Alpha Error Rate Research Articles

Total neoadjuvant therapy with short-course radiotherapy Versus long-course neoadjuvant chemoradiotherapy in Locally Advanced Rectal cancer, Korean trial (TV-LARK trial): study protocol of a multicentre randomized controlled trial

BackgroundFor locally advanced rectal cancer (LARC), total neoadjuvant therapy (TNT) may enhance tumour response, reduce recurrence, and improve patient compliance compared to upfront surgery. Recent studies have shown that chemoradiotherapy (CRT) followed by consolidation chemotherapy leads to higher rate of pathologic complete response (pCR) than induction chemotherapy followed by CRT. However, an optimal TNT regimen that maximise the pCR rate and minimise toxicity has not been established. Therefore, the aim of this trial was to investigate whether preoperative short-course radiotherapy followed by chemotherapy with four cycles of CAPOX can double the pCR rate compared to a standard schedule of long-course preoperative CRT in patients with LARC.MethodsThis is a multi-centre, prospective, open label, randomised controlled trial. Patients with clinical primary tumour stage 3 and higher or regional node-involved rectal cancer located within 10 cm from the anal verge were randomly assigned equally to short-course radiotherapy (25 Gy in 5 fractions over 1 week) followed by four cycles of CAPOX (intravenous oxaliplatin [130 mg/m2, once a day] on day 1 and capecitabine [1,000 mg/m2, twice a day] from days 1 to 14) (TNT) or CRT (50.4 Gy in 28 fractions over 5 weeks, concurrently with concomitant oral capecitabine 825 mg/m2 twice a day). After preoperative treatment, total mesorectal excision was performed 2–4 weeks in the TNT group and 6–10 weeks in the CRT group, followed by optional additional adjuvant chemotherapy. The primary endpoint is the pCR rate, and secondary endpoints include disease-related treatment failure, quality of life, and cost-effectiveness. Assuming a pCR rate of 28% and 15% in the TNT and CRT groups, respectively, and one-side alpha error rate of 0.025 and power of 80%, 348 patients will be enrolled considering 10% dropout rate.DiscussionThe TV-LARK trial will evaluate the superiority of employed TNT regimen against the standard CRT regimen for patients with LARC. We aimed to identify a TNT regimen that will improve the pCR rate and decrease systemic recurrence in these patients.Trial registrationCris.nih.go.kr ID: KCT0007169 (April 08, 2022). The posted information will be updated as needed to reflect the protocol amendments and study progress.

The Effect of Health Education on Knowledge of Health Reproductive of Junior High School Students.

When they reach puberty, adolescents need to learn about reproductive health. Giving adolescents health education to prevent issues with their reproductive health is one method to boost their awareness of reproductive health. The purpose of this study is to determine how health education has affected students' knowledge of reproductive health. 24 persons were gathered using the convenience sample method. Pre-experimental design with one-group pretest-post-test design is the technique employed. A questionnaire was employed as a research tool during the data collection process. The Wilcoxon test is the method of data analysis that is utilized. The findings revealed that students' knowledge had an average value of 82 percent before receiving health education, and an average value of 84 percent after receiving health education. There was no significant difference in the knowledge of adolescents before and after receiving health education, according to the findings of the hypothesis test, which had an alpha error rate of 0.05. It might be said that health education has little impact on the degree of knowledge held by teenagers.

PENGARUH INTENSITAS MENONTON SINETRON REMAJA TERHADAP PERILAKU MORAL ANAK USIA 5-6 TAHUN (STUDI EX POST FACTO DI KELURAHAN KELAPA GADING TIMUR, JAKARTA UTARA)

AbstrackThis study aims to determine the effect of the intensity of watching teen soap operas on the moral behavior of children aged 5-6 years in the Kelapa Gading Timur Village, North Jakarta. The research method used is the Ex Post Facto method. The sampling technique used cluster random sampling and simple random sampling with a total sample of 30 children.The data analysis technique used for hypothesis testing is the t-test after first testing the requirements consisting of normality test and homogeneity test. The results of hypothesis testing with t-test obtained tcount of 10.392, while ttable of 2.25 so 10.392 2.25, and a significance level of 0.00 with an alpha error rate of 0.05 then 0.00 0.05 so that based on the statistical hypothesis H0 is rejected and Ha is accepted, meaning there are differences in moral behavior children in the high intensity group watching teen soap operas with the moral behavior of children in the low intensity group watching teen soap operas. The results showed that the moral behavior of children in the high intensity group watching teen soap operas would be lower than the moral behavior of children in the low intensity group watching teen soap operas. The implication of this research is the role and supervision of parents on teen soap operas that are watched by children. Parents must guide and give signs in watching television. Parental control in the selection of television shows will be a preventive measure so that children are not mistaken in choosing television shows to watch. Keywords: Teenage soap operas, moral behavior of children aged 5-6 years

