Better together: Integrating biomedical informatics and healthcare IT operations to create a learning health system during the COVID-19 pandemic

The growing availability of multi-scale biomedical data sources that can be used to enable research and improve healthcare delivery has brought about what can be described as a healthcare data age. This new era is defined by the explosive growth in bio-molecular, clinical, and population-level data that can be readily accessed by researchers, clinicians, and decision-makers, and utilized for systems-level approaches to hypothesis generation and testing as well as operational decision-making. However, taking full advantage of these unprecedented opportunities presents an opportunity to revisit the alignment between traditionally academic biomedical informatics (BMI) and operational healthcare information technology (HIT) personnel and activities in academic health systems. While the history of the academic field of BMI includes active engagement in the delivery of operational HIT platforms, in many contemporary settings these efforts have grown distinct. Recent experiences during the COVID-19 pandemic have demonstrated greater coordination of BMI and HIT activities that have allowed organizations to respond to pandemic-related changes more effectively, with demonstrable and positive impact as a result. In this position paper, we discuss the challenges and opportunities associated with driving alignment between BMI and HIT, as viewed from the perspective of a learning healthcare system. In doing so, we hope to illustrate the benefits of coordination between BMI and HIT in terms of the quality, safety, and outcomes of care provided to patients and populations, demonstrating that these two groups can be better together

Implementation of Patient Engagement Tools in Electronic Health Records to Enhance Patient-Centered Communication: Protocol for Feasibility Evaluation and Preliminary Results

BACKGROUND: Patient-physician communication during clinical encounters is essential to ensure quality of care. Many studies have attempted to improve patient-physician communication. Incorporating patient priorities into agenda setting and medical decision-making are fundamental to patient-centered communication. Efficient and scalable approaches are needed to empower patients to speak up and prepare physicians to respond. Leveraging electronic health records (EHRs) in engaging patients and health care teams has the potential to enhance the integration of patient priorities in clinical encounters. A systematic approach to eliciting and documenting patient priorities before encounters could facilitate effective communication in such encounters. OBJECTIVE: In this paper, we report the design and implementation of a set of EHR tools built into clinical workflows for facilitating patient-physician joint agenda setting and the documentation of patient concerns in the EHRs for ambulatory encounters. METHODS: We engaged health information technology leaders and users in three health care systems for developing and implementing a set of EHR tools. The goal of these tools is to standardize the elicitation of patient priorities by using a previsit patient important issue questionnaire distributed through the patient portal to the EHR. We built additional EHR documentation tools to facilitate patient-staff communication when the staff records the vital signs and the reason for the visit in the EHR while in the examination room, with a simple transmission method for physicians to incorporate patient concerns in EHR notes. RESULTS: The study is ongoing. The anticipated completion date for survey data collection is November 2021. A total of 34,037 primary care patients from three health systems (n=26,441; n=5136; and n=2460 separately recruited from each system) used the previsit patient important issue questionnaire in 2020. The adoption of the digital previsit questionnaire during the COVID-19 pandemic was much higher in one health care system because it expanded the use of the questionnaire from physicians participating in trials to all primary care providers midway through the year. It also required the use of this previsit questionnaire for eCheck-ins, which are required for telehealth encounters. Physicians and staff suggested anecdotally that this questionnaire helped patient-clinician communication, particularly during the COVID-19 pandemic. CONCLUSIONS: EHR tools have the potential to facilitate the integration of patient priorities into agenda setting and documentation in real-world primary care practices. Early results suggest the feasibility and acceptability of such digital tools in three health systems. EHR tools can support patient engagement and clinicians\u27 work during in-person and telehealth visits. They could potentially exert a sustained influence on patient and clinician communication behaviors in contrast to prior ad hoc educational efforts targeting patients or clinicians. TRIAL REGISTRATION: ClinicalTrials.gov NCT03385512; https://clinicaltrials.gov/ct2/show/NCT03385512. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/30431

Loss of β-III Spectrin Leads to Purkinje Cell Dysfunction Recapitulating the Behavior and Neuropathology of Spinocerebellar Ataxia Type 5 in Humans

Mutations in SPTBN2, the gene encoding β-III spectrin, cause spinocerebellar ataxia type 5 in humans (SCA5), a neurodegenerative disorder resulting in loss of motor coordination. How these mutations give rise to progressive ataxia and what the precise role β-III spectrin plays in normal cerebellar physiology are unknown. We developed a mouse lacking full length β-III spectrin and found that homozygous mice reproduced features of SCA5 including gait abnormalities, tremor, deteriorating motor coordination, Purkinje cell loss and cerebellar atrophy (molecular layer thinning). In vivo analysis reveals an age-related reduction in simple spike firing rate in surviving β-III(−/−) Purkinje cells while in vitro studies show these neurons to have reduced spontaneous firing, smaller sodium currents and dysregulation of glutamatergic neurotransmission. Our data suggest an early loss of EAAT4- (protein interactor of β-III spectrin) and subsequent loss of GLAST-mediated uptake may play a role in neuronal pathology. These findings implicate a loss of β-III spectrin function in SCA5 pathogenesis and indicate there are at least two physiological effects of β-III spectrin loss that underpin a progressive loss of inhibitory cerebellar output, namely an intrinsic Purkinje cell membrane defect due to reduced sodium currents and alterations in glutamate signaling

Interactive Effect of UVR and Phosphorus on the Coastal Phytoplankton Community of the Western Mediterranean Sea: Unravelling Eco- Physiological Mechanisms

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Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre