Anatomic position determines oncogenic specificity in melanoma.

Oncogenic alterations to DNA are not transforming in all cellular contexts1,2. This may be due to pre-existing transcriptional programmes in the cell of origin. Here we define anatomic position as a major determinant of why cells respond to specific oncogenes. Cutaneous melanoma arises throughout the body, whereas the acral subtype arises on the palms of the hands, soles of the feet or under the nails3. We sequenced the DNA of cutaneous and acral melanomas from a large cohort of human patients and found a specific enrichment for BRAF mutations in cutaneous melanoma and enrichment for CRKL amplifications in acral melanoma. We modelled these changes in transgenic zebrafish models and found that CRKL-driven tumours formed predominantly in the fins of the fish. The fins are the evolutionary precursors to tetrapod limbs, indicating that melanocytes in these acral locations may be uniquely susceptible to CRKL. RNA profiling of these fin and limb melanocytes, when compared with body melanocytes, revealed a positional identity gene programme typified by posterior HOX13 genes. This positional gene programme synergized with CRKL to amplify insulin-like growth factor (IGF) signalling and drive tumours at acral sites. Abrogation of this CRKL-driven programme eliminated the anatomic specificity of acral melanoma. These data suggest that the anatomic position of the cell of origin endows it with a unique transcriptional state that makes it susceptible to only certain oncogenic insults.

Device-measured physical activity and cardiometabolic health: the Prospective Physical Activity, Sitting, and Sleep (ProPASS) consortium.

BACKGROUND AND AIMS: Physical inactivity, sedentary behaviour (SB), and inadequate sleep are key behavioural risk factors of cardiometabolic diseases. Each behaviour is mainly considered in isolation, despite clear behavioural and biological interdependencies. The aim of this study was to investigate associations of five-part movement compositions with adiposity and cardiometabolic biomarkers. METHODS: Cross-sectional data from six studies (n = 15 253 participants; five countries) from the Prospective Physical Activity, Sitting and Sleep consortium were analysed. Device-measured time spent in sleep, SB, standing, light-intensity physical activity (LIPA), and moderate-vigorous physical activity (MVPA) made up the composition. Outcomes included body mass index (BMI), waist circumference, HDL cholesterol, total:HDL cholesterol ratio, triglycerides, and glycated haemoglobin (HbA1c). Compositional linear regression examined associations between compositions and outcomes, including modelling time reallocation between behaviours. RESULTS: The average daily composition of the sample (age: 53.7 ± 9.7 years; 54.7% female) was 7.7 h sleeping, 10.4 h sedentary, 3.1 h standing, 1.5 h LIPA, and 1.3 h MVPA. A greater MVPA proportion and smaller SB proportion were associated with better outcomes. Reallocating time from SB, standing, LIPA, or sleep into MVPA resulted in better scores across all outcomes. For example, replacing 30 min of SB, sleep, standing, or LIPA with MVPA was associated with -0.63 (95% confidence interval -0.48, -0.79), -0.43 (-0.25, -0.59), -0.40 (-0.25, -0.56), and -0.15 (0.05, -0.34) kg/m2 lower BMI, respectively. Greater relative standing time was beneficial, whereas sleep had a detrimental association when replacing LIPA/MVPA and positive association when replacing SB. The minimal displacement of any behaviour into MVPA for improved cardiometabolic health ranged from 3.8 (HbA1c) to 12.7 (triglycerides) min/day. CONCLUSIONS: Compositional data analyses revealed a distinct hierarchy of behaviours. Moderate-vigorous physical activity demonstrated the strongest, most time-efficient protective associations with cardiometabolic outcomes. Theoretical benefits from reallocating SB into sleep, standing, or LIPA required substantial changes in daily activity.

Relationship of device measured physical activity type and posture with cardiometabolic health markers: pooled dose-response associations from the Prospective Physical Activity, Sitting and Sleep Consortium.