Impact of tight blood glucose control within normal fasting ranges with insulin titration prescribed by the Leuven algorithm in adult critically ill patients: the TGC-fast randomized controlled trial

BackgroundIt remains controversial whether critical illness-related hyperglycemia should be treated or not, since randomized controlled trials (RCTs) have shown context-dependent outcome effects. Whereas pioneer RCTs found improved outcome by normalizing blood glucose in patients receiving early parenteral nutrition (PN), a multicenter RCT revealed increased mortality in patients not receiving early PN. Although withholding early PN has become the feeding standard, the multicenter RCT showing harm by tight glucose control in this context has been criticized for its potentially unreliable glucose control protocol. We hypothesize that tight glucose control is effective and safe using a validated protocol in adult critically ill patients not receiving early PN.MethodsThe TGC-fast study is an investigator-initiated, multicenter RCT. Patients unable to eat, with need for arterial and central venous line and without therapy restriction, are randomized upon ICU admission to tight (80–110 mg/dl) or liberal glucose control (only initiating insulin when hyperglycemia >215 mg/dl, and then targeting 180–215 mg/dl). Glucose measurements are performed on arterial blood by a blood gas analyzer, and if needed, insulin is only administered continuously through a central venous line. If the arterial line is no longer needed, glucose is measured on capillary blood. In the intervention group, tight control is guided by the validated LOGIC-Insulin software. In the control arm, a software alert is used to maximize protocol compliance. The intervention is continued until ICU discharge, until the patient is able to eat or no longer in need of a central venous line, whatever comes first. The study is powered to detect, with at least 80% power and a 5% alpha error rate, a 1-day difference in ICU dependency (primary endpoint), and a 1.5% increase in hospital mortality (safety endpoint), for which 9230 patients need to be included. Secondary endpoints include acute and long-term morbidity and mortality, and healthcare costs. Biological samples are collected to study potential mechanisms of organ protection.DiscussionThe ideal glucose target for critically ill patients remains debated. The trial will inform physicians on the optimal glucose control strategy in adult critically ill patients not receiving early PN.Trial registrationClinicalTrials.gov NCT03665207. Registered on 11 September 2018.

Complications after interval postpartum intrauterine device insertion

BACKGROUND:In the United States, up to 57% of women report resumption of sexual activity by the 6 week postpartum visit. Effective contraception should be addressed and provided at that time, to avoid unintended pregnancies and optimize interpregnancy intervals. Long-acting reversible contraceptives are the most effective forms of reversible contraception and are increasingly popular during the postpartum period. However, timing of postpartum intrauterine device (IUD) placement varies among providers and many delay insertion due to concerns for uterine perforation or expulsion of the IUD.OBJECTIVE:This study aimed to evaluate uterine perforation and expulsion rates with IUD insertion at 4–8 weeks postpartum vs 9–36 weeks postpartum.STUDY DESIGN:We performed a retrospective cohort study using the Kaiser Permanente Southern California electronic medical record from 2010 to 2016. We calculated the proportion of perforations and expulsions with IUD insertion at 4–8 weeks vs 9–36 weeks postpartum. Our primary outcome was the perforation rate. Secondarily, we evaluated the expulsion rate. For our minimum sample size calculation, to detect a difference of 0.5% in the perforation rate, with a baseline perforation rate of 0.5% for the 9–36 week postpartum IUD placement group, 80% power, and 5% alpha error rate, we would need at least 4221 participants per group, 8442 in total.RESULTS:A total of 24,959 patients met inclusion criteria (n=13,180 in the 4–8 week group, n=11,777 in the 9–36 week group). Of 430 patients with a confirmed complication, 157 uterine perforations and 273 IUD expulsions were identified. Perforation rates were significantly higher with placement at 4–8 weeks than at 9–36 weeks (0.78% vs 0.46%; P=.001). After adjusting for race and ethnicity, breastfeeding, IUD type, provider type, parity, most recent delivery, and body mass index, the odds of perforation remained higher with placement at 4–8 weeks than at 9–36 weeks (adjusted odds ratio, 1.92; 95% confidence interval, 1.28–2.89). Our Kaplan-Meier survival curve showed that the risk of uterine perforation remained elevated until approximately 22–23 weeks postpartum. Expulsion rates were similar between the 2 groups (1.02 vs 1.17; P=.52).CONCLUSION:Uterine perforation after interval postpartum IUD insertion is greater at 4–8 weeks than at 9–36 weeks, although perforation rates remain low at <1%. Expulsion rates did not differ between the groups. Because overall rates of uterine perforation are low, women can safely be offered IUDs at any interval beyond 4 weeks with minimal concern for perforation.

