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Objective To validate a previously published machine learning model of delirium risk in hospitalized patients with coronavirus disease 2019 (COVID-19). Method Using data from six hospitals across two academic medical networks covering care occurring after initial model development, we calculated the predicted risk of delirium using a previously developed risk model applied to diagnostic, medication, laboratory, and other clinical features available in the electronic health record (EHR) at time of hospital admission. We evaluated the accuracy of these predictions against subsequent delirium diagnoses during that admission. Results Of the 5102 patients in this cohort, 716 (14%) developed delirium. The model's risk predictions produced a c-index of 0.75 (95% CI, 0.73–0.77) with 27.7% of cases occurring in the top decile of predicted risk scores. Model calibration was diminished compared to the initial COVID-19 wave. Conclusion This EHR delirium risk prediction model, developed during the initial surge of COVID-19 patients, produced consistent discrimination over subsequent larger waves; however, with changing cohort composition and delirium occurrence rates, model calibration decreased. These results underscore the importance of calibration, and the challenge of developing risk models for clinical contexts where standard of care and clinical populations may shift.

Purpose To objectively identify the 50 most influential studies in knee arthroscopy and provide an analysis of their key characteristics. Methods The Clarivate Analytics Web of Knowledge database was used to gather data and metrics of knee arthroscopy research. The search list was sorted by the number of citations, and articles were included or excluded based on relevance to knee arthroscopy. The information extracted for each article included author name, publication year, country of origin, journal name, article type, and the level of evidence. Results For these 50 studies, the total number of citations was calculated to be 12,168, with an average of 243.4 citations per paper. The most-cited article was cited 1,220 times. The 50 studies included in this analysis were published between 1972 and 2013. All 50 articles were published in English and came from 10 different orthopaedic journals. The United States was responsible for the majority of articles (n = 26); however, many other countries were represented. The most prevalent study designs were case series (n = 20). Conclusions The 50 most influential articles in knee arthroscopy were cited a total of 12,168 times. The study designs most commonly used were case series and cohort studies. This article serves as a reference to direct orthopaedic practitioners to the 50 most influential studies in knee arthroscopy. We hope that these 50 studies and the analysis we provide help health care professionals efficiently assess consensus, trends, and needs within the field. Clinical Relevance This analysis of the 50 most influential studies in knee arthroscopy will provide medical students, residents, fellows, and attending physicians with a comprehensive inventory and citation analysis of the most impactful academic contributions to one of the most important fields within orthopaedic surgery.

Purpose In response to the outbreak of COVID-19 in Ireland, the government implemented a nationwide stay-at-home order, with the closure of all non-essential businesses. During this period, there was a significant increase in supermarket expenditure. It has been shown that stress, anxiety and boredom are triggers for unhealthy eating habits. Fat consumption is a risk factor for both the development of gallstones and, additionally, the development of acute calculous cholecystitis. The aim of this study was to assess the incidence of acute calculous cholecystitis during the nationwide lockdown and compare it to the same period one year prior. Methods A retrospective review of all emergency abdominal imaging performed during the first 5 weeks of the lockdown was completed using the hospital PACS (picture archiving and communication system). All cases of acute calculous cholecystitis were identified and compared with the same period 1 year prior. Results Eighteen cases of acute calculous cholecystitis were identified from 24 March to 27 April 2020. Eleven cases were identified during the same period in 2019. This represented an increase of 63%. Non-COVID-19-related emergency presentations decreased during this period, and imaging of emergency presentations decreased by 24%. The rate of scans positive for acute cholecystitis more than doubled (p

This study aims to predict death after COVID-19 using only the past medical information routinely collected in electronic health records (EHRs) and to understand the differences in risk factors across age groups. Combining computational methods and clinical expertise, we curated clusters that represent 46 clinical conditions as potential risk factors for death after a COVID-19 infection. We trained age-stratified generalized linear models (GLMs) with component-wise gradient boosting to predict the probability of death based on what we know from the patients before they contracted the virus. Despite only relying on previously documented demographics and comorbidities, our models demonstrated similar performance to other prognostic models that require an assortment of symptoms, laboratory values, and images at the time of diagnosis or during the course of the illness. In general, we found age as the most important predictor of mortality in COVID-19 patients. A history of pneumonia, which is rarely asked in typical epidemiology studies, was one of the most important risk factors for predicting COVID-19 mortality. A history of diabetes with complications and cancer (breast and prostate) were notable risk factors for patients between the ages of 45 and 65 years. In patients aged 65–85 years, diseases that affect the pulmonary system, including interstitial lung disease, chronic obstructive pulmonary disease, lung cancer, and a smoking history, were important for predicting mortality. The ability to compute precise individual-level risk scores exclusively based on the EHR is crucial for effectively allocating and distributing resources, such as prioritizing vaccination among the general population.

BackgroundHemodynamic stress, conditioned by the morphology of the surrounding vasculature, plays an important role in aneurysm formation. Our goal was to identify image-based location-specific parameters that are associated with posterior communicating artery (PCoA) aneurysms.MethodsThree-dimensional morphological parameters obtained from CT angiography or digital subtraction angiography from 187 patients with unilateral PCoA aneurysms, diagnosed at the Brigham and Women’s Hospital and Massachusetts General Hospital between 1990 and 2016, were evaluated. In order to control for genetic and clinical risk factors, we chose the contralateral unaffected PCoA as a control group. We examined diameters and angles of the surrounding parent and daughter vessels. Univariable and multivariable statistical analyses were performed to determine statistical significance. Sensitivity analyses with small aneurysms (≤5 mm) only and an unmatched analysis of 432 PCoA aneurysms and 197 control patients without PCoA aneurysms were also performed.ResultsIn a multivariable conditional logistic regression model we showed that smaller diameter size ratio (OR 1.45×10−5, 95% CI 1.12×10−7 to 1.88×10−3) and larger daughter-daughter angle (OR 1.04, 95% CI 1.02 to 1.07) were significantly associated with PCoA aneurysm presence after correcting for other variables. In subgroup analyses of small aneurysms (≤5 mm) and in an unmatched analysis the significance and direction of these results were preserved.ConclusionsLarger daughter-daughter angles and smaller diameter size ratio are significantly associated with the presence of PCoA aneurysms. These simple parameters can be utilized to guide the risk assessment for the formation of PCoA aneurysms in high risk patients.

Pneumothoraces may occur rarely in coronavirus (COVID-19) patients, often resulting from a combination of fibrotic parenchymal changes and prolonged high-pressure ventilation. Very few studies have been published describing the management of pneumothorax in the novel COVID-19 pneumonia patients. Although chest drain insertion represents the first line of treatment, a persistent pneumothorax and air leak requiring intervention could be managed by a thoracoscopic procedure or, as is the case here, by endobronchial valve insertion. Endobronchial valve insertion is a minimally invasive technique that provides a treatment option in patients with severe parenchymal COVID-19 related lung disease. As far as the authors are aware this is the first report of the use of endobronchial valves in a COVID-19 patient.

Background Treatment decisions for Coronavirus Disease 2019 (COVID-19) depend on disease severity, but the prescribing pattern by severity and drivers of therapeutic choices remain unclear. Objectives The objectives of the study were to evaluate pharmacological treatment patterns by COVID-19 severity and identify the determinants of prescribing for COVID-19. Methods Using electronic health record data from a large Massachusetts-based healthcare system, we identified all patients aged ≥ 18 years hospitalized with laboratory-confirmed COVID-19 from 1 March to 24 May, 2020. We defined five levels of COVID-19 severity at hospital admission: (1) hospitalized but not requiring supplemental oxygen; (2–4) hospitalized and requiring oxygen ≤ 2, 3–4, and ≥ 5 L per minute, respectively; and (5) intubated or admitted to an intensive care unit. We assessed the medications used to treat COVID-19 or as supportive care during hospitalization. Results Among 2821 patients hospitalized for COVID-19, we found inpatient mortality increased by severity from 5% for level 1 to 23% for level 5. As compared to patients with severity level 1, those with severity level 5 were 3.53 times (95% confidence interval 2.73–4.57) more likely to receive a medication used to treat COVID-19. Other predictors of treatment were fever, low oxygen saturation, presence of co-morbidities, and elevated inflammatory biomarkers. The use of most COVID-19 relevant medications has dropped substantially while the use of remdesivir and therapeutic anticoagulants has increased over the study period. Conclusions Careful consideration of disease severity and other determinants of COVID-19 drug use is necessary for appropriate conduct and interpretation of non-randomized studies evaluating outcomes of COVID-19 treatments. Electronic supplementary material The online version of this article (10.1007/s40265-020-01424-7) contains supplementary material, which is available to authorized users.

