Background Olive oil contains monounsaturated oleic acid up to 83% and phenolic compounds, making it an excellent source of fat. Due to its economic importance, the quantity and quality of olive oil should be improved in parallel with international standards. In this study, we analyzed the raw RNA-seq data with a meta-analysis approach to identify important genes and their metabolic pathways involved in olive oil quality. Results A deep search of RNA-seq published data shed light on thirty-nine experiments associated with the olive transcriptome, four of these proved to be ideal for meta-analysis. Meta-analysis confrmed the genes identifed in previous studies and released new genes, which were not identifed before. According to the IDR index, the meta-analysis had good power to identify new diferentially expressed genes. The key genes were investigated in the metabolic pathways and were grouped into four classes based on the biosynthetic cycle of fatty acids and factors that afect oil quality. Galactose metabolism, glycolysis pathway, pyruvate metabolism, fatty acid biosynthesis, glycerolipid metabolism, and terpenoid backbone biosynthesis were the main pathways in olive oil quality. In galactose metabolism, rafnose is a suitable source of carbon along with other available sources for carbon in fruit development. The results showed that the biosynthesis of acetyl-CoA in glycolysis and pyruvate metabolism is a stable pathway to begin the biosynthesis of fatty acids. Key genes in oleic acid production as an indicator of oil quality and critical genes that played an important role in production of triacylglycerols were identifed in diferent developmental stages. In the minor compound, the terpenoid backbone biosynthesis was investigated and important enzymes were identifed as an interconnected network that produces important precursors for the synthesis of a monoterpene, diterpene, triterpene, tetraterpene, and sesquiterpene biosynthesis. Conclusions The results of the current investigation can produce functional data related to the quality of olive oil and would be a useful step in reducing the time of cultivar screening by developing gene specifc markers in olive breeding programs, releasing also new genes that could be applied in the genome editing approach.

Bats frequently inhabit caves and other subterranean habitats and play a critical role in subterranean food webs. With escalating threats to subterranean ecosystems, identifying the most effective measures to protect subterranean-roosting bats is critical. We conducted a meta-analysis to evaluate the effectiveness of conservation and management interventions for subterranean-roosting bats. We used network analyses to determine to what extent interventions for bats overlap those used for other subterranean taxa. We conducted our analyses with data extracted from 345 papers recommending a total of 910 conservation interventions. Gating of roost entrances was applied to preserve bat populations in 21 studies, but its effectiveness was unclear. Habitat restoration and disturbance reduction positively affected bat populations and bat behavior, respectively, in =4 studies. Decontamination was assessed in 2 studies and positively affected bat populations, particularly in studies focused on reducing fungal spores associated with white-nose syndrome in North America. Monitoring of bat populations as an effective conservation strategy was unclear and infrequently tested. Only 4% of bat studies simultaneously considered other subterranean organisms. However, effective interventions for bat conservation had similarities with all other organisms. If other subterranean organisms are considered when applying interventions to conserve bats, they might also benefit.

Clinical research is gaining interest among healthcare professionals. This review provides an in-depth analysis of key study designs used in epidemiology, which can help researchers use the right methodology to design and conduct a research project. Case-control studies evaluate the association between an exposure to a specific risk factor and a study endpoint. Cross-sectional studies are indicated to assess the prevalence of a given risk factor. Cohort studies consist of longitudinal studies, in which a population is followed over time. These studies allow to evaluate the association between a risk factor and one or more study endpoints which are absent at the time of the population enrollment. Experimental studies are designed to test the efficacy and safety of an intervention. Generally, they include two groups of individuals who are assigned to either an experimental treatment or a standard treatment, respectively. Meta-analyses are studies that summarize the evidence already published concerning a specific research question and constitute an important source for evidence-based medicine and for the production and updating of guidelines.

In the era of Big Data, many scientific disciplines and engineering activities rely on cumulative databases, consisting of many entries derived from different experiments and studies, to investigate complex problems. Their contents can be analysed with much finer granularity than with the usual meta-analytic tools, based on summary statistics such as means and standard deviations. At the same time, not being primary studies, also traditional statistical techniques are not adequate to investigate them. New meta-analysis methods have therefore been adapted to study these cumulative databases and to ensure their validity and consistency. Information theoretic and neural computational tools represent a series of complementary techniques, which can be deployed to identify the most important variables to analyse the problem at hand, to detect whether quantities are missing and to determine the coherence between the entries provided by the individual experiments and studies. The performances of the developed methodologies are verified with a systematic series of tests with synthetic data. An application to thermonuclear fusion proves the capability of the tools to handle real data, in one of the most complex fields of modern physics.

