Immune-related serious adverse events with immune checkpoint inhibitors: Systematic review and network meta-analysis.

PURPOSE: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, though uncertainty exists regarding their immune-related safety. The objective of this study was to assess the comparative safety profile (odds ratio) of ICIs and estimate the absolute rate of immune-related serious adverse events (irSAEs) in cancer patients undergoing treatment with ICIs. METHODS: We searched for randomized trials till February 2021, including all ICIs for all cancers. Primary outcome was overall irSAEs, and secondary outcomes were pneumonitis, colitis, hepatitis, hypophysitis, myocarditis, nephritis, and pancreatitis. We conducted Bayesian network meta-analyses, estimated absolute rates and ranked treatments according to the surface under the cumulative ranking curve (SUCRA). RESULTS: We included 96 trials (52,811 participants, median age 62 years). Risk of bias was high in most trials. Most cancers were non-small cell lung cancer (28 trials) and melanoma (15 trials). The worst-ranked ICI was ipilimumab (SUCRA 14%; event rate 848/10,000 patients) while the best-ranked ICI was atezolizumab (SUCRA 82%; event rate 119/10,000 patients). CONCLUSION: Each ICI showed a unique safety profile, with certain events more frequently observed with specific ICIs, which should be considered when managing cancer patients.

Efficacy and safety of adjunctive oral therapy in Parkinson's disease with motor complications: a systematic review and network meta-analysis.

Background: The aim of this manuscript is to review the evidence and compare the efficacy and safety of catechol-O-methyltransferase inhibitors (COMT-Is), dopamine receptor agonists (DRAs) and monoamine-oxidase B inhibitors (MAOB-Is) as adjunctive treatment to levodopa in patients with Parkinson's disease (PD) experiencing motor complications. Methods: In this systematic review and network meta-analysis, literature searches were performed in MEDLINE and Embase to identify eligible randomised controlled trials (RCTs) with a minimal follow-up of at least 4 weeks published in English between 1980 and 2021. RCTs were included if either a COMT-I, DRA or MAOB-I was evaluated as an adjunctive therapy to levodopa in patients with PD experiencing motor complications and dyskinesia. The main outcomes included daily off-medication time, motor and non-motor examination scales, and adverse events including dyskinesia. Results: 74 RCTs reporting on 18 693 patients were included. All three studied drug classes decreased daily off-medication time compared with placebo (COMT-Is mean -0.8 hours (95% CI -1.0 to -0.6), DRAs -1.1 hours (95% CI -1.4 to -0.8), MAOB-Is -0.9 hours (95% CI -1.2 to -0.6)). Safety analysis showed an increased risk of dyskinesia for all three drug classes (COMT-Is OR 3.3 (95% CI 2.7 to 4.0), DRAs 3.0 (95% CI 2.5 to 3.5), MAOB-Is 1.6 (95% CI 1.2 to 2.2)). According to surface under the cumulative ranking curve scores, pramipexole IR was associated with the most favourable benefit-risk profile. Conclusions: COMT-Is, DRAs and MAOB-Is effectively reduce motor complications and increase incidence of dyskinesia. In the network meta-analysis, adjunctive use of DRAs appeared most effective.

Prognosis of polymerase epsilon (POLE) mutation in high-grade endometrioid endometrial cancer: Systematic review and meta-analysis.

BACKGROUND: POLE mutated endometrial carcinomas may represent a subspecific type of tumors harboring a more favorable prognosis. Grade 3 (G3 or high-grade) endometrioid endometrial carcinomas remain a clinical dilemma, with some tumors behaving as the low-grade counterparts and others presenting a more aggressive behavior. OBJECTIVES: To determine the association between POLE mutational status and the overall-survival (OS) and progression-free-survival (PFS) of patients with G3 endometrioid endometrial cancer (EC). We also aimed to determine the prevalence of POLE mutations in G3 endometrioid EC. METHODS: We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (PROSPERO No: CRD4202340008). We searched the following electronic databases: PubMed/Medline, EMBASE, Cochrane Library, Scopus, and Web of Science. For time-to-event data, the effect of POLE mutation in G3 EC was described using hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). Individual patient data for each study was investigated if available from the study authors. If individual patient data were not available, information regarding time-to-event outcomes was extracted using an appropriate methodology. OS and PFS were analyzed using both one-stage and two-stage approaches, the Kaplan-Meier method, and Cox-proportional hazards models. RESULTS: This systematic review and meta-analysis included 19 studies with 3092 patients who had high-grade endometrioid EC. Patients with POLE mutations had lower risks of death (HR = 0.36, 95% CI 0.26 to 0.50, I2 = 0%, 10 trials) and disease progression (HR = 0.31, 95% CI 0.17 to 0.57, I2 = 33%, 10 trials). The pooled prevalence of POLE mutation was 11% (95% CI 9 to 13, I2 = 68%, 18 studies). CONCLUSION: POLE mutations in high-grade endometrioid EC are associated with a more favorable prognosis with increased OS and PFS.

