Machine learning to understand risks for severe COVID-19 outcomes: a retrospective cohort study of immune-mediated inflammatory diseases, immunomodulatory medications, and comorbidities in a large US health-care system.

BACKGROUND: In the context of immune-mediated inflammatory diseases (IMIDs), COVID-19 outcomes are incompletely understood and vary considerably depending on the patient population studied. We aimed to analyse severe COVID-19 outcomes and to investigate the effects of the pandemic time period and the risks associated with individual IMIDs, classes of immunomodulatory medications (IMMs), chronic comorbidities, and COVID-19 vaccination status. METHODS: In this retrospective cohort study, clinical data were derived from the electronic health records of an integrated health-care system serving patients in 51 hospitals and 1085 clinics across seven US states (Providence St Joseph Health). Data were observed for patients (no age restriction) with one or more IMID and for unmatched controls without IMIDs. COVID-19 was identified with a positive nucleic acid amplification test result for SARS-CoV-2. Two timeframes were analysed: March 1, 2020-Dec 25, 2021 (pre-omicron period), and Dec 26, 2021-Aug 30, 2022 (omicron-predominant period). Primary outcomes were hospitalisation, mechanical ventilation, and mortality in patients with COVID-19. Factors, including IMID diagnoses, comorbidities, long-term use of IMMs, and COVID-19 vaccination status, were analysed with multivariable logistic regression (LR) and extreme gradient boosting (XGB). FINDINGS: Of 2 167 656 patients tested for SARS-CoV-2, 290 855 (13·4%) had confirmed COVID-19: 15 397 (5·3%) patients with IMIDs and 275 458 (94·7%) without IMIDs. In the pre-omicron period, 169 993 (11·2%) of 1 517 295 people who were tested for COVID-19 tested positive, of whom 23 330 (13·7%) were hospitalised, 1072 (0·6%) received mechanical ventilation, and 5294 (3·1%) died. Compared with controls, patients with IMIDs and COVID-19 had higher rates of hospitalisation (1176 [14·6%] vs 22 154 [13·7%]; p=0·024) and mortality (314 [3·9%] vs 4980 [3·1%]; p<0·0001). In the omicron-predominant period, 120 862 (18·6%) of 650 361 patients tested positive for COVID-19, of whom 14 504 (12·0%) were hospitalised, 567 (0·5%) received mechanical ventilation, and 2001 (1·7%) died. Compared with controls, patients with IMIDs and COVID-19 (7327 [17·3%] of 42 249) had higher rates of hospitalisation (13 422 [11·8%] vs 1082 [14·8%]; p<0·0001) and mortality (1814 [1·6%] vs 187 [2·6%]; p<0·0001). Age was a risk factor for worse outcomes (adjusted odds ratio [OR] from 2·1 [95% CI 2·0-2·1]; p<0·0001 to 3·0 [2·9-3·0]; p<0·0001), whereas COVID-19 vaccination (from 0·082 [0·080-0·085]; p<0·0001 to 0·52 [0·50-0·53]; p<0·0001) and booster vaccination (from 2·1 [2·0-2·2]; p<0·0001 to 3·0 [2·9-3·0]; p<0·0001) status were associated with better outcomes. Seven chronic comorbidities were significant risk factors during both time periods for all three outcomes: atrial fibrillation, coronary artery disease, heart failure, chronic kidney disease, chronic obstructive pulmonary disease, chronic liver disease, and cancer. Two IMIDs, asthma (adjusted OR from 0·33 [0·32-0·34]; p<0·0001 to 0·49 [0·48-0·51]; p<0·0001) and psoriasis (from 0·52 [0·48-0·56] to 0·80 [0·74-0·87]; p<0·0001), were associated with a reduced risk of severe outcomes. IMID diagnoses did not appear to be significant risk factors themselves, but results were limited by small sample size, and vasculitis had high feature importance in LR. IMMs did not appear to be significant, but less frequently used IMMs were limited by sample size. XGB outperformed LR, with the area under the receiver operating characteristic curve for models across different time periods and outcomes ranging from 0·77 to 0·92. INTERPRETATION: Our results suggest that age, chronic comorbidities, and not being fully vaccinated might be greater risk factors for severe COVID-19 outcomes in patients with IMIDs than the use of IMMs or the IMIDs themselves. Overall, there is a need to take age and comorbidities into consideration when developing COVID-19 guidelines for patients with IMIDs. Further research is needed for specific IMIDs (including IMID severity at the time of SARS-CoV-2 infection) and IMMs (considering dosage and timing before a patient's first COVID-19 infection). FUNDING: Pfizer, Novartis, Janssen, and the National Institutes of Health.

