Mortality surrogates in combined pulmonary fibrosis and emphysema.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) with coexistent emphysema, termed combined pulmonary fibrosis and emphysema (CPFE) may associate with reduced forced vital capacity (FVC) declines compared to non-CPFE IPF patients. We examined associations between mortality and functional measures of disease progression in two IPF cohorts. METHODS: Visual emphysema presence (>0% emphysema) scored on computed tomography identified CPFE patients (CPFE/non-CPFE: derivation cohort n=317/n=183, replication cohort n=358/n=152), who were subgrouped using 10% or 15% visual emphysema thresholds, and an unsupervised machine-learning model considering emphysema and interstitial lung disease extents. Baseline characteristics, 1-year relative FVC and diffusing capacity of the lung for carbon monoxide (D LCO) decline (linear mixed-effects models), and their associations with mortality (multivariable Cox regression models) were compared across non-CPFE and CPFE subgroups. RESULTS: In both IPF cohorts, CPFE patients with ≥10% emphysema had a greater smoking history and lower baseline D LCO compared to CPFE patients with <10% emphysema. Using multivariable Cox regression analyses in patients with ≥10% emphysema, 1-year D LCO decline showed stronger mortality associations than 1-year FVC decline. Results were maintained in patients suitable for therapeutic IPF trials and in subjects subgrouped by ≥15% emphysema and using unsupervised machine learning. Importantly, the unsupervised machine-learning approach identified CPFE patients in whom FVC decline did not associate strongly with mortality. In non-CPFE IPF patients, 1-year FVC declines ≥5% and ≥10% showed strong mortality associations. CONCLUSION: When assessing disease progression in IPF, D LCO decline should be considered in patients with ≥10% emphysema and a ≥5% 1-year relative FVC decline threshold considered in non-CPFE IPF patients.

Prevalence and management of dyslipidemia in primary care practices in Canada.

OBJECTIVE: To estimate the prevalence of dyslipidemia and to describe its management in Canadian primary care. DESIGN: Retrospective cohort study using primary care electronic medical record data. SETTING: Canada. PARTICIPANTS: Adults aged 40 years or older who saw a Canadian Primary Care Sentinel Surveillance Network contributor between January 1, 2018, and December 31, 2019. MAIN OUTCOME MEASURES: Presence or absence of dyslipidemia as identified by a validated case definition and the treatment status of patients identified as having dyslipidemia based on having been prescribed a lipid-lowering agent (LLA). RESULTS: In total, 50.0% of the 773,081 patients 40 years of age or older who had had a primary care visit in 2018 or 2019 were identified as having dyslipidemia. Dyslipidemia was more prevalent in patients 65 or older (61.5%), in males (56.7%) versus females (44.7%), and in those living in urban areas (50.0%) versus rural areas (45.2%). In patients with documented dyslipidemia, 42.8% had evidence of treatment with an LLA. Stratifying patients by Framingham risk score revealed that those in the high-risk category were more likely to have been prescribed an LLA (65.0%) compared with those in the intermediate-risk group (48.7%) or the low-risk group (22.8%). The strongest determinants of receiving LLA treatment for dyslipidemia include sex, with males being 1.95 times more likely to have been treated compared with females (95% CI 1.91 to 1.98; P<.0001); and body mass index, with those with obesity having a significantly increased likelihood of being treated with an LLA (adjusted odds ratio of 1.36, 95% CI 1.32 to 1.41; P<.0001). CONCLUSION: This study provides an updated look at the prevalence and treatment of dyslipidemia among Canadians. Half of patients aged 40 years or older have dyslipidemia, with an even higher prevalence observed among adults aged 65 years or older, males, and those with obesity or other chronic conditions. There are still gaps in treatment among those with documented dyslipidemia, principally among those calculated to have high or intermediate Framingham risk scores. Particular attention should also be paid to those at higher risk for not receiving treatment, including female patients and those within normal body mass index ranges.

