Safety Profile and Clinical and Virological Outcomes of Nirmatrelvir-Ritonavir Treatment in Patients With Advanced Chronic Kidney Disease and Coronavirus Disease 2019.

BACKGROUND: Nirmatrelvir-ritonavir is currently not recommended in patients with an estimated glomerular filtration rate (eGFR) <30 mL/minute/1.73 m2. METHODS: To determine the safety profile and clinical and virological outcomes of nirmatrelvir-ritonavir use at a modified dosage in adults with chronic kidney disease (CKD), a prospective, single-arm, interventional trial recruited patients with eGFR <30 mL/minute/1.73 m2 and on dialysis. Primary outcomes included safety profile, adverse/serious adverse events, and events leading to drug discontinuation. Disease symptoms, virological outcomes by serial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral polymerase chain reaction (PCR) tests, rapid antigen tests, and virological and symptomatic rebound were also recorded. RESULTS: Fifty-nine (69.4%) of the 85 participants had stage 5 CKD and were on dialysis. Eighty (94.1%) completed the full treatment course; 9.4% and 5.9% had adverse and serious adverse events, and these were comparable between those with eGFR < or >30 mL/minute/1.73 m2. The viral load significantly decreased on days 5, 15, and 30 (P < .001 for all), and the reduction was consistent in the subgroup with eGFR <30 mL/minute/1.73 m2. Ten patients had virological rebound, which was transient and asymptomatic. CONCLUSIONS: Among patients with CKD, a modified dose of nirmatrelvir-ritonavir is a well-tolerated therapy in mild COVID-19 as it can effectively suppress the SARS-CoV-2 viral load with a favorable safety profile. Virological and symptomatic rebound, although transient with low infectivity, may occur after treatment. Nirmatrelvir-ritonavir should be considered for use in patients with CKD, including stage 5 CKD on dialysis. Clinical Trials Registration. Clinical Trials.gov; identifier: NCT05624840.

Age-related cognitive decline and associations with sex, education and apolipoprotein E genotype across ethnocultural groups and geographic regions: a collaborative cohort study.

BACKGROUND: The prevalence of dementia varies around the world, potentially contributed to by international differences in rates of age-related cognitive decline. Our primary goal was to investigate how rates of age-related decline in cognitive test performance varied among international cohort studies of cognitive aging. We also determined the extent to which sex, educational attainment, and apolipoprotein E ε4 allele (APOE*4) carrier status were associated with decline. METHODS AND FINDINGS: We harmonized longitudinal data for 14 cohorts from 12 countries (Australia, Brazil, France, Greece, Hong Kong, Italy, Japan, Singapore, Spain, South Korea, United Kingdom, United States), for a total of 42,170 individuals aged 54-105 y (42% male), including 3.3% with dementia at baseline. The studies began between 1989 and 2011, with all but three ongoing, and each had 2-16 assessment waves (median = 3) and a follow-up duration of 2-15 y. We analyzed standardized Mini-Mental State Examination (MMSE) and memory, processing speed, language, and executive functioning test scores using linear mixed models, adjusted for sex and education, and meta-analytic techniques. Performance on all cognitive measures declined with age, with the most rapid rate of change pooled across cohorts a moderate -0.26 standard deviations per decade (SD/decade) (95% confidence interval [CI] [-0.35, -0.16], p < 0.001) for processing speed. Rates of decline accelerated slightly with age, with executive functioning showing the largest additional rate of decline with every further decade of age (-0.07 SD/decade, 95% CI [-0.10, -0.03], p = 0.002). There was a considerable degree of heterogeneity in the associations across cohorts, including a slightly faster decline (p = 0.021) on the MMSE for Asians (-0.20 SD/decade, 95% CI [-0.28, -0.12], p < 0.001) than for whites (-0.09 SD/decade, 95% CI [-0.16, -0.02], p = 0.009). Males declined on the MMSE at a slightly slower rate than females (difference = 0.023 SD/decade, 95% CI [0.011, 0.035], p < 0.001), and every additional year of education was associated with a rate of decline slightly slower for the MMSE (0.004 SD/decade less, 95% CI [0.002, 0.006], p = 0.001), but slightly faster for language (-0.007 SD/decade more, 95% CI [-0.011, -0.003], p = 0.001). APOE*4 carriers declined slightly more rapidly than non-carriers on most cognitive measures, with processing speed showing the greatest difference (-0.08 SD/decade, 95% CI [-0.15, -0.01], p = 0.019). The same overall pattern of results was found when analyses were repeated with baseline dementia cases excluded. We used only one test to represent cognitive domains, and though a prototypical one, we nevertheless urge caution in generalizing the results to domains rather than viewing them as test-specific associations. This study lacked cohorts from Africa, India, and mainland China. CONCLUSIONS: Cognitive performance declined with age, and more rapidly with increasing age, across samples from diverse ethnocultural groups and geographical regions. Associations varied across cohorts, suggesting that different rates of cognitive decline might contribute to the global variation in dementia prevalence. However, the many similarities and consistent associations with education and APOE genotype indicate a need to explore how international differences in associations with other risk factors such as genetics, cardiovascular health, and lifestyle are involved. Future studies should attempt to use multiple tests for each cognitive domain and feature populations from ethnocultural groups and geographical regions for which we lacked data.