We present the case of a 29-year-old male healthcare worker with a 6 month history of progressive left foot pain resulting in presentation to the emergency department on 3 occasions. He denied systemic symptoms. Multimodal imaging demonstrated an expansile erosive inflammatory lesion centered on the neck of the second metatarsal with aggressive features. CT of the thorax, abdomen, and pelvis demonstrated calcified mediastinal lymph nodes and left inguinal adenopathy. The lesion was biopsied under ultrasound guidance demonstrating a necrotizing granulomatous osteomyelitis with acid fact bacilli. This is consistent with TB dactylitis (spina ventosa). Treatment with antimycobacterial drugs was commenced.

Background Stroboscopic visual training (SVT) has been shown to improve cognitive skills and perceptual performance by carrying out events under situations of intermittent vision. Aims The aim of this study was to investigate whether an SVT training period could improve the eye–hand coordination (EHC) performance on a practiced task for a group of sports participants. Methods Sixty-two male participants were randomly assigned to either a strobe group (SG n = 31), or control group (CG n = 31). The method employed a Sport Vision Trainer™ 80 sensor pad to measure the mean speed of reaction time of participants extinguishing randomly illuminated lights on an electronic board. One trial consists of 20 lights. One week following pre-testing on the Sport Vision Trainer™ (4 × 6 trials), a pre-training baseline assessment of 1 × 6 trials was conducted to measure their abilities to complete the EHC task. Four × six trials (480 lights) were then completed in the training phase with the CG continuing to train with unimpaired vision, whilst the SG wore Nike Vapor Strobe® (controlled rate of 100 ms visible to 150 ms opaque). Post-training assessments were administered immediately, 10 min and 10 days after SVT each consisting of six trials (120 lights). A visual search (VS) non-trained transfer test was also administered pre-SVT and after 10 days. This involved an e-prime programme using a laptop where participants had to identify a target stimulus located amongst distractor stimuli. Results Treatment effects were observed at each time point. Baseline performance was significantly related to retention performance immediately (p = .003), 10-min post (p = .001) and 10 days post-training (p = .002). No significant differences were found for the VS test. Conclusion An acute SVT exposure using stroboscopic goggles significantly improved EHC performance. Future research should explore these mechanisms further using different exposure, frequencies, and focused identification of training drills as a complementary intervention for individual or team sports.

Background ‘Slaintecare’ aims to address complex patient care needs in an integrated fashion with an emphasis on patient-centred, patient-empowered community care.Currently there is a lack of knowledge of the impact of rare disease management in primary care and of the information tools required by general practitioners to deliver integrated care for rare disease patients. Aims To complete a pilot survey to estimate the general practice clinical workload attributable to selected rare diseases and assess the use of relevant information sources. Methods A retrospective cross-sectional survey was carried out of general practice consultations (2013–2017) for patients with 22 commonly recognised rare diseases. Results Around 31 general practitioners from 10 Irish practices completed information on 171 patients with rare diseases over 3707 consultations. General practice-specific coding systems were inadequate for rare disease patient identification. Over 139 (81.3%) patients were adult, and 32 (18.7%) were children. Management of care was hospital and not primary care based in 63%. Those eligible for state-reimbursed care had a significantly higher median number of consultations (23 consultations, IQR = 13–37, or 5.8 consultations/year) than those who paid privately (10 consultations, IQR = 4–19, or 2.5 consultations/year) (p Conclusions Both specific rare disease-specific coding and use of the relevant rare disease information sources are lacking in general practice in Ireland.

We present a cohort of patients with anterior communicating artery (ACoA) aneurysms to investigate morphological characteristics and clinical factors associated with rupture of the aneurysms. 505 patients with ACoA aneurysms were identified at the Brigham and Women’s Hospital and Massachusetts General Hospital between 1990 and 2016, with available CT angiography (CTA). Three-dimensional (3D) reconstructions were performed to evaluate aneurysmal morphologic features, including location, projection, irregularity, the presence of daughter dome, height, height/width ratio, and relationships between surrounding vessels. Patient risk factors assessed included patient age, sex, tobacco use, alcohol use, and family history of aneurysms and aneurysmal subarachnoid hemorrhage. Logistic regression was used to build a predictive ACoA score for rupture. Morphologic features associated with ruptured ACoA aneurysms were the presence of a daughter dome (OR 21.4, 95% CI 10.6–43.1), smaller neck diameter (OR 0.55, 95% CI 0.42–0.71), larger aspect ratio (OR 3.57, 95% CI 2.05–6.24), larger flow angle (OR 1.03, 95% CI 1.02–1.05), and smaller ipsilateral A2-ACoA angle (OR 0.98, 95% CI 0.97–1.00). Tobacco use was predominantly associated with morphological factors intrinsic to the aneurysm that were associated with rupture while younger age was also associated with morphologic features extrinsic to the aneurysm that were associated with rupture. The ACoA score had good predictive capacity for rupture with AUC = 0.92 using the 0.632 bootstrap cross-validation for correction of overfitting bias. Ruptured ACoA aneurysms were associated with morphological features that are simple to assess using a simple scoring system. Tobacco use and younger age were predominantly associated with intrinsic and extrinsic morphological features characteristic of rupture, respectively.

We implemented the BioFire® FilmArray® Meningitis/Encephalitis Panel (MEP) with guidance for use based on patient age, cerebrospinal fluid (CSF) white blood cell (WBC) count and immune system status. MEPs results over 2 years (1/1/2017 to 12/31/18) were reviewed and clinical significance of positive MEP results in patients with CSF WBC ≤ 10 evaluated. Overall, 12% (51/453) of MEPs were positive with 4/184 (2%) positive in nonimmunocompromised (non-IC) with ≤ 10 CSF WBCs. Among positive results in non-IC patient with ≤10 CSF WBCs, none were judged clinically significant. Four of 6 results in immunocompromised patients with ≤10 CSF WBCs were clinically significant. Redundant testing was common and guideline adherence could have safely decreased MEPs use 41% saving$56,000. Guideline adherence was poor and MEP use can be safely avoided in non-IC adults with10 CSF WBC, but clinically significant results did occur in IC patients with low CSF WBC. Clinical decision support could reduce unneeded testing and result in significant cost savings.

Lipid-related metabolic disorders (LRMD) are prevalent in early lactation dairy cows, and have detrimental effects on productivity and health. Our objectives were to identify cows resistant or susceptible to LRMD using a ketosis induction protocol (KIP) to discover differentially expressed liver genes and metabolic pathways associated with disposition. Clustering cows based on postpartum lipid metabolite concentrations within dietary treatments identified cows more or less susceptible (MS vs. LS) to LRMD within the control treatment, and more or less resistant (MR vs. LR) within the KIP treatment. Whole-transcriptome RNA sequencing was performed on liver samples (−28, +1, and +14 days relative to calving) to assess differential gene and pathway expression (LS vs. MS, MR vs. LR, n = 3 cows per cluster). Cows within the MS and LR clusters had evidence of greater blood serum β-hydroxybutyrate concentration and liver triglyceride content than the LS and MR clusters, respectively. The inferred metabolism of differentially expressed genes suggested a role of immune response (i.e., interferon-inducible proteins and major histocompatibility complex molecules). Additionally, unique roles for glutathione metabolism and eicosanoid metabolism in modulating susceptibility and resistance, respectively, were implicated. Overall, this research provides novel insight into the role of immunometabolism in LRMD pathology, and suggests the potential for unique control points for LRMD progression and severity.

