Myocardial Recovery in Recent Onset Dilated Cardiomyopathy: Role of CDCP1 and Cardiac Fibrosis.

BACKGROUND: Dilated cardiomyopathy (DCM) is a major cause of heart failure and carries a high mortality rate. Myocardial recovery in DCM-related heart failure patients is highly variable, with some patients having little or no response to standard drug therapy. A genome-wide association study may agnostically identify biomarkers and provide novel insight into the biology of myocardial recovery in DCM. METHODS: A genome-wide association study for change in left ventricular ejection fraction was performed in 686 White subjects with recent-onset DCM who received standard pharmacotherapy. Genome-wide association study signals were subsequently functionally validated and studied in relevant cellular models to understand molecular mechanisms that may have contributed to the change in left ventricular ejection fraction. RESULTS: The genome-wide association study identified a highly suggestive locus that mapped to the 5'-flanking region of the CDCP1 (CUB [complement C1r/C1s, Uegf, and Bmp1] domain containing protein 1) gene (rs6773435; P=7.12×10-7). The variant allele was associated with improved cardiac function and decreased CDCP1 transcription. CDCP1 expression was significantly upregulated in human cardiac fibroblasts (HCFs) in response to the PDGF (platelet-derived growth factor) signaling, and knockdown of CDCP1 significantly repressed HCF proliferation and decreased AKT (protein kinase B) phosphorylation. Transcriptomic profiling after CDCP1 knockdown in HCFs supported the conclusion that CDCP1 regulates HCF proliferation and mitosis. In addition, CDCP1 knockdown in HCFs resulted in significantly decreased expression of soluble ST2 (suppression of tumorigenicity-2), a prognostic biomarker for heart failure and inductor of cardiac fibrosis. CONCLUSIONS: CDCP1 may play an important role in myocardial recovery in recent-onset DCM and mediates its effect primarily by attenuating cardiac fibrosis.

Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span.

Senescence is the consequence of a signaling mechanism activated in stressed cells to prevent proliferation of cells with damage. Senescent cells (Sncs) often develop a senescence-associated secretory phenotype to prompt immune clearance, which drives chronic sterile inflammation and plays a causal role in aging and age-related diseases. Sncs accumulate with age and at anatomical sites of disease. Thus, they are regarded as a logical therapeutic target. Senotherapeutics are a new class of drugs that selectively kill Sncs (senolytics) or suppress their disease-causing phenotypes (senomorphics/senostatics). Since 2015, several senolytics went from identification to clinical trial. Preclinical data indicate that senolytics alleviate disease in numerous organs, improve physical function and resilience, and suppress all causes of mortality, even if administered to the aged. Here, we review the evidence that Sncs drive aging and disease, the approaches to identify and optimize senotherapeutics, and the current status of preclinical and clinical testing of senolytics.

"It's a stressful, trying time for the caretaker": an interpretive description qualitative study of postoperative transitions in care for older adults with frailty from the perspectives of informal caregivers.

BACKGROUND: Older adults with frailty have surgery at a high rate. Informal caregivers often support the postoperative transition in care. Despite the growing need for family and caregiver support for this population, little is known about the experience of providing informal care to older adults with frailty during the postoperative transition in care. The purpose of this study was to explore what is important during a postoperative transition in care for older adults with frailty from the perspective of informal caregivers. METHODS: This was a qualitative study using an interpretive description methodology. Seven informal caregivers to older adults [aged ≥ 65 years with frailty (Clinical Frailty Scale score ≥ 4) who had an inpatient elective surgery] participated in a telephone-based, semi-structured interview. Audio files were transcribed and analyzed using reflexive thematic analysis. RESULTS: Four themes were constructed: (1) being informed about what to expect after surgery; (2) accessible communication with care providers; (3) homecare resources are needed for the patient; and (4) a support network for the caregivers. Theme 4 included two sub-themes: (a) respite and emotional support and (b) occupational support. CONCLUSIONS: Transitions in care present challenges for informal caregivers of older adults with frailty, who play an important role in successful transitions. Future postoperative transitional care programs should consider making targeted information, accessible communication, and support networks available for caregivers as part of facilitating successful transitions in care.