Do We Overestimate the Within-Variability? The Impact of Measurement Error on Intraclass Coefficient Estimation.

Many psychological phenomena have a multilevel structure (e.g., individuals within teams or events within individuals). In these cases, the proportion of between-variance to total-variance (i.e., the sum between-variance and within-variance) is of special importance and usually estimated by the intraclass coefficient (1)1 [ICC(1)]. Our contribution firstly shows via mathematical proof that measurement error increases the within-variance, which in turn decreases the ICC(1). Further, we provide a numerical example, and examine the RMSEs, alpha error rates and the inclusion of zero in the confidence intervals for ICC(1) estimation with and without measurement error. Secondly, we propose two corrections [i.e., the reliability-adjusted ICC(1) and the measurement model-based ICC(1)] that yield correct estimates for the ICC(1), and prove that they are unaffected by measurement error mathematically. Finally, we discuss our findings, point out examples of the underestimation of the ICC(1) in the literature, and reinterpret the results of these examples in the light of our new estimator. We also illustrate the potential application of our work to other ICCs. Finally, we conclude that measurement error distorts the ICC(1) to a non-negligible extent.

A Bayesian structural equation model in general pedigree data analysis

AbstractStructural equation modeling (SEM) is a powerful, comprehensive, and flexible multivariate statistical method for modeling relationships between observed and latent variables. However, in genetic association analysis, frequentist approaches to fitting SEMs do not always lead to convergence and admissible solutions for complex models, categorical variables, complicated data structures such as pedigree data and small sample sizes. Accordingly, to conduct a SEM pedigree data analysis, Stan platform as a probabilistic programming language was applied in our study to propose a new version of the Bayesian approach that adopts Hamiltonian Monte Carlo (HMC) and data augmentation techniques. At first, a comprehensive simulation study was conducted to compare the precision of each parameter of the suggested method with that of the classic technique in terms of bias, alpha error rate, and coverage probability. After that, the method was applied to real data with a conceptual model including ordinal indicators in order to conduct genetic association analysis of two well‐known genetic markers with metabolic syndrome trait. The simulation findings revealed the proposed Bayesian method was a more efficient technique than MLE approach. Moreover, Bayesian approach yielded a better statistical performance in solving the problems than did classic approach.

66 Comparison of Patient Demographics, Disposition, and Outcomes Using a Chief-Complaint-Based Denominator versus Administrative Claims-Based Denominator for Emergency Department Patients With Chest Pain

International Classification of Diseases (ICD) codes are used by many quality measures to identify cohorts of patients with disease positive states. Because emergency department (ED) patients are evaluated and managed in real-time according to their chief complaint, we hypothesize that quality measures utilizing a chief complaint-based denominator may be a more accurately reflect care delivered in the ED. In this study, we sought to compare patient demographics, disposition, and outcomes using 2 unique yet overlapping denominators using medical record data from a large health care network. Using electronic medical record data between 1/1/2017 - 4/13/2018 from 16 different emergency departments in Western Pennsylvania, we included all patients ≥ 18 years old, afebrile (temp ≤ 38°C), for whom an ECG and troponin were ordered in the ED. We excluded any patient not evaluated in an in-network outpatient office within 365 days before the index ED visit in order to allow reliable estimation of patient comorbidities in our patient cohort. We then identified ED patients with chest pain using 2 different methods. In our chief complaint cohort, patients were selected using a text string matching algorithm. In our ICD cohort, patients were selected using a predefined set of ICD-10 diagnostic codes for chest pain which matched the denominator of a quality measure currently used by the Emergency Quality Network (E-QUAL). Patient outcomes, including 30-day rates of acute myocardial infarction and mortality were determined from subsequent medical records, including office visits, and the national death index. We compared patient demographics, ED disposition, and outcomes between our 2 patient cohorts using a Pearson’s Chi-square test with alpha error rate of 0.05. Of 78,619 patients meeting our initial inclusion and exclusion criteria, 22,092 patients were identified using the chief-complaint algorithm while 21,800 patients were identified using the ICD coding method. Although there was no difference in overall admission rates between the chief complaint cohort and the ICD cohort, more patients in the ICD cohort were admitted to observation status (46.7 versus 41.4, p<0.001). In terms of 30-day outcomes, there was a higher rate of acute myocardial infarction and mortality in the chief complaint cohort relative to the ICD cohort (AMI: 2.0 versus 1.1, p<0.001; mortality: 0.8 versus 0.7, p=0.027). Similarly, there was a higher rate of diabetes mellitus and underlying coronary artery disease in the chief complaint cohort relative to the ICD cohort (diabetes: 20.6 versus 19.6, p=0.008; coronary artery disease: 18.7 versus 16.9, p<0.001). In comparison to a chief-complaint-based denominator, an ICD-based denominator may select for a lower risk ED population with a lower incidence of short-term morbidity and mortality.

