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Background Graft-derived cell-free DNA (GcfDNA), which is released into the blood stream by necrotic and apoptotic cells, is a promising noninvasive organ integrity biomarker. In liver transplantation (LTx), neither conventional liver function tests (LTFs) nor immunosuppressive drug monitoring are very effective for rejection monitoring. We therefore hypothesized that the quantitative measurement of donor-derived cell-free DNA (cfDNA) would have independent value for the assessment of graft integrity, including damage from acute rejection. Methods and findings Traditional LFTs were performed and plasma GcfDNA was monitored in 115 adults post-LTx at three German transplant centers as part of a prospective, observational, multicenter cohort trial. GcfDNA percentage (graft cfDNA/total cfDNA) was measured using droplet digital PCR (ddPCR), based on a limited number of predefined single nucleotide polymorphisms, enabling same-day turn-around. The same method was used to quantify blood microchimerism. GcfDNA was increased >50% on day 1 post-LTx, presumably from ischemia/reperfusion damage, but rapidly declined in patients without graft injury within 7 to 10 d to a median Conclusions In this study, determination of GcfDNA in plasma by ddPCR allowed for earlier and more sensitive discrimination of acute rejection in LTx patients as compared with conventional LFTs. Potential blood microchimerism was quantitatively low and had no significant influence on GcfDNA value. Further research, which should ideally include protocol biopsies, will be needed to establish the practical value of GcfDNA measurements in the management of LTx patients., Author(s): Ekkehard Schütz 1, Anna Fischer 2, Julia Beck 1, Markus Harden 3, Martina Koch 4, Tilo Wuensch 5, Martin Stockmann 5, Björn Nashan 4, Otto Kollmar 6, Johannes Matthaei [...]

Aim: The association of standard 12-lead electrocardiogram (ECG) markers with benefits of the primary prophylactic implantable cardioverter-defibrillator (ICD) has not been determined in the contemporary era. We analysed traditional and novel ECG variables in a large prospective, controlled primary prophylactic ICD population to assess the predictive value of ECG in terms of ICD benefit.Methods and Results: Electrocardiograms from 1477 ICD patients and 700 control patients (EU-CERT-ICD; non-randomized, controlled, prospective multicentre study; ClinicalTrials.gov Identifier: NCT02064192), who met ICD implantation criteria but did not receive the device, were analysed. The primary outcome was all-cause mortality. In ICD patients, the co-primary outcome of first appropriate shock was used. Mean follow-up time was 2.4 ± 1.1 years to death and 2.3 ± 1.2 years to the first appropriate shock. Pathological Q waves were associated with decreased mortality in ICD patients [hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.35-0.84; P < 0.01] and patients with pathological Q waves had significantly more benefit from ICD (HR 0.44, 95% CI 0.21-0.93; P = 0.03). QTc interval increase taken as a continuous variable was associated with both mortality and appropriate shock incidence, but commonly used cut-off values, were not statistically significantly associated with either of the outcomes.Conclusion: Pathological Q waves were a strong ECG predictor of ICD benefit in primary prophylactic ICD patients. Excess mortality among Q wave patients seems to be due to arrhythmic death which can be prevented by ICD. [ABSTRACT FROM AUTHOR]

Purpose: Many studies have reported satisfactory clinical outcomes and low redislocation rates after reconstruction of the medial patellofemoral ligament (MPFL) for the treatment of lateral patellar instability. Despite uncorrected severe trochlear dysplasia (Dejour type B to D) being acknowledged as a major reason for less favourable clinical outcomes and a higher incidence of patellar redislocations after an isolated MPFL reconstruction, the evidence for a deepening trochleoplasty procedure remains scarce in the current literature. The hypothesis of this systematic review and meta-analysis was that a deepening trochleoplasty in combination with an a la carte extensor apparatus balancing procedure provides lower redislocation rates and superior clinical outcomes than isolated MPFL reconstruction in patients with lateral patellar instability caused by severe trochlear dysplasia.Methods: A systematic review of the literature was conducted using specific inclusion and exclusion criteria for clinical studies reporting index operations (trochleoplasty and MPFL reconstruction) for the treatment of patellar instability caused by severe trochlear dysplasia. The Kujala score was analysed as the primary clinical outcome parameter in a random effects meta-analysis.Results: Ten uncontrolled studies with a total of 407 knees (374 patients) were included in this analysis. The MPFL group comprised 4 studies with a total of 221 knees (210 patients), and the trochleoplasty group comprised 6 studies with a total of 186 knees (164 patients). The mean preoperative Kujala score ranged between 50.4 and 70.5 in the MPFL group and between 44.8 and 75.1 in the trochleoplasty group. The pooled Kujala score increased significantly by 26.4 (95% CI 21.4, 31.3; P < 0.00001) points in the MPFL group and by 26.2 (95% CI 19.8, 32.7; P < 0.00001) points in the trochleoplasty group. The post-operative patellar redislocation/subluxation rate was 7% in the MPFL group and 2.1% in the trochleoplasty group.Conclusion: This analysis found significant post-operative improvements in patient-reported outcomes for patients undergoing both an MPFL reconstruction and in those undergoing a trochleoplasty plus an individual extensor apparatus balancing procedure when assessed using the Kujala score. The likelihood of preventing the patella from subsequent post-operative redislocation/subluxation was, however, greater in patients who underwent trochleoplasty plus extensor balancing.Level Of Evidence: IV. [ABSTRACT FROM AUTHOR]

