Strain-release trifluoromethoxylation and pentafluorosulfanoxylation of [1.1.0]bicyclobutanes: expanded access to fluorinated cyclobutane hybrid bioisosteres.

Methods for formal bromo-trifluoromethoxylation and bromo-pentafluorosulfanoxylation of [1.1.0]bicyclobutanes using AgOCF or AgOSF and 1,3-dibromo-5,5-dimethylhydantoin are disclosed.

Scalable deep learning artificial intelligence histopathology slide analysis and validation.

Deep learning involves an artificial intelligence (AI) approach and has been shown to provide superior performance for automating image recognition tasks, as well as exceeding human capabilities in both time and accuracy. Histopathology diagnostics is one of the more popular challenges at the intersection of artificial intelligence, computer vision, and medicine. Developing methods to automatically detect and identify pathologies in digitized histology slides imposes unique challenges due to the large size of these images and the complexity of the features present in biological tissue.

Accessing Active Fragments for Drug Discovery Utilising Nitroreductase Biocatalysis.

Biocatalysis has played a limited role in the early stages of drug discovery. This is often attributed to the limited substrate scope of enzymes not affording access to vast areas of novel chemical space. Here, we have shown a promiscuous nitroreductase enzyme (NR-55) can be used to produce a panel of functionalised anilines from a diverse panel of aryl nitro starting materials.

Aberrant cognitive empathy in individuals with elevated social anxiety and regulation with emotional working memory training.

Social anxiety may disrupt the empathic process, and well-regulated empathy is critical for navigating the social world. Two studies aimed to further understand empathy in the context of social anxiety. Study 1 compared individuals with elevated or normative social anxiety on a measure assessing cognitive and affective empathy for positive and negative emotions conveyed by other people ("targets"), completed under social threat.

Multiple generation distinct toxicant exposures induce epigenetic transgenerational inheritance of enhanced pathology and obesity.

Three successive multiple generations of rats were exposed to different toxicants and then bred to the transgenerational F5 generation to assess the impacts of multiple generation different exposures. The current study examines the actions of the agricultural fungicide vinclozolin on the F0 generation, followed by jet fuel hydrocarbon mixture exposure of the F1 generation, and then pesticide dichlorodiphenyltrichloroethane on the F2 generation gestating females. The subsequent F3 and F4 generations and F5 transgenerational generation were obtained and F1-F5 generations examined for male sperm epigenetic alterations and pathology in males and females.

Identifying unique exposure-specific transgenerational differentially DNA methylated region epimutations in the genome using hybrid deep learning prediction models.

Exposure to environmental toxicants can lead to epimutations in the genome and an increase in differential DNA methylated regions (DMRs) that have been linked to increased susceptibility to various diseases. However, the unique effect of particular toxicants on the genome in terms of leading to unique DMRs for the toxicants has been less studied. One hurdle to such studies is the low number of observed DMRs per toxicants.

Hybrid deep learning approach to improve classification of low-volume high-dimensional data.

Background: The performance of machine learning classification methods relies heavily on the choice of features. In many domains, feature generation can be labor-intensive and require domain knowledge, and feature selection methods do not scale well in high-dimensional datasets. Deep learning has shown success in feature generation but requires large datasets to achieve high classification accuracy.

Indolo[2,3-]benzazocines and indolo[2,3-]benzazonines and their copper(II) complexes as microtubule destabilizing agents.

A series of four indolo[2,3-]benzazocines HL1-HL4 and two indolo[2,3-]benzazonines HL5 and HL6, as well as their respective copper(II) complexes 1-6, were synthesized and characterized by H and C NMR spectroscopy, ESI mass spectrometry, single crystal X-ray diffraction (SC-XRD) and combustion analysis (C, H, N). SC-XRD studies of precursors Vd, VIa·0.5MeOH, of ligands HL4 and HL6·DCM, and complexes 2·2DMF, 5·2DMF, 5'·iPrOH·MeOH provided insights into the energetically favored conformations of eight- and nine-membered heterocycles in the four-ring systems.

Multimodal Fusion of Smart Home and Text-based Behavior Markers for Clinical Assessment Prediction.