COSMIC (Cohort Studies of Memory in an International Consortium): an international consortium to identify risk and protective factors and biomarkers of cognitive ageing and dementia in diverse ethnic and sociocultural groups.

BACKGROUND: A large number of longitudinal studies of population-based ageing cohorts are in progress internationally, but the insights from these studies into the risk and protective factors for cognitive ageing and conditions like mild cognitive impairment and dementia have been inconsistent. Some of the problems confounding this research can be reduced by harmonising and pooling data across studies. COSMIC (Cohort Studies of Memory in an International Consortium) aims to harmonise data from international cohort studies of cognitive ageing, in order to better understand the determinants of cognitive ageing and neurocognitive disorders. METHODS/DESIGN: Longitudinal studies of cognitive ageing and dementia with at least 500 individuals aged 60 years or over are eligible and invited to be members of COSMIC. There are currently 17 member studies, from regions that include Asia, Australia, Europe, and North America. A Research Steering Committee has been established, two meetings of study leaders held, and a website developed. The initial attempts at harmonising key variables like neuropsychological test scores are in progress. DISCUSSION: The challenges of international consortia like COSMIC include efficient communication among members, extended use of resources, and data harmonisation. Successful harmonisation will facilitate projects investigating rates of cognitive decline, risk and protective factors for mild cognitive impairment, and biomarkers of mild cognitive impairment and dementia. Extended implications of COSMIC could include standardised ways of collecting and reporting data, and a rich cognitive ageing database being made available to other researchers. COSMIC could potentially transform our understanding of the epidemiology of cognitive ageing, and have a world-wide impact on promoting successful ageing.

Cognitive predictors for five-year conversion to dementia in community-dwelling Chinese older adults.

BACKGROUND: This study evaluates which cognitive measure is best for predicting incident dementia in a population-based random sample of Chinese older adults without dementia over a five-year period. METHODS: A total of 787 community-dwelling Chinese older adults without dementia in Hong Kong were assessed at baseline (T0), at two years (T1), and at five years (T2). RESULTS: The annual conversion rate to dementia was 1.6% and 6.3% for baseline normal participants and baseline mild cognitive impairment (MCI) participants, respectively. The Cantonese version of Mini-mental State Examination (CMMSE) scores declined significantly over time. In participants who progressed to dementia, Category Verbal Fluency Test (CVFT) scores dropped significantly from T0 to T1. A 1-SD drop of either CMMSE or CVFT in two years predicted dementia at five years with 91.5% sensitivity and 62.0% specificity. A stable CMMSE and CVFT at two years predicted a 91% chance of not progressing to clinical dementia at five years. CONCLUSION: In this community sample of Chinese older adults, a decline in cognitive screening tests in short term (two years) offered useful information in predicting dementia conversion over a longer period.

