Cerebral Folate Metabolism in Post-Mortem Alzheimer's Disease Tissues: A Small Cohort Study.

We investigated the cerebral folate system in post-mortem brains and matched cerebrospinal fluid (CSF) samples from subjects with definite Alzheimer's disease (AD) (n = 21) and neuropathologically normal brains (n = 21) using immunohistochemistry, Western blot and dot blot. In AD the CSF showed a significant decrease in 10-formyl tetrahydrofolate dehydrogenase (FDH), a critical folate binding protein and enzyme in the CSF, as well as in the main folate transporter, folate receptor alpha (FRα) and folate. In tissue, we found a switch in the pathway of folate supply to the cerebral cortex in AD compared to neurologically normal brains. FRα switched from entry through FDH-positive astrocytes in normal, to entry through glial fibrillary acidic protein (GFAP)-positive astrocytes in the AD cortex. Moreover, this switch correlated with an apparent change in metabolic direction to hypermethylation of neurons in AD. Our data suggest that the reduction in FDH in CSF prohibits FRα-folate entry via FDH-positive astrocytes and promotes entry through the GFAP pathway directly to neurons for hypermethylation. This data may explain some of the cognitive decline not attributable to the loss of neurons alone and presents a target for potential treatment.

Outcomes of COVID-19 in Solid Organ Transplant Recipients: A Propensity-matched Analysis of a Large Research Network.

BACKGROUND: Organ transplant recipients comprise an immunocompromised and vulnerable cohort. Outcomes of coronavirus disease 2019 (COVID-19) in solid organ transplant (SOT) recipients remain understudied. METHODS: We used a multicenter federated research network to compare clinical outcomes of COVID-19 in patients with SOT to a propensity--matched cohort of patients without SOT. RESULTS: We identified 2307 SOT recipients and 231 047 nontransplant patients with COVID-19. Transplant patients were more likely to be male individuals, older, have a body mass index >30 kg/m2, and have comorbid hypertension, diabetes, nicotine dependence, heart failure, and ischemic heart disease compared with the nontransplant group (P < 0.05). One-to-one matching was performed for diabetes, hypertension, chronic lung diseases, race, nicotine dependence, heart failure, ischemic heart disease, and gender. There was no difference in the composite outcome of intubation or mechanical ventilation at 30 days (risk ratio [RR], 1.04; 95% confidence interval [CI], 0.86-1.26) or 60 days (RR, 1.03; 95% CI, 0.86-1.24) between the 2 groups. Hospitalization rate was higher in the transplant cohort (30.97% versus 25.47%; RR, 1.22; 95% CI, 1.11-1.34). There was no difference in mortality at 30 days (6.45% versus 5.29%; RR, 1.22; 95% CI, 0.88-1.68) or 60 days postdiagnosis (RR, 1.05; 95% CI, 0.83-1.32). More patients in the SOT group developed acute renal injury compared with non-SOT cohort (24.73% versus 14.29%; RR, 1.73; 95% CI, 1.53-1.96). CONCLUSIONS: Patients with SOT have high COVID-19-related mortality; however, propensity-matched analyses reveal that this increased risk is secondary to higher burden of comorbidities. SOT status independently increases risk of hospital admission and acute kidney injury.

Outcomes of SARS-CoV-2 infection in patients with cystic fibrosis: A multicenter retrospective research network study.

BACKGROUND: In this study, we report clinical outcomes in COVID-19 infection in a large cohort of people with cystic fibrosis (pwCF) and compare these outcomes to a propensity score matched cohort of people without CF. METHODS: Analysis of a multicenter research network TriNETX was performed including patients more than 16 years of age diagnosed with COVID-19. Outcomes in COVID-19 positive pwCF were compared with a propensity-matched cohort of people without CF. RESULTS: A total of 507,810 patients with COVID-19 were included (422 patients, 0.08% with CF; 507,388 patients, 99.92% without CF. Mean age at COVID-19 diagnosis in CF cohort was 46.6 ± 19.3 years, with female predominance (n = 225, 53.32%). Majority of the participants were Caucasian (n = 309, 73.22%). In the crude, unmatched analysis, mortality, hospitalization, critical care need, mechanical ventilation, acute kidney injury and composite (combination of intubation and mortality) outcome at 30 days was higher in the pwCF. Following robust propensity matching, pwCF had higher hospitalization rate (RR 1.56, 95% CI 1.20-2.04), critical care need (RR 1.78, 95% CI 1.13-2.79), and acute renal injury (RR 1.60, 95% CI 1.07-2.39) as compared to patients without CF. CONCLUSION: People with CF are at risk of poor outcomes with COVID-19.5.2% of these patients died within one month of COVID-19 diagnosis, and more than one in 10 patients required critical care. Therefore, the relatively young median age of cystic fibrosis patients, and lower prevalence of obesity do not protect these patients from severe disease contrary to prior reports.

Outcomes of SARS-CoV-2 infection in patients with pulmonary sarcoidosis: A multicenter retrospective research network study.

