The latest medical research on Geriatric Medicine

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ceRNA network analysis reveals AP-1 transcription factor components as potential biomarkers for Alzheimer's disease.

Current Alzheimer Research

Alzheimer's disease (AD) is a progressive neurodegenerative disease affecting the elderly, characterized by decreased cognitive function. Non-coding RNAs contribute to AD pathogenesis.

To identify potential therapeutic targets for AD, competing endogenous RNA (ceRNA) networks were constructed using the hippocampus of 6-month-old amyloid precursor protein/presenilin 1 double transgenic (APP/PS1) and wild-type mice.

RNA-seq data (GSE158995), generated from the hippocampus of APP/PS1 and wild-type mice, were analyzed with the limma R package to identify significantly differentially expressed mRNAs and circRNAs (DEMs and DECs, respectively). DEM Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed using Enrichr (https://maayanlab.cloud/Enrichr/). Correlations between DEMs and DECs were determined using the ggcorrplot R package. Main clusters and hub DEMs were selected using the STRING database and Cytoscape software. ceRNA interactions were predicted with the miRTarbase and Starbase tools and constructed with the ggalluvial R package and Cytoscape software. ceRNA networks were validated using the quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot.

198 DEMs and 90 DECs were differentially expressed in APP/PS1 vs. wild-type hippocampus. DEM GO analysis revealed significant enrichment in transcription regulation, which was subdivided into three main clusters: transcription regulation, synaptic plasticity, and protein refolding. Within the transcription regulation cluster, AP-1 transcription factor components serve as hub genes. The mmu_circ_0001787(circGLCE)/miR-339-5p/Junb and mmu_circ_0001899(circFAM120C)/miR-181a-5p/Egr1 ceRNA networks were established based on qRT-PCR and Western blot analysis.

Two AP-1 transcription factor component-related ceRNA networks, circGLCE/miR-339-5p/Junb and circFAM120C/miR-181a-5p/Egr1, were constructed using a mouse model of AD. These ceRNA networks may contribute to transcription regulation in AD and provide potential biomarkers for AD diagnosis and treatment.

Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit.

N Engl J

Studies that have evaluated the use of intravenous vitamin C in adults with sepsis who were receiving vasopressor therapy in the intensive care unit (ICU) have shown mixed results with respect to the risk of death and organ dysfunction.

In this randomized, placebo-controlled trial, we assigned adults who had been in the ICU for no longer than 24 hours, who had proven or suspected infection as the main diagnosis, and who were receiving a vasopressor to receive an infusion of either vitamin C (at a dose of 50 mg per kilogram of body weight) or matched placebo administered every 6 hours for up to 96 hours. The primary outcome was a composite of death or persistent organ dysfunction (defined by the use of vasopressors, invasive mechanical ventilation, or new renal-replacement therapy) on day 28.

A total of 872 patients underwent randomization (435 to the vitamin C group and 437 to the control group). The primary outcome occurred in 191 of 429 patients (44.5%) in the vitamin C group and in 167 of 434 patients (38.5%) in the control group (risk ratio, 1.21; 95% confidence interval [CI], 1.04 to 1.40; P = 0.01). At 28 days, death had occurred in 152 of 429 patients (35.4%) in the vitamin C group and in 137 of 434 patients (31.6%) in the placebo group (risk ratio, 1.17; 95% CI, 0.98 to 1.40) and persistent organ dysfunction in 39 of 429 patients (9.1%) and 30 of 434 patients (6.9%), respectively (risk ratio, 1.30; 95% CI, 0.83 to 2.05). Findings were similar in the two groups regarding organ-dysfunction scores, biomarkers, 6-month survival, health-related quality of life, stage 3 acute kidney injury, and hypoglycemic episodes. In the vitamin C group, one patient had a severe hypoglycemic episode and another had a serious anaphylaxis event.

In adults with sepsis receiving vasopressor therapy in the ICU, those who received intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo. (Funded by the Lotte and John Hecht Memorial Foundation; LOVIT ClinicalTrials.gov number, NCT03680274.).

Effects of Previous Infection and Vaccination on Symptomatic Omicron Infections.

N Engl J

The protection conferred by natural immunity, vaccination, and both against symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with the BA.1 or BA.2 sublineages of the omicron (B.1.1.529) variant is unclear.

We conducted a national, matched, test-negative, case-control study in Qatar from December 23, 2021, through February 21, 2022, to evaluate the effectiveness of vaccination with BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna), natural immunity due to previous infection with variants other than omicron, and hybrid immunity (previous infection and vaccination) against symptomatic omicron infection and against severe, critical, or fatal coronavirus disease 2019 (Covid-19).

