COVID-19 and Influenza Vaccine Coadministration Among Older U.S. Adults.

INTRODUCTION: Coadministering COVID-19 and influenza vaccines is recommended by public health authorities and intended to improve uptake and convenience; however, the extent of vaccine coadministration is largely unknown. Investigations into COVID-19 and influenza vaccine coadministration are needed to describe compliance with newer recommendations and to identify potential gaps in the implementation of coadministration. METHODS: A descriptive, repeated cross-sectional study between September 1, 2021 to November 30, 2021 (Period 1) and September 1, 2022 to November 30, 2022 (Period 2) was conducted. This study included community-dwelling Medicare beneficiaries ≥ 66 years who received an mRNA COVID-19 booster vaccine in Periods 1 and 2. The outcome was an influenza vaccine administered on the same day as the COVID-19 vaccine. Adjusted ORs and 99% CIs were estimated using logistic regression to describe the association between beneficiaries' characteristics and vaccine coadministration. Statistical analysis was performed in 2023. RESULTS: Among beneficiaries who received a COVID-19 vaccine, 78.8% in Period 1 (N=6,292,777) and 89.1% in Period 2 (N=4,757,501), received an influenza vaccine at some point during the study period (i.e., before, after, or on the same day as their COVID-19 vaccine), though rates were lower in non-White and rural individuals. Vaccine coadministration increased from 11.1% to 36.5% between periods. Beneficiaries with dementia (aORPeriod 2=1.31; 99%CI=1.29-1.32) and in rural counties (aORPeriod 2=1.19; 99%CI=1.17-1.20) were more likely to receive coadministered vaccines, while those with cancer (aORPeriod 2=0.90; 99%CI=0.89-0.91) were less likely. CONCLUSIONS: Among Medicare beneficiaries vaccinated against COVID-19, influenza vaccination was high, but coadministration of the 2 vaccines was low. Future work should explore which factors explain variation in the decision to receive coadministered vaccines.

Comparative Risks of Potential Adverse Events Following COVID-19 mRNA Vaccination Among Older US Adults.

Importance: Head-to-head safety comparisons of the mRNA vaccines for SARS-CoV-2 are needed for decision making; however, current evidence generalizes poorly to older adults, lacks sufficient adjustment, and inadequately captures events shortly after vaccination. Additionally, no studies to date have explored potential variation in comparative vaccine safety across subgroups with frailty or an increased risk of adverse events, information that would be useful for tailoring clinical decisions. Objective: To compare the risk of adverse events between mRNA vaccines for COVID-19 (mRNA-1273 and BNT162b2) overall, by frailty level, and by prior history of the adverse events of interest. Design, Setting, and Participants: This retrospective cohort study was conducted between December 11, 2020, and July 11, 2021, with 28 days of follow-up following the week of vaccination. A novel linked database of community pharmacy and Medicare claims data was used, representing more than 50% of the US Medicare population. Community-dwelling, fee-for-service beneficiaries aged 66 years or older who received mRNA-1273 vs BNT162b2 as their first COVID-19 vaccine were identified. Data analysis began on October 18, 2022. Exposure: Dose 1 of mRNA-1273 vs BNT162b2 vaccine. Main Outcomes and Measures: Twelve potential adverse events (eg, pulmonary embolism, thrombocytopenia purpura, and myocarditis) were assessed individually. Frailty was measured using a claims-based frailty index, with beneficiaries being categorized as nonfrail, prefrail, and frail. The risk of diagnosed COVID-19 was assessed as a secondary outcome. Generalized linear models estimated covariate-adjusted risk ratios (RRs) and risk differences (RDs) with 95% CIs. Results: This study included 6 388 196 eligible individuals who received the mRNA-1273 or BNT162b2 vaccine. Their mean (SD) age was 76.3 (7.5) years, 59.4% were women, and 86.5% were White. A total of 38.1% of individuals were categorized as prefrail and 6.0% as frail. The risk of all outcomes was low in both vaccine groups. In adjusted models, the mRNA-1273 vaccine was associated with a lower risk of pulmonary embolism (RR, 0.96 [95% CI, 0.93-1.00]; RD, 9 [95% CI, 1-16] events per 100 000 persons) and other adverse events in subgroup analyses (eg, 11.0% lower risk of thrombocytopenia purpura among individuals categorized as nonfrail). The mRNA-1273 vaccine was also associated with a lower risk of diagnosed COVID-19 (RR, 0.86 [95% CI, 0.83-0.87]), a benefit that was attenuated by frailty level (frail: RR, 0.94 [95% CI, 0.89-0.99]). Conclusions and Relevance: In this cohort study of older US adults, the mRNA-1273 vaccine was associated with a slightly lower risk of several adverse events compared with BNT162b2, possibly due to greater protection against COVID-19. Future research should seek to formally disentangle differences in vaccine safety and effectiveness and consider the role of frailty in assessments of COVID-19 vaccine performance.

