Cell-type-specific origins of locomotor rhythmicity at different speeds in larval zebrafish.

Different speeds of locomotion require heterogeneous spinal populations, but a common mode of rhythm generation is presumed to exist. Here, we explore the cellular versus synaptic origins of spinal rhythmicity at different speeds by performing electrophysiological recordings from premotor excitatory interneurons in larval zebrafish. Chx10-labeled V2a neurons are divided into at least two morphological subtypes proposed to play distinct roles in timing and intensity control. Consistent with distinct rhythm generating and output patterning functions within the spinal V2a population, we find that descending subtypes are recruited exclusively at slow or fast speeds and exhibit intrinsic cellular properties suitable for rhythmogenesis at those speeds, while bifurcating subtypes are recruited more reliably at all speeds and lack appropriate rhythmogenic cellular properties. Unexpectedly, however, phasic firing patterns during locomotion in rhythmogenic and non-rhythmogenic V2a neurons alike are best explained by distinct modes of synaptic inhibition linked to cell-type and speed. At fast speeds reciprocal inhibition in descending V2a neurons supports phasic firing, while recurrent inhibition in bifurcating V2a neurons helps pattern motor output. In contrast, at slow speeds recurrent inhibition in descending V2a neurons supports phasic firing, while bifurcating V2a neurons rely on reciprocal inhibition alone to pattern output. Our findings suggest cell-type-specific, not common, modes of rhythmogenesis generate and coordinate different speeds of locomotion.

Bringing Generalists to Global Health: a Missed Opportunity and Call to Action.

The credo of the generalist physician has always been the promotion of health for all, in every aspect: not just multiple vulnerable organ systems, but multiple social, cultural, and political factors that contribute to poor health and exacerbate health inequity. In recent years, the field of global health has also adopted this same mission: working across both national and clinical specialty borders to improve health for all and end health disparities worldwide. Yet within the Society for General Internal Medicine, and among American generalists, engagement in global health, both within and outside the USA, remains uncommon. We see this gap as an opportunity, because in fact generalists in America already have the skills and experience that global health badly needs. SGIM could promote generalists to global health's vanguard, with three core steps. First, we generalists must continue to integrate health for the vulnerable into our domestic work, generating care models applicable in low-resource settings around the globe. Conversely, we must also engage with and implement international ideas and solutions for universal access to primary care for vulnerable patients in the USA. And lastly, we must build platforms to connect ourselves with colleagues worldwide to exchange these learnings.

Mixed synapses reconcile violations of the size principle in zebrafish spinal cord.

Mixed electrical-chemical synapses potentially complicate electrophysiological interpretations of neuronal excitability and connectivity. Here, we disentangle the impact of mixed synapses within the spinal locomotor circuitry of larval zebrafish. We demonstrate that soma size is not linked to input resistance for interneurons, contrary to the biophysical predictions of the 'size principle' for motor neurons. Next, we show that time constants are faster, excitatory currents stronger, and mixed potentials larger in lower resistance neurons, linking mixed synapse density to resting excitability. Using a computational model, we verify the impact of weighted electrical synapses on membrane properties, synaptic integration and the low-pass filtering and distribution of coupling potentials. We conclude differences in mixed synapse density can contribute to excitability underestimations and connectivity overestimations. The contribution of mixed synaptic inputs to resting excitability helps explain 'violations' of the size principle, where neuron size, resistance and recruitment order are unrelated.

Essential medicines for cardiovascular diseases in India: Rapid appraisal of policies and processes at the subnational level.

