A holistic approach to integrating patient, family, and lived experience voices in the development of the BrainHealth Databank: a digital learning health system to enable artificial intelligence in the clinic.

Artificial intelligence, machine learning, and digital health innovations have tremendous potential to advance patient-centred, data-driven mental healthcare. To enable the clinical application of such innovations, the Krembil Centre for Neuroinformatics at the Centre for Addiction and Mental Health, Canada's largest mental health hospital, embarked on a journey to co-create a digital learning health system called the BrainHealth Databank (BHDB). Working with clinicians, scientists, and administrators alongside patients, families, and persons with lived experience (PFLE), this hospital-wide team has adopted a systems approach that integrates clinical and research data and practices to improve care and accelerate research. PFLE engagement was intentional and initiated at the conception stage of the BHDB to help ensure the initiative would achieve its goal of understanding the community's needs while improving patient care and experience. The BHDB team implemented an evolving, dynamic strategy to support continuous and active PFLE engagement in all aspects of the BHDB that has and will continue to impact patients and families directly. We describe PFLE consultation, co-design, and partnership in various BHDB activities and projects. In all three examples, we discuss the factors contributing to successful PFLE engagement, share lessons learned, and highlight areas for growth and improvement. By sharing how the BHDB navigated and fostered PFLE engagement, we hope to motivate and inspire the health informatics community to collectively chart their paths in PFLE engagement to support advancements in digital health and artificial intelligence.

Characterization and prediction of individual functional outcome trajectories in schizophrenia spectrum disorders (PREDICTS study): Study protocol.

Schizophrenia spectrum disorders (SSDs) are associated with significant functional impairments, disability, and low rates of personal recovery, along with tremendous economic costs linked primarily to lost productivity and premature mortality. Efforts to delineate the contributors to disability in SSDs have highlighted prominent roles for a diverse range of symptoms, physical health conditions, substance use disorders, neurobiological changes, and social factors. These findings have provided valuable advances in knowledge and helped define broad patterns of illness and outcomes across SSDs. Unsurprisingly, there have also been conflicting findings for many of these determinants that reflect the heterogeneous population of individuals with SSDs and the challenges of conceptualizing and treating SSDs as a unitary categorical construct. Presently it is not possible to identify the functional course on an individual level that would enable a personalized approach to treatment to alter the individual's functional trajectory and mitigate the ensuing disability they would otherwise experience. To address this ongoing challenge, this study aims to conduct a longitudinal multimodal investigation of a large cohort of individuals with SSDs in order to establish discrete trajectories of personal recovery, disability, and community functioning, as well as the antecedents and predictors of these trajectories. This investigation will also provide the foundation for the co-design and testing of personalized interventions that alter these functional trajectories and improve outcomes for people with SSDs.

Postoperative analgesia for upper gastrointestinal surgery: a retrospective cohort analysis.

BACKGROUND: Thoracic epidural analgesia is commonly used for upper gastrointestinal surgery. Intrathecal morphine is an appealing opioid-sparing non-epidural analgesic option, especially for laparoscopic gastrointestinal surgery. METHODS: Following ethics committee approval, we extracted data from the electronic medical records of patients at Royal North Shore Hospital (Sydney, Australia) that had upper gastrointestinal surgery between November 2015 and October 2020. Postoperative morphine consumption and pain scores were modelled with a Bayesian mixed effect model. RESULTS: A total of 427 patients were identified who underwent open (n = 300), laparoscopic (n = 120) or laparoscopic converted to open (n = 7) upper gastrointestinal surgery. The majority of patients undergoing open surgery received a neuraxial technique (thoracic epidural [58%, n = 174]; intrathecal morphine [21%, n = 63]) compared to a minority in laparoscopic approaches (thoracic epidural [3%, n = 4]; intrathecal morphine [12%, n = 14]). Intrathecal morphine was superior over non-neuraxial analgesia in terms of lower median oral morphine equivalent consumption and higher probability of adequate pain control; however, this effect was not sustained beyond postoperative day 2. Thoracic epidural analgesia was superior to both intrathecal and non-neuraxial analgesia options for both primary outcomes, but at the expense of higher rates of postoperative hypotension (60%, n = 113) and substantial technique failure rates (32%). CONCLUSIONS: We found that thoracic epidural analgesia was superior to intrathecal morphine, and intrathecal morphine was superior to non-neuraxial analgesia, in terms of reduced postoperative morphine requirements and the probability of adequate pain control in patients who underwent upper gastrointestinal surgery. However, the benefits of thoracic epidural analgesia and intrathecal morphine were not sustained across all time periods regarding control of pain. The study is limited by its retrospective design, heterogenous group of upper gastrointestinal surgeries and confounding by indication.

