Efficacy and dose-response relationships of antidepressants in the acute treatment of major depressive disorders: a systematic review and network meta-analysis.

BACKGROUND: The optimal antidepressant dosages remain controversial. This study aimed to analyze the efficacy of antidepressants and characterize their dose-response relationships in the treatments of major depressive disorders (MDD). METHODS: We searched multiple databases, including the Embase, Cochrane Central Register of Controlled Trials, PubMed, and Web of Science, for the studies that were conducted between January 8, 2016, and April 30, 2023. The studies are double-blinded, randomized controlled trials (RCTs) involving the adults (≥18 years) with MDD. The primary outcomes were efficacy of antidepressant and the dose-response relationships. A frequentist network meta-analysis was conducted, treating participants with various dosages of the same antidepressant as a single therapy. We also implemented the model-based meta-analysis (MBMA) using a Bayesian method to explore the dose-response relationships. RESULTS: The network meta-analysis comprised 135,180 participants from 602 studies. All the antidepressants were more effective than the placebo; toludesvenlafaxine had the highest odds ratio (OR) of 4.52 (95% confidence interval [CI]: 2.65-7.72), and reboxetine had the lowest OR of 1.34 (95%CI: 1.14-1.57). Moreover, amitriptyline, clomipramine, and reboxetine showed a linear increase in effect size from low to high doses. The effect size of toludesvenlafaxine increased significantly up to 80 mg/day and subsequently maintained the maximal dose up to 160 mg/day while the predictive curves of nefazodone were fairly flat in different dosages. CONCLUSIONS: Although most antidepressants were more efficacious than placebo in treating MDD, no consistent dose-response relationship between any antidepressants was observed. For most antidepressants, the maximum efficacy was achieved at lower or middle prescribed doses, rather than at the upper limit.

Medication adherence and costs of medical care among patients with Parkinson's disease: an observational study using electronic medical records.

BACKGROUND: Adherence to antiparkinsonian drugs (APDs) is critical for patients with Parkinson's disease (PD), for which medication is the main therapeutic strategy. Previous studies have focused on specific disorders in a single system when assessing clinical factors affecting adherence to PD treatment, and no international comparative data are available on the medical costs for Chinese patients with PD. The present study aimed to evaluate medication adherence and its associated factors among Chinese patients with PD using a systematic approach and to explore the impact of adequate medication adherence on direct medical costs. METHODS: A retrospective analysis was conducted using the electronic medical records of patients with PD from a medical center in China. Patients with a minimum of two APD prescriptions from January 1, 2016 to August 15, 2018 were included. Medication possession ratio (MPR) and proportion of days covered were used to measure APD adherence. Multiple linear regression analysis was used to identify factors affecting APD adherence. Gamma regression analysis was used to explore the impact of APD adherence on direct medical costs. RESULTS: In total, 1,712 patients were included in the study, and the mean MPR was 0.68 (± 0.25). Increased number of APDs and all medications, and higher daily levodopa-equivalent doses resulted in higher MPR (mean difference [MD] = 0.04 [0.03-0.05]; MD = 0.02 [0.01-0.03]; MD = 0.03 [0.01-0.04], respectively); combined digestive system diseases, epilepsy, or older age resulted in lower MPR (MD = -0.06 [-0.09 to -0.03]; MD = -0.07 [-0.14 to -0.01]; MD = -0.02 [-0.03 to -0.01], respectively). Higher APD adherence resulted in higher direct medical costs, including APD and other outpatient costs. For a 0.3 increase in MPR, the two costs increased by $34.42 ($25.43-$43.41) and $14.63 ($4.86-$24.39) per year, respectively. CONCLUSIONS: APD adherence rate among Chinese patients with PD was moderate and related primarily to age, comorbidities, and healthcare costs. The factors should be considered when prescribing APDs.

Lifetime effects and cost-effectiveness of standard and higher-intensity statin therapy across population categories in the UK: a microsimulation modelling study.