Citations remain a prime, yet controversial, measure of academic performance. Ideally, how often a paper is cited should solely depend on the quality of the science reported therein. However, non-scientific factors, including structural elements (e.g., length of abstract, number of references) or attributes of authors (e.g., prestige and gender), may all influence citation outcomes. Knowing the predicted effect of these features on citations might make it possible to 'game the system' of citation counts when writing a paper. We conducted a meta-analysis to build a quantitative understanding of the effect of similar non-scientific features on the impact of scientific articles in terms of citations. We showed that article length, number of authors, author experience and their collaboration network, Impact Factors, availability as open access, online sharing, different referencing practice, and number of figures all exerted a positive influence on citations. These patterns were consistent across most disciplines. We also documented temporal trends towards a recent increase in the effect of journal Impact Factor and number of authors on citations. We suggest that our approach can be used as a benchmark to monitor the influence of these effects over time, minimising the influence of non-scientific features as a means to game the system of citation counts, and thus enhancing their usefulness as a measure of scientific quality.

Background Historically, the molecular classification of colorectal cancer (CRC) was based on the global genomic status, which identified microsatellite instability in mismatch repair (MMR) deficient CRC, and chromosomal instability in MMR proficient CRC. With the introduction of immune checkpoint inhibitors, the microsatellite and chromosomal instability classification regained momentum as the microsatellite instability condition predicted sensitivity to immune checkpoint inhibitors, possibly due to both high tumor mutation burden (TMB) and high levels of infiltrating lymphocytes. Conversely, proficient MMR CRC are mostly resistant to immunotherapy. To better understand the relationship between the microsatellite and chromosomal instability classification, and eventually discover additional CRC subgroups relevant for therapeutic decisions, we developed a computational pipeline that include molecular integrative analysis of genomic, epigenomic and transcriptomic data. Results The first step of the pipeline was based on unsupervised hierarchical clustering analysis of copy number variations (CNVs) versus hypermutation status that identified a first CRC cluster with few CNVs enriched in Hypermutated and microsatellite instability samples, a second CRC cluster with a high number of CNVs mostly including non-HM and microsatellite stable samples, and a third cluster (7.8% of the entire dataset) with low CNVs and low TMB, which shared clinical-pathological features with Hypermutated CRCs and thus defined Hypermutated-like CRCs. The mutational features, DNA methylation profile and base substitution fingerprints of these tumors revealed that Hypermutated-like patients are molecularly distinct from Hypermutated and non-Hypermutated tumors and are likely to develop and progress through different genetic events. Transcriptomic analysis highlighted further differences amongst the three groups and revealed an inflamed tumor microenvironment and modulation Immune Checkpoint Genes in Hypermutated-like CRCs. Conclusion Therefore, our work highlights Hypermutated-like tumors as a distinct and previously unidentified CRC subgroup possibly responsive to immune checkpoint inhibitors. If further validated, these findings can lead to expanding the fraction of patients eligible to immunotherapy.

Aggregating transcriptomics data across hospitals can increase sensitivity and robustness of differential expression analyses, yielding deeper clinical insights. As data exchange is often restricted by privacy legislation, meta-analyses are frequently employed to pool local results. However, the accuracy might drop if class labels are inhomogeneously distributed among cohorts. Flimma (https://exbio.wzw.tum.de/flimma/) addresses this issue by implementing the state-of-the-art workflow limma voom in a federated manner, i.e., patient data never leaves its source site. Flimma results are identical to those generated by limma voom on aggregated datasets even in imbalanced scenarios where meta-analysis approaches fail.

