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Conventional seamless phase 2/3 design with fixed sample size determination (SSD) has gained its popularity in oncology drug development due to attractive features such as significantly shortening the development timeline, minimizing sample size, as well as early decision making. However, this design is not immune to inaccurate treatment effect assumption when only limited efficacy data are available at study design stage. We propose an innovative seamless phase 2/3 study design with flexible SSD for oncology trials, in which the trial is designed under a distribution of treatment effect instead of one single assumption due to huge uncertainty of treatment effect at design stage and the sample size for end of phase 3 analysis is not predetermined at design stage, but rather dynamically determined based on observed treatment effect at phase 2 portion. Some practical sample size determination rules for end of phase 3 analysis will be discussed. The proposed design can lead to reduced sample size or/and improved power compared with conventional seamless phase 2/3 design with fixed SSD. This innovative study design can be especially useful for programs with aggressive development strategy to expedite the process in delivering efficacious treatment to patients.

In oncology trials, non-inferiority concepts (e.g., shortening duration of chemotherapy) have sometimes been evaluated without preliminary knowledge of an experimental treatment being non-inferior ...

BackgroundBayesian methods are increasing in popularity in clinical research. The design of Bayesian clinical trials requires a prior distribution, which can be elicited from experts. Current elicitation approaches either use face-to-face sessions or expert surveys. In diseases with international differences in management, the elicitation exercise should recruit internationally, requiring expensive face-to-face sessions or surveys, which suffer low response rates. To address this, we developed a remote, real-time elicitation exercise to construct prior distributions. These elicited distributions were then used to determine the sample size of the Bronchiolitis in Infants with Placebo Versus Epinephrine and Dexamethasone (BIPED) Study, an international randomized controlled trial trial in the Pediatric Emergency Research Network (PERN). The BIPED study aims to determine whether the combination of epinephrine and dexamethasone, compared to placebo, is effective in reducing hospital admission for infants presenting with bronchiolitis to the emergency department.MethodsWe developed a web-based tool to support the elicitation of the probability of hospitalization for infants with bronchiolitis. Experts participated in online workshops to specify their individual prior distributions, which were aggregated using the equal-weighted linear pooling method. The Average Length Criterion determined the BIPED sample size.ResultsFifteen paediatric emergency medicine clinicians from Canada, USA, Australia and New Zealand participated in three workshops to provide their elicitied prior distributions. The elicited probability of admission for infants with bronchiolitis was slightly lower for those receiving epinephrine and dexamethasone compared to supportive care in the aggregate distribution. There were substantial differences in the individual beliefs but limited differences between North America and Australaisia. From this aggregate distribution, a sample size of 410 patients per arm results in an average 95% credible interval length of less than 9% and a relative predictive power of 90%.ConclusionRemote expert elicitation is a feasible, useful and practical tool to determine a prior distribution for international randomized controlled trials. Bayesian methods can then determine the trial sample size using these elicited prior distributions. The ease and low cost of remote expert elicitation means that this approach is suitable for future international randomized controlled trials.Trial Registration: clinicaltrials.gov Identifier: NCT03567473

A randomized exploratory clinical trial comparing an experimental treatment with a control treatment on a binary endpoint is often conducted to make a go or no-go decision. Such an exploratory trial needs to have an adequate sample size such that it will provide convincing evidence that the experimental treatment is either worthwhile or unpromising relative to the control treatment. In this paper, we propose three new sample-size determination methods for an exploratory trial, which utilize the posterior probabilities calculated from predefined efficacy and inefficacy criteria leading to a declaration of the worthwhileness or unpromisingness of the experimental treatment. Simulation studies, including numerical investigation, showed that all three methods could declare the experimental treatment as worthwhile or unpromising with a high probability when the true response probability of the experimental treatment group is higher or lower, respectively, than that of the control treatment group.

–It is common for clinical trials to include strata of patients with different risks of disease. In cancer trial settings, patients with different prior treatment history, tumor stages, metastatic sites may be included in a single trial. This is especially so for early phase studies that are exploratory in nature. In many cases, patient responses from these strata may be ordered. For example, earlier stage patients should have better outcomes than later stage patients. Incorporating such stratum information can lead to increased statistical efficiency and therefore possibly reduce sample sizes. Recent works have begun to deal with this issue for single-arm phase II cancer trials in terms of sample size determination. However, no approaches yet exist to explicitly consider the order constraint. In this article, we propose to use likelihood ratio tests with order constraints for both one-stage and two-stage designs. Our numerical results show that the proposed designs tend to have better power profiles compared with existing methods. A real application of our method to an ongoing phase II study is also included.

The small n, Sequential, Multiple Assignment, Randomized Trial (snSMART) is a two-stage clinical trial design for rare diseases motivated by the comparison of three active treatments for isolated skin vasculitis in the ongoing clinical trial ARAMIS (a randomized multicenter study for isolated skin vasculitis, NCT09239573). In Stage 1, all patients are randomized to one of three treatments. In Stage 2, patients who respond to their initial treatment receive the same treatment again, while those who fail to respond are re-randomized to one of the two remaining treatments. A Bayesian method for estimating the response rate of each individual treatment in a three-arm snSMART demonstrated efficiency gains for a given sample size relative to other existing frequentist approaches. However, these efficiency gains are dependent upon knowing how many subjects are required to determine a specific difference in the treatment response rates. Because few sample size calculation methods for snSMARTs exist, we propose a Bayesian sample size calculation for an snSMART designed to distinguish the best treatment from the second-best treatment. Although our methods are based on asymptotic approximations, we demonstrate via simulations that our proposed sample size calculation approach produces the desired statistical power, even in small samples. Moreover, our methods and applet produce sample sizes quickly, thereby saving time relative to using simulations to determine the appropriate sample size. We compare our proposed sample size to an existing frequentist method based upon a weighted

Background: Sample-size calculations are critical to ensure that randomised control trials return robust and reliable results. The estimated treatment effects used in these calculations is often significantly different from the actual treatment effect and can dramatically impact trial validity.Methods: This study examined sample-size calculations in randomised controlled trials designed to show superiority between two-arm parallel groups with a single primary outcome that were published in the top five anaesthetic journals for 2014 (as per Thomson Reuters impact factors). In particular, it sought to determine treatment effect estimations used in a priori sample-size calculations and compare them with actual treatment effects.Results: A PubMed search identified 209 possible articles; 52 were drawn for full text review; and 28 were included in the final analysis. The relative difference between expected and actual event rates was greater than 20% in 80% of trials and greater than 50% in 44% of trials.Conclu...

The selection of progression-free survival (PFS) or overall survival (OS) as the most suitable primary endpoint (PE) in oncology Phase 3 trials is currently under intense debate. Because of substantial limitations in the single use of PFS (or OS) as the PE, trial designs that include PFS and OS as co-primary endpoints are attracting increasing interest. In this article, we report on the formulation of determining the sample size for a trial that sequentially tests PFS and OS by treating them as co-PEs. Using a three-component model of OS, the proposed method overcomes the drawbacks of an existing method that requires unreasonable assumption of the exponential distribution for OS, although the hazard function is nonconstant because effective subsequent therapy has prolonged postprogression survival in recent oncology trials. Alternative estimation method of hazard ratio for OS under a three-component mode is also discussed by checking the appropriateness of assuming proportionality of hazards for OS. In order to examine the performance of our proposed method, we performed three numerical studies using both simulated and actual data of cancer Phase 3 trials. We find that the proposed method preserves a prespecified target value of power with a feasible increment of trial scale.

