Importance: Fatigue is the most commonly reported symptom of post-COVID-19 condition (also known as long COVID) and impairs various functions. One of the underlying mechanisms may be intracerebral inflammation due to decreases in acetylcholine levels.
Objective: To examine the effects of donepezil hydrochloride, an acetylcholinesterase inhibitor, on post-COVID-19 fatigue and psychological symptoms.
Design, setting, and participants: A multicenter, double-blind randomized clinical trial was performed in Japan. Between December 14, 2022, and March 31, 2024, adult patients within 52 weeks of the onset of COVID-19 and with a global binary fatigue score of 4 or greater on the Chalder Fatigue Scale were randomized into a donepezil or a placebo group.
Exposure: The intervention was conducted during a 3-week period, with donepezil hydrochloride being administered at a dosage of 3 mg/d for the first week and then 5 mg/d for 2 weeks.
Main outcomes and measures: The primary outcome was a change in the Chalder Fatigue Scale score and the absolute score 3 weeks after the initiation of treatment. Other outcomes at 3 and 8 weeks, such as psychological symptoms and quality of life, were evaluated as secondary outcomes.
Results: A total of 120 eligible patients were enrolled and 10 withdrew or were lost to follow-up; therefore, 110 patients (55 in each group) were included in the efficacy analysis (64 [58%] female; mean [SD] age, 43 [12] years). No significant differences were observed in baseline characteristics between the 2 groups. The baseline-adjusted estimating treatment effect of donepezil, measured as the mean difference on Chalder Fatigue Scale scores at 3 weeks, was 0.34 (95% CI, -2.23 to 2.91), showing no significant effect of the intervention (P = .79). Scores for the Hospital Anxiety and Depression Scale, Impact of Event Scale-Revised, EuroQol 5-Dimension 5-Level Version, Patient Health Questionnaire, and Daily Health Status at 3 and 8 weeks were similar. No serious adverse events occurred in either group.
Conclusions and relevance: In this randomized clinical trial of donepezil to treat post-COVID-19 condition, the efficacy for fatigue and psychological symptoms was not confirmed in a general population. The development of effective therapeutics for post-COVID-19 symptoms is needed, and more clinical trials should be conducted in the future.
Trial registration: Japan Registry of Clinical Trials Identifier: jRCT 2031220510.
Importance: In the US, transgender, nonbinary, and gender diverse (TGD) adults have high rates of depression. Gender-affirming hormone therapy (GAHT) is associated with improved mental health outcomes, yet existing US studies have short follow ups and lack sample diversity.
Objective: To evaluate the use of GAHT delivered in primary care as an intervention for moderate-to-severe depressive symptoms in diverse TGD adult patients.
Design, setting, and participants: LEGACY was an observational cohort study conducted in federally qualified community health centers in Boston and New York that followed up TGD patients (N = 3592) from calendar years 2016 to 2019 (48 months). Participants included individuals aged 18 years or older, gender identity different from sex at birth, a past 12-month medical visit, and signed patient consent form in the electronic health record (EHR).
Exposures: Prescriptions for GAHT obtained from EHR data, using the date of the first and last GAHT prescription in each calendar year of observation (GAHT within the year vs no GAHT during the year).
Main outcomes and measures: A binary outcome of patient-reported moderate-to-severe depressive symptoms was obtained using the validated Patient-Health Questionnaire (PHQ), scoring 10 or greater on the PHQ-9 or scoring 3 or greater on the PHQ-2. Following multiple imputation, generalized estimating equations (GEE) longitudinally modeled GAHT and moderate-to-severe depressive symptoms (n = 20 320 observations) and adjusted for age, gender identity, race and ethnicity, health insurance, federal poverty level, HIV serostatus, number of cohort years, and clinical site.
Results: The median age of the 3592 patients was 28 (IQR, 24-36) years. Race and ethnicity was diverse (1.3% Asian/Pacific Islander, 11.7% Black, 16.1% Hispanic/Latinx, 63.1% White, 6.8% multiracial, and 1.4% other). In addition, 18.9% were nonbinary, 52.1% lived below the federal poverty level, 34.2% were publicly insured, 4.1% were uninsured, and 5.1% were living with HIV. At baseline, 84.5% of the individuals were prescribed GAHT and 15.3% reported moderate-to-severe depressive symptoms. Patients prescribed GAHT had a statistically significantly lower risk of moderate-to-severe depressive symptoms over follow-up compared with those not prescribed GAHT (adjusted risk ratio, 0.85; 95% CI, 0.75-0.98).
Conclusions and relevance: In this longitudinal observational cohort study, GAHT was associated with lower rates of moderate-to-severe depressive symptoms, highlighting the importance of gender-affirming primary care models for TGD patients.