Phase II study of enzalutamide monotherapy with radiation therapy for intermediate risk prostate cancer.

58 Background: Castrating androgen deprivation therapy (ADT) is standardly prescribed in combination with radiation therapy (RT) for intermediate or high-risk prostate cancer (PCa). ADT is associated with multiple side effects including weight gain, loss of libido, hot flashes and muscle atrophy. In contrast, enzalutamide monotherapy is associated with much fewer side effects. Methods: At Dana-Farber/ Harvard Cancer Center we performed an open label phase II study of enzalutamide for 6 months as neo- and adjuvant treatment for intermediate risk PCa patients (NCCN criteria) receiving RT. The primary endpoint was the proportion of patients achieving a PSA response of ≤0.2 . This endpoint is predictive of long term PSA response in a similar risk-group of patients treated with RT and ADT. PSA values were obtained at baseline and monthly on 6 cycles of enzalutamide (160mg/day). 79.2 Gy in 44 fractions of IMRT was started between 6 and 10 weeks after the initiation of enzalutamide. Quality of life questionnaires, hormone levels and anthropomorphic measurements were obtained. Results: 45 of 60 evaluable patients had a PSA ≤0.2 at the end of 6 months of enzalutamide. With a sample size of 64 evaluable patients, if the number achieving a PSA level is ≤0.2 is 44 or more, the null hypothesis is rejected with a target error rate of alpha = 0.10. Also 54 of 60 evaluable patients had a PSA of ≤0.5ng/ml. Importantly, less than half of the participants experienced erectile dysfunction or decreased libido and these were predominantly grade I. Less than a quarter of patients reported hot flashes (all grade I). Waist circumference did not change with therapy. The most frequent grade 2 or greater events were hypertension and gynecomastia. Testosterone and free testosterone levels rose significantly on enzalutamide therapy. Conclusions: Enzalutamide monotherapy with RT may be as effective as castrating ADT, and associated with fewer side effects. Larger, randomized trials are needed to further evaluate enzalutamide monotherapy, instead of ADT, to be used in combination with RT. Clinical trial information: NCT0208988.

Slimming World in Stop Smoking Services (SWISSS): study protocol for a randomized controlled trial

BackgroundQuitting smokers gain weight. This deters some from trying to stop smoking and may explain the increased incidence of type 2 diabetes after cessation. Dieting when stopping smoking may be counterproductive. Hunger increases cravings for smoking and tackling two behaviours together may undermine quitting success. A meta-analysis of randomized controlled trials (RCTs) showed individualized dietary support may prevent weight gain, although there is insufficient evidence whether it undermines smoking cessation. Commercial weight management providers (CWMPs), such as Slimming World, provide individualized dietary support for National Health Service (NHS) patients; however, there is no evidence that they can prevent cessation-related weight gain.Our objective is to determine whether attending Slimming World from quit date, through referral from NHS Stop Smoking Services, is more effective than usual care at preventing cessation-related weight gain.MethodsThis RCT will examine the effectiveness of usual cessation support plus referral to Slimming World compared to usual cessation support alone. Healthy weight, overweight and obese adult smokers attending Stop Smoking Services will be included. The primary outcome is weight change in quitters 12 weeks post-randomization. Multivariable linear regression analysis will compare weight change between trial arms and adjust for known predictors of cessation-related weight gain.We will recruit 320 participants, with 160 participants in each arm. An alpha error rate of 5% and 90% power will detect a 2 kg (SD = 2.5) difference in weight gain at 12 weeks, assuming 20% remain abstinent by then.DiscussionThis trial will establish whether referral to the 12-week Slimming World programme plus usual care is an effective intervention to prevent cessation-related weight gain. If so, we will seek to establish whether weight control comes at the expense of a successful quit attempt in a further non-inferiority trial.Positive results from both these trials would provide a potential solution to cessation-related weight gain, which could be rolled out across England within Stop Smoking Services to better meet the needs of 0.75 million smokers stopping with NHS support every year.Trial registrationCurrent Controlled Trials ISRCTN65705512

