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Introduction: Patients with coronary artery disease (CAD) remain vulnerable to future major atherosclerotic events after revascularization, despite effective secondary prevention strategies. Inflammation plays a central role in the pathogenesis of CAD and recurrent events. To date, there is no specific anti-inflammatory medicine available with proven effective, cost-efficient, and favorable benefit-risk profile, except for colchicine. Initial studies with colchicine have sparked major interest in targeting atherosclerotic events with anti-inflammatory agents, but further studies are warranted to enforce the role of colchicine role as a major treatment pillar in CAD. Given colchicine's low cost and established acceptable long-term safety profile, confirming its efficacy through a pragmatic trial holds the potential to significantly impact the global burden of cardiovascular disease., Methods: The COL BE PCI trial is an investigator-initiated, multicenter, double-blind, event-driven trial. It will enroll 2,770 patients with chronic or acute CAD treated with percutaneous coronary intervention (PCI) at 19 sites in Belgium, applying lenient in- and exclusion criteria and including at least 30% female participants. Patients will be randomized between 2 hours and 5 days post-PCI to receive either colchicine 0.5 mg daily or placebo on top of contemporary optimal medical therapy and without run-in period. All patients will have baseline hsCRP measurements and a Second Manifestations of Arterial Disease (SMART) risk score calculation. The primary endpoint is the time from randomization to the first occurrence of a composite endpoint consisting of all-cause death, spontaneous non-fatal myocardial infarction, non-fatal stroke, or coronary revascularization. The trial is event-driven and will continue until 566 events have been reached, providing 80% power to detect a 21 % reduction in the primary endpoint taking a premature discontinuation of 15% into account. We expect a trial duration of approximately 44 months., Conclusion: The COL BE PCI Trial aims to assess the effectiveness and safety of administering low-dose colchicine for the secondary prevention in patients with both chronic and acute coronary artery disease undergoing PCI., Trial Registration: ClinicalTrials.gov: NCT06095765., Competing Interests: Conflict of Interest The authors have no conflict of interest related to the content of this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Observational studies in cutaneous melanoma (CM) have indicated an inverse relationship between levels of 25-hydroxyvitamin D and Breslow thickness, in addition to a protective effect of high 25-hydroxyvitamin D levels on clinical outcome., Objectives: To evaluate whether high-dose vitamin D supplementation in curatively resected CM reduces melanoma relapse., Methods: In a prospective randomized double-blind placebo-controlled trial, 436 patients with resected CM stage IA to III (8th American Joint Committee on Cancer staging) were randomized. Among them, 218 received a placebo while 218 received monthly 100 000 IU cholecalciferol for a minimum of 6 months and a maximum of 42 months (treatment arm). Following randomization, patients were followed for a median of 52 months, with a maximum follow-up of 116 months. The primary endpoint was relapse-free survival. Secondary endpoints were melanoma-related mortality, overall survival, and the evolution of 25-hydroxyvitamin D serum levels over time., Results: In our population (mean age 55 years, 54% female sex) vitamin D supplementation increased 25-hydroxyvitamin D serum levels after 6 months of supplementation in the treatment arm by a median 17 ng mL-1 [95% confidence interval (CI) 9-26] compared with 0 ng mL-1 (95% CI 6-8) in the placebo arm (P < 0.001, Wilcoxon test) and remained at a steady state during the whole treatment period. The estimated event rate for relapse-free survival at 72 months after inclusion was 26.51% in the vitamin D supplemented arm (95% CI 19.37-35.64) vs. 20.70% (95% CI 14.26-29.52) in the placebo arm (hazard ratio 1.27, 95% CI 0.79-2.03; P = 0.32). After adjusting for confounding factors (including baseline stage, body mass index, age, sex and baseline season), the hazard ratio was 1.20 (95% CI 0.74-1.94, P = 0.46). The number of deaths from progression of CM and nonmelanoma-related deaths was similar in both the vitamin D supplemented and placebo groups (deaths from progression of CM, n = 10 and n = 11, respectively; nonmelanoma-related deaths, n = 3 and n = 2, respectively). No major adverse events were observed during the study., Conclusions: In patients with CM, monthly high-dose vitamin D supplementation was safe, resulted in a sustained increase in 25-hydroxyvitamin D levels during the treatment period, but did not improve relapse-free survival, melanoma-related death or overall survival., Competing Interests: Conflicts of interest The authors declare they have no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The role of immunosuppressive therapy on SARS-CoV-2 infection risk and COVID-19 severity remains unclear in unvaccinated solid organ transplant recipients. We included 1957 organ transplant recipients between July 2020 and April 2021 to analyze whether baseline immunosuppressive therapy and other risk factors are associated with SARS-CoV-2 infection and severe COVID-19. In total, 247 (12.6%) had SARS-CoV-2 (defined as positive nasopharyngeal swab and/or positive antibody titer). Of these, 57 (23.1%) had severe COVID-19, defined as oxygen supplementation, intensive care unit admission or death. Multivariable analysis identified diabetes (hazard ratio (HR) 1.39 (95% confidence interval (CI) 1.05-1.83)), chronic lung disease (HR 1.71 (95% CI 1.13-2.60)) and contact with a COVID-19 positive individual (HR 3.61 (95% CI 2.61-4.99) as independent risk factors for SARS-CoV-2 infection. There was no association between immunosuppressive therapy and infection risk. Severe COVID-19 was multivariably associated with hypertension (OR 5.45 (95% CI 1.66-17.84)), chronic kidney disease (OR 3.55 (95% CI 1.75-7.19)), corticosteroid use (OR 2.93 (95% CI 1.03-2.55)) and having a COVID-19 positive housemate (OR 6.77 (95% CI 2.65-17.28)). In conclusion, baseline corticosteroid use, but no other immunosuppressive agent, is independently associated with severe COVID-19 in unvaccinated SOT recipients after correction for hypertension, chronic kidney disease, housemates affected by COVID-19 and transplant type., (© 2024. The Author(s).)

In this perspective paper, we propose a novel tech-driven method to evaluate body representations (BRs) in autistic individuals. Our goal is to deepen understanding of this complex condition by gaining continuous and real-time insights through digital phenotyping into the behavior of autistic adults. Our innovative method combines cross-sectional and longitudinal data gathering techniques to investigate and identify digital phenotypes related to BRs in autistic adults, diverging from traditional approaches. We incorporate ecological momentary assessment and time series data to capture the dynamic nature of real-life events for these individuals. Statistical techniques, including multivariate regression, time series analysis, and machine learning algorithms, offer a detailed comprehension of the complex elements that influence BRs. Ethical considerations and participant involvement in the development of this method are emphasized, while challenges, such as varying technological adoption rates and usability concerns, are acknowledged. This innovative method not only introduces a novel vision for evaluating BRs but also shows promise in integrating traditional and dynamic assessment approaches, fostering a more supportive atmosphere for autistic individuals during assessments compared to conventional methods.

Background: No randomized data exist on ultrathin-strut stents in patients at high bleeding risk (HBR) undergoing an abbreviated dual antiplatelet therapy after coronary stenting. The aim of this study was to compare the safety and effectiveness of the ultrathin-strut biodegradable-polymer sirolimus-eluting Supraflex Cruz stent with the thin-strut biodegradable-polymer sirolimus-eluting Ultimaster Tansei stent in patients at HBR with abbreviated dual antiplatelet therapy after stenting., Methods: In the investigator-initiated, randomized, open-label COMPARE 60/80 HBR trial (Comparison of the Supraflex Cruz 60 Micron Stent Strut Versus the Ultimaster Tansei 80 Micron Stent Strut in HBR Percutaneous Coronary Intervention Population), 741 patients at HBR according to the Academic Research Consortium HBR criteria were randomized to receive either the ultrathin-strut biodegradable-polymer sirolimus-eluting Supraflex Cruz stent or thin-strut biodegradable-polymer sirolimus-eluting Ultimaster Tansei stent. Dual antiplatelet therapy was recommended according to the applicable guidelines and trial data for patients at HBR. The primary outcome was net adverse clinical events, the composite of cardiovascular death, myocardial infarction, target vessel revascularization, stroke, and major bleeding, and was powered for noninferiority with an absolute margin of 4.0% at 1-sided 2.5% alpha., Results: Between September 2020 and August 2022, 371 patients were randomized to the ultrathin-strut biodegradable-polymer sirolimus-eluting Supraflex Cruz stent and 370 patients to the thin-strut biodegradable-polymer sirolimus-eluting Ultimaster Tansei stent at 11 sites in the Netherlands. At 1 year, the primary outcome was observed in 56 (15.4%) patients in the ultrathin-strut biodegradable-polymer sirolimus-eluting Supraflex Cruz stent group and 61 (17.1%) in the thin-strut biodegradable-polymer sirolimus-eluting Ultimaster Tansei stent group (risk difference, -1.65%; upper boundary of the 1-sided 95% CI, 3.74; P =0.02 for noninferiority at a 0.025 significance level and P =0.55 for 2-sided superiority at a 0.05 significance level)., Conclusions: Among patients at HBR with abbreviated dual antiplatelet therapy post-stenting, the use of an ultrathin-strut biodegradable-polymer sirolimus-eluting Supraflex Cruz stent was noninferior compared with the use of a thin-strut biodegradable-polymer sirolimus-eluting Ultimaster Tansei stent., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04500912., Competing Interests: Dr Smits reports personal fees from Terumo and Abiomed, institutional grants and personal fees from Abbott Vascular and Microport, and institutional grants from SMT. Dr Hofma reports an institutional grant from Terumo. Dr Oemrawsingh reports speaker fees from Abbott Vascular and Philips. Dr Paradies reports speaker fees from Boston Scientific and Abbott Vascular and institutional grants from Abbott Vascular. The other authors report no conflicts.