Background: Cardiovascular disease incidence and mortality have declined across developed economies and granular up-to-date cost-effectiveness evidence is required for treatments targeting large populations. To assess the health benefits and cost-effectiveness of standard and higher intensity statin therapy in the contemporary UK population 40-70 years old. Methods: A cardiovascular disease microsimulation model, developed using the Cholesterol Treatment Trialists' Collaboration data (117,896 participants; 5 years follow-up), and calibrated in the UK Biobank cohort (501,854 participants; 9 years follow-up), projected risks of myocardial infarction, stroke, coronary revascularization, diabetes, cancer and vascular and nonvascular death for all UK Biobank participants without and with statin treatment. Meta-analyses of trials and cohort studies informed statins' relative effects on cardiovascular events, incident diabetes, myopathy and rhabdomyolysis. UK healthcare perspective was taken (2020/2021 UK£) with costs per 28 tablets of £1.10 for standard (35%-45% LDL cholesterol (LDL-C) reduction) and £1.68 for higher intensity (≥45% LDL-C reduction) generic statin. Findings: Across categories by sex, age, LDL-C, and cardiovascular disease history/10-year cardiovascular risk, lifetime standard statin increased survival by 0.28-1.85 years (0.20-1.09 quality-adjusted life years (QALYs)), and higher intensity statin by further 0.06-0.40 years (0.03-0.20 QALYs) per person. Standard statin was cost-effective across all categories with incremental cost per QALY from £280 to £8530, with higher intensity statin cost-effective at higher cardiovascular risks and higher LDL-C levels. Stopping statin early reduced benefits and was not cost-effective. Interpretation: Lifetime low-cost statin therapy is cost-effective across all 40-70 years old in UK. Strengthening and widening statin treatment could cost-effectively improve population health. Funding: UK NIHR Health Technology Assessment Programme (17/140/02).

Long-term cardiovascular risks and the impact of statin treatment on socioeconomic inequalities: a microsimulation model.

BACKGROUND: UK cardiovascular disease (CVD) incidence and mortality have declined in recent decades but socioeconomic inequalities persist. AIM: To present a new CVD model, and project health outcomes and the impact of guideline-recommended statin treatment across quintiles of socioeconomic deprivation in the UK. DESIGN AND SETTING: A lifetime microsimulation model was developed using 117 896 participants in 16 statin trials, 501 854 UK Biobank (UKB) participants, and quality-of-life data from national health surveys. METHOD: A CVD microsimulation model was developed using risk equations for myocardial infarction, stroke, coronary revascularisation, cancer, and vascular and non-vascular death, estimated using trial data. The authors calibrated and further developed this model in the UKB cohort, including further characteristics and a diabetes risk equation, and validated the model in UKB and Whitehall II cohorts. The model was used to predict CVD incidence, life expectancy, quality-adjusted life years (QALYs), and the impact of UK guideline-recommended statin treatment across socioeconomic deprivation quintiles. RESULTS: Age, sex, socioeconomic deprivation, smoking, hypertension, diabetes, and cardiovascular events were key CVD risk determinants. Model-predicted event rates corresponded well to observed rates across participant categories. The model projected strong gradients in remaining life expectancy, with 4-5-year (5-8 QALYs) gaps between the least and most socioeconomically deprived quintiles. Guideline-recommended statin treatment was projected to increase QALYs, with larger gains in quintiles of higher deprivation. CONCLUSION: The study demonstrated the potential of guideline-recommended statin treatment to reduce socioeconomic inequalities. This CVD model is a novel resource for individualised long-term projections of health outcomes of CVD treatments.

Estimating Costs Associated with Disease Model States Using Generalized Linear Models: A Tutorial.