"Like fighting a fire with a water pistol": A qualitative study of the work experiences of critical care nurses during the COVID-19 pandemic.

AIM: To understand the experience of critical care nurses during the COVID-19 pandemic, through the application of the Job-Demand-Resource model of occupational stress. DESIGN: Qualitative interview study. METHODS: Twenty-eight critical care nurses (CCN) working in ICU in the UK NHS during the COVID-19 pandemic took part in semi-structured interviews between May 2021 and May 2022. Interviews were guided by the constructs of the Job-Demand Resource model. Data were analysed using framework analysis. RESULTS: The most difficult job demands were the pace and amount, complexity, physical and emotional effort of their work. Prolonged high demands led to CCN experiencing emotional and physical exhaustion, burnout, post-traumatic stress symptoms and impaired sleep. Support from colleagues and supervisors was a core job resource. Sustained demands and impaired physical and psychological well-being had negative organizational consequences with CCN expressing increased intention to leave their role. CONCLUSIONS: The combination of high demands and reduced resources had negative impacts on the psychological well-being of nurses which is translating into increased consideration of leaving their profession. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: The full impacts of the pandemic on the mental health of CCN are unlikely to resolve without appropriate interventions. IMPACT: Managers of healthcare systems should use these findings to inform: (i) the structure and organization of critical care workplaces so that they support staff to be well, and (ii) supportive interventions for staff who are carrying significant psychological distress as a result of working during and after the pandemic. These changes are required to improve staff recruitment and retention. REPORTING METHOD: We used the COREQ guidelines for reporting qualitative studies. PATIENT AND PUBLIC CONTRIBUTION: Six CCN provided input to survey content and interview schedule. Two authors and members of the study team (T.S. and S.C.) worked in critical care during the pandemic.

Length-independent telomere damage drives post-mitotic cardiomyocyte senescence.

Ageing is the biggest risk factor for cardiovascular disease. Cellular senescence, a process driven in part by telomere shortening, has been implicated in age-related tissue dysfunction. Here, we address the question of how senescence is induced in rarely dividing/post-mitotic cardiomyocytes and investigate whether clearance of senescent cells attenuates age-related cardiac dysfunction. During ageing, human and murine cardiomyocytes acquire a senescent-like phenotype characterised by persistent DNA damage at telomere regions that can be driven by mitochondrial dysfunction and crucially can occur independently of cell division and telomere length. Length-independent telomere damage in cardiomyocytes activates the classical senescence-inducing pathways, p21CIP and p16INK4a, and results in a non-canonical senescence-associated secretory phenotype, which is pro-fibrotic and pro-hypertrophic. Pharmacological or genetic clearance of senescent cells in mice alleviates detrimental features of cardiac ageing, including myocardial hypertrophy and fibrosis. Our data describe a mechanism by which senescence can occur and contribute to age-related myocardial dysfunction and in the wider setting to ageing in post-mitotic tissues.

"I can't imagine having to do it on your own": a qualitative study on postoperative transitions in care from the perspectives of older adults with frailty.

BACKGROUND: Adults aged 65 and older have surgery more often than younger people and often live with frailty. The postoperative transition in care from hospital to home after surgey is a challenging time for older adults with frailty as they often experience negative outcomes. Improving postoperative transitions in care for older adults with frailty is a priority. However, little knowledge from the perspective of older adults with frailty is available to support meaningful improvements in postoperative transitions in care. OBJECTIVE: To explore what is important to older adults with frailty during a postoperative transition in care. METHODS: This qualitative study used an interpretive description methodology. Twelve adults aged ≥ 65 years with frailty (Clinical Frailty Scale score ≥ 4) who had an inpatient elective surgery and could speak in English participated in a telephone-based, semi-structured interview. Audio files were transcribed and analyzed using thematic analysis. RESULTS: Five themes were constructed: 1) valuing going home after surgery; 2) feeling empowered through knowledge and resources; 3) focusing on medical and functional recovery; 4) informal caregivers and family members play multiple integral roles; and 5) feeling supported by healthcare providers through continuity of care. Each theme had 3 sub-themes. CONCLUSION: Future programs should focus on supporting patients to return home by empowering patients with resources and clear communication, ensuring continuity of care, creating access to homecare and virtual support, focusing on functional and medical recovery, and recognizing the invaluable role of informal caregivers.

