Geospatial assessment of the convergence of communicable and non-communicable diseases in South Africa.

Introduction: Several low-and middle-income countries are undergoing rapid epidemiological transition with a rising burden of non-communicable diseases (NCDs). South Africa (SA) is a country with one of the largest HIV epidemics worldwide and a growing burden of NCDs where the collision of these epidemics poses a major public health challenge. Methods: Using data from a large nationally representative survey, the South Africa Demographic and Health Survey (SADHS 2016), we conducted a geospatial analysis of several diseases including HIV, tuberculosis (TB), cardiovascular, respiratory, and metabolic diseases to identify areas with a high burden of co-morbidity within the country. We explored the spatial structure of each disease and associations between diseases using different spatial and visual data methodologies. We also assessed the individual level co-occurrence of HIV and the other diseases included in the analysis. Results: The spatial distribution for HIV prevalence showed that this epidemic is most intense in the eastern region of the country, mostly within the Gauteng, Mpumalanga, and Kwazulu-Natal provinces. In contrast, chronic diseases had their highest prevalence rates the southern region of the country, particularly in the Eastern and Western Cape provinces. Individual-level analyses were consistent with the spatial correlations and found no statistically significant associations between HIV infection and the presence of any NCDs. Conclusions: We found no evidence of geospatial overlap between the HIV epidemic and NCDs in SA. These results evidence the complex epidemiological landscape of the country, characterized by geographically distinct areas exhibiting different health burdens. The detailed description of the heterogenous prevalence of HIV and NCDs in SA reported in this study could be a useful tool to inform and direct policies to enhance targeted health service delivery according to the local health needs of each community.

Sympathetic Motor Neuron Dysfunction is a Missing Link in Age-Associated Sympathetic Overactivity.

Overactivity of the sympathetic nervous system is a hallmark of aging. The cellular mechanisms behind this overactivity remain poorly understood, with most attention paid to likely central nervous system components. In this work, we hypothesized that aging also affects the function of motor neurons in the peripheral sympathetic ganglia. To test this hypothesis, we compared the electrophysiological responses and ion-channel activity of neurons isolated from the superior cervical ganglia of young (12 weeks), middle-aged (64 weeks), and old (115 weeks) mice. Additionally, we assessed whether rapamycin, an anti-aging treatment, reverses the age-related changes in sympathetic motor neurons. These approaches showed that aging does impact the intrinsic properties of sympathetic motor neurons, increasing spontaneous and evoked firing responses. A reduction of KCNQ channel currents emerged as a major contributor to age-related hyperexcitability. The administration of rapamycin in food for 12 weeks in middle-aged mice partially reverted the KCNQ current reduction and hyperexcitability associated with age. Thus, it is essential to consider the effect of aging on motor components of the sympathetic reflex as a crucial part of the mechanism involved in sympathetic overactivity. Further, our data suggest that rapamycin's beneficial anti-aging effects may be partly attributed to its potential to impact sympathetic nervous system components, providing novel insights into therapeutic strategies for age-related conditions.

Narrative minireview of the spatial epidemiology of substance use disorder in the United States: Who is at risk and where?

Drug overdose is the leading cause of death by injury in the United States. The incidence of substance use disorder (SUD) in the United States has increased steadily over the past two decades, becoming a major public health problem for the country. The drivers of the SUD epidemic in the United States have changed over time, characterized by an initial heroin outbreak between 1970 and 1999, followed by a painkiller outbreak, and finally by an ongoing synthetic opioid outbreak. The nature and sources of these abused substances reveal striking differences in the socioeconomic and behavioral factors that shape the drug epidemic. Moreover, the geospatial distribution of the SUD epidemic is not homogeneous. The United States has specific locations where vulnerable communities at high risk of SUD are concentrated, reaffirming the multifactorial socioeconomic nature of this epidemic. A better understanding of the SUD epidemic under a spatial epidemiology framework is necessary to determine the factors that have shaped its spread and how these patterns can be used to predict new outbreaks and create effective mitigation policies. This narrative minireview summarizes the current records of the spatial distribution of the SUD epidemic in the United States across different periods, revealing some spatiotemporal patterns that have preceded the occurrence of outbreaks. By analyzing the epidemic of SUD-related deaths, we also describe the epidemic behavior in areas with high incidence of cases. Finally, we describe public health interventions that can be effective for demographic groups, and we discuss future challenges in the study and control of the SUD epidemic in the country.