Background The burden of cardiovascular diseases (CVDs) and response to health systems vary widely at the subnational level in India. Our study aimed to assess the variation in state-level access to medicines for CVDs by comparing the essential medicines lists (EMLs) at the national and subnational levels in India and by rapid appraisal of the existing policies and processes of drug procurement. Methods We assessed the inclusion of six classes of medicines for CVDs in the recent and publicly available national and subnational EMLs from July to September 2018 in the states of Telangana and Madhya Pradesh. We examined the drug procurement and distribution policies and processes using documentary review and five key informant interviews between March and June 2018. Results The WHO's EML, India's national EML, and 21 of 28 publicly available (75%) Indian state and Union Territory EMLs included all six classes of essential medicines for CVDs. However, some medicines were not included in the policy packages of essential medicines meant for primary health centres. Both the states used centralized tendering and decentralized distribution as part of the public sector drug procurement process. The requirement was based on the previous year's consumption. The approximate time between procurement planning and distribution was 7-8 months in both the states. Conclusion Substantial variation exists in the selection of drugs for CVDs in EMLs at the subnational level in India. Improving forecasting techniques for requirement of medicines and reducing time lags between forecasting and distribution to health facilities may allow for better access to essential medicines.

The success of behavioral economics in improving patient retention within an intensive primary care practice.

BACKGROUND: A minority of the U.S. population comprises a majority of health care expenses. Health system interventions for high-cost populations aim to improve patient outcomes while reducing costly over-utilization. Missed and inconsistent appointments are associated with poor patient outcomes and increased health care utilization. PEAK Health- Mount Sinai's intensive primary care clinic for high-cost patients- employed a novel behavioral economics-based intervention to reduce the rate of missed appointments at the practice. Behavioral economics has accomplished numerous successes across the health care field; the effect of a clinic-based behavioral economics intervention on reducing missed appointments has yet to be assessed. METHODS: This was a single-arm, pre-post trial conducted over 1 year involving all active patients at PEAK Health. The intervention consisted of: a) clinic signage, and b) appointment reminder cards containing behavioral economics messaging designed to increase the likelihood patients would complete their subsequent visit; appointment cards (t1) were transitioned to an identical EMR template (t2) at 6 months to boost provider utilization. The primary objective, the success of scheduled appointments, was assessed with visit adherence: the proportion of successful over all scheduled appointments, excluding those cancelled or rescheduled. The secondary objective, the consistency of appointments, was assessed with a 2-month visit constancy rate: the percentage of patients with at least one successful visit every 2 months for 1 year. Both metrics were assessed via a χ2 analysis and together define patient retention. RESULTS: The visit adherence rate increased from 74.7% at baseline to 76.5% (p = .22) during t1 and 78.0% (p = .03) during t2. The 2-month visit constancy rate increased from 59.5% at baseline to 74.3% (p = .01) post-intervention. CONCLUSIONS: A low-resource, clinic-based behavioral economics intervention was capable of improving patient retention within a traditionally high-cost population. A renewed focus on patient retention- employing the metrics described here- could bolster chronic care efforts and significantly improve the outcomes of high-cost programs by reducing the deleterious effects of missed and inconsistent appointments.

Performance of crisis standards of care guidelines in a cohort of critically ill COVID-19 patients in the United States.

Many US states published crisis standards of care (CSC) guidelines for allocating scarce critical care resources during the COVID-19 pandemic. However, the performance of these guidelines in maximizing their population benefit has not been well tested. In 2,272 adults with COVID-19 requiring mechanical ventilation drawn from the Study of the Treatment and Outcomes in Critically Ill Patients with COVID-19 (STOP-COVID) multicenter cohort, we test the following three approaches to CSC algorithms: Sequential Organ Failure Assessment (SOFA) scores grouped into ranges, SOFA score ranges plus comorbidities, and a hypothetical approach using raw SOFA scores not grouped into ranges. We find that area under receiver operating characteristic (AUROC) curves for all three algorithms demonstrate only modest discrimination for 28-day mortality. Adding comorbidity scoring modestly improves algorithm performance over SOFA scores alone. The algorithm incorporating comorbidities has modestly worse predictive performance for Black compared to white patients. CSC algorithms should be empirically examined to refine approaches to the allocation of scarce resources during pandemics and to avoid potential exacerbation of racial inequities.

Empirical Assessment of U.S. Coronavirus Disease 2019 Crisis Standards of Care Guidelines.