Aim: The association of standard 12-lead electrocardiogram (ECG) markers with benefits of the primary prophylactic implantable cardioverter-defibrillator (ICD) has not been determined in the contemporary era. We analysed traditional and novel ECG variables in a large prospective, controlled primary prophylactic ICD population to assess the predictive value of ECG in terms of ICD benefit., Methods and Results: Electrocardiograms from 1477 ICD patients and 700 control patients (EU-CERT-ICD; non-randomized, controlled, prospective multicentre study; ClinicalTrials.gov Identifier: NCT02064192), who met ICD implantation criteria but did not receive the device, were analysed. The primary outcome was all-cause mortality. In ICD patients, the co-primary outcome of first appropriate shock was used. Mean follow-up time was 2.4 ± 1.1 years to death and 2.3 ± 1.2 years to the first appropriate shock. Pathological Q waves were associated with decreased mortality in ICD patients [hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.35-0.84; P < 0.01] and patients with pathological Q waves had significantly more benefit from ICD (HR 0.44, 95% CI 0.21-0.93; P = 0.03). QTc interval increase taken as a continuous variable was associated with both mortality and appropriate shock incidence, but commonly used cut-off values, were not statistically significantly associated with either of the outcomes., Conclusion: Pathological Q waves were a strong ECG predictor of ICD benefit in primary prophylactic ICD patients. Excess mortality among Q wave patients seems to be due to arrhythmic death which can be prevented by ICD., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: This study was performed to develop and externally validate prediction models for appropriate implantable cardioverter-defibrillator (ICD) shock and mortality to identify subgroups with insufficient benefit from ICD implantation., Methods and Results: We recruited patients scheduled for primary prevention ICD implantation and reduced left ventricular function. Bootstrapping-based Cox proportional hazards and Fine and Gray competing risk models with likely candidate predictors were developed for all-cause mortality and appropriate ICD shock, respectively. Between 2014 and 2018, we included 1441 consecutive patients in the development and 1450 patients in the validation cohort. During a median follow-up of 2.4 (IQR 2.1-2.8) years, 109 (7.6%) patients received appropriate ICD shock and 193 (13.4%) died in the development cohort. During a median follow-up of 2.7 (IQR 2.0-3.4) years, 105 (7.2%) received appropriate ICD shock and 223 (15.4%) died in the validation cohort. Selected predictors of appropriate ICD shock were gender, NSVT, ACE/ARB use, atrial fibrillation history, Aldosterone-antagonist use, Digoxin use, eGFR, (N)OAC use, and peripheral vascular disease. Selected predictors of all-cause mortality were age, diuretic use, sodium, NT-pro-BNP, and ACE/ARB use. C-statistic was 0.61 and 0.60 at respectively internal and external validation for appropriate ICD shock and 0.74 at both internal and external validation for mortality., Conclusion: Although this cohort study was specifically designed to develop prediction models, risk stratification still remains challenging and no large group with insufficient benefit of ICD implantation was found. However, the prediction models have some clinical utility as we present several scenarios where ICD implantation might be postponed., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Implantable cardioverter defibrillators (ICDs) prevent sudden cardiac death. ICD implantation decisions are currently based on reduced left ventricular ejection fraction (LVEF≤35%). However, in some patients, the non-arrhythmic death risk predominates thus diminishing ICD-therapy benefits. Based on previous observations, we tested the hypothesis that compared to the others, patients with nocturnal respiratory rate (NRR) ≥18 breaths per minute (brpm) benefit less from prophylactic ICD implantations., Methods: This prospective cohort study was a pre-defined sub-study of EU-CERT-ICD trial conducted at 44 centers in 15 EU countries between May 12, 2014, and September 6, 2018. Patients with ischaemic or non-ischaemic cardiomyopathy were included if meeting primary prophylactic ICD implantation criteria. The primary endpoint was all-cause mortality. NRR was assessed blindly from pre-implantation 24-hour Holters. Multivariable models and propensity stratification evaluated the interaction between NRR and the ICD mortality effect. This study is registered with ClinicalTrials.gov (NCT0206419)., Findings: Of the 2,247 EU-CERT-ICD patients, this sub-study included 1,971 with complete records. In 1,363 patients (61.7 (12) years; 244 women) an ICD was implanted; 608 patients (63.2 (12) years; 108 women) were treated conservatively. During a median 2.5-year follow-up, 202 (14.8%) and 95 (15.6%) patients died in the ICD and control groups, respectively. NRR statistically significantly interacted with the ICD mortality effect ( p  = 0.0070). While the 1,316 patients with NRR<18 brpm showed a marked ICD benefit on mortality (adjusted HR 0.529 (95% CI 0.376-0.746); p  = 0.0003), no treatment effect was demonstrated in 655 patients with NRR≥18 brpm (adjusted HR 0.981 (95% CI 0.669-1.438); p  = 0.9202)., Interpretation: In the EU-CERT-ICD trial, patients with NRR≥18 brpm showed limited benefit from primary prophylactic ICD implantation. Those with NRR<18 brpm benefitted substantially., Funding: European Community's 7th Framework Programme FP7/2007-2013 (602299)., Competing Interests: MH and MM reports grant from European Commission. TF reports grant from European Commission and personal fees from Novartis, Bayer, Janssen, Roche, Boehringer Ingelheim, Daiichi Sankyo, Galapagos, Penumbra, Parexel, Vifor, BiosenseWebster, CSL Behring, Fresenius Kabi, and Coherex Medical. BM reports grants from Boston Scientific and Medtronic, and he reports personal fees from Biotronik and Abbott. RW reports grants from European Commission, Medtronic, Biotronik, Abbott, and Boston Scientific. He is funded as a postdoctoral clinical researcher by the Fund for Scientific Research Flanders (FWO Vlaanderen). MZ reports grants from European Commission and Biotronik. All other authors declare no competing interests., (© 2020 The Author(s).)