Synthesis and biological profile of 2,3-dihydro[1,3]thiazolo[4,5-b]pyridines, a novel class of acyl-ACP thioesterase inhibitors.

The present work covers novel herbicidal lead structures that contain a 2,3-dihydro[1,3]thiazolo[4,5-b]pyridine scaffold as structural key feature carrying a substituted phenyl side chain. These new compounds show good acyl-ACP thioesterase inhibition in line with strong herbicidal activity against commercially important weeds in broadacre crops, e.g., wheat and corn. The desired substituted 2,3-dihydro[1,3]thiazolo[4,5-b]pyridines were prepared via an optimized BH3-mediated reduction involving tris(pentafluorophenyl)borane as a strong Lewis acid. Remarkably, greenhouse trials showed that some of the target compounds outlined herein display promising control of grass weed species in preemergence application, combined with a dose response window that enables partial selectivity in certain crops.

Investigations into Simplified Analogues of the Herbicidal Natural Product (+)-Cornexistin.

We report the design, synthesis and biological evaluation of simplified analogues of the herbicidal natural product (+)-cornexistin. Guided by an X-Ray co-crystal structure of cornexistin bound to transketolase from Zea mays, we attempted to identify the key interactions that are necessary for cornexistin to maintain its herbicidal profile. This resulted in the preparation of three novel analogues investigating the importance of substituents that are located on the nine-membered ring of cornexistin. One analogue maintained a good level of biological activity and could provide researchers insights in how to further optimize the structure of cornexistin for commercialization in the future.

Considerations for Creating a Restricted Data Environment with Complete Primary Care Electronic Medical Record Data.

Background: Historically, primary care databases have been limited to subsets of the full electronic medical record (EMR) data to maintain privacy. With the progression of artificial intelligence (AI) techniques (i.e., machine learning, natural language processing, and deep learning), practice-based research networks (PBRNs) have an opportunity to utilize previously difficult to access data to conduct essential primary care research and quality improvement. However, to ensure patient privacy and data security, novel infrastructure and processes are required. We describe the considerations related to accessing complete EMR data on a large-scale within a Canadian PBRN. Setting: Queen's Family Medicine Restricted Data EnviroNment (QFAMR), Department of Family Medicine (DFM), Queen's University, Canada Methods: QFAMR is a central holding repository hosted at the Centre for Advanced Computing at Queen's University. Complete, de-identified EMR records (e.g., full chart notes, PDFs, and free text) from approximately 18,000 patients from Queen's DFM can be accessed. An iterative process over 2021-2022 was used to develop QFAMR infrastructure in collaboration with Queen's DFM members and stakeholders. Results: In May 2021, the QFAMR standing research committee was established for review and approval of all potential projects. DFM members consulted with Queen's University computing, privacy, legal, and ethics experts to develop data access processes, policies and governance, agreements, and associated documents. Initial QFAMR projects involved applying and improving de-identification processes for DFM-specific full-chart notes. Five major elements were recurrent throughout the QFAMR development process: data and technology, privacy, legal documentation, decision-making frameworks, and ethics and consent. Conclusion: Overall, the development of the QFAMR has provided a secure platform to successfully access data-rich primary care EMR records without data ever leaving Queen's University. Although accessing complete primary care EMR records has certain technological, privacy, legal, and ethical considerations and challenges, QFAMR is a significant opportunity to conduct novel and innovative primary care research.

Baseline Inappropriate Antibiotic Use in Primary Care Patients with Viral Respiratory Tract Infections with 2019 and 2020.