The association between receipt of home care rehabilitation services and acute care hospital utilization in clients with multimorbidity following an acute care unit discharge: a retrospective cohort study.

BACKGROUND: Individuals experiencing multimorbidity have more complex healthcare needs, use more healthcare services, and access multiple service providers across the healthcare continuum. They also experience higher rates of functional decline. Rehabilitation therapists are well positioned to address these functional needs; however, little is known about the influence of rehabilitation therapy on patient outcomes, and subsequent unplanned healthcare utilization for people with multimorbidity. The aims of this study were to: 1) describe and compare the characteristics of people with multimorbidity receiving: home care rehabilitation therapy alone, other home care services without rehabilitation therapy, and the combination of home care rehabilitation therapy and other home care services, and 2) determine the association between home care rehabilitation therapy and subsequent healthcare utilization among those recently discharged from an acute care unit. METHODS: This retrospective cohort study used linked health administrative data housed within ICES, Ontario, Canada. The cohort included long-stay home care clients experiencing multimorbidity who were discharged from acute care settings between 2007-2015 (N = 43,145). Descriptive statistics, ANOVA's, t-tests, and chi-square analyses were used to describe and compare cohort characteristics. Multivariable logistic regression was used to understand the association between receipt of rehabilitation therapy and healthcare utilization. RESULTS: Of those with multimorbidity receiving long-stay home care services, 45.5% had five or more chronic conditions and 46.3% required some assistance with ADLs. Compared to people receiving other home care services, those receiving home care rehabilitation therapy only were less likely to be readmitted to the hospital (OR = 0.78; 95% CI: 0.73-0.83) and use emergency department services (OR = 0.73; 95% CI: 0.69-0.78) within the first 3-months following hospital discharge. CONCLUSIONS: Receipt of rehabilitation therapy was associated with less unplanned healthcare service use when transitioning from hospital to home among persons with multimorbidity. These findings suggest rehabilitation therapy may help to reduce the healthcare burden for individuals and health systems. Future research should evaluate the potential cost savings and health outcomes associated with providing rehabilitation therapy services for people with multimorbidity.

Investigating the Effects of Threatening Language, Message Framing, and Reactance in Opt-Out Organ Donation Campaigns.

BACKGROUND: Under opt-out organ donation policies, individuals are automatically considered to have agreed to donate their organs in the absence of a recorded opt-out decision. Growing evidence suggests that the language used within organ donation campaigns influences donor intentions and decision-making. PURPOSE: As awareness campaigns to promote opt-out consent in the UK are ongoing, the objectives of this study were to investigate the effect of language and message framing used in opt-out organ donation campaigns on donor intentions and psychological reactance. METHODS: Individuals from Scotland and England (N = 1,350) completed this online experiment. Participants were randomized to view one of four messages, designed in the format of a newspaper article, which described the upcoming opt-out system. This followed a 2 × 2 design whereby the degree of threatening language (high threat vs. low threat) and message framing (loss vs. gain) of the newspaper article was experimentally manipulated. Measures of intention (pre-exposure and postexposure) and postmessage reactance (threat to freedom and anger and counter-arguing) were obtained. RESULTS: A mixed analysis of variance revealed a significant Group × Time interaction on donor intentions; post hoc analysis revealed that intentions significantly decreased for individuals exposed to the High threat × Loss frame article but significantly increased for those exposed to the High threat × Gain frame article. CONCLUSIONS: In campaigns to promote opt-out legislation, high-threat language combined with loss-frame messages should be avoided. If high-threat language is used, gain-frame messaging that highlights the benefits of organ donation should also be incorporated.

Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan.

Cellular senescence, a stress-induced irreversible growth arrest often characterized by expression of p16(Ink4a) (encoded by the Ink4a/Arf locus, also known as Cdkn2a) and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing. Senescent cells accumulate in various tissues and organs over time, and have been speculated to have a role in ageing. To explore the physiological relevance and consequences of naturally occurring senescent cells, here we use a previously established transgene, INK-ATTAC, to induce apoptosis in p16(Ink4a)-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. We show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. The clearance of p16(Ink4a)-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels and adipocytes, respectively. Thus, p16(Ink4a)-positive cells that accumulate during adulthood negatively influence lifespan and promote age-dependent changes in several organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan.

Evaluations of postoperative transitions in care for older adults: a scoping review.

BACKGROUND: Most people having major surgery are over the age of 65. The transition out of hospital is a vulnerable time for older adults, particularly after major surgery. Research on postoperative transitions in care is growing, but it is not clear how postoperative transitions are being evaluated. The objective of this scoping review was to synthesize processes and outcomes used to evaluate postoperative transitions in care for older adults. METHODS: We conducted a scoping review that included articles evaluating a postoperative transition in care among adults aged > 65 having major elective surgery. We searched Medline (Ovid), EMBASE (Ovid), CINHAL, and Cochrane Central Register of Controlled Trials (CENTRAL) from their respective inception dates to April 6, 2021. We also searched The World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov from their respective inception dates to April 6, 2021. Screening and data extraction was completed by reviewers in duplicate. Data relevant to study design and objective, intervention description, and process or outcome evaluations were extracted. Process evaluations were categorized using the Ideal Transitions in Care Framework, and outcome evaluations were categorized using the Institute for Healthcare Improvement Triple Aim Framework. RESULTS: After screening titles and abstracts and full-text article review, we included 20 articles in our final synthesis. There was variability in the processes and outcomes used to evaluate postoperative transitions in care. The most common outcomes evaluated were health service utilization (n = 9), including readmission and Emergency Department visits, experiential outcomes (n = 9) and quality of life (n = 7). Process evaluations included evaluating the education provided to patients to promote self-management (n = 6), coordination of care among team members (n = 3) and outpatient follow-up (n = 3). Only two articles measured frailty, one article used theory to guide their evaluations and no articles engaged knowledge users. CONCLUSIONS: There is inconsistency in how postoperative transitions in care were evaluated. There is a need to use theories and to engage key stakeholders involved in postoperative transitions in care, including older adults and their caregivers, to identify the most appropriate approaches for developing and evaluating interventions to meaningfully improve care.

Health care providers' understanding of self-management support for people with chronic low back pain in Ethiopia: an interpretive description.

BACKGROUND: Healthcare providers play a key role in supporting people with chronic low back pain to self-manage their condition. The study aimed at exploring how health care providers understand and conceptualize self-management and how they provide self-management support for people with chronic low back pain in Ethiopia. METHODS: Health care providers who have supported people with low back pain, including medical doctors and physiotherapists, were approached and recruited from three hospitals in Ethiopia. This study employed an interpretive descriptive approach using semi-structured interviews. FINDINGS: Twenty-four participants (7 women; 17 men) with a median age of 28 (range 24 to 42) years and a median of 9.5 years (range 1 to 11 years) of helping people with chronic low back pain were interviewed. Seven major themes related to health care providers' understanding of self-management support for people with chronic low back pain in Ethiopia emerged. The findings show that self-management was a new concept to many and health care providers' had a fragmented understanding of self-management. They used or suggested several self-management support strategies to help people with CLBP self-manage their condition without necessarily focusing on enhancing their self-efficacy skills. The participants also discussed several challenges to facilitate self-management support for people with chronic low back pain. Despite the lack of training on the concept, the providers discussed the potential of providing self-management support for people with the condition. CONCLUSIONS: Self-management was a new concept to health care providers. The providers lack the competencies to provide self-management support for people with chronic low back pain. There is a need to enhance the health care providers' self-management support competencies through training.

