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Background and aims Psychosocial factors are associated with increased risk of cardiovascular disease (CVD). However, associations with peripheral artery disease (PAD) remain uncharacterized. We aimed to compare associations of psychosocial factors with the risk of PAD and two other major atherosclerotic CVD: coronary heart disease (CHD) and ischemic stroke, in the Atherosclerosis Risk in Communities (ARIC) Study. Methods In 11,104 participants (mean age 56.7 [SD 5.7] years) without a clinical history of PAD and CHD/stroke at baseline (1990–1992), we evaluated four psychosocial domains: depressive/fatigue symptoms by the Maastricht Questionnaire, social support by the Interpersonal Evaluation List, social networks by the Lubben Scale, and trait anger by the Spielberger Scale. PAD was defined as hospitalizations with diagnosis or related procedures. CHD included adjudicated coronary heart disease and stroke included ischemic stroke. Results We observed 397 PAD and 1940 CHD/stroke events during a median follow-up of 23.1 years. Higher depressive/fatigue symptoms and less social support were significantly associated with incident PAD (adjusted hazard ratios for top vs. bottom quartile 1.65 [95%CI, 1.25–2.19] and 1.40 [1.05–1.87], respectively). When these factors were simultaneously modeled, only depressive/fatigue symptoms remained significant. Incident CHD/stroke was not associated with either of depressive/fatigue symptoms or social support. Social networks and trait anger were not independently associated with PAD or CHD/stroke. Conclusions Depressive/fatigue symptoms and social support (especially the former) were independently associated with the risk of hospitalizations with PAD but not CHD/stroke in the general population. Our results support the importance of depressive/fatigue symptoms in vascular health and suggest the need of including PAD when studying the impact of psychosocial factors on CVD.

Early onset familial Paget's disease of bone (EoPDB), familial expansile osteolysis, and expansile skeletal hyperphosphatasia are related disorders caused by insertion mutations in exon 1 of the TNFRSF11A gene, which encodes receptor activator of nuclear factor κB (RANK) protein. To understand the mechanisms underlying these disorders, we developed a mouse model carrying the 75dup27 mutation which causes EoPDB. Mice heterozygous for the mutation (Tnfrsf11a75dup27/- ) developed a PDB-like disorder with focal osteolytic lesions in the hind limbs with increasing age. Treatment of these mice with zoledronic acid completely prevented the development of lesions. Studies in vitro showed that RANK ligand (RANKL)-induced osteoclast formation and signaling was impaired in bone marrow cells from Tnfrsf11a75dup27/- animals, but that osteoclast survival was increased independent of RANKL stimulation. Surprisingly, Tnfrsf11a75dup27/75dup27 homozygotes had osteopetrosis at birth, with complete absence of osteoclasts. Bone marrow cells from these mice failed to form osteoclasts in response to RANKL and macrophage colony-stimulating factor (M-CSF) stimulation. This intriguing study has shown that in heterozygous form, the 75dup27 mutation causes focal osteolytic lesions in vivo reminiscent of the human disorder and extends osteoclast survival independently of RANKL signaling. In homozygous form, however, the mutation causes osteopetrosis due to failure of osteoclast formation and insensitivity to RANKL stimulation. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..

Introduction Daily aspirin use for primary cardiovascular disease prevention is common among adults. Numerous clinical trials observe reduced cardiovascular disease with regular low-dose aspirin. The U.S. Preventive Services Task Force in 2016 published guidelines for aspirin use, but controversy exists about the side effects, and overuse or underuse may be common despite the guidelines. Using the Task Force recommendations, this paper describes the prevalence of appropriate aspirin use and physician advice in a population sample. Methods A random sample of men and women (aged 50-69 years) living in the Upper Midwest in 2017-2018 were surveyed, collecting demographic data, health history, and aspirin use. Appropriate primary prevention with aspirin was defined as having ≥10% cardiovascular disease risk (hypertension, hyperlipidemia, diabetes, smoking) with daily or every other day aspirin use. Those with prevalent cardiovascular disease were labeled as secondary prevention. Results A total of 1,352 adults were surveyed (697 women, 655 men). The criteria for secondary prevention were fulfilled in 188 participants, and these were eliminated from the analysis. In the remaining group, aspirin was indicated in 32.9% (383 of 1,164). Among those, 46.0% (176 of 383) were appropriate users, and 54.0% (207 of 383) were nonusers despite indications. Overuse, where aspirin is not indicated, was common at 26.9% (210 of 781). Discussion with a physician, although reported in 29% of subjects, was associated with some improvement in the appropriate use but also with overuse and underuse. Conclusions Aspirin use for primary cardiovascular disease prevention is common. However, many adults are medicating without indication (overuse) or are not using aspirin despite guidelines (underuse).

Cardiovascular disease (CVD) persists as the leading cause of death and disability in many Americans including Hispanics. Primary prevention for CVD may be achieved through regular aspirin use in high risk individuals. This study examined regular aspirin use and specific attitudes and social norms toward CVD and aspirin use within an urban Hispanic population in Minnesota. A sample of primary prevention Hispanics aged 45–79 years were surveyed about CVD history and risk factors, aspirin use, demographic characteristics, and health beliefs and social norms in relation to CVD and aspirin. Relative risk estimation using Poisson regression with robust error variance was used to examine associations with aspirin use. In this sample of 152 Hispanics (55% women), the mean age was 53 years, 70% had a regular healthcare provider, and 22% used aspirin. Aspirin discussions with a regular healthcare provider were strongly associated with aspirin use (adjusted risk ratio 3.02, 95% CI 1.20–7.60). There was a positive association between health beliefs and social norms that affirm preventive behaviors and aspirin use (adjusted linear risk ratio 1.23, 95% CI 1.04–1.45) while uncertainty about the role of aspirin for individual use and in the community was negatively associated with aspirin use (adjusted linear risk ratio 0.85, 95% CI 0.70–1.03). This growing population may benefit from health education about CVD risk and the role of aspirin in prevention.

Background Cost-effective primary prevention of cardiovascular disease (CVD) relies on accuracy of risk assessment. Current risk scores require clinical and laboratory measures, are expensive and are often difficult to apply in the population setting. Objective This study sought to estimate CVD risk from individuals' knowledge of their own CVD risk factors and compare it to the risk calculated from measured risk factors. Methods Using the ACC/AHA Pooled Cohort Risk Equations (PCE), we calculated 10-year CVD risk for 9856 primary prevention individuals aged 40-79 in the Minnesota Heart Survey (MHS). Using log-linear regression models, we estimated PCE risk from the individual's self-reported knowledge of four dichotomous risk factors: hypertension, hypercholesterolemia, diabetes, and smoking. Age was included in all models, and models were developed separately in women and men. Model performance was assessed internally using leave-one-out cross-validation. Results The median measured PCE CVD risk in women was 2.1% (IQR: 0.8-5.6%), and in men was 6.3% (3.1-13.0%). Using the newly developed equations, the median estimated risk was 2.2% (0.9-5.8%) in women, and 6.9% (3.2-13.1%) in men. Using a threshold of 7.5% to categorize low and high risk, the novel risk calculation gave an accuracy of 95% for women and 87% for men compared to the measured PCE risk. The negative predictive value was 97% for women and 91% in men. Conclusion Self-reported knowledge of risk may be useful in the identification of individuals at low risk for CV events, however, should always be followed up with measurement of risk factors if symptoms or history suggest CVD.

BACKGROUND: Young adult heart transplant (HT) recipients transferring to adult care are at risk for poor health outcomes. We conducted a pilot randomized controlled trial to determine feasibility and test a transition intervention for young adults who underwent HT as children and transferred to adult care. METHODS: Participants were randomized to the transition intervention (4 months long, focused on HT knowledge, self-care, self-advocacy, and social support) or usual care. Self-report questionnaires and medical records data were collected at baseline and 3 and 6 months after the initial adult clinic visit. Longitudinal analyses comparing outcomes over time were performed using generalized estimating equations and linear mixed models. RESULTS: Transfer to adult care was successful and feasible (i.e., excellent participation rates). The average patient standard deviation of mean tacrolimus levels was similar over time in both study arms and < 2.5, indicating adequate adherence. There were no between group and within group differences in percent of tacrolimus bioassays within target range (>50%). Average overall adherence to treatment was similarly good for both groups. Rates of appointment keeping through 6 months after transfer declined over time in both groups. CONCLUSIONS: Feasibility of the study was demonstrated. Our transition intervention did not improve outcomes.