AIMS/HYPOTHESIS: The aim of this study was to examine the dose-response associations of device-measured physical activity types and postures (sitting and standing time) with cardiometabolic health. METHODS: We conducted an individual participant harmonised meta-analysis of 12,095 adults (mean ± SD age 54.5±9.6 years; female participants 54.8%) from six cohorts with thigh-worn accelerometry data from the Prospective Physical Activity, Sitting and Sleep (ProPASS) Consortium. Associations of daily walking, stair climbing, running, standing and sitting time with a composite cardiometabolic health score (based on standardised z scores) and individual cardiometabolic markers (BMI, waist circumference, triglycerides, HDL-cholesterol, HbA1c and total cholesterol) were examined cross-sectionally using generalised linear modelling and cubic splines. RESULTS: We observed more favourable composite cardiometabolic health (i.e. z score <0) with approximately 64 min/day walking (z score [95% CI] -0.14 [-0.25, -0.02]) and 5 min/day stair climbing (-0.14 [-0.24, -0.03]). We observed an equivalent magnitude of association at 2.6 h/day standing. Any amount of running was associated with better composite cardiometabolic health. We did not observe an upper limit to the magnitude of the dose-response associations for any activity type or standing. There was an inverse dose-response association between sitting time and composite cardiometabolic health that became markedly less favourable when daily durations exceeded 12.1 h/day. Associations for sitting time were no longer significant after excluding participants with prevalent CVD or medication use. The dose-response pattern was generally consistent between activity and posture types and individual cardiometabolic health markers. CONCLUSIONS/INTERPRETATION: In this first activity type-specific analysis of device-based physical activity, ~64 min/day of walking and ~5.0 min/day of stair climbing were associated with a favourable cardiometabolic risk profile. The deleterious associations of sitting time were fully attenuated after exclusion of participants with prevalent CVD and medication use. Our findings on cardiometabolic health and durations of different activities of daily living and posture may guide future interventions involving lifestyle modification.

Long-term effects and predictors of change of internet-delivered cognitive behavioural therapy on cardiac anxiety in patients with non-cardiac chest pain: a randomized controlled trial.

BACKGROUND: Approximately half of patients who seek care at Emergency Departments due to chest pain are diagnosed with Non-Cardiac Chest Pain (NCCP). Concerns for heart disease and misinterpretation of the symptoms increase cardiac anxiety and have a negative impact on patients' lives. Psychological interventions such as internet-delivered cognitive behavioral therapy (iCBT) are effective in treating psychological conditions such as anxiety, by helping patients to learn how to manage chest pain. AIMS: To evaluate the effects of a nurse-led iCBT program on cardiac anxiety and secondary outcomes, as bodily sensations, depressive symptoms, health-related quality of life and chest pain frequency in patients with NCCP at 6- and 12-month follow-up, and to explore predictors that can have impact on the effects of the iCBT program on psychological distress. METHODS: A longitudinal study of a Randomized Controlled Trial (RCT) evaluating the long-term effects of an iCBT program (n = 54) in patients with NCCP, compared to psychoeducation (n = 55). The primary outcome, cardiac anxiety was measured using the Cardiac Anxiety Questionnaire (CAQ), and the secondary outcomes were measured with The Body Sensations Questionnaire (BSQ), Patient Health Questionnaire-9 (PHQ-9), The EuroQol Visual Analog Scale (EQ-VAS) and a self-developed question to measure chest pain frequency. All measurements were performed before and after the intervention, and 3, 6 and 12 months after the intervention. Linear mixed model was used to test between-group differences in primary and secondary outcomes and multiple regression analysis was used to explore factors that may have an impact on the treatment effect of iCBT on cardiac anxiety. RESULTS: A total of 85% (n = 93/109) participants completed the 12-month follow-up. Mixed model analysis showed no statistically significant interaction effect of time and group between the iCBT and psychoeducation groups regarding cardiac anxiety over the 12-month follow-up. However, there was a statistically significant interaction effect of time and group (p = .009) regarding chest pain frequency favouring the iCBT group. In addition, we found a group effect in health-related quality of life (p = .03) favouring the iCBT group. The regression analysis showed that higher avoidance scores at baseline were associated with improvement in cardiac anxiety at 12-month follow-up. CONCLUSIONS: Cardiac anxiety was reduced in patients with NCCP, but iCBT was not more effective than psychoeducation. Patients with a high tendency to avoid activities or situations that they believe could trigger cardiac symptoms may benefit more from psychological interventions targeting cardiac anxiety. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov NCT03336112 on 08/11/2017.

Translation, cross-cultural adaptation, and preliminary validation of a patient-reported outcome measure for genetic counseling outcomes in Sweden.

Genetic counseling is key for understanding the consequences of hereditary and genetic diseases and, therefore, crucial for patients, their families, and healthcare providers. Genetic counseling facilitates individuals' comprehension, decision-making, and adaptation to hereditary diseases. This study focuses on the Swedish adaptation of the Genetic Counseling Outcome Scale-24 (GCOS-24), an internationally validated, patient-reported outcome measure (PROM) for quantifying patient empowerment in genetic counseling. This study aimed to translate and cross-culturally adapt the GCOS-24 to measure patient-reported outcome from genetic counseling in Sweden. The adaptation process was meticulously conducted, adhering to international guidelines, with cross-cultural adaptation, translation, and back translation, to ensure semantic, conceptual, and idiomatic equivalence with the original English version. Face validity and understandability was assured using qualitative cognitive interviews conducted with patient representatives, and by a committee of experts in the field. The psychometric properties of the Swedish version of GCOS-24 (GCOS-24swe) were evaluated using a robust sample of 374 patients. These individuals received genetic counseling by telephone or video, necessitated by the constraints of the COVID-19 pandemic. Participants responded to GCOS-24swe both before and after genetic counseling. The GCOS-24swe demonstrated face validity, good internal consistency (Cronbach's alpha = 0.86), significant responsiveness (Cohen's d = 0.65, p < 0.001), and good construct validity. The study's findings underscore the GCOS-24swe's potential as an effective instrument in both clinical practice and research within Sweden. It offers a valuable means for assessing patient empowerment, a key goal of genetic counseling. Additional psychometric assessment of test-retest reliability and interpretability would further enhance the utility of GCOS-24swe.