Context: Respiratory tract infection (RTI) is the leading cause of avoidable antimicrobial use in primary care. How the COVID-19 pandemic has impacted antibiotic prescribing practices across Canada is unknown. The purpose of this study was to examine rates of antibiotic prescribing for RTI in primary care during the first year of the pandemic (2020), compared to baseline in 2019. Study Design and Analysis: Cross sectional study. Dataset: Canadian Primary Care Sentinel Surveillance Network electronic medical record data from sites in British Columbia, Alberta, Manitoba, Ontario, Quebec, Nova Scotia and Newfoundland. Population Studied: Patients that met the case definition criteria for an RTI or a Urinary Tract Infection (UTI) in 2019, and in 2020. Outcome measures: We examined oral antibiotic prescribing for patients who were identified as having a primary care visit for RTI. The same analysis was repeated for urinary tract infection (UTI) as a tracer condition. The antibiotic use considered avoidable for RTI was defined by Choosing Wisely Canada. Results: A total of 1,692,876 patients with a valid birth year and sex and at least one visit to primary care in 2019 and 2020 were included. Patient visits for RTI decreased from 2.3% in 2019 to 1.6% in 2020 (p<.0001), as did patient visits for UTI (1.1% vs 0.7%, p<.0001). In 2019, 28.0% of patients visits for RTI were prescribed an antibiotic, and this proportion decreased significantly to 20.6% in 2020 (<.0001). The drop in antibiotic prescriptions for RTI was driven by a decrease in prescribing for common cold (13.6% vs. 11.3%, <.0001) and for acute bronchitis/asthma (15.2% vs. 7.3%, p<.0001). In comparison, antibiotic prescribing for visits related to UTI increased marginally between 2019 and 2020 (71.6% vs. 72.3%, p=0.007). Conclusions: A significant decrease in antibiotic prescribing for RTI across primary care was observed during the first year of the COVID-19 pandemic, likely related to the changes in epidemiology and care delivery models in primary care. CPCSSN can provide pan-Canadian surveillance of antibiotic prescribing practices in primary care that can be used for provider feedback and quality improvement.

Integrating data types to estimate spatial patterns of avian migration across the Western Hemisphere.

For many avian species, spatial migration patterns remain largely undescribed, especially across hemispheric extents. Recent advancements in tracking technologies and high-resolution species distribution models (i.e., eBird Status and Trends products) provide new insights into migratory bird movements and offer a promising opportunity for integrating independent data sources to describe avian migration. Here, we present a three-stage modeling framework for estimating spatial patterns of avian migration. First, we integrate tracking and band re-encounter data to quantify migratory connectivity, defined as the relative proportions of individuals migrating between breeding and nonbreeding regions. Next, we use estimated connectivity proportions along with eBird occurrence probabilities to produce probabilistic least-cost path (LCP) indices. In a final step, we use generalized additive mixed models (GAMMs) both to evaluate the ability of LCP indices to accurately predict (i.e., as a covariate) observed locations derived from tracking and band re-encounter data sets versus pseudo-absence locations during migratory periods and to create a fully integrated (i.e., eBird occurrence, LCP, and tracking/band re-encounter data) spatial prediction index for mapping species-specific seasonal migrations. To illustrate this approach, we apply this framework to describe seasonal migrations of 12 bird species across the Western Hemisphere during pre- and postbreeding migratory periods (i.e., spring and fall, respectively). We found that including LCP indices with eBird occurrence in GAMMs generally improved the ability to accurately predict observed migratory locations compared to models with eBird occurrence alone. Using three performance metrics, the eBird + LCP model demonstrated equivalent or superior fit relative to the eBird-only model for 22 of 24 species-season GAMMs. In particular, the integrated index filled in spatial gaps for species with over-water movements and those that migrated over land where there were few eBird sightings and, thus, low predictive ability of eBird occurrence probabilities (e.g., Amazonian rainforest in South America). This methodology of combining individual-based seasonal movement data with temporally dynamic species distribution models provides a comprehensive approach to integrating multiple data types to describe broad-scale spatial patterns of animal movement. Further development and customization of this approach will continue to advance knowledge about the full annual cycle and conservation of migratory birds.

Screening patterns and identification of non-alcoholic fatty liver disease in obese children in canadian primary care.