Crohn's disease (CD) and ulcerative colitis (UC) are heterogeneous. With availability of therapeutic classes with distinct immunologic mechanisms of action, it has become imperative to identify markers that predict likelihood of response to each drug class. However, robust development of such tools has been challenging because of need for large prospective cohorts with systematic and careful assessment of treatment response using validated indices. Most hospitals in the United States use electronic health records (EHRs) that warehouse a large amount of narrative (free-text) and codified (administrative) data generated during routine clinical care. These data have been used to construct virtual disease cohorts for epidemiologic research as well as for defining genetic basis of disease states or discrete laboratory values.1-3 Whether EHR-based data can be used to validate genetic associations for more nuanced outcomes such as treatment response has not been examined previously.

Although optimal pharmacological therapy for heart failure with reduced ejection fraction (HFrEF) is carefully scripted by treatment guidelines, many eligible patients are not treated with guideline‐directed medical therapy (GDMT) in clinical practice. We designed a strategy for remote optimization of GDMT on a population scale in patients with HFrEF leveraging nonphysician providers. An electronic health record‐based algorithm was used to identify a cohort of patients with a diagnosis of heart failure (HF) and ejection fraction (EF) ≤ 40% receiving longitudinal follow‐up at our center. Those with end‐stage HF requiring inotropic support, mechanical circulatory support, or transplantation and those enrolled in hospice or palliative care were excluded. Treating providers were approached for consent to adjust medical therapy according to a sequential, stepped titration algorithm modeled on the current American College of Cardiology (ACC)/American Heart Association (AHA) HF Guidelines within a collaborative care agreement. The program was approved by the institutional review board at Brigham and Women's Hospital with a waiver of written informed consent. All patients provided verbal consent to participate. A navigator then facilitated medication adjustments by telephone and conducted longitudinal surveillance of laboratories, blood pressure, and symptoms. Each titration step was reviewed by a pharmacist with supervision as needed from a nurse practitioner and HF cardiologist. Patients were discharged from the program to their primary cardiologist after achievement of an optimal or maximally tolerated regimen. A navigator‐led remote management strategy for optimization of GDMT may represent a scalable population‐level strategy for closing the gap between guidelines and clinical practice in patients with HFrEF.

BACKGROUND: The extent to which obesity and genetics determine post-operative complications is incompletely understood. METHODS: We performed a retrospective study using two population cohorts with electronic health record (EHR) data. The first included 736,726 adults with body mass index (BMI) recorded between 1990-2017 at Vanderbilt University Medical Center. The second cohort consisted of 65,174 individuals from 12 institutions contributing EHR and genome-wide genotyping data to the Electronic Medical Records & Genomics (eMERGE) Network. Pairwise logistic regression analyses were used to measure the association of BMI categories with postoperative complications derived from International Classification of Disease-9 codes, including postoperative infection, incisional hernia, and intestinal obstruction. A genetic risk score (GRS) was constructed from 97 obesity-risk single nucleotide polymorphisms for a Mendelian randomization study to determine the association of genetic risk for obesity on postoperative complications. Logistic regression analyses were adjusted for sex, age, site, and race/principal components. RESULTS: Individuals with overweight or obese BMI (≥25 kg/m(2)) had increased risk for incisional hernia (Odds ratio [OR] 1.7-5.5, p

Background Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver illness with a genetically heterogeneous background that can be accompanied by considerable morbidity and attendant health care costs. The pathogenesis and progression of NAFLD is complex with many unanswered questions. We conducted genome-wide association studies (GWASs) using both adult and pediatric participants from the Electronic Medical Records and Genomics (eMERGE) Network to identify novel genetic contributors to this condition. Methods First, a natural language processing (NLP) algorithm was developed, tested, and deployed at each site to identify 1106 NAFLD cases and 8571 controls and histological data from liver tissue in 235 available participants. These include 1242 pediatric participants (396 cases, 846 controls). The algorithm included billing codes, text queries, laboratory values, and medication records. Next, GWASs were performed on NAFLD cases and controls and case-only analyses using histologic scores and liver function tests adjusting for age, sex, site, ancestry, PC, and body mass index (BMI). Results Consistent with previous results, a robust association was detected for the PNPLA3 gene cluster in participants with European ancestry. At the PNPLA3-SAMM50 region, three SNPs, rs738409, rs738408, and rs3747207, showed strongest association (best SNP rs738409 p = 1.70 × 10− 20). This effect was consistent in both pediatric (p = 9.92 × 10− 6) and adult (p = 9.73 × 10− 15) cohorts. Additionally, this variant was also associated with disease severity and NAFLD Activity Score (NAS) (p = 3.94 × 10− 8, beta = 0.85). PheWAS analysis link this locus to a spectrum of liver diseases beyond NAFLD with a novel negative correlation with gout (p = 1.09 × 10− 4). We also identified novel loci for NAFLD disease severity, including one novel locus for NAS score near IL17RA (rs5748926, p = 3.80 × 10− 8), and another near ZFP90-CDH1 for fibrosis (rs698718, p = 2.74 × 10− 11). Post-GWAS and gene-based analyses identified more than 300 genes that were used for functional and pathway enrichment analyses. Conclusions In summary, this study demonstrates clear confirmation of a previously described NAFLD risk locus and several novel associations. Further collaborative studies including an ethnically diverse population with well-characterized liver histologic features of NAFLD are needed to further validate the novel findings. Electronic supplementary material The online version of this article (10.1186/s12916-019-1364-z) contains supplementary material, which is available to authorized users.

Zusammenfassung Hintergrund Acrylnagel beherbergen mehr Bakterien als Naturnagel, und die Nutzung wird fur Gesundheitspersonal (HCWs) nicht empfohlen. Uber die neuen und beliebten Gel-Nagelprodukte ist wenig bekannt. Diese Studie untersucht die bakterielle Belastung von Gel-Nageln, Standard-Nagellack und Naturnageln an den Handen von HCWs. Methode Die Studie wurde in 3 Gesundheitszentren durchgefuhrt. Nagel auf der dominierenden Hand von 88 HCWs waren lackiert mit Standard Nagellack oder Gel. Kulturen wurden an den Tagen 1, 7 und 14 vor und nach der Handehygiene mit Alkohol-Handgel abgenommen. Ergebnisse Insgesamt wurden 741 Kulturen gewonnen. Die bakterielle Belastung ist bei allen Nageltypen gestiegen (P ≤ .0001). Eine Reduktion der bakteriellen Belastung konnte nach der Handehygiene bei den Naturnageln und dem Standardnagellack, jedoch nicht bei Gel-Nageln nachgewiesen werden (P = .001, P = .0028 bzw. P = .98). Alle 3 Nageltypen waren im Laufe der Zeit mit mehr Bakterien kontaminiert. Standard-Nagellack und Naturnagel konnen fur die Handehygiene geeigneter sein als Gel-Nagel. Schlussfolgerungen Diese Studie zeigt keine erhohte Anzahl von Mikroorganismen auf Nageln mit Gel; jedoch konnen Gelnagel mit Alkohol-Handgel schwieriger zu desinfizieren sein.