Impact of healthcare capacity disparities on the COVID-19 vaccination coverage in the United States: A cross-sectional study.

Background: The impact of the COVID-19 vaccination campaign in the US has been hampered by a substantial geographical heterogeneity of the vaccination coverage. Several studies have proposed vaccination hesitancy as a key driver of the vaccination uptake disparities. However, the impact of other important structural determinants such as local disparities in healthcare capacity is virtually unknown. Methods: In this cross-sectional study, we conducted causal inference and geospatial analyses to assess the impact of healthcare capacity on the vaccination coverage disparity in the US. We evaluated the causal relationship between the healthcare system capacity of 2417 US counties and their COVID-19 vaccination rate. We also conducted geospatial analyses using spatial scan statistics to identify areas with low vaccination rates. Findings: We found a causal effect of the constraints in the healthcare capacity of a county and its low-vaccination uptake. Counties with higher constraints in their healthcare capacity were more probable to have COVID-19 vaccination rates ≤50, with 35% higher constraints in low-vaccinated areas (vaccination rates ≤ 50) compared to high-vaccinated areas (vaccination rates > 50). We also found that COVID-19 vaccination in the US exhibits a distinct spatial structure with defined "vaccination coldspots". Interpretation: We found that the healthcare capacity of a county is an important determinant of low vaccine uptake. Our study highlights that even in high-income nations, internal disparities in healthcare capacity play an important role in the health outcomes of the nation. Therefore, strengthening the funding and infrastructure of the healthcare system, particularly in rural underserved areas, should be intensified to help vulnerable communities. Funding: None.

Adenylyl cyclase isoform 1 contributes to sinoatrial node automaticity via functional microdomains.

Sinoatrial node (SAN) cells are the heart's primary pacemaker. Their activity is tightly regulated by ß-adrenergic receptor (ß-AR) signaling. Adenylyl cyclase (AC) is a key enzyme in the ß-AR pathway that catalyzes the production of cAMP. There are current gaps in our knowledge regarding the dominant AC isoforms and the specific roles of Ca2+-activated ACs in the SAN. The current study tests the hypothesis that distinct AC isoforms are preferentially expressed in the SAN and compartmentalize within microdomains to orchestrate heart rate regulation during ß-AR signaling. In contrast to atrial and ventricular myocytes, SAN cells express a diverse repertoire of ACs, with ACI as the predominant Ca2+-activated isoform. Although ACI-KO (ACI-/-) mice exhibit normal cardiac systolic or diastolic function, they experience SAN dysfunction. Similarly, SAN-specific CRISPR/Cas9-mediated gene silencing of ACI results in sinus node dysfunction. Mechanistically, hyperpolarization-activated cyclic nucleotide-gated 4 (HCN4) channels form functional microdomains almost exclusively with ACI, while ryanodine receptor and L-type Ca2+ channels likely compartmentalize with ACI and other AC isoforms. In contrast, there were no significant differences in T-type Ca2+ and Na+ currents at baseline or after ß-AR stimulation between WT and ACI-/- SAN cells. Due to its central characteristic feature as a Ca2+-activated isoform, ACI plays a unique role in sustaining the rise of local cAMP and heart rates during ß-AR stimulation. The findings provide insights into the critical roles of the Ca2+-activated isoform of AC in sustaining SAN automaticity that is distinct from contractile cardiomyocytes.

Association Between Vaccination Coverage Disparity and the Dynamics of the COVID-19 Delta and Omicron Waves in the US.

