Publications by authors named "Peter Johansson"

236 Publications

Dismantling, optimising, and personalising internet cognitive behavioural therapy for depression: a systematic review and component network meta-analysis using individual participant data.

Lancet Psychiatry 2021 May 3. Epub 2021 May 3.

Department of Clinical Psychology, Faculty of Psychology, University of Bergen, Bergen, Norway.

Background: Internet cognitive behavioural therapy (iCBT) is a viable delivery format of CBT for depression. However, iCBT programmes include training in a wide array of cognitive and behavioural skills via different delivery methods, and it remains unclear which of these components are more efficacious and for whom.

Methods: We did a systematic review and individual participant data component network meta-analysis (cNMA) of iCBT trials for depression. We searched PubMed, PsycINFO, Embase, and the Cochrane Library for randomised controlled trials (RCTs) published from database inception to Jan 1, 2019, that compared any form of iCBT against another or a control condition in the acute treatment of adults (aged ≥18 years) with depression. Studies with inpatients or patients with bipolar depression were excluded. We sought individual participant data from the original authors. When these data were unavailable, we used aggregate data. Two independent researchers identified the included components. The primary outcome was depression severity, expressed as incremental mean difference (iMD) in the Patient Health Questionnaire-9 (PHQ-9) scores when a component is added to a treatment. We developed a web app that estimates relative efficacies between any two combinations of components, given baseline patient characteristics. This study is registered in PROSPERO, CRD42018104683.

Findings: We identified 76 RCTs, including 48 trials contributing individual participant data (11 704 participants) and 28 trials with aggregate data (6474 participants). The participants' weighted mean age was 42·0 years and 12 406 (71%) of 17 521 reported were women. There was suggestive evidence that behavioural activation might be beneficial (iMD -1·83 [95% credible interval (CrI) -2·90 to -0·80]) and that relaxation might be harmful (1·20 [95% CrI 0·17 to 2·27]). Baseline severity emerged as the strongest prognostic factor for endpoint depression. Combining human and automated encouragement reduced dropouts from treatment (incremental odds ratio, 0·32 [95% CrI 0·13 to 0·93]). The risk of bias was low for the randomisation process, missing outcome data, or selection of reported results in most of the included studies, uncertain for deviation from intended interventions, and high for measurement of outcomes. There was moderate to high heterogeneity among the studies and their components.

Interpretation: The individual patient data cNMA revealed potentially helpful, less helpful, or harmful components and delivery formats for iCBT packages. iCBT packages aiming to be effective and efficient might choose to include beneficial components and exclude ones that are potentially detrimental. Our web app can facilitate shared decision making by therapist and patient in choosing their preferred iCBT package.

Funding: Japan Society for the Promotion of Science.
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http://dx.doi.org/10.1016/S2215-0366(21)00077-8DOI Listing
May 2021

Psychological distress in patients with cardiovascular disease: time to do something about it?

Eur J Cardiovasc Nurs 2021 Apr 11. Epub 2021 Apr 11.

Department of Health, Medicine and Caring Sciences, Linköping University, 602 21 Norrköping, Sweden.

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http://dx.doi.org/10.1093/eurjcn/zvab007DOI Listing
April 2021

Meta-Analysis and Systematic Review of the Genomics of Mucosal Melanoma.

Mol Cancer Res 2021 Mar 11. Epub 2021 Mar 11.

QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

Mucosal melanoma is a rare subtype of melanoma. To date, there has been no comprehensive systematic collation and statistical analysis of the aberrations and aggregated frequency of driver events across multiple studies. Published studies using whole genome, whole exome, targeted gene panel, or individual gene sequencing were identified. Datasets from these studies were collated to summarize mutations, structural variants, and regions of copy-number alteration. Studies using next-generation sequencing were divided into the "main" cohort ( = 173; fresh-frozen samples), "validation" cohort ( = 48; formalin-fixed, paraffin-embedded samples) and a second "validation" cohort comprised 104 tumors sequenced using a targeted panel. Studies assessing mutations in , and were summarized to assess hotspot mutations. Statistical analysis of the main cohort variant data revealed , and as significantly mutated genes. and mutations occurred more commonly in lower anatomy melanomas and in the upper anatomy. , and were commonly affected by chromosomal copy loss, while , and were commonly amplified. Further notable genomic alterations occurring at lower frequencies indicated commonality of signaling networks in tumorigenesis, including MAPK, PI3K, Notch, Wnt/β-catenin, cell cycle, DNA repair, and telomere maintenance pathways. This analysis identified genomic aberrations that provide some insight to the way in which specific pathways may be disrupted. IMPLICATIONS: Our analysis has shown that mucosal melanomas have a diverse range of genomic alterations in several biological pathways. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/00/0/000/F1.large.jpg.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0839DOI Listing
March 2021

Trajectories and associations between depression and physical activity in patients with cardiovascular disease during participation in an internet-based cognitive behavioural therapy programme.

Eur J Cardiovasc Nurs 2020 Aug 6. Epub 2020 Aug 6.

Department of Health, Medicine and Caring Sciences, Linköping University, Sweden.

Background: There is a lack of knowledge about internet-based cognitive behavioural therapy in patients with cardiovascular disease, and its effects on depressive symptoms and physical activity.

Aim: To examine trajectories of depressive symptoms and physical activity, and to explore if these trajectories are linked with the delivery of internet-based cognitive behavioural therapy.

Methods: A secondary-analysis of data collected in a randomised controlled trial that evaluated the effects of a 9-week internet-based cognitive behavioural therapy programme compared to an online discussion forum on depressive symptoms in cardiovascular disease patients. Data were collected at baseline, once weekly during the 9-week intervention period and at the 9-week follow-up. The Montgomery Åsberg depression rating scale - self-rating (MADRS-S) was used to measure depressive symptoms. Two modified items from the physical activity questionnaire measuring frequency and length of physical activity were merged to form a physical activity factor.

