Efficacy of migraine prophylaxis treatments for treatment-naïve patients and those with prior treatment failure: a protocol for systematic review and network meta-analysis of randomised controlled trials.

INTRODUCTION: Migraine headache is a significant health problem affecting patients' psychological well-being and quality of life. Several network meta-analyses (NMAs) have compared the efficacy of migraine prophylaxis medications. However, some have focused exclusively on oral medications, while others were limited to injectable medications. Moreover, none of these NMAs conducted a stratified analysis between treatment-naïve patients and those with prior treatment failure. Therefore, this systematic review and NMA will compare the efficacy among all treatments for migraine prophylaxis, stratified by the treatment status of patients (ie, treatment-naïve and previous treatment failure). METHODS AND ANALYSIS: Randomised-controlled trials that included patients with chronic or episodic migraine, assessed the efficacy of oral or injectable treatments for migraine prophylaxis and measured the outcomes as monthly migraine day, monthly headache day, migraine-related disability, health-related quality of life or adverse drug events will be eligible for inclusion in this review. Relevant studies will be searched from Medline, Scopus, the US National Institutes of Health Register, and the World Health Organization International Clinical Trials Registry Platform (WHO-ICTRP) databases since inception through 15 August 2023. Risk of bias assessment will be performed using a revised tool for assessing the risk of bias in randomised trials. Two-stage NMA will be applied to compare relative treatment effects among all treatments of migraine prophylaxis. Surface under the cumulative ranking curve will be applied to estimate and rank the probability to be the best treatment. Consistency assumption will be assessed using a design-by-treatment interaction model. Publication bias will be assessed by comparison-adjusted funnel plot. All analyses will be stratified according to patients' status (ie, treatment-naïve and prior treatment failure). ETHICS AND DISSEMINATION: This study is a systematic review protocol collecting data from published literature and does not require approval from an institutional review board. Results from this systematic review will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42020171843.

Multidimensional sleep health and diabetic retinopathy: Systematic review and meta-analysis.

Diabetic retinopathy (DR) is one of the most prevalent microvascular diabetic complications. Poor sleep health and obstructive sleep apnea (OSA) are risk factors for diabetes and poor glycemic control. Recent studies have suggested associations between poor sleep health/OSA and DR. Furthermore, there have been suggestions of melatonin dysregulation in the context of DR. We conducted a systematic review and meta-analysis exploring the associations between multidimensional sleep health (duration, satisfaction, efficiency, timing/regularity and alertness), OSA and melatonin with DR. Forty-two studies were included. Long, but not short sleep, was significantly associated with DR, OR 1.41 (95%CI 1.21, 1.64). Poor sleep satisfaction was also significantly associated with DR, OR 2.04 (1.41, 2.94). Sleep efficiency and alertness were not associated with DR, while the evidence on timing/regularity was scant. Having OSA was significantly associated with having DR, OR 1.34 (1.07, 1.69). Further, those with DR had significantly lower melatonin/melatonin metabolite levels than those without DR, standardized mean difference -0.94 (-1.44, -0.44). We explored whether treating OSA with continuous positive airway pressure (CPAP) led to improvement in DR (five studies). The results were mixed among studies, but potential benefits were observed in some. This review highlights the association between poor multidimensional sleep health and DR.

Efficacy of Time-Restricted Eating and Behavioral Economic Intervention in Reducing Fasting Plasma Glucose, HbA1c, and Cardiometabolic Risk Factors in Patients with Impaired Fasting Glucose: A Randomized Controlled Trial.

This randomized controlled trial is aimed at assessing the efficacy of combining time-restricted eating (TRE) with behavioral economic (BE) interventions and comparing it to TRE alone and to the usual care for reducing fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), and other cardiometabolic risk factors among patients with impaired fasting glucose (IFG). Seventy-two IFG patients aged 18-65 years were randomly allocated for TRE with BE interventions (26 patients), TRE alone (24 patients), or usual care (22 patients). Mean FPG, HbA1c, and other cardiometabolic risk factors among the three groups were compared using a mixed-effect linear regression analysis. Mean body weight, FPG, HbA1c, fasting insulin, and lipid profiles did not significantly differ among the three groups. When considering only patients who were able to comply with the TRE protocol, the TRE group showed significantly lower mean FPG, HbA1c, and fasting insulin levels compared to the usual care group. Our results did not show significant differences in body weight, blood sugar, fasting insulin, or lipid profiles between TRE plus BE interventions, TRE alone, and usual care groups. However, TRE might be an effective intervention in lowering blood sugar levels for IFG patients who were able to adhere to the TRE protocol.

Efficacy of anti-tuberculosis drugs for the treatment of latent tuberculosis infection: a systematic review and network meta-analysis.