Purpose: A lateral ankle sprain is the most common musculoskeletal injury in the physically active population. However, it is unclear how the clinical condition evolves during the period after the injury and what proportion of patients develops chronic symptoms. Therefore, the purpose of this study is to assess the evolution of patient-reported outcome measures after a first time lateral ankle sprain., Methods: A prospective clinical study assessed the patient-reported outcome measures (PROMs) of a consecutive group of 100 patients during 1 year after a first lateral ankle sprain. The Karlsson score and Foot and Ankle Outcome Score (FAOS) were assessed at 6 weeks, 3 months, 6 months, 9 months and 1 year. The Cumberland Ankle Instability Tool (CAIT)-score was assessed at 6 months, 9 months and 1 year. The difference between the time points of all scores was analysed using the positive change over time (binomial test versus 50%) and the difference in score (signed rank test). The time to sustained excellent level was also assessed overall and in several subgroups: age, gender, degree of injury (2 or 3), avulsion fracture, use of crutches, use of cast. Differences between subgroups were assessed by a generalized log-rank test., Results: All clinical scores demonstrated an improvement up to 12 months after the sprain. The median Karlsson score (interquartile range) improved from 62 (50-80) at 6 weeks to 90 (72-100) at 3 months, to 97 (82-100) at 6 months to 100 (90-100) at 9 months, to 100 (100-100) at 1 year. The analysis of positive change over time demonstrated a significant positive change (P-value <.0005) between all time points except between 6 weeks and 12 weeks when using the FAOS quality score. The difference in score demonstrated a significant change (P-value <.01) between all time points except between 36 weeks and 48 weeks when using the FAOS pain and FAOS sports score. Age and presence of an avulsion fracture were correlated with a slower recovery and worse results. At 1 year, in total 13 patients (13%) had a worse outcome corresponding to a Karlsson score < 81 or CAIT score < 24., Conclusion: The clinical condition after a first ankle sprain demonstrated a significant improvement in PROMs between the different time points in the first year. Twelve months after a first lateral ankle sprain 13% had a fair or poor outcome. Higher age and presence of an avulsion fracture were correlated with a slower recovery and worse results. This information is useful in clinical practice to predict further progression and inform patients. Moreover, it is valuable to improve treatment strategies., Level of Evidence: Level II (prospective cohort study)., Competing Interests: Declaration of Competing Interest None of the authors has a conflict of interest that could inappropriately influence this work., (Copyright © 2024 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.)

Introduction/aims: Magnetic resonance imaging (MRI) findings in peroneal neuropathy are not well documented and the prognostic value of imaging remains uncertain. Upper limits of cross-sectional area (CSA) on ultrasound (US) have been established, but uncertainty regarding generalizability remains. We aimed to describe MRI findings of the peroneal nerve in patients and healthy controls and to compare these results to US findings and clinical characteristics., Methods: We prospectively included patients with foot drop and electrodiagnostically confirmed peroneal neuropathy, and performed clinical follow-up, US and MRI of both peroneal nerves. We compared MRI findings to healthy controls. Two radiologists evaluated MRI features in an exploratory analysis after images were anonymized and randomized., Results: Twenty-two patients and 38 healthy controls were included. Whereas significant increased MRI CSA values were documented in patients (mean CSA 20 mm 2 vs. 13 mm 2 in healthy controls), intra- and interobserver variability was substantial (variability of, respectively, 7 and 9 mm 2 around the mean in 95% of repeated measurements). A pathological T2 hyperintense signal of the nerve was found in 52.6% of patients (50% interobserver agreement). Increased CSA measurements (MRI/US), pathological T2 hyperintensity of the nerve and muscle edema were not predictive for recovery., Discussion: Imaging is recommended in all patients with peroneal neuropathy to exclude compressive intrinsic and extrinsic masses but we do not advise routine MRI for diagnosis or prediction of outcome in patients with peroneal neuropathy due to high observer variability. Further studies should aim at reducing MRI observer variability potentially by semi-automation., (© 2024 Wiley Periodicals LLC.)

Background: The latest generation ultrathin Supraflex Cruz (Sahajanand Medical Technologies Limited, Surat, India) sirolimus-eluting stent (SES) has shown early healing properties and represents an attractive percutaneous coronary intervention (PCI) device in a high bleeding risk (HBR) population. The aim of this Cruz HBR registry was to assess safety and efficacy of the Supraflex Cruz SES in a large cohort of all-comer patients, of whom about one third were patients at HBR., Methods: Patients undergoing PCI were enrolled in this prospective, multi-centre, open label registry and stratified into non-HBR and HBR groups. The primary endpoint was a device-oriented composite endpoint (DOCE), a composite of cardiovascular death, myocardial infarction not clearly attributable to a non-target vessel and clinically driven target lesion revascularization within 12 months after PCI. The predefined aims were to show non-inferiority of the non-HBR group to the Supraflex arm of the TALENT Trial, and of the HBR group to polymer-free biolimus-coated stent arm of LEADERS FREE Trial., Results: A total of 1203 patients were enrolled across 26 European centers, including a significant proportion (38.7%; N.=466) of HBR patients. A total of 1745 lesions were treated in 1203 patients and 2235 stents were implanted. The DOCE occurred within the total cohort in 5.8% of patients with a significant difference between HBR patients and non-HBR patients (8.1% vs. 4.4%; P<0.001). All-cause mortality at 12 months was significantly (P<0.0001) different among HBR (9.0%) and non-HBR patients (1.7%), respectively. At 12 months, the overall incidence of definite and probable stent thrombosis was 1.0%. Major bleeding occurred in 5.9% patients of the HBR group. These results met the non-inferiority criteria with respect to the TALENT trial for the non-HBR group (P<0.0001), and the LEADERS FREE trial for the HBR group (P<0.0001)., Conclusions: The Cruz HBR registry confirms that PCI with the Supraflex Cruz SES is associated with a favorable clinical outcome in an all-comer population, including complex patients with HBR.

Background: The DAWN antivirals trial was a multicentric, randomised placebo-controlled trial evaluating antiviral medication for COVID-19 in general practice. The trial was prematurely terminated because of insufficient recruitment., Aim: To explore which factors contributed to the premature termination., Design & Setting: General practice in Belgium., Method: Patients were randomised to camostat or placebo (patients and physicians blinded) between June 2021 and July 2022; a third arm evaluating molnupiravir (open label) was opened in March 2022. The outcome assessor was blinded for all comparisons except for the patient reported outcomes in case of molnupiravir. The authors analysed available trial data and evaluated trial context, implementation, and mechanisms of impact based on semi-structured interviews with trial stakeholders., Results: The trial recruited 44 participants; 19 were allocated to camostat (median age 55 years), 8 to molnupiravir (median age 60 years), and 17 to placebo (median age 56 years). There were no serious adverse events in either group. Most difficulties were related to the pandemic context: disruption to routine clinical services; multiple changes to the service model for COVID-19 patients; overwhelmed clinical staff; delays of trial medication; and staff shortages in the sponsor and clinical team. In addition, regulatory approval processes were lengthy and led to additional study procedures. It was felt that the trial started too late, when vaccinations had already begun., Conclusion: The DAWN antivirals trial was stopped prematurely. Although many barriers were related to the pandemic itself, hurdles such as a small and inexperienced sponsor and clinical teams, delays in regulatory processes, and research capacity in routine settings could be overcome by established research infrastructure and standardisation of processes., (Copyright © 2024, The Authors.)

We assessed the real-world effectiveness of sacubitril/valsartan in patients with chronic heart failure (HF) and reduced ejection fraction (HFrEF) with an emphasis on those with older age (≥ 75 years) or with New York Heart Association (NYHA) class IV, for whom greater uncertainty existed regarding clinical outcomes. We conducted a retrospective cohort study based on patient-level linkage of electronic healthcare datasets. Data from all adults with HFrEF in Belgium receiving a prescription for sacubitril/valsartan between 01-November-2016 and 31-December-2018 were collected, with a follow-up of > 6 years. The total study population comprised 5446 patients, older than the PARADIGM-HF trial participants, and with higher NYHA class (all P < 0.0001). NYHA class improved following sacubitril/valsartan initiation (P < 0.0001 baseline vs. reassessment). Most concomitant medications were reduced. Remarkably, the risk of hospitalization for a cardiovascular reason and for HF was reduced by > 26% in the overall cohort, and in subgroups of patients ≥ 75 years, with NYHA class III/IV (all P < 0.0001) or with NYHA class IV (P < 0.05), vs. baseline. All-cause mortality did not increase in real-world patients with NYHA class III/IV. The results support the long-term beneficial effects of sacubitril/valsartan in older patients and in those experiencing the most severe symptoms., (© 2024. The Author(s).)