Results: After 2 weeks the internet-based cognitive behavioural therapy group had a temporary worsening in depressive symptoms. At 9-week follow-up, depressive symptoms (P<0.001) and physical activity (P=0.02) had improved more in the internet-based cognitive behavioural therapy group. Only in the internet-based cognitive behavioural therapy group, was a significant correlation (r=-0.39, P=0.002) between changes in depressive symptoms and changes in physical activity found. Structural equation analyses revealed that internet-based cognitive behavioural therapy decreased depressive symptoms, and that a decrease in depression, in turn, resulted in an increase in physical activity.

Conclusions: Internet-based cognitive behavioural therapy was more effective than an online discussion forum to decrease depressive symptoms and increase physical activity. Importantly, a decrease in depressive symptoms needs to precede an increase in physical activity.
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http://dx.doi.org/10.1177/1474515120947250DOI Listing
August 2020

The effect of nurse-led Internet-based cognitive behavioural therapy for insomnia on patients with cardiovascular disease: A randomized controlled trial with 6-month follow-up.

Nurs Open 2021 Feb 20. Epub 2021 Feb 20.

Department of Nursing Science, School of Health and Welfare, Jönköping University, Jönköping, Sweden.

Aim: To test the effect of nurse-led Internet-based cognitive behavioural therapy for insomnia (I-CBTI), tailored for patients with cardiovascular disease (CVD), with a 6-month follow-up.

Design: A two-arm parallel-group randomized controlled trial (RCT) registered at clinicaltrials.gov (NTC03938805) and reported according to the CONSORT checklist.

Methods: Forty-eight patients (mean age 72 years, 65% men) diagnosed with CVD and insomnia were randomized to either 9-week nurse-led I-CBTI with support, or an Internet-based self-study programme without support (control group). Insomnia Severity Index (ISI) and Short Form Health Survey (SF-12) were used as primary and secondary outcomes.

Results: ISI showed a significant treatment effect of I-CBTI compared to the control group at 9-week follow-up. The mean ISI score in the I-CBTI group at 9 weeks post-treatment was maintained at the 6-month follow-up. Patients' adherence to I-CBTI was associated with a better effect on both the ISI and SF-12.
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http://dx.doi.org/10.1002/nop2.817DOI Listing
February 2021

Microsimulation Model for Evaluating the Cost-Effectiveness of Surveillance in Pathogenic Variant Carriers.

JCO Clin Cancer Inform 2021 Jan;5:143-154

QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

Purpose: Pathogenic germline variants cause a tumor-predisposition syndrome (-TPDS) linked to uveal melanoma, mesothelioma, cutaneous melanoma, and renal cell carcinoma. Surveillance of carriers of pathogenic variants provides an opportunity for early tumor detection; however, there are no evidence-based guidelines for management of -TPDS, nor health economic evaluation; this study aims to provide this evidence.

Methods: We created a Markov microsimulation health state transition model of germline carriers to predict if active surveillance for the four main tumors influences survival and improves associated economic costs with a time horizon of 100 years from the perspective of the healthcare system (N = 10,000). Model inputs were derived from data published by the BAP1 Interest Group Consortium and other studies. Management and healthcare costs were extracted from Australian costing schedules (final figures converted to US dollars [USD]), and outcomes compared for individuals receiving surveillance with those in a nonsurveillance arm. Robustness was evaluated on 10,000 iterations of a 100-sample random sampling of the model output.

Results: On average, surveillance of carriers increased survival by 4.9 years at an additional cost of $6,197 USD for the healthcare system including surveillance costs ($1,265 USD per life year gained). The nonsurveillance arm had more diagnosed late tumors (62.8% 10.7%) and a higher rate of -related deaths (50.2% 35.4%; a 29.5% increase). The model was cost-effective under all sensitivity analyses. Our secondary robustness analysis estimated that 99.86% of 100-sample iterations were cost-effective and 19.67% of these were cost-saving.

Conclusion: It is recommended that carriers of germline variants are identified and undertake active surveillance, as this model suggests that this could improve survival and be cost-effective for the healthcare system.
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http://dx.doi.org/10.1200/CCI.20.00124DOI Listing
January 2021

The cost-effectiveness of dapagliflozin in treating high-risk patients with type 2 diabetes mellitus: An economic evaluation using data from the DECLARE-TIMI 58 trial.

Diabetes Obes Metab 2021 Apr 25;23(4):1020-1029. Epub 2021 Jan 25.

University of Liverpool, Liverpool, UK.

Aim: To undertake a cost-effectiveness analysis of dapagliflozin in treating high-risk patients with type 2 diabetes mellitus (T2DM), using both directly observed events in the DECLARE-TIMI 58 trial and surrogate risk factors to predict endpoints not captured within the trial.

Methods: An established T2DM model was adapted to integrate survival curves derived from the DECLARE-TIMI 58 trial, and extrapolated over a lifetime for all-cause mortality, hospitalization for heart failure, stroke, myocardial infarction, hospitalization for unstable angina, and end-stage kidney disease. The economic analysis considered the overall DECLARE trial population, as well as reported patient subgroups. Total and incremental costs, life-years and quality-adjusted life-years associated with dapagliflozin versus placebo were estimated from the perspective of the UK healthcare payer.

Results: In the UK setting, treatment with dapagliflozin compared to placebo was estimated to be dominant, with an expected increase in quality-adjusted life-years from 10.43 to 10.48 (+0.06) and a reduction in lifetime total costs from £39 451 to £36 899 (-£2552). Across all patient subgroups, dapagliflozin was estimated to be dominant, with the greatest absolute benefit in the prior heart failure subgroup (incremental lifetime costs -£4150 and quality-adjusted life-years +0.11).