Despite the availability of three network meta-analyses (NMA) examining the efficacy, treatment completion, and adverse events associated with all latent tuberculosis infection (LTBI) treatments, there is currently no evidence to support the notion that the benefits of these treatments outweigh the potential risks. This NMA aimed to conduct a comprehensive comparison and update of the efficacy, treatment completion rates and adverse events associated with recommended treatment options for LTBI for individuals with confirmed LTBI, as outlined in the 2020 World Health Organization (WHO) Consolidated Guidelines for TB preventive treatment. A comprehensive search of the MEDLINE and Scopus databases was conducted until April 2023. The NMA was applied to estimate the risk difference and corresponding 95% confidence interval (CI) using a combination of direct and indirect evidence. The risk-benefit assessment was employed to evaluate the feasibility of the extra benefits in relation to the extra risks. The primary outcomes of interest in this study were active TB disease, completion rates, and adverse events. The meta-analysis incorporated data from 15 studies, which collectively demonstrated that the administration of a placebo resulted in a significant increase in the risk of developing TB disease by 1.279%, compared to the daily intake of isoniazid for 6 months (6H). Furthermore, treatment completion rates were significantly higher when using isoniazid plus rifapentine weekly for 3 months (3HP) and rifampicin daily for 4 months (4R), as compared to 6H. Considering adverse events, the combination of 3HP, 4R, and isoniazid administered daily for 9 months (referred to as 9H) significantly decreased adverse events by 4.53% in comparison to 6H. The risk-benefit assessment showed that alternative treatment regimens (9H, 4R, 3HR and 3HP) had a lower incidence of adverse events, while demonstrating a higher efficacy in preventing TB, as compared to 6H. This review indicates that there were no significant differences observed among various active treatment options in terms of their efficacy in preventing active TB. Moreover, completion rates were higher in 3HP and 4R, and a reduction in adverse events was observed in 3HP, 4R, and 9H.

Prevalence of Intestinal Parasitic Infections, Genotypes, and Drug Susceptibility of Giardia lamblia among Preschool and School-Aged Children: A Cross-Sectional Study in Thailand.

This study aimed to estimate the prevalence of intestinal parasitic infections in children and assess the drug susceptibility and genotypes/assemblages of Giardia lamblia in Thailand. This cross-sectional study was conducted among children aged 3-12 years in Sangkhlaburi District, Kanchanaburi Province, Thailand, between 25 September 2017 and 12 January 2018. Parasites were identified by stool microscopic examination, cultivation of intestinal parasitic protozoa, and enzyme-linked immunosorbent assay (ELISA). Drug susceptibility and genotype of G. lamblia were performed, respectively, by a resazurin assay and Triosephosphate Isomerase A and B genes using modified primers and probes. Among the 661 participants, 445 had an intestinal parasitic infection, resulting in a prevalence of 67.32% (95% CI: 63.60-70.89%). Blastocystis hominis was the most prevalent protozoa infection (49.32%; 95% CI: 45.44-53.22%), while Ascaris lumbricoides was the most prevalent helminth infection (0.91%; 95% CI: 0.33-1.97%). The prevalence of G. lamblia was 17.40%, with genotype B being the most common. According to our study, intestinal parasitic infections were commonly found in Thai children. G. lamblia was the most common pathogenic protozoa infection identified and exhibited less susceptibility to metronidazole compared to furazolidone and mebendazole.

New anti-diabetic agents for the treatment of non-alcoholic fatty liver disease: a systematic review and network meta-analysis of randomized controlled trials.

Objectives: This network meta-analysis aims to compare the efficacy and safety of new anti-diabetic medications for the treatment of non-alcoholic fatty liver disease (NAFLD). Materials and methods: PubMed and Scopus were searched from inception to 27th March 2022 to identify all randomized controlled trials (RCTs) in NAFLD patients. Outcomes included reductions in intrahepatic steatosis (IHS) and liver enzyme levels. The efficacy and safety of DPP-4 inhibitors, GLP-1 agonists, SGLT-2 inhibitors, and other therapies were indirectly compared using a NMA approach. Unstandardized mean difference (USMD) with 95% confidence intervals (CI) were calculated. Results: 2,252 patients from 31 RCTs were included. "Add-on" GLP-1 agonists with standard of care (SoC) treatment showed significantly reduced IHS compared to SoC alone [USMD (95%CI) -3.93% (-6.54%, -1.33%)]. Surface under the cumulative ranking curve (SUCRA) identified GLP-1 receptor agonists with the highest probability to reduce IHS (SUCRA 88.5%), followed by DPP-4 inhibitors (SUCRA 69.6%) and pioglitazone (SUCRA 62.2%). "Add-on" GLP-1 receptor agonists were also the most effective treatment for reducing liver enzyme levels; AST [USMD of -5.04 (-8.46, -1.62)], ALT [USMD of -9.84 (-16.84, -2.85)] and GGT [USMD of -15.53 (-22.09, -8.97)] compared to SoC alone. However, GLP-1 agonists were most likely to be associated with an adverse event compared to other interventions. Conclusion: GLP-1 agonists may represent the most promising anti-diabetic treatment to reduce hepatic steatosis and liver enzyme activity in T2DM and NAFLD patients. Nevertheless, longer-term studies are required to determine whether this delays progression of liver cirrhosis in patients with NAFLD and T2DM. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021259336.1.

