The Influence of Stakeholder Interests on Safety Outcome Reporting in Psychedelic Research and Implications for Science Communication.

Psychedelics are a group of psychoactive substances which produce complex and subjective changes to consciousness and carry unique safety considerations. There is a growing body of work investigating the use of psychedelics for mental health treatment alongside increasing socio-cultural and political acceptance. This rapid evolution has prompted corporations to fund psychedelic clinical trials, leading to a potential rise in conflicts of interest in relevant studies and publications. However, the body of evidence for the safety and efficacy of psychedelic-assisted psychotherapy for psychiatric illnesses is early. There is concern regarding the introduction of bias in psychedelic clinical trials and the selective reporting of results amidst and beyond corporate involvement. At a crucial time in psychedelic drug reform, this paper explores the safety concerns associated with psychedelics, the potential influences of financial stakeholders on safety outcome reporting and the importance of balanced science communication in maintaining public health and safety.

Periodontal evaluation after maxillary expansion with a tooth-bone-borne expander in growing patients : A randomized clinical trial.

PURPOSE: This two-arm parallel randomized controlled trial aimed to evaluate and compare periodontal changes due to rapid maxillary expansion (RME) using tooth-bone-borne and tooth-borne devices in growing patients via clinical examinations and cone-beam computed tomography (CBCT). MATERIALS AND METHODS: Forty-two eligible patients (aged 11-14 years; transverse maxillary deficiency, posterior crossbite) were screened and divided into two groups based on the treatment received (randomization was performed using computer-generated numeric sequences): hybrid hyrax tooth-bone-borne group (TBB) and hyrax tooth-borne group (TB). The primary outcome was the change in cortical bone thickness (by CBCT). In addition, the clinical attachment level (CAL), gingival recession, and bleeding were assessed. Both examinations were performed before and 3 months after the activation phase. Intergroup comparisons were performed using analysis of covariance (ANCOVA; P < 0.05). RESULTS: Twenty-one patients (12 girls and 9 boys; mean initial age, 13.3 years) were included in the TBB group and 21 (5 girls and 16 boys; mean initial age, 13.2 years) were included in the TB group. The TB group exhibited a decrease in buccal bone thickness in the first premolars and first molars at all three evaluated levels. Specifically, tooth 14 at 3 mm from the enamel-cement junction showed a significant width reduction (0.7 mm; p < 0.001), accompanied by a notable increase in palatal cortical thickness at 6 mm of enamel-cement junction (1.13 mm; p < 0.001). CONCLUSIONS: RME resulted in buccal bone thickness reduction at the first premolar with hyrax treatment. In the molar region, both devices resulted in cortical bone alterations that were less pronounced in the TBB group.

Representation of Low- and Middle-Income Countries in CKD Drug Trials: A Systematic Review.

RATIONALE & OBJECTIVE: Almost 80% of individuals with chronic kidney disease (CKD) reside in low- and middle-income countries (LMICs) and are potentially underrepresented in randomized controlled clinical trials (RCTs). We assessed the global distribution of RCTs comparing pharmacological treatments for CKD over the past 2 decades, as well as the magnitude and evolution of participation by LMICs. STUDY DESIGN: Systematic review. SETTING & STUDY POPULATIONS: RCTs evaluating pharmacological interventions in adults with CKD. SELECTION CRITERIA FOR STUDIES: RCTs published between 2003-2023 and indexed in MEDLINE. DATA EXTRACTION: Each trial was reviewed and extracted independently by 2 investigators with disagreements settled by consensus or a third reviewer. ANALYTICAL APPROACH: RCT participation of World Bank-defined income groups and geographic regions were described, and the representation indices (RI) according to RCT participants and estimated CKD prevalences were calculated. RCTs were also categorized as global, regional, or national in scope. RESULTS: Among 7,760 identified studies, we included 1,366 RCTs conducted in 84 countries with 301,158 participants. National, regional, and global RCTs represented 85.4%, 3.5%, and 11.1% of studies, respectively. LMICs were included in 34.7% of RCTs. No RCTs included participants from low-income countries, and lower-middle-income countries participated in 13.2%. Of participants from RCTs with available information, 25.4% (n=64,843 of 255,237) were from LMICs. According to the RI, 6 LMICs were overrepresented (>1.25), 7 were adequately represented (0.75-1.25), and 26 were underrepresented (<0.75). Most global CKD RCTs (80.2%) included LMICs; however, LMIC participants constituted only 32.9% of the global trial population. We observed a positive trend in LMIC inclusion over time, rising from 22.9% (n=71of 310) in 2003-2007 to 45.5% (n=140of 308) in 2018-2023. LIMITATIONS: The use of an income-group dichotomy, exclusion of nonrandomized studies of intervention, and studies identified in 1 database. CONCLUSIONS: Despite an increase in participation over the past 2 decades, individuals with CKD from LMICs remain significantly underrepresented in RCTs. These findings suggest that increased efforts are warranted to increase LMIC representation in pharmacological CKD RCTs. PLAIN-LANGUAGE SUMMARY: Chronic kidney disease (CKD) substantially affects people from low- and middle-income countries (LMICs). However, the participation of these countries in randomized controlled trials (RCTs) remains uncertain. To assess the global distribution and representation of these countries in kidney disease research, we reviewed 1,366 CKD drug RCTs published from 2003-2023, conducted in 84 countries involving more than 300,000 participants. LMICs were included in approximately a third of these studies, with their participants making up approximately one-quarter of the total; lower-middle-income countries were poorly represented, and low-income countries were absent. LMICs constituted a third of participants in multinational RCTs. Most LMICs were underrepresented relative to the prevalence of CKD. We observed an increasing inclusion of LMICs, particularly in the last decade. Nonetheless, individuals with CKD from LMICs remain underrepresented in drug RCTs, suggesting that increased efforts are warranted to include representation of these populations in these studies.

