Suprachiasmatic Nucleus and Subparaventricular Zone Lesions Disrupt Circadian Rhythmicity but Not Light-Induced Masking Behavior in Nile Grass Rats

The ventral subparaventricular zone (vSPVZ) receives direct retinal input and influences the daily patterning of activity in rodents, making it a likely candidate for the mediation of acute behavioral responses to light (i.e., masking). We performed chemical lesions aimed at the vSPVZ of diurnal grass rats (Arvicanthis niloticus) using N-methyl-D,L-aspartic acid (NMA), a glutamate agonist. Following NMA lesions, we placed grass rats in various lighting conditions (e.g., 12:12 light-dark, constant dark, constant light); presented a series of light pulses at circadian times (CT) 6, 14, 18, and 22; and placed them in a 7-h ultradian cycle to assess behavioral masking. Extensive bilateral lesions of the vSPVZ disrupted the expression of circadian rhythms of activity and abolished the circadian modulation of masking responses to light, without affecting light-induced masking behavior per se. We also found that in diurnal grass rats, NMA was capable of destroying not only neurons of the vSPVZ but also those of the suprachiasmatic nucleus (SCN), even though excitotoxins have been ineffective at destroying cells within the SCN of nocturnal rodents. The vulnerability of the grass rat\u27s SCN to NMA toxicity raises the possibility of a difference in density of receptors for glutamate between nocturnal and diurnal species. In cases in which damage extended to the SCN, masking responses to light were present and similar to those displayed by animals with damage restricted to the vSPVZ. Thus, extensive bilateral lesions of the SCN and vSPVZ disrupted the expression of circadian rhythms without affecting acute responses to light in a diurnal species. Our present and previous results suggest that retinorecipient brain areas other than the SCN or vSPVZ, such as the intergeniculate leaflet or olivary pretectal nucleus, may be responsible for the mediation of masking responses to light in the diurnal grass rat

Prevalence of hypertension and its treatment among adults presenting to primary health clinics in rural Zambia: analysis of an observational database

Abstract Background Hypertension constitutes a growing burden of illness in developing countries like Zambia. Adequately screening and treating hypertension could greatly reduce the complications of stroke and coronary disease. Our objective was to determine the prevalence of hypertension and identify current treatment practices among adult patients presenting for routine care to rural health facilities in the Better Health Outcomes through Mentoring and Assessments (BHOMA) project. Methods We conducted a retrospective analysis of routinely collected clinical data from 46 rural government clinics in Zambia. Our analysis cohort comprised patients ≥ 25 years with recorded blood pressure measurements, who sought care at primary health centers. Consistent with prior research, in our primary analysis, we only included data from first visits. Hypertension was defined as a systolic blood pressure ≥140 mmHg, or diastolic blood pressure ≥90 mmHg, or reported use of antihypertensive medication. A sensitivity analysis was performed using median blood pressure for individuals with multiple visits. Results and Discussion From January 2011 to December 2014, 116,130 first visits by adult patients met eligibility criteria. The crude prevalence of hypertension by onsite measurement or reported use of antihypertensive medication was 23.1 % [95 % CI: 22.8-23.3] (23.6 % in females, 22.3 % in males). The age standardized prevalence of hypertension across participating sites was 28.0 % [95 % CI: 27.7-28.3] (29.7 % in females, 25.8 % in males). Sensitivity analysis revealed a similar prevalence using data from all visits. Only 5.6 % of patients had a diagnosis of hypertension documented in their medical record. Among patients with hypertension, only 18.0 % had any antihypertensive drug prescribed, with nifedipine (8.9 %), furosemide (8.3 %), and propranolol (2.4 %) as the most common. Conclusions Age standardized prevalence of hypertension in rural primary health clinics in Zambia was high compared to other studies in rural Africa; however, we diagnosed hypertension with only one measurement and this may have biased our findings. Future efforts to improve hypertension control should focus on population preventive care and primary healthcare provider education on individual management

Hypertension management in rural primary care facilities in Zambia: a mixed methods study

Abstract Background Improved primary health care is needed in developing countries to effectively manage the growing burden of hypertension. Our objective was to evaluate hypertension management in Zambian rural primary care clinics using process and outcome indicators to assess the screening, monitoring, treatment and control of high blood pressure. Methods Better Health Outcomes through Mentoring and Assessment (BHOMA) is a 5-year, randomized stepped-wedge trial of improved clinical service delivery underway in 46 rural Zambian clinics. Clinical data were collected as part of routine patient care from an electronic medical record system, and reviewed for site performance over time according to hypertension related indicators: screening (blood pressure measurement), management (recorded diagnosis, physical exam or urinalysis), treatment (on medication), and control. Quantitative data was used to develop guides for qualitative in-depth interviews, conducted with health care providers at a proportional sample of half (20) of clinics. Qualitative data was iteratively analyzed for thematic content. Results From January 2011 to December 2014, 318,380 visits to 46 primary care clinics by adults aged ≥ 25 years with blood pressure measurements were included. Blood pressure measurement at vital sign screening was initially high at 89.1% overall (range: 70.1–100%), but decreased to 62.1% (range: 0–100%) by 48 months after intervention start. The majority of hypertensive patients made only one visit to the clinics (57.8%). Out of 9022 patients with at least two visits with an elevated blood pressure, only 49.3% had a chart recorded hypertension diagnosis. Process indicators for monitoring hypertension were <10% and did not improve with time. In in-depth interviews, antihypertensive medication shortages were common, with 15/20 clinics reporting hydrochlorothiazide-amiloride stockouts. Principal challenges in hypertension management included 1) equipment and personnel shortages, 2) provider belief that multiple visits were needed before official management, 3) medication stock-outs, leading to improper prescriptions and 4) poor patient visit attendance. Conclusions Our findings suggest that numerous barriers stand in the way of hypertension diagnosis and management in Zambian primary health facilities. Future work should focus on performance indicator development and validation in low resource contexts, to facilitate regular and systematic data review to improve patient outcomes. Trial registration ClinicalTrials.gov, Identifier NCT01942278 . Date of Registration: September 2013