Evaluating the validity of the Amharic Brief Pain Inventory among people with chronic primary musculoskeletal pain in Ethiopia.

BACKGROUND: The Brief Pain Inventory (BPI) is a multidimensional pain assessment tool used to evaluate pain severity and pain interference. The BPI has been translated and validity estimated across multiple languages and patient populations for clinical and research settings. This study aimed to assess the reliability and validity of Amharic BPI test scores among patients with chronic primary musculoskeletal pain living in Ethiopia. METHODS: This study had two parts: cognitive interviews and psychometric testing. An expert committee reviewed the Amharic BPI, and fifteen participants participated in the cognitive interviews. The results from the cognitive interviews were evaluated, and the committee approved recommendations for the tool prior to psychometric testing. Two hundred and sixty-nine patients were recruited from three sites for the psychometric testing. The results were summarised using descriptive statistics. Cronbach's alpha was calculated to estimate the internal consistency. To assess test-retest reliability, the intraclass coefficient was examined, and a Bland-Altman plot was created. Construct validity was determined using confirmatory factor analysis by testing BPI's previously suggested two or three-factor dimensionalities. Convergent validity was assessed by estimating the correlation between the Amharic BPI and SF-36 subscales. RESULTS: The Amharic BPI scores showed a good internal consistency using a 2-factor model with α = 0.89 for pain severity and α = 0.91 for pain interference. Good internal consistency was also observed in the 3-factor model, with α = 0.89 for pain severity, α = 0.84 for activity interference, and α = 0.86 for affective interference items. The test-retest reliability testing resulted in an ICC = 0.82 for pain severity and ICC = 0.90 for the pain interference. The severity scale had the highest correlation with bodily pain subscale of the SF-36 at r = - 0.44, and the interference scale with Physical functioning scale of SF-36 at r = - 0.63. Confirmatory factor analysis support rating Amharic BPI using a two-factor approach. CONCLUSIONS: Our findings showed that Amharic BPI scores demonstrate internal consistency, test-retest reliability, and construct validity among patients with chronic primary musculoskeletal pain in Ethiopia. Accordingly, the tool can be used in clinical practice or research in similar settings.

Interprofessional primary care during COVID-19: a survey of the provider perspective.

BACKGROUND: Interprofessional primary care (IPC) teams provide comprehensive and coordinated care and are ideally equipped to support those populations most at risk of adverse health outcomes during the COVID-19 pandemic, including older adults, and patients with chronic physical and mental health conditions. There has been little focus on the experiences of healthcare teams and no studies have examined IPC practice during the early phase of the COVID-19 pandemic. The objective of the study was to describe the state of interprofessional health provider practice within IPC teams during the COVID-19 pandemic. METHODS: Observational cross-sectional design. A web-based survey was deployed to IPC providers working in team-based primary care clinics in the province of Ontario, Canada. The survey included 26 close-ended and six open-ended questions. Close-ended questions were analyzed using descriptive statistics. Content analysis was used to analyze the open-ended questions. RESULTS: 445 surveys were included in the final analysis. Service delivery shifted from in-person care (77% pre-COVID-19) to telephone (76.5% during the COVID-19 pandemic). Less than half of the respondents (40%) reported receiving any training for virtual delivery. Wait times to access team members were reported to have decreased. There has also been a shift in what IPC providers report as the most commonly seen conditions, with increases in visits related to mental health concerns, acute infections (including COVID-19), social isolation, and resource navigation. Respondents also reported a reduction in healthcare provision for multiple chronic conditions including diabetes, cardiovascular disease, and chronic pain. CONCLUSIONS: IPC teams are rapidly shifting their practice to supporting their patients during the pandemic. A surge in mental health issues has been seen and is expected to continue to increase in response to COVID-19. Understanding early experiences can help plan for future pandemic waves.

