP amplitude. Thus, the standardized use of CMAP surveillance during CB-PVI is easily applicable, reliable and compared with other studies, results in a lower number of PNIs.

Background In combination with systematic routine screening, brief alcohol interventions have the potential to promote population health. Little is known on the optimal screening interval. Therefore, this study pursued 2 research questions: (i) How stable are screening results for at‐risk drinking over 12 months? (ii) Can the transition from low‐risk to at‐risk drinking be predicted by gender, age, school education, employment, or past week alcohol use? Methods A sample of 831 adults (55% female; mean age = 30.8 years) from the general population was assessed 4 times over 12 months. The Alcohol Use Disorders Identification Test—Consumption was used to screen for at‐risk drinking each time. Participants were categorized either as low‐risk or at‐risk drinkers at baseline, 3, 6, and 12 months later. Stable and instable risk status trajectories were analyzed descriptively and graphically. Transitioning from low‐risk drinking at baseline to at‐risk drinking at any follow‐up was predicted using a logistic regression model. Results Consistent screening results over time were observed in 509 participants (61%). Of all baseline low‐risk drinkers, 113 (21%) received a positive screening result in 1 or more follow‐up assessments. Females (vs. males; OR = 1.66; 95% confidence intervals [95% CI] = 1.04; 2.64), 18‐ to 29‐year‐olds (vs. 30‐ to 45‐year‐olds; OR = 2.30; 95% CI = 1.26; 4.20), and those reporting 2 or more drinking days (vs. less than 2; OR = 3.11; 95% CI = 1.93; 5.01) and heavy episodic drinking (vs. none; OR = 2.35; 95% CI = 1.06; 5.20) in the week prior to the baseline assessment had increased odds for a transition to at‐risk drinking. Conclusions Our findings suggest that the widely used time frame of 1 year may be ambiguous regarding the screening for at‐risk alcohol use although generalizability may be limited due to higher‐educated people being overrepresented in our sample.

Background. General population data on associations between mental disorders and total mortality are rare. The aim was to analyze whether the number of mental disorders, single substance use, mood, anxiety, somatoform or eating disorders during the lifetime and whether treatment utilization may predict time to death 20 years later in the general adult population. Methods. We used data from the Composite International Diagnostic Interview, which includes DSM-IV diagnoses for substance use, mood, anxiety, somatoform, and eating disorders, for a sample of 4,075 residents in Germany who were 18–64 years old in 1996. Twenty years later, mortality was ascertained using the public mortality database for 4,028 study participants. Cox proportional hazards models were applied for disorders that existed at any time in life before the interview. Results. The data revealed increased hazard ratios (HRs) for number of mental disorders (three or more; HR 1.4; 95% confidence interval [CI] 1.1–1.9) and for single disorders (alcohol dependence, dysthymia, panic disorder with agoraphobia, and hypochondriasis), with the reference group being study participants who had not suffered from any of the mental disorders analyzed and with adjustments made for age, sex, and education. Among individuals with any mental disorder during their lifetimes, having been an inpatient in treatment for a mental disorder was related to a higher HR (2.2; CI 1.6–3.0) than was not having been in any treatment for a mental disorder. Conclusions. In this sample of adults in the general population, three or more mental disorders, alcohol dependence, dysthymia, panic disorder with agoraphobia, and hypochondriasis were related to premature death.