Context. Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children. There is no epidemiological data on rates of pediatric NAFLD in Canada. Primary care physicians (PCPs) are often the first contact healthcare professionals to manage potential pediatric patients with NAFLD. Objective: Evaluate patterns of screening and identification of pediatric NAFLD in Canadian primary care using administrative health care database. Study Design: Cross-sectional observational study. Dataset: The Canadian Primary Care Sentinel Surveillance Network (CPCSSN), a repository of clinical electronic medical record data drawn from primary care practices across Canada. Population Studied: Children aged 9-18 years old between July 1, 2018 and December 31, 2019. Outcome Measures: The proportion of children eligible for screening (BMI≥95th percentile) as per NASPGHAN guidelines using ALT levels. Logistic Regression was used to evaluate the predictors for screening. Suspected NAFLD was defined as elevated ALT (>22 U/L for girls and > 26 U/L for boys) in the absence of viral hepatitis, metabolic conditions, alcohol use, hepatotoxic medications. Results: The study sample consisted of 66,872 children, of which 15.8% (n=10,539) had a BMI≥95th percentile and only 10.1% (n=1,067/10539) were screened in the last year using ALT. Children were more likely to get screened if they were a) older (13-18 year vs 9-12 year, OR=1.63, 95% CI 1.38-1.93); b) living in an urban setting (OR=1.34, 95% CI 1.0-1.63); and c) had a higher BMI (≥99th percentile vs 95th-98th, OR=1.34, 95% CI 1.14, 1.56). We identified 855 cases of suspected NAFLD, most children (78.5%) were older (13-18 years), male (55.0%), and lived in an urban setting (71.5%). A significant proportion (40.4%) had a BMI in the 99th percentile and 60.3% had at least one comorbidity, and 35.9% were prescribed a psychotropic, antidiabetic or antihypertensive medications. Only 19.9% were referred to a specialist (pediatrician, gastroenterologist). Conclusions: This is the first study to estimate the screening patterns of pediatric NAFLD in primary care in Canada at a national level. The study revealed low screening rates in primary care, these results will help facilitate prioritization of care and future work that could evaluate successful implementation strategies while emphasizing the role of PCPs in screening and managing pediatric NAFLD in Canadian health care setting.

Methods for Interpreting the Partitioning and Fate of Petroleum Hydrocarbons in a Sea Ice Environment.

Decreases in Arctic Sea ice extent and thickness have led to more open ice conditions, encouraging both shipping traffic and oil exploration within the northern Arctic. As a result, the increased potential for accidental releases of crude oil or fuel into the Arctic environment threatens the pristine marine environment, its ecosystem, and local inhabitants. Thus, there is a need to develop a better understanding of oil behavior in a sea ice environment on a microscopic level. Computational quantum chemistry was used to simulate the effects of evaporation, dissolution, and partitioning within sea ice. Vapor pressures, solubilities, octanol-water partition coefficients, and molecular volumes were calculated using quantum chemistry and thermodynamics for pure liquid solutes (oil constituents) of interest. These calculations incorporated experimentally measured temperatures and salinities taken throughout an oil-in-ice mesocosm experiment conducted at the University of Manitoba in 2017. Their potential for interpreting the relative movements of oil constituents was assessed. Our results suggest that the relative movement of oil constituents is influenced by differences in physical properties. Lighter molecules showed a greater tendency to be controlled by brine advection processes due to their greater solubility. Molecules which are more hydrophobic were found to concentrate in areas of lower salt concentration.

Factors influencing primary care provider referral for bariatric surgery: Systematic review.

