Community-engaged artificial intelligence research: A scoping review.

The degree to which artificial intelligence healthcare research is informed by data and stakeholders from community settings has not been previously described. As communities are the principal location of healthcare delivery, engaging them could represent an important opportunity to improve scientific quality. This scoping review systematically maps what is known and unknown about community-engaged artificial intelligence research and identifies opportunities to optimize the generalizability of these applications through involvement of community stakeholders and data throughout model development, validation, and implementation. Embase, PubMed, and MEDLINE databases were searched for articles describing artificial intelligence or machine learning healthcare applications with community involvement in model development, validation, or implementation. Model architecture and performance, the nature of community engagement, and barriers or facilitators to community engagement were reported according to PRISMA extension for Scoping Reviews guidelines. Of approximately 10,880 articles describing artificial intelligence healthcare applications, 21 (0.2%) described community involvement. All articles derived data from community settings, most commonly by leveraging existing datasets and sources that included community subjects, and often bolstered by internet-based data acquisition and subject recruitment. Only one article described inclusion of community stakeholders in designing an application-a natural language processing model that detected cases of likely child abuse with 90% accuracy using harmonized electronic health record notes from both hospital and community practice settings. The primary barrier to including community-derived data was small sample sizes, which may have affected 11 of the 21 studies (53%), introducing substantial risk for overfitting that threatens generalizability. Community engagement in artificial intelligence healthcare application development, validation, or implementation is rare. As healthcare delivery occurs primarily in community settings, investigators should consider engaging community stakeholders in user-centered design, usability, and clinical implementation studies to optimize generalizability.

Cannabis Use and Inhalational Anesthesia Administration in Older Adults: A Propensity-matched Retrospective Cohort Study.

BACKGROUND: Cannabis use is associated with higher intravenous anesthetic administration. Similar data regarding inhalational anesthetics are limited. With rising cannabis use prevalence, understanding any potential relationship with inhalational anesthetic dosing is crucial. Average intraoperative isoflurane or sevoflurane minimum alveolar concentration equivalents between older adults with and without cannabis use were compared. METHODS: The electronic health records of 22,476 surgical patients 65 yr or older at the University of Florida Health System between 2018 and 2020 were reviewed. The primary exposure was cannabis use within 60 days of surgery, determined via (1) a previously published natural language processing algorithm applied to unstructured notes and (2) structured data, including International Classification of Diseases codes for cannabis use disorders and poisoning by cannabis, laboratory cannabinoids screening results, and RxNorm codes. The primary outcome was the intraoperative time-weighted average of isoflurane or sevoflurane minimum alveolar concentration equivalents at 1-min resolution. No a priori minimally clinically important difference was established. Patients demonstrating cannabis use were matched 4:1 to non-cannabis use controls using a propensity score. RESULTS: Among 5,118 meeting inclusion criteria, 1,340 patients (268 cannabis users and 1,072 nonusers) remained after propensity score matching. The median and interquartile range age was 69 (67 to 73) yr; 872 (65.0%) were male, and 1,143 (85.3%) were non-Hispanic White. The median (interquartile range) anesthesia duration was 175 (118 to 268) min. After matching, all baseline characteristics were well-balanced by exposure. Cannabis users had statistically significantly higher average minimum alveolar concentrations than nonusers (mean ± SD, 0.58 ± 0.23 vs. 0.54 ± 0.22, respectively; mean difference, 0.04; 95% confidence limits, 0.01 to 0.06; P = 0.020). CONCLUSION: Cannabis use was associated with administering statistically significantly higher inhalational anesthetic minimum alveolar concentration equivalents in older adults, but the clinical significance of this difference is unclear. These data do not support the hypothesis that cannabis users require clinically meaningfully higher inhalational anesthetics doses.

Cannabis use and acute postoperative pain outcomes in older adults: a propensity matched retrospective cohort study.