Estimates of costs associated with disease states are required to inform decision analytic disease models to evaluate interventions that modify disease trajectory. Increasingly, decision analytic models are developed using patient-level data with a focus on heterogeneity between patients, and there is a demand for costs informing such models to reflect individual patient costs. Statistical models of health care costs need to recognize the specific features of costs data which typically include a large number of zero observations for non-users, and a skewed and heavy right-hand tailed distribution due to a small number of heavy healthcare users. Different methods are available for modelling costs, such as generalized linear models (GLMs), extended estimating equations and latent class approaches. While there are tutorials addressing approaches to decision modelling, there is no practical guidance on the cost estimation to inform such models. Therefore, this tutorial aims to provide a general guidance on estimating healthcare costs associated with disease states in decision analytic models. Specifically, we present a step-by-step guide to how individual participant data can be used to estimate costs over discrete periods for participants with particular characteristics, based on the GLM framework. We focus on the practical aspects of cost modelling from the conceptualization of the research question to the derivation of costs for an individual in particular disease states. We provide a practical example with step-by-step R code illustrating the process of modelling the hospital costs associated with disease states for a cardiovascular disease model.

Adverse effects of 21 antidepressants on sleep during acute-phase treatment in major depressive disorder: a systemic review and dose-effect network meta-analysis.

STUDY OBJECTIVES: Sleep-related adverse effects during acute treatment with antidepressants undermine adherence and impede remission. We aimed to address subtypes of sleep-related adverse effects and depict the relationship between dose and sleep-related adverse events. METHODS: We searched PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science for double-blind randomized controlled trials of depression published before April 30th, 2023. Eligible studies reporting sleep-related adverse effects during short-term monotherapy were included. The odds ratios (ORs) for sleep-related adverse effects were addressed with network meta-analysis. A Bayesian approach was used to depict the dose-effect relationship. Heterogeneity among studies was assessed using the τ2 and I2 statistics. Sensitivity analyses were performed without studies featuring high risk of bias. RESULTS: Studies with 64 696 patients were examined from 216 trials. Compared to placebo, 13 antidepressants showed higher ORs for somnolence, of which fluvoxamine (OR = 6.32; 95% CI: 3.56 to 11.21) ranked the top. Eleven had higher risks for insomnia, reboxetine ranked the top (OR = 3.47; 95% CI: 2.77 to 4.36). The dose-effect relationships curves between somnolence or insomnia and dose included linear shape, inverted U-shape, and other shapes. There was no significant heterogeneity among individual studies. The quality of evidence for results in network meta-analyses was rated as very low to moderate by Grading of Recommendations Assessment, Development, and Evaluation. CONCLUSIONS: Most antidepressants had higher risks for insomnia or somnolence than placebo. The diverse relationship curves between somnolence or insomnia and dose of antidepressants can guide clinicians to adjust the doses. These findings suggest clinicians pay more attention to sleep-related adverse effects during acute treatment with antidepressants.

A systematic review of the factors associated with suicide attempts among sexual-minority youth

Background and objectives: Recent literature reported a higher risk of suicide attempts among sexual minority youth. Discovering the risk and protective factors of suicide attempts among this vulnerable population can play a key role in reducing the suicide rate. Our research aims to systematically search for the risk and protective factors for suicide attempts among sexual minority youth.MethodsWe have conducted a systematic review of published studies of associated factors for suicide attempts in sexual minority youth. Four databases up to 2020 were searched to find relevant studies.ResultsTwelve articles were included. For sexual minority youth, the identified risk factors associated with suicide attempts are early coming out, being unacceptable by families, dissatisfaction with sexual minority friendships, too few friends, physical abuse, sexual abuse, and bullying. The identified protective factors for suicide attempts are feeling safe at school, teacher support, anti-bullying policy, and other adult support.ConclusionBoth risk and protective factors for suicide attempts stem directly from the environments in which youth grew up: family, school, and the internet. Effective preventive measures among sexual minority youth need to be developed and implemented. Societal-level anti-stigma interventions are needed to reduce the risk of victimization and awareness should be raised among family and friends. (AU)

Cost-effectiveness of endovascular thrombectomy with alteplase versus endovascular thrombectomy alone for acute ischemic stroke secondary to large vessel occlusion.