OBJECTIVE: To identify barriers to and facilitators of primary care provider (PCP) referral for bariatric surgery in patients with obesity. DATA SOURCES: MEDLINE, EMBASE, and PsycINFO databases were searched and reference lists of included articles were screened to identify additional relevant articles. Two reviewers independently reviewed citations and full-text articles, and appraised the quality of the included articles using the Critical Appraisal Skills Programme Tool Qualitative Checklist and the Appraisal Tool for Cross-Sectional Studies. They extracted data on the study characteristics and the barriers to and facilitators of PCP referral for bariatric surgery. Appraisal discrepancies were resolved through consensus among authors. STUDY SELECTION: Overall, 882 citations were identified and 18 articles were then selected for this review. SYNTHESIS: Barriers included fear of surgery complications and side effects, cost, lack of availability, perception that surgery is a quick fix or a last resort, and prior negative experiences. Facilitators included direct requests from patients, patient motivation, previously failed weight-loss interventions, and obesity-related comorbidities. Those PCPs who were knowledgeable about the risks and benefits of bariatric surgery were more likely to refer their patients. CONCLUSION: Education and continuing professional development programs regarding bariatric surgery are needed to improve PCP knowledge and capacity to manage patients with obesity. Also, educating the general public on obesity, weight management, and available treatment options can empower patients and families to manage their weight and pursue evidence-informed treatments.

Comprehensiveness of care for women with depression: Association between primary care use and cervical cancer screening.

OBJECTIVE: To explore comprehensiveness of care in patients with depression by examining associations between a diagnosis of depression, frequency of primary care visits, and Papanicolaou test completion. DESIGN: Cross-sectional retrospective survey using electronic medical record data from the Canadian Primary Care Sentinel Surveillance Network. SETTING: Primary care practices in Ontario. PARTICIPANTS: Women aged 21 to 69 eligible to receive Pap tests in 2015. MAIN OUTCOME MEASURES: Associations between 2 predictors (depression and number of primary care visits in 2015) and Pap test completion were measured. RESULTS: Overall, 125,258 women were included: 20.5% completed a Pap test and 16.4% had a diagnosis of depression. Having a diagnosis of depression was associated with lower likelihood of Pap test completion (adjusted odds ratio [AOR]=0.92, 95% CI 0.88 to 0.95). A greater number of primary care visits was associated with a higher likelihood of Pap test completion; this association was stronger in women with a diagnosis of depression (AOR=4.9, 95% CI 4.16 to 5.69) than in those without (AOR=3.4, 95% CI 3.25 to 3.60). CONCLUSION: While depression was associated with fewer completed Pap tests, women with depression who saw their family doctors more often were more likely to be screened for cervical cancer. More primary care visits for depression treatment may be associated with an improved likelihood of screening for cervical cancer.

Does availability of point of care C-reactive protein measurement affect provision of antibiotics in a community respiratory service?

Antibiotic resistance presents a growing threat to health systems and patients at a global scale. Point of care (POC) C-reactive protein (CRP) measurement, as an adjunct to exacerbation assessment, has been studied in primary and secondary care and may represent a useful tool for community teams. A retrospective service review was conducted to determine the effect of CRP measurement on antibiotic provision in a community respiratory setting, with chronic obstructive pulmonary disease (COPD) and bronchiectasis exacerbations. This review compared antibiotic provision for COPD and bronchiectasis patients for those where CRP was measured versus those where it was not. It was found that antibiotic provision dropped by almost 25% points for COPD exacerbations, and almost 59% in bronchiectasis, when a CRP measurement was taken as a component of a respiratory assessment. Antibiotics were also provided at a greater amount based on symptom presentation. Therefore, it is concluded that CRP measurement correlates with a reduction in antibiotic provision, highlighting its use alongside symptom assessment in future work.

Awareness, management, and practice patterns of pediatric NAFLD by primary care physicians.

Background: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children. Primary-care physicians (PCPs) play a key role in identifying patients requiring specialist referral. In this study, we aim to determine PCPs' practice patterns for paediatric NAFLD, as knowledge gaps have been reported for adult NAFLD. Methods: A survey was sent to 60 PCPs in the Eastern Ontario Network from July 2019 to January 2020. Results: Thirty-seven (62%) PCPs responded to the survey. Twenty-one incorrectly considered the prevalence of paediatric NAFLD to be ≤10%. The majority (35/36) cared for less than five paediatric NAFLD patients. Thirty-four (92%) were only 'slightly familiar' or 'not familiar at all' with paediatric NAFLD. Only one PCP routinely screens for NAFLD. Only one PCP was aware of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) clinical guidelines for paediatric NAFLD. Twenty-five (68%) correctly selected lifestyle modifications as a treatment option. Lack of confidence in the knowledge of NAFLD was the most common barrier for managing paediatric cases. Conclusion: The majority of PCPs are not screening for paediatric NAFLD and are not familiar with its clinical spectrum, citing a lack of knowledge regarding NAFLD as the greatest barrier. This may cause delays in diagnosis and a presentation with advanced fibrosis at the time of specialist referral. Dissemination and implementation of clinical guidelines have the potential to improve knowledge and screening rates for NAFLD in children at the primary-care level.