The ATM Ser49Cys Variant Effects ATM Function as a Regulator of Oncogene-Induced Senescence.

An apical component of the cell cycle checkpoint and DNA damage repair response is the ataxia-telangiectasia mutated (ATM) Ser/Thr protein kinase. A variant of ATM, Ser49Cys (rs1800054; minor allele frequency = 0.011), has been associated with an elevated risk of melanoma development; however, the functional consequence of this variant is not defined. ATM-dependent signalling in response to DNA damage has been assessed in a panel of patient-derived lymphoblastoid lines and primary human melanocytic cell strains heterozygous for the ATM Ser49Cys variant allele. The ATM Ser49Cys allele appears functional for acute p53-dependent signalling in response to DNA damage. Expression of the variant allele did reduce the efficacy of oncogene expression in inducing senescence. These findings demonstrate that the ATM 146C>G Ser49Cys allele has little discernible effect on the acute response to DNA damage but has reduced function observed in the chronic response to oncogene over-expression. Analysis of melanoma, naevus and skin colour genomics and GWAS analyses have demonstrated no association of this variant with any of these outcomes. The modest loss of function detected suggest that the variant may act as a modifier of other variants of ATM/p53-dependent signalling.

Rationale and design of the DAPA-MI trial: Dapagliflozin in patients without diabetes mellitus with acute myocardial infarction.

BACKGROUND: Therapies that could further prevent the development of heart failure (HF) and other cardiovascular and metabolic events in patients with recent myocardial infarction (MI) represent a large and unmet medical need. METHODS: DAPA-MI is a multicenter, parallel-group, registry-based, randomized, double-blind, placebo-controlled phase 3 trial in patients without known diabetes or established HF, presenting with MI and impaired left ventricular systolic function or Q-wave MI. The trial evaluated the effect of dapagliflozin 10 mg vs placebo, given once daily in addition to standard of care therapy, on death, hospitalization for HF (HHF), and other cardiometabolic outcomes. The primary objective of the trial was to determine, using the win-ratio method, if dapagliflozin is superior to placebo by comparing the hierarchical composite outcome of death, HHF, nonfatal MI, atrial fibrillation/flutter, new onset of type 2 diabetes mellitus, HF symptoms as measured by New York Heart Association Functional Classification at last visit, and body weight decrease ≥5% at last visit. Assuming a true win-ratio of 1.20 between dapagliflozin and placebo, 4,000 patients provide a statistical power of 80% for the test of the primary composite outcome. A registry-based randomized controlled trial framework allowed for recruitment, randomization, blinding, and pragmatic data collection of baseline demographics, medications, and clinical outcomes using existing national clinical registries (in Sweden and the UK) integrated with the trial database. CONCLUSIONS: The trial explores opportunities to improve further the outcome of patients with impaired LV function after MI. The innovative trial design of DAPA-MI, incorporating national clinical registry data, has facilitated efficient patient recruitment as well as outcome ascertainment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT04564742.

Modifications of 24-h movement behaviors to prevent obesity in retirement: a natural experiment using compositional data analysis.

BACKGROUND: Retirement often leads to a more passive lifestyle and may therefore lead to weight gain. This study aims to investigate longitudinal associations between changes in 24-h movement behaviors and BMI and waist circumference in relation to the transition from work to retirement. METHODS: The study population included 213 retiring public sector workers (mean age 63.5 years, standard deviation 1.1) from the Finnish Retirement and Aging study. Before and after retirement participants wore an Axivity accelerometer on their thigh and filled in a daily log for at least four days to measure daily time spent sleeping, in sedentary behavior (SED), light physical activity (LPA) and moderate-to-vigorous physical activity (MVPA). Also, their body mass index (BMI) and waist circumference were measured repeatedly. Compositional linear regression analysis and isotemporal substitution analysis were used to study associations between one-year changes in 24-h movement behaviors and concurrent changes in BMI and waist circumference. RESULTS: An increase in MVPA in relation to sleep, SED and LPA was associated with a decreasing BMI (ß = -0.60, p = 0.04) and waist circumference (ß = -2.14, p = 0.05) over one year from before retirement to after retirement. In contrast, increasing sleep in relation to SED, LPA and MVPA was associated with an increasing BMI (ß = 1.34, p = 0.02). Reallocating 60 min from MVPA to SED or sleep was estimated to increase BMI by on average 0.8-0.9 kg/m2 and waist circumference by 3.0 cm during one year. CONCLUSIONS: During the transition from work to retirement, increasing MVPA was associated with a slight decrease in BMI and waist circumference, whereas increasing sleep was associated with an increasing BMI. Common life transitions, like retirement, should be considered when giving recommendations and guidance for physical activity and sleep.