Nine-month results of intravitreal bevacizumab versus triamcinolone for the treatment of diffuse diabetic macular oedema: a retrospective analysis

To compare efficacy of intravitreal bevacizumab versus triamcinolone in the treatment of diffuse diabetic macular oedema (DME). This retrospective nonrandomized study includes 60 patients with diffuse DME treated with at least one intravitreal triamcinolone injection (ITA) or intravitreal bevacizumab injection (IBe). Regression analysis was performed for pretreatment, glycosylated haemoglobin level, visual acuity (VA) at baseline and central macular thickness (CMT) at baseline. After 1-, 3-, 6- and 9-month follow-up, there was no significant change in either VA or CMT treatment in the ITA and IBe groups. There was no statistically significant difference between the two treatment groups. Changes in CMT and VA in the subgroups were not significant. Only predictive factor independent of HbA1c level and VA was CMT at baseline in both treatment groups. The thicker CMT at baseline, the higher was reduction in CMT. After 1 month, the IBe group had a significantly higher decrement than the ITA group. In our study collective, neither IBe nor ITA treatment was able to improve VA during follow-up, significantly. CMT was reduced in both treatment groups, however not significantly. Our data demonstrates that reduction in CMT with either IBe or ITA treatment was significantly influenced by degree of CMT at baseline.

Author's reply to comments on Shyam et al.: Leg lengthening by distraction osteogenesis using the Ilizarov apparatus: a novel concept of tibia callus subsidence and its influencing factors

We really appreciate the thoughtful and detailed comments by the readers in referencing our paper on subsidence in tibia lengthening [1]. In almost all our cases we used the 160 ring. Also, as seen in the figure in our article the patient is a child (as are most of our patients), and thus the first assumption in the comment is erroneous (although as stated below this will have minimal effect on the magnification). Also, as per the comments, for a 180 ring the plate bone distance will be 12.3 and not 13.3, and thus the magnification will be 11.9% (for standard plate focus distance of 115 cm as calculated from formula given below) and not 14.4% as mentioned. Beginning with these two comments on erroneous assumptions made by the readers, we need to take into account here that the subsidence is the difference between two readings. Thus, these magnifications are also subtracted to give us the final magnification of the subsidence fragment which, according to the authors' calculations, will be 14.4% minus 5.8%, which is 8.6%. If we consider the subsidence of mean 1.19 ± 0.78 cm (range 0.4–3.2 cm) to which if the magnification correction of 8.6% is applied (keeping in mind that if the distance is corrected from 14.4 to 11.9 as shown above, then this correction will be 6.1%), it becomes 1.09 ± 0.718 (range 0.36–2.94). Thus, although the reported figures definitely are erroneous in the original paper, we do not think they are completely off the mark. Now we will consider the more accurate assumption in terms of using a 160 ring as was the case in our series. Although the comments have used the centre of tibia as the reference point, we would like to point out that the distracted fragment is rarely at the centre. In our cases the position of the limb in the ring was determined by the posterior clearance of the calf; in fact, this is the point that dictates the use of various ring sizes. If we consider that 5.5 cm is the bone plate distance without ring, we can predict the bone plate distance with the ring. In the ring, the posterior clearance was ideally taken as 2 cm while the ring is 1.5 cm across; this sums to 9 cm bone plate distance [5.5 + 2 + 1.5]. Hence, the size of the ring will have minimal effect on the bone plate distance, which will remain constant irrespective of the ring used (as the breadth of the ring remains constant). To validate this point we made actual measurements in our current patients with similar profile and the distance from calf to the plate was indeed an average of 4.2 cm. Thus, from the examples, the two distances would be 5.5 and 9 cm with corresponding magnification calculated by the formula in Fig. 1 [2]. The standard film focus distance was 115 cm (1150 mm). Fig. 1 Formula for calculation of magnification [2] In this formula the standard film focus distance was taken as 1000 mm while in our case it was 1150 mm. Therefore, when the distance is 55 mm, magnification = 1150/1095 = 1.0502 (i.e. magnification of 5.02%) and when the distance is 90 mm, magnification = 1150/1160 = 1.084 (i.e. magnification of 8.4%). Thus, the respective magnifications would be 5.02% and 8.4% with final magnification of 3.36%, which is well within the 5% alpha error rate (p value 0.05). Once again, although there exists a measurement error in our paper, this was small and well within the acceptable error rates. Apart from mathematical calculations, we are required here to make an important point. Our paper was based on our observations that at two- to three-years follow-up, a few of our patients who underwent bilateral lengthening reported significant difficulties in walking barefoot (without the footwear correction) even though all patients were quite satisfied with the overall results. These patients also had a difference of more than 1 cm between the two lengthened legs, which were originally lengthened by the same amount. This led us to consider the presence of tibial subsidence as a factor, and we performed the investigation in question to study whether such a subsidence actually occurs and to what extent. With our measurements we did find differences in the follow-up lengthening from the final distraction in almost all patients and we tried to quantify this difference (although with error!). In effect, the aim of the paper was to introduce the concept of tibial subsidence, so that more and more of our colleagues would try and measure the subsidence in order to collectively devise a method to avoid this complication which led to unsatisfactory results in quite a few of our patients.