Efficacy of drug treatment for severe melioidosis and eradication treatment of melioidosis: A systematic review and network meta-analysis.

BACKGROUND: This systematic review and network meta-analysis (NMA) aimed to compare the efficacy of all available treatments for severe melioidosis in decreasing hospital mortality and to identify eradication therapies with low disease recurrence rates and minimal risk of adverse drug events (AEs). METHODOLOGY: Relevant randomized controlled trials (RCT) were searched from Medline and Scopus databases from their inception until July 31, 2022. RCTs that compared the efficacy between treatment regimens for severe melioidosis or eradication therapy of melioidosis, measured outcomes of in-hospital mortality, disease recurrence, drug discontinuation, or AEs, were included for review. A two-stage NMA with the surface under the cumulative ranking curve (SUCRA) was used to estimate the comparative efficacy of treatment regimens. PRINCIPAL FINDINGS: Fourteen RCTs were included in the review. Ceftazidime plus granulocyte colony-stimulating factor (G-CSF), ceftazidime plus trimethoprim-sulfamethoxazole (TMP-SMX), and cefoperazone-sulbactam plus TMP-SMX had a lower mortality rate than other treatments and were ranked as the top three most appropriate treatments for severe melioidosis with the SUCRA of 79.7%, 66.6%, and 55.7%, respectively. However, these results were not statistically significant. For eradication therapy, treatment with doxycycline monotherapy for 20 weeks was associated with a significantly higher risk of disease recurrence than regimens containing TMP-SMX (i.e.,TMP-SMX for 20 weeks, TMP-SMX plus doxycycline plus chloramphenicol for more than 12 weeks, and TMP-SMX plus doxycycline for more than 12 weeks). According to the SUCRA, TMP-SMX for 20 weeks was ranked as the most efficacious eradication treatment (87.7%) with the lowest chance of drug discontinuation (86.4%), while TMP-SMX for 12 weeks had the lowest risk of AEs (95.6%). CONCLUSION: Our results found a non-significant benefit of ceftazidime plus G-CSF and ceftazidime plus TMP-SMX over other treatments for severe melioidosis. TMP-SMX for 20 weeks was associated with a lower recurrence rate and minimal risk of adverse drug events compared to other eradication treatments. However, the validity of our NMA may be compromised by the limited number of included studies and discrepancies in certain study parameters. Thus, additional well-designed RCTs are needed to improve the therapy of melioidosis.

The association between rest-activity parameters and hemoglobin A1c in patients with prediabetes.

Circadian abnormalities can adversely affect glucose metabolism. This study determined whether behavioral circadian parameters, as assessed by rest-activity rhythm, were predictors of glycemic control in patients with prediabetes. Seventy-nine patients with prediabetes participated. Nonparametric rest-activity rhythm parameters, sleep duration and efficiency were obtained from 7-d actigraphy recordings. Sleep-disordered breathing severity was assessed using a home sleep apnea test. Hemoglobin A1c (HbA1c) was obtained to evaluate glycemic control. The results revealed that shorter sleep duration, lower relative amplitude and higher L5 (average activity of the least active 5-h period) were associated with higher HbA1c, while other sleep variables were not related to HbA1c. Multiple stepwise regression analysis adjusting for age, sex, body mass index and sleep duration revealed that lower relative amplitude, but not L5, was independently associated with higher HbA1c (B = -0.027, p = 0.031). In summary, among patients with prediabetes, an abnormal circadian rhythm was associated with higher HbA1c, implying a greater risk of developing diabetes. These results support the role of circadian rhythmicity in glucose control among those with prediabetes.

Comparison of diagnostic accuracy for diabetes diagnosis: A systematic review and network meta-analysis.

Aim: Fasting Plasma Glucose (FPG) and Hemoglobin A1c (HbA1c) are used as diagnostic tests for diagnosing diabetes mellitus, but it is unclear which test has the best diagnostic accuracy. This systematic review and network meta-analysis aimed to estimate the diagnostic accuracy of HbA1c ≥ 6.5%, FPG ≥ 126 mg/dl, and the combination of HbA1c ≥ 6.5% or FPG ≥ 126 mg/dl (HbA1c| FPG), compared with Oral Glucose Tolerance Test (OGTT) ≥ 200 mg/dl for diagnosis diabetes. Materials and methods: We performed a comprehensive search in PubMed, Embase, Cochrane Library, and Scopus from inception to September 24th, 2021. Inclusion criteria were any study design comparing HbA1c ≥ 6.5%, FPG ≥ 126 mg/dl, and HbA1c ≥ 6.5% or FPG ≥ 126 mg/dl with OGTT ≥ 200 mg/dl as the reference test. Data were independently extracted, risk of bias was assessed using QUADAS-2 by two reviewers. Network meta-analysis was done using a bivariate regression model using the Bayesian framework. The relative ranking of all tests was also assessed. Results: Out of 5,026 studies, 73 were included. The sensitivities of HbA1c, FPG, and HbA1c| FPG were 0.51 [95% Credible Interval (CrI): 0.43, 0.58], 0.49 (95% CrI: 0.43, 0.55), and 0.64 (95% CrI: 0.51, 0.75), while the specificities were 0.96 (95% CrI: 0.94, 0.97), 0.98 (95% CrI: 0.97, 0.98), and 0.95 (95% CrI: 0.88, 0.98), respectively. The corresponding positive likelihood ratios (LR) were 13.36 (95% CrI: 8.91, 20.72), 21.94 (95% CrI: 15.04, 31.88), and 11.78 (95% CrI: 5.48, 26.56). HbA1c| FPG is superior based on sensitivity, whereas FPG is ranked best based on specificity and positive LR. Conclusion: Our findings suggest that FPG ≥ 126 mg/dl should be recommended as the best diagnostic test for diabetes. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021282856.

