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Molecular Psychiatry Oct 2021Breakthroughs in molecular medicine have positioned the amyloid-β (Aβ) pathway at the center of Alzheimer's disease (AD) pathophysiology. While the detailed molecular... (Review)
Review
Breakthroughs in molecular medicine have positioned the amyloid-β (Aβ) pathway at the center of Alzheimer's disease (AD) pathophysiology. While the detailed molecular mechanisms of the pathway and the spatial-temporal dynamics leading to synaptic failure, neurodegeneration, and clinical onset are still under intense investigation, the established biochemical alterations of the Aβ cycle remain the core biological hallmark of AD and are promising targets for the development of disease-modifying therapies. Here, we systematically review and update the vast state-of-the-art literature of Aβ science with evidence from basic research studies to human genetic and multi-modal biomarker investigations, which supports a crucial role of Aβ pathway dyshomeostasis in AD pathophysiological dynamics. We discuss the evidence highlighting a differentiated interaction of distinct Aβ species with other AD-related biological mechanisms, such as tau-mediated, neuroimmune and inflammatory changes, as well as a neurochemical imbalance. Through the lens of the latest development of multimodal in vivo biomarkers of AD, this cross-disciplinary review examines the compelling hypothesis- and data-driven rationale for Aβ-targeting therapeutic strategies in development for the early treatment of AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Humans; tau Proteins
PubMed: 34456336
DOI: 10.1038/s41380-021-01249-0 -
British Journal of Sports Medicine Jun 2022Physical activity (PA) is associated with a decreased incidence of dementia, but much of the evidence comes from short follow-ups prone to reverse causation. This... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Physical activity (PA) is associated with a decreased incidence of dementia, but much of the evidence comes from short follow-ups prone to reverse causation. This meta-analysis investigates the effect of study length on the association.
DESIGN
A systematic review and meta-analysis. Pooled effect sizes, dose-response analysis and funnel plots were used to synthesise the results.
DATA SOURCES
CINAHL (last search 19 October 2021), PsycInfo, Scopus, PubMed, Web of Science (21 October 2021) and SPORTDiscus (26 October 2021).
ELIGIBILITY CRITERIA
Studies of adults with a prospective follow-up of at least 1 year, a valid cognitive measure or cohort in mid-life at baseline and an estimate of the association between baseline PA and follow-up all-cause dementia, Alzheimer's disease or vascular dementia were included (n=58).
RESULTS
PA was associated with a decreased risk of all-cause dementia (pooled relative risk 0.80, 95% CI 0.77 to 0.84, n=257 983), Alzheimer's disease (0.86, 95% CI 0.80 to 0.93, n=128 261) and vascular dementia (0.79, 95% CI 0.66 to 0.95, n=33 870), even in longer follow-ups (≥20 years) for all-cause dementia and Alzheimer's disease. Neither baseline age, follow-up length nor study quality significantly moderated the associations. Dose-response meta-analyses revealed significant linear, spline and quadratic trends within estimates for all-cause dementia incidence, but only a significant spline trend for Alzheimer's disease. Funnel plots showed possible publication bias for all-cause dementia and Alzheimer's disease.
CONCLUSION
PA was associated with lower incidence of all-cause dementia and Alzheimer's disease, even in longer follow-ups, supporting PA as a modifiable protective lifestyle factor, even after reducing the effects of reverse causation.
Topics: Alzheimer Disease; Dementia, Vascular; Disease Progression; Exercise; Humans; Prospective Studies; Protective Factors
PubMed: 35301183
DOI: 10.1136/bjsports-2021-104981 -
Clinical Microbiology and Infection :... Aug 2022Precise estimates of mortality in Staphylococcus aureus bacteraemia (SAB) are important to convey prognosis and guide the design of interventional studies. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Precise estimates of mortality in Staphylococcus aureus bacteraemia (SAB) are important to convey prognosis and guide the design of interventional studies.
OBJECTIVES
We performed a systematic review and meta-analysis to estimate all-cause mortality in SAB and explore mortality change over time.
DATA SOURCES
The MEDLINE and Embase databases, as well as the Cochrane Database of Systematic Reviews, were searched from January 1, 1991 to May 7, 2021.
STUDY ELIGIBILITY CRITERIA
Human observational studies on patients with S. aureus bloodstream infection were included.
PARTICIPANTS
The study analyzed data of patients with a positive blood culture for S. aureus.
METHODS
Two independent reviewers extracted study data and assessed risk of bias using the Newcastle-Ottawa Scale. A generalized, linear, mixed random effects model was used to pool estimates.