More and more studies have shown that genetic determinants may mediate variability among persons in the response to a drug. In other words, some therapeutics benefit only a subset of treated patien...

Heart rate variability (HRV) is a physiologic phenomenon that occurs due to changing autonomic tone resulting in variable RR intervals. A reduction in HRV is used as an index of pain in neonatal human patients. Objective measures of pain would be valuable in the evaluation of canine patients and assessment of response to pain management strategies. We hypothesized that dogs with diseases associated with discomfort (osteoarthritis and bone neoplasia) would have reduced HRV compared with normal, healthy dogs. The aim of the study was to calculate the sample size necessary to investigate this hypothesis. Seventeen dogs from the Ryan Veterinary Hospital of the University of Pennsylvania patient population or owned by Ryan Veterinary Hospital of the University of Pennsylvania staff were enrolled in this single-blind, prospective pilot study. A 30 min electrocardiogram (ECG) was obtained from each dog using an ambulatory electrocardiographic monitor. All ECGs were obtained between 10 a.m. and 2 p.m. ECGs were analyzed and time-domain HRV indices computed. Sample size calculations suggest that 207 dogs would be necessary to ascertain if HRV is reduced in dogs experiencing discomfort or pain (50 in the arthritis group, 79 in the bone cancer group, and 78 in the control group).

Clinical trials with event-time outcomes as co-primary contrasts are common in many areas such as infectious disease, oncology, and cardiovascular disease. We discuss methods for calculating the sample size for randomized superiority clinical trials with two correlated time-to-event outcomes as co-primary contrasts when the time-to-event outcomes are exponentially distributed. The approach is simple and easily applied in practice.

Dermatologic surgery is a fruitful research area that has spawned numerous randomized control trials (RCTs).To assess the quality of reporting of randomization, blinding, sample size, and power analysis in RCTs published in the journal Dermatologic Surgery.Randomized control trials published in Dermatologic Surgery between 1995 and 2012 were assessed regarding the quality of trial reporting. Data extraction performed independently by 2 data extractors.Dramatic increases in the numbers of RCTs in dermatologic surgery were noted in successive 5-year periods, from 39 in 1995 to 1999 to 66 in 2000 to 2004 and 131 in 2005 to 2009. The median Jadad score for articles from 1995 to 1999 was 1 and was 2 for articles since 2000. Subjects per study were 20 during 1995 to 1999, 25.5 from 2000 to 2004, and over 30 since 2005. Power analysis with sample size determination was reported in 0 articles during 1995 to 1999; greater than 13% of articles since 2005. Alpha level was specified for 37% of RCTs from 1995 to 1999 and 64% to 70% since 2005.During the last 20 years, the number of RCTs in Dermatologic Surgery has grown rapidly, almost doubling every 5 years, because the number of subjects per study has also increased and the quality of reporting has significantly improved.

A fundamental issue in regulatory decision making is the assessment of the benefit/risk profile of a compound. In order to do this, establishing the existence of a treatment effect by a significance test is not sufficient, but the clinical relevance of a potential benefit must also be taken into account. A number of regulatory guidelines propose that clinical relevance should be assessed by considering the rate of responders, i.e. the proportion of patients who are observed to achieve an apparently meaningful benefit. In this paper, we present methods for planning clinical trials that aim at demonstrating both statistical and clinical significance in superiority trials. Procedures based on analytical calculations are derived for normally distributed data and the case of a single endpoint as well as multiple primary outcomes. A bootstrap procedure is proposed that can be applied to non-normal data. Application is illustrated by a clinical trial in Alzheimer's disease.

Prior to the evaluation of protective efficacy, experimental vaccines conventionally undergo phase II randomized controlled clinical trials to evaluate safety and immunogenicity. Typically, an experimental vaccine is compared to another vaccine or to a placebo with respect to adverse events or immune responses, or both. Various strategies and methods are available for design and analysis of such studies. A key aspect of design is the determination of sample size. Often a sample size is chosen that gives a high probability ("power") of finding a statistically significant difference in an outcome of interest, if a difference of a specified size exists. This approach is appropriate when the primary goal of the study is to demonstrate that a difference exists between two groups or treatments. It may not, however, give adequate assurance that a confidence interval around the observed difference will be narrow enough to exclude the possibility of an unacceptably low immune response or unacceptably high adverse event frequency in recipients of the experimental vaccine. In this paper, we apply the "non-inferiority" trial design to phase II vaccine studies; that is, we design the trial to rule out a difference between the vaccine and control in immunogenicity or reactogenicity that is considered unacceptable. We also consider a setting in which the desire is to show that the difference between immune response rates for vaccine and control is greater than a specified value.

In the design of clinical trials, sample size determination is usually undertaken by statisticians and clinicians. It is rare for health economists to be involved in this aspect of trial design. However, there are a number of outcome changes that are of 'economic significance', and it is important for trial designers and funders to be aware of these before planning, funding and mounting a trial. In this paper we demonstrate through the use of three examples (prevention of osteoporosis, management of infertility, and endometriosis) how economics can be used to influence the size of a clinical trial. Trials that are too small or too large waste research resources; health economics can lead to more efficient trial designs.

Objective — To determine the efficacy of screening for breast cancer in women aged 40 to 49. Methods — A large number of women will have to be enrolled to ensure adequate statistical power. Attention will be restricted to the deaths from breast cancer that occur among comparable groups of patients with breast cancer rather than to an analysis in which all women entering into the trial are considered at risk of dying from breast cancer (population mortality analysis). As the new trial is likely to be conducted in regions where screening has been established for all women from age SO onward, comparability may be reached by including the breast cancers detected at the routine screening examination at age 50. Conclusions — When comparability of cases can be reached, such a case mortality analysis requires 15–30% fewer women to be enrolled than a population approach.

Summary Objectives The vocal tract discomfort scale is a self-rating seven-point Likert scale that quantifies frequency and severity of eight qualitative descriptors including burning, tight, dry, aching, tickling, sore, irritable, and lump in the throat, and ranges from 0 (never/none) to 6 (always/extreme; Mathieson et al. 2009). The objectives of the current study were to compare the vocal tract discomfort scale results between elementary school teachers and high school teachers and between male and female teachers using the Persian vocal tract discomfort scale. Also, teachers in different age ranges and with different experiences were compared regarding vocal tract discomfort symptoms. Methods The researchers chose 20 elementary and high schools by simple random sampling in Khorramabad, Iran. The survey was given to available teachers of the selected schools. Considering the inclusion criteria, required sample size, and after excluding questionnaires that were not correctly answered, 120 were selected such that 30 were chosen for each subgroup. Subjects consisted of 60 elementary school teachers (30 females and 30 males) with the mean age of 40.92 years (standard deviation = 6.07) and 60 high school teachers (30 females and 30 males) with the mean age of 40.67 years (standard deviation = 6.00). SPSS 25 was used for analyzing the data. Results Results indicated that the frequency and severity of the vocal tract discomfort in elementary school teachers were significantly higher than for the high school teachers with a medium to large effect size. Although the frequency and severity of the symptoms were higher in female compared with male teachers, those differences were not significantly different. Younger teachers had lower frequency and severity ratings of vocal tract discomfort symptoms than older teachers. Teaching experience was not an important factor in predicting vocal tract discomfort symptoms in teachers. Conclusions The results of this study suggest that there is higher frequency, greater severity, and higher percentages of vocal tract discomfort symptoms in elementary compared with high school teachers. In addition, although the mean frequency and severity of vocal tract discomfort symptoms were not significantly different between females and males, females reported higher percentages of the symptoms. Because each of the eight vocal tract symptoms was experienced at the time of testing by between 42% (tightness) and 68% (dryness) of the participants, it is suggested that an educational program regarding vocal tract discomfort may be helpful for this profession.