Cell‐based therapy for the treatment of inflammatory disorders has focused on the application of mesenchymal stromal cells (MSCs) and multipotent adult progenitor cells (MAPCs). Despite the recent positive findings in industry‐sponsored clinical trials of MSCs and MAPCs for graft vs host disease (GvHD), cell therapy is efficacious in some but not all patients, highlighting the need to identify strategies to enhance cell‐based therapeutic efficacy. Here, we demonstrate the capacity for interferon (IFN)‐γ licensing to enhance human MAPC efficacy and retention following early administration in a humanized mouse model of acute GvHD (aGvHD). Activation of the nuclear receptor peroxisome proliferator‐activated receptor delta (PPARδ) negatively influenced the retention and efficacy of human MAPCs as well as IFN‐γ‐licensed MAPCs in the aGvHD model. PPARδ antagonism significantly enhanced the efficacy of human MAPCs when administered early in the humanized aGvHD model. COX‐2 expression in human MAPC was significantly decreased in IFN‐γ licensed MAPCs exposed to a PPARδ agonist. Importantly, MAPC exposure to the PPARδ antagonist in the presence of a COX‐2 inhibitor indomethacin before administration significantly reduced the efficacy of PPARδ antagonized MAPCs in the aGvHD humanized mouse model. This is the first study to demonstrate the importance of PPARδ in human MAPC efficacy in vivo and highlights the importance of understanding the disease microenvironment in which cell‐based therapies are to be administered. In particular, the presence of PPARδ ligands may negatively influence MAPC or MSC therapeutic efficacy., Interferon‐γ (IFN‐γ) licensing enhances the therapeutic efficacy of human multipotent adult progenitor cells (MAPCs) in a mouse model of acute graft vs host disease (aGvHD). Activation of peroxisome proliferator‐activated receptor (PPAR) δ reduces, whereas antagonism of PPARδ(−) enhances MAPC efficacy in aGvHD. PPARδ agonism reduces COX‐2 expression in IFN‐γ licensed MAPC. Figure created with BioRender.com.

Background: Patients using dual antiplatelet therapy after percutaneous coronary intervention are at risk for bleeding. It is currently unknown whether thrombin generation can be used to identify patients receiving dual antiplatelet therapy with increased bleeding risk.Objectives: To investigate whether thrombin generation measurement in plasma provides additional insight into the assessment of bleeding risk for high clinical-risk patients using dual antiplatelet therapy.Methods: Coagulation factors and thrombin generation in platelet-poor plasma were measured in 93 high clinical-risk frail patients using dual antiplatelet therapy after percutaneous coronary intervention. During 12-month follow-up, clinically relevant bleedings were reported. Thrombin generation at 1 and 6 months after percutaneous coronary intervention was compared between patients with and without bleeding events.Results: One month after percutaneous coronary intervention, the parameters of thrombin generation, endogenous thrombin potential, peak height, and velocity index were significantly lower in patients with bleeding in the following months compared to patients without bleeding. At 6 months follow-up, endogenous thrombin potential, peak height, and velocity index were still (significantly) decreased in the bleeding group as compared to non-bleeders. Thrombin generation in the patients' plasma was strongly dependent on factor II, V, and VIII activity and fibrinogen.Conclusion: High clinical-risk patients using dual antiplatelet therapy with clinically relevant bleeding during follow-up show reduced and delayed thrombin generation in platelet-poor plasma, possibly due to variation in coagulation factors. Thus, impaired thrombin-generating potential may be a “second hit” on top of dual antiplatelet therapy, increasing the bleeding risk in high clinical-risk patients. Thrombin generation has the potential to improve the identification of patients using dual antiplatelet therapy at increased risk of bleeding.

Organized health promotion efforts sometimes compete with news media, social media, and other sources when providing recommendations for healthy behavior. In recent years, patients have faced a complicated information environment regarding aspirin use as a prevention tool for heart health. We explored the possibility that campaign promotion of low-dose aspirin use might have been undermined by news coverage in the USA detailing controversies regarding aspirin use. Using time series data on low-dose aspirin sales in Minnesota, USA, we assessed whether news coverage of aspirin or audience engagement with the Ask About Aspirin campaign website predicted subsequent changes in low-dose aspirin sales, over and above any secular trend. News coverage predicted actual low-dose aspirin purchases whereas exposure to a state-level campaign did not. While a campaign effort to encourage people at risk to discuss low-dose aspirin use with their health care providers did not generate substantive changes in low-dose aspirin tablet sales in the areas of Minnesota monitored for this study, past news coverage about aspirin use, including news about negative side effects, may have suppressed low-dose aspirin sales during this same period. The extent of news coverage about aspirin and heart health had a negative effect on tablet sales recorded in greater Minnesota approximately a month later in an ARIMA time series model, coefficient = −.014, t = −2.33, p = .02. Presented evidence of news coverage effect suggests health campaign assessment should consider trends in the public information environment as potential countervailing forces.

Health care should be informed by the physical, socioeconomic, mental, and emotional well-being of the person, and account for social circumstances and culture. Patient-generated outcome measures can contribute positively to mental health research in culturally diverse populations. In this study, we analysed qualitative responses to the Psychological Outcome Profiles (PSYCHLOPS) Questionnaire—a patient-generated outcome measure based on open-ended questions, and compared the qualitative responses gathered to conventional, nomothetic measures used alongside the PSYCHLOPS in two studies. Data were collected as part of outcome research on a psychological intervention in Pakistan ( N = 346) and Kenya ( N = 521). Two researchers coded the qualitative responses to the PSYCHLOPS and identified overarching themes. We compared the overarching themes identified to the items in the conventional, nomothetic outcome measures to investigate conceptual equivalence. Using the PSYCHLOPS, the most frequently reported problems in Kenya were financial constraints, poor health, and unemployment. In Pakistan, the most frequent problems were poor health and emotional problems. Most of the person-generated problem concepts were covered also in nomothetic measures that were part of the same study. However, there was no item equivalence in the nomothetic measures for the most frequent PSYCHLOPS problem cited in both countries. Response bias and measurement bias may not be excluded. More research on the use of PSYCHLOPS alongside conventional outcome measures is needed to further explore the extent to which it may bring added value. Use of a PSYCHLOPS semistructured interview schedule and efforts to minimise response biases should be considered.

Contains fulltext : 202710.pdf (Publisher’s version ) (Open Access) BACKGROUND: An early invasive strategy (EIS) is recommended in high-risk patients with non-ST-elevation acute coronary syndrome (NSTE-ACS), defined as coronary angiography (CAG), within 24h of admission. The aim of the present study is to investigate guideline adherence, patient characteristics associated with timing of the intervention and clinical outcome. METHODS: In a prospective registry, the use and timing of CAG and the characteristics and clinical outcome associated with timing were evaluated in high-risk ACS patients. The outcome of early versus delayed invasive strategy (DIS) was compared. RESULTS: Between 2006 and 2014, 2,299 high-risk NSTE-ACS patients were included. The use of CAG increased from 77% in 2006 to 90% in 2014 (p trend

Cardiovascular disease (CVD) disproportionately affects African Americans. Aspirin has long been recommended to reduce cardiovascular events. However, national guideline changes in 2016 limited the aspirin recommended population and several clinical trials questioning the utility of primary prevention aspirin were published in 2018. In light of the recent guidelines and study findings, we investigated primary prevention aspirin use among urban African American adults. Using three cross-sectional surveys, we collected data from self-identified African Americans with no CVD in 2015, 2017 and 2019, querying information on CVD risk factors, health behaviors and beliefs, and aspirin use. Poisson regression modeling was used to estimate age- and risk-factor adjusted aspirin prevalence, trends and associations. A total of 1491 African Americans adults, ages 45-79, were included in this analysis; 61% were women. There was no change in age- and risk factor-adjusted aspirin use over the 3 surveys for women (37%, 34% and 35% respectively) or men (27%, 25%, 30% respectively). However, fewer participants believed aspirin was helpful in 2019 compared to 2015-75% versus 84% (p 0.001). Aspirin discussions with a health care practitioner were highly associated with aspirin use (adjusted RR 2.97, 95% CI 2.49-3.54) and aspirin use was 2.56 times higher (adjusted RR 95% CI 2.17-3.03) in respondents who agreed that people close to them thought they should take aspirin compared with those who disagreed or did not know. Despite major changes in national guidelines, overall primary prevention aspirin use did not significantly change in these African American samples from 2015 to 2019.

Background USPSTF evidence-based recommendations for the use of low-dose aspirin for primary prevention of cardiovascular disease were published in 2009. We describe a statewide campaign using innovative methods to educate the public and health communities about appropriate aspirin use. Methods/design The “Ask About Aspirin” initiative is designed to lower the number of first heart attacks and strokes in the State of Minnesota by promoting the appropriate use of low dose aspirin. A health system intervention combined with an aspirin awareness media campaign will be evaluated in a pragmatic group randomized controlled trial including 267 primary care clinics within 84 health systems over a four year period. Matched pairs of geographic territories will be randomized to intervention (12 territories) or control (12 territories). The primary outcome of appropriate aspirin use will be measured at the individual level, by community-based telephone surveys of 100 participants in each of the 24 geographically determined clusters. Discussion We briefly describe the rationale for the interventions being studied, as well as the major design choices. Rigorous research designs such as the one described here are necessary to determine whether evidence-based recommendations can be effectively disseminated in multiple health systems. Trial registration ClinicalTrials.gov: NCT02607917 .