Objective: Diabetes increases the risk of all-cause mortality and sudden cardiac death (SCD). The exact mechanisms leading to sudden death in diabetes are not well known. We compared the incidence of appropriate shocks and mortality in patients with versus without diabetes with a prophylactic implantable cardioverter defibrillator (ICD) included in the retrospective EU-CERT-ICD registry., Research Design and Methods and Results: A total of 3,535 patients from 12 European EU-CERT-ICD centers with a mean age of 63.7 ± 11.2 years (82% males) at the time of ICD implantation were included in the analysis. A total of 995 patients (28%) had a history of diabetes. All patients had an ICD implanted for primary SCD prevention. End points were appropriate shock and all-cause mortality. Mean follow-up time was 3.2 ± 2.3 years. Diabetes was associated with a lower risk of appropriate shocks (adjusted hazard ratio [HR] 0.77 [95% CI 0.62-0.96], P = 0.02). However, patients with diabetes had significantly higher mortality (adjusted HR 1.30 [95% CI 1.11-1.53], P = 0.001)., Conclusions: All-cause mortality is higher in patients with diabetes than in patients without diabetes with primary prophylactic ICDs. Subsequently, patients with diabetes have a lower incidence of appropriate ICD shocks, indicating that the excess mortality might not be caused primarily by ventricular tachyarrhythmias. These findings suggest a limitation of the potential of prophylactic ICD therapy to improve survival in patients with diabetes with impaired left ventricular function., (© 2019 by the American Diabetes Association.)

Background and Objectives: Hospitalisation influences drug therapy in ambulatory care and this influence is generally negatively perceived. The few studies that have explored changes in benzodiazepine or sleep medication use as a function of hospitalisation failed to precisely determine the hospital's role in initiating, continuing and discontinuing these drugs on a valid basis. The aim of the study was to ascertain the overall influence of hospitalisation on the prescription of benzodiazepines and Z-drugs in outpatient care with a special focus on the role of different hospital departments and drug classes., Methods: In a secondary data analysis, we used prescription data for 181 037 patients who visited 127 hospitals and compared the numbers of patients with prescriptions of benzodiazepines and Z-drugs 50 days before and 50 or 100 days after hospitalisation., Results: The proportion of patients who received benzodiazepines or Z-drugs increased from 3.1% before admission to 3.6% at 50 days after discharge and fell to the former level after an additional 50 days. A multivariable logistic regression showed that gender and department had an additional impact on these results. Of those patients without a prescription for a benzodiazepine or Z-drug before admission, 0.6% received a prescription in both time-windows after discharge. Of those patients who were prescribed a benzodiazepine, 38.0% received short-acting substances and 40.3% received long-acting substances before hospitalisation. After hospitalisation, these rates changed to favour short-acting substances (44.4% and 34.4%, respectively)., Conclusions: The hospital effect on initiating and increasing hypnotic or sedative drug use seems to be only moderate and temporary. A change in favour of short-acting substances is even welcome. In less than 1% of patients, the hospital initiated the continuous use of benzodiazepines and Z-drugs, which may put pressure on primary care physicians. However, the widespread use of these drugs in hospitals does not seem to be continued on a large scale in primary care.