OBJECTIVES: Observational studies report mixed findings regarding the association between vitamin D and JIA incidence or activity, however such studies are susceptible to considerable bias. Since low vitamin D levels are common within the general population and easily corrected, there is potential public health benefit in identifying a causal association between vitamin D insufficiency and JIA incidence. To limit bias due to confounding and reverse causation we examined the causal effect of the major circulating form of vitamin D, 25-(OH)D, on JIA incidence using Mendelian randomization (MR).METHODS: In this two sample MR analysis we used summary level data from the largest and most recent genome wide association study (GWAS) of 25-(OH)D levels (sample size 443,734), alongside summary data from two JIA GWASs (sample sizes 15,872 and 12,501), all from European populations. To test and account for potential bias due to pleiotropy we employed multiple MR methods and sensitivity analyses.RESULTS: We found no evidence of a causal relationship between genetically predicted 25-(OH)D levels and JIA incidence (OR 1.00, 95% CI 0.76-1.33 per standard deviation increase in standardised natural-log transformed 25-(OH)D levels). This estimate was consistent across all methods tested. Additonally there was no evidence that genetically predicted JIA causally influences 25-(OH)D levels (-0.002 standard deviation change in standardised natural-log transformed 25-(OH)D levels per doubling odds in genetically predicted JIA, 95% CI -0.006-0.002).CONCLUSION: Given the lack of a causal relationship between 25-(OH)D levels and JIA, population level vitamin D supplementation is unlikely to reduce JIA incidence.

Introduction: Hydroxychloroquine (HCQ) has recently become the focus of attention in the current COVID-19 pandemic. With an increase in the off-label use of HCQ, concern for the safety of HCQ has been raised. We, therefore, performed this systematic review to analyze the safety data of HCQ against placebo and active treatment in various disease conditions. Methods: We searched PubMed, Embase, and Cochrane for Randomized Controlled Trials (RCTs) and Observational Studies (OSs) that evaluated HCQ for the treatment of any disease other than COVID19 in adult patients up to May 2020. We assessed the quality of the included studies using Risk of Bias 2 (for RCTs) and Newcastle–Ottawa Scale (for OSs). Data were analyzed with randomeffect meta-analysis. Sensitivity and subgroup analyses were performed to identify heterogeneity. Results: A total of 6641 studies were screened, and 49 studies (40 RCTs and 9 OSs) with a total sample size of 35044 patients were included. The use of HCQ was associated with higher risks of TDAEs as compared to placebo/no active treatment [RR 1.47, 95%CI 1.03-2.08]. When HCQ was compared with active treatments, the risks of AEs [RR 0.74, 95% CI 0.63-0.86] and TDAEs were less in the HCQ arm [RR 0.57, 95% CI 0.39-0.81]. The outcomes did not differ in the sensitivity analysis. Conclusion: The results suggest that the use of HCQ was associated with a lower risk of AEs and TDAEs as compared to active treatment, whereas posing higher risk of TDAEs as compared to placebo.

Summary Introduction Prehabilitation is defined as preoperative conditioning of patients in order to improve post-operative outcomes. Some studies showed an increase in functional recovery following colorectal surgery, but its effect in hepato-pancreato-biliary (HPB) surgery is unclear. The aim of this study was to realize a systematic literature review and meta-analysis on the current available evidence on prehabilitation in HPB surgery. Materials and methods A systematic review and a metanalysis were carried out on prehabilitation (physical, nutritional and psychological interventions) in HPB surgery (2009-2019). Assessed outcomes were postoperative complications, length of stay (LOS), 30-day readmission, and mortality. Main results Four studies among the 191 screened were included in this systematic review (3 randomized controlled trials, 1 case-control propensity score study), involving 419 patients (prehabilitation group, n = 139; control group, n = 280). After pooling, no difference was observed on LOS ((−4.37 days [95% CI: −8.86; 0.13]) or postoperative complications (RR 0.83 [95%CI: 0.62; 1.10]), reported by all the included studies. Two trials reported on readmission rate, but given the high heterogeneity, a meta-analysis was not realized. No deaths were reported among the included studies. Conclusion No effect of prehabilitation programs in HPB surgery was observed on LOS or postoperative complications rate. Future trials with standardized outcomes of measure, and adequately powered samples calculations are thus required. PROSPERO registration CRD42020165218.

Background Three-dimensional (3D) models improve the comprehension of renal anatomy. Objective To evaluate the impact of novel 3D-derived parameters, to predict surgical outcomes after robot-assisted partial nephrectomy (RAPN). Design, setting, and participants Sixty-nine patients with cT1-T2 renal mass scheduled for RAPN were included. Three-dimensional virtual modeling was achieved from computed tomography. The following volumetric and morphological 3D parameters were calculated: VT (volume of the tumor); VT/VK (ratio between tumor volume and kidney volume); CSA3D (ie, contact surface area); UCS3D (contact to the urinary collecting system); Tumor-Artery3D: tumor’s blood supply by tertiary segmental arteries (score = 1), secondary segmental artery (score = 2), or primary segmental/main renal artery (scoren = 3); ST (tumor’s sphericity); ConvT (tumor’s convexity); and Endophyticity3D (ratio between the CSA3D and the global tumor surface). Intervention RAPN with a 3D model. Outcome measurements and statistical analysis Three-dimensional parameters were compared between patients with and without complications. Univariate logistic regression was used to predict overall complications and type of clamping; linear regression was used to predict operative time, warm ischemia time, and estimated blood loss. Results and limitations Overall, 11 (15%) individuals experienced overall complications (7.2% had Clavien ≥3 complications). Patients with urinary collecting system (UCS) involvement at 3D model (UCS3D = 2), tumor with blood supply by primary or secondary segmentary arteries (Tumor-Artery3D = 1 and 2), and high Endophyticity3D values had significantly higher rates of overall complications (all p ≤ 0.03). At univariate analysis, UCS3D, Tumor-Artery3D, and Endophyticity3D are significantly associated with overall complications; CSA3D and Endophyticity3D were associated with warm ischemia time; and CSA3D was associated with selective clamping (all p ≤ 0.03). Sample size and the lack of interobserver variability are the main limits. Conclusions Three-dimensional modeling provides novel volumetric and morphological parameters to predict surgical outcomes after RAPN. Patient summary Novel morphological and volumetric parameters can be derived from a three-dimensional model to describe surgical complexity of renal mass and to predict surgical outcomes after robot-assisted partial nephrectomy.