Efficacy and safety of 0.5% colchicine cream versus 5% 5-fluorouracil cream in the treatment of cutaneous field cancerization: a randomized clinical trial

Abstract Background 5-Fluorouracil (5-FU) is a first-line drug to treat cutaneous field cancerization (CFC). There are few clinical trials with topical colchicine (COL). Objective To evaluate the effectiveness of 0.5% COL cream versus 5% 5-FU cream in the treatment of CFC. Method This was a randomized, open, self-controlled clinical trial. Forty-five patients (90 forearms), with three to ten actinic keratoses (AK) on each forearm, used 0.5% COL cream 2×/day for seven days on one forearm, and 5% 5-FU cream 2× /day, for 21 days, on the other forearm. The dosages were defined based on previous clinical trials for each drug. Adverse effects were evaluated after 14 days and outcomes after 90 days of inclusion. The primary outcome was complete AK clearance and the secondary outcomes were: partial clearance (≥50%), reduction in AK count, assessment of the Forearm Photoaging Scale (FPS), AK Severity Score (AKSS), and adverse effects. Results After 90 days, there was complete clearance of AK in 37% (95% CI 24%-49%) and partial clearance in 85% (95% CI 76%-93%) of the forearms treated with 5-FU,versus 17% (95% CI 7%-27%) and 78% (95% CI 66%-88%) for COL (p > 0.07). There was a percentage reduction of 75% in the AK count of the forearms treated with 5-FU (95% CI 66%-83%) and 64% in those treated with COL (95% CI 55%-72%). Regarding FPS and AKSS, there was improvement in both groups, with no difference regarding FPS (p = 0.654), and 5-FU superiority for AKSS (p = 0.012). Study limitations Single-center study. Conclusions 5-FU and COL are effective for treating CFC, with neither showing superiority regarding the reduction in AK counts.

Clinical trial trends over the last 5 years among the BRICS (Brazil, Russia, India, China, and South Africa) nations.

Purpose: Although the Americas and Europe have historically dominated the global research landscape, emerging economies - Brazil, Russia, India, China, and South Africa (BRICS) have significantly increased their contributions in recent years. This article studies clinical trial trends in the BRICS nations between 2018 and 2022 and compares it with trends in the G7 nations (comprising Canada, France, Germany, Italy, Japan, the UK, the USA, and the European Union). This will help stakeholders in planning drug development strategies. Materials and Methods: Data were collected from the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and the World Bank database. An electronic search was done for the total number of trials registered between January 1, 2018, and March 15, 2023. Information was analyzed based on the year of registration, therapeutic area, type of intervention, sponsorship, and type of special population. The trial density indices (TDIs) were calculated based on population (Xi) and gross domestic product (GDP) (Yi) using author-derived formulae. Results: Altogether 2, 77, 536 trials from the BRICS and G7 were registered. China and the US had the most trials among the BRICS and G7, respectively. Between 2018 and 2022, the gap between the BRICS and G7 steadily reduced. The most common indication for clinical trials among the BRICS was cancer. Based on population, the TDI was the highest in China and the lowest in Russia. In proportion to the GDP, the TDI was maximum in Russia and minimum in India. Conclusion: There is a remarkable reduction in the gap in clinical trial trends between the BRICS and G7 nations. Among the BRICS, India and China are at the forefront in drug development. There is scope for improvement in trial density based on India's population and GDP. Stakeholders are likely to utilize the strengths of the BRICS as an attractive destination for investment in this area.

