Application of Myocardial Salvage Index as a Clinical Endpoint: Assessment Methods and Future Prospects.

In patients with acute myocardial infarction (AMI), traditional clinical endpoints used to assess drug efficacy and prognosis include infarct size (IS), incidence of heart failure, and mortality rates. Although these metrics are commonly employed to evaluate outcomes in AMI patients, their utility is limited in small-scale studies. The introduction of the myocardial salvage index (MSI) reduces variability in assessments across multiple dimensions, thereby enhancing the sensitivity of outcome measures and reducing the required sample size. Moreover, MSI is increasingly utilized to evaluate drug efficacy, prognosis, and risk stratification in AMI patients. Although a variety of methodologies for measuring the MSI are currently available, the incorporation of these methods as clinical endpoints remains limited. In the clinical application of cardioprotective strategies, it is recommended that MSI be evaluated using late gadolinium enhancement measured along the endocardial surface length combined with IS in cardiac magnetic resonance. In dynamic single-photon emission computed tomography, an assessment of MSI using methods based on abnormalities in myocardial wall thickening combined with perfusion anomalies is advocated. This review comprehensively outlines the principles, advantages, and limitations of different MSI assessment methods and discusses the prospects and challenges of MSI in cardiac protective therapies. Additionally, we summarize recommended strategies for employing MSI as a clinical surrogate endpoint in various clinical scenarios, providing direction for future clinical practice and research. EVIDENCE LEVEL: 5 TECHNICAL EFFICACY: Stage 4.

Diabetic Peripheral Neuropathy: Emerging Treatments of Neuropathic Pain and Novel Diagnostic Methods.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is a prevalent and debilitating complication of diabetes, often leading to severe neuropathic pain. Although other diabetes-related complications have witnessed a surge of emerging treatments in recent years, DPN has seen minimal progression. This stagnation stems from various factors, including insensitive diagnostic methods and inadequate treatment options for neuropathic pain. METHODS: In this comprehensive review, we highlight promising novel diagnostic techniques for assessing DPN, elucidating their development, strengths, and limitations, and assessing their potential as future reliable clinical biomarkers and endpoints. In addition, we delve into the most promising emerging pharmacological and mechanistic treatments for managing neuropathic pain, an area currently characterized by inadequate pain relief and a notable burden of side effects. RESULTS: Skin biopsies, corneal confocal microscopy, transcutaneous electrical stimulation, blood-derived biomarkers, and multi-omics emerge as some of the most promising new techniques, while low-dose naltrexone, selective sodium-channel blockers, calcitonin gene-related peptide antibodies, and angiotensin type 2 receptor antagonists emerge as some of the most promising new drug candidates. CONCLUSION: Our review concludes that although several promising diagnostic modalities and emerging treatments exist, an ongoing need persists for the further development of sensitive diagnostic tools and mechanism-based, personalized treatment approaches.

Using multistate models with clinical trial data for a deeper understanding of complex disease processes.

A clinical trial represents a large commitment from all individuals involved and a huge financial obligation given its high cost; therefore, it is wise to make the most of all collected data by learning as much as possible. A multistate model is a generalized framework to describe longitudinal events; multistate hazards models can treat multiple intermediate/final clinical endpoints as outcomes and estimate the impact of covariates simultaneously. Proportional hazards models are fitted (one per transition), which can be used to calculate the absolute risks, that is, the probability of being in a state at a given time, the expected number of visits to a state, and the expected amount of time spent in a state. Three publicly available clinical trial datasets, colon, myeloid, and rhDNase, in the survival package in R were used to showcase the utility of multistate hazards models. In the colon dataset, a very well-known and well-used dataset, we found that the levamisole+fluorouracil treatment extended time in the recurrence-free state more than it extended overall survival, which resulted in less time in the recurrence state, an example of the classic "compression of morbidity." In the myeloid dataset, we found that complete response (CR) is durable, patients who received treatment B have longer sojourn time in CR than patients who received treatment A, while the mutation status does not impact the transition rate to CR but is highly influential on the sojourn time in CR. We also found that more patients in treatment A received transplants without CR, and more patients in treatment B received transplants after CR. In addition, the mutation status is highly influential on the CR to transplant transition rate. The observations that we made on these three datasets would not be possible without multistate models. We want to encourage readers to spend more time to look deeper into clinical trial data. It has a lot more to offer than a simple yes/no answer if only we, the statisticians, are willing to look for it.

