Comparison of Short-Term Health Care Utilization Between Telemedicine-Delivered vs In-Person Care Visits for Heart Failure.

Background: Patients with heart failure (HF) are a medically complex population with frequent hospitalizations. Downstream health care utilization following primary care delivered by telemedicine compared to in-person is unknown. Objectives: The purpose of this study was to understand differences in return in-person visits, emergency department (ED) encounters, and hospitalizations following a telemedicine vs an in-person primary care visit for patients with HF seen for a HF-related complaint. Methods: This was an observational study of all primary care visits for HF from January 1, 2022, to December 31, 2022, in an integrated health care delivery system. We compared 7-day in-person follow-up visits, ED visits, and hospitalizations (all-cause and HF-specific) by index visit type. Results: We included 3,902 primary care visits with a primary diagnosis of HF. Most visits utilized telephone or video visits (58.4% total; 44.9% telephone, 13.5% video). After adjustment, telephone visits were associated with more in-person follow-up visits (6.14% vs 4.20%; adjusted OR: 1.08-2.21; P < 0.05) but fewer ED visits (6.12% vs 8.07%; adjusted OR: 0.55-0.97; P < 0.05) compared to in-person visits. Most hospitalized patients (74%) had an admitting diagnosis of HF. There was no difference between 7-day all-cause hospitalization following telephone or video visits compared to in-person visits. Conclusions: Most patients used telemedicine to address HF-specific primary care concerns. Telephone visits were associated with slightly higher short-term in-person primary care follow-up but lower ED utilization. Overall, downstream ED visits and hospitalizations were low. Telephone and video visits appear to offer safe alternatives to in-person care for HF-related primary care and are a promising health care delivery strategy.

Association Between Cardiovascular Health Status and Healthcare Utilization in a Large Integrated Healthcare System.

Introduction: The American Heart Association Life's Simple 7 schema can be used to categorize patients' cardiovascular health status as poor, intermediate, or ideal on the basis of smoking, BMI, physical activity, dietary patterns, blood pressure, cholesterol, and fasting blood sugar. This study examined the association between cardiovascular health status and subsequent healthcare utilization. Methods: This was an observational cohort study of adults from an integrated healthcare delivery system-Kaiser Permanente Northern California-that had outpatient care between 2013 and 2014. Patients were categorized by American Heart Association cardiovascular health status: poor, intermediate, or ideal. Individual-level healthcare utilization and costs in 2015 were accumulated for each patient and compared across the 3 cardiovascular health categories and stratified by age groups. Results: A total of 991,698 patients were included in the study. A total of 194,003 (19.6%) were aged 18-39 years; 554,129 (55.9%) were aged 40-64 years; and 243,566 (24.6%) were aged ≥65 years. A total of 259,931 (26.2%) had ideal cardiovascular health; 521,580 (52.6%) had intermediate cardiovascular health; and 210,187 (21.2%) had poor cardiovascular health. Healthcare utilization measured by average relative cost per patient increased monotonically across age categories (p<0.001). In addition, cardiovascular health category was inversely associated with lower cost in each age group (p<0.001). Conclusions: Adults who were younger and had more ideal cardiovascular health had relatively lower healthcare costs across age groups. Interventions to promote better cardiovascular health may improve patient outcomes and reduce overall healthcare expenditures.

Eligibility and Potential Benefit of Transcatheter Edge-to-Edge Repair in a Contemporary Cohort With Heart Failure: Evidence From a Large Integrated Health Care Delivery System.