Importance: Genetic and environmental factors are linked to Parkinson disease (PD), but the role of genetic susceptibility in the association between traffic-related air pollution (TRAP) and PD remains unclear.
Objective: To assess the gene-environment interaction between the polygenic risk score (PRS) for PD and long-term TRAP exposure and to estimate the joint effect with PD risk.
Design, setting, and participants: This population-based case-control study used a meta-analytical assessment of studies conducted in central California and Denmark. The Parkinson Environment and Genes (PEG) study in California (June 1, 2000, to July 31, 2017) included 634 patients with PD and 733 controls; the Parkinson Disease in Denmark (PASIDA) study (January 1, 2006, to December 31, 2017) included 966 patients with PD and 1045 controls. Data were analyzed from July 1 to October 31, 2024.
Exposures: PRS was computed by summing the effect estimates of well-known risk alleles from an existing genome-wide association study's summary statistics using participants' genetic arrays. TRAP exposure was estimated using dispersion models to calculate long-term exposure (10- or 15-year means with a 5-year lag) to traffic-related pollutants (represented by carbon monoxide [CO] levels) at participants' residences.
Main outcomes and measures: The main outcome was diagnosis of PD. Using multivariable logistic regression, PD risk was estimated from interactions between PRS (per SD) and TRAP exposure (per IQR), with joint effects based on low (quartiles 1-3) and high (quartile 4) exposure levels.
Results: A total of 1600 patients with PD (mean [SD] age, 65.1 [9.9] years; 990 [61.9%] male) and 1778 controls (mean [SD] age, 64.5 [10.3] years; 992 [55.8%] male) were included. Meta-analytical estimates suggest that both higher PRS and increased TRAP exposure increased PD risk, with an interaction effect estimate of 1.06 (95% CI, 1.00-1.12). Joint effect analysis indicated that individuals with both high PRS and high TRAP exposure were at greatest risk of PD (odds ratio, 3.05; 95% CI, 2.23-4.19) compared with the reference group with a low PRS and low TRAP exposure, suggesting a synergistic effect.
Conclusions and relevance: In this gene-environment interaction study, a combination of long-term air pollution exposure and genetic susceptibility strongly contributed to the risk of developing PD. Widespread exposure to air pollution makes TRAP an important modifiable risk factor affecting large populations globally, particularly individuals with genetic vulnerability.
Importance: For younger postmenopausal women, clinical guidelines recommend using osteoporosis risk prediction tools to identify candidates with low bone mineral density (BMD). However, the performance of these tools is not well quantified.
Objective: To examine the performance of Osteoporosis Risk Assessment Instrument (ORAI) and Osteoporosis Index of Risk (OSIRIS), compared with Osteoporosis Self-Assessment Tool (OST), in identifying the presence of osteoporotic BMD in younger postmenopausal women.
Design, setting, and participants: This cross-sectional study used data from the Women's Health Initiative Bone Density Substudy, which was conducted at 3 clinical centers in Tucson and Phoenix, Arizona; Pittsburgh, Pennsylvania; and Birmingham, Alabama. Participants were healthy postmenopausal women aged 50 to 64 years with BMD measurements evaluated using the 3 risk prediction tools: OSIRIS, ORAI, and OST. Risk factors and other participant characteristics were compared across osteoporosis status. Data were collected from October 1993 to December 1998 and analyzed between September 23, 2023, and April 10, 2024.
Exposures: The primary exposures were OSIRIS, ORAI, and OST risk scores.
Main outcomes and measures: Primary outcome was osteoporosis defined by BMD T score of -2.5 or lower at 1 or more of 3 anatomical locations: femoral neck, total hip, and/or lumbar spine. The tools were evaluated via area under the receiver operating characteristic curve (AUC) at published score cutoffs and at alternate cutoffs.
Results: Among 6067 included participants (mean [SD] age at baseline, 57.7 [4.1] years), the prevalence of osteoporosis was 14.1% (n = 857) at any 1 of 3 anatomical sites. AUC for identifying osteoporosis at any site was 0.633 (95% CI, 0.633-0.634) for OSIRIS, 0.663 (95% CI, 0.663-0.664) for ORAI, and 0.654 (95% CI, 0.654-0.655) for OST.
Conclusions and relevance: In this cross-sectional study, 3 guideline-recommended osteoporosis risk assessment tools had fair to moderate discrimination in identifying osteoporosis defined by lowest BMD at any 1 of 3 skeletal sites. Screening is essential to reducing individual and societal burden of osteoporosis and related fractures, and this study showed a gap in identifying younger postmenopausal women using common clinical risk factors.
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