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Abstract Research projects, initiatives and conferences that include patients as partners rather than as participants are becoming more common. Including patients as partners (what we will call ‘patient partners’) is an approach called patient engagement or involvement in research, and we will call it patient engagement throughout this paper. Patient engagement moves traditional health research conferences and events to include a broader audience for their knowledge exchange and community building efforts, beyond academics and healthcare professionals. However, there are few examples of conferences where patients are given the opportunity to fully lead. Our conference went beyond patient engagement – it was patient-led. Patient partners conceived, planned, and decided on all aspects of a virtual conference. We present the work and processes we undertook throughout 2023 to create and produce a free conference called “PxP: For patients, by patients” or PxP for short, with a tagline of “Partnering to make research stronger.” PxP was patient-led and about patient engagement in research rather than a specific disease or condition. PxP was supported by the Canadian Institutes of Health Research Institute of Musculoskeletal Health and Arthritis. The PxP website, known as the PxP Hub, now houses the conference recordings along with resources about patient engagement in research. These resources were recommended by the PxP Steering Committee members, speakers, and others who attended the 2023 conference. Here we lead you through how the idea for PxP was generated; how the international patient partner Steering Committee was convened and supported; how PxP was brought to life over nine months; the PxP 3-day event and feedback collected to improve future efforts; trade-offs, challenges and learnings; and resources required to support this type of event. We close with what the future holds for PxP in 2024 and beyond. It’s time to elevate patients into leadership roles for conferences and events, and we encourage you to adopt the PxP ethos by using or adapting our approach and resources to support your opportunity.

Abstract Melanoma presents increasing prevalence and poor outcomes. Progression to aggressive stages is characterized by overexpression of the transcription factor E2F1 and activation of downstream prometastatic gene regulatory networks (GRNs). Appropriate therapeutic manipulation of the E2F1-governed GRNs holds the potential to prevent metastasis however, these networks entail complex feedback and feedforward regulatory motifs among various regulatory layers, which make it difficult to identify druggable components. To this end, computational approaches such as mathematical modeling and virtual screening are important tools to unveil the dynamics of these signaling networks and identify critical components that could be further explored as therapeutic targets. Herein, we integrated a well-established E2F1-mediated epithelial-mesenchymal transition (EMT) map with transcriptomics data from E2F1-expressing melanoma cells to reconstruct a core regulatory network underlying aggressive melanoma. Using logic-based in silico perturbation experiments of a core regulatory network, we identified that simultaneous perturbation of Protein kinase B (AKT1) and oncoprotein murine double minute 2 (MDM2) drastically reduces EMT in melanoma. Using the structures of the two protein signatures, virtual screening strategies were performed with the FDA-approved drug library. Furthermore, by combining drug repurposing and computer-aided drug design techniques, followed by molecular dynamics simulation analysis, we identified two potent drugs (Tadalafil and Finasteride) that can efficiently inhibit AKT1 and MDM2 proteins. We propose that these two drugs could be considered for the development of therapeutic strategies for the management of aggressive melanoma. Graphical abstract

Abstract Background Eating frequency may affect body weight and cardiometabolic health. Intervention trials and observational studies have both indicated that high- and low-frequency eating can be associated with better health outcomes. There are currently no guidelines to inform how to advise healthy adults about how frequently to consume food or beverages. Aim To establish whether restricted- (≤ three meals per day) frequency had a superior effect on markers of cardiometabolic health (primary outcome: weight change) compared to unrestricted-eating (≥ four meals per day) frequency in adults. Methods We searched Medline (Ovid), Embase, CINAHL (EBSCO), Cochrane Central Register of Controlled Trials (CENTRAL), CAB Direct and Web of Science Core Collection electronic databases from inception to 7 June 2022 for clinical trials (randomised parallel or cross-over trials) reporting on the effect of high or low-frequency eating on cardiometabolic health (primary outcome: weight change). Trial interventions had to last for at least two weeks, and had to have been conducted in human adults. Bias was assessed using the Cochrane Risk of Bias tool 2.0. Standardized mean differences (SMD) and 95% confidence intervals were calculated for all outcomes. Certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Results Seventeen reports covering 16 trials were included in the systematic review. Data from five trials were excluded from meta-analysis due to insufficient reporting. 15 of 16 trials were at high risk of bias. There was very low certainty evidence of no difference between high- and low-frequency eating for weight-change (MD: -0.62 kg, CI95: -2.76 to 1.52 kg, p = 0.57). Conclusions There was no discernible advantage to eating in a high- or low-frequency dietary pattern for cardiometabolic health. We cannot advocate for either restricted- or unrestricted eating frequency to change markers of cardiometabolic health in healthy young to middle-aged adults. Protocol registration CRD42019137938.

Abstract Background Bilirubin neurotoxicity (BN) occurs in premature infants at lower total serum bilirubin levels than term infants and causes neurodevelopmental impairment. Usual dose lipid infusions in preterm infants may increase free fatty acids sufficiently to cause bilirubin displacement from albumin, increasing passage of unbound bilirubin (UB) into the brain leading to BN and neurodevelopmental impairment not reliably identifiable in infancy. These risks may be influenced by whether cycled or continuous phototherapy is used to control bilirubin levels. Objective To assess differences in wave V latency measured by brainstem auditory evoked responses (BAER) at 34–36 weeks gestational age in infants born ≤ 750 g or

Abstract Background The World Health Organization (WHO) recommends the diagnosis of tuberculosis (TB) using molecular tests, such as Xpert MTB/RIF (MTB/RIF) or Xpert Ultra (Ultra). These tests are expensive and resource-consuming, and cost-effective approaches are needed for greater coverage. Methods We evaluated the cost-effectiveness of pooling sputum samples for TB testing by using a fixed amount of 1,000 MTB/RIF or Ultra cartridges. We used the number of people with TB detected as the indicator for cost-effectiveness. Cost-minimization analysis was conducted from the healthcare system perspective and included the costs to the healthcare system using pooled and individual testing. Results There was no significant difference in the overall performance of the pooled testing using MTB/RIF or Ultra (sensitivity, 93.9% vs. 97.6%, specificity 98% vs. 97%, p-value > 0.1 for both). The mean unit cost across all studies to test one person was 34.10 international dollars for the individual testing and 21.95 international dollars for the pooled testing, resulting in a savings of 12.15 international dollars per test performed (35.6% decrease). The mean unit cost per bacteriologically confirmed TB case was 249.64 international dollars for the individual testing and 162.44 international dollars for the pooled testing (34.9% decrease). Cost-minimization analysis indicates savings are directly associated with the proportion of samples that are positive. If the TB prevalence is ≥ 30%, pooled testing is not cost-effective. Conclusion Pooled sputum testing can be a cost-effective strategy for diagnosis of TB, resulting in significant resource savings. This approach could increase testing capacity and affordability in resource-limited settings and support increased testing towards achievement of WHO End TB strategy.

Abstract Alzheimer’s disease (AD) poses an ever-increasing public health concern as the population ages, affecting more than 6 million Americans. AD patients present with mood and sleep changes in the prodromal stages that may be partly driven by loss of monoaminergic neurons in the brainstem, but a causal relationship has not been firmly established. This is due in part to a dearth of animal models that recapitulate early AD neuropathology and symptoms. The goal of the present study was to evaluate depressive and anxiety-like behaviors in a mouse model of AD that overexpresses human wild-type tau (htau) prior to the onset of cognitive impairments and assess these behavior changes in relationship to tau pathology, neuroinflammation, and monoaminergic dysregulation in the dorsal raphe nucleus (DRN) and locus coeruleus (LC). We observed depressive-like behaviors at 4 months in both sexes and hyperlocomotion in male htau mice. Deficits in social interaction persisted at 6 months and were accompanied by an increase in anxiety-like behavior in males. The behavioral changes at 4 months coincided with a lower density of serotonergic (5-HT) neurons, downregulation of 5-HT markers, reduced excitability of 5-HT neurons, and hyperphosphorylated tau in the DRN. Inflammatory markers were also upregulated in the DRN along with protein kinases and transglutaminase 2, which may promote tau phosphorylation and aggregation. Loss of 5-HT innervation to the entorhinal cortex and dentate gyrus of the hippocampus was also observed and may have contributed to depressive-like behaviors. There was also reduced expression of noradrenergic markers in the LC along with elevated phospho-tau expression, but this did not translate to a functional change in neuronal excitability. In total, these results suggest that tau pathology in brainstem monoaminergic nuclei and the resulting loss of serotonergic and/or noradrenergic drive may underpin depressive- and anxiety-like behaviors in the early stages of AD.

