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PURPOSE: Digital methods to augment traditional contact tracing approaches were developed and deployed globally during the COVID-19 pandemic. These Exposure Notification (EN) systems present new opportunities to support public health interventions. To date, there have been attempts to model the impact of such systems, yet no reports have explored the value of real-time system data for predictive epidemiological modeling. METHODS: We investigated the potential to short-term forecast COVID-19 caseloads using data from Californias implementation of the Google Apple Exposure Notification (GAEN) platform, branded as CA Notify. CA Notify is a digital public health intervention leveraging residents smartphones for anonymous EN. We extended a published statistical model that uses prior case counts to investigate the possibility of predicting short-term future case counts and then added EN activity to test for improved forecast performance. Additional predictive value was assessed by comparing the pandemic forecasting models with and without EN activity to the actual reported caseloads from 1-7 days in the future. RESULTS: Observation of time series presents noticeable evidence for temporal association of system activity and caseloads. Incorporating earlier ENs in our model improved prediction of the caseload counts. Using Bayesian inference, we found nonzero influence of EN terms with probability one. Furthermore, we found a reduction in both the mean absolute percentage error and the mean squared prediction error, the latter of at least 5% and up to 32% when using ENs over the model without. CONCLUSIONS: This preliminary investigation suggests smartphone based ENs can significantly improve the accuracy of short-term forecasting. These predictive models can be readily deployed as local early warning systems to triage resources and interventions.

INTRODUCTION: Limited population-based data exist about children with primary nephrotic syndrome (NS). METHODS: We identified a cohort of children with primary NS receiving care in Kaiser Permanente Northern California, an integrated healthcare delivery system caring for >750,000 children. We identified all children 3500 mg/g, urine PCR>3.5 mg/mg, 24-hour urine protein>3500 mg or urine dipstick>300 mg/dL) in laboratory databases or a diagnosis of NS in electronic health records. Nephrologists reviewed health records for clinical presentation and laboratory and biopsy results to confirm primary NS. RESULTS: Among 365 cases of confirmed NS, 179 had confirmed primary NS attributed to presumed minimal change disease (MCD) (72%), focal segmental glomerulosclerosis (FSGS) (23%) or membranous nephropathy (MN) (5%). The overall incidence of primary NS was 1.47 (95% Confidence Interval:1.27-1.70) per 100,000 person-years. Biopsy data were available in 40% of cases. Median age for patients with primary NS was 6.9 (interquartile range:3.7 to 12.9) years, 43% were female and 26% were white, 13% black, 17% Asian/Pacific Islander, and 32% Hispanic. CONCLUSION: This population-based identification of children with primary NS leveraging electronic health records can provide a unique approach and platform for describing the natural history of NS and identifying determinants of outcomes in children with primary NS.

IntroductionPeriprosthetic joint infection (PJI) represents a devastating complication of total joint arthroplasty associated with significant morbidity and mortality. Literature suggests a possible higher incidence of periprosthetic joint infection (PJI) in patients with rheumatoid arthritis (RA). There is, however, no consensus on this purported risk nor a well-defined mechanism. This study investigates how collagen-induced arthritis (CIA), a validated animal model of RA, impacts infectious burden in a well-established model of PJI.MethodsControl mice were compared against CIA mice. Whole blood samples were collected to quantify systemic IgG levels via ELISA. Ex vivo respiratory burst function was measured via dihydrorhodamine assay. Ex vivo Staphylococcus aureus Xen36 burden was measured directly via colony forming unit (CFU) counts and crystal violet assay to assess biofilm formation. In vivo, surgical placement of a titanium implant through the knee joint and inoculation with S. aureus Xen36 was performed. Bacterial burden was then quantified by longitudinal bioluminescent imaging.ResultsMice with CIA demonstrated significantly higher levels of systemic IgG compared with control mice (p = 0.003). Ex vivo, there was no significant difference in respiratory burst function (p = 0.89) or S. aureus bacterial burden as measured by CFU counts (p = 0.91) and crystal violet assay (p = 0.96). In vivo, no significant difference in bacterial bioluminescence between groups was found at all postoperative time points. CFU counts of both the implant and the peri-implant tissue were not significantly different between groups (p = 0.82 and 0.80, respectively).ConclusionThis study demonstrated no significant difference in S. aureus infectious burden between mice with CIA and control mice. These results suggest that untreated, active RA may not represent a significant intrinsic risk factor for PJI, however further mechanistic translational and clinical studies are warranted.

BackgroundBreast arterial calcification (BAC) may be a predictor of cardiovascular events and is highly prevalent in persons with end-stage kidney disease. However, few studies to date have examined the association between mild-to-moderate kidney function and proteinuria with BAC.MethodsWe prospectively enrolled women with no prior cardiovascular disease aged 60 to 79 years undergoing mammography screening at Kaiser Permanente Northern California between 10/24/2012 and 2/13/2015. Urine albumin-to-creatinine ratio (uACR), along with specific laboratory, demographic, and medical data, were measured at the baseline visit. Baseline estimated glomerular filtration rate (eGFR), medication history, and other comorbidities were identified from self-report and/or electronic medical records. BAC presence and gradation (mass) was measured by digital quantification of full-field mammograms.ResultsAmong 3,507 participants, 24.5% were aged ≥70 years, 63.5% were white, 7.5% had eGFR 0 mg) was 27.9%. Neither uACR ≥30 mg/g nor uACR ≥300 were significantly associated with BAC in crude or multivariable analyses. Reduced eGFR was associated with BAC in univariate analyses (odds ratio 1.53, 95% CI: 1.18-2.00), but the association was no longer significant after adjustment for potential confounders. Results were similar in various sensitivity analyses that used different BAC thresholds or analytic approaches.ConclusionsAmong women without cardiovascular disease undergoing mammography screening, reduced eGFR and albuminuria were not significantly associated with BAC.

BackgroundBlood pressure, grip strength and lung function are frequently assessed in longitudinal population studies, but the measurement devices used differ between studies and within studies over time. We aimed to compare measurements ascertained from different commonly used devices.MethodsWe used a randomised cross-over study. Participants were 118 men and women aged 45-74 years whose blood pressure, grip strength and lung function were assessed using two sphygmomanometers (Omron 705-CP and Omron HEM-907), four handheld dynamometers (Jamar Hydraulic, Jamar Plus+ Digital, Nottingham Electronic and Smedley) and two spirometers (Micro Medical Plus turbine and ndd Easy on-PC ultrasonic flow-sensor) with multiple measurements taken on each device. Mean differences between pairs of devices were estimated along with limits of agreement from Bland-Altman plots. Sensitivity analyses were carried out using alternative exclusion criteria and summary measures, and using multilevel models to estimate mean differences.ResultsThe mean difference between sphygmomanometers was 3.9mmHg for systolic blood pressure (95% Confidence Interval (CI):2.5,5.2) and 1.4mmHg for diastolic blood pressure (95% CI:0.3,2.4), with the Omron HEM-907 measuring higher. For maximum grip strength, the mean difference when either one of the electronic dynamometers was compared with either the hydraulic or spring-gauge device was 4-5kg, with the electronic devices measuring higher. The differences were small when comparing the two electronic devices (difference = 0.3kg, 95% CI:-0.9,1.4), and when comparing the hydraulic and spring-gauge devices (difference = 0.2kg, 95% CI:-0.8,1.3). In all cases limits of agreement were wide. The mean difference in FEV1 between spirometers was close to zero (95% CI:-0.03,0.03), limits of agreement were reasonably narrow, but a difference of 0.47l was observed for FVC (95% CI:0.53,0.42), with the ndd Easy on-PC measuring higher.ConclusionOur study highlights potentially important differences in measurement of key functions when different devices are used. These differences need to be considered when interpreting results from modelling intra-individual changes in function and when carrying out cross-study comparisons, and sensitivity analyses using correction factors may be helpful.