Objective: The US recently suffered the fourth and most severe wave of the COVID-19 pandemic. This wave was driven by the SARS-CoV-2 Omicron, a highly transmissible variant that infected even vaccinated people. Vaccination coverage disparities have played an important role in shaping the epidemic dynamics. Analyzing the epidemiological impact of this uneven vaccination coverage is essential to understand local differences in the spread and outcomes of the Omicron wave. Therefore, the objective of this study was to quantify the impact of vaccination coverage disparity in the US in the dynamics of the COVID-19 pandemic during the third and fourth waves of the pandemic driven by the Delta and Omicron variants. Methods: This cross-sectional study used COVID-19 cases, deaths, and vaccination coverage from 2,417 counties. The main outcomes of the study were new COVID-19 cases (incidence rate per 100,000 people) and new COVID-19 related deaths (mortality rate per 100,000 people) at county level and the main exposure variable was COVID-19 vaccination rate at county level. Geospatial and data visualization analyses were used to estimate the association between vaccination rate and COVID-19 incidence and mortality rates for the Delta and Omicron waves. Results: During the Omicron wave, areas with high vaccination rates (>60%) experienced 1.4 (95% confidence interval [CI] 1.3-1.7) times higher COVID-19 incidence rate compared to areas with low vaccination rates (<40%). However, mortality rate was 1.6 (95% CI 1.5-1.7) higher in these low-vaccinated areas compared to areas with vaccination rates higher than 60%. As a result, areas with low vaccination rate had a 2.2 (95% CI 2.1-2.2) times higher case-fatality ratio. Geospatial clustering analysis showed a more defined spatial structure during the Delta wave with clusters with low vaccination rates and high incidence and mortality located in southern states. Conclusions: Despite the emergence of new virus variants with differential transmission potential, the protective effect of vaccines keeps generating marked differences in the distribution of critical health outcomes, with low vaccinated areas having the largest COVID-19 related mortality during the Delta and Omicron waves in the US. Vulnerable communities residing in low vaccinated areas, which are mostly rural, are suffering the highest burden of the COVID-19 pandemic during the vaccination era.

Aging Alters the Formation and Functionality of Signaling Microdomains Between L-type Calcium Channels and ß2-Adrenergic Receptors in Cardiac Pacemaker Cells.

Heart rate is accelerated to match physiological demands through the action of noradrenaline on the cardiac pacemaker. Noradrenaline is released from sympathetic terminals and activates ß1-and ß2-adrenergic receptors (ΑRs) located at the plasma membrane of pacemaker cells. L-type calcium channels are one of the main downstream targets potentiated by the activation of ß-ARs. For this signaling to occur, L-type calcium channels need to be located in close proximity to ß-ARs inside caveolae. Although it is known that aging causes a slowdown of the pacemaker rate and a reduction in the response of pacemaker cells to noradrenaline, there is a lack of in-depth mechanistic insights into these age-associated changes. Here, we show that aging affects the formation and function of adrenergic signaling microdomains inside caveolae. By evaluating the ß1 and ß2 components of the adrenergic regulation of the L-type calcium current, we show that aging does not alter the regulation mediated by ß1-ARs but drastically impairs that mediated by ß2-ARs. We studied the integrity of the signaling microdomains formed between L-type calcium channels and ß-ARs by combining high-resolution microscopy and proximity ligation assays. We show that consistent with the electrophysiological data, aging decreases the physical association between ß2-ARs and L-type calcium channels. Interestingly, this reduction is associated with a decrease in the association of L-type calcium channels with the scaffolding protein AKAP150. Old pacemaker cells also have a reduction in caveolae density and in the association of L-type calcium channels with caveolin-3. Together the age-dependent alterations in caveolar formation and the nano-organization of ß2-ARs and L-type calcium channels result in a reduced sensitivity of the channels to ß2 adrenergic modulation. Our results highlight the importance of these signaling microdomains in maintaining the chronotropic modulation of the heart and also pinpoint the direct impact that aging has on their function.

Interventions in sexual and reproductive health services addressing violence against women in low-income and middle-income countries: a mixed-methods systematic review.

OBJECTIVES: To synthesise evidence on the effectiveness, cost-effectiveness and barriers to responding to violence against women (VAW) in sexual and reproductive health (SRH) services in low/middle-income countries (LMICs). DESIGN: Mixed-methods systematic review. DATA SOURCES: Medline, Embase, Psycinfo, Cochrane, Cinahl, IMEMR, Web of Science, Popline, Lilacs, WHO RHL, ClinicalTrials.gov, Google, Google Scholar, websites of key organisations through December 2019. ELIGIBILITY CRITERIA: Studies of any design that evaluated VAW interventions in SRH services in LMICs. DATA EXTRACTION AND SYNTHESIS: Concurrent narrative quantitative and thematic qualitative syntheses, integration through line of argument and mapping onto a logic model. Two reviewers extracted data and appraised quality. RESULTS: 26 studies of varied interventions using heterogeneous outcomes. Of ten interventions that strengthened health systems capacity to respond to VAW during routine SRH consultation, three reported no harm and reduction in some types of violence. Of nine interventions that strengthened health systems and communities' capacity to respond to VAW, three reported conflicting effects on re-exposure to some types of VAW and mixed effect on SRH. The interventions increased identification of VAW but had no effect on the provision (75%-100%) and uptake (0.6%-53%) of referrals to VAW services. Of seven psychosocial interventions in addition to SRH consultation that strengthened women's readiness to address VAW, four reduced re-exposure to some types of VAW and improved health. Factors that disrupted the pathway to better outcomes included accepting attitudes towards VAW, fear of consequences and limited readiness of the society, health systems and individuals. No study evaluated cost-effectiveness. CONCLUSIONS: Some VAW interventions in SRH services reduced re-exposure to some types of VAW and improved some health outcomes in single studies. Future interventions should strengthen capacity to address VAW across health systems, communities and individual women. First-line support should be better tailored to women's needs and expectations. PROSPERO REGISTRATION NUMBER: CRD42019137167.