Strategies to promote contraception use by female volunteers in Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease (API ADAD) Colombia trial.

BACKGROUND/AIMS: Including women of childbearing age in a clinical trial makes it necessary to consider two factors from a bioethical perspective: first, the lack of knowledge about the potential teratogenic effects of an investigational product, and also, the principle of justice not to exclude any population from the benefits of research. The most common way to address this issue is by requiring volunteers to use contraceptives before, during, and a few weeks after the clinical trial. This work presents all the strategies used to promote contraception use and prevent pregnancy during the Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease (API ADAD) Colombia clinical trial. Two characteristics of this trial make it of special interest for closely monitoring contraception use. One is that the trial lasted more than 7 years, and the other is that participants could be carriers of the E280A PSEN1 mutation, leading to a mild cognitive impairment as early as their late 30s. METHODS: An individual medical evaluation to select the contraception method that best fits the volunteer was carried out during the screening visit, remitting to the gynecologist when necessary. All non-surgical contraception methods were supplied by the sponsor. Staff were trained on contraception counseling, correctly dispensing contraceptive drugs to volunteers, and identifying, reporting, and following up on pregnancies. Two comprehensive educational campaigns on contraception use were performed, and the intervention included all volunteers. In addition, volunteers were asked on an annual survey to evaluate the dispensing procedure. Finally, the effectiveness of these strategies was retrospectively evaluated, comparing by extrapolation the number of pregnancies presented throughout the trial with the General Fertility Rate in Colombia. RESULTS: A total of 159 female volunteers were recruited. All strategies were implemented as planned, even during the COVID-19 contingency. Ten pregnancies occurred during the evaluation period (2015-2021). Two were planned; the rest were associated with a potential therapeutic failure or incorrect use of contraceptive methods for a contraceptive failure of 0.49% per year. Sixty percent of pregnancies led to an abortion, either miscarriage or therapeutic abortion. However, there was not enough data to associate the pregnancy outcome with the administration of the investigational product. Finally, we observed a lower fertility rate in women participating in the trial compared to the Colombian population. CONCLUSION: The lower rates of contraceptive failure and the decrease in the incidence of pregnancies in women participating in the trial compared to the Colombian population across the 7 years of evaluation suggest that the strategies used in API ADAD Colombia were adequate and effective in addressing contraception use.

Monoclonal antibodies and aptamers: The future therapeutics for Alzheimer's disease.

Alzheimer's disease (AD) is considered the most common and prevalent form of dementia of adult-onset with characteristic progressive impairment in cognition and memory. The cure for AD has not been found yet and the treatments available until recently were only symptomatic. Regardless of multidisciplinary approaches and efforts made by pharmaceutical companies, it was only in the past two years that new drugs were approved for the treatment of the disease. Amyloid beta (Aß) immunotherapy is at the core of this therapy, which is one of the most innovative approaches looking to change the course of AD. This technology is based on synthetic peptides or monoclonal antibodies (mAb) to reduce Aß levels in the brain and slow down the advance of neurodegeneration. Hence, this article reviews the state of the art about AD neuropathogenesis, the traditional pharmacologic treatment, as well as the modern active and passive immunization describing approved drugs, and drug prototypes currently under investigation in different clinical trials. In addition, future perspectives on immunotherapeutic strategies for AD and the rise of the aptamer technology as a non-immunogenic alternative to curb the disease progression are discussed.

Cannabidiol and Alzheimer's disease.