Background Limited clinical evidence and literature are available about the potential impact of sex on permanent pacemaker implantation (PPI) after transcatheter aortic valve implantation (TAVI). The aim of this work was to evaluate the relationship between sexes and atrioventricular conduction disturbances requiring PPI after TAVI. Methods and Results Data were obtained from 46 studies from PubMed reporting information about the impact of patient sex on PPI after TAVI. Total proportions with 95% Cls were reported. Funnel plot and Egger test were used for estimation of publication bias. The primary end point was 30‐day or in‐hospital PPI after TAVI, with odds ratios and 95% CIs extracted. A total of 70 313 patients were included, with a cumulative proportion of 51.5% of women (35 691 patients; 95% CI, 50.2–52.7). The proportion of women undergoing TAVI dropped significantly over time ( P P =0.0022]). By meta‐regression analysis, age ( P =0.874) and ventricular function ( P =0.302) were not significantly associated with PPI among the sexes. Balloon‐expandable TAVI significantly decrease the advantage of women for PPI, approaching the same rate as in men ( P =0.0061). Conclusions Female sex is associated with a reduced rate of PPI after TAVI, without influence of age or ventricular function. Balloon‐expandable devices attenuate this advantage in favor of women. Additional investigations are warranted to elucidate sex‐based differences in developing conduction disturbances after TAVI.

Item does not contain fulltext BACKGROUND: Gender differences in the thrombotic and bleeding risk have been suggested to condition the benefits of antithrombotic therapies in Acute Coronary Syndrome (ACS) patients, and mainly among those undergoing percutaneous coronary interventions with drug eluting stents (DES). The impact of gender on the optimal duration of dual antiplatelet therapy (DAPT) in ACS patients is still unexplored and was, therefore, the aim of the present sub-study. METHODS: REDUCE was a prospective, multicenter, randomized investigator-initiated study designed to enroll 1500 ACS patients after treatment with the COMBO Dual Stent Therapy, based on a noninferiority design. Patients were randomized in a 1:1 fashion to either 3 or 12 months of DAPT. Primary study endpoint was a composite of all-cause mortality, myocardial infarction, definite/probable stent thrombosis (ST), stroke, target-vessel revascularization (TVR) and bleedings (BARC II, III, V) at 12 months. Secondary endpoints were cardiovascular mortality and the individual components of the primary endpoint within 24 months. RESULTS: From June 2014 to May 2016 300 women and 1196 men were included in the study. Among them, 43.7% of females and 51.9% of males were assigned to the 3 months DAPT treatment. Baseline characteristics were well matched between the two arms, with the exception of a lower rate of TIMI flow

Cardiovascular disease prevention strategies include aspirin use as a preventive measure. The internet can be used to raise public awareness, promote healthy lifestyles, and improve disease management. This pilot study describes the feasibility of an educational website to recruit and follow adult internet users to examine whether they talked to their physician about aspirin and initiated aspirin use. As part of a statewide intervention promoting an aspirin regimen to prevent heart attacks and strokes in Minnesota, visitors to the website were encouraged to complete an aspirin candidacy tool. Between October, 2015 and February, 2016, men 45–79 and women 55–79 who identified as aspirin candidates were invited to participate in a 6-month study involving four, 5 min online surveys to examine physician discussions about aspirin, aspirin use, and mobile technology use. During the 5-month recruitment period, 234 adults enrolled in the study. Of the 174 who completed the baseline survey and at least one follow-up survey, 74 (43.5%) did not use aspirin at baseline. During follow-up, 12 (16.2%) talked to their doctor about aspirin and 31 (41.8%) initiated aspirin use. Internet, social media, and mobile technology use were high among this population. An educational website may have provided a cue to action for aspirin discussions with physicians and aspirin initiation. More research is needed to evaluate the utility of on-line tools to increase appropriate aspirin use among internet-using populations.

Background E-mental health interventions may help to bridge the mental health treatment gap. Evidence on their effectiveness is compelling in high-income countries. Not enough evidence has been generated on their use with communities affected by adversity in low- and middle-income countries. The World Health Organization (WHO), the National Mental Health Programme (NMMP) at Ministry of Public Health (MoPH) in Lebanon and other partners have adapted a WHO intervention called Step-by-Step for use with Lebanese and displaced people living in Lebanon. Step-by-Step is a minimally guided, internet-based intervention for adults with depression. In this study, a feasibility randomised controlled trial (RCT) and a qualitative process evaluation were conducted to explore the feasibility and the acceptability of the research methods, and the intervention, in preparation for two fully powered trials to assess the effectiveness and cost-effectiveness of Step-by-Step in Lebanon. Method Participants were recruited through social media. Inclusion criteria were: being able to understand and speak Arabic or English; access to an internet connected device; aged over 18; living in Lebanon; scores above cut-off on the Patient Health Questionnaire and the WHO Disability Assessment Schedule 2.0. Participants were randomly assigned to the intervention or enhanced care as usual. They completed post-assessments eight weeks after baseline, and follow-up assessments another three months later. Primary outcomes were depression and level of functioning, secondary outcomes were anxiety, post-traumatic stress, and well-being. Qualitative interviews were conducted to evaluate the feasibility and acceptability of the research procedures and the intervention. Results A total of N = 138 participants, including 33 Syrians, were recruited and randomised into two equal groups. The dropout rate was higher in the control group (73% post- and 82% follow-up assessment) than in the intervention group (63% post- and 72% follow-up assessment). The intervention was perceived as relevant, acceptable and beneficial to those who completed it. Suggestions were made to further adapt the content and to make the intervention more engaging. Statistical analyses were conducted despite the small sample size. Complete cases analysis showed a statistically significant symptom reduction in depression, anxiety, disability, and post-traumatic stress, and statistically significant improvement in well-being and functioning. Intention-to-treat analysis revealed non-significant effects. Conclusion The research design, methods and procedures are feasible and acceptable in the context of Lebanon and can be applied in the RCTs. Preliminary findings suggest that Step-by-Step may be effective in reducing symptoms of depression and anxiety and improving functioning and well-being., Highlights • An e-intervention was tested among people affected by adversities in Lebanon. • The study showed that the intervention and methods can be applied in full RCTs. • The intervention may reduce symptoms of depression and improve functioning.

AimsPermanent pacemaker implantation (PPI) still limits the expansion of indications for transcatheter aortic valve implantation (TAVI). Comparison between different systems remains scarce. We aimed to determine the impact of the device type used on post-TAVI PPI.Methods and resultsA systematic literature review was performed to identify studies reporting the use of balloon-expandable valve (BEV), self-expandable valve (SEV), and mechanically expandable valve (MEV) and post-TAVI PPI. A network meta-analysis was used to compare TAVI mechanisms (Analysis A) and transcatheter heart valves (Analysis B) with respect to post-TAVI PPI. Analysis A included 40 181 patients with a pooled PPI rate of 19.2% in BEV, 24.7% in SEV, and 34.8% in MEV. Balloon-expandable valve showed lower risk compared to either SEV or MEV and SEV demonstrated lower risk for PPI than MEV. Implantation of BEV was associated with 39% and 62% lower PPI rate with respect to SEV and MEV. Implantation of SEV was associated with 38% lower PPI rate with respect to MEV. Analysis B included 36.143 patients with the lowest pooled PPI rate of 9.6% for Acurate Neo or others, and the highest pooled PPI rate of 34.3% for Lotus. CoreValve, Evolut Portico, and Lotus influenced significantly PPI rate, while Sapien group did not.ConclusionImplantation of BEV and also SEV were associated with lower post-TAVI PPI rate, while MEV were associated with higher post-TAVI PPI. Patient tailored-approach including devices characteristics may help to reduce post-TAVI PPI and to allow TAVI to take the leap towards extension of use in younger patients.Prospero numberCRD42021238671.

Data regarding the impact of infra-Hisian conduction disturbances leading to permanent pacemaker implantation (PPI) after transcatheter aortic valve implantation (TAVI) remain limited. The aim of this study was to determine the impact of right and/or left bundle branch block (RBBB/LBBB) on post-TAVI PPI. We performed a systematic literature review to identify studies reporting on RBBB and/or LBBB status and post-TAVI PPI. Study design, patient characteristics, and the presence of branch block were analyzed. Odds ratios (ORs) with 95% CI were extracted. The final analysis included 36 studies, reporting about 55,851 patients. Data on LBBB were extracted from 33 studies. Among 51,026 patients included, 5503 showed pre-implant LBBB (11.9% (10.4%–13.8%)). The influence of LBBB on post-TAVI PPI was not significant OR 1.1474 (0.9025, 1.4588), p = 0.2618. Data on RBBB were extracted from 28 studies. Among 46,663 patients included, 31,603 showed pre-implant RBBB (9.2% (7.3%–11.6%)). The influence of RBBB on post-TAVI PPI was significant OR 4.8581 (4.1571, 5.6775), p &lt, 0.0001. From this meta-analysis, the presence of RBBB increased the risk for post-TAVI PPI, independent of age or LVEF, while this finding was not confirmed for patients experimenting with LBBB. This result emphasizes the need for pre-operative evaluation strategies in patient selection for TAVI.