Slowing down as we age: aging of the cardiac pacemaker's neural control.

The cardiac pacemaker ignites and coordinates the contraction of the whole heart, uninterruptedly, throughout our entire life. Pacemaker rate is constantly tuned by the autonomous nervous system to maintain body homeostasis. Sympathetic and parasympathetic terminals act over the pacemaker cells as the accelerator and the brake pedals, increasing or reducing the firing rate of pacemaker cells to match physiological demands. Despite the remarkable reliability of this tissue, the pacemaker is not exempt from the detrimental effects of aging. Mammals experience a natural and continuous decrease in the pacemaker rate throughout the entire lifespan. Why the pacemaker rhythm slows with age is poorly understood. Neural control of the pacemaker is remodeled from birth to adulthood, with strong evidence of age-related dysfunction that leads to a downshift of the pacemaker. Such evidence includes remodeling of pacemaker tissue architecture, alterations in the innervation, changes in the sympathetic acceleration and the parasympathetic deceleration, and alterations in the responsiveness of pacemaker cells to adrenergic and cholinergic modulation. In this review, we revisit the main evidence on the neural control of the pacemaker at the tissue and cellular level and the effects of aging on shaping this neural control.

Rape survivors in South Africa: analysis of the baseline socio-demographic and health characteristics of a rape cohort.

BACKGROUND: Little is known about women who have experienced a recent rape, and how they differ from women without this exposure. Identifying factors linked to rape is important for preventing rape and developing effective responses in countries like South Africa with high levels of sexual violence. OBJECTIVE: To describe the socio-demographic and health profile of women recently exposed to rape and to compare them with a non-rape-exposed group. METHODS: The Rape Impact Cohort Evaluation Study (RICE) enrolled 852 women age 16-40 years exposed to rape from post-rape care centres in Durban (South Africa) and a control group of 853 women of the same age range who have never been exposed to rape recruited from public health services. Descriptive analyses include logistic regression modelling of socio-demographic characteristics associated with recent rape exposure. RESULTS: Women with recent rape reported poorer health and more intimate partner violence than those who were not raped. They had a lower likelihood of having completed school (Odds Ratio [OR] 0.46 95% Confidence Interval (CI): 0.24-0.87) and dependence on a government grant as a main source of income (OR 0.61: 95%CI 0.49-0.77). They were more likely to live in informal housing (OR 1.88 95%CI: 1.43-2.46) or rural areas (OR 2.24: 95%CI 1.61-3.07) than formal housing areas - however they were also more likely to report full-time employment (OR 4.24: 95%CI 2.73-6.57). CONCLUSION: The study shows that structural factors, such as lower levels of education, poverty, and living in areas of poor infrastructure are associated with women's vulnerability to rape. It also shows possible protection from rape afforded by the national financial safety net. It highlights the importance of safe transportation in commuting to work. Preventing rape is critical for enabling women's full social and economic development, and structural interventions are key for reducing women's vulnerability.

Role of ion channels during cell division.

Ion channels are transmembrane proteins whose canonical function is the transport of ions across the plasma membrane to regulate cell membrane potential and play an essential role in neural communication, nerve conduction, and muscle contraction. However, over the last few years, non-canonical functions have been identified for many channels, having active roles in phagocytosis, invasiveness, proliferation, among others. The participation of some channels in cell proliferation has raised the question of whether they may play an active role in mitosis. There are several reports showing the participation of channels during interphase, however, the direct participation of ion channels in mitosis has received less attention. In this article, we summarize the current evidence on the participation of ion channels in mitosis. We also summarize some tools that would allow the study of ion channels and cell cycle regulatory molecules in individual cells during mitosis.

A toolbox of nanobodies developed and validated for use as intrabodies and nanoscale immunolabels in mammalian brain neurons.