Alzheimer's disease (AD) stands as the most prevalent form of neuropsychiatric disorder among the elderly population, impacting a minimum of 50 million individuals worldwide. Current pharmacological treatments rely on the prescribing cholinesterase inhibitors and memantine. However,recently anecdotal findings based on low-quality real-world data had prompted physicians, patients, and their relatives to consider the use of cannabinoids, especially Cannabidiol (CBD), for alleviating of AD symptoms. CBD the primary non-psychotomimetic compound found in the Cannabis sp. plant, exhibits promising therapeutic potential across various clinical contexts. Pre-clinical and in vitro studies indicate that CBD could mitigate cognitive decline and amyloid-beta-induced neurodegeneration by modulating oxidative stress and neuroinflammation. In addition, CBD demonstrates significant effects in promoting neuroplasticity, particularly in brain regions such as the hippocampus. However, the available clinical evidence presents conflicting results, and no randomized placebo-controlled trials have been published to date. In conclusion, although pre-clinical and in vitro studies offer encouraging insights into the potential benefits of CBD in AD models, new and well-designed clinical trials are imperative to ascertain the clinical relevance of CBD use in the management of AD symptoms, especially in comparison to conventional treatments.

Cannabidiol as an antipsychotic drug.

Cannabidiol (CBD) is a major phytocannabinoid in the Cannabis sativa plant. In contrast to Δ9-tetrahydrocannabinol (THC), CBD does not produce the typical psychotomimetic effects of the plant. In addition, CBD has attracted increased interest due to its potential therapeutic effects in various psychiatric disorders, including schizophrenia. Several studies have proposed that CBD has pharmacological properties similar to atypical antipsychotics. Despite accumulating evidence supporting the antipsychotic potential of CBD, the mechanisms of action in which this phytocannabinoid produces antipsychotic effects are still not fully elucidated. Here, we focused on the antipsychotic properties of CBD indicated by a series of preclinical and clinical studies and the evidence currently available about its possible mechanisms. Findings from preclinical studies suggest that CBD effects may depend on the animal model (pharmacological, neurodevelopmental, or genetic models for schizophrenia), dose, treatment schedule (acute vs. repeated) and route of administration (intraperitoneal vs local injection into specific brain regions). Clinical studies suggest a potential role for CBD in the treatment of psychotic disorders. However, future studies with more robust sample sizes are needed to confirm these positive findings. Overall, although more studies are needed, current evidence indicates that CBD may be a promising therapeutic option for the treatment of schizophrenia.

Primary outcomes and characteristics of clinical trial registries (up to October 2021) on COVID-19 vaccines.

OBJECTIVES: To analyse the general and primary outcome-related characteristics of clinical trials protocols on COVID-19 vaccines. STUDY DESIGN AND SETTING: A meta-research study. A search for clinical trial protocols on COVID-19 vaccines was conducted on the ClinicalTrials.gov platform. We considered all protocols of comparative trials registered up to October 26, 2021. RESULTS: Two hundred and eighty-two trials were analysed. The median expected trial duration was 445 days (interquartile range [IQR] = 225), and the median target sample size was 420 participants (IQR = 1638). A retrospective registry (after the start date) was observed for 42.55% of the trials. Randomization procedures were planned by 84.75% and full-blinding procedures by 34.75% of the 282 trials. Most trials were labelled as active or still recruiting, and 14 trials (5%) were completed. None of the 14 trials labelled as completed on our search date had results available. Industry funding was reported by 198 trials (70.2%). Most studies declared more than one primary outcome, usually a safety or immunogenicity outcome, and 59 studies (20.9%) had at least one primary efficacy outcome. The description of the primary efficacy outcomes was limited in most cases, referred to as a non-specified 'efficacy' outcome (18.6%) or described as 'COVID-19 cases' (32.2%). CONCLUSION: the primary outcomes of clinical trials on COVID-19 vaccines are poorly described, and the registers provide insufficient information about them. The registry was retrospectively fulfilled for many trials, which may lead to bias and research waste. Outcomes were generically described and did not provide transparent information for replication in practice, further trials or meta-analyses.

False claims of equivalence in the neurosurgical trauma literature: prevalence and associated factors-a systematic review protocol.