Abstract Objective To identify and assess the globally available valid, reliable and acceptable tools for assessing health research partnership outcomes and impacts. Methods We searched Ovid MEDLINE, Embase, CINAHL Plus and PsycINFO from origin to 2 June 2021, without limits, using an a priori strategy and registered protocol. We screened citations independently and in duplicate, resolving discrepancies by consensus and retaining studies involving health research partnerships, the development, use and/or assessment of tools to evaluate partnership outcomes and impacts, and reporting empirical psychometric evidence. Study, tool, psychometric and pragmatic characteristics were abstracted using a hybrid approach, then synthesized using descriptive statistics and thematic analysis. Study quality was assessed using the quality of survey studies in psychology (Q-SSP) checklist. Results From 56 123 total citations, we screened 36 027 citations, assessed 2784 full-text papers, abstracted data from 48 studies and one companion report, and identified 58 tools. Most tools comprised surveys, questionnaires and scales. Studies used cross-sectional or mixed-method/embedded survey designs and employed quantitative and mixed methods. Both studies and tools were conceptually well grounded, focusing mainly on outcomes, then process, and less frequently on impact measurement. Multiple forms of empirical validity and reliability evidence was present for most tools; however, psychometric characteristics were inconsistently assessed and reported. We identified a subset of studies (22) and accompanying tools distinguished by their empirical psychometric, pragmatic and study quality characteristics. While our review demonstrated psychometric and pragmatic improvements over previous reviews, challenges related to health research partnership assessment and the nascency of partnership science persist. Conclusion This systematic review identified multiple tools demonstrating empirical psychometric evidence, pragmatic strength and moderate study quality. Increased attention to psychometric and pragmatic requirements in tool development, testing and reporting is key to advancing health research partnership assessment and partnership science. PROSPERO CRD42021137932

Abstract Background To describe the key findings and lessons learned from an international pilot study that surveyed spinal cord injury programs in acute and rehabilitation facilities to understand the status of spinal cord injury care. Methods An online survey with two questionnaires, a 74-item for acute care and a 51-item for rehabilitation, was used. A subset of survey items relevant to the themes of specialized care, timeliness, patient-centeredness, and evidence-based care were operationalized as structure or process indicators. Percentages of facilities reporting the structure or process to be present, and percentages of indicators met by each facility were calculated and reported separately for facilities from high-income countries (HIC) and from low and middle-income countries (LMIC) to identify “hard to meet” indicators defined as those met by less than two-thirds of facilities and to describe performance level. Results A total of 26 acute and 26 rehabilitation facilities from 25 countries participated in the study. The comparison of the facilities based on the country income level revealed three general observations: 1) some indicators were met equally well by both HIC and LMIC, such as 24-hour access to CT scanners in acute care and out-patient services at rehabilitation facilities; 2) some indicators were hard to meet for LMIC but not for HIC, such as having a multidisciplinary team for both acute and rehabilitation settings; and 3) some indicators were hard to meet by both HIC and LMIC, including having peer counselling programs. Variability was also observed for the same indicator between acute and rehabilitation facilities, and a wide range in the total number of indicators met among HIC facilities (acute 59–100%; rehabilitation 36–100%) and among LMIC facilities (acute: 41–82%; rehabilitation: 36–93%) was reported. Conclusions Results from this international pilot study found that the participating acute and rehabilitation facilities on average adhered to 74% of the selected indicators, suggesting that the structure and processes to provide ideal traumatic spinal cord injury care were broadly available. Recruiting a representative sample of SCI facilities and incorporating regional attributes in future surveys will be helpful to examine factors affecting adherence to indicators.

Abstract Introduction Following the COVID-19 directive to cease non-essential services, a rapid shift was made in the delivery of Speech Language Pathology (SLP) dysphagia management in the 3-arm, randomized PRO-ACTIVE trial. To inform future programs, this study explored patients’ experiences with telehealth when the planned in-person SLP intervention was moved to a telehealth modality. Methods A theory-guided qualitative descriptive approach was used. Willing participants who had received at least one telehealth swallowing therapy session participated in a one-time semi-structured interview. Interview transcripts were subjected to a standard qualitative content/theme analysis. Researchers reviewed all transcripts and used a multi-step analysis process to build a coding framework through consensus discussion. Summaries and key messages were generated for each code. Results Eleven participants recounted their telehealth experiences and reported feeling satisfied, comfortable and confident with the session(s). They identified that previous experience with teleconferencing, access to optimal technical equipment, clinician skill, and caregiver assistance facilitated their telehealth participation. Participants highlighted that telehealth was beneficial as it reduced commuting time, COVID-19 exposure and fatigue from travel; and also allowed caregiver participation particularly during COVID. In comparing their in-person SLP sessions to telehealth sessions, limitations were also identified, including: lack of previous experience with and/or poor access to technology, and less opportunity for personalization. Participants indicated that use of phone alone was less preferred than an audio/video platform. Discussion Patients reported that overall, telehealth sessions did not compromise their learning experience when compared to in-person sessions. Patients benefited from use of telehealth in several ways despite some limitations of the use of technology. Patient feedback about telehealth provides an important perspective that may be critical to inform best practices for care delivery.

Abstract Background Financing healthcare through out-of-pocket (OOP) payment is a major barrier in accessing healthcare for the poor people. The Health Economics Unit (HEU) of the Ministry of Health and Family Welfare of the government of Bangladesh has developed Shasthyo Suroksha Karmasuchi (SSK), a health protection scheme, with the aim of reducing OOP expenditure and improving access of the below-poverty-line (BPL) population to healthcare. The scheme started piloting in 2016 at Kalihati sub-district of Tangail District. Our objective was to assess healthcare utilization by the enrolled BPL population and to identify the factors those influencing their utilization of the scheme. Method A cross-sectional household survey was conducted from July to September 2018 in the piloting sub-district. A total of 806 households were surveyed using a semi-structured questionnaire. Information on illness and sources of healthcare service were captured for the last 90 days before the survey. Multiple logistic regression models were applied to determine the factors related to utilization of healthcare from the SSK scheme and other medically trained providers (MTPs) by the SSK members for both inpatient and outpatient care. Result A total of 781 (24.6%) people reported of suffering from illness of which 639 (81.8%) sought healthcare from any sources. About 8.0% (51 out of 639) of them sought healthcare from SSK scheme and 28.2% from other MTPs within 90 days preceding the survey. Households with knowledge about SSK scheme were more likely to utilize healthcare from the scheme and less likely to utilize healthcare from other MTPs. Non-BPL status and suffering from an accident/injury were significantly positively associated with utilization of healthcare from SSK scheme. Conclusion Among the BPL population, healthcare utilization from the SSK scheme was very low compared to that of other MTPs. Effective strategies should be in place for improving knowledge of BPL population on SSK scheme and the benefits package of the scheme should be updated as per the need of the target population. Such initiative can be instrumental in increasing utilization of the scheme and ultimately will reduce the barriers of OOP payment among BPL population for accessing healthcare.

Abstract Background Recent investigations of the meninges have highlighted the importance of the dura layer in central nervous system immune surveillance beyond a purely structural role. However, our understanding of the meninges largely stems from the use of pre-clinical models rather than human samples. Methods Single-cell RNA sequencing of seven non-tumor-associated human dura samples and six primary meningioma tumor samples (4 matched and 2 non-matched) was performed. Cell type identities, gene expression profiles, and T cell receptor expression were analyzed. Copy number variant (CNV) analysis was performed to identify putative tumor cells and analyze intratumoral CNV heterogeneity. Immunohistochemistry and imaging mass cytometry was performed on selected samples to validate protein expression and reveal spatial localization of select protein markers. Results In this study, we use single-cell RNA sequencing to perform the first characterization of both non-tumor-associated human dura and primary meningioma samples. First, we reveal a complex immune microenvironment in human dura that is transcriptionally distinct from that of meningioma. In addition, we characterize a functionally diverse and heterogenous landscape of non-immune cells including endothelial cells and fibroblasts. Through imaging mass cytometry, we highlight the spatial relationship among immune cell types and vasculature in non-tumor-associated dura. Utilizing T cell receptor sequencing, we show significant TCR overlap between matched dura and meningioma samples. Finally, we report copy number variant heterogeneity within our meningioma samples. Conclusions Our comprehensive investigation of both the immune and non-immune cellular landscapes of human dura and meningioma at single-cell resolution builds upon previously published data in murine models and provides new insight into previously uncharacterized roles of human dura.

