Experimental TET2 Clonal Hematopoiesis Predisposes to Renal Hypertension Through an Inflammasome-Mediated Mechanism.

BACKGROUND: Hypertension incidence increases with age and represents one of the most prevalent risk factors for cardiovascular disease. Clonal events in the hematopoietic system resulting from somatic mutations in driver genes are prevalent in elderly individuals who lack overt hematologic disorders. This condition is referred to as age-related clonal hematopoiesis (CH), and it is a newly recognized risk factor for cardiovascular disease. It is not known whether CH and hypertension in the elderly are causally related and, if so, what are the mechanistic features. METHODS AND RESULTS: A murine model of adoptive bone marrow transplantation was employed to examine the interplay between Tet2 (ten-eleven translocation methylcytosine dioxygenase 2) CH and hypertension. In this model, a subpressor dose of Ang II (angiotensin II) resulted in elevated systolic and diastolic blood pressure as early as 1 day after the challenge. These conditions led to the expansion of Tet2-deficient proinflammatory monocytes and bone marrow progenitor populations. Tet2-deficiency promoted renal CCL5 chemokine expression and macrophage infiltration into the kidney. Consistent with macrophage involvement, Tet2-deficiency in myeloid cells promoted hypertension when mice were treated with a subpressor dose of Ang II. The hematopoietic Tet2-/- condition led to sodium retention, renal inflammasome activation, and elevated levels of IL (interleukin)-1ß and IL-18. Analysis of the sodium transporters indicated NCC (Na+-Cl- cotransporter) and NKCC2 activation at residues Thr53 and Ser105, respectively. Administration of the NLRP3 inflammasome inhibitor MCC950 reversed the hypertensive state, sodium retention, and renal transporter activation. CONCLUSIONS: Tet2-mediated CH sensitizes mice to a hypertensive stimulus. Mechanistically, the expansion of hematopoietic Tet2-deficient cells promotes hypertension due to elevated renal immune cell infiltration and activation of the NLRP3 inflammasome, with consequences on sodium retention. These data indicate that carriers of TET2 CH could be at elevated risk for the development of hypertension and that immune modulators could be useful in treating hypertension in this patient population.

Regulators of clonal hematopoiesis and physiological consequences of this condition.

Clonal hematopoiesis (CH) is a prevalent condition that results from somatic mutations in hematopoietic stem cells. When these mutations occur in "driver" genes, they can potentially confer fitness advantages to the affected cells, leading to a clonal expansion. While most clonal expansions of mutant cells are generally considered to be asymptomatic since they do not impact overall blood cell numbers, CH carriers face long-term risks of all-cause mortality and age-associated diseases, including cardiovascular disease and hematological malignancies. While considerable research has focused on understanding the association between CH and these diseases, less attention has been given to exploring the regulatory factors that contribute to the expansion of the driver gene clone. This review focuses on the association between environmental stressors and inherited genetic risk factors in the context of CH development. A better understanding of how these stressors impact CH development will facilitate mechanistic studies and potentially lead to new therapeutic avenues to treat individuals with this condition.

Disruption of the Uty epigenetic regulator locus in hematopoietic cells phenocopies the profibrotic attributes of Y chromosome loss in heart failure.

Heart failure affects millions of people worldwide, with men exhibiting a higher incidence than women. Our previous work has shown that mosaic loss of the Y chromosome (LOY) in leukocytes is causally associated with an increased risk for heart failure. Here, we show that LOY macrophages from the failing hearts of humans with dilated cardiomyopathy exhibit widespread changes in gene expression that correlate with cardiac fibroblast activation. Moreover, we identify the ubiquitously transcribed t et ratricopeptide Y-linked (Uty) gene in leukocytes as a causal locus for an accelerated progression of heart failure in male mice with LOY. We demonstrate that Uty disruption leads to epigenetic alterations in both monocytes and macrophages, increasing the propensity of differentiation into profibrotic macrophages. Treatment with a transforming growth factor-ß-neutralizing antibody prevented the cardiac pathology associated with Uty deficiency in leukocytes. These findings shed light on the mechanisms that contribute to the higher incidence of heart failure in men.

Novel Mouse Model of Myocardial Infarction, Plaque Rupture, and Stroke Shows Improved Survival With Myeloperoxidase Inhibition.

