Prognostic implications of pre-existing medical comorbidity in Takotsubo cardiomyopathy.

Takotsubo cardiomyopathy (TC) is associated with significant short-term morbidity and mortality. Several risk factors for poor outcomes have been identified; however, the prognostic implications of pre-existing comorbidity in TC are poorly delineated. We sought to assess the association of aggregate pre-existing comorbidity with short-term outcomes in TC. We performed a retrospective observational study of adult subjects diagnosed with TC at two academic tertiary care hospitals between 2005 and 2018. Overall burden of medical comorbidity was estimated using the Charlson comorbidity index (CCI). Multivariable logistic regression was used to test for independent association of CCI with 30-day mortality and severe shock at index presentation. Multivariable poisson regression was performed to assess the association of CCI with duration of hospitalization. Five-hundred and thirty-eight subjects were diagnosed with TC during the study period. The median CCI score of all subjects was 2 (IQR 1-4). Among subjects with physical triggers of TC, the median CCI score was 2 (IQR 1-4) compared to a median CCI score of 1 (IQR 0-1) in subjects with non-physical triggers of TC (P < 0.001). Seventy-six (14%) subjects died within 30 days of index diagnosis and 185 (34%) subjects experienced severe shock. The median duration of hospitalization was 7 days (IQR 3-14 days). In multivariable logistic regression, CCI was not associated with 30-day mortality or severe shock. In multivariable Poisson regression, CCI (IRR 1.17, 95% CI 1.16-1.18, P < 0.001) was associated with duration of hospitalization. Increased burden of pre-existing medical comorbidity was not independently associated with 30-day mortality or severe shock at index presentation, but was associated with increased duration of hospitalization after diagnosis of TC.

A respiratory chain controlled signal transduction cascade in the mitochondrial intermembrane space mediates hydrogen peroxide signaling.

Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) govern cellular homeostasis by inducing signaling. H2O2 modulates the activity of phosphatases and many other signaling molecules through oxidation of critical cysteine residues, which led to the notion that initiation of ROS signaling is broad and nonspecific, and thus fundamentally distinct from other signaling pathways. Here, we report that H2O2 signaling bears hallmarks of a regular signal transduction cascade. It is controlled by hierarchical signaling events resulting in a focused response as the results place the mitochondrial respiratory chain upstream of tyrosine-protein kinase Lyn, Lyn upstream of tyrosine-protein kinase SYK (Syk), and Syk upstream of numerous targets involved in signaling, transcription, translation, metabolism, and cell cycle regulation. The active mediators of H2O2 signaling colocalize as H2O2 induces mitochondria-associated Lyn and Syk phosphorylation, and a pool of Lyn and Syk reside in the mitochondrial intermembrane space. Finally, the same intermediaries control the signaling response in tissues and species responsive to H2O2 as the respiratory chain, Lyn, and Syk were similarly required for H2O2 signaling in mouse B cells, fibroblasts, and chicken DT40 B cells. Consistent with a broad role, the Syk pathway is coexpressed across tissues, is of early metazoan origin, and displays evidence of evolutionary constraint in the human. These results suggest that H2O2 signaling is under control of a signal transduction pathway that links the respiratory chain to the mitochondrial intermembrane space-localized, ubiquitous, and ancient Syk pathway in hematopoietic and nonhematopoietic cells.

Positive Childhood Experiences and Adult Health Outcomes.

OBJECTIVES: Adverse childhood experiences (ACEs) can drive poor adult mental and physical health, but the impact of early life protective factors should not be overlooked. Positive childhood experiences (PCEs) measures quantify protective factors, but evidence is lacking on their link to health conditions independent of ACEs in nationally representative studies. This study examines associations between composite PCE score and adult health, adjusting for ACEs. METHODS: The most recent 2017 wave of the Panel Study of Income Dynamics, a nationally representative study and its 2014 Childhood Retrospective Circumstances supplement (n = 7496) collected adult health outcomes, PCEs, and ACEs. Multivariable logistic regression assessed associations between PCE score and adult self-rated health or condition diagnosis, with and without ACEs adjustment. Cox proportional hazards models examined relationships between PCEs, ACEs, and annual risk of diagnosis. RESULTS: Adults with 5 to 6 PCEs had 75% (95% confidence interval [CI], 0.58-0.93) of the risk of fair/poor overall health and 74% of the risk of any psychiatric diagnosis (CI, 0.59-0.89) compared with those with 0 to 2 PCEs, independent of ACEs. In survival analysis models accounting for PCEs and ACEs, reporting 5 to 6 PCEs was associated with a 16% lower annual hazard of developing any adult psychiatric or physical condition (hazard ratio, 0.84; CI, 0.75-0.94); reporting 3+ ACEs was associated with a 42% higher annual hazard (CI, 1.27-1.59). CONCLUSIONS: PCEs were independently associated with lower risks of fair or poor adult health, adult mental health problems, and developing any physical or mental health condition at any given age after adjusting for ACEs.