The neuronal chromatin landscape in adult schizophrenia brains is linked to early fetal development.

Non-coding variants increase risk of neuropsychiatric disease. However, our understanding of the cell-type specific role of the non-coding genome in disease is incomplete. We performed population scale (N=1,393) chromatin accessibility profiling of neurons and non-neurons from two neocortical brain regions: the anterior cingulate cortex and dorsolateral prefrontal cortex. Across both regions, we observed notable differences in neuronal chromatin accessibility between schizophrenia cases and controls. A per-sample disease pseudotime was positively associated with genetic liability for schizophrenia. Organizing chromatin into cis- and trans-regulatory domains, identified a prominent neuronal trans-regulatory domain (TRD1) active in immature glutamatergic neurons during fetal development. Polygenic risk score analysis using genetic variants within chromatin accessibility of TRD1 successfully predicted susceptibility to schizophrenia in the Million Veteran Program cohort. Overall, we present the most extensive resource to date of chromatin accessibility in the human cortex, yielding insights into the cell-type specific etiology of schizophrenia.

The neuronal chromatin landscape in adult schizophrenia brains is linked to early fetal development.

Non-coding variants increase risk of neuropsychiatric disease. However, our understanding of the cell-type specific role of the non-coding genome in disease is incomplete. We performed population scale (N=1,393) chromatin accessibility profiling of neurons and non-neurons from two neocortical brain regions: the anterior cingulate cortex and dorsolateral prefrontal cortex. Across both regions, we observed notable differences in neuronal chromatin accessibility between schizophrenia cases and controls. A per-sample disease pseudotime was positively associated with genetic liability for schizophrenia. Organizing chromatin into cis- and trans-regulatory domains, identified a prominent neuronal trans-regulatory domain (TRD1) active in immature glutamatergic neurons during fetal development. Polygenic risk score analysis using genetic variants within chromatin accessibility of TRD1 successfully predicted susceptibility to schizophrenia in the Million Veteran Program cohort. Overall, we present the most extensive resource to date of chromatin accessibility in the human cortex, yielding insights into the cell-type specific etiology of schizophrenia.

Risk factors for severe COVID-19 outcomes: a study of immune-mediated inflammatory diseases, immunomodulatory medications, and comorbidities in a large US healthcare system.

Background: COVID-19 outcomes, in the context of immune-mediated inflammatory diseases (IMIDs), are incompletely understood. Reported outcomes vary considerably depending on the patient population studied. It is essential to analyse data for a large population, while considering the effects of the pandemic time period, comorbidities, long term use of immunomodulatory medications (IMMs), and vaccination status. Methods: In this retrospective case-control study, patients of all ages with IMIDs were identified from a large U.S. healthcare system. COVID-19 infections were identified based on SARS-CoV-2 NAAT test results. Controls without IMIDs were selected from the same database. Severe outcomes were hospitalisation, mechanical ventilation (MV), and death. We analysed data from 1 March 2020 to 30 August 2022, looking separately at both pre-Omicron and Omicron predominant periods. Factors including IMID diagnoses, comorbidities, long term use of IMMs, and vaccination and booster status were analysed using multivariable logistic regression (LR) and extreme gradient boosting (XGB). Findings: Out of 2 167 656 patients tested for SARS-CoV-2, there were 290 855 with confirmed COVID-19 infection: 15 397 patients with IMIDs and 275 458 controls (patients without IMIDs). Age and most chronic comorbidities were risk factors for worse outcomes, whereas vaccination and boosters were protective. Patients with IMIDs had higher rates of hospitalisation and mortality compared with controls. However, in multivariable analyses, few IMIDs were rarely risk factors for worse outcomes. Further, asthma, psoriasis and spondyloarthritis were associated with reduced risk. Most IMMs had no significant association, but less frequently used IMM drugs were limited by sample size. XGB outperformed LR, with the AUROCs for models across different time periods and outcomes ranging from 0·77 to 0·92. Interpretation: For patients with IMIDs, as for controls, age and comorbidities were risk factors for worse COVID-19 outcomes, whereas vaccinations were protective. Most IMIDs and immunomodulatory therapies were not associated with more severe outcomes. Interestingly, asthma, psoriasis and spondyloarthritis were associated with less severe COVID-19 outcomes than those expected for the population overall. These results can help inform clinical, policy and research decisions. Funding: Pfizer, Novartis, Janssen, NIH.