Which interventions for alcohol use should be included in a universal healthcare benefit package? An umbrella review of targeted interventions to address harmful drinking and dependence.

BACKGROUND: This study aimed to identify targeted interventions for the prevention and treatment of harmful alcohol use. Umbrella review methodology was used to summarise the effectiveness across a broad range of interventions, in order to identify which interventions should be considered for inclusion within universal health coverage schemes in low- and middle-income countries. METHODS AND FINDINGS: We included systematic reviews with meta-analysis of randomised controlled trials (RCTs) on targeted interventions addressing alcohol use in harmful drinkers or individuals with alcohol use disorder. We only included outcomes related to alcohol consumption, heavy drinking, binge drinking, abstinence, or alcohol-attributable accident, injury, morbidity or mortality. PubMed, Embase, PsycINFO, Cochrane Database of Systematic Reviews, and the International HTA Database were searched from inception to 3 September 2021. Risk of bias of reviews was assessed using the AMSTAR2 tool. After reviewing the abstracts of 9,167 articles, results were summarised narratively and certainty in the body of evidence for each intervention was assessed using GRADE. In total, 86 studies met the inclusion criteria, of which the majority reported outcomes for brief intervention (30 studies) or pharmacological interventions (29 studies). Overall, methodological quality of included studies was low. CONCLUSIONS: For harmful drinking, brief interventions, cognitive behavioural therapy, and motivational interviewing showed a small effect, whereas mentoring in adolescents and children may have a significant long-term effect. For alcohol use disorder, social network approaches and acamprosate showed evidence of a significant and durable effect. More evidence is required on the effectiveness of gamma-hydroxybutyric acid (GHB), nalmefene, and quetiapine, as well as optimal combinations of pharmacological and psychosocial interventions. As an umbrella review, we were unable to identify the extent to which variation between studies stemmed from differences in intervention delivery or variation between country contexts. Further research is required on applicability of findings across settings and best practice for implementation. Funded by the Thai Health Promotion Foundation, grant number 61-00-1812.

The efficacy of gait rehabilitations for the treatment of incomplete spinal cord injury: a systematic review and network meta-analysis.

BACKGROUND: Recent pieces of evidence about the efficacy of gait rehabilitation for incomplete spinal cord injury remain unclear. We aimed to estimate the treatment effect and find the best gait rehabilitation to regain velocity, distance, and Walking Index Spinal Cord Injury (WISCI) among incomplete spinal cord injury patients. METHOD: PubMed and Scopus databases were searched from inception to October 2022. Randomized controlled trials (RCTs) were included in comparison with any of the following: conventional physical therapy, treadmill, functional electrical stimulation and robotic-assisted gait training, and reported at least one outcome. Two reviewers independently selected the studies and extracted the data. Meta-analysis was performed using random-effects or fixed-effect model according to the heterogeneity. Network meta-analysis (NMA) was indirectly compared with all interventions and reported as pooled unstandardized mean difference (USMD) and 95% confidence interval (CI). Surface under the cumulative ranking curve (SUCRA) was calculated to identify the best intervention. RESULTS: We included 17 RCTs (709 participants) with the mean age of 43.9 years. Acute-phase robotic-assisted gait training significantly improved the velocity (USMD 0.1 m/s, 95% CI 0.05, 0.14), distance (USMD 64.75 m, 95% CI 27.24, 102.27), and WISCI (USMD 3.28, 95% CI 0.12, 6.45) compared to conventional physical therapy. In NMA, functional electrical stimulation had the highest probability of being the best intervention for velocity (66.6%, SUCRA 82.1) and distance (39.7%, SUCRA 67.4), followed by treadmill, functional electrical stimulation plus treadmill, robotic-assisted gait training, and conventional physical therapy, respectively. CONCLUSION: Functional electrical stimulation seems to be the best treatment to improve walking velocity and distance for incomplete spinal cord injury patients. However, a large-scale RCT is required to study the adverse events of these interventions. TRIAL REGISTRATION: PROSPERO number CRD42019145797.