Evolution of a Strategy for the Total Synthesis of (+)-Cornexistin.

Herein is given a full account of the evolution of the first total synthesis of (+)-cornexistin. Initial efforts were based on masking the reactive maleic anhydride moiety as a 3,4-substituted furan and on forming the nine-membered carbocycle in an intramolecular Conia-ene or Nozaki-Hiyama-Kishi (NHK) reaction. Those strategies suffered from low yields and were jeopardized by a late-stage installation of the Z-alkene, as well as the stereocenters along the eastern periphery. These issues were addressed by employing a chiral-pool strategy that involved construction of the crucial stereocenters at C2, C3 and C8 at an early stage with installation of the maleic anhydride as late as possible. The successful approach featured an intermolecular NHK coupling to install the Z-alkene, a syn-Evans-aldol reaction to forge the stereocenters along the eastern periphery, an intramolecular allylic alkylation to close the nine-membered carbocycle, and a challenging stepwise hydrolysis of a ß-keto nitrile to furnish the maleic anhydride.

Survey of perceptions and educational needs of primary care providers regarding management of patients with class II and III obesity in Ontario, Canada.

BACKGROUND: Primary care providers (PCPs) are typically the primary contact for patients with obesity seeking medical and surgical weight loss interventions; however, previous studies suggest that fewer than 7% of eligible adult patients are referred to publically funded medical and surgical weight loss interventions (MSWLI). METHODS: We performed an anonymous survey study between October 2017 and June 2018 to explore the knowledge, experiences, perceptions, and educational needs of PCPs in Southeastern Ontario in managing patients with class II and III obesity. RESULTS: Surveys were distributed to 591 PCPs (n = 538 family physicians; n = 53 nurse practitioners) identified as practicing in the Southeastern Ontario and 92 (15.6%) participated. PCPs serving a rural population estimated that 14.2 ± 10.9% of patients would qualify for MSWLI compared to 9.9 ± 8.5% of patients of PCPs serving an urban population (p = .049). Overall, 57.5% of respondents did not feel competent prescribing MSWLI to patients with class II/III obesity, while 69.8% stated they had 'good' knowledge of the referral criteria for MSWLI. 22.2% of respondents were hesitant to refer patients for bariatric surgery (BS) due to concerns about postoperative surgical complications and risks associated with surgery. Only 25% of respondents were comfortable providing long-term follow up after BS, and only 39.1% had participated in continuing education on management of patients with class II/III obesity in the past 5 years. CONCLUSION: The majority of PCPs believe there is a need for additional education about MSWLI for patients with class II/III obesity. Future studies are needed to develop and compare the effectiveness of additional education and professional development around risks of contemporary BS, indications to consider referral for MSWLI, management and long-term follow-up of patients after BS.

Patients eligible and referred for bariatric surgery in southeastern Ontario: Retrospective cohort study.