Decrease of vitamin D receptor (VDR) expression is observed in melanocytic naevi and melanoma compared to normal skin. Little is known about factors influencing VDR expression in cutaneous melanoma (CM). We investigated the correlation of VDR expression in CM with 25-hydroxy vitamin D (25OHD) levels, demographic/clinical parameters, genetic variants of VDR and pathology of the primary tumor. Demographic/clinical parameters were recorded in 407 prospectively recruited CM patients of a multi-center controlled study (ViDMe trial). We determined VDR expression both in the nucleus and in the cytoplasm by semi-quantitative assessment in CM tissue using histochemistry in 279 patients, expressed in percentages and histoscore (H-score). Genomic DNA from 332 patients was extracted to genotype thirteen VDR single nucleotide polymorphisms (SNPs) using TaqMan. VDR expression in CM tissue from 279 patients was correlated with clinical/demographic parameters and 25OHD levels (univariable and multivariable analysis), VDR SNPs (univariable analysis) and pathology parameters of primary CM tissue (univariable analysis). Cytoplasmic VDR expression was increased in patients who stated to have a high sun exposure during their life compared to patients with low sun exposure (p H-score,univariable : 0.001, p H-score,multivariable : 0.004). The A allele of the genetic VDR polymorphism Fok1 was associated with a higher expression of the VDR in the cytoplasm (p cytoplasmic, univariable : 0.001 and p H-score, univariable : 0.02). In the primary tumor, presence of mitosis (p nucleus,%, univariable : 0.002) and perineural invasion (p nucleus,%,univariable : 0.03) were significantly associated with low nuclear VDR expression. ClinicalTrials.gov Identifier: NCT01748448., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Alterations in postural control have been found in individuals with low back pain (LBP), particularly during challenging postural tasks. Moreover, higher levels of negative pain-related psychological variables are associated with increased trunk muscle activity, reduced spinal movement, and worse maximal physical performance in individuals with LBP., Research Question: Are pain-related psychological variables associated with postural control during static bipedal standing tasks in individuals with LBP?, Methods: A systematic review and meta-analysis were conducted. Pubmed, Web of Science, and PsycINFO were searched until March 2023. Studies were included if they evaluated postural control during static bipedal standing in individuals with LBP by measuring center of pressure (CoP) variables, and reported at least one pain-related psychological variable. Correlation coefficients between pain-related psychological variables and CoP variables were extracted. Study quality was assessed with the "Quality In Prognosis Studies" tool (QUIPS). Random-effect models were used to calculate pooled correlation coefficients for different postural tasks. Sub-analyses were performed for positional or dynamic CoP variables. Certainty of evidence was assessed with an adjusted "Grading of Recommendations, Assessment, Development, and Evaluations" tool (GRADE). The protocol was registered on PROSPERO (CRD42021241739)., Results: Sixteen studies (n = 723 participants) were included. Pain-related fear (16 studies) and pain catastrophizing (three studies) were the only reported pain-related psychological variables. Both pain-related fear (-0.04 < pooled r < 0.14) and pain catastrophizing (0.28 < pooled r < 0.29) were weakly associated with CoP variables during different postural tasks. For all associations, the certainty of evidence was very low., Significance: Pain-related fear and pain catastrophizing are only weakly associated with postural control during static bipedal standing in individuals with LBP, regardless of postural task difficulty. Certainty of evidence is very low thus it is conceivable that future studies accounting for current study limitations might reveal different findings., Competing Interests: Declaration of Competing Interest This work was supported by Research Foundation Flanders (FWO, grant G072122N). The funders played no role in the design, data collection, data analysis, interpretation of results, or writing of this study., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Diagnosis-to-ablation time (DAT) strongly predicts recurrence of atrial fibrillation (AF) after ablation. Whether this association holds with any lower and/or upper limits is unknown., Objectives: The goal of this study was to assess the impact of DAT on AF recurrence in search of lower and upper DAT thresholds., Methods: A total of 2,000 patients with AF from 2 cohorts of 1,000 patients each (69% male; age 62 ± 10 years) undergoing pulmonary vein isolation (PVI) between 2005-2014 and 2017-2019 were followed up for 3 years., Results: Clinical success was achieved in 61.7% of patients. Median DAT decreased over time from 36 months (Q1-Q3: 12-72 months) in the first cohort to 12 months (Q1-Q3: 5-48 months) in the second cohort (P < 0.001). A multivariable Cox proportional hazards fitted model of AF recurrence rate in relation to DAT (range: 0-288 months) showed a steep rise in AF recurrence, from 27% to 40% in the first 36 months (d%/dt = 0.36), with a first inflection point at 36 months, and a less steep rise to 45% until 90 months (d%/dt = 0.09), with flattening beyond 90 months (d%/dt = 0.026). Rise in AF recurrence rate in the first 36 months was higher in patients with persistent AF (from 40% to 54%; d%/dt = 0.39) than in patients with paroxysmal AF (19% to 29%; d%/dt = 0.28)., Conclusions: The association between DAT and AF recurrence has no lower limit ("the shorter the better"), whereas little gain is to be expected beyond 36 months ("the longer the more irrelevant"). Our data advocate for performing PVI as early as possible, certainly within 3 years of AF diagnosis, and even more so in persistent AF., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Based on the lack of literature to support any treatment strategy in patients with foot drop due to peroneal nerve entrapment, a prospective study randomizing patients between surgery and conservative treatment is warranted. Since studies comparing surgery to no surgery are often challenging, we first examined the feasibility of such a randomized controlled trial., Methods/design: An internal feasibility pilot study was conducted to assess several aspects of process, resource, management, and scientific feasibility. The main objective was the assessment of the recruitment rate. The criterion to embark on a full study was the recruitment of at least 14 patients in 6 participating centers within 6 months. Cross-over rate, blinding measures, training strategies, and trial assessments were evaluated. The trial was entirely funded by the KCE Trials public funding program of the Belgian Health Care Knowledge Centre (ID KCE19-1232)., Results: The initial duration was prolonged due to the COVID-19 pandemic. Between April 2021 and October 2022, we included 19 patients of which 15 were randomized. Fourteen patients were treated as randomized. One drop-out occurred after randomization, prior to surgery. We did not document any cross-over or accidental unblinding. Training strategies were successful. Patients perceived the quality of life questionnaire as the least relevant assessment. Assessment of ankle dorsiflexion range of motion was prone to interobserver variability. All other trial assessments were adequate., Discussion: Recruitment of the anticipated 14 patients was feasible although slower than expected. The Short-Form Health Survey (SF-36) and assessment of ankle dorsiflexion range of motion will no longer be included in the full-scale FOOTDROP trial., Conclusion: The FOOTDROP study is feasible., Trial Registration: ClinicalTrials.gov, identifier NCT04695834 . Registered 4 January 2021., (© 2023. The Author(s).)

Background: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly used in patients with cardiogenic shock despite the lack of evidence from adequately powered randomised clinical trials. Three trials reported so far were underpowered to detect a survival benefit; we therefore conducted an individual patient-based meta-analysis to assess the effect of VA-ECMO on 30-day death rate., Methods: Randomised clinical trials comparing early routine use of VA-ECMO versus optimal medical therapy alone in patients presenting with infarct-related cardiogenic shock were identified by searching MEDLINE, Cochrane Central Register of Controlled Trials, Embase, and trial registries until June 12, 2023. Trials were included if at least all-cause death rate 30 days after in-hospital randomisation was reported and trial investigators agreed to collaborate (ie, providing individual patient data). Odds ratios (ORs) as primary outcome measure were pooled using logistic regression models. This study is registered with PROSPERO (CRD42023431258)., Findings: Four trials (n=567 patients; 284 VA-ECMO, 283 control) were identified and included. Overall, there was no significant reduction of 30-day death rate with the early use of VA-ECMO (OR 0·93; 95% CI 0·66-1·29). Complication rates were higher with VA-ECMO for major bleeding (OR 2·44; 95% CI 1·55-3·84) and peripheral ischaemic vascular complications (OR 3·53; 95% CI 1·70-7·34). Prespecified subgroup analyses were consistent and did not show any benefit for VA-ECMO (p interaction ≥0·079)., Interpretation: VA-ECMO did not reduce 30-day death rate compared with medical therapy alone in patients with infarct-related cardiogenic shock, and an increase in major bleeding and vascular complications was observed. A careful review of the indication for VA-ECMO in this setting is warranted., Funding: Foundation Institut für Herzinfarktforschung., Competing Interests: Declaration of interests HT is President of the German Cardiac Society. PO reports lecture fees from Abiomed, Getinge, Edwards, and Xenios/Fresenius. JB reports lecture fees from Abiomed, Resuscitec, and Xenios. DA reports funding to support a clinical research fellow from Abbott Vascular; has received funding from AstraZeneca for unrelated research; has conducted unrelated consultancy for General Electric; holds patents for medical devices, including a cardiac assist device (EP3277337A1, PCT/GB2017/050877, UK patent application number 2211616.4); received royalties from Elsevier for The ECG Made Practical and ECG Problems books; is Chair of the ESC-ACVC SCAD Study Group and ESC-EORP SCAD Registry; and reports participation on an advisory board for Beat SCAD. MS reports consultant fees from Abbott Vascular and iVascular. AB reports that the EURO SHOCK trial received European Commission Horizons 2020 funding (reference number 754946-2), University of Leicester as beneficiary. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: ST-segment-elevation myocardial infarction (STEMI) guidelines recommend pharmaco-invasive treatment if timely primary percutaneous coronary intervention (PCI) is unavailable. Full-dose tenecteplase is associated with an increased risk of intracranial hemorrhage in older patients. Whether pharmaco-invasive treatment with half-dose tenecteplase is effective and safe in older patients with STEMI is unknown., Methods: STREAM-2 (Strategic Reperfusion in Elderly Patients Early After Myocardial Infarction) was an investigator-initiated, open-label, randomized, multicenter study. Patients ≥60 years of age with ≥2 mm ST-segment elevation in 2 contiguous leads, unable to undergo primary PCI within 1 hour, were randomly assigned (2:1) to half-dose tenecteplase followed by coronary angiography and PCI (if indicated) 6 to 24 hours after randomization, or to primary PCI. Efficacy end points of primary interest were ST resolution and the 30-day composite of death, shock, heart failure, or reinfarction. Safety assessments included stroke and nonintracranial bleeding., Results: Patients were assigned to pharmaco-invasive treatment (n=401) or primary PCI (n=203). Median times from randomization to tenecteplase or sheath insertion were 10 and 81 minutes, respectively. After last angiography, 85.2% of patients undergoing pharmaco-invasive treatment and 78.4% of patients undergoing primary PCI had ≥50% resolution of ST-segment elevation; their residual median sums of ST deviations were 4.5 versus 5.5 mm, respectively. Thrombolysis In Myocardial Infarction flow grade 3 at last angiography was ≈87% in both groups. The composite clinical end point occurred in 12.8% (51/400) of patients undergoing pharmaco-invasive treatment and 13.3% (27/203) of patients undergoing primary PCI (relative risk, 0.96 [95% CI, 0.62-1.48]). Six intracranial hemorrhages occurred in the pharmaco-invasive arm (1.5%): 3 were protocol violations (excess anticoagulation in 2 and uncontrolled hypertension in 1). No intracranial bleeding occurred in the primary PCI arm. The incidence of major nonintracranial bleeding was low in both groups (<1.5%)., Conclusions: Halving the dose of tenecteplase in a pharmaco-invasive strategy in this early-presenting, older STEMI population was associated with electrocardiographic changes that were at least comparable to those after primary PCI. Similar clinical efficacy and angiographic end points occurred in both treatment groups. The risk of intracranial hemorrhage was higher with half-dose tenecteplase than with primary PCI. If timely PCI is unavailable, this pharmaco-invasive strategy is a reasonable alternative, provided that contraindications to fibrinolysis are observed and excess anticoagulation is avoided., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT02777580., Competing Interests: Disclosures Dr Van de Werf reports institutional grants from Boehringer Ingelheim. Dr Ristić reports grants from Boehringer-Ingelheim and Novartis and travel fees from Astra Zeneca and Pfizer. Dr Arias-Mendoza reports grants from Merck and Novo Nordisk and personal fees from Novartis, Roche, Bayer, Boehringer Ingelheim, and Asofarma. Dr Saraiva received personal fees from Boehringer Ingelheim, Astra Zeneca, Novo Nordisk, Lily, Janssen, Daichii Sankyo, Bayer, Novartis, Nova Quimica Brazil, and Albert Einstein ARO Brazil. Dr Musić reports a grant from Boehringer Ingelheim and travel fees from Astra Zeneca and Pfizer. Dr Westerhout reports consulting fees from Bayer Canada. Dr Pagès is a senior medical advisor of Boehringer Ingelheim. Dr Danays reports consulting fees from Boehringer Ingelheim. Dr Bainey reports personal fees from Bayer, Astra Zeneca, Boehringer Ingelheim, and HLS Therapeutics. Dr Sinnaeve reports consulting fees to his institution (KU Leuven). Dr Welsh reports personal fees and travel fees from Boehringer Ingelheim. Dr Armstrong reports institutional and personal grants from Merck, Bayer, CLS Limited, Eli Lilly, and Boehringer Ingelheim and personal fees from Merck, Boehringer Ingelheim, Bayer, and Novo Nordisk. All other authors report no competing interests.