Abstract Background Accumulating evidence suggests that refractive stabilization occurs rapidly following small incision cataract surgery. Nonetheless, many guidelines still suggest waiting four to 6 weeks before prescribing corrective lenses. This study was undertaken to supplement the existing literature regarding refractive stabilization, and evaluate multiple contributing factors that could dissuade clinicians from confidently correcting refractive error in the early post-operative course following routine cataract surgeries. Methods Adult patients undergoing phacoemulsification cataract surgery with uncomplicated surgeries and post-surgical courses at the Calgary Ophthalmology Centre (Calgary, Alberta, Canada) were included in this prospective observational case series. Exclusion criteria included known corneal dystrophies, infectious keratitis, complicated surgery or toric/multifocal IOLs. Data was collected at weekly intervals for a total of 6 weeks. Collected data included autorefraction, visual acuity, corneal pachymetry, and effective lens position. Results One hundred six eyes of 104 patients were included in this study. Post-operative sphere, cylinder and spherical equivalent were not significantly different at any post-operative week compared with week six, and 80–86% of patients were within 0.5D of last follow-up spherical equivalent at any week. The secondary outcomes of central corneal thickness, effective lens position and visual acuity did, however, exhibit significant differences between early post-operative weeks and last follow-up values. Conclusions These data suggest that refractive error can be effectively measured and corrected as early as one-week post-operatively in the majority of patients, though other measures of post-operative stability including central corneal thickness, effective lens position and visual acuity can require up to 4 weeks to stabilize. Thus a conservative and pragmatic approach may be to wait until 4 weeks post-operatively prior to obtaining refractive correction following uncomplicated phacoemulsification cataract surgery.

Abstract Background Mood disorders (MDS) are a type of mental health illness that effects millions of people in the United States. Early prediction of MDS can give providers greater opportunity to treat these disorders. We hypothesized that longitudinal cardiovascular health (CVH) measurements would be informative for MDS prediction. Methods To test this hypothesis, the American Heart Association’s Guideline Advantage (TGA) dataset was used, which contained longitudinal EHR from 70 outpatient clinics. The statistical analysis and machine learning models were employed to identify the associations of the MDS and the longitudinal CVH metrics and other confounding factors. Results Patients diagnosed with MDS consistently had a higher proportion of poor CVH compared to patients without MDS, with the largest difference between groups for Body mass index (BMI) and Smoking. Race and gender were associated with status of CVH metrics. Approximate 46% female patients with MDS had a poor hemoglobin A1C compared to 44% of those without MDS; 62% of those with MDS had poor BMI compared to 47% of those without MDS; 59% of those with MDS had poor blood pressure (BP) compared to 43% of those without MDS; and 43% of those with MDS were current smokers compared to 17% of those without MDS. Conclusions Women and ethnoracial minorities with poor cardiovascular health measures were associated with a higher risk of development of MDS, which indicated the high utility for using routine medical records data collected in care to improve detection and treatment for MDS among patients with poor CVH.

Abstract Background Biology has entered the era of big data with the advent of high-throughput omics technologies. Biological databases provide public access to petabytes of data and information facilitating knowledge discovery. Over the years, sequence data of pathogens has seen a large increase in the number of records, given the relatively small genome size and their important role as infectious and symbiotic agents. Humans are host to numerous pathogenic diseases, such as that by viruses, many of which are responsible for high mortality and morbidity. The interaction between pathogens and humans over the evolutionary history has resulted in sharing of sequences, with important biological and evolutionary implications. Results This study describes a large-scale, systematic bioinformatics approach for identification and characterization of shared sequences between the host and pathogen. An application of the approach is demonstrated through identification and characterization of the Flaviviridae-human share-ome. A total of 2430 nonamers represented the Flaviviridae-human share-ome with 100% identity. Although the share-ome represented a small fraction of the repertoire of Flaviviridae (~ 0.12%) and human (~ 0.013%) non-redundant nonamers, the 2430 shared nonamers mapped to 16,946 Flaviviridae and 7506 human non-redundant protein sequences. The shared nonamer sequences mapped to 125 species of Flaviviridae, including several with unclassified genus. The majority (~ 68%) of the shared sequences mapped to Hepacivirus C species; West Nile, dengue and Zika viruses of the Flavivirus genus accounted for ~ 11%, ~ 7%, and ~ 3%, respectively, of the Flaviviridae protein sequences (16,946) mapped by the share-ome. Further characterization of the share-ome provided important structural-functional insights to Flaviviridae-human interactions. Conclusion Mapping of the host-pathogen share-ome has important implications for the design of vaccines and drugs, diagnostics, disease surveillance and the discovery of unknown, potential host-pathogen interactions. The generic workflow presented herein is potentially applicable to a variety of pathogens, such as of viral, bacterial or parasitic origin.

Abstract Background Mosaic chromosomal alterations (mCAs) are large chromosomal gains, losses and copy-neutral losses of heterozygosity (LOH) in peripheral leukocytes. While many individuals with detectable mCAs have no notable adverse outcomes, mCA-associated gene dosage alterations as well as clonal expansion of mutated leukocyte clones could increase susceptibility to disease. Results We performed a phenome-wide association study (PheWAS) using existing data from 482,396 UK Biobank (UKBB) participants to investigate potential associations between mCAs and incident disease. Of the 1290 ICD codes we examined, our adjusted analysis identified a total of 50 incident disease outcomes associated with mCAs at PheWAS significance levels. We observed striking differences in the diseases associated with each type of alteration, with autosomal mCAs most associated with increased hematologic malignancies, incident infections and possibly cancer therapy-related conditions. Alterations of chromosome X were associated with increased lymphoid leukemia risk and, mCAs of chromosome Y were linked to potential reduced metabolic disease risk. Conclusions Our findings demonstrate that a wide range of diseases are potential sequelae of mCAs and highlight the critical importance of careful covariate adjustment in mCA disease association studies.

Abstract Background Older adults are particularly vulnerable to the adverse health effects of extreme temperature-related events. A growing body of literature highlights the importance of the natural environment, including air pollution and sunlight, on cognitive health. However, the relationship between exposure to outdoor temperatures and cognitive functioning, and whether there exists any differences across climate region, remains largely unexplored. We address this gap by examining the temperature-cognition association, and whether there exists any variation across climate regions in a national cohort of aging adults. Methods In this cross-sectional study, we obtained data on temperature exposure based on geocoded residential location of participants in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. For each participant, this information was linked to their cognitive scores from Word List Learning and Recall tests to assess cognitive functioning. We used distributed lag non-linear models (dlnm) to model temperature effects over 2 days. Multivariable linear regression was used to compute temperature-cognitive functioning associations, adjusted for important covariates. Region-specific (“Dry”, “Mediterranean/oceanic”, “Tropical” and “Continental”) associations were examined by including an interaction term between climate region and temperature. Results Amongst 20,687 individuals (mean age = 67.8; standard deviation = 9.2), exposure to region-specific extreme cold temperatures in the “dry” region (e.g., Arizona) over 2 days was associated with lower cognitive scores (Mean Difference [MD]: -0.76, 95% Confidence Interval [CI]: − 1.45, − 0.07). Associations remained significant for cumulative effects of temperature over 2 days. Extremely cold exposure in the “Mediterranean/oceanic” region (e.g., California) over 2 days was also associated with significantly lower cognitive performance (MD: -0.25, 95% CI: − 0.47, − 0.04). No significant associations were observed for exposure to hot temperatures. Cognitive performance was slightly higher in late summer and fall compared to early summer. Conclusion We noted adverse cognitive associations with cold temperatures in traditionally warmer regions of the country and improved cognition in summer and early fall seasons. While we did not observe very large significant associations, this study deepens understanding of the impact of climate change on the cognitive health of aging adults and can inform clinical care and public health preparedness plans.

Abstract Background Cardiovascular disease (CVD) is the leading cause of death in the United States (US). Better cardiovascular health (CVH) is associated with CVD prevention. Predicting future CVH levels may help providers better manage patients’ CVH. We hypothesized that CVH measures can be predicted based on previous measurements from longitudinal electronic health record (EHR) data. Methods The Guideline Advantage (TGA) dataset was used and contained EHR data from 70 outpatient clinics across the United States (US). We studied predictions of 5 CVH submetrics: smoking status (SMK), body mass index (BMI), blood pressure (BP), hemoglobin A1c (A1C), and low-density lipoprotein (LDL). We applied embedding techniques and long short-term memory (LSTM) networks – to predict future CVH category levels from all the previous CVH measurements of 216,445 unique patients for each CVH submetric. Results The LSTM model performance was evaluated by the area under the receiver operator curve (AUROC): the micro-average AUROC was 0.99 for SMK prediction; 0.97 for BMI; 0.84 for BP; 0.91 for A1C; and 0.93 for LDL prediction. Model performance was not improved by using all 5 submetric measures compared with using single submetric measures. Conclusions We suggest that future CVH levels can be predicted using previous CVH measurements for each submetric, which has implications for population cardiovascular health management. Predicting patients’ future CVH levels might directly increase patient CVH health and thus quality of life, while also indirectly decreasing the burden and cost for clinical health system caused by CVD and cancers.