INTRODUCTION: Research quality within the neurosurgical field remains suboptimal. Therefore, many studies published in the neurosurgical literature lack enough statistical power to establish the presence or absence of clinically important differences between treatment arms. The field of neurotrauma deals with additional challenges, with fewer financial incentives and restricted resources in low-income and middle-income countries with the highest burden of neurotrauma diseases. In this systematic review, we aim to estimate the prevalence of false claims of equivalence in the neurosurgical trauma literature and identify its predictive factors. METHODS AND ANALYSIS: The Preferred Reporting Items for Systematic Review and Meta-Analyses recommendations were followed. Randomised clinical trials that enrolled only traumatic brain injury patients and investigated any type of intervention (surgical or non-surgical) will be eligible for inclusion. The MEDLINE/PubMed database will be searched for articles in English published from January 1960 to July 2020 in 15 top-ranked journals. A false claim of equivalence will be identified by insufficient power to detect a clinically meaningful effect: for categorical outcomes, a difference of at least 25% and 50%, and for continuous outcomes, a Cohen's d of at least 0.5 and 0.8. Using the number of patients in each treatment arm and the minimum effect sizes to be detected, the power of each study will be calculated with the assumption of a two-tailed alpha that equals 0.05. Standardised differences between the groups with and without a false claim of equivalence will be calculated, and the variables with a standardised difference equal or above 0.2 and 0.5 will be considered weakly and strongly associated with false claims of equivalence, respectively. The data analysis will be blinded to the authors and institutions of the studies. ETHICS AND DISSEMINATION: This study will not involve primary data collection. Therefore, formal ethical approval will not be required. The final systematic review will be published in a peer-reviewed journal and presented at appropriate conferences.

Analysing vaccine efficacy evaluated in phase 3 clinical trials carried out during outbreaks.

In this paper we examine several definitions of vaccine efficacy (VE) that we found in the literature, for diseases that express themselves in outbreaks, that is, when the force of infection grows in time, reaches a maximum and then vanishes. The fact that the disease occurs in outbreaks results in several problems that we analyse. We propose a mathematical model that allows the calculation of VE for several scenarios. Vaccine trials usually needs a large number of volunteers that must be enrolled. Ideally, all volunteers should be enrolled in approximately the same time, but this is generally impossible for logistic reasons and they are enrolled in a fashion that can be replaced by a continuous density function (for example, a Gaussian function). The outbreak can also be replaced by a continuous density function, and the use of these density functions simplifies the calculations. Assuming, for example Gaussian functions, one of the problems one can immediately notice is that the peak of the two curves do not occur at the same time. The model allows us to conclude: First, the calculated vaccine efficacy decreases when the force of infection increases; Second, the calculated vaccine efficacy decreases when the gap between the peak in the force of infection and the peak in the enrollment rate increases; Third, different trial protocols can be simulated with this model; different vaccine efficacy definitions can be calculated and in our simulations, all result are approximately the same. The final, and perhaps most important conclusion of our model, is that vaccine efficacy calculated during outbreaks must be carefully examined and the best way we can suggest to overcome this problem is to stratify the enrolled volunteer's in a cohort-by-cohort basis and do the survival analysis for each cohort, or apply the Cox proportional hazards model for each cohort.

CONSORT statement adherence and risk of bias in randomized controlled trials on deep caries management: a meta-research.

BACKGROUND: Recently, trials have supported changes in deep caries management. However, reporting might lack details, affecting interpretation and implementation. Thus, we aimed to evaluate the adherence to the CONSORT statement and the risk of bias of randomized controlled trials (RCTs) on deep caries management published in pediatric dental journals. METHODS: We searched PubMed for RCTs in six pediatric dental journals between 2010 and 2022, focusing on deep caries lesion management. Adherence to the CONSORT guideline and the risk of bias were assessed using a modified tool with 19 items; each scored from 0 to 2 (maximum of 38 points), and the Cochrane risk-of-bias (RoB 2) tool. We performed descriptive and regression analyses (α = 5%). RESULTS: We analyzed 127 RCTs. The mean (standard deviation) CONSORT adherence score was 21.1 (6.7). Notably, 96.1% of the studies received a score of 2 for the "intervention" item, whereas 83.5% scored 0 for the "estimated effect size". The risk of bias assessment revealed that 40.2% of the RCTs were at high risk, 59% were at low risk, and 0.8% were at low risk. RCTs with a high risk of bias had lower CONSORT scores (p<0.001) than those with low or some concerns. RCTs published in journals without the endorsement of the CONSORT statement had lower scores than those in journals with the endorsement of the CONSORT statement. Older RCTs (6-10 years old and more than 10 years old) showed significantly lower CONSORT statement compliance than trials published recently within 5 years. CONCLUSION: Adherence to the CONSORT was relatively low among the investigated RCTs. Moreover, lower adherence to the CONSORT was associated with a higher risk of bias. TRIAL REGISTRATION: This study protocol was prospectively registered on the Open Science Framework - DOI ( 10.17605/OSF.IO/V6SYZ ).