INTRODUCTION: Cannabis use is increasing among older adults, but its impact on postoperative pain outcomes remains unclear in this population. We examined the association between cannabis use and postoperative pain levels and opioid doses within 24 hours of surgery. METHODS: We conducted a propensity score-matched retrospective cohort study using electronic health records data of 22 476 older surgical patients with at least 24-hour hospital stays at University of Florida Health between 2018 and 2020. Of the original cohort, 2577 patients were eligible for propensity-score matching (1:3 cannabis user: non-user). Cannabis use status was determined via natural language processing of clinical notes within 60 days of surgery and structured data. The primary outcomes were average Defense and Veterans Pain Rating Scale (DVPRS) score and total oral morphine equivalents (OME) within 24 hours of surgery. RESULTS: 504 patients were included (126 cannabis users and 378 non-users). The median (IQR) age was 69 (65-72) years; 295 (58.53%) were male, and 442 (87.70%) were non-Hispanic white. Baseline characteristics were well balanced. Cannabis users had significantly higher average DVPRS scores (median (IQR): 4.68 (2.71-5.96) vs 3.88 (2.33, 5.17); difference=0.80; 95% confidence limit (CL), 0.19 to 1.36; p=0.01) and total OME (median (IQR): 42.50 (15.00-60.00) mg vs 30.00 (7.50-60.00) mg; difference=12.5 mg; 95% CL, 3.80 mg to 21.20 mg; p=0.02) than non-users within 24 hours of surgery. DISCUSSION: This study showed that cannabis use in older adults was associated with increased postoperative pain levels and opioid doses.

Association of Sociodemographic Factors With Overtriage, Undertriage, and Value of Care After Major Surgery.

Objective: To determine whether certain patients are vulnerable to errant triage decisions immediately after major surgery and whether there are unique sociodemographic phenotypes within overtriaged and undertriaged cohorts. Background: In a fair system, overtriage of low-acuity patients to intensive care units (ICUs) and undertriage of high-acuity patients to general wards would affect all sociodemographic subgroups equally. Methods: This multicenter, longitudinal cohort study of hospital admissions immediately after major surgery compared hospital mortality and value of care (risk-adjusted mortality/total costs) across 4 cohorts: overtriage (N = 660), risk-matched overtriage controls admitted to general wards (N = 3077), undertriage (N = 2335), and risk-matched undertriage controls admitted to ICUs (N = 4774). K-means clustering identified sociodemographic phenotypes within overtriage and undertriage cohorts. Results: Compared with controls, overtriaged admissions had a predominance of male patients (56.2% vs 43.1%, P < 0.001) and commercial insurance (6.4% vs 2.5%, P < 0.001); undertriaged admissions had a predominance of Black patients (28.4% vs 24.4%, P < 0.001) and greater socioeconomic deprivation. Overtriage was associated with increased total direct costs [$16.2K ($11.4K-$23.5K) vs $14.1K ($9.1K-$20.7K), P < 0.001] and low value of care; undertriage was associated with increased hospital mortality (1.5% vs 0.7%, P = 0.002) and hospice care (2.2% vs 0.6%, P < 0.001) and low value of care. Unique sociodemographic phenotypes within both overtriage and undertriage cohorts had similar outcomes and value of care, suggesting that triage decisions, rather than patient characteristics, drive outcomes and value of care. Conclusions: Postoperative triage decisions should ensure equality across sociodemographic groups by anchoring triage decisions to objective patient acuity assessments, circumventing cognitive shortcuts and mitigating bias.

Human IPSC-Derived PreBötC-Like Neurons and Development of an Opiate Overdose and Recovery Model.