Abstract Household responses to COVID-19 in different corners of the world represent the primary health care that communities have relied on for preventing and mitigating symptoms. During a very complex and confusing time, in which public health services in multiple countries have been completely overwhelmed, and in some cases even collapsed, these first-line household responses have been quintessential for building physical, mental, and social resilience, and for improving individual and community health. This editorial discusses the outcomes of a rapid-response preliminary survey during the first phase of the pandemic among social and community contacts in five metropolises heavily affected by the COVID-19 health crisis (Wuhan, Milan, Madrid, New York, and Rio de Janeiro), and in twelve rural areas or countries initially less affected by the pandemic (Appalachia, Jamaica, Bolivia, Romania, Belarus, Lithuania, Poland, Georgia, Turkey, Pakistan, Cambodia, and South Africa). We summarized our perspectives as 17 case studies, observing that people have relied primarily on teas and spices (“food-medicines”) and that there exist clear international plant favorites, popularized by various new media. Urban diasporas and rural households seem to have repurposed homemade plant-based remedies that they use in normal times for treating the flu and other respiratory symptoms or that they simply consider healthy foods. The most remarkable shift in many areas has been the increased consumption of ginger and garlic, followed by onion, turmeric, and lemon. Our preliminary inventory of food medicines serves as a baseline for future systematic ethnobotanical studies and aims to inspire in-depth research on how use patterns of plant-based foods and beverages, both “traditional” and “new”, are changing during and after the COVID-19 pandemic. Our reflections in this editorial call attention to the importance of ethnobiology, ethnomedicine, and ethnogastronomy research into domestic health care strategies for improving community health.

Abstract Objective In this study, we investigate the effect of the external environmental and institutional factors on the efficiency and the performance of the public hospitals affiliated to the Ministry of Health (MOH) in the Kingdom of Saudi Arabia (KSA). We estimate the demographic and socioeconomic characteristics of catchment populations that explain the demand for health services. Methods We apply descriptive analysis to explore what external factors (demographic and socioeconomic factors) can explain the observed differences in technical efficiency scores. We use Spearman’s rank correlation, multivariate Tobit regression and Two-part model to measure the impact of the explanatory variables (i.e. population density, nationality, gender, age groups, economic status, health status, medical interventions and geographic location) on the efficiency scores. Results The analysis shows that the external factors had a significant influence on efficiency scores. We find significant associations between hospitals efficiency scores and number of populations in the catchment area, percentage of children (0–5 years old), the prevalence of infectious diseases, and the number of prescriptions dispensed from hospital’s departments. Also, the scores significantly associate with the number of populations who faced financial hardships during medical treatments, and those received financial support from social administration. That indicates the hospitals that serve more patients in previous characteristics are relatively more technically efficient. Conclusions The environmental and institutional factors have a crucial effect on efficiency and performance in public hospitals. In these regards, we suggested improvement of health policies and planning in respect to hospital efficiency and resource allocation, which consider the different demographic, socioeconomic and health status of the catchment populations (e.g., population density, poverty, health indicators and services utilization). The MOH should pay more attention to ensure appropriate allocation mechanisms of health resources and improve utilization of health services among the target populations, for securing efficient and equitable health services.

Abstract Background Critical stakeholder-identified gaps in current health research engagement strategies include the exclusion of voices traditionally less heard and a lack of consideration for the role of trauma in lived experience. Previous work has advocated for a trauma-informed, intersectional, and critical reflexive approach to patient and public involvement in health research. The Valuing All Voices Framework embodies these theoretical concepts through four key components: trust, self-awareness, empathy, and relationship building. The goal of this framework is to provide the context for research teams to conduct patient engagement through the use of a social justice and health equity lens, to improve safety and inclusivity in health research. The aim of this study was to revise the proposed Valuing All Voices Framework with members of groups whose voices are traditionally less heard in health research. Methods A qualitative descriptive approach was used to conduct a thematic analysis of participant input on the proposed framework. Methods were co-developed with a patient co-researcher and community organizations. Results Group and individual interviews were held with 18 participants identifying as Inuit; refugee, immigrant, and/or newcomer; and/or as a person with lived experience of a mental health condition. Participants supported the proposed framework and underlying theory. Participant definitions of framework components included characterizations, behaviours, feelings, motivations, and ways to put components into action during engagement. Emphasis was placed on the need for a holistic approach to engagement; focusing on open and honest communication; building trusting relationships that extend beyond the research process; and capacity development for both researchers and patient partners. Participants suggested changes that incorporated some of their definitions; simplified and contextualized proposed component definitions; added a component of “education and communication”; and added a ‘how to’ section for each component. The framework was revised according to participant suggestions and validated through member checking. Conclusions The revised Valuing All Voices Framework provides guidance for teams looking to employ trauma-informed approaches, intersectional analysis, and critical reflexive practice in the co-development of meaningful, inclusive, and safe engagement strategies. Plain English Summary Patient engagement in health research continues to exclude many people who face challenges in accessing healthcare, including (but not limited to) First Nations, Inuit, and Metis people; immigrants, refugees, and newcomers; and people with lived experience of a mental health condition. We proposed a new guide to help researchers engage with patients and members of the public in research decision-making in a meaningful, inclusive, and safe way. We called this the Valuing All Voices Framework, and met with people who identify as members of some of these groups to help define the key parts of the framework (trust; self-awareness; empathy; and relationship building), to tell us what they liked and disliked about the proposed framework, and what needed to be changed. Input from participants was used to change the framework, including clarifying definitions of the key parts, adding another key part called “education and communication”, and providing action items so teams can put these key parts into practice.

Abstract Background Chondroclasts and osteoclasts have been previously identified as the cells capable of resorbing mineralized cartilage and bone matrices, respectively. While both cell types appear morphologically similar, contain comparable ultrastructural features, and express tartrate-resistant acid phosphatase (TRAP), however, no information is available about the genomic similarities and differences between osteoclasts and chondroclasts. Methods To address this question, we laser captured homogeneous populations of TRAP-positive cells that interact with bone (osteoclasts) and TRAP-positive cells that interact with mineralized cartilage (chondroclasts) on the same plane from murine femoral fracture callus sections. We then performed a global transcriptome profiling of chondroclasts and osteoclasts by utilizing a mouse genome Agilent GE 4X44K V2 microarray platform. Multiple computational approaches and interaction networks were used to analyze the transcriptomic landscape of osteoclasts and chondroclasts. Results Our systematic and comprehensive analyses using hierarchical clustering and principal component analysis (PCA) demonstrate that chondroclasts and osteoclasts are transcriptionally distinct cell populations and exhibit discrete transcriptomic signatures as revealed by multivariate analysis involving scatter plot, volcano plot, and heatmap analysis. TaqMan qPCR was used to validate the microarray results. Intriguingly, the functional enrichment and integrated network analyses revealed distinct Gene Ontology terms and molecular pathways specific to chondroclasts and osteoclasts and further suggest that subsets of metabolic genes were specific to chondroclasts. Protein-protein interaction (PPI) network analysis showed an abundance of structured networks of metabolic pathways, ATP synthesis, and proteasome pathways in chondroclasts. The regulatory network analysis using transcription factor-target gene network predicted a pool of genes including ETV6, SIRT1, and ATF1 as chondroclast-specific gene signature. Conclusions Our study provides an important genetic resource for further exploration of chondroclast function in vivo. To our knowledge, this is the first demonstration of genetic landscape of osteoclasts from chondroclasts identifying unique molecular signatures, functional clustering, and interaction network.

Abstract Background The objective of this study was to assess the overall quality of study-level meta-analyses in high-ranking journals using commonly employed guidelines and standards for systematic reviews and meta-analyses. Methods 100 randomly selected study-level meta-analyses published in ten highest-ranking clinical journals in 2016–2017 were evaluated by medical librarians against 4 assessments using a scale of 0–100: the Peer Review of Electronic Search Strategies (PRESS), Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), Institute of Medicine’s (IOM) Standards for Systematic Reviews, and quality items from the Cochrane Handbook. Multiple regression was performed to assess meta-analyses characteristics’ associated with quality scores. Results The overall median (interquartile range) scores were: PRESS 62.5(45.8–75.0), PRISMA 92.6(88.9–96.3), IOM 81.3(76.6–85.9), and Cochrane 66.7(50.0–83.3). Involvement of librarians was associated with higher PRESS and IOM scores on multiple regression. Compliance with journal guidelines was associated with higher PRISMA and IOM scores. Conclusion This study raises concerns regarding the reporting and methodological quality of published MAs in high impact journals Early involvement of information specialists, stipulation of detailed author guidelines, and strict adherence to them may improve quality of published meta-analyses.