3-Chymotrypsin-like Protease (3CLpro) of SARS-CoV-2: Validation as a Molecular Target, Proposal of a Novel Catalytic Mechanism, and Inhibitors in Preclinical and Clinical Trials.

Proteases represent common targets in combating infectious diseases, including COVID-19. The 3-chymotrypsin-like protease (3CLpro) is a validated molecular target for COVID-19, and it is key for developing potent and selective inhibitors for inhibiting viral replication of SARS-CoV-2. In this review, we discuss structural relationships and diverse subsites of 3CLpro, shedding light on the pivotal role of dimerization and active site architecture in substrate recognition and catalysis. Our analysis of bioinformatics and other published studies motivated us to investigate a novel catalytic mechanism for the SARS-CoV-2 polyprotein cleavage by 3CLpro, centering on the triad mechanism involving His41-Cys145-Asp187 and its indispensable role in viral replication. Our hypothesis is that Asp187 may participate in modulating the pKa of the His41, in which catalytic histidine may act as an acid and/or a base in the catalytic mechanism. Recognizing Asp187 as a crucial component in the catalytic process underscores its significance as a fundamental pharmacophoric element in drug design. Next, we provide an overview of both covalent and non-covalent inhibitors, elucidating advancements in drug development observed in preclinical and clinical trials. By highlighting various chemical classes and their pharmacokinetic profiles, our review aims to guide future research directions toward the development of highly selective inhibitors, underscore the significance of 3CLpro as a validated therapeutic target, and propel the progression of drug candidates through preclinical and clinical phases.

Reporting of confidence intervals, achievement of intended sample size, and adjustment for multiple primary outcomes in randomised trials of physical therapy interventions: an analysis of 100 representatively sampled trials.

BACKGROUND: The physical therapy profession has made efforts to increase the use of confidence intervals due to the valuable information they provide for clinical decision-making. Confidence intervals indicate the precision of the results and describe the strength and direction of a treatment effect measure. OBJECTIVES: To determine the prevalence of reporting of confidence intervals, achievement of intended sample size, and adjustment for multiple primary outcomes in randomised trials of physical therapy interventions. METHODS: We randomly selected 100 trials published in 2021 and indexed on the Physiotherapy Evidence Database. Two independent reviewers extracted the number of participants, any sample size calculation, and any adjustments for multiple primary outcomes. We extracted whether at least one between-group comparison was reported with a 95 % confidence interval and whether any confidence intervals were interpreted. RESULTS: The prevalence of use of confidence intervals was 47 % (95 % CI 38, 57). Only 6 % of trials (95 % CI: 3, 12) both reported and interpreted a confidence interval. Among the 100 trials, 59 (95 % CI: 49, 68) calculated and achieved the required sample size. Among the 100 trials, 19 % (95 % CI: 13, 28) had a problem with unadjusted multiplicity on the primary outcomes. CONCLUSIONS: Around half of trials of physical therapy interventions published in 2021 reported confidence intervals around between-group differences. This represents an increase of 5 % from five years earlier. Very few trials interpreted the confidence intervals. Most trials reported a sample size calculation, and among these most achieved that sample size. There is still a need to increase the use of adjustment for multiple comparisons.

Comparison of the Functional Outcomes of Arthroscopic Anterior Cruciate Ligament Reconstruction through the All-inside and Outside-in Techniques: A Double-Blinded Randomized Controlled Trial / Comparação dos resultados funcionais da reconstrução artroscópica do ligamento cruzado anterior pelas técnicas all-inside e outside-in: Um ensaio clínico controlado, randomizado e duplo-cego

Abstract Objective To compare the functional outcomes of anterior cruciate ligament (ACL) reconstruction with hamstring autograft (HA) through the all-inside (AI) technique with adjustable-loop cortical Endobutton (Smith & Nephew, Watford, Hertfordshire, England) on the sides of the femur and tibia and through the outside-in (OI) technique using an interference screw on the tibial side and a cortical Endobutton on the femoral side. Materials and Methods The present is a double-blinded randomized controlled trial (RCT) of 44 patients undergoing arthroscopic ACL reconstruction from February 2019 to February 2022 in a tertiary care hospital. As per computer-based randomization, the patients were distributed into two groups: the AI and OI groups. Both groups were evaluated for 12 months using the Visual Analog Scale (VAS), the Lysholm Knee Scoring Scale, and part I (pain score) and part II (function score) of the Knee Society Score (KSS). Results On postoperative day 2,the VAS score was significantly higher in the OI group (p = 0.0001), but insignificant (p = 0.807) at 6 weeks. At 3, 6, and 12 months of follow-up, the score on the Lysholm Knee Scoring Scale was significantly higher (p = 0.001) in the AI group. At 6 months, both parts of the KSS showed a significant difference, with the AI group presenting a better outcome (p = 0.04). However, at 12 months, the AI group presented a better score on part I of the KSS, but no differences were observed regarding part II. Conclusion In a follow-up of 12 months, the patients submitted to the AI technique presented better outcome scores and pain relief than those submitted to the OI technique.