Out with AI, in with the psychiatrist: a preference for human-derived clinical decision support in depression care.

Advancements in artificial intelligence (AI) are enabling the development of clinical support tools (CSTs) in psychiatry to facilitate the review of patient data and inform clinical care. To promote their successful integration and prevent over-reliance, it is important to understand how psychiatrists will respond to information provided by AI-based CSTs, particularly if it is incorrect. We conducted an experiment to examine psychiatrists' perceptions of AI-based CSTs for treating major depressive disorder (MDD) and to determine whether perceptions interacted with the quality of CST information. Eighty-three psychiatrists read clinical notes about a hypothetical patient with MDD and reviewed two CSTs embedded within a single dashboard: the note's summary and a treatment recommendation. Psychiatrists were randomised to believe the source of CSTs was either AI or another psychiatrist, and across four notes, CSTs provided either correct or incorrect information. Psychiatrists rated the CSTs on various attributes. Ratings for note summaries were less favourable when psychiatrists believed the notes were generated with AI as compared to another psychiatrist, regardless of whether the notes provided correct or incorrect information. A smaller preference for psychiatrist-generated information emerged in ratings of attributes that reflected the summary's accuracy or its inclusion of important information from the full clinical note. Ratings for treatment recommendations were also less favourable when their perceived source was AI, but only when recommendations were correct. There was little evidence that clinical expertise or familiarity with AI impacted results. These findings suggest that psychiatrists prefer human-derived CSTs. This preference was less pronounced for ratings that may have prompted a deeper review of CST information (i.e. a comparison with the full clinical note to evaluate the summary's accuracy or completeness, assessing an incorrect treatment recommendation), suggesting a role of heuristics. Future work should explore other contributing factors and downstream implications for integrating AI into psychiatric care.

Essential requirements for the governance and management of data trusts, data repositories, and other data collaborations.

Introduction: Around the world, many organisations are working on ways to increase the use, sharing, and reuse of person-level data for research, evaluation, planning, and innovation while ensuring that data are secure and privacy is protected. As a contribution to broader efforts to improve data governance and management, in 2020 members of our team published 12 minimum specification essential requirements (min specs) to provide practical guidance for organisations establishing or operating data trusts and other forms of data infrastructure. Approach and Aims: We convened an international team, consisting mostly of participants from Canada and the United States of America, to test and refine the original 12 min specs. Twenty-three (23) data-focused organisations and initiatives recorded the various ways they address the min specs. Sub-teams analysed the results, used the findings to make improvements to the min specs, and identified materials to support organisations/initiatives in addressing the min specs. Results: Analyses and discussion led to an updated set of 15 min specs covering five categories: one min spec for Legal, five for Governance, four for Management, two for Data Users, and three for Stakeholder & Public Engagement. Multiple changes were made to make the min specs language more technically complete and precise. The updated set of 15 min specs has been integrated into a Canadian national standard that, to our knowledge, is the first to include requirements for public engagement and Indigenous Data Sovereignty. Conclusions: The testing and refinement of the min specs led to significant additions and improvements. The min specs helped the 23 organisations/initiatives involved in this project communicate and compare how they achieve responsible and trustworthy data governance and management. By extension, the min specs, and the Canadian national standard based on them, are likely to be useful for other data-focused organisations and initiatives.

Digitization of Measurement-Based Care Pathways in Mental Health Through REDCap and Electronic Health Record Integration: Development and Usability Study.