Background: The conventional approach for clinical studies is to identify a cohort of potentially eligible patients and then screen for enrollment. In an effort to reduce the cost and manual effort involved in the screening process, several studies have leveraged electronic health records (EHR) to refine cohorts to better match the eligibility criteria, which is referred to as phenotyping. We extend this approach to dynamically identify a cohort by repeating phenotyping in alternation with manual screening. Methods: Our approach consists of multiple screen cycles. At the start of each cycle, the phenotyping algorithm is used to identify eligible patients from the EHR, creating an ordered list such that patients that are most likely eligible are listed first. This list is then manually screened, and the results are analyzed to improve the phenotyping for the next cycle. We describe the preliminary results and challenges in the implementation of this approach for an intervention study on heart failure. Results: A total of 1,022 patients were screened, with 223 (23%) of patients being found eligible for enrollment into the intervention study. The iterative approach improved the phenotyping in each screening cycle. Without an iterative approach, the positive screening rate (PSR) was expected to dip below the 20% measured in the first cycle; however, the cyclical approach increased the PSR to 23%. Conclusions: Our study demonstrates that dynamic phenotyping can facilitate recruitment for prospective clinical study. Future directions include improved informatics infrastructure and governance policies to enable real-time updates to research repositories, tooling for EHR annotation, and methodologies to reduce human annotation. J Clin Med Res. 2019;11(6):458-463 doi: https://doi.org/10.14740/jocmr3830

The All of Us Research Program was designed to enable broad-based precision medicine research in a cohort of unprecedented scale and diversity. Hypertension (HTN) is a major public health concern. The validity of HTN data and definition of hypertension cases in the All of Us (AoU) Research Program for use in rule-based algorithms is unknown. In this cross-sectional, population-based study, we compare HTN prevalence in the AoU Research Program to HTN prevalence in the 2015–2016 National Health and Nutrition Examination Survey (NHANES). We used AoU baseline data from patient (age ≥ 18) measurements (PM), surveys, and electronic health record (EHR) blood pressure measurements. We retrospectively examined the prevalence of HTN in the EHR cohort using Systemized Nomenclature of Medicine (SNOMED) codes and blood pressure medications recorded in the EHR. We defined HTN as the participant having at least 2 HTN diagnosis/billing codes on separate dates in the EHR data AND at least one HTN medication. We calculated an age-standardized HTN prevalence according to the age distribution of the U.S. Census, using 3 groups (18–39, 40–59, and ≥ 60). Among the 185,770 participants enrolled in the AoU Cohort (mean age at enrollment = 51.2 years) available in a Researcher Workbench as of October 2019, EHR data was available for at least one SNOMED code from 112,805 participants, medications for 104,230 participants, and 103,490 participants had both medication and SNOMED data. The total number of persons with SNOMED codes on at least two distinct dates and at least one antihypertensive medication was 33,310 for a crude prevalence of HTN of 32.2%. AoU age-adjusted HTN prevalence was 27.9% using 3 groups compared to 29.6% in NHANES. The AoU cohort is a growing source of diverse longitudinal data to study hypertension nationwide and develop precision rule-based algorithms for use in hypertension treatment and prevention research. The prevalence of hypertension in this cohort is similar to that in prior population-based surveys.

ObjectivesTo perform an international comparison of the trajectory of laboratory values among hospitalized patients with COVID-19 who develop severe disease and identify optimal timing of laboratory value collection to predict severity across hospitals and regions.DesignRetrospective cohort study.SettingThe Consortium for Clinical Characterization of COVID-19 by EHR (4CE), an international multi-site data-sharing collaborative of 342 hospitals in the US and in Europe.ParticipantsPatients hospitalized with COVID-19, admitted before or after PCR-confirmed result for SARS-CoV-2.Primary and secondary outcome measuresPatients were categorized as “ever-severe” or “never-severe” using the validated 4CE severity criteria. Eighteen laboratory tests associated with poor COVID-19-related outcomes were evaluated for predictive accuracy by area under the curve (AUC), compared between the severity categories. Subgroup analysis was performed to validate a subset of laboratory values as predictive of severity against a published algorithm. A subset of laboratory values (CRP, albumin, LDH, neutrophil count, D-dimer, and procalcitonin) was compared between North American and European sites for severity prediction.ResultsOf 36,447 patients with COVID-19, 19,953 (43.7%) were categorized as ever-severe. Most patients (78.7%) were 50 years of age or older and male (60.5%). Longitudinal trajectories of CRP, albumin, LDH, neutrophil count, D-dimer, and procalcitonin showed association with disease severity. Significant differences of laboratory values at admission were found between the two groups. With the exception of D-dimer, predictive discrimination of laboratory values did not improve after admission. Sub-group analysis using age, D-dimer, CRP, and lymphocyte count as predictive of severity at admission showed similar discrimination to a published algorithm (AUC=0.88 and 0.91, respectively). Both models deteriorated in predictive accuracy as the disease progressed. On average, no difference in severity prediction was found between North American and European sites.ConclusionsLaboratory test values at admission can be used to predict severity in patients with COVID-19. Prediction models show consistency across international sites highlighting the potential generalizability of these models.

Objective The Consortium for Clinical Characterization of COVID-19 by EHR (4CE) is an international collaboration addressing coronavirus disease 2019 (COVID-19) with federated analyses of electronic health record (EHR) data. We sought to develop and validate a computable phenotype for COVID-19 severity. Materials and Methods Twelve 4CE sites participated. First, we developed an EHR-based severity phenotype consisting of 6 code classes, and we validated it on patient hospitalization data from the 12 4CE clinical sites against the outcomes of intensive care unit (ICU) admission and/or death. We also piloted an alternative machine learning approach and compared selected predictors of severity with the 4CE phenotype at 1 site. Results The full 4CE severity phenotype had pooled sensitivity of 0.73 and specificity 0.83 for the combined outcome of ICU admission and/or death. The sensitivity of individual code categories for acuity had high variability—up to 0.65 across sites. At one pilot site, the expert-derived phenotype had mean area under the curve of 0.903 (95% confidence interval, 0.886-0.921), compared with an area under the curve of 0.956 (95% confidence interval, 0.952-0.959) for the machine learning approach. Billing codes were poor proxies of ICU admission, with as low as 49% precision and recall compared with chart review. Discussion We developed a severity phenotype using 6 code classes that proved resilient to coding variability across international institutions. In contrast, machine learning approaches may overfit hospital-specific orders. Manual chart review revealed discrepancies even in the gold-standard outcomes, possibly owing to heterogeneous pandemic conditions. Conclusions We developed an EHR-based severity phenotype for COVID-19 in hospitalized patients and validated it at 12 international sites.

Simple Summary Treatment decisions represent a significant dilemma for patients diagnosed with prostate cancer. The prediction of early treatment failure would inform appropriate decision making and allow the clinician and patient to consider appropriate primary treatments and adjuvant therapies. We have developed and validated a serum biomarker-based model for predicting risk of biochemical reoccurrence in prostate cancer after radical prostatectomy. This study shows that the pre-operative biomarker PEDF can improve the accuracy of the clinical factors to predict risk of biochemical reoccurrence. PEDF has anti-inflammatory effects impacting on cytokine production. This non-invasive tool can be employed prior to treatment and demonstrates significant benefit over current clinical practice, impacting on patients’ outcomes and quality of life. Abstract This study undertook to predict biochemical recurrence (BCR) in prostate cancer patients after radical prostatectomy using serum biomarkers and clinical features. Three radical prostatectomy cohorts were used to build and validate a model of clinical variables and serum biomarkers to predict BCR. The Cox proportional hazard model with stepwise selection technique was used to develop the model. Model evaluation was quantified by the AUC, calibration, and decision curve analysis. Cross-validation techniques were used to prevent overfitting in the Irish training cohort, and the Austrian and Norwegian independent cohorts were used as validation cohorts. The integration of serum biomarkers with the clinical variables (AUC = 0.695) improved significantly the predictive ability of BCR compared to the clinical variables (AUC = 0.604) or biomarkers alone (AUC = 0.573). This model was well calibrated and demonstrated a significant improvement in the predictive ability in the Austrian and Norwegian validation cohorts (AUC of 0.724 and 0.606), compared to the clinical model (AUC of 0.665 and 0.511). This study shows that the pre-operative biomarker PEDF can improve the accuracy of the clinical factors to predict BCR. This model can be employed prior to treatment and could improve clinical decision making, impacting on patients’ outcomes and quality of life.

An estimated 4.2 million premature deaths globally are influenced by ambient air pollution, mainly from heart disease, stroke, chronic obstructive pulmonary disease and lung cancer, besides attribu...