BACKGROUND: Recent randomized trials have suggested that endovascular thrombectomy (EVT) alone may provide similar functional outcomes as the current standard of care, EVT combined with intravenous alteplase treatment, for acute ischemic stroke secondary to large vessel occlusion. We conducted an economic evaluation of these 2 therapeutic options. METHODS: We constructed a decision analytic model with a hypothetical cohort of 1000 patients to assess the cost-effectiveness of EVT with intravenous alteplase treatment versus EVT alone for acute ischemic stroke secondary to large vessel occlusion from both the societal and public health care payer perspectives. We used studies and data published in 2009-2021 for model inputs, and acquired cost data for Canada and China, representing high- and middle-income countries, respectively. We calculated incremental cost-effectiveness ratios (ICERs) using a lifetime horizon and accounted for uncertainty using 1-way and probabilistic sensitivity analyses. All costs are reported in 2021 Canadian dollars. RESULTS: In Canada, the difference in quality-adjusted life-years (QALYs) gained between EVT with alteplase and EVT alone was 0.10 from both the societal and health care payer perspectives. The difference in cost was $2847 from a societal perspective and $2767 from the payer perspective. In China, the difference in QALYs gained was 0.07 from both perspectives, and the difference in cost was $1550 from the societal perspective and $1607 from the payer perspective. One-way sensitivity analyses showed that the distributions of modified Rankin Scale scores at 90 days after stroke were the most influential factor on ICERs. For Canada, compared to EVT alone, the probability that EVT with alteplase would be cost-effective at a willingness-to-pay threshold of $50 000 per QALY gained was 58.7% from a societal perspective and 58.4% from a payer perspective. The corresponding values for at a willingness-to-pay threshold of $47 185 (3 times the Chinese gross domestic product per capita in 2021) were 65.2% and 67.4%. INTERPRETATION: For patients with acute ischemic stroke due to large vessel occlusion eligible for immediate treatment with both EVT alone and EVT with intravenous alteplase treatment, it is uncertain whether EVT with alteplase is cost-effective compared to EVT alone in Canada and China.

Efficacy and safety of selegiline for the treatment of Parkinson's disease: A systematic review and meta-analysis.

Background: Drug efficacy generally varies with different durations. There is no systematic review analyzing the effect of selegiline for Parkinson's disease (PD) on different treatment duration. This study aims to analyze how the efficacy and safety of selegiline changes for PD over time. Methods: PubMed, the Cochrane Library, Embase, China National Knowledge Infrastructure and Wanfang Database were systematically retrieved for randomized controlled trials (RCTs) and observational studies of selegiline for PD. The search period was from inception to January 18th, 2022. The efficacy outcomes were measured by the mean change from baseline in the total and sub Unified Parkinson's Disease Rating Scale (UPDRS), Hamilton Depression Rating Scale (HAMD) and Webster Rating Scale (WRS) scores. The safety outcomes were measured by the proportion of participants having any adverse events overall and that in different system organ classes. Results: Among the 3,786 studies obtained, 27 RCTs and 11 observational studies met the inclusion criteria. Twenty-three studies reported an outcome which was also reported in at least one other study, and were included in meta-analyses. Compared with placebo, selegiline was found with a stronger reduction of total UPDRS score with increasing treatment duration [mean difference and 95% CIs in 1 month: -3.56 (-6.67, -0.45); 3 months: -3.32 (-3.75, -2.89); 6 months: -7.46 (-12.60, -2.32); 12 months: -5.07 (-6.74, -3.41); 48 months: -8.78 (-13.75, -3.80); 60 months: -11.06 (-16.19, -5.94)]. A similar trend was also found from the point estimates in UPDRS I, II, III, HAMD and WRS score. The results of observational studies on efficacy were not entirely consistent. As for safety, compared with placebo, selegiline had higher risk of incurring any adverse events [rate: 54.7% vs. 62.1%; odd ratio and 95% CIs: 1.58 (1.02, 2.44)], with the excess adverse events mainly manifested as neuropsychiatric disorders [26.7% vs. 31.6%; 1.36 (1.06, 1.75)] and no significant change over time. The statistically difference in overall adverse event between selegiline and active controls was not found. Conclusion: Selegiline was effective in improving total UPDRS score with increasing treatment duration, and had a higher risk of incurring adverse events, especially the adverse events in the neuropsychiatric system. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: PROSPERO CRD42021233145.

