Lower Limit Of Confidence Interval Research Articles

Sample size planning for estimating the global win probability with precision and assurance

Randomized controlled trials commonly employ multiple endpoints to collectively assess the intended effects of the new intervention on multiple aspects of the disease. Focusing on the estimation of the global win probability (WinP), defined as the (weighted) mean of the WinPs across the endpoints that a treated participant would have a better outcome than a control participant, we propose a closed-form sample size formula incorporating pre-specified precision and assurance, with precision denoted by the lower limit of confidence interval and assurance denoted by the probability of achieving that lower limit. We make use of the equivalence of the WinP and the area under the receiver operating characteristic curve (AUC) and adapt a formula originally developed for the difference between two AUCs to handle the global WinP. Unequal variances between treatment groups are allowed. Simulation results suggest that the method performs very well. We illustrate the proposed formula using a Parkinson's disease clinical trial design example.

Reliability of cervicocephalic sense of force

Cervicocephalic proprioception (CCP) is an important assessment item for people with a range of clinical conditions, where reduced CCP is associated with neck pain and imbalance. Reliability has been established for a range of positional and movements tests, but there is limited data regarding sense of force, particularly across three planes of movement. The current test–retest study assessed reliability when evaluating sense of force in healthy adults (8 males, 6 females, mean age 31.50 years [SD 10.14]) over two sessions, 4–7 days apart. A force matching protocol was used to evaluate reliability of absolute error (AE), constant error (CE), and variable error (VE) for 10 % and 25 % maximal voluntary contraction (MVC) target forces for flexion, extension, lateral flexion, and rotation. Participants were strapped to a chair to limit trunk movement and data was captured using a compressive force transducer fixed to an adjustable wall mount. Six trials were performed for each contraction-type, totaling 72 submaximal MVCs per session. ICC estimates for AE (0.15–0.77), CE (0.01–0.85), and VE (0.00–0.83) were varied and confidence intervals were mostly wide. Considering lower limits of confidence intervals, CE had best reliability values generally, but more specifically the most reliable contraction type and movement was 25 % MVC flexion (ICC 0.85, confidence interval 0.54–0.95). This study found that reliability for sense of force testing was dependent upon contraction, type of error, and target force utilized. Further reliability analysis should be performed when applying this test to measure validity outcomes in clinical populations.

Estimation of urinary cadmium benchmark dose thresholds for preschool children in a cadmium-polluted area based on Bayesian model averaging.

Urinary cadmium (U-Cd) values are indicators for determining chronic cadmium toxicity, and previous studies have calculated U-Cd indicators using renal injury biomarkers. However, most of these studies have been conducted in adult populations, and there is a lack of research on U-Cd thresholds in preschool children. We aimed to apply benchmark dose (BMD) analysis to estimate the U-Cd threshold level associated with renal impairment in preschool children in the cadmium-polluted area. 518 preschool children aged 3-5years were selected by systematic sampling (275 boys, 243 girls). Urinary cadmium and three biomarkers of early renal injury (urinary N-acetyl-β-D-glucosaminidase, UNAG; urinary β2-microglobulin, Uβ2-MG; urinary retinol-binding protein, URBP) were determined. Bayesian model averaging estimated the BMD and lower confidence interval limit (BMDL) of U-Cd. The medians U-Cd levels in both boys and girls exceeded the recommended national standard threshold (5μg/gcr) and U-Cd levels were higher in girls than in boys. Urinary N-acetyl-β-D-glucosaminidase (UNAG) was the most sensitive biomarker of renal effects in preschool children. The overall BMDL5 (BMDL at a benchmark response value of 5) was 2.76μg/gcr. In the gender analysis, the BMDL5 values were 1.92μg/gcr for boys and 4.12μg/gcr for girls. This study shows that the U-Cd threshold (BMDL5) is lower than the national standard (5μg/gcr) and boys' BMDL5 was lower than the limit set by the European Parliament and Council in 2019 (2μg/gcr), which provides a reference point for making U-Cd thresholds for preschool children.

The safety and efficacy of Houtou Jianweiling tablet in patients with chronic non-atrophic gastritis: a double-blind, non-inferiority, randomized controlled trial.