Considerations of sample size in medical research

Considerations of sample size in medical research

Phase II study of irinotecan and paclitaxel for patients with recurrent small cell lung cancer (SCLC)

18011 Background: Recurrent SCLC has a poor prognosis and is devoid of treatment options that improve overall survival. Irinotecan and paclitaxel are both active agents against SCLC, and have synergistic preclinical interactions. We conducted a phase II study to evaluate the efficacy and safety of the combination of irinotecan and paclitaxel for patients with recurrent SCLC. Methods: Patients with SCLC who relapsed following one prior chemotherapy regimen were eligible. Other pertinent inclusion criteria were: ECOG performance status 0–2, adequate bone marrow, hepatic and renal function and willingness to provide informed consent. Patients with untreated brain metastasis were excluded. Paclitaxel (75 mg/m2) and irinotecan (50 mg/m2) were administered on days 1 &amp; 8 of every 3-week cycle. Treatment was continued until progression up to a maximum of 6 cycles or unacceptable toxicity. The primary endpoint was response rate. Toxicity was graded by CTC version 2.0. The simon two-stage design was utilized and the estimated sample size was 55 patients (stage I - 23 patients; stage 2 - 32 patients). The study has a 90% power to detect a response rate of 30%, with an alpha error rate of 10%. Results: 55 patients have been enrolled and complete data are available for 32 patients at the time of this report. Patient baseline characteristics are: male 53%, PS 0–44%; PS 1–47% and PS 2–6%. The median age is 61 years. Fifteen patients received ≥ 4 cycles. Salient grades 3–5 toxicities seen: neutropenia (13%), fatigue (13%); diarrhea (3%), hypersensitivity (3%) and hyponatremia (3%).The objective response rate is 37% (95% CI 19%-55%) with 9 PRs and 1 CR. Additional 8 patients (24%) had stable disease. The median survival is 19.6 weeks (95% CI 15.1–29.4) and the 1-year survival rate is 15%. Conclusions: The combination of irinotecan and paclitaxel is well tolerated and has promising anti-cancer activity in recurrent SCLC. Updated data on all 55 patients will be available at the time of the presentation. No significant financial relationships to disclose.

TACT method for non-inferiority testing in active controlled trials.

In active controlled trials without a placebo arm, non-inferiority testing is often considered but has different objectives. For the objective of demonstrating the efficacy of an experimental treatment or retention of a fraction of the control effect by the treatment, there are two types of statistical methods for testing - the synthesis method and the confidence interval method. According to the study of Wang, Hung and Tsong, the former is efficient under the so-called constancy condition but may have the alpha error rate inflate rapidly if the condition does not hold. In contrast, the latter method with careful selection of the non-inferiority margin tends to be conservative if the condition holds and may still have a valid alpha error otherwise unless the effect of the active control is less to a large extent in the active controlled trial than in the historical trials. We developed the TACT method, Two-stage Active Control Testing, as a viable compromise between the two methods. Through the TACT method, the uninterpretable non-inferiority testing may be avoided prior to the end of the trial. The TACT method carefully constructed can have a valid alpha error rate and the power close to the synthesis method if the constancy condition holds. In addition, the TACT method is more powerful than the confidence interval method for testing for the efficacy of the new treatment relative to the putative placebo and for showing that the new treatment is not inferior to the active control comparator.

