Ranking Of Efficacy Research Articles

Drugs for preventing postoperative nausea and vomiting in adults after general anaesthesia: an abridged Cochrane network meta-analysis.

Postoperative nausea and vomiting is a common adverse effect of anaesthesia. Although dozens of different anti-emetics are available for clinical practice, there is currently no comparative ranking of efficacy and safety of these drugs to inform clinical practice. We performed a systematic review with network meta-analyses to compare, and rank in terms of efficacy and safety, single anti-emetic drugs and their combinations, including 5-hydroxytryptamine3 , dopamine-2 and neurokinin-1 receptor antagonists; corticosteroids; antihistamines; and anticholinergics used to prevent postoperative nausea and vomiting in adults after general anaesthesia. We systematically searched for placebo-controlled and head-to-head randomised controlled trials up to November 2017 (updated in April 2020). We assessed how trustworthy the evidence was using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) and Confidence In Network Meta-Analysis (CINeMA) approaches for vomiting within 24h postoperatively, serious adverse events, any adverse event and drug class-specific side-effects. We included 585 trials (97,516 participants, 83% women) testing 44 single drugs and 51 drug combinations. The studies' overall risk of bias was assessed as low in only 27% of the studies. In 282 trials, 29 out of 36 drug combinations and 10 out of 28 single drugs lowered the risk of vomiting at least 20% compared with placebo. In the ranking of treatments, combinations of drugs were generally more effective than single drugs. Single neurokinin-1 receptor antagonists were as effective as other drug combinations. Out of the 10 effective single drugs, certainty of evidence was high for aprepitant, with risk ratio (95%CI) 0.26 (0.18-0.38); ramosetron, 0.44 (0.32-0.59); granisetron, 0.45 (0.38-0.54); dexamethasone, 0.51 (0.44-0.57); and ondansetron, 0.55 (0.51-0.60). It was moderate for fosaprepitant, 0.06 (0.02-0.21) and droperidol, 0.61 (0.54-0.69). Granisetron and amisulpride are likely to have little or no increase in any adverse event compared with placebo, while dimenhydrinate and scopolamine may increase the number of patients with any adverse event compared with placebo. So far, there is no convincing evidence that other single drugs effect the incidence of serious, or any, adverse events when compared with placebo. Among drug class specific side-effects, evidence for single drugs is mostly not convincing. There is convincing evidence regarding the prophylactic effect of at least seven single drugs for postoperative vomiting such that future studies investigating these drugs will probably not change the estimated beneficial effect. However, there is still considerable lack of evidence regarding safety aspects that does warrant investigation.

Fecal Microbiota Transplantation May Be the Best Option in Treating Multiple Clostridioides difficile Infection: A Network Meta-Analysis.

IntroductionClostridioides difficile (formerly Clostridium) infection (CDI) is the most common cause of healthcare-associated diarrhea with high mortality and recurrence rate; furthermore, the treatment of recurrent cases is a challenge. In this network meta-analysis, we aimed to compare all available therapies against multiple recurrent CDI (mrCDI) and rank them by efficacy.MethodsAfter a systematic search, randomized controlled trials (RCT) with any interventions against mrCDI were included. Data were extracted to the study database using Excel. Risk of bias assessment was performed with the Cochrane RoB 2 tool. The primary outcome was the clinical cure of CDI and the secondary outcome was the recurrence of CDI. A Bayesian method was performed to investigate the efficacy rank order of therapies. We registered our protocol with the Prospero Center for Reviews and Dissemination (registration no. CRD42020160365).ResultsSix RCTs with seven interventions were included in the quantitative synthesis. According to the surface under the cumulative ranking curve values, fecal microbiota transplantation (FMT) after a short course of vancomycin therapy (83%) shows the highest efficacy for clinical cure. Tolevamer and vancomycin + FMT seemed to be the most effective in preventing recurrence (87% and 75%, respectively).ConclusionVancomycin + FMT is perhaps the most effective option for the treatment and prevention of mrCDI, while tolevamer is also effective in preventing recurrence.Electronic Supplementary MaterialThe online version of this article (10.1007/s40121-020-00356-9) contains supplementary material, which is available to authorized users.

Effectiveness and safety of different traditional Chinese medicine therapies for allergic rhinitis: A protocol for systematic review and network meta analysis.