Conclusions: The results of this study demonstrate that dapagliflozin compared to placebo appears to be cost-effective, when considering evidence reported from the DECLARE-TIMI 58 trial, at established UK willingness-to-pay thresholds. The findings highlight the potential of dapagliflozin to have a meaningful impact in reducing the economic burden of T2DM and its associated complications across a broad T2DM population.
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http://dx.doi.org/10.1111/dom.14308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048502PMC
April 2021

The Prognostic Impact of Circulating Tumour DNA in Melanoma Patients Treated with Systemic Therapies-Beyond Mutant Detection.

Cancers (Basel) 2020 Dec 16;12(12). Epub 2020 Dec 16.

School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia 6027, Australia.

In this study, we evaluated the predictive value of circulating tumour DNA (ctDNA) to inform therapeutic outcomes in metastatic melanoma patients receiving systemic therapies. We analysed 142 plasma samples from metastatic melanoma patients prior to commencement of systemic therapy: 70 were treated with BRAF/MEK inhibitors and 72 with immunotherapies. Patient-specific droplet digital polymerase chain reaction assays were designed for ctDNA detection. Plasma ctDNA was detected in 56% of patients prior to first-line anti-PD1 and/or anti-CTLA-4 treatment. The detection rate in the immunotherapy cohort was comparably lower than those with BRAF inhibitors (76%, = 0.0149). Decreasing ctDNA levels within 12 weeks of treatment was strongly concordant with treatment response (Cohen's k = 0.798, < 0.001) and predictive of longer progression free survival. Notably, a slower kinetic of ctDNA decline was observed in patients treated with immunotherapy compared to those on BRAF/MEK inhibitors. Whole exome sequencing of ctDNA was also conducted in 9 patients commencing anti-PD-1 therapy to derive tumour mutational burden (TMB) and neoepitope load measurements. The results showed a trend of high TMB and neoepitope load in responders compared to non-responders. Overall, our data suggest that changes in ctDNA can serve as an early indicator of outcomes in metastatic melanoma patients treated with systemic therapies and therefore may serve as a tool to guide treatment decisions.
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http://dx.doi.org/10.3390/cancers12123793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765660PMC
December 2020

Whole-genome sequencing of acral melanoma reveals genomic complexity and diversity.

Nat Commun 2020 10 16;11(1):5259. Epub 2020 Oct 16.

Center for Rare Melanomas, University of Colorado Cancer Center, Aurora, Colorado, USA.

To increase understanding of the genomic landscape of acral melanoma, a rare form of melanoma occurring on palms, soles or nail beds, whole genome sequencing of 87 tumors with matching transcriptome sequencing for 63 tumors was performed. Here we report that mutational signature analysis reveals a subset of tumors, mostly subungual, with an ultraviolet radiation signature. Significantly mutated genes are BRAF, NRAS, NF1, NOTCH2, PTEN and TYRP1. Mutations and amplification of KIT are also common. Structural rearrangement and copy number signatures show that whole genome duplication, aneuploidy and complex rearrangements are common. Complex rearrangements occur recurrently and are associated with amplification of TERT, CDK4, MDM2, CCND1, PAK1 and GAB2, indicating potential therapeutic options.
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http://dx.doi.org/10.1038/s41467-020-18988-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567804PMC
October 2020

Tumor Mutation Burden and Structural Chromosomal Aberrations Are Not Associated with T-cell Density or Patient Survival in Acral, Mucosal, and Cutaneous Melanomas.

Cancer Immunol Res 2020 11 11;8(11):1346-1353. Epub 2020 Sep 11.

Melanoma Institute Australia, The University of Sydney, North Sydney, New South Wales, Australia.

Tumor mutation burden (TMB) has been proposed as a key determinant of immunogenicity in several cancers, including melanoma. The evidence presented thus far, however, is often contradictory and based mostly on RNA-sequencing data for the quantification of immune cell phenotypes. Few studies have investigated TMB across acral, mucosal, and cutaneous melanoma subtypes, which are known to have different TMB. It is also unknown whether chromosomal structural mutations [structural variant (SV) mutations] contribute to the immunogenicity in acral and mucosal melanomas where such aberrations are common. We stained 151 cutaneous and 35 acral and mucosal melanoma patient samples using quantitative IHC and correlated immune infiltrate phenotypes with TMB and other genomic profiles. TMB and SVs did not correlate with the densities of CD8 lymphocytes, CD103 tumor-resident T cells (Trm), CD45RO cells, and other innate and adaptive immune cell subsets in cutaneous and acral/mucosal melanoma tumors, respectively, including in analyses restricted to the site of disease and in a validation cohort. In 43 patients with stage III treatment-naïve cutaneous melanoma, we found that the density of immune cells, particularly Trm, was significantly associated with patient survival, but not with TMB. Overall, TMB and chromosomal structural aberrations are not associated with protective antitumor immunity in treatment-naïve melanoma.
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http://dx.doi.org/10.1158/2326-6066.CIR-19-0835DOI Listing
November 2020

Highly increased risk of fracture in patients with myeloproliferative neoplasm.

Leuk Lymphoma 2021 01 10;62(1):211-217. Epub 2020 Sep 10.

Section of Hematology, Department of Internal Medicine, Sahlgrenska University Hospital, Göteborg, Sweden.