Background: Cardiogenic shock (CGS) occurs in 10% of patients presenting with acute myocardial infarction (MI), with in-hospital mortality rates of 40-50% despite revascularisation., Aims: The EURO SHOCK trial aimed to determine if early use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) could improve outcomes in patients with persistent CGS following primary percutaneous coronary intervention (PPCI)., Methods: This multicentre, pan-European trial randomised patients with persistent CGS 30 minutes after PPCI of the culprit lesion to receive either VA-ECMO or continue with standard therapy. The primary outcome measure was 30-day all-cause mortality in an intention-to-treat analysis. Secondary endpoints included 12-month all-cause mortality and 12-month composite of all-cause mortality or rehospitalisation due to heart failure., Results: Due to the impact of the COVID-19 pandemic, the trial was stopped before completion of recruitment, after randomisation of 35 patients (standard therapy n=18, VA-ECMO n=17). Thirty-day all-cause mortality occurred in 43.8% of patients randomised to VA-ECMO and in 61.1% of patients randomised to standard therapy (hazard ratio [HR] 0.56, 95% confidence interval [CI]: 0.21-1.45; p=0.22). One-year all-cause mortality was 51.8% in the VA-ECMO group and 81.5% in the standard therapy arm (HR 0.52, 95% CI: 0.21-1.26; p=0.14). Vascular and bleeding complications occurred more often in the VA-ECMO arm (21.4% vs 0% and 35.7% vs 5.6%, respectively)., Conclusions: Due to the limited number of patients recruited to the trial, no definite conclusions could be drawn from the available data. Our study demonstrates the feasibility of randomising patients with CGS complicating acute MI but also illustrates the challenges. We hope these data will inspire and inform the design of future large-scale trials.

Functional somatic syndromes (FSS) include fibromyalgia, irritable bowel syndrome (IBS), and others. In FSS patients, merely viewing negative affective pictures can elicit increased physical symptoms. Our aim was to investigate the neural mechanisms underlying such negative affect-induced physical symptoms in FSS patients. Thirty patients with fibromyalgia and/or IBS and 30 healthy controls (all women) watched neutral, positive and negative affective picture blocks during functional MRI scanning and rated negative affect and physical symptoms after every block. We compared brain-wide activation during negative versus neutral picture viewing in FSS patients versus controls using robust general linear model analysis. Further, we compared neurologic pain signature (NPS), stimulus intensity-independent pain signature (SIIPS) and picture-induced negative emotion signature (PINES) responses to the negative versus neutral affect contrast and investigated whether they mediated between-group differences in affective picture-induced physical symptom reporting. More physical symptoms were reported after viewing negative compared to neutral pictures, and this effect was larger in patients than controls (p = 0.025). Accordingly, patients showed stronger activation in somatosensory regions during negative versus neutral picture viewing. NPS, but not SIIPS nor PINES, responses were higher in patients than controls during negative versus neutral pictures (p = 0.026). These differential NPS responses partially mediated between-group differences in physical symptoms. In conclusion, picture-induced negative affect elicits physical symptoms in FSS patients as a result of activation of somatosensory and nociceptive brain patterns, supporting the idea that affect-driven alterations in processing of somatic signals is a critical mechanism underlying FSS., (© 2023. Springer Nature Limited.)

Objectives: After total hip arthroplasty (THA), over 30% of individuals report activity limitations and participation restrictions. This systematic review aimed to determine the association between contextual factors and outcomes in the activity and participation domain after THA for hip osteoarthritis (OA)., Methods: This systematic review was developed according to the PRISMA guidelines for systematic reviews. PubMed, Web of Science, Embase and Scopus were searched until August 2022. Risk of bias was assessed with the Quality in Prognosis Studies tool (QUIPS)., Results: Twenty-nine articles were included. Eighteen had a high risk of bias, 3 had a low risk of bias, and 8 had a moderate risk of bias. Anxiety was only investigated in studies with high risk of bias but showed a consistent negative association with activities and participation after THA across multiple studies. Evidence was inconsistent regarding the associations between depression, trait anxiety, sense of coherence, big 5 personality traits, educational level, marital status, employment status, job position, expectations and social support, and the activity and participation domain. Optimism, general self-efficacy, cognitive appraisal processes, illness perception, ethnicity, and positive life events were associated with activities and participation but were only investigated in 1 study. No associations were identified across multiple studies for living or smoking status. Control beliefs, kinesiophobia, race, discharge location, level of poverty in neighbourhood, negative life events and occupational factors, were not associated with the activity and participation domain but were only investigated in 1 study., Conclusion: Methodological quality of the included studies was low. Anxiety was the only factor consistently associated with worse outcomes in the activity and participation domain after THA but was only investigated in studies with high risk of bias. Further research is needed to confirm relationships between other contextual factors and activities and participation after THA., Registration: PROSPERO CRD42020199070., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

A dysregulated autonomic stress physiology is hypothesized to play an important role in the etiology and perpetuation of somatic symptoms that cannot be (fully) explained by an organic disease. The aim of this study was to focus on the role of the respiratory system. We examined end-tidal CO 2 concentration (PetCO 2 ) in healthy controls (n = 30), patients with panic disorder (n = 36), and patients with stress-related (overstrain; n = 35, burnout; n = 44) or functional syndromes [fibromyalgia (FM) and/or chronic fatigue syndrome (CFS); n = 36]. Participants went through a rest period and a respiratory challenge with recovery, whilst PetCO 2 was continuously monitored by a capnograph. Taken together, our results suggest: (1) an overactive respiratory system to be a possible transdiagnostic underlying factor of overstrain, burnout, and panic disorder, and (2) the presence of a less active respiratory fight-flight response in the more chronic and severe functional syndromes (FM/CFS)., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Drug eluting stents (DES) are associated with a 2% to 4% annual rate of target lesion failure through 5-to-10-year follow-up. The presence of a metallic protheses is a trigger for neo-atherosclerosis and very late stent thrombosis. A "leave nothing behind" strategy using Drug Coated Balloons has been suggested; however, paclitaxel coated balloons are only recommended in selected indications. Recently a novel sirolimus eluting balloon, the SELUTION SLR TM 014 PTCA balloon (SEB) (M.A. MedAlliance SA, Nyon, Switzerland) has been developed., Hypothesis: A strategy of percutaneous coronary intervention (PCI) with SEB and provisional DES is non-inferior to a strategy of systematic DES on target vessel failure (TVF) at one and five years. If non-inferiority is met at 5 years, superiority will be tested., Design: SELUTION DeNovo is a multi-center international open-label randomized trial. Subjects meeting eligibility criteria are randomized 1:1 to treatment of all lesions with either SEB and provisional DES or systematic DES. Major inclusion criteria are PCI indicated for ≥1 lesion considered suitable for treatment by either SEB or DES and clinical presentation with chronic coronary syndrome, unstable angina or non-ST segment elevation myocardial infarction (NSTEMI). There is no limitation in the number of lesions to be treated. Target lesions diameters are between 2 and 5 mm. Major exclusion criteria are lesions in the left main artery, chronic total occlusions, ST segment elevation myocardial infarction and unstable non-ST segment elevation myocardial infarction. Three thousand three hundred twenty six patients will be included in 50 sites in Europe and Asia. TVF rates and their components will be determined at 30 days, 6 months and annually up to 5 years post-intervention. Among secondary endpoints, bleeding events, cost-effectiveness data and net clinical benefits will be assessed., Summary: SELUTION DeNovo trial is an open-label, multi-center international randomized trial comparing a strategy of PCI with SEB and provisional DES to a strategy of PCI with systematic DES on TVF at one and five years. Non-inferiority will be tested at one and five years. If non-inferiority is met at five years, superiority will be tested., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Rates and modulators of SARS-CoV-2 vaccine nonresponse and breakthrough infections remain unclear in serially vaccinated transplant recipients. In a prospective, mono-centric, observational study, 1878 adult solid organ and hematopoietic cell transplant recipients, with prior SARS-CoV-2 vaccination, were included between March 2021 and February 2022. SARS-CoV-2 anti-spike IgG antibodies were measured at inclusion and details on SARS-CoV-2 vaccine doses and infection were collected. No life-threatening adverse events were reported after a total of 4039 vaccine doses. In transplant recipients without prior SARS-CoV-2 infection (n = 1636), antibody response rates ranged widely, from 47% in lung transplant to 90% in liver transplant and 91% in hematopoietic cell transplant recipients after third vaccine dose. Antibody positivity rate and levels increased after each vaccine dose in all types of transplant recipients. In multivariable analysis, older age, chronic kidney disease and daily dose of mycophenolate and corticosteroids were negatively associated with antibody response rate. Overall rate of breakthrough infections was 25.2% and mainly (90.2%) occurred after third and fourth vaccine dose. Lung transplant recipients had the highest rates of severe breakthrough infection (10.5%) and death (2.5%). In multivariable analysis, older age, daily dose of mycophenolate and corticosteroids were associated with severe breakthrough infection. Transplant recipients with infection before first vaccine dose (n = 160) had higher antibody response rates and levels after each vaccine dose, and a significantly lower overall rate of breakthrough infections compared to those without prior infection. Antibody response after SARS-CoV-2 vaccination and rate of severe breakthrough infections vary largely between different transplant types and are modulated by specific risk factors. The observed heterogeneity supports a tailored approach against COVID-19 in transplant recipients., (© 2023 Wiley Periodicals LLC.)

Background: Large heterogeneity exists in the clinical manifestation of hip osteoarthritis (OA). It is therefore not surprising that pain and disability in individuals with hip OA and after total hip arthroplasty (THA) cannot be explained by biomedical variables alone. Indeed, also maladaptive pain-related cognitions and emotions can contribute to pain and disability, and can lead to poor treatment outcomes. Traumatic experiences, mental disorders, self-efficacy and social support can influence stress appraisal and strategies to cope with pain, but their influence on pain and disability has not yet been established in individuals with hip OA undergoing THA. This study aims (1) to determine the influence of traumatic experiences and mental disorders on pain processing before and shortly after THA (2) to identify preoperative clinical phenotypes in individuals with hip OA eligible for THA, (3) to identify pre- and early postoperative prognostic factors for outcomes in pain and disability after THA, and (4) to identify postoperative clinical phenotypes in individuals after THA., Methods: This prospective longitudinal cohort study will investigate 200 individuals undergoing THA for hip OA. Phenotyping variables and candidate prognostic factors include pain-related fear-avoidance behaviour, perceived injustice, mental disorders, traumatic experiences, self-efficacy, and social support. Peripheral and central pain mechanisms will be assessed with thermal quantitative sensory testing. The primary outcome measure is the hip disability and osteoarthritis outcome score. Other outcome measures include performance-based measures, hip muscle strength, the patient-specific functional scale, pain intensity, global perceived effect, and outcome satisfaction. All these measurements will be performed before surgery, as well as 6 weeks, 3 months, and 12 months after surgery. Pain-related cognitions and emotions will additionally be assessed in the early postoperative phase, on the first, third, fifth, and seventh day after THA. Main statistical methods that will be used to answer the respective research questions include: LASSO regression, decision tree learning, gradient boosting algorithms, and recurrent neural networks., Discussion: The identification of clinical phenotypes and prognostic factors for outcomes in pain and disability will be a first step towards pre- and postoperative precision medicine for individuals with hip OA undergoing THA., Trial Registration: ClinicalTrials.gov: NCT05265858. Registered on 04/03/2022., (© 2023. The Author(s).)