Racial and ethnic disparities in COVID-19 booster vaccination among U.S. older adults differ by geographic region and Medicare enrollment.

Introduction: COVID-19 booster vaccines are highly effective at reducing severe illness and death from COVID-19. Research is needed to identify whether racial and ethnic disparities observed for the primary series of the COVID-19 vaccines persist for booster vaccinations and how those disparities may vary by other characteristics. We aimed to measure racial and ethnic differences in booster vaccine receipt among U.S. Medicare beneficiaries and characterize potential variation by demographic characteristics. Methods: We conducted a cohort study using CVS Health and Walgreens pharmacy data linked to Medicare claims. We included community-dwelling Medicare beneficiaries aged ≥66 years who received two mRNA vaccine doses (BNT162b2 and mRNA-1273) as of 8/1/2021. We followed beneficiaries from 8/1/2021 until booster vaccine receipt, death, Medicare disenrollment, or end of follow-up (12/31/2021). Adjusted Poisson regression was used to estimate rate ratios (RRs) and 95% confidence intervals (CIs) comparing vaccine uptake between groups. Results: We identified 11,339,103 eligible beneficiaries (mean age 76 years, 60% female, 78% White). Overall, 67% received a booster vaccine (White = 68.5%; Asian = 67.0%; Black = 57.0%; Hispanic = 53.3%). Compared to White individuals, Black (RR = 0.78 [95%CI = 0.78-0.78]) and Hispanic individuals (RR = 0.72 [95% = CI 0.72-0.72]) had lower rates of booster vaccination. Disparities varied by geographic region, urbanicity, and Medicare plan/Medicaid eligibility. The relative magnitude of disparities was lesser in areas where vaccine uptake was lower in White individuals. Discussion: Racial and ethnic disparities in COVID-19 vaccination have persisted for booster vaccines. These findings highlight that interventions to improve vaccine uptake should be designed at the intersection of race and ethnicity and geographic location.

Antibiotic Prescribing in United States Nursing Homes, 2013-2017.

In this national cohort of older adults residing long-term in US nursing homes between 2013 and 2017, we calculated period prevalence estimates for antibiotic prescribing, rates of prescribing, and days of therapy. Among 1 375 062 residents, 66.2% were prescribed at least 1 antibiotic during the nursing home stay. The most prevalent antibiotic classes were fluoroquinolones, sulfonamides and related agents, and first-generation cephalosporins. Levofloxacin, ciprofloxacin, and sulfamethoxazole-trimethoprim were the most prevalent antibiotics. These results can inform antibiotic stewardship interventions to reduce antibiotic overprescribing, improve appropriateness, and reduce related adverse outcomes in nursing homes.

Data resource profile: COVid VAXines effects on the aged (COVVAXAGE).