Chlorogenic acid exhibits cholesterol lowering and fatty liver attenuating properties by up-regulating the gene expression of PPAR-α in hypercholesterolemic rats induced with a high-cholesterol diet.

Hypercholesterolemia is a major risk factor for the development of cardiovascular disease and nonalcoholic fatty liver disease. Natural compounds have been proved to be useful in lowering serum cholesterol to slow down the progression of cardiovascular disease and nonalcoholic fatty liver disease. In the present study, the hypocholesterolemic and hepatoprotective effects of the dietary consumption of chlorogenic acid were investigated by monitoring plasma lipid profile (total cholesterol, triglycerides, high-density lipoprotein and low-density lipoprotein) in Sprague-Dawley rats fed with a normal diet, a high-cholesterol diet or a high-cholesterol diet supplemented with chlorogenic acid (1 or 10 mg/kg/day p.o.) for 28 days. Chlorogenic acid markedly altered the increased plasma total cholesterol and low-density lipoprotein but decreased high-density lipoprotein induced by a hypercholesterolemic diet with a dose-dependent improvement on both atherogenic index and cardiac risk factor. Lipid depositions in liver were attenuated significantly in hypercholesterolemic animals supplemented with chlorogenic acid. It is postulated that hypocholesterolemic effect is the primary beneficial effect given by chlorogenic acid, which leads to other secondary beneficial effects such as atheroscleroprotective, cardioprotective and hepatoprotective functions. The hypocholesterolemic functions of chlorogenic acid are probably due to the increase in fatty acids unitization in liver via the up-regulation of peroxisome proliferation-activated receptor α mRNA.

Physical Exercise Helped to Maintain and Restore Functioning in Chinese Older Adults With Mild Cognitive Impairment: A 5-Year Prospective Study of the Hong Kong Memory and Ageing Prospective Study (HK-MAPS).

OBJECTIVE: This study investigated the potential of physical exercise habit as a lifestyle modification against cognitive and functional decline at the community level. METHODS: A total of 454 community-dwelling Chinese older adults without dementia participated in the Hong Kong Memory and Ageing Prospective Study at baseline and follow-up at 5 years. Their cognitive and functional performances were assessed by the Cantonese version of the Mini-Mental State Examination (CMMSE) and the Chinese version of Disability Assessment in Dementia (DAD). Hierarchical multiple regression analyses were performed to examine whether physical exercise was a significant predictor of the follow-up CMMSE and DAD scores after controlling for the covariates. Subgroup analyses were performed with a group of 127 participants with mild cognitive impairment at baseline. RESULTS: Physical exercise habit was a significant predictor for both the follow-up CMMSE scores and DAD scores. Participants with exercise habits of 5 years or more showed better cognitive and functional performances at follow-up. Participants who picked up exercise habits only after the baseline assessment also demonstrated better functioning at follow-up. The same patterns were observed in the subgroup analyses with the mild cognitive impairment group. CONCLUSION: Results suggested that prolonged exercise habit is required for positive effects on cognition to emerge, but benefits on functioning can be observed when individuals take up an exercise habit later in life or even after the beginning of cognitive decline. These findings are encouraging in promoting an exercise habit among older adults living in the community.

Spectrum of critical illness in undocumented border crossers. The Arizona-Mexico border experience.