High BMI z-Scores from Different Growth References Are Not Comparable: An Example from a Weight Management Trial with an Anti-Obesity Medication in Pubertal Adolescents with Obesity.

Background: The BMI z-score is a standardized measure of weight status and weight change in children and adolescents. BMI z-scores from various growth references are often considered comparable, and differences among them are underappreciated. Methods: This study reanalyzed data from a weight management clinical study of liraglutide in pubertal adolescents with obesity using growth references from CDC 2000, CDC Extended, World Health Organization (WHO), and International Obesity Task Force. Results: BMI z-score treatment differences varied 2-fold from -0.13 (CDC 2000) to -0.26 (WHO) overall and varied almost 4-fold from -0.05 (CDC 2000) to -0.19 (WHO) among adolescents with high baseline BMI z-score. Conclusions: Depending upon the growth reference used, BMI z-score endpoints can produce highly variable treatment estimates and alter interpretations of clinical meaningfulness. BMI z-scores cited without the associated growth reference cannot be accurately interpreted.

Preferences and perceptions of 617 migraine patients on acute and preventive migraine treatment attributes and clinical trial endpoints.

BACKGROUND: To identify the preferences and perceptions of migraine patients for acute and preventive treatment options and to investigate which treatment outcomes are the most important. DESIGN AND METHODS: The authors performed a choice-format survey in a cohort of migraine patients from Greece and Cyprus. A self-administered questionnaire developed in collaboration with the Greek Society of Migraine Patients was used. RESULTS: Questionnaires were collected from 617 migraine patients. Efficacy was preferred over safety as the single most important parameter, both in acute and preventive treatment. When analyzing single outcomes, patients prioritized a complete pain remission at 1-hour post-dose for acute therapies. Regarding migraine prevention, a 75% reduction in frequency, intensity of pain, accompanying symptoms and acute medication intake were considered as most important. Conversely, outcomes routinely used in clinical trials, namely complete or partial pain remission at 2-hours post-dose for acute treatment and 50% or 30% reduction in migraine frequency for prevention, were not deemed particularly relevant. Tablet formulation was mostly preferred, both in acute and preventive treatment. Conclusion: Listening to patients' needs may add a piece of the puzzle that is generally missing in clinical practice and often explains the lack of adherence in both acute and preventative anti-migraine therapies.

The relative vaccine effectiveness of high-dose vs standard-dose influenza vaccines in preventing hospitalization and mortality: A meta-analysis of evidence from randomized trials.

OBJECTIVES: To summarize current evidence of high-dose influenza vaccine (HD-IV) vs standard-dose (SD-IV) regarding severe clinical outcomes. METHODS: A prespecified meta-analysis was conducted to assess relative vaccine effectiveness (rVE) of HD-IV vs SD-IV in reducing the rates of (1) pneumonia and influenza (P&I) hospitalization, (2) all hospitalizations, and (3) all-cause death in adults ≥ 65 years in randomized controlled trials. Pooled effect sizes were estimated using fixed-effects models with the inverse variance method. RESULTS: Five randomized trials were included encompassing 105,685 individuals. HD-IV vs SD-IV reduced P&I hospitalizations (rVE: 23.5 %, [95 %CI: 12.3 to 33.2]). HD-IV vs SD-IV also reduced rate of all-cause hospitalizations (rVE: 7.3 %, [95 %CI: 4.5 to 10.0]). No significant differences were observed in death rates (rVE = 1.6 % ([95 %CI: -2.0 to 5.0]) in HD-IV vs SD-IV. Sensitivity analyses omitting trials with participants sharing the same comorbidity, trials with ≥ 100 events, and random-effects models provided comparable estimates for all outcomes. CONCLUSIONS: HD-IV reduced the incidence of P&I and all-cause hospitalization vs SD-IV in adults ≥ 65 years in randomized trials, through no significant difference was observed in all-cause death rates. These findings, supported by evidence from several randomized studies, can benefit from replication in a fully powered, individually randomized trial.