BACKGROUND: The delivery of standardized self-report assessments is essential for measurement-based care in mental health. Paper-based methods of measurement-based care data collection may result in transcription errors, missing data, and other data quality issues when entered into patient electronic health records (EHRs). OBJECTIVE: This study aims to help address these issues by using a dedicated instance of REDCap (Research Electronic Data Capture; Vanderbilt University)-a free, widely used electronic data capture platform-that was established to enable the deployment of digitized self-assessments in clinical care pathways to inform clinical decision making. METHODS: REDCap was integrated with the primary clinical information system to facilitate the real-time transfer of discrete data and PDF reports from REDCap into the EHR. Both technical and administrative components were required for complete implementation. A technology acceptance survey was also administered to capture physicians' and clinicians' attitudes toward the new system. RESULTS: The integration of REDCap with the EHR transitioned clinical workflows from paper-based methods of data collection to electronic data collection. This resulted in significant time savings, improved data quality, and valuable real-time information delivery. The digitization of self-report assessments at each appointment contributed to the clinic-wide implementation of the major depressive disorder integrated care pathway. This digital transformation facilitated a 4-fold increase in the physician adoption of this integrated care pathway workflow and a 3-fold increase in patient enrollment, resulting in an overall significant increase in major depressive disorder integrated care pathway capacity. Physicians' and clinicians' attitudes were overall positive, with almost all respondents agreeing that the system was useful to their work. CONCLUSIONS: REDCap provided an intuitive patient interface for collecting self-report measures and accessing results in real time to inform clinical decisions and an extensible backend for system integration. The approach scaled effectively and expanded to high-impact clinics throughout the hospital, allowing for the broad deployment of complex workflows and standardized assessments, which led to the accumulation of harmonized data across clinics and care pathways. REDCap is a flexible tool that can be effectively leveraged to facilitate the automatic transfer of self-report data to the EHR; however, thoughtful governance is required to complement the technical implementation to ensure that data standardization, data quality, patient safety, and privacy are maintained.

The Canadian Biomarker Integration Network in Depression (CAN-BIND): magnetic resonance imaging protocols

Studies of clinical populations that combine MRI data generated at multiple sites are increasingly common. The Canadian Biomarker Integration Network in Depression (CAN-BIND; www.canbind.ca) is a national depression research program that includes multimodal neuroimaging collected at several sites across Canada. The purpose of the current paper is to provide detailed information on the imaging protocols used in a number of CAN-BIND studies. The CAN-BIND program implemented a series of platform-specific MRI protocols, including a suite of prescribed structural and functional MRI sequences supported by real-time monitoring for adherence and quality control. The imaging data are retained in an established informatics and databasing platform. Approximately 1300 participants are being recruited, including almost 1000 with depression. These include participants treated with antidepressant medications, transcranial magnetic stimulation, cognitive behavioural therapy and cognitive remediation therapy. Our ability to analyze the large number of imaging variables available may be limited by the sample size of the substudies. The CAN-BIND program includes a multimodal imaging database supported by extensive clinical, demographic, neuropsychological and biological data from people with major depression. It is a resource for Canadian investigators who are interested in understanding whether aspects of neuroimaging ­ alone or in combination with other variables ­ can predict the outcomes of various treatment modalities.

Symptomatic and Functional Outcomes and Early Prediction of Response to Escitalopram Monotherapy and Sequential Adjunctive Aripiprazole Therapy in Patients With Major Depressive Disorder: A CAN-BIND-1 Report.