Background: The eligibility and potential benefit of transcatheter edge-to-edge repair (TEER) in addition to guideline-directed medical therapy to treat moderate-severe or severe secondary mitral regurgitation (MR) has not been reported in a contemporary heart failure (HF) population. Methods: Eligibility for TEER based on Food and Drug Administration (FDA) labeling: (1) HF symptoms, (2) moderate-severe or severe MR, (3) left ventricular ejection fraction (LVEF) 20% to 50%, (4) left ventricular end-systolic dimension 7.0 cm, and (5) receiving GDMT (blocker + angiotensin-converting enzyme inhibitor/angiotensin receptor blocker). The proportion (%) of patients eligible for TEER. The hypothetical number needed to treat to prevent or postpone adverse outcomes was estimated using relative risk reductions from published hazard ratios in the registration trial and the observed event rates. Results: We identified 50,841 adults with HF and known LVEF. After applying FDA criteria, 2461 patients (4.8%) were considered eligible for transcatheter mitral valve replacement (FDA+), with the vast majority of patients excluded (FDA-) based on a lack of clinically significant MR (N = 47,279). FDA+ patients had higher natriuretic peptide levels and were more likely to have a prior HF hospitalization compared to FDA- patients. Although FDA+ patients had a more dilated left ventricle and lower LVEF, median (25th-75th) left ventricular end-systolic dimension (cm) was low at 4.4 (3.7-5.1) and only 30.8% had severely reduced LVEF. FDA+ patients were at higher risk of HF-related morbidity and mortality. The estimated number needed to treat to potentially prevent or postpone all-cause hospitalization was 4.4, 8.8 for HF hospitalization, and 5.3 for all-cause death at 24 months in FDA+ patients. Conclusions: There is a low prevalence of TEER eligibility based on FDA criteria primarily due to absence of moderate-severe or severe MR. FDA+ patients are a high acuity population and may potentially derive a robust clinical benefit from TEER based on pivotal studies. Additional research is necessary to validate the scope of eligibility and comparative effectiveness of TEER in real-world populations.

Physician assessment of aortic stenosis severity, quantitative parameters, and long-term outcomes: Results from the KP-VALVE project.

BACKGROUND: Contemporary outcomes for aortic stenosis (AS) and the association between physician-assessed AS severity and quantitative parameters is poorly understood. We aimed to evaluate AS natural history, compare outcomes for physicians' AS assessment vs. quantitative parameters, and identify AS parameters with the most explanatory power. METHODS: We ascertained physician-assessed AS severity, echocardiographic parameters, and clinical data for 546,769 patients from 2008-2018, examined multivariable associations of physician-assessed AS severity and number of quantitative severe AS parameters with death, cardiovascular hospitalization, and aortic valve replacement, and estimated the relative contribution of different quantitative AS parameters on outcomes. RESULTS: Among 49,604 AS patients (mean [SD] age 77 [11] years), 17.6% had moderate, 3.6% moderate-severe, and 9.4% severe AS. During median 3.7 [IQR 1.7-6.8] years, physician-assessed AS severity strongly correlated with outcomes, with moderate AS patients tracking closest to mild AS, and moderate-to-severe AS patients more comparable to severe AS. Although the number of quantitative severe AS parameters strongly predicted outcomes (adjusted HR [95% CI] for death 1.40 [1.34-1.46], 1.70 [1.56-1.85], and 1.78 [1.63-1.94] for 1, 2, and 3 parameters, respectively), aortic valve area <1.0 cm2 was the most frequent severe AS parameter, explained the largest relative contribution (67%), and was common in patients classified as moderate (21%) or moderate-severe (56%) AS. CONCLUSIONS: Physician-assessed AS severity predicts outcomes, with cumulative effects for each severe AS parameter. Moderate AS includes a wide spectrum of patients, with discordant AVA <1.0 cm2 being both common and predictive. Better identification of non-classical severe AS phenotypes may improve outcomes.

Lymph node targeted multi-epitope subunit vaccine promotes effective immunity to EBV in HLA-expressing mice.

The recent emergence of a causal link between Epstein-Barr virus (EBV) and multiple sclerosis has generated considerable interest in the development of an effective vaccine against EBV. Here we describe a vaccine formulation based on a lymph node targeting Amphiphile vaccine adjuvant, Amphiphile-CpG, admixed with EBV gp350 glycoprotein and an engineered EBV polyepitope protein that includes 20 CD8+ T cell epitopes from EBV latent and lytic antigens. Potent gp350-specific IgG responses are induced in mice with titers >100,000 in Amphiphile-CpG vaccinated mice. Immunization including Amphiphile-CpG also induces high frequencies of polyfunctional gp350-specific CD4+ T cells and EBV-specific CD8+ T cells that are 2-fold greater than soluble CpG and are maintained for >7 months post immunization. This combination of broad humoral and cellular immunity against multiple viral determinants is likely to provide better protection against primary infection and control of latently infected B cells leading to protection against the development of EBV-associated diseases.