Background: Common symptoms of Chronic Non-atrophic Gastritis (CNAG) include nausea, stomach distension, and abdominal pain. The Houtou Jianweiling Tablet (HTJWT) is a chinese patent medicine (CN1368229A) and it has been used clinically for more than 20years with proven clinical efficacy in treating CNAG, prompted us to establish the clinical efficacy and safety of HTJWT on patients with mild to moderate CNAG symptoms in Pakistani population. Methods: This phase II, double-blind, randomized, parallel-controlled trial was conducted in a single center between November 2022 and February 2023 in Pakistan. In a ratio of 1:1, total 240 CNAG patients with erosion identified by pathological biopsy and gastroscopy were randomly assigned to control (Omeprazole) group (n = 120) and the treatment (HTJWT) group (n = 120). Patients in the treatment group received orally four HTJWT (0.38g/tablet), three times a day and one placebo of Omeprazole enteric-coated tablet prior to breakfast, daily. On the other hand, patients in the control group received one Omeprazole enteric-coated tablet (20 mg/tablet) prior to breakfast and four placebo of HTJWT, thrice a day. The patients consumed the investigated drugs (i.e., treatment and control) treatment regimen was followed for a duration of 28days. The safety of the patients were evaluated through adverse events, serious adverse events and laboratory tests such as blood biochemistry, urine analysis, liver and renal function tests. Vital signs like; blood pressure, pulse rate, body temperature, respiratory rate for all the patients were recorded. The cardiac status of the patients were assessed through electrocardiogram (ECG). The primary efficacy indicators were the improvement rate of gastric distention and gastralgia as the main clinical symptoms. Secondary indicators were visual analogue score (VAS); improvement rate of secondary clinical symptoms and signs; improvement rate of total clinical signs and symptoms; the disappearance/remission rate of Gastric pain and, remission/disappearance time of gastric distension; and the negative conversion rate of Helicobacter pylori (H. pylori). The outcomes among each group were compared using the chi-square test. Results: Patients in both groups had good drug compliance (80%-120%), and there was no statistically significant difference in the patients' baseline characteristics. The clinical improvement rate was found to be 91.1% in the treatment group and 91.0% in the control group with negligible variation among the two groups (p = 0.9824; 95% confidence interval: -0.0781-0.0798). Similarly, hardly no difference was found in the negative conversion rate of H. pylori between the treatment group and the control group (i.e., 70.1% and 71.8% respectively, p = 0.8125). There were no significant differences in respiratory rate, vital signs, blood pressure, laboratory results for blood biochemistry, urine analysis, liver and renal function tests between the two groups. The ECG assessment carried out for the treatment and control group revealed no considerable difference. Margin variation in the disappearance time of gastric pain (p = 0.1860) and remission rate (p = 0.5784) between the two groups were observed. The control group exhibited a faster remission period for gastrointestinal discomfort indications as compared to treatment group (p = 0.0430). Only one patient in the control group experienced mild to moderate adverse events, namely,; epigastric pain and dyspepsia. The results were consistent with the intention-to-treat and per-protocol analysis that included patients who were 100% compliant to the assigned therapy. Conclusion: The lower limit of confidence interval (CI, 95%) for the differences in the effective rate between the treatment and the control groups was found to be -0.0781 which is greater than -0.15, hence the treatment group is non-inferior to the control group. The therapeutic dosage used in the trial and treatment period did not cause any significant adverse event, and there were no obvious changes in the ECG profile, vital signs and biochemistry of the patients. Based on the clinical efficacy evaluation and reported adverse events, it can be concluded that the HTJWT is a safe and effective traditional chinese medicine for the treatment of patients suffering from chronic non-atrophic gastritis with mild to moderate symptoms. Clinical Trial Registration: [www.clinicaltrials.gov], identifier [NCT04672018].

Revisiting sample size planning for receiver operating characteristic studies: A confidence interval approach with precision and assurance.

