The Use of Allograft Bone in the Lateral Approach of Sinus Floor Elevation: A Systematic Review of Clinical Studies.

Background and Objectives: The aim of this systematic review was to assess the efficiency of using allografts for sinus lift. Materials and Methods: This systematic review was written under the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and recommendation of the Cochrane Handbook for Systematic Reviews of Interventions. Three electronic databases were screened until October 2023. The risk of bias was assessed according to the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines. Statistical analysis was performed for median bone volume and implant survival rate. Results: From 321 articles retrieved, 7 articles were included in this review. A comparison between freeze-dried bone allograft (FDBA) and deproteinized bovine bone (DBB) for mean bone volume indicated a weighted mean difference (WMD) of -0.17 [-0.69, 0.36] (95% confidence interval (CI)), p = 0.53. For implant survival rate, a comparison was made between FDBA and autogenous bone indicating a risk ratio (RR) of 1.00 [0.96, 1.05] (95% CI), p = 1.00. Conclusions: The available evidence suggested that allograft bone can be used in sinus lift procedures. The results obtained are insufficient to compare with other types of bone graft, requiring a longer follow-up time. Future clinical trials are needed in order to evaluate the advantages of using allograft bone.

Choosing the most appropriate PROM for clinical studies in sports medicine.

Choosing the most appropriate patient-reported outcome measure (PROM) for a clinical study is essential in order to achieve trustworthy results. This choice will depend on (a) the objective of the study and hence the research question; (b) the choice of a theoretical framework, such as the World Health Organization's International Classification of Functioning, Disability, and Health (ICF); (c) whether there currently is a PROM that possesses high content validity and high construct validity for the specific patient group and objective, and if not; (d) the decision on whether to use a suboptimal PROM or develop and validate a new PROM. This paper presents the steps that should be followed in order to assess the relevance of PROMs and suggests ways to enhance the choice depending on the goal of the study.

How Large a Study Is Needed to Detect TKA Revision Rate Reductions Attributable to Robotic or Navigated Technologies? A Simulation-based Power Analysis.