The effectiveness of previous infection alone against symptomatic BA.2 infection was 46.1% (95% confidence interval [CI], 39.5 to 51.9). The effectiveness of vaccination with two doses of BNT162b2 and no previous infection was negligible (-1.1%; 95% CI, -7.1 to 4.6), but nearly all persons had received their second dose more than 6 months earlier. The effectiveness of three doses of BNT162b2 and no previous infection was 52.2% (95% CI, 48.1 to 55.9). The effectiveness of previous infection and two doses of BNT162b2 was 55.1% (95% CI, 50.9 to 58.9), and the effectiveness of previous infection and three doses of BNT162b2 was 77.3% (95% CI, 72.4 to 81.4). Previous infection alone, BNT162b2 vaccination alone, and hybrid immunity all showed strong effectiveness (>70%) against severe, critical, or fatal Covid-19 due to BA.2 infection. Similar results were observed in analyses of effectiveness against BA.1 infection and of vaccination with mRNA-1273.

No discernable differences in protection against symptomatic BA.1 and BA.2 infection were seen with previous infection, vaccination, and hybrid immunity. Vaccination enhanced protection among persons who had had a previous infection. Hybrid immunity resulting from previous infection and recent booster vaccination conferred the strongest protection. (Funded by Weill Cornell Medicine-Qatar and others.).

Treatment of Anal High-Grade Squamous Intraepithelial Lesions to Prevent Anal Cancer.

N Engl J

The incidence of anal cancer is substantially higher among persons living with the human immunodeficiency virus (HIV) than in the general population. Similar to cervical cancer, anal cancer is preceded by high-grade squamous intraepithelial lesions (HSILs). Treatment for cervical HSIL reduces progression to cervical cancer; however, data from prospective studies of treatment for anal HSIL to prevent anal cancer are lacking.

We conducted a phase 3 trial at 25 U.S. sites. Persons living with HIV who were 35 years of age or older and who had biopsy-proven anal HSIL were randomly assigned, in a 1:1 ratio, to receive either HSIL treatment or active monitoring without treatment. Treatment included office-based ablative procedures, ablation or excision under anesthesia, or the administration of topical fluorouracil or imiquimod. The primary outcome was progression to anal cancer in a time-to-event analysis. Participants in the treatment group were treated until HSIL was completely resolved. All the participants underwent high-resolution anoscopy at least every 6 months; biopsy was also performed for suspected ongoing HSIL in the treatment group, annually in the active-monitoring group, or any time there was concern for cancer.

Of 4459 participants who underwent randomization, 4446 (99.7%) were included in the analysis of the time to progression to cancer. With a median follow-up of 25.8 months, 9 cases were diagnosed in the treatment group (173 per 100,000 person-years; 95% confidence interval [CI], 90 to 332) and 21 cases in the active-monitoring group (402 per 100,000 person-years; 95% CI, 262 to 616). The rate of progression to anal cancer was lower in the treatment group than in the active-monitoring group by 57% (95% CI, 6 to 80; P = 0.03 by log-rank test).

Among participants with biopsy-proven anal HSIL, the risk of anal cancer was significantly lower with treatment for anal HSIL than with active monitoring. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT02135419.).

Chapare Hemorrhagic Fever and Virus Detection in Rodents in Bolivia in 2019.

N Engl J

In June 2019, the Bolivian Ministry of Health reported a cluster of cases of hemorrhagic fever that started in the municipality of Caranavi and expanded to La Paz. The cause of these cases was unknown.

We obtained samples for next-generation sequencing and virus isolation. Human and rodent specimens were tested by means of virus-specific real-time quantitative reverse-transcriptase-polymerase-chain-reaction assays, next-generation sequencing, and virus isolation.

Nine cases of hemorrhagic fever were identified; four of the patients with this illness died. The etiologic agent was identified as Mammarenavirus Chapare mammarenavirus, or Chapare virus (CHAPV), which causes Chapare hemorrhagic fever (CHHF). Probable nosocomial transmission among health care workers was identified. Some patients with CHHF had neurologic manifestations, and those who survived had a prolonged recovery period. CHAPV RNA was detected in a variety of human body fluids (including blood; urine; nasopharyngeal, oropharyngeal, and bronchoalveolar-lavage fluid; conjunctiva; and semen) and in specimens obtained from captured small-eared pygmy rice rats (Oligoryzomys microtis). In survivors of CHHF, viral RNA was detected up to 170 days after symptom onset; CHAPV was isolated from a semen sample obtained 86 days after symptom onset.

M. Chapare mammarenavirus was identified as the etiologic agent of CHHF. Both spillover from a zoonotic reservoir and possible person-to-person transmission were identified. This virus was detected in a rodent species, O. microtis. (Funded by the Bolivian Ministry of Health and others.).

Sequential Stem Cell-Kidney Transplantation in Schimke Immuno-osseous Dysplasia.

N Engl J

Lifelong immunosuppression is required for allograft survival after kidney transplantation but may not ultimately prevent allograft loss resulting ...

A National Assessment of Alzheimer Disease and Antipsychotic Medication Prescribing Among Older Adults in Ambulatory Care Settings.

Alzheimer Disease and Associated Disorders

The objective of this study was to assess antipsychotic prescribing within ambulatory settings in the United States among older adults with Alzheimer disease after adjusting for demographic, provider, and clinical factors.

This cross-sectional cohort study utilized Centers for Disease Control's (CDC) National Ambulatory Medical Care Survey (NAMCS) ambulatory care data from 2014 to 2016 among visits 65 years old or older with any listed diagnosis of Alzheimer. Multivariable logistic regression analyses assessed the association between the outcome of antipsychotic prescribing after controlling for numerous demographic, provider, and clinical covariates. An extension of the Oacaxa-Blinder decomposition was used to assess observed differentials.

An estimated 15,471,125 ambulatory visits involving Alzheimer disease among those 65 years old or older occurred from 2014 to 2016. Antipsychotics were prescribed in 9.3% of these visits, equating to 6.81 times higher multivariable-adjusted odds relative to non-Alzheimer visits (95% confidence interval: 2.86-16.20, P<0.001). The decomposition analysis indicated that the study's predictor variables explained 15.6% of the outcome gap between Alzheimer versus non-Alzheimer visits.

Despite potential mortality risks with antipsychotics in adults 65 years old or older with Alzheimer disease and recommendations discouraging their use, this nationally representative study observed significantly higher odds of prescribing independent of demographic, provider, and clinical characteristics. Polypharmacy may be a risk factor that warrants continued assessment regarding the appropriateness of antipsychotic prescribing in this vulnerable population.

Impact of COVID-19 Pandemic on Research Participation Among Older African Americans.

Alzheimer Disease and Associated Disorders

COVID-19 represents the newest health disparity faced by African Americans (AA). This study assessed the impact of COVID-19 on barriers and willing...

Phase 1 Single Ascending and Multiple Ascending Dose Studies of Phosphodiesterase-9 Inhibitor E2027: Confirmation of Target Engagement and Selection of Phase 2 Dose in Dementia With Lewy Bodies Trial.

Alzheimer Disease and Associated Disorders

E2027 is a novel, highly selective and potent inhibitor of phosphodiesterase9 (PDE9) being evaluated as a treatment for dementia with Lewy bodies.

Phase 1, randomized, double-blind, single ascending dose (SAD, n=96) and multiple ascending dose (MAD, n=68) studies evaluated E2027 doses (5 to 1200 mg) in healthy subjects. The impact of age, race (Japanese/non-Japanese), and food on pharmacokinetics (PK)/pharmacodynamics were evaluated. Serial cerebrospinal fluid (CSF) samples were collected to assess the target engagement.

E2027 PK profiles were biphasic (elimination half-life: ~30 hours. Approximately 3-fold accumulation was observed following multiple once-daily dosing. E2027 single doses of 50 to 400 mg resulted in mean maximum increases in CSF cyclic guanosine monophosphate ranging from 293% to 461% within 5.37 to 12.9 hours after dose administration to assess target engagement. Dose-response modelling of steady-state predose CSF cyclic guanosine monophosphate concentrations showed ≥200% increase from baseline is maintained with doses of ≥50 mg QD. The most common adverse events with E2027 were post-LP syndrome and back pain. PK profiles were similar between Japanese and non-Japanese. Higher exposure observed in fed versus fasted state was not considered clinically significant. PK exposure was higher in elderly subjects.

S.E2027 was well-tolerated following single and multiple administration. E2027 achieved maximal and sustained target engagement at 50 mg QD, the dose selected for the phase 2 clinical trial.

Pelargonidin and Berry Intake Association with Alzheimer's Disease Neuropathology: A Community-Based Study.

Journal of Alzheimer's Disease

An anthocyanidin, pelargonidin, primarily found in berries, has antioxidant and anti-inflammatory properties, and is associated with better cognition and reduced Alzheimer's dementia risk.

This study investigated if pelargonidin or berry intake is associated with Alzheimer's disease (AD) neuropathology in human brains.