Vertical Slot Fishways: Incremental Knowledge to Define the Best Solution.

River artificial fragmentation is arguably the most imperilling threat for freshwater-dependent fish species. Fish need to be able to freely move along river networks as not only spawning grounds but also refuge and feeding areas may be spatially and temporally separated. This incapacity of free displacement may result in genetic depletion of some populations, density reduction and even community changes, which may in turn affect how meta-community balances are regulated, potentially resulting in functional resilience reduction and ecosystem processes' malfunction. Fishways are the most common and widely used method to improve connectivity for fish species. These structures allow fish to negotiate full barriers, thus reducing their connectivity impairment. Among all technical fishway types, vertical slot fishways (VSF) are considered to be the best solution, as they remain operational even with fluctuating water discharges and allow fish to negotiate each cross-wall at their desired depth. In the present study, we collected both published and original data on fish experiments within VSF, to address two questions, (1) What variables affect fish passage during experimental fishway studies? and (2) What is the best VSF configuration? We used Bayesian Generalized Mixed Models accounting for random effects of non-controlled factors, limiting inherent data dependencies, that may influence the model outcome. Results highlight that fish size, regardless of the species, is a good predictor of fishway negotiation success. Generally, multiple slot fishways with one orifice proved to be the best solution. Future work should be focused on small-sized fish to further improve the design of holistic fishways.

Frequency of Depressive Disorders in Parkinson's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Depressive disorders are recognized as a common neuropsychiatric disorder of Parkinson's disease (PD). Reported frequencies vary widely among studies and depend on the diagnostic criteria, the methods of ascertainment used, and the population sampled. OBJECTIVE: We aimed to evaluate the frequency of depressive disorders in PD and to investigate the relationship with PD clinical variables. METHODS: A systematic review and meta-analysis of observational studies (community-based, prospective and retrospective cohort, case-control, and cross-sectional studies) reporting the frequency of depressive disorders in PD patients. RESULTS: Electronic database search wielded 3,536 articles; an additional 91 were identified through citation chaining. 163 full-text articles were assessed for eligibility. Of these, 49 met the inclusion criteria for our analysis. The pooled frequency of depressive disorders was 30.7% (95% confidence interval [CI] 25.6 to 36.2; I2 = 95%; 49 studies; combined n = 10,039). The pooled frequency of major depressive disorder was 14.0% (95% CI 10.5 to 18.5; I2 = 88%; 23 studies; combined n = 5,218). Subgroup/meta-regression analyses were conducted to investigate the relationship between frequency and study inclusion criteria, methodology used for diagnosis, and study design. We found a statistically significant correlation between study design and depressive disorders frequency (ranging from 8% in the community-based study to 44% in the retrospective studies) and a statistically significant positive correlation between mean baseline PD duration and major depressive disorder frequency. CONCLUSION: The current meta-analysis found a global frequency of depressive disorders of 30.7% and major depressive disorder of 14.0%. Study design influenced the frequency of depressive disorders in PD. Mean baseline PD duration and major depressive disorder frequency were positively correlated.

Half Friend, Half Enemy? Comparative Phytophagy between Two Dicyphini Species (Hemiptera: Miridae).

Despite their importance as biological control agents, zoophytophagous dicyphine mirids can produce economically important damage. We evaluated the phytophagy and potential impact on tomato plants of Dicyphus cerastii and Nesidiocoris tenuis. We developed a study in three parts: (i) a semi-field trial to characterize the type of plant damage produced by these species on caged tomato plants; (ii) a laboratory experiment to assess the effect of fruit ripeness, mirid age, and prey availability on feeding injuries on fruit; and (iii) a laboratory assay to compare the position of both species on either fruit or plants, over time. Both species produced plant damage, however, although both species produced scar punctures on leaves and necrotic patches on petioles, only N. tenuis produced necrotic rings. Both species caused flower abortion at a similar level. Overall, N. tenuis females produced more damage to tomato fruit than D. cerastii. There was an increased frequency of D. cerastii females found on the plants over time, which did not happen with N. tenuis. Our results suggested that, although D. cerastii caused less damage to fruit than N. tenuis, it still fed on them and could cause floral abortion, which requires field evaluation and caution in its use in biological control strategies.

