Search

INTRODUCTION: The use of antidepressants in major depressive disorder (MDD) has been reported to influence long‐term risk of Alzheimer's disease (AD) and AD‐related dementias (AD/ADRD), but studies are conflicting. METHODS: We used inverse probability weighted (IPW) Cox models with time‐varying covariates in a retrospective cohort study among midlife veterans with MDD within the US Veterans Affairs healthcare system from January 1, 2000 to June 1, 2022. RESULTS: A total of 35,200 patients with MDD were identified. No associations were seen regarding the effect of being exposed to any antidepressant versus no exposure on AD/ADRD risk (events = 1,056, hazard ratio = 0.94, 95% confidence interval: 0.81 to 1.09) or the exposure to specific antidepressant classes versus no exposure. A risk reduction was observed for female patients in a stratified analysis; however, the number of cases was small. DISCUSSION: Our study suggests that antidepressant exposure has no effect on AD/ADRD risk. The association in female patients should be interpreted with caution and requires further attention. Highlights: We studied whether antidepressant use was associated with future dementia risk.We specifically focused on patients after their first‐ever diagnosis of depression.We used IPW Cox models with time‐varying covariates and a large observation window.Our study did not identify an effect of antidepressant use on dementia risk.A risk reduction was observed in female patients, but the number of cases was small. [ABSTRACT FROM AUTHOR]

Background: Patients taking immune‐suppressive drugs are at increased risk of severe coronavirus disease 2019 (COVID‐19), not fully ameliorated by vaccination. We assessed the contributions of clinical and demographic factors to the risk of severe disease despite vaccination in patients taking immune‐suppressive medications for solid organ transplantation (SOT), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), or psoriasis. Methods: Veterans Health Administration electronic health records were used to identify patients diagnosed with RA, IBD, psoriasis, or SOT who had been vaccinated against severe acute respiratory syndrome coronavirus 2, were subsequently infected, and had received immune‐suppressive drugs within 3 months before infection. The association of severe (defined as hypoxemia, mechanical ventilation, dexamethasone use, or death) versus non‐severe COVID‐19 with the use of immune‐suppressive and antiviral drugs and clinical covariates was assessed by multivariable logistic regression. Results: Severe COVID‐19 was more common in patients with SOT (230/1011, 22.7%) than RA (173/1355, 12.8%), IBD (51/742, 6.9%), or psoriasis (82/1125, 7.3%). Age was strongly associated with severe COVID‐19, adjusted odds ratio (aOR) of 1.04 (CI 1.03–1.05) per year. Comorbidities indicating chronic brain, heart, lung, or kidney damage were also associated with severity, aOR 1.35–2.38. The use of glucocorticoids was associated with increased risk (aOR 1.66, CI 1.39–2.18). Treatment with antivirals was associated with reduced severity, for example, aOR 0.28 (CI 0.13–0.62) for nirmatrelvir/ritonavir. Conclusion: The risk of severe COVID‐19 despite vaccination is substantial in patients taking immune‐suppressive drugs, more so in patients with SOT than in patients with inflammatory diseases. Age and severe comorbidities contribute to risk, as in the general population. Oral antivirals were very beneficial but not widely used. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder (MDD) is associated with dementia risk. The use of antidepressants in MDD has been reported to influence long term risk of Alzheimer's disease and related dementias (ADRD), but studies are conflicting. Methods: We used inverse probability weighted Cox models with time‐varying covariates in a retrospective cohort study among Veterans with MDD within the US Veterans Affairs health‐care system from 1/1/2000 to 6/1/2022. We focused on patients receiving their first diagnosis of MDD at the age of 60 or above. Our outcome was incident ADRD and unrelated death was considered as a competing risk event. Exposed intervals were defined using prescription data. Models were weighted for the inverse probability of falling in each of the treatment arms (exposed or not) at the beginning of each treatment period based on demographic and clinical covariates updated with most recent information (1‐year prior). The cumulative effect of antidepressant exposure (No. days) was also studied. Result: A total of 24,964 patients with MDD were identified, of which 45% were on antidepressants (Table 1). Median treatment time was 4.10 years [2.56, 6.10]. No relationship was observed between the number of days on antidepressants and the risk of ADRD (Figure 1). No significant associations were seen for the effect of being exposed to antidepressants (any) vs unexposed (HR = 0.94, 95%; CI: 0.81‐1.09) or exposed to each antidepressant drug classes vs unexposed (SSRI HR = 0.93, 95%; CI: 0.79‐1.10; NDRI HR = 0.80, 95%; CI: 0.42‐1.54; SNRI HR = 0.87, 95%; CI: 0.54‐1.41). (Table II). In sensitivity analysis stratified by sex, a reduction in risk due to antidepressant exposure was suggested in female patients, however the number of cases was small (HR = 0.30, 95%; CI: 0.12‐0.81; P = 0.02)). Conclusion: Our study conducted in a large population and after accounting for confounders shows that antidepressant exposure has no effect on ADRD risk. Our result suggesting an association in female patients should be interpreted with caution due to a small sample size and deserves further attention. Replication of results in an external population with a larger representation of female patients is needed for further validation [ABSTRACT FROM AUTHOR]