People living with HIV/AIDS (PLH) experience high rates of depression and related psychosocial risk factors that vary by gender. This study examines gender differences in depression severity among antiretroviral therapy (ART) patients (n = 362) from a large government ART clinic in Kolkata, India. Hypotheses for multiple linear regression models were guided by an integrated gendered stress process model focusing on variables reflecting social status (age, partner status), stressors (stigma), and resources (income, social support). Depressive symptoms were assessed with the Hospital Anxiety and Depression Scale (HADS); 22% of the sample reached the cutoff for severe depression, 56% moderate, and 13% mild depression. Compared to men, women reported lower income, education (50% no formal education vs. 20% men), availability of emotional and instrumental support, and were less likely to be married or cohabiting (53% women vs. 72% of men). However, more women had partners who were HIV-positive (78% women vs. 46% men). Overall, depression severity was negatively associated with availability of emotional support and self-distraction coping, and positively associated with internalized HIV/AIDS stigma, availability of instrumental support, and behavioral disengagement coping. Interactions for instrumental support by income and partner status by age varied significantly by gender. Analyses stratified by gender indicated that: 1) Frequently seeking instrumental support from others was protective for men at all income levels, but only for high-income women; and 2) having a partner was protective for men as they aged, but not for women. These results suggest that gender disparities in depression severity are created and maintained by women's lower social status and limited access to resources. The effect of stigma on depression severity did not vary by gender. These findings may inform the tailoring of future interventions to address mental health needs of PLH in India, particularly gender disparities in access to material and social resources for coping with HIV. Trial Registration: ClinicalTrials.gov registration #NCT02118454, registered April 2014.

The Precautionary Approach to Fisheries Management requires an assessment of the impact of uncertainty on the risk of achieving management objectives. However, the main quantities, such as spawning stock biomass (SSB) and fish mortality (F), used in management metrics cannot be directly observed. This requires the use of models to provide guidance, for which there are three paradigms: the best assessment, model ensemble, and Management Strategy Evaluation (MSE). It is important to validate the models used to provide advice. In this study, we demonstrate how stock assessment models can be validated using a diagnostic toolbox, with a specific focus on prediction skill. Prediction skill measures the precision of a predicted value, which is unknown to the model, in relation to its observed value. By evaluating the accuracy of model predictions against observed data, prediction skill establishes an objective framework for accepting or rejecting model hypotheses, as well as for assigning weights to models within an ensemble. Our analysis uncovers the limitations of traditional stock assessment methods. Through the quantification of uncertainties and the integration of multiple models, our objective is to improve the reliability of management advice considering the complex interplay of factors that influence the dynamics of fish stocks. [ABSTRACT FROM AUTHOR]

Hemodialysis using hollow-fiber membranes provides life-sustaining treatment for nearly 2 million patients worldwide with end stage renal disease (ESRD). However, patients on hemodialysis have worse long-term outcomes compared to kidney transplant or other chronic illnesses. Additionally, the underlying membrane technology of polymer hollow-fiber membranes has not fundamentally changed in over four decades. Therefore, we have proposed a fundamentally different approach using microelectromechanical systems (MEMS) fabrication techniques to create thin-flat sheets of silicon-based membranes for implantable or portable hemodialysis applications. The silicon nanopore membranes (SNM) have biomimetic slit-pore geometry and uniform pores size distribution that allow for exceptional permeability and selectivity. A quantitative diffusion model identified structural limits to diffusive solute transport and motivated a new microfabrication technique to create SNM with enhanced diffusive transport. We performed in vitro testing and extracorporeal testing in pigs on prototype membranes with an effective surface area of 2.52 cm2 and 2.02 cm2, respectively. The diffusive clearance was a two-fold improvement in with the new microfabrication technique and was consistent with our mathematical model. These results establish the feasibility of using SNM for hemodialysis applications with additional scale-up.

Phytophthora species are primary causal agents of raspberry root rot and wilting complex (RRWC), a disease complex that is of major concern to raspberry producers worldwide. Accurate identification of the causal agents is a first step for effective disease management. Advancements in molecular diagnostics can facilitate the detection of multiple pathogen species associated with this disease complex. We developed multiplex targeted-sequencing methods using degenerate primers for heat shock protein 90, elongation factor 1α and β-tubulin genes to identify Phytophthora species causing RRWC. One hundred and twenty-eight isolates recovered during 2018 to 2020 from diverse fields in major raspberry growing areas of British Columbia (BC) were sequenced and identified by comparing with known reference sequences of 142 Phytophthora species, 111 Pythium species, and nine Phytopythium species in the NCBI database. This multiplex targeted-sequencing method was highly specific and identified two species of Phytophthora associated with RRWC. These were P. rubi (85% of isolates) and P. gonapodyides (15% of isolates). Phytophthora rubi was predominantly isolated from the cultivars 'Chemainus' (51%), 'Rudi' (27%) and 'Meeker' (15%), whereas P. gonapodyides was predominately isolated from the moderately resistant cultivar 'Cascade Bounty'. Pathogenicity studies on intact plants and detached leaves confirmed that P. rubi and P. gonapodyides can cause symptoms of RRWC on raspberry, thus fulfilling Koch's postulates. To our knowledge, this is the first report of P. gonapodyides as a causal agent of RRWC on raspberry in BC. This study provides novel insights into the identification and species composition of Phytophthora associated with RRWC in raspberry production systems.

UDP-glucose dehydrogenase (UGDH) generates essential precursors of hyaluronic acid (HA) synthesis, however mechanisms regulating its activity are unclear. We used enzyme histostaining and quantitative image analysis to test whether cytokines that stimulate HA synthesis upregulate UGDH activity. Fibroblast-like synoviocytes (FLS, from N = 6 human donors with knee pain) were cultured, freeze-thawed, and incubated for 1 hour with UDP-glucose, NAD+ and nitroblue tetrazolium (NBT) which allows UGDH to generate NADH, and NADH to reduce NBT to a blue stain. Compared to serum-free medium, FLS treated with PDGF showed 3-fold higher UGDH activity and 6-fold higher HA release, but IL-1beta/TGF-beta1 induced 27-fold higher HA release without enhancing UGDH activity. In selected proliferating cells, UGDH activity was lost in the cytosol, but preserved in the nucleus. Cell-free assays led us to discover that diaphorase, a cytosolic enzyme, or glutathione reductase, a nuclear enzyme, was necessary and sufficient for NADH to reduce NBT to a blue formazan dye in a 1-hour timeframe. Primary synovial fibroblasts and transformed A549 fibroblasts showed constitutive diaphorase/GR staining activity that varied according to supplied NADH levels, with relatively stronger UGDH and diaphorase activity in A549 cells. Unilateral knee injury in New Zealand White rabbits (N = 3) stimulated a coordinated increase in synovial membrane UGDH and diaphorase activity, but higher synovial fluid HA in only 2 out of 3 injured joints. UGDH activity (but not diaphorase) was abolished by N-ethyl maleimide, and inhibited by peroxide or UDP-xylose. Our results do not support the hypothesis that UGDH is a rate-liming enzyme for HA synthesis under catabolic inflammatory conditions that can oxidize and inactivate the UGDH active site cysteine. Our novel data suggest a model where UGDH activity is controlled by a redox switch, where intracellular peroxide inactivates, and high glutathione and diaphorase promote UGDH activity by maintaining the active site cysteine in a reduced state, and by recycling NAD+ from NADH.

BackgroundDegenerative cervical myelopathy (DCM) is a chronic neurological condition estimated to affect 1 in 50 adults. Due to its diverse impact, trajectory and management options, patient-centred care and shared decision making are essential. In this scoping review, we aim to explore whether information needs in DCM are currently being met in available DCM educational resources. This forms part of a larger Myelopathy.org project to promote shared decision making in DCM.MethodsA search was completed encompassing MEDLINE, Embase and grey literature. Resources relevant to DCM were compiled for analysis. Resources were grouped into 5 information types: scientific literature, videos, organisations, health education websites and patient information leaflets. Resources were then further arranged into a hierarchical framework of domains and subdomains, formed through inductive analysis. Frequency statistics were employed to capture relative popularity as a surrogate marker of potential significance.ResultsOf 2674 resources, 150 information resources addressing DCM were identified: 115 scientific literature resources, 28 videos, 5 resources from health organisations and 2 resources from health education websites. Surgical management was the domain with the largest number of resources (66.7%, 100/150). The domain with the second largest number of resources was clinical presentation and natural history (28.7%, 43/150). Most resources (83.3%, 125/150) were designed for professionals. A minority (11.3% 17/150) were written for a lay audience or for a combined audience (3.3%, 5/150).ConclusionEducational resources for DCM are largely directed at professionals and focus on surgical management. This is at odds with the needs of stakeholders in a lifelong condition that is often managed without surgery, highlighting an unmet educational need.