Incidence and Prevalence of Thoracic Aortic Aneurysms: A Systematic Review and Meta-analysis of Population-Based Studies.

Thoracic aortic aneurysms (TAA) may grow asymptomatically until they rupture, with a mortality over 90%. The true incidence and prevalence of this condition is uncertain and epidemiologic data is scarce, understudied and dispersed. Therefore, we aimed to conduct a systematic review and meta-analysis of the incidence and prevalence of TAAs in population-based studies. We searched MEDLINE, EMBASE and CENTRAL from inception to October 2020 for all population-based studies reporting on incidence and/or prevalence of TAAs. Data were pooled using a random effects model. The main outcome was the overall available worldwide incidence and prevalence of TAAs. The secondary outcomes were to evaluate the incidence of ruptured TAAs, differences in the location of these aneurysms (either ascending, arch or descending aorta) and differences in prevalence/incidence across different study designs. Twenty-two studies were included in the review and meta-analysis. The pooled incidence and prevalence of TAAs was 5.3 per 100,000 individuals/year (95% confidence interval [CI]: 3.0; 8.3) and 0.16% (95% CI: 0.12; 0.20), respectively. The pooled incidence of ruptured aneurysms was 1.6 per 100,000 individuals/year (95% CI: 1.3; 2.1). We found a significant difference of the prevalence in autopsy-only studies, which was 0.76% (95% CI: 0.47; 1.13) and the prevalence of TAAs dropped down to 0.07% (95% CI: 0.05;0.11) when these studies were excluded from the overall analysis. The current epidemiologic information provided serve as a base for future public-health decisions. The lack of well-design population-base studies and the limitations encountered serve as calling for future research in this field.

An MDS Evidence-Based Review on Treatments for Huntington's Disease.

BACKGROUND: Huntington's disease (HD) is a rare neurodegenerative disorder with protean clinical manifestations. Its management is challenging, consisting mainly of off-label treatments. OBJECTIVES: The International Parkinson and Movement Disorder Society commissioned a task force to review and evaluate the evidence of available therapies for HD gene expansion carriers. METHODS: We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Eligible randomized controlled trials were identified via an electronic search of the CENTRAL, MEDLINE, and EMBASE databases. All eligible trials that evaluated one or more of 33 predetermined clinical questions were included. Risk of bias was evaluated using the Cochrane Risk of Bias tool. A framework was adapted to allow for efficacy and safety conclusions to be drawn from the balance between the GRADE level of evidence and the importance of the benefit/harm of the intervention. RESULTS: Twenty-two eligible studies involving 17 interventions were included, providing data to address 8 clinical questions. These data supported a likely effect of deutetrabenazine on motor impairment, chorea, and dystonia and of tetrabenazine on chorea. The data did not support a disease-modifying effect for premanifest and manifest HD. There was no eligible evidence to support the use of specific treatments for depression, psychosis, irritability, apathy, or suicidality. Similarly, no evidence was eligible to support the use of physiotherapy, occupational therapy, exercise, dietary, or surgical treatments. CONCLUSIONS: Data for therapeutic interventions in HD are limited and support only the use of VMAT2 inhibitors for specific motor symptoms. © 2021 International Parkinson and Movement Disorder Society.