Multi-luminance mobility testing after gene therapy in the context of retinal functional diagnostics.

BACKGROUND: Voretigene neparvovec (Luxturna®) is the first approved gene therapy for RPE65-linked Leber congenital amaurosis (LCA). Though individual effects are highly variable, most recipients report improved vision in everyday life. To describe such effects, visual navigation tests are now frequently used in clinical trials. However, it is still unclear how their results should be interpreted compared to conventional parameters of visual function. METHODS: Seven LCA patients underwent a multi-luminance visual navigation test (Ora-VNCTM) before and 3 months after receiving Luxturna gene therapy. Their performance was rated based on the luminance level at which they passed the course. Differences between the first and second test were correlated to changes in visual acuity, full-field stimulus thresholds, chromatic pupil campimetry, and dark-adapted perimetry. RESULTS: A few patients displayed notable improvements in conventional measures of visual function whereas patients with advanced retinal degeneration showed no relevant changes. Independent of these results, almost all participants improved in the visual navigation task by one or more levels. The improvement in the mobility test was best correlated to the change in full-field stimulus thresholds. Other measures of visual functions showed no clear correlation with visual navigation. DISCUSSION: In patients who passed the test's more difficult levels, improved visual navigation can be attributed to the reactivation of rods. However, the performance of patients with low vision seemed to depend much more on confounding factors in the easier levels. In sum, such tests might only be meaningful for patients with better preserved visual functions.

Test-retest repeatability and agreement of the quantitative contrast sensitivity function test: towards the validation of a new clinical endpoint.

PURPOSE: The purpose of this study is to investigate test-retest reliability and agreement of the quantitative contrast sensitivity function test (qCSF) in the retina clinic. METHODS: A total of 121 right eyes of 121 patients were tested and consecutively re-tested with qCSF in the retina clinic. Outcomes included area under the logarithm of contrast sensitivity function curve (AULCSF), contrast acuity, and contrast sensitivity thresholds at 1-18 cycles per degree (cpd). Test-retest means were compared with paired t-test, variability was compared with the Brown-Forsythe test, and intraclass correlation coefficient (ICC) and Bland Altman plots evaluated reliability and agreement. RESULTS: Mean test-retest differences for all qCSF metrics ranged from 0.02 to 0.05 log units without statistically significant differences in variability. Standard deviations ranged from 0.08 to 0.14. Coefficients of repeatability ranged from 0.16 to 0.27 log units. ICC > 0.9 for all metrics except 1cpd (ICC = 0.84, all p < 0.001); AULCSF ICC = 0.971. CONCLUSION: qCSF-measured contrast sensitivity shows great test-retest repeatability and agreement in the retina clinic.

Caregiver involvement in applied behavior-analytic research: A scoping review and discussion.

We conducted a scoping review to characterize the role of caregiver involvement in behavior-analytic research. We reviewed eight behavioral-learning journals from 2011-2022 for works that included children or caregivers as participants and characterized caregiver involvement as passive (implications for caregivers, input, social validity) and active (implementation, caregiver behavior, training, caregiver-collected data). The review identified 228 studies, and almost all (96.1%; n = 219) involved caregivers in some capacity; 94.3% (n = 215) had passive involvement (26.8% had only passive involvement; n = 61), 69.3% (n = 158) had active involvement (1.8% had only active involvement; n = 4), and 3.9% (n = 9) had neither passive nor active involvement. Involvement generally increased over publication years. The most common types of involvement were implications for caregivers, implementation, and input; caregiver-collected data were rare. We propose considerations when engaging caregivers in research and suggest new avenues of inquiry related to caregivers' treatment objectives and social validity, treatment implementers, and caregiver-collected data.

