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.

Male harm suppresses female fitness, affecting the dynamics of adaptation and evolutionary rescue.

One of the most pressing questions we face as biologists is to understand how climate change will affect the evolutionary dynamics of natural populations and how these dynamics will in turn affect population recovery. Increasing evidence shows that sexual selection favors population viability and local adaptation. However, sexual selection can also foster sexual conflict and drive the evolution of male harm to females. Male harm is extraordinarily widespread and has the potential to suppress female fitness and compromise population growth, yet we currently ignore its net effects across taxa or its influence on local adaptation and evolutionary rescue. We conducted a comparative meta-analysis to quantify the impact of male harm on female fitness and found an overall negative effect of male harm on female fitness. Negative effects seem to depend on proxies of sexual selection, increasing inversely to the female relative size and in species with strong sperm competition. We then developed theoretical models to explore how male harm affects adaptation and evolutionary rescue. We show that, when sexual conflict depends on local adaptation, population decline is reduced, but at the cost of slowing down genetic adaptation. This trade-off suggests that eco-evolutionary feedback on sexual conflict can act like a double-edged sword, reducing extinction risk by buffering the demographic costs of climate change, but delaying genetic adaptation. However, variation in the mating system and male harm type can mitigate this trade-off. Our work shows that male harm has widespread negative effects on female fitness and productivity, identifies potential mechanistic factors underlying variability in such costs across taxa, and underscores how acknowledging the condition-dependence of male harm may be important to understand the demographic and evolutionary processes that impact how species adapt to environmental change.

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.

Management of allergic rhinitis symptoms in the pharmacy Pocket guide 2022.

Background: Allergic rhinitis (AR) management requires a coordinated effort from healthcare providers and patients. Pharmacists are key members of these integrated care pathways resolving medication-related problems, optimizing regimens, improving adherence and recommending therapies while establishing liaisons between patients and physicians. Methods: Allergic Rhinitis and its Impact on Asthma (ARIA) first published a reference document on the pharmacist's role in allergic rhinitis management in 2004. Several guidelines were developed over the past 20 years improving the care of allergic rhinitis patients through an evidence-based, integrated care approach. Results: This ARIA/EAACI/FIP Position Paper is based on the latest ARIA in the Pharmacy guidelines and provides: (a) a structured approach to pharmacists identifying people with AR and/or allergic conjunctivitis as well as those at risk of poor disease control; (b) an evidence-based clinical decision support tool for optimising the management of allergic rhinitis in the community pharmacy; and (c) a framework of referral to the physician. Conclusion: This document is not intended to be a mandatory standard of care but is provided as a basis for pharmacists and their staff to develop relevant local standards of care for their patients, within their local practice environment. Pharmacy care varies between countries, and the guide should be adapted to the local situation.

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.

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.

[18F]Atorvastatin Pharmacokinetics and Biodistribution in Healthy Female and Male Rats.

Statins are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors that are widely used to prevent cardiovascular diseases. However, a series of pleiotropic mechanisms have been associated with statins, particularly with atorvastatin. Therefore, the assessment of [18F]atorvastatin kinetics with positron emission tomography (PET) may elucidate the mechanism of action of statins and the impact of sexual dimorphism, which is one of the most debated interindividual variations influencing the therapeutic efficacy. [18F]Atorvastatin was synthesized via a previously optimized 18F-deoxyfluorination strategy, used for preclinical PET studies in female and male Wistar rats (n = 7 for both groups), and for subsequent ex vivo biodistribution assessment. PET data were fitted to several pharmacokinetic models, which allowed for estimating relevant kinetic parameters. Both PET imaging and biodistribution studies showed negligible uptake of [18F]atorvastatin in all tissues compared with the primary target organ (liver), excretory pathways (kidneys and small intestine), and stomach. Uptake of [18F]atorvastatin was 38 ± 3% higher in the female liver than in the male liver. The irreversible 2-tissue compartment model showed the best fit to describe [18F]atorvastatin kinetics in the liver. A strong correlation (R2 > 0.93) between quantitative Ki (the radiotracer's unidirectional net rate of influx between compartments) and semi-quantitative liver's SUV (standard uptake value), measured between 40 to 90 min, showed potential to use the latter parameter, which circumvents the need for blood sampling as a surrogate of Ki for monitoring [18F]atorvastatin uptake. Preclinical assays showed faster uptake and clearance for female rats compared to males, seemingly related to a higher efficiency for exchanges between the arterial input and the hepatic tissue. Due to the slow [18F]atorvastatin kinetics, equilibrium between the liver and plasma concentration was not reached during the time frame studied, making it difficult to obtain sufficient and accurate kinetic information to quantitatively characterize the radiotracer pharmacokinetics over time. Nevertheless, the reported results suggest that the SUV can potentially be used as a simplified measure, provided all scans are performed at the same time point. Preclinical PET-studies with [18F]atorvastatin showed faster uptake and clearance in female compared to male rats, apparently related to higher efficiency for exchange between arterial blood and hepatic tissue.

