A multidimensional frailty approach in predicting and preventing dementia

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Direction of arrival estimation using a cluster of beams in a cone-shaped digital array radar'

In this paper some potential system and processing advantages of conformal cone shaped digital array radar have been investigated, in particular in relation to potential alternative approaches for angle estimation with respect to the traditional monopulse. First of all potential benefit in terms of reduction of the number of radiating elements is shown when a conical array is considered with respect to a traditional system formed by four planar arrays, if a coverage of 360° must be assured. Secondly, having in mind an innovative digital array system where the received signals are analog to digital converted at element level and the corresponding data are possibly transferred to a central elaboration unit, an alternative approach is investigated for angular estimation. In this paper we derive the theoretical expression of the Cramer Rao Lower Bound for elevation angle estimation using a cluster of beams; we compare the limit performance of the traditional approach for angle estimation based on Sum and Difference beams with the approach based on a crowded cluster of RX beams properly spaced. The approaches show approximately equivalent performance, making the second particularly interesting for those situations where monopulse is known to experience performance degradation, as low elevation angle estimation; in this particular case an example of cluster design is shown, where the direct signal from a low altitude target must compete with a specular multipath

Studying informal care during the pandemic: mental health, gender and job status

Unexpected negative health shocks such as COVID-19 put pressure on households to provide more care to relatives and friends. This study uses data from the UK Household Longitudinal Study to investigate the impact of informal caregiving on mental health during the COVID-19 pandemic. Using a difference-in-differences analysis, we find that individuals who started providing care after the pandemic began reported more mental health issues than those who never provided care. Additionally, the gender gap in mental health widened during the pandemic, with women more likely to report mental health issues. We also find that those who began providing care during the pandemic reduced their work hours compared to those who never provided care. Our results suggest that the COVID-19 pandemic has had a negative impact on the mental health of informal caregivers, particularly for women

Alternative pharmacological treatment options for agitation in Alzheimer's disease

In patients with dementia and Alzheimer's disease (AD), treatment of neuropsychiatric symptoms (NPS) is a major concern in the management of these devastating diseases. Among NPS in AD, agitation and aggression are common with earlier institutionalization, increased morbidity and mortality, and greater caregiver burden. Pharmacological treatments for AD-related agitation, specifically off-label use of atypical antipsychotics, showed only modest improvements, with increased side-effect burden and risk of mortality. Non-pharmacological treatment approaches have become the preferred firstline option. However, when such treatments fail, pharmacological options are often used. Therefore, there is an urgent need to identify effective and safe pharmacological treatments for agitation/aggression in AD and dementia. Unfortunately, progresses have been slow, with a small number of methodologically heterogeneous randomized controlled trials (RCTs), with disappointing results. However, evidence coming from recently completed RCTs on novel or repositioned drugs (mibampator, dextromethorphan/ quinidine, cannabinoids, and citalopram) showed some promise in treating agitation in AD, but still with safety concerns. Further evidence will come from ongoing Phase II and III trials on promising novel drugs for treating these distressing symptoms in patients with AD and dementia

The metabolic fingerprints of HCV and HBV infections studied by Nuclear Magnetic Resonance Spectroscopy

Abstract Few studies are available on metabolic changes in liver injuries and this is the first metabolomic study evaluating a group of HCV-positive patients, before and after viral eradication via DAA IFN-free regimens, using 1H-NMR to characterize and compare their serum fingerprints to naïve HBV-patients and healthy donors. The investigation clearly shows differences in the metabolomic profile of HCV patients before and after effective DAA treatment. Significant changes in metabolites levels in patients undergoing therapy suggest alterations in several metabolic pathways. It has been shown that 1H-NMR fingerprinting approach is an optimal technique in predicting the specific infection and the healthy status of studied subjects (Monte-Carlo cross validated accuracies: 86% in the HCV vs HBV model, 98.7% in the HCV vs HC model). Metabolite data collected support the hypothesis that the HCV virus induces glycolysis over oxidative phosphorylation in a similar manner to the Warburg effect in cancer, moreover our results have demonstrated a different action of the two viruses on cellular metabolism, corroborating the hypothesis that the metabolic perturbation on patients could be attributed to a direct role in viral infection. This metabolomic study has revealed some alteration in metabolites for the first time (2-oxoglutarate and 3-hydroxybutrate) concerning the HCV-infection model that could explain several extrahepatic manifestations associated with such an infection