New modes of technology are offering unprecedented opportunities to unobtrusively collect data about people's behavior. While there are many use cases for such information, we explore its utility for predicting multiple clinical assessment scores. Because clinical assessments are typically used as screening tools for impairment and disease, such as mild cognitive impairment (MCI), automatically mapping behavioral data to assessment scores can help detect changes in health and behavior across time.

Automated Cognitive Health Assessment Using Partially Complete Time Series Sensor Data.

Background: Behavior and health are inextricably linked. As a result, continuous wearable sensor data offer the potential to predict clinical measures. However, interruptions in the data collection occur, which create a need for strategic data imputation.

Improving cardiovascular health with the patient-centered, integrated primary care HEARTS model in Trinidad and Tobago.

This article describes the introduction of the Pan American Health Organization's HEARTS in the Americas program in Trinidad and Tobago and the successful experiences and challenges encountered in introducing and scaling it up as a strategy for strengthening the health system's response to cardiovascular diseases. Evidence about implementation of the HEARTS program in the World Health Organization's Region of the Americas was reviewed to identify the progress made, barriers, success factors and lessons learned. In 2019, the Ministry of Health commenced implementation of the program in 5 (4.

Predicting environmentally responsive transgenerational differential DNA methylated regions (epimutations) in the genome using a hybrid deep-machine learning approach.

Background: Deep learning is an active bioinformatics artificial intelligence field that is useful in solving many biological problems, including predicting altered epigenetics such as DNA methylation regions. Deep learning (DL) can learn an informative representation that addresses the need for defining relevant features. However, deep learning models are computationally expensive, and they require large training datasets to achieve good classification performance.

Partnering a Compensatory Application with Activity-Aware Prompting to Improve Use in Individuals with Amnestic Mild Cognitive Impairment: A Randomized Controlled Pilot Clinical Trial.

Background: Compensatory aids can help mitigate the impact of progressive cognitive impairment on daily living.

Objective: We evaluate whether the learning and sustained use of an Electronic Memory and Management Aid (EMMA) application can be augmented through a partnership with real-time, activity-aware transition-based prompting delivered by a smart home.

Methods: Thirty-two adults who met criteria for amnestic mild cognitive impairment (aMCI) were randomized to learn to use the EMMA app on its own (N = 17) or when partnered with smart home prompting (N = 15).

Shifting as a key executive function underlying cognitive restructuring for individuals with elevated social anxiety.

Objectives: Previous studies have examined the relationship between executive functions and performance on cognitive behavioural therapy (CBT) tasks, such as cognitive restructuring. However, previous studies have used samples of older adults and only traditional measures of executive functions involving non-emotional stimuli. This study extends previous research to examine the specific executive function of shifting with regard to non-emotional and emotional stimuli and its relationship with cognitive restructuring, in a sample of young to middle-aged adults with elevated social anxiety.

Discovery and Optimization of DNA Gyrase and Topoisomerase IV Inhibitors with Potent Activity against Fluoroquinolone-Resistant Gram-Positive Bacteria.

Herein, we describe the discovery and optimization of a novel series that inhibits bacterial DNA gyrase and topoisomerase IV binding to, and stabilization of, DNA cleavage complexes. Optimization of this series led to the identification of compound , which has potent activity against Gram-positive bacteria, a favorable safety profile, and excellent pharmacokinetic properties. Compound was found to be efficacious against fluoroquinolone-sensitive infection in a mouse thigh model at lower doses than moxifloxacin.

Incidence of Access to Ambulatory Mental Health Care Prior to a Psychiatric Emergency Department Visit Among Adults in Ontario, 2010-2018.

Importance: Psychiatric emergency department (ED) visits may be avoidable if individuals have access to adequate outpatient care, but the extent to which individuals use the ED itself as a key point of access is largely unknown.

Objective: To describe the extent to which the ED is a first point of contact for mental health care among adults, and identify key factors associated with this outcome.

Design, Setting, And Participants: This cohort study was conducted from 2010 to 2018 in Ontario, Canada.