A molecular test based on RT-LAMP for rapid, sensitive and inexpensive colorimetric detection of SARS-CoV-2 in clinical samples.

Until there is an effective implementation of COVID-19 vaccination program, a robust testing strategy, along with prevention measures, will continue to be the most viable way to control disease spread. Such a strategy should rely on disparate diagnostic tests to prevent a slowdown in testing due to lack of materials and reagents imposed by supply chain problems, which happened at the beginning of the pandemic. In this study, we have established a single-tube test based on RT-LAMP that enables the visual detection of less than 100 viral genome copies of SARS-CoV-2 within 30 min. We benchmarked the assay against the gold standard test for COVID-19 diagnosis, RT-PCR, using 177 nasopharyngeal RNA samples. For viral loads above 100 copies, the RT-LAMP assay had a sensitivity of 100% and a specificity of 96.1%. Additionally, we set up a RNA extraction-free RT-LAMP test capable of detecting SARS-CoV-2 directly from saliva samples, albeit with lower sensitivity. The saliva was self-collected and the collection tube remained closed until inactivation, thereby ensuring the protection of the testing personnel. As expected, RNA extraction from saliva samples increased the sensitivity of the test. To lower the costs associated with RNA extraction, we performed this step using an alternative protocol that uses plasmid DNA extraction columns. We also produced the enzymes needed for the assay and established an in-house-made RT-LAMP test independent of specific distribution channels. Finally, we developed a new colorimetric method that allowed the detection of LAMP products by the visualization of an evident color shift, regardless of the reaction pH.

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.

Mapping Arginase Expression with 18F-Fluorinated Late-Generation Arginase Inhibitors Derived from Quaternary α-Amino Acids.

Arginase hydrolyzes L-arginine and influences levels of polyamines and nitric oxide. Arginase overexpression is associated with inflammation and tumorigenesis. Thus, radiolabeled arginase inhibitors may be suitable PET tracers for staging arginase-related pathophysiologies. We report the synthesis and evaluation of 2 radiolabeled arginase inhibitors, 18F-FMARS and 18F-FBMARS, developed from α-substituted-2-amino-6-boronohexanoic acid derivatives. Methods: Arylboronic ester-derived precursors were radiolabeled via copper-mediated fluorodeboronation. Binding assays using arginase-expressing PC3 and LNCaP cells were performed. Autoradiography of lung sections from a guinea pig model of asthma overexpressing arginase and dynamic small-animal PET imaging with PC3-xenografted mice evaluated the radiotracers' specific binding and pharmacokinetics. Results:18F-fluorinated compounds were obtained with radiochemical yields of up to 5% (decay-corrected) and an average molar activity of 53 GBq⋅µmol-1 Cell and lung section experiments indicated specific binding that was blocked up to 75% after pretreatment with arginase inhibitors. Small-animal PET studies indicated fast clearance of the radiotracers (7.3 ± 0.6 min), arginase-mediated uptake, and a selective tumor accumulation (SUV, 3.0 ± 0.7). Conclusion: The new 18F-fluorinated arginase inhibitors have the potential to map increased arginase expression related to inflammatory and tumorigenic processes. 18F-FBMARS showed the highest arginase-mediated uptake in PET imaging and a significant difference between uptake in control and arginase-inhibited PC3 xenografted mice. These results encourage further research to examine the suitability of 18F-FBMARS for selecting patients for treatments with arginase inhibitors.

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.

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.

Once- versus Twice-Daily Aspirin in Patients at High Risk of Thrombotic Events: Systematic Review and Meta-Analysis.