Estimation of areas under receiver operating characteristic curves and their differences is a key task in diagnostic studies. Here we develop closed-form sample size formulas for such studies with a focus on estimation rather than hypothesis testing, by explicitly incorporating pre-specified precision and assurance, with precision denoted by the lower limit of confidence interval and assurance denoted by the probability of achieving that lower limit. For sample size estimation purposes, we introduce a normality-based variance function for valid estimation allowing for unequal variances of observations in the disease and non-disease groups. Simulation results demonstrate that the proposed formulas produce empirical assurance probability close to the pre-specified assurance probability and empirical coverage probability close to the nominal level. Compared with a frequently used existing variance function, the proposed function provides more accurate and efficient sample size estimates. For an illustration of the proposed formulas, we present real-world worked examples. To facilitate implementation, we have developed an online calculator openly available at https://dishu.page/calculator/.

Stressful experiences impact clinical symptoms in people with endometriosis

Endometriosis is a chronic condition that affects ~10% of women globally. Its symptoms include chronic pelvic pain, heavy periods and tiredness/fatigue, which have been associated with poorer quality of life and mental health. We aim to explore the impact of the COVID-19 pandemic on pain and fatigue symptoms and their interactions with the impact on mental health in people with endometriosis. This global cross-sectional online survey study collected data from 4717 adults with self-reported surgical/radiological diagnosis of endometriosis between May and June 2020. The survey included questions on the current status and changes of endometriosis symptoms (pelvic pain, tiredness/fatigue, and bleeding patterns), mental health, pain catastrophising, and the impact of the COVID-19 pandemic on the respondents’ lives. Compared to 6 months earlier, Respondents reported a marked worsening of their endometriosis symptoms (endometriosis-associated pain (39.3%; 95% CI: 37.7, 40.5), tiredness/fatigue (49.9%; 95% CI: 48.4, 51.2) and bleeding patterns (39.6%; 95% CI: 38.2, 41)) and mental health (38.6%; 95% CI: 37.2, 39.9). Those with a pre-existing mental health diagnosis (38.8%) were more likely to report their symptoms worsening. Worsening of pain and tiredness/fatigue was significantly correlated with worsening of mental health (P < 0.001). The relationship between changes in mental health and (a) change in pain and (b) change in fatigue was found to be weakly mediated by pain catastrophising scores (pain: B = 0.071, lower limit of confidence interval (LLCI) = 0.060, upper limit of confidence interval (ULCI) = 0.082, tiredness/fatigue: B = 0.050, LLCI = 0.040, ULCI = 0.060). This study demonstrates that stressful experiences impact the physical and mental health of people with endometriosis. The findings highlight the need to consider psychological approaches in the holistic management of people with endometriosis. Lay summary Endometriosis is a chronic condition in which tissue similar to that of the lining of the womb grows outside it. It affects around 10% of women globally, and the symptoms often include persistent pelvic pain, heavy periods and tiredness/fatigue. These symptoms are associated with impaired mental health and life quality. This study used an online questionnaire to assess the experiences of people with endometriosis during the first months of the pandemic. Results from 4717 adults revealed that pelvic pain, tiredness/fatigue and bleeding worsened in more than 39% of the participants. Poor mental health was also exacerbated and associated with worsening in tiredness/fatigue. Further analysis revealed that this relationship could be partially explained by ‘pain catastrophising’, which measures how participants think about their pain. Our results suggest that stressful experiences like the pandemic negatively impact the already burdened mental health of people with endometriosis, who could benefit from psychological interventions.

A Comprehensive Comparison of Additional Benefit Assessment Methods Applied by Institute for Quality and Efficiency in Health Care and European Society for Medical Oncology for Time-to-Event Endpoints After Significant Phase III Trials—A Simulation Study