Background: Neuroticism is linked to mood disorders and Alzheimer's disease, but fewer studies have tested the prospective association with Parkinson's disease. Objectives: To examine the association between neuroticism and risk of Parkinson's disease in a large cohort and a meta-analysis of prospective cohort studies. Method: Participants from the UK Biobank (N = 490.755) completed a neuroticism scale in 2006-2010. Incident Parkinson's disease was ascertained using electronic health records or death records up to 2018. The systematic search and meta-analysis followed the MOOSE guidelines. Results: During 11.91 years of follow-up (mean = 8.88 years; 4.360.105 person-years) 1,142 incident Parkinson's disease cases were identified. Neuroticism was associated with higher risk of incident Parkinson's disease, both as continuous (HR = 1.28; 95%CI: 1.21-1.36) and categorical variable (top vs. bottom quartiles: HR = 1.88; 95%CI: 1.60-2.22). The association remained significant after accounting for age, sex, smoking, physical activity, anxiety, and depressed mood, and after excluding cases that occurred within the first five years of follow-up. The associations were similar for women and men and across levels of socioeconomic status. Random-effect meta-analysis of four prospective studies (N = 548.284) found neuroticism associated with increased risk of incident Parkinson's disease (HR = 1.82; 95%CI: 1.59-2.08; p = 7.31-19). There was no evidence of heterogeneity across studies with follow-ups ranging from one to four decades. Conclusions: The results from the large UK biobank and meta-analysis of prospective studies indicate that neuroticism is consistently associated with a higher risk of incident Parkinson's disease.

Background: Growing evidence shows that grape polyphenols can improve cardiovascular risk factors. Although there are clear data supporting a beneficial effect of grape supplementation on blood pressure and glucose metabolism, the effects of grape polyphenols on lipid metabolism are still controversial. Objective: We performed a meta-analysis of randomized controlled trials (RCTs) to assess the effect of grape products on lipid profile. Design: A systematic search was performed in the PubMed, Web of Science, Scopus, and EMBASE databases without any language or publication year restriction. The reference lists of all retrieved articles were manually reviewed. RCTs evaluating the impact of grape products/juice/extracts on lipid profile were included. Difference in total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), oxidized low-density lipoprotein cholesterol (oxLDL-C), apolipoprotein (apo) A, apo B before and after administration of grape products or placebo were expressed as mean differences (MD) with pertinent 95% confidence intervals (95% CI). The impact of clinical and demographic features on effect size was assessed by meta-regression. Results: The administration of grape products is associated with a significant improvement of lipid profile, as evidenced by changes in TC (MD: -7.6 mg/dL (-0.2 mmol/L); 95% CI: -10.8, -4.4; p < 0.001), HDL-C (MD: 1.4 mg/dL (0.04 mmol/L); 95% CI: 0.8, 1.9; p < 0.001, I = 74.7%, p < 0.001), LDL-C (-6.3 mg/dL (-0.16 mmol/L); 95% CI: -9.5, -3.0; p < 0.001), oxLDL-C (MD: -4.5 U/L; 95% CI: -7.5, -1.5; p = 0.003, I = 90.6%, p < 0.001), apo B (MD: -2.4 mg/dL (-0.05 ?mol/L); 95% CI: -4.5, -0.3; p = 0.026), and TG (MD: -14.5 mg/dL (-0.16 mmol/L); 95% CI: -17.7, -11.2; p < 0.001) levels in subjects receiving grape products compared to placebo. With regard to the extent of the lipid-lowering effect, compared to baseline values, the highest reduction was reported for LDL-C (MD: -5.6 mg/dL (-0.14 mmol/L); 95% CI: -9.5, -1.7; p = 0.005) and for oxLDL-C (MD: -5.0 U/L; 95% CI: -8.8, -1.2; p = 0.010, I = 0%, p = 0.470). Conclusions: Grape polyphenols exert a favorable effect on lipid profile in humans by significantly reducing plasma levels of LDL-C and oxLDL-C.