Do hospitals that participate in COVID-19 research differ from non-trial hospitals? A cross-sectional study of US hospitals.

OBJECTIVES: To compare hospitals that did and did not participate in clinical trials evaluating potential inpatient COVID-19 therapeutics. METHODS: We conducted a cross-sectional study of hospitals participating in trials that were registered on clinicaltrials.gov between April and August 2020. Using the 2019 RAND Hospital Dataset and 2019 American Community Survey, we used logistic regression modeling to compare hospital-level traits including demographic features between trial and non-trial hospitals. RESULTS: We included 488 hospitals that were participating in 298 interventional trials and 4232 non-participating hospitals. After controlling for demographic and other hospital traits, we found that teaching status (OR 2.11, 95% CI 1.52-2.95), higher patient acuity (OR 7.48, 4.39, 13.1), and location in the Northeast (OR 1.83, 95% CI 1.18, 2.85) and in wealthier counties (OR: 1.32, 95% CI 1.16-1.51) were associated with increased odds of trial participation, while being in counties with more White residents was associated with reduced odds (OR 0.98, 95% CI 0.98-0.99). CONCLUSIONS: Hospitals participating and not participating in COVID-19 inpatient treatment clinical trials differed in many ways, resulting in important implications for the generalizability of trial data.

Specific domains of positive childhood experiences (PCEs) associated with improved adult health: A nationally representative study.

Background: Positive childhood experiences (PCEs) are supportive relationships and environments associated with improved health when aggregated into composite scores. Adverse childhood experiences (ACEs), a reciprocal measure to PCEs, are associated with worse health in aggregate scores and when disaggregated into measures of specific ACE types (hereafter domains). Understanding the associations between specific PCE domains and health, while accounting for ACEs, may direct investigations and intervention planning to foster PCE exposure. Methods: We analyzed data from the nationally representative United States longitudinal Panel Study of Income Dynamics. Five PCE domains were examined: (i) peer support and healthy school climate, (ii) neighborhood safety, (iii) neighborhood support, and nurturing relationships with (iv) maternal and (v) paternal figures. Survey weighted logistic regression models tested associations between each PCE domain measure and adult general health rating, controlling for demographic covariates and nine ACE exposures: physical, emotional, or sexual abuse/assault; emotional neglect; witnessing intimate partner violence or household substance use; having a parent with mental illness; any parental separation or divorce; and/or having a deceased or estranged parent. Secondary outcomes included adult functional status and mental and physical health diagnoses. We also tested for statistical interactions between PCE domain and ACE score measures. Results: The sample included 7105 adults. Higher scores for the "peer support and healthy school climate" and "neighborhood safety" domain measures showed the most protective relationships with the adverse health conditions tested, most notably for mental illness. The relationship between PCE domain measures and health outcomes was attenuated, but not statistically moderated by ACE exposure. Conclusion: Experiencing childhood peer support, a healthy school climate, and neighborhood safety were especially protective against multiple adult health conditions, including for ACE exposed individuals. Interventions that promote PCEs may yield population health gains.

Efficacy of synthetic peptides RP-1 and AA-RP-1 against Leishmania species in vitro and in vivo.

Host defense peptides are naturally occurring molecules that play essential roles in innate immunity to infection. Based on prior structure-function knowledge, we tested two synthetic peptides (RP-1 and AA-RP-1) modeled on the conserved, microbicidal α-helical domain of mammalian CXCL4 platelet kinocidins. These peptides were evaluated for efficacy against Leishmania species, the causative agents of the group of diseases known as leishmaniasis. In vitro antileishmanial activity was assessed against three distinct Leishmania strains by measuring proliferation, metabolic activity and parasite viability after exposure to various concentrations of peptides. We demonstrate that micromolar concentrations of RP-1 and AA-RP-1 caused dose-dependent growth inhibition of Leishmania promastigotes. This antileishmanial activity correlated with rapid membrane disruption, as well as with a loss of mitochondrial transmembrane potential. In addition, RP-1 and AA-RP-1 demonstrated distinct and significant in vivo antileishmanial activities in a mouse model of experimental visceral leishmaniasis after intravenous administration. These results establish efficacy of RP-1 lineage synthetic peptides against Leishmania species in vitro and after intravenous administration in vivo and provide further validation of proof of concept for the development of these and related systemic anti-infective peptides targeting pathogens that are resistant to conventional antibiotics.