Background: No detailed data on left bundle branch block (LBBB) and permanent pacemaker implantation (PPI) exist from randomised clinical trials comparing the ACURATE neo and CoreValve Evolut devices., Aims: Our aim was to assess the incidence and impact of new LBBB and PPI with self-expanding prostheses from a powered randomised comparison., Methods: From the SCOPE 2 trial, 648 patients with no previous pacemaker were analysed for PPI at 30 days, and 426 patients without previous LBBB were adopted for analysis of LBBB at 30 days.  Results: At 30 days, 16.5% of patients required PPI; rates were higher in CoreValve Evolut compared to ACURATE neo recipients (21.0% vs 12.3%; p=0.004). Previous right bundle branch block (odds ratio [OR] 6.11, 95% confidence interval [CI]: 3.19-11.73; p<0.001) was associated with an increased risk of PPI at 30 days, whereas the use of the ACURATE neo (OR 0.50, 95% CI: 0.31-0.81; p=0.005) was associated with a decreased risk. One-year mortality was similar in patients with and without new PPI. A total of 9.4% of patients developed persistent LBBB at 30 days, with higher incidences in CoreValve Evolut recipients (13.4% vs 5.5%; p=0.007). New LBBB at 30 days was associated with lower ejection fraction at 1 year (65.7%±11.0 vs 69.1%±7.6; p=0.041)., Conclusions: New LBBB and PPI rates were lower in ACURATE neo compared to CoreValve Evolut recipients. The ACURATE neo valve was associated with a lower risk of PPI at 30 days. No effect on 1-year mortality was determined for PPI at 30 days, while LBBB at 30 days was associated with reduced ejection fraction at 1 year.

A phase II study (PRIMMO) of patients with pretreated persistent/recurrent/metastatic cervical or endometrial cancer is presented. Patients received an immunomodulatory five-drug cocktail (IDC) consisting of low-dose cyclophosphamide, aspirin, lansoprazole, vitamin D, and curcumin starting 2 weeks before radioimmunotherapy. Pembrolizumab was administered three-weekly from day 15 onwards; one of the tumor lesions was irradiated (8Gyx3) on days 15, 17, and 19. The primary endpoint was the objective response rate per immune-related response criteria (irORR) at week 26 (a lower bound of the 90% confidence interval [CI] of > 10% was considered efficacious). The prespecified 43 patients (cervical, n = 18; endometrial, n = 25) were enrolled. The irORR was 11.1% (90% CI 2.0-31.0) in cervical cancer and 12.0% (90% CI 3.4-28.2) in endometrial cancer. Median duration of response was not reached in both cohorts. Median interval-censored progression-free survival was 4.1 weeks (95% CI 4.1-25.7) in cervical cancer and 3.6 weeks (95% CI 3.6-15.4) in endometrial cancer; median overall survival was 39.6 weeks (95% CI 15.0-67.0) and 37.4 weeks (95% CI 19.0-50.3), respectively. Grade ≥ 3 treatment-related adverse events were reported in 10 (55.6%) cervical cancer patients and 9 (36.0%) endometrial cancer patients. Health-related quality of life was generally stable over time. Responders had a significantly higher proportion of peripheral T cells when compared to nonresponders (p = 0.013). In conclusion, PRIMMO did not meet its primary objective in both cohorts; pembrolizumab, radiotherapy, and an IDC had modest but durable antitumor activity with acceptable but not negligible toxicity.Trial registration ClinicalTrials.gov (identifier NCT03192059) and EudraCT Registry (number 2016-001569-97)., (© 2022. The Author(s).)

Background: High-quality evidence is lacking to support one treatment strategy over another in patients with foot drop due to peroneal nerve entrapment. This leads to strong variation in daily practice., Methods/design: The FOOTDROP (Follow-up and Outcome of Operative Treatment with Decompressive Release Of The Peroneal nerve) trial is a randomized, multi-centre study in which patients with peroneal nerve entrapment and persistent foot drop, despite initial conservative treatment, will be randomized 10 (± 4) weeks after onset between non-invasive treatment and surgical decompression. The primary endpoint is the difference in distance covered during the 6-min walk test between randomization and 9 months later. Time to recovery is the key secondary endpoint. Other secondary outcome measures encompass ankle dorsiflexion strength (MRC score and isometric dynamometry), gait assessment (10-m walk test, functional ambulation categories, Stanmore questionnaire), patient-reported outcome measures (EQ5D-5L), surgical complications, neurological deficits (sensory changes, motor scores for ankle eversion and hallux extension), health economic assessment (WPAI) and electrodiagnostic assessment., Discussion: The results of this randomized trial may elucidate the role of surgical decompression of the peroneal nerve and aid in clinical decision-making., Trial Registration: ClinicalTrials.gov NCT04695834. Registered on 4 January 2021., (© 2022. The Author(s).)

Background: The Academic Research Consortium - High Bleeding Risk (ARC-HBR) initiative defined conditions associated with percutaneous coronary intervention (PCI)-related bleeding., Aims: We sought to further explore these HBR conditions in the setting of transcatheter aortic valve replacement (TAVR)., Methods: Patients from the SCOPE 2 trial were stratified by their bleeding risk status based on the ARC-HBR definitions. Baseline and procedural characteristics, as well as key clinical outcomes including Bleeding Academic Research Consortium (BARC) 3-5 bleeding, were compared in ARC-HBR positive (HBR+) and ARC-HBR negative (HBR-) patients., Results: Of 787 patients randomised in SCOPE 2 and included in this study, 633 were HBR+ (80.4%). Compared with HBR- patients, those HBR+ were older and more frequently presented with diabetes, a history of coronary artery disease, atrial fibrillation, prior cerebrovascular accident, and a Society of Thoracic Surgeons predicted risk of 30-day mortality (STS-PROM) (4.9±2.9% vs 3.3%±2.1%; p<0.0001). In addition, HBR+ patients were more frequently on oral anticoagulation therapy. At 1 year, HBR+ patients had higher rates of all-cause death (12.4% vs 4.3%, respectively, risk difference 8.09%; 95% confidence interval [CI]: 3.76-12.41; p=0.0002); the rates of BARC 3-5 type bleeding were relatively high but not statistically different compared with HBR- patients (7.7% vs 6.1%, risk difference 1.67%; 95% CI: -2.72 to 6.06; p=0.46). Subgroup analyses for bleeding events showed no significant interaction in terms of STS-PROM score, age, or medications., Conclusions: The ARC-HBR criteria failed to isolate a subgroup of patients at higher bleeding risk in TAVR patients from a randomised trial. These findings have potential implications, especially for the selection of post-TAVR antithrombotic regimens based on individual bleeding-risk profiles. Specific HBR criteria should be defined for TAVR patients.

Vitamin D status is influenced by well-known determinants, but factors associated with low 25-hydroxyvitamin D levels in the cutaneous melanoma population are not well defined. The aim of this study was to confirm the well-known determinants and to assess new determinants for 25-hydroxyvitamin D levels in a cutaneous melanoma population. In a prospectively included cohort of 387 patients with cutaneous melanoma the association of 25-hydroxyvitamin D levels with sex, age, body mass index, time of blood withdrawal, Fitzpatrick phototype, vitamin D supplementation, score for intensity of lifetime sun exposure, smoking, education level, hair and skin colour, eye colour, total number of benign naevi, freckles and parameters of chronic sun damage was investigated. In addition, 25-hydroxyvitamin D levels were correlated with pathological parameters of the primary tumour and melanoma stage (8th edition of the American Joint Committee on Cancer (AJCC). Univariate and multivariate logistic regressions were performed using R software. The following factors had a significant effect on vitamin D status: body mass index, seasonal time of blood sampling, vitamin D supplementation, and a subtype of skin, and hair colour.

Background: Previous studies indicated that about 20% of the individuals undergoing back surgery are unable to return to work 3 months to 1 year after surgery. The specific factors that predict individual trajectories in postoperative pain, recovery, and work resumption are largely unknown. The aim of this study is to identify modifiable predictors of work resumption after back surgery., Methods: In this multisite, prospective, longitudinal study, 300 individuals with radicular pain undergoing a lumbar decompression will be followed until 1-year post-surgery. Prior to surgery, participants will perform a computer task to assess fear of movement-related pain, avoidance behavior, and their generalization to novel situations. Before and immediately after surgery, participants will additionally complete questionnaires to assess fear of movement-related pain, avoidance behavior, optimism, expectancies towards recovery and work resumption, and the duration and severity of the pain. Six weeks, 3 months, 6 months, and 12 months after surgery, they will again complete questionnaires to assess sustainable work resumption, pain severity, disability, and quality of life. The primary hypothesis is that (generalization of) fear of movement-related pain and avoidance behavior will negatively affect sustainable work resumption after back surgery. Second, we hypothesize that (generalization of) fear of movement-related pain and avoidance behavior, negative expectancies towards recovery and work resumption, longer pain duration, and more severe pain before the surgery will negatively affect work resumption, pain severity, disability, and quality of life after back surgery. In contrast, optimism and positive expectancies towards recovery and work resumption are expected to predict more favorable work resumption, better quality of life, and lower levels of pain severity and disability after back surgery., Discussion: With the results of this research, we hope to contribute to the development of strategies for early identification of risk factors and appropriate guidance and interventions before and after back surgery. Trial registration The study was preregistered on ClinicalTrials.gov: NCT04747860 on February 9, 2021., (© 2022. The Author(s).)