Purpose The relationship between 100% fruit juice (100%FJ) consumption and cardiovascular risk is object of debate: indeed, recently published investigations provided new but discrepant evidence on this important question and International dietary guidelines are not in agreement on recommendations about fruit juice consumption. Therefore, we performed a meta-analysis of the prospective studies and the randomised controlled trials (RCTs) that explored the relationship between 100%FJ intake, cardiovascular risk profile and risk of cardiovascular events. Methods We performed a systematic search of publications up to August 2019. Summary relative risks and exploration of linearity of the association were estimated for prospective studies and summary mean differences (MDs) calculated for RCTs. Results A total of 21 prospective studies and 35 RCTs met the inclusion criteria. Dose-response analysis detected a significant inverse association between low-moderate 100%FJ consumption and risk of stroke (up to 200 ml/day) or total CV events (up to 170 ml/day) compared with no consumption, with a non-linear relationship (p for non-linearity < 0.05). No significant association was found for coronary heart disease and diabetes risk. In RCTs, a favorable and significant effect of 100%FJ intake was detected on blood pressure (systolic, MD: - 3.14 mmHg; diastolic, MD: - 1.68 mmHg), arterial compliance (carotid-femoral pulse wave velocity, - 0.38 m/s) and endothelial function (flow-mediated dilation, 2.10%). Neutral effects were found on body weight, blood lipids and glucose metabolism. Conclusions The results of these analyses indicate that 100%FJ consumption is not associated with higher CV risk. A non-linear inverse dose-response relationship occurs between 100%FJ consumption and CV disease, in particular for risk of stroke, probably mediated by the decrease in blood pressure.

Purpose: To map and grade all health outcomes associated with magnesium (Mg) intake and supplementation using an umbrella review. Methods: Umbrella review of systematic reviews with meta-analyses of observational studies and randomized controlled trials (RCTs) using placebo/no intervention as control group. We assessed meta-analyses of observational studies based on random-effect summary effect sizes and their p values, 95% prediction intervals, heterogeneity, small-study effects and excess significance. For meta-analyses of RCTs, outcomes with a random-effect p value < 0.005 and a high-GRADE assessment were classified as strong evidence. Results: From 2048 abstracts, 16 meta-analyses and 55 independent outcomes were included (36 in RCTs and 19 in observational studies). In RCTs of Mg versus placebo/no active treatment, 12 over 36 outcomes reported significant results (p < 0.05). A strong evidence for decreased need for hospitalization in pregnancy and for decreased risk of frequency and intensity of migraine relapses in people with migraine was observed using the GRADE assessment. In observational studies, 9/19 outcomes were significant (p < 0.05). However, only one outcome presented highly suggestive evidence (lower incidence of type 2 diabetes in people with higher Mg intake at baseline) and one suggestive (lower incidence of stroke associated with higher Mg intake at baseline). Conclusion: Strong evidence according to the GRADE suggests that Mg supplementation can decrease the risk of hospitalization in pregnant women and reduce the intensity/frequency of migraine. Higher Mg intake is associated with a decreased risk of type 2 diabetes and stroke with highly suggestive and suggestive evidence, respectively, in observational studies.

Background: Evidence provides inconsistent findings on risk factors and health outcomes associated with loneliness. The aim of this work was to grade the evidence on risk factors and health outcomes associated with loneliness, using an umbrella review approach. Methods: For each meta-analytic association, random-effects summary effect size, 95% confidence intervals (CIs), heterogeneity, evidence for small-study effect, excess significance bias and 95% prediction intervals were calculated, and used to grade significant evidence (p<0.05) from convincing to weak. For narrative systematic reviews, findings were reported descriptively. Results: From 210 studies initially evaluated, 14 publications were included, reporting on 18 outcomes, 795 studies, and 746,706 participants. Highly suggestive evidence (class II) supported the association between loneliness and incident dementia (relative risk, RR=1.26; 95%CI: 1.14-1.40, I2 23.6%), prevalent paranoia (odds ratio, OR=3.36; 95%CI: 2.51-4.49, I2 92.8%) and prevalent psychotic symptoms (OR=2.33; 95%CI: 1.68-3.22, I2 56.5%). Pooled data supported the longitudinal association between loneliness and suicide attempts and depressive symptoms. In narrative systematic reviews, factors cross-sectionally associated with loneliness were age (in a U-shape way), female sex, quality of social contacts, low competence, socio-economic status and medical chronic conditions. Limitations: Low quality of the studies included; mainly cross-sectional evidence. Conclusions: This work is the first meta-evidence synthesis showing that highly suggestive and significant evidence supports the association between loneliness and adverse mental and physical health outcomes. More cohort studies are needed to disentangle the direction of the association between risk factors for loneliness and its related health outcomes