During the COVID-19 pandemic, there has been an increasing rollout of non-contact fever screening solutions to assist in curbing the spread of disease. This study begins by describing how screening for disease has historically been performed. It proposes four measurement characteristics of an ideal screening solution: non-contact, effective, rapid and low-cost measurements. Next, it reviews the existing literature on fever-screening using non-contact infrared thermometer (NCIT) devices as well as infrared thermography (IRT) devices, as these are two technologies which have experienced increasing use. For this review, 185 research papers were identified, 21 research studies were included after inclusion and exclusion criteria were applied. A total of 35 experiments were identified for analysis and their results tabulated. Of these studies, 66% are IRT and 34% are NCIT, with a median sample size of 430 subjects. 26 experiments involve febrile participants, with a median febrile percentage of 11.22 % of population. The reported sensitivity of febrile detection using NCIT varies from 3.7% to 97% and when using IRT it varies from 15% to 100%. Both indoor and outdoor studies are investigated, as well as those conducted in acute and non-acute settings. The results of this review show a clear lack of consensus on the effectiveness of these systems. Overall, these results indicate that sensitivity and specificity are reduced when using IRT and NCIT technologies compared to other thermometers used in medical practice. Their use should be carefully assessed based on the risks present in each particular measurement scenario. CCBY

BACKGROUND Donepezil had been recognized to have impact on sleep quality in demented patients. However, there was insufficient evidences about the actual effect of donepezil in the sleep architectures. Our meta-analysis aimed to evaluate the changes of sleep architectures related to donepezil use. METHODS Followed the PRISMA2020 and AMSTAR2 guidelines, electronic search had been performed on the databases of PubMed, Embase, ScienceDirect, ClinicalKey, Cochrane CENTRAL, ProQuest, Web of Science, and ClinicalTrials.gov. The outcome measurement was changes of sleep parameters detected by polysomnography. A random-effects meta-analysis was conducted. RESULTS Total twelve studies had been involved. The percentage of REM sleep would significantly increase after donepezil treatment (Hedges' g = 0.694, p

Background: The use of levetiracetam (LEV) has been increasing given its favorable pharmacokinetic profile. Numerous population pharmacokinetic studies for LEV have been conducted. However, there are some discrepancies regarding factors affecting its pharmacokinetic variability. Therefore, this systematic review aimed to summarize significant predictors for LEV pharmacokinetics as well as the need for dosage adjustments. Methods: We performed a systematic search for population pharmacokinetic studies of LEV conducted using a nonlinear-mixed effect approach from PubMed, Scopus, CINAHL Complete, and Science Direct databases from their inception to March 2020. Information on study design, model methodologies, significant covariate-parameter relationships, and model evaluation was extracted. The quality of the reported studies was also assessed. Results: A total of 16 studies were included in this review. Only two studies were conducted with a two-compartment model, while the rest were performed with a one-compartment structure. Bodyweight and creatinine clearance were the two most frequently identified covariates on LEV clearance (CLLEV). Additionally, postmenstrual age (PMA) or postnatal age (PNA) were significant predictors for CLLEV in neonates. Only three studies externally validated the models. Two studies conducted pharmacodynamic models for LEV with relatively small sample size. Conclusion: Significant predictors for LEV pharmacokinetics are highlighted in this review. For future research, a population pharmacokinetic-pharmacodynamic model using a larger sample size should be conducted. From a clinical perspective, the published models should be externally evaluated before clinical implementation.

In the analysis of a clinical trial an investigator may fail to discern a statistically significant difference in outcome between control and experimental groups, when in fact one exists. Failure to demonstrate such a difference when it actually exists is known as "type II" error, and its probability of occurring is termed "beta." The purpose of our study was to determine the distribution of beta errors in negative trials in the Journal of the American College of Emergency Physicians (JACEP) (1972-1979) and Annals of Emergency Medicine (1980-1984). All negative comparative clinical trials appearing in JACEP and Annals from volume 1 (1972) to volume 13 (1984) were surveyed and were eligible for inclusion in the study. A trial was defined as negative if the investigator specifically stated that there was no significant difference in outcome between the experimental and control groups. For each negative trial the following parameters were calculated: beta error, based on the sample size used and the difference determined to be important to detect clinically; sample size required to detect a clinically meaningful difference as determined by the authors of this study; and minimum true difference that had to be detected in the trial at a beta equal to 0.20, to discern a statistically significant result. For the 13 years surveyed, we found 21 endpoints in 14 negative trials that were analyzable. Only one of the trials (7.1%) addressed the issues of beta errors and sample size determination. In the remaining 13 negative trials, the calculated beta error ranged from .60 to .97. For the endpoints analyzed, a sample size of up to 450 times larger than that used would have been required to detect a clinically important difference.(ABSTRACT TRUNCATED AT 250 WORDS)

Context Athletes with anterior cruciate ligament (ACL) reconstruction (ACLR) exhibit increased cortical motor planning during simple sensorimotor tasks compared with healthy athletes serving as control groups. This may interfere with proper decision making during time-constrained movements, elevating the reinjury risk. Objective To compare cortical motor planning and biomechanical stability during jump landings between participants with ACLR and healthy individuals. Design Cross-sectional study. Setting Laboratory. Patients or Other Participants Ten men with ACLR (age = 28 ± 4 years, time after surgery = 63 ± 35 months) and 17 healthy men (age = 28 ± 4 years) completed 43 ± 4 preplanned (landing leg shown before takeoff) and 51 ± 5 unplanned (visual cue during flight) countermovement jumps with single-legged landings. Main Outcome Measure(s) Movement-related cortical potentials (MRCPs) and frontal θ frequency power before the jump were analyzed using electroencephalography. Movement-related cortical potentials were subdivided into 3 successive 0.5-second time periods (readiness potential [RP]-1, RP-2, and negative slope [NS]) relative to movement onset, with higher values indicating more motor planning. Theta power was calculated for the last 0.5 second before movement onset, with higher values demonstrating more focused attention. Biomechanical landing stability was measured via peak vertical ground reaction force, time to stabilization, and center of pressure. Results Both the ACLR and healthy groups evoked MRCPs at all 3 time periods. During the unplanned task analyzed using P values and Cohen d, the ACLR group exhibited slightly higher but not different MRCPs, achieving medium effect sizes (RP-1: P = .25, d = 0.44; RP-2: P = .20, d = 0.53; NS: P = .28, d = 0.47). The ACLR group also showed slightly higher θ power values that were not different during the preplanned (P = .18, d = 0.29) or unplanned (P = .42, d = 0.07) condition, achieving small effect sizes. The groups did not differ in their biomechanical outcomes (P values > .05). No condition × group interactions occurred (P values > .05). Conclusions Our jump-landing task evoked MRCPs. Although not different between groups, the observed effect sizes provided the first indication that men with ACLR might have consistently relied on more cortical motor planning associated with unplanned jump landings. Confirmatory studies with larger sample sizes are warranted.