Background: New-generation drug-eluting stents (DES) have mostly been investigated in head-to-head non-inferiority trials against early-generation DES and have typically shown similar efficacy and superior safety. How the safety profile of new-generation DES compares with that of bare-metal stents (BMS) is less clear. Methods: We did an individual patient data meta-analysis of randomised clinical trials to compare outcomes after implantation of new-generation DES or BMS among patients undergoing percutaneous coronary intervention. The primary outcome was the composite of cardiac death or myocardial infarction. Data were pooled in a one-stage random-effects meta-analysis and examined at maximum follow-up and a 1-year landmark. Risk estimates are reported as hazard ratios (HRs) with 95% CIs. This study is registered in PROSPERO, number CRD42017060520. Findings: We obtained individual data for 26 616 patients in 20 randomised trials. Mean follow-up was 3·2 (SD 1·8) years. The risk of the primary outcome was reduced in DES recipients compared with BMS recipients (HR 0·84, 95% CI 0·78–0·90, p

Introduction: Cardiovascular disease (CVD) disproportionately affects African Americans. Aspirin has long been recommended as an option to reduce cardiovascular events. However, recent clinical trials involving primary prevention aspirin have prompted changes in national guidelines restricting the aspirin recommended population. Hypothesis: Primary prevention aspirin use will decline over the 5 year period 2015-2019. Methods: Using 3 cross-sectional surveys, data were collected from self-identified African Americans in 2015, 2017 and 2019, querying information on CVD risk factors, health behaviors and beliefs, and aspirin use. Poisson regression modeling was used to estimate age- and risk-factor adjusted aspirin prevalence, trends and associations. Results: A total of 1,491 African Americans adults, ages 45-79, 61% women and no prior CVD completed surveys and were included in this analysis. There was no change in age- and risk factor-adjusted aspirin use over the 3 surveys for women (37%, 34% and 35% respectively) or men (27%, 25%, 30% respectively). However, fewer participants believed aspirin was helpful in 2019--75% vs 84% in 2015 (p Conclusion: Despite major changes in national guidelines and negative perceptions of aspirin effectiveness in the media, overall primary prevention aspirin use did not significantly change in this African American sample from 2015 to 2019.

Background Globally, 235 million people are impacted by humanitarian emergencies worldwide, presenting increased risk of experiencing a mental disorder. Our objective was to test the effectiveness of a brief group psychological treatment delivered by trained facilitators without prior professional mental health training in a disaster-prone setting. Methods and findings We conducted a cluster randomized controlled trial (cRCT) from November 25, 2018 through September 30, 2019. Participants in both arms were assessed at baseline, midline (7 weeks post-baseline, which was approximately 1 week after treatment in the experimental arm), and endline (20 weeks post-baseline, which was approximately 3 months posttreatment). The intervention was Group Problem Management Plus (PM+), a psychological treatment of 5 weekly sessions, which was compared with enhanced usual care (EUC) consisting of a family psychoeducation meeting with a referral option to primary care providers trained in mental healthcare. The setting was 72 wards (geographic unit of clustering) in eastern Nepal, with 1 PM+ group per ward in the treatment arm. Wards were eligible if they were in disaster-prone regions and residents spoke Nepali. Wards were assigned to study arms based on covariate constrained randomization. Eligible participants were adult women and men 18 years of age and older who met screening criteria for psychological distress and functional impairment. Outcomes were measured at the participant level, with assessors blinded to group assignment. The primary outcome was psychological distress assessed with the General Health Questionnaire (GHQ-12). Secondary outcomes included depression symptoms, posttraumatic stress disorder (PTSD) symptoms, “heart–mind” problems, social support, somatic symptoms, and functional impairment. The hypothesized mediator was skill use aligned with the treatment’s mechanisms of action. A total of 324 participants were enrolled in the control arm (36 wards) and 319 in the Group PM+ arm (36 wards). The overall sample (N = 611) had a median age of 45 years (range 18–91 years), 82% of participants were female, 50% had recently experienced a natural disaster, and 31% had a chronic physical illness. Endline assessments were completed by 302 participants in the control arm (36 wards) and 303 participants in the Group PM+ arm (36 wards). At the midline assessment (immediately after Group PM+ in the experimental arm), mean GHQ-12 total score was 2.7 units lower in Group PM+ compared to control (95% CI: 1.7, 3.7, p < 0.001), with standardized mean difference (SMD) of −0.4 (95% CI: −0.5, −0.2). At 3 months posttreatment (primary endpoint), mean GHQ-12 total score was 1.4 units lower in Group PM+ compared to control (95% CI: 0.3, 2.5, p = 0.014), with SMD of −0.2 (95% CI: −0.4, 0.0). Among the secondary outcomes, Group PM+ was associated with endline with a larger proportion attaining more than 50% reduction in depression symptoms (29.9% of Group PM+ arm versus 17.3% of control arm, risk ratio = 1.7, 95% CI: 1.2, 2.4, p = 0.002). Fewer participants in the Group PM+ arm continued to have “heart–mind” problems at endline (58.8%) compared to the control arm (69.4%), risk ratio = 0.8 (95% CI, 0.7, 1.0, p = 0.042). Group PM+ was not associated with lower PTSD symptoms or functional impairment. Use of psychosocial skills at midline was estimated to explain 31% of the PM+ effect on endline GHQ-12 scores. Adverse events in the control arm included 1 suicide death and 1 reportable incidence of domestic violence; in the Group PM+ arm, there was 1 death due to physical illness. Study limitations include lack of power to evaluate gender-specific effects, lack of long-term outcomes (e.g., 12 months posttreatment), and lack of cost-effectiveness information. Conclusions In this study, we found that a 5-session group psychological treatment delivered by nonspecialists modestly reduced psychological distress and depression symptoms in a setting prone to humanitarian emergencies. Benefits were partly explained by the degree of psychosocial skill use in daily life. To improve the treatment benefit, future implementation should focus on approaches to enhance skill use by PM+ participants. Trial registration ClinicalTrials.gov NCT03747055., Mark Jordans and co-workers evaluate a group therapy intervention in adults affected by psychological distress in Nepal., Author summary Why was this study done? Millions of people worldwide are affected by humanitarian emergencies such as war, environmental disasters, and pandemics. Most populations in these settings lack access to mental health services. In prior studies, people who are not mental health specialists have been trained to effectively deliver psychological treatments, including Problem Management Plus (PM+), which is a brief 5-session intervention. However, there has only been one prior study of a group-based format of PM+ delivered by nonspecialists. As the use of nonspecialists increases, there are new questions about how these psychological interventions work when delivered by someone who is not a mental health professional. Studying potential mechanisms of action (i.e., how the intervention works) could be instrumental to increasing effectiveness when scaling up. What did the researchers do and find? The researchers evaluated the effectiveness of Group PM+ in a setting prone to humanitarian emergencies with delivery of the intervention by briefly trained nonspecialists, and the researchers evaluated a potential mechanism of action involved in reducing psychological distress. Adults who received Group PM+ delivered by nonspecialists in their communities showed greater reduction in psychological distress at 3 months after the intervention compared to adults who had been offered referral options for services. At 3 months after the intervention, approximately 1 out of 3 adults in Group PM+ had a 50% reduction in depression symptoms compared to 1 out of 6 who were in the control arm receiving referral options for services. Regarding how the intervention produced changes, a third of the differences between study arms was explained by participants’ use of psychosocial skills taught in Group PM+, such as breathing exercises, problem-solving techniques, and seeking social support. What do these findings mean? In humanitarian emergencies with a lack of mental health specialists, a 5-session group psychological treatment delivered by nonspecialists can be used to modestly reduce psychological distress and depression symptoms. The benefits of Group PM+ are partly explained by the degree of psychosocial skill use being promoted through the intervention. Therefore, future use of the intervention should explore how to enhance practice of these skills in daily life. Further research is needed to evaluate how the impact of Group PM+ differs by gender because the study points toward potentially less benefit among men compared to women.

Osteoarthritis (OA) is a whole joint disease that affects all joint tissues, with changes in the articular cartilage (AC), subchondral bone and synovium. Pathologies in menisci and ligaments, however, are rarely analysed, although both are known to play vital roles in the mechanical stability of the joint. The aim of our study was to describe the pathological changes in menisci and ligament during disease development in murine spontaneous and post-traumatic surgically-induced OA and to quantify tissue mineralisation in the joint space using µCT imaging during OA progression.Knees of Str/ort mice (spontaneous OA model; 26-40wks) and C57CBA F1 mice following destabilisation of medial meniscus (DMM) surgery (post-traumatic OA model; 8wks after DMM), were used to assess histological meniscal and ligament pathologies. Joint space mineralised tissue volume was quantified by µCT.Meniscal pathological changes in Str/ort mouse knees were associated with articular cartilage lesion severity. These meniscal changes included ossification, hyperplasia, cell hypertrophy, collagen type II deposition and SOX9 expression in the fibrous region near the attachment to the knee joint capsule. Anterior cruciate ligaments exhibited extracellular matrix changes and chondrogenesis particularly at the tibial attachment site, and ossification was seen in collateral ligaments. Similar changes were confirmed in the post-traumatic DMM model. µCT analysis showed increased joint space mineralised tissue volume with OA progression in both the post-traumatic and spontaneous OA models.Modifications in meniscal and ligament mineralisation and chondrogenesis are seen with overt AC degeneration in murine OA. Although the aetiology and the consequences of such changes remain unknown, they will influence stability and load transmission of the joint and may therefore contribute to OA progression. In addition, these changes may have important roles in movement restriction and pain, which represent major human clinical symptoms of OA. Description of such soft tissue changes, in addition to AC degradation, should be an important aspect of future studies in mouse models in order to furnish a more complete understanding of OA pathogenesis.Summary statementThis manuscript describes histological changes in mouse knee joints in two models of osteoarthritis and correlates joint space mineralised tissue volume measured by µCT with disease severity.