BACKGROUND: Thromboembolic events, including myocardial infarction (MI) or stroke, caused by the rupture or erosion of unstable atherosclerotic plaques are the leading cause of death worldwide. Although most mouse models of atherosclerosis develop lesions in the aorta and carotid arteries, they do not develop advanced coronary artery lesions. Moreover, they do not undergo spontaneous plaque rupture with MI and stroke or do so at such a low frequency that they are not viable experimental models to study late-stage thrombotic events or to identify novel therapeutic approaches for treating atherosclerotic disease. This has stymied the development of more effective therapeutic approaches for reducing these events beyond what has been achieved with aggressive lipid lowering. Here, we describe a diet-inducible mouse model that develops widespread advanced atherosclerosis in coronary, brachiocephalic, and carotid arteries with plaque rupture, MI, and stroke. METHODS: We characterized a novel mouse model with a C-terminal mutation in the scavenger receptor class B, type 1 (SR-BI), combined with Ldlr knockout (designated SR-BI∆CT/∆CT/Ldlr-/-). Mice were fed Western diet (WD) for 26 weeks and analyzed for MI and stroke. Coronary, brachiocephalic, and carotid arteries were analyzed for atherosclerotic lesions and indices of plaque stability. To validate the utility of this model, SR-BI∆CT/∆CT/Ldlr-/- mice were treated with the drug candidate AZM198, which inhibits myeloperoxidase, an enzyme produced by activated neutrophils that predicts rupture of human atherosclerotic lesions. RESULTS: SR-BI∆CT/∆CT/Ldlr-/- mice show high (>80%) mortality rates after 26 weeks of WD feeding because of major adverse cardiovascular events, including spontaneous plaque rupture with MI and stroke. Moreover, WD-fed SR-BI∆CT/∆CT/Ldlr-/- mice displayed elevated circulating high-sensitivity cardiac troponin I and increased neutrophil extracellular trap formation within lesions compared with control mice. Treatment of WD-fed SR-BI∆CT/∆CT/Ldlr-/- mice with AZM198 showed remarkable benefits, including >90% improvement in survival and >60% decrease in the incidence of plaque rupture, MI, and stroke, in conjunction with decreased circulating high-sensitivity cardiac troponin I and reduced neutrophil extracellular trap formation within lesions. CONCLUSIONS: WD-fed SR-BI∆CT/∆CT/Ldlr-/- mice more closely replicate late-stage clinical events of advanced human atherosclerotic disease than previous models and can be used to identify and test potential new therapeutic agents to prevent major adverse cardiac events.

Diverse elements comprising studies of peer support complicate evidence synthesis.

BACKGROUND: Innovative approaches to care, such as peer support, are needed to address the substantial and frequently unmet needs of people with serious mental illnesses such as schizophrenia. Although peer support services continue to expand in mental healthcare, findings of effectiveness from systematic reviews are mixed. However, the studies evaluated in these reviews consisted of diverse elements which the review methods neglected to consider. AIMS: This review aims to demonstrate the substantial diversity in intervention components and measured outcomes among studies of peer support and lay the groundwork for more focused reviews of individual intervention components. METHODS: As part of a realist review of the literature, here we synthesize evidence in a way that examines the substantial diversity in intervention components and measured outcomes comprising studies of peer support. RESULTS: Seven categories of outcomes were represented, including recovery, symptoms and functioning, and care utilization. Importantly, seven distinct intervention components were represented in 26 studies: "being there," assistance in self-management, linkage to clinical care and community resources, social and emotional support, ongoing support, explicit utilization of shared lived experience or peer support values, and systems advocacy. Reflecting diversity in approaches, no study reported all intervention components, and no component was found among all studies. IMPLICATIONS: Peer support services constitute a category of intervention approaches far too varied to evaluate as a single entity. Results suggest intervention components deserving more focused research, including assistance in self-management, "being there," and explicit utilization of shared lived experience or peer support values. PRISMA/PROSPERO: As this article reports results from a realist review of the literature, we did not follow the PRISMA guidance which is suitable for systematic reviews. We did follow the Realist and Meta-narrative Evidence Syntheses: Evolving Standards (RAMESES) guidelines.This review was not registered on PROSPERO as it is not a systematic review.

From an election to an insurrection: Investigating differential engagement and sentiment in the #defundthepolice and #defendthepolice network on Twitter.

Social movements and their respective countermovements have evolved to use online social media platforms to recruit followers, share pertinent information, discuss relevant issues, and draw the attention of political figures. Movements' strategic use of Twitter has increasingly been studied, though there are relatively few studies that compare social movements and their corresponding countermovements simultaneously. We examine engagement in the #DefundthePolice social movement and #DefendthePolice countermovement in a Twitter network comprised of retweets using both hashtags from August 2020 to January 2021. Text and sentiment analysis as well as a content analysis of a random sample of retweets in the network's 20 largest subgroups reveal four key patterns. First, information commonly communicated in historical social movements is communicated in the online, Twitter network. Second, the use of movement and countermovement hashtags to criticize is common, suggesting Twitter engagement with the movement/countermovement is not a sufficient indicator of support for the movement. Third, social movements are inextricably embedded in politics, with political discourse present in all the 20 largest subgroups. Finally, though we do not include geo-tagged tweets in the analysis, physical geography is key theme in multiple subgroups. Broadly, our findings demonstrate the breadth of topics communicated within movement networks and highlight the importance of qualitatively examining Twitter data in the study of social movements.