OBJECTIVE: To evaluate the proportion of eligible individuals, within one health region in Ontario, who were referred for publicly funded medical and surgical weight-loss interventions (MSWLI). DESIGN: A retrospective cohort study that used primary care data from the Canadian Primary Care Sentinel Surveillance Network (CPCSSN) and referral data from the Ontario Bariatric Network (OBN). SETTING: Primary care practices within southeastern Ontario that contribute data to CPCSSN. PARTICIPANTS: Patients with class II (body mass index [BMI] 35.0 to 39.9 kg/m2) or III (BMI ≥ 40 kg/m2) obesity who were eligible for referral to the OBN for MSWLI. MAIN OUTCOME MEASURES: Primary care data about patients within the CPCSSN database were linked to referral records within the OBN database using 3 indirect identifiers to determine the proportion of patients with class II and III obesity who were referred to the OBN for MSWLI. An adjusted multivariate logistic regression model was used to determine the most significant predictors of referral. RESULTS: Of the 87 276 patients within one health region in Ontario, 15 526 (17.8%) patients had class II or III obesity and were eligible for referral for MSWLI. Only 966 out of those 15 526 (6.2%) patients were actually referred for MSWLI. In the multivariate regression analysis, BMI had the strongest association with referral in terms of adjusted odds ratio (AOR), varying from 2.50 (95% CI 2.04 to 3.06) for a BMI of 40.0 to 44.9 kg/m2, to 5.15 (95% CI 4.21 to 6.30) for a BMI of 50.0 kg/m2 or greater. Referral was more likely for female than male patients (AOR = 2.18; 95% CI 1.86 to 2.57), those living rurally than for urban dwellers (AOR = 1.39; 95% CI 1.20 to 1.60), and those aged 30 to 39 (AOR = 1.61; 95% CI 1.24 to 2.09) and 40 to 49 (AOR = 1.53; 95% CI 1.18 to 1.98) compared with other age groups. CONCLUSION: Within one health region in Ontario, the referral rate of patients with class II and III obesity for MSWLI was low. Our findings highlight the need for further research to understand and address the barriers to referral of patients with class II and III obesity for MSWLI.

Steroidogenic acute regulatory protein transcription is regulated by estrogen receptor signaling in largemouth bass ovary.

Estrogenic contaminants in the environment are linked to the occurrence of reproductive abnormalities in many aquatic species, including largemouth bass (Micropterus salmoides; LMB). Previous work has shown that many different types of xenoestrogens regulate expression of the Steroidogenic Acute Regulatory protein (StAR), a cholesterol-transporting protein vital to steroid hormone biosynthesis; however, the regulatory mechanisms of StAR are incompletely characterized in fish. To learn more about endogenous expression patterns of StAR in the ovary, LMB were collected from the St. John's River (Florida, USA) over an entire breeding season to investigate StAR expression. Plasma 17ß-estradiol (E2) and StAR mRNA levels were positively correlated in females, and StAR mRNA levels displayed ~ 100-fold increase between primary oocyte growth stages and final maturation. To further study the regulation of StAR, female LMB in the laboratory were fed at ≃2% of their weight on a diet laden with 17α-ethinylestradiol (EE2, 70 or 200 ng EE2 per gram feed). Diets were designed to achieve a physiologically-relevant exposure to EE2, and StAR expression was assessed in vivo. We observed a dose-dependent suppression of StAR mRNA levels, however both diets led to high, pharmacological levels in the blood and do not represent normal physiological ranges of estrogens. In the 200 ng EE2/gm feed group, ovarian StAR mRNA levels were suppressed to approximately 5% of that of the LMB control group. These investigations suggest that LMB StAR increases in expression during oocyte maturation and that it is suppressed by E2 feedback when estrogen levels are high, through the HPG axis. A 2.9 kb segment of the LMB StAR promoter was examined for putative E2 response elements using in silico software, and a putative estrogen receptor binding element (ERE/-1745) was predicted in the promoter. The functionality of the ERE was examined using MA-10 mouse Leydig cells transfected with the LMB StAR promoter. Estrogen receptor (ER) interaction with ERE/-1745 was evaluated under basal and human chorionic gonadotropin (hCG)-treated conditions in the presence and absence of E2. Chromatin immunoprecipitation (ChIP) experiments revealed that ESR1 binding to the promoter was enriched under basal conditions and E2 exposure elicited an increase in enrichment (4-fold) above that observed under basal conditions. ESR2 was not strongly enriched at the ERE/-1745 site, suggesting that StAR may be preferentially regulated by LMB estrogen receptor 1 (esr1). Taken together, these different experiments provide evidence that LMB StAR is under the control of estrogens and that ESR1 binds directly to the LMB StAR promoter in an E2-responsive manner.