Objective: This study aimed to validate the Interoceptive Sensitivity and Attention Questionnaire (ISAQ), a 17-item self-report measure assessing sensitivity and attention to interoceptive signals., Methods: In study 1, exploratory and confirmatory factor analysis was performed in a student convenience sample (n = 1868). In study 2, ISAQ data of a healthy sample (n = 144) and various patient groups experiencing stress-related syndromes (overstrain, n = 63; burnout, n = 37; panic disorder [PD]. n = 60) and/or persistent somatic symptoms in daily life (irritable bowel syndrome, n = 38; fibromyalgia and/or chronic fatigue syndrome, n = 151; medically unexplained dyspnea [MUD], n = 29) were compared., Results: Three subscales were revealed: (F1) sensitivity to neutral bodily sensations, (F2) attention to unpleasant bodily sensations, and (F3) difficulty disengaging from unpleasant bodily sensations. Overall, patients with fibromyalgia and/or chronic fatigue syndrome and patients with MUD scored significantly higher on F1 (p = .009 and p = .027, respectively) and F2 (p = .002 and p < .001, respectively) than healthy controls. Patients with PD had higher scores on subscales F2 (p < .001) and F3 (p < .001) compared with healthy controls, as well as higher scores on F2 compared with all other patient groups (pPD versus MUD = .008; all other p values < .001)., Conclusions: Interoceptive sensibility-the self-reported aspect of interoception-is not a homogeneous or unitary construct. The subscales of the ISAQ differentiate healthy controls from patients with persistent somatic and/or stress-related complaints in daily life and distinguish different patient groups. The ISAQ can be used as a concise, reliable, and clinically relevant research tool to further disentangle adaptive and maladaptive aspects of interoceptive ability., (Copyright © 2021 by the American Psychosomatic Society.)

Objectives: Report the results at 2 years of the patients included in the SENIOR trial., Background: Patients above 75 years of age represent a fast-growing population in the cathlab. In the SENIOR trial, patients treated by percutaneous coronary intervention (PCI) with drug eluting stent (DES) and a short duration of P2Y12 inhibitor (1 and 6 months for stable and unstable coronary syndromes, respectively) compared with bare metal stents (BMS) was associated with a 29% reduction in the rate of all-cause mortality, myocardial infarction (MI), stroke, and ischaemia-driven target lesion revascularization (ID-TLR) at 1 year. The results at 2 years are reported here., Methods and Results: We randomly assigned 1,200 patients (596[50%] to the DES group and 604[50%] to the BMS group). At 2 years, the composite endpoint of all-cause mortality, MI, stroke and ID-TLR had occurred in 116 (20%) patients in the DES group and 131 (22%) patients in the BMS group (RR 0.90 [95%CI 0.72-1.13], p = .37). IDTLR occurred in 14 (2%) patients in the DES group and 41 (7%) patients in the BMS group (RR 0.35 [95%CI 0.16-0.60], p = .0002). Major bleedings (BARC 3-5) occurred in 27(5%) patients in both groups (RR 1.00, [95%CI 0.58-1.75], p = .99). Stent thrombosis rates were low and similar between DES and BMS (0.8 vs 1.3%, (RR 0.52 [95%CI 0.01-1.95], p = .27)., Conclusion: Among elderly PCI patients, a strategy combining a DES together with a short duration of DAPT is associated with a reduction in revascularization up to 2 years compared with BMS with very few late events and without any increased in bleeding complications or stent thrombosis., (© 2021 Wiley Periodicals LLC.)

Research Question: How do cumulative live birth rates (CLBR), cumulative multiple live birth rates (CMLBR) and dropout rates over six IVF and intracytoplasmic sperm injection (ICSI) cycles change over time?, Design: Prospective longitudinal cohort (n = 16,073 patients; 48,946 cycles) starting a first fresh assisted reproductive technology cycle between 1 January 2014 and 31 December 2016, with follow-up until 31 December 2017. Outcomes between the periods 2014-2017 and 2009-2012 were compared., Results: Conservative estimates of CLBR after six complete cycles were significantly higher in women younger than 35 years after every cycle: one to three, adjusted P-value [p adj] < 0.0001; four, p = 0.01; five, p adj = 0.03; six, p adj = 0.04) and after the first cycle in women aged 35-37 years (p adj = 0.04) in 2014-2017 versus 2009-2012. For an optimal estimate, the CLBR was significantly higher after the first three cycles in women younger than 35 years (all p adj < 0.0001) and after the first cycle in women aged 35-37 years (p adj = 0.04). The CMLBR rate decreased from 5.1% ± 0.19 (SE) to 4.1% ± 0.16 for the conservative estimate and from 8.6% ±0.37 (SE) to 6.7% ± 0.30 for the optimal estimate after six complete cycles for the whole cohort. Dropout rates of complete cycles were 26.5% 29.4%, 33.4%, 38.9% and 47.3% after the first to fifth cycle, respectively. Compared with 2009-2012, the dropout rate in the current period was significantly higher for the first (P < 0.0001) and second (P = 0.0124) cycle., Conclusion: Over six complete IVF/ICSI cycles, CLBR and dropout rates increased and multiple live birth rates decreased when 2014-2017 was compared with 2009-2012., (Copyright © 2021 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Aims: Cardiogenic shock (CGS) occurs in 6-10% of patients with acute coronary syndromes (ACS). Mortality has fallen over time from 80% to approximately 50% consequent on acute revascularisation but has plateaued since the 1990s. Once established, patients with CGS develop adverse compensatory mechanisms that contribute to the downward spiral towards death, which becomes difficult to reverse. We aimed to test in a robust, prospective, randomised controlled trial whether early support with veno-arterial extracorporeal membrane oxygenation (VA-ECMO) provides clinical benefit by improving mortality and morbidity., Methods and Results: The EURO SHOCK trial will test the benefit or otherwise of mechanical cardiac support using VA-ECMO, initiated early after acute percutaneous coronary intervention (PCI) for CGS. The trial sets out to randomise 428 patients with CGS complicating ACS, following primary PCI (P-PCI), to either very early ECMO plus standard pharmacotherapy, or standard pharmacotherapy alone. It will be conducted in 39 European centres. The primary endpoint is 30-day all-cause mortality with key secondary endpoints: 1) 12-month all-cause mortality or admission for heart failure, 2) 12-month all-cause mortality, 3) 12-month admission for heart failure. Cost-effectiveness analysis (including quality of life measures) will be embedded. Mechanistic and hypothesis-generating substudies will be undertaken., Conclusions: The EURO SHOCK trial will determine whether early initiation of VA-ECMO in patients presenting with ACS-CGS persisting after PCI improves mortality and morbidity.

The Kidney Solid Organ Response Test (kSORT) blood gene expression assay was developed to noninvasively detect acute rejection (AR) after kidney transplantation. Its performance in a setting with natural disease prevalence has not been evaluated. A retrospective, multicenter cohort study was conducted across all single kidney transplant recipients, transplanted between 2011 and 2015, with samples within the first year after transplantation available in existing biobanks. The primary objective was to determine the diagnostic performance of the kSORT assay to detect AR (T cell-mediated and/or antibody-mediated rejection) as compared to a concomitant renal biopsy. AR was reported on the concomitant biopsy in 188 of 1763 (10.7%) blood samples and any rejection (including borderline changes) in 614 of 1763 (34.8%) blood samples. In 320 of 1763 samples (18.2%) the kSORT risk category was indeterminate. The kSORT assay had no diagnostic value for AR (area under the curve [AUC] 0.51, 95% confidence interval [CI] 0.50-0.56; P = .46) overall, or when considering indication biopsies (N = 487) and protocol-specified biopsies (N = 1276) separately (AUC of 0.53, 95% CI 0.50-0.59, P = .44 and 0.55, 95% CI 0.50-0.61, P = .09, respectively). This large retrospective study utilizing samples obtained under real-world clinical conditions, was unable to validate the kSORT assay for detection of AR in the first year after transplantation., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Few randomized trials have compared bioprostheses for transcatheter aortic valve replacement, and no trials have compared bioprostheses with supra-annular design. The SCOPE 2 trial (Safety and Efficacy Comparison of Two TAVI Systems in a Prospective Randomized Evaluation 2) was designed to compare the clinical outcomes of the ACURATE neo and CoreValve Evolut bioprostheses for transcatheter aortic valve replacement., Methods: SCOPE 2 was a randomized trial performed at 23 centers in 6 countries between April 2017 and April 2019. Patients ≥75 years old with an indication for transfemoral transcatheter aortic valve replacement as agreed by the heart team were randomly assigned to receive treatment with either the ACURATE neo (n=398) or the CoreValve Evolut bioprostheses (n=398). The primary end point, powered for noninferiority of the ACURATE neo bioprosthesis, was all-cause death or stroke at 1 year. The key secondary end point, powered for superiority of the ACURATE neo bioprosthesis, was new permanent pacemaker implantation at 30 days., Results: Among 796 randomized patients (mean age, 83.2±4.3 years; mean Society of Thoracic Surgeons Predicted Risk of Mortality score, 4.6±2.9%), clinical follow-up information was available for 778 (98%) patients. Within 1 year, the primary end point occurred in 15.8% of patients in the ACURATE neo group and in 13.9% of patients in the CoreValve Evolut group (absolute risk difference, 1.8%, upper 1-sided 95% confidence limit, 6.1%; P =0.0549 for noninferiority). The 30-day rates of new permanent pacemaker implantation were 10.5% in the ACURATE neo group and 18.0% in the CoreValve Evolut group (absolute risk difference, -7.5% [95% CI, -12.4 to -2.60]; P =0.0027). No significant differences were observed in the components of the primary end point. Cardiac death at 30 days (2.8% versus 0.8%; P =0.03) and 1 year (8.4% versus 3.9%; P =0.01), and moderate or severe aortic regurgitation at 30 days (10% versus 3%; P =0.002) were significantly increased in the ACURATE neo group., Conclusions: Transfemoral transcatheter aortic valve replacement with the self-expanding ACURATE neo did not meet noninferiority compared with the self-expanding CoreValve Evolut in terms of all-cause death or stroke at 1 year, and it was associated with a lower incidence of new permanent pacemaker implantation. In secondary analyses, the ACURATE neo was associated with more moderate or severe aortic regurgitation at 30 days and cardiac death at 30 days and 1 year. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03192813.