Introduction and objectives Most of the studies evaluating the effect of cross links on spinal stability are performed in vitro on porcine or human spine segments and there is limited data regarding clinical benefits of cross link augmentation in traumatic injuries. In this study we aimed to evaluate the effects of cross-links insertion between rods on the fusion rates and post-surgical patients’ satisfaction among patients with traumatic thoracolumbar fractures who underwent posterior spinal fixation with pedicle screws. Materials and methods This study was conducted as a randomized clinical trial on 60 patients suffering from traumatic thoracolumbar vertebrae fractures. Patients were randomized into three groups: A (without any cross-link), B (One cross-link insertion) and C (two cross-links insertion). Six months after surgery outcomes were evaluated: fusion rates (plain X-ray and CT scan), Back pain (Visual Analog Scale) and patient satisfaction (fair, good, excellent). Results In group A 13 (65%) patients had structured bone fusion, but in 7 (35%) patients bone fusion was not observed. In both groups B and C, 19 patients (95%) had bone fusion, but only in 1 patient (5%) fusion failed (p = 0.009). In group A, fair satisfaction has the highest rate (8 patients (40%)) compared to the other groups. The highest reported severity of back pain was observed in group A while the lowest reported intensity of back pain was related to group B (p = 0.001). Conclusions Adding cross link to posterior spinal fixations of patients with traumatic thoracolumbar fractures can be associated with better final fusion results and patients’ satisfaction. However it is necessary to design studies with greater sample sizes to confirm this theory. Trial registration number: IRCT20120527009878N3.

The status of malnutrition and malnutrition is caused by various interrelated factors, including family behavior factors in providing food, breastfeeding and complementary feeding, and nutrition service efforts. This study aims to analyze the relationship between nutritionally conscious families (Kadarzi) and the nutritional status of children under five in the Work Area of the Puskesmas Pelambuan, Banjarmasin. This study used an analytic method with a cross sectional approach. The sampling technique used was proportional random sampling with a sample size of 82 parents of children under five. The measuring instrument used was a questionnaire and observation with weighing tools, the data analysis used the Spearman rank test. The location of this research was conducted in the Working Area of the Pelambuan Health Center, Banjarmasin City. Based on the results of the study, families who were aware of nutrition tended to have normal nutritional status totaling 27 (79.4%) and more than 7 (20.6%). Meanwhile, families who were not aware of nutrition tended to have malnutrition status, amounting to 31 people (64.6%) and malnutrition status 17 (35.4%). The spearman rank statistical test obtained p value 0.000 smaller than α = 0.05. There is a relationship between nutritionally conscious families (adarzi) with the nutritional status of children under five in the working area of Puskesmas Pelambuan, Banjarmasin City. Keywords : Nutritional awareness family, nutritional status, children

Objective There is an unmet need for therapies that target the underlying pathophysiology of osteoarthritis (OA). However, defining appropriate measures for clinical trials of such therapies is challenging. Our objective is to propose concept clinical endpoints that directly capture clinical benefit in this setting and evaluate the feasibility of their use. Methods This analysis used the multi-center, longitudinal, observational Osteoarthritis Initiative (OAI) database. OAI participants primarily had knee OA, with follow-up of up to nine years and assessments of joints, surgical interventions, performance outcomes, and patient-reported outcomes (PROs). We examined this dataset to identify existing outcome measures of direct clinical benefit. We evaluated the feasibility of conducting trials using these candidate endpoints by estimating incidence rates and resulting required sample sizes and study durations in time-to-event analyses. Results We identified candidate endpoints based on total knee replacement (TKR) and composite endpoints defined by TKR and conservative thresholds of PROs of pain and function. Using time to TKR as an endpoint, a study with an average follow-up time of three years requires approximately 3,000 to 18,000 subjects depending on effect size. Alternatively, a composite endpoint such as 'time to TKR or severe pain or severely impaired functioning', the required sample sizes ranged from approximately 2,000 to 11,000 for a three-year study. Conclusion The proposed concept endpoints can reliably and feasibly evaluate effectiveness of therapies for this unmet need. In particular, the composite endpoint approach can substantially reduce sample sizes (up to approximately 40%) compared to the use of TKR alone.

Background: This study aimed at understanding the trend in extracellular fluid (ECF) change and estimating the efficacy of the early complex decongestive therapy (CDT) program in terms of prevalence of lower limb lymphedema, as well as at identifying the quality of life (QoL) associated with response to CDT after gynecological cancer therapy. Methods and Results: Thirty-one patients undergoing gynecological cancer treatment were enrolled and randomly assigned to the CDT and control groups. In the CDT group, CDT was started within 2 weeks after surgery for 30 minutes a day, for 2 weeks (5 days per week). The patients' QoL was assessed through the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire; version 3. Inbody S10® (Biospace, Seoul, South Korea) was used to calculate the ECF. The assessment was performed at pre- and post-surgery and at 3, 6, and 12 months after surgery. Statistically significant differences, in favor of the CDT group, were encountered at the 3-month follow-up visit, especially with respect to the QoL score. Regarding the prevalence of lymphedema, no significant difference was observed between groups. The mean value of the impedance ratio was low in the CDT group during the entire 12 month follow-up. Conclusions: The results of the present study show that early CDT had a positive effect on the prevalence of lymphedema and body composition. Long-term follow-up studies with a larger sample size are needed to warrant the time-group effect of early rehabilitation.

BACKGROUND/SIGNIFICANCE The pain-reducing effect of applying vibration, which is used as a nonpharmacological method in pain management, is explained by the gate control theory developed by Melzack and Wall. Studies that are based on this theory have shown similar results to those of Melzack and Wall, indicating that pain-transmitting nerves are suppressed by vibrations, leading to higher pain thresholds. PURPOSE The study aimed to evaluate the effect of applying vibration to manage pain during heel lance procedures in newborns. METHODS This is a randomized, controlled experimental study. The study sample included 56 newborns determined using power analysis (vibration group = 28; control group = 28). For those in the vibration group, a vibrating device was used for approximately 30 seconds before the heel lance procedure and then continued throughout the procedure. No interventions were provided to the newborns in the control group. Pain in the newborns was evaluated by the nurse who performed the heel lance procedures, before the procedures and 15 to 20 seconds and 5 minutes after procedures, and by 2 specialists who viewed the video footage and conducted the Neonatal Infant Pain Scale examination. RESULTS The pain scores were significantly lower at 15 to 20 seconds and 5 minutes after the heel lance procedures in the group that received vibrations than in the control group (P < .05). IMPLICATIONS FOR PRACTICE The application of vibration, which is effective, nonpharmacological, and noninvasive, could help nurses manage pain in newborns as a nonpharmacological method. IMPLICATIONS FOR RESEARCH The number of studies that examine the effect that vibration has on pain associated with heel lance procedures in newborns is very limited, and it is recommended that further studies be conducted with larger sample sizes.

This list includes some of the reference ranges laboratory values used most frequently in pediatric endocrinology with standards, sample preparation and sample sizes from Quest Diagnostics/Nichols Institute and Esoterix/Labcorp. Other laboratories perform these tests and a few also have pediatric standards (e.g., ARUP). However, we do not recommend using a laboratory that has not established pediatric standards because the lower detectable limits, or the accurate area of the standard curves of the laboratory, might be well above pediatric values. Laboratories that are set up for pediatric endocrine samples will accept smaller volumes than requested of adult patients. The minimum volumes listed here can be used for smaller children but there may not be a duplicate test available to check results when such small quantities are utilized; consult with the laboratory for details of the most recent collection size, storage, and transport. You must check your results against the standards of the laboratory you choose, as the laboratories recommend, as the reference ranges can change since the time of publication of this book; the following is only a guide.