Development and performance of a sleep estimation algorithm using a single accelerometer placed on the thigh: an evaluation against polysomnography.

Accelerometers placed on the thigh provide accurate measures of daily physical activity types, postures and sedentary behaviours, over 24 h and across consecutive days. However, the ability to estimate sleep duration or quality from thigh-worn accelerometers is uncertain and has not been evaluated in comparison with the 'gold-standard' measurement of sleep polysomnography. This study aimed to develop an algorithm for sleep estimation using the raw data from a thigh-worn accelerometer and to evaluate it in comparison with polysomnography. The algorithm was developed and optimised on a dataset consisting of 23 single-night polysomnography recordings, collected in a laboratory, from 15 asymptomatic adults. This optimised algorithm was then applied to a separate evaluation dataset, in which, 71 adult males (mean [SD] age 57 [11] years, height 181 [6] cm, weight 82 [13] kg) wore ambulatory polysomnography equipment and a thigh-worn accelerometer, simultaneously, whilst sleeping at home. Compared with polysomnography, the algorithm had a sensitivity of 0.84 and a specificity of 0.55 when estimating sleep periods. Sleep intervals were underestimated by 21 min (130 min, Limits of Agreement Range [LoAR]). Total sleep time was underestimated by 32 min (233 min LoAR). Our results evaluate the performance of a new algorithm for estimating sleep and outline the limitations. Based on these results, we conclude that a single device can provide estimates of the sleep interval and total sleep time with sufficient accuracy for the measurement of daily physical activity, sedentary behaviour, and sleep, on a group level in free-living settings.

Whole-genome landscapes of major melanoma subtypes.

Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting non-coding sequences was similar to that affected by recurrent mutations to coding sequences. Significantly mutated genes included BRAF, CDKN2A, NRAS and TP53 in cutaneous melanoma, BRAF, NRAS and NF1 in acral melanoma and SF3B1 in mucosal melanoma. Mutations affecting the TERT promoter were the most frequent of all; however, neither they nor ATRX mutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. Most melanomas had potentially actionable mutations, most in components of the mitogen-activated protein kinase and phosphoinositol kinase pathways. The whole-genome mutation landscape of melanoma reveals diverse carcinogenic processes across its subtypes, some unrelated to sun exposure, and extends potential involvement of the non-coding genome in its pathogenesis.

Developing and designing an internet-based support and education program for patients awaiting kidney transplantation with deceased donors through: a Delphi study.

AIMS: The aim of this study was to develop and refine the content and design of an internet-based support and education program for patients awaiting kidney transplantation from deceased donors. DESIGN: A Delphi process was used. METHODS: A prototype internet-based intervention was drafted, based on previous research. The intervention included educational and psychological support to manage the uncertain waiting time and specific education enabling preparation for transplantation and adjustment to life after transplantation. In a two-round Delphi process, patients who had received a kidney transplant from a deceased donor within the last 2 years (n = 27), significant others (n = 6), health-care personnel with renal (n = 20) or transplant (n = 14) expertise, rated importance of content and design aspects of the prototype intervention on a 5-point scale using web questionnaires. A median of ≥ 3 was considered as consensus. Quantitative data was analyzed using descriptive statistics. Free text answers were encouraged and analyzed using deductive content analysis. The STROBE-checklist was used. RESULTS: Consensus was reached for all suggested content and design items in round 1, with median ratings of 4 or 5. Qualitative analysis from round 1 suggested four new content and design items which were rated in round 2, on all which consensus was reached; information about life with young children as relatives, expansion of kidney transplantation specific information, program extension by one week and individualization by making information available based on individual needs. CONCLUSION: There was consensus among heterogenous experts regarding suggested educational and psychological support content and design aspects, and additional content and design aspects were identified for an internet-based support and education program for patients awaiting kidney transplantation from deceased donors.

Experience of internet-delivered cognitive behavioural therapy among patients with non-cardiac chest pain.