Introduction:Traditional Chinese medicine has been widely used in the treatment of allergic rhinitis. However, currently randomized controlled trials (RCTs) and meta-analysis only compare 1 or 2 types of traditional Chinese medicine therapies, and the comprehensive ranking of efficacy and safety of multiple traditional Chinese medicine therapies for the treatment of allergic rhinitis has not been completed. Therefore, the purpose of this network meta-analysis is to evaluate the efficacy and safety of different traditional Chinese medicine therapies for the treatment of allergic rhinitis.Methods and analysis:Three English databases of PubMed, Embase, Cochrane Library, and 2 Chinese databases of CNKI and Wanfang were searched from their inceptions to September 1, 2020. At the same time, in order to prevent omissions, we also compared the previous meta-analysis to determine the final included trials. The main evaluation outcome was the total Clinical Score (total nasal symptom score [TNSS]), the secondary evaluation outcome was the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) and adverse events. The Cochrane Collaboration's Tool was used to evaluate the methodological quality of articles, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) instrument was used to evaluate the quality of evidence. Network meta-analysis was completed by using Stata Statistical Software (Version 14.0, Stata Corporation, College Station, TX).Results:This study will compare and rank the different traditional Chinese medicine therapies for allergic rhinitis.Conclusion:This study is the first time to use network meta-analysis (NMA) to compare the efficacy and safety of traditional Chinese medicine for the treatment of allergic rhinitis, which will provide ideas and methods for the clinical treatment for allergic rhinitis.INPLASY registration number:No. INPLASY202080119

Interventions for Preventing Chemotherapy-Induced Alopecia: A Systematic Review and Network Meta-analysis of Randomized Controlled Trials.

Chemotherapy-induced alopecia (CIA) is a common adverse effect among patients undergoing chemotherapy. Patients experiencing CIA suffer psychological distress and even refuse or discontinue chemotherapy. A variety of interventions have been applied to prevent CIA. However, the best intervention option remains unknown. To evaluate and determine the comparative effects of all available interventions for preventing CIA. A comprehensive literature search of four English and 3 Chinese electronic databases was performed to identify potential studies from database inception to August 2018. Two reviewers conducted data selection, data extraction, and risk of bias assessment independently. The consistency model was used to conduct a network meta-analysis based on a frequentist framework to evaluate the relative effects of different interventions. Rankings of interventions were evaluated by the surface under the cumulative ranking curve values. Seventeen eligible trials including 1378 patients were included. Scalp cooling (odds ratio, 0.13; 95% confidence interval, 0.07-0.25) and scalp compression (odds ratio, 0.13; 95% confidence interval, 0.03-0.52) had significant effects relative to usual care. Ranking of efficacy indicated that scalp cooling was the most effective, followed by scalp compression with tourniquets, topical Chinese medicinal herbs, oral Chinese medicinal herbs, minoxidil, and usual care. The results of this study indicate that scalp cooling is the most effective method to prevent CIA during chemotherapy. Our results could provide a reference to prevent CIA. Updated studies with high quality, sufficient sample sizes, and direct comparison between interventions are needed in the future.

Comparative efficacy of placebos in short-term antidepressant trials for major depression: a secondary meta-analysis of placebo-controlled trials

BackgroundThe issue of unblinded outcome-assessors and patients has repeatedly been stressed as a flaw in allegedly double-blind antidepressant trials. Unblinding bias can for example result from a drug‘s marked side effects. If such unblinding bias is present for a given drug, then it might be expected that the placebos of that drug are rated significantly less effective than that of other antidepressants.MethodsTo test this hypothesis, the present exploratory analysis conducted a Bayesian network meta-analysis (NMA) comparing the efficacy of 19 different placebos in placebo-controlled trials provided in the dataset by Cipriani et al. (Lancet 2018; 391: 1357–66). Primary outcome was efficacy (continuous) estimated on the standardized mean difference (SMD) scale and defined as the pre-post change on the Hamilton Depression scale (HAMD-17), on which information was available in N = 258 trials.ResultsComparative placebo ranking suggested mirtazapine-placebo (SMD -2.0 [− 5.0–1.0 95% CrI]) to be the most, and amitriptyline- (SMD 1.2 [− 1.6–3.9 95% CrI]) and trazodone- (SMD 2.1 [− 0.9–5.2 95% CrI]) placebos to be the least effective placebos. Other placebos suggested to be more effective than amitriptyline- and trazodone-placebos (based on 95% CrIs excluding zero) were citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, and venlafaxine placebos. These NMA results were corroborated by the observation that the relative efficacy between drug and placebo was considerably larger for amitriptyline and trazodone than for instance mirtazapine, duloxetine, and venlafaxine, supported by a small and insignificant correlation between drug-efficacy and placebo-efficacy (r = − 0.202, p = 0.408).DiscussionThe present exploratory NMA indicates that distinguishable side effects of older drugs may unblind outcome-assessors thus resulting in overestimation of the average drug-placebo difference and underrating bias in placebo-arms, particularly for the older antidepressant drugs amitriptyline and trazodone. If confirmed in prospective studies, these findings suggest that efficacy rankings for antidepressants are susceptible to bias and should be considered unreliable or misleading. The analysis is limited by the focus on the single-comparison placebos (76%, i.e., placebos assessed in two-arm trials), since double-comparison placebos (25%, i.e., placebos assessed in three-arm trials) are hard to interpret and therefore not included in the present interpretation. Another limitation is the problem of multiplicity, which was only approximately accounted for in the Bayesian NMA by modelling treatment effects as exchangeable.