Effectiveness of contact tracing in the control of infectious diseases: a systematic review.

BACKGROUND: Contact tracing is used for multiple infectious diseases, most recently for COVID-19, but data regarding its effectiveness in disease control are scarce. To address this knowledge gap and inform public health decision making for COVID-19, we systematically reviewed the existing literature to determine the effectiveness of contact tracing in the control of communicable illness. METHODS: We searched PubMed, Embase, and the Cochrane Library from database inception up to Nov 22, 2021, for published studies evaluating associations between provider-initiated contact tracing for transmissible infectious diseases and one of three outcomes of interest: case detection rates among contacts or at the community level, overall forward transmission, or overall disease incidence. Clinical trials and observational studies were eligible, with no language or date restrictions. Reference lists of reviews were searched for additional studies. We excluded studies without a control group, using only mathematical modelling, not reporting a primary outcome of interest, or solely examining patient-initiated contact tracing. One reviewer applied eligibility criteria to each screened abstract and full-text article, and two reviewers independently extracted summary effect estimates and additional data from eligible studies. Only data reported in published manuscripts or supplemental material was extracted. Risk of bias for each included study was assessed with the Cochrane Risk of Bias 2 tool (randomised studies) or the Newcastle-Ottawa Scale (non-randomised studies). FINDINGS: We identified 9050 unique citations, of which 47 studies met the inclusion criteria: six were focused on COVID-19, 20 on tuberculosis, eight on HIV, 12 on curable sexually transmitted infections (STIs), and one on measles. More than 2 million index patients were included across a variety of settings (both urban and rural areas and low-resource and high-resource settings). Of the 47 studies, 29 (61·7%) used observational designs, including all studies on COVID-19, and 18 (38·3%) were randomised controlled trials. 40 studies compared provider-initiated contact tracing with other interventions or evaluated expansions of provider-initiated contact tracing, and seven compared programmatic adaptations within provider-initiated contact tracing. 29 (72·5%) of the 40 studies evaluating the effect of provider-initiated contact tracing, including four (66·7%) of six COVID-19 studies, found contact tracing interventions were associated with improvements in at least one outcome of interest. 23 (48·9%) studies had low risk of bias, 22 (46·8%) studies had some risk of bias, and two (4·3%) studies (both randomised controlled trials on curable STIs) had high risk of bias. INTERPRETATION: Provider-initiated contact tracing can be an effective public health tool. However, the ability of authorities to make informed choices about its deployment might be limited by heterogenous approaches to contact tracing in studies, a scarcity of quantitative evidence on its effectiveness, and absence of specificity of tracing parameters most important for disease control. FUNDING: The Sullivan Family Foundation, Massachusetts General Hospital Executive Committee on Research, and US National Institutes of Health.

Does the diabetes health plan have a differential impact on medication adherence among beneficiaries with fewer financial resources?

BACKGROUND: The Diabetes Health Plan (DHP), a value-based insurance plan that reduces cost sharing, was previously shown to modestly increase employer-level medication adherence. It is unclear how the DHP might impact individuals with different incomes. OBJECTIVE: To examine the impact of the DHP on individual-level medication adherence, by income level. METHODS: This is a retrospective, quasiexperimental study. An employer-level propensity score match was done to identify suitable control employers, followed by individual-level propensity score weighing. These weights were applied to difference-in-difference models examining the effect of the DHP and the effect of income on changes in adherence to metformin, statins, and angiotensin-converting enzymes/angiotensin receptor blockers. The weights were then applied to a differences-in-differences-in-differences model to estimate the differential impact of DHP status on changes in adherence by income group. RESULTS: The study population included 2,065 beneficiaries with DHP and 17,704 matched controls. There were no significant differences in changes to adherence for any medications between beneficiaries enrolled in the DHP vs standard plans. However, adherence to all medications was higher among those with incomes greater than $75,000 (year 1: metformin: +7.3 percentage points; statin +4.3 percentage points; angiotensin-converting enzymes/angiotensin receptor blockers: +6.2 percentage points; P < 0.01) compared with those with incomes less than $50,000. The differences-in-differences-in-differences term examining the impact of income on the DHP effect was not significant for any comparisons. CONCLUSIONS: We did not find significant associations between the DHP and changes in individual-level medication adherence, even for low-income beneficiaries. New strategies to improve consumer engagement may be needed to translate value-based insurance designs into changes in patient behavior. DISCLOSURES: Drs Ettner and Moin received grants from the Centers for Disease Control and Prevention and National Institute of Diabetes and Digestive and Kidney Diseases (Principal Investigator: Carol Mangione). Mr Luchs received support for attending meetings and/or travel (minimal-mileage and hotel on 2 occasions). Mr Chan has an employee benefit to purchase stock for UnitedHealth Group.