BACKGROUND: Acetylsalicylic acid (ASA) is a frequently used antiplatelet agent, although some individuals have reduced antiplatelet responses on ASA, with recurrent ischemic events. It has been proposed that shortening the ASA dosing interval may overcome the time-dependent renewal of the drug target, leading to a greater antiplatelet effect. We conducted a systematic review of randomized controlled trials (RCTs) to determine the efficacy of once- versus twice-daily ASA in conditions with increased platelet turnover. METHODS: We conducted a systematic review and meta-analysis by searching the CENTRAL, MEDLINE, and Embase databases for RCTs assessing once- versus twice-daily ASA. Data were screened, extracted, and appraised by two independent reviewers, and were pooled using a random-effects model. The primary outcomes were major adverse cardiovascular events (MACEs) and serum thromboxane B2 (TxB2). Other pharmacodynamic measures were retrieved as secondary outcomes. Results were reported as mean differences with corresponding 95% confidence intervals (CIs). We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Seven RCTs were included, enrolling 379 participants overall. None of the studies reported clinical outcomes. Pooled results showed that compared with once-daily ASA, twice-daily ASA was associated with a decrease in mean TxB2 of 1.42 ng/mL (95% CI - 2.71 to - 0.13; I2 = 66%). We found no differences in subgroup analyses based on disease subtype, trial blinding, or trial design. A greater antiplatelet activity of the twice-daily regimen was also found when using PFA-100-ADP methods, although not when using the VerifyNow, LTA-AA, and multiplate methods. CONCLUSIONS: Twice-daily ASA was associated with a greater antiplatelet effect compared with standard once-daily ASA.

Satisfaction of Patients with Nonvitamin K Anticoagulants Compared to Vitamin K Antagonists: a Systematic Review and Meta-analysis.

OBJECTIVE: To undertake a systematic review and meta-analysis to assess the satisfaction of patients receiving nonvitamin K anticoagulants (NOACs), compared with vitamin K antagonists (VKAs). METHODS: We searched CENTRAL, MEDLINE, Embase, and Clinicaltrials.gov for randomized controlled trials (RCTs) and observational studies. Two reviewers screened, extracted, and appraised data independently. We pooled data using a random-effects model. Outcome included treatment satisfaction, which was assessed by scores of Duke Anticoagulation Satisfaction Scale (DASS), Anticlot Treatment Scale (ACTS), Perception of Anticoagulant Treatment Questionnaire 2 (PACT-Q2), or Treatment Satisfaction Questionnaire for Medication version II (TSQM-VII) and their domains reported with 95% confidence intervals (95% CIs). We followed MOOSE and PRISMA guidelines. RESULTS: We included four RCTs and 16 observational studies, enrolling 18,684 participants overall. Compared with VKAs, treatment with NOACs improved the ACTS Burdens score by 4.21 points (95% CI: 2.99-5.43, I 2 = 95%, combined n = 6,180), and ACTS Benefits by 0.49 points (95% CI: 0.18-0.81, I 2 = 85%, combined n = 6,171). Switching from VKAs to NOACs improved the ACTS Burdens score by 5.33 points (95% CI: 3.53-7.14, combined n = 3,097). Compared with VKAs, treatment with NOACs improved the TSQM-VII Global Satisfaction score by 6.86 points (95% CI: 3.00-10.73, combined n = 5,535). CONCLUSION: In patients with nonvalvular atrial fibrillation or venous thromboembolism, NOAC treatment is associated with greater satisfaction compared with VKAs. The switch from VKAs to NOACs was associated with improved patients' satisfaction. These effects were largely due to a lower degree of treatment burden with NOAC treatment.

Botulinum toxin type A therapy for blepharospasm.