AIMS AND OBJECTIVE: To explore the experiences of patients with non-cardiac chest pain and cardiac anxiety regarding participation in an internet-delivered cognitive behavioural therapy program. BACKGROUND: Non-cardiac chest pain is common and leads to cardiac anxiety. Internet-delivered cognitive behavioural therapy may be a possible option to decrease cardiac anxiety in these patients. We have recently evaluated the effect of an internet-delivered cognitive behavioural therapy program on cardiac anxiety. DESIGN: An inductive qualitative study using content analysis and the COREQ checklist. METHODS: Semi-structured interviews with 16 Swedish patients, who had participated in the internet-delivered cognitive behavioural therapy program. RESULTS: Three categories were found. The first, 'Driving factors for participation in the internet-delivered cognitive behavioural therapy program' described the impact of pain on their lives and struggle that led them to participating in the program. The second, 'The program as a catalyst' described that the program was helpful, trustworthy and useful and the last category, 'Learning to live with chest pain' described the program as a tool for gaining the strength and skills to live a normal life despite chest pain. CONCLUSIONS: The program was experienced as an opportunity to return to a normal life. The program was perceived as helpful, trustworthy and useful, which helped the participants challenge their fear of chest pain and death, and gain strength and new insights into their ability to live a normal life. RELEVANCE TO CLINICAL PRACTICE: A tailored internet-delivered cognitive behavioural therapy program delivered by a nurse therapist with clinical experience of the patient group is important to improve cardiac anxiety. PATIENT OR PUBLIC CONTRIBUTION: Patients or the general public were not involved in the design, analysis or interpretation of the data of this study, but two patients with experience of non-cardiac chest pain were involved in the development of the pilot study. TRIAL REGISTRATION: ClinicalTrials.gov NCT03336112; https://www. CLINICALTRIALS: gov/ct2/show/NCT03336112.

Multiplex melanoma families are enriched for polygenic risk.

Cancers, including cutaneous melanoma, can cluster in families. In addition to environmental etiological factors such as ultraviolet radiation, cutaneous melanoma has a strong genetic component. Genetic risks for cutaneous melanoma range from rare, high-penetrance mutations to common, low-penetrance variants. Known high-penetrance mutations account for only about half of all densely affected cutaneous melanoma families, and the causes of familial clustering in the remainder are unknown. We hypothesize that some clustering is due to the cumulative effect of a large number of variants of individually small effect. Common, low-penetrance genetic risk variants can be combined into polygenic risk scores. We used a polygenic risk score for cutaneous melanoma to compare families without known high-penetrance mutations with unrelated melanoma cases and melanoma-free controls. Family members had significantly higher mean polygenic load for cutaneous melanoma than unrelated cases or melanoma-free healthy controls (Bonferroni-corrected t-test P = 1.5 × 10-5 and 6.3 × 10-45, respectively). Whole genome sequencing of germline DNA from 51 members of 21 families with low polygenic risk for melanoma identified a CDKN2A p.G101W mutation in a single family but no other candidate high-penetrance melanoma susceptibility genes. This work provides further evidence that melanoma, like many other common complex disorders, can arise from the joint action of multiple predisposing factors, including rare high-penetrance mutations, as well as via a combination of large numbers of alleles of small effect.

Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes.

BACKGROUND: The cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, is undefined. METHODS: We randomly assigned patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease to receive either dapagliflozin or placebo. The primary safety outcome was a composite of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke. The primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Secondary efficacy outcomes were a renal composite (≥40% decrease in estimated glomerular filtration rate to <60 ml per minute per 1.73 m2 of body-surface area, new end-stage renal disease, or death from renal or cardiovascular causes) and death from any cause. RESULTS: We evaluated 17,160 patients, including 10,186 without atherosclerotic cardiovascular disease, who were followed for a median of 4.2 years. In the primary safety outcome analysis, dapagliflozin met the prespecified criterion for noninferiority to placebo with respect to MACE (upper boundary of the 95% confidence interval [CI], <1.3; P<0.001 for noninferiority). In the two primary efficacy analyses, dapagliflozin did not result in a lower rate of MACE (8.8% in the dapagliflozin group and 9.4% in the placebo group; hazard ratio, 0.93; 95% CI, 0.84 to 1.03; P=0.17) but did result in a lower rate of cardiovascular death or hospitalization for heart failure (4.9% vs. 5.8%; hazard ratio, 0.83; 95% CI, 0.73 to 0.95; P=0.005), which reflected a lower rate of hospitalization for heart failure (hazard ratio, 0.73; 95% CI, 0.61 to 0.88); there was no between-group difference in cardiovascular death (hazard ratio, 0.98; 95% CI, 0.82 to 1.17). A renal event occurred in 4.3% in the dapagliflozin group and in 5.6% in the placebo group (hazard ratio, 0.76; 95% CI, 0.67 to 0.87), and death from any cause occurred in 6.2% and 6.6%, respectively (hazard ratio, 0.93; 95% CI, 0.82 to 1.04). Diabetic ketoacidosis was more common with dapagliflozin than with placebo (0.3% vs. 0.1%, P=0.02), as was the rate of genital infections that led to discontinuation of the regimen or that were considered to be serious adverse events (0.9% vs. 0.1%, P<0.001). CONCLUSIONS: In patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, treatment with dapagliflozin did not result in a higher or lower rate of MACE than placebo but did result in a lower rate of cardiovascular death or hospitalization for heart failure, a finding that reflects a lower rate of hospitalization for heart failure. (Funded by AstraZeneca; DECLARE-TIMI 58 ClinicalTrials.gov number, NCT01730534 .).

