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.

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.

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.