Changes to Registered and Pivotal Clinical Trials after the 2011 Tri-Societies Guidelines for Clinical Endpoints and Response Criteria in Mycosis Fungoides and Sézary Syndrome.

Guidelines for mycosis fungoides and Sézary syndrome clinical trials were published in 2011 to standardize endpoint criteria and trial design. Our retrospective cohort study of mycosis fungoides/Sézary syndrome clinical trials registered on ClinicalTrials.gov and pivotal trials supporting drug approvals and label extensions evaluates adherence to these guidelines. Sixty-three trials met our inclusion criteria. In a subpopulation of trials, mean adherence to the guidelines was approximately 60%. When comparing trials that began in the first 6 years after their publication with those that started after, we found no difference in mean adherence (4.12 vs 3.41) (P = .15). Among the 8 pivotal trials supporting new mycosis fungoides or Sézary syndrome systemic therapies from 1990 to 2020, systemic trials published after 2011 were more likely to randomize patients (100 vs 0%, P = .036), perform superiority testing (100 vs 0%, P = .036), and use an intention-to-treat analysis (100 vs 0%, P = .036). The design of trials registered on Clinicaltrials.gov did not change significantly between the first 6 years after the publication of the guidelines and after. This demonstrates that the guidelines are still not consistently implemented across all trials. However, registrational trials were more likely to implement the recommendations.

Ability change across multiple domains in mucopolysaccharidosis (Sanfilippo syndrome) type IIIA.

The objective of this paper is 1) to expand the scope of the domains previously published in a natural history study of Mucopolysaccharidosis IIIA (Sanfilippo syndrome type A) (MPS IIIA) and 2) to present evidence regarding the capacity of a new metric, Growth Scale Values (GSVs), in comparison with traditional metrics, to show changes in skills as assessed by the Bayley Scales of Infant Development -III (BSID-III) and the Vineland Adaptive Behavior Scales, Second Edition (VABS-II). We re-analyzed a cohort of 25 children, 20 with rapid progressing disease and 5 with slow progression, who had been followed over two years using the BSID-III, and the VABS-II. Previously findings were reported using age equivalent scores; now we are also presenting findings with GSVs. For the re-analysis, Language and Motor scores were added to the Cognitive scale on the BSID-III, and Domain- and Subdomain-level scores added to the Total VABS-II score (i.e., ABC Composite). We evaluated raw scores, age equivalent scores, and GSVs (and standard scores for the VABS-II only). Individual patient data can be found in the appendices to this publication. Results indicate that 1) Cognition as measured by GSVs was the most sensitive to decline; 2) GSVs showed significant decline in the range of 4 to 6 years of age; 3) For children under 4 years of age, positive growth occurs on most scales and most metrics, with the exception of language which slows somewhat earlier; 4) Other than the Cognitive scale, Receptive Language on the BSID-III and Receptive Communication on the VABS-II showed the most sensitivity to change; 5) Gross Motor skills showed the least decline over time and appeared to lack sensitivity to MPS IIIA motor concerns; and 6) No evidence for sensitivity to change for any metric was found in time intervals less than one year. We conclude that GSVs are a precise measurement of change to detect decline in function, and they are a valuable method for future clinical trials in MPS IIIA. Evidence continues to support cognition as a primary endpoint. Additional work is needed to identify sensitive measures of meaningful endpoints to families.

Effectiveness of adding a defibrillator with cardiac resynchronization therapy in heart failure according to the modified Model for End-stage Liver Disease-Albumin score.