To establish the feasibility of empirically testing crisis standards of care guidelines. DESIGN: Retrospective single-center study. SETTING: ICUs at a large academic medical center in the United States. SUBJECTS: Adult, critically ill patients admitted to ICU, with 27 patients admitted for acute respiratory failure due to coronavirus disease 2019 and 37 patients admitted for diagnoses other than coronavirus disease 2019. INTERVENTIONS: Review of electronic health record. MEASUREMENTS AND MAIN RESULTS: Many U.S. states released crisis standards of care guidelines with algorithms to allocate scarce healthcare resources during the coronavirus disease 2019 pandemic. We compared state guidelines that represent different approaches to incorporating disease severity and comorbidities: New York, Maryland, Pennsylvania, and Colorado. Following each algorithm, we calculated priority scores at the time of ICU admission for a cohort of patients with primary diagnoses of coronavirus disease 2019 and diseases other than coronavirus disease 2019 (n = 64). We assessed discrimination of 28-day mortality by area under the receiver operating characteristic curve. We simulated real-time decision-making by applying the triage algorithms to groups of two, five, or 10 patients. For prediction of 28-day mortality by priority scores, area under the receiver operating characteristic curve was 0.56, 0.49, 0.53, 0.66, and 0.69 for New York, Maryland, Pennsylvania, Colorado, and raw Sequential Organ Failure Assessment score algorithms, respectively. For groups of five patients, the percentage of decisions made without deferring to a lottery were 1%, 57%, 80%, 88%, and 95% for New York, Maryland, Pennsylvania, Colorado, and raw Sequential Organ Failure Assessment score algorithms, respectively. The percentage of decisions made without lottery was higher in the subcohort without coronavirus disease 2019, compared with the subcohort with coronavirus disease 2019. CONCLUSIONS: Inclusion of comorbidities does not consistently improve an algorithm's performance in predicting 28-day mortality. Crisis standards of care algorithms result in a substantial percentage of tied priority scores. Crisis standards of care algorithms operate differently in cohorts with and without coronavirus disease 2019. This proof-of-principle study demonstrates the feasibility and importance of empirical testing of crisis standards of care guidelines to understand whether they meet their goals.

Variation in the availability and cost of essential medicines for non-communicable diseases in Uganda: A descriptive time series analysis.

BACKGROUND: Availability of essential medicines for non-communicable diseases (NCDs) is poor in low- and middle-income countries. Availability and cost are conventionally assessed using cross-sectional data. However, these characteristics may vary over time. METHODS: We carried out a prospective, descriptive analysis of the availability and cost of essential medicines in 23 Ugandan health facilities over a five-week period. We surveyed facility pharmacies in-person up to five times, recording availability and cost of 19 essential medicines for NCDs and four essential medicines for communicable diseases. RESULTS: Availability of medicines varied substantially over time, especially among public facilities. Among private-for-profit facilities, the cost of the same medicine varied from week to week. Private-not-for-profit facilities experienced less dramatic fluctuations in price. CONCLUSIONS: We conclude that there is a need for standardized, continuous monitoring to better characterize the availability and cost of essential medicines, understand demand for these medicines, and reduce uncertainty for patients.

Orderly compartmental mapping of premotor inhibition in the developing zebrafish spinal cord.

In vertebrates, faster movements involve the orderly recruitment of different types of spinal motor neurons. However, it is not known how premotor inhibitory circuits are organized to ensure alternating motor output at different movement speeds. We found that different types of commissural inhibitory interneurons in zebrafish form compartmental microcircuits during development that align inhibitory strength and recruitment order. Axonal microcircuits develop first and provide the most potent premotor inhibition during the fastest movements, followed by perisomatic microcircuits, and then dendritic microcircuits that provide the weakest inhibition during the slowest movements. The conversion of a temporal sequence of neuronal development into a spatial pattern of inhibitory connections provides an "ontogenotopic" solution to the problem of shaping spinal motor output at different speeds of movement.

Correction: Prevalence of multiple chronic conditions by U.S. state and territory, 2017.

[This corrects the article DOI: 10.1371/journal.pone.0232346.].