Hemodynamic stress is thought to play an important role in the formation of intracranial aneurysms, which is conditioned by the geometry of the surrounding vasculature. Our goal was to identify image-based morphological parameters that were associated with basilar artery tip aneurysms (BTA) in a location-specific manner. Three-dimensional morphological parameters obtained from CT-angiography (CTA) or digital subtraction angiography (DSA) from 207 patients with BTAs and a control group of 106 patients with aneurysms elsewhere to control for non-morphological factors, who were diagnosed at the Brigham and Women’s Hospital and Massachusetts General Hospital between 1990 and 2016, were evaluated. We examined the presence of hypoplastic, aplastic or fetal PCoAs, vertebral dominance, and diameters and angles of surrounding parent and daughter vessels. Univariable and multivariable statistical analyses were performed to determine statistical significance. Sensitivity analyses with small (≤ 3 mm) aneurysms only and with angles excluded, were also performed. In multivariable analysis, daughter–daughter angle was directly, and parent artery diameter and diameter size ratio were inversely associated with BTAs. These results remained significant in the subgroup analysis of small aneurysms (width ≤ 3 mm) and when angles were excluded. These easily measurable and robust parameters that are unlikely to be affected by aneurysm formation could aid in risk stratification for the formation of BTAs in high-risk patients.

IntroductionThe Consortium for Clinical Characterization of COVID-19 by EHR (4CE) includes hundreds of hospitals internationally using a federated computational approach to COVID-19 research using the EHR.ObjectiveWe sought to develop and validate a standard definition of COVID-19 severity from readily accessible EHR data across the Consortium.MethodsWe developed an EHR-based severity algorithm and validated it on patient hospitalization data from 12 4CE clinical sites against the outcomes of ICU admission and/or death. We also used a machine learning approach to compare selected predictors of severity to the 4CE algorithm at one site.ResultsThe 4CE severity algorithm performed with pooled sensitivity of 0.73 and specificity 0.83 for the combined outcome of ICU admission and/or death. The sensitivity of single code categories for acuity were unacceptably inaccurate - varying by up to 0.65 across sites. A multivariate machine learning approach identified codes resulting in mean AUC 0.956 (95% CI: 0.952, 0.959) compared to 0.903 (95% CI: 0.886, 0.921) using expert-derived codes. Billing codes were poor proxies of ICU admission, with 49% precision and recall compared against chart review at one partner institution.DiscussionWe developed a proxy measure of severity that proved resilient to coding variability internationally by using a set of 6 code classes. In contrast, machine-learning approaches may tend to overfit hospital-specific orders. Manual chart review revealed discrepancies even in the gold standard outcomes, possibly due to pandemic conditions.ConclusionWe developed an EHR-based algorithm for COVID-19 severity and validated it at 12 international sites.

Introduction The rising prevalence of heart failure due to an aging population, higher post–myocardial infarction survival and the increasing burden of cardio–metabolic diseases, presents public health and economic challenges. Optimisation of heart failure therapy is essential in preventing the morbidity and mortality associated with this disease. The landmark DAPA–HF trial identified a 26% relative reduction in a composite primary outcome of worsening heart failure or death with use of dapagliflozin in patients with heart failure and reduced ejection fraction (HFrEF), irrespective of diabetic status. Although this class of drug is not yet incorporated into ESC guidelines, such a marked benefit may prompt consideration. The objective of this study is to determine the proportion of patients eligible for dapagliflozin at our site, based on inclusion and exclusion criteria of the DAPA–HF trial. Methods This retrospective observational study was conducted at Our Lady of Lourdes Hospital, Heart Failure Clinic. Data was collected on all patients referred from January 2018 to December 2019. We employed four data sources: CELLMA, a programme used to record clinical information; PACS (radiology); WinPath (blood work); and patient charts. This multipronged approach served to limit missing data. Eligibility required: EF ≤40%; NYHA ≥II; absence of type 1 diabetes mellitus (T1DM); SBP ≥95 mmHg; eGFR ≥30 ml/min; commensurate elevated BNP levels; and taking at least an ACE inhibitor, ARB or sacubitril/valsartan combined with a beta blocker (BB). Complete case analysis was used, as data was complete for >90% patients. Results In all, there were 587 referrals during this period, of which 278 (47.4%) had HFrEF and 130 (22.1%) had an EF Conclusion In a real–life Heart Failure Clinic almost one quarter of HFrEF patients fulfilled the DAPA–HF inclusion criteria. These patients may stand to benefit from dapagliflozin in terms of reduced hospitalisations and mortality, were this drug prescribed in addition to guideline–recommended heart failure therapies.

Introduction Heart failure with preserved ejection fraction (HFpEF) is a common but heterogenous clinical syndrome. Transthyretin amyloidosis cardiomyopathy (ATTR-CM) can now be diagnosed non-invasively with high sensitivity incorporating Technitium-99m, 3,3-diphosphono-1,2-propanodicarboxylic acid (Tc-DPD) scintigraphy. ATTR-CM has been found as the underlying aetiology of heart failure in 13% in HFpEF syndrome with left ventricular hypertrophy (LVH). Timely diagnosis of ATTR-CM has become even more relevant given the recent availability of targeted treatments. However, the prevalence and spectrum of ATTR-CM has not previously been studied in all-comer HFpEF cohort. Aims To determine the prevalence and spectrum of ATTR-CM in an undifferentiated multicentre HFpEF population using the non-invasive diagnostic pathway incorporating Tc-DPD scintigraphy. Methods Consecutive patients ≥60 years attending the heart failure services with a diagnosis of HFpEF and New York Heart Association class II-IV symptoms across 4 sites were prospectively enrolled. Severe valvular pathology or a prior history of symptomatic myeloma, AL amyloidosis or monoclonal gammopathy of unknown significance (MGUS) were excluded. Transthoracic 2D strain echocardiography, 12 lead electrocardiogram (ECG), biomarker analysis and Tc-DPD scintigraphy were performed. Tc-DPD findings were graded visually according to the Perugini classification (grades 0–3). Those patients with Perugini grade 2–3 on Tc-DPD (moderate-severe uptake; highly suggestive of ATTR-CM) underwent additional laboratory and haematological assessment and transthyretin (TTR) gene sequencing. Results To date, 45 patients (49% female, mean age 77.6 ± 7.9 years) have been prospectively enrolled. A history of atrial fibrillation and hypertension were present in 60% and 80% respectively. In keeping with ATTR-CM, no participant had a low voltage pattern on ECG. Three patients (6.7%) had Perugini grade 3 uptake on Tc-DPD and 6 patients (13.3%) had grade 1 uptake (mild uptake, inferior to bone; diagnostic significance undetermined). No patients had grade 2 uptake. All those with grade 3 uptake had AL amyloid excluded on further haematological testing and no mutation was detected in the TTR gene confirming wild type ATTR-CM. Significant differences across Tc-DPD uptake grades were seen according to increasing age and LV wall thickness (figure 1). Conclusion ATTR-CM, characterised by high grade uptake (Perugini 3) on Tc-DPD scintigraphy and negative haematological markers, was present in 6.7% of this undifferentiated HFpEF cohort and was associated with older age, and increased left ventricular wall thickness. Low grade uptake (Perugini grade 1) was present in a further 13.3%. While the diagnostic significance of this phenotype is undetermined, this may represent early ATTR-CM, suggesting that Tc-DPD scintigraphy may be able to identify a spectrum of disease according to uptake that correlates with wall thickness. Further follow up in this study will explore this potential.