Current guidelines lack clear recommendations between the implantation of cardiac resynchronization therapy (CRT) with defibrillator (CRT-D) and CRT with pacemaker (CRT-P). We hypothesized that modified model for end-stage liver disease score including albumin (MELD-Albumin score), could be used to select patients who may not benefit from CRT-D. We consecutively included patients with CRT-P or CRT-D implantation between 2010 and 2022. The primary endpoint was the composite of all-cause mortality or worsening heart failure. We performed multivariable-adjusted Cox proportional hazard regression. We assessed the interaction between the MELD-Albumin score and the effect of adding a defibrillator with CRT.A total of 752 patients were included in this study, with 291 implanted CRT-P. During a median follow-up of 880 days, 205 patients reached the primary endpoint. MELD-Albumin score was significantly associated with the primary endpoint in the CRT-D group [HR 1.16 (1.09-1.24); P < 0.001] but not in the CRT-P group [HR 1.03 (0.95-1.12); P = 0.49]. There was a significant interaction between the MELD-Albumin score and the effect of CRTD (P = 0.013). The optimal cut-off value of the MELD-Albumin score was 12. For patients with MELD-Albumin ≥ 12, CRT-D was associated with a higher occurrence of the primary endpoint [HR 1.99 (1.10-3.58); P = 0.02], whereas not in patients with MELD-Albumin < 12 [HR 1.19 (0.83-1.70); P = 0.35). Our findings suggest that CRT-D is associated with an excess risk of composite clinical endpoints in HF patients with higher MELD-Albumin score.

Correlations Between Gastrointestinal Symptoms and Endoscopic-Histologic Disease Activity in Adults with Ulcerative Colitis.

INTRODUCTION: Discordance between gastrointestinal (GI) symptoms and endoscopic inflammation in patients with ulcerative colitis (UC) is known. However, the correlations between symptoms and endoscopic and histologic (endo-histologic) mucosal healing and remains unknown. METHODS: We performed a secondary analysis of prospectively collected clinical, endoscopic, and histologic data on 254 colonoscopies from 179 unique adults at a tertiary referral center from 2014 to 2021. Spearman's rank was used to assess the correlation between patient reported outcomes and objective assessments of disease activity, as measured by validated instruments: Two-item patient-reported outcome measure (PRO-2) for stool frequency and rectal bleeding, the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) for endoscopic inflammation, and the Geboes score for histologic inflammation. The predictive value of objective assessments of inflammation and clinical symptoms was described using sensitivity, specificity, and positive/negative predictive value. RESULTS: One-quarter (28%, 72/254) of cases were in endo-histologic remission; of these, 25% (18/72) report GI symptoms (22% diarrhea; 6% rectal bleeding). Endo-histologically active disease had higher sensitivity (95% rectal bleeding; 87% diarrhea) and negative predictive value (94% rectal bleeding, 78% diarrhea) for clinically active disease compared to active disease on endoscopic (77%) or histologic assessment only (80%). The specificity of endo/histologic inflammation for GI symptoms was < 65%. PRO-2 was positively correlated with endoscopic disease activity (Spearman's rank 0.57, 95% CI 0.54-0.60, p < 0.0001) and histologic disease activity (Spearman's rank 0.49, 0.45-0.53, p < 0.0001). CONCLUSION: One-quarter of patients with ulcerative colitis in endo-histologic (deep) remission have gastrointestinal symptoms, more commonly with diarrhea than rectal bleeding. Endo-histologic inflammation has high sensitivity (≥ 87%) for diarrhea/rectal bleeding.

Staged or Simultaneous Surgery for Colon or Rectal Cancer with Synchronous Liver Metastases: Implications for Study Design and Clinical Endpoints.

In patients presenting with colorectal cancer and synchronous liver metastases, the disease burden related to the liver metastasis is the driving cause of limited longevity and, eventually, risk of death. Surgical resection is the potentially curative treatment for colorectal cancer liver metastases. In the synchronous setting where both the liver metastases and the primary tumor are resectable with a relative low risk, the oncological surgeon and the patient may consider three potential treatment strategies. Firstly, a "staged" or a "simultaneous" surgical approach. Secondly, for a staged strategy, a 'conventional approach' will suggest removal of the primary tumor first (either colon or rectal cancer) and plan for liver surgery after recovery from the first operation. A "Liver first" strategy is prioritizing the liver resection before resection of the primary tumor. Planning a surgical trial investigating a two-organ oncological resection with highly variable extent and complexity of resection as well as the potential impact of perioperative chemo(radio)therapy makes it difficult to find the optimal primary endpoint. Here, we suggest running investigational trials with carefully chosen composite endpoints as well as embedded risk-stratification strategies to identify subgroups of patients who may benefit from simultaneous surgery.