Frequency and Characteristics of Psychosis in Parkinson's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Psychotic symptoms are highly frequent in Parkinson's disease (PD) patients and are associated with poor prognosis. They include hallucinations, delusions, and minor psychotic phenomena, including sense of presence, passage hallucinations, and illusions. OBJECTIVE: To evaluate the frequency of psychosis in PD patients. METHODS: A systematic review and meta-analysis of clinical trials, prospective and retrospective cohort studies, case-control studies, and cross-sectional studies reporting the frequency of psychosis, hallucinations, and delusions in PD. RESULTS: Electronic database search wielded 3536 articles, an additional 91 were identified through citation chaining. Of these, 163 were fully inspected, 57 removed, and 106 included as relevant for neuropsychiatric events frequency, with 32 meeting our inclusion criteria (psychosis and/or specific psychotic phenomena). The pooled frequency of psychosis was 20.7% (95% CI 14.5 to 28.6; I2 = 94%, 15 studies; combined n = 2919). None of the pre-defined meta-regressions or subgroup analyses were statistically significant or helped explain the statistical heterogeneity. The pooled frequency of any form of hallucination was 21.6% (95% CI 14.7 to 30.6; I2 = 95%; 18 studies; combined n = 3161). Duration of PD at baseline and mean baseline Hoehn & Yahr stage helped explain the statistical heterogeneity in the meta-analysis of hallucinations. CONCLUSION: Based on the available evidence, around a fifth of PD patients experience psychosis or hallucinations. The risk of developing hallucinations is likely moderated by the disease duration, Hoehn & Yahr stage, and the cognitive status.

iPODfish - A new method to infer the historical occurrence of diadromous fish species along river networks.

Available information on diadromous fish species historical occurrences is generally biased and incomplete across species distribution range and spatial scales. This work aims to establish a new methodological framework (iPODfish - Inferring Past Occurrences of Diadromous Fish) to obtain a more complete representation of the historical occurrences of diadromous fish species over their full distribution range. The iPODfish is based on assumptions, rules and thresholds derived from the interplay between freshwater network features, diadromous fish species ecology and known historical occurrence. These are used to establish historical pseudo-occurrences at the segment scale, i.e., locations where the species was most likely to be present or absent. The methodology is expressed by a tree-like representation of a stepwise, information supported, decision process. It has five steps (separating main river segments from tributary segments; accounting for segments specificities; imposing the relative distance threshold; imposing the Strahler value threshold, and; establishing the sub-basin Strahler threshold), divides into two moments of application (main river followed by the tributaries) and establishes presences, pseudo-presences and pseudo-absences. The iPODfish can deal with multiple information sources, cope with data bias and provide a reliable consistent historical occurrence output at the segment scale for the known historical geographical range of the species. Despite its inference nature, iPODfish is still a conservative procedure leading to ecologically coherent outputs that may be applied to any diadromous fish species (with a relevant amount of historical data available) in any river network throughout the globe because the concepts and definitions used are general ecological features of diadromous and freshwater networks. The method outputs are applicable in biogeographical and/or macroecological studies using historical data and may prove useful to the management and conservation of diadromous fish species.

Knowledge Gaps in the Definition of Threats for the Red List Assessment of European Freshwater-Dependent Fish Species.

Freshwater ecosystems are disproportionally important for biodiversity conservation, as they support more than 9% of known animal species while representing less than 1% of the Earth's surface. However, the vast majority of the threats (99%, or 826 out of 837) identified by the International Union for Conservation of Nature Red List of Threatened Species known to affect the 434 known freshwater-dependent fish and lampreys of Europe are not supported by validated published scientific knowledge. This general lack of information about freshwater-dependent fish and lamprey species may have deleterious effects on species conservation, and additional funding is required to fill baseline knowledge gaps.

Major threats to European freshwater fish species.

In Europe, freshwater fish are the richest group amongst European vertebrates and the second most threatened animal group, surpassed only by freshwater molluscs. The identification of threats is a major benefit for conservation efforts, as it allows actions to be bespoke to specific threats imperilling fish communities in sensitive areas. In this work, we analyse all threats identified under the International Union for Conservation of Nature (IUCN) Red List of Threatened Species for all European native freshwater dependent fish and lamprey species and relate them with the species distribution, conservation status and migratory phenology. Results show that the current level of imperilment of European freshwater fish fauna is high, especially in the Iberian Peninsula fish communities where low richness is combined with a proportion of threatened species surpassing 50% in several catchments The most relevant threats affecting European freshwater fish are: "Dams & Water Management/Use", "Droughts", "Invasive Non-Native/Alien Species/Diseases", "Agricultural & Forestry Effluents" and "Fishing & Harvesting Aquatic Resources". The present work contributes to the ultimate goal of species conservation by highlighting the main threats affecting freshwater fish species in Europe and by demonstrating how specific regions need particular attention. Increasing longitudinal connectivity stands out as a measure with the potential to increase species' resilience to the several threats affecting them, and it should be coupled with additional efforts to reduce water pollution, control alien species and effectively manage fishing.