Prediction Models for Individual-Level Healthcare Costs Associated with Cardiovascular Events in the UK.

OBJECTIVES: The aim of this study was to develop prediction models for the individual-level impacts of cardiovascular events on UK healthcare costs. METHODS: In the UK Biobank, people 40-70 years old, recruited in 2006-2010, were followed in linked primary (N = 192,983 individuals) and hospital care (N = 501,807 individuals) datasets. Regression models of annual primary and annual hospital care costs (2020 UK£) associated with individual characteristics and experiences of myocardial infarction (MI), stroke, coronary revascularization, incident diabetes mellitus and cancer, and vascular and nonvascular death are reported. RESULTS: For both people without and with previous cardiovascular disease (CVD), primary care costs were modelled using one-part generalised linear models (GLMs) with identity link and Poisson distribution, and hospital costs with two-part models (part 1: logistic regression models the probability of incurring costs; part 2: GLM with identity link and Poisson distribution models the costs conditional on incurring any). In people without previous CVD, mean annual primary and hospital care costs were £360 and £514, respectively. The excess primary care costs were £190 and £360 following MI and stroke, respectively, whereas excess hospital costs decreased from £4340 and £5590, respectively, in the year of these events, to £190 and £410 two years later. People with previous CVD had more than twice higher annual costs, and incurred higher excess costs for cardiovascular events. Other characteristics associated with higher costs included older age, female sex, south Asian ethnicity, higher socioeconomic deprivation, smoking, lower level of physical activities, unhealthy body mass index, and comorbidities. CONCLUSIONS: These individual-level healthcare cost prediction models could inform assessments of the value of health technologies and policies to reduce cardiovascular and other disease risks and healthcare costs. An accompanying Excel calculator is available to facilitate the use of the models.

Generation of Environmentally Persistent Free Radicals on Metal-Organic Frameworks.

Environmentally persistent free radicals (EPFRs) have been recognized as one of the important emerging contaminants with biological toxicity, environmental persistence, and global mobility. Previous studies have identified the catalytic role of surface metal oxides in EPFRs formation and illustrated the metal-dependence of EPFRs by studying on various metal oxide nanoparticles and single crystals. However, there is still lack of an understanding on the formation of EPFRs from the point of view of metal sites. Various factors (e.g., crystalline phases and surface species) of metal oxides are regarded to contribute to the generation of EPFRs, which present profound difficulties for scientists to tease apart the impact of metal type. Herein, a laboratory investigation, in terms of the acidity and oxidation strength of metal cations, was conducted by selecting metal-variable isostructural metal-organic frameworks as material platforms. Specifically, we evaluated EPFRs generation on MIL-100(M) (M = Al, Cr, Fe) from chlorine-substituted phenol vapor and catechol under thermal conditions. It is found that high Lewis acidity of metal sites is crucial for capturing the above two phenolic precursors, activating the O-H bond and promoting EPFRs formation. Radical species with half-life as long as 70 days were generated on MIL-100 rich in 5-fold coordinated Al3+ sites. The unpaired electron spin density donation was further confirmed by using 27Al solid-state nuclear magnetic resonance spectroscopy. Despite their higher oxidation power than Al3+, the exposed Cr3+ and Fe3+ sites show undetectable catalytic activity for the formation of EPFRs, because of their insufficient Lewis acidity. Our results suggest that the surface species rather than Lewis acid sites may be a major contributor to the formation of EPFRs on metal oxides like Fe2O3.

Nanoporous Graphene via a Pressing Organization Calcination Strategy for Highly Efficient Electrocatalytic Hydrogen Peroxide Generation.