BACKGROUND: Robotic and navigated TKA procedures have been introduced to improve component placement precision in the hope of improving implant survivorship and other clinical outcomes. Although numerous comparative studies have shown enhanced precision and accuracy in placing components, most comparative studies have not shown that such interventions result in improved implant survival. Given what we know about effect sizes from large arthroplasty registries, large cohort studies, and large randomized controlled trials (RCTs), we wondered how large randomized trials would need to be to detect such small differences, and if the number is very high, what that would tell us about the value of these treatments for preventing revision surgery. QUESTIONS/PURPOSES: In this simulation study, we asked: Given that survivorship differences between technology-assisted TKA (TA-TKA, which we defined as either navigated or robot-assisted TKA) and conventional TKA are either small or absent based on large arthroplasty registries, large cohort studies, and large RCTs, how large would randomized trials need to be to detect small differences between TA-TKA and conventional TKA if they exist, and how long would the follow-up period need to be to have a reasonable chance to detect those differences? METHODS: We used estimated effect sizes drawn from previous clinical and registry studies, combined with estimates of the accuracy and precision of various navigation and robotic systems, to model and simulate the likely outcomes of potential comparative clinical study designs. To characterize the ranges of patients enrolled and general follow-up times associated with traditional RCT studies, we conducted a structured search of previously published studies evaluating the effect of robotics and navigation on revision rates compared with that of conventional TKA. The structured search of the University of British Columbia's library database (which automatically searches medical publication databases such as PubMed, Embase, Medline, and Web of Science) and subsequent searching through included studies' reference lists yielded 103 search results. Only clinical studies assessing implant survival differences between patient cohorts of TA-TKA and conventional TKA were included. Studies analyzing registry data, using cadaver specimens, assessing revision TKA, conference proceedings, and preprint services were excluded. Twenty studies met all our inclusion criteria, but only one study reported a statistically significant difference between the conventional and robotic or navigated groups. Next, we generated a large set of patients with simulated TKA (1.5 million), randomly assigning each simulated patient a set of patient-specific factors (age at the index surgery, gender, and BMI) drawn from data from registries and published information. We divided this set of simulated procedures into four groups, each associated with a coronal alignment precision reported for different types of surgical procedures, and randomly assigned each patient an overall coronal alignment consistent with their group's precision. TA procedures were modeled based on the alignment precision that an intervention could deliver, regardless of whether the technology used was navigation- or robot-assisted. To evaluate the power associated with using different cohort sizes, we ran a Monte Carlo simulation generating 3000 simulated populations that were drawn (with replacement) from the large set of simulated patients with TKA. We simulated the time to revision for aseptic loosening for each patient, computed the corresponding Kaplan-Meier survival curves, and applied a log-rank test to each study for statistical differences in revision rates at concurrent follow-up timepoints (1-25 years). From each simulation associated with a given cohort size, we determined the percentage of simulated studies that found a statistically significant difference at each follow-up interval. For each alternative precision, we then also calculated the expected reduction in revision rates (effect size) attributable to TA-TKA intervention and the number needed to treat (NNT) using TA-TKA to prevent one revision at 2, 5, 10, and 15 years after index surgery for the entire set of Kaplan-Meier survival analyses. RESULTS: The results from our simulation found survivorship differences favoring TA-TKA ranging from 1.4% to 2.0% at 15 years of follow-up. Comparative studies would need to enroll between 2500 and 4000 patients in each arm of the study, depending on the precision of the navigated or robotic procedure, to have an 80% chance of showing this reduction in revision rates at 15 years of follow-up. For the highest precision simulated intervention, the NNT using TA-TKA to prevent one revision was 1000 at 2 years, 334 at 5 years, 100 at 10 years, and 50 at 15 years post-index surgery. CONCLUSION: Based on these simulations, it appears that TA-TKA interventions could potentially result in a relative reduction in revision rates as large as 27% (from 7.5% down to about 5.5% at 15 years for the intervention with the most precise coronal alignment); however, since this 2% absolute reduction in revision rates is relatively small in comparison with the baseline success rate of TKA and would not be realized until 15 years after the index surgery, traditional RCT studies would require excessively large numbers of patients to be enrolled and excessively long follow-up times to demonstrate whether such a reduction actually exists. CLINICAL RELEVANCE: Given that the NNTs to avoid revisions at various time points are predicted to be high, it would require correspondingly low system costs to justify broad adoption of TA-TKA based on avoided revision costs alone, though we speculate that technology assistance could perhaps prove to be cost effective in the care of patients who are at an elevated risk of revision.

Recruitment of US Adolescents and Young Adults (AYA) into Human Immunodeficiency Virus (HIV)-Related Behavioral Research Studies: A Scoping Review.

PURPOSE OF REVIEW: The objective of this scoping review was to examine the range of published evidence on recruitment approaches and outcomes of US adolescents and young adults (AYA) ages (18-29 years) into human immunodeficiency virus (HIV)-related behavioral research studies during the past 10 years. RECENT FINDINGS: Implementation of effective behavioral research strategies among HIV at-risk and infected AYA is key to ending the HIV epidemic and necessitates successful recruitment strategies. A comprehensive search was executed across four electronic databases. Of the 1697 identified studies, seven met inclusion criteria with six of these seven directed to HIV prevention. Most studies used online recruitment as part of a hybrid strategy, and combined field-based/in-person and online methods. Recruitment strategies and outcomes, resources and compensation, procedures for consent, and timelines varied among all seven studies. Our results highlight the need for development of recruitment models in alignment with behavioral strategies aimed to treat and prevent HIV among US AYA.

Introduction to clinical research based on modern epidemiology.

Over the past 20 years, recent advances in science technologies have dramatically changed the styles of clinical research. Currently, it has become more popular to use recent modern epidemiological techniques, such as propensity score, instrumental variable, competing risks, marginal structural modeling, mixed effects modeling, bootstrapping, and missing data analyses, than before. These advanced techniques, also known as modern epidemiology, may be strong tools for performing good clinical research, especially in large-scale observational studies, along with relevant research questions, good databases, and the passion of researchers. However, to use these methods effectively, we need to understand the basic assumptions behind them. Here, I will briefly introduce the concepts of these techniques and their implementation. In addition, I would like to emphasize that various types of clinical studies, not only large database studies but also small studies on rare and intractable diseases, are equally important because clinicians always do their best to take care of many kinds of patients who suffer from various kidney diseases and this is our most important mission.

