Toxic Effects of Carbaryl Exposure on Juvenile Asian Seabass (Lates calcarifer).

This study examines the physiological and immunological effects of 0.5 ppm carbaryl exposure on juvenile Asian seabass (Lates calcarifer) over 12 h to 72 h. Notable results include decreased activities of liver enzymes catalase (CAT), lactate dehydrogenase (LDH), and glutathione peroxidase (GSH-PX), while superoxide dismutase (SOD) levels remained stable, with the lowest activities of CAT and GSH-PX observed at 72 h. Serum biochemistry revealed increased alkaline phosphatase (AKP) and acid phosphatase (ACP) at 24 h, with declining aspartate aminotransferase (AST) and a peak in creatinine at 48 h. Histopathological analysis showed carbaryl-induced necrosis in liver and spleen cells, and increased melanomacrophage centers in both organs. Additionally, immune gene expression analysis indicated an upregulation of heat shock proteins and consistent elevation of complement component C3 and interleukin-8 (IL-8). These findings suggest that carbaryl exposure significantly impairs organ function and modulates immune responses in L. calcarifer, underlining the need for further research on protective strategies against pesticide impacts in aquaculture.

Response of antioxidation and immunity to combined influences of pH and ammonia nitrogen in the spotted babylon (Babylonia areolata).

Spotted babylon were exposed to three different pH levels (7.0, 8.0 and 9.0) and four different concentrations of ammonia nitrogen (0.02, 1.02, 5.10 and 10.20 mg/L) in seawater to determine their acute toxicity and physiological responses to environmental fluctuation. The study evaluated four antioxidant enzymes: catalase (CAT), alkaline, superoxide dismutase (SOD), peroxidase (POD) and glutathione peroxidase (GSH-PX), and two immunoenzymes: acid phosphatase (ACP) and phosphatase (AKP). Over time, the immunoenzyme activity was significantly affected by pH and ammonia nitrogen concentration. After being exposed to pH and ammonia nitrogen, the spotted babylon showed signs of unresponsiveness to external stimuli, reduced vitality, slow movement, and an inability to maintain an upright position. Over time, the spotted babylon exhibited a trend of increasing and then decreasing GSH-PX, CAT, and SOD activities to adapt to the changing environment and enhance its immunity. On the contrary, the POD and ACP activities exhibited a decreasing trend initially, followed by an increasing trend over time and the AKP activity showed a gradual increase with time. The combined effect of pH and ammonia was found to be stronger than the effect of either factor alone. The interaction between pH and ammonia increased the activity of the spotted babylon antioxidant enzymes, induced oxidative stress, and reduced the ability of the spotted babylon's non-specific immune system to reverse it. Thus, the reverse-back of the spotted babylon was higher when pH and ammonia stress were dual than when pH or ammonia were single-factor stresses. The study results will establish a theoretical basis for analyzing the risk of multiple factors to the spotted babylon, and also enrich the basic information about the shellfish immune system.

Extended dual antiplatelet therapy following percutaneous coronary intervention in clinically important patient subgroups: a systematic review and meta-analysis.