Objective: There is an increased risk of fracture in individuals with ankylosing spondylitis (AS) compared to the general population, possibly due to systemic inflammatory effects. The use of tumor necrosis factor inhibitors (TNFi) may reduce fracture risk by inhibiting inflammation. We assessed fracture rates in AS versus non‐AS comparators and whether these rates have changed since the introduction of TNFi. Methods: We used the national Veterans Affairs database to identify adults ≥18 years old with ≥1 International Classification of Diseases, Ninth Revision (ICD‐9)/ICD‐10 code for AS and at least 1 disease‐modifying antirheumatic drug prescription. As comparators, we selected a random sample of adults without AS diagnosis codes. We calculated fracture incidence rates for AS and comparators, with direct standardization to the cohort structure in 2017. To compare fracture rates from 2000 to 2002 (pre‐TNFi) versus 2004–2020 (TNFi era), we performed an interrupted time series analysis. Results: We included 3,794 individuals with AS (mean age 53 years, 92% male) and 1,152,805 comparators (mean age 60 years, 89% male). For AS, the incidence rate of fractures increased from 7.9/1,000 person‐years in 2000 to 21.6/1,000 person‐years in 2020. The rate also increased among comparators, although the ratio of fracture rates (AS/comparators) remained relatively stable. In the interrupted time series, the fracture rate for AS patients in the TNFi era was nonsignificantly increased compared to the pre‐TNFi era. Conclusion: Fracture rates have increased over time for both AS and non‐AS comparators. The fracture rate in individuals with AS did not decrease after TNFi introduction in 2003. [ABSTRACT FROM AUTHOR]

Background: Electronic frailty indices (eFIs) can expand measurement of frailty in research and practice and have demonstrated predictive validity in associations with clinical outcomes. However, their construct validity is less well studied. We aimed to assess the construct validity of the VA‐FI, an eFI developed for use in the U.S. Veterans Affairs Healthcare System. Methods: Veterans who underwent comprehensive geriatric assessments between January 31, 2019 and June 6, 2022 at VA Boston and had sufficient data documented for a comprehensive geriatric assessment‐frailty index (CGA‐FI) were included. The VA‐FI, based on diagnostic and procedural codes, and the CGA‐FI, based on geriatrician‐measured deficits, were calculated for each patient. Geriatricians also assessed the Clinical Frailty Scale (CFS), functional status (ADLs and IADLs), and 4‐meter gait speed (4MGS). Results: A total of 132 veterans were included, with median age 81.4 years (IQR 75.8–88.7). Across increasing levels of VA‐FI (<0.2; 0.2–0.4; >0.4), mean CGA‐FI increased (0.24; 0.30; 0.40). The VA‐FI was moderately correlated with the CGA‐FI (r 0.45, p < 0.001). Every 0.1‐unit increase in the VA‐FI was associated with an increase in the CGA‐FI (linear regression beta 0.05; 95% confidence interval [CI] 0.03–0.06), higher CFS category (ordinal regression OR 1.69; 95% CI 1.24–2.30), higher odds of ADL dependency (logistic regression OR 1.59; 95% CI 1.20–2.11), IADL dependency (logistic regression OR 1.68; 95% CI 1.23–2.30), and a decrease in 4MGS (linear regression beta −0.07, 95% CI −0.12 to −0.02). All models were adjusted for age and race, and associations held after further adjustment for the Charlson Comorbidity Index. Conclusion: Our results demonstrate the construct validity of the VA‐FI through its associations with clinical measures of frailty, including summary frailty measures, functional status, and objective physical performance. Our findings complement others' in showing that eFIs can capture functional and mobility domains of frailty beyond just comorbidity and may be useful to measure frailty among populations and individuals. [ABSTRACT FROM AUTHOR]