Nanoporous graphenes (NPGs) have recently attracted huge attention owing to their designable structures and diverse properties. Many important properties of NPGs are determined by their structural regularity and homogeneity. The mass production of NPGs with periodic well-defined pore structures under a solvent-free green synthesis poses a great challenge and is largely unexplored. A facile synthetic strategy of NPGs via pressing organization calcination (POC) of readily available halogenated polycyclic aromatic hydrocarbons is developed. The gram-scale synthesized NPGs have ordered structures and possess well-defined nanopores, which can be easily exfoliated to few layers and oxidized in controllable approaches. After being decorated with oxygen species, the oxidized NPGs with tunable catalytic centers exhibit high activity, selectivity, and stability toward electrochemical hydrogen peroxide generation.

Incorporating future unrelated medical costs in cost-effectiveness analysis in China.

The occurrence of future unrelated medical costs is a direct consequence of life-prolonging interventions, but most pharmacoeconomic guidelines recommend the exclusion of these costs. The Chinese guidelines were updated in 2020, taking an exclusion approach for the future unrelated medical cost. We notice the research surrounding this issue continues in other countries and leads to an inclusion recommendation in some guidelines. Meanwhile, this issue has not been discussed in China, reflecting an urgent need for extensive research on its impact. We reviewed the theoretical and practical studies surrounding the inclusion of future unrelated medical costs, summarised the landscape of guidelines in other jurisdictions. We found that the inclusion would increase the internal and external consistency of economic evaluation and the comparability of results between different jurisdictions. However, more research is needed surrounding this issue. We proposed a future research agenda to inform the update of Chinese guidelines. We recommend research on individual-level healthcare reimbursement data and end-of-life costs from hospital administrative data to generate the age-specific, sex-specific and condition-specific costs. We also recommend establishing a formal process to evaluate the ethical and economic impact of including future unrelated medical costs and adjust the threshold accordingly in the guidelines.

Evaluation of rivaroxaban-, apixaban- and dabigatran-associated hemorrhagic events using the FDA-Adverse event reporting system (FAERS) database.

Background Rivaroxaban, apixaban and dabigatran are non-vitamin K antagonist oral anticoagulants (NOACs) that are widely used for treatment or prevention of venous thromboembolism and stroke in patients with atrial fibrillation. Objective To estimate and compare hemorrhagic events report of rivaroxaban, apixaban and dabigatran. Setting FDA Adverse Event Reporting System (FAERS) database. Methods The reporting odds ratio (ROR) was used to assess the signal of hemorrhagic events of different NOACs. Main outcome measure The overall hemorrhagic events and hemorrhagic events in different physiological systems. Results From January 1, 2014 to December 31, 2019, the total number of reports of hemorrhage related to rivaroxaban was 53,085, and the numbers of apixaban and dabigatran were 13,151 and 14,100 respectively. The overall ROR (95% CI) of hemorrhagic events reporting for rivaroxaban versus dabigatran and apixaban versus dabigatran were 1.58 (1.54-1.62) and 0.47 (0.46-0.48) respectively. The ROR (95% CI) for rivaroxaban versus dabigatran in gastrointestinal system, nervous system, renal and urinary system, skin and subcutaneous tissue, and eye system was 1.38 (1.34-1.42), 0.94 (0.90-0.98), 1.07 (1.01-1.13), 0.80 (0.70-0.90), and 1.38 (1.19-1.60) respectively. The RORs (95% CI) for apixaban versus dabigatran in gastrointestinal system, nervous system, renal and urinary system, skin and subcutaneous tissue, and eye system were 0.28 (0.27-0.29), 0.69 (0.66-0.73), 0.31 (0.29-0.34), 0.98 (0.86-1.12), and 1.18 (1.00-1.39), respectively. Conclusions Overall, we found a moderate signal of higher frequency of reporting hemorrhage in rivaroxban compared with dabigatran and decreased hemorrhagic event reporting in apixaban compared with dabigatran. While this potential signal has not been confirmed in clinical trials or observational studies, in clinical practice, attention should be paid to the risk of potential hemorrhage when the patients switch from apixaban to dabigatran or rivaroxban.

Which Criteria are Considered and How are They Evaluated in Health Technology Assessments? A Review of Methodological Guidelines Used in Western and Asian Countries.