Health systems performance for hypertension control using a cascade of care approach in South Africa, 2011–2017

Hypertension is a major contributor to global morbidity and mortality. In South Africa, the government has employed a whole systems approach to address the growing burden of non-communicable diseases. We used a novel incident care cascade approach to measure changes in the South African health system's ability to manage hypertension between 2011 and 2017. We used data from Waves 1-5 of the National Income Dynamics Study (NIDS) to estimate trends in the hypertension care cascade and unmet treatment need across four successive cohorts with incident hypertension. We used a negative binomial regression to identify factors that may predict higher rates of hypertension control, controlling for socio-demographic and healthcare factors. In 2011, 19.6% (95%CI 14.2, 26.2) of individuals with incident hypertension were diagnosed, 15.4% (95%CI 10.8, 21.4) were on treatment and 7.1% had controlled blood pressure. By 2017, the proportion of individuals with diagnosed incident hypertension had increased to 24.4% (95%CI 15.9, 35.4). Increases in treatment (23.3%, 95%CI 15.0, 34.3) and control (22.1%, 95%CI 14.1, 33.0) were also observed, translating to a decrease in unmet need for hypertension care from 92.9% in 2011 to 77.9% in 2017. Multivariable regression showed that participants with incident hypertension in 2017 were 3.01 (95%CI 1.77, 5.13) times more likely to have a controlled blood pressure compared to those in 2011. Our data show that while substantial improvements in the hypertension care cascade occurred between 2011 and 2017, a large burden of unmet need remains. The greatest losses in the incident hypertension care cascades came before diagnosis. Nevertheless, whole system programming will be needed to sufficiently address significant morbidity and mortality related to having an elevated blood pressure

Increasing incidence of hemorrhagic fever with renal syndrome could be associated with livestock husbandry in Changchun, Northeastern China

Background: Since the end of the 1990s, the incidence of hemorrhagic fever with renal syndrome (HFRS) has been increasing dramatically in Changchun, northeastern China. However, it is unknown which, and how, underlying risk factors have been involved in the reemergence of the disease.Methods: Data on HFRS cases at the county scale were collected from 1998 to 2012. Data on livestock husbandry including the numbers of large animals (cattle, horses, donkeys and mules), sheep, and deer, and on climatic and land cover variables were also collected. Epidemiological features, including the spatial, temporal and human patterns of disease were characterized. The potential factors related to spatial heterogeneity and temporal trends were analyzed using standard and time-series Poisson regression analysis, respectively.Results: Annual incidence varied among the 10 counties. Shuangyang County in southeastern Changchun had the highest number of cases (1,525 cases; 35.9% of all cases), but its population only accounted for 5.6% of the total population. Based on seasonal pattern in HFRS incidence, two epidemic phases were identified. One was a single epidemic peak at the end of each year from 1988 to 1997 and the other consisted of dual epidemic peaks at both the end and the beginning of each year from 1998 to the end of the study period. HFRS incidence was higher in males compared to females, and most of the HFRS cases occurred in peasant populations. The results of the Poisson regression analysis indicated that the spatial distribution and the increasing incidence of HFRS were significantly associated with livestock husbandry and climate factors, particularly with deer cultivation.Conclusions: Our results indicate that the re-emergence of HFRS in Changchun has been accompanied by changing seasonal patterns over the past 25 years. Integrated measures focusing on areas related to local livestock husbandry could be helpful for the prevention and control of HFRS

Conflicts of Interest in Sell-side Research and The Moderating Role of Institutional Investors

Because sell-side analysts are dependent on institutional investors for performance ratings and trading commissions, we argue that analysts are less likely to succumb to investment banking or brokerage pressure in stocks highly visible to institutional investors. Examining a comprehensive sample of analyst recommendations over the 1994-2000 period, we find that analysts’ recommendations relative to consensus are positively associated with investment banking relationships and brokerage pressure, but negatively associated with the presence of institutional investor owners. The presence of institutional investors is also associated with more accurate earnings forecasts and more timely re-ratings following severe share price falls

Expression profiling of blood samples from an SU5416 Phase III metastatic colorectal cancer clinical trial: a novel strategy for biomarker identification