Validation of an EMR algorithm to measure the prevalence of ADHD in the Canadian Primary Care Sentinel Surveillance Network (CPCSSN).

BACKGROUND: Building and validating electronic algorithms to identify patients with specific disease profiles using health data is becoming increasingly important to disease surveillance and population health management. The aim of this study was to develop and validate an algorithm to find patients with ADHD diagnoses within primary care electronic medical records (EMR); and then use the algorithm to describe the epidemiology of ADHD from 2008 to 2015 in a Canadian Primary care sample. METHODS: This was a cross sectional time series that used data from the Canadian Primary Care Sentinel Surveillance Network (CPCSSN), a repository of primary care EMR data. A sample of electronic patient charts from one local clinic were manually reviewed to determine the positive predictive value (PPV) and negative predictive value (NPV) of an ADHD case-finding algorithm. In each study year a practice population was determined, and the algorithm was used to measure an observed prevalence of ADHD. The observed prevalence was adjusted for misclassification, as measured by the validity indices, to obtain an estimate of the true prevalence. Estimates were calculated by age group (4-17 year olds, 18 to 34 year olds, and 35 to 64 year olds) and gender, and compared over time. RESULTS: The EMR algorithm had a PPV of 98.0% (95% CI [92.5, 99.5]) and an NPV of 95.0% (95% CI [92.9, 98.6]). After adjusting for misclassification, it was determined that the prevalence of patients with a clinical diagnosis of ADHD has risen in all age groups between 2008 and 2015, most notably in children and young adults (6.92, 95% CI [5.62, 8.39] to 8.57, 95% CI [7.32, 10.00]; 5.73, 95% CI [4.40, 7.23] to 7.33, 95% CI [6.04, 8.78], respectively). The well-established gender gap persisted in all age groups across time but was considerably smaller in older adults compared to children and young adults. CONCLUSION: Overall, the ADHD case-finding algorithm was found to be a valid tool to assess the epidemiology of ADHD in Canadian primary care practice. The increased prevalence of ADHD between 2008 and 2015 may reflect an improvement in the recognition and treatment of this disorder within primary care.

Total Synthesis of (+)-Cornexistin.

Herein, we describe the first total synthesis of (+)-cornexistin as well as its 8-epi-isomer starting from malic acid. The robust and scalable route features a Nozaki-Hiyama-Kishi reaction, an auxiliary-controlled syn-Evans-aldol reaction, and a highly efficient intramolecular alkylation to form the nine-membered carbocycle. The delicate maleic anhydride moiety of the nonadride skeleton was constructed from a ß-keto nitrile. The developed route enabled the synthesis of 165 mg (+)-cornexistin.

Catalytic Enantioselective Direct Aldol Addition of Aryl Ketones to α-Fluorinated Ketones.

The catalytic enantioselective synthesis of α-fluorinated chiral tertiary alcohols from (hetero)aryl methyl ketones is described. The use of a bifunctional iminophosphorane (BIMP) superbase was found to facilitate direct aldol addition by providing the strong Brønsted basicity required for rapid aryl enolate formation. The new synthetic protocol is easy to perform and tolerates a broad range of functionalities and heterocycles with high enantioselectivity (up to >99:1 e.r.). Multi-gram scalability has been demonstrated along with catalyst recovery and recycling. 1 H NMR studies identified a 1400-fold rate enhancement under BIMP catalysis, compared to the prior state-of-the-art catalytic system. The utility of the aldol products has been highlighted with the synthesis of various enantioenriched building blocks and heterocycles, including 1,3-aminoalcohol, 1,3-diol, oxetane, and isoxazoline derivatives.