BACKGROUND: Dual antiplatelet therapy (DAPT) is routinely given to patients after percutaneous coronary intervention (PCI) with stenting; however, optimal duration remains uncertain in some situations. We assessed the benefits and harms of extending DAPT beyond 1 year after PCI in clinically important patient subgroups. METHODS: We conducted a systematic review and meta-analysis. We searched electronic databases (Embase, MEDLINE, PubMed, Cochrane Library) and grey literature (from inception to Nov. 5, 2021) and included randomized controlled trials (RCTs) of extended DAPT (> 12 mo) compared with DAPT for 6-12 months following PCI with stenting. The primary outcome was death (all cause, cardiovascular, noncardiovascular); secondary outcomes included major adverse cardiovascular and cerebrovascular events, myocardial infarction (MI), stroke, stent thrombosis and bleeding. Subgroups were based on prespecified patient characteristics (prior MI, acute coronary syndrome [ACS], diabetes mellitus, age, smoking status). Data were analyzed by random-effects pairwise meta-analysis. RESULTS: We identified 9 RCTs that provided subgroup data. We found that extended DAPT reduced the risk of MI and stent thrombosis but increased the risk of bleeding, compared with standard DAPT, with no difference in the risk of all-cause death (relative risk [RR] 1.07, 95% confidence interval [CI] 0.80-1.42) or cardiovascular death (RR 0.98, 95% CI 0.74-1.30). We found that patients with a prior MI, with ACS at presentation, without diabetes or aged younger than 75 years may derive the most benefit from extended DAPT. Among patients who received extended DAPT, the risk of all-cause death was significantly increased among those with no prior MI (RR 1.64, 95% CI 1.08-2.24), whereas there was no significant difference in the risk of all-cause death between standard and extended DAPT for patients with ACS (RR 1.20, 95% CI 0.51-2.83), with diabetes (RR 1.27, 95% CI 0.86-1.89), aged older than 75 years (RR 1.32, 95% CI 0.39-4.54) or who smoked (RR 0.90, 95% CI 0.42-1.92). Similar results were found for cardiovascular death, where data were available. INTERPRETATION: Patients with a previous MI with ACS at presentation, without diabetes, or aged younger than 75 years may derive the most benefit from extended DAPT. These findings support the need for careful selection of patients who may benefit most from extended DAPT. STUDY REGISTRATION: PROSPERO no. CRD42018082587.

Effectiveness and Safety of Antibiotic Prophylaxis for Persons Exposed to Cases of Invasive Group A Streptococcal Disease: A Systematic Review.

Among close contacts of patients with invasive group A streptococcal (iGAS) infection, the benefits and harms of chemoprophylaxis are uncertain. We conducted a systematic review of studies that reported on persons who, after being exposed to a case of laboratory-confirmed or probable iGAS, received any antibiotic prophylaxis for the prevention of GAS infection or carriage. Thirty-seven studies including 26 outbreak investigations and 11 case series or reports were included with predominantly descriptive information that suggested that antibiotic prophylaxis may be effective in preventing GAS infection or GAS carriage, with very few serious adverse events. However, current available evidence is scant (with limited information on contacts of iGAS cases) and largely based on studies with weak design and small sample size. Therefore, definitive conclusions on effectiveness of antibiotic prophylaxis cannot be drawn. Well designed prospective studies are required to establish the benefit-harm profile of antibiotic prophylaxis for secondary prevention of GAS disease among close contacts of iGAS cases.

Comparative efficacy and safety of antihyperglycemic drug classes for patients with type 2 diabetes following failure with metformin monotherapy: A systematic review and network meta-analysis of randomized controlled trials.

AIMS: To compare the efficacy and safety of antihyperglycemic agents, taken in combination with metformin, for the treatment of type 2 diabetes mellitus (T2DM). METHODS: A previous 2016 comprehensive search of Ovid MEDLINE, PubMed, and Cochrane CENTRAL was updated to October 2018, and a systematic review and network meta-analysis (NMA) was conducted. Randomized controlled trials (RCTs) of patients with T2DM taking an antihyperglycemic agent in combination with metformin were included. Bayesian NMA was performed to assess the relative efficacy and safety of the antihyperglycemic classes. RESULTS: In total, 204 RCTs were included, which assessed the efficacy and safety of eight antihyperglycemic drug classes (i.e., sulfonylureas, meglitinides, alpha-glucosidase inhibitors, thiazolidinediones, basal and biphasic insulin, dipeptidyl peptidase 4 inhibitors, glucagon-like-peptide-1 receptor agonists and sodium-glucose cotransport-2 inhibitors). All drug classes significantly reduced haemoglobin A1c (HbA1c) compared to metformin monotherapy (mean reduction from 0.50 to 0.92). The drug classes varied in their relative effects on hypoglycemia, body weight, body mass index, systolic and diastolic blood pressure, total cholesterol, high and low density lipoprotein cholesterol, and the classes had differing safety profiles on total adverse events, urogenital adverse events, heart failure, serious adverse events, and withdraw due to adverse events. CONCLUSIONS: All eight antihyperglycemic drug classes, taken in combination with metformin, reduced HbA1c levels; however, the effects of the agents on other outcomes varied among the classes.