The risk for hip and vertebral fracture was determined in 10,752 patients diagnosed with myeloproliferative neoplasms (MPN) in Sweden 1995-2015. The mean follow-up time were 6.34 years. Five percent developed hip fracture and 1.3% a vertebral fracture. There was a significant increased risk for fracture among the MPN patients compared with the Swedish population. The ratio of observed (obs) and expected (exp) number of hip fracture in all MPN patients, polycythemia vera (PV), essential thrombocythemia and MPN undetermined (MPNu) was 1.20 (95% confidence interval (CI): 1.10-1.31), 1.37 (95% CI: 1.19-1.58), 1.02 (95% CI: 0.87-1.19), and 1.28 (95% CI: 1.07-1.52), respectively. Corresponding figures for vertebral fractures were 1.94 (95% CI: 1.64-2.29), 2.09 (95% CI: 1.56-2.75), 1.50 (95% CI: 1.06-2.07) and 2.47 (95% CI: 1.77-3.35), respectively. Patients with MPN had an increased risk of hip and vertebral fracture, especially patients with PV and MPNu in comparison with the entire Swedish population.
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http://dx.doi.org/10.1080/10428194.2020.1817437DOI Listing
January 2021

Loss-of-function variants in predispose to uveal melanoma.

J Med Genet 2021 Apr 9;58(4):234-236. Epub 2020 Sep 9.

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

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http://dx.doi.org/10.1136/jmedgenet-2020-107098DOI Listing
April 2021

Genomic analysis of adult case of ocular surface giant congenital melanocytic nevus and associated clinicopathological findings.

Ophthalmic Genet 2020 12 20;41(6):616-620. Epub 2020 Aug 20.

Department of Oncogenomics , QIMR Berghofer Medical Research Institute , Brisbane, QLD, Australia.

Introduction: Conjunctival nevi are the most common tumor of the ocular surface. There are some rare reports of so-called 'giant' conjunctival nevi. We report a case of a 47-year-old female with a cutaneous and ocular surface giant congenital melanocytic nevus and describe her clinical course.

Case Description: This is a retrospective case report of a single patient. A 47-year-old female with a history of biopsy-proven periorbital congenital melanocytic nevus, with an associated giant conjunctival nevus presented for structural and functional rehabilitation. Serial surgeries were performed and excised tissue was sent for histopathological and genetic examination. The conjunctival nevus had a low tumor mutation burden, and of the 647 somatic mutations, only one occurred within a protein coding region, namely p.Gln61Arg.

Conclusion: This is the first reported adult case including genomic analysis of an ocular surface giant congenital melanocytic nevus. The case shows a possible association between periorbital congenital melanocytic nevi and giant conjunctival nevi, and underscores the possible role that targeted drug therapies may have in malignant transformation of these conditions.
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http://dx.doi.org/10.1080/13816810.2020.1810281DOI Listing
December 2020

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

Circulation 2020 Aug 3;142(8):734-747. Epub 2020 Aug 3.

TIMI (Thrombolysis in Myocardial Infarction) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital Heart and Harvard Medical School, Boston, MA (M.P.B., S.D.W., T.A.Z., D.L.B., E.L.G., M.S.S.).

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], =0.094) and significantly higher adjusted risk of CV death/HHF (adjusted HR, 1.60 [95% CI, 1.21-2.12], =0.0010) and progression of kidney disease (adjusted HR, 1.51 [95% CI, 1.13 - 2.03], =0.0058), and limb adverse events (adjusted HR, 8.37, <0.001). The relative risk reductions with dapagliflozin for CV death/HHF (HR, 0.86, PAD; HR, 0.82, no-PAD; -interaction=0.79) and progression of kidney disease (HR, 0.78, PAD; HR, 0.76, no-PAD; -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 (-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.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.044775DOI Listing
August 2020

Trajectories and associations between depression and physical activity in patients with cardiovascular disease during participation in an internet-based cognitive behavioural therapy programme.

Eur J Cardiovasc Nurs 2020 Aug 5:1474515120947250. Epub 2020 Aug 5.

Department of Health, Medicine and Caring Sciences, Linköping University, Sweden.

Background: There is a lack of knowledge about internet-based cognitive behavioural therapy in patients with cardiovascular disease, and its effects on depressive symptoms and physical activity.

Aim: To examine trajectories of depressive symptoms and physical activity, and to explore if these trajectories are linked with the delivery of internet-based cognitive behavioural therapy.

Methods: A secondary-analysis of data collected in a randomised controlled trial that evaluated the effects of a 9-week internet-based cognitive behavioural therapy programme compared to an online discussion forum on depressive symptoms in cardiovascular disease patients. Data were collected at baseline, once weekly during the 9-week intervention period and at the 9-week follow-up. The Montgomery Åsberg depression rating scale - self-rating (MADRS-S) was used to measure depressive symptoms. Two modified items from the physical activity questionnaire measuring frequency and length of physical activity were merged to form a physical activity factor.

Results: After 2 weeks the internet-based cognitive behavioural therapy group had a temporary worsening in depressive symptoms. At 9-week follow-up, depressive symptoms (<0.001) and physical activity (=0.02) had improved more in the internet-based cognitive behavioural therapy group. Only in the internet-based cognitive behavioural therapy group, was a significant correlation (=-0.39, =0.002) between changes in depressive symptoms and changes in physical activity found. Structural equation analyses revealed that internet-based cognitive behavioural therapy decreased depressive symptoms, and that a decrease in depression, in turn, resulted in an increase in physical activity.

Conclusions: Internet-based cognitive behavioural therapy was more effective than an online discussion forum to decrease depressive symptoms and increase physical activity. Importantly, a decrease in depressive symptoms needs to precede an increase in physical activity.
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http://dx.doi.org/10.1177/1474515120947250DOI Listing
August 2020

Multiplex melanoma families are enriched for polygenic risk.

Hum Mol Genet 2020 Oct;29(17):2976-2985

Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.

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.
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http://dx.doi.org/10.1093/hmg/ddaa156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566496PMC
October 2020

Attack of the Subclones: Accurate Detection of Mutational Heterogeneity in Bulk DNA from Tumors.