The number needed to treat (NNT) is a method of reporting outcomes from clinical trials.1 Treatment efficacy is determined by evaluating the outcome of one treatment relative to another treatment or to a control group when the only difference between the groups is the intervention of interest. The NNT can also be used to express the size of the outcome of one treatment relative to another. The NNT is expressed in terms designed to help decide whether the intervention might be valuable in clinical practice: the number of patients who need to be treated before a therapist can be sure that one patient improved who would not have improved without the intervention. For example, when comparing treatment X and treatment Y, an NNT score of 5 for treatment X indicates that, on average, after treating 5 patients, treatment X will have achieved one more positive outcome than if treatment Y had been used. The NNT does not tell the clinician which of those 5 patients will respond, only that 1 patient is likely to do so. The NNT was described in 1988 by Laupacis et al,2 and, although its use is becoming more popular, it is still not widely used. A search of MEDLINE back to 1991 using the search terms “number needed to treat” or “NNT” identified 121 citations reporting NNT information. Of these citations, only 3 concerned outcomes of physical therapy3–5 and, of these, only one5 described the use of NNT in a journal with content relevant to physical therapists. The NNT can be used to gauge the relative effectiveness of different treatments in restoring normal function or preventing future disability. If the treatment has a potentially harmful outcome (eg, stroke, headache, death from cervical manipulation), a similar calculation can be used …

Physical activity (PA) and exercise have numerous benefits in Cystic Fibrosis (CF) including improved lung function, exercise capacity and quality of life. Despite these benefits, the effectiveness of interventions to promote PA in this population are still largely unknown. The objective of this review was to synthesise existing research and determine whether exercise interventions are effective in promoting PA in people with CF. Using the PRISMA guidelines, a comprehensive search was conducted. Fifteen studies (463 participants) met the inclusion criteria. Eleven studies demonstrated improvements in PA in both short- and long-term interventions. However, the interventions were variable across the included studies, with a large inconsistency in PA assessment tools used. Aerobic training and activity counselling were the two elements identified in this review which most consistently improved PA. Future research should consider larger sample sizes and the use of accurate instruments to assess and track PA levels longitudinally.

Background Misclassification bias is introduced into medical claims-based research because of reliance on diagnostic coding rather than full medical record review. We sought to characterize this bias for idiopathic intracranial hypertension (IIH) and evaluate strategies to reduce it. Methods A retrospective review of medical records was conducted using a clinical data warehouse containing medical records and administrative data from an academic medical center. Patients with 1 or more instances of International Classification of Diseases (ICD)-9 or -10 codes for IIH (348.2 or G93.2) between 1989 and 2017 and original results of neuroimaging (head CT or MRI), lumbar puncture, and optic nerve examination were included in the study. Diagnosis of IIH was classified as definite, probable, possible, or inaccurate based on review of medical records. The positive predictive value (PPV) for IIH ICD codes was calculated for all subjects, subjects with an IIH code after all testing was completed, subjects with high numbers of IIH ICD codes and codes spanning longer periods, subjects with IIH ICD codes associated with expert encounters (ophthalmology, neurology, or neurosurgery), and subjects with acetazolamide treatment. Results Of 1,005 patients with ICD codes for IIH, 103 patients had complete testing results and were included in the study. PPV of ICD-9/-10 codes for IIH was 0.63. PPV in restricted samples was 0.82 (code by an ophthalmologist n = 57), 0.70 (acetazolamide treatment n = 87), and 0.72 (code after all testing, n = 78). High numbers of code instances and longer duration between the first and last code instance also increased the PPV. Conclusions An ICD-9 or -10 code for IIH had a PPV of 63% for probable or definite IIH in patients with necessary diagnostic testing performed at a single institution. Coding accuracy was improved in patients with an IIH ICD code assigned by an ophthalmologist. Use of coding algorithms considering treatment providers, number of codes, and treatment is a potential strategy to reduce misclassification bias in medical claims-based research on IIH. However, these are associated with a reduced sample size.

Atrial fibrillation after cardiac surgery (AFACS) is a serious postoperative complication. There is significant research interest in this field but also relevant heterogeneity in reported AFACS definitions and approaches used for its identification. Few data exist on the extent of this variation in clinical studies. The authors reviewed the literature since 2001 and included manuscripts reporting outcomes of AFACS in adults. They excluded smaller studies and studies in which patients did not undergo a sternotomy. The documented protocol in each manuscript was analyzed according to six different categories to determine how AFACS was defined, which techniques were used to identify it, and the inclusion and/or exclusion criteria. They also noted when a category was not described in the documented protocol. The authors identified 302 studies, of which 92 were included. Sixty-two percent of studies were randomized controlled trials. There was significant heterogeneity in the manuscripts, including the exclusion of patients with preoperative AF, the definition and duration of AF needed to meet the primary endpoint, the type of screening approach (continuous, episodic, or opportunistic), the duration of monitoring during the study period in days, the diagnosis with predefined electrocardiogram criteria, and the requirement for independent confirmation by study investigators. Furthermore, the definitions of these criteria frequently were not described. Consistent reporting standards for AFACS research are needed to advance scientific progress in the field. The authors here propose pragmatic standards for trial design and reporting standards. These include adequate sample size estimation, a clear definition of the AFACS endpoints, and a protocol for AFACS detection.

PURPOSE To compare Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) with traditional ("legacy") patient-reported outcome measures (PROMs) in regard to correlations, ease of use, and quality criteria for upper (UE) and lower extremity (LE) orthopaedic conditions. METHODS A systematic search of the PubMed/MEDLINE database was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to identify published articles that referenced the various PROMIS PF measures. Two authors independently reviewed selected studies. The search returned 857 studies, 85 of which were selected for independent review by 2 authors. Of these, 54 were selected for inclusion. Mixed linear models were performed to assess for differences between legacy PROMs and PROMIS measures. RESULTS The combined sample size of all included studies yielded 6,074 UE and 9,366 LE patients. Overall, PROMIS PF measures demonstrated strong correlations with legacy PROMs among UE (weighted Pearson correlation, 0.624, standard error [SE] = 0.042; weighted Spearman correlation, 0.566, SE = 0.042) and LE patients (weighted Pearson correlation, 0.645, SE = 0.062; weighted Spearman correlation, 0.631, SE = 0.041). PROMIS PF questionnaires completed by UE patients had fewer questions than legacy PROMs (5.9 vs 17.7, P = .0093) and were completed in less time (90.5 vs 223.8 seconds, P = .084). PROMIS PF questionnaires completed by LE patients had fewer questions than legacy PROMs (4.81 vs 15.33, P < .001) and were completed in less time (63.6 vs 203.2 seconds, P = .0063). The differences for the reliability measures were not significant. CONCLUSIONS PROMIS PF scores correlate strongly with commonly used legacy PROMs in orthopaedics, particularly in UE and LE patients. PROMIS PF forms can be administered efficiently and to a broad patient population while remaining highly reliable. Therefore, they can be justified for standardized use among orthopaedic patients with UE and LE conditions, improving the ability to aggregate and compare outcomes in orthopaedic research. LEVEL OF EVIDENCE Level IV, systematic review of Level I-IV evidence.