BACKGROUND: This is an update of a Cochrane Review first published in 2005. Blepharospasm is the second most common form of focal dystonia. It is a disabling disorder, characterised by chronic, intermittent or persistent, involuntary eyelid closure, due to spasmodic contractions of the orbicularis oculi muscles. Currently, botulinum toxin type A (BtA) is considered the first line of therapy for this condition. OBJECTIVES: To compare the efficacy, safety, and tolerability of BtA versus placebo in people with blepharospasm. SEARCH METHODS: We searched Cochrane Movement Disorders' Trials Register, CENTRAL, MEDLINE, Embase, reference lists of included articles, and conference proceedings. We ran all elements of the search, with no language restrictions, in July 2020. SELECTION CRITERIA: Double-blind, parallel, randomised, placebo-controlled trials (RCTs) of BtA versus placebo in adults with blepharospasm. 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. We resolved disagreements by consensus, or by consulting a third review author. We performed meta-analyses using a random-effects model, for the comparison of BtA versus placebo, to estimate pooled effects and corresponding 95% confidence intervals (95% CI). We did not carry out any prespecified subgroup analyses. The primary efficacy outcome was improvement on any validated symptomatic rating scale. The primary safety outcome was the proportion of participants with any adverse event. MAIN RESULTS: We included three RCTs, assessed at low to moderate overall risk of bias, which randomised 313 participants with blepharospasm. Two studies excluded participants with poorer prior responses to BtA treatment, therefore, they included an enriched population with a higher probability of benefiting from this therapy. All trials were industry-funded. All RCTs evaluated the effect of a single BtA treatment session. BtA resulted in a moderate to large improvement in blepharospasm-specific severity, with a reduction of 0.93 points on the Jankovic Rating Scale (JRS) severity subscale at four to six weeks after injection (95% confidence interval (CI) 0.61 to 1.25; I² = 9%) compared to placebo. BtA was also resulted in a moderate to large improvement in blepharospasm-specific disability and blepharospasm-specific involuntary movements at four to six weeks after injection (disability: 0.69 JRS disability subscale points, 95% CI 0.18 to 1.19; I² = 74%; blepharospasm-specific involuntary movements: standardised mean difference (SMD) 0.79, 0.31 to 1.27; I² = 58%) compared to placebo. BtA did not show a risk of adverse events (risk ratio (RR) 1.18, 95% CI 0.87 to 1.60; I² = 0%). However, BtA increased the risk of vision complaints and eyelid ptosis (vision complaints: RR 5.73, 95% CI 1.79 to 18.36; I² = 51%; eyelid ptosis: RR 4.02, 95% CI 1.61 to 10.00; I² = 39%). There was no distinction between BtA and placebo in the number of participants who dropped out of the trial. A single trial estimated the duration of effects to be 10.6 weeks (range 6.1 to 19.1). We found no evidence supporting the existence of a clear dose-response relationship with BtA. We found no data reporting the impact of BtA on health-related quality of life, or the development of secondary non-responsiveness. AUTHORS' CONCLUSIONS: We are moderately certain that a single BtA treatment resulted in a clinically relevant reduction of blepharospasm-specific severity and disability, and have low certainty that it is well tolerated, when compared with placebo. There is low-certainty evidence that people treated with BtA are not at an increased risk of developing adverse events, though BtA treatment likely increases the risk of visual complaints and eyelid ptosis. There are no data from RCTs evaluating the effectiveness and safety of repeated BtA injection cycles. There is no evidence from RCTs to allow us to draw definitive conclusions on the optimal treatment intervals and doses, or the impact on quality of life.

Botulinum toxin type A therapy for hemifacial spasm.

BACKGROUND: This is an update of a Cochrane Review, first published in 2005. Hemifacial spasm (HFS) is characterised by unilateral, involuntary contractions of the muscles innervated by the facial nerve. It is a chronic disorder, and spontaneous recovery is very rare. The two treatments routinely available are microvascular decompression and intramuscular injections with botulinum toxin type A (BtA). OBJECTIVES: To compare the efficacy, safety, and tolerability of BtA versus placebo in people with HFS. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, reference lists of articles, and conference proceedings in July 2020. We ran the electronic database search, with no language restrictions, in July 2020. SELECTION CRITERIA: Double-blind, parallel, randomised, placebo-controlled trials (RCTs) of BtA versus placebo in adults with HFS. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed records. We planned to select included studies, extract data using a paper pro forma, and evaluate the risk of bias. We resolved disagreements by consensus, or by consulting a third review author. We planned to perform meta-analyses. The primary efficacy outcome was HFS-specific improvement. The primary safety outcome was the proportion of participants with any adverse event. MAIN RESULTS: We found no parallel-group randomised controlled trials comparing BtA and placebo in HFS. AUTHORS' CONCLUSIONS: We did not find any randomised trials that evaluated the efficacy and safety of botulinum toxin type A in people with hemifacial spasm, so we are unable to draw any conclusions. Observational data show a strong association between BtA treatment and symptom improvement, and a favourable safety profile. While it is unlikely that future placebo-controlled RCTs will evaluate absolute efficacy and safety, they should address relevant questions for both people with HFS (such as long-term effects, quality of life, and other patient-reported outcomes), and clinicians (such as relative effectiveness of different BtA formulations and schemes of treatment) to better guide clinical practice.).