Chronic alcohol consumption leads to a spectrum of liver disease that is associated with significant global mortality and morbidity. Alcohol is known to deplete hepatic vitamin A content, which has been linked to the pathogenesis of alcoholic liver disease. It has been suggested that induction of Cytochrome P450 2E1 (CYP2E1) contributes to alcohol-induced hepatic vitamin A depletion, but the possible contributions of other retinoid-catabolizing CYPs have not been well studied. The main objective of this study was to better understand alcohol-induced hepatic vitamin A depletion and test the hypothesis that alcohol-induced depletion of hepatic vitamin A is due to CYP-mediated oxidative catabolism. This hypothesis was tested in a mouse model of chronic alcohol consumption, including wild type and Cyp2e1-/- mice. Our results show that chronic alcohol consumption is associated with decreased levels of hepatic retinol, retinyl esters, and retinoic acid. Moreover, the depletion of hepatic retinoid is associated with the induction of multiple retinoid catabolizing CYPs, including CYP26A1, and CYP26B1 in alcohol fed wild type mice. In Cyp2e1-/- mice, alcohol-induced retinol decline is blunted but retinyl esters undergo a change in their acyl composition and decline upon alcohol exposure like WT mice. In conclusion, the alcohol induced decline in hepatic vitamin A content is associated with increased expression of multiple retinoid-catabolizing CYPs, including the retinoic acid specific hydroxylases CYP26A1 and CYP26B1.

Objective Indices of cardiovascular disease (CVD) risk, vascular endothelial dilation, arterial stiffness and endothelial repair were examined in persons with HIV (PWH) on an antiretroviral therapy (ART) that included abacavir (ABC+) in comparison with PWH on ART without abacavir (ABC-), and with HIV seronegative (HIV-) individuals. Approach The 115 participants (63% men), aged 30–50 years, did not have CVD, metabolic, endocrine, or chronic renal conditions. PWH were on stable ART for six-months or more. Vascular assessments included flow-mediated dilation (FMD), aortic, radial and femoral arterial stiffness (cAIx, crPWV, cfPWV), and thigh and calf arterial compliance (Vmax50). Endothelial repair was indexed by endothelial progenitor cell colony forming units (EPC-CFU). Traditional CVD risk measures included blood pressure, central adiposity, lipids, insulin resistance (HOMA-IR), CRP and ASCVD score. Analyses controlled for demographics (age, sex, education), medications (antihypertensive, statin/fibrate, antipsychotic), and substance abuse (ASSIST). Results No group differences were observed in central adiposity, HOMA-IR, CRP, or ASCVD risk score. However, the ABC- group displayed greater dyslipidemia. The ABC+ group displayed no difference on FMD, cAIx, cfPWV or calf Vmax50 compared with other groups. When CD4 count and viral load were controlled, no additional differences between the ABC+ and ABC- groups emerged. Analyses of crPWV and thigh Vmax50 suggested supported by a trend toward lower EPC-CFU in the HIV+ groups than the HIV- group. Conclusions Findings indicate that ABC treatment of 30–50 year-old PWH on stable ART is not likely to contribute in a robust way to higher CVD risk.

BackgroundType 2 diabetes mellitus (T2DM) worldwide continues to increase, in particular in India. Early T2DM diagnosis followed by appropriate management will result in more cardiovascular event free life years. However, knowledge of the cardiovascular profile of newly diagnosed T2DM patients is still limited. The aim of this study was to understand the extent of cardiovascular disease (CVD) risk of newly diagnosed T2DM patients in India.MethodsA cross sectional observational study was conducted to evaluate clinical laboratory and socio-demographic parameters of 5,080 newly diagnosed T2DM patients (48.3 ± 12.8 years of age; 36.7% female). In addition, we determined their cardiovascular risk according to the guidelines of the Lipid Association of India (LAI) and the criteria of the QRISK3 score.ResultsOf the newly T2DM diagnosed patients in India 2,007(39.5%) were classified as "High risk" and 3,073 (60.5%) were classified as "Very high risk" based on LAI criteria. On average, patients had 1.7 ± 0.9 major atherosclerotic cardiovascular disease (ASCVD) risk factors. Low HDL-C value was the most frequent major risk (2,823; 55.6%) followed by high age (2,502; 49.3%), hypertension (2,141; 42.1%), smoking/tobacco use (1,078; 21.2%) and chronic kidney disease stage 3b or higher (568; 11.2%). In addition, 4,192 (82.5%) patients appeared to have at least one cholesterol abnormality and, if the latest LAI recommendations are applied, 96.5% (4,902) presented with lipid values above recommended targets. Based on the QRISK3 calculation Indian diabetes patients had an average CVD risk of 15.3 ± 12.3%, (12.2 ± 10.1 vs. 17.1 ± 13.5 [pConclusionsNewly diagnosed Indian T2DM patients are at high ASCVD risk. Our data therefore support the notion that further extension of nationwide ASCVD risk identification programs and prevention strategies to reduce the occurrence of cardiovascular diseases are warranted.

Plants encounter and respond to numerous abiotic stresses during their lifetimes. These stresses are often related and could therefore elicit related responses. There are, however, relatively few detailed comparisons between multiple different stresses at the molecular level. Here, we investigated the phenotypic and transcriptomic response of cultivated sunflower (Helianthus annuus L.) seedlings to three water-related stresses (i.e., dry-down, an osmotic challenge, and salt stress), as well as a generalized low-nutrient stress. All four stresses negatively impacted seedling growth, with the nutrient stress having a more divergent response from control as compared to the water-related stresses. Phenotypic responses were consistent with expectations for growth in low-resource environments, including increased (i.e., less negative) carbon fractionation values and leaf C:N ratios, as well as increased belowground biomass allocation. The number of differentially expressed genes (DEGs) under stress was greater in leaf tissue, but roots exhibited a higher proportion of DEGs unique to individual stresses. Overall, the three water-related stresses had a more similar transcriptomic response to each other vs. nutrient stress, though this pattern was more pronounced in root vs. leaf tissue. In contrast to our DEG analyses, co-expression network analysis revealed that there was little indication of a shared response between the four stresses in despite the majority of DEGs being shared between multiple stresses. Importantly, osmotic stress, which is often used to simulate drought stress in experimental settings, had little transcriptomic resemblance to true water limitation (i.e., dry-down) in our study, calling into question its utility as a means for simulating drought.

BackgroundResuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) is controversial as a hemorrhage control adjunct due to lack of data with a suitable control group. We aimed to determine outcomes of trauma patients in shock undergoing REBOA versus no-REBOA.MethodsThis single-center, retrospective, matched cohort study analyzed patients ≥16 years in hemorrhagic shock without cardiac arrest (2000-2019). REBOA (R; 2015-2019) patients were propensity matched 2:1 to historic (H; 2000-2012) and contemporary (C; 2013-2019) groups. In-hospital mortality and 30-day survival were analyzed using chi-squared and log rank testing, respectively.ResultsA total of 102,481 patients were included (R = 57, C = 88,545, H = 13,879). Propensity scores were assigned using age, race, mechanism, lowest systolic blood pressure, lowest Glasgow Coma Score (GCS), and body region Abbreviated Injury Scale scores to generate matched groups (R = 57, C = 114, H = 114). In-hospital mortality was significantly lower in the REBOA group (19.3%) compared to the contemporary (35.1%; p = 0.024) and historic (44.7%; p = 0.001) groups. 30-day survival was significantly higher in the REBOA versus no-REBOA groups.ConclusionIn a high-volume center where its use is part of a coordinated hemorrhage control strategy, REBOA is associated with improved survival in patients with noncompressible torso hemorrhage.