ObjectivesAfter a successful Marketing Authorization Application for clinical trials with time-to-event endpoints, the degree of the added benefit from new treatments remains unknown and needs to be assessed. Unfortunately, until now no clear definition for added benefit determination of a treatment exists. Nevertheless, European authorities / societies have developed 2 “additional benefit assessment” methods, which have up to now not been compared: the European Society for Medical Oncology (ESMO) developed a dual rule considering relative and absolute benefit. The German Institute for Quality and Efficiency in Health Care (IQWiG) developed a method using upper 95% hazard ratio confidence interval. MethodsWe evaluate and compare both methods in an extensive simulation study including different censoring rates, failure time distributions, and treatment effects for sample size calculation. The methods’ performance is assessed via Receiver Operating Characteristic curves, Spearman correlation, and percentage of achieved maximal scores. ResultsThe results show that IQWiG’s method has in many situations a lower maximal scoring proportion than ESMO’s rule, that is, up to 28.5% versus 94.7%. Various failure time distributions lead to strongly changed maximal scoring percentages for ESMO. High positive correlation between the methods is present for moderate treatment effects. ConclusionsIQWiG’s method is usually more conservative than ESMO’s. ESMO’s rule tends to be more susceptible for various failure time distributions. Using the lower confidence interval limit seems to be a better solution resulting in a higher true-positive rate without increasing the false-positive rate. Thus, IQWiG’s method might need to be adapted accordingly to achieve a better overall classification.

Anthelmintic Resistance of Gastrointestinal Strongyles Infecting Sheep in Nziih, West Cameroon

Aims: This study aimed to investigate the levels of efficacy of anthelmintics that were most commonly used in sheep farms in Nziih locality.
 Study Design: Longitudinal prospective study.
 Place and Duration of Study: The study was carried out in Nziih locality in August 2019 and September 2020.
 Methodology: Resistance against Albendazole (12.5 mg/kg) and Ivermectin (0.2 mg/kg) was evaluated using faecal egg count reduction test in naturally occurring gastrointestinal strongyles of sheep in Nziih. A total of 300 young animals were randomly selected from 5 farms in 2019 and in 2020. Faecal samples were collected from each animal on the first day of treatment (D0) and collected again 14 days later (D14). Faecal Egg Counts were performed using the Willis and Mac Master techniques and resistance was declared when faecal egg count reduction (FECR) was less than 95 % and the lower limit of confidence interval (LCI) less than 90%. Pooled faecal samples for each treatment group were set for D0 and D14 to identify resistant strongyles genera by calculating persistent larval rate (PLR).
 Results: Resistance against Ivermectin was detected while there was none against Albendazole. Moreover, it was declared only in 2 farms out of the 5 selected. From 2019 to 2020, the status of resistance has shifted from suspicion to resistance for ivermectin and from absence of resistance to suspicion to Albendazole. Resistance was recorded in 2 sites: Pastorale1 (FECR= 85 %, LCI= 42.61 %) and Pastorale 3 (FECR=90.5 %, LCI= 72.26 %) in large flock herds and in farms where sheep were dewormed at least 4 times per year. Trichostrongylus were more persistent than Haemonchus and Oesophagostomum/Chabertia with PLR of 21.22 %, 13.71 %, and 7.40 % respectively.
 Conclusion: Anthelmintics must be used correctly in conjunction with farmer education in Nziih.

Hydrochlorothiazide use and risk of non-melanoma skin cancer in Spain: A case/non-case study.

In 2018, the Pharmacological Risk Assessment Committee alerted to a potential relationship between accumulated hydrochlorothiazide dosage and the risk of non-melanoma skin cancer. To study this relationship we used data from the Spanish Pharmacovigilance System for Medicinal Products of Human Use. Following a case search for every thiazide potentially associated with (SMQ/MedDRA) "Malignant Skin Neoplasms and not Otherwise Specified Skin Neoplasms", a series of disproportionality analyses were conducted by estimating the reporting odds ratio (95% confidence interval). Registered adverse drug reactions and disproportionality through the reported odds ratio were the main outcome measures. For basal cell carcinoma, reporting odds ratio was 4.8 (2.2 - 10.7); squamous cell carcinoma 3.2 (0.9 - 10.5); malignant melanoma, 0.8 (0.2 - 3.5). We found both disproportionality and association between hydrochlorothiazide and basal cell carcinoma, but none of these were found regarding malignant skin melanoma. In the case of squamous cell carcinoma, the lower confidence interval limit was below 1, thus the disproportionality value was not statistically significant. The accumulated hydrochlorothiazide dose was 36,714 mg for basal cell carcinoma; 98,288mg for squamous cell carcinoma; and 38,444mg for malignant melanoma. The results in Spain, where sun exposure is significant, are consistent with the data in the Pharmacological Risk Assessment Committee's alert, which were obtained in Denmark for both basal cell carcinoma and malignant melanoma. However, the results for squamous cell carcinoma did not reach statistical significance, although the reporting odds ratio value suggested a potential relationship between hydrochlorothiazide and squamous cell carcinoma.