Antiinflammatory and anti-cancer activities of pomegranate and its constituent, ellagic acid: Evidence from cellular, animal, and clinical studies.

Inflammation is commonly characterized as a defensive and protective reaction of the body to various exogenous or endogenous stimuli, which aims to maintain the body health. Punica granatum (pomegranate) and its constituent ellagic acid (EA) are recently more taken into accounts since their promising pharmacological effects. Therefore, we aimed to obtain a comprehensive review regarding antiinflammatory, anticancer, and antioxidant activities of both pomegranate and EA and their possible involved mechanisms. In the procedure, scientific databases, including Web of Science, PubMed, Scopus, and Google Scholar, were searched in the English language, until the end of January 2019. Pomegranate belonging to the Punicaceae has been used for medical purposes from ancient and in different cultures. Several studies have also supported that EA is the major active compound of pomegranate and possesses antimutagenic, antiinflammatory, antifibrosis, anticancer, and antiaging properties. It has been suggested that pomegranate and EA possess promising immunomodulatory effects in preclinical models as well as human studies through regulation of the T-cell function and suppressing humoral immunity. Hopefully, we wish that this review and information could be helpful for designing further experiments to investigate the potential protective effects of pomegranate and EA.

Out damn bot, out: Recruiting real people into substance use studies on the internet.

While the Internet has become a popular and effective strategy for recruiting substance users into research, there is a large risk of recruiting duplicate individuals and Internet bots that pose as humans. Strategies to mitigate these issues are outlined and categorized into two groups: (1) automatic techniques which are often embedded into surveys and (2) ongoing manual techniques implemented during recruitment. Potential limitations of these strategies are discussed, and an example of the prevalence of duplicate data within a substance using sample is provided. Overall, it is recommended that researchers consider the use of routine strategies to mitigate the risks associated with recruiting online samples such as: verifying participant contact information, IP address checks, and ongoing cross-checking of participant information for duplicates, similarities and inconsistencies.

Bridging the gap between the laboratory and the clinic for patients with sarcopenia.

Sarcopenia-the age-related loss of skeletal muscle mass and strength-is a major public health issue. Sarcopenia is associated with an increased risk of falls, disability, dependency, institutionalization, hospital stay and early death. Finding interventions to stabilize, reverse or prevent sarcopenia is therefore a key goal for clinical ageing research. If patients are to eventually benefit from discovery science on ageing skeletal muscle, we need to build a translational pipeline that facilitates progress from laboratory science and epidemiology, through feasibility testing to early-phase, and eventually late-phase clinical trials. A number of barriers need to be overcome to make this pipeline work-in particular challenges around identifying people with sarcopenia in routine clinical practice, ensuring that we study patients with clearly defined sarcopenia rather than related conditions such as functional impairment, developing capacity to run trials for older people, and selecting trial outcomes of relevance to older people with multimorbidity. A further key point is that interventions should ideally have pleiotropic actions-i.e. beneficial actions across multiple organ systems, rather than treating sarcopenia alone. Such pleiotropic interventions may be the only way to avoid the perils of polypharmacy and drug interactions that bedevil care for many older people. Maximising the potential for scientific discoveries in the biology of ageing muscle to improve health requires that discovery scientists, translational clinical scientists and clinicians come together to exchange findings and shape each others ideas within a shared culture.

Quantitative analysis of multi-element synergy stabilizing performance: comparison of three methods with respect to their use in clinical studies.

A number of analyses associated with the uncontrolled manifold (UCM) hypothesis have been used recently to investigate stability of actions across populations. We explored whether some of those methods have an advantage for clinical studies because they require fewer trials to achieve consistent findings. We compared the number of trials needed for the analysis of inter-trial variance, analysis of motor equivalence, and analysis in the space of referent coordinates. Young healthy adults performed four-finger accurate force production tasks under visual feedback with the right (dominant) and left hand over three days. Three methods [analytical (M1), experimental (M2), and cumulative mean (M3) methods] were used to define the minimal number of trials required to reach certain statistical criteria. Two of these methods, M1 and M2, showed qualitatively similar results. Fewer trials (M1: 5-13, M2: 4-10) were needed for analysis of motor equivalence compared to inter-trial variance analysis (M1: 14-24, M2: 10-14). The third method (M3) showed no major differences among the outcome variables. The index of synergy in the inter-trial variance analysis required a very small number of trials (M1, M2: 2-4). Variables related to referent coordinates required only a few trials (under 3), whereas the synergy index in this analysis required the largest number of trials (M1: 24-34, M2: 12-16). This is the first study to quantify the number of trials needed for UCM-based methods of assessing motor coordination broadly used in clinical studies. Clinical studies can take advantage of specific recommendations based on the current data regarding the number of trials needed for each analysis thus allowing minimizing the test session duration without compromising data reliability.