Resumo Objetivo Comparar os resultados funcionais da reconstrução do ligamento cruzado anterior (LCA) com autoenxerto de isquiotibiais pela técnica all-inside (AI) com Endobutton (Smith & Nephew, Watford, Hertfordshire, Inglaterra) cortical de alça ajustável nos lados do fêmur e da tíbia e pela técnica outside-in (OI) com parafuso de interferência no lado tibial e Endobutton cortical no lado femoral. Métodos Trata-se de um ensaio clínico controlado, randomizado e duplo-cego com 44 pacientes submetidos à reconstrução artroscópica do LCA de fevereiro de 2019 a fevereiro de 2022 em um hospital de cuidados terciários. De acordo com a randomização por computador, os pacientes foram distribuídos em dois grupos: AI e OI. Ambos os grupos foram avaliados durante 12 meses pela Escala Visual Analógica (EVA), a Escala de Pontuação do Joelho de Lysholm e pela parte I (pontuação de dor) e a parte II (pontuação de função) da escala Knee Society Score (KSS). Resultados No segundo dia de pós-operatório, a pontuação média na EVA foi significativamente maior no grupo OI (p = 0,0001), mas insignificante (p 0,807) às 6 semanas. Aos 3, 6 e 12 meses de acompanhamento, a pontuação na Escala de Lysholm (p = 0,001) foi significativamente maior no grupo AI. Aos 6 meses, ambas as partes da KSS apresentam uma diferença significativa, com o grupo AI apresentando um desfecho melhor (p = 0,04). No entanto, aos 12 meses, o grupo AI apresentou uma pontuação melhor na parte I da KSS, mas não foram observadas diferenças na parte II. Conclusão Em um acompanhamento de 12 meses, os pacientes submetidos à técnica AI apresentaram melhores pontuações de desfecho e alívio da dor do que aqueles submetidos à técnica OI.

The Polypill: A New Alternative in the Prevention and Treatment of Cardiovascular Disease.

Cardiovascular disease (CVD) is the primary cause of death and disability worldwide. Although age-standardized CVD mortality rates decreased globally by 14.5% between 2006 and 2016, the burden of CVD remains disproportionately higher in low- and middle-income countries compared to high-income countries. Even though proven, effective approaches based on multiple-drug intake aimed at the prevention and treatment of CVD are currently available, poor adherence, early discontinuation of treatment, and suboptimal daily execution of the prescribed therapeutic regimes give rise to shortfalls in drug exposure, leading to high variability in the responses to the prescribed medications. Wald and Law, in their landmark paper published in BMJ 2003, hypothesized that the use of a fixed-dose combination of statins, ß-blockers, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and aspirin (classic Polypill composition) may increase adherence and decrease CVD by up to 80% when prescribed as primary prevention or in substitution of traditional protocols. Since then, many clinical trials have tested this hypothesis, with comparable results. This review aims to describe the available clinical trials performed to assess the impact of fixed-dose combinations on adherence, cost-effectiveness, and the risk factors critical to the onset of CVD.

Effects of cinnamon supplementation on metabolic biomarkers in individuals with type 2 diabetes: a systematic review and meta-analysis.