Objective: We investigated the effectiveness of a self-help intervention named PERANTARA, which aims to improve adherence to diagnostic procedures among women with breast cancer (BC) symptoms to reduce the time to a definitive diagnosis. Methods: With a cluster randomized crossover design across four hospitals, PERANTARA and treatment as usual (TAU) or TAU only was provided at successive periods in a randomly determined order. The main outcome was the time between the first medical consultation and the definitive diagnosis. Secondary outcomes were BC knowledge, measured by the Breast Cancer Knowledge Test (BCKT); symptoms of anxiety and depression, measured by the Hospital Anxiety and Depression Scale (HADS); quality of life, measured by the World Health Organization Quality of Life-BREF (WHOQOL-BREF); and health status, measured by the EQ-5D-5L. A linear mixed model analysis was conducted to analyse the outcomes. Results: We recruited 132 women with BC symptoms from four hospitals; 67 participants were in the intervention group, and 65 participants were in the control group. PERANTARA reduced the time to definitive diagnosis by 13.3 days (M [SD]: 25.90 [23.20] in the intervention group vs 39.29 [35.10] in the control group; mean difference = −13.26, 95% CI = −24.51 to −2.00, P =.02). No significant difference was found between the groups in BC knowledge, symptoms of anxiety, depression, quality of life, or health status. Conclusions: PERANTARA reduced the time to definitive diagnosis among Indonesian women with BC symptoms. Psychoeducation may be an important addition to regular BC care to prevent undue delays in diagnostic procedures.

Background: Cardiovascular disease (CVD) and CVD risk factors are high among people of color. Aspirin (ASA) can reduce CVD risk. Yet little is known about primary prevention ASA use and its determinants among people of color. This study examined associations for ASA-related health beliefs and social norms, CVD risk factors and ASA use among Hispanic/Latino (HL) and African American (AA) adults without CVD history. Methods: In-person surveys were administered to adults ages 45-79 years at health fairs and community events in the Minneapolis-St. Paul metro querying demographics, CVD history, CVD risk factors and ASA use. CVD risk perceptions and ASA-related health beliefs and social norms were evaluated using a 4-point Likert scale. Poisson regression with adjustment for age, sex and risk factors was used to examine associations with ASA use. Surveys were offered in English or Spanish. Results: Of the 583 survey participants with no CVD history, 152 identified as HL and 431 as Non-Hispanic-AA. Compared with AA, the HL sample was younger, mean (SD) age of 53.0 (8.6) years vs 59.3 (9.3) years; 54.6% vs 65.7% were female. Risk factors were common among HL and AA, including diabetes (37.5% and 29.0%), hyperlipidemia (28.3% and 36.7%), hypertension (36.8% and 61.0%) and smoking (13.8% and 21.1%). Twenty-two percent of HL and 34% of AA participants regularly used ASA. When asked questions regarding health beliefs and social norms, HL adults had a high frequency of “Don’t Know” responses compared with AA’s (Figure). Participants with more “Don’t Know” responses were less likely to use ASA—RR of 0.87 (95% CI 0.77-0.99). Conversely, ASA use was positively associated with “Agree” responses (RR 1.40, 95% CI 1.29-1.52) and CVD risk factors (RR 1.43 95% CI 1.28-1.59). Associations did not differ by race/ethnicity (interaction p >0.05). Conclusion: ASA uncertainty is more pronounced among HL adults than AA and is associated with less preventive ASA use. Efforts should be made to improve knowledge regarding the appropriate use of ASA in this population.

Introduction: Smoking is the strongest risk factor for abdominal aortic aneurysm (AAA), and male ever smokers who are recommended for one-time screening for AAA with ultrasonography at age of 65 to 75 years. However, the proportion of eligible individuals who receive this screening remains small (~1%). Few studies have evaluated the association of key smoking parameters with incident AAA by sex. Methods: In 14,889 ARIC participants free of a history of AAA at baseline (1987-89), we quantified the associations of smoking parameters (pack-years, duration, and intensity [pack/day]) with incident AAA (hospitalizations with AAA diagnosis [ICD code: 441.3, 441.4, 38.44, 39.71] or a death certificate ICD code: 441.3, 441.4, I71.3, I71.4) using Cox models. Years since quitting in former smokers were explored as time-varying variables. Results: Over a median follow-up of 20 years, there were 567 cases of AAA. The incident rate of AAA was 5.98 per 1,000 person-years in male current smokers and 2.65 per 1,000 person-years in female current smokers. Pack-years was significantly associated with incident AAA (HR 7.31 [95% CI 5.48-9.74] for those smoked ≥40 pack-years vs. never smokers) and the association was stronger in women than men (8.53 [5.03-14.45] vs. 5.97 [4.21-8.47], p-for-interaction =0.02). Both smoking duration and intensity showed significant associations with AAA. Smoking cessation demonstrated a graded association with lower risk of AAA in both sexes, but significantly increased risk lasted longer in men (2.16 [1.39-3.36] in 30- Conclusions: All smoking parameters tested consistently show significant associations with incident AAA in both sexes. After cessation, the residual risk lasted at least 40 years in men and 20 years in women. Our results further emphasize the importance of smoking prevention and early cessation for preventing AAA and the potential need of AAA screening in female current smokers and recent quitters.

Background and aims: Psychosocial factors such as depression, character traits, and lack of social support have been associated with increased risk of cardiovascular disease (CVD). However, data of peripheral artery disease (PAD) in this regard are sparse. Since risk factor profiles differ across atherosclerotic CVD (ASCVD) subtypes, to appreciate the contribution of psychosocial factors to overall ASCVD, we aimed to comprehensively explore the association of psychosocial factors with the risk of PAD and ASCVD in a community cohort. Methods: We included 12,090 participants from the Atherosclerosis Risk in Communities (ARIC) Study (mean age 56.7 [SD 5.7] years) free of PAD and ASCVD at baseline (1990-1992). Depressive symptom was evaluated by the Maastricht Questionnaire (MQ). Trait anger was assessed by the Spielberger Trait Anger Scale. Social support was measured by the Interpersonal Support Evaluation List, while the extent of social networks was evaluated by the Lubben Social Network Scale. PAD events were defined as hospitalizations with PAD diagnosis and procedures. ASCVD included adjudicated myocardial infarction, fatal coronary disease, and ischemic stroke events. Results: We observed 429 PAD and 2,539 ASCVD events during a median follow-up of 23.1 years. The cumulative incidence of PAD was highest in the highest quartile of MQ score. This association remained after adjusting for traditional CVD risk factors, socioeconomic status, and physical activity. A weaker association was observed for ASCVD. Social support also showed independent association with incident PAD, but not with ASCVD. Trait anger and social network were not significantly associated with either PAD or ASCVD (Table). Conclusions: Psychosocial factors demonstrated more evident associations with PAD than ASCVD. Our results suggest the importance of considering PAD when assessing the overall impact of those factors on CVD. Future studies are needed to explore potential mechanisms behind our observation.

Background: E-mental health is an established mode of delivering treatment for common mental disorders in many high income countries. However, evidence of its effectiveness in lower income countries is lacking. This mixed methods study presents lessons learned and preliminary data on the feasibility of a minimally guided e-mental health intervention in Lebanon. The aim was to pilot test Step-by-Step, a WHO guided e-mental health intervention, and research methods prior to future, controlled testing. Methods: Participants were recruited using social media and advertisements in primary care clinics. Participants completed baseline and post-intervention questionnaires on depression symptoms (primary outcome, PHQ-8), anxiety symptoms, well-being, disability and self-perceived problem severity, and a client satisfaction questionnaire. In addition, seven completers, four drop-outs, 11 study staff, and four clinic managers were interviewed with responses thematically analyzed. Website analytics were used to understand participant behavior when using the website. Results: A total of 129 participants signed up via the Step-by-Step website. Seventy-four participants started session 1 after completing pre-test questionnaires and 26 completed both baseline and post-intervention data. Among those who completed post-assessments, depression symptoms improved (PHQ-8 scores (t=5.62, p < 0.001 two-tailed, df = 25). Wilcoxon signed ranks tests showed a significant difference between baseline and post-Step-by-Step scores on all secondary outcome measures. Client satisfaction data was positive. Interview responses suggested that the intervention could be made more appropriate for younger, single people, more motivating, and easier to use. Those who utilized the support element of the intervention were happy with their relationship with the non-specialist support person (e-helper), though some participants would have preferred specialist support. E-helpers would have liked more training on complex cases. Website analytics showed that many users dropped out before intervention start, and that some re-entered screening data having been excluded from the study. Conclusion: Step-by-Step skills and techniques, model of service integration, and its non-specialist support element are acceptable. Though the sample was small and non-controlled and drop-out was high, results suggest that it may be effective in reducing depression and anxiety symptoms and increasing well-being. Lessons learned will inform content revision, the development of an app version of Step-by-Step, and the research methodology of upcoming effectiveness studies.