Comparative efficacy and safety of drug treatment for premature ejaculation: A systemic review and Bayesian network meta-analysis.

To assess the comparative efficacy and safety of drug treatments for premature ejaculation. A systemic review and Bayesian network meta-analysis were executed on randomised controlled trials of drug interventions for premature ejaculation. Intravaginal ejaculation latency time and related adverse effects were outcome measures. A total of 44 RCTs with 11,008 patients were included in our NMA. In therapy <8weeks, the ranking of drug efficacy was topical creams >selective serotonin reuptake inhibitor (SSRI)+ phosphodiesterase 5 inhibitor (PDE5i)>PDE5i>sertraline>clomipramine>paroxetine>dapoxetine 60 milligram (mg)>dapoxetine 30mg>fluoxetine>citalopram>duloxetine>placebo. In therapy≥8weeks, the ranking of drug efficacy was SSRI+PDE5i>topical creams>paroxetine>tramadol>PDE5i>fluoxetine>dapoxetine 60mg>dapoxetine 30mg>clomipramine>citalopram>placebo. For total adverse events, clomipramine, dapoxetine 30mg, dapoxetine 60mg, paroxetine, PDE5i, SSRI+PDE5i and tramadol had a higher risk than placebo. In conclusion, in ≥8weeks of therapy, the drug combination of SSRI+PDE5i was the most effective PE therapy. In <8weeks of therapy, the efficacy of local anaesthetics was best. All drug treatments were ranked better than placebo. In general, drugs with better effects had more obvious side effects.

Model-based simulation to support the extended dosing regimens of atezolizumab.

The currently recommended dosages of atezolizumab for patients with non-small cell lung cancer (NSCLC) and urothelial carcinoma (UC) is 840 mg every 2 weeks, 1200 mg every 3 weeks (q3w), and 1680 mg every 4 weeks (q4w). However, it has been argued that these dosages may not be optimal. This study aimed to explore the feasibility of extended dosing regimens by population pharmacokinetics (PK) simulations and exposure-response (E-R) relationships. All simulations were conducted based on the established population PK and E-R model for safety (i.e., adverse events of special interest, AESI) and efficacy (i.e., objective response rate, ORR) for patients with NSCLC or UC. The PK, AESI, and ORR profiles of the following dosing regimens were simulated: (i) 840 mg q4w, (ii) 1200 mg every 6 weeks (q6w), and (iii) 1680 mg q8w. These regimens were compared with those of the 1200 mg q3w standard regimen. The simulation revealed that the ranking of efficacy for different extended dosing regimens were 1680 mg q8w ≅ 1200 mg q3w ≅ 1200 mg q6w > 840 mg q4w based on the predicted probability of ORR in patients with NSCLC and UC, and this ranking order was similar to that of the safety outcome of the AESI. The minimum serum concentration at steady-state (Cmin,ss) values for all dosing regimens was all higher than the target effective concentration of 6 μg/mL. The findings from this simulation suggest that extended dosing regimens are unlikely to significantly impair clinical outcomes and may provide more therapeutic benefits to patients in terms of safety.

Regional Survey of Diamondback Moth (Lepidoptera: Plutellidae) Response to Maximum Dosages of Insecticides in Georgia and Florida.