Background: The STREAM study demonstrated that a pharmaco-invasive strategy was at least as effective as primary PCI (pPCI) in patients presenting early with ST-elevation myocardial infarction (STEMI). The current trial is a response to the finding that reduced intracranial hemorrhage (ICH) in patients ≥75 years occurred after halving the dose of tenecteplase. Additionally, a subsequent analysis of full dose tenecteplase or alteplase in the Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT) trials demonstrated a steep increase in bleeding events beginning around the age of 60 years., Methods: STREAM-2 will compare the efficacy and safety of a novel pharmaco-invasive strategy as compared to routine pPCI in STEMI patients ≥60 years presenting within 3 hours from symptom onset. In the pharmaco-invasive arm patients will receive half-dose tenecteplase, as soon as possible before transport to a PCI center. In the pPCI arm, patients will be treated according to optimal standard of care defined by local practice. The key criteria for efficacy will be the number of patients achieving ≥50% ST-segment resolution before and after PCI in lead with maximal ST elevation at baseline and the clinical endpoints of death, congestive heart failure, shock or re-infarction, rescue PCI and aborted myocardial infarction, both singularly and as a composite at 30 days. Key safety criteria are total stroke, ICH and major non-intracranial bleeds. Approximately 600 patients will be randomized (400 to pharmaco-invasive treatment and 200 to pPCI). An interim analysis is planned after 300 patients are enrolled to consider adapting the trial to include a larger sample size aimed at undertaking a formal confirmatory trial., Discussion: The study will provide new insights aimed at establishing an effective and safer pharmaco-invasive treatment for the growing population of older STEMI patients who cannot undergo timely pPCI., Competing Interests: Disclosures The study is sponsored by Leuven Research & Development at the University of Leuven (KU Leuven) Belgium and supported by a grant from Boehringer Ingelheim GmbH to KU Leuven. The executive committee was responsible for the design and conduct of the trial. The academic authors vouch for the integrity and completeness of the data and analyses. Paul W. Armstrong has served as a consultant for Bayer and Merck. He has received research grants from CSL, Boehringer-Ingelheim, Bayer and Merck. Kris Bogaerts received consultancy fees through his institution from Boehringer Ingelheim GmbH. Robert Welsh has received research funding and honoraria from Astra Zeneca, Bayer, Boerhinger Ingelheim GmbH, and Pfizer. Peter Sinnaeve received Speaker’s and consultancy fees from Boehringer-Ingelheim. Patrick Goldstein reports travel support and lecture fees from Boehringer Ingelheim GmbH. Alain Pages is an employee of Boehringer Ingelheim GmbH. Thierry Danays is a former employee of Boehringer Ingelheim France, received consultancy fees from Boehringer Ingelheim GmbH. Frans Van de Werf received study grants to institution and lectures fees from Boehringer Ingelheim GmbH., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Attentional distraction from pain has been shown to be largely ineffective for obtaining a hypoalgesic effect in patients with chronic pain when compared to a control condition. It has been hypothesized that this may be due to the non-engaging types of distraction that have been used so far. Moreover, it is suggested that the hypoalgesic effects of distraction may be attenuated by pain-related cognitions and emotions, as they may increase the attention to pain., Methods: In this randomized controlled trial, patients with chronic nonspecific low back pain in the intervention group (n = 42) performed a single exercise session with nonimmersive VR games, while those in the control group (n = 42) performed the same exercises without VR games. We investigated whether VR distraction had a hypoalgesic effect during and immediately after the exercises, and whether it reduced the time spent thinking of pain during the exercises. We further explored whether pain-related fear, pain catastrophizing and baseline pain intensity moderated the effects of VR distraction., Results: VR distraction had a hypoalgesic effect during (Cohen's d = 1.29) and immediately after (Cohen's d = 0.85) the exercises, and it also reduced the time spent thinking of pain (Cohen's d = 1.31). Preliminary exploratory analyses showed that pain-related fear, pain catastrophizing and baseline pain intensity did not moderate the effects of VR distraction., Conclusions: Large effect sizes of VR distraction induced hypoalgesia were observed. This suggests that nonimmersive VR games can be used when it is deemed important to reduce the pain during exercises in patients with chronic nonspecific low back pain., Trial Registration: NCT02679300. This trial was registered on 10 February 2016.

Background: In the BACE trial, a 3-month (3 m) intervention with azithromycin, initiated at the onset of an infectious COPD exacerbation requiring hospitalization, decreased the rate of a first treatment failure (TF); the composite of treatment intensification (TI), step-up in hospital care (SH) and mortality., Objectives: (1) To investigate the intervention's effect on recurrent events, and (2) to identify clinical subgroups most likely to benefit, determined from the incidence rate of TF and hospital readmissions., Methods: Enrolment criteria included the diagnosis of COPD, a smoking history of ≥10 pack-years and ≥ 1 exacerbation in the previous year. Rate ratio (RR) calculations, subgroup analyses and modelling of continuous variables using splines were based on a Poisson regression model, adjusted for exposure time., Results: Azithromycin significantly reduced TF by 24% within 3 m (RR = 0.76, 95%CI:0.59;0.97, p = 0.031) through a 50% reduction in SH (RR = 0.50, 95%CI:0.30;0.81, p = 0.006), which comprised of a 53% reduction in hospital readmissions (RR = 0.47, 95%CI:0.27;0.80; p = 0.007). A significant interaction between the intervention, CRP and blood eosinophil count at hospital admission was found, with azithromycin significantly reducing hospital readmissions in patients with high CRP (> 50 mg/L, RR = 0.18, 95%CI:0.05;0.60, p = 0.005), or low blood eosinophil count (<300cells/μL, RR = 0.33, 95%CI:0.17;0.64, p = 0.001). No differences were observed in treatment response by age, FEV1, CRP or blood eosinophil count in continuous analyses., Conclusions: This post-hoc analysis of the BACE trial shows that azithromycin initiated at the onset of an infectious COPD exacerbation requiring hospitalization reduces the incidence rate of TF within 3 m by preventing hospital readmissions. In patients with high CRP or low blood eosinophil count at admission this treatment effect was more pronounced, suggesting a potential role for these biomarkers in guiding azithromycin therapy., Trial Registration: ClinicalTrials.gov number. NCT02135354 .

Rationale: Azithromycin prevents acute exacerbations of chronic obstructive pulmonary disease (AECOPDs); however, its value in the treatment of an AECOPD requiring hospitalization remains to be defined. Objectives: We investigated whether a 3-month intervention with low-dose azithromycin could decrease treatment failure (TF) when initiated at hospital admission and added to standard care. Methods: In an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial, patients who had been hospitalized for an AECOPD and had a smoking history of ≥10 pack-years and one or more exacerbations in the previous year were randomized (1:1) within 48 hours of hospital admission to azithromycin or placebo. The study drug (500 mg/d for 3 d) was administered on top of a standardized acute treatment of systemic corticosteroids and antibiotics, and subsequently continued for 3 months (250 mg/2 d). The patients were followed for 6 months thereafter. Time-to-first-event analyses evaluated the TF rate within 3 months as a novel primary endpoint in the intention-to-treat population, with TF defined as the composite of treatment intensification with systemic corticosteroids and/or antibiotics, a step-up in hospital care or readmission for respiratory reasons, or all-cause mortality. Measurements and Main Results: A total of 301 patients were randomized to azithromycin ( n  = 147) or placebo ( n  = 154). The TF rate within 3 months was 49% in the azithromycin group and 60% in the placebo group (hazard ratio, 0.73; 95% confidence interval, 0.53-1.01; P  = 0.0526). Treatment intensification, step-up in hospital care, and mortality rates within 3 months were 47% versus 60% ( P  = 0.0272), 13% versus 28% ( P  = 0.0024), and 2% versus 4% ( P  = 0.5075) in the azithromycin and placebo groups, respectively. Clinical benefits were lost 6 months after withdrawal. Conclusions: Three months of azithromycin for an infectious AECOPD requiring hospitalization may significantly reduce TF during the highest-risk period. Prolonged treatment seems to be necessary to maintain clinical benefits.

Background: Most studies fail to show an association between higher levels of pain-related fear and protective movement behaviour in patients with chronic low back pain (CLBP). This may be explained by the fact that only general measures of pain-related fear have been used to examine the association with movement patterns. This study explored whether task-specific, instead of general measures of pain-related fear can predict movement behaviour., Methods: Fifty-five patients with CLBP and 54 healthy persons performed a lifting task while kinematic measurements were obtained to assess lumbar range of motion (ROM). Scores on the Photograph Daily Activities Series-Short Electronic Version (PHODA-SeV), Tampa Scale for Kinesiophobia and its Activity Avoidance and Somatic Focus subscales were used as general measures of pain-related fear. The score on a picture of the PHODA-SeV, showing a person lifting a heavy object with a bent back, was used as task-specific measure of pain-related fear., Results: Lumbar ROM was predicted by task-specific, but not by general measures of pain-related fear. Only the scores on one other picture of the PHODA-SeV, similar to the task-specific picture regarding threat value and movement characteristics, predicted the lumbar ROM. Compared to healthy persons, patients with CLBP used significantly less ROM, except the subgroup with a low score on the task-specific measure of pain-related fear, who used a similar ROM., Conclusions: Our results suggest to use task-specific measures of pain-related fear when assessing the relationship with movement. It would be of interest to investigate whether reducing task-specific fear changes protective movement behaviour., Significance: This study shows that lumbar range of motion in CLBP is predicted by task-specific, but not by general measures of pain-related fear. This suggests that both in clinical practice and for research purposes, it might be recommended to use task-specific measures of pain-related fear when assessing the relationship with movement behaviour. This may help to disentangle the complex interactions between pain-related fear, movement and disability in patients with CLBP., (© 2019 European Pain Federation - EFIC®.)

Objective: Patients with functional somatic syndromes show reduced correspondence between induced physiological changes and self-reported symptoms in a rebreathing paradigm, as well as elevated symptoms unrelated to physiological changes after induction of negative affective states in an affective picture-viewing paradigm. Detailed results of both paradigms separately were published elsewhere. The main goal of the current report is to describe the relationship between the responses to these two paradigms measuring distortions in symptom perception in a well-described sample of patients with fibromyalgia and/or chronic fatigue syndrome., Methods: Patients (N = 81) with fibromyalgia and/or chronic fatigue syndrome participated in a test session comprising four well-validated paradigms, including the picture-viewing and rebreathing paradigm. Using mixed model analyses, we tested whether the amount of affective modulation of symptom reporting was related to distorted perception of induced dyspnea. In an exploratory way, we assessed the role of several individual difference variables as moderators., Results: There was no relationship between patients' amount of affective modulation of symptom reporting, as assessed with the picture paradigm, and level of distortion in dyspnea perception, as assessed with the rebreathing paradigm (effect of affective modulation in the subjective recovery from induced dyspnea: F1,70 = 0.16, p = .70; time by affective modulation interaction effect: F4,70 = 0.14, p = .97)., Conclusions: Biased symptom reporting in one paradigm is unrelated to biased symptom reporting in the other paradigm, indicating that distortions in symptom perception in patients with functional somatic syndromes are not a trait-like, cross-situationally stable condition, but a versatile dysfunction that is context dependent.