OBJECTIVES: This study aimed to provide an exhaustive description of criteria and methodological recommendations for evaluating them in health technology assessment (HTA) in Western and Asian countries. METHODS: We conducted a system literature review of HTA-related guidelines by searching the websites of HTA agencies and related data sources. The guidelines, reports, or recommendations introducing the HTA evaluation methods, processes, decision-making frameworks, and criteria for priority setting were eligible to be included. The review was limited to guidelines from countries belonging to the European Network for Health Technology Assessment (EUnetHTA) and HTAsiaLink organisations and other countries with well-established available guidelines. RESULTS: A total of 52 guidelines from 24 countries were identified, including 13 countries from the EUnetHTA organisation, 9 countries from the HTAsiaLink organisation and 2 other countries (Canada and the USA). A strong consensus was observed among the HTA agencies on the core set of criteria including efficacy or effectiveness, cost-effectiveness, safety, and budget impact. More similarities were observed than differences in methodological recommendations for clinical and economic evaluations among the agencies. CONCLUSIONS: Substantial convergence is seen in the criteria included in the HTA process, as well as the methods to evaluate and quantify them. Further efforts are needed to verify whether the criteria identified from the guidelines are incorporated in real HTA decisions, and how they are assessed and weighted in practice.

Pharmacokinetics and anticoccidial activity of ethanamizuril in broiler chickens.

The treatment effect of ethanamizuril (EZL) to broiler chickens experimentally infected with 8 × 104Eimeria tenella was evaluated. On the third day after infection, the broiler chickens were treated with EZL by gavage at doses of 2, 4, and 8 mg/kg body weight (bw) for once. For double administration, the challenged broiler chickens were administered EZL at doses of 1, 2, 4, and 8 mg/kg bw by gavage continually on the third day and fourth day and once a day. Throughout the experimental period, performance parameters including body weight gain, mortality, cecal lesion score, bloody diarrhoea and oocyst output were recorded. The anticoccidial efficacy was evaluated using the anticoccidial index (ACI). Meanwhile, the concentrations of EZL in chicken cecal contents were measured, and the data were analyzed with a non-compartmental model. The results indicated that EZL showed good anticoccidial activity at single dose of 4 mg/kgbw, with the corresponding ACI of 175.73. When the challenged chickens were treated with EZL under double administration, the EZL showed a medium level of anticoccidial activity at a dose of 2 mg/kg bw, with the corresponding ACI of 162.48. The maximum concentrations (Cmax) of EZL in content were 2.43 ±â€¯1.16, 4.28 ±â€¯1.56, and 8.57 ±â€¯1.33 mg/kg after the chickens were administrated at doses of 2, 4, and 8 mg/kg bw, respectively. The respective areas under the curve were 36.93 ±â€¯8.91, 96 ±â€¯16.31, and 262.76 ±â€¯51.52 mg/kg h. The respective half-lives (T1/2) were 10.82 ±â€¯2.02, 10.53 ±â€¯2.23, and 10.60 ±â€¯1.50 h. The results show that when the concentrations of EZL in chicken cecal contents reached 4.28 ±â€¯1.56 mg/kg, there is a significant therapeutic effect on chicken coccidiosis.

Synthesis and antimicrobial activity of the hybrid molecules between amoxicillin and derivatives of benzoic acid.

Due to the increasing problem of bacterial resistance worldwide, the demand for new antibiotics is becoming increasingly urgent. We wished to: (a) prepare hybrid molecules by linking different pharmacophores by chemical bonds; (b) investigate the antib acterial activity of these hybrids using drug-sensitive and drug-resistant pathogens in vitro and vivo. A series of hybrid molecules with a diester structure were designed and synthesized that linked amoxicillin and derivatives of benzoic acid via a methylene bridge. Synthesized compounds were evaluated for activities against Gram-positive bacteria (Staphylococcus aureus American Type Culture Collection [ATCC] 29213, ATCC 11632; methicillin-resistant S. aureus [MRSA] 11; Escherichia coli ATCC 25922) and Gram-negative bacteria (Salmonella LS677, GD836, GD828, GD3625) by microdilution of broth. Synthesized compounds showed good activity against Gram-positive and Gram-negative bacteria in vitro. In particular, amoxicillin-p-nitrobenzoic acid (6d) showed good activity against Salmonella species and had better activity against methicillin-resistant S. aureus (minimum inhibitory concentration [MIC] = 64 µg/ml) than the reference drug, amoxicillin (MIC = 128 µg/ml). Amoxicillin-p-methoxybenzoic acid (6b) had the best antibacterial activity in vivo (ED50 = 13.2496 µg/ml). The hybrid molecules of amoxicillin and derivatives of benzoic acid synthesized based on a diester structure can improve the activity of amoxicillin against Salmonella species and even improve the activity against MRSA.