Functional Response and Predation Rate of Dicyphus cerastii Wagner (Hemiptera: Miridae).

Dicyphine mirids are important biological control agents (BCAs) in horticultural crops. Dicyphus cerastii Wagner can be found in protected tomato crops in Portugal, and has been observed feeding on several tomato pests. However, the predation capacity of this species is poorly studied. In order to investigate the predation capacity of D. cerastii, and how it is affected by prey size and mobility, we evaluated the functional response (FR) and predation rate of female predators on different densities of four prey species: Myzus persicae 1st instar nymphs (large mobile prey), Bemisia tabaci 4th instar nymphs, Ephestia kuehniella eggs (large immobile prey) and Tuta absoluta eggs (small immobile prey). Experiments were performed on tomato leaflets in Petri dish arenas for 24 h. Dicyphus cerastii exhibited type II FR for all prey tested. The predator effectively preyed upon all prey, consuming an average of 88.8 B. tabaci nymphs, 134.4 E. kuehniella eggs, 37.3 M. persicae nymphs and 172.3 T. absoluta eggs. Differences in the FR parameters, attack rate and handling time, suggested that prey size and mobility affected predation capacity. Considering the very high predation rates found for all prey species, D. cerastii proved to be an interesting candidate BCA for tomato crops.

Botulinum toxin type A versus anticholinergics for cervical dystonia.

BACKGROUND: This is an update of a Cochrane Review first published in 2005. Cervical dystonia is the most common form of focal dystonia and is a highly disabling movement disorder, characterised by involuntary, usually painful, head posturing. Currently, botulinum toxin type A (BtA) is considered the first line therapy for this condition. Before BtA, anticholinergics were the most widely accepted treatment. OBJECTIVES: To compare the efficacy, safety, and tolerability of BtA versus anticholinergic drugs in adults with cervical dystonia. SEARCH METHODS: We searched the Cochrane Movement Disorders' Trials Register to June 2003, screened reference lists of articles and conference proceedings to September 2018, and searched CENTRAL, MEDLINE, and Embase, with no language restrictions, to July 2020. SELECTION CRITERIA: Double-blind, parallel, randomised trials (RCTs) of BtA versus anticholinergic drugs in adults with cervical dystonia. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed records, selected included studies, extracted data using a paper pro forma, and evaluated the risk of bias and quality of the evidence. We resolved disagreements by consensus or by consulting a third review author. If enough data had been available, we were to perform meta-analyses using a random-effects model for the comparison of BtA versus anticholinergic drugs to estimate pooled effects and corresponding 95% confidence intervals (95% CI). The primary efficacy outcome was improvement in cervical dystonia-specific impairment. The primary safety outcome was the proportion of participants with any adverse event. MAIN RESULTS: We included one RCT of moderate overall risk of bias (as multiple domains were at unclear risk of bias), which included 66 BtA-naive participants with cervical dystonia. Two doses of BtA (Dysport; week 0 and 8; mean dose 262 to 292 U) were compared with daily trihexyphenidyl (up to 24 mg daily). The trial was sponsored by the BtA producer. BtA reduced cervical dystonia severity by an average of 2.5 points (95% CI 0.68 to 4.32) on the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) severity subscale 12 weeks after injection, compared to trihexyphenidyl. More participants reported adverse events in the trihexyphenidyl treatment group (76 events), compared with the BtA group (31 events); however, the difference in dropouts due to adverse events was inconclusive between groups. There was a decreased risk of dry mouth, and memory problems with BtA, but the differences were inconclusive between groups for the other reported side effects (blurred vision, dizziness, depression, fatigue, pain at injection site, dysphagia, and neck weakness). AUTHORS' CONCLUSIONS: We found very low-certainty evidence that BtA is more effective, better tolerated, and safer than trihexyphenidyl. We found no information on a dose-response relationship with BtA, differences between BtA formulations or different anticholinergics, the utility of electromyography-guided injections, or the duration of treatment effect.

Can EEG Be Adopted as a Neuroscience Reference for Assessing Software Programmers' Cognitive Load?