BackgroundIn 2019, 2.4 million neonates died globally, with most deaths occurring in low-resource settings. Despite the introduction of neonatal intensive care units (NICUs) in these settings, neonatal mortality remains high, and caring for sick neonates around the clock can be challenging due to limited staff and resources.ObjectiveTo evaluate whether neonatal intensive care admissions during daytime and overnight hours affects in-hospital neonatal mortality.MethodsA retrospective case-control study was conducted using 2016 chart data at a University hospital in Ethiopia. Cases were defined as neonates who died in the NICU, and controls were defined as neonates who survived. Overnight hours were defined as 17:00 to 07:59, and day hours were defined as 08:00 to 16:59. Univariate and multivariate logistic regressions were used to investigate the relationship between time of admission and mortality, along with perinatal characteristics.ResultsA total of 812 neonates, 207 cases and 605 controls, met inclusion criteria. There were 342 admissions during the day and 470 overnight. Neonatal mortality (aOR 1.02, 95% CI [0.64-1.62], p = 0.93) was not associated with overnight admissions after controlling for maternal age, parity, C-section, birthweight, and gestational age, respiratory distress, and admission level of consciousness. Admission heart rate >160 (aOR 0.52, 95% CI [0.30-0.91], p = 0.02) was the only variable significantly associated with overnight admissions.ConclusionBeing admitted overnight to the NICU in Gondar, Ethiopia was not associated with increased mortality, consistent with a constant level of care, regardless of the time of admission. Further qualitative and implementation research are needed to understand contextual factors that have affected these data.

BackgroundThe data on the COVID-19 patients who were discharged to self-quarantine is lacking.AimThe aim of the study was to investigate the percentage of COVID-19 positive patients that were hospitalized within a three-week period after discharge from ED to self-quarantine.MethodsThe patients who had confirmed SARS-CoV-2 on RT-PCR of the nasopharyngeal swab and were discharged from ED of a tertiary care hospital in the USA to self-quarantine from March 01- July 31, 2020, were included. Patients were divided into two groups based on serum albumin levels and were followed up for three weeks to see if low level of albumin increased the risk of hospitalization. Univariate and multivariate logistic regression analyses were performed to study the effect of albumin level and outcomes.ResultsA total of 112 patients were included in the study out of which 65 had low serum albumin (ConclusionThe low serum albumin was not associated with the risk of hospitalization in COVID-19 patients who were initially discharged to self-quarantine.

IntroductionThe United States Food and Drug Administration (FDA) Gastrointestinal Drug Advisory Committee (GIDAC) is involved in gastrointestinal drug application reviews. Characteristics and conflicts of interest (COI) in GIDAC meetings are not well described. This study analyzed FDA GIDAC meetings and characteristics that predict recommendations.MethodsIn this cross-sectional study, all publicly available GIDAC meetings where proposed medications were voted on were included. Data were collected regarding indications, medication sponsor, primary efficacy studies, and voting member characteristics (e.g. committee membership, COI). Univariate analyses were conducted at per-meeting and per-vote levels to assess for predictors of committee recommendation and individual votes respectively.ResultsThirty-four meetings with 476 individual votes from 1998-2018 were included. Twenty-three (68%) proposals were recommended for approval and 25 (74%) received FDA approval. Most proposals involved >1 primary study (n = 27, 79%). At least one voting member had a COI in 24 (71%) of 34 meetings. Twelve (35%) meetings had at least one sponsor COI. Among 476 individual votes, 74 (15.5%) involved a COI, with 33 (6.9%) sponsor COI. COI decreased significantly over time, with fewer COI in 2006-2010, 2011-2015, and 2016-2020 compared to 1996-2000 and 2001-2005 (p0.05 for all univariate analyses).ConclusionsThe GIDAC reviewed 34 proposals from 1998-2018. The majority were recommended for approval and later approved by the FDA, highlighting the GIDAC's prominence in the regulatory process. COI are present among GIDAC panelists but decreasing over time and not associated with recommendations.

While chemotherapy is the most effective therapeutic approach for treating a variety of cancer patients, commonly used chemotherapeutic agents, often induce several adverse effects. Escalating evidence indicates that chemotherapeutics, particularly doxorubicin (DOX) and cyclophosphamide (CPS), induce cognitive impairment associated with central nervous system toxicity. This study was performed to determine neuroprotective effects of Oroxylum indicum extract (OIE) in regard to preventing chemotherapy induced cognitive impairment (CICI) occurring after 4 cycles of DOX (2mg/kg) and CPS (50mg/kg) combination chemotherapy in male C57BL/6J mice. OIE significantly prevented the chemotherapy impaired short-term cognitive performance, exploratory behavior associated with cognitive performance, cognitive performance, and spatial learning and memory in the Y-maze, Open-Field, Novel Object Recognition, and Morris Water Maze tests, respectively. These data suggest that OIE protects from the CICI. OIE decreased the reactive oxygen species and lipid peroxide generated by the chemotherapy treatment in the brain, while also blocking the chemotherapy-induced glutathione depletion. These results establish that OIE exhibits potent antioxidant activity in chemotherapy treated mice. Notably, OIE significantly increased the Complex-I and Complex-IV activities in the brain, indicating that OIE enhances mitochondrial function in the brain. In silico analysis of the major active chemical constituents (Oroxylin A, Baicalein and Chrysin) of OIE indicated that OIE has a favorable absorption, distribution, metabolism and excretion (ADME) profile. Taken together, our results are consistent with the conclusion that OIE prevents CICI by counteracting oxidative stress and perhaps by improving mitochondrial function.

BackgroundEjection fraction (EF) is an important prognostic factor in heart failure (HF), but administrative claims databases lack information on EF. We previously developed a model to predict EF class from Medicare claims. Here, we evaluated the performance of this model in an external validation sample of commercial insurance enrollees.MethodsTruven MarketScan claims linked to electronic medical records (EMR) data (IBM Explorys) containing EF measurements were used to identify a cohort of US patients with HF between 01-01-2012 and 10-31-2019. By applying the previously developed model, patients were classified into HF with reduced EF (HFrEF) or preserved EF (HFpEF). EF values recorded in EMR data were used to define gold-standard HFpEF (LVEF ≥45%) and HFrEF (LVEFResultsA total of 7,001 HF patients with an average age of 71 years were identified, 1,700 (24.3%) of whom had HFrEF. An overall accuracy of 0.81 (95% CI: 0.80-0.82) was seen in this external validation sample. For HFpEF, the model had sensitivity of 0.96 (95%CI, 0.95-0.97) and PPV of 0.81 (95% CI, 0.81-0.82); while for HFrEF, the sensitivity was 0.32 (95%CI, 0.30-0.34) and PPV was 0.73 (95%CI, 0.69-0.76). These results were consistent with what was previously published in US Medicare claims data.ConclusionsThe successful validation of the Medicare claims-based model provides evidence that this model may be used to identify patient subgroups with specific EF class in commercial claims databases as well.

IntroductionPeriprosthetic joint infection (PJI) represents a devastating complication of total joint arthroplasty associated with significant morbidity and mortality. Literature suggests a possible higher incidence of periprosthetic joint infection (PJI) in patients with rheumatoid arthritis (RA). There is, however, no consensus on this purported risk nor a well-defined mechanism. This study investigates how collagen-induced arthritis (CIA), a validated animal model of RA, impacts infectious burden in a well-established model of PJI.MethodsControl mice were compared against CIA mice. Whole blood samples were collected to quantify systemic IgG levels via ELISA. Ex vivo respiratory burst function was measured via dihydrorhodamine assay. Ex vivo Staphylococcus aureus Xen36 burden was measured directly via colony forming unit (CFU) counts and crystal violet assay to assess biofilm formation. In vivo, surgical placement of a titanium implant through the knee joint and inoculation with S. aureus Xen36 was performed. Bacterial burden was then quantified by longitudinal bioluminescent imaging.ResultsMice with CIA demonstrated significantly higher levels of systemic IgG compared with control mice (p = 0.003). Ex vivo, there was no significant difference in respiratory burst function (p = 0.89) or S. aureus bacterial burden as measured by CFU counts (p = 0.91) and crystal violet assay (p = 0.96). In vivo, no significant difference in bacterial bioluminescence between groups was found at all postoperative time points. CFU counts of both the implant and the peri-implant tissue were not significantly different between groups (p = 0.82 and 0.80, respectively).ConclusionThis study demonstrated no significant difference in S. aureus infectious burden between mice with CIA and control mice. These results suggest that untreated, active RA may not represent a significant intrinsic risk factor for PJI, however further mechanistic translational and clinical studies are warranted.