A study of the factors associated with emergency department visits in advanced cancer patients receiving palliative care.

PURPOSE: Several studies demonstrated that cancer patients visited the emergency department (ED) frequently. This indicates unmet needs and poor-quality palliative care. We aimed to investigate the factors that contribute to ED visits among patients with advanced cancer in order to identify strategies for reducing unnecessary ED visits among these patients. METHODS: A retrospective study was conducted between January and December, 2019. Eligible patients were previously enrolled in the comprehensive palliative care program prior to their ED visit. All patients older than 18 were included. Patients were excluded if they had died at the initial consultation, were referred to other programs at the initial consultation, or had an incomplete record. The trial ended when the patients died, were referred to other palliative programs, or the study ended. The time between the initial palliative consultation and study endpoints was categorized into three groups: 16 days, 16-100 days, and > 100 days, based on the literature review. To investigate the factors associated with ED visits, a logistic regression analysis was conducted. The variables with a P value < 0.15 from the univariate logistic regression analysis were included in the multiple logistic regression analysis. RESULTS: Among a total of 227 patients, 93 visited the ED and 134 did not. Mean age was 65.5 years. Most prevalent cancers were colorectal (18.5%), lung (16.3%), and hepatobiliary (11.9%). At the end, 146 patients died, 45 were alive, nine were referred to other programs, and 27 were lost to follow-up. In univariate logistic regression analysis, patients with > 100 days from palliative consultation (OR 0.23; 95%CI 0.08, 0.66; p-value 0.01) were less likely to attend the ED. In contrast, PPS 50-90% (OR 2.02; 95%CI 1.18, 3.47; p-value 0.01) increased the ED visits. In the multiple logistic regression analysis, these two factors remained associated with ED visits:> 100 days from the palliative consultation (OR 0.18; 95%CI 0.06, 0.55; p-value 0.01) and PPS 50-90% (OR 2.62; 95%CI 1.44, 4.79; p-value 0.01). CONCLUSIONS: There was reduced ED utilization among cancer patients with > 100 days of palliative care. Patients having a lower PPS were associated with a lower risk of ED visits.

Prevention of salivary gland dysfunction in patients treated with radioiodine for differentiated thyroid cancer: A systematic review of randomized controlled trials.

Introduction: Salivary gland dysfunction (e.g., sialadenitis and xerostomia) is the most common complication of radioactive iodine (RAI) therapy for differentiated thyroid cancer (DTC). Several methods have been used to reduce/prevent this adverse effect. We aimed to systematically review the effectiveness of non-pharmacological and pharmacological interventions in preventing RAI-induced salivary gland dysfunction in patients with DTC. Methods: A systematic review was conducted, according to PRISMA guidelines. The protocol was registered (PROSPERO: CRD42022295229). PubMed, Embase, Scopus, and the Cochrane Library electronic databases were searched from inception to November 2021. Inclusion criteria were randomized controlled trials of DTC patients who were older than 18 years and underwent RAI after thyroidectomy in which at least one studied group received an intervention to prevent salivary gland dysfunction. Results: Twelve studies (a total of 667 participants) were included. Among DTC patients who were treated with RAI, nonpharmacological treatment such as parotid gland massage and aromatherapy ameliorated salivary gland dysfunction. Antioxidants such as vitamin E and selenium demonstrated radioprotective effects on the salivary gland, while other antioxidants did not show radioprotective benefits. Vitamin C showed no significant effects on preventing salivary gland dysfunction. Amifostine had inconsistent outcomes among studies. Among cholinergic agonists, pilocarpine did not demonstrate the radioprotective effect on parotid glands, while bethanechol lowered salivary gland dysfunction. However, the negative results from pilocarpine may be explained by the strong sialorrheic effect of the Cincinnati regimen in both study arms. Conclusion: Among non-pharmacological and pharmacological methods, parotid gland massage, aromatherapy, vitamin E, selenium, amifostine, and bethanechol may have benefits in minimizing RAI-induced salivary gland dysfunction in patients with DTC. The results are limited by a small number of patients and should be confirmed in future larger randomized controlled trials. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=295229, PROSPERO, identifier CRD42022295229.

Efficacy of time-restricted eating and behavioural economic interventions in reducing fasting plasma glucose, HbA1c and cardiometabolic risk factors compared with time-restricted eating alone or usual care in patients with impaired fasting glucose: protocol for an open-label randomised controlled trial.