RATIONALE: Approximately 150-250 migrants die each year while attempting to cross the border from Mexico to the Southwest United States. Many border crossers survive the journey, but some develop life-threatening medical complications. Such complications have been subject to little formal analysis. OBJECTIVES: We sought to determine the causes of critical illness in this population and to analyze the hospital course and outcomes of these patients. METHODS: We retrospectively identified border crossers admitted to the intensive care units (ICUs) of two major teaching hospitals in southern Arizona. We recorded admitting diagnoses, severity of illness, length of stay, resource use, discharge diagnoses, and mortality. RESULTS: Our investigation identified 55 admissions to adult ICUs between January 1, 2010 and December 31, 2012. The median age of patients was 27 years. The median hospital length of stay was 7 days, with a median ICU length of stay of 3 days. The median temperature on arrival to the emergency department was 36.8°C. The most common admission diagnoses included trauma (40), rhabdomyolysis (27), acute liver injury (25), dehydration (24), acute kidney injury (19), and encephalopathy (17). Thirteen patients presented with respiratory failure, six patients with severe sepsis, and two with septic shock. A total of 19 patients required ventilator support during their hospital stay, and 30 required at least one surgical intervention. One patient required renal replacement therapy. The median Acute Physiology and Chronic Health Evaluation II score was 6. All but one patient survived to discharge from the hospital. CONCLUSIONS: Border crossers are a unique population of young individuals exposed to high temperatures and extreme conditions. Our review of border crosser admissions showed that most patients demonstrated signs of dehydration and leukocytosis, despite a normal median temperature. The median ICU stay was short, despite a high number of patients requiring ventilator support and surgical intervention. Only one death occurred in this cohort.

The Prevalence of Mild Cognitive Impairment in Diverse Geographical and Ethnocultural Regions: The COSMIC Collaboration.

BACKGROUND: Changes in criteria and differences in populations studied and methodology have produced a wide range of prevalence estimates for mild cognitive impairment (MCI). METHODS: Uniform criteria were applied to harmonized data from 11 studies from USA, Europe, Asia and Australia, and MCI prevalence estimates determined using three separate definitions of cognitive impairment. RESULTS: The published range of MCI prevalence estimates was 5.0%-36.7%. This was reduced with all cognitive impairment definitions: performance in the bottom 6.681% (3.2%-10.8%); Clinical Dementia Rating of 0.5 (1.8%-14.9%); Mini-Mental State Examination score of 24-27 (2.1%-20.7%). Prevalences using the first definition were 5.9% overall, and increased with age (P < .001) but were unaffected by sex or the main races/ethnicities investigated (Whites and Chinese). Not completing high school increased the likelihood of MCI (P ≤ .01). CONCLUSION: Applying uniform criteria to harmonized data greatly reduced the variation in MCI prevalence internationally.

Subjective complaints and self-evaluation of memory test performance in Questionable dementia.

BACKGROUND: The clinical significance of subjective memory complaints in elderly subjects has been an area of active research. In this study, we evaluated subjective complaints and self-evaluation of memory test performance in subjects with Questionable dementia (QD) and mild Alzheimer's disease (AD). METHODS: Ninety-two subjects (35 cognitively intact normal controls NC, 33 QD, and 24 mild AD) were assessed. Subjective memory complaints were evaluated using a memory inventory for the Chinese (MIC); objective assessment of awareness was assessed by the self-evaluation of own memory test performance. Cognitive function was assessed with the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), Category Verbal Fluency Test (CVFT) and Executive Interview (EXIT-25). Depressive symptoms were evaluated with the Cornell Scale for Depression in Dementia (CSDD). RESULTS: The total number of subjective memory complaints (MI-tol) were significantly different between different subject groups (Kruskal Wallis test, chi2 = 13.19, p = 0.001). Significant correlations between scores of the MI-tol and CSDD (r = 0.33, p < 0.001), CMMSE (r = -0.33, p < 0.001), CDR (r = 0.36, p < 0.001) were found. In self-evaluation of memory test performance, the NC group tended to under-estimate while the AD subjects tended to over-estimate their performance. Group differences in the discrepancies of self-evaluation of memory performance were significant for both the immediate (Kruskal Wallis test, chi2 = 9.86, p = 0.007) and delayed recall (Kruskal Wallis test, chi2 = 10.55, p < 0.001) trials. CONCLUSIONS: Subjects with QD and mild AD showed higher frequency of subjective memory complaints, reflecting that the subjects still retain some ability to appreciate own memory function. However, the trend for over-estimation of performance in AD subjects suggests that the precision of estimation may be suboptimal. Moreover, depressive symptoms may affect the presentation of memory complaints and this factor should be carefully considered in future prospective studies.