We conducted maximum dose bioassays of insecticide for the control of diamondback moth (DBM), Plutella xylostella (Linnaeus), in cole crops, from 2016 to 2019 at several commercial locations in Georgia and Florida. The nominal maximum dose was defined as the highest labeled rate of an insecticide at the beginning of the survey in the equivalent of 935 liters/ha dilution. The results indicated low insecticide efficacy for high labeled rates of the following insecticides by common name (Insecticide Resistance Action Committee group number in parentheses). Our 4-yr survey identified very low levels of DBM larval control (<47%) by lambda-cyhalothrin (3), methoxyfenozide (18), pyriproxyfen (7C), novaluron (15), bifenthrin (3), chlorantraniliprole (28), indoxacarb (22A), and methomyl (1A). The best products for DBM control (>74%) listed in decreasing average levels of efficacy were naled (1B), cyclaniliprole (28), tolfenpyrad (21A), emamectin benzoate (6), and cyantraniliprole (28). Intermediate levels of control (61-71%) were obtained with Bacillus thuringiensis subspecies aizawai (11A), Bacillus thuringiensis, subsp. kurstaki, strain ABTS-351 (11A), and spinetoram (5). This rapid bioassay provided the grower with a ranking of insecticide efficacy for the control the DBM population for that farm site. These data allowed growers to make an informed decision on control quickly and plan for resistance management rotations for DBM that season.

Network Meta-analysis of oral Chinese patent medicine in treatment of acute cerebral infarction

The efficacy of oral Chinese patent medicine in the treatment of acute cerebral infarction was systematically evaluated by network Meta-analysis. The literature search was conducted in three English databases(Medline, EMbase and Cochrane Library) and four Chinese databases(CNKI, VIP, WanFang and SinoMed) from inception to June 2018, and the randomized controlled trials of acute cerebral infarction were screened out according to the pre-set criteria. Two reviewers independently screened out the literature by using pre-specified eligibility criteria, and assessed the quality of included studies according to the risk of bias tool of Cochrane Handbook 5.1.0. Data analysis was conducted by using Stata 13.0 and WinBUGS 1.4.3 software. Finally, 52 RCT were included, involving 11 kinds of oral Chinese patent medicines. The results of the network Meta-analysis showed that in terms of the total effective rate, the order of efficacy was as follows: Naomaitai Capsules&gt;Xiaoshuan Changrong Capsules&gt;Angong Niuhuang Pills&gt;Yangxue Qingnao Granules&gt;Compound Danshen Dripping Pills&gt;Naoxintong Capsules&gt;Tongxinluo Capsules&gt;Naoxueshu Oral Liquid&gt;Zhuyu Tongmai Capsules&gt;Yinxingye Tablets&gt;Compound Danshen Tablets; in terms of neurological deficit scores, the order of efficacy was: Tongxinluo Capsules&gt;Angong Niuhuang Pills&gt;Compound Danshen Dripping Pills&gt;Xiaoshuan Changrong Capsules&gt;Yangxue Qingnao Granules&gt;Zhuyu Tongmai Capsules&gt;Naoxintong Capsules&gt;Naoxueshu Oral Liquid; in terms of Barthel index score, the order of efficacy was: Xiaoshuan Changrong Capsules&gt;Naomaitai Capsules&gt;Naoxueshu Oral Liquid&gt;Angong Niuhuang Pills&gt;Tongxinluo Capsules&gt;Zhuyu Tongmai Capsules. Although different oral Chinese patent medicines can improve these outcomes, the difference in efficacy ranking was relatively large. Because of the small number and low quality of research literature, the conclusion still needs to be proved by multi-center, large-sample, and double-blind randomized trials.

Systemic review and network meta-analysis: Prophylactic antibiotic therapy for spontaneous bacterial peritonitis.

Spontaneous bacterial peritonitis (SBP) is an important prognostic factor for outcomes in patients with cirrhosis. Antibiotic prophylaxis is recommended in patients at high risk for developing SBP, but the choice of antibiotics remains unclear. To evaluate the efficacy of various antibiotics for prophylaxis of SBP based on randomized control trials (RCTs). Electronic databases were searched through November 2018 for RCTs evaluating the efficacy of therapies for primary or secondary prophylaxis of SBP. The primary outcome was the development of SBP. Sensitivity analyses limited to studies of primary or secondary prophylaxis and studies reported after 2010 were performed. The secondary outcome was the risk of all-cause mortality or transplant. The outcomes were assessed by rank of therapies based on network meta-analyses. Individual meta-analyses were also performed. Thirteen RCTs (1742 patients) including norfloxacin, ciprofloxacin, rifaximin, trimethoprim-sulfamethoxazole (TMP-SMX), or placebo/no comparator were identified. Individual meta-analyses showed superiority of rifaximin over norfloxacin as well as norfloxacin and TMP-SMX over placebo. Network meta-analysis demonstrated the rank of efficacy in reducing the risk of SBP as: Rifaximin, ciprofloxacin, TMP-SMX, norfloxacin, and placebo/no comparator. Rifaximin ranked highest in sensitivity analyses limited to studies of primary or secondary prophylaxis and studies reported after 2010. Similarly, rifaximin ranked highest in reducing the risk of death/transplant. The present comprehensive network meta-analysis provides RCT based evidence for superior efficacy of rifaximin compared to other antibiotics for the prophylaxis of SBP and reducing risk of death/transplant. Further RCTs are warranted to confirm our findings.