Opioid overdose is the leading cause of drug overdose lethality, posing an urgent need for investigation. The key brain region for inspiratory rhythm regulation and opioid-induced respiratory depression (OIRD) is the preBötzinger Complex (preBötC) and current knowledge has mainly been obtained from animal systems. This study aims to establish a protocol to generate human preBötC neurons from induced pluripotent cells (iPSCs) and develop an opioid overdose and recovery model utilizing these iPSC-preBötC neurons. A de novo protocol to differentiate preBötC-like neurons from human iPSCs is established. These neurons express essential preBötC markers analyzed by immunocytochemistry and demonstrate expected electrophysiological responses to preBötC modulators analyzed by patch clamp electrophysiology. The correlation of the specific biomarkers and function analysis strongly suggests a preBötC-like phenotype. Moreover, the dose-dependent inhibition of these neurons' activity is demonstrated for four different opioids with identified IC50's comparable to the literature. Inhibition is rescued by naloxone in a concentration-dependent manner. This iPSC-preBötC mimic is crucial for investigating OIRD and combating the overdose crisis and a first step for the integration of a functional overdose model into microphysiological systems.

Increasing SARS-CoV-2 seroprevalence among UK pediatric patients on dialysis and kidney transplantation between January 2020 and August 2021.

BACKGROUND: Coronavirus disease 2019 (COVID-19) was officially declared a pandemic by the World Health Organisation (WHO) on 11 March 2020, as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread rapidly across the world. We investigated the seroprevalence of anti-SARS-CoV-2 antibodies in pediatric patients on dialysis or kidney transplantation in the UK. METHODS: Excess sera samples were obtained prospectively during outpatient visits or haemodialysis sessions and analysed using a custom immunoassay calibrated with population age-matched healthy controls. Two large pediatric centres contributed samples. RESULTS: In total, 520 sera from 145 patients (16 peritoneal dialysis, 16 haemodialysis, 113 transplantation) were analysed cross-sectionally from January 2020 until August 2021. No anti-SARS-CoV-2 antibody positive samples were detected in 2020 when lockdown and enhanced social distancing measures were enacted. Thereafter, the proportion of positive samples increased from 5% (January 2021) to 32% (August 2021) following the emergence of the Alpha variant. Taking all patients, 32/145 (22%) were seropositive, including 8/32 (25%) with prior laboratory-confirmed SARS-CoV-2 infection and 12/32 (38%) post-vaccination (one of whom was also infected after vaccination). The remaining 13 (41%) seropositive patients had no known stimulus, representing subclinical cases. Antibody binding signals were comparable across patient ages and dialysis versus transplantation and highest against full-length spike protein versus spike subunit-1 and nucleocapsid protein. CONCLUSIONS: Anti-SARS-CoV-2 seroprevalence was low in 2020 and increased in early 2021. Serological surveillance complements nucleic acid detection and antigen testing to build a greater picture of the epidemiology of COVID-19 and is therefore important to guide public health responses. A higher resolution version of the Graphical abstract is available as Supplementary information.

Developing and validating a natural language processing algorithm to extract preoperative cannabis use status documentation from unstructured narrative clinical notes.

OBJECTIVE: This study aimed to develop a natural language processing algorithm (NLP) using machine learning (ML) techniques to identify and classify documentation of preoperative cannabis use status. MATERIALS AND METHODS: We developed and applied a keyword search strategy to identify documentation of preoperative cannabis use status in clinical documentation within 60 days of surgery. We manually reviewed matching notes to classify each documentation into 8 different categories based on context, time, and certainty of cannabis use documentation. We applied 2 conventional ML and 3 deep learning models against manual annotation. We externally validated our model using the MIMIC-III dataset. RESULTS: The tested classifiers achieved classification results close to human performance with up to 93% and 94% precision and 95% recall of preoperative cannabis use status documentation. External validation showed consistent results with up to 94% precision and recall. DISCUSSION: Our NLP model successfully replicated human annotation of preoperative cannabis use documentation, providing a baseline framework for identifying and classifying documentation of cannabis use. We add to NLP methods applied in healthcare for clinical concept extraction and classification, mainly concerning social determinants of health and substance use. Our systematically developed lexicon provides a comprehensive knowledge-based resource covering a wide range of cannabis-related concepts for future NLP applications. CONCLUSION: We demonstrated that documentation of preoperative cannabis use status could be accurately identified using an NLP algorithm. This approach can be employed to identify comparison groups based on cannabis exposure for growing research efforts aiming to guide cannabis-related clinical practices and policies.