Using real-time, quantitative PCR for rapid genotyping of the steroid 21-hydroxylase gene in a north Florida population.

The most common cause of congenital adrenal hyperplasia is steroid 21-hydroxylase deficiency. The molecular genetics of this disease are such that genotyping is a potentially useful tool in its diagnosis. An assay was developed using real-time, quantitative PCR to detect deletions of the steroid 21-hydroxylase gene (CYP21A2). This assay was able to detect heterozygous gene deletions with an alpha error rate of less than 5%, with a power greater than 95%. When combined with allele-specific PCR, genotyping for the nine most common mutations can be completed within hours of blood sampling. This technique was used to study subjects with 21-hydroxylase deficiency in North Florida. Twenty-eight subjects with congenital adrenal hyperplasia, seven first-degree relatives and thirteen normal subjects, were characterized. Of 96 chromosomes, 69 abnormal alleles were identified. Among unrelated abnormal alleles, the frequency of specific mutations was 28% for a gene deletion, 24% for the intron 2 splice mutation, 10% for ile172asn, 8% each for val281leu and the exon 6 cluster, and 6% for gln318x mutations. These frequencies, as well as the genotype/phenotype correlation, were similar to those found in comparable populations. The utility of genotyping in the diagnosis of 21-hydroxylase deficiency is increased by the rapidity of the analysis. With quantitative PCR, the need for more expensive and time consuming Southern blot analysis is reduced and limited to the clarification of certain genotypes. Faster results will allow for more timely initiation of appropriate therapy and limit the exposure of potentially unnecessary therapy.

D ELAYS IN THE EMS R ESPONSE TO AND THE E VACUATION OF P ATIENTS IN H IGH-RISE B UILDINGS IN S INGAPORE

Background. Singapore is a highly urbanized and cosmopolitan city situated at the crossroads of Southeast Asia. High-rise buildings and “vertical living” are common, and the city serves as a major business, financial, and industrial hub in the region. More than 80% of the population live in high-rise apartments. This poses unique problems and challenges for emergency ambulance services personnel in the access to and evacuation of patients. Objective. To estimate the arrival-to-patient contact delay when accessing patients in high-rise buildings and evacuating them to the hospital, compared with accessing patients in ground-level premises. Methods. This was a prospective study carried out from February 2 to March 1, 1998, for emergency calls from two of the busiest fire stations. The first 150 consecutive cases were enrolled into each of the two groups. Cases of road traffic accidents were excluded because these did not require the crew to get into a building. The times were clocked by one of the paramedics, using a stopwatch. A high-rise building was defined as one where the crew had to ascend at least one flight of stairs. A ground-level building did not involve any stair climbing. We set forth to determine whether the interval between the following was statistically significant when comparing high-rise vs ground-level premises: 1) time when the ambulance arrives at the scene (taken as the time when the driver turns the engine off) and time of arrival at the patient's side; 2) time of leaving the dwelling with the patient and time when the ambulance starts its journey to the hospital (taken as the time when the driver starts the engine). Data analysis was done with the use of SPSS, and the one-tailed unpaired Student's t-test was used for significance testing, with the alpha error rate set at 0.05. Results. One hundred fifty runs were analyzed for each group. The mean delay from arrival to patient contact was 2.49 ± 0.98 minutes for the high-rise group compared with 1.02 ± 1.41 minutes for the ground-level group (difference was statistically significant with 95% CI: 1.20, 1.74 minutes; p = 0.0106). The mean delays from the time of leaving the building with the patient to the time when the ambulance turned its engine on to start its journey to the hospital were 3.24 ± 1.58 minutes and 1.27 ± 0.71 minutes for the two groups, respectively (difference was statistically significant with 95% CI: 1.68, 2.04 minutes; p = 0.0098). Conclusion. There were significant delays present when accessing patients in high-rise buildings and evacuating them to the hospital. Modification to buildings and increasing public awareness and education have been suggested to help minimize these delays.

Reliability of linear alveolar bone loss measurements of mandibular posterior teeth from digitized bitewing radiographs.