Nanobodies (nAbs) are small, minimal antibodies that have distinct attributes that make them uniquely suited for certain biomedical research, diagnostic and therapeutic applications. Prominent uses include as intracellular antibodies or intrabodies to bind and deliver cargo to specific proteins and/or subcellular sites within cells, and as nanoscale immunolabels for enhanced tissue penetration and improved spatial imaging resolution. Here, we report the generation and validation of nAbs against a set of proteins prominently expressed at specific subcellular sites in mammalian brain neurons. We describe a novel hierarchical validation pipeline to systematically evaluate nAbs isolated by phage display for effective and specific use as intrabodies and immunolabels in mammalian cells including brain neurons. These nAbs form part of a robust toolbox for targeting proteins with distinct and highly spatially-restricted subcellular localization in mammalian brain neurons, allowing for visualization and/or modulation of structure and function at those sites.

A stochastic model of ion channel cluster formation in the plasma membrane.

Ion channels are often found arranged into dense clusters in the plasma membranes of excitable cells, but the mechanisms underlying the formation and maintenance of these functional aggregates are unknown. Here, we tested the hypothesis that channel clustering is the consequence of a stochastic self-assembly process and propose a model by which channel clusters are formed and regulated in size. Our hypothesis is based on statistical analyses of the size distributions of the channel clusters we measured in neurons, ventricular myocytes, arterial smooth muscle, and heterologous cells, which in all cases were described by exponential functions, indicative of a Poisson process (i.e., clusters form in a continuous, independent, and memory-less fashion). We were able to reproduce the observed cluster distributions of five different types of channels in the membrane of excitable and tsA-201 cells in simulations using a computer model in which channels are "delivered" to the membrane at randomly assigned locations. The model's three parameters represent channel cluster nucleation, growth, and removal probabilities, the values of which were estimated based on our experimental measurements. We also determined the time course of cluster formation and membrane dwell time for CaV1.2 and TRPV4 channels expressed in tsA-201 cells to constrain our model. In addition, we elaborated a more complex version of our model that incorporated a self-regulating feedback mechanism to shape channel cluster formation. The strong inference we make from our results is that CaV1.2, CaV1.3, BK, and TRPV4 proteins are all randomly inserted into the plasma membranes of excitable cells and that they form homogeneous clusters that increase in size until they reach a steady state. Further, it appears likely that cluster size for a diverse set of membrane-bound proteins and a wide range of cell types is regulated by a common feedback mechanism.

Inequality in the distribution of ear, nose and throat specialists in 15 Latin American countries: an ecological study.

OBJECTIVE: To explore sociogeographical inequalities in the availability and distribution of ear, nose and throat specialists (ENTs) in 15 Latin American (LA) countries. DESIGN: Ecological. SETTING: Spanish and Portuguese-speaking countries of LA.The number of registered ENTs in 2017 was obtained from the National ENT Society in each country. OUTCOME MEASURES: The ENT rate/million population was calculated at the national and subnational (eg, state) level. Three measures were calculated to assess subnational distributive inequality of ENTs: (1) absolute and (2) relative index of dissimilarity; and (3) concentration index (using the Human Development Index as the equity stratifier). Finally, the ratio of ENTs/million population in the capital area compared with the rest of the country was calculated. RESULTS: There was more than a 30-fold difference in the number of ENTs/million population across the included countries-from 61.0 in Argentina (95% CI 58.7 to 63.4) to 2.8 in Guatemala (95% CI 2.1 to 3.8). In all countries, ENTs were more prevalent in advantaged areas and in capital areas. To attain distributive equality, Paraguay would need to redistribute the greatest proportion of its ENT workforce (67.3%; 95% CI 57.8% to 75.6%) and Brazil the least (18.5%; 95% CI 17.6% to 19.5%). CONCLUSIONS: There is high inequality in the number and distribution of ENTs between and within the 15 studied countries in LA. This evidence can be used to inform policies that improve access to ear and hearing services in the region, such as scale-up of training of ENTs and incentives to distribute specialists equally. These actions to reduce inequities, alongside addressing the social determinants of ear and hearing health, are essential to realise Universal Health Coverage.

[From words to action: measuring health inequalities to "leave no one behind"Da retórica à ação: mensurar as desigualdades em saúde para não deixar ninguém atrás]. / De la retórica a la acción: medir desigualdades en salud para "no dejar a nadie atrás".