Abstract Background Sri Lanka has a high prevalence of β-thalassaemia major. Clinical management is complex and long-term and includes regular blood transfusion and iron chelation therapy. The economic burden of β-thalassaemia for the Sri Lankan healthcare system and households is currently unknown. Methods A prevalence-based, cost-of-illness study was conducted on the Thalassaemia Unit, Department of Paediatrics, Kandy Teaching Hospital, Sri Lanka. Data were collected from clinical records, consultations with the head of the blood bank and a consultant paediatrician directly involved with the care of patients, alongside structured interviews with families to gather data on the personal costs incurred such as those for travel. Results Thirty-four children aged 2–17 years with transfusion dependent thalassaemia major and their parent/guardian were included in the study. The total average cost per patient year to the hospital was $US 2601 of which $US 2092 were direct costs and $US 509 were overhead costs. Mean household expenditure was $US 206 per year with food and transport per transfusion ($US 7.57 and $US 4.26 respectively) being the highest cost items. Nine (26.5%) families experienced catastrophic levels of healthcare expenditure (> 10% of income) in the care of their affected child. The poorest households were the most likely to experience such levels of expenditure. Conclusions β-thalassaemia major poses a significant economic burden on health services and the families of affected children in Sri Lanka. Greater support is needed for the high proportion of families that suffer catastrophic out-of-pocket costs.

Abstract Background Conducting research in partnership with stakeholders (e.g. policy-makers, practitioners, organisations, patients) is a promising and popular approach to improving the implementation of research findings in policy and practice. This study aimed to identify the principles, strategies, outcomes and impacts reported in different types of reviews of research partnerships in order to obtain a better understanding of the scope of the research partnership literature. Methods This review of reviews is part of a Coordinated Multicenter Team approach to synthesise the research partnership literature with five conceptually linked literature reviews. The main research question was ‘What principles, strategies, outcomes and impacts are reported in different types of research partnership approaches?’. We included articles describing a literature review of research partnerships using a systematic search strategy. We used an adapted version of the Revised Assessment of Multiple Systematic Reviews tool to assess quality. Nine electronic databases were searched from inception to April 2018. Principles, strategies, outcomes and impacts were extracted from the included reviews and analysed using direct content analysis. Results We included 86 reviews using terms describing several research partnership approaches (e.g. community-based participatory research, participatory research, integrated knowledge translation). After the analyses, we synthesised 17 overarching principles and 11 overarching strategies and grouped them into one of the following subcategories: relationship between partners; co-production of knowledge; meaningful stakeholder engagement; capacity-building, support and resources; communication process; and ethical issues related to the collaborative research activities. Similarly, we synthesised 20 overarching outcomes and impacts on researchers, stakeholders, the community or society, and the research process. Conclusions This review of reviews is the first that presents overarching principles, strategies, outcomes and impacts of research partnerships. This review is unique in scope as we synthesised literature across multiple research areas, involving different stakeholder groups. Our findings can be used as a first step to guide the initiation and maintenance of research partnerships and to create a classification system of the key domains of research partnerships, which may improve reporting consistency in the research partnership literature. Trial registration This study is registered via Open Science Framework: https://doi.org/10.17605/OSF.IO/GVR7Y .

Abstract Background Onchocerciasis is a priority neglected tropical disease targeted for elimination by 2025. The standard strategy to combat onchocerciasis is annual Community-Directed Treatment with ivermectin (CDTi). Yet, high prevalence rates and transmission persist following > 12 rounds in South-West Cameroon. Challenges include programme coverage, adherence to, and acceptability of ivermectin in an area of Loa loa co-endemicity. Loiasis patients harbouring heavy infections are at risk of potentially fatal serious adverse events following CDTi. Alternative strategies are therefore needed to achieve onchocerciasis elimination where CDTi effectiveness is suboptimal. Methods/design We designed an implementation study to evaluate integrating World Health Organisation-endorsed alternative strategies for the elimination of onchocerciasis, namely test-and-treat with the macrofilaricide, doxycycline (TTd), and ground larviciding for suppression of blackfly vectors with the organophosphate temephos. A community-based controlled before-after intervention study will be conducted among > 2000 participants in 20 intervention (Meme River Basin) and 10 control (Indian River Basin) communities. The primary outcome measure is O. volvulus prevalence at follow-up 18-months post-treatment. The study involves four inter-disciplinary components: parasitology, entomology, applied social sciences and health economics. Onchocerciasis skin infection will be diagnosed by skin biopsy and Loa loa infection will be diagnosed by parasitological examination of finger-prick blood samples. A simultaneous clinical skin disease assessment will be made. Eligible skin-snip-positive individuals will be offered directly-observed treatment for 5 weeks with 100 mg/day doxycycline. Transmission assessments of onchocerciasis in the communities will be collected post-human landing catch of the local biting blackfly vector prior to ground larviciding with temephos every week (0.3 l/m3) until biting rate falls below 5/person/day. Qualitative research, including in-depth interviews and focus-group discussions will be used to assess acceptability and feasibility of the implemented alternative strategies among intervention recipients and providers. Health economics will assess the cost-effectiveness of the implemented interventions. Conclusions Using a multidisciplinary approach, we aim to assess the effectiveness of TTd, alone or in combination with ground larviciding, following a single intervention round and scrutinise the acceptability and feasibility of implementing at scale in similar hotspots of onchocerciasis infection, to accelerate onchocerciasis elimination.

Abstract Background The sequence diversity of dengue virus (DENV) is one of the challenges in developing an effective vaccine against the virus. Highly conserved, serotype-specific (HCSS), immune-relevant DENV sequences are attractive candidates for vaccine design, and represent an alternative to the approach of selecting pan-DENV conserved sequences. The former aims to limit the number of possible cross-reactive epitope variants in the population, while the latter aims to limit the cross-reactivity between the serotypes to favour a serotype-specific response. Herein, we performed a large-scale systematic study to map and characterise HCSS sequences in the DENV proteome. Methods All reported DENV protein sequence data for each serotype was retrieved from the NCBI Entrez Protein (nr) Database (txid: 12637). The downloaded sequences were then separated according to the individual serotype proteins by use of BLASTp search, and subsequently removed for duplicates and co-aligned across the serotypes. Shannon’s entropy and mutual information (MI) analyses, by use of AVANA, were performed to measure the diversity within and between the serotype proteins to identify HCSS nonamers. The sequences were evaluated for the presence of promiscuous T-cell epitopes by use of NetCTLpan 1.1 and NetMHCIIpan 3.2 server for human leukocyte antigen (HLA) class I and class II supertypes, respectively. The predicted epitopes were matched to reported epitopes in the Immune Epitope Database. Results A total of 2321 nonamers met the HCSS selection criteria of entropy 0.8. Concatenating these resulted in a total of 337 HCSS sequences. DENV4 had the most number of HCSS nonamers; NS5, NS3 and E proteins had among the highest, with none in the C and only one in prM. The HCSS sequences were immune-relevant; 87 HCSS sequences were both reported T-cell epitopes/ligands in human and predicted epitopes, supporting the accuracy of the predictions. A number of the HCSS clustered as immunological hotspots and exhibited putative promiscuity beyond a single HLA supertype. The HCSS sequences represented, on average, ~ 40% of the proteome length for each serotype; more than double of pan-DENV sequences (conserved across the four serotypes), and thus offer a larger choice of sequences for vaccine target selection. HCSS sequences of a given serotype showed significant amino acid difference to all the variants of the other serotypes, supporting the notion of serotype-specificity. Conclusion This work provides a catalogue of HCSS sequences in the DENV proteome, as candidates for vaccine target selection. The methodology described herein provides a framework for similar application to other pathogens.