IntroductionLimited population-based data exist about children with primary nephrotic syndrome (NS).MethodsWe identified a cohort of children with primary NS receiving care in Kaiser Permanente Northern California, an integrated healthcare delivery system caring for >750,000 children. We identified all children 3500 mg/g, urine PCR>3.5 mg/mg, 24-hour urine protein>3500 mg or urine dipstick>300 mg/dL) in laboratory databases or a diagnosis of NS in electronic health records. Nephrologists reviewed health records for clinical presentation and laboratory and biopsy results to confirm primary NS.ResultsAmong 365 cases of confirmed NS, 179 had confirmed primary NS attributed to presumed minimal change disease (MCD) (72%), focal segmental glomerulosclerosis (FSGS) (23%) or membranous nephropathy (MN) (5%). The overall incidence of primary NS was 1.47 (95% Confidence Interval:1.27-1.70) per 100,000 person-years. Biopsy data were available in 40% of cases. Median age for patients with primary NS was 6.9 (interquartile range:3.7 to 12.9) years, 43% were female and 26% were white, 13% black, 17% Asian/Pacific Islander, and 32% Hispanic.ConclusionThis population-based identification of children with primary NS leveraging electronic health records can provide a unique approach and platform for describing the natural history of NS and identifying determinants of outcomes in children with primary NS.

The endangered snow leopard Panthera uncia occurs in human use landscapes in the mountains of South and Central Asia. Conservationists generally agree that snow leopards must be conserved through a land-sharing approach, rather than land-sparing in the form of strictly protected areas. Effective conservation through land-sharing requires a good understanding of how snow leopards respond to human use of the landscape. Snow leopard density is expected to show spatial variation within a landscape because of variation in the intensity of human use and the quality of habitat. However, snow leopards have been difficult to enumerate and monitor. Variation in the density of snow leopards remains undocumented, and the impact of human use on their populations is poorly understood. We examined spatial variation in snow leopard density in Spiti Valley, an important snow leopard landscape in India, via spatially explicit capture-recapture analysis of camera trap data. We camera trapped an area encompassing a minimum convex polygon of 953 km2. Our best model estimated an overall density of 0.5 (95% CI: 0.31-0.82) mature snow leopards per 100 km2. Using AIC, our best model showed the density of snow leopards to depend on estimated wild prey density, movement about activity centres to depend on altitude, and the expected number of encounters at the activity centre to depend on topography. Models that also used livestock biomass as a density covariate ranked second, but the effect of livestock was weak. Our results highlight the importance of maintaining high density pockets of wild prey populations in multiple-use landscapes to enhance snow leopard conservation.

ObjectiveEvidence for the management of acute otitis externa (AOE) is limited, with unclear diagnostic criteria and variably reported outcome measures that may not reflect key stakeholder priorities. We aimed to develop 1) a definition, 2) diagnostic criteria and 3) a core outcome set (COS) for AOE.Study designCOS development according to Core Outcome Measures in Effectiveness Trials (COMET) methodology and parallel consensus selection of diagnostic criteria/definition.SettingStakeholders from the United Kingdom.Subjects and methodsComprehensive literature review identified candidate items for the COS, definition and diagnostic criteria. Nine individuals with past AOE generated further patient-centred candidate items. Candidate items were rated for importance by patient and professional (ENT doctors, general practitioners, microbiologists, nurses, audiologists) stakeholders in a three-round online Delphi exercise. Consensus items were grouped to form the COS, diagnostic criteria, and definition.ResultsCandidate COS items from patients (n = 28) and literature (n = 25) were deduplicated and amalgamated to a final candidate list (n = 46). Patients emphasised quality-of-life and the impact on daily activities/work. Via the Delphi process, stakeholders agreed on 31 candidate items. The final COS covered six outcomes: pain; disease severity; impact on quality-of-life and daily activities; patient satisfaction; treatment-related outcome; and microbiology. 14 candidate diagnostic criteria were identified, 8 reaching inclusion consensus. The final definition for AOE was 'diffuse inflammation of the ear canal skin of less than 6 weeks duration'.ConclusionThe development and adoption of a consensus definition, diagnostic criteria and a COS will help to standardise future research in AOE, facilitating meta-analysis. Consulting former patients throughout development highlighted deficiencies in the outcomes adopted previously, in particular concerning the impact of AOE on daily life.

BackgroundSince 2008, the Canadian Institutes of Health Research (CIHR) has mandated that studies it funds either in whole or in part are required to publish their results as open access (OA) within 12 months of publication using either online repositories and/or OA journals. Yet, there is evidence that authors are poorly compliant with this mandate. Specifically, there has been an apparent decrease in OA publication after 2015, which coincides with a change in the OA policy during the same year. One particular policy change that may have contributed to this decline was lifting the requirement that authors deposit their article in an OA repository immediately upon publication. We investigated the proportion of OA compliance of CIHR-funded studies in the period before and after the policy change of 2015 with manual confirmation of both CIHR funding and OA status.Methods and findingsWe identified CIHR-funded studies published between the years 2014 to 2017 using a comprehensive search in the Web of Science (WoS). We took a stratified random sample from all four years (i.e. 2014 to 2017), with 250 studies from each year. Two authors independently reviewed the final full-text publications retrieved from the journal web page to determine to confirm CIHR funding, as indicated in the acknowledgements or elsewhere in the paper. For each study, we also collected bibliometric data that included citation count and Altmetric attention score Statistical analyses were conducted using two-tailed Fisher's exact test with relative risk (RR). Among the 851 receiving CIHR funding published from 2014 to 2017, the percentage of CIHR-funded studies published as OA significantly decreased from 79.6% in 2014 to 70.3% in 2017 (RR = 0.88, 95% CI: 0.79-0.99, P = 0.028). When considering all four years, there was no significant difference in the percentage of CIHR-funded studies published as OA in both 2014 and 2015 compared to both 2016 and 2017 (RR = 0.97, 95% CI: 0.90-1.05, P = 0.493). Additionally, OA publications had significantly higher citation count (both in year of publication and in total) and higher attention scores (PConclusionsOverall, we found that there was a significant decrease in the proportion of CIHR funded studies published as OA from 2014 compared to 2017, though this difference did not persist when comparing both 2014-2015 to 2016-2017. The primary limitation was the reliance of self-reported data from authors on CIHR funding status. We posit that this decrease may be attributable to CIHR's OA policy change in 2015. Further exploration is warranted to both validate these studies using a larger dataset and, if valid, investigate the effects of potential interventions to improve the OA compliance, such as use of a CIHR publication database, and reinstatement of a policy for authors to immediately submit their findings to OA repositories upon publication.

The conserved oligomeric Golgi (COG) complex maintains correct Golgi structure and function during retrograde trafficking. Glycine max has 2 paralogs of each COG gene, with one paralog of each gene family having a defense function to the parasitic nematode Heterodera glycines. Experiments presented here show G. max COG paralogs functioning in defense are expressed specifically in the root cells (syncytia) undergoing the defense response. The expressed defense COG gene COG7-2-b is an alternate splice variant, indicating specific COG variants are important to defense. Transcriptomic experiments examining RNA isolated from COG overexpressing and RNAi roots show some COG genes co-regulate the expression of other COG complex genes. Examining signaling events responsible for COG expression, transcriptomic experiments probing MAPK overexpressing roots show their expression influences the relative transcript abundance of COG genes as compared to controls. COG complex paralogs are shown to be found in plants that are agriculturally relevant on a world-wide scale including Manihot esculenta, Zea mays, Oryza sativa, Triticum aestivum, Hordeum vulgare, Sorghum bicolor, Brassica rapa, Elaes guineensis and Saccharum officinalis and in additional crops significant to U.S. agriculture including Beta vulgaris, Solanum tuberosum, Solanum lycopersicum and Gossypium hirsutum. The analyses provide basic information on COG complex biology, including the coregulation of some COG genes and that MAPKs functioning in defense influence their expression. Furthermore, it appears in G. max and likely other crops that some level of neofunctionalization of the duplicated genes is occurring. The analysis has identified important avenues for future research broadly in plants.