Outcomes of Adults with Severe Aortic Stenosis Undergoing Urgent or Emergent vs. Elective Transcatheter Aortic Valve Replacement Within an Integrated Health Care Delivery System.

Background: Transcatheter aortic valve replacement (TAVR) may be used to urgently or emergently treat severe aortic stenosis, but outcomes for this high-risk population have not been well-characterized. We sought to describe the incidence, clinical characteristics, and outcomes of patients undergoing urgent or emergent vs. elective TAVR. Methods: We identified all adults who received TAVR for primary aortic stenosis between 2013 and 2019 within an integrated health care delivery system in Northern California. Elective or urgent/emergent procedure status was based on standard Society of Thoracic Surgeons definitions. Data were obtained from electronic health records, the Society of Thoracic Surgeons-American College of Cardiology Transcatheter Valve Therapy Registry, and state/national reporting databases. Logistic regression and Cox proportional hazard models were performed. Results: Among 1564 eligible adults that underwent TAVR, 81 (5.2%) were classified as urgent/emergent. These patients were more likely to have heart failure (63.0% vs. 47.4%), reduced left ventricular ejection fraction (21.0% vs. 11.8%), or a prior aortic valve balloon valvuloplasty (13.6% vs. 5.0%) and experienced higher unadjusted rates of 30-day and 1-year morbidity and mortality. Urgent/emergent TAVR status was independently associated with non-improved quality of life at 30-days (hazard ratio, 4.87; p < 0.01) and acute kidney injury within 1-year post-TAVR (hazard ratio, 2.11; p = 0.01). There was not a significant difference in adjusted 1-year mortality with urgent/emergent TAVR. Conclusions: Urgent/emergent TAVR status was uncommon and associated with high-risk clinical features and higher unadjusted rates of short- and long-term morbidity and mortality. Procedure status may be useful to identify patients less likely to experience significant short term improvement in health-related quality of life post-TAVR.

The association of intensive blood pressure treatment and non-fatal cardiovascular or serious adverse events in older adults with mortality: mediation analysis in SPRINT.

AIMS: Randomized clinical trials of hypertension treatment intensity evaluate the effects on incident major adverse cardiovascular events (MACEs) and serious adverse events (SAEs). Occurrences after a non-fatal index event have not been rigorously evaluated. The aim of this study was to evaluate the association of intensive (<120 mmHg) to standard (<140 mmHg) blood pressure (BP) treatment with mortality mediated through a non-fatal MACE or non-fatal SAE in 9361 participants in the Systolic Blood Pressure Intervention Trial. METHODS AND RESULTS: Logistic regression and causal mediation modelling to obtain direct and mediated effects of intensive BP treatment. Primary outcome was all-cause mortality (ACM). Secondary outcomes were cardiovascular (CVM) and non-CV mortality (non-CVM). The direct effect of intensive treatment was a lowering of ACM [odds ratio (OR) 0.75, 95% confidence interval (CI): 0.60-0.94]. The MACE-mediated effect substantially attenuated (OR 0.96, 95% CI: 0.92-0.99) ACM, while the SAE-mediated effect was associated with increased (OR 1.03, 95% CI: 1.01-1.05) ACM. Similar patterns were noted for intensive BP treatment on CVM and non-CVM. We also noted that SAE incidence was 3.9-fold higher than MACE incidence (13.7 vs. 3.5%), and there were a total of 365 (3.9%) ACM cases, with non-CVM being 2.6-fold higher than CVM [2.81% (263/9361) vs. 1.09% (102/9361)]. The SAE to MACE and non-CVM to CVM preponderance was found across all age groups, with the ≥80-year age group having the highest differences. CONCLUSION: The current analytic techniques demonstrated that intensive BP treatment was associated with an attenuated mortality benefit when it was MACE-mediated and possibly harmful when it was SAE-mediated. Current cardiovascular trial reporting of treatment effects does not allow expansion of the lens to focus on important occurrences after the index event.