Investigational drugs for the treatment of kidney transplant rejection.

INTRODUCTION: Kidney transplant rejection remains an important clinical problem despite the development of effective immunosuppressive therapy. Two major types of rejection are recognized, T-cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR), which have a different pathophysiology and are treated differently. Unfortunately, long-term outcomes of both TCMR and ABMR remain unsatisfactory despite current therapy. Hence, alternative therapeutic drugs are urgently needed. AREAS COVERED: This review covers novel and investigational drugs for the pharmacological treatment of kidney transplant rejection. Potential therapeutic strategies and future directions are discussed. EXPERT OPINION: The development of alternative pharmacologic treatment of rejection has focused mostly on ABMR, since this is the leading cause of kidney allograft loss and currently lacks an effective, evidence-based therapy. At present, there is insufficient high-quality evidence for any of the covered investigational drugs to support their use in ABMR. However, with the emergence of targeted therapies, the potential arises for individualized treatment strategies. In order to generate more high-quality evidence for such strategies and overcome the obstacles of classic randomized controlled trials, we advocate the implementation of adaptive trial designs and surrogate clinical endpoints. We believe such adaptive trial designs could help to understand the risks and benefits of promising drugs such as tocilizumab, clazakizumab, belimumab, and imlifidase.

Metastasis Within Three Years from Radical Nephroureterectomy as a Potential Surrogate for Overall Survival.

INTRODUCTION: The only phase III trial that evaluated the role of adjuvant chemotherapy following radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) was terminated early. Thus, eventual overall survival (OS) surrogacy, as per Prentice, cannot be assessed in this setting. We aimed to identify an intermediate clinical endpoint (ICE) that could serve as an OS surrogate after RNU for UTUC. PATIENTS AND METHODS: We retrospectively analyzed 823 high-grade UTUC patients treated with RNU at 8 tertiary referral centers. We explored the role of any recurrence (aR), defined as recurrence in the urinary tract or in the resection bed as well the presence of distant metastasis (DM), defined as metastatic disease outside the urinary tract and regional lymph nodes, on OS through a time-varying Cox regression analyses fitted at the landmark points of 1, 2, 3, and 4 years from RNU. Models' discrimination was assessed using Harrell's c index, after internal validation. RESULTS: Median follow-up for survivors was 5.6 years (interquartile range: 2.0-8.8). Overall, 391 and 212 patients experienced aR and DM, respectively. In a time-varying model, aR and DM were predictors of OS: hazard ratio [HR]:1.20, 95% confidence interval [CI]: 1.13-1.28 (P < .001) and HR:1.26, 95% CI: 1.18-1.34 (P < .001), respectively. Progression to DM within 3 years from RNU was the most informative ICE for predicting OS (c index: 0.81; HR: 4.40; 95%CI: 2.45-7.92; P < .001), compared to DM within 1, 2, and 4 years (c indexes: 0.74, 0.76, and 0.78, respectively). Progression to DM within 3 years from RNU was further found superior for predicting OS compared to aR at any landmark points. CONCLUSIONS: Progression to DM within 3 years represents a potential OS surrogate for surgically-treated UTUC. This information could help in patient counseling, future study design and expedite results release of ongoing randomized controlled trials.

SARS-CoV-2 vaccines: Clinical endpoints and psychological perspectives: A literature review.