J Invest Dermatol 2020 08;140(8):1501-1503

Genetics and Immunology, University of the Highlands and Islands, Inverness, Scotland, United Kingdom; Oncogenomics, QIMR Berghofer Medical Research Institute, Queensland, Australia. Electronic address:

Tumors are often polyclonal and are therefore heterogenous in their genomic and molecular profiles, which contributes to drug resistance and treatment failure. The methods used to detect these heterogenous differences in tumor samples are critical, but findings have been hindered by methodological inability to detect low-frequency subclones in bulk DNA. Chang et al. (2020) have addressed some of these methodological issues.
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http://dx.doi.org/10.1016/j.jid.2020.02.017DOI Listing
August 2020

Correction to: Swedish translation and validation of the Pediatric Insomnia Severity Index.

BMC Pediatr 2020 Jul 4;20(1):333. Epub 2020 Jul 4.

Department of Pediatric Dentistry, Institute for Postgraduate Dental Education, Jönköping, Sweden.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s12887-020-02232-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334842PMC
July 2020

Swedish translation and validation of the Pediatric Insomnia Severity Index.

BMC Pediatr 2020 05 26;20(1):253. Epub 2020 May 26.

Department of Pediatric Dentistry, Institute for Postgraduate Dental Education, Jönköping, Sweden.

Background: To increase health and well-being in young children, it is important to acknowledge and promote the child's sleep behaviour. However, there is a lack of brief, validated sleep screening instruments for children. The aims of the study were to (1) present a Swedish translation of the PISI, (2) examine the factor structure of the Swedish version of PISI, and test the reliability and validity of the PISI factor structure in a sample of healthy children in Sweden.

Methods: The English version of the PISI was translated into Swedish, translated back into English, and agreed upon before use. Parents of healthy 3- to 10-year-old children filled out the Swedish version of the PISI and the generic health-related quality of life instrument KIDSCREEN-27 two times. Exploratory and confirmatory factor analyses for baseline and test-retest, structural equation modelling, and correlations between the PISI and KIDSCREEN-27 were performed.

Results: In total, 160 parents filled out baseline questionnaires (test), whereof 100 parents (63%) filled out the follow-up questionnaires (retest). Confirmative factor analysis of the PISI found two correlated factors: sleep onset problems (SOP) and sleep maintenance problems (SMP). The PISI had substantial construct and test-retest reliability. The PISI factors were related to all KIDSCREEN-27 dimensions.

Conclusions: The Swedish version of the PISI is applicable for screening sleep problems and is a useful aid in dialogues with families about sleep.
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http://dx.doi.org/10.1186/s12887-020-02150-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249377PMC
May 2020

Supplemental selenium and coenzyme Q10 reduce glycation along with cardiovascular mortality in an elderly population with low selenium status - A four-year, prospective, randomised, double-blind placebo-controlled trial.

J Trace Elem Med Biol 2020 May 4;61:126541. Epub 2020 May 4.

Department of Medical Sciences, Uppsala University, SE-751 85 Uppsala, Sweden.

Background: A low intake of selenium has been shown to increase the risk of cardiovascular mortality, and supplementation of selenium and coenzyme Q10 influences this. The mechanism behind is unclear although effects on inflammation, oxidative stress and microRNA expression have been reported. Fructosamine, a marker of long-term glycaemic control, is also a marker of increased risk of heart disease and death, even in non-diabetics.

Objective: To analyse the impact of selenium and coenzyme Q10 supplementation on the concentration of fructosamine. Also, the relation between pre-intervention serum selenium concentration and the effect on fructosamine of the intervention was studied.

Methods: Fructosamine plasma concentration was determined in 219 participants after six and 42 months of intervention with selenium yeast (200 μg/day) and coenzyme Q10 (200 mg/ day) (n = 118 of which 20 had diabetes at inclusion), or placebo (n = 101 of which 18 had diabetes at inclusion). Pre-intervention, the serum selenium levels were 67 μg/L (active treatment group: 66.6 μg/L; placebo group: 67.4 μg/L), corresponding to an estimated intake of 35 μg/day. Changes in concentrations of fructosamine following intervention were assessed by the use of T-tests, repeated measures of variance, and ANCOVA analyses.

Results: Post-intervention selenium concentrations were 210 μg/L in the active group and 72 μg/L in the placebo group. A lower concentration of fructosamine could be seen as a result of the intervention in the total population (P = 0.001) in both the males (P = 0.04) and in the females (P = 0.01) in the non-diabetic population (P = 0.002), and in both the younger (<76 years) (P = 0.01) and the older (≥76 years) participants (P = 0.03). No difference could be demonstrated in fructosamine concentration in the diabetic patients, but the total sample was small (n = 38). In subjects with a low pre-intervention level of serum selenium the intervention gave a more pronounced decrease in fructosamine compared with those with a higher baseline selenium level.

Conclusion: A significantly lower concentration of fructosamine was observed in the elderly community-living participants supplemented with selenium and coenzyme Q10 for 42 months compared to those on the placebo. As oxidative mechanisms are involved in the glycation of proteins, less glycoxidation could be a result of the supplementation of selenium and coenzyme Q10, which could have contributed to lower cardiac mortality and less inflammation, as has earlier been reported. This study was registered at Clinicaltrials.gov, and has the identifier NCT01443780.
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http://dx.doi.org/10.1016/j.jtemb.2020.126541DOI Listing
May 2020

Whole genome landscapes of uveal melanoma show an ultraviolet radiation signature in iris tumours.

Nat Commun 2020 05 15;11(1):2408. Epub 2020 May 15.

QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

Uveal melanoma (UM) is the most common intraocular tumour in adults and despite surgical or radiation treatment of primary tumours, ~50% of patients progress to metastatic disease. Therapeutic options for metastatic UM are limited, with clinical trials having little impact. Here we perform whole-genome sequencing (WGS) of 103 UM from all sites of the uveal tract (choroid, ciliary body, iris). While most UM have low tumour mutation burden (TMB), two subsets with high TMB are seen; one driven by germline MBD4 mutation, and another by ultraviolet radiation (UVR) exposure, which is restricted to iris UM. All but one tumour have a known UM driver gene mutation (GNAQ, GNA11, BAP1, PLCB4, CYSLTR2, SF3B1, EIF1AX). We identify three other significantly mutated genes (TP53, RPL5 and CENPE).
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http://dx.doi.org/10.1038/s41467-020-16276-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229209PMC
May 2020

Safety of dapagliflozin in a broad population of patients with type 2 diabetes: Analyses from the DECLARE-TIMI 58 study.

Diabetes Obes Metab 2020 08 27;22(8):1357-1368. Epub 2020 Apr 27.

Li Ka Shing Knowledge Institute, Department of Medicine, St Michael's Hospital, University of Toronto, Toronto, Canada.

Aims: To evaluate comprehensively the safety of dapagliflozin in patients with type 2 diabetes (T2DM), with emphasis placed on potential safety concerns related to the sodium-glucose co-transporter-2 inhibitor class.

Methods: In the Dapagliflozin Effect on Cardiovascular Events - Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) study, 17 160 patients with T2DM were randomized to dapagliflozin or placebo and followed for a median of 4.2 years. Safety was evaluated in 17 143 patients receiving at least one dose of study drug.

Results: Acute kidney injury occurred less frequently with dapagliflozin, and adverse events suggestive of volume depletion were balanced between treatment groups, both irrespective of baseline estimated glomerular filtration rate, blood pressure, diuretic or loop diuretic use (interaction P values >0.05). Fractures and malignancies were balanced between the groups, irrespective of sex, diabetes duration or smoking (interaction P values >0.05) and fewer cases of bladder cancer occurred in the dapagliflozin versus the placebo group. Diabetic ketoacidosis was very rare, but more frequent with dapagliflozin versus placebo (27 vs. 12 patients with events; P = 0.02), yet signs, symptoms and contributing factors were similar in the two groups. Major hypoglycaemia occurred less frequently with dapagliflozin versus placebo, regardless of baseline use of either insulin or sulphonylureas (interaction P values >0.05). There were more adverse events of genital infections leading to discontinuation of study drug in the dapagliflozin versus the placebo group, but serious genital infections were few and balanced between treatment groups. Urinary tract infections, acute pyelonephritis and urosepsis were also balanced between treatment groups.

Conclusions: Dapagliflozin was well tolerated. The long duration and large number of patient-years in DECLARE-TIMI 58 comprehensively addressed previous safety questions, confirming the robust safety profile of dapagliflozin.
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http://dx.doi.org/10.1111/dom.14041DOI Listing
August 2020

Increased Risk of Hip Fracture in Patients with Lymphoma, a Swedish Population Study of 37,236 Lymphoma Patients.

Calcif Tissue Int 2020 06 13;106(6):591-598. Epub 2020 Mar 13.

Section of Hematology and Coagulation, Department of Internal Medicine, Institute of Medicine, Sahlgrenska University Hospital, Sahlgrenska Academy,, University of Gothenburg, Bruna Stråket 5, 413 45, Gothenburg, Sweden.

Increased bone loss has been noted in lymphoma patients; however, the incidence of hip fracture is not known. The aim of our study was to explore the risk for hip fracture in patients with lymphoma compared with the entire Swedish population. The risk of hip fracture was determined in a retrospective population cohort study of adult Swedish lymphoma patients (n = 37,236), diagnosed 1995-2015 and compared with the entire Swedish population during the same period. The incidence of hip fracture in lymphoma patients was higher in women than in men, increased by age, and decreased by calendar year as also demonstrated in the total population. 2.2% of the men and 4.7% of women with lymphoma sustained a hip fracture. For the total group of females, the hazard ratio (HR) was 1.19 (95% CI 1.11-1.28) and for men, the hazard ratio was 1.06 (95% CI 0.97-1.17) compared with the Swedish population. The HR for hip fracture (2016) was 2.80 (95% CI 1.20-6.53), 2.04 (95% CI 1.30-3.20), 1.56 (95% CI 1.21-2.01), 1.08 (95% CI 0.89-1.30), and 1.07 (95% CI 0.92-1.25) in females aged 40, 50, 60, 70, and 80 years, respectively. Corresponding figures for men were not significant in 2016. Unmarried men with lymphoma had a two times higher risk for hip fracture (HR 2.02 95% CI 1.63-2.50) compared with married men. Patients with lymphoma had an increased risk of hip fracture, especially younger women and unmarried men. The incidence of hip fracture is decreased by calendar year in the lymphoma patients and the entire Swedish population.
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http://dx.doi.org/10.1007/s00223-020-00674-7DOI Listing
June 2020

The associations between psychological distress and health-related quality of life in patients with non-cardiac chest pain.

Health Qual Life Outcomes 2020 Mar 12;18(1):68. Epub 2020 Mar 12.

Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.

Background: Recurrent chest pain episodes with no clear explanation may affect patients' psychological wellbeing and health-related quality of life (HRQoL) negatively. Despite the fact that a significant amount of patients with non-cardiac chest pain (NCCP) might have a history of Cardiac Disease (CD), there is today a lack of knowledge on how CD influences the association between psychological wellbeing and HRQoL in patients with NCCP. Therefore, the aim of this study is to describe HRQoL in patients with NCCP, with or without history of CD, and to explore the association between HRQoL and cardiac anxiety, depressive symptoms, fear of body sensations and somatization.