Summary: To compare the clinical efficacy and safety of Thulium laser enucleation of prostate (ThuLEP) and Holmium laser enucleation of prostate (HoLEP). We systematically searched PubMed, Embase, and Cochrane Library databases within a period from the date of database establishment to October 2020. RevMan 5.4. was used for calculation and statistical analyses. 8 studies of 2125 patients were included. ThuLEP provided less hemoglobin decrease (MD: −0.37, 95%CI -0.61 to −0.14, P = 0.002) and shorter length of hospital stay (MD: −0.41, 95%CI -0.72 to −0.10, P = 0.01). During the postoperative follow-ups, statistically significant differences only were found in IPSS (MD: −0.96; 95%CI -1.27 to −0.65; P

Introduction Hyperinflammatory state has a role in the pathogenesis of COVID‐19. Anakinra could reduce inflammation and help to combat the condition. In this study, we aimed to assess the safety and efficacy of anakinra (PerkinRA®) in severe COVID‐19. Method The study was an open‐label, randomized, controlled trial conducted in Imam Hossein Medical Center from May to July 2020. Patients with a confirmed diagnosis of COVID‐19 were included in this study. We administered anakinra 100 mg daily intravenously. All patients received COVID‐19 pharmacotherapy based on the represented national guideline. The need for invasive mechanical ventilation is considered the primary outcome. Results Thirty patients were included in this study, and 15 of them received Anakinra. Nineteen patients were male (63.3%), and 11 were female (36.7%). The mean age of patients was 55.77 ± 15.89 years. In the intervention group, the need for invasive mechanical ventilation was significantly reduced compared to the control group (20.0% vs. 66.7%, p = .010). Also, these patients had a significantly lower length of hospital stay (p = .043). No significant higher rate of infection was recorded. Conclusion Anakinra as an immunomodulatory agent has been associated with the reduced need for mechanical ventilation in patients admitted to intensive care units because of severe COVID‐19. The medication reduced the hospital length of stay. Furthermore, no increased risk of infection was observed. Further randomized placebo‐controlled trials with a larger sample size are needed to confirm these findings., Anakinra administration significantly reduces the need for mechanical ventilation. No increased risk of infection was observed because of anakinra use. Reduced hospitalization duration observed in patients who received anakinra.

BackgroundThe number of new noncommercial clinical studies conducted in Japan declined within the first year of the implementation of the Clinical Trials Act (CTA) on April 1, 2018. This study aimed to examine the impact of the CTA’s enforcement on the number of new noncommercial clinical studies registered in the Japanese Clinical Trial Registry.MethodsAn interrupted time-series design was used in the analysis, which was conducted for the period of April 2015 to March 2019. We collected data for trials registered in the Clinical Trial Registry, managed by the University Hospital Medical Information Network.ResultsIn total, 35,811 studies were registered in the registry; of these, 16,455 fulfilled the eligibility criteria. The difference in the trend of monthly number of new trials after CTA enforcement decreased significantly by 15.0 trials (95% CI, −18.7 to −11.3), and the level decreased by 40.8 (95% CI, −68.2 to −13.3) from the pre-enforcement to the post-enforcement period. Multigroup analyses indicated that the act exerted a significant effect on the trend of new clinical trials, particularly those with smaller sample sizes, interventional study designs, and nonprofit funding sponsors.ConclusionsThe number of Japanese noncommercial clinical studies declined significantly following implementation of the CTA. It is necessary to establish a system to promote clinical studies in Japan while ensuring transparency and safety.

Metabolic and bariatric surgery helps women achieve a healthier weight, reduce co-morbid conditions, increase fertility rates, and improve pregnancy outcomes compared with counterparts who are obese. Breastfeeding is known to provide both infant and maternal health benefits as well. Less is known about the impact of bariatric surgery on breastfeeding. The objective of this study was to review the impact of bariatric surgery on breastfeeding following the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. PubMed and Medline databases were searched using terms such as “bariatric surgery,” “postnatal care,” “lactation,” and “breastfeeding.” Reference lists were also used to find relevant articles. A total of 49 records were identified. Abstracts were screened, and 11 observational studies were identified after meeting inclusion criteria, which included the use of original research on breastfeeding and women who have had bariatric surgery. The available research shows that breast milk after bariatric surgery is adequate in nutrients and that no long-term effects were reported in cases studies when nutrient deficiencies were corrected. Limitations include observational study design and small sample sizes. This systematic review suggests that breastfeeding after bariatric surgery should be recommended along with monitoring and micronutrient supplementation. However, additional research and increased sample sizes are needed to further examine the relationship, and such studies should be conducted to strengthen the evidence and explore ways to improve breastfeeding rates in this population.

Background Sarcopenia is defined as either low pre-operative muscle mass or low muscle density on abdominal CT imaging. It has been associated with worse short-term outcomes after surgery for colorectal liver metastases. This study aimed to evaluate whether sarcopenia also impacts long-term survival outcomes in these patients. Methods A random-effects meta-analysis was conducted following the PRISMA guidelines. Overall survival (OS) and disease-free survival (DFS) outcomes were evaluated. Results Eleven studies were included, ten reporting on the impact of low muscle mass and four on low muscle density. Sample sizes ranged between 47 and 539 (2124 patients in total). Altogether, 897 (42%) patients were considered sarcopenic, although definitions varied between studies. Median follow-up was 21–74 months. Low muscle mass (hazard ration (HR) 1.35, 95%CI 1.08–1.68) and low muscle density (HR 1.97, 95%CI 1.07–3.62) were associated with impaired OS. Low muscle mass (pooled HR 1.17, 95%CI 0.94–1.46) and low muscle density (pooled HR 1.13, 95%CI 0.85–1.50) were not associated with impaired RFS. Discussion Sarcopenia is associated with poorer OS, but not RFS, in patients with CRLM. Additional studies with standardized sarcopenia definitions are needed to better assess the impact of sarcopenia in patients with CRLM.

Background The diagnosis of subclinical depression (SD) currently relies exclusively on subjective clinical scores and structured interviews, which shares great similarities with major depression (MD) and increases the risk of misdiagnosis of SD and MD. This study aimed to develop a method of disease classification for SD and MD by resting-state functional features using radiomics strategy. Methods Twenty-six SD, 36 MD subjects and 33 well-matched healthy controls (HC) were recruited and underwent resting-state functional magnetic resonance imaging (rs-fMRI). A novel radiomics analysis was proposed to discriminate SD from MD. Multi-scale brain functional features were extracted to explore a comprehensive representation of functional characteristics. A two-level feature selection strategy and support vector machine (SVM) were employed for classification. Results The overall classification accuracy among SD, MD and HC groups was 84.21%. Particularly, the model excellently distinguished SD from MD with 96.77% accuracy, 100% sensitivity, and 92.31% specificity. Moreover, features with high discriminative power to distinguish SD from MD showed a strong association with default mode network, frontoparietal network, affective network, and visual network regions. Limitation The sample size was relatively small, which may limit the application in clinical translation to some extent. Conclusion These findings demonstrated that a valid radiomics approach based on functional measures can discriminate SD from MD with a high classification performance, facilitating an objective and reliable diagnosis individually in clinical practice. Features with high discriminative power may provide insight into a profound understanding of the brain functional impairments and pathophysiology of SD and MD.