Flexed lumbar spine postures are associated with greater strength and efficiency than lordotic postures during a maximal lift in pain-free individuals.

Background: Inspite of common lifting advice to maintain a lordotic posture, there is debate regarding optimal lumbar spine posture during lifting. To date, the influence of lumbar posture on trunk muscle recruitment, strength and efficiency during high intensity lifting has not been fully explored.

Research Question: How do differences in lumbar posture influence trunk extensor strength (moment), trunk muscle activity, and neuromuscular efficiency during maximal lifting?

Methods: Twenty-six healthy participants adopted three lumbar postures (maximal extension (lordotic), mid-range (flat-back), and fully flexed) in a free lifting position.

Validating viral hepatitis B and C diagnosis codes: a retrospective analysis using Ontario's health administrative data.

Objective: We aimed to determine the criterion validity of using diagnosis codes for hepatitis B virus (HBV) and hepatitis C virus (HCV) to identify infections.

Methods: Using linked laboratory and administrative data in Ontario, Canada, from January 2004 to December 2014, we validated HBV/HCV diagnosis codes against laboratory-confirmed infections. Performance measures (sensitivity, specificity, and positive predictive value) were estimated via cross-validated logistic regression and we explored variations by varying time windows from 1 to 5 years before (i.

Peri-complication diagnosis of hepatitis C infection: Risk factors and trends over time.

Background & Aims: Hepatitis C virus (HCV) is a common and treatable cause of cirrhosis and its complications, yet many chronically infected individuals remain undiagnosed until a late stage. We sought to identify the frequency of and risk factors for HCV diagnosis peri-complication, that is within six months of an advanced liver disease complication.

Methods: This was a retrospective cohort study of Ontario residents diagnosed with chronic HCV infection between 2003 and 2014.

Diagnosis of Chronic Hepatitis B Pericomplication: Risk factors and Trends Over Time.

Background And Aims: Hepatitis B virus (HBV) is a major cause of chronic liver disease, which can progress to cirrhosis, hepatocellular carcinoma, and death. A timely diagnosis allows for antiviral treatment, which can prevent liver-related complications. Conversely, a late diagnosis signals a missed opportunity for earlier care and treatment.

Quality of Antenatal Care for Women Who Experience Imprisonment in Ontario, Canada.

Importance: Women who experience imprisonment have high morbidity and an increased risk of adverse pregnancy outcomes. Antenatal care could modify pregnancy-related risks, but there is a lack of evidence regarding antenatal care in this population.

Objectives: To examine antenatal care quality indicators for women who experience imprisonment and to compare these data with data for the general population.

Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria.

Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert their activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates of resistance, driven largely by target-based mutations in the GyrA/ParC quinolone resistance determining region, have eroded the utility and threaten the future use of this vital class of antibiotics. Herein we describe the discovery and optimization of a series of 4-(aminomethyl)quinolin-2(1)-ones, exemplified by , that inhibit bacterial DNA gyrase and topoisomerase IV and display potent activity against ciprofloxacin-resistant Gram-negative pathogens.

Deprivation and mortality related to pediatric respiratory tract infection: a cohort study in 3 high-income jurisdictions.

Background: Deaths from respiratory tract infections (RTIs) in children are preventable through timely access to public health and medical interventions. We aimed to assess whether socioeconomic disparities in mortality related to pediatric RTI persisted after accounting for health status at birth.

Methods: We compared the prevalence of and risk factors for RTI-related death in singletons aged 28 days to 4 years across Ontario (Canada), Scotland and England (jurisdictions with universal health care) using linked administrative data for 2003-2013.

Does physician compensation for declaration of involuntary status increase the likelihood of involuntary admission? A population-level cross-sectional linked administrative database study.

Background: There is substantial variability in involuntary psychiatric admission rates across countries and sub-regions within countries that are not fully explained by patient-level factors. We sought to examine whether in a government-funded health care system, physician payments for filling forms related to an involuntary psychiatric hospitalization were associated with the likelihood of an involuntary admission.

Methods: This is a population-based, cross-sectional study in Ontario, Canada of all adult psychiatric inpatients in Ontario (2009-2015, n = 122 851).