Two-drug fixed-dose combinations of blood pressure-lowering drugs as WHO essential medicines: An overview of efficacy, safety, and cost.

Cardiovascular diseases (CVD) are the world's leading cause of death. High blood pressure (BP) is the leading global risk factor for all-cause preventable morbidity and mortality. Globally, only about 14% of patients achieve BP control to systolic BP <140 mm Hg and diastolic BP <90 mm Hg. Most patients (>60%) require two or more drugs to achieve BP control, yet poor adherence to therapy is a major barrier to achieving this control. Fixed-dose combinations (FDCs) of BP-lowering drugs are one means to improve BP control through greater adherence and efficacy, with favorable safety and cost profiles. The authors present a review of the supporting data from a successful application to the World Health Organization (WHO) for the inclusion of FDCs of two BP-lowering drugs on the 21st WHO Essential Medicines List. The authors discuss the efficacy and safety of FDCs of two BP-lowering drugs for the management of hypertension in adults, relevant hypertension guideline recommendations, and the estimated cost of such therapies.

Empirical Assessment of COVID-19 Crisis Standards of Care Guidelines.

BACKGROUND: Several states have released Crisis Standards of Care (CSC) guidelines for the allocation of scarce critical care resources. Most guidelines rely on Sequential Organ Failure Assessment (SOFA) scores to maximize lives saved, but states have adopted different stances on whether to maximize long-term outcomes (life-years saved) by accounting for patient comorbidities. METHODS: We compared 4 representative state guidelines with varying approaches to comorbidities and analyzed how CSC prioritization correlates with clinical outcomes. We included 27 laboratory-confirmed COVID-19 patients admitted to ICUs at Brigham and Women's Hospital from March 12 to April 3, 2020. We compared prioritization algorithms from New York, which assigns priority based on SOFA alone; Maryland, which uses SOFA plus severe comorbidities; Pennsylvania, which uses SOFA plus major and severe comorbidities; and Colorado, which uses SOFA plus a modified Charlson comorbidity index. RESULTS: In pairwise comparisons across all possible pairs, we found that state guidelines frequently resulted in tie-breakers based on age or lottery: New York 100% of the time (100% resolved by lottery), Pennsylvania 86% of the time (18% by lottery), Maryland 93% of the time (35% by lottery), and Colorado: 32% of the time (10% by lottery). The prioritization algorithm with the strongest correlation with 14-day outcomes was Colorado (rs = -0.483. p = 0.011) followed by Maryland (rs = -0.394, p =0.042), Pennsylvania (rs = -0.382, p = 0.049), and New York (rs = 0). An alternative model using raw SOFA scores alone was moderately correlated with outcomes (rs = -0.448, p = 0.019). CONCLUSIONS: State guidelines for scarce resource allocation frequently resulted in identical priority scores, requiring tie-breakers based on age or lottery. These findings suggest that state CSC guidelines should be further assessed empirically to understand whether they meet their goals.

Prevalence of multiple chronic conditions by U.S. state and territory, 2017.

Having multiple (two or more) chronic conditions (MCC) is associated with an increased risk of mortality and functional decline, health resource utilization, and healthcare expenditures. As a result, understanding the prevalence of MCC is increasingly being recognized as a public health imperative. This research describes the prevalence and distribution of adults with MCC across the United States using 2017 data from the Behavioral Risk Factors Surveillance System (BRFSS). Prevalence of MCC was calculated for each U.S. state and territory overall, by sex and by age. Additionally, the most common condition dyads (two condition combinations) and triads (three condition combinations) were assessed for each state. Prevalence of MCC ranged from 37.9% in the District of Columbia to 64.4% in West Virginia. Females had a higher prevalence than males in 47 of 53 states and territories, and MCC prevalence increased with age in every state and territory. Overall prevalence estimates were higher than estimates using data from the National Health Interview Survey (NHIS), especially in the younger population (aged 18-44), due partly to the inclusion of high cholesterol, obesity, and depression as chronic conditions. Analysis of the most prevalent dyads and triads revealed the greatest state-by-state variability in the 18-44-year-old population. Multiple states' most prevalent dyads and triads for this population included obesity and depression. These findings build an accurate picture of the prevalence of multiple chronic conditions across the United States and will aid public health officials in creating programs targeted to their region.