OBJECTIVE: To report the symptomatic and functional outcomes in patients with major depressive disorder (MDD) during a 2-phase treatment trial and to estimate the value of early improvement after 2 weeks in predicting clinical response to escitalopram and subsequently to adjunctive treatment with aripiprazole. METHODS: Participants with MDD (N = 211) identified with the Montgomery-Asberg Depression Rating Scale (MADRS) and confirmed with the Mini-International Neuropsychiatric Interview were recruited from 6 outpatient centers across Canada (August 2013 through December 2016) and treated with open-label escitalopram (10-20 mg) for 8 weeks (Phase 1). Clinical and functional outcomes were evaluated using the MADRS, Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR), Sheehan Disability Scale (SDS), and Lam Employment Absence and Productivity Scale (LEAPS). Participants were evaluated at 8 and 16 weeks for clinical and functional response and remission. Phase 1 responders continued escitalopram while nonresponders received adjunctive aripiprazole (2-10 mg) for a further 8 weeks (Phase 2). RESULTS: After Phase 1, MADRS response (≥ 50% decrease from baseline) and remission (score ≤ 10) were, respectively, 47% and 31%, and SDS response (score ≤ 12) and remission (score ≤ 6) were, respectively, 53% and 24%. Response to escitalopram was maintained in 91% of participants at week 16, while 61% of the adjunctive aripiprazole group achieved MADRS response during Phase 2. Response and remission rates with the QIDS-SR were lower than with the MADRS. The LEAPS demonstrated significant occupational improvement (P < .05). Early symptomatic improvement predicted outcomes with modest accuracy. CONCLUSIONS: This study demonstrates comparable symptomatic and functional outcomes to those of other large practical-design studies. There was a high response rate with the adjunctive use of aripiprazole in escitalopram nonresponders. Given the limited value of early clinical improvement to predict outcome, integration of clinical and biological markers deserves further exploration. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01655706.

Birth-weight centiles and the risk of serious adverse neonatal outcomes at term.

BACKGROUND: Birth-weight is an important determinant of perinatal outcome with low birth-weight being a particular risk factor for adverse consequences. AIM: To investigate the impact of neonatal sex, mode of birth and gestational age at birth according to birth-weight centile on serious adverse neonatal outcomes in singleton term pregnancies. MATERIALS AND METHODS: This was a retrospective cohort study of singleton term births at the Mater Mother's Hospital, Brisbane, Australia. Serious adverse neonatal outcome was defined as a composite of severe acidosis at birth (pH ≤7.0 and/or lactate ≥6 mmol/L and/or base excess ≤-12 mmol/L), Apgar <3 at 5 min, neonatal intensive-care unit admission and antepartum or neonatal death. The main exposure variable was birth-weight centile. RESULTS: Of the 69,210 babies in our study, the overall proportion of serious adverse neonatal outcomes was 9.1% (6327/69,210). Overall, neonates in the <3rd birth-weight centile category had the highest adjusted odds ratio (OR) for serious adverse neonatal outcomes [OR 3.53, 95% confidence interval (CI) 3.06-4.07], whilst those in the ≥97th centile group also had elevated odds (OR 1.51, 95% CI 1.30-1.75). Regardless of birth modality, smaller babies in the <3rd centile group had the highest adjusted OR and predicted probability for serious adverse neonatal outcomes. When stratified by sex, male babies consistently demonstrated a higher predicted probability of serious adverse neonatal outcomes across all birth-weight centiles. The adjusted odds, when stratified by gestational age at birth, were the highest from 37+0 to 38+6 weeks in the <3rd centile group (OR 5.97, 95% CI 4.60-7.75). CONCLUSIONS: Low and high birth-weights are risk factors for serious adverse neonatal outcomes. The adjusted OR appears to be greatest for babies in the <3rd birth-weight centile group, although an elevated risk was also found in babies within the ≥97th centile category.

The tyrosine kinase receptor Tyro3 enhances lifespan and neuropeptide Y (Npy) neuron survival in the mouse anorexia (anx) mutation.

Severe appetite and weight loss define the eating disorder anorexia nervosa, and can also accompany the progression of some neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). Although acute loss of hypothalamic neurons that produce appetite-stimulating neuropeptide Y (Npy) and agouti-related peptide (Agrp) in adult mice or in mice homozygous for the anorexia (anx) mutation causes aphagia, our understanding of the factors that help maintain appetite regulatory circuitry is limited. Here we identify a mutation (C19T) that converts an arginine to a tryptophan (R7W) in the TYRO3 protein tyrosine kinase 3 (Tyro3) gene, which resides within the anx critical interval, as contributing to the severity of anx phenotypes. Our observation that, like Tyro3-/- mice, anx/anx mice exhibit abnormal secondary platelet aggregation suggested that the C19T Tyro3 variant might have functional consequences. Tyro3 is expressed in the hypothalamus and other brain regions affected by the anx mutation, and its mRNA localization appeared abnormal in anx/anx brains by postnatal day 19 (P19). The presence of wild-type Tyro3 transgenes, but not an R7W-Tyro3 transgene, doubled the weight and lifespans of anx/anx mice and near-normal numbers of hypothalamic Npy-expressing neurons were present in Tyro3-transgenic anx/anx mice at P19. Although no differences in R7W-Tyro3 signal sequence function or protein localization were discernible in vitro, distribution of R7W-Tyro3 protein differed from that of Tyro3 protein in the cerebellum of transgenic wild-type mice. Thus, R7W-Tyro3 protein localization deficits are only detectable in vivo Further analyses revealed that the C19T Tyro3 mutation is present in a few other mouse strains, and hence is not the causative anx mutation, but rather an anx modifier. Our work shows that Tyro3 has prosurvival roles in the appetite regulatory circuitry and could also provide useful insights towards the development of interventions targeting detrimental weight loss.