CONTEXT: The global prevalence of type 2 diabetes mellitus (DM2) has been rising significantly over the years. Recent studies have shown beneficial effects of cinnamon on metabolic biomarkers. OBJECTIVE: The objective of this review was to assess the effect of cinnamon supplementation on metabolic biomarkers in patients with DM2. DATA SOURCES: The Pubmed/MEDLINE, Cochrane CENTRAL, and Embase databases were searched up to November 10, 2022. DATA EXTRACTION: A systematic search was performed for randomized controlled trials (RCTs) evaluating the effect of cinnamon supplementation on metabolic biomarkers, in adults and the elderly with DM2, and comparing the data for a cinnamon intervention group with that for a placebo group or a control group. The main exclusion criteria were studies (1) with other types of diabetes (ie, gestational diabetes or type 1 diabetes), (2) without cinnamon consumption, (3) that did not evaluate metabolic biomarkers, or (4) in vitro and animal studies. Two researchers independently screened 924 records, evaluated full-text studies, extracted data, and appraised their quality. A third researcher was consulted to resolve any discrepancies. The data were pooled using random-effects models and expressed as the weighted mean difference (WMD) with 95% CI. Heterogeneity was assessed using Cochran's Q test and quantified using I2 statistics. Risk of bias was assessed using the Joanna Briggs Institute (JBI) instrument. Sensitivity analysis and the GRADE system were used to assess the robustness and certainty of the findings. DATA ANALYSIS: In total, 28 RCTs with a duration ranging from 30 to 120 days and a total enrollment of 3054 patients with DM2 were included. Participants consuming cinnamon showed a significant reduction in fasting blood glucose (FBG) (WMD: -15.26 mg/dL; 95% CI: -22.23 to -8.30; I2 = 88%), postprandial glucose (WMD: -39.22 mg/dL; 95% CI: -63.90 to -14.55; I2 = 100%), HbA1c (WMD: -0.56 mg/dL; 95% CI: -0.99 to -0.13; I2 = 94%), and HOMA-IR (WMD = -0.76, 95% CI: -1.13 to -0.39; I2 = 22%) compared with the control group. An intervention of cinnamon in capsule form reduced FBG (WMD:-18.43 mg/dL, 95% CI: -26.32 to -10.53; I2 = 89%), postprandial glucose (WMD: -44.83 mg/dL, 95% CI: -70.67 to -18.99; I2 = 100%), HbA1c (WMD: -0.56 mg/dL, 95% CI: -1.02 to -0.09; I2 = 94%), total cholesterol (WMD: -13.39 mg/dL; 95% CI: -24.71 to -2.07; I2 = 96%), LDL-C (WMD: -6.49 mg/dL, 95% CI: -12.69 to -0.29; I2 = 92%), and triglycerides (WND: -19.75 mg/dL; 95% CI, -33.71 to -5.80; I2 = 88%). Both doses (≤2 g/day and >2 g/day) reduced FBG and postprandial glucose. Only cinnamon doses of ≤2 g/day reduced HbA1c (WMD: -0.68 mg/dL, 95% CI: -1.16 to -0.1; I2 = 92%), HOMA-IR (WMD: -0.94 mg/dL; 95% CI: -1.21 to -0.67; I2 = 0%), and BMI (WMD: -1.18 kg/m2; 95% CI: -1.97 to -0.39; I2 = 0%). CONCLUSION: The data suggest that cinnamon improves the glycemic and lipid profile and reduces the BMI, particularly in DM2 patients who receive cinnamon supplementation in capsule form and at a dose of ≤2 g/day. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42022370332.

Statistical Considerations for the Design and Analysis of Pragmatic Trials in Aging Research.

Pragmatic trials aim to assess intervention efficacy in usual patient care settings, contrasting with explanatory trials conducted under controlled conditions. In aging research, pragmatic trials are important designs for obtaining real-world evidence in elderly populations, which are often underrepresented in trials. In this review, we discuss statistical considerations from a frequentist approach for the design and analysis of pragmatic trials. When choosing the dependent variable, it is essential to use an outcome that is highly relevant to usual medical care while also providing sufficient statistical power. Besides traditionally used binary outcomes, ordinal outcomes can provide pragmatic answers with gains in statistical power. Cluster randomization requires careful consideration of sample size calculation and analysis methods, especially regarding missing data and outcome variables. Mixed effects models and generalized estimating equations (GEEs) are recommended for analysis to account for center effects, with tools available for sample size estimation. Multi-arm studies pose challenges in sample size calculation, requiring adjustment for design effects and consideration of multiple comparison correction methods. Secondary analyses are common but require caution due to the risk of reduced statistical power and false-discovery rates. Safety data collection methods should balance pragmatism and data quality. Overall, understanding statistical considerations is crucial for designing rigorous pragmatic trials that evaluate interventions in elderly populations under real-world conditions. In conclusion, this review focuses on various statistical topics of interest to those designing a pragmatic clinical trial, with consideration of aspects of relevance in the aging research field.