Pharmacologic treatment of attention deficit hyperactivity disorder in adults: A systematic review and network meta-analysis.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) affects approximately 3% of adults globally. Many pharmacologic treatments options exist, yet the comparative benefits and harms of individual treatments are largely unknown. We performed a systematic review and network meta-analysis to assess the relative effects of individual pharmacologic treatments for adults with ADHD. METHODS: We searched English-language published and grey literature sources for randomized clinical trials (RCTs) involving pharmacologic treatment of ADHD in adults (December 2018). The primary outcome was clinical response; secondary outcomes were quality of life, executive function, driving behaviour, withdrawals due to adverse events, treatment discontinuation, serious adverse events, hospitalization, cardiovascular adverse events, and emergency department visits. Data were pooled via pair-wise meta-analyses and Bayesian network meta-analyses. Risk of bias was assessed by use of Cochrane's Risk of Bias tool, and the certainty of the evidence was assessed by use of the GRADE framework. RESULTS: Eighty-one unique trials that reported at least one outcome of interest were included, most of which were at high or unclear risk of at least one important source of bias. Notably, only 5 RCTs were deemed at overall low risk of bias. Included pharmacotherapies were methylphenidate, atomoxetine, dexamfetamine, lisdexamfetamine, guanfacine, bupropion, mixed amphetamine salts, and modafinil. As a class, ADHD pharmacotherapy improved patient- and clinician-reported clinical response compared with placebo (range: 4 to 15 RCTs per outcome); however, these findings were not conserved when the analyses were restricted to studies at low risk of bias, and the certainty of the finding is very low. There were few differences among individual medications, although atomoxetine was associated with improved patient-reported clinical response and quality of life compared with placebo. There was no significant difference in the risk of serious adverse events or treatment discontinuation between ADHD pharmacotherapies and placebo; however, the proportion of participants who withdrew due to adverse events was significantly higher among participants who received any ADHD pharmacotherapy. Few RCTs reported on the occurrence of adverse events over a long treatment duration. CONCLUSIONS: Overall, despite a class effect of improving clinical response relative to placebo, there were few differences among the individual ADHD pharmacotherapies, and most studies were at risk of at least one important source of bias. Furthermore, the certainty of the evidence was very low to low for all outcomes, and there was limited reporting of long-term adverse events. As such, the choice between ADHD pharmacotherapies may depend on individual patient considerations, and future studies should assess the long-term effects of individual pharmacotherapies on patient-important outcomes, including quality of life, in robust blinded RCTs. REGISTRATION: PROSPERO no. CRD 42015026049.

ALK inhibitors for non-small cell lung cancer: A systematic review and network meta-analysis.

BACKGROUND: We sought to assess the relative effects of individual anaplastic lymphoma kinase (ALK) inhibitors for the treatment of non-small cell lung cancer (NSCLC). METHODS: We searched MEDLINE, Embase, Cochrane CENTRAL, and grey literature (July 23, 2019) for randomized controlled trials (RCTs) that included participants with ALK- or ROS1-positive NSCLC who received any ALK inhibitor compared with placebo, another ALK inhibitor, or the same ALK inhibitor at a different dose. The primary outcome was treatment-related death. Secondary outcomes were overall survival (OS), progression-free survival (PFS), and serious adverse events. Data were pooled via meta-analysis and network meta-analysis, and risk of bias was assessed. PROSPERO: CRD42017077046. RESULTS: Thirteen RCTs reporting outcomes of interest among participants with ALK-positive NSCLC were identified. Treatment-related deaths were rare, with 10 deaths attributed to crizotinib (risk difference v. chemotherapy: 0.49, 95% credible interval [CrI] -0.16 to 1.46; odds ratio 2.58 (0.76-11.37). All ALK inhibitors improved PSF relative to chemotherapy (hazard ratio [95% CrI]: crizotinib 0.46 [0.39-0.54]; ceritinib 0.52 [0.42-0.64]; alectinib 300 BID 0.16 [0.08-0.33]; alectinib 600 BID 0.23 [0.17-0.30]; brigatinib 0.23 [0.15-0.35]), while alectinib and brigatinib improved PFS over crizotinib and ceritinib (alectinib v. crizotinib 0.34 [0.17-0.70]; alectinib v. ceritinib 0.30 [0.14-0.64]; brigatinib v. crizotinib 0.49 [0.33-0.73]; brigatinib v. ceritinib 0.43 [0.27-0.70]). OS was improved with alectinib compared with chemotherapy (HR 0.57 [95% CrI 0.39-0.83]) and crizotinib (0.68 [0.48-0.96]). Use of crizotinib (odds ratio 2.08 [95% CrI 1.56-2.79]) and alectinib (1.60 [1.00-2.58]) but not ceritinib (1.25 [0.90-1.74), increased the risk of serious adverse events compared with chemotherapy. Results were generally consistent among treatment-experienced or naïve participants. CONCLUSION(S): Treatment-related deaths were infrequent among ALK-positive NSCLC. PFS may be improved by alectinib and brigatinib relative to other ALK inhibitors; however, the assessment of OS is likely confounded by treatment crossover and should be interpreted with caution.