Draft Genome Sequence of Mycobacterium elephantis Strain Lipa.

We report the draft genome sequence of Mycobacterium elephantis strain Lipa from a sputum sample of a patient with pulmonary disease. This is the first draft genome sequence of M. elephantis, a rapidly growing mycobacterium.

Draft Genome Sequence of Mycobacterium obuense Strain UC1, Isolated from Patient Sputum.

We report the draft genome sequence of Mycobacterium obuense strain UC1 from a patient sputum sample. This is the first draft genome sequence of Mycobacterium obuense, a rapidly growing scotochromogenic mycobacterium.

Draft Genome Sequence of Mycobacterium arupense Strain GUC1.

We report the draft genome sequence of Mycobacterium arupense strain GUC1 from a sputum sample of a patient with bronchiectasis. This is the first draft genome sequence of Mycobacterium arupense, a rapidly growing nonchromogenic mycobacteria.

Accurate and efficient method for predicting thermochemistry of furans and ortho-arynes: expansion of the bond-centered group additivity method.

The bond-centered group additivity method (BCGA) method for the estimation of the thermochemical properties of polycyclic aromatic molecules is expanded to aromatic molecules containing furan ring(s) and ortho-arynes. The method is based on enthalpies of formation (deltaH(o)f), entropies (S(o)298), and heat capacities (C(o)p) obtained from B3LYP/6-31G(d) calculations. The enthalpies of formation were obtained using a set of homodesmic reactions that include only aromatic molecules as the reference. Two new atom-centered groups are defined for the description of furan ring(s) and ortho-arynes, leading to the addition of 17 new bond-centered groups to the BCGA method. The deltaH(o)f, S(o)298, and C(o)p contributions of these bond-centered groups is derived.

A genetic screen for mutations that affect cranial nerve development in the mouse.

Cranial motor and sensory nerves arise stereotypically in the embryonic hindbrain, act as sensitive indicators of general and region-specific neuronal development, and are directly or indirectly affected in many human disorders, particularly craniofacial syndromes. The molecular genetic hierarchies that regulate cranial nerve development are mostly unknown. Here, we describe the first mouse genetic screen that has used direct immunohistochemical visualization methods to systematically identify genetic loci required for cranial nerve development. After screening 40 pedigrees, we recovered seven new neurodevelopmental mutations. Two mutations model human genetic syndromes. Mutation 7-1 causes facial nerve anomalies and a reduced lower jaw, and is located in a region of conserved synteny with an interval associated with the micrognathia and mental retardation of human cri-du-chat syndrome. Mutation 22-1 is in the Pax3 gene and, thus, models human Waardenburg syndrome. Three mutations cause global axon guidance deficits: one interferes with initial motor axon extension from the neural tube, another causes overall axon defasciculation, and the third affects general choice point selection. Another two mutations affect the oculomotor nerve specifically. Oculomotor nerve development, which is disrupted by six mutations, appears particularly sensitive to genetic perturbations. Phenotypic comparisons of these mutants identifies a "transition zone" that oculomotor axons enter after initial outgrowth and in which new factors govern additional progress. The number of interesting neurodevelopmental mutants revealed by this small-scale screen underscores the promise of similar focused genetic screens to contribute significantly to our understanding of cranial nerve development and human craniofacial syndromes.

WW domains provide a platform for the assembly of multiprotein networks.