Abstract Background Radon is a high impact environmental pollutant and is the second leading cause of lung cancer in Canada. Building design, extended winter, and geographical location expose residents of Ottawa-Gatineau (the national capital region in Canada) to an increased risk. It is surprising that residents have an inadequate awareness of the risk - despite its gravity - and have taken minimum preventive actions. This study explores perceptions of radon health risk and examines the factors that enable and hinder the adoption of preventive measures among Ottawa-Gatineau residents. Methods We conducted semi-structured interviews with 35 residents with varying educational and income levels to inquire about their knowledge and perception of radon, and to explore their views of enablers and obstacles to taking action to reduce radon risks. Thematic, inductive data analysis was undertaken. Results The results indicate that: 1) Residents obtained information on radon from various sources that include the media, their education or occupation, their social network, and home renovation events. Limited references were made to the National Radon Program responsible for testing for radon and informing residents. 2) Awareness of radon risk varied, and the knowledge retained by some residents is insufficient to adequately protect their health. 3) Enablers for taking protective action included: having an understanding of the risk along with health consciousness; caring for family and children; knowing others who had contracted lung cancer and having financial resources. Obstacles consisted of: lack of awareness; cost; lack of home ownership; and potential difficulty in selling the house. 4) Residents attributed primary responsibility to public agencies for disseminating information, and incentivizing or mandating action through more stringent regulation. Conclusion Risk perceptions are subjective, and are influenced by micro and macro level factors. Inducing protective action to reduce risk requires comprehensive interventions taking into account the dual cognitive and emotional aspects of risk perception. Future research may explore the dual aspects of risk perception and examine the contents of the risk communication message. Policy should address the responsibility of both governments and residents in tackling the issue.

Abstract Background District hospitals (DHs) provide secondary level of healthcare to a wide range of population in Bangladesh. Efficient utilization of resources in these secondary hospitals is essential for delivering health services at a lower cost. Therefore, we aimed to estimate the technical efficiency of the DHs in Bangladesh. Methods We used input-oriented data envelopment analysis method to estimate the variable returns to scale (VRS) and constant returns to scale (CRS) technical efficiency of the DHs using data from Local Health Bulletin, 2015. In this model, we considered workforce as well as number of inpatient beds as input variables and number of inpatient, outpatient, and maternal services provided by the DHs as output variables. A Tobit regression model was applied for assessing the association of institutional and environmental characteristics with the technical efficiency scores. Results The average scale, VRS, and CRS technical efficiency of the DHs were estimated to 85%, 92%, and 79% respectively. Population size, poverty headcount, bed occupancy ratio, administrative divisions were significantly associated with the technical efficiency of the DHs. The mean VRS and CRS technical efficiency demonstrated that the DHs, on an average, could reduce their input mix by 8% and 21% respectively while maintaining the same level of output. Conclusion Since the average technical efficiency of the DHs was 79%, there is little scope for overall improvements in these facilities by adjusting inputs. Therefore, we recommend to invest further in the DHs for improvement of services. The Ministry of Health and Family Welfare (MoHFW) should improve the efficiency in resource allocation by setting an input-mix formula for DHs considering health and socio-economic indicators (e.g., population density, poverty, bed occupancy ratio). The formula can be designed by learning from the input mix in the more efficient DHs. The MoHFW should conduct this kind of benchmarking study regularly to assess the efficiency level of health facilities which may contribute to reduce the wastage of resources and consequently to provide more affordable and accessible public hospital care.

Abstract Background Many youth and young adults experience high noise exposure compounded by lack of access to hearing health education. Although the need for hearing health education programs is evident, the efficacy of these programs for youth is unclear. We evaluated the literature for efficacy of various hearing conservation programs aimed at youth and young adults, and analyzed their strengths and limitations. Methods Studies reporting results of hearing conservation or hearing loss prevention programs with youth or young adults, using randomized controlled trials, quasi-experimental designs, experimental design, or qualitative research, and published in peer-reviewed journals in English between 2001 and 2018 were included. Studies were found through searches of selected literature databases (i.e., PubMed, Google Scholar, NIOSH Toxline, and Scopus). Identified publications were assessed for relevance, and data were extracted from the studies deemed relevant. Results A total of 10 studies were included. Very little evidence of efficacy of hearing conservation educational programs was found in these studies. Several methodological limitations including lack of rigorous study designs, inadequate power, and application of inappropriate statistical analysis were noted. Some use of technology in programs (e.g., smartphone apps, mobile phone text messages, and computers) was observed, but conclusions as to the effectiveness of these tools were limited by the small number of studies and small sample sizes. Conclusions The number of studies of educational hearing conservation programs for youth and young adults was low. The efficacy of the program was not reported in most studies, and it is difficult to draw public health conclusions from these studies due to their multiple methodological limitations. While use of technology in hearing conservation educational programs offers promise, its effectiveness has not been studied.

Abstract Background Compared to ST-segment elevation myocardial infarction (STEMI) patients who present at centres with catheterization facilities, those transferred for primary percutaneous coronary intervention (PCI) have substantially longer door-in to door-out (DIDO) times, where DIDO is defined as the time interval from arrival at a non-PCI hospital, to transfer to a PCI hospital. We aimed to identify potentially modifiable factors to improve DIDO times in Ontario, Canada and to assess the impact of DIDO times on 30-day mortality. Methods A population-based, retrospective cohort study of 966 STEMI patients transferred for primary PCI in Ontario in 2012 was conducted. Baseline factors were examined across timely DIDO status. Multivariate logistic regression was used to examine independent predictors of timely DIDO as well as the association between DIDO times and 30-day mortality. Results The median DIDO time was 55 min, with 20.1% of patients achieving the recommended DIDO benchmark of ≤30 min. Age (OR> 75 vs 18–55 0.30, 95% CI: 0.16–0.56), symptom-to-first medical contact (FMC) time (OR61-120mins vs 120mins vs 90 min had significantly higher adjusted 30-day mortality rates (OR 2.82, 95% CI:1.10–7.19). Conclusions While benchmark DIDO times were still rarely achieved in the province, we identified several potentially modifiable factors in the STEMI system that might be targeted to improve DIDO times. Our findings that patients who received a pre-hospital ECG were still being transferred to non-PCI capable centres suggest strategies addressing this gap may improve patient outcomes.

Abstract Background Lead (Pb), a heavy metal, and quinolinic acid (QA), a metabolite of the kynurenine pathway of tryptophan metabolism, are known neurotoxicants. Both Pb and QA impair spatial learning and memory. Pb activates astrocytes and microglia, which in turn induce the synthesis of QA. We hypothesized increased QA production in response to Pb exposure as a novel mechanism of Pb-neurotoxicity. Methods Two experimental paradigms were used. In experiment one, Wistar rat pups were exposed to Pb via their dams’ drinking water from postnatal day 1 to 21. Control group was given regular water. In the second protocol, QA (9 mM) or normal saline (as Vehicle Control) was infused into right lateral ventricle of 21-day old rats for 7 days using osmotic pumps. Learning and memory were assessed by Morris water maze test on postnatal day 30 or 45 in both Pb- and QA-exposed rats. QA levels in the Pb exposed rats were measured in blood by ELISA and in the brain by immunohistochemistry on postnatal days 45 and 60. Expression of various molecules involved in learning and memory was analyzed by Western blot. Means of control and experimental groups were compared with two-way repeated measure ANOVA (learning) and t test (all other variables). Results Pb exposure increased QA level in the blood (by ~ 58%) and increased (p

Abstract Background Rodent malaria parasites where the gene encoding circumsporozoite protein (CSP) has been replaced with csp genes from the human malaria parasites, Plasmodium falciparum or Plasmodium vivax, are used as pre-clinical tools to evaluate CSP vaccines in vivo. These chimeric rodent parasites produce sporozoites in Anopheles stephensi mosquitoes that are capable of infecting rodent and human hepatocytes. The availability of chimeric P. falciparum parasites where the pfcsp gene has been replaced by the pvcsp would open up possibilities to test P. vivax CSP vaccines in small scale clinical trials using controlled human malaria infection studies. Methods Using CRISPR/Cas9 gene editing two chimeric P. falciparum parasites, were generated, where the pfcsp gene has been replaced by either one of the two major pvcsp alleles, VK210 or VK247. In addition, a P. falciparum parasite line that lacks CSP expression was also generated. These parasite lines have been analysed for sporozoite production in An. stephensi mosquitoes. Results The two chimeric Pf-PvCSP lines exhibit normal asexual and sexual blood stage development in vitro and produce sporozoite-containing oocysts in An. stephensi mosquitoes. Expression of the corresponding PvCSP was confirmed in oocyst-derived Pf-PvCSP sporozoites. However, most oocysts degenerate before sporozoite formation and sporozoites were not found in either the mosquito haemocoel or salivary glands. Unlike the chimeric Pf-PvCSP parasites, oocysts of P. falciparum parasites lacking CSP expression do not produce sporozoites. Conclusions Chimeric P. falciparum parasites expressing P. vivax circumsporozoite protein fail to produce salivary gland sporozoites. Combined, these studies show that while PvCSP can partially complement the function of PfCSP, species-specific features of CSP govern full sporozoite maturation and development in the two human malaria parasites.