An emergent research area in software engineering and software reliability is the use of wearable biosensors to monitor the cognitive state of software developers during software development tasks. The goal is to gather physiologic manifestations that can be linked to error-prone scenarios related to programmers' cognitive states. In this paper we investigate whether electroencephalography (EEG) can be applied to accurately identify programmers' cognitive load associated with the comprehension of code with different complexity levels. Therefore, a controlled experiment involving 26 programmers was carried. We found that features related to Theta, Alpha, and Beta brain waves have the highest discriminative power, allowing the identification of code lines and demanding higher mental effort. The EEG results reveal evidence of mental effort saturation as code complexity increases. Conversely, the classic software complexity metrics do not accurately represent the mental effort involved in code comprehension. Finally, EEG is proposed as a reference, in particular, the combination of EEG with eye tracking information allows for an accurate identification of code lines that correspond to peaks of cognitive load, providing a reference to help in the future evaluation of the space and time accuracy of programmers' cognitive state monitored using wearable devices compatible with software development activities.

Analysis of clinical and methodological characteristics of early COVID-19 treatment clinical trials: so much work, so many lost opportunities.

BACKGROUND: The COVID-19 pandemic continues to rage on, and clinical research has been promoted worldwide. We aimed to assess the clinical and methodological characteristics of treatment clinical trials that have been set forth as an early response to the COVID-19 pandemic. METHODS: First, we reviewed all registered clinical trials on COVID-19. The World Health Organization International Trials Registry Platform and national trial registries were searched for COVID-19 trials through April 19th, 2020. For each record, independent researchers extracted interventions, participants, and methodological characteristics. Second, on September 14th, 2020 we evaluated the recruitment status and availability of the results of COVID-19 treatment trials previously identified. RESULTS: In April 2020, a total of 580 trials evaluating COVID-19 treatment were registered. Reporting quality was poor (core participant information was missing in 24.1 to 92.7%). Between 54.0 and 93.8% of the trials did not plan to include older people or those with a higher baseline risk. Most studies were randomised (67.9%), single-centre (58.3%), non-industry-funded (81.1%), to be conducted in China (47.6%), with a median duration of 184 days and a median sample size of 100 participants. Core endpoints (mortality, clinical status, and hospitalization length) were planned to be assessed in 5.2 to 13.1% of the trials. Five months later, 66 trials (11.4%) were reported as "Completed", and only 46 (7.9%) had public results available. One hundred forty-four of 580 trials (24.8%) either had the status "Not yet recruiting" or "Suspended", and 18 (3.1%) trials were prematurely stopped ("Terminated" or "Withdrawn") The number of completed trials and trials with results are much lower than anticipated, considering the planned follow-up. CONCLUSIONS: Our results raise concerns about the success of the initial global research effort on COVID-19 treatment. The clinical and methodological characteristics of early COVID-19 treatment trials limit their capability to produce clear answers to critical questions in the shortest possible time.

Parkinson's Disease Drug Development Since 1999: A Story of Repurposing and Relative Success.

BACKGROUND: A global overview of drug development programs in Parkinson's disease over the last few decades is lacking, while such programs are challenging given the multifaceted and heterogeneous nature of the disease. OBJECTIVE: To indirectly assess drug development programs in Parkinson's disease, exploring some factors associated with compound attrition at different trial phases. METHODS: We assessed all Parkinson's disease trials in the WHO trials portal, from inception (1999) to September 2019. Independent authors selected trials and extracted data. The success rate was the number of compounds that progressed to the next drug development phase divided by the number of compounds in that phase. RESULTS: Overall, 357 trials (studying 152 compounds) fulfilled our inclusion criteria, with 62 (17.3%) phase 1 trials, 135 (37.8%) phase 2 trials, 85 (23.8%) phase 3 trials, and 53 (14.8%) phase 4 trials. The success rate was 42.4% from phase 2 to 3. Original compounds received regulatory approval by the FDA in 21.4% of cases, compared with 6.7% of repurposed compounds, representing an overall success rate of 14.9%. We found 172 trials (48.2%) conducted for repurposing previously licensed compounds. These figures were approximately the same regarding approval by the EMA. Most compounds were approved to treat parkinsonism and motor fluctuations. CONCLUSION: We found a moderate-to-high success rate in all phases of drug development. This was largely based on the success of original compounds, despite almost half of the identified trials attempting compound repurposing.

Safety and tolerability of sacubitril-valsartan: a systematic review and meta-analysis.