Risk factors for severe COVID-19 differ by age for hospitalized adults.

Risk stratification for hospitalized adults with COVID-19 is essential to inform decisions about individual patients and allocation of resources. So far, risk models for severe COVID outcomes have included age but have not been optimized to best serve the needs of either older or younger adults. Models also need to be updated to reflect improvements in COVID-19 treatments. This retrospective study analyzed data from 6906 hospitalized adults with COVID-19 from a community health system across five states in the western United States. Risk models were developed to predict mechanical ventilation illness or death across one to 56 days of hospitalization, using clinical data available within the first hour after either admission with COVID-19 or a first positive SARS-CoV-2 test. For the seven-day interval, models for age ≥ 18 and < 50 years reached AUROC 0.81 (95% CI 0.71-0.91) and models for age ≥ 50 years reached AUROC 0.82 (95% CI 0.77-0.86). Models revealed differences in the statistical significance and relative predictive value of risk factors between older and younger patients including age, BMI, vital signs, and laboratory results. In addition, for hospitalized patients, sex and chronic comorbidities had lower predictive value than vital signs and laboratory results.

Angiotensin-Converting Enzyme (ACE) Inhibitors May Moderate COVID-19 Hyperinflammatory Response: An Observational Study with Deep Immunophenotyping.

Background: Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-II receptor blockers (ARB), the most commonly prescribed antihypertensive medications, counter renin-angiotensin-aldosterone system (RAAS) activation via induction of angiotensin-converting enzyme 2 (ACE2) expression. Considering that ACE2 is the functional receptor for SARS-CoV-2 entry into host cells, the association of ACEi and ARB with COVID-19 outcomes needs thorough evaluation. Methods: We conducted retrospective analyses using both unmatched and propensity score (PS)-matched cohorts on electronic health records (EHRs) to assess the impact of RAAS inhibitors on the risk of receiving invasive mechanical ventilation (IMV) and 30-day mortality among hospitalized COVID-19 patients. Additionally, we investigated the immune cell gene expression profiles of hospitalized COVID-19 patients with prior use of antihypertensive treatments from an observational prospective cohort. Results: The retrospective analysis revealed that there was no increased risk associated with either ACEi or ARB use. In fact, the use of ACEi showed decreased risk for mortality. Survival analyses using PS-matched cohorts suggested no significant relationship between RAAS inhibitors with a hospital stay and in-hospital mortality compared to non-RAAS medications and patients not on antihypertensive medications. From the analysis of gene expression profiles, we observed a noticeable up-regulation in the expression of 1L1R2 (an anti-inflammatory receptor) and RETN (an immunosuppressive marker) genes in monocytes among prior users of ACE inhibitors. Conclusion: Overall, the findings do not support the discontinuation of ACEi or ARB treatment and suggest that ACEi may moderate the COVID-19 hyperinflammatory response.

Development of video animations to encourage patient-driven deprescribing: A Team Alice Study.

OBJECTIVE: Patient-driven deprescribing initiatives aim to increase patient knowledge and strengthen self-advocacy skills. This article describes the development of three animated videos designed to educate older adults about unsafe prescribing and medication harm, based on the actionable lessons from the death, by polypharmacy, of an older adult in our community. METHODS: Using a community based participatory research approach (CBPR), members of three senior centers (n = 53) and the Deprescribing Partnership of Western New York (n = 30) were recruited and participated in two rounds of focus groups to guide the video development. RESULTS: Stakeholder input led to changes in content, wording, and visual presentation. The final versions of the videos emphasize the following messages (1) "New medications and what you should know about the risks", (2) "What you should do when a doctor tells you never to take a certain medication", (3) "What you should know about medications when you are in the hospital." CONCLUSION: The study highlights the successful process of using CBPR to develop a series of videos designed to provide information on the risks of polypharmacy, and empower older adults to advocate for themselves. PRACTICE IMPLICATIONS: Animated educational videos are a novel strategy to address medication harm in older adults. This research is a critical first step to increasing patient-led discussions that reduce the incidence of medication harm and inappropriate medication use among older adults.

Opportunities and Recommendations for Improving Medication Safety: Understanding the Medication Management System in Primary Care Through an Abstraction Hierarchy.