The benefit of intensive (<120 mmHg) blood pressure (BP) treatment, reduction in all-cause mortality (ACM), was attenuated when mediated through non-fatal major adverse cardiovascular events. This was driven by cardiovascular mortality (CVM). The harm of intensive BP treatment, increase in ACM, was amplified when mediated through serious adverse events. This was driven by non-CVM. Current reporting of treatment effects in cardiovascular trials does not allow for expansion of the lens to focus on important occurrences after the index event.

P2Y12 Inhibitors in Acute Coronary Syndromes: A Real-World, Community-Based Comparison of Ischemic and Bleeding Outcomes.

Background: Randomized trials have shown superiority of the novel P2Y12 inhibitors over clopidogrel in patients with acute coronary syndrome (ACS), but clinical benefit in the community remains controversial. Our objective was to compare the safety and efficacy of clopidogrel to ticagrelor and prasugrel in patients with ACS undergoing percutaneous coronary intervention (PCI) in a real-world population. Methods: We conducted a retrospective cohort study of patients with ACS who underwent PCI and were discharged with clopidogrel, ticagrelor, or prasugrel from 2012 to 2018 within Kaiser Permanente Northern California. We used Cox proportional hazard models with propensity-score matching to evaluate the association of the P2Y12 agent with the primary outcomes of all-cause mortality, myocardial infarction (MI), stroke, and bleeding events. Results: The study included 15,476 patients (93.1% on clopidogrel, 3.6% on ticagrelor and 3.2% on prasugrel). Compared to the clopidogrel group, ticagrelorand prasugrel patients were younger with less comorbidities. In multivariable models with propensity-score matching, we found a lower risk of all-cause mortality in the ticagrelor vs the clopidogrel group (HR (95% CI) 0.43 (0.20-0.92)), but no differences in the other endpoints, and no difference between prasugrel and clopidogrel among any endpoints. A larger proportion of patients on ticagrelor or prasugrel switched to an alternative P2Y12 agent vs. clopidogrel (p < 0.01), and a higher level of persistence was seen among patients on clopidogrel vs. ticagrelor (p = 0.03) or prasugrel (p < 0.01). Conclusion: Among patients with ACS who underwent PCI, we observed a lower risk of all-cause mortality in patients treated with ticagrelor vs clopidogrel, but no difference in other clinical endpoints nor any differences in endpoints between prasugrel vs. clopidogrel users. These results suggest that further study is needed to identify an optimal P2Y12 inhibitor in a real-world population.

Clinical decision support to Optimize Care of patients with Atrial Fibrillation or flutter in the Emergency department: protocol of a stepped-wedge cluster randomized pragmatic trial (O'CAFÉ trial).

BACKGROUND: Management of adults with atrial fibrillation (AF) or atrial flutter in the emergency department (ED) includes rate reduction, cardioversion, and stroke prevention. Different approaches to these components of care may lead to variation in frequency of hospitalization and stroke prevention actions, with significant implications for patient experience, cost of care, and risk of complications. Standardization using evidence-based recommendations could reduce variation in management, preventable hospitalizations, and stroke risk. METHODS: We describe the rationale for our ED-based AF treatment recommendations. We also describe the development of an electronic clinical decision support system (CDSS) to deliver these recommendations to emergency physicians at the point of care. We implemented the CDSS at three pilot sites to assess feasibility and solicit user feedback. We will evaluate the impact of the CDSS on hospitalization and stroke prevention actions using a stepped-wedge cluster randomized pragmatic clinical trial across 13 community EDs in Northern California. DISCUSSION: We hypothesize that the CDSS intervention will reduce hospitalization of adults with isolated AF or atrial flutter presenting to the ED and increase anticoagulation prescription in eligible patients at the time of ED discharge and within 30 days. If our hypotheses are confirmed, the treatment protocol and CDSS could be recommended to other EDs to improve management of adults with AF or atrial flutter. TRIAL REGISTRATION: ClinicalTrials.gov NCT05009225 .  Registered on 17 August 2021.

Temporal trends in the prevalence and severity of aortic stenosis within a contemporary and diverse community-based cohort.