BACKGROUND: Microarray-based gene expression profiling is a powerful approach for the identification of molecular biomarkers of disease, particularly in human cancers. Utility of this approach to measure responses to therapy is less well established, in part due to challenges in obtaining serial biopsies. Identification of suitable surrogate tissues will help minimize limitations imposed by those challenges. This study describes an approach used to identify gene expression changes that might serve as surrogate biomarkers of drug activity. METHODS: Expression profiling using microarrays was applied to peripheral blood mononuclear cell (PBMC) samples obtained from patients with advanced colorectal cancer participating in a Phase III clinical trial. The PBMC samples were harvested pre-treatment and at the end of the first 6-week cycle from patients receiving standard of care chemotherapy or standard of care plus SU5416, a vascular endothelial growth factor (VEGF) receptor tyrosine kinase (RTK) inhibitor. Results from matched pairs of PBMC samples from 23 patients were queried for expression changes that consistently correlated with SU5416 administration. RESULTS: Thirteen transcripts met this selection criterion; six were further tested by quantitative RT-PCR analysis of 62 additional samples from this trial and a second SU5416 Phase III trial of similar design. This method confirmed four of these transcripts (CD24, lactoferrin, lipocalin 2, and MMP-9) as potential biomarkers of drug treatment. Discriminant analysis showed that expression profiles of these 4 transcripts could be used to classify patients by treatment arm in a predictive fashion. CONCLUSIONS: These results establish a foundation for the further exploration of peripheral blood cells as a surrogate system for biomarker analyses in clinical oncology studies

miR-132 Enhances Dendritic Morphogenesis, Spine Density, Synaptic Integration, and Survival of Newborn Olfactory Bulb Neurons

An array of signals regulating the early stages of postnatal subventricular zone (SVZ) neurogenesis has been identified, but much less is known regarding the molecules controlling late stages. Here, we investigated the function of the activity-dependent and morphogenic microRNA miR-132 on the synaptic integration and survival of olfactory bulb (OB) neurons born in the neonatal SVZ. In situ hybridization revealed that miR-132 expression occurs at the onset of synaptic integration in the OB. Using in vivo electroporation we found that sequestration of miR-132 using a sponge-based strategy led to a reduced dendritic complexity and spine density while overexpression had the opposite effects. These effects were mirrored with respective changes in the frequency of GABAergic and glutamatergic synaptic inputs reflecting altered synaptic integration. In addition, timely directed overexpression of miR-132 at the onset of synaptic integration using an inducible approach led to a significant increase in the survival of newborn neurons. These data suggest that miR-132 forms the basis of a structural plasticity program seen in SVZ-OB postnatal neurogenesis. miR-132 overexpression in transplanted neurons may thus hold promise for enhancing neuronal survival and improving the outcome of transplant therapies

The United States COVID-19 Forecast Hub dataset

Academic researchers, government agencies, industry groups, and individuals have produced forecasts at an unprecedented scale during the COVID-19 pandemic. To leverage these forecasts, the United States Centers for Disease Control and Prevention (CDC) partnered with an academic research lab at the University of Massachusetts Amherst to create the US COVID-19 Forecast Hub. Launched in April 2020, the Forecast Hub is a dataset with point and probabilistic forecasts of incident cases, incident hospitalizations, incident deaths, and cumulative deaths due to COVID-19 at county, state, and national, levels in the United States. Included forecasts represent a variety of modeling approaches, data sources, and assumptions regarding the spread of COVID-19. The goal of this dataset is to establish a standardized and comparable set of short-term forecasts from modeling teams. These data can be used to develop ensemble models, communicate forecasts to the public, create visualizations, compare models, and inform policies regarding COVID-19 mitigation. These open-source data are available via download from GitHub, through an online API, and through R packages

Evaluation of individual and ensemble probabilistic forecasts of COVID-19 mortality in the United States

Short-term probabilistic forecasts of the trajectory of the COVID-19 pandemic in the United States have served as a visible and important communication channel between the scientific modeling community and both the general public and decision-makers. Forecasting models provide specific, quantitative, and evaluable predictions that inform short-term decisions such as healthcare staffing needs, school closures, and allocation of medical supplies. Starting in April 2020, the US COVID-19 Forecast Hub (https://covid19forecasthub.org/) collected, disseminated, and synthesized tens of millions of specific predictions from more than 90 different academic, industry, and independent research groups. A multimodel ensemble forecast that combined predictions from dozens of groups every week provided the most consistently accurate probabilistic forecasts of incident deaths due to COVID-19 at the state and national level from April 2020 through October 2021. The performance of 27 individual models that submitted complete forecasts of COVID-19 deaths consistently throughout this year showed high variability in forecast skill across time, geospatial units, and forecast horizons. Two-thirds of the models evaluated showed better accuracy than a naïve baseline model. Forecast accuracy degraded as models made predictions further into the future, with probabilistic error at a 20-wk horizon three to five times larger than when predicting at a 1-wk horizon. This project underscores the role that collaboration and active coordination between governmental public-health agencies, academic modeling teams, and industry partners can play in developing modern modeling capabilities to support local, state, and federal response to outbreaks