Abstract Background: Halophytes are better than glycophytes at employing mechanisms to avoid salt injury, but both types of plants can undergo damage due to high soil salinity. Arbuscular mycorrhizal fungi (AMF) can mitigate the damage from salt stress in both halophytes and glycophytes by enhancing salt tolerance and improving energy efficiency. However, variations in mycorrhizal symbiotic efficiency between halophytes and glycophytes were still poorly under - stood. Therefore, we evaluated the magnitude of AMF effects on plant growth and determined the mechanisms that regulate the growth response of halophytes and glycophytes by performing a meta-analysis of 916 studies (from 182 publications). Results: Arbuscular mycorrhizal fungi significantly enhance biomass accumulation, osmolytes synthesis (soluble sugar and soluble protein), nutrients acquisition (nitrogen, phosphorus, and potassium ion), antioxidant enzyme activ- ities (superoxide dismutase and catalase), and photosynthetic capacity (chlorophyll and carotenoid contents, photo- synthetic rate, stomatal conductance, and transpiration rate). AMF also substantially decreased sodium ion acquisition and malondialdehyde levels in both halophytes and glycophytes under salt stress conditions. Mycorrhizal halophytes deploy inorganic ions (potassium and calcium ions) and limited organic osmolytes (proline and soluble sugar) to achieve energy-efficient osmotic adjustment and further promote biomass accumulation. Mycorrhizal glycophytes depend on the combined actions of soluble sugar accumulation, nutrients acquisition, sodium ion exclusion, super- oxide dismutase elevation, and chlorophyll synthesis to achieve biomass accumulation. Conclusions: Arbuscular mycorrhizal fungi inoculation is complementary to plant function under salt stress condi- tions, not only facilitating energy acquisition but also redistributing energy from stress defence to growth. Glyco- phytes are more dependent on AMF symbiosis than halophytes under salt stress conditions.

Background The growing "process" of burnout impair performance and quality of professional services, with consequences for physicians, healthcare care organization, and patient's outcomes. Aims We aim to evaluate which strategy of intervention, individual or organization directed, is more effective to reduce physician burnout and to provide management suggestions in terms of actual organizational strategies and intensity leading to reductions in physician burnout. Methods The meta analysis was conducted according to the PRISMA guidelines. We included physicians of any specialty in the primary, secondary, or intensive care setting, including residents and fellows. Eligible interventions were any intervention designed to relieve stress and/or improve the performance of physicians and reported burnout outcomes, including physician-directed interventions and organization-directed interventions. The electronic search strategy applied standard filters for identification of the different studies. Databases searched were the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE (from inception to September 2018), and EMBASE (from beginning to September 2018). Meta analysis was performed with mixed random effect using DerSimonian and Laird method. The standardized mean difference (SMD) and 95% CI for each outcome were separately calculated for each trial pooling data when needed, according to an intention-to-treat principle. Results Pooled interventions were associated with small significant reductions in burnout (SMD = - 0.289; 95% CI, - 0.419 to - 0.159; I2 = 29%) (Fig.2). Organization-directed interventions were associated with a medium reduction in burnout score (SMD = - 0.446; 95% CI, - 0.619 to - 0.274; I2 = 8%) while physician-directed interventions were associated with a moderate reduction in burnout score (SMD = - 0.178; 95% CI, - 0.322 to - 0.035; I2 = 11%). Discussion This systematic review and meta-analysis showed that (1) organization-directed interventions were associated with moderate reduction in burnout score, (2) physician-directed interventions were associated with small reduction in burnout score, (3) organization-directed interventions reduced more the depersonalization than physician-directed interventions, (4) organization-directed interventions were related to a more improvement of the personal accomplishment than physician-directed interventions. Conclusions This meta analysis found that physicians could gain important benefits from interventions to reduce burnout, especially from organizational strategies, by viewing burnout rooted in issues related to the working environment and organizational culture.