BACKGROUND: Data on the epidemiology of aortic stenosis (AS) are primarily derived from single center experiences and administrative claims data that do not delineate by degree of disease severity. METHODS: An observational cohort study of adults with echocardiographic AS was conducted January 1st, 2013-December 31st, 2019 at an integrated health system. The presence/grade of AS was based on physician interpretation of echocardiograms. RESULTS: A total of 66,992 echocardiogram reports for 37,228 individuals were identified. The mean ± standard deviation (SD) age was 77.5 ± 10.5, 50.5% (N = 18,816) were women, and 67.2% (N = 25,016) were non-Hispanic whites. The age-standardized AS prevalence increased from 589 (95% Confidence Interval [CI] 580-598) to 754 (95% CI 744-764) cases per 100,000 during the study period. The age-standardized AS prevalences were similar in magnitude among non-Hispanic whites (820, 95% CI 806-834), non-Hispanic blacks (728, 95% CI 687-769), and Hispanics (789, 95% CI 759-819) and substantially lower for Asian/Pacific Islanders (511, 95% CI 489-533). Finally, the distribution of AS by degree of severity remained relatively unchanged over time. CONCLUSIONS AND RELEVANCE: The population prevalence of AS has grown considerably over a short timeframe although the distribution of AS severity has remained stable.

Risk of cardiac events after elective versus urgent or emergent noncardiac surgery: Implications for quality measurement and improvement.

INTRODUCTION: Patient populations differ for elective vs urgent and emergent surgery. The effect of this difference on surgical outcome is not well understood and may be important for improving surgical safety. Our primary hypothesis was that there is an association of surgical acuity with risk of postoperative cardiac events. Secondarily, we examined elective vs urgent and emergent patients separately to understand patient characteristics that are associated with postoperative cardiac events. METHODS: We performed a retrospective cohort study of patients ≥65 years undergoing noncardiac elective or urgent/emergent surgery. Logistic regression estimated the association of surgical acuity with a postoperative cardiac event, which was defined as myocardial infarction or cardiac arrest within 30 days of surgery. For the secondary analysis, we modeled the outcome after stratifying by acuity. RESULTS: The study included 161,177 patients with 1014 cardiac events. The unadjusted risk of a postoperative cardiac event was 3.2 per 1000 among elective patients and 28.7 per 1000 among urgent and emergent patients (adjusted odds ratio 4.10, 95% confidence interval 3.56-4.72). After adjustment, increased age, higher baseline cardiac risk, peripheral vascular disease, hypertension, worse American Society of Anesthesiologist (ASA) physical classification, and longer operative time were associated with a postoperative cardiac event. Higher baseline cardiac risk was more strongly associated with postoperative cardiac events in elective patients. In contrast, worse ASA physical classification was more strongly associated with postoperative cardiac events in urgent and emergent patients. Black patients had higher odds of a postoperative cardiac event only in urgent and emergent patients compared to White patients. CONCLUSIONS: Quality measurement and improvement to address postoperative cardiac risk should consider patients based on surgical acuity.

Association of Thoracic Aortic Aneurysm Size With Long-term Patient Outcomes: The KP-TAA Study.