RESULTS
A total of 341 studies were included, describing a total of 536,791 patients. From 2011 onward, the estimated mortality was 10.4% (95% CI, 9.0%-12.1%) at 7 days, 13.3% (95% CI, 11.1%-15.8%) at 2 weeks, 18.1% (95% CI, 16.3%-20.0%) at 1 month, 27.0% (95% CI, 21.5%-33.3%) at 3 months, and 30.2% (95% CI, 22.4%-39.3%) at 1 year. In a meta-regression model of 1-month mortality, methicillin-resistant S. aureus had a higher mortality rate (adjusted OR (aOR): 1.04; 95% CI, 1.02-1.06 per 10% increase in methicillin-resistant S. aureus proportion). Compared with prior to 2001, more recent time periods had a lower mortality rate (aOR: 0.88; 95% CI, 0.75-1.03 for 2001-2010; aOR: 0.82; 95% CI, 0.69-0.97 for 2011 onward).
CONCLUSIONS
SAB mortality has decreased over the last 3 decades. However, more than one in four patients will die within 3 months, and continuous improvement in care remains necessary.
Topics: Anti-Bacterial Agents; Bacteremia; Humans; Methicillin-Resistant Staphylococcus aureus; Sepsis; Staphylococcal Infections; Staphylococcus aureus
PubMed: 35339678
DOI: 10.1016/j.cmi.2022.03.015 -
The Journal of Headache and Pain Jun 2022A previous European Headache Federation (EHF) guideline addressed the use of monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway to... (Review)
Review
BACKGROUND
A previous European Headache Federation (EHF) guideline addressed the use of monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway to prevent migraine. Since then, randomized controlled trials (RCTs) and real-world evidence have expanded the evidence and knowledge for those treatments. Therefore, the EHF panel decided to provide an updated guideline on the use of those treatments.
METHODS
The guideline was developed following the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. The working group identified relevant questions, performed a systematic review and an analysis of the literature, assessed the quality of the available evidence, and wrote recommendations. Where the GRADE approach was not applicable, expert opinion was provided.
RESULTS
We found moderate to high quality of evidence to recommend eptinezumab, erenumab, fremanezumab, and galcanezumab in individuals with episodic and chronic migraine. For several important clinical questions, we found not enough evidence to provide evidence-based recommendations and guidance relied on experts' opinion. Nevertheless, we provided updated suggestions regarding the long-term management of those treatments and their place with respect to the other migraine preventatives.
CONCLUSION
Monoclonal antibodies targeting the CGRP pathway are recommended for migraine prevention as they are effective and safe also in the long-term.
Topics: Antibodies, Monoclonal; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Headache; Humans; Migraine Disorders
PubMed: 35690723
DOI: 10.1186/s10194-022-01431-x -
Obesity (Silver Spring, Md.) Jul 2021Dietary supplements and alternative therapies are commercialized as a panacea for obesity/weight gain as a result of the minimal regulatory requirements in demonstrating... (Review)
Review
OBJECTIVE
Dietary supplements and alternative therapies are commercialized as a panacea for obesity/weight gain as a result of the minimal regulatory requirements in demonstrating efficacy. These products may indirectly undermine the value of guideline-driven obesity treatments. Included in this study is a systematic review of the literature of purported dietary supplements and alternative therapies for weight loss.
METHODS
A systematic review was conducted to evaluate the efficacy of dietary supplements and alternative therapies for weight loss in participants aged ≥18 years. Searches of Medline (PubMed), Cochrane Library, Web of Science, CINAHL, and Embase (Ovid) were conducted. Risk of bias and results were summarized qualitatively.
RESULTS
Of the 20,504 citations retrieved in the database search, 1,743 full-text articles were reviewed, 315 of which were randomized controlled trials evaluating the efficacy of 14 purported dietary supplements, therapies, or a combination thereof. Risk of bias and sufficiency of data varied widely. Few studies (n = 52 [16.5%]) were classified as low risk and sufficient to support efficacy. Of these, only 16 (31%) noted significant pre/post intergroup differences in weight (range: 0.3-4.93 kg).
CONCLUSIONS
Dietary supplements and alternative therapies for weight loss have a limited high-quality evidence base of efficacy. Practitioners and patients should be aware of the scientific evidence of claims before recommending use.
Topics: Adolescent; Adult; Complementary Therapies; Dietary Supplements; Humans; Obesity; Weight Loss
PubMed: 34159755
DOI: 10.1002/oby.23110 -
The Journal of Headache and Pain Oct 2020Migraine and sleep disorders are common and often burdensome chronic conditions with a high prevalence in the general population, and with considerable socio-economic...