Applications of Artificial Intelligence in the Radiology Roundtrip: Process Streamlining, Workflow Optimization, and Beyond.

There are many impactful applications of artificial intelligence (AI) in the electronic radiology roundtrip and the patient's journey through the healthcare system that go beyond diagnostic applications. These tools have the potential to improve quality and safety, optimize workflow, increase efficiency, and increase patient satisfaction. In this article, we review the role of AI for process improvement and workflow enhancement which includes applications beginning from the time of order entry, scan acquisition, applications supporting the image interpretation task, and applications supporting tasks after image interpretation such as result communication. These non-diagnostic workflow and process optimization tasks are an important part of the arsenal of potential AI tools that can streamline day to day clinical practice and patient care.

Predictive Modeling for Readmission to Intensive Care: A Systematic Review.

To evaluate the methodologic rigor and predictive performance of models predicting ICU readmission; to understand the characteristics of ideal prediction models; and to elucidate relationships between appropriate triage decisions and patient outcomes. DATA SOURCES: PubMed, Web of Science, Cochrane, and Embase. STUDY SELECTION: Primary literature that reported the development or validation of ICU readmission prediction models within from 2010 to 2021. DATA EXTRACTION: Relevant study information was extracted independently by two authors using the Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies checklist. Bias was evaluated using the Prediction model Risk Of Bias ASsessment Tool. Data sources, modeling methodology, definition of outcomes, performance, and risk of bias were critically evaluated to elucidate relevant relationships. DATA SYNTHESIS: Thirty-three articles describing models were included. Six studies had a high overall risk of bias due to improper inclusion criteria or omission of critical analysis details. Four other studies had an unclear overall risk of bias due to lack of detail describing the analysis. Overall, the most common (50% of studies) source of bias was the filtering of candidate predictors via univariate analysis. The poorest performing models used existing clinical risk or acuity scores such as Acute Physiologic Assessment and Chronic Health Evaluation II, Sequential Organ Failure Assessment, or Stability and Workload Index for Transfer as the sole predictor. The higher-performing ICU readmission prediction models used homogenous patient populations, specifically defined outcomes, and routinely collected predictors that were analyzed over time. CONCLUSIONS: Models predicting ICU readmission can achieve performance advantages by using longitudinal time series modeling, homogenous patient populations, and predictor variables tailored to those populations.

Building an automated, machine learning-enabled platform for predicting post-operative complications.

Objective. In 2019, the University of Florida College of Medicine launched theMySurgeryRiskalgorithm to predict eight major post-operative complications using automatically extracted data from the electronic health record.Approach. This project was developed in parallel with our Intelligent Critical Care Center and represents a culmination of efforts to build an efficient and accurate model for data processing and predictive analytics.Main Results and Significance. This paper discusses how our model was constructed and improved upon. We highlight the consolidation of the database, processing of fixed and time-series physiologic measurements, development and training of predictive models, and expansion of those models into different aspects of patient assessment and treatment. We end by discussing future directions of the model.

Overtriage, Undertriage, and Value of Care after Major Surgery: An Automated, Explainable Deep Learning-Enabled Classification System.