Importance: The risk of adverse events from ascending thoracic aorta aneurysm (TAA) is poorly understood but drives clinical decision-making. Objective: To evaluate the association of TAA size with outcomes in nonsyndromic patients in a large non-referral-based health care delivery system. Design, Setting, and Participants: The Kaiser Permanente Thoracic Aortic Aneurysm (KP-TAA) cohort study was a retrospective cohort study at Kaiser Permanente Northern California, a fully integrated health care delivery system insuring and providing care for more than 4.5 million persons. Nonsyndromic patients from a regional TAA safety net tracking system were included. Imaging data including maximum TAA size were merged with electronic health record (EHR) and comprehensive death data to obtain demographic characteristics, comorbidities, medications, laboratory values, vital signs, and subsequent outcomes. Unadjusted rates were calculated and the association of TAA size with outcomes was evaluated in multivariable competing risk models that categorized TAA size as a baseline and time-updated variable and accounted for potential confounders. Data were analyzed from January 2018 to August 2021. Exposures: TAA size. Main Outcomes and Measures: Aortic dissection (AD), all-cause death, and elective aortic surgery. Results: Of 6372 patients with TAA identified between 2000 and 2016 (mean [SD] age, 68.6 [13.0] years; 2050 female individuals [32.2%] and 4322 male individuals [67.8%]), mean (SD) initial TAA size was 4.4 (0.5) cm (828 individuals [13.0% of cohort] had initial TAA size 5.0 cm or larger and 280 [4.4%] 5.5 cm or larger). Rates of AD were low across a mean (SD) 3.7 (2.5) years of follow-up (44 individuals [0.7% of cohort]; incidence 0.22 events per 100 person-years). Larger initial aortic size was associated with higher risk of AD and all-cause death in multivariable models, with an inflection point in risk at 6.0 cm. Estimated adjusted risks of AD within 5 years were 0.3% (95% CI, 0.3-0.7), 0.6% (95% CI, 0.4-1.3), 1.5% (95% CI, 1.2-3.9), 3.6% (95% CI, 1.8-12.8), and 10.5% (95% CI, 2.7-44.3) in patients with TAA size of 4.0 to 4.4 cm, 4.5 to 4.9 cm, 5.0 to 5.4 cm, 5.5 to 5.9 cm, and 6.0 cm or larger, respectively, in time-updated models. Rates of the composite outcome of AD and all-cause death were higher than for AD alone, but a similar inflection point for increased risk was observed at 6.0 cm. Conclusions and Relevance: In a large sociodemographically diverse cohort of patients with TAA, absolute risk of aortic dissection was low but increased with larger aortic sizes after adjustment for potential confounders and competing risks. Our data support current consensus guidelines recommending prophylactic surgery in nonsyndromic individuals with TAA at a 5.5-cm threshold.

Limitations to Health Care Quality Measurement: Assessing Hospital Variation in Risk of Cardiac Events After Noncardiac Surgery.

Limited sample size, incomplete measures, and inadequate risk adjustment adversely influence accurate health care quality measurements, surgical quality measurements, and accurate comparisons among hospitals. Since these measures are linked to resources for quality improvement and reimbursement, improving the accuracy of measurement has substantial implications for patients, clinicians, hospital administrators, insurers, and purchasers. The team examined risk-adjusted differences of postoperative cardiac events among 20 geographically dispersed, community-based medical centers within an integrated health care system and compared it with the National Surgical Quality Improvement Program (NSQIP) hospital-specific differences. The exposure included the hospital at which patients received noncardiac surgical care, with stratification of patients by the acuity of surgery (elective vs. urgent/emergent). Among 157,075 surgery patients, the unadjusted risk of cardiac event per 1000 ranged among hospitals from 2.1 to 6.9 for elective surgery and from 10.3 to 44.5 for urgent/emergent surgery. Across the 20 hospitals, hospital rankings estimated in the present analysis differed significantly from ranking reported by NSQIP (P for difference: elective, P = 0.0001; urgent/emergent, P < 0.0001) with significantly and substantially lower variation after risk adjustment. Current surgical quality measures may not adequately account for limitations of sample size, data capture, adequate risk adjustment, and surgical acuity in a given hospital, particularly for rare outcomes. These differences have implications for quality reporting and may introduce bias into hospital comparisons, particularly for hospitals with incomplete capture of their patients' baseline risk and acuity.

Thromboembolism after treatment with 4-factor prothrombin complex concentrate or plasma for warfarin-related bleeding.