INTRODUCTION: Impaired fasting glucose (IFG) is a significant risk factor for diabetes mellitus. Time-restricted eating (TRE) is one type of diet showing positive effects on metabolic signal pathways. However, effects of TRE on cardiometabolic risk factors in humans are limited. Additionally, compliance with TRE remains problematic despite having intention to follow the diet control. Therefore, this study aims to investigate the efficacy of TRE with behavioural economic interventions or TRE alone relative to usual care, in reducing fasting plasma glucose (FPG), haemoglobin A1c (HbA1c) and other cardiometabolic risk factors in patients with IFG. METHODS AND ANALYSIS: This parallel-group, open-label randomised controlled trial will be conducted at the outpatient clinic of the Department of Family Medicine, Faculty of Medicine, Ramathibodi Hospital, Bangkok, Thailand. Patients aged 18-65 years with IFG defined as FPG 100-125 mg/dL and body mass index ≥25 kg/m2 will be recruited between October 2021 and October 2022. Patients will be randomly allocated to three groups (1:1:1 ratio) as (1) TRE with behavioural economic interventions including financial incentives and text reminders, (2) TRE alone or (3) usual care. The number of participants will be 38 per group (a total of 114). The duration of the intervention will be 12 weeks. Primary outcome is FPG levels measured at 12 weeks after randomisation. Secondary outcomes are HbA1c, body weight, systolic and diastolic blood pressure, fasting insulin, serum triglyceride, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and high-sensitivity C reactive protein. P value of <0.05 of two-sided test will be considered as statistical significance. ETHICS AND DISSEMINATION: The study protocol has been approved by the Ethics Committee of the Faculty of Medicine, Ramathibodi Hospital, Mahidol University (MURA2021/389). All patients will be informed about the details of the study and sign written informed consent before enrollment in the study. Results from this study will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: TCTR20210520002.

Assessing the cost-effectiveness of precision medicine: protocol for a systematic review and meta-analysis.

INTRODUCTION: Precision medicine (PM) involves gene testing to identify disease risk, enable early diagnosis or guide therapeutic choice, and targeted gene therapy. We aim to perform a systematic review and meta-analysis to quantify the cost-effectiveness profile of PM stratified by intervention type, identify sources of heterogeneity in the value-for-money of PM. METHODS AND ANALYSIS: We will perform a systematic search in Embase, MEDLINE, EconLit and CRD databases for studies published in English language or with translation in English between 1 January 2011 and 8 July 2021 on the topic of cost-effectiveness analysis of PM interventions. The focus will be on studies that reported health and economic outcomes. Study quality will be assessed using the Biases in Economic Studies checklist. The incremental net benefit of PM screening, diagnostic, treatment-targeting and therapeutic interventions over conventional strategies will be respectively pooled across studies using a random-effect model if heterogeneity is present, otherwise a fixed-effect model. Subgroup analyses will be performed based on disease area, WHO region and World Bank country-income level. Additionally, we will identify the potential sources of heterogeneity with random-effect meta-regressions. Finally, biases will be detected using jackknife sensitivity analysis, funnel plot assessment and Egger's tests. ETHICS AND DISSEMINATION: For this type of study ethics approval or formal consent is not required. The results will be disseminated at various presentations and feedback sessions, in conference abstracts and manuscripts that will be submitted to peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42021272956.

Comparative efficacy and safety of pharmacologic interventions to prevent mother-to-child transmission of hepatitis B virus: a systematic review and network meta-analysis.

OBJECTIVE: This study investigated the efficacy and safety of pharmacologic interventions to prevent vertical transmission of the hepatitis B virus. DATA SOURCES: Medline, Cochrane, and Scopus databases were searched up to October 28, 2020. STUDY ELIGIBILITY CRITERIA: All randomized controlled trials reporting vertical hepatitis B virus transmission with pharmacologic intervention were included. METHODS: Risk of bias was assessed using the Cochrane Risk-of-Bias tool, version 2. Treatment efficacy was estimated using stratified network meta-analysis on the basis of maternal hepatitis B envelope antigen status. RESULTS: Nineteen studies were included for mothers positive for hepatitis B surface and envelope antigens. Pooling indicated that a combination of hepatitis B vaccination and hepatitis B immunoglobulin in infants significantly reduced transmission risk compared with vaccination alone, with a risk ratio of 0.52 (95% confidence interval; 0.30-0.91). Only the addition of maternal tenofovir disoproxil fumarate, but not telbivudine, lamivudine, or maternal hepatitis B immunoglobulin further reduced transmission risk compared with a combination of hepatitis B vaccination and hepatitis B immunoglobulin in infants, with a pooled risk ratio of 0.10 (0.03-0.35). Twelve studies conducted in mothers with hepatitis B surface antigen positivity and mixed, unknown, or negative hepatitis B envelope antigen status provided limited evidence to suggest that maternal hepatitis B immunoglobulin combined with hepatitis B vaccination and immunoglobulin in infants was the likely best treatment, but this failed to reach statistical significance compared with a combination of hepatitis B vaccination and immunoglobulin in infants. Similarly, infant hepatitis B immunoglobulin, added to vaccination, likely provides additional benefit but failed to reach statistical significance. CONCLUSION: A combination of hepatitis B vaccination and immunoglobulin in infants is the cornerstone for prevention of vertical transmission for mothers positive for both hepatitis B surface and envelope antigens. The addition of maternal tenofovir to this infant combination regimen was considered the likely most effective treatment. For infants of mothers with hepatitis B surface antigen positivity and mixed, unknown, or negative hepatitis B envelop antigen status, no additional agents provided further benefit beyond hepatitis B vaccination alone.