Listening to the Voices of Health Care Workers During the COVID-19 Pandemic: A Qualitative Study Providing In-Depth Insights Into Ethical and Individual Challenges.

In their daily practice, health care workers (HCWs) experience the effects of tensions between professional ethos and work realities, which can lead to ethical dilemmas. We aim to explore the ethical dilemmas that affected HCWs in Germany during the COVID-19 pandemic and to understand these in the context of the German health system. Between April and December 2022, we interviewed HCWs from various levels of care and key informants responsible for decisions related to HCWs in Germany. Three themes were identified in the data analyzed from 78 participants. The first highlighted the potency of pre-existing health system problems during the COVID-19 pandemic. The second captured the ethical dilemmas that were described as having arisen due to the tension between professional ethos and structural constraints. The third included factors related to increasing or diminishing the implications of ethical dilemmas. A lack of opportunities for HCWs to participate in political and managerial decisions was suggested to result in policies that do not meet the needs of HCWs and patients. Positive interpersonal interactions were described as helpful when coping with dilemmatic decision-making situations. In order to avoid negative consequences caused by unresolved ethical dilemmas, including moral distress, among HCWs, staff shortages and decision-making in the German health system urgently need to be addressed. HCWs' working conditions regularly evoke ethical dilemmas, particularly during public health emergencies. Together with HCWs, decision-makers must develop new models for working in health care settings that are in line with HCWs' professional ethos.

Corymbiform cutaneous disorders in pediatric dermatology: Exploring this pattern of presentation beyond secondary syphilis.

"Corymbiform" is a term found in medical literature as early as 1876 to describe a central larger lesion with smaller surrounding lesions, leading to the appearance of an irregular border. While the term in current medical literature most often describes a possible morphology of secondary syphilis, the authors have noted this pattern presenting in other cutaneous conditions. We present a commentary on the corymbiform pattern in dermatology including a series of photographs of cutaneous disorders presenting in a corymbiform morphology in pediatric patients. While the term corymbiform is not commonly used in the present-day dermatologic literature, increased recognition and use of this term may aid in the recognition of various dermatologic diagnoses presenting in a less common morphology and may also lend to increased fluidity of dermatologic descriptions in the literature.

Clonal Hematopoiesis in Clinical and Experimental Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Clonal hematopoiesis (CH), which results from an array of nonmalignant driver gene mutations, can lead to altered immune cell function and chronic disease, and has been associated with worse outcomes in patients with heart failure (HF) with reduced ejection fraction. However, the role of CH in the prognosis of HF with preserved ejection fraction (HFpEF) has been understudied. This study aimed to characterize CH in patients with HFpEF and elucidate its causal role in a murine model. METHODS: Using a panel of 20 candidate CH driver genes and a variant allele fraction cutoff of 0.5%, ultradeep error-corrected sequencing identified CH in a cohort of 81 patients with HFpEF (mean age, 71±6 years; ejection fraction, 63±5%) and 36 controls without a diagnosis of HFpEF (mean age, 74±7 years; ejection fraction, 61.5±8%). CH was also evaluated in a replication cohort of 59 individuals with HFpEF. RESULTS: Compared with controls, there was an enrichment of TET2-mediated CH in the HFpEF patient cohort (12% versus 0%, respectively; P=0.02). In the HFpEF cohort, patients with CH exhibited exacerbated diastolic dysfunction in terms of E/e' (14.9 versus 11.7, respectively; P=0.0096) and E/A (1.69 versus 0.89, respectively; P=0.0206) compared with those without CH. The association of CH with exacerbated diastolic dysfunction was corroborated in a validation cohort of individuals with HFpEF. In accordance, patients with HFpEF, an age ≥70 years, and CH exhibited worse prognosis in terms of 5-year cardiovascular-related hospitalization rate (hazard ratio, 5.06; P=0.042) compared with patients with HFpEF and an age ≥70 years without CH. To investigate the causal role of CH in HFpEF, nonconditioned mice underwent adoptive transfer with Tet2-wild-type or Tet2-deficient bone marrow and were subsequently subjected to a high-fat diet/L-NAME (Nω-nitro-l-arginine methyl ester) combination treatment to induce features of HFpEF. This model of Tet2-CH exacerbated cardiac hypertrophy by heart weight/tibia length and cardiomyocyte size, diastolic dysfunction by E/e' and left ventricular end-diastolic pressure, and cardiac fibrosis compared with the Tet2-wild-type condition. CONCLUSIONS: CH is associated with worse heart function and prognosis in patients with HFpEF, and a murine experimental model of Tet2-mediated CH displays greater features of HFpEF.