Risk of intracranial aneurysm rupture could be affected by geometric features of intracranial aneurysms and the surrounding vasculature in a location specific manner. Our goal is to investigate the morphological characteristics associated with ruptured posterior communicating artery (PCoA) aneurysms, as well as patient factors associated with the morphological parameters. Three-dimensional morphological parameters in 409 patients with 432 PCoA aneurysms diagnosed at the Brigham and Women’s Hospital and Massachusetts General Hospital between 1990 and 2016 who had available CT angiography (CTA) or digital subtraction angiography (DSA) were evaluated. Morphological parameters examined included aneurysm wall irregularity, presence of a daughter dome, presence of hypoplastic or aplastic A1 arteries and hypoplastic or fetal PCoA, perpendicular height, width, neck diameter, aspect and size ratio, height/width ratio, and diameters and angles of surrounding parent and daughter vessels. Univariable and multivariable statistical analyses were performed to determine the association of morphological parameters with rupture of PCoA aneurysms. Additional analyses were performed to determine the association of patient factors with the morphological parameters. Irregular, multilobed PCoA aneurysms with larger height/width ratios and larger flow angles were associated with ruptured PCoA aneurysms, whereas perpendicular height was inversely associated with rupture in a multivariable model. Older age was associated with lower aspect ratio, with a trend towards lower height/width ratio and smaller flow angle, features that are associated with a lower rupture risk. Morphological parameters are easy to assess and could help in risk stratification in patients with unruptured PCoA aneurysms. PCoA aneurysms diagnosed at older age have morphological features associated with lower risk.

Lower respiratory tract infections, including hospital-acquired and ventilator-associated pneumonia, are common in hospitalized patient populations. Standard methods frequently fail to identify the infectious etiology due to the polymicrobial nature of respiratory specimens and the necessity of ordering specific tests to identify viral agents. The potential severity of these infections combined with a failure to clearly identify the causative pathogen results in administration of empirical antibiotic agents based on clinical presentation and other risk factors., Lower respiratory tract infections, including hospital-acquired and ventilator-associated pneumonia, are common in hospitalized patient populations. Standard methods frequently fail to identify the infectious etiology due to the polymicrobial nature of respiratory specimens and the necessity of ordering specific tests to identify viral agents. The potential severity of these infections combined with a failure to clearly identify the causative pathogen results in administration of empirical antibiotic agents based on clinical presentation and other risk factors. We examined the impact of the multiplexed, semiquantitative BioFire FilmArray Pneumonia panel (PN panel) test on laboratory reporting for 259 adult inpatients submitting bronchoalveolar lavage (BAL) specimens for laboratory analysis. The PN panel demonstrated a combined 96.2% positive percent agreement (PPA) and 98.1% negative percent agreement (NPA) for the qualitative identification of 15 bacterial targets compared to routine bacterial culture. Semiquantitative values reported by the PN panel were frequently higher than values reported by culture, resulting in semiquantitative agreement (within the same log10 value) of 43.6% between the PN panel and culture; however, all bacterial targets reported as >105 CFU/ml in culture were reported as ≥105 genomic copies/ml by the PN panel. Viral targets were identified by the PN panel in 17.7% of specimens tested, of which 39.1% were detected in conjunction with a bacterial target. A review of patient medical records, including clinically prescribed antibiotics, revealed the potential for antibiotic adjustment in 70.7% of patients based on the PN panel result, including discontinuation or de-escalation in 48.2% of patients, resulting in an average savings of 6.2 antibiotic days/patient.

We leveraged the largely untapped resource of electronic health record data to address critical clinical and epidemiological questions about Coronavirus Disease 2019 (COVID-19). To do this, we formed an international consortium (4CE) of 96 hospitals across 5 countries (www.covidclinical.net). Contributors utilized the Informatics for Integrating Biology and the Bedside (i2b2) or Observational Medical Outcomes Partnership (OMOP) platforms to map to a common data model. The group focused on comorbidities and temporal changes in key laboratory test values. Harmonized data were analyzed locally and converted to a shared aggregate form for rapid analysis and visualization of regional differences and global commonalities. Data covered 27,584 COVID-19 cases with 187,802 laboratory tests. Case counts and laboratory trajectories were concordant with existing literature. Laboratory tests at the time of diagnosis showed hospital-level differences equivalent to country-level variation across the consortium partners. Despite the limitations of decentralized data generation, we established a framework to capture the trajectory of COVID-19 disease in patients and their response to interventions.

Background and objectives Treatment guidelines emphasize patients' readiness for transitioning from opiate substitution treatment (OST) to opiate withdrawal and abstinence. Psychological preparedness indicators for this transition were examined. Methods Patients (all male) were recruited from three treatment settings: prison, an inpatient detoxification unit, and an outpatient clinic. Time 1 (T1) was admission to methadone-assisted withdrawal in all settings. Time 2 (T2) was a 6-month follow-up. With n = 24 at T1 for each group (N = 72), a battery of instruments relevant to psychological preparedness was administered. Results At T1, inpatients had higher self-efficacy beliefs for successful treatment completion than prison patients. For patients contactable at T2, T1 self-efficacy positively predicted T2 opiate abstinence. No other variable improved prediction. T1 SOCRATES (Stages of Change Readiness and Treatment Eagerness Scale) ambivalence scores, age, and lifetime heroin use duration predicted maintenance of contact or not with treatment services and contactability by the researcher. Measures of mood did not differ between groups at T1 or predict T2 outcomes. Discussion and conclusions Self-efficacy beliefs are a potentially useful indicator of readiness for transitioning from OST to a medically assisted opiate withdrawal and subsequent abstinence. Ambivalence regarding change, age, and lifetime heroin use duration are potentially useful predictors of patients maintaining contact with services, and of being retained in research. Scientific significance These findings advance existing literature and knowledge by highlighting the importance of self-efficacy in psychological preparedness for opiate abstinence, and the predictive utility to clinicians of this and other variables measurable at admission, in the clinical management of opiate users. (© 2020 The Authors. The American Journal on Addictions published by Wiley Periodicals LLC on behalf of The American Academy of Addiction Psychiatry). (Am J Addict 2021;30:11-20).

The ability to provide timely identification of the causative agents of lower respiratory tract infections can promote better patient outcomes and support antimicrobial stewardship efforts. Current diagnostic testing options include culture, molecular testing, and antigen detection. These methods may require collection of various specimens, involve extensive sample treatment, and can suffer from low sensitivity and long turnaround times. This study assessed the performance of the BioFire FilmArray Pneumonia Panel (PN panel) and Pneumonia Plus Panel (PNplus panel), an FDA-cleared sample-to-answer assay that enables the detection of viruses, atypical bacteria, bacteria, and antimicrobial resistance marker genes from lower respiratory tract specimens (sputum and bronchoalveolar lavage [BAL] fluid)., The ability to provide timely identification of the causative agents of lower respiratory tract infections can promote better patient outcomes and support antimicrobial stewardship efforts. Current diagnostic testing options include culture, molecular testing, and antigen detection. These methods may require collection of various specimens, involve extensive sample treatment, and can suffer from low sensitivity and long turnaround times. This study assessed the performance of the BioFire FilmArray Pneumonia Panel (PN panel) and Pneumonia Plus Panel (PNplus panel), an FDA-cleared sample-to-answer assay that enables the detection of viruses, atypical bacteria, bacteria, and antimicrobial resistance marker genes from lower respiratory tract specimens (sputum and bronchoalveolar lavage [BAL] fluid). Semiquantitative results are also provided for the bacterial targets. This paper describes selected analytical and clinical studies that were conducted to evaluate performance of the panel for regulatory clearance. Prospectively collected respiratory specimens (846 BAL and 836 sputum specimens) evaluated with the PN panel were also tested by quantitative reference culture and molecular methods for comparison. The PN panel showed a sensitivity of 100% for 15/22 etiologic targets using BAL specimens and for 10/24 using sputum specimens. All other targets had sensitivities of ≥75% or were unable to be calculated due to low prevalence in the study population. Specificity for all targets was ≥87.2%, with many false-positive results compared to culture that were confirmed by alternative molecular methods. Appropriate adoption of this test could provide actionable diagnostic information that is anticipated to impact patient care and antimicrobial stewardship decisions.