Inhibition of Polycomb Repressive Complex2 activity reduces trimethylation of H3K27 and affects development in Arabidopsis seedlings

Background: Polycomb repressive complex 2 (PRC2) is an epigenetic transcriptional repression system, whose catalytic subunit (ENHANCER OF ZESTE HOMOLOG 2, EZH2 in animals) is responsible for trimethylating histone H3 at lysine 27 (H3K27me3). In mammals, gain-of-function mutations as well as overexpression of EZH2 have been associated with several tumors, therefore making this subunit a suitable target for the development of selective inhibitors. Indeed, highly specific small-molecule inhibitors of EZH2 have been reported. In plants, mutations in some PRC2 components lead to embryonic lethality, but no trial with any inhibitor has ever been reported. Results: We show here that the 1,5-bis (3-bromo-4-methoxyphenyl)penta-1,4-dien-3-one compound (RDS 3434), previously reported as an EZH2 inhibitor in human leukemia cells, is active on the Arabidopsis catalytic subunit of PRC2, since treatment with the drug reduces the total amount of H3K27me3 in a dose-dependent fashion. Consistently, we show that the expression level of two PRC2 targets is significantly increased following treatment with the RDS 3434 compound. Finally, we show that impairment of H3K27 trimethylation in Arabidopsis seeds and seedlings affects both seed germination and root growth. Conclusions: Our results provide a useful tool for the plant community in investigating how PRC2 affects transcriptional control in plant development

Different Cognitive Frailty Models and Health- and Cognitive-related Outcomes in Older Age: From Epidemiology to Prevention

Frailty, a critical intermediate status of the aging process that is at increased risk for negative health-related events, includes physical, cognitive, and psychosocial domains or phenotypes. Cognitive frailty is a condition recently defined by operationalized criteria describing coexisting physical frailty and mild cognitive impairment (MCI), with two proposed subtypes: potentially reversible cognitive frailty (physical frailty/MCI) and reversible cognitive frailty (physical frailty/pre- MCI subjective cognitive decline). In the present article, we reviewed the framework for the definition, different models, and the current epidemiology of cognitive frailty, also describing neurobiological mechanisms, and exploring the possible prevention of the cognitive frailty progression. Several studies suggested a relevant heterogeneity with prevalence estimates ranging 1.0–22.0% (10.7–22.0% in clinical-based settings and 1.0–4.4% in population-based settings). Cross-sectional and longitudinal population-based studies showed that different cognitive frailty models may be associated with increased risk of functional disability, worsened quality of life, hospitalization, mortality, incidence of dementia, vascular dementia, and neurocognitive disorders. The operationalization of clinical constructs based on cognitive impairment related to physical causes (physical frailty, motor function decline, or other physical factors) appears to be interesting for dementia secondary prevention given the increased risk for progression to dementia of these clinical entities. Multidomain interventions have the potential to be effective in preventing cognitive frailty. In the near future, we need to establish more reliable clinical and research criteria, using different operational definitions for frailty and cognitive impairment, and useful clinical, biological, and imaging markers to implement intervention programs targeted to improve frailty, so preventing also late-life cognitive disorders

Tau-Centric Targets and Drugs in Clinical Development for the Treatment of Alzheimer's Disease