Access to Cardiovascular Disease and Hypertension Medicines in Developing Countries: An Analysis of Essential Medicine Lists, Price, Availability, and Affordability.

Background Access to medicines is important for long-term care of cardiovascular diseases and hypertension. This study provides a cross-country assessment of availability, prices, and affordability of cardiovascular disease and hypertension medicines to identify areas for improvement in access to medication treatment. Methods and Results We used the World Health Organization online repository of national essential medicines lists (EMLs) for 53 countries to transcribe the information on the inclusion of 12 cardiovascular disease/hypertension medications within each country's essential medicines list. Data on availability, price, and affordability were obtained from 84 surveys in 59 countries that used the World Health Organization's Health Action International survey methodology. We summarized and compared the indicators across lowest-price generic and originator brand medicines in the public and private sectors and by country income groups. The average availability of the select medications was 54% in low- and lower-middle-income countries and 60% in high- and upper-middle-income countries, and was higher for generic (61%) than brand medicines (41%). The average patient median price ratio was 80.3 for brand and 16.7 for generic medicines and was higher for patients in low- and lower-middle-income countries compared with high- and upper-middle-income countries across all medicine categories. The costs of 1 month's antihypertensive medications were, on average, 6.0 days' wage for brand medicine and 1.8 days' wage for generics. Affordability was lower in low- and lower-middle-income countries than high- and upper-middle-income countries for both brand and generic medications. Conclusions The availability and accessibility of pharmaceuticals is an ongoing challenge for health systems. Low availability and high costs are major barriers to the use of and adherence to essential cardiovascular disease and antihypertensive medications worldwide, particularly in low- and lower-middle-income countries.

An integrated intervention for chronic care management in rural Nepal: protocol of a type 2 hybrid effectiveness-implementation study.

BACKGROUND: In Nepal, the burden of noncommunicable, chronic diseases is rapidly rising, and disproportionately affecting low and middle-income countries. Integrated interventions are essential in strengthening primary care systems and addressing the burden of multiple comorbidities. A growing body of literature supports the involvement of frontline providers, namely mid-level practitioners and community health workers, in chronic care management. Important operational questions remain, however, around the digital, training, and supervisory structures to support the implementation of effective, affordable, and equitable chronic care management programs. METHODS: A 12-month, population-level, type 2 hybrid effectiveness-implementation study will be conducted in rural Nepal to evaluate an integrated noncommunicable disease care management intervention within Nepal's new municipal governance structure. The intervention will leverage the government's planned roll-out of the World Health Organization's Package of Essential Noncommunicable Disease Interventions (WHO-PEN) program in four municipalities in Nepal, with a study population of 80,000. The intervention will leverage both the WHO-PEN and its cardiovascular disease-specific technical guidelines (HEARTS), and will include three evidence-based components: noncommunicable disease care provision using mid-level practitioners and community health workers; digital clinical decision support tools to ensure delivery of evidence-based care; and training and digitally supported supervision of mid-level practitioners to provide motivational interviewing for modifiable risk factor optimization, with a focus on medication adherence, and tobacco and alcohol use. The study will evaluate effectiveness using a pre-post design with stepped implementation. The primary outcomes will be disease-specific, "at-goal" metrics of chronic care management; secondary outcomes will include alcohol and tobacco consumption levels. DISCUSSION: This is the first population-level, hybrid effectiveness-implementation study of an integrated chronic care management intervention in Nepal. As low and middle-income countries plan for the Sustainable Development Goals and universal health coverage, the results of this pragmatic study will offer insights into policy and programmatic design for noncommunicable disease care management in the future. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04087369. Registered on 12 September 2019.

Assessment of Barriers and Facilitators to the Delivery of Care for Noncommunicable Diseases by Nonphysician Health Workers in Low- and Middle-Income Countries: A Systematic Review and Qualitative Analysis.