Community organization guides standardization, adaptability, and innovation: lessons from peer support in the Shanghai Integration Model.

Although there is broad evidence for the value of peer support (PS) in preventing and managing diabetes and other chronic diseases, identifying approaches to stage, scale, and adapt PS interventions is a challenge. Community organization may provide a process for such adaptation of standardized PS and diabetes management to individual communities. This community organization approach was used to develop PS in 12 communities in Shanghai, China. Through a convergent mixed methods design, project records, semi-structured interviews, and an implementation assessment characterized processes of adaptation of standardized materials, examined the extent to which the program was implemented, and identified key success factors and challenges. Findings from both interviews and the implementation assessment indicated that communities adapted standardized intervention components to meet the needs of their communities and assumed responsibility for implementation of different components of the program based on their community's available capacity. Additionally, community innovations occurring as part of the project were reported and standardized for dissemination in future iterations of the program. Key success factors identified included cooperation and collaboration among varied partners within and across communities. Two challenges illustrate the resilience of the community organization model in response to COVID-19 and the need for further adaptation in rural communities. Community organization provided a useful approach to standardization, adaptation, innovation, and reporting of PS interventions for diabetes management.

Spatial assessment of the attributable burden of disease due to transportation noise in England.

BACKGROUND: Noise pollution from transportation is one of the leading contributors to the environmental disease burden in Europe. We provide a novel assessment of spatial variations of these health impacts within a country, using England as an example. METHODS: We estimated the burden of annoyance (highly annoyed), sleep disturbance (highly sleep disturbed), ischemic heart disease (IHD), stroke, and diabetes attributable to long-term transportation noise exposures in England for the adult population in 2018 down to local authority level (average adult population: 136,000). To derive estimates, we combined literature-informed exposure-response relationships, with population data on noise exposures, disease, and mortalities. Long-term average noise exposures from road, rail and aircraft were sourced from strategic noise mapping, with a lower exposure threshold of 50 dB (decibels) Lden and Lnight. RESULTS: 40 %, 4.5 % and 4.8 % of adults in England were exposed to road, rail, and aircraft noise exceeding 50 dB Lden. We estimated close to a hundred thousand (∼97,000) disability adjusted life years (DALY) lost due to road-traffic, ∼13,000 from railway, and âˆ¼ 17,000 from aircraft noise. This excludes some noise-outcome pairs as there were too few studies available to provide robust exposure-response estimates. Annoyance and sleep disturbance accounted for the majority of the DALYs, followed by strokes, IHD, and diabetes. London, the South East, and North West regions had the greatest number of road-traffic DALYs lost, while 63 % of all aircraft noise DALYs were found in London. The strategic noise mapping did not include all roads, which may still have significant traffic flows. In sensitivity analyses using modelled noise from all roads in London, the DALYs were 1.1x to 2.2x higher. CONCLUSION: Transportation noise exposures contribute to a significant and unequal environmental disease burden in England. Omitting minor roads from the noise exposure modelling leads to underestimation of the disease burden.

Children's visual acuity tests without professional supervision: a prospective repeated measures study.

BACKGROUND: Home visual acuity tests could ease pressure on ophthalmic services by facilitating remote review of patients. Home tests may have further utility in giving service users frequent updates of vision outcomes during therapy, identifying vision problems in an asymptomatic population, and engaging stakeholders in therapy. METHODS: Children attending outpatient clinics had visual acuity measured 3 times at the same appointment: Once by a registered orthoptist per clinical protocols, once by an orthoptist using a tablet-based visual acuity test (iSight Test Pro, Kay Pictures), and once by an unsupervised parent/carer using the tablet-based test. RESULTS: In total, 42 children were recruited to the study. The mean age was 5.6 years (range 3.3 to 9.3 years). Median and interquartile ranges (IQR) for clinical standard, orthoptic-led and parent/carer-led iSight Test Pro visual acuity measurements were 0.155 (0.18 IQR), 0.180 (0.26 IQR), and 0.300 (0.33 IQR) logMAR respectively. The iSight Test Pro in the hands of parents/carers was significantly different from the standard of care measurements (P = 0.008). In the hands of orthoptists. There was no significant difference between orthoptists using the iSight Test Pro and standard of care (P = 0.289), nor between orthoptist iSight Test Pro and parents/carer iSight Test Pro measurements (P = 0.108). CONCLUSION: This technique of unsupervised visual acuity measures for children is not comparable to clinical measures and is unlikely to be valuable to clinical decision making. Future work should focus on improving the accuracy of the test through better training, equipment/software or supervision/support.