Multiple Myeloma Incidence and Mortality Around the Globe; Interrelations Between Health Access and Quality, Economic Resources, and Patient Empowerment.

BackgroundThe interrelation between the worldwide incidence, mortality, and survival of patients with multiple myeloma (MM) and relevant factors such as Health Care Access and Quality (HAQ) index, gross domestic product (GDP), health care expenditures, access to cancer drugs, and patient empowerment has not been addressed before.Material and MethodsEpidemiologic data were obtained from the International Agency for Research on Cancer. The mortality‐to‐incidence ratio (expressed as 1‐MIR) was used as proxy for 5‐year survival. Information on health expenditure was obtained from Bloomberg Health‐Care Efficacy ranking, the HAQ Index was used as a measure of available health care. For patient empowerment, visits to the Web site of the International Myeloma Foundation were used as proxy. Data on GDP and population per country were assessed from the International Monetary Fund and the United Nations Population Division, respectively. Possible associations were analyzed using Spearman's rank‐order correlation.ResultsThe worldwide incidence of MM is currently 160,000, and mortality is 106,000. Age‐standardized myeloma incidence varies between 0.54 and 5.3 per 100,000 and correlates with 1‐MIR, patient empowerment, HAQ Index, and access to cancer drugs. The 1‐MIR varies between 9% and 64% and is closely related to myeloma incidence, HAQ Index, patient empowerment, access to cancer drugs, and health care expenditures.ConclusionThe global incidence and outcome of MM shows significant disparities, indicating under‐recognition and suboptimal treatment in many parts of the globe. Results also highlight the importance of economic resources, access to and quality of health care, and patient education for improving diagnosis and survival of patients with MM.Implications for PracticeMultiple myeloma accounts for 10% of all hematological malignancies and has moved to the forefront of clinical interest because of the significant advances in medical treatment. Diagnosis depends on laboratory tests, imaging, and professional expertise, particularly in patients without a significant M‐component. The present data show a substantial worldwide variation in incidence and mortality, that is mainly due (apart from variations due to ethnicity and lifestyle) to disparities in access to and quality of health care, a parameter strongly related to the economic development of individual countries. Improvement of quality of care and, consequently, in outcome is associated with patient empowerment.

In vitro profiling of opioid ligands using the cAMP formation inhibition assay and the β-arrestin2 recruitment assay: No two ligands have the same profile

Previously, we showed that no two of seven opioids administered by the intracerebroventricular route had the same potency rank order for evoking antinociception, constipation and respiratory depression in rats. To gain insight at the cellular level, this study was designed to systematically investigate the activity profiles of six commonly used opioid ligands using the forskolin-stimulated cAMP assay and a β-arrestin2 recruitment assay in cultured HEK-293 cells transfected with MOP(μ), DOP(δ) or KOP(κ) receptors(-r).Morphine was a potent agonist at the MOP-r in the cAMP assay whereas it was a weak agonist at the KOP-r and DOP-r. Oxycodone had moderate efficacy and low potency at the MOP-r. Buprenorphine was a potent MOP-r and DOP-r agonist; its efficacy rank order was DOP > MOP > KOP. Fentanyl was a potent agonist at the MOP-r; its efficacy rank order was MOP > DOP > KOP. For DPDPE, its agonist efficacy was confined to the DOP-r, whereas for U69593, its efficacy rank order was KOP>> MOP.For the β-arrestin2 assay, fentanyl had full efficacy at the MOP-r whereas morphine and oxycodone were weak with insignificant efficacy at DOP and KOP receptors. Buprenorphine did not recruit β-arrestin2 at all three opioid-receptors. DPDPE and U69593 had full efficacy for β-arrestin2 recruitment to the DOP-r and KOP-r respectively.Despite the low efficacy and potency of morphine, oxycodone and buprenorphine in recruiting β-arrestin2 to the MOP-r herein, these opioids all evoked respiratory depression and constipation in rats. Together, our findings discount a key role for β-arrestin2 recruitment at the MOP-r in evoking opioid-related side-effects.