Health equity is a guiding principle for public health action. Its noble purpose is to build healthier, sustainable societies that are also more just and inclusive. This is reflected in the global commitment to "leave no one behind", expressed in the 2030 Agenda for Sustainable Development, although none of the Agenda's 169 targets focuses on reducing health inequalities, either conceptually or quantitatively. Recognizing the urgency to go beyond words and move forward decidedly in the design and implementation of pro-equity social and health policies at both the local and global levels, this special report reviews the conceptual and methodological framework for tackling health equity. Concepts and methodology are explicitly linked in a practical proposal that promotes the analytical use of subnationally disaggregated administrative data to inform decision-making in that area. This report concludes by proposing the need to institutionalize the measurement, analysis, and monitoring of social disparities in health to create effective national capacity to act on the social and environmental determinants of health and ensure accountability in the commitment to "leave no one behind" on the road to sustainable development, universal health, and social justice.

A equidade em saúde é um princípio norteador da ação em saúde pública cujo propósito nobre é edificar sociedades mais saudáveis e sustentáveis e, ao mesmo tempo, mais justas e inclusivas. Isso está refletido no compromisso mundial de "não deixar ninguém atrás" que guia a Agenda 2030 para o Desenvolvimento Sustentável, apesar de nenhuma das 169 metas estabelecer de forma conceitual ou quantitativa a redução das desigualdades em saúde. Reconhecendo a urgência de transcender a retórica e avançar na formulação e implementação de políticas sociais e de saúde pró-equitativas do nível local ao global, são revistas as bases conceituais e metodológicas para a abordagem da equidade em saúde, vinculadas explicitamente em uma proposta instrumental e prática que promove o uso analítico dos dados administrativos disponíveis desagregados ao nível subnacional para subsidiar a tomada de decisão. Em conclusão, faz-se necessário institucionalizar a mensuração, análise e monitoramento das desigualdades sociais em saúde para efetivamente estabelecer capacidades nacionais para atuar nos determinantes sociais e ambientais da saúde e prestar contas quanto ao compromisso de não deixar ninguém atrás no rumo ao desenvolvimento sustentável, saúde universal e justiça social.

De la retórica a la acción: medir desigualdades en salud para “no dejar a nadie atrás”

[RESUMEN]. La equidad en salud es un principio rector de la acción en salud pública –cuyo noble propósito es construir sociedades más saludables y sostenibles y, al mismo tiempo, más justas e inclusivas. Ello se refleja en el compromiso mundial por ‘no dejar a nadie atrás’ que preside la Agenda 2030 para el desarrollo sostenible, aunque en ninguna de sus 169 metas se establezca ni conceptual ni cuantitativamente la reducción de desigualdades en salud. Reconociendo la urgencia de trascender la retórica y avanzar consecuentemente en la formulación y puesta en marcha de políticas sociales y de salud pro-equitativas –de lo local a lo global–, en este informe especial se revisan las bases conceptuales y metodológicas para el abordaje de la equidad en salud, se vinculan explícitamente en una propuesta instrumental y práctica que promueve el uso analítico de los datos administrativos disponibles desagregados subnacionalmente para informar la toma de decisiones en esa dirección, y se concluye planteando la necesidad de institucionalizar la medición, análisis y monitoreo de las desigualdades sociales en salud para crear efectivamente capacidades nacionales para actuar sobre los determinantes sociales y ambientales de la salud y rendir cuentas sobre el compromiso de no dejar a nadie atrás en el camino hacia el desarrollo sostenible, la salud universal y la justicia social.

[ABSTRACT]. Health equity is a guiding principle for public health action. Its noble purpose is to build healthier, sustainable societies that are also more just and inclusive. This is reflected in the global commitment to “leave no one behind”, expressed in the 2030 Agenda for Sustainable Development, although none of the Agenda’s 169 targets focuses on reducing health inequalities, either conceptually or quantitatively. Recognizing the urgency to go beyond words and move forward decidedly in the design and implementation of pro-equity social and health policies at both the local and global levels, this special report reviews the conceptual and methodological framework for tackling health equity. Concepts and methodology are explicitly linked in a practical proposal that promotes the analytical use of subnationally disaggregated administrative data to inform decision-making in that area. This report concludes by proposing the need to institutionalize the measurement, analysis, and monitoring of social disparities in health to create effective national capacity to act on the social and environmental determinants of health and ensure accountability in the commitment to “leave no one behind” on the road to sustainable development, universal health, and social justice.