Aims To compare ischaemia-driven complete coronary revascularisation by percutaneous coronary intervention (PCI) with usual care in patients with non-ST-elevation myocardial infarction (non-STEMI) and multivessel disease (MVD). Methods The South Limburg Myocardial Infarction (SLIM) trial (NCT03562572) is an investigator-initiated, prospective, multicentre, randomised controlled trial that compares fractional flow reserve (FFR)-guided complete revascularisation during the index procedure with usual care in non-STEMI patients with MVD. A total of 414 patients will be randomised in a 1:1 fashion. The primary endpoint is the composite of all-cause mortality, non-fatal myocardial infarction, and any revascularisation and stroke (MACCE) at 12 months. The secondary endpoints are: MACCE at 24 and 36 months, and the composite of cardiac death, myocardial infarction, any revascularisation, stroke, major bleeding and left ventricular ejection fraction below 45% at 12, 24 and 36 months. Furthermore, quality of life will be assessed by the Patient Health Questionnaire (PHQ-9) and the Short Form (36) Health Survey (SF-36) at 1 and 12 months of follow-up. Conclusion The SLIM trial aims to provide evidence whether FFR-guided complete revascularisation by PCI is superior to usual care with respect to clinical outcomes (major adverse cardiovascular events) in non-STEMI patients with MVD.

This paper presents a first study to apply a computational approach to Genito-Pelvic Pain/Penetration Disorder (GPPPD) using a Fear Avoidance Model. An adaptive temporal-causal network model for fear avoidance was designed and therapeutic interventions were incorporated targeting one or two emotional states. Validation with empirical data shows that for one type of individual therapeutic intervention targeting two states can reduce pain and other complaints. For three other types of individuals, targeting two emotional states was not sufficient to reduce pain and other complaints. The computational model can address large individual differences and supports the claim that interventions for GPPPD should be multidisciplinary.

Objectives The aim of this study was to evaluate 1-year clinical safety and efficacy of the dual-therapy COMBO stent in a large, all-comers patient-level pooled cohort. Background The COMBO stent (OrbusNeich Medical, Fort Lauderdale, Florida) is a novel stent with abluminal sirolimus elution from a biodegradable polymer and a luminal pro-healing anti-CD34+ antibody layer, which attracts circulating endothelial progenitor cells. These endothelial progenitor cells can quickly mature into normal endothelium, providing rapid endothelialization. Methods The MASCOT (Multinational Abluminal Sirolimus Coated biO-engineered stenT) (N = 2,614, 61 global sites) and REMEDEE (Randomized study to Evaluate the safety and effectiveness of an abluMinal sirolimus coatED bio-Engineered StEnt Post Market Registry) (N = 1,000, 9 European sites) registries are 2 prospective, multicenter studies evaluating clinical outcomes after attempted COMBO stent placement in all-comer patients undergoing percutaneous coronary intervention. In this patient-level pooled analysis we analyzed 1-year target lesion failure (TLF), a composite of cardiac death, target vessel myocardial infarction, or clinically driven target lesion revascularization. Furthermore, we determined predictors of 1-year TLF. Results A total of 3,614 patients (63.5 ± 11.2 years of age; 23.8% women) were included in this analysis. The prevalence of diabetes mellitus was 29.3%, and 54.3% patients presented with acute coronary syndrome. The primary endpoint of 1-year TLF occurred in 140 (3.9%) patients, with incidence of cardiac death in 1.6%, target vessel myocardial infarction in 1.2%, clinically driven target lesion revascularization in 2.2%, and definite stent thrombosis in 0.5% patients. Insulin-treated diabetes mellitus, chronic renal failure, and American College of Cardiology/American Heart Association lesion type B2/C were independent predictors of 1-year TLF. Conclusions In this large patient-level pooled analysis of patients treated with the dual-therapy COMBO stent excellent results at 1-year were observed. (MASCOT - Post Marketing Registry [MASCOT]; NCT02183454; Prospective Registry to Assess the Long-term Safety and Performance of the COMBO Stent [REMEDEE Reg]; NCT01874002)

The prevalence of common mental disorders increases in humanitarian emergencies while access to services to address them decreases. Problem Management Plus (PM+) is a brief five-session trans-diagnostic psychological WHO intervention employing empirically supported strategies that can be delivered by non-specialist lay-providers under specialist supervision to adults impaired by distress. Two recent randomized controlled trials in Pakistan and Kenya demonstrated the efficacy of individually delivered PM+. To make PM+ more scalable and acceptable in different contexts, it is important to develop a group version as well, with 6–8 participants in session. A study is needed to demonstrate the feasibility and acceptability of both the intervention in a new cultural context and the procedures to evaluate Group PM+ in a cluster randomized controlled trial. This protocol describes a feasibility trial to Group PM+ in Sindhuli, Nepal. This study will evaluate procedures for a cluster randomized controlled trial (c-RCT) with Village Development Committees (VDCs), which are the second smallest unit of government administration, as the unit of randomization. Adults with high levels of psychological distress and functional impairment will receive either Group PM+ (n = 60) or enhanced usual care (EUC; n = 60). Psychological distress, functional impairment, depression symptoms, posttraumatic stress disorder (PTSD) symptoms, and perceived problems will be measured during screening, pre-treatment baseline, and 7–10 days after the intervention. Qualitative data will be collected from beneficiaries, their families, local stakeholders, and staff to support quantitative data and to identify themes reporting that those involved and/or effected by Group PM+ perceived it as being acceptable, feasible, and useful. The primary objective of this trial is to evaluate the acceptability and feasibility of the intervention; to identify issues around implementation of local adaptation methods, training, supervision, and outcomes measures; and to assure that procedures are adequate for a subsequent effectiveness c-RCT. Outcomes from this trial will contribute to optimizing feasibility and acceptability through cultural adaptation and contextualization of the intervention as well as refining the design for a c-RCT, which will evaluate the effectiveness of Group PM+ in Nepal. ClinicalTrials.gov identifier: NCT03359486

Approximately 32,000 infants are born with CHDs each year in the United States of America. Of every 1000 live births, 2.3 require surgical or transcatheter intervention in the first year of life. There are few more stressful times for parents than when their neonate receives a diagnosis of complex CHD requiring surgery. The stress of caring for these infants is often unrelenting and may last for weeks, months, and often years, placing parents at risk for developing post-traumatic stress disorder, as well as a drastic decrease in quality of life. Anxiety often peaks in the days and weeks after discharge from the hospital as families no longer have immediate access to nursing and medical staff. The purpose of this paper is to describe the methods of a randomised controlled trial that was designed to determine whether REACH would favourably affect parental and infant outcomes by decreasing parental stress, improve parental quality of life, increase infant stability, and decrease resource utilisation in infants with complex CHD.

Foxp3 is essential for T regulatory cell (Treg) function. Broad complex-Tramtrack-Bric-a-brac domain (BTB) and Cap'n'collar (CNC) homology 1, transcription factor 2 (BACH2) stabilizes Treg immune homeostasis in murine studies. However, little is known regarding what role, if any, BACH2 may have in Foxp3 regulation in human-induced Treg (iTreg). We examined Foxp3 expression and regulation comparing iTreg differentiated from umbilical cord blood (UCB) vs. adult blood (AB) naive CD4+ T-cells. Foxp3 expression was higher in UCB vs. AB-derived iTreg, and was sustained during 21-day expansion in vitro. The number of Foxp3+ iTreg generated from UCB vs. AB naive CD4+ T-cells was higher in iTreg differentiation conditions. In addition, UCB iTreg were more potent in suppressing T-cell proliferation compared to AB iTreg. Naive UCB CD4+ T-cells highly expressed BACH2 protein compared to AB. Putative transcriptional BACH2 binding sites were identified at the Foxp3 promoter, using BACH2 consensus sequence. Cross-linking chromatin immunoprecipitation (ChIP) showed that BACH2 binds to the Foxp3 proximal promoter in UCB iTreg, but not AB iTreg. BACH2 was transcriptionally active, as shRNA-mediated BACH2 knockdown resulted in reduction of Foxp3 gene transcription in UCB CD4+ T-cells. In summary, BACH2 serves to stabilize robust Foxp3 expression in UCB CD4+ T-cell-derived iTreg.