Propensity score methods and regression adjustment for analysis of nonrandomized studies with health-related quality of life outcomes.

PURPOSE: The aim of this study was to investigate the potential added value of combining propensity score (PS) methods with multivariable linear regression (MLR) in estimating the average treatment effect on the treated (ATT) in nonrandomized studies with health-related quality of life (HRQoL) outcomes. METHODS: We first used simulations to compare the performances of different PS-based methods, either alone or in combination with further MLR adjustment, in estimating ATT. PS methods were, respectively, optimal pair (OPM) and full (OFM) PS matching, subclassification on the PS (SBC), and the inverse probability of treatment weighting (IPTW). We simulated several scenarios, according to different sample sizes, proportions of treated vs untreated subjects, and types of HRQoL outcomes. We also applied the same methods to a real clinical data set. RESULTS: OPM and IPTW provided the closest Type I error to the nominal threshold α = 0.05 across all scenarios. Overall, both methods showed also lower variability in estimates than SBC and OFM. SBC performed worst, generally providing the highest levels of bias. Further MLR adjustment lessened bias for all methods, however providing higher Type I error for SBC and OFM. In the real case, all methods provided similar ATT estimates except for one outcome. CONCLUSIONS: Our findings suggest that for sample sizes up to n = 200, OPM and IPTW are to be preferred to OFM and SBC in estimating ATT on HRQoL outcomes. Specifically, OPM performed best in sample sizes of n ≥ 80, IPTW for smaller sample sizes. Additional MLR adjustment can further improve ATT estimates.

[On the use of mathematical statistics methods in clinical and experimental studies.]

In the paper a number of issues, including conceptual ones, related to the specific features of making statistical decisions, choosing tests and computing characteristics that will strengthen the evidence base of the conclusions obtained when analyzing data using methods of mathematical statistics, are considered. The paper aims not to describe the methods of mathematical statistics themselves, but to analyze the conditions and the need to apply the most common tests. In particular, the magnitude of the indicator of the statistical significance of the observed effects - p-value - and the sample size to obtain a significant effect are discussed, the effect of multiple comparisons, the application of the Bayesian approach, and others are considered.

Response-adaptive treatment allocation for survival trials with clustered right-censored data.

A comparison of 2 treatments with survival outcomes in a clinical study may require treatment randomization on clusters of multiple units with correlated responses. For example, for patients with otitis media in both ears, a specific treatment is normally given to a single patient, and hence, the 2 ears constitute a cluster. Statistical procedures are available for comparison of treatment efficacies. The conventional approach for treatment allocation is the adoption of a balanced design, in which half of the patients are assigned to each treatment arm. However, considering the increasing acceptability of responsive-adaptive designs in recent years because of their desirable features, we have developed a response-adaptive treatment allocation scheme for survival trials with clustered data. The proposed treatment allocation scheme is superior to the balanced design in that it allows more patients to receive the better treatment. At the same time, the test power for comparing treatment efficacies using our treatment allocation scheme remains highly competitive. The advantage of the proposed randomization procedure is supported by a simulation study and the redesign of a clinical study.

From Theory-Inspired to Theory-Based Interventions: A Protocol for Developing and Testing a Methodology for Linking Behaviour Change Techniques to Theoretical Mechanisms of Action.