WW domains are protein modules that mediate protein-protein interactions through recognition of proline-rich peptide motifs and phosphorylated serine/threonine-proline sites. To pursue the functional properties of WW domains, we employed mass spectrometry to identify 148 proteins that associate with 10 human WW domains. Many of these proteins represent novel WW domain-binding partners and are components of multiprotein complexes involved in molecular processes, such as transcription, RNA processing, and cytoskeletal regulation. We validated one complex in detail, showing that WW domains of the AIP4 E3 protein-ubiquitin ligase bind directly to a PPXY motif in the p68 subunit of pre-mRNA cleavage and polyadenylation factor Im in a manner that promotes p68 ubiquitylation. The tested WW domains fall into three broad groups on the basis of hierarchical clustering with respect to their associated proteins; each such cluster of bound proteins displayed a distinct set of WW domain-binding motifs. We also found that separate WW domains from the same protein or closely related proteins can have different specificities for protein ligands and also demonstrated that a single polypeptide can bind multiple classes of WW domains through separate proline-rich motifs. These data suggest that WW domains provide a versatile platform to link individual proteins into physiologically important networks.

Accurate and efficient method for predicting thermochemistry of polycyclic aromatic hydrocarbons - bond-centered group additivity.

A self-consistent estimation method for the thermochemical properties of polycyclic aromatic hydrocarbons (PAH) is presented. This method is based on enthalpies of formation (DeltaHf(degrees), entropies (S(degrees)298, and heat capacities (C(degrees)p obtained from B3LYP/6-31G(d) calculations of the total energies and frequencies for 139 PAHs, including C(60) and C(70) fullerenes. The enthalpies of formation were calculated using an optimized set of homodesmic reactions given the available experimental DeltaHf(degrees) of PAHs. The theoretical entropies were compared with the existing experimental entropies, and some inconsistencies in the experimental data were identified. The estimation method presented here is a systematic extension of the widely employed atom-centered group additivity method originally proposed by Benson. This new method is based on bond-centered groups that define bonds linking two atom-centered groups and specify the size of the rings to which they belong. In addition, a term to describe the resonance energy is included. The thermochemical properties of PAHs up to C(70) fullerene are estimated with a mean average deviation of 2.8 kcal mol(-1) in DeltaHf(degrees), 0.7 cal K(-1) mol(-1) in S(degrees)298, and about 0.5 cal K(-1) mol(-1) in the C(degrees)p. This bond-centered group additivity method for the thermochemical properties of PAHs significantly expands both the range of systems that can be estimated and the accuracy of the estimations. The results of this work also allow us to assess the quality of available experimental data. For example, there are strong indications that the literature DeltaHf(degrees)of benzo[k]fluoranthene is about 10 kcal mol(-1) too low.

The mouse Kreisler (Krml1/MafB) segmentation gene is required for differentiation of glomerular visceral epithelial cells.

Molecular components of the glomerular filtration mechanism play critical roles in renal diseases. Many of these components are produced during the final stages of differentiation of glomerular visceral epithelial cells, also known as podocytes. While basic domain leucine zipper (bZip) transcription factors of the Maf subfamily have been implicated in cellular differentiation processes, Kreisler (Krml1/MafB), the gene affected in the mouse kreisler (kr) mutation, is known for its role in hindbrain patterning. Here we show that mice homozygous for the kr(enu) mutation develop renal disease and that Kreisler is essential for cellular differentiation of podocytes. Consistent with abnormal podocyte differentiation, kr(enu) homozygotes show proteinuria, and fusion and effacement of podocyte foot processes, which are also observed in the nephrotic syndrome. Kreisler acts during the final stages of glomerular development-the transition between the capillary loop and mature stages-and downstream of the Pod1 basic domain helix-loop-helix transcription factor. The levels of Podocin, the gene mutated in autosomal recessive steroid-resistant nephrotic syndrome (NPHS2), and Nephrin, the gene mutated in congenital nephrotic syndrome of the Finnish type (NPHS1), are slightly reduced in kr(enu)/kr(enu) podocytes. However, these observations alone are unlikely to account for the aberrant podocyte foot process formation. Thus, Kreisler must regulate other unknown genes required for podocyte function and with possible roles in kidney disease.