The study was conducted among 575 deceased participants (age at death = 91.3±6.1 years; 70% females) of the Rush Memory and Aging Project, with dietary data (assessed using a food frequency questionnaire) and neuropathological evaluations. Calorie-adjusted pelargonidin intake was modeled in quartiles and berry intake as continuous (servings/week). Mean amyloid-beta load and phosphorylated tau neuronal neurofibrillary tangle density across multiple cortical regions were assessed using immunohistochemistry. Global AD pathology burden, a quantitative summary score of neurofibrillary tangles, and diffuse and neuritic plaques using Bielschowsky silver stains in multiple brain regions, was also assessed.

In a linear regression model adjusted for age at death, sex, education, APOE ɛ4 status, vitamin E, and vitamin C, participants in the highest quartile of pelargonidin intake when compared to those in the lowest quartile, had less amyloid-β load (β (SE) = -0.293 (0.14), p = 0.038), and fewer phosphorylated tau tangles (β (SE) = -0.310, p = 0.051). Among APOE ɛ4 non-carriers, higher strawberry (β (SE) = -0.227 (0.11), p = 0.037) and pelargonidin (Q4 versus Q1: β (SE) = -0.401 (0.16), p = 0.011; p trend = 0.010) intake was associated with less phosphorylated tau tangles, no association was observed in APOE ɛ4 carriers. Berry intake was not associated with AD pathology. However, excluding participants with dementia or mild cognitive impairment at baseline, strawberry (p = 0.004) and pelargonidin (ptrend = 0.007) intake were associated with fewer phosphorylated tau tangles.

Higher intake of pelargonidin, a bioactive present in strawberries, is associated with less AD neuropathology, primarily phosphorylated tau tangles.

Effects of Tianeptine Treatment on Depression and Cognitive Function in Patients with Alzheimer's Disease: A 12-Month Retrospective Observational Study.

Journal of Alzheimer's Disease

Depression is a common manifestation in Alzheimer's disease (AD). In clinical practice, antidepressant medication is often used for depression in AD.

We explore the effectiveness of the atypical antidepressant tianeptine compared with other conventional antidepressants in AD patients with depression in a real-life setting.

We retrospectively identified 126 AD patients who had received antidepressant treatment for 12 months with tianeptine or other antidepressants. Subjects were divided into two groups according to the treatment they had received: tianeptine group (n = 38) or other antidepressant group (n = 88). Drug effects on depression, cognition, behavior, and functional performance were evaluated at baseline, 6, and 12 months. A Mixed Effects Model Analysis was carried out to evaluate changes in performance scores.

Both tianeptine and other antidepressants showed an antidepressant effect after 12 months with significant improvement on the Cornell Scale for Depression in Dementia, the Hamilton Depression Rating Scale, and the Neuropsychiatric Inventory-Depression subscale. A statistically significant improvement at 12 months was shown in the tianeptine group versus the other antidepressants group on most of the cognitive measures such as the Mini-Mental State Examination, the Letter and Category Fluency Test, the Rey Auditory Verbal Learning Test, and the Boston Naming Test.

Our results suggest that tianeptine reduces depressive symptoms and improve cognition in AD patients. This could be considered clinically relevant and should inspire the design of future long-term randomized controlled trials that contribute to supporting the use of tianeptine for improving cognitive function in AD patients.

The Impact of Agitation in Dementia on Caregivers: A Real-World Survey.

Journal of Alzheimer's Disease

Dementia patients frequently depend on caregivers. Agitation is a common behavioral dementia symptom particularly burdensome to patients and caregivers.

To assess the association of agitation severity with non-professional caregiver hours, burden, health status, and productivity. Secondarily, to assess the association of agitation severity with these outcomes for patients receiving remote (not living with the patient) and proximate (living with the patient) caregiving.

A retrospective analysis of physician and non-professional caregiver-reported data from a US point-in-time survey. Patients were aged ≥50 years, with early cognitive impairment or dementia. Regression analyses compared outcomes by agitation severity; covariates included age, sex, and clinical characteristics.

Data were included for 1,349 patients (non-agitated n = 656, agitated n = 693; no care n = 305, remote care n = 248, proximate care n = 691; unknown care n = 105). Greater agitation was significantly associated (p <  0.05) in all caregivers with increasing: Zarit Burden Interview (ZBI) Total Caregiver Burden, Personal Strain, Role Strain, and Guilt; Work Productivity and Activity Index (WPAI) presenteeism, overall work impairment, and total activity impairment. Higher ZBI Total Caregiver Burden, Personal Strain, and Role Strain were associated with greater agitation in proximate caregivers and higher ZBI Guilt associated with greater agitation in remote caregivers (p <  0.05). Higher WPAI presenteeism and total activity impairment were associated (p <  0.05) with greater agitation in proximate caregivers. Caregiving hours increased with increasing agitation for proximate caregiving (p = 0.001).

Greater agitation severity was associated with higher caregiver burden and lower productivity, with higher indirect costs a likely outcome of agitation.