BackgroundThe use of ≥30 mL/Kg fluid bolus in congestive heart failure (CHF) patients presenting with severe sepsis or septic shock remained controversial due to the paucity of data.MethodsThe retrospective case-control study included 671 adult patients who presented to the emergency department of a tertiary care hospital from January 01, 2017 to December 31, 2019 with severe sepsis or septic shock. Patients were categorized into the CHF group and the non-CHF group. The primary outcome was to evaluate the compliance with ≥30 mL/Kg fluid bolus within 6 hours of presentation. The comparison of baseline characteristics and secondary outcomes were done between the groups who received ≥30 mL/Kg fluid bolus. For the subgroup analysis of the CHF group, it was divided based on if they received ≥30 mL/Kg fluid bolus or not, and comparison was done for baseline characteristics and secondary outcomes. Univariate and multivariable analyses were performed to explore the differences between the groups for in-hospital mortality and mechanical ventilation.ResultsThe use of ≥30 mL/Kg fluid bolus was low in both the CHF and non-CHF groups [39% vs. 66% (pConclusionThe use of ≥30 mL/Kg fluid bolus seems to confer protection against in-hospital mortality and is not associated with increased chances of mechanical ventilation in heart failure patients presenting with severe sepsis or septic shock.

Early presentation for childhood cataract surgery is an important first step in preventing related visual impairment and blindness. In the absence of neonatal eye screening programmes in developing countries, the early identification of childhood cataract remains a major challenge. The primary aim of this study was to identify potential barriers to accessing childhood cataract services from the perspective of parents and carers, as a critical step towards increasing the timely uptake of cataract surgery. In-depth interviews were conducted using a pre-designed topic guide developed for this study to seek the views of parents and carers in nine geographic locations across eight states in India regarding their perceived barriers and enablers to accessing childhood cataract services. A total of 35 in-depth interviews were conducted including 30 at the hospital premises and 5 in the participants’ homes. All interviews were conducted in the local language and audio taped for further transcription and analysis. Data were organised using NVivo 11 and a thematic analysis was conducted utilising the Theoretical Domains Framework (TDF), an integrative framework of behavioural theories. The themes identified from interviews related to 11 out of 12 TDF domains. TDF domains associated with barriers included: ‘Environmental context and resources’, ‘Beliefs about consequences’ and ‘Social influences’. Reported enablers were identified in three theoretical domains: ‘Social influences’, ‘Beliefs about consequences’ and ‘Motivations and goals’. This comprehensive TDF approach enabled us to understand parents’ perceived barriers and enablers to accessing childhood cataract services, which could be targeted in future interventions to improve timely uptake.

IntroductionWith increasing rates of opioid overdoses in the US, a surveillance tool to identify high-risk patients may help facilitate early intervention.ObjectiveTo develop an algorithm to predict overdose using routinely-collected healthcare databases.MethodsWithin a US commercial claims database (2011-2015), patients with ≥1 opioid prescription were identified. Patients were randomly allocated into the training (50%), validation (25%), or test set (25%). For each month of follow-up, pooled logistic regression was used to predict the odds of incident overdose in the next month based on patient history from the preceding 3-6 months (time-updated), using elastic net for variable selection. As secondary analyses, we explored whether using simpler models (few predictors, baseline only) or different analytic methods (random forest, traditional regression) influenced performance.ResultsWe identified 5,293,880 individuals prescribed opioids; 2,682 patients (0.05%) had an overdose during follow-up (mean: 17.1 months). On average, patients who overdosed were younger and had more diagnoses and prescriptions. The elastic net model achieved good performance (c-statistic 0.887, 95% CI 0.872-0.902; sensitivity 80.2, specificity 80.1, PPV 0.21, NPV 99.9 at optimal cutpoint). It outperformed simpler models based on few predictors (c-statistic 0.825, 95% CI 0.808-0.843) and baseline predictors only (c-statistic 0.806, 95% CI 0.787-0.26). Different analytic techniques did not substantially influence performance. In the final algorithm based on elastic net, the strongest predictors were age 18-25 years (OR: 2.21), prior suicide attempt (OR: 3.68), opioid dependence (OR: 3.14).ConclusionsWe demonstrate that sophisticated algorithms using healthcare databases can be predictive of overdose, creating opportunities for active monitoring and early intervention.

BackgroundQuarantine often is an unpleasant experience. The aim of this study is to explore the degree of psychological distress in terms of-Depression, Anxiety and Stress among the adult population in India during the strict 21 days mandatory lockdown. We hypothesize that quantification of psychological impact of current situation will help us to modify the policies and implementation strategies. This assessment might also help in future to keep targeted services in place, to cope up with the psychological distress of the quarantined population.MethodA cross sectional survey design was adopted to assess the psychological state of general population in India, during the COVID-19 mandatory lockdown period, with the help of a validated questionnaire.FindingsThe reported prevalence of depression was around 30.5%, which was the highest among the variables of psychological health. Anxiety was reported by 22.4%, followed by stress which was seen in 10.8% of respondents. In the third week the incidence of depression (37.8% versus 23.4%; pInterpretationOur results suggest a progressively detrimental impact of lockdown on various aspects of psychological health. We noticed around eight to ten fold increase in the prevalence of depression (30.5%) and anxiety (22.4%) during lockdown, as compared to baseline statistics in Indian population (3·1-3·6% for depressive disorders and 3·0-3·5% for anxiety disorders).

A patient's death can pose significant stress on the family and the treating anaesthetist. Anaesthetists' attitudes about the benefits of and barriers to attending a patient's funeral are unknown. Therefore, we performed a prospective, cross-sectional study to ascertain the frequency of anaesthetists' attendance at a patient's funeral and their perceptions about the benefits and barriers. The primary aim was to investigate the attitudes of anaesthetists towards attending the funeral of a patient. The secondary aims were to examine the perceived benefits of and barriers to attending the funeral and to explore the rate of bonds being formed between anaesthetists, patients and families. Of the 424 anaesthetists who completed the survey (response rate 21.2%), 25 (5.9%) had attended a patient's funeral. Of the participants, 364 (85.9%) rarely formed special bonds with patients or their families; 233 (55%) believed that forming a special bond would increase the likelihood of their attendance. Showing respect to patients or their families was the most commonly perceived benefit of attending a funeral. Participants found expression of personal grief and caring for the patient at the end-of-life and beyond beneficial to themselves and the family. Fear of their attendance being misinterpreted or perceived as not warranted by the family as well as time restraints were barriers for their attendance. Most anaesthetists had never attended a patient's funeral. Few anaesthetists form close relationships with patients or their families. Respect, expression of grief and caring beyond life were perceived benefits of attendance. Families misinterpreting the purpose of attendance or not expecting their attendance and time restraints were commonly perceived barriers. Trial registration: ACTRN 12618000503224.