Methods: Five hundred fifty-two patients discharged with NCCP from four hospitals in Southeast Sweden completed the EQ-5D, Cardiac Anxiety Questionnaire, Patient Health Questionnaire-9, Body Sensations Questionnaire, and Patient Health Questionnaire-15.

Results: Fifty precent reported at least moderate problems regarding pain/discomfort and 25% reported at least moderate problems in the HRQoL dimensions mobility, usual activities, and anxiety/depression. Patients with NCCP and history of CD reported significantly lower HRQoL (p ≤ 0.05) compared to patients with NCCP without CD. In the total study population, cardiac anxiety, depressive symptoms, and somatization had weak significant negative associations (beta = 0.187-0.284, p < 0.001) with HRQoL. In patients with history of CD, the association between depressive symptoms and HRQoL was moderate (beta = - 0.339, p < 0.001), compared to weak association in patients without CD (beta = - 0.193, p < 0.001). On the other hand, the association between cardiac anxiety and HRQoL was weak in both patients with history of CD (beta = - 0.156, p = 0.05), and in those without (beta = - 0.229, p < 0.001).

Conclusions: Patients with NCCP, in particular those with history of CD, reported low levels of HRQoL, which was associated with psychological distress. This should be considered when developing psychological interventions aiming to improve HRQoL in patients with NCCP.
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http://dx.doi.org/10.1186/s12955-020-01297-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066800PMC
March 2020

How Healthcare Professionals in Cardiac Care Address Depressive Symptoms: Experiences of Patients With Cardiovascular Disease.

J Cardiovasc Nurs 2020 Feb 21. Epub 2020 Feb 21.

Mats Westas, RN Department of Health, Medicine and Caring Science, Linköping University, Sweden. Johan Lundgren, PhD Department of Health, Medicine and Caring Science, Linköping University, Sweden. Ghassan Mourad, PhD Department of Health, Medicine and Caring Science, Linköping University, Sweden. Margit Neher, PhD Department of Medical and Health Sciences, Linköping University, Sweden. Peter Johansson, PhD Department of Health, Medicine and Caring Science, and Internal Medicine, Linköping University, Norrkoping, Sweden.

Background: Depressive symptoms are common in patients with cardiovascular disease (CVD) and are associated with a poorer quality of life and prognosis. Despite the high prevalence and negative consequences, the recognition of depressive symptoms is low. More knowledge about patients' perceptions of how depressive symptoms are addressed by healthcare professionals is therefore needed.

Objectives: The aim of this study was to explore the experiences of patients with CVD of how healthcare professionals address and manage depressive symptoms in clinical cardiac care encounters.

Methods: A qualitative, semistructured interview study was performed. Data were analyzed using inductive thematic analysis.

Results: In total, 20 patients with CVD previously treated for depressive symptoms were included (mean age, 62 [range, 34-79] years; 45% women). Three main themes emerged: (1) "not being seen as a whole person," (2) "denying depressive symptoms," and (3) "being provided with help." The patients perceived that healthcare professionals mainly focused on somatic symptoms and disregarded their need for help for depressive symptoms when patients raised the issue. Some patients stated that they received help for depressive symptoms, but this depended on the patients' own ability to communicate their needs and/or having social support that could alert them to the importance of doing so. Patients also described that they downplayed the burden of depressive symptoms and/or did not recognize themselves as having depressive symptoms.

Conclusion: Depressive symptoms were overlooked in patients with CVD, and psychological needs had not been met. A good ability to address needs and having good social support were useful for receiving help with depressive symptoms.
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http://dx.doi.org/10.1097/JCN.0000000000000669DOI Listing
February 2020

Whole Exome Sequencing Identifies Candidate Genes Associated with Hereditary Predisposition to Uveal Melanoma.

Ophthalmology 2020 05 18;127(5):668-678. Epub 2019 Nov 18.

Department of Ophthalmology and Visual Science, Havener Eye Institute, The Ohio State University, Columbus, Ohio.

Purpose: To identify susceptibility genes associated with hereditary predisposition to uveal melanoma (UM) in patients with no detectable germline BAP1 alterations.

Design: Retrospective case series from academic referral centers.

Participants: Cohort of 154 UM patients with high risk of hereditary cancer defined as patients with 1 or more of the following: (1) familial UM, (2) young age (<35 years) at diagnosis, (3) personal history of other primary cancers, and (4) family history of 2 or more primary cancers with no detectable mutation or deletion in BAP1 gene.

Methods: Whole exome sequencing, a cancer gene panel, or both were carried out. Probands included 27 patients with familial UM, 1 patient with bilateral UM, 1 patient with congenital UM, and 125 UM patients with strong personal or family histories, or both, of cancer. Functional validation of variants was carried out by immunohistochemistry, reverse-transcriptase polymerase chain reaction, and genotyping.

Main Outcome Measures: Clinical characterization of UM patients with germline alterations in known cancer genes.

Results: We identified actionable pathogenic variants in 8 known hereditary cancer predisposition genes (PALB2, MLH1, MSH6, CHEK2, SMARCE1, ATM, BRCA1, and CTNNA1) in 9 patients, including 3 of 27 patients (11%) with familial UM and 6 of 127 patients (4.7%) with a high risk for cancer. Two patients showed pathogenic variants in CHEK2 and PALB2, whereas variants in the other genes each occurred in 1 patient. Biallelic inactivation of PALB2 and MLH1 was observed in tumors from the respective patients. The frequencies of pathogenic variants in PALB2, MLH1, and SMARCE1 in UM patients were significantly higher than the observed frequencies in noncancer controls (PALB2: P = 0.02; odds ratio, 8.9; 95% confidence interval, 1.5-30.6; MLH1: P = 0.04; odds ratio, 25.4; 95% confidence interval, 1.2-143; SMARCE1: P = 0.001; odds ratio, 2047; 95% confidence interval, 52-4.5e15, respectively).