Under peculiar climatic conditions, the beneficial form of the necrotrophic fungus Botrytis cinerea can develop on grape berries as a latent infection, known as noble rot, which induces positive biochemical and metabolic changes in the berries, including an increase in the sugar content and the production of aromatic compounds that improve wine quality. The infected berries undergo rapid withering, which is required to produce famous sweet white wines such as Sauternes and Tokaj. To gain insight into the molecular interactions between grapevine berries (Vitis vinifera) and B. cinerea during the establishment of noble rot, we prepared a large-scale transcriptomics dataset representing noble rot development and carried out a comparative meta-analysis with gray mold infection and natural post-harvest withering. In particular, we artificially induced berry botrytization of two grape varieties (Garganega and Moller-Thurgau) and sampled them at different stages of noble rot for comparative whole-transcriptome analysis, highlighting important common transcriptional reprogramming in both varieties reflecting an accelerated withering process. Simultaneously, we analyzed the modulation of B. cinerea genes and compared the expression profile during noble rot development with the previously reported gray mold infection profile, revealing the onset of an infection process by the fungus in its beneficial form associated with reduced virulence. This, together with the restrained plant defense response observed in botrytized berries, may favour the development of noble rot instead of gray mold. Finally, the comprehensive meta-analysis of gene expression during noble rot infection, gray mold and post-harvest withering led to the identification of key genes specifically modulated during noble rot infection.

Several environmental factors, such as drought, salinity, and extreme temperatures, negatively affect plant growth and development, which leads to yield losses. The tolerance or sensitivity to abiotic stressors are the expression of a complex machinery involving molecular, biochemical, and physiological mechanisms. Here, a meta-analysis on previously published RNA-Seq data was performed to identify the genes conferring tolerance to chilling, osmotic, and salt stresses, by comparing the transcriptomic changes between tolerant and susceptible rice genotypes. Several genes encoding transcription factors (TFs) were identified, suggesting that abiotic stress tolerance involves upstream regulatory pathways. A gene co-expression network defined the metabolic and signalling pathways with a prominent role in the differentiation between tolerance and susceptibility: (i) the regulation of endogenous abscisic acid (ABA) levels, through the modulation of genes that are related to its biosynthesis/catabolism, (ii) the signalling pathways mediated by ABA and jasmonic acid, (iii) the activity of the "Drought and Salt Tolerance" TF, involved in the negative regulation of stomatal closure, and (iv) the regulation of flavonoid biosynthesis by specific MYB TFs. The identified genes represent putative key players for conferring tolerance to a broad range of abiotic stresses in rice; a fine-tuning of their expression seems to be crucial for rice plants to cope with environmental cues.

A databank on the pellets of a widespread owl species (the Barn Owl, Tyto alba) was used in order to evaluate the differences in taxonomical composition and community metrics of small mammals (Rodentia and Soricomorpha) along an altitude gradient in Italy. The databank consisted of data from 292 sites, with altitudes ranging between -6 and 1292 m a.s.l. GLM models showed that the number of Rodentia species decreased significantly with elevation gradient, but increased significantly in Soricomorpha. Although there was no overall effect of the altitude on the number of species of Rodentia + Soricomorpha pooled, when we focused only on the central Apennine sites, there was a marginally significant negative correlation between number of species and altitude. There was also a significant increase in abundance with elevation in Soricinae and a significant decrease of abundance with elevation in Crocidurinae. Concerning the smallest sized Soricomorpha, there was a gradual substitution effect of one species (Suncus etruscus) with another (Sorex minutus) with elevation increases, and a logistic regression model revealed that elevation negatively affected the probability of presence of S. etruscus whereas it affected positively that of S. minutus. We think that the decrease in number of species of Rodentia with altitude may depend on the higher rate of agricultural land existing at lower elevations in Italy. The overall pattern of Soricomorpha would depend on the dominance of Soricinae species over the Crocidurinae (in terms of both number of species and relative abundance per site), with the Soricinae being more linked to temperate bioclimates than the Mediterranean-bioclimate-linked Crocidurinae.