AIM:To determine choroidal thickness in healthy Indian subjects using Swept source optical coherence tomography (SS-OCT). METHODS:In this prospective, observational, cross-sectional study; healthy Indian subjects (n = 230) with no history of ocular and/or systemic disorders were enrolled in the study. Choroidal thickness was measured for 230 eyes using SS-OCT. Subjects were divided into six age groups. Main outcome measures were subfoveal choroidal thickness (SFCT) and macular choroidal thickness (MCT) up to 3 mm at 500-micron interval from the fovea was measured in eight different quadrants. RESULTS:The mean SFCT was 307±79 μm and mean MCT was 285±75 μm. No difference in the choroidal thickness was found among genders. Mean SFCT of the different age groups was 327±68 μm (12-18 years), 364±70 μm (18.1-30 years), 321±78 μm (30.1-40 years), 304±79 μm (40.1-50 years), 283±69 μm (50.1-60 years) and 262±72μm (above 60 years; p

Cost-effective heat mitigation strategies are imperative for maintaining milk production and dairy farm profitability in the U.S. with projected climate change. This study investigated the cost-effectiveness of four heat abatement strategies, including Minimal (open barn or shading), Moderate (forced ventilation), High (fans and misting), and Intense (air conditioning). Heat stress and subsequent impacts on milk production per cow were predicted across nine climatic regions in the U.S. for early (2015 to 2034), mid (2045 to 2064) and late (2081 to 2100) 21st century, using downscaled climate projections. Heat abatements were used to adjust predicted milk production losses and illustrate the potential to reduce milk production losses due to heat stress. Economic analysis included a cost-benefit ratio calculation associated with the implementation of each heat abatement. Results showed that milk production losses were expected to accelerate across the U.S. at a mean rate of 174±7 kg/cow/decade, with the fastest rate in the Southeast region. Relative to Minimal heat abatement, Moderate, High, and Intense heat abatements increased annual milk production per cow by 3%, 4%, and 6% during early-21st century, 3%, 6%, and 11% during mid-21st century, and 3%, 8%, and 21% during late-21st century, respectively. The cost effectiveness of different heat abatement strategies generally increased with subsequently stronger heat abatements. In mid- and late-21st century, mean annual net values of High and Intense heat stress abatement implementation approached -$30 to $190 /cow and -$20 to $590 /cow, respectively, with the largest net annual benefit in late-21st century under Intense abatement. Findings from the study demonstrate the value of using downscaled climate projections to shed light on local and regional strategies to abate heat stress on cattle and mitigate potential milk production losses due to climate change.

BackgroundBreast arterial calcification (BAC) may be a predictor of cardiovascular events and is highly prevalent in persons with end-stage kidney disease. However, few studies to date have examined the association between mild-to-moderate kidney function and proteinuria with BAC.MethodsWe prospectively enrolled women with no prior cardiovascular disease aged 60 to 79 years undergoing mammography screening at Kaiser Permanente Northern California between 10/24/2012 and 2/13/2015. Urine albumin-to-creatinine ratio (uACR), along with specific laboratory, demographic, and medical data, were measured at the baseline visit. Baseline estimated glomerular filtration rate (eGFR), medication history, and other comorbidities were identified from self-report and/or electronic medical records. BAC presence and gradation (mass) was measured by digital quantification of full-field mammograms.ResultsAmong 3,507 participants, 24.5% were aged ≥70 years, 63.5% were white, 7.5% had eGFR 0 mg) was 27.9%. Neither uACR ≥30 mg/g nor uACR ≥300 were significantly associated with BAC in crude or multivariable analyses. Reduced eGFR was associated with BAC in univariate analyses (odds ratio 1.53, 95% CI: 1.18-2.00), but the association was no longer significant after adjustment for potential confounders. Results were similar in various sensitivity analyses that used different BAC thresholds or analytic approaches.ConclusionsAmong women without cardiovascular disease undergoing mammography screening, reduced eGFR and albuminuria were not significantly associated with BAC.

PurposeTo evaluate optical coherence tomography angiography (OCTA) characteristics of choroidal neovascularization (CNV) in eyes requiring different treatment frequency of anti-vascular endothelial growth factor (VEGF) therapy for neovascular age-related macular degeneration (NVAMD).DesignProspective observational case series.MethodsSubjects who had undergone anti-VEGF treatment for NVAMD in the AVATAR study were subdivided into 3 groups depending on required anti-VEGF dosing: (i) treat-and-extend requiring every 4-6 weeks dosing (TEq4-6w), (ii) treat-and-extend requiring every 7-12 weeks dosing (TEq7-12w), (iii) eyes not requiring injection within last 12 months (PRN >12mo). OCTA images were evaluated for the morphological characteristics of CNV and the choriocapillaris flow void.ResultsStudy consisted 40 eyes of 31 patients with a mean age of 79.9 ± 6.2 years. CNV morphology analysis on OCTA was feasible in 29 (73%) eyes. Ninety percent of CNVs in TEq7-12w group were irregular in shape involving foveal center, while 67% of CNVs in PRN>12mo group were circular in shape sparing foveal center. Among three groups, statistical difference was found in CNV shape (P = .012) and CNV location (P = .003), while no statistical difference was found in the CNV area (P = .14), vessel density (P = .19), presence of core vessels (P = .23), the presence of small margin loops (P = .20), large margin loops (P = .14), CNV maturity (P = .40), or the mean percentage of choriocapillaris area with flow void (P = .66).ConclusionThe combination of CNV sparing the foveal center with higher circularity may suggest a clinically inactive CNV following initial anti-VEGF therapy. We found minimal distinguishing OCTA characteristics between those eyes that required ongoing therapy with the treat-and-extend regimen. More research is needed to identify specific CNV characteristics on OCTA that may become a useful tool for the management of NVAMD and timing of treatment.

[This corrects the article DOI: 10.1371/journal.pone.0207055.].

Corn has been a pillar of American agriculture for decades and continues to receive much attention from the scientific community for its potential to meet the food, feed and fuel needs of a growing human population in a changing climate. By midcentury, global temperature increase is expected to exceed 2°C where local effects on heat, cold and precipitation extremes will vary. The Northeast United States is a major dairy producer, corn consumer, and is cited as the fastest warming region in the contiguous U.S. It is important to understand how key agronomic climate variables affect corn growth and development so that adaptation strategies can be tailored to local climate changes. We analyzed potential local effects of climate change on corn growth and development at three major dairy locations in the Northeast (Syracuse, New York; State College, Pennsylvania and Landisville, Pennsylvania) using downscaled projected climate data (2000-2100) from nine Global Climate Models under two emission pathways (Representative Concentration Pathways (RCP) 4.5 and 8.5). Our analysis indicates that corn near the end of the 21st century will experience fewer spring and fall freezes, faster rate of growing degree day accumulation with a reduction in time required to reach maturity, greater frequencies of daily high temperature ≥35°C during key growth stages such as silking-anthesis and greater water deficit during reproductive (R1-R6) stages. These agronomic anomalies differ between the three locations, illustrating varying impacts of climate change in the more northern regions vs. the southern regions of the Northeast. Management strategies such as shifting the planting dates based on last spring freeze and irrigation during the greatest water deficit stages (R1-R6) will partially offset the projected increase in heat and drought stress. Future research should focus on understanding the effects of global warming at local levels and determining adaptation strategies that meet local needs.

Gout patients have a high burden of co-morbid conditions including diabetes mellitus (DM), chronic kidney disease (CKD), and cardiovascular disease (CVD). We sought to evaluate the association between changes in serum uric acid (SUA) levels over time and the risk of incident DM, CVD, and renal function decline in gout patients.An observational cohort study was conducted among enrollees of private health insurance programs in the US between 2004 and 2015. Gout patients were included on the index date of a SUA measurement ≥6.8 mg/dl. The exposure of interest was cumulative change in SUA levels from baseline. Hazard ratios (HR) and 95% confidence intervals (CI) for incident DM, incident CVD, and renal function decline (≥30% reduction in glomerular filtration rate) were derived using marginal structural models with stabilized inverse probability weights accounting for baseline confounders (age, gender, co-morbidities, co-medications) and time-varying confounders (serum creatinine, blood urea nitrogen, glycated hemoglobin).Among 26,341 patients with gout, the average age was 62, 75% were men, and the median baseline SUA was 8.6 mg/dl (interquartile range 7.7 to 9.5). The incidence rates/100 person-years (95% CI) were 1.63 (1.51-1.75) for DM, 0.77 (0.70-0.84) for CVD, and 4.32 (4.14-4.49) for renal function decline. The adjusted HR (95% CI) per 3 mg/dl reduction in SUA, corresponding on average to achieving the target level of

[This corrects the article DOI: 10.1371/journal.pone.0186603.].