The failure of several Phase II/III clinical trials in Alzheimer's disease (AD) with drugs targeting \u3b2-amyloid accumulation in the brain fuelled an increasing interest in alternative treatments against tau pathology, including approaches targeting tau phosphatases/kinases, active and passive immunization, and anti-tau aggregation. The most advanced tau aggregation inhibitor (TAI) is methylthioninium (MT), a drug existing in equilibrium between a reduced (leuco-methylthioninium) and oxidized form (MT+). MT chloride (methylene blue) was investigated in a 24-week Phase II clinical trial in 321 patients with mild to moderate AD that failed to show significant positive effects in mild AD patients, although long-term observations (50 weeks) and biomarker studies suggested possible benefit. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected AD patients and cerebral blood flow in mildly affected patients. Further clinical evidence will come from the large ongoing Phase III trials for the treatment of AD and the behavioral variant of frontotemporal dementia on a new form of this TAI, more bioavailable and less toxic at higher doses, called TRx0237. More recently, inhibitors of tau acetylation are being actively pursued based on impressive results in animal studies obtained by salsalate, a clinically used derivative of salicylic acid

CYP2D6 genotypes in revolving door patients with bipolar disorders: A case series

RATIONALE: In psychiatric disorders, interindividual differences in cytochrome P450 (CYP)2D6 (CYP2D6) enzymatic activity could be responsible of adverse drug reactions (ADRs) and therapeutic failures (TFs) for CYP2D6-metabolized drugs, contributing to the periodical hospital readmissions of the revolving door (RD) condition.PATIENT CONCERNS: We investigated CYP2D6 genotypes in a controlled series of 5 consecutive RD patients with Bipolar Disorder (BD).DIAGNOSES: Psychiatric patients affected by Bipolar Disorder.INTERVENTIONS: We defined TFs as a difference at the Brief Psychiatric Rating Scale score \u394BPRS\u200a<\u200a25% at each 1-week of stable treatment, and ADRs as the onset of extrapyramidal symptoms and/or metabolic impairment with weight gain.OUTCOMES: At 3 months, a mean number of 2.75\u200a\ub1\u200a1.26 ADR and a mean \u394BPRS score of 16.07\u200a\ub1\u200a0.05% were observed. At 6 months of follow-up, compared to the only patient without BD (\u394BPRS\u200a<\u200a32.10%), BD patients (n\u200a=\u200a4) showed TFs (\u394BPRS\u200a<\u200a25%). CYP2D6 genotyping revealed intermediate metabolizer phenotypes for BD patients and an extensive metabolizer phenotype for the patient without BD. In BD patients, the ratio of drugs maintained/discontinued for TFs or ADRs was 1.75 for non-CYP2D6 versus 0.33 for CYP2D6 interacting drugs, while the proportion of ADR:TF was 0:4 versus 6:3.LESSONS: Our findings may suggest that CYP2D6 clinically relevant genotypes may be involved in the unwanted outcomes observed in RD patients with BD

Design, synthesis and biological evaluation of new pyrimidine derivatives as anticancer agents

BACKGROUND: Anticancer drug resistance is a challenging phenomenon of growing concern which arises from alteration in drug targets. Despite the fast speed of new chemotherapeutic agent design, the increasing prevalence of this phenomenon requires further research and treatment development. Recently, we reported a new aminopyrimidine compound-namely RDS 344-as a potential innovative anticancer agent.METHODS: Herein, we report the design, synthesis, and anti-proliferative activity of new aminopyrimidine derivatives structurally related to RDS 3442 obtained by carrying out substitutions at position 6 of the pyrimidine core and/or on the 2-aniline ring of our hit. The ability to inhibit cell proliferation was evaluated on different types of tumors, glioblastoma, triple-negative breast cancer, oral squamous cell carcinomas and colon cancer plus on human dermal fibroblasts chosen as control of normal cells.RESULTS: The most interesting compound was the N-benzyl counterpart of RDS 3442, namely 2a, that induced a significant decrease in cell viability in all the tested tumor cell lines, with EC50s ranging from 4 and 8 muM, 4-13 times more active of hit.CONCLUSIONS: These data suggest a potential role for this class of molecules as promising tool for new approaches in treating cancers of different histotype