Improved cardiovascular health by supplementation with selenium and coenzyme Q10: applying structural equation modelling (SEM) to clinical outcomes and biomarkers to explore underlying mechanisms in a prospective randomized double-blind placebo-controlled intervention project in Sweden.

PURPOSE: Selenium and coenzyme Q10 have synergistic antioxidant functions. In a four-year supplemental trial in elderly Swedes with a low selenium status, we found improved cardiac function, less cardiac wall tension and reduced cardiovascular mortality up to 12 years of follow-up. Here we briefly review the main results, including those from studies on biomarkers related to cardiovascular risk that were subsequently conducted. In an effort, to explain underlying mechanisms, we conducted a structured analysis of the inter-relationship between biomarkers. METHODS: Selenium yeast (200 µg/day) and coenzyme Q10 (200 mg/ day), or placebo was given to 443 elderly community-living persons, for 48 months. Structural Equation Modelling (SEM) was used to investigate the statistical inter-relationships between biomarkers related to inflammation, oxidative stress, insulin-like growth factor 1, expression of microRNA, fibrosis, and endothelial dysfunction and their impact on the clinical effects. The main study was registered at Clinicaltrials.gov at 30th of September 2011, and has the identifier NCT01443780. RESULTS: In addition to positive clinical effects, the intervention with selenium and coenzyme Q10 was also associated with favourable effects on biomarkers of cardiovascular risk. Using these results in the SEM model, we showed that the weights of the first-order factors inflammation and oxidative stress were high, together forming a second-order factor inflammation/oxidative stress influencing the factors, fibrosis (ß = 0.74; p < 0.001) and myocardium (ß = 0.65; p < 0.001). According to the model, the intervention impacted fibrosis and myocardium through these factors, resulting in improved cardiac function and reduced CV mortality. CONCLUSION: Selenium reduced inflammation and oxidative stress. According to the SEM analysis, these effects reduced fibrosis and improved myocardial function pointing to the importance of supplementation in those low on selenium and coenzyme Q10.

The experience of participating in an internet-based cognitive behavioral therapy program among patients with cardiovascular disease and depression: a qualitative interview study.

BACKGROUND: Depression in conjunction with cardiovascular disease (CVD) is associated with worsening in CVD, higher mortality, and poorer quality of life. Despite the poor outcomes there is a treatment gap of depression in CVD patients. Recently we found that an Internet-based cognitive behavioral therapy (iCBT) tailored for CVD patients led to reduced symptoms of depression. However, we still have little knowledge about CVD patients' experiences of working with iCBT. The aim of this study was therefore to explore CVD patients' experiences of engaging in a tailored iCBT program. METHODS: A qualitative interview study using inductive thematic analysis. Data was obtained from 20 patients with CVD and depressive symptoms who had participated in a randomized controlled trial (RCT) evaluating the impact of a nine-week iCBT program on depression. RESULTS: Three main themes emerged: (1) Taking control of the disease, (2) Not just a walk in the park, and (3) Feeling a personal engagement with the iCBT program. The first theme included comments that the tailored program gave the patients a feeling of being active in the treatment process and helped them achieve changes in thoughts and behaviors necessary to take control of their CVD. The second theme showed that patients also experienced the program as demanding and emotionally challenging. However, it was viewed as helpful to challenge negative thinking about living with CVD and to change depressive thoughts. In the third theme patients reported that the structure inherent in the program, in the form of organizing their own health and the scheduled feedback from the therapist created a feeling of being seen as an individual. The feeling of being acknowledged as a person also made it easier to continuously work with the changes necessary to improve their health. CONCLUSIONS: Engaging in an iCBT program tailored for patients with CVD and depression was by the patients perceived as helpful in the treatment of depression. They experienced positive changes in emotions, thoughts, and behaviors which a result of learning to take control of their CVD, being confirmed and getting support. The patients considered working with the iCBT program as demanding and emotionally challenging, but necessary to achieve changes in emotions, thoughts, and behaviors.