Optimal Duration of Dual Antiplatelet Therapy Following Percutaneous Coronary Intervention: An Umbrella Review.

BACKGROUND: The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention with stenting requires consideration of patient characteristics, and decision makers require a comprehensive overview of the evidence. METHODS: We performed an umbrella review of systematic reviews (SRs) of randomized controlled trials of extended DAPT (> 12 months) compared with DAPT for 6 to 12 months after percutaneous coronary intervention with stenting. Outcomes of interest were death, myocardial infarction (MI), stroke, stent thrombosis, major adverse cardiac and cerebrovascular events, bleeding, and urgent revascularization. We aimed to assess the evidence of benefits and harms among clinically important subgroups (eg, elderly patients, those with diabetes, prior MI, acute coronary syndrome). We assessed the quality of the included reviews by use of A Measurement Tool to Assess Systematic Reviews (AMSTAR). RESULTS: Sixteen SRs involving 8 randomized controlled trials were included. Most scored 7 or more points on the AMSTAR checklist. There was no significant difference in outcomes with extended DAPT compared with 6 months of DAPT in most SRs, with the exception of an increased risk of major bleeding. Compared with 12 months, extended DAPT may reduce the risk of MI and stent thrombosis; however, the findings were not consistent across all reviews. There have been conflicting reports of an increased risk of death with extended DAPT. Few SRs assessed outcomes among patient subgroups. CONCLUSIONS: Extended DAPT may reduce the risk of MI and stent thrombosis but increase the risk of major bleeding and death. Whether the effects of extended DAPT are consistent across patient subgroups is unclear, and future SRs should address this knowledge gap.

Dual antiplatelet therapy following percutaneous coronary intervention: protocol for a systematic review.

INTRODUCTION: Dual antiplatelet therapy (DAPT) is routinely given to patients after percutaneous coronary intervention (PCI) with stenting; however, there is ongoing debate about the optimal duration, especially in specific patient groups. In the proposed systematic review, we intend to assess the optimal duration of DAPT following PCI with stenting, with a focus on clinically relevant patient subgroups. METHODS AND ANALYSIS: We will perform a comprehensive search of the published literature for randomised controlled trials (RCTs) assessing the benefits and harms of extended DAPT (>12 months) compared with short-term DAPT (6-12 months) following PCI with stenting (bare metal or drug eluting). ClinicalTrials.gov and ICTRP will also be searched to identify ongoing and completed clinical trials. Two independent reviewers will select studies for inclusion, and the risk of bias will be assessed by use of Cochrane's Risk of Bias tool. The primary outcome of interest is death (all-cause, cardiovascular, non-cardiovascular). Secondary outcomes are bleeding (major, minor, gastrointestinal), urgent target vessel revascularisation, major adverse cardiovascular events, myocardial infarction, stroke and stent thrombosis. Subgroup data will be sought for patients with prior myocardial infarction, acute coronary syndrome at presentation and diabetes, and based on smoking status and age group. Data will be analysed by random-effects meta-analysis, and separate analyses will be performed for patient subgroups. Bayesian network meta-analysis will be performed to investigate the effect of individual P2Y12 inhibitors at different DAPT durations longer than 6 months. ETHICS AND DISSEMINATION: This review will provide a comprehensive overview of the available evidence of the benefits and harms associated with extending DAPT beyond 12 months following PCI with stenting and the effects on clinically important subgroups. The results of this review will inform clinical and policy decisions regarding the optimal treatment duration of DAPT following PCI with stenting. SYSTEMATIC REVIEW REGISTRATION: PROSPERO no. CRD42018082587.