Cross-cultural translation, adaptation, and validation of the Amharic version pain self-efficacy questionnaire in people with low back pain in Ethiopia.

BACKGROUND: The Pain Self-Efficacy Questionnaire (PSEQ) is a valid and reliable instrument that evaluates pain self-efficacy beliefs in people with pain conditions. However, it has not been validated and used in Ethiopia. We conducted this study to translate, adapt, and test the psychometric properties of the PSEQ in the Amharic language and Ethiopian context for its use with people experiencing low back pain (LBP). METHODS: The PSEQ was translated into Amharic and then back-translated into English. An expert review committee created a final Amharic version of the tool (PSEQ-Am), followed by pilot testing and cognitive debriefing with a sample of 20 people with LBP. The psychometric properties of the final version of PSEQ-Am were assessed in a sample of 240 people with LBP recruited from three rehabilitation centers in Ethiopia. Cronbach's alpha and Intra-class correlation coefficient were calculated to describe the reliability and internal consistency of the tool. The SF-36-Am bodily pain subscale was used to assess convergent validity. Confirmatory Factor Analysis (CFA) and Exploratory Factor Analysis (EFA) were performed to determine the dimensionality of the instrument. RESULTS: PSEQ-Am demonstrated excellent test-retest reliability (ICC = 0.93) and internal consistency (Cronbach's alpha = 0.91). As hypothesized, the tool demonstrated a significant moderate correlation with the Bodily Pain subscale of the SF-36-Am (Rho = 0.51, p < 0.01). EFA analysis shows that the Amharic version of PSEQ is a dominant one factor and secondary two factor structure. CONCLUSION: This study shows that PSEQ-Am is a reliable and valid tool that can be used in both clinical practice and research in the Ethiopian low back pain population.

Smooth muscle brain-derived neurotrophic factor contributes to airway hyperreactivity in a mouse model of allergic asthma.

Recent studies have demonstrated an effect of neurotrophins, particularly brain-derived neurotrophic factor (BDNF), on airway contractility [ via increased airway smooth muscle (ASM) intracellular calcium [Ca2+]i] and remodeling (ASM proliferation and extracellular matrix formation) in the context of airway disease. In the present study, we examined the role of BDNF in allergen-induced airway inflammation using 2 transgenic models: 1) tropomyosin-related kinase B (TrkB) conditional knockin (TrkBKI) mice allowing for inducible, reversible disruption of BDNF receptor kinase activity by administration of 1NMPP1, a PP1 derivative, and 2) smooth muscle-specific BDNF knockout (BDNFfl/fl/SMMHC11Cre/0) mice. Adult mice were intranasally challenged with PBS or mixed allergen ( Alternaria alternata, Aspergillus fumigatus, house dust mite, and ovalbumin) for 4 wk. Our data show that administration of 1NMPP1 in TrkBKI mice during the 4-wk allergen challenge blunted airway hyperresponsiveness (AHR) and reduced fibronectin mRNA expression in ASM layers but did not reduce inflammation per se. Smooth muscle-specific deletion of BDNF reduced AHR and blunted airway fibrosis but did not significantly alter airway inflammation. Together, our novel data indicate that TrkB signaling is a key modulator of AHR and that smooth muscle-derived BDNF mediates these effects during allergic airway inflammation.-Britt, R. D., Jr., Thompson, M. A., Wicher, S. A., Manlove, L. J., Roesler, A., Fang, Y.-H., Roos, C., Smith, L., Miller, J. D., Pabelick, C. M., Prakash, Y. S. Smooth muscle brain-derived neurotrophic factor contributes to airway hyperreactivity in a mouse model of allergic asthma.

Promoting Participation in Physical Activity and Exercise Among People Living with Chronic Pain: A Qualitative Study of Strategies Used by People with Pain and Their Recommendations for Health Care Providers.