Accelerometer derived physical activity patterns in 27.890 middle-aged adults: The SCAPIS cohort study.

The present study aims to describe accelerometer-assessed physical activity (PA) patterns and fulfillment of PA recommendations in a large sample of middle-aged men and women, and to study differences between subgroups of socio-demographic, socio-economic, and lifestyle-related variables. A total of 27 890 (92.5% of total participants, 52% women, aged 50-64 years) middle-aged men and women with at least four days of valid hip-worn accelerometer data (Actigraph GT3X+, wGT3X+ and wGT3X-BT) from the Swedish CArdioPulmonary bioImage Study, SCAPIS, were included. In total, 54.5% of daily wear time was spent sedentary, 39.1% in low, 5.4% in moderate, and only 0.1% in vigorous PA. Male sex, higher education, low financial strain, born in Sweden, and sedentary/light working situation were related to higher sedentary time, but also higher levels of vigorous PA. High BMI and having multiple chronic diseases associated strongly with higher sedentary time and less time in all three PA intensities. All-year physically active commuters had an overall more active PA pattern. The proportion fulfilling current PA recommendations varied substantially (1.4% to 92.2%) depending on data handling procedures and definition used. Twenty-eight percent was defined as having an "at-risk" behavior, which included both high sedentary time and low vigorous PA. In this large population-based sample, a majority of time was spent sedentary and only a fraction in vigorous PA, with clinically important variations between subgroups. This study provides important reference material and emphasizes the importance of a comprehensive assessment of all aspects of the individual PA pattern in future research and clinical practice.

Perspectives of Policy Makers and Service Users Concerning the Implementation of eHealth in Sweden: Interview Study.

BACKGROUND: Increasing life spans of populations and a growing demand for more advanced care make effective and cost-efficient provision of health care necessary. eHealth technology is often proposed, although research on barriers to and facilitators of the implementation of eHealth technology is still scarce and fragmented. OBJECTIVE: The aim of this study is to explore the perceptions concerning barriers to and facilitators of the implementation of eHealth among policy makers and service users and explore the ways in which their perceptions converge and differ. METHODS: This study used interview data from policy makers at different levels of health care (n=7) and service users enrolled in eHealth interventions (n=25). The analysis included separate qualitative content analyses for the 2 groups and then a second qualitative content analysis to explore differences and commonalities. RESULTS: Implementation barriers perceived by policy makers were that not all service users benefit from eHealth and that there is uncertainty about the impact of eHealth on the work of health care professionals. Policy makers also perceived political decision-making as complex; this included problems related to provision of technical infrastructure and lack of extra resources for health care digitalization. Facilitators were policy makers' conviction that eHealth is what citizens want, their belief in eHealth solutions as beneficial for health care practice, and their belief in the importance of health care digitalization. Barriers for service users comprised capability limitations and varied preferences of service users and a mismatch of technology with user needs, lack of data protection, and their perception of eHealth as being more time consuming. Facilitators for service users were eHealth technology design and match with their skill set, personal feedback and staff support, a sense of privacy, a credible sender, and flexible use of time.There were several commonalities between the 2 stakeholder groups. Facilitators for both groups were the strong impetus toward technology adoption in society and expectations of time flexibility. Both groups perceived barriers in the difficulties of tailoring eHealth, and both groups expressed uncertainty about the care burden distribution. There were also differences: policy makers perceived that their decision-making was very complex and that resources for implementation were limited. Service users highlighted their need to feel that their digital data were protected and that they needed to trust the eHealth sender. CONCLUSIONS: Perceptions about barriers to and facilitators of eHealth implementation varied among stakeholders in different parts of the health care system. The study points to the need to reach an enhanced mutual understanding of priorities and overcome challenges at both the micro and macro levels of the health care system. More well-balanced decisions at the policy-maker level may lead to more effective and sustainable development and future implementation of eHealth.

The Effect of Internet-Delivered Cognitive Behavioral Therapy Versus Psychoeducation Only on Psychological Distress in Patients With Noncardiac Chest Pain: Randomized Controlled Trial.