Importance: Cardiovascular disease, cancer, and other noncommunicable diseases (NCDs) are the leading causes of mortality in low- and middle-income countries. Previous studies show that nonphysician health workers (NPHWs), including nurses and volunteers, can provide effective diagnosis and treatment of NCDs. However, the factors that facilitate and impair these programs are incompletely understood. Objective: To identify health system barriers to and facilitators of NPHW-led care for NCDs in low- and middle-income countries. Data Sources: All systematic reviews in PubMed published by May 1, 2018. Study Selection: The search terms used for this analysis included "task shifting" and "non-physician clinician." Only reviews of NPHW care that occurred entirely or mostly in low- and middle-income countries and focused entirely or mostly on NCDs were included. All studies cited within each systematic review that cited health system barriers to and facilitators of NPHW care were reviewed. Data Extraction and Synthesis: Assessment of study eligibility was performed by 1 reviewer and rechecked by another. The 2 reviewers extracted all data. Reviews were performed from November 2017 to July 2018. All analyses were descriptive. Main Outcomes and Measures: All barriers and facilitators mentioned in all studies were tallied and sorted according to the World Health Organization's 6 building blocks for health systems. Results: This systematic review and qualitative analysis identified 15 review articles, which cited 156 studies, of which 71 referenced barriers to and facilitators of care. The results suggest 6 key lessons: (1) select qualified NPHWs embedded within the community they serve; (2) provide detailed, ongoing training and supervision; (3) authorize NPHWs to prescribe medication and render autonomous care; (4) equip NPHWs with reliable systems to track patient data; (5) furnish NPHWs consistently with medications and supplies; and (6) compensate NPHWs adequately commensurate with their roles. Conclusions and Relevance: Although the health system barriers to NPHW screening, treatment, and control of NCDs and their risk factors are numerous and complex, a diverse set of care models has demonstrated strategies to address nearly all of these challenges. These facilitating approaches-which relate chiefly to strong, consistent NPHW training, guidance, and logistical support-generate a blueprint for the creation and scale-up of such programs adaptable across multiple chronic diseases, including in high-income countries.

Multiple chronic conditions at a major urban health system: a retrospective cross-sectional analysis of frequencies, costs and comorbidity patterns.

OBJECTIVE: To (1) examine the burden of multiple chronic conditions (MCC) in an urban health system, and (2) propose a methodology to identify subpopulations of interest based on diagnosis groups and costs. DESIGN: Retrospective cross-sectional study. SETTING: Mount Sinai Health System, set in all five boroughs of New York City, USA. PARTICIPANTS: 192 085 adult (18+) plan members of capitated Medicaid contracts between the Healthfirst managed care organisation and the Mount Sinai Health System in the years 2012 to 2014. METHODS: We classified adults as having 0, 1, 2, 3, 4 or 5+ chronic conditions from a list of 69 chronic conditions. After summarising the demographics, geography and prevalence of MCC within this population, we then described groups of patients (segments) using a novel methodology: we combinatorially defined 18 768 potential segments of patients by a pair of chronic conditions, a sex and an age group, and then ranked segments by (1) frequency, (2) cost and (3) ratios of observed to expected frequencies of co-occurring chronic conditions. We then compiled pairs of conditions that occur more frequently together than otherwise expected. RESULTS: 61.5% of the study population suffers from two or more chronic conditions. The most frequent dyad was hypertension and hyperlipidaemia (19%) and the most frequent triad was diabetes, hypertension and hyperlipidaemia (10%). Women aged 50 to 65 with hypertension and hyperlipidaemia were the leading cost segment in the study population. Costs and prevalence of MCC increase with number of conditions and age. The disease dyads associated with the largest observed/expected ratios were pulmonary disease and myocardial infarction. Inter-borough range MCC prevalence was 16%. CONCLUSIONS: In this low-income, urban population, MCC is more prevalent (61%) than nationally (42%), motivating further research and intervention in this population. By identifying potential target populations in an interpretable manner, this segmenting methodology has utility for health services analysts.