Background: Common variable immunodeficiency disorders (CVID) are a group of rare innate disorders characterized by specific antibody deficiency and increased rates of infections, comorbidities and mortality. The burden of CVID in Europe has not been previously estimated. We performed a retrospective analysis of the European Society for Immunodeficiencies (ESID) registry data on the subset of patients classified by their immunologist as CVID and treated between 2004 and 2014. The registered deaths and comorbidities were used to calculate the annual average age-standardized rates of Years of Life Lost to premature death (YLL), Years Lost to Disability (YLD) and Disability Adjusted Life Years (DALY=YLL + YLD). These outcomes were expressed as a rate per 10 5 of the CVID cohort (the individual disease burden), and of the general population (the societal disease burden)., Results: Data of 2700 patients from 23 countries were analysed. Annual comorbidity rates: bronchiectasis, 21.9%; autoimmunity, 23.2%; digestive disorders, 15.6%; solid cancers, 5.5%; lymphoma, 3.8%, exceeded the prevalence in the general population by a factor of 34.0, 7.6, 8.1, 2.4 and 32.6, respectively. The comorbidities of CVID caused 8722 (6069; 12,363) YLD/10 5 in this cohort, whereas 44% of disability burden was attributable to infections and bronchiectasis. The total individual burden of CVID was 36,785 (33,078, 41,380) DALY/10 5 . With estimated CVID prevalence of ~ 1/ 25,000, the societal burden of CVID ensued 1.5 (1.3, 1.7) DALY/10 5 of the general population. In exploratory analysis, increased mortality was associated with solid tumor, HR (95% CI): 2.69 (1.10; 6.57) p = 0.030, lymphoma: 5.48 (2.36; 12.71) p < .0001 and granulomatous-lymphocytic interstitial lung disease: 4.85 (1.63; 14.39) p = 0.005. Diagnostic delay (median: 4 years) was associated with a higher risk of death: 1.04 (1.02; 1.06) p = .0003, bronchiectasis: 1.03 (1.01; 1.04) p = .0001, solid tumor: 1.08 (1.04; 1.11) p < .0001 and enteropathy: 1.02 (1.00; 1.05) p = .0447 and stayed unchanged over four decades (p = .228)., Conclusions: While the societal burden of CVID may seem moderate, it is severe to the individual patient. Delay in CVID diagnosis may constitute a modifiable risk factor of serious comorbidities and death but showed no improvement. Tools supporting timely CVID diagnosis should be developed with high priority.

Objectives: Several chronic pain syndromes are characterized by deficient endogenous pain modulation as well as elevated negative affectivity and reduced resting heart rate variability. In order to elucidate the relationships between these characteristics, we investigated whether negative affectivity and heart rate variability are associated with endogenous pain modulation in a healthy population., Design, Subjects, and Methods: An offset analgesia paradigm with noxious thermal stimulation calibrated to the individual's pain threshold was used to measure endogenous pain modulation magnitude in 63 healthy individuals. Pain ratings during constant noxious heat stimulation to the arm (15 seconds) were compared with ratings during noxious stimulation comprising a 1 °C rise and return of temperature to the initial level (offset trials, 15 seconds). Offset analgesia was defined as the reduction in pain following the 1 °C decrease relative to pain at the same time point during continuous heat stimulation., Results: Evidence for an offset analgesia effect could only be found when noxious stimulation intensity (and, hence, the individual's pain threshold) was intermediate (46 °C or 47 °C). Offset analgesia magnitude was also moderated by resting heart rate variability: a small but significant offset effect was found in participants with high but not low heart rate variability. Negative affectivity was not related to offset analgesia magnitude., Conclusions: These results indicate that resting heart rate variability (HRV) is related to endogenous pain modulation (EPM) in a healthy population. Future research should focus on clarifying the causal relationship between HRV and EPM and chronic pain by using longitudinal study designs.

Aims: The clinical value of percutaneous coronary intervention (PCI) for chronic coronary total occlusions (CTOs) is not established by randomized trials. This study should compare the benefit of PCI vs. optimal medical therapy (OMT) on the health status in patients with at least one CTO., Method and Results: Three hundred and ninety-six patients were enrolled in a prospective randomized, multicentre, open-label, and controlled clinical trial to compare the treatment by PCI with OMT with a 2:1 randomization ratio. The primary endpoint was the change in health status assessed by the Seattle angina questionnaire (SAQ) between baseline and 12 months follow-up. Fifty-two percent of patients have multi-vessel disease in whom all significant non-occlusive lesions were treated before randomization. An intention-to-treat analysis was performed including 13.4% failed procedures in the PCI group and 7.3% cross-overs in the OMT group. At 12 months, a greater improvement of SAQ subscales was observed with PCI as compared with OMT for angina frequency [5.23, 95% confidence interval (CI) 1.75; 8.71; P = 0.003], and quality of life (6.62, 95% CI 1.78-11.46; P = 0.007), reaching the prespecified significance level of 0.01 for the primary endpoint. Physical limitation (P = 0.02) was also improved in the PCI group. Complete freedom from angina was more frequent with PCI 71.6% than OMT 57.8% (P = 0.008). There was no periprocedural death or myocardial infarction. At 12 months, major adverse cardiac events were comparable between the two groups., Conclusion: Percutaneous coronary intervention leads to a significant improvement of the health status in patients with stable angina and a CTO as compared with OMT alone., Trial Registration: NCT01760083.

Aims: Chronic stress is an important factor for a variety of health problems, highlighting the importance of early detection of stress-related problems. This methodological pilot study investigated whether the physiological response to and recovery from a stress task can differentiate healthy participants and persons with stress-related complaints., Methods and Results: Healthy participants (n = 20) and participants with stress-related complaints (n = 12) participated in a laboratory stress test, which included 3 stress tasks. Three physiological signals were recorded: galvanic skin response (GSR), heart rate (HR), and skin temperature (ST). From these signals, 126 features were extracted, including static (eg, mean) and dynamic (eg, recovery time) features. Unsupervised feature selection reduced the set to 26 features. A logistic regression model was developed for 6 feature sets, analysing single-parameter and multiparameter models as well as models using recovery vs response-related features. The highest classification performance (accuracy = 78%) was obtained using the response-related feature set, including all physiological signals and using GSR-related features. A worse performance was obtained using single-signal feature sets based on HR (accuracy = 66%) and ST (accuracy = 59%). Response-related features outperformed recovery-related features (accuracy = 63%)., Conclusion: Participants with stress-related complaints may be differentiated from healthy controls by physiological responses to stress tasks. We aimed to bring attention to new exploratory methodologies; further research is needed to validate and replicate the results on larger populations and patients on different areas along the stress continuum.

Aims: The aim of this study was to provide contemporary outcome data for patients with de novo coronary disease and Medina 1,1,1 lesions who were treated with a culotte two-stent technique, and to compare the performance of two modern-generation drug-eluting stent (DES) platforms, the 3-connector XIENCE and the 2-connector SYNERGY., Methods and Results: Patients with Medina 1,1,1 bifurcation lesions who had disease that was amenable to culotte stenting were randomised 1:1 to treatment with XIENCE or SYNERGY DES. A total of 170 patients were included. Technical success and final kissing balloon inflation occurred in >96% of cases. Major adverse cardiovascular or cerebrovascular events (MACCE: a composite of death, myocardial infarction [MI], cerebrovascular accident [CVA] and target vessel revascularisation [TVR]) occurred in 5.9% of patients by nine months. The primary endpoint was a composite of death, MI, CVA, target vessel failure (TVF), stent thrombosis and binary angiographic restenosis. At nine months, the primary endpoint occurred in 19% of XIENCE patients and 16% of SYNERGY patients (p=0.003 for non-inferiority for platform performance)., Conclusions: MACCE rates for culotte stenting using contemporary everolimus-eluting DES are low at nine months. The XIENCE and SYNERGY stents demonstrated comparable performance for the primary endpoint.

Background: Several studies have shown that patients with functional somatic syndromes (FSS) have, on average, deficient endogenous pain modulation (EPM), as well as elevated levels of negative affectivity (NA) and high comorbidity with depression and reduced resting heart rate variability (HRV) compared to healthy controls (HC). The goals of this study were (1) to replicate these findings and (2) to investigate the moderating role of NA, depression, and resting HRV in EPM efficiency within a patient group with fibromyalgia and/or chronic fatigue syndrome (CFS). Resting HRV was quantified as the root mean square of successive differences between inter-beat intervals (RMSSD) in rest, a vagally mediated time domain measure of HRV. Methods: Seventy-eight patients with fibromyalgia and/or CFS and 33 HC completed a counter-irritation paradigm as a measure of EPM efficiency. Participants rated the painfulness of electrocutaneous stimuli (of individually calibrated intensity) on the ankle before (baseline phase), during (counter-irritation phase) and after (recovery phase) the application of a cold pain stimulus on the forearm. A larger reduction in pain in the counter-irritation phase compared to the baseline phase reflects a more efficient EPM. Results: In contrast to our expectations, there was no difference between pain ratings in the baseline compared to counter-irritation phase for both patients and HC. Therefore, reliable conclusions on the moderating effect of NA, depression, and RMSSD could not be made. Surprisingly, patients reported more pain in the recovery compared to the counter-irritation and baseline phase, while HC did not. This latter effect was more pronounced in patients with comorbid depression, patients who rated the painfulness of the counter-irritation stimulus as high and patients who rated the painfulness of the electrocutaneous stimuli as low. We did not manage to successfully replicate the counter-irritation effect in HC or FSS patients. Therefore, no valid conclusions on the association between RMSSD, depression, NA and EPM efficiency can be drawn from this study. Possible reasons for the lack of the counter-irritation effect are discussed.

Objective: Dyspnea perception is distorted in patients with medically unexplained dyspnea. The goals of this study were 1) to replicate these results in patients with fibromyalgia and/or chronic fatigue syndrome (CFS), and 2) to investigate predictors of distorted symptom perception within the patient group, with a focus on negative affectivity (NA), psychiatric comorbidity and somatic symptom severity., Methods: Seventy-three patients diagnosed with fibromyalgia and/or CFS and 38 healthy controls (HC) completed a rebreathing paradigm, consisting of a baseline (60s of room air), a rebreathing phase (150s, gradually increasing ventilation, partial pressure of CO 2 in the blood, and self-reported dyspnea), and a recovery phase (150s of room air). Dyspnea, respiratory flow and FetCO 2 levels were measured continuously., Results: Patients reported more dyspnea than HC in the recovery phase (p=0.039), but no differences between patients and HC were found in the baseline (p=0.07) or rebreathing phase (p=0.17). No significant differences between patients and HC were found in physiological reactivity. Within the patient group, the effect in the recovery phase was predicted by somatic symptom severity (p=0.046), but not by negative affectivity or by the number of psychiatric comorbidities., Conclusion: This study extended earlier findings in patients with medically unexplained dyspnea to patients with fibromyalgia and CFS. This suggests that altered symptom perception is a non-symptom-specific mechanism underlying functional somatic syndromes in general, particularly in patients with high levels of somatic symptom severity. The results are discussed in a predictive coding framework of symptom perception., (Copyright © 2018 Elsevier Inc. All rights reserved.)