BACKGROUND: Analyses of COVID-19 infection outcomes in patients with preexisting pulmonary sarcoidosis are lacking and are limited to case reports or small case series with the largest study reporting outcomes of 37 patients. RESEARCH QUESTION: Retrospective cohort study to assess clinical outcomes of 945 patients with pulmonary sarcoidosis, presenting with COVID 19, compared to a propensity matched cohort of patients without sarcoidosis. STUDY DESIGN AND METHODS: Analysis of a multi-center research network TriNETX was performed including patients more than 16 years of age diagnosed with COVID-19. Outcomes in COVID-19 positive patients with concurrent pulmonary sarcoidosis were compared with a propensity score matched cohort of patients without pulmonary sarcoidosis. RESULTS: A total of 278,271 patients with COVID-19 on the research network were identified, 954 patients (0.34 %) carried a diagnosis of pulmonary sarcoidosis. Mean age of patients with sarcoidosis was 56.3 ± 13.2 years, with female predominance (n = 619, 64.89 %). 49.69 % of the participants were African American (n = 474). Co-morbidities including hypertension, chronic lower respiratory diseases, diabetes mellitus, ischemic heart disease, nicotine dependence, and chronic kidney disease were more common in patients with pulmonary sarcoidosis when compared to the non-pulmonary sarcoidosis cohort (all p values < 0.01). In unmatched analysis, pulmonary sarcoidosis group had higher mortality, increased risk for hospitalization, intubation and need for renal replacement therapy. After propensity score matching, no difference in any of the outcome measures was observed. INTERPRETATION: Crude COVID-19 mortality and other clinical outcome measures are poor in pulmonary sarcoidosis cohort; however, propensity-matched analyses revealed no difference in outcomes, showing that higher mortality is driven by higher burden of comorbidities.

Are We Overradiating Patients with Irritable Bowel Syndrome?

INTRODUCTION: Protracted exposures to small doses of radiation, even cumulative effective doses (CED) as low as 50-100 mSv, may increase the risk for malignancy. Medical radiation exposure has not been rigorously examined for patients with irritable bowel syndrome (IBS). We examined medical radiation exposure in patients with IBS at a tertiary care center in the USA. METHODS: Patients diagnosed with IBS at our institute from 2009 to 2018 were included in a retrospective cohort study. Medical charts were examined to calculate total and annual CED. RESULTS: 221 patients were included; mean CED was 40.32 mSv (SD: 54.36). Fifty-nine participants (26.7%) received >50 mSv of CED with 27 participants (12.2%) exceeding 100 mSv. Conventional imaging, nuclear medicine, and fluoroscopy accounted for 74.08, 12.93, and 12.98% of total CED, respectively. CT scans contributed to 66.61% of total CED. Outpatient orders accounted for 37.96% of total CED, while 31.4% of total CED was ordered in the emergency department. Population-specific high total CED was calculated as 105.65 mSv. Multivariable binomial logistic regression model found that comorbid anxiety, chronic pain medication use, and diarrhea-predominant IBS were independently positively associated with population-specific high CED exposure. No significant temporal trend in peri-diagnostic mean CED was found. CONCLUSION: Patients with IBS receive high amounts of medical radiation, with 1 in 4 patients reaching at-risk levels of 50 mSv or more. Usage of pain medication at home, comorbid anxiety, and IBS-D are independently linked to an increased risk of high CED.

Characteristics and outcomes of COVID-19 in patients with HIV: a multicentre research network study.

OBJECTIVE: We studied clinical outcomes of COVID-19 infection in patients living with HIV (PLH) in comparison to non-HIV population. DESIGN: Analysis of a multicentre research network TriNETX was performed including patients more than 10 years of age diagnosed with COVID-19. METHODS: Outcomes in COVID-19 positive patients with concurrent HIV (PLH) were compared with a propensity-matched cohort of patients without HIV (non-PLH). RESULTS: Fifty thousand one hundred and sixty-seven patients with COVID-19 were identified (49,763 non-PLH, 404 PLH). PLH were more likely to be men, African-American, obese and have concurrent hypertension, diabetes, chronic kidney disease and nicotine dependence compared with non-PLH cohort (all P values <0.05). We performed 1 : 1 matching for BMI, diabetes, hypertension, chronic lung diseases, chronic kidney disease, race, history of nicotine dependence and sex. In unmatched analysis, PLH had higher mortality at 30 days [risk ratio 1.55, 95% confidence interval (95% CI): 1.01-2.39] and were more likely to need inpatient services (risk ratio 1.83, 95% CI: 1.496-2.24). After propensity score matching, no difference in mortality was noted (risk ratio 1.33, 95% CI: 0.69-2.57). A higher proportion of PLH group needed inpatient services (19.31 vs. 11.39%, risk ratio 1.696, 95% CI: 1.21-2.38). Mean C-reactive protein, ferritin, erythrocyte sedimentation rate and lactate dehydrogenase levels after COVID-19 diagnosis were not statistically different and mortality was not different for PLH with a history of antiretroviral treatment. CONCLUSION: Crude COVID-19 mortality is higher in PLH; however, propensity-matched analyses revealed no difference in outcomes, showing that higher mortality is driven by higher burden of comorbidities. Early diagnosis and intensive surveillance are needed to prevent a 'Syndemic' of diseases in this vulnerable cohort.