Background: Understanding links between behaviour change techniques (BCTs) and mechanisms of action (the processes through which they affect behaviour) helps inform the systematic development of behaviour change interventions. Purpose: This research aims to develop and test a methodology for linking BCTs to their mechanisms of action. Methods: Study 1 (published explicit links): Hypothesised links between 93 BCTs (from the 93-item BCT taxonomy, BCTTv1) and mechanisms of action will be identified from published interventions and their frequency, explicitness and precision documented. Study 2 (expert-agreed explicit links): Behaviour change experts will identify links between 61 BCTs and 26 mechanisms of action in a formal consensus study. Study 3 (integrated matrix of explicit links): Agreement between studies 1 and 2 will be evaluated and a new group of experts will discuss discrepancies. An integrated matrix of BCT-mechanism of action links, annotated to indicate strength of evidence, will be generated. Study 4 (published implicit links): To determine whether groups of co-occurring BCTs can be linked to theories, we will identify groups of BCTs that are used together from the study 1 literature. A consensus exercise will be used to rate strength of links between groups of BCT and theories. Conclusions: A formal methodology for linking BCTs to their hypothesised mechanisms of action can contribute to the development and evaluation of behaviour change interventions. This research is a step towards developing a behaviour change 'ontology', specifying relations between BCTs, mechanisms of action, modes of delivery, populations, settings and types of behaviour.

Standardized Methods for Enhanced Quality and Comparability of Tuberculous Meningitis Studies.

Tuberculous meningitis (TBM) remains a major cause of death and disability in tuberculosis-endemic areas, especially in young children and immunocompromised adults. Research aimed at improving outcomes is hampered by poor standardization, which limits study comparison and the generalizability of results. We propose standardized methods for the conduct of TBM clinical research that were drafted at an international tuberculous meningitis research meeting organized by the Oxford University Clinical Research Unit in Vietnam. We propose a core dataset including demographic and clinical information to be collected at study enrollment, important aspects related to patient management and monitoring, and standardized reporting of patient outcomes. The criteria proposed for the conduct of observational and intervention TBM studies should improve the quality of future research outputs, can facilitate multicenter studies and meta-analyses of pooled data, and could provide the foundation for a global TBM data repository.

A new framework for the documentation and interpretation of oral food challenges in population-based and clinical research.

BACKGROUND: The conduct of oral food challenges as the preferred diagnostic standard for food allergy (FA) was harmonized over the last years. However, documentation and interpretation of challenge results, particularly in research settings, are not sufficiently standardized to allow valid comparisons between studies. Our aim was to develop a diagnostic toolbox to capture and report clinical observations in double-blind placebo-controlled food challenges (DBPCFC). METHODS: A group of experienced allergists, paediatricians, dieticians, epidemiologists and data managers developed generic case report forms and standard operating procedures for DBPCFCs and piloted them in three clinical centres. The follow-up of the EuroPrevall/iFAAM birth cohort and other iFAAM work packages applied these methods. RECOMMENDATIONS: A set of newly developed questionnaire or interview items capture the history of FA. Together with sensitization status, this forms the basis for the decision to perform a DBPCFC, following a standardized decision algorithm. A generic form including details about severity and timing captures signs and symptoms observed during or after the procedures. In contrast to the commonly used dichotomous outcome FA vs no FA, the allergy status is interpreted in multiple categories to reflect the complexity of clinical decision-making. CONCLUSION: The proposed toolbox sets a standard for improved documentation and harmonized interpretation of DBPCFCs. By a detailed documentation and common terminology for communicating outcomes, these tools hope to reduce the influence of subjective judgment of supervising physicians. All forms are publicly available for further evolution and free use in clinical and research settings.

Sample size calculations based on a difference in medians for positively skewed outcomes in health care studies.

BACKGROUND: In healthcare research, outcomes with skewed probability distributions are common. Sample size calculations for such outcomes are typically based on estimates on a transformed scale (e.g. log) which may sometimes be difficult to obtain. In contrast, estimates of median and variance on the untransformed scale are generally easier to pre-specify. The aim of this paper is to describe how to calculate a sample size for a two group comparison of interest based on median and untransformed variance estimates for log-normal outcome data. METHODS: A log-normal distribution for outcome data is assumed and a sample size calculation approach for a two-sample t-test that compares log-transformed outcome data is demonstrated where the change of interest is specified as difference in median values on the untransformed scale. A simulation study is used to compare the method with a non-parametric alternative (Mann-Whitney U test) in a variety of scenarios and the method is applied to a real example in neurosurgery. RESULTS: The method attained a nominal power value in simulation studies and was favourable in comparison to a Mann-Whitney U test and a two-sample t-test of untransformed outcomes. In addition, the method can be adjusted and used in some situations where the outcome distribution is not strictly log-normal. CONCLUSIONS: We recommend the use of this sample size calculation approach for outcome data that are expected to be positively skewed and where a two group comparison on a log-transformed scale is planned. An advantage of this method over usual calculations based on estimates on the log-transformed scale is that it allows clinical efficacy to be specified as a difference in medians and requires a variance estimate on the untransformed scale. Such estimates are often easier to obtain and more interpretable than those for log-transformed outcomes.