We leveraged the largely untapped resource of electronic health record data to address critical clinical and epidemiological questions about Coronavirus Disease 2019 (COVID-19). To do this, we formed an international consortium (4CE) of 96 hospitals across five countries (www.covidclinical.net). Contributors utilized the Informatics for Integrating Biology and the Bedside (i2b2) or Observational Medical Outcomes Partnership (OMOP) platforms to map to a common data model. The group focused on temporal changes in key laboratory test values. Harmonized data were analyzed locally and converted to a shared aggregate form for rapid analysis and visualization of regional differences and global commonalities. Data covered 27,584 COVID-19 cases with 187,802 laboratory tests. Case counts and laboratory trajectories were concordant with existing literature. Laboratory tests at the time of diagnosis showed hospital-level differences equivalent to country-level variation across the consortium partners. Despite the limitations of decentralized data generation, we established a framework to capture the trajectory of COVID-19 disease in patients and their response to interventions.

Decreased adipose tissue oxygen tension and increased HIF-1α expression can trigger adipose tissue inflammation and dysfunction in obesity. Our current understanding of obesity-associated decreased adipose tissue oxygen tension is mainly focused on changes in oxygen supply and angiogenesis. Here, we demonstrate that increased adipocyte O2 demand, mediated by ANT2 activity, is the dominant cause of adipocyte hypoxia. Deletion of adipocyte Ant2 improves obesity-induced intracellular adipocyte hypoxia by decreasing obesity-induced adipocyte oxygen demand, without effects on mitochondrial number or mass, or oligomycin-sensitive respiration. This led to decreased adipose tissue HIF-1α expression and inflammation with improved glucose tolerance and insulin resistance in both a preventative or therapeutic setting. Our results suggest that ANT2 may be a target for the development of insulin sensitizing drugs and that ANT2 inhibition might have clinical utility.

Background and Purpose— Both low serum calcium and magnesium levels have been associated with the extent of bleeding in patients with intracerebral hemorrhage, suggesting hypocalcemia- and hypomagnesemia-induced coagulopathy as a possible underlying mechanism. We hypothesized that serum albumin-corrected total calcium and magnesium levels are associated with ruptured intracranial aneurysms. Methods— The medical records of 4701 patients, including 1201 prospective patients, diagnosed at the Brigham and Women’s Hospital and Massachusetts General Hospital between 1990 and 2016 were reviewed and analyzed. One thousand two hundred seventy-five patients had available serum calcium, magnesium, and albumin values within 1 day of diagnosis. Individuals were divided into cases with ruptured aneurysms and controls with unruptured aneurysms. Univariable and multivariable logistic regression analyses were performed to determine the association between serum albumin-corrected total calcium and magnesium levels and ruptured aneurysms. Results— In multivariable analysis, both albumin-corrected calcium (odds ratio, 0.33; 95% confidence interval, 0.27–0.40) and magnesium (odds ratio, 0.40; 95% confidence interval, 0.28–0.55) were significantly and inversely associated with ruptured intracranial aneurysms. Conclusions— In this large case–control study, hypocalcemia and hypomagnesemia at diagnosis were significantly associated with ruptured aneurysms. Impaired hemostasis caused by hypocalcemia and hypomagnesemia may explain this association.

Background The relationship between inflammation and blood pressure (BP) has been studied mainly in the general population. In this study, we examined the association between inflammation and BP across a broader range of inflammation observed in rheumatoid arthritis (RA) and non-RA outpatients. Methods We studied subjects from a tertiary care outpatient population with C-reactive protein (CRP) and BP measured on the same date in 2009–2010; RA outpatients were identified using a validated algorithm. General population data were obtained from the National Health and Nutrition Examination Survey (NHANES) as comparison. To study the cross-sectional association between CRP and BP in the three groups, we constructed a generalized additive model. Longitudinal association between CRP and BP was examined using a repeated-measures linear mixed-effects model in RA outpatients with significant change in inflammation at two consecutive time points. Results We studied 24,325 subjects from the outpatient population, of whom 1811 had RA, and 5561 were from NHANES. In RA outpatients, we observed a positive relationship between CRP and systolic BP (SBP) at CRP

Bipolar disorder (BD) is a heritable mood disorder characterized by episodes of mania and depression. Although genomewide association studies (GWAS) have successfully identified genetic loci contributing to BD risk, sample size has become a rate-limiting obstacle to genetic discovery. Electronic health records (EHRs) represent a vast but relatively untapped resource for high-throughput phenotyping. As part of the International Cohort Collection for Bipolar Disorder (ICCBD), we previously validated automated EHR-based phenotyping algorithms for BD against in-person diagnostic interviews (Castro et al. Am J Psychiatry 172:363–372, 2015). Here, we establish the genetic validity of these phenotypes by determining their genetic correlation with traditionally ascertained samples. Case and control algorithms were derived from structured and narrative text in the Partners Healthcare system comprising more than 4.6 million patients over 20 years. Genomewide genotype data for 3330 BD cases and 3952 controls of European ancestry were used to estimate SNP-based heritability (h2g) and genetic correlation (rg) between EHR-based phenotype definitions and traditionally ascertained BD cases in GWAS by the ICCBD and Psychiatric Genomics Consortium (PGC) using LD score regression. We evaluated BD cases identified using 4 EHR-based algorithms: an NLP-based algorithm (95-NLP) and three rule-based algorithms using codified EHR with decreasing levels of stringency—“coded-strict”, “coded-broad”, and “coded-broad based on a single clinical encounter” (coded-broad-SV). The analytic sample comprised 862 95-NLP, 1968 coded-strict, 2581 coded-broad, 408 coded-broad-SV BD cases, and 3 952 controls. The estimated h2g were 0.24 (p = 0.015), 0.09 (p = 0.064), 0.13 (p = 0.003), 0.00 (p = 0.591) for 95-NLP, coded-strict, coded-broad and coded-broad-SV BD, respectively. The h2g for all EHR-based cases combined except coded-broad-SV (excluded due to 0 h2g) was 0.12 (p = 0.004). These h2g were lower or similar to the h2g observed by the ICCBD + PGCBD (0.23, p = 3.17E−80, total N = 33,181). However, the rg between ICCBD + PGCBD and the EHR-based cases were high for 95-NLP (0.66, p = 3.69 × 10–5), coded-strict (1.00, p = 2.40 × 10−4), and coded-broad (0.74, p = 8.11 × 10–7). The rg between EHR-based BD definitions ranged from 0.90 to 0.98. These results provide the first genetic validation of automated EHR-based phenotyping for BD and suggest that this approach identifies cases that are highly genetically correlated with those ascertained through conventional methods. High throughput phenotyping using the large data resources available in EHRs represents a viable method for accelerating psychiatric genetic research.

Background and Purpose— Previous studies have suggested a protective effect of diabetes mellitus on aneurysmal subarachnoid hemorrhage risk. However, reports are inconsistent, and objective measures of hyperglycemia in these studies are lacking. Our aim was to investigate the association between aneurysmal subarachnoid hemorrhage and antihyperglycemic agent use and glycated hemoglobin levels. Methods— The medical records of 4701 patients with 6411 intracranial aneurysms, including 1201 prospective patients, diagnosed at the Massachusetts General Hospital and Brigham and Women’s Hospital between 1990 and 2016 were reviewed and analyzed. Patients were separated into ruptured and nonruptured groups. Univariate and multivariate logistic regression analyses were performed to determine the association between aneurysmal subarachnoid hemorrhage and antihyperglycemic agents and glycated hemoglobin levels. Propensity score weighting was used to account for selection bias. Results— In both unweighted and weighted multivariate analysis, antihyperglycemic agent use was inversely and significantly associated with ruptured aneurysms (unweighted odds ratio, 0.58; 95% confidence interval, 0.39–0.87; weighted odds ratio, 0.57; 95% confidence interval, 0.34–0.96). In contrast, glycated hemoglobin levels were not significantly associated with rupture status. Conclusions— Antihyperglycemic agent use rather than hyperglycemia is associated with decreased risk of aneurysmal subarachnoid hemorrhage, suggesting a possible protective effect of glucose-lowering agents in the pathogenesis of aneurysm rupture.