Limited data exist in large, representative populations about whether the risk of thromboembolic events varies after receiving four-factor human prothrombin complex concentrate (4F-PCC) versus treatment with human plasma for urgent reversal of oral vitamin K antagonist therapy. We conducted a multicenter observational study to compare the 45-day risk of thromboembolic events in adults with warfarin-associated major bleeding after treatment with 4F-PCC (Kcentra®) or plasma. Hospitalized patients in two large integrated healthcare delivery systems who received 4F-PCC or plasma for reversal of warfarin due to major bleeding from January 1, 2008 to March 31, 2020 were identified and were matched 1:1 on potential confounders and a high-dimensional propensity score. Arterial and venous thromboembolic events were identified up to 45 days after receiving 4F-PCC or plasma from electronic health records and adjudicated by physician review. Among 1119 patients receiving 4F-PCC and a matched historical cohort of 1119 patients receiving plasma without a recent history of thromboembolism, mean (SD) age was 76.7 (10.5) years, 45.6% were women, and 9.4% Black, 14.6% Asian/Pacific Islander, and 15.7% Hispanic. The 45-day risk of thromboembolic events was 3.4% in those receiving 4F-PCC and 4.1% in those receiving plasma (P = 0.26; adjusted hazard ratio 0.76; 95% confidence interval 0.49-1.16). The adjusted risk of all-cause death at 45 days post-treatment was lower in those receiving 4F-PCC compared with plasma. Among a large, ethnically diverse cohort of adults treated for reversal of warfarin-associated bleeding, receipt of 4F-PCC was not associated with an excess risk of thromboembolic events at 45 days compared with plasma therapy.

The effect of concurrent access to alcohol and oxycodone on self-administration and reinstatement in rats.

RATIONALE: Although polysubstance use is highly prevalent, preclinical studies that assess voluntary consumption of multiple substances at the same time are rather uncommon. Overlooking drug taking patterns commonly observed in humans may limit the translational value of preclinical models. OBJECTIVES: Here, we aimed to develop a model of polysubstance use that could be used to assess oral operant self-administration patterns under concurrent access to alcohol and the prescription opioid oxycodone. METHODS: After a training period where animals associated specific cues and levers with each drug, rats self-administered alcohol and oxycodone solutions concurrently in daily sessions. Oxycodone was then removed to assess potential changes in alcohol consumption. The role of cues and stress on alcohol consumption and oxycodone seeking was also examined under reinstatement conditions. RESULTS: We found that females consumed more alcohol and oxycodone than males when given access to both drugs, and this effect on alcohol intake persisted when oxycodone was removed. Additionally, re-exposure to oxycodone cues in combination with the administration of the pharmacological stressor yohimbine drove reinstatement of oxycodone seeking in females but did not have a strong effect in males, possibly due to low levels of oxycodone intake during active self-administration in male rats. Additionally, yohimbine drove increased alcohol consumption, in line with prior findings from our group and others. CONCLUSIONS: Taken together, this study demonstrates that rats will concurrently self-administer both oxycodone and alcohol in operant chambers, and this procedure can serve as a platform for future investigations in polysubstance use and relapse-like behavior.

Risk of severe COVID-19 infection among adults with prior exposure to children.

Susceptibility and severity of COVID-19 infection vary widely. Prior exposure to endemic coronaviruses, common in young children, may protect against SARS-CoV-2. We evaluated risk of severe COVID-19 among adults with and without exposure to young children in a large, integrated healthcare system. Adults with children 0-5 years were matched 1:1 to adults with children 6-11 years, 12-18 years, and those without children based upon a COVID-19 propensity score and risk factors for severe COVID-19. COVID-19 infections, hospitalizations, and need for intensive care unit (ICU) were assessed in 3,126,427 adults, of whom 24% (N = 743,814) had children 18 years or younger, and 8.8% (N = 274,316) had a youngest child 0-5 years. After 1:1 matching, propensity for COVID-19 infection and risk factors for severe COVID-19 were well balanced between groups. Rates of COVID-19 infection were slightly higher for adults with exposure to older children (incident risk ratio, 1.09, 95% confidence interval, [1.05-1.12] and IRR 1.09 [1.05-1.13] for adults with children 6-11 and 12-18, respectively), compared to those with children 0-5 years, although no difference in rates of COVID-19 illness requiring hospitalization or ICU admission was observed. However, adults without exposure to children had lower rates of COVID-19 infection (IRR 0.85, [0.83-0.87]) but significantly higher rates of COVID-19 hospitalization (IRR 1.49, [1.29-1.73]) and hospitalization requiring ICU admission (IRR 1.76, [1.19-2.58]) compared to those with children aged 0-5. In a large, real-world population, exposure to young children was associated with less severe COVID-19 illness. Endemic coronavirus cross-immunity may play a role in protection against severe COVID-19.