Botulinum toxin type A therapy 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. OBJECTIVES: To compare the efficacy, safety, and tolerability of BtA versus placebo, in people with cervical dystonia. SEARCH METHODS: We searched Cochrane Movement Disorders' Trials Register, CENTRAL, MEDLINE, Embase, reference lists of articles, and conference proceedings in July 2020. All elements of the search, with no language restrictions, were last run in July 2020. SELECTION CRITERIA: Double-blind, parallel, randomised, placebo-controlled trials (RCTs) of BtA versus placebo 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. We resolved disagreements by consensus or by consulting a third review author. We performed meta-analyses using a random-effects model, for the comparison of BtA versus placebo, to estimate pooled effects and corresponding 95% confidence intervals (95% CI). We performed preplanned subgroup analyses according to BtA dose used, the BtA formulation used, and the use (or not) of guidance for BtA injections. 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 nine RCTs, with moderate, overall risk of bias, that included 1144 participants with cervical dystonia. Seven studies excluded participants with poorer responses to BtA treatment, therefore, including an enriched population with a higher probability of benefiting from this therapy. Only one trial was independently funded. All RCTs evaluated the effect of a single BtA treatment session, using doses from 150 U to 500 U of onabotulinumtoxinA (Botox), 120 U to 240 U of incobotulinumtoxinA (Xeomin), and 250 U to 1000 U of abobotulinumtoxinA (Dysport). BtA resulted in a moderate to large improvement from the participant's baseline clinical status, assessed by the investigators, with a mean reduction of 8.09 points in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS total score) at week four after injection (95% CI 6.22 to 9.96; I² = 0%) compared to placebo. This corresponded, on average, to a 18.4% improvement from baseline. The mean difference (MD) in TWSTRS pain subscore at week four was 2.11 (95% CI 1.38 to 2.83; I² = 0%) compared to placebo. Overall, both participants and clinicians reported an improvement of subjective clinical status. It was unclear if dropouts due to adverse events differed (risk ratio (RR) 2.51; 95% CI 0.42 to 14.94; I² = 0%) However, BtA treatment increased the risk of experiencing an adverse event (R) 1.23; 95% CI 1.05 to 1.43; I² = 28%). Neck weakness (14%; RR 3.40; 95% CI 1.19 to 9.71; I² = 15%), dysphagia (11%; RR 3.19; 95% CI 1.79 to 5.70; I² = 0%), and diffuse weakness or tiredness (8%; RR 1.80; 95% CI 1.10 to 2.95; I² = 0%) were the most common treatment-related adverse events. Treatment with BtA resulted in a decreased risk of dropouts. We have moderate certainty in the evidence across all of the aforementioned outcomes, with the exception of subjective assessment and tolerability, in which we have high confidence in the evidence. We found no evidence supporting the existence of a clear dose-response relationship between BtA and improvement in cervical dystonia-specific impairment, a destinction between BtA formulations, or a variation with use of EMG-guided injection for efficacy outcomes. Due to clinical heterogeneity, we did not pool health-related quality of life data, duration of clinical effect, or the development of secondary non-responsiveness. AUTHORS' CONCLUSIONS: We are moderately certain in the evidence that a single BtA treatment session resulted in a clinically relevant reduction of cervical dystonia-specific impairment, and pain, and highly certain that it is well tolerated, compared with placebo. There is moderate-certainty evidence that people treated with BtA are at an increased risk of developing adverse events, most notably, dysphagia, neckweakness and diffuse weakness or tiredness. There are no data from RCTs evaluating the effectiveness and safety of repeated BtA injection cycles. There is no evidence from RCTs to allow us to draw definitive conclusions on the optimal treatment intervals and doses, the usefulness of guidance techniques for injection, the impact on quality of life, or the duration of treatment effect.