OBJECTIVE: To explore strategies used by people living with chronic pain when participating in physical activity and exercise and their recommendations for health care providers when promoting participation in physical activity and exercise. DESIGN: Interpretive description qualitative study. SETTING: Participants were recruited from primary care sites and a hospital-based chronic pain clinic in Kingston, Ontario, Canada. SUBJECTS: Adults (>18 years of age) who self-identified as experiencing chronic pain (three months' duration) were interviewed. METHODS: In-depth semistructured interviews were conducted with participants. Interviews were audio-recorded, transcribed verbatim, and reviewed for accuracy by the interviewer. Transcripts were analyzed using thematic analysis. Peer debriefing, reflexivity, and multiple in-person meetings were used to establish trustworthiness. RESULTS: Sixteen adults (five men, 11 women) with a median age of 53 years were interviewed. Strategies used by people living with chronic pain to participate in physical activity and exercise included 1) finding the motivation, 2) setting up for success, 3) leveraging social support, and 4) managing pain and discomfort during activity. Recommendations for health care providers when promoting participation in physical activity and exercise for people living with chronic pain included 1) the importance of listening, 2) providing tailored advice, 3) being supportive, and 4) making physical activity and exercise programming accessible. CONCLUSIONS: People living with chronic pain reported using multiple strategies to participate in physical activity and exercise. Recommendations for health care providers centered on the importance of listening and taking a supportive approach when promoting engagement in physical activity and exercise for this population.

Chronic Pain Self-Management Support With Pain Science Education and Exercise (COMMENCE) for People With Chronic Pain and Multiple Comorbidities: A Randomized Controlled Trial.

OBJECTIVE: To investigate the effectiveness of chronic pain self-management support with pain science education and exercise (COMMENCE) on improving function, pain interference, work status, pain intensity, fatigue, psychological factors associated with pain, health care visits, satisfaction, and perceived change compared with usual care. DESIGN: Parallel group randomized controlled trial with 1- and 12-week follow-ups. SETTING: Community health center. PARTICIPANTS: Adults (N=102) with chronic noncancer pain referred for self-management support. Eighty of 102 participants completed 12-week follow-up assessments. No participants withdrew with adverse events. INTERVENTIONS: Participants were randomized to COMMENCE or usual care. MAIN OUTCOME MEASURES: Primary: Function measured using the Short Musculoskeletal Function Assessment-Dysfunction Index. Secondary: Short Musculoskeletal Function Assessment-Bother Index, Patient Reported Outcomes Measurement Information System pain interference, work status, numeric pain, and fatigue rating scales, Tampa Scale of Kinesiophobia, Pain Catastrophizing Scale, Pain Self-Efficacy Scale, Neurophysiology of Pain Questionnaire, number of health care visits, satisfaction, and global rating of change. RESULTS: COMMENCE resulted in greater improvements in function (mean difference [MD] at 12-wk follow-up=-8.0; 95% CI, -14.7 to -1.3), bother with functional difficulties (MD, -12.0; 95% CI, -20.8 to -3.2), pain intensity (MD, -1.0; 95% CI, -2.1 to -0.1), catastrophizing (MD , -8.2; 95% CI, -14.5 to -2.0), self-efficacy (MD, 7.0; 95% CI, 0.8-13.2), knowledge (MD, 2.8; 95% CI, 1.6-3.9), satisfaction (MD, 1.2; 95% CI, 0.7-1.8), and perceived change (MD, 1.4; 95% CI, 0.8-2.1). There were no significant between-group differences in pain interference, work, fatigue, depressive symptoms, or health care visits. CONCLUSION: COMMENCE is more effective than usual care at improving function, pain, catastrophic thinking, self-efficacy, pain knowledge, satisfaction, and perceived change but not pain interference, work status, fatigue, depressive symptoms, or health care visits.

Influence of Germline Genetics on Tacrolimus Pharmacokinetics and Pharmacodynamics in Allogeneic Hematopoietic Stem Cell Transplant Patients.