BACKGROUND: Among patients with STEMI in the ATLANTIC study, pre-hospital administration of ticagrelor improved post-PCI ST-segment resolution and 30-day stent thrombosis. We investigated whether this clinical benefit with pre-hospital ticagrelor differs by ischemic duration.METHODS: In a post hoc analysis we compared absence of ST-segment resolution post-PCI and stent thrombosis at 30 days between randomized treatment groups (pre- versus in-hospital ticagrelor) stratified by symptom onset to first medical contact (FMC) duration [≤1 hour (n = 773), >1 to ≤3 hours (n = 772), and >3 hours (n = 311)], examining the interaction between randomized treatment strategy and duration of symptom onset to FMC for each outcome.RESULTS: Patients presenting later after symptom onset were older, more likely to be female, and have higher baseline risk. Patients with symptom onset to FMC >3 hours had the greatest improvement in post-PCI ST-segment elevation resolution with pre- versus in-hospital ticagrelor (absolute risk difference: ≤1 hour, 2.9% vs. >1 to ≤3 hours, 3.6% vs. >3 hours, 12.2%; adjusted p for interaction = 0.13), while patients with shorter duration of ischemia had greater improvement in stent thrombosis at 30 days with pre- versus in-hospital ticagrelor (absolute risk difference: ≤1 hour, 1.3% vs. >1 hour to ≤3 hours, 0.7% vs. >3 hours, 0.4%; adjusted p for interaction = 0.55). Symptom onset to active ticagrelor administration was independently associated with stent thrombosis at 30 days (adjusted OR 1.89 per 100 minute delay, 95%CI 1.20-2.97, P < .01), but not post-PCI ST-segment resolution (P = .41).CONCLUSIONS: The effect of pre-hospital ticagrelor to reduce stent thrombosis was most evident when given early within 3 hours after symptom onset, with delay in ticagrelor administration after symptom onset associated with higher rate of stent thrombosis. These findings re-emphasize the need for early ticagrelor administration in primary PCI treated STEMI patients.

Extracellular signal-regulated protein kinase 5 (ERK5) has been implicated during development and carcinogenesis. Nkx3.1-mediated Cre expression is a useful strategy to genetically manipulate the mouse prostate. While grossly normal at birth, we observed an unexpected phenotype of spinal protrusion in Nkx3.1:Cre;Erk5fl/fl (Erk5fl/fl) mice by ~6–8 weeks of age. X-ray, histological and micro CT (µCT) analyses showed that 100% of male and female Erk5fl/fl mice had a severely deformed curved thoracic spine, with an associated loss of trabecular bone volume. Although sex-specific differences were observed, histomorphometry measurements revealed that both bone resorption and bone formation parameters were increased in male Erk5fl/fl mice compared to wild type (WT) littermates. Osteopenia occurs where the rate of bone resorption exceeds that of bone formation, so we investigated the role of the osteoclast compartment. We found that treatment of RANKL-stimulated primary bone marrow-derived macrophage (BMDM) cultures with small molecule ERK5 pathway inhibitors increased osteoclast numbers. Furthermore, osteoclast numbers and expression of osteoclast marker genes were increased in parallel with reduced Erk5 expression in cultures generated from Erk5fl/fl mice compared to WT mice. Collectively, these results reveal a novel role for Erk5 during bone maturation and homeostasis in vivo.

Background It remains unclear whether radial access (RA), compared with femoral access (FA), mitigates the risk of acute kidney injury (AKI). Objectives The authors assessed the incidence of AKI in patients with acute coronary syndrome (ACS) enrolled in the MATRIX-Access (Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox) trial. Methods Among 8,404 patients, 194 (2.3%) were excluded due to missing creatinine values, no or an incomplete coronary angiogram, or previous dialysis. The primary AKI-MATRIX endpoint was AKI, defined as an absolute (>0.5 mg/dl) or a relative (>25%) increase in serum creatinine (sCr). Results AKI occurred in 634 patients (15.4%) with RA and 712 patients (17.4%) with FA (odds ratio [OR]: 0.87; 95% confidence interval [CI]: 0.77 to 0.98; p = 0.0181). A >25% sCr increase was noted in 633 patients (15.4%) with RA and 710 patients (17.3%) with FA (OR: 0.87; 95% CI: 0.77 to 0.98; p = 0.0195), whereas a >0.5 mg/dl absolute sCr increase occurred in 175 patients (4.3%) with RA versus 223 patients (5.4%) with FA (OR: 0.77; 95% CI: 0.63 to 0.95; p = 0.0131). By implementing the Kidney Disease Improving Global Outcomes criteria, AKI was 3-fold less prevalent and trended lower with RA (OR: 0.85; 95% CI: 0.70 to 1.03; p = 0.090), with stage 3 AKI occurring in 28 patients (0.68%) with RA versus 46 patients (1.12%) with FA (p = 0.0367). Post-intervention dialysis was needed in 6 patients (0.15%) with RA and 14 patients (0.34%) with FA (p = 0.0814). Stratified analyses suggested greater benefit with RA than FA in patients at greater risk for AKI. Conclusions In ACS patients who underwent invasive management, RA was associated with a reduced risk of AKI compared with FA. (Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and Systemic Implementation of angioX [MATRIX]; NCT01433627 )

Sentinel-5 is an Earth atmospheric monitoring mission developed within the Copernicus program. The mission objective is to monitor the composition of the Earth's atmosphere on a daily basis. TNO is developing the UV1 spectrometer subsystem as well as the two telescope subsystems. In this paper, the design of the UV1 spectrometer is described and its major design and verification challenges are discussed. The UV1 optical design is based on a classical Offner-type spectrometer which has been adapted to employ freeform optics and an aspheric off-axis grating. It generates a magnification of 0.4. A structural, monolithic housing has been designed that is optimized for stability, accessibility and integration of optical components. To realize a thermo-mechanically stable construction, both housing and mirror bodies are built from aluminum. Four out of five mirrors have a dedicated black coating for absorbing out-of-band light. For further stray light suppression, a graded short-pass filter is employed on the last optical element just in front of the detector. Performance verification of a standalone spectrometer without telescope, entrance slit, limiting aperture stop and flight detector is a major challenge. For this verification TNO developed dedicated ground support equipment that will be used under both ambient and vacuum conditions; a dedicated optical stimulus that mimics the illumination from the telescope in terms of pointing and NA, a Slit Assembly that mimics the homogenizer entrance slit and a Test Detector to determine the image plane and to measure the optical performance with high accuracy. At the time of writing this article, the first (proto-flight) model has been aligned and performance verification is about to start.

Introduction Knowledge about effectiveness of cardiac rehabilitation (CR) in the elderly is limited. Participation rates in supervised CR are consistently lower in the elderly and innovative interventions are needed. The EU has granted a CR study project; a randomised controlled trial conducted in 5 European countries, investigating the effectiveness of mobile telemonitoring guided CR (mCR) in elderly cardiac patients who declined regular CR. Methods Patients ≥65 years with indication for CR who declined regular CR were eligible for inclusion. Patients were randomised between regular care (without CR) and a 6-month mCR programme: dedicated programmed smartphone, heartrate monitoring (target HR zones) and coaching. The primary endpoint is the difference in VO2peak between 6-months follow-up and baseline. Results Between 2015 and 2018 179 patients were included. Baseline characteristics between groups (table 1) did not differ significantly, except for hypertension. The difference in VO2peak was significantly better in the mCR group (table 1). After correction (mixed linear model) for baseline VO2 peak (fixed factor) and centre (random factor) this difference remained significant. Mean number of registered activity sessions was 4.79 (95% CI; 4.07–5.50) per patient per week. Table 1. Baseline and primary outcome parameters Baseline Control Programme (n=90) mCR Programme (n=89) P-value Gender (m/f) 76/14 69/20 0.238 Age (mean±SD) 73.57±5.46 72.38±5.37 0.121 Diabetes 15 (16.7%) 23 (25.8%) 0.133 Hypertension 60 (66.7%) 73 (82.0%) 0.019* Hypercholesteremia 71 (78.3%) 74 (83.1%) 0.468 Normal LV-function 48/89 (53.9%) 53/89 (59.6%) 0.497 Index event (CABG/Valve/PCI/none) 0.735 Cardiac history prior to index event 48/89 (53.9%) 53/89 (59.6%) 0.702 Non cardiac comorbidity 40 (44.4%) 44 (49.4%) 0.503 Results Baseline VO2peak (ml/kg/min) (95% CI) 19.83 (18.65–21.01) 18.78 (18.67–19.89) 0.191 Delta VO2peak at 6 months (ml/kg/min) (95% CI) 0.20 4 (−0.34–0.83) 1.62 (0.86–2.39) 0.005* Corrected delta VO2peak at 6 months (ml/kg/min) 0.50 (−1.04–2.04) 1.65 (0.11–3.2) 0.015* *Significant. Conclusions The application of mCR in elderly patients who declined regular CR results in a better physical condition after 6 months. Compliance to mCR was excellent. Acknowledgement/Funding European Union's Horizon 2020 research and innovation programme under grant agreement number 634439, and funding from the Swiss Government.