Migraine and sleep disorders are common and often burdensome chronic conditions with a high prevalence in the general population, and with considerable socio-economic impact and costs.The existence of a relationship between migraine and sleep disorders has been recognized from centuries by clinicians and epidemiological studies. Nevertheless, the exact nature of this association, the underlying mechanisms and interactions are complex and not completely understood. Recent biochemical and functional imaging studies identified central nervous system structures and neurotransmitters involved in the pathophysiology of migraine and also important for the regulation of normal sleep architecture, suggesting a possible causative role, in the pathogenesis of both disorders, of a dysregulation in these common nervous system pathways.This systematic review summarizes the existing data on migraine and sleep disorders with the aim to evaluate the existence of a causal relationship and to assess the presence of influencing factors. The identification of specific sleep disorders associated with migraine should induce clinicians to systematically assess their presence in migraine patients and to adopt combined treatment strategies.
Topics: Humans; Migraine Disorders; Sleep; Sleep Wake Disorders
PubMed: 33109076
DOI: 10.1186/s10194-020-01192-5 -
Acta Neuropathologica Communications Mar 2023In the contexts of aging, injury, or neuroinflammation, activated microglia signaling with TNF-α, IL-1α, and C1q induces a neurotoxic astrocytic phenotype, classified... (Review)
Review
In the contexts of aging, injury, or neuroinflammation, activated microglia signaling with TNF-α, IL-1α, and C1q induces a neurotoxic astrocytic phenotype, classified as A1, A1-like, or neuroinflammatory reactive astrocytes. In contrast to typical astrocytes, which promote neuronal survival, support synapses, and maintain blood-brain barrier integrity, these reactive astrocytes downregulate supportive functions and begin to secrete neurotoxic factors, complement components like C3, and chemokines like CXCL10, which may facilitate recruitment of immune cells across the BBB into the CNS. The proportion of pro-inflammatory reactive astrocytes increases with age through associated microglia activation, and these pro-inflammatory reactive astrocytes are particularly abundant in neurodegenerative disorders. As the identification of astrocyte phenotypes progress, their molecular and cellular effects are characterized in a growing array of neuropathologies.
Topics: Humans; Astrocytes; Microglia; Central Nervous System; Blood-Brain Barrier; Chemokines; Neurotoxicity Syndromes
PubMed: 36915214
DOI: 10.1186/s40478-023-01526-9 -
The International Journal of... Mar 2023Psychedelics are a unique class of drug that commonly produce vivid hallucinations as well as profound psychological and mystical experiences. A grouping of...
Psychedelics are a unique class of drug that commonly produce vivid hallucinations as well as profound psychological and mystical experiences. A grouping of interconnected brain regions characterized by increased temporal coherence at rest have been termed the Default Mode Network (DMN). The DMN has been the focus of numerous studies assessing its role in self-referencing, mind wandering, and autobiographical memories. Altered connectivity in the DMN has been associated with a range of neuropsychiatric conditions such as depression, anxiety, post-traumatic stress disorder, attention deficit hyperactive disorder, schizophrenia, and obsessive-compulsive disorder. To date, several studies have investigated how psychedelics modulate this network, but no comprehensive review, to our knowledge, has critically evaluated how major classical psychedelic agents-lysergic acid diethylamide, psilocybin, and ayahuasca-modulate the DMN. Here we present a systematic review of the knowledge base. Across psychedelics there is consistent acute disruption in resting state connectivity within the DMN and increased functional connectivity between canonical resting-state networks. Various models have been proposed to explain the cognitive mechanisms of psychedelics, and in one model DMN modulation is a central axiom. Although the DMN is consistently implicated in psychedelic studies, it is unclear how central the DMN is to the therapeutic potential of classical psychedelic agents. This article aims to provide the field with a comprehensive overview that can propel future research in such a way as to elucidate the neurocognitive mechanisms of psychedelics.
Topics: Hallucinogens; Default Mode Network; Psilocybin; Lysergic Acid Diethylamide; Brain; Magnetic Resonance Imaging
PubMed: 36272145
DOI: 10.1093/ijnp/pyac074 -
Annals of Surgical Oncology May 2022Esophageal and gastric cancer surgery are associated with considerable morbidity, specifically postoperative pulmonary complications (PPCs), potentially accentuated by... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Esophageal and gastric cancer surgery are associated with considerable morbidity, specifically postoperative pulmonary complications (PPCs), potentially accentuated by underlying challenges with malnutrition and cachexia affecting respiratory muscle mass. Physiotherapy regimens aim to increase the respiratory muscle strength and may prevent postoperative morbidity.