[RESUMO]. A equidade em saúde é um princípio norteador da ação em saúde pública cujo propósito nobre é edificar sociedades mais saudáveis e sustentáveis e, ao mesmo tempo, mais justas e inclusivas. Isso está refletido no compromisso mundial de “não deixar ninguém atrás” que guia a Agenda 2030 para o Desenvolvimento Sustentável, apesar de nenhuma das 169 metas estabelecer de forma conceitual ou quantitativa a redução das desigualdades em saúde. Reconhecendo a urgência de transcender a retórica e avançar na formulação e implementação de políticas sociais e de saúde pró-equitativas do nível local ao global, são revistas as bases conceituais e metodológicas para a abordagem da equidade em saúde, vinculadas explicitamente em uma proposta instrumental e prática que promove o uso analítico dos dados administrativos disponíveis desagregados ao nível subnacional para subsidiar a tomada de decisão. Em conclusão, faz-se necessário institucionalizar a mensuração, análise e monitoramento das desigualdades sociais em saúde para efetivamente estabelecer capacidades nacionais para atuar nos determinantes sociais e ambientais da saúde e prestar contas quanto ao compromisso de não deixar ninguém atrás no rumo ao desenvolvimento sustentável, saúde universal e justiça social.

BIN1 Induces the Formation of T-Tubules and Adult-Like Ca2+ Release Units in Developing Cardiomyocytes.

Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) are at the center of new cell-based therapies for cardiac disease, but may also serve as a useful in vitro model for cardiac cell development. An intriguing feature of hESC-CMs is that although they express contractile proteins and have sarcomeres, they do not develop transverse-tubules (T-tubules) with adult-like Ca2+ release units (CRUs). We tested the hypothesis that expression of the protein BIN1 in hESC-CMs promotes T-tubules formation, facilitates CaV 1.2 channel clustering along the tubules, and results in the development of stable CRUs. Using electrophysiology, [Ca2+ ]i imaging, and super resolution microscopy, we found that BIN1 expression induced T-tubule development in hESC-CMs, while increasing differentiation toward a more ventricular-like phenotype. Voltage-gated CaV 1.2 channels clustered along the surface sarcolemma and T-tubules of hESC-CM. The length and width of the T-tubules as well as the expression and size of CaV 1.2 clusters grew, as BIN1 expression increased and cells matured. BIN1 expression increased CaV 1.2 channel activity and the probability of coupled gating within channel clusters. Interestingly, BIN1 clusters also served as sites for sarcoplasmic reticulum (SR) anchoring and stabilization. Accordingly, BIN1-expressing cells had more CaV 1.2-ryanodine receptor junctions than control cells. This was associated with larger [Ca2+ ]i transients during excitation-contraction coupling. Our data support the view that BIN1 is a key regulator of T-tubule formation and CaV 1.2 channel delivery. By studying the role of BIN1 during the differentiation of hESC-CMs, we show that BIN1 is also important for CaV 1.2 channel clustering, junctional SR organization, and the establishment of excitation-contraction coupling. Stem Cells 2019;37:54-64.

De la retórica a la acción: medir desigualdades en salud para "no dejar a nadie atrás" / From words to action: measuring health inequalities to "leave no one behind" / Da retórica à ação: mensurar as desigualdades em saúde para não deixar ninguém atrás

RESUMEN La equidad en salud es un principio rector de la acción en salud pública -cuyo noble propósito es construir sociedades más saludables y sostenibles y, al mismo tiempo, más justas e inclusivas. Ello se refleja en el compromiso mundial por 'no dejar a nadie atrás' que preside la Agenda 2030 para el desarrollo sostenible, aunque en ninguna de sus 169 metas se establezca ni conceptual ni cuantitativamente la reducción de desigualdades en salud. Reconociendo la urgencia de trascender la retórica y avanzar consecuentemente en la formulación y puesta en marcha de políticas sociales y de salud pro-equitativas -de lo local a lo global-, en este informe especial se revisan las bases conceptuales y metodológicas para el abordaje de la equidad en salud, se vinculan explícitamente en una propuesta instrumental y práctica que promueve el uso analítico de los datos administrativos disponibles desagregados subnacionalmente para informar la toma de decisiones en esa dirección, y se concluye planteando la necesidad de institucionalizar la medición, análisis y monitoreo de las desigualdades sociales en salud para crear efectivamente capacidades nacionales para actuar sobre los determinantes sociales y ambientales de la salud y rendir cuentas sobre el compromiso de no dejar a nadie atrás en el camino hacia el desarrollo sostenible, la salud universal y la justicia social.