Medications development for the treatment of alcohol use disorder: insights into the predictive value of animal and human laboratory models.

Development of effective treatments for alcohol use disorder (AUD) represents an important public health goal. This review provides a summary of completed preclinical and clinical studies testing pharmacotherapies for the treatment of AUD. We discuss opportunities for improving the translation from preclinical findings to clinical trial outcomes, focusing on the validity and predictive value of animal and human laboratory models of AUD. Specifically, while preclinical studies of medications development have offered important insights into the neurobiology of the disorder and alcohol's molecular targets, limitations include the lack of standardized methods and streamlined processes whereby animal studies can readily inform human studies. Behavioral pharmacology studies provide a less expensive and valuable opportunity to assess the feasibility of a pharmacotherapy prior to initiating larger scale clinical trials by providing insights into the mechanism of the drug, which can then inform recruitment, analyses, and assessments. Summary tables are provided to illustrate the wide range of preclinical, human laboratory, and clinical studies of medications development for alcoholism. Taken together, this review highlights the challenges associated with animal paradigms, human laboratory studies, and clinical trials with the overarching goal of advancing treatment development and highlighting opportunities to bridge the gap between preclinical and clinical research.

Facilitating Clinical Studies in Rare Diseases.

In recent years, there have been many scientific advances and new collaborations for rare diseases research and, ultimately, the health of patients living with rare diseases. However, for too many rare diseases, there still is no effective treatment, and our understanding of the incidence, prevalence, and underlying etiology is incomplete. To facilitate the studies needed to answer the many open questions there is a great need for the active involvement of all stakeholders, most importantly of patient groups. Also, the creation of streamlined infrastructure for performing multi-site clinical studies is critical, as is the engagement of multi-disciplinary teams with shared focus on a group of diseases. Another essential component of such efforts is to collect standardized data so that downstream meta-analyses and data sharing can be facilitated. To ensure high-quality protocols and datasets, a central data management and coordinating center is important. Since there are more than 6000 rare diseases, instead of focusing on single rare disease, it is more impactful to create platforms and methods that can support a group of rare diseases.

Can an early phase clinical pharmacology study replace a thorough QT study? Experience with a novel H3-receptor antagonist/inverse agonist.

OBJECTIVE: The objective of the present study was to compare the effects of pitolisant on QTcF interval in a single ascending dose (SAD) study and a thorough QT (TQT) study. METHODS: The SAD study at three dose levels of pitolisant enrolled 24 males and the TQT study at two dose levels 25 males. Both studies intensively monitored ECGs and pitolisant exposure. Effect on QTcF interval was analysed by Intersection Union Test (IUT) and by exposure-response (ER) analysis. Results from the two studies were compared. RESULTS: In both studies, moxifloxacin effect established assay sensitivity. IUT analysis revealed comparable pitolisant-induced maximum mean (90 % confidence interval (CI)) placebo-corrected increase from baseline (ΔΔQTcF) in both the studies, being 13.3 (8.1; 18.5) ms at 200-mg and 9.9 (4.7; 15.1) ms at 240-mg doses in SAD study and 5.27 (2.35; 8.20) ms at 120-mg dose in TQT study. ER analysis revealed that ER slopes in SAD and TQT studies were comparable and significantly positive (0.031 vs 0.027 ms/ng/mL, respectively). At geometric mean concentrations, bootstrap predicted ΔΔQTcF (90 % CI) were 9.23 (4.68; 14.4) ms at 279 ng/mL (240-mg dose) in the SAD study and 4.97 (3.42; 8.19) ms at 156 ng/mL (120-mg dose) in the TQT study. CONCLUSION: Pitolisant lacked an effect of regulatory concern on QTc interval in both the studies, however analysed, suggesting that the results from the SAD study could have mitigated the need for a TQT study. Our findings add to the growing evidence that intensive ECG monitoring in early phase clinical studies can replace a TQT study.