A systematic review of clinical practice guidelines on the use of low molecular weight heparin and fondaparinux for the treatment and prevention of venous thromboembolism: Implications for research and policy decision-making.

BACKGROUND: Venous thromboembolism (VTE) is a major global cause of morbidity and mortality. Low molecular weight heparin (LMWH) and fondaparinux (FDP) are frequently used to treat and prevent VTE and have a variety of safety and practical advantages over other anticoagulants, including use in outpatient settings. These medications are commonly listed on drug formularies, which act as a gateway for health plan prescription coverage by outlining the circumstances under which patients will be covered for specific drugs and drug products. Because patient access to medications is impacted by the nature of their listing on formularies, they must be rigorously reviewed and modernized as new evidence emerges. METHODS: As part of a broader drug class review team, we completed a systematic review of clinical practice guidelines to determine whether the recommendations they reported aligned with the indications listed for the coverage of LMWH and FDP in an outpatient drug formulary. Guideline quality was assessed using the Appraisal of Guidelines for Research & Evaluation (AGREE) II tool. Recommendation matrices were used to systematically compare, categorize, and summarize included recommendations. RESULTS: Twenty-seven guidelines were included from which 168 eligible recommendations were identified. Generally, AGREE II domains were adequately addressed; however, domain five (applicability) was poorly addressed. Most recommendations were based on moderate- to low-quality/limited evidence and reported on the use of LMWHs generally; few reported on specific agents. CONCLUSIONS: Our findings contributed to the recommendation that the formulary listing for LMWH and FDP be streamlined to include coverage for specific outpatient indications. The paucity of available evidence on the comparative efficacy of specific LMWH agents against each other and FDP limited agent-specific listing recommendations, highlighting the need for high-quality comparative studies on this topic.

Testosterone therapy in hypogonadal men: a systematic review and network meta-analysis.

OBJECTIVE: To assess the relative effects of individual testosterone products among hypogonadal men. DESIGN: Systematic review and network meta-analysis. METHODS: We searched MEDLINE, Embase, Cochrane CENTRAL, and grey literature (25 May 2017) for randomised-controlled trials (RCTs) and non-randomised studies (NRS) that involved hypogonadal men given testosterone replacement therapy (TRT) for ≥3 months. Comparators were placebo, another TRT, or the same product at a different dose. Outcomes were quality of life, depression, libido, erectile function, activities of daily living and testosterone levels, as well as cardiovascular death, myocardial infarction, stroke, prostate cancer, heart disease, diabetes, serious adverse events, withdrawals due to adverse events and erythrocytosis. RCT data were pooled via meta-analysis and network meta-analysis. Risk of bias was assessed using Cochrane's risk of bias tool (RCTs) andScottish Intercollegiate Guidelines Network (SIGN)50 (NRS). RESULTS: Eighty-seven RCTs and 51 NRS were included. Most were at high or unclear risk of bias, with short treatment duration and follow-up. When compared as a class against placebo, TRT improved quality of life (standardised mean difference (SMD) -0.26, 95% CI -0.41 to -0.11), libido (SMD 0.33, 95% CI 0.16 to 0.50), depression (SMD -0.23, 95% CI -0.44 to -0.01) and erectile function (SMD 0.25, 95% CI 0.10 to 0.41). Most individual TRTs were significantly better than placebo at improving libido (6/10). Only one TRT was better than placebo at improving quality of life, and no individual TRTs improved depression or erectile function. There was no increased risk of adverse events, with the exception of withdrawals due to adverse events with the use of some TRTs. CONCLUSION: Despite a class effect of improving quality of life, depression, erectile function and libido, major improvements were not observed with the use of any individual product. We observed no statistically significant increase in the risk of adverse events; however, longer-term high-quality trials are needed to fully assess the risk of harm. PROSPERO REGISTRATION NUMBER: CRD42014009963.

Optimal duration of dual antiplatelet therapy following percutaneous coronary intervention: protocol for an umbrella review.