ABSTRACT Health equity is a guiding principle for public health action. Its noble purpose is to build healthier, sustainable societies that are also more just and inclusive. This is reflected in the global commitment to "leave no one behind", expressed in the 2030 Agenda for Sustainable Development, although none of the Agenda's 169 targets focuses on reducing health inequalities, either conceptually or quantitatively. Recognizing the urgency to go beyond words and move forward decidedly in the design and implementation of pro-equity social and health policies at both the local and global levels, this special report reviews the conceptual and methodological framework for tackling health equity. Concepts and methodology are explicitly linked in a practical proposal that promotes the analytical use of subnationally disaggregated administrative data to inform decision-making in that area. This report concludes by proposing the need to institutionalize the measurement, analysis, and monitoring of social disparities in health to create effective national capacity to act on the social and environmental determinants of health and ensure accountability in the commitment to "leave no one behind" on the road to sustainable development, universal health, and social justice.

RESUMO A equidade em saúde é um princípio norteador da ação em saúde pública cujo propósito nobre é edificar sociedades mais saudáveis e sustentáveis e, ao mesmo tempo, mais justas e inclusivas. Isso está refletido no compromisso mundial de "não deixar ninguém atrás" que guia a Agenda 2030 para o Desenvolvimento Sustentável, apesar de nenhuma das 169 metas estabelecer de forma conceitual ou quantitativa a redução das desigualdades em saúde. Reconhecendo a urgência de transcender a retórica e avançar na formulação e implementação de políticas sociais e de saúde pró-equitativas do nível local ao global, são revistas as bases conceituais e metodológicas para a abordagem da equidade em saúde, vinculadas explicitamente em uma proposta instrumental e prática que promove o uso analítico dos dados administrativos disponíveis desagregados ao nível subnacional para subsidiar a tomada de decisão. Em conclusão, faz-se necessário institucionalizar a mensuração, análise e monitoramento das desigualdades sociais em saúde para efetivamente estabelecer capacidades nacionais para atuar nos determinantes sociais e ambientais da saúde e prestar contas quanto ao compromisso de não deixar ninguém atrás no rumo ao desenvolvimento sustentável, saúde universal e justiça social.

Proximal clustering between BK and CaV1.3 channels promotes functional coupling and BK channel activation at low voltage.

CaV-channel dependent activation of BK channels is critical for feedback control of both calcium influx and cell excitability. Here we addressed the functional and spatial interaction between BK and CaV1.3 channels, unique CaV1 channels that activate at low voltages. We found that when BK and CaV1.3 channels were co-expressed in the same cell, BK channels started activating near -50 mV, ~30 mV more negative than for activation of co-expressed BK and high-voltage activated CaV2.2 channels. In addition, single-molecule localization microscopy revealed striking clusters of CaV1.3 channels surrounding clusters of BK channels and forming a multi-channel complex both in a heterologous system and in rat hippocampal and sympathetic neurons. We propose that this spatial arrangement allows tight tracking between local BK channel activation and the gating of CaV1.3 channels at quite negative membrane potentials, facilitating the regulation of neuronal excitability at voltages close to the threshold to fire action potentials.

Distance constraints on activation of TRPV4 channels by AKAP150-bound PKCα in arterial myocytes.

TRPV4 (transient receptor potential vanilloid 4) channels are Ca2+-permeable channels that play a key role in regulating vascular tone. In arterial myocytes, opening of TRPV4 channels creates local increases in Ca2+ influx, detectable optically as "TRPV4 sparklets." TRPV4 sparklet activity can be enhanced by the action of the vasoconstrictor angiotensin II (AngII). This modulation depends on the activation of subcellular signaling domains that comprise protein kinase C α (PKCα) bound to the anchoring protein AKAP150. Here, we used super-resolution nanoscopy, patch-clamp electrophysiology, Ca2+ imaging, and mathematical modeling approaches to test the hypothesis that AKAP150-dependent modulation of TRPV4 channels is critically dependent on the distance between these two proteins in the sarcolemma of arterial myocytes. Our data show that the distance between AKAP150 and TRPV4 channel clusters varies with sex and arterial bed. Consistent with our hypothesis, we further find that basal and AngII-induced TRPV4 channel activity decays exponentially as the distance between TRPV4 and AKAP150 increases. Our data suggest a maximum radius of action of ∼200 nm for local modulation of TRPV4 channels by AKAP150-associated PKCα.