Background: To improve the assessment of COVID-19 vaccine use, safety, and effectiveness in older adults and persons with complex multimorbidity, the COVid VAXines Effects on the Aged (COVVAXAGE) database was established by linking CVS Health and Walgreens pharmacy customers to Medicare claims. Methods: We deterministically linked CVS Health and Walgreens customers who had a pharmacy dispensation/encounter paid for by Medicare to Medicare enrollment and claims records. Linked data include U.S. Medicare claims, Medicare enrollment files, and community pharmacy records. The data currently span 01/01/2016 to 08/31/2022. "Research-ready" files were created, with weekly indicators for vaccinations, censoring, death, enrollment, demographics, and comorbidities. Data are updated quarterly. Results: As of November 2022, records for 27,086,723 CVS Health and 23,510,025 Walgreens unique customer IDs were identified for potential linkage. Approximately 91% of customers were matched to a Medicare beneficiary ID (95% for those aged 65 years or older). In the final linked cohort, there were 38,250,873 unique beneficiaries representing ~60% of the Medicare population. Among those alive and enrolled in Medicare as of January 1, 2020 (n = 33,721,568; average age = 73 years, 74% White, 51% Medicare Fee-for-Service, and 11% dual-eligible for Medicaid), the average follow-up time was 130 weeks. The cohort contains 16,021,055 beneficiaries with evidence a first COVID-19 vaccine dose. Data are stored on the secure Medicare & Medicaid Resource Information Center Health & Aging Data Enclave. Data access: Investigators with funded or in-progress funding applications to the National Institute on Aging who are interested in learning more about the database should contact Dr Vincent Mor [Vincent_mor@brown.edu] and Dr Kaleen Hayes [kaley_hayes@brown.edu]. A data dictionary can be provided under reasonable request. Conclusions: The COVVAXAGE cohort is a large and diverse cohort that can be used for the ongoing evaluation of COVID-19 vaccine use and other research questions relevant to the Medicare population.

Healthcare Utilization, Costs, and Adverse Events of Real-Time Continuous Glucose Monitoring versus Traditional Blood Glucose Monitoring Among US Adults with Type 1 Diabetes.

OBJECTIVE: To compare healthcare utilization, costs, and incidence of diabetes-specific adverse events (ie, hyperglycemia, diabetic ketoacidosis, and hypoglycemia) in type 1 diabetes adult patients using real-time continuous glucose monitoring (rtCGM) versus traditional blood glucose monitoring (BG). METHODS: Adult patients (≥18 years old) with type 1 diabetes in a large national administrative claims database between 2013 and 2015 were identified. rtCGM patients with 6-month continuous health plan enrollment and ≥1 pharmacy claim for insulin during pre-index and post-index periods were propensity-score matched with BG patients. Healthcare utilization associated with diabetic adverse events were examined. A difference-in-difference (DID) method was used to compare the change in costs between rtCGM and BG cohorts. RESULTS: Six-month medical costs for rtCGM patients (N = 153) increased from pre- to post-index period, while they decreased for matched BG patients (N = 153). DID analysis indicated a $2,807 (P = .062) higher post-index difference in total medical costs for rtCGM patients. Pharmacy costs for both cohorts increased. DID analysis indicated a $1,775 (P < .001) higher post-index difference in pharmacy costs for rtCGM patients. The incidence of hyperglycemia for both cohorts increased minimally from pre- to post-index period. The incidence of hypoglycemia for rtCGM patients decreased, while it increased marginally for BG patients. Inpatient hospitalizations for rtCGM and BG patients increased and decreased marginally, respectively. CONCLUSIONS: rtCGM users had non-significantly higher pre-post differences in medical costs but significantly higher pre-post differences in pharmacy costs (mostly due to the rtCGM costs themselves) compared to BG users. Changes in adverse events were minimal.

Altered serotonergic circuitry in SSRI-resistant major depressive disorder patient-derived neurons.