Background: We aimed to evaluate and compare the performance of multiple myeloma (MM) selection algorithms for use in Veterans Affairs (VA) research. Methods: Using the VA Corporate Data Warehouse (CDW), the VA Cancer Registry (VACR), and VA pharmacy data, we randomly selected 500 patients from 01/01/1999 to 06/01/2021 who had (1) either one MM diagnostic code OR were listed in the VACR as having MM AND (2) at least one MM treatment code. A team reviewed oncology notes for each veteran to annotate details regarding MM diagnosis and initial treatment within VA. We evaluated inter‐annotator agreement and compared the performance of four published algorithms (two developed and validated external to VA data and two used in VA data). Results: A total of 859 patients were reviewed to obtain 500 patients who were annotated as having MM and initiating MM treatment in VA. Agreement was high among annotators for all variables: MM diagnosis (98.3% agreement, Kappa = 0.93); initial treatment in VA (91.8% agreement; Kappa = 0.77); and initial treatment classification (87.6% agreement; Kappa = 0.86). VA Algorithms were more specific and had higher PPVs than non‐VA algorithms for both MM diagnosis and initial treatment in VA. We developed the "VA Recommended Algorithm," which had the highest PPV among all algorithms in identifying patients diagnosed with MM (PPV = 0.98, 95% CI = 0.95–0.99) and in identifying patients who initiated their MM treatment in VA (PPV = 0.93, 95% CI = 0.90–0.96). Conclusion: Our VA Recommended Algorithm optimizes sensitivity and PPV for cohort selection and treatment classification. [ABSTRACT FROM AUTHOR]

Background: Older patients with non‐small cell lung cancer (NSCLC) are a heterogeneous population with varying degrees of frailty. An electronic frailty index such as the Veterans Affairs Frailty Index (VA‐FI) can potentially help identify vulnerable patients at high risk of poor outcomes. Methods: NSCLC patients ≥65 years old and diagnosed in 2002–2017 were identified using the VA Central Cancer Registry. The VA‐FI was calculated using administrative codes from VA electronic health records data linked with Medicare and Medicaid data. We assessed associations between the VA‐FI and times to mortality, hospitalization, and emergency room (ER) visit following diagnosis by Kaplan–Meier analysis and multivariable stratified Cox models. We also evaluated the change in discrimination and calibration of reference prognostic models after adding VA‐FI. Results: We identified a cohort of 42,204 older NSCLC VA patients, in which 55.5% were classified as frail (VA‐FI >0.2). After adjustment, there was a strong association between VA‐FI and the risk of mortality (HR = 1.23 for an increase of four deficits or, equivalently, an increase of 0.129 on VA‐FI, p < 0.001), hospitalization (HR = 1.16 for four deficits, p < 0.001), and ER visit (HR = 1.18 for four deficits, p < 0.001). Adding VA‐FI to baseline prognostic models led to statistically significant improvements in time‐dependent area under curves and did not have a strong impact on calibration. Conclusion: Older NSCLC patients with higher VA‐FI have significantly elevated risks of mortality, hospitalizations, and ER visits following diagnosis. An electronic frailty index can serve as an accessible tool to identify patients with vulnerabilities to inform clinical care and research. [ABSTRACT FROM AUTHOR]