Background and Purpose— Growing evidence from experimental animal models and clinical studies suggests the protective effect of statin use against rupture of intracranial aneurysms; however, results from large studies detailing the relationship between intracranial aneurysm rupture and total cholesterol, HDL (high-density lipoprotein), LDL (low-density lipoprotein), and lipid-lowering agent use are lacking. Methods— The medical records of 4701 patients with 6411 intracranial aneurysms diagnosed at the Massachusetts General Hospital and the Brigham and Women’s Hospital between 1990 and 2016 were reviewed and analyzed. Patients were separated into ruptured and nonruptured groups. Univariable and multivariable logistic regression analyses were performed to determine the effects of lipids (total cholesterol, LDL, and HDL) and lipid-lowering medications on intracranial aneurysm rupture risk. Propensity score weighting was used to account for differences in baseline characteristics of the cohorts. Results— Lipid-lowering agent use was significantly inversely associated with rupture status (odds ratio, 0.58; 95% confidence interval, 0.47–0.71). In a subgroup analysis of complete cases that includes both lipid-lowering agent use and lipid values, higher HDL levels (odds ratio, 0.95; 95% confidence interval, 0.93–0.98) and lipid-lowering agent use (odds ratio, 0.41; 95% confidence interval, 0.23–0.73) were both significantly and inversely associated with rupture status, whereas total cholesterol and LDL levels were not significant. A monotonic exposure–response curve between HDL levels and risk of aneurysmal rupture was obtained. Conclusions— Higher HDL values and the use of lipid-lowering agents are significantly inversely associated with ruptured intracranial aneurysms.

While cocaine use is thought to be associated with aneurysmal rupture, it is not known whether heroin use increases the risk of rupture in patients with non-mycotic saccular aneurysms. Our goal was to investigate the association between heroin and cocaine use and the rupture of saccular non-mycotic aneurysms. The medical records of 4701 patients with 6411 intracranial aneurysms, including 1201 prospective patients, diagnosed at the Brigham and Women’s Hospital and Massachusetts General Hospital between 1990 and 2016 were reviewed and analyzed. Patients were separated into ruptured and non-ruptured groups. Univariable and multivariable logistic regression analyses were performed to determine the association between heroin, cocaine, and methadone use and the presence of ruptured intracranial aneurysms. In multivariable analysis, current heroin use was significantly associated with rupture status (OR 3.23, 95% CI 1.33–7.83) whereas former heroin use (with and without methadone replacement therapy), and current and former cocaine use were not significantly associated with intracranial aneurysm rupture. In the present study, heroin rather than cocaine use is significantly associated with intracranial aneurysm rupture in patients with non-mycotic saccular cerebral aneurysms, emphasizing the possible role of heroin in the pathophysiology of aneurysm rupture and the importance of heroin cessation in patients harboring unruptured intracranial aneurysms.

ObjectiveTo determine the association between ruptured saccular aneurysms and aspirin use/aspirin dose.MethodsFour thousand seven hundred one patients who were diagnosed at the Massachusetts General Hospital and Brigham and Women's Hospital between 1990 and 2016 with 6,411 unruptured and ruptured saccular intracranial aneurysms were evaluated. Univariable and multivariable logistic regression analyses were performed to determine the association between aneurysmal subarachnoid hemorrhage and aspirin use, including aspirin dose. Inverse probability weighting using propensity scores was used to adjust for potential differences in baseline characteristics between cases and controls. Additional analyses were performed to examine the association of aspirin use and rerupture before treatment.ResultsIn multivariate analysis with propensity score weighting, aspirin use (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.45–0.80) was significantly associated with decreased risk of ruptured intracranial aneurysms. There was a significant inverse dose-response relationship between aspirin dose and aneurysmal subarachnoid hemorrhage (OR 0.65, 95% CI 0.53–0.81). In contrast, there was a significant association between aspirin use and increased risk of rerupture before treatment (OR 8.15, 95% CI 2.22–30.0).ConclusionsIn this large case-control study, aspirin therapy at diagnosis was associated with a significantly decreased risk of subarachnoid hemorrhage, with an inverse dose-response relationship among aspirin users. However, once rupture has occurred, aspirin is associated with an increased risk of rerupture before treatment.

Alcohol consumption may be a modifiable risk factor for rupture of intracranial aneurysms. Our aim is to evaluate the association between ruptured aneurysms and alcohol consumption, intensity, and cessation. The medical records of 4701 patients with 6411 radiographically confirmed intracranial aneurysms diagnosed at the Brigham and Women's Hospital and Massachusetts General Hospital between 1990 and 2016 were reviewed. Individuals were divided into cases with ruptured aneurysms and controls with unruptured aneurysms. Univariable and multivariable logistic regression analyses were performed to determine the association between alcohol consumption and rupture of intracranial aneurysms. In multivariable analysis, current alcohol use (OR 1.36, 95% CI 1.17-1.58) was associated with rupture status compared with never drinkers, whereas former alcohol use was not significant (OR 1.23, 95% CI 0.92-1.63). In addition, the number of alcoholic beverages per day among current alcohol users (OR 1.13, 95% CI 1.04-1.23) was significantly associated with rupture status, whereas alcohol use intensity was not significant among former users (OR 1.02, 95% CI 0.94-1.11). Current alcohol use and intensity are significantly associated with intracranial aneurysm rupture. However, this increased risk does not persist in former alcohol users, emphasizing the potential importance of alcohol cessation in patients harboring unruptured aneurysms.

Electronic health record (EHR)-discontinuity, i.e., having medical information recorded outside of the study EHR system, is associated with substantial information bias in EHR-based comparative effectiveness research (CER). We aimed to develop and validate a prediction model identifying patients with high EHR-continuity to reduce this bias. Based on 183,739 patients aged ≥65 in EHRs from two US provider networks linked with Medicare claims data from 2007-2014, we quantified EHR-continuity by mean proportion of encounters captured (MPEC) by the EHR system. We built a prediction model for MPEC using one EHR system as training and the other as the validation set. Patients with top 20% predicted EHR-continuity had 3.5-5.8-fold smaller misclassification of 40 CER-relevant variables, compared to the remaining study population. The comorbidity profiles did not differ substantially by predicted EHR-continuity. These findings suggest that restriction of CER to patients with high predicted EHR-continuity may confer a favorable validity to generalizability trade-off.

Rationale Lysosomal associated membrane protein type-2 (LAMP-2) is a highly conserved, ubiquitous protein that is critical for autophagic flux. Loss of function mutations in the LAMP-2 gene cause Danon disease, a rare X-linked disorder characterized by developmental delay, skeletal muscle weakness, and severe cardiomyopathy. We previously found that human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from Danon patients exhibited significant mitochondrial oxidative stress and apoptosis. Understanding how loss of LAMP-2 expression leads to cardiomyocyte dysfunction and heart failure has important implications for the treatment of Danon disease as well as a variety of other cardiac disorders associated with impaired autophagy. Objective Elucidate the pathophysiology of cardiac dysfunction in Danon disease. Methods and results We created hiPSCs from two patients with Danon disease and differentiated those cells into hiPSC-CMs using well-established protocols. Danon hiPSC-CMs demonstrated an accumulation of damaged mitochondria, disrupted mitophagic flux, depressed mitochondrial respiratory capacity, and abnormal gene expression of key mitochondrial pathways. Restoring the expression of LAMP-2B, the most abundant LAMP-2 isoform in the heart, rescued mitophagic flux as well as mitochondrial health and bioenergetics. To confirm our findings in vivo, we evaluated Lamp-2 knockout (KO) mice. Impaired autophagic flux was noted in the Lamp-2 KO mice compared to WT reporter mice, as well as an increased number of abnormal mitochondria, evidence of incomplete mitophagy, and impaired mitochondrial respiration. Physiologically, Lamp-2 KO mice demonstrated early features of contractile dysfunction without overt heart failure, indicating that the metabolic abnormalities associated with Danon disease precede the development of end-stage disease and are not merely part of the secondary changes associated with heart failure. Conclusions Incomplete mitophagic flux and mitochondrial dysfunction are noted in both in vitro and in vivo models of Danon disease, and proceed overt cardiac contractile dysfunction. This suggests that impaired mitochondrial clearance may be central to the pathogenesis of disease and a potential target for therapeutic intervention.