Abstract The pathway leading from beta-amyloid deposition to cognitive impairment is believed to be a cornerstone of the pathogenesis of Alzheimer’s disease (AD). However, what drives amyloid ...build-up in sporadic non-genetic cases of AD is still unknown. AD brains feature an inflammatory reaction around amyloid plaques, and a specific subset of the gut microbiota (GMB) may promote brain inflammation. We investigated the possible role of the GMB in AD pathogenesis by studying the association of brain amyloidosis with (i) GMB taxa with pro- and anti-inflammatory activity, and (ii) peripheral inflammation in cognitively impaired patients. We measured the stool abundance of selected bacterial GMB taxa ( Escherichia/Shigella, Pseudomonas aeruginosa , Eubacterium rectale, Eubacterium hallii, Faecalibacterium prausnitzii and Bacteroides fragilis ) and the blood expression levels of cytokines (pro-inflammatory cytokines: CXCL2, CXCL10, IL-1β, IL-6, IL-18, IL-8, NLRP3, TNF-α; anti-inflammatory cytokines: IL-4, IL-10, IL-13) in cognitively impaired patients with (n=40, Amy+) and with no brain amyloidosis (n=33, Amy-), and also in a group of controls (n=10, no brain amyloidosis and no cognitive impairment, HC). Amy+ patients showed higher levels of pro-inflammatory cytokines (IL-6, CXCL2, NLRP3 and IL-1β) compared to both controls and to Amy- patients. A reduction of the anti-inflammatory cytokine IL-10 was observed in Amy+ versus Amy-. Amy+ showed lower abundance of Eubacterium rectale and higher abundance of Escherichia/Shigella as compared to both HC (Fold Change, FC=-9.6, p<0.001 and FC=+12.8, p<0.001, respectively ) and to Amy- (FC=-7.7, p<0.001 and FC=+7.4, p=0.003 ). A positive correlation was observed between pro-inflammatory cytokines IL-1β, NLRP3 and CXCL2 with abundance of the inflammatory bacteria taxon Escherichia/Shigella (rho=0.60, p<0.001; rho=0.57, p<0.001; and rho=0.30, p=0.007, respectively) and a negative correlation with the anti-inflammatory Eubacterium rectale ( rho=-0.48, p<0.001; rho=-0.25, p=0.024; rho=-0.49, p<0.001). Our data indicate that an increase in the abundance of a pro-inflammatory GMB taxon, Escherichia/Shigella , and a reduction in the abundance of an anti-inflammatory taxon, Eubacterium rectale , are possibly associated with a peripheral inflammatory state in patients with cognitive impairment and brain amyloidosis. A possible causal relation between GMB-related inflammation and amyloidosis deserves further investigation.
This study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium ...channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated anti-inflammatory and anti-tau activity in preclinical studies, properties that could have disease-modifying effects for Alzheimer disease. We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease.
NILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015. The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine). Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged >50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of ≥12 and <27. Participants were randomly assigned to 8 mg sustained-release nilvadipine or matched placebo. The a priori defined primary outcome was progression on the Alzheimer's Disease Assessment Scale Cognitive Subscale-12 (ADAS-Cog 12) in the modified intention-to-treat (mITT) population (n = 498), with the Clinical Dementia Rating Scale sum of boxes (CDR-sb) as a gated co-primary outcome, eligible to be promoted to primary end point conditional on a significant effect on the ADAS-Cog 12. The analysis set had a mean age of 73 years and was 62% female. Baseline demographic and Alzheimer disease-specific characteristics were similar between treatment groups, with reported mean of 1.7 years since diagnosis and mean SMMSE of 20.4. The prespecified primary analyses failed to show any treatment benefit for nilvadipine on the co-primary outcome (p = 0.465). Decline from baseline in ADAS-Cog 12 on placebo was 0.79 (95% CI, -0.07-1.64) at 13 weeks, 6.41 (5.33-7.49) at 52 weeks, and 9.63 (8.33-10.93) at 78 weeks and on nilvadipine was 0.88 (0.02-1.74) at 13 weeks, 5.75 (4.66-6.85) at 52 weeks, and 9.41 (8.09-10.73) at 78 weeks. Exploratory analyses of the planned secondary outcomes showed no substantial effects, including on the CDR-sb or the Disability Assessment for Dementia. Nilvadipine appeared to be safe and well tolerated. Mortality was similar between groups (3 on nilvadipine, 4 on placebo); higher counts of adverse events (AEs) on nilvadipine (1,129 versus 1,030), and serious adverse events (SAEs; 146 versus 101), were observed. There were 14 withdrawals because of AEs. Major limitations of this study were that subjects had established dementia and the likelihood that non-Alzheimer subjects were included because of the lack of biomarker confirmation of the presence of brain amyloid.