Abstract Background Rapidly increasing healthcare costs and the growing burden of non-communicable diseases have increased the out-of-pocket (OOP) spending (63.3% of total health expenditure) in Bangladesh. This increasing OOP spending for healthcare has catastrophic economic impact on households. To reduce this burden, the Health Economics Unit (HEU) of the Ministry of Health and Family Welfare has developed the Shasthyo Surokhsha Karmasuchi (SSK) health protection scheme for the below-poverty line (BPL) population. The key actors in the scheme are HEU, contracted scheme operator and hospital. Under this scheme, each enrolled household is provided 50,000 BDT (620 USD) coverage per year for healthcare services against a government financed premium of 1000 BDT (12 USD). This initiative faces some challenges e.g., delays in scheme activities, registering the targeted population, low utilization of services, lack of motivation of the providers, and management related difficulties. It is also important to estimate the financial requirement for nationwide scale-up of this project. We aim to identify these implementation-related challenges and provide feedback to the project personnel. Methods This is a concurrent process documentation using mixed-method approaches. It will be conducted in the rural Kalihati Upazila where the SSK is being implemented. To validate the BPL population selection process, we will estimate the positive predictive value. A community survey will be conducted to assess the knowledge of the card holders about SSK services. From the SSK information management system, numbers of different services utilized by the card holders will be retrieved. Key-informant interviews with personnel from three key actors will be conducted to understand the barriers in the implementation of the project as per plan and gather their suggestions. To estimate the project costs, all inputs to be used will be identified, quantified and valued. The nationwide scale-up cost of the project will be estimated by applying economic modeling. Discussion SSK is the first ever government initiated health protection scheme in Bangladesh. The study findings will enable decision makers to gain a better understanding of the key challenges in implementation of such scheme and provide feedback towards the successful implementation of the program.

Abstract Background Pear (Pyrus) is a globally grown fruit, with thousands of cultivars in five domesticated species and dozens of wild species. However, little is known about the evolutionary history of these pear species and what has contributed to the distinct phenotypic traits between Asian pears and European pears. Results We report the genome resequencing of 113 pear accessions from worldwide collections, representing both cultivated and wild pear species. Based on 18,302,883 identified SNPs, we conduct phylogenetics, population structure, gene flow, and selective sweep analyses. Furthermore, we propose a model for the divergence, dissemination, and independent domestication of Asian and European pears in which pear, after originating in southwest China and then being disseminated throughout central Asia, has eventually spread to western Asia, and then on to Europe. We find evidence for rapid evolution and balancing selection for S-RNase genes that have contributed to the maintenance of self-incompatibility, thus promoting outcrossing and accounting for pear genome diversity across the Eurasian continent. In addition, separate selective sweep signatures between Asian pears and European pears, combined with co-localized QTLs and differentially expressed genes, underline distinct phenotypic fruit traits, including flesh texture, sugar, acidity, aroma, and stone cells. Conclusions This study provides further clarification of the evolutionary history of pear along with independent domestication of Asian and European pears. Furthermore, it provides substantive and valuable genomic resources that will significantly advance pear improvement and molecular breeding efforts.

Abstract Background In Canada, government insurance covers eye care services provided by ophthalmologists and other physicians. However, government coverage for services provided by optometrists, non-medical school trained primary eye care providers, varies regionally. Little is known about the impact of a funding model in which ophthalmologist services are government-insured but services provided by optometrists are not, on eye care utilization and eye disease detection and treatment. We aimed to address this question by examining geographic variations in eye care service utilization on Prince Edward Island (PEI). Methods PEI physician-billing data from 2010 to 2012 was analyzed across five distinct geographic regions (Charlottetown, Summerside, Prince, Queens & Kings and Stratford). The residential location of patients and practice locations of eye care providers were identified using the first three digits of their respective postal code. Age-standardized rates were computed for comparisons across different regions. Results There were six ophthalmologists practicing on PEI, five with offices in Charlottetown. Twenty optometrists practiced on the island with offices across the province. Stratford is closest and Prince farthest from Charlottetown. Age-standardized utilization rates of ophthalmologists per 100 populations were 10.44 in Charlottetown and 10.90 in Stratford, which was significantly higher than in other regions (7.74–8.92; p

Abstract Background Utilization of Antenatal Care (ANC) is very low in Nigeria. Self-reported patient satisfaction may be useful to identify provider- and facility-specific factors that can be improved to increase ANC satisfaction and utilization. Methods Exit interview data collected from ANC users and facility assessment survey data from 534 systematically selected facilities in four northern Nigerian states were used. Associations between patient satisfaction (satisfied, not-satisfied) and patient ratings of the provider’s interactions, care processes, out-of-pocket costs, and quality of facility infrastructure were studied. Results Of 1336 mothers, 90% were satisfied with ANC. Patient satisfaction was positively associated with responsive service (prompt, unrushed service, convenient clinic hours and privacy during consultation, AOR 2.42, 95% CI 2.05–2.87), treatment-facilitation (medical care-related provider communication and ease of receiving medicines, AOR 2.03, 95% CI 1.46–2.80), equipment availability (AOR 1.10, 95% CI 1.01–1.21), staff empathy (AOR 1.82, 95% CI 1.03–3.23), non-discriminatory treatment regardless of patient’s socioeconomic status (AOR: 1.87, 95% CI 1.09–3.22), provider assurance (courtesy and patient’s confidence in provider’s competence, AOR 1.48, 95% CI 1.26–1.75), and number of clinical examinations received (AOR 1.28, 95% CI 1.10–1.50). ANC satisfaction was negatively impacted by out-of-pocket payment for care (vs. free care, AOR 0.44, 95% CI 0.23–0.82). Conclusions ANC satisfaction in Nigeria may be enhanced by improving responsiveness to clients, clinical care quality, ensuring equipment availability, optimizing easy access to medicines, and expanding free ANC services.

Abstract Background Suicide is a major global public health problem with more than 800,000 incidents worldwide annually. Seventy-five percent of the global suicides occur in low and middle-income countries (LMICs). Pakistan is a LMIC where information on suicidal behavior is limited. The aim of the review is to map available literature on determinants, risk factors and other variables of suicidal behavior in Pakistan. Method This study was based on Arksey and O’Malley’s methodological framework of scoping review, combining peer reviewed publications with grey literature. Ten databases including Applied Social Sciences Index and Abstracts (ASSIA), Cochrane Trials Register (CRG), Cumulative Index to Nursing and Allied Health (CINAHL), National Library of Medicine Gateway (NLMG), ExcerptaMedica (EMBASE), National Library of Medicine’s MEDLINE (PUBMED), PSYCHINFO, Social Science Citation Index and Science Citation Index (SCI) and Pakmedinet.com were searched from the beginning of their time frames until December 2016 using a combination of key terms. The inclusion criteria included studies of various study designs covering different aspects of suicidal behavior in English language. Results Six hundred and twenty three articles were initially retrieved from all ten databases. Two independent reviewers screened the titles and abstracts for relevance. One hundred and eighteen articles were read in full, out of which 11 were excluded because they did not fit the eligibility criteria. One hundred and ten articles, including two student theses and one report, were included in the final review. Most studies were descriptive in nature, with only three that used a case-control design. Majority of the studies were from urban areas, and addressed determinants rather than risk factors. Gender differences and age were predominantly reported, with more males committing suicide. Suicidal behavior was more common among individuals younger than 30 years of age. The three most common methods for suicides were hanging, poisoning and use of firearms. Mental illness as a risk factor for suicides was mentioned in only three studies. Conclusions This review is the first attempt to synthesize available literature on suicidal behavior in Pakistan. The evidence is limited, and calls for more robust analytical research designs, along with a focus on risk factors.