BACKGROUND: In single-institution studies, overtriaging low-risk postoperative patients to ICUs has been associated with a low value of care; undertriaging high-risk postoperative patients to general wards has been associated with increased mortality and morbidity. This study tested the reproducibility of an automated postoperative triage classification system to generating an actionable, explainable decision support system. STUDY DESIGN: This longitudinal cohort study included adults undergoing inpatient surgery at two university hospitals. Triage classifications were generated by an explainable deep learning model using preoperative and intraoperative electronic health record features. Nearest neighbor algorithms identified risk-matched controls. Primary outcomes were mortality, morbidity, and value of care (inverted risk-adjusted mortality/total direct costs). RESULTS: Among 4,669 ICU admissions, 237 (5.1%) were overtriaged. Compared with 1,021 control ward admissions, overtriaged admissions had similar outcomes but higher costs ($15.9K [interquartile range $9.8K to $22.3K] vs $10.7K [$7.0K to $17.6K], p < 0.001) and lower value of care (0.2 [0.1 to 0.3] vs 1.5 [0.9 to 2.2], p < 0.001). Among 8,594 ward admissions, 1,029 (12.0%) were undertriaged. Compared with 2,498 control ICU admissions, undertriaged admissions had longer hospital length-of-stays (6.4 [3.4 to 12.4] vs 5.4 [2.6 to 10.4] days, p < 0.001); greater incidence of hospital mortality (1.7% vs 0.7%, p = 0.03), cardiac arrest (1.4% vs 0.5%, p = 0.04), and persistent acute kidney injury without renal recovery (5.2% vs 2.8%, p = 0.002); similar costs ($21.8K [$13.3K to $34.9K] vs $21.9K [$13.1K to $36.3K]); and lower value of care (0.8 [0.5 to 1.3] vs 1.2 [0.7 to 2.0], p < 0.001). CONCLUSIONS: Overtriage was associated with low value of care; undertriage was associated with both low value of care and increased mortality and morbidity. The proposed framework for generating automated postoperative triage classifications is reproducible.

Cysteine-Selective Modification of Peptides and Proteins via Desulfurative C-C Bond Formation.

The site-selective modification of peptides and proteins facilitates the preparation of targeted therapeutic agents and tools to interrogate biochemical pathways. Among the numerous bioconjugation techniques developed to install groups of interest, those that generate C(sp3 )-C(sp3 ) bonds are significantly underrepresented despite affording proteolytically stable, biogenic linkages. Herein, a visible-light-mediated reaction is described that enables the site-selective modification of peptides and proteins via desulfurative C(sp3 )-C(sp3 ) bond formation. The reaction is rapid and high yielding in peptide systems, with comparable translation to proteins. Using this chemistry, a range of moieties is installed into model systems and an effective PTM-mimic is successfully integrated into a recombinantly expressed histone.

Postoperative Overtriage to an Intensive Care Unit Is Associated With Low Value of Care.

OBJECTIVE: We test the hypothesis that for low-acuity surgical patients, postoperative intensive care unit (ICU) admission is associated with lower value of care compared with ward admission. BACKGROUND: Overtriaging low-acuity patients to ICU consumes valuable resources and may not confer better patient outcomes. Associations among postoperative overtriage, patient outcomes, costs, and value of care have not been previously reported. METHODS: In this longitudinal cohort study, postoperative ICU admissions were classified as overtriaged or appropriately triaged according to machine learning-based patient acuity assessments and requirements for immediate postoperative mechanical ventilation or vasopressor support. The nearest neighbors algorithm identified risk-matched control ward admissions. The primary outcome was value of care, calculated as inverse observed-to-expected mortality ratios divided by total costs. RESULTS: Acuity assessments had an area under the receiver operating characteristic curve of 0.92 in generating predictions for triage classifications. Of 8592 postoperative ICU admissions, 423 (4.9%) were overtriaged. These were matched with 2155 control ward admissions with similar comorbidities, incidence of emergent surgery, immediate postoperative vital signs, and do not resuscitate order placement and rescindment patterns. Compared with controls, overtraiged admissions did not have a lower incidence of any measured complications. Total costs for admission were $16.4K for overtriage and $15.9K for controls ( P =0.03). Value of care was lower for overtriaged admissions [2.9 (2.0-4.0)] compared with controls [24.2 (14.1-34.5), P <0.001]. CONCLUSIONS: Low-acuity postoperative patients who were overtriaged to ICUs had increased total costs, no improvements in outcomes, and received low-value care.