The results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease.
Clinicaltrials.gov NCT02017340, EudraCT number 2012-002764-27.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Challenges in the management of chronic wound infections Falcone, Marco; De Angelis, Barbara; Pea, Federico ...
Journal of global antimicrobial resistance,
September 2021, 2021-09-00, 20210901, 2021-09-01, Letnik:
26
Journal Article
Recenzirano
Odprti dostop
•Distinction between chronic uninfected from infected wounds is challenging.•Culturing of all chronic wounds is inappropriate.•Debridement is an important step to facilitate the wound healing ...process.•Patients with chronic wound infections require a multidisciplinary approach.•Systemic antibiotics should not be limited to infected cases.
Chronic wound infections may delay the healing process and are responsible for a significant burden on healthcare systems. Since inappropriate management may commonly occur in the care of these patients, this review aims to provide a practical guide underlining actions to avoid in the management of chronic wound infections.
We performed a systematic review of the literature available in PubMed in the last 10 years, identifying studies regarding the management of patients with chronic wound infections. A panel of experts discussed the potential malpractices in this area. A list of ‘Don'ts’, including the main actions to be avoided, was drawn up using the ‘Choosing Wisely’ methodology.
In this review, we proposed a list of actions to avoid for optimal management of patients with chronic wound infections. Adequate wound bed preparation and wound antisepsis should be combined, as the absence of one of them leads to delayed healing and a higher risk of wound complications. Moreover, avoiding inappropriate use of systemic antibiotics is an important point because of the risk of selection of multidrug-resistant organisms as well as antibiotic-related adverse events.
A multidisciplinary team of experts in different fields (surgeon, infectious disease expert, microbiologist, pharmacologist, geriatrician) is required for the optimal management of chronic wound infections. Implementation of this approach may be useful to improve the management of patients with chronic wound infections.
People with dementia and informal carers often access formal care late in the process of dementia. The barriers and facilitators to service use from the perspectives of different stakeholders ...involved are not well understood. Thus, we aimed to explore the barriers and facilitators of access to and utilisation of formal care from the perspectives of people with dementia, their informal carers and health and social care professionals.
Focus groups with people with dementia, informal carers and professionals were conducted in eight European countries. Recruitment targeted people with dementia, informal carers with experience of formal care and professionals involved in providing (access to) formal care. Qualitative content analysis using open coding was used on a national level. Cross-national synthesis was based on the translated national reports.
Overall, 55 focus groups with 261 participants were conducted, involving 51 people with dementia, 96 informal carers and 114 professionals. Sixteen categories describing barriers and facilitators were identified, referring to three global themes: Aspects related to 1) individuals involved, 2) the system or 3) overarching aspects. The attitudes and beliefs of people with dementia and their carers may have a major impact, and they often serve as barriers. Formal care was perceived as a threat to the individual independence of people with dementia and was thus avoided as long as possible. A healthcare professional serving as a constant key contact person could be an essential facilitator to overcome these barriers. Contact should be initiated proactively, as early as possible, and a trusting and consistent relationship needs to be established. Beyond that, the findings largely confirm former research and show that barriers to accessing and using formal care still exist across Europe despite a number of national and European initiatives.
Further investigations are needed to elaborate how the concept of a key contact person could be integrated with existing case management approaches and how the independence and autonomy of people with dementia can be strengthened when formal care needs to be accessed and used. These may be meaningful facilitators regarding enhanced access to formal care for people with dementia and their families.