Abstract Background Diarrheal diseases are a major threat to human health and still represent a leading cause of morbidity and mortality worldwide. Although the burden of the diarrheal diseases is much lower in developed countries, it is a significant public health problem in low and middle-income countries like Bangladesh. Though diarrhea is preventable and managed with low-cost interventions, it is still the leading cause of morbidity according to the patient who sought care from public hospitals in Bangladesh indicating that significant resources are consumed in treating those patients. The aim of the study is to capture the inpatients and outpatient treatment cost of diarrheal disease and to measure the cost burden and coping mechanisms associated with diarrheal illness. Methods This study was conducted in six randomly selected district hospitals from six divisions (larger administrative units) in Bangladesh. The study was performed from the societal perspective which means all types of costs were identified, measured and valued no matter who incurred them. Cost analysis was estimated using the guideline proposed by the World Health Organization for estimating the economic burden of diarrheal diseases. The study adopted quantitative techniques to collect the household and hospital level data including structured and semi-structured questionnaires, observation checklists, analysis of hospital database, telephone interviews and compilation of service statistics. Results The average total societal cost of illness per episode was BDT 5274.02 (US $ 67.18) whereas the average inpatient and outpatient costs were BDT 8675.09 (US $ 110.51) and BDT 1853.96 (US $ 23.62) respectively. The cost burden was significantly highest for poorest households, 21.45% of household income, compared to 4.21% of the richest quintile. Conclusions Diarrheal diseases continue to be an overwhelming problem in Bangladesh. The economic impact of any public health interventions (either preventive or promotive) that can reduce the prevalence of diarrheal diseases can be estimated from the data generated from this study.

Abstract Background Ebolavirus (EBOV) is responsible for one of the most fatal diseases encountered by mankind. Cellular T-cell responses have been implicated to be important in providing protection against the virus. Antigenic variation can result in viral escape from immune recognition. Mapping targets of immune responses among the sequence of viral proteins is, thus, an important first step towards understanding the immune responses to viral variants and can aid in the identification of vaccine targets. Herein, we performed a large-scale, proteome-wide mapping and diversity analyses of putative HLA supertype-restricted T-cell epitopes of Zaire ebolavirus (ZEBOV), the most pathogenic species among the EBOV family. Methods All publicly available ZEBOV sequences (14,098) for each of the nine viral proteins were retrieved, removed of irrelevant and duplicate sequences, and aligned. The overall proteome diversity of the non-redundant sequences was studied by use of Shannon’s entropy. The sequences were predicted, by use of the NetCTLpan server, for HLA-A2, -A3, and -B7 supertype-restricted epitopes, which are relevant to African and other ethnicities and provide for large (~86%) population coverage. The predicted epitopes were mapped to the alignment of each protein for analyses of antigenic sequence diversity and relevance to structure and function. The putative epitopes were validated by comparison with experimentally confirmed epitopes. Results & discussion ZEBOV proteome was generally conserved, with an average entropy of 0.16. The 185 HLA supertype-restricted T-cell epitopes predicted (82 (A2), 37 (A3) and 66 (B7)) mapped to 125 alignment positions and covered ~24% of the proteome length. Many of the epitopes showed a propensity to co-localize at select positions of the alignment. Thirty (30) of the mapped positions were completely conserved and may be attractive for vaccine design. The remaining (95) positions had one or more epitopes, with or without non-epitope variants. A significant number (24) of the putative epitopes matched reported experimentally validated HLA ligands/T-cell epitopes of A2, A3 and/or B7 supertype representative allele restrictions. The epitopes generally corresponded to functional motifs/domains and there was no correlation to localization on the protein 3D structure. These data and the epitope map provide important insights into the interaction between EBOV and the host immune system.

Abstract Background Viral vaccine target discovery requires understanding the diversity of both the virus and the human immune system. The readily available and rapidly growing pool of viral sequence data in the public domain enable the identification and characterization of immune targets relevant to adaptive immunity. A systematic bioinformatics approach is necessary to facilitate the analysis of such large datasets for selection of potential candidate vaccine targets. Results This work describes a computational methodology to achieve this analysis, with data of dengue, West Nile, hepatitis A, HIV-1, and influenza A viruses as examples. Our methodology has been implemented as an analytical pipeline that brings significant advancement to the field of reverse vaccinology, enabling systematic screening of known sequence data in nature for identification of vaccine targets. This includes key steps (i) comprehensive and extensive collection of sequence data of viral proteomes (the virome), (ii) data cleaning, (iii) large-scale sequence alignments, (iv) peptide entropy analysis, (v) intra- and inter-species variation analysis of conserved sequences, including human homology analysis, and (vi) functional and immunological relevance analysis. Conclusion These steps are combined into the pipeline ensuring that a more refined process, as compared to a simple evolutionary conservation analysis, will facilitate a better selection of vaccine targets and their prioritization for subsequent experimental validation.

An amendment to this paper has been published and can be accessed via the original article.

Abstract Background Hearing loss remains a neglected public health issue in the rural and agricultural communities in the United States and therefore, promotion of a low-cost hearing screening may be important for these underserved populations. The major objectives of our study were to assess feasibility of a low-cost telephone-administered hearing test in rural Indiana and to identify the challenges, barriers and viable implementation strategies associated with this test. Also, we evaluated whether a focus group session could change the hearing health attitude of rural residents. Methods We recruited 126 adults from six rural Indiana counties who participated in study activities in the following order: 1) a pre-focus group demographic, knowledge and attitude survey, 2) a focus group for discussing the feasibility of a telephone-administered hearing screening, 3) a post focus group attitude survey and 4) hearing was screened using an audiometer and self-assessment scale. These activities generated both qualitative and quantitative data, which were subsequently analyzed. Results Hearing impairment was perceived as an important public health issue. Many participants expressed interests to try the low-cost National Hearing Test (NHT). However, participants recommended NHT to be facilitated by community organizations to provide access to landline phones. The focus group turned out to be an excellent awareness building activity producing significant improvement in hearing health attitudes. Comparison of self and audiometric evaluations indicated underestimation of hearing handicap in our rural study population. Conclusions The study results underscore the urgent need for an effective strategy to promote low-cost hearing screening in rural US communities.

Abstract Background Efficacy-safety of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, alirocumab (ALI) and evolocumab (EVO), have previously been evaluated through controlled clinical trials with selective patient groups. Post-commercially, in 69 patients with heterozygous familial hypercholesterolemia (HeFH) and/or cardiovascular disease (CVD) with suboptimal LDL cholesterol (LDLC) lowering on maximal tolerated LDLC therapy, we assessed efficacy and safety of ALI and EVO. Methods Post-commercially, we started 29 patients on ALI 75 mg, 18 on ALI 150 mg, and 22 on EVO 140 mg every 2 weeks added to a maximally tolerated LDLC-lowering regimen. Since LDLC lowering did not differ between ALI 150 and EVO 140 mg, ALI 150-EVO 140 data were pooled (ALI-EVO). Changes in LDLC and AHA and NIH calculated 10-year CVD risks were assessed. Results Of the 69 patients, 25 had HeFH, 25 CVD, and 19 had both. At entry, 23 (33%) took statins and 46 (67%) were statin-intolerant. Mean ± SD and median follow-up were 49 ± 13 and 49 weeks on ALI 75 mg, and 37 ± 12 and 33 weeks on ALI-EVO. In the ALI-EVO group (n = 40), median LDLC fell from 165 mg/dl at entry to 70 mg/dl (median − 59%, p 0.05) between ALI 75 mg and ALI-EVO. Conclusion In patients with HeFH and/or CVD, LDLC decreased from 115 to 68 mg/dl (39%) on ALI 75 mg with mean follow-up of 49 weeks, and from 165 to 70 mg/dl (59%) on ALI-EVO over 37 weeks, p

Abstract Background Counseling has a significant role in improving knowledge, attitude and practice outcomes of pregnant women towards medication use. Proper counseling thus could be beneficial to prevent any medication related misadventure during pregnancy. The present study was aimed to assess the knowledge, attitude and practice (KAP) of pregnant women towards their medications, to provide counseling regarding their understanding of medication use during pregnancy and evaluate the impacts of such counseling. Methods Pre- post interventional (counseling) study was conducted at Manipal Teaching Hospital, Nepal among pregnant women who presented with complication and were prescribed at least one medication. A total of 275 pregnant women were included in the study. A structured questionnaire was used to assess the knowledge, attitude and practice of pregnant women before and after counseling. The impacts of counseling were then evaluated using suitable statistical methods. Results Of the total participants 229 completed the post counseling survey. Majority of the participants were in the age group 20-24 (43.2%), primigravida (59.4%) and in third trimester (58.6%). Housewives comprised 61.1% of participants and majority had received a University degree (33.2%). The mean and median scores assessed before counseling showed that there was no significant difference in the KAP scores with respect to age, trimester and gravidity whereas KAP scores with respect to occupation and level of education were statistically significant. There was an increase in mean and median KAP scores after counseling and the impacts of counseling was found to be statistically significant (p =

Following publication of the original article [1], the authors notified us of an error in the spelling of second author’s name. The correct name spelling is Suad A. Telity.