BACKGROUND: About 270 million cases have been confirmed, and 5.3 million fatalities Worldwide due to SARS-CoV-2. Several vaccine candidates have entered phase 3 of the clinical trial and are being investigated to provide immunity to the maximum percentage of people. A safe and effective vaccine is required to tackle the current COVID-19 waves. There have been reports that clinical endpoints and psychological parameters are necessary to consider vaccine efficacy. This review examines the clinical endpoints required for a successful SARS-CoV-2 vaccine and the influences of psychological parameters on its efficacy. METHODS: The main research question was to find out the clinical endpoints that determine the vaccine efficacy? And what kind of psychological parameters affect the vaccine efficacy? The information was taken from several journals, databases, and scientific search engines like Googe scholar, Pubmed, Scopus, Web of Science, Science direct, WHO website, and other various sites. The research studies were searched using keywords; SAR-CoV-2 vaccine efficacy, psychological effect on SARS-CoV-2 vaccine, SARS-CoV-2 vaccine endpoints. RESULTS: This review has highlighted various clinical endpoints that are the main determinants of clinical vaccine efficacy. Currently, vaccinations are being carried out throughout the world; it is important to investigate the main determinants affecting vaccine efficacy. We have focused on the clinical endpoints and the influence of psychological parameters that affect the vaccine efficacy in clinical settings. The primary endpoints include the risk of infection, symptoms, and severity of COVID-19, while hospitalization length, supplemental oxygen requirement, and mechanical ventilation are secondary endpoints in the clinical endpoints. Some tangential endpoints were also considered, including organ dysfunction, stroke, and MI. Many psychological associated things have influenced the vaccine efficacy, like the lower antibody titers in the vaccinated people. In addition to that, Short- and long-term stress and sleep deprivation were also found to affect the vaccine efficacy. CONCLUSION: The review summarizes the important clinical endpoints required for a successful vaccine candidate. In addition to primary and secondary endpoints, auxiliary endpoints and the disease burden also play an important role in modulating vaccine efficacy. Moreover, the psychological perspective also influences vaccine efficacy. Effective follow-up of participants should follow to examine the clinical endpoints to reach any conclusion about vaccine efficacy.

The Impact of Cognitive Impairment on Treatment Toxicity, Treatment Completion, and Survival among Older Adults Receiving Chemotherapy: A Systematic Review.

Cognitive impairment (CI) is common among older adults with cancer, but its effect on cancer outcomes is not known. This systematic review sought to identify research investigating clinical endpoints (toxicity risk, treatment completion, and survival) of chemotherapy treatment in those with baseline CI. A systematic search of five databases (inception to March 2021) was conducted. Eligible studies included randomized trials, prospective studies, and retrospective studies in which the sample or a subgroup were older adults (aged ≥ 65) screened positive for CI prior to receiving chemotherapy. Risk of bias assessment was performed using the Quality in Prognosis Studies (QUIPS) tool. Twenty-three articles were included. Sample sizes ranged from n = 31 to 703. There was heterogeneity of cancer sites, screening tools and cut-offs used to ascertain CI, and proportion of patients with CI within study samples. Severity of CI and corresponding proportion of each level within study samples were unclear in all but one study. Among studies investigating CI in a qualified multivariable model, statistically significant findings were found in 4/6 studies on survival and in 1/1 study on nonhematological toxicity. The lack of robust evidence indicates a need for further research on the role of CI in predicting survival, treatment completion, and toxicity among older adults receiving chemotherapy, and the potential implications that could shape treatment decisions.

Red Yeast Rice Preparations Reduce Mortality, Major Cardiovascular Adverse Events, and Risk Factors for Metabolic Syndrome: A Systematic Review and Meta-analysis.