Tacrolimus exhibits high inter-patient pharmacokinetics (PK) variability, as well as a narrow therapeutic index, and therefore requires therapeutic drug monitoring. Germline mutations in cytochrome P450 isoforms 4 and 5 genes (CYP3A4/5) and the ATP-binding cassette B1 gene (ABCB1) may contribute to interindividual tacrolimus PK variability, which may impact clinical outcomes among allogeneic hematopoietic stem cell transplantation (HSCT) patients. In this study, 252 adult patients who received tacrolimus for acute graft versus host disease (aGVHD) prophylaxis after allogeneic HSCT were genotyped to evaluate if germline genetic variants associated with tacrolimus PK and pharmacodynamic (PD) variability. Significant associations were detected between germline variants in CYP3A4/5 and ABCB1 and PK endpoints (e.g., median steady-state tacrolimus concentrations and time to goal tacrolimus concentration). However, significant associations were not observed between CYP3A4/5 or ABCB1 germline variants and PD endpoints (e.g., aGVHD and treatment-emergent nephrotoxicity). Decreased age and CYP3A5*1/*1 genotype were independently associated with subtherapeutic tacrolimus trough concentrations while CYP3A5*1*3 or CYP3A5*3/*3 genotypes, myeloablative allogeneic HSCT conditioning regimen (MAC) and increased weight were independently associated with supratherapeutic tacrolimus trough concentrations. Future lines of prospective research inquiry are warranted to use both germline genetic and clinical data to develop precision dosing tools that will optimize both tacrolimus dosing and clinical outcomes among adult HSCT patients.

'If I donate my organs it's a gift, if you take them it's theft': a qualitative study of planned donor decisions under opt-out legislation.

BACKGROUND: There is a worldwide shortage of donor organs for transplantation. To overcome this, several countries have introduced an opt-out donor consent system. This system, soon planned for Scotland and England means individuals are automatically deemed to consent for organ donation unless they register an opt-out decision. This study was designed to explore the reasons underpinning donor choices for people who plan to actively opt-in to the register, take no action and be on the register via deemed consent, opt-out, and those who are unsure of their decision. METHODS: This study reports the analysis of free-text responses obtained from a large survey of intentions towards opt-out legislation in Scotland, England and Northern Ireland (n = 1202). Of the n = 1202 participants who completed the questionnaire, n = 923 provided a free text response explaining their views. Thematic analysis was used to explore the reasons why participants plan to: opt-in (n = 646), follow deemed consent (n = 205), opt-out (n = 32) and those who were not sure (n = 40). RESULTS: A key theme for people planning to opt-in is that it ensures one's donor choice is explicitly clear and unequivocal. Some regarded deemed consent as unclear and open to ambiguity, thus actively opting-in was viewed as a way of protecting against family uncertainty and interference. For the deemed consent group, a key theme is that it represents a simple effortless choice. This is important from both a pragmatic time-saving point of view and because it protects ambivalent participants from making a challenging emotive choice about organ donation. Key themes for those planning to opt-out relate to fears around medical mistrust and bodily integrity. Notably, both participants who plan to opt-out and opt-in perceived presumed consent as "authoritarian" and a method of increasing Government control of organs. In response, registering an active decision protected their freedom of choice. CONCLUSIONS: The findings highlight the importance of registering deliberate active consent for people who choose opt-in, due to concerns over possible family refusal under deemed consent. These findings could inform the development of communication campaigns that encourage family communication before the implementation of opt-out legislation.

Pathophysiology of Aortic Valve Stenosis: Is It Both Fibrocalcific and Sex Specific?

Our understanding of the fundamental biology and identification of efficacious therapeutic targets in aortic valve stenosis has lagged far behind the fields of atherosclerosis and heart failure. In this review, we highlight the most clinically relevant problems facing men and women with fibrocalcific aortic valve stenosis, discuss the fundamental biology underlying valve calcification and fibrosis, and identify key molecular points of intersection with sex hormone signaling.