Background The EU-CaRE project aims to obtain the evidence base to improve, tailor and optimise cardiac rehabilitation (CR) programmes regarding sustainable effectiveness, cost-effectiveness and participation level in the elderly. Purpose To compare the effect of CR programmes in 7 European countries on the main outcome. Methods The observational EU-CaRE study is a prospective study with eight participating CR sites in seven countries (Denmark, France, Germany, Italy, the Netherlands, Spain and Switzerland). Consecutive patients age 65 or older with coronary heart disease or valve surgery undergoing CR were included. Data were obtained at baseline (T0), at the end of CR (T1) and at 1 year (T2). VO2peak was assessed by cardiopulmonary exercise test. We compared changes in VO2peak across sites in multilevel regression models for repeated measures, adjusting for age, gender, baseline VO2peak, comorbidities, CVD risk factors and educational attainment. Results are reported separately for patients undergoing surgery (CABG/valve replacement) and other indications (MI/stable CAD/PCI). Results 1633 patients were included, and VO2peak was available at all three timepoints for 1243 patients (76%), 492 undergoing surgery and 751 for other indications. Lag time from index event to first CPET and baseline VO2peak varied significantly across centres. Mean age was 72.9 (range 65–90), mean VO2peak at T0 was 16.49 (SD 4.94), at T1, 18.55 (5.33) and at T2 19.03 (5.43) ml/kg/min. For patients not undergoing surgery mean improvement T0-T1 was 1.57 (2.98) and T0-T2 was 1.40 (3.17) ml/kg/min (both p In addition to age and gender, baseline and one-year VO2peak was lower in patients with diabetes, hypertension, smokers, patients with other co-morbidity, lower educational attainment and lower mental component score of the SF36. These factors had no systematic impact on the effect of CR. VO2peak at baseline, after CR and 1 year Conclusions The study provides high-quality data on the effectiveness of current CR programmes in Western Europe. Overall, CR was effective in achieving significant improvements in exercise and maintaining these effects. There were significant differences in effect between sites indicating a potential for improvement by adapting CR programs. Acknowledgement/Funding Horizon 2020

Background Previous analyses from EU-CaRE study have shown that elderly cardiac patients with basic education have a greater burden of cardiovascular risk factors and a lower exercise capacity at baseline of cardiac rehabilitation (CR). We hypothesize that participation in CR will diminish this socioeconomic gap. Purpose To describe if educational level predicts the benefits of CR in an elderly population in Europe. Methods The observational EU-CaRE study is a prospective study with eight participating CR centers in seven countries (Denmark, France, Germany, the Netherlands, Italy, Spain and Switzerland). Consecutive patients age 65 or older with coronary heart disease or valve surgery participating in CR were included. Data were obtained at baseline (T0) and at the end of CR (T1) and include risk factors for cardiovascular disease, clinical and psychological assessment, medical treatment and exercise capacity. Patients were divided into basic, intermediate and higher educational levels. We compared changes from T0-T1 by multiple regression models. Results A total of 1621 (99% of included) patients were eligible for follow-up analyses. At baseline patients with basic education had more diabetes, higher BMI, lower exercise capacity (VO2 peak) and higher scores for depression (GAD) and anxiety (PHQ-9). At T1 they had improved significantly less on these parameters. The results were not affected by adjustment for gender, age, country and baseline value of the variable. Use of evidence-based medication did not differ by level of education. Difference between T0 and T1 Factor High Intermediate Basic p-value* N total 1621 N=386 N=775 N=460 BMI, mean (SD) −0.16 (0.71) −0.08 (0.82) −0.26 (0.95) 0.794 LDL (mmol/L), mean (SD) −0.07 (0.63) −0.11 (0.62) −0.04 (0.58) 0.978 HbA1c (mmol/mol), mean (SD) 0.23 (3.70) 0.52 (4.39) 0.04 (5.79) 0.021 GAD score, mean (SD) −0.92 (2.72) −0.76 (3.07) −0.13 (3.47) 0.003 PHQ-9 score, mean (SD) −1.45 (3.21) −1.16 (3.36) −0.93 (4.49) Difference in VO2peak, GAD and PHQ score Conclusions In this large European study with high-quality data from 7 CR centers we found an increased gap disfavoring the lower educated elderly patients participating in CR. These results indicate that “one-size cardiac rehabilitation” does not fit all and indicate that a more personalized CR with attention to the different needs of some patient groups is appropriate. Acknowledgement/Funding Horizon2020

Background In the setting of AMI, rapid platelet inhibition is desirable but the onset of pharmacodynamic (PD) effect of oral platelet P2Y12 inhibitors is delayed, sometimes for hours. Subcutaneous (s.c) administration of a rapidly-acting P2Y12 inhibitor would overcome many of the limitations of available therapies. Patients with stable CAD were investigated initially. Purpose To characterise the inhibition of platelet aggregation and pharmacokinetics (PK) of a single dose of selatogrel, a novel s.c P2Y12 inhibitor, in patients with stable CAD. Methods Patients with stable CAD receiving oral antiplatelet therapy (aspirin and/or oral P2Y12 inhibitor) were randomized to 1 of 8 groups based on treatment (selatogrel or matching placebo), dose (8 mg or 16 mg) and s.c injection site (thigh or abdomen). Venous blood samples were collected into PPACK anticoagulant tubes. Platelet reactivity was assessed by VerifyNow PRU (P2Y12 reaction units) test before and 15 min, 30 min and 1, 2, 4, 8 and 24 h after injection. Light-transmittance aggregometry (LTA; ADP 20 uM) was also performed. PK samples were collected up to 24 h post-dose. Adverse events occurring within 30 days were recorded. Responders were defined as having PRU Results 345 patients (mean age 65 y; 20% female; 31% diabetes) received selatogrel 8 mg (n=114), selatogrel 16 mg (n=115) or placebo (n=116). 97% were on background therapy with aspirin (or its derivative carbasalate) and 35% with oral P2Y12 inhibitor (clopidogrel 23%, prasugrel 4%, ticagrelor 8%). 89% of subjects were responders to selatogrel 8 mg, 90% to selatogrel 16 mg and 16% to placebo (P Conclusions Selatogrel has a rapid PD effect following s.c injection in patients with stable CAD, within 15 min in most patients. The consistent and high levels of P2Y12 inhibition with a single 8 mg or 16 mg dose are sustained for over 4 hours, following which platelet reactivity progressively recovers over 24 h. Selatogrel was well tolerated, with mostly mild, transient dyspnoea observed in Acknowledgement/Funding Fully funded by Idorsia Pharmaceuticals Ltd

Background A socioeconomic gap in cardiac rehabilitation (CR) has been described in younger populations but whether this is also true in the ageing population is unknown. Purpose To describe if poorer education is a predictor for exercise capacity, comorbidity, lifestyle- and risk factors and medical treatment at baseline in CR in an elderly population. Methods The observational EU-CaRE study is a European prospective study with eight participating CR centers in seven countries (Denmark, France, Germany, the Netherlands, Italy, Spain and Switzerland). Patients aged 65 or older with CHD or valve surgery participating in CR were consecutively included. Educational attainment was divided into basic, intermediate and high Results A total of 1626 patients were included. Educational attainment differed across centers (p Demographics and risk factor control N=1626 High (N=388) Intermediate (N=788) Basic (N=460) p-value* DEMOGRAPHICS Age (yrs), median (IQR) 72 (68, 76) 71 (68, 75) 74 (70, 78) 1.8 mmol/l*** 255 (66.1%) 518 (66.8%) 293 (63.7%) 0.060 Systolic BP >140 mmHg 85 (22.0%) 179 (23.1%) 100 (21.7%) 0.601 Smoker 26 (6.8%) 80 (10.3%) 46 (10.0%) 0.214 Moderate exercise 27 kg/m2 133 (35.5%) 389 (50.2%) 255 (55.4%) 48mmol/mol*** 115 (29.8%) 264 (34.1%) 230 (50.0%) Conclusions The results emphasize the need of CR in this patient-group and that a targeted CR approach should be considered to achieve equal health opportunities also in the elderly. Acknowledgement/Funding Horizon2020

Background Malaria vector control and research rely heavily on monitoring mosquito populations for the development of resistance to public health insecticides. One standard method for determining resistance in adult mosquito populations is the World Health Organization test (WHO bioassay). The WHO bioassay kit consists of several acrylic pieces that are assembled into a unit. Parts of the kit commonly break, reducing the capacity of insectaries to carry out resistance profiling. Since there is at present only a single supplier for the test kits, replacement parts can be hard to procure in a timely fashion. Methods Using computer-aided design software and widely available polylactic acid (PLA) filament as a printing material, we 3D designed and printed replacement parts for the WHO bioassay system. We conducted a comparison experiment between original WHO bioassay kits and 3D printed kits to assess congruence between results. The comparison experiment was performed on two Kenyan laboratory strains of Anopheles gambiae (s.s.), Kilifi and Mbita. Studentʼs t-tests were used to assess significant differences between tube types. Finally, we exposed the PLA filament to common solutions used with the bioassay kit. Results We were able to design and print functional replacements for each piece of the WHO bioassay kit. Replacement parts are functionally identical to and interchangeable with original WHO bioassay parts. We note no significant difference in mortality results obtained from PLA printed tubes and WHO acrylic tubes. Additionally, we observed no degradation of PLA in response to prolonged exposure times of commonly used cleaning solutions. Conclusions Our designs can be used to produce replacement parts for the WHO bioassay kit in any facility with a 3D printer, which are becoming increasingly widespread. 3D printing technologies can affordably and rapidly address equipment shortages and be used to develop bespoke equipment in laboratories.