Neoadjuvant Treatment with HER2-Targeted Therapies in HER2-Positive Breast Cancer: A Systematic Review and Network Meta-Analysis.

This systematic review aimed to identify neoadjuvant anti-human epidermal growth factor receptor 2 (HER2) therapies with the best balance between efficacy and safety. METHODS: A network meta-analysis was applied to estimate the risk ratios along with 95% confidence intervals (CIs) for pathological complete response (pCR) and serious adverse events (SAE). A mixed-effect parametric survival analysis was conducted to assess the disease-free survival (DFS) between treatments. RESULTS: Twenty-one RCTs with eleven regimens of neoadjuvant anti-HER2 therapy (i.e., trastuzumab + chemotherapy (TC), lapatinib + chemotherapy (LC), pertuzumab + chemotherapy (PC), pertuzumab + trastuzumab (PT), trastuzumab emtansine + pertuzumab (T-DM1P), pertuzumab + trastuzumab + chemotherapy (PTC), lapatinib + trastuzumab + chemotherapy (LTC), trastuzumab emtansine + lapatinib + chemotherapy (T-DM1LC), trastuzumab emtansine + pertuzumab + chemotherapy(T-DM1PC), PTC followed by T-DM1P (PTC_T-DM1P), and trastuzumab emtansine (T-DM1)) and chemotherapy alone were included. When compared to TC, only PTC had a significantly higher DFS with a hazard ratio (95% CI) of 0.54 (0.32-0.91). The surface under the cumulative ranking curve (SUCRA) suggested that T-DM1LC (91.9%) was ranked first in achieving pCR, followed by the PTC_T-DM1P (90.5%), PTC (74.8%), and T-DM1PC (73.5%) regimens. For SAEs, LTC, LC, and T-DM1LC presented with the highest risks (SUCRA = 10.7%, 16.8%, and 20.8%), while PT (99.2%), T-DM1P (88%), and T-DM1 (83.9%) were the safest regimens. The T-DM1PC (73.5% vs. 71.6%), T-DM1 (70.5% vs. 83.9%), and PTC_T-DM1P (90.5% vs. 47.3%) regimens offered the optimal balance between pCR and SAE. CONCLUSIONS: The T-DM1PC, T-DM1, and PTC_T-DM1P regimens had the optimal balance between efficacy and safety, while DFS was highest for the PTC regimen. However, these results were based on a small number of studies, and additional RCTs assessing the efficacy of regimens with T-DM1 are still needed to confirm these findings.

Drug treatment for panic disorder with or without agoraphobia: systematic review and network meta-analysis of randomised controlled trials.

OBJECTIVE: To identify drug classes and individual selective serotonin reuptake inhibitors (SSRIs) with high rates of remission and low risk of adverse events in the treatment of panic disorder with or without agoraphobia. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Embase, Medline, and ClinicalTrials.gov from inception to 17 June 2021. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Randomised controlled trials that included adults aged ≥18 years with a diagnosis of panic disorder, compared drugs used to treat the panic disorder, and measured the outcomes of interest, including remissions, dropouts, and adverse events. METHODS: Risk of bias in the included studies was assessed using the revised Cochrane risk of bias tool for randomised trials. Direct meta-analyses were performed using random effects models. A two stage network meta-analysis with surface under the cumulative ranking curve (SUCRA) was used to estimate the comparative efficacy of drug classes and individual SSRIs. RESULTS: 87 studies including a total of 12 800 participants and 12 drug classes were eligible for inclusion. Almost all the studies (86/87) had some concern or were at high risk of bias. Network meta-analysis of remission with consistent results indicated that tricyclic antidepressants, benzodiazepines, monoamine oxidase inhibitors, SSRIs, and serotonin-noradrenaline reuptake inhibitors (SNRIs) were associated with significantly higher remission rates than placebo, with risk ratios of 1.39 (95% confidence interval 1.26 to 1.54), 1.47 (1.36 to 1.60), 1.30 (1.00 to 1.69), 1.38 (1.26 to 1.50), and 1.27 (1.12 to 1.45), respectively. SUCRAs identified benzodiazepines (84.5%, mean rank=2.4), tricyclic antidepressants (68.7%, 3.8), and SSRIs (66.4%, 4.0) as the top three best treatments for remission. However, tricyclic antidepressants, benzodiazepines, and SSRIs were also significantly associated with increased risk of adverse events compared with placebo, with risk ratios of 1.79 (1.47 to 2.19), 1.76 (1.50 to 2.06), and 1.19 (1.01 to 1.41), respectively. Consistency assumption of adverse events was upheld but could still be present on removal of studies with high percentages of women participants and those with agoraphobia. A SUCRA cluster ranking plot considering both remission and adverse events among all drug classes indicated that SSRIs were associated with high remission and low risk of adverse events. Among individual SSRIs, sertraline and escitalopram provided high remission with an acceptable risk of adverse events. CONCLUSION: The findings suggest that SSRIs provide high rates of remission with low risk of adverse events for the treatment of panic disorder. Among SSRIs, sertraline and escitalopram were associated with high remission and low risk of adverse events. The findings were, however, based on studies of moderate to very low certainty levels of evidence, mostly as a result of within study bias, inconsistency, and imprecision of the findings reported. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020180638.