Background Instability constitutes over 20% of revisions after total hip arthroplasty (THA). Dual mobility (DM) designs were introduced as a solution to this problem. However, the few publications that have reported promising results for monobloc DM constructs have been limited by sample size or length of follow-up. The purpose of this study is to evaluate mid-term outcomes (minimum 5-year follow-up) of a single-surgeon series utilizing a monobloc DM acetabular component in patients with high risk for dislocation. Methods This is a single-surgeon consecutive series of 207 primary THAs implanted with a monobloc DM component in patients who were considered at high risk for dislocation. Patient demographics and case-specific data were collected retrospectively. All patients had a minimum of 5-year follow-up. The Mann-Whitney U test was used to assess continuous variables, whereas categorical variables were analyzed using the chi-square test. Survival probability was calculated using the Kaplan-Meier method. Results Radiographic analysis did not reveal acetabular radiolucency in any patients, and there were no revisions for aseptic loosening. In addition, there were no dislocations. Seven of 205 patients (3.4%) were revised, 5 on the femoral side due to periprosthetic fracture and the remaining two for infection. Survivorship of the acetabular component from revision was 99%. The mean Veteran RAND (VR-12) physical score improved from 7 (standard deviation [SD]: 13.7) preoperatively to 9.5 (SD: 17.6) at the final follow-up. Similarly, the hip disability osteoarthritis score improved from 8 (SD: 17.9) preoperatively to 21.2 (SD: 37). Conclusion Monobloc DM components reliably prevent dislocation after primary THA in high-risk patients. At mid-term follow-up, this DM monobloc component demonstrates excellent implant survivorship, radiographic fixation, and improved functional outcomes.

PURPOSE This study evaluated clinician adherence to the American College of Physicians Best Practice Advice for diagnosis of pulmonary embolism. DESIGN A prospective, single-center, descriptive design was utilized. METHODS A heterogeneous sample of 111 hemodynamically stable adult inpatients with a computed tomography pulmonary angiogram ordered was consented. Electronic medical records were reviewed for demographic and clinical variables to determine adherence. The 6 individual best practice statements and the overall adherence were evaluated by taking the sum of "yes" answers divided by the sample size. RESULTS Overall adherence was 0%. Partial adherence was observed with clinician-recorded clinical decisions rules and obtaining d-dimer (3.6% [4/111] and 10.2% [9/88], respectively) of low/intermediate probability scorers. Age adjustment of d-dimer was not recorded. Computed tomography pulmonary angiogram was the first diagnostic test in 89.7% (79/88) in low/intermediate probability patients. CONCLUSION In hemodynamically stable, hospitalized adults, adherence to best practice guidelines for diagnosis of pulmonary embolism was minimal. Clinical utility of the guidelines in hospitalized adults needs further evaluation. Systems problems (eg, lack of standardized orders, age-adjusted d-dimer values, information technology support) likely contributed to poor guideline adherence.

In node positive breast cancer patients who are treated with neoadjuvant systemic therapy, axillary staging and treatment is still a topic of debate. This multicenter study will contribute to evidence-based guidelines with regard to the oncologic safety and impact on quality of life of less vs. more invasive axillary staging and treatment strategies.Background: Node positive breast cancer (cN+) patients with an axillary pathologic complete response after neoadjuvant systemic therapy (NST) are not expected to benefit from axillary lymph node dissection (ALND). Therefore, less invasive axillary staging procedures have been introduced to establish response-guided treatment. However, evidence is lacking with regard to their oncologic safety and impact on quality of life (QoL). We hypothesize that if response-guided treatment is given, less invasive staging procedures are non-inferior to standard ALND in terms of oncologic safety, and superior to standard ALND in terms of QoL. Patients and Methods: MINIMAX is a Dutch multicenter registry study that includes patients with cN1-3M0 unilateral invasive breast cancer, who receive NST, followed by axillary staging and treatment according to local protocols. In a retrospective registry of +/- 4000 patients, the primar y endpoint is oncologic safety at 5 and 10 years (disease-free, breast-cancer-specific and overall survival, and axillary recurrence rate). In a prospective multicenter registry, the primar y endpoints are QoL at 1 and 5 years, and we aim to verify the 5-year oncologic safety. With an estimated 5-year disease-free survival of 72.5% and anticipated loss to follow-up of 10%, a sample size of 549 is needed to have 80% power to detect non-infer iority (with a 10% margin) of less invasive staging procedures. Conclusion: In cN+ patients treated with NST, less invasive axillary staging procedures are already implemented globally. Evidence is needed to support the assumed oncologic safety and superior QoL of such procedures. This study will contribute to evidence-based guidelines. (C) 2021 The Authors. Published by Elsevier Inc.

Objectives Recent advancements in high-resolution imaging have improved the diagnostic assessment of magnetic resonance imaging (MRI) for intralabyrinthine schwannoma (ILS). This systematic review aimed to evaluate the diagnostic performance of MRI for patients with ILS. Methods Ovid-MEDLINE and EMBASE databases were searched for related studies on the diagnostic performance of MRI for patients with ILS published up to February 10, 2020. The primary endpoint was the diagnostic performance of MRI for ILS. The quality of the enrolled studies was assessed using tailored questionnaires and the Quality Assessment of Diagnostic Accuracy Studies-2 criteria. Results Overall, 6 retrospective studies that included 122 patients with ILS from a parent population of 364 were included. The sample size, parent population and its composition, reference standard, detailed parameters of MRI, and even the diagnostic methods varied between the studies. The studies had moderate quality. The sensitivity of combination of T2WI and CE-T1WI was over 90%. Relative sensitivity of T2WI comparative to CE-T1WI ranged from 62% to 100%, and the specificity were 100%. Conclusions MRI has acceptable diagnostic performance for ILS. There is a need for well-organized research to reduce the factors causing heterogeneity.

The FOURIER (Further Cardiovascular Outcomes Research with PCSK9 inhibition in Subjects with Elevated Risk) trial was conducted to study cardiovascular outcomes of treatment with evolocumab. The trial was terminated after a median follow-up of 2.2 years instead of the planned 3.6 years. We question this decision. According to the investigators, the event rate was 50% higher than expected. However, the accrued number of key secondary events (1829) was only 12% higher than the targeted number (1630). Also, around one-third of the events consisted of non-atherosclerotic myocardial infarctions, hemorrhagic strokes, and cardiovascular deaths unrelated to myocardial infarction or stroke. Moreover, halfway through the trial, the sample size changed from 22,500 to 27,500, even though the accrual of the targeted number of events was on track. Finally, the rate of all-cause mortality had started to diverge in favor of placebo after 2 years of follow-up. It was 4.8% for evolocumab and 4.3% for placebo in participants with > 2.5 years of follow-up. A long-term follow-up would have yielded more events and thus more power to evaluate the effect of evolocumab on all-cause mortality. We conclude that adaptive designs carry a recognized risk of false-positive efficacy results, but the risk of false-negative safety results is underappreciated.