With climate change and an ever-increasing human population threatening food security, developing a better understanding of the genetic basis of crop performance under stressful conditions has become increasingly important. Here, we used genome-wide association studies to genetically dissect variation in seedling growth traits in cultivated sunflower (Helianthus annuus L.) under well-watered and water-limited (i.e., osmotic stress) conditions, with a particular focus on root morphology. Water limitation reduced seedling size and produced a shift toward deeper rooting. These effects varied across genotypes, and we identified 13 genomic regions that were associated with traits of interest across the two environments. These regions varied in size from a single marker to 186.2 Mbp and harbored numerous genes, some of which are known to be involved in the plant growth/development as well as the response to osmotic stress. In many cases, these associations corresponded to growth traits where the common allele outperformed the rare variant, suggesting that selection for increased vigor during the evolution of cultivated sunflower might be responsible for the relatively high frequency of these alleles. We also found evidence of pleiotropy across multiple traits, as well as numerous environmentally independent genetic effects. Overall, our results indicate the existence of genetic variation in root morphology and allocation and further suggest that the majority of alleles associated with these traits have consistent effects across environments.

Chili peppers are an important constituent of many foods and contain medicinally valuable compounds, such as capsaicin and dihydrocapsaicin. As various dietary botanicals have anticancer properties, this study was aimed to examine the effect of Ghost pepper (Bhut Jolokia), one of the hottest chili peppers in the world, on cell proliferation, apoptosis, senescence and the global proteomic profile in human renal cell adenocarcinoma in vitro. 769-P human renal adenocarcinoma cells were cultured on RPMI-1640 media supplemented with fetal bovine serum (10%) and antibiotic-antimycotic solution (1%). Treatment stock solutions were prepared in ethanol. Cell proliferation was tested with phenol red-free media with capsaicin (0-400 μM), dihydrocapsaicin (0-400 μM), capsaicin + dihydrocapsaicin (5:1), and dry Ghost peppers (0-3 g L-1) for 24, 48 and 72 h. Polycaspase and senescence associated-beta-galactosidase (SA-beta-gal) activities were tested with capsaicin (400 μM), dihydrocapsaicin (400 μM), capsaicin (400 μM) + dihydrocapsaicin (80 μM), and ghost pepper (3 g L-1) treatments. Global proteomic profile of cells in control and ghost pepper treatment (3 g L-1) was analyzed after 6 h by a shotgun proteomic approach using tandem mass spectrometry. At 24 h after treatment (24 HAT), relative to control, cell proportion with capsaicin (400 μM), dihydrocapsaicin (400 μM), capsaicin (400 μM) + dihydrocapsaicin (80 μM), and ghost pepper (3 g L-1) treatments was reduced to 36%, 18%, 33% and 20%, respectively, and further reduced at 48 and 72 HAT. All treatments triggered an early polycaspase response. SA-beta-gal activity was normal or suppressed with all treatments. About 68,220 protein isoforms were identified by shotgun proteomic approach. Among these, about 8.2% were significantly affected by ghost pepper. Ghost pepper regulated various proteins involved in intrinsic and extrinsic apoptotic pathways, Ras, Rb/E2F, p53, TGF-beta, WNT-beta catenin, and calcium induced cell death pathways. Ghost pepper also induced changes in proteins related to methylation, acetylation, genome stability, cell cycle check points, carbohydrate, protein and other metabolism and cellular mechanisms. Ghost pepper exhibited antiproliferation activity by inducing apoptosis through a complex network of proteins in human renal cell adenocarcinoma in vitro.

Undernutrition during pregnancy leads to low birthweight, poor growth and inter-generational undernutrition. We did a non-blinded cluster-randomised controlled trial in the plains districts of Dhanusha and Mahottari, Nepal to assess the impact on birthweight and weight-for-age z-scores among children aged 0-16 months of community-based participatory learning and action (PLA) women's groups, with and without food or cash transfers to pregnant women.We randomly allocated 20 clusters per arm to four arms (average population/cluster = 6150). All consenting married women aged 10-49 years, who had not had tubal ligation and whose husbands had not had vasectomy, were monitored for missed menses. Between 29 Dec 2013 and 28 Feb 2015 we recruited 25,092 pregnant women to surveillance and interventions: PLA alone (n = 5626); PLA plus food (10 kg/month of fortified wheat-soya 'Super Cereal', n = 6884); PLA plus cash (NPR750≈US$7.5/month, n = 7272); control (existing government programmes, n = 5310). 539 PLA groups discussed and implemented strategies to improve low birthweight, nutrition in pregnancy and hand washing. Primary outcomes were birthweight within 72 hours of delivery and weight-for-age z-scores at endline (age 0-16 months). Only children born to permanent residents between 4 June 2014 and 20 June 2015 were eligible for intention to treat analyses (n = 10936), while in-migrating women and children born before interventions had been running for 16 weeks were excluded. Trial status: completed.In PLA plus food/cash arms, 94-97% of pregnant women attended groups and received a mean of four transfers over their pregnancies. In the PLA only arm, 49% of pregnant women attended groups. Due to unrest, the response rate for birthweight was low at 22% (n = 2087), but response rate for endline nutritional and dietary measures exceeded 83% (n = 9242). Compared to the control arm (n = 464), mean birthweight was significantly higher in the PLA plus food arm by 78·0 g (95% CI 13·9, 142·0; n = 626) and not significantly higher in PLA only and PLA plus cash arms by 28·9 g (95% CI -37·7, 95·4; n = 488) and 50·5 g (95% CI -15·0, 116·1; n = 509) respectively. Mean weight-for-age z-scores of children aged 0-16 months (average age 9 months) sampled cross-sectionally at endpoint, were not significantly different from those in the control arm (n = 2091). Differences in weight for-age z-score were as follows: PLA only -0·026 (95% CI -0·117, 0·065; n = 2095); PLA plus cash -0·045 (95% CI -0·133, 0·044; n = 2545); PLA plus food -0·033 (95% CI -0·121, 0·056; n = 2507). Amongst many secondary outcomes tested, compared with control, more institutional deliveries (OR: 1.46 95% CI 1.03, 2.06; n = 2651) and less colostrum discarding (OR:0.71 95% CI 0.54, 0.93; n = 2548) were found in the PLA plus food arm but not in PLA alone or in PLA plus cash arms.Food supplements in pregnancy with PLA women's groups increased birthweight more than PLA plus cash or PLA alone but differences were not sustained. Nutrition interventions throughout the thousand-day period are recommended.ISRCTN75964374.

People living with HIV/AIDS (PLH) experience high rates of depression and related psychosocial risk factors that vary by gender. This study examines gender differences in depression severity among antiretroviral therapy (ART) patients (n = 362) from a large government ART clinic in Kolkata, India. Hypotheses for multiple linear regression models were guided by an integrated gendered stress process model focusing on variables reflecting social status (age, partner status), stressors (stigma), and resources (income, social support). Depressive symptoms were assessed with the Hospital Anxiety and Depression Scale (HADS); 22% of the sample reached the cutoff for severe depression, 56% moderate, and 13% mild depression. Compared to men, women reported lower income, education (50% no formal education vs. 20% men), availability of emotional and instrumental support, and were less likely to be married or cohabiting (53% women vs. 72% of men). However, more women had partners who were HIV-positive (78% women vs. 46% men). Overall, depression severity was negatively associated with availability of emotional support and self-distraction coping, and positively associated with internalized HIV/AIDS stigma, availability of instrumental support, and behavioral disengagement coping. Interactions for instrumental support by income and partner status by age varied significantly by gender. Analyses stratified by gender indicated that: 1) Frequently seeking instrumental support from others was protective for men at all income levels, but only for high-income women; and 2) having a partner was protective for men as they aged, but not for women. These results suggest that gender disparities in depression severity are created and maintained by women's lower social status and limited access to resources. The effect of stigma on depression severity did not vary by gender. These findings may inform the tailoring of future interventions to address mental health needs of PLH in India, particularly gender disparities in access to material and social resources for coping with HIV. Trial Registration: ClinicalTrials.gov registration #NCT02118454, registered April 2014.