INTRODUCTION: Although dual antiplatelet therapy (DAPT) is routinely given to patients after percutaneous coronary intervention (PCI) with stenting, the optimal duration is unknown. Recent evidence indicates there may be benefits in extending the duration beyond 12 months but such decisions may increase the risk of bleeding. Our objective is to provide a comprehensive overview of the literature for clinicians and policymakers via an umbrella review assessing the optimal duration of DAPT. METHODS AND ANALYSIS: We will perform a comprehensive search of the published and grey literature for systematic reviews involving randomised controlled trials (RCTs) assessing the optimal duration of DAPT following PCI with stenting. The intervention of interest is extended DAPT (beyond 12 months) compared with short-term DAPT (6-12 months). Studies will be selected for inclusion by two reviewers, and the quality will be assessed. The primary outcomes of interest are all-cause mortality and cardiovascular mortality. Secondary outcomes will be bleeding (major, minor and gastrointestinal), urgent target vessel revascularisation, major adverse cardiovascular events, myocardial infarction, stroke and stent thrombosis. Outcomes will be assessed while on DAPT and after withdrawal of DAPT. Data will be summarised with respect to the number of included RCTs, number of participants, effect estimates and heterogeneity. Data will be reported separately based on patient demographics, procedural parameters (eg, stent types, lesion complexity and concurrent disease) and clinical presentation (eg, acute coronary syndromes, infarct type). ETHICS AND DISSEMINATION: Our umbrella review aims to provide a comprehensive overview of the benefits and harms associated with extending DAPT beyond 12 months following PCI with stenting. The results of this review will inform clinical and policy decisions regarding the optimal treatment duration and reimbursement of DAPT following PCI with stenting. Results will be disseminated through a peer-reviewed publication and conference presentations. Ethics approval is not required for this study. TRIAL REGISTRATION NUMBER: CRD42016047735.

Efficacy and safety of insulin analogues for the management of diabetes mellitus: a meta-analysis.

BACKGROUND: Although insulin analogues are commonly prescribed for the management of diabetes mellitus, there is uncertainty regarding their optimal use. We conducted meta-analyses to compare the outcomes of insulin analogues with conventional insulins in the treatment of type 1, type 2 and gestational diabetes. METHODS: We updated 2 earlier systematic reviews of the efficacy and safety of rapid-and long-acting insulin analogues. We searched electronic databases, conference proceedings and "grey literature" up to April 2007 to identify randomized controlled trials that compared insulin analogues with conventional insulins. Study populations of interest were people with type 1 and type 2 diabetes (adult and pediatric) and women with gestational diabetes. RESULTS: We included 68 randomized controlled trials in the analysis of rapid-acting insulin analogues and 49 in the analysis of long-acting insulin analogues. Most of the studies were of short to medium duration and of low quality. In terms of hemoglobin A1c, we found minimal differences between rapid-acting insulin analogues and regular human insulin in adults with type 1 diabetes (weighted mean difference for insulin lispro: -0.09%, 95% confidence interval [CI] -0.16% to -0.02%; for insulin aspart: -0.13%, 95% CI -0.20% to -0.07%). We observed similar outcomes among patients with type 2 diabetes (weighted mean difference for insulin lispro: -0.03%, 95% CI -0.12% to -0.06%; for insulin aspart: -0.09%, 95% CI -0.21% to 0.04%). Differences between long-acting insulin analogues and neutral protamine Hagedorn insulin in terms of hemoglobin A1c were marginal among adults with type 1 diabetes (weighted mean difference for insulin glargine: -0.11%, 95% CI -0.21% to -0.02%; for insulin detemir: -0.06%, 95% CI -0.13% to 0.02%) and among adults with type 2 diabetes (weighted mean difference for insulin glargine: -0.05%, 95% CI -0.13% to 0.04%; for insulin detemir: 0.13%, 95% CI 0.03% to 0.22%). Benefits in terms of reduced hypoglycemia were inconsistent. There were insufficient data to determine whether insulin analogues are better than conventional insulins in reducing long-term diabetes-related complications or death. INTERPRETATION: Rapid-and long-acting insulin analogues offer little benefit relative to conventional insulins in terms of glycemic control or reduced hypoglycemia. Long-term, high-quality studies are needed to determine whether insulin analogues reduce the risk of long-term complications of diabetes.