OBJECTIVE
The aim of this study was to assess the impact of physiotherapy regimens in patients treated with esophagectomy or gastrectomy.
METHODS
An electronic database search was performed in the MEDLINE, EMBASE, CENTRAL, CINAHL and Pedro databases. A meta-analysis was performed to assess the impact of physiotherapy on the functional capacity, incidence of PPCs and postoperative morbidity, in-hospital mortality rate, length of hospital stay (LOS) and health-related quality of life (HRQoL).
RESULTS
Seven randomized controlled trials (RCTs) and seven cohort studies assessing prehabilitation totaling 960 patients, and five RCTs and five cohort studies assessing peri- or postoperative physiotherapy with 703 total patients, were included. Prehabilitation resulted in a lower incidence of postoperative pneumonia and morbidity (Clavien-Dindo score ≥ II). No difference was observed in functional exercise capacity and in-hospital mortality following prehabilitation. Meanwhile, peri- or postoperative rehabilitation resulted in a lower incidence of pneumonia, shorter LOS, and better HRQoL scores for dyspnea and physical functioning, while no differences were found for the QoL summary score, global health status, fatigue, and pain scores.
CONCLUSION
This meta-analysis suggests that implementing an exercise intervention may be beneficial in both the preoperative and peri- or postoperative periods. Further investigation is needed to understand the mechanism through which exercise interventions improve clinical outcomes and which patient subgroup will gain the maximal benefit.
Topics: Esophagectomy; Gastrectomy; Humans; Length of Stay; Physical Therapy Modalities; Pneumonia; Postoperative Complications
PubMed: 34961901
DOI: 10.1245/s10434-021-11122-7 -
Advances in Therapy Jan 2020International guidelines support the use of low molecular weight heparins for the treatment of thromboembolism and thromboprophylaxis during pregnancy. However, evidence... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
International guidelines support the use of low molecular weight heparins for the treatment of thromboembolism and thromboprophylaxis during pregnancy. However, evidence of the benefit and harm associated with specific low molecular weight heparins such as enoxaparin is dated. No current systematic review and meta-analysis describing the safety and efficacy of enoxaparin for thromboembolism and thromboprophylaxis during pregnancy exists.
METHODS
PubMed, Embase, and Cochrane databases were searched on August 17, 2018 for clinical trials or observational studies in pregnant women receiving enoxaparin; patients with a prosthetic heart valve were excluded. Risk ratios (RR) with 95% confidence intervals (CI) were calculated using a random effects model, and heterogeneity was measured using the I statistic.
RESULTS
Of the 485 records identified in the search, 24 studies published clinical trials, and observational studies were found dating back to 2000. Only one observational cohort and one randomized control trial focused on the use of enoxaparin for thromboprophylaxis and therefore efficacy was not assessed; the other studies included women with recurrent pregnancy loss (15 studies), history of placental vascular complications (five studies), and recurrent in vitro fertilization failure (two studies) and were therefore analyzed in terms of safety only. Bleeding events were non-significantly more often reported for enoxaparin compared to untreated controls (RR 1.35 [0.88-2.07]) but less often reported for enoxaparin versus aspirin (RR 0.93 [0.62-1.39]); thromboembolic events, thrombocytopenia, and teratogenicity were rarely reported events; in patients with a history of recurrent pregnancy loss, encouragingly the rates of pregnancy loss were significantly lower for enoxaparin compared to untreated controls (RR 0.58 [0.34-0.96]) and enoxaparin + aspirin versus aspirin alone (RR 0.42 [0.32-0.56]) as well as observably lower for enoxaparin versus aspirin alone (RR 0.39 [0.15-1.01]), though significant heterogeneity was observed (I > 60).
CONCLUSION
Literature on the efficacy and safety of enoxaparin for thromboembolism and thromboprophylaxis remains scanty, and therefore efficacy was not assessed; in terms of safety, when including other indications for enoxaparin in pregnancy, we found that enoxaparin was associated with significantly lower complications than aspirin. Given differences in study design and study heterogeneity, pregnancy loss results should be interpreted with caution. Moreover, reports of thromboembolic events, thrombocytopenia, and congenital malformations were rare.
FUNDING
Sanofi.
Topics: Anticoagulants; Aspirin; Enoxaparin; Female; Hemorrhage; Humans; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Venous Thromboembolism
PubMed: 31673991
DOI: 10.1007/s12325-019-01124-z