Comparative Efficacy and Safety of 37 Regimens of Anti-Vascular Endothelial Growth Factor for Neovascular Age-Related Macular Degeneration: A Network Meta-Analysis of Randomized Controlled Trials

Background: Nowadays, there are more than forty therapeutic regimens of anti-vascular endothelial growth factor agents existing for neovascular age-related macular degeneration (nAMD), while numerous controversies exist regarding the ideal agent and optimum strategy. We aimed to give a comprehensive efficacy and safety ranking of these regimens by quantifying data from randomized controlled trials (RCT). Methods: Electronic database searches were conducted on PubMed, Embase and the Cochrane Central Register of Controlled Trials up to December 1, 2019 to identify relevant RCTs on different regimens of anti-VEGF agents for the treatment of nAMD. Two authors screened studies and extracted data independently. Primary outcomes were changes of best-corrected visual acuity (BCVA) for efficacy and the incidence of severe ocular adverse events (ADEs) for safety. The standardized mean difference (SMD), odds ratios (OR), their 95% credible intervals (CI), the surface under the cumulative ranking curves and the mean ranks of each outcome were estimated using network meta-analyses by Stata 14.0. Findings: We identified 47 RCTs, which included 17872 nAMD patients randomly assigned to 36 different therapeutic regimens of anti-VEGF agents or sham treatment. Ranibizumab 0.5mg (TE The combination of radiation, topical NSAIDs and photodynamic therapy might provide additional effect in terms of central retinal thickness (CRT) reduction; All these therapeutic regimens of different anti-VEGF agents do not significantly increase the risk of severe ocular or cardiocerebral vascular ADEs compared with sham treatment (P>0.05). Interpretation: Based on the currently available evidence base, T&E strategy showed top-level effect in terms of visual improvement and there is no significant difference in efficacy or safety between Ranibizumab, Bevacizumab and Aflibercept. The combination of topical NSAIDs provides additional effect in terms of CRT reduction and all the included regimens have acceptable risk of ADEs. Further study is worth to evaluate whether T&E strategy of anti-VEGF agents plus topical NSAIDs could achieve better efficacy than current regimens. Funding Statement: No funding was received for this research. Declaration of Interests: All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or nonfinancial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. Ethics Approval Statement: This study was performed in accordance with the PRISMA guideline of network meta-analysis.

Comparative efficacy and safety of anti-vascular endothelial growth factor regimens for neovascular age-related macular degeneration: systematic review and Bayesian network meta-analysis.

Background:As a debilitating neurodegenerative disease, neovascular age-related macular degeneration (nAMD) accounts for more than 90% of severe visual loss or legal blindness among AMD patients. Anti-vascular endothelial growth factor (VEGF) had been applied widely in nAMD treatment. To date, debate regarding efficacy and safety still exists among different anti-VEGF regimens as management of nAMD. To provide substantial evidence for clinical nAMD treatment, this study ranks the priority of anti-VEGF regimens via Bayesian network meta-analysis (NMA), comparing data collected from randomized controlled trials (RCTs).Methods:We searched PubMed Central, MEDLINE Ovid, Embase Ovid, ISRCTN, ICTRP and ClinicalTrials. gov from a database established until 1 April 2019 systematically for anti-VEGF regimens. Bayesian NMA with random-effect was conducted to compare efficacy and safety and rank priority of anti-VEGF regimens. The primary efficacy and safety outcomes were the proportion of patients gaining 15 or more letters, and the incidence of arterial thromboembolic (ATC) events. The effect measure is the standard mean difference (SMD), or the odds ratio (OR) with their 95% confidence interval (CI). The study protocol is registered with PROSPERO, number CRD42019132243.Results:We obtained 6467 citations and identified 29 RCTs including 13,596 participants; 86% of these trials were low risk or of uncertain risk bias. In NMA, ORs compared with sham injection for the proportion of patients gaining 15 or more letters (12,699 participants from 23 trials) ranged from 4.05 [95% Bayesian credible interval (CrI) 1.62–10.11] for ranibizumab quarterly regimen to 8.57 (95% CrI 4.66–15.73) for a ranibizumab treat-and-extend regimen. No difference was found between sham injection and anti-VEGF regimens for ATC events (11,500 participants from 18 trials). Results for the primary outcome did not substantially change in sensitivity analyses after removing studies at high risk of bias and small sample size (n < 100), respectively.Conclusion:The treat-and-extend regimen of ranibizumab and aflibercept are the preferred anti-VEGF regimens for nAMD. Bevacizumab treat-and-extend regimens need more head-to-head comparisons with other regimens or sham injection for advanced application. The treat-and-extend regimen proved to be the most effective regimen for each anti-VEGF drug in the NMA. Pegaptanib every 6 weeks and Conbercept quarterly are unable to satisfy the best corrected visual acuity (BCVA) improvement requirement of nAMD patients.