BACKGROUND: Despite making great strides in improving the treatment of diseases, the minimization of unintended harm by medication therapy continues to be a major hurdle facing the health care system. Medication error and prescription of potentially inappropriate medications (PIMs) represent a prevalent source of harm to patients and are associated with increased rates of adverse events, hospitalizations, and increased health care costs. Attempts to improve medication management systems in primary care have had mixed results. Implementation of new interventions is difficult because of complex contextual factors within the health care system. Abstraction hierarchy (AH), the first step in cognitive work analysis (CWA), is used by human factors practitioners to describe complex sociotechnical systems. Although initially intended for the nuclear power domain and interface design, AH has been used successfully to aid the redesign of numerous health care systems such as the design of decision support tools, mobile patient monitoring apps, and a telephone triage system. OBJECTIVE: This paper aims to refine our understanding of the primary care office in relation to a patient's medication through the development of an AH. Emphasis was placed on the elements related to medication safety to provide guidance for the design of a safer medication management system in primary care. METHODS: The AH development was guided by the methodology used by seminal CWA literature. It was initially developed by 2 authors and later fine-tuned by an expert panel of clinicians, social scientists, and a human factors engineer. It was subsequently refined until an agreement was reached. A means-ends analysis was performed and described for the nodes of interest. The model represents the primary care office space through functional purposes, values and priorities, function-related purposes, object-related processes, and physical objects. RESULTS: This model depicts the medication management system at various levels of abstraction. The resulting components must be balanced and coordinated to provide medical treatment with limited health care resources. Understanding the physical and informational constraints on activities that occur in a primary care office depicted in the AH defines areas in which medication safety can be improved. CONCLUSIONS: Numerous means-ends relationships were identified and analyzed. These can be further evaluated depending on the specific needs of the user. Recommendations for optimizing a medication management system in a primary care facility were made. Individual practices can use AH for clinical redesign to improve prescribing and deprescribing practices.

Interventions to deprescribe potentially inappropriate medications in the elderly: Lost in translation?

WHAT IS KNOWN AND OBJECTIVE: Use of potentially inappropriate medications (PIMs) remains common in older adults, despite the easy availability of screening tools such as the Beers and Screening Tool of Older Person's Prescriptions (STOPP) criteria. Multiple published studies have implemented these screening tools to encourage deprescribing of PIMs, with mixed results. Little is known about the reasons behind the success or failure of these interventions, or what could be done to improve their impact. Implementation science (IS) provides a set of theories, models and frameworks to address these questions. The goal of this study was to conduct a focused narrative review of the deprescribing literature through an IS lens-to determine the extent to which implementation factors were identified and the intermediate steps in the intervention were measured. A better understanding of the existing literature, including its gaps, may provide a roadmap for future research. METHODS: PubMed search from 2000-2019 using appropriate MeSH headings. INCLUSION CRITERIA: controlled trials or prospective cohort studies intended to reduce PIMs in the elderly that used hospitalizations and/or emergency department visits as outcome measures. Studies were reviewed to identify potential implementation factors (known as determinants), using the Consolidated Framework for Implementation Research (CFIR) as a guide. In addition, intermediate outcomes were extracted. RESULTS AND DISCUSSION: Of the 548 reviewed abstracts, 14 studies met the inclusion criteria and underwent detailed analysis. Of the 14 studies, 10 acknowledged potential implementation determinants that could be mapped onto CFIR. The most commonly identified determinant was the degree of pharmacist integration into the medical team (seven of 14 studies), which mapped onto the CFIR construct of 'networks and communication'. Several important CFIR constructs were absent in the reviewed literature. Intermediate measures were captured by 12 of the 14 reviewed papers, but the choice of measures was inconsistent across studies. WHAT IS NEW AND CONCLUSION: In recent high-quality studies of deprescribing interventions, we found limited acknowledgement of factors known to be important to successful implementation and inconsistent reporting of intermediate outcomes. These findings indicate missed opportunities to understand the factors underlying study outcomes. As a result, we run the risk of rejecting worthwhile interventions due to negative results, when the correct interpretation might be that they failed in implementation. In other words, they were 'lost in translation'. Studies that rigorously examine and report on the implementation process are needed to tease apart this important distinction.

Gallbladder Fossa Abscess Masquerading as Cholecystitis After Cholecystectomy.

We present a case of a 59-y-old woman who had undergone cholecystectomy and was subsequently found to have an abscess within the gallbladder fossa. A hepatobiliary scan using (99m)Tc-diisopropyliminodiacetic acid demonstrated the characteristic rim sign, a photopenic defect surrounded by a rim of mildly increased activity immediately adjacent to the gallbladder fossa. The rim sign was thought to be the result of reactive inflammation in the hepatic tissue adjacent to a postoperative abscess within the gallbladder fossa.