BACKGROUND: Patients with recurrent episodes of noncardiac chest pain (NCCP) experience cardiac anxiety as they misinterpret the pain to be cardiac related and avoid physical activity that they think could threaten their lives. Psychological interventions, such as internet-delivered cognitive behavioral therapy (iCBT), targeting anxiety can be a feasible solution by supporting patients to learn how to perceive and handle their chest pain. OBJECTIVE: This study aims to evaluate the effects of a nurse-led iCBT program on cardiac anxiety and other patient-reported outcomes in patients with NCCP. METHODS: Patients with at least two health care consultations because of NCCP during the past 6 months, and who were experiencing cardiac anxiety (Cardiac Anxiety Questionnaire score ≥24), were randomized into 5 weeks of iCBT (n=54) or psychoeducation (n=55). Patients were aged 54 (SD 17) years versus 57 (SD 16) years and were mainly women (32/54, 59% vs 35/55, 64%). The iCBT program comprised psychoeducation, mindfulness, and exposure to physical activity, with weekly homework assignments. The primary outcome was cardiac anxiety. The secondary outcomes were fear of bodily sensations, depressive symptoms, health-related quality of life, and chest pain frequency. Intention-to-treat analysis was applied, and the patients were followed up for 3 months. Mixed model analysis was used to determine between-group differences in primary and secondary outcomes. RESULTS: No significant differences were found between the iCBT and psychoeducation groups regarding cardiac anxiety or any of the secondary outcomes in terms of the interaction effect of time and group over the 3-month follow-up. iCBT demonstrated a small effect size on cardiac anxiety (Cohen d=0.31). In the iCBT group, 36% (16/44) of patients reported a positive reliable change score (≥11 points on the Cardiac Anxiety Questionnaire), and thus an improvement in cardiac anxiety, compared with 27% of (13/48) patients in the psychoeducation group. Within-group analysis showed further significant improvement in cardiac anxiety (P=.04) at the 3-month follow-up compared with the 5-week follow-up in the iCBT group but not in the psychoeducation group. CONCLUSIONS: iCBT was not superior to psychoeducation in decreasing cardiac anxiety in patients with NCCP. However, iCBT tends to have better long-term effects on psychological distress, including cardiac anxiety, health-related quality of life, and NCCP frequency than psychoeducation. The effects need to be followed up to draw more reliable conclusions. TRIAL REGISTRATION: ClinicalTrials.gov NCT03336112; https://www.clinicaltrials.gov/ct2/show/NCT03336112.

Dapagliflozin and Cardiac, Kidney, and Limb Outcomes in Patients With and Without Peripheral Artery Disease in DECLARE-TIMI 58.

BACKGROUND: Patients with peripheral artery disease (PAD) are at heightened risk of cardiovascular complications. The sodium-glucose cotransporter 2 inhibitor dapagliflozin reduces the risk for hospitalization for heart failure (HHF) and kidney events in patients with type 2 diabetes mellitus. An increased risk of amputation has been observed with canagliflozin in 1 previous trial. We examined cardiovascular and kidney efficacy and the risk of limb-related events in patients with and without PAD in an exploratory analysis. METHODS: A total of 17 160 patients with type 2 diabetes mellitus, including 1025 (6%) with PAD, were randomized. Key efficacy outcomes were MACE (cardiovascular [CV] death, myocardial infarction, stroke), CV death/HHF, and progression of kidney disease. Amputations, peripheral revascularization, and limb ischemic adverse events were site-reported and categorized by a blinded reviewer. RESULTS: Patients in the placebo arm with PAD versus those without tended to have higher adjusted risk of CV death, myocardial infarction, or stroke (adjusted hazard ratio [HR], 1.23 [95% CI, 0.97-1.56], P=0.094) and significantly higher adjusted risk of CV death/HHF (adjusted HR, 1.60 [95% CI, 1.21-2.12], P=0.0010) and progression of kidney disease (adjusted HR, 1.51 [95% CI, 1.13 - 2.03], P=0.0058), and limb adverse events (adjusted HR, 8.37, P<0.001). The relative risk reductions with dapagliflozin for CV death/HHF (HR, 0.86, PAD; HR, 0.82, no-PAD; P-interaction=0.79) and progression of kidney disease (HR, 0.78, PAD; HR, 0.76, no-PAD; P-interaction=0.84) were consistent regardless of PAD. There were 560 patients who had at least 1 limb ischemic event, 454 patients with at least 1 peripheral revascularization, and 236 patients with at least 1 amputation, with a total of 407 amputations reported. Overall, there were no significant differences in any limb outcome with dapagliflozin versus placebo including limb ischemic adverse events (HR, 1.07 [95% CI, 0.90-1.26]) and amputation (HR, 1.09 [95% CI, 0.84-1.40]), with no significant interactions by a history of PAD versus not (P-interactions=0.30 and 0.093, respectively). CONCLUSIONS: Patients with versus without PAD are at a higher risk of CV death of CV death, HHF, and kidney outcomes, and have a consistent benefits for CV death/HHF and progression of kidney disease with dapagliflozin. Patients with PAD had a higher risk of limb events, with no consistent pattern of incremental risk observed with dapagliflozin. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01730534.