Observer reliability in performing linear measurements between the cementoenamel junction and alveolar crest was determined for mandibular posterior teeth from digitized clinical bitewing radiographs acquired during recall examinations. 6 measurements (corresponding to traditional probing measurements) were made per tooth by 3 observers. Mesial and distal measurements made to the most coronal aspects of the alveolar crest were the most reliable and least biased. As was anticipated, intra-observer reliability was better than inter-observer reliability although the 3 observers of our study were able to detect a significant mean change (0.1 mm, p<0.0001) in alveolar bone height over a 1-year period for 10 patients. For our most reliable and unbiased measurements (mesial measurements to the alveolar crest), a change of 0.54 mm (90th percentile) would be required to indicate change at a site from one time to the next. Based on the reliability of our digital radiographic measurements, with the alpha error rate set at 0.05 and beta at 0.20, a difference in alveolar bone height of 0.3 mm could be detected with a patient sample size of between 13 (best case) and 54 (worst case).

A comparison of chest compressions between mechanical and manual CPR by monitoring end-tidal Pco 2 during human cardiac arrest

To compare the use of mechanical and manual chest compressions during cardiac arrest based on continuous monitoring of end-tidal PCO2 (PETCO2). Prospective, randomized, crossover design. Fifteen consecutive adults ranging in age from 33 to 78 years who presented in nontraumatic cardiac arrest to the emergency department of a large teaching hospital. Study protocols were begun late in the resuscitation after initial resuscitation attempts were unsuccessful. Patients received four alternating five-minute trials (two manual and two mechanical), being randomized to begin with either technique. Mechanical compressions were performed by a mechanical device at a compression depth of 2 in. Both mechanical and manual compressions were delivered at a rate of 80 with a ventilation delivered after every fifth compression. Persons performing manual CPR were experienced American Heart Association basic life support providers, and no person performed manual CPR more than once during the study period. No resuscitative drugs were administered during the study period. PETCO2 was monitored continuously; those performing manual CPR were blinded to the PETCO2 monitor. Data were analyzed with repeated-measures analysis of variance and Scheffé multiple comparisons with the alpha error rate set of .05. Mean PETCO2 during mechanical CPR was 13.6 +/- 4.14 mm Hg compared with 6.9 +/- 2.42 mm Hg during manually performed CPR (P < .001), a difference of 97%. Average mechanical CPR PETCO2 was higher in all cases. No patient was resuscitated successfully. Capnography also indicated that most CPR providers were inconsistent in their chest compressions. This study suggests that cardiac output produced with mechanical chest compressions is greater than that produced with manual compressions as demonstrated by the significantly higher PETCO2 levels during mechanical CPR. Reasons for this are unclear. In addition, monitoring of PETCO2 may help optimize chest compressions during CPR.

A Meta-Analysis of Hepatitis B Serologic Marker Prevalence in EMS Personnel

AbstractIntroduction:The risk of exposure to the Hepatitis B Virus (HBV) is a known occupational health risk in medical personnel. The specific risk in emergency medical services (EMS) personnel in the United States (U.S.) is not known. Estimates have ranged from 0.6 to 30.0% The purpose of this investigation was to provide an estimate of the prevalence of this exposure, to determine if this risk is homogeneous throughout the U.S., and to provide an estimate of relative risk. The study hypothesis was that the risk of exposure to HBV is not homogeneous throughout the U.S.Methods:All articles containing HBV studies of non-immunized EMS personnel (physicians, nurses, and emergency medical service technicians [EMTs]) were considered, provided they reported at least two of the following seromarkers: hepatitis B (HB) surface antigen; HB surface antibody; and/or HB core antibody. A computerized literature search of a database (MEDLARS) from 1980–1989 was performed. Reference sections of relevant articles and texts also were searched. The chi-square test of homogeneity of proportion was used, assuming binomial distribution. The alpha error rate was set at 0.05.Results:Seven articles from 1982 to 1989 qualified for inclusion. The average rate of prevalence for all studies was 14.04% (160/1,140), with a 95% confidence interval of 11.40 to 16.68%. The chi-square test was statistically significant (chi-square=12.59, 6 df, p&lt;.01), suggesting that the risk of exposure is not homogeneous throughout the U.S., and may not be homogeneous within a city, nor between prehospital and hospital personnel. When compared to CDC estimates for the general population in the U.S., this analysis suggests that the EMS personnel tested run three times (2.8) greater risk of HBV exposure than does the general population.Conclusion:EMS personnel run a great risk of exposure to HBV with a nationwide prevalence of 14.04%, but this risk is not spread homogeneously throughout the country.