In vitro determination of the efficacy of illicit synthetic cannabinoids at CB1 receptors.

The morbidity and mortality associated with recreational use of synthetic cannabinoid receptor agonists (SCRAs) may reflect strong activation of CB1 receptors and is a major health concern. The properties of SCRA at CB1 receptors are not well defined. Here we have developed an assay to determine acute CB1 receptor efficacy using receptor depletion with the irreversible CB1 receptor antagonist AM6544, with application of the Black and Leff operational model to calculate efficacy. Receptor depletion in mouse AtT-20 pituitary adenoma cells stably expressing human CB1 receptors was achieved by pretreatment of cells with AM6544 (10μM, 60 min). The CB1 receptor-mediated hyperpolarisation of AtT-20 cells was measured using fluorescence-based membrane potential dye. From data fit to the operational model, the efficacy (τ) and affinity (KA ) parameters were obtained for each drug. AM6544 did not affect the potency or maximal effect of native somatostatin receptor-induced hyperpolarization. The τ value of ∆9 -THC was 80-fold less than the reference CB receptor agonist CP55940 and 260-fold less than the highest efficacy SCRA, 5F-MDMB-PICA. The operational efficacy of SCRAs ranged from 233 (5F-MDMB-PICA) to 28 (AB-PINACA), with CP55940 in the middle of the efficacy rank order. There was no correlation between the τ and KA values. All SCRAs tested showed substantially higher efficacy at CB1 receptors than ∆9 -THC, which may contribute to the adverse effects seen with these drugs but not ∆9 -THC.

A New Calcium Oral Controlled-Release System Based on Zeolite for Prevention of Osteoporosis.

Osteoporosis, a systemic skeleton disease, can be prevented by increasing calcium levels in serum via administration of calcium salts. However, traditional calcium-based formulations have not appeared to be effective, hence the purpose of the present work has been to prepare and test in vitro/vivo a formulation able to gradually release calcium during transit over the GI tract, thus increasing bioavailability and reducing daily dose, and hence, side effects. Calcium controlled-release granules based on zeolite and Precirol® were prepared. In the best case, represented by granules sized 1.2 mm, containing 20% Precirol®, 19% zeolite, 60% calcium (granule), the release lasted ≈6 h. The release is controlled by diffusion of calcium ions through the aqueous channels forming within granules, once these come into contact with physiological fluids. Such a diffusion is hindered by the interaction of calcium ions with the negatively charged surface of the zeolite. Ovariectomy was used to make rats osteopenic. For in vivo studies, rats were divided into the following groups. Sham: not treated; ova: ovariectomized (ova); CaCl2 1.0 g: ova, treated with 1.0 g/die Ca2+; CaCl2 0.5 g: ova, treated with 0.5 g/die Ca2+; granule 1.0 g, or granule 0.5 g: ova, treated with granules equivalent to 1.0 g/die or 0.5 g/die Ca2+ in humans. Ca2+ amounts in femur bone and bone marrow, femur mechanical characteristics, and femur medullary canalicule diameter were measured and the same efficacy rank order was obtained: ova < CaCl2 0.5 g < CaCl2 1.0 g < granule 0.5 g ≈ granule 1.0 g ≈ sham. The results show promise of an effective prevention of osteoporosis, based on a controlled-rate administration of a calcium dose half that administered by the current therapy, with reduced side effects.

Synbiotics for prevention of ventilator-associated pneumonia: a probiotics strain-specific network meta-analysis.

ObjectiveProbiotics may be efficacious in preventing ventilator-associated pneumonia (VAP). The aim of this network meta-analysis (NMA) was to clarify the efficacy of different types of probiotics for preventing VAP.MethodsThis systematic review and NMA was conducted according to the updated preferred reporting items for systematic review and meta-analysis. A systematic literature search of public databases from inception to 17 June 2018 was performed.ResultsNMA showed that “Bifidobacterium longum + Lactobacillus bulgaricus + Streptococcus thermophiles” was more efficacious than “Ergyphilus” in preventing VAP (odds ratio: 0.15, 95% confidence interval: 0.03–0.94). According to pairwise meta-analysis, “B. longum + L. bulgaricus + S. thermophiles” and “Lactobacillus rhamnosus” were superior to placebo in preventing VAP. Treatment rank based on surface under the cumulative ranking curves revealed that the most efficacious treatment for preventing VAP was “B. longum + L. bulgaricus + S. thermophiles” (66%). In terms of reducing hospital mortality and ICU mortality, the most efficacious treatment was Synbiotic 2000FORTE (34% and 46%, respectively).ConclusionsBased on efficacy ranking, “B. longum + L. bulgaricus + S. thermophiles” should be the first choice for prevention of VAP, while Synbiotic 2000FORTE has the potential to reduce in-hospital mortality and ICU mortality.