Introduction: Sacubitril-valsartan is a recently approved drug. However, there are few data regarding safety issues. We aimed to summarize the available evidence regarding sacubitril-valsartan's safety and tolerability.Methods: We conducted a systematic review with meta-analysis of randomized controlled trials (RCTs) enrolling patients receiving sacubitril-valsartan for any condition, compared with standard therapy or placebo. Database search was performed in October 2019. Outcomes were adverse events (AEs), serious AEs (SAEs), discontinuation due to AEs, and five AEs of special interest. Data were reported using risk ratio (RR) and 95% confidence interval (95%CI).Results: We included 20 RCTs (22510 participants). When compared with active controls, there were no differences in SAEs (RR=0.93, 95%CI 0.86-1.01) and AEs (RR=1.00, 95%CI 0.97-1.03). However, sacubitril-valsartan resulted in an 8% risk reduction in discontinuation due to AEs (95%CI 0.85-0.99) and an increased risk of hypotension (RR=1.45, 95%CI 1.27-1.67). The risk of angioedema was higher with follow-ups greater than 12 months (RR=2.36, 95%CI 1.29-4.33). There were no further significant differences in the remaining AEs' risk.Conclusions: Sacubitril-valsartan was at least as safe and tolerable as active control, with a similar need of administration cautiousness, except for a higher risk of hypotension. However, one should consider the study's limitations.

Pneumococcal vaccination in adults at very high risk or with established cardiovascular disease: systematic review and meta-analysis.

AIMS: There are several guidelines that recommend pneumococcal vaccination (PPSV23 and/or PCV13) in adults with a history of cardiovascular disease (established heart failure, coronary disease, and cerebrovascular disease) or at a very high risk of cardiovascular disease. However, there is no randomized controlled trial (RCT) systematic review that evaluates the impact of vaccination on all-cause mortality compared to no vaccination in this particular population. Our objective is to conduct a systematic review and meta-analysis of the impact of pneumococcal vaccination in the referred population. METHODS AND RESULTS: We searched CENTRAL and MEDLINE for relevant RCTs and observational studies. Data were screened, extracted, and appraised by two independent reviewers. We pooled results using a random effects model, and used hazard ratios (HRs) with 95% confidence intervals (CIs) to assess measure of effect. The primary outcome was all-cause mortality and we assessed the confidence in the evidence using the GRADE framework. No RCTs were found. Seven observational studies were included for analyses. Pooled results from five studies enrolling a total of 163 756 participants showed a significant decrease in all-cause mortality (HR 0.78, 95% CI 0.73-0.83, very low confidence), without statistically significant heterogeneity (χ2 test P = 0.21; I2 = 32%). CONCLUSIONS: Pneumococcal vaccination was associated with a 22% decrease of all-cause mortality in patients with cardiovascular disease or at a very high cardiovascular risk. However, limitations due to study design and the serious risk of bias in three of the included studies leads to a decreased level of result confidence.

The impact of influenza vaccination in patients with cardiovascular disease: An overview of systematic reviews.

Whether influenza vaccination can play a prognostic role in patients with cardiovascular (CV) disease (coronary artery disease (CAD), heart failure, stroke, peripheral artery disease (PAD)) is still not completely well-established. We conducted this overview of systematic reviews (SR) evaluating the effects of influenza vaccination in secondary prevention of CV disease. An electronic search was performed in the MEDLINE (to November 2019). Eligibility criteria included SR evaluating the effect of influenza vaccination in patients with CV disease. The risk of bias of the included systematic reviews was evaluated using the ROBIS tool. All-cause mortality, CV mortality, major adverse cardiovascular events (MACE) and hospitalizations were evaluated. Whenever required, data were recalculated through a random-effects meta-analysis to obtain pooled data for the patients at secondary CV prevention. The search process yielded four SR: two in CAD, one in heart failure and one in stroke. There were no SR evaluating the vaccine in PAD. The risk of bias was unclear (2 SR) and high (2 SR). Influenza vaccination in patients with CAD showed a risk reduction in all-cause mortality (data recalculated), cardiovascular mortality and MACE, particularly in patients with recent acute coronary syndrome. In patients with heart failure, vaccination was associated with a decreased risk of all-cause mortality. There was a non-significant trend in recurrent stroke risk reduction in patients with previous stroke. The available evidence suggests that influenza vaccination was associated with a protective effect in CAD and HF patients. However, these results need to be clarified with higher quality evidence studies.