Malnutrition plays a role in the development of poor physical performance, frailty and sarcopenia. The use of nutritional supplementations for improving physical performance and muscle strength parameters in older people is unclear. We therefore aimed to summarize the effect of nutritional supplementations compared to placebo on physical performance (i.e. tests more investigating physical function, utilising aerobic capacity & muscle power) and muscle strength (i.e. tests depending on muscle power) outcomes in older people in randomized controlled trials (RCTs). A literature search in major databases was undertaken until the 01st September 2018. Eligible studies were RCTs investigating the effect of nutritional supplementations vs. placebo in older people (people having an age > 60 years). Standardized mean differences (SMD) and 95% confidence intervals (CIs) were used through a random effect model. Over 4007 potentially eligible articles, 32 RCTs for a total of 4137 older participants (2097 treated and 2040 placebo) (mean age: 76.3 years; 65% females) were included. Compared to placebo, multi-nutrient supplementations significantly improved chair rise time (n = 3; SMD = -0.90; 95%CI: -1.46 to -0.33; I-2 = 87%). Multi-nutrients significantly improved handgrip strength when compared to placebo (n = 6; 780 participants; SMD = 0.41; 95%CI: 0.06 to 0.76; I-2 = 79%), as did nutritional supplementations including protein (n = 7; 535 participants; SMD = 0.24; 95%CI: 0.07 to 0.41; I-2 = 16%).Nutritional supplementations also led to a significant improvement in chair rise time and in handgrip strength in participants affected by frailty/sarcopenia and in those affected by medical conditions. In conclusion, nutritional supplementation can improve a number of physical performance outcomes in older people, particularly when they include multi-nutrients and in people already affected by specific medical conditions, or by frailty/sarcopenia.

Background&aims:The literature regarding the potential health benefits of chocolate consumption areunclear and the epidemiological credibility has not been systematically scrutinized, while the strength ofthe evidence is undetermined. We therefore aimed to map and grade the diverse health outcomesassociated with chocolate consumption using an umbrella review of systematic reviews.Methods:Umbrella review of systematic reviews of observational and intervention studies (randomizedplacebo-controlled trials, RCTs). For each association, random-effects summary effect size, 95% confi-dence interval, and 95% prediction interval were estimated. We also assessed heterogeneity, evidence forsmall-study effect and evidence for excess significance bias. For significant outcomes of the RCTs, theGRADE assessment was furtherly used.Results:From 240 articles returned, 10 systematic reviews were included (8 of which included a meta-analysis), including a total of 84 studies (36 prospective observational studies and 48 interventional).Nineteen different outcomes were included. Among observational studies, including a total of 1,061,637participants, the best available evidence suggests that chocolate consumption is associated with reducedrisk of cardiovascular disease (CVD) death (n¼4 studies), acute myocardial infarction (n¼6), stroke(n¼5) and diabetes (n¼6), although this was based on a weak evidence of credibility. Across meta-analyses of intervention studies, chocolate consumption was positively associated withflow-mediateddilatation at 90e150 min (n¼3) and at 2e18 weeks (n¼3), and insulin resistance markers (n¼2).However, using the GRADE assessment, the evidence for these outcomes was low or very low. Data fromtwo systematic reviews, reported that chocolate consumption was not associated with better depressivemood or cognitive function.Conclusions:There is weak evidence to suggest that chocolate consumption may be associated withfavorable health outcomes

Background: ADHD is frequently comorbid with anxiety and mood disorders, which may increase the severity of inattention and hyperactivity symptoms. Emotional symptoms (anxiety, irritability, mood lability) also affect patients without comorbidity or emerge as adverse drug events. The influence of ADHD drugs on emotional symptoms demands investigation to improve therapies. Methods: Systematic review of trials reporting adverse events in patients pharmacologically treated for ADHD. Meta-analysis of the occurrence of irritability, anxiety, apathy, reduced talk, sadness, crying, emotional lability, biting nails, staring, perseveration, euphoria. Meta-regression analysis. Results: Forty-five trials were meta-analysed. The most frequently reported outcomes were irritability, anxiety, sadness, and apathy. Methylphenidates, especially immediate-release formulations, were most studied; amphetamines were half as studied and were predominantly mixed amphetamine salts. Reports on atomoxetine were scant. Meta-analysis showed that methylphenidates reduced the risk of irritability, anxiety, euphoria, whereas they worsened the risk of apathy and reduced talk; amphetamines worsened the risk of emotional lability. Factors influencing risks were study year and design, patients' sex and age, drug dose and release formulation. Limitations: Possible discrepancy between adverse events as indicated in clinical trials and as summarised herein. Confounding due to the aggregation of drugs into groups; uninvestigated sources of bias; incomplete lists of adverse events; lack of observations on self-injury. Conclusions: Methylphenidates appeared safer than amphetamines, although younger patients and females may incur higher risks, especially with high-dose, immediate-release methylphenidates. Only atomoxetine holds a black-box warning, but amphetamines and methylphenidates also did not show a safe profile regarding mood and emotional symptoms.