Disrupted serotonergic neurotransmission has long been implicated in major depressive disorder (MDD), for which selective serotonin reuptake inhibitors (SSRIs) are the first line of treatment. However, a significant percentage of patients remain SSRI-resistant and it is unclear whether and how alterations in serotonergic neurons contribute to SSRI resistance in these patients. Induced pluripotent stem cells (iPSCs) facilitate the study of patient-specific neural subtypes that are typically inaccessible in living patients, enabling the discovery of disease-related phenotypes. In our study of a well-characterized cohort of over 800 MDD patients, we generated iPSCs and serotonergic neurons from three extreme SSRI-remitters (R) and SSRI-nonremitters (NR). We studied serotonin (5-HT) biochemistry and observed no significant differences in 5-HT release and reuptake or in genes related to 5-HT biochemistry. NR patient-derived serotonergic neurons exhibited altered neurite growth and morphology downstream of lowered expression of key Protocadherin alpha genes as compared to healthy controls and Rs. Furthermore, knockdown of Protocadherin alpha genes directly regulated iPSC-derived neurite length and morphology. Our results suggest that intrinsic differences in serotonergic neuron morphology and the resulting circuitry may contribute to SSRI resistance in MDD patients.

Serotonin-induced hyperactivity in SSRI-resistant major depressive disorder patient-derived neurons.

Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressants. They regulate serotonergic neurotransmission, but it remains unclear how altered serotonergic neurotransmission may contribute to the SSRI resistance observed in approximately 30% of major depressive disorder (MDD) patients. Patient stratification based on pharmacological responsiveness and the use of patient-derived neurons may make possible the discovery of disease-relevant neural phenotypes. In our study from a large cohort of well-characterized MDD patients, we have generated induced pluripotent stem cells (iPSCs) from SSRI-remitters and SSRI-nonremitters. We studied serotonergic neurotransmission in patient forebrain neurons in vitro and observed that nonremitter patient-derived neurons displayed serotonin-induced hyperactivity downstream of upregulated excitatory serotonergic receptors, in contrast to what is seen in healthy and remitter patient-derived neurons. Our data suggest that postsynaptic forebrain hyperactivity downstream of SSRI treatment may play a role in SSRI resistance in MDD.

Structure-Based Design, Synthesis, Biological Evaluation, and Molecular Docking of Novel PDE10 Inhibitors With Antioxidant Activities.

Phosphodiesterase 10 is a promising target for the treatment of a series of central nervous system (CNS) diseases. Imbalance between oxidative stress and antioxidant defense systems as a universal condition in neurodegenerative disorders is widely studied as a potential therapy for CNS diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). To discover multifunctional pharmaceuticals as a treatment for neurodegenerative diseases, a series of quinazoline-based derivatives with PDE10 inhibitory activities and antioxidant activities were designed and synthesized. Nine out of 13 designed compounds showed good PDE10 inhibition at the concentration of 1.0 µM. Among these compounds, eight exhibited moderate to excellent antioxidant activity with ORAC (oxygen radical absorbance capacity) value above 1.0. Molecular docking was performed for better understanding of the binding patterns of these compounds with PDE10. Compound 11e, which showed remarkable inhibitory activity against PDE10 and antioxidant activity may serve as a lead for the further modification.

Prostaglandin Derivatives: Nonaromatic Phosphodiesterase-4 Inhibitors from the Soft Coral Sarcophyton ehrenbergi.

Ten new prostaglandin derivatives (PGs), sarcoehrendins A-J (1-10), together with five known analogues (11-15) were isolated from the soft coral Sarcophyton ehrenbergi. Compounds 4-8 represented the first examples of PGs featuring an 18-ketone group. The structures including the absolute configurations were elucidated on the basis of spectroscopic analysis and chemical evidence. All of the isolates and six synthetic analogues (3a, 3b, 4a, and 11a-11c) were screened for inhibitory activity against phosphodiesterase-4 (PDE4), which is a drug target for the treatment of asthma and chronic obstructive pulmonary disease. Compounds 2, 10, 11a, 11b, and 13-15 exhibited inhibition with IC50 values less than 10 µM, and compound 15 (IC50 = 1.4 µM) showed comparable activity to the positive control rolipram (IC50 = 0.60 µM). The active natural PGs (2, 10, and 13-15) represent the first examples of PDE4 inhibitors without an aromatic moiety, and a preliminary structure-activity relationship is also proposed.