Plant-Derived Compounds as a Tool for the Control of Gastrointestinal Nematodes: Modulation of Abamectin Pharmacological Action by Carvone.

The combination of synthetic anthelmintics and bioactive phytochemicals may be a pharmacological tool for improving nematode control in livestock. Carvone (R-CNE) has shown in vitro activity against gastrointestinal nematodes; however, the anthelmintic effect of bioactive phytochemicals either alone or combined with synthetic drugs has been little explored in vivo. Here, the pharmacological interaction of abamectin (ABM) and R-CNE was assessed in vitro and in vivo. The efficacy of this combination was evaluated in lambs naturally infected with resistant gastrointestinal nematodes. Additionally, the ligand and molecular docking of both molecules to P-glycoprotein (P-gp) was studied in silico. The presence of R-CNE produced a significant (p < 0.05) increase of Rho123 and ABM accumulation in the intestinal explants. After 60 min of incubation, Rho123 incubated with R-CNE had a 67 ± 21% higher concentration (p < 0.01) than when it was incubated alone. In the case of ABM, a significant increase in the intestinal concentrations was observed at 15 and 30 min after incubation with R-CNE. In the in vivo assay, no undesirable effects were observed after the oral administration of R-CNE. The coadministration of the natural compound prolonged ABM absorption in lambs. ABM T½ absorption was 1.57-fold longer (p < 0.05) in the coadministered group. Concentrations of R-CNE between 420 and 2,593 ng/mL were detected in the bloodstream between 1 and 48 h posttreatment. The in vivo efficacy of ABM against gastrointestinal nematodes increased from 94.9 to 99.8% in the presence of R-CNE, with the lower confidence interval limit being >90%. In vitro/in vivo pharmacoparasitological studies are relevant for the knowledge of the interactions and the efficacy of bioactive natural products combined with synthetic anthelmintics. While ADMET (absorption, distribution, metabolism, excretion, and toxicity) predictions and the molecular docking study showed a good interaction between ABM and P-gp, R-CNE does not appear to modulate this efflux protein. Therefore, the pharmacokinetic–pharmacodynamic effect of R-CNE on ABM should be attributed to its effect on membrane permeability. The development of pharmacology-based information is critical for the design of successful strategies for the parasite control.

Precise Evaluation of the Cochlear Duct Length by Flat-panel Volume Computed Tomography (fpVCT)-Implication of Secondary Reconstructions.

Flat-panel volume computed tomography (fpVCT) and secondary reconstruction allow for more accurate measurements of two-turn length (2TL), cochlear duct length (CDL), and angular length (AL). Cochlear geometry is a controversially debated topic. In the meantime, there are many different studies partly reporting highly divergent values. Our aim is to discuss the differences and to propose a radiological possibility to improve cochlear measurements using 3D-curved multiplanar reconstruction and fpVCT. Performing different image modalities and settings, we tried to find a clinically usable option that allows for a high degree of accuracy. Therefore, we tested them against reference values of high-definition micro-computed tomography. Comparison of 99 μm slice thickness secondary reconstruction of fpVCT and reference showed no significant differences for 2TL and CDL (p ≥ 0.05). Accordingly, ICC (intraclass correlation) values were excellent (ICC ≥ 0.75; lower limit of confidence interval [CI] ≥ 0.75; Cronbach's alpha [α] ≥ 0.9). Evaluating AL, there was a significant difference (difference: -17.27°; p = 0.002). The lower limit of the CI of the ICC was unacceptable (ICC = 0.944; lower limit of CI = 0.248; α = 0.990). Regarding the Bland-Altman plots, there were no clinically unacceptable errors, but a systematic underestimation of AL. Secondary reconstruction is a suitable tool for producing reliable data that allow the accurate measurement of 2TL and CDL. The option of generating these reconstructions from raw data limits the need for higher radiation doses. Nevertheless, there is an underestimation of AL using secondary reconstructions.