Conclusions: The study provided moderate evidence of gene and disease association of germline mutations in PALB2 and MLH1 with hereditary predisposition to UM. It also identified several other candidate susceptibility genes. The results suggest locus heterogeneity in predisposition to UM. Genetic testing for hereditary predisposition to cancer is warranted in UM patients with strong personal or family history of cancers, or both.
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http://dx.doi.org/10.1016/j.ophtha.2019.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183432PMC
May 2020

ASXL1 mutations, previous vascular complications and age at diagnosis predict survival in 85 WHO-defined polycythaemia vera patients.

Br J Haematol 2020 06 17;189(5):913-919. Epub 2020 Feb 17.

Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden.

Polycythaemia vera (PV) patients have an overall comparatively favourable prognosis, but disease progression is very heterogeneous and life-threatening thrombosis and bleedings are frequent complications in untreated disease. Moreover, transformation to more severe secondary myelofibrosis and acute myeloid leukaemia can occur. The aim of this study was to identify gene mutations that could be used together with clinical data as prognostic markers to guide treatment decisions in PV patients. A well-characterized WHO-defined cohort of PV patients was used. Clinical data and blood values were evaluated and a myeloid sequencing panel was used to screen for additional mutations other than the diagnostic JAK2 V617F and JAK2 exon 12 mutations. In 78% of the PV patients, at least one mutation additional to JAK2 V617F was detected. Additional mutations in genes coding for epigenetic modifiers, like TET2, DNMT3A and ASXL1, were most frequent. When correlated to overall survival, mutations in ASXL1 were significantly associated with inferior survival. In an attempt to obtain prognostic guidance in a larger number of patients, the presence of ASXL1 mutations was combined with age and vascular complications prior to diagnosis. Based on these data we were able to define three risk groups that predicted survival.
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http://dx.doi.org/10.1111/bjh.16450DOI Listing
June 2020

Experiences and Management of Incidents That Influence Sleep in Patients With Cardiovascular Disease and Insomnia.

J Cardiovasc Nurs 2020 Jul/Aug;35(4):364-374

Background: Insomnia is a global problem and an important risk factor for patients living with cardiovascular disease (CVD), causing poor well-being and worsening disease prognosis. Yet, there is a lack of effective intervention strategies targeting sleep problems. To deliver patient-centered interventions and achieve good quality of sleep for this group, the own experiences of patients with CVD need to be understood.

Objective: The aim of this study was to describe experiences that influence the sleep situation and management of sleep problems among patients with CVD and insomnia.

Method: A qualitative descriptive design with critical incident technique methodology was used. Twenty patients (13 men and 7 women; mean age, 73 years; range, 47-83 years) with single or multiple verified CVD diagnoses and insomnia were included.

Results: Four underlying categories of sleep disruptors were identified: cognitive, social, physical, and behavioral. Participants experienced distress from the heart condition at night, physically and cognitively, with high levels of concern about its consequences for themselves and their families. Participants' sleep management preferences and responses included cognitive, behavioral, and pharmacological management strategies. Participants preferred their own nonpharmacological insomnia management over professional advice.

Conclusion: Patients with CVD and insomnia experienced both physical and cognitive distress from their heart condition and chose to adopt nonpharmacological insomnia management. Tailored professional support is needed to change precipitating behavioral factors to be able to treat insomnia, improve sleep, reduce symptom burden, and enhance quality of life.
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http://dx.doi.org/10.1097/JCN.0000000000000626DOI Listing
January 2020

Efficacy and Safety of Dapagliflozin in the Elderly: Analysis From the DECLARE-TIMI 58 Study.

Diabetes Care 2020 02 16;43(2):468-475. Epub 2019 Dec 16.

Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Hebrew University of Jerusalem, The Faculty of Medicine, Jerusalem, Israel.

Objective: Data regarding the effects of sodium-glucose cotransporter 2 inhibitors in the elderly (age ≥65 years) and very elderly (age ≥75 years) are limited.

Research Design And Methods: The Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 assessed cardiac and renal outcomes of dapagliflozin versus placebo in patients with type 2 diabetes. Efficacy and safety outcomes were studied within age subgroups for treatment effect and age-based treatment interaction.

Results: Of the 17,160 patients, 9,253 were <65 years of age, 6,811 ≥65 to <75 years, and 1,096 ≥75 years. Dapagliflozin reduced the composite of cardiovascular death or hospitalization for heart failure consistently, with a hazard ratio (HR) of 0.88 (95% CI 0.72, 1.07), 0.77 (0.63, 0.94), and 0.94 (0.65, 1.36) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction value 0.5277). Overall, dapagliflozin did not significantly decrease the rates of major adverse cardiovascular events, with HR 0.93 (95% CI 0.81, 1.08), 0.97 (0.83, 1.13), and 0.84 (0.61, 1.15) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction value 0.7352). The relative risk reduction for the secondary prespecified cardiorenal composite outcome ranged from 18% to 28% in the different age-groups with no heterogeneity. Major hypoglycemia was less frequent with dapagliflozin versus placebo, with HR 0.97 (95% CI 0.58, 1.64), 0.50 (0.29, 0.84), and 0.68 (0.29, 1.57) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction value 0.2107). Safety outcomes, including fractures, volume depletion, cancer, urinary tract infections, and amputations were balanced with dapagliflozin versus placebo, and acute kidney injury was reduced, all regardless of age. Genital infections that were serious or led to discontinuation of the study drug and diabetic ketoacidosis were uncommon, yet more frequent with dapagliflozin versus placebo, without heterogeneity (interaction values 0.1058 and 0.8433, respectively).

Conclusions: The overall efficacy and safety of dapagliflozin are consistent regardless of age.
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http://dx.doi.org/10.2337/dc19-1476DOI Listing
February 2020