Financial toxicity in cancer care: origins, impact, and solutions.

Financial toxicity describes the financial burden and distress that can arise for patients, and their family members, as a result of cancer treatment. It includes direct out-of-pocket costs for treatment and indirect costs such as travel, time, and changes to employment that can increase the burden of cancer. While high costs of cancer care have threatened the sustainability of access to care for decades, it is only in the past 10 years that the term "financial toxicity" has been popularized to recognize that the financial burdens of care can be just as important as the physical toxicities traditionally associated with cancer therapy. The past decade has seen a rapid growth in research identifying the prevalence and impact of financial toxicity. Research is now beginning to focus on innovations in screening and care delivery that can mitigate this risk. There is a need to determine the optimal strategy for clinicians and cancer centers to address costs of care in order to minimize financial toxicity, promote access to high value care, and reduce health disparities. We review the evolution of concerns over costs of cancer care, the impact of financial burdens on patients, methods to screen for financial toxicity, proposed solutions, and priorities for future research to identify and address costs that threaten the health and quality of life for many patients with cancer.

Outcomes of an Integrated Urology-Palliative Care Clinic for Patients With Advanced Urological Cancers: Maintenance of Quality of Life and Satisfaction and High Rate of Hospice Utilization Through End of Life.

INTRODUCTION: Systematic integration of palliative care in a surgical setting is important, but has yet to be achieved. Despite evidence of early palliative care improving patients' quality of life, hospice utilization remains low. Through an integrated palliative care-urology clinic, we aim to assess the effect of early outpatient palliative care on hospice utilization, health-related quality of life (HRQOL) and satisfaction in patients with advanced urological cancers. METHODS: Participants were recruited from 2012 through 2016 in the Greater Los Angeles Veterans Affairs Hospital. We partnered with palliative care clinicians to develop an integrated urology-palliative care clinic, where participants were seen by the palliative care team on the same day as their urological visit. The 12-item Short-Form Survey, Patient Satisfaction Questionnaire Short-Form, Patient Health Questionnaire, and Brief Pain Inventory were administered at initial and subsequent visits. Follow-up questionnaire results were compared between baseline and the 2 follow-up visits, and hospice utilization rates were assessed. RESULTS: Fifty-three participants completed baseline questionnaires. Of those 22 (42%) patients completed at least one follow-up assessment. The median time for the first and second follow-up visits was 2.9 and 7.8 months, respectively. There were no significant differences in HRQOL and satisfaction between baseline and subsequent follow-up visits. A total of 36 (68%) of 53 participants who were enrolled at the start of the study were deceased. Of those, 29 (81%) expired within a home or inpatient hospice. CONCLUSIONS: Rates of hospice use were high in an integrated palliative care-urology model. Health-related quality of life and satisfaction did not worsen over time.

MicroRNAs are required for the feature maintenance and differentiation of brown adipocytes.

Brown adipose tissue (BAT) is specialized to burn lipids for heat generation as a natural defense against cold and obesity. Previous studies established microRNAs (miRNAs) as essential regulators of brown adipocyte differentiation, but whether miRNAs are required for the feature maintenance of mature brown adipocytes remains unknown. To address this question, we ablated Dgcr8, a key regulator of the miRNA biogenesis pathway, in mature brown as well as in white adipocytes. Adipose tissue-specific Dgcr8 knockout mice displayed enlarged but pale interscapular brown fat with decreased expression of genes characteristic of brown fat and were intolerant to cold exposure. Primary brown adipocyte cultures in vitro confirmed that miRNAs are required for marker gene expression in mature brown adipocytes. We also demonstrated that miRNAs are essential for the browning of subcutaneous white adipocytes in vitro and in vivo. Using this animal model, we performed miRNA expression profiling analysis and identified a set of BAT-specific miRNAs that are upregulated during brown adipocyte differentiation and enriched in brown fat compared with other organs. We identified miR-182 and miR-203 as new regulators of brown adipocyte development. Taken together, our study demonstrates an essential role of miRNAs in the maintenance as well as in the differentiation of brown adipocytes.