Ideal algorithms in healthcare: Explainable, dynamic, precise, autonomous, fair, and reproducible.

Established guidelines describe minimum requirements for reporting algorithms in healthcare; it is equally important to objectify the characteristics of ideal algorithms that confer maximum potential benefits to patients, clinicians, and investigators. We propose a framework for ideal algorithms, including 6 desiderata: explainable (convey the relative importance of features in determining outputs), dynamic (capture temporal changes in physiologic signals and clinical events), precise (use high-resolution, multimodal data and aptly complex architecture), autonomous (learn with minimal supervision and execute without human input), fair (evaluate and mitigate implicit bias and social inequity), and reproducible (validated externally and prospectively and shared with academic communities). We present an ideal algorithms checklist and apply it to highly cited algorithms. Strategies and tools such as the predictive, descriptive, relevant (PDR) framework, the Standard Protocol Items: Recommendations for Interventional Trials-Artificial Intelligence (SPIRIT-AI) extension, sparse regression methods, and minimizing concept drift can help healthcare algorithms achieve these objectives, toward ideal algorithms in healthcare.

Multi-dimensional patient acuity estimation with longitudinal EHR tokenization and flexible transformer networks.

Transformer model architectures have revolutionized the natural language processing (NLP) domain and continue to produce state-of-the-art results in text-based applications. Prior to the emergence of transformers, traditional NLP models such as recurrent and convolutional neural networks demonstrated promising utility for patient-level predictions and health forecasting from longitudinal datasets. However, to our knowledge only few studies have explored transformers for predicting clinical outcomes from electronic health record (EHR) data, and in our estimation, none have adequately derived a health-specific tokenization scheme to fully capture the heterogeneity of EHR systems. In this study, we propose a dynamic method for tokenizing both discrete and continuous patient data, and present a transformer-based classifier utilizing a joint embedding space for integrating disparate temporal patient measurements. We demonstrate the feasibility of our clinical AI framework through multi-task ICU patient acuity estimation, where we simultaneously predict six mortality and readmission outcomes. Our longitudinal EHR tokenization and transformer modeling approaches resulted in more accurate predictions compared with baseline machine learning models, which suggest opportunities for future multimodal data integrations and algorithmic support tools using clinical transformer networks.

Phenotype clustering in health care: A narrative review for clinicians.

Human pathophysiology is occasionally too complex for unaided hypothetical-deductive reasoning and the isolated application of additive or linear statistical methods. Clustering algorithms use input data patterns and distributions to form groups of similar patients or diseases that share distinct properties. Although clinicians frequently perform tasks that may be enhanced by clustering, few receive formal training and clinician-centered literature in clustering is sparse. To add value to clinical care and research, optimal clustering practices require a thorough understanding of how to process and optimize data, select features, weigh strengths and weaknesses of different clustering methods, select the optimal clustering method, and apply clustering methods to solve problems. These concepts and our suggestions for implementing them are described in this narrative review of published literature. All clustering methods share the weakness of finding potential clusters even when natural clusters do not exist, underscoring the importance of applying data-driven techniques as well as clinical and statistical expertise to clustering analyses. When applied properly, patient and disease phenotype clustering can reveal obscured associations that can help clinicians understand disease pathophysiology, predict treatment response, and identify patients for clinical trial enrollment.

Perioperative Use of Gabapentinoids and Risk for Postoperative Long-Term Opioid Use in Older Adults Undergoing Total Knee or Hip Arthroplasty.