Introduction: Tumor necrosis factor (TNF) inhibitors are widely used to treat rheumatoid arthritis (RA) and their potential to retard Alzheimer's disease (AD) progression has been reported. However, their long‐term effects on the dementia/AD risk remain unknown. Methods: A propensity scored matched retrospective cohort study was conducted among 40,207 patients with RA within the US Veterans Affairs health‐care system from 2000 to 2020. Results: A total of 2510 patients with RA prescribed TNF inhibitors were 1:2 matched to control patients. TNF inhibitor use was associated with reduced dementia risk (hazard ratio [HR]: 0.64, 95% confidence interval [CI]: 0.52–0.80), which was consistent as the study period increased from 5 to 20 years after RA diagnosis. TNF inhibitor use also showed a long‐term effect in reducing the risk of AD (HR: 0.57, 95% CI: 0.39–0.83) during the 20 years of follow‐up. Conclusion: TNF inhibitor use is associated with lower long‐term risk of dementia/AD among US veterans with RA. [ABSTRACT FROM AUTHOR]

The etiology of schizophrenia's cognitive symptoms may have its basis in prenatal alterations of glutamate N-methyl- D-aspartate (NMDA) receptor functioning. Therefore, the current study investigated the effects of ketamine (an NMDA receptor blocking drug) on both a conditioned taste aversion (CTA) and latent inhibition (LI; a model of attentional capacity) in rat fetuses. We first sought to determine if a CTA could be diminished by nonreinforced preexposure to a CS in fetal rats (i.e., LI). We injected E18 pregnant Sprague-Dawley rats with 100% allicin (garlic taste) or an equal volume of saline. Some of the pregnant dams also received ketamine (100 mg/kg, i.p.). One day later (E19), the dams received a second injection of the CS, followed by either lithium chloride (the US) or saline. Finally, on E21 pups received oral lavage with allicin and observations of ingestive orofacial motor responses were recorded. When allicin had been paired with LiCl in utero, E21 fetuses exhibited a conditioned suppression of orofacial movements, indicative of an aversion to this taste. Preexposure to the garlic taste on E18 produced a LI of this CTA. Ketamine significantly disrupted the formation of the CTA and had some impact on LI. However, the direct effect of ketamine on LI is less certain since the drug also blocked the original CTA. © 2013 Wiley Periodicals, Inc. © 2013 Wiley Periodicals, Inc. Dev Psychobiol 56: 435-447, 2014. [ABSTRACT FROM AUTHOR]

Many Prunus species, including sweet cherry and Japanese apricot, of the Rosaceae, display an S-RNase-based gametophytic self-incompatibility (GSI). The specificity of this outcrossing mechanism is determined by a minimum of two genes that are located in a multigene complex, termed the S locus, which controls the pistil and pollen specificities. SFB, a gene located in the S locus region, encodes an F-box protein that has appropriate S haplotype-specific variation to be the pollen determinant in the self-incompatibility reaction. This study characterizes SFBs of two self-compatible (SC) haplotypes, S4′ and Sf, of Prunus. S4′ of sweet cherry is a pollen-part mutant (PPM) that was produced by X-ray irradiation, while Sf of Japanese apricot is a naturally occurring SC haplotype that is considered to be a PPM. DNA sequence analysis revealed defects in both SFB4′ and SFB f. A 4 bp deletion upstream from the HVa coding region of SFB4′ causes a frame-shift that produces transcripts of a defective SFB lacking the two hypervariable regions, HVa and HVb. Similarly, the presence of a 6.8 kbp insertion in the middle of the SFB f coding region leads to transcripts for a defective SFB lacking the C-terminal half that contains HVa and HVb. As all reported SFBs of functional S haplotypes encode intact SFB, the fact that the partial loss-of-function mutations in SFB are present in SC mutant haplotypes of Prunus provides additional evidence that SFB is the pollen S gene in GSI in Prunus. [ABSTRACT FROM AUTHOR]