Consistent evidence indicates the involvement of the brain-derived neurotrophic factor (BDNF) in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson’s disease (PD). In the ...present study, we compared serum BDNF in 624 subjects: 266 patients affected by AD, 28 by frontotemporal dementia (FTD), 40 by Lewy body dementia (LBD), 91 by vascular dementia (VAD), 30 by PD, and 169 controls. Our results evidenced lower BDNF serum levels in AD, FTD, LBD, and VAD patients (P<0.001) and a higher BDNF concentration in patients affected by PD (P=0.045). Analyses of effects of pharmacological treatments suggested significantly higher BDNF serum levels in patients taking mood stabilizers/antiepileptics (P=0.009) and L-DOPA (P<0.001) and significant reductions in patients taking benzodiazepines (P=0.020). In conclusion, our results support the role of BDNF alterations in neurodegenerative mechanisms common to different forms of neurological disorders and underline the importance of including drug treatment in the analyses to avoid confounding effects.
Background:
Long-Term Care Facilities (LTCF) in Italy have been particularly affected by the COVID-19 pandemic, especially in terms of mortality rates of older residents. However, it is still unclear ...the actual extent of this situation. The aim of this manuscript is to assess the extent of mortality rates of older adults in LTCF during the pandemic across different regions of Italy, compared to the previous years and to older general population not resident in LTCF.
Methods:
We extracted and analyzed data collected by three Italian institutions (i.e., Italian Statistician Institute ISTAT, Italian N.I.H, Milan Health Unit) about the number of deaths among older people living in the community and among LTCF residents during the pandemic and the previous years. We also compared the observed mortality rate among LTCF residents in each Italian Region with the corresponding expected number of deaths of the general older adult population to obtain an observed/expected ratio (O/E ratio).
Results:
During the pandemic, about 8.5% (
N
= 6,797) of Italian older adults residents in LTCF died. Findings resulting from the O/E ratio suggest that LTCF residents (in particular in the Lombardy Region) show higher mortality rates when compared to expected values of mortality rates among the older general population living in the community. Furthermore, we found that the risk of death among LTCF residents increased about 4 times during the pandemic when compared to the previous years.
Conclusions:
Mortality rates in LTCF were high during the pandemic, especially in Lombardy. Possible causes of higher mortality rates in LTCF and suggestions for specific targeted interventions are discussed.
Depression is estimated to be a leading contributor to the global mental health-related burden. The determinants of this huge prevalence lie in the fact that depressive symptoms may be comorbid in a ...wide variety of disorders, thus complicating and exacerbating their clinical framework. This makes the treatment of depressive symptoms difficult, since many pharmacological interactions should be considered by physicians planning therapy. Hence, depression still represents a challenge for both psychiatrists and other clinicians, in terms of its high rates of relapse and resistance despite well-established protocols. It is also complicated by the well-known latency in its complete response to current antidepressant treatments. In this context, the search for new strategies regarding antidepressant treatment is mandatory. Revising the use of “old” pharmacotherapies by considering their specific features may help to perfecting the treatment of depression, both in its standalone psychiatric manifestation and in the framework of other clinical conditions. Using a nominal group technique approach, the results of a consensus of expert physicians regarding the possible use of trazodone as a valuable strategy for addressing the “real world” unmet needs of depression treatment in different fields (psychiatry, primary care, neurology and geriatrics) is herein provided. This idea is based on the unique characteristics of this drug which delivers a more rapid antidepressant action as compared to other selective serotonin reuptake inhibitors. It also has pharmacodynamic malleability (i.e., the possibility of exerting different effects on depressive symptoms at different dosages) and pharmacokinetic tolerability (i.e., the possibility of being used as an add-on to other antidepressants with scarce interaction and achieving complimentary effects) when used in the milieu of other drugs in treating comorbid depressive symptoms. Moreover, the large number of formulations available permits finite dosage adjustments, and the use of trazodone for specific pathologies, such as dysphagia. Therefore, although additional studies exploring the real-world conditions of antidepressant treatment are warranted, experts agree on the idea that depressive disorder, in both its standalone and its comorbid manifestations, may surely take advantage of the particular characteristics of trazodone, thus attempting to reach the greatest effectiveness in different contexts.