BACKGROUND: Gabapentinoids are recommended by guidelines as a component of multimodal analgesia to manage postoperative pain and reduce opioid use. It remains unknown whether perioperative use of gabapentinoids is associated with a reduced or increased risk of postoperative long-term opioid use (LTOU) after total knee or hip arthroplasty (TKA/THA). METHODS: Using Medicare claims data from 2011 to 2018, we identified fee-for-service beneficiaries aged ≥ 65 years who were hospitalized for a primary TKA/THA and had no LTOU before the surgery. Perioperative use of gabapentinoids was measured from 7 days preadmission through 7 days postdischarge. Patients were required to receive opioids during the perioperative period and were followed from day 7 postdischarge for 180 days to assess postoperative LTOU (ie, ≥90 consecutive days). A modified Poisson regression was used to estimate the relative risk (RR) of postoperative LTOU in patients with versus without perioperative use of gabapentinoids, adjusting for confounders through propensity score weighting. RESULTS: Of 52,788 eligible Medicare older beneficiaries (mean standard deviation [SD] age 72.7 [5.3]; 62.5% females; 89.7% White), 3,967 (7.5%) received gabapentinoids during the perioperative period. Postoperative LTOU was 3.8% in patients with and 4.0% in those without perioperative gabapentinoids. After adjusting for confounders, the risk of postoperative LTOU was similar comparing patients with versus without perioperative gabapentinoids (RR = 1.07; 95% confidence interval [CI] = 0.91-1.26, P = .408). Sensitivity and bias analyses yielded consistent results. CONCLUSION: Among older Medicare beneficiaries undergoing a primary TKA/THA, perioperative use of gabapentinoids was not associated with a reduced or increased risk for postoperative LTOU.

Concurrent use of prescription gabapentinoids with opioids and risk for fall-related injury among older US Medicare beneficiaries with chronic noncancer pain: A population-based cohort study.

BACKGROUND: Gabapentinoids are increasingly prescribed to manage chronic noncancer pain (CNCP) in older adults. When used concurrently with opioids, gabapentinoids may potentiate central nervous system (CNS) depression and increase the risks for fall. We aimed to investigate whether concurrent use of gabapentinoids with opioids compared with use of opioids alone is associated with an increased risk of fall-related injury among older adults with CNCP. METHODS AND FINDINGS: We conducted a population-based cohort study using a 5% national sample of Medicare beneficiaries in the United States between 2011 and 2018. Study sample consisted of fee-for-service (FFS) beneficiaries aged ≥65 years with CNCP diagnosis who initiated opioids. We identified concurrent users with gabapentinoids and opioids days' supply overlapping for ≥1 day and designated first day of concurrency as the index date. We created 2 cohorts based on whether concurrent users initiated gabapentinoids on the day of opioid initiation (Cohort 1) or after opioid initiation (Cohort 2). Each concurrent user was matched to up to 4 opioid-only users on opioid initiation date and index date using risk set sampling. We followed patients from index date to first fall-related injury event ascertained using a validated claims-based algorithm, treatment discontinuation or switching, death, Medicare disenrollment, hospitalization or nursing home admission, or end of study, whichever occurred first. In each cohort, we used propensity score (PS) weighted Cox models to estimate the adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) of fall-related injury, adjusting for year of the index date, sociodemographics, types of chronic pain, comorbidities, frailty, polypharmacy, healthcare utilization, use of nonopioid medications, and opioid use on and before the index date. We identified 6,733 concurrent users and 27,092 matched opioid-only users in Cohort 1 and 5,709 concurrent users and 22,388 matched opioid-only users in Cohort 2. The incidence rate of fall-related injury was 24.5 per 100 person-years during follow-up (median, 9 days; interquartile range [IQR], 5 to 18 days) in Cohort 1 and was 18.0 per 100 person-years during follow-up (median, 9 days; IQR, 4 to 22 days) in Cohort 2. Concurrent users had similar risk of fall-related injury as opioid-only users in Cohort 1(aHR = 0.97, 95% CI 0.71 to 1.34, p = 0.874), but had higher risk for fall-related injury than opioid-only users in Cohort 2 (aHR = 1.69, 95% CI 1.17 to 2.44, p = 0.005). Limitations of this study included confounding due to unmeasured factors, unavailable information on gabapentinoids' indication, potential misclassification, and limited generalizability beyond older adults insured by Medicare FFS program. CONCLUSIONS: In this sample of older Medicare beneficiaries with CNCP, initiating gabapentinoids and opioids simultaneously compared with initiating opioids only was not significantly associated with risk for fall-related injury. However, addition of gabapentinoids to an existing opioid regimen was associated with increased risks for fall. Mechanisms for the observed excess risk, whether pharmacological or because of channeling of combination therapy to high-risk patients, require further investigation. Clinicians should consider the risk-benefit of combination therapy when prescribing gabapentinoids concurrently with opioids.