Estimation and Control for Industrial Products Reliability under Failure Trials

In practices, most industrial products are subject to sudden failure and only failure information can be collected, which presents a great challenge for reliability prediction of modern devices. To address this issue, our paper proposes a dynamic reliability estimation and control for industrial products under regular failure trials. The failure trial is performed at different operational time points of the products, which provides sole data source for evaluating the status of industrial products. We use Bayesian approach to dynamically estimate the industrial products when the failure trial is available. The estimated reliability is updated using a point estimate with new available data. To maintain the reliability of products at a desirable status, a reliability control method is presented to monitor the confidence interval of reliability distribution. The lower limit of confidence interval is maintained above a control limit, which indicates that a corresponding quality-assurance action is preferable. The proposed reliability estimation and control approach is demonstrated using a case of light-emitting diodes under failure trials at production process. The obtained results indicate the effectiveness of our estimation and control model.

Tapentadol Prolonged Release for Long-Term Treatment of Pain in Children.

PurposeInvestigation of the efficacy and safety of tapentadol prolonged release (PR) compared with morphine PR for long-term treatment of pain in children.Patients and MethodsChildren aged 6 to <18 years requiring long-term treatment with opioids were studied in a 12-month, 2-part, multi-center trial: Part 1, 14-day open-label, randomized, active-controlled, parallel group non-inferiority trial comparing twice daily tapentadol PR with morphine PR; Part 2, open-label treatment with tapentadol PR for up to 12 months or no treatment “safety observation period”. Pain intensity was rated with visual analogue scale or Faces Pain Scale-Revised, and non-inferiority was assessed by comparison of “treatment responders” (those completing the 14-day treatment period and showing pre-defined changes in pain rating) in each group.ResultsTwenty-three of 48 centers enrolled 73 patients. In Part 1, 45 and 24 patients received tapentadol or morphine, respectively, of which 40 and 22 completed 14-day treatment. In Part 2, thirty-six and 58 patients entered the tapentadol PR or observation periods, respectively, with 20/36 completing at least 12 weeks of treatment; 10 of the 36 had received morphine in Part 1. Forty-four of the 58 patients in the safety observation period had received tapentadol. Tapentadol PR was non-inferior to morphine PR (lower limit of confidence interval above negative non-inferiority margin of −0.2) in Part 1. Rates of adverse events were as expected with nausea (22.2%) and constipation (15.6%) in the tapentadol PR group, and with vomiting (33.3%), nausea and constipation (each 16.7%) in the morphine PR group. No new safety issues were identified; the safety profile of tapentadol over the 12 months treatment and observation periods was comparable to that established in subjects >18 years old.ConclusionTapentadol PR was well tolerated and equivalent to morphine PR for both efficacy and safety in children (6 to <18 years old) requiring long-term treatment with opioids.

Prevalence of corrected arterial hypertension based on the self-reported prevalence estimated by the Brazilian National Health Survey.

The objective was to correct the self-reported prevalence of systemic arterial hypertension (SAH) obtained from the Brazilian National Health Survey (PNS 2013). SAH prevalence estimates were corrected by means of sensitivity/specificity of information. Sensitivity and specificity values from a similar study (same self-report question, age range and gold standard) were used to this end. A sensitivity analysis was also performed, by using the upper and lower limits of confidence intervals as sensitivity and specificity parameters. The corrected prevalence of SAH for Brazil as a whole was 14.5% (self-reported: 22.1%). Women presented a higher rate of self-reported SAH but, after correction, men were found to have a higher prevalence. Among younger women (18-39 age range), the self-reported prevalence was 6.2%, a value that, after correction, dropped to 0.28%. There was not much difference between self-reported and corrected SAH among the elderly (51.1% vs. 49.2%). For certain groups the corrected results were greatly different from the self-reported prevalence, what may severely impact public health policy strategies.