Background and aims
: Epidemiological studies have examined the association between the use of non-steroidal anti-inflammatory drugs (NSAIDs) and the risk of Alzheimer’s disease (AD). Recently, a ...variety of experimental studies indicates that a subset of NSAIDs, such as ibuprofen or flurbiprofen, also have Aβ-lowering properties in both AD transgenic mice and cell cultures of peripheral, glial and neuronal origin. In this trial, we evaluated whether the non-selective NSAID ibuprofen slows disease progression in patients with mild to moderate AD.
Methods
: This was a 12-month multicenter, randomized, double-blind, placebo-controlled, parallel group trial. Participants with mild-moderate AD (Mini-Mental State Examination score >15, <26; Clinical Dementia Rating= 0.5–1), 65 years or older, with reliable caregivers, were recruited between April 2003 and September 2004. Seven AD Outpatient Treatment Centers screened 530 patients, 132 of whom were enrolled. Interventionconsisted of 400 mg ibuprofen twice a day or placebo, together with 20 mg once a day of esomeprazol, or placebo. The primary measure was any one-year change in the Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog) subscale score. Secondary measures included changes in MMSE, CDR, Basic and Instrumental Activities of Daily Living scales, and Neuropsychiatry Inventory (NPI).
Results
: Fifty-one patients (77%) in the ibuprofen vs 46 (70%) in the placebo group completed the protocol (p>0.20). In intention-to-treat analysis, ADAS-Cog score worsening was similar in the two groups (p=0.951, treatment difference= 0.1, CI-2.7; 2.9). No differences were found for any secondary outcomes. In a subsample of genotyped patients, ApoE ε4 carriers treated with ibuprofen (n=27) were the only group without significant cognitive decline.
Conclusions
: Ibuprofen, if used for relatively short periods of time and although well tolerated thanks to gastroprotection, does not seem to be effective in tertiary prevention of mild-moderate AD. Our results suggest the need to examine whether differences in the response to NSAIDs exist, based on ApoE ε4 carrier status.
Purpose
Informal care constitutes an important part of the total care for people with dementia. Therefore, the impact of the syndrome on their caregivers as well as that of health and social care ...services for people with dementia should be considered. This study investigated the convergent and clinical validity of the CarerQol instrument, which measures and values the impact of providing informal care, in a multi-country sample of caregivers for people with dementia.
Methods
Cross-sectional data from a sample of 451 respondents in eight European countries, collected by the Actifcare project, were evaluated. Convergent validity was analysed with Spearman’s correlation coefficients and multivariate correlations between the CarerQol-7D utility score and dimension scores, and other similar quality of life measures such as CarerQol-VAS, ICECAP-O, and EQ-5D. Clinical validity was evaluated by bivariate and multivariate analyses of the degree to which the CarerQol instrument can differentiate between characteristics of caregivers, care receivers and caregiving situation. Country dummies were added to test CarerQol score differences between countries.
Results
The mean CarerQol utility score was 77.6 and varied across countries from 74.3 (Italy) to 82.3 (Norway). The scores showed moderate to strong positive correlations with the CarerQol-VAS, ICECAP-O, and EQ-5D health problems score of the caregiver. Multivariate regression analysis showed that various characteristics of the caregiver, care receiver and caregiving situation were associated with caregiver outcomes, but there was no evidence of a country-level effect.
Conclusion
This study demonstrates the convergent and clinical validity of the CarerQol instrument to evaluate the impact of providing informal care for people with dementia.
Given the limited effectiveness of pharmacological treatments, non-pharmacological interventions to treat Alzheimer's disease (AD) have gained attention in recent years. The aim of the present study ...is to investigate the effects of anodal tDCS (AtDCS) combined with memory training on face-name associations in an AD patient sample.
Thirty six AD patients were randomly assigned to one of three study groups: Group 1, AtDCS plus individualized computerized memory training; Group 2, placebo tDCS plus individualized computerized memory training; Group 3, AtDCS plus motor training.
A general improvement in performance was observed after 2 weeks of memory training. Both the anodal tDCS plus individualized computerized memory training and the placebo tDCS plus individualized computerized memory training groups had significantly improved performances at 2 weeks compared with the AtDCS plus motor training group.
Our findings suggest a beneficial effect of individualized memory rehabilitation in AD patients.
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