A systematic review of methodological approaches for evaluating real-world effectiveness of COVID-19 vaccines: Advising resource-constrained settings.

Real-world effectiveness studies are important for monitoring performance of COVID-19 vaccination programmes and informing COVID-19 prevention and control policies. We aimed to synthesise methodological approaches used in COVID-19 vaccine effectiveness studies, in order to evaluate which approaches are most appropriate to implement in low- and middle-income countries (LMICs). For this rapid systematic review, we searched PubMed and Scopus for articles published from inception to July 7, 2021, without language restrictions. We included any type of peer-reviewed observational study measuring COVID-19 vaccine effectiveness, for any population. We excluded randomised control trials and modelling studies. All data used in the analysis were extracted from included papers. We used a standardised data extraction form, modified from STrengthening the Reporting of OBservational studies in Epidemiology (STROBE). Study quality was assessed using the REal Life EVidence AssessmeNt Tool (RELEVANT) tool. This study is registered with PROSPERO, CRD42021264658. Our search identified 3,327 studies, of which 42 were eligible for analysis. Most studies (97.5%) were conducted in high-income countries and the majority assessed mRNA vaccines (78% mRNA only, 17% mRNA and viral vector, 2.5% viral vector, 2.5% inactivated vaccine). Thirty-five of the studies (83%) used a cohort study design. Across studies, short follow-up time and limited assessment and mitigation of potential confounders, including previous SARS-CoV-2 infection and healthcare seeking behaviour, were major limitations. This review summarises methodological approaches for evaluating real-world effectiveness of COVID-19 vaccines and highlights the lack of such studies in LMICs, as well as the importance of context-specific vaccine effectiveness data. Further research in LMICs will refine guidance for conducting real-world COVID-19 vaccine effectiveness studies in resource-constrained settings.

Association of Hormonal Contraceptive Use With Adverse Health Outcomes: An Umbrella Review of Meta-analyses of Randomized Clinical Trials and Cohort Studies.

Importance: Meta-analyses have reported conflicting data on the safety of hormonal contraception, but the quality of evidence for the associations between hormonal contraceptive use and adverse health outcomes has not been quantified in aggregate. Objective: To grade the evidence from meta-analyses of randomized clinical trials (RCTs) and cohort studies that assessed the associations between hormonal contraceptive use and adverse health outcomes among women. Data Sources: MEDLINE, Embase, and the Cochrane Database of Systematic Reviews were searched from database inception to August 2020. Search terms included hormonal contraception, contraceptive agents, progesterone, desogestrel, norethindrone, megestrol, algestone, norprogesterones, and levonorgestrel combined with terms such as systematic review or meta-analysis. Evidence Review: The methodological quality of each meta-analysis was graded using the Assessment of Multiple Systematic Reviews, version 2, which rated quality as critically low, low, moderate, or high. The Grading of Recommendation, Assessment, Development and Evaluations approach was used to assess the certainty of evidence in meta-analyses of RCTs, with evidence graded as very low, low, moderate, or high. Evidence of associations from meta-analyses of cohort studies was ranked according to established criteria as nonsignificant, weak, suggestive, highly suggestive, or convincing. Results: A total of 2996 records were screened; of those, 310 full-text articles were assessed for eligibility, and 58 articles (13 meta-analyses of RCTs and 45 meta-analyses of cohort studies) were selected for evidence synthesis. Sixty associations were described in meta-analyses of RCTs, and 96 associations were described in meta-analyses of cohort studies. Among meta-analyses of RCTs, 14 of the 60 associations were nominally statistically significant (P ≤ .05); no associations between hormonal contraceptive use and adverse outcomes were supported by high-quality evidence. The association between the use of a levonorgestrel-releasing intrauterine system and reductions in endometrial polyps associated with tamoxifen use (odds ratio [OR], 0.22; 95% CI, 0.13-0.38) was graded as having high-quality evidence, and this evidence ranking was retained in the subgroup analysis. Among meta-analyses of cohort studies, 40 of the 96 associations were nominally statistically significant; however, no associations between hormonal contraceptive use and adverse outcomes were supported by convincing evidence in the primary and subgroup analyses. The risk of venous thromboembolism among those using vs not using oral contraception (OR, 2.42; 95% CI, 1.76-3.32) was initially supported by highly suggestive evidence, but this evidence was downgraded to weak in the sensitivity analysis. Conclusions And Relevance: The results of this umbrella review supported preexisting understandings of the risks and benefits associated with hormonal contraceptive use. Overall, the associations between hormonal contraceptive use and cardiovascular risk, cancer risk, and other major adverse health outcomes were not supported by high-quality evidence.