Use of Grape Pomace Phenolics to Counteract Endogenous and Exogenous Formation of Advanced Glycation End-Products.

The increase in consumption of “ultra-processed” foods has raised attention because of the possible adverse effects deriving from the Maillard reaction leading to the formation of toxic advanced glycation end-products (AGEs) during food processing. Additionally, the increasing trend and consumption of sugar-added foods and sweetened beverages is related to the endogenous formation of the same toxic compounds. However, ultra-processing in the context of food technology can bring challenges as well as a wealth of opportunities. Indeed, re-processing of grape pomace, a by-product of winemaking, can yield phenolic-rich fractions that efficiently counteract the effects of AGEs. In this review, the process of endogenous and exogenous AGE formation is illustrated. Then, the ability of grape phenolics to act as inhibitors of AGE formation is presented, including the efficacy ranking of various individual compounds measured in vitro and the outcome of in vivo double-blinded randomized crossover trials designed to prove the efficacy of grape phenolics as inhibitors of protein carbonylation. Finally, a survey of model functional foods added with grape phenolics, either to lower the dietary load of AGEs or to deliver antiglycation agents in vivo is listed in order to highlight the opportunity to develop safe and tailor-made “anti-AGEs” food applications.

Differential inhibitory effects of resveratrol on excitotoxicity and synaptic plasticity: involvement of NMDA receptor subtypes

ABSTRACT Objectives: The neuroprotective effects of resveratrol against excitatory neurotoxicity have been associated with N-methyl-D-aspartate receptor (NMDAR) inhibition. This study examined the differential inhibitory effects of resveratrol on NMDAR-mediated responses in neuronal cells with different NMDAR subtype composition. Methods: The effects of resveratrol on NMDA-induced cell death and calcium influx in immature and mature rat primary cortical neurons were determined and compared. Moreover, the potencies and efficacies of resveratrol to inhibit NR1/NR2A, NR1/NR2B, NR1/NR2C, and NR1/NR2D NMDAR expressed in HEK 293 cells were evaluated. Results: Resveratrol significantly attenuated NMDA-induced cell death in mature neurons, but not in immature neurons. Resveratrol also concentration-dependently reduced NMDA-induced calcium influx among all NMDAR subtypes, but displayed NR2 subunit selectivity, with a potency rank order of NR2B = NR2D > NR2A = NR2C and an efficacy rank order of NR2B = NR2C > NR2A = NR2D. Data show the stronger inhibitory effects of resveratrol on NR1/NR2B than other subtypes. Moreover, resveratrol did not affect hippocampal long-term potentiation (LTP), but impaired long-term depression (LTD). Discussion: These findings reveal the specific NMDAR modulating profile of resveratrol, providing further insight into potential mechanisms underlying the protective effects of resveratrol on neurological disorders.

Analyzing diffusion patterns of big open data as policy innovation in public sector

The Fourth Industrial Revolution begins, and policies are being formulated by economies as well as efforts are being made to meet the needs of the current times. Among other technologies which are part of Fourth Industrial Revolution, big open data is also the part of Pakistan’s digital policy framework. Scholarship is available to explore and examine the determinants of BOD diffusion and adoption, a little literature is available to understand big open data as policy innovation and its diffusion. Therefore, this study drew on Diffusion of Innovation (DOI) theory and its application to public policy innovation research to examine patterns of BOD policy innovation diffusion at government and public bodies’ level in Pakistan. These patterns are based on policy declaration timing by the governments, policy adoption timing, development of technological applications, and proactively released datasets statistics in public bodies. An Event History Analysis was carried out to examine BOD policy innovation diffusion patterns. Results showed that Federal government is the innovator for the policy innovation diffusion across different governments and subsequent public bodies. It was also found that efficacy ranking of public bodies is quite low in terms of developing BOD technological platforms and proactive release of datasets in large quantities. Therefore, government and policy-makers should focus on effective implementation of big open data policy innovation in Pakistan to equip with 21st century needs.