HLA-DR polymorphism in SARS-CoV-2 infection and susceptibility to symptomatic COVID-19.

SARS-CoV-2 infection results in different outcomes ranging from asymptomatic infection to mild or severe disease and death. Reasons for this diversity of outcome include differences in challenge dose, age, gender, comorbidity and host genomic variation. Human leukocyte antigen (HLA) polymorphisms may influence immune response and disease outcome. We investigated the association of HLAII alleles with case definition symptomatic COVID-19, virus-specific antibody and T-cell immunity. A total of 1364 UK healthcare workers (HCWs) were recruited during the first UK SARS-CoV-2 wave and analysed longitudinally, encompassing regular PCR screening for infection, symptom reporting, imputation of HLAII genotype and analysis for antibody and T-cell responses to nucleoprotein (N) and spike (S). Of 272 (20%) HCW who seroconverted, the presence of HLA-DRB1*13:02 was associated with a 6·7-fold increased risk of case definition symptomatic COVID-19. In terms of immune responsiveness, HLA-DRB1*15:02 was associated with lower nucleocapsid T-cell responses. There was no association between DRB1 alleles and anti-spike antibody titres after two COVID vaccine doses. However, HLA DRB1*15:01 was associated with increased spike T-cell responses following both first and second dose vaccination. Trial registration: NCT04318314 and ISRCTN15677965.

Serum Levels of Proinflammatory Lipid Mediators and Specialized Proresolving Molecules Are Increased in Patients With Severe Acute Respiratory Syndrome Coronavirus 2 and Correlate With Markers of the Adaptive Immune Response.

BACKGROUND: Specialized proresolution molecules (SPMs) halt the transition to chronic pathogenic inflammation. We aimed to quantify serum levels of pro- and anti-inflammatory bioactive lipids in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients, and to identify potential relationships with innate responses and clinical outcome. METHODS: Serum from 50 hospital admitted inpatients (22 female, 28 male) with confirmed symptomatic SARS-CoV-2 infection and 94 age- and sex-matched controls collected prior to the pandemic (SARS-CoV-2 negative), were processed for quantification of bioactive lipids and anti-nucleocapsid and anti-spike quantitative binding assays. RESULTS: SARS-CoV-2 serum had significantly higher concentrations of omega-6-derived proinflammatory lipids and omega-6- and omega-3-derived SPMs, compared to the age- and sex-matched SARS-CoV-2-negative group, which were not markedly altered by age or sex. There were significant positive correlations between SPMs, proinflammatory bioactive lipids, and anti-spike antibody binding. Levels of some SPMs were significantly higher in patients with an anti-spike antibody value >0.5. Levels of linoleic acid and 5,6-dihydroxy-8Z,11Z,14Z-eicosatrienoic acid were significantly lower in SARS-CoV-2 patients who died. CONCLUSIONS: SARS-CoV-2 infection was associated with increased levels of SPMs and other pro- and anti-inflammatory bioactive lipids, supporting the future investigation of the underlying enzymatic pathways, which may inform the development of novel treatments.