Increased Antimicrobial Activity of Colistin in Combination With Gamithromycin Against Pasteurella multocida in a Neutropenic Murine Lung Infection Model.

We investigate the antimicrobial activity of combined colistin and gamithromycin against nine Pasteurella multocida strains by testing in vitro susceptibility. Two high-colistin minimal inhibitory concentration (MIC) isolates (D18 and T5) and one low-colistin MIC isolate (WJ11) were used in time-kill tests and therapeutic effect experiments using a neutropenic murine pneumonia model over 24 h. Pharmacokinetics (PK) in plasma was calculated along with pharmacodynamics (PD) to determine the PK/PD index. Synergy between colistin and gamithromycin was observed using high-colistin MIC isolates, equating to a 128- or 256-fold and 4- or 8-fold reduction in colistin and gamithromycin concentration, respectively. Interestingly, no synergistic effect of the combination on low-colistin MIC isolates was observed. However, regardless of the MIC difference among isolates, each drug tended to reach the same concentration in all isolates subjected to combined treatments, which was verified by the time-kill tests presenting similar rates and extent of killing for isolates D18, T5, and WJ11. The AUC( 0 - 24 h)/MIC index was used to evaluate the relationship between PK and PD, and the correlation was >0.89. The relevant gamithromycin doses for combined therapy were determined, and the value decreased from 6- to 35-fold compared with monotherapy. Combined colistin and gamithromycin therapy provides a more potent therapeutic regimen than monotherapy against P. multocida strains.

Syngas production from biomass pyrolysis in a continuous microwave assisted pyrolysis system.

In light of the knowledge gap in the scale-up of microwave-assisted pyrolysis technology, this study developed a continuous microwave-assisted pyrolysis (CMAP) system and examined its feasibility for syngas production. Wood pellets were pyrolyzed in the system under various temperatures, and the product distribution and energy efficiency were investigated. At a processing temperature of 800 °C, the CMAP system obtained a high quality producer gas (lower heating value 18.0 MJ/Nm3 and a 67 vol% syngas content) at a yield of 72.2 wt% or 0.80 Nm3/kg d.a.f. wood, outperforming several conventional pyrolysis processes probably due to two factors: 1) reactions between primary tar and biochar enhanced by microwave irradiation, and 2) the absence of carrier gas in the process. Energy efficiency of the process was also assessed. Potentially the electricity consumption could be reduced from 7.2 MJ to 3.45 MJ per kg of wood, enabling net electricity production from the process.

Synergistic Effects of Inorganic-Organic Protective Layer for Robust Cycling Dendrite-Free Lithium Metal Batteries.

The advantages in high theoretical capacity and low electrochemical potential have made Li metal one of the most promising anode materials satisfying the surging requirement of high energy density for the next-generation batteries. However, safety issues caused by the Li dendrite growth during cycling have greatly thwarted its application. Herein, a hybrid artificial protective layer, constructed by the one-step method through chemical reactions between Li metal and 1H,1H,1H,2H-perfluorodecyltrimethoxysilane, is demonstrated to guide Li deposition and protect lithium batteries from the destruction of Li dendrites. A synergistic effect of the inorganic and organic components in the protective layer significantly enhances the electrochemical performance of symmetric Li|Li and Li|LiFePO4 cells. This work provides a facile, simple, and scalable method to design a hybrid artificial protective layer for long-lifespan Li metal batteries.