Background: Metabolic syndrome (MetS) is characterized by the cooccurrence of obesity, insulin resistance, dyslipidaemia, and hypertension. Red yeast rice (RYR) preparations might be beneficial for the prevention and treatment of MetS. Objective: To implement a systematic review and meta-analysis to determine whether RYR preparations improve clinical endpoints and reduce risk factors for MetS. Methods: The PubMed, Cochrane Library, EMBASE, Scopus, China National Knowledge Infrastructure, Chinese VIP Information, and WanFang databases were searched for randomized controlled trials (published up to September 2020), and a meta-analysis was performed using fixed- or random-effects models. The primary outcome measures were mortality and major adverse cardiovascular events (MACEs), and the secondary outcome measures were biochemical parameters of blood glucose, blood lipids, and blood pressure. The registration number is CRD42020209186. Results: A total of 921 articles were identified, of which 30 articles were included in this article. RYR preparations group demonstrated significant improvements in MetS compared with control group. RYR preparations reduced the mortality and MACEs (RR = 0.62, 95% CI [0.49, 0.78]; RR = 0.54, 95% CI [0.43, 0.66]). In terms of blood glucose metabolism, fasting plasma glucose (FPG) (MD = -0.46 mmol/L, 95% CI [-0.71, -0.22]), haemoglobin A1c (HbA1c) (MD = -0.49, 95% CI [-0.71, -0.26]) and the homeostasis model assessment of insulin resistance (HOMA-IR) (MD = -0.93, 95% CI [-1.64, -0.21]) were decreased. Regarding the lipid metabolism, total cholesterol (TC) (MD = -0.74 mmol/L, 95% CI [-1.02, -0.46]), triglycerides (TG) (MD = -0.45 mmol/L, 95% CI [-0.70, -0.21]), and low-density lipoprotein cholesterol (LDL) (MD = -0.42 mmol/L, 95% CI [-0.78, -0.06]) were decreased, while high-density lipoprotein cholesterol (HDL) (MD = 0.14 mmol/L, 95% CI [0.09, 0.20]) was increased. Regarding blood pressure, the mean arterial pressure (MAP) (MD = -3.79 mmHg, 95% CI [-5.01, -2.57]) was decreased. In addition, RYR preparations did not increase the incidence of adverse reactions (RR = 1.00, 95% CI [0.69, 1.43]). Conclusion: RYR preparations reduce mortality, MACEs, and multiple risk factors for MetS without compromising safety, which supports its application for the prevention and treatment of MetS. However, additional high-quality studies are needed to provide more evidence for the effect of RYR on MetS due to the heterogeneity in this study. Systematic Review Registration: www.crd.york.ac.uk/PROSPERO, identifier CRD42020209186.

A protocol for the Development of Core Outcome Sets for Endodontic Treatment modalities (COSET): an international consensus process.

BACKGROUND: The outcome of endodontic treatment is generally assessed using a range of patient and clinician-centred, non-standardised clinical and radiographic outcome measures. This makes it difficult to synthesise evidence for systematic analysis of the literature and the development of clinical guidelines. Core outcome sets (COS) represent a standardised list of outcomes that should be measured and reported in all clinical studies in a particular field. Recently, clinical researchers and guideline developers have focussed on the need for the integration of a patient-reported COS with clinician-centred measures. This study aims to develop a COS that includes both patient-reported outcomes and clinician-centred measures for various endodontic treatment modalities to be used in clinical research and practice. METHODS: To identify reported outcomes (including when and how they are measured), systematic reviews and their included clinical studies, which focus on the outcome of endodontic treatment and were published between 1990 and 2020 will be screened. The COSs will be defined by a consensus process involving key stakeholders using semi-structured interviews and an online Delphi methodology followed by an interactive virtual consensus meeting. A heterogeneous group of key 'stakeholders' including patients, general dental practitioners, endodontists, endodontic teachers, clinical researchers, students and policy-makers will be invited to participate. Patients will establish, via interactive interviews, which outcomes they value and feel should be included in a COS. In the Delphi process, other stakeholders will be asked to prioritise outcomes identified from the literature and patient interviews and will have the opportunity at the end of the first round to add outcomes that are not included, but which they consider relevant. Feedback will be provided in the second round, when participants will be asked to prioritise the list again. If consensus is reached, the remaining outcomes will be discussed at an online meeting and agreement established via defined consensus rules of outcome inclusion. If consensus is not reached after the second round, a third round will be conducted with feedback, followed by the online meeting. Following the identification of a COS, we will proceed to identify how and when these outcomes are measured. DISCUSSION: Using a rigorous methodology, the proposed consensus process aims to develop a COS for endodontic treatment that will be relevant to stakeholders. The results of the study will be shared with participants and COS users. To increase COS uptake, it will also be actively shared with clinical guideline developers, research funders and the editors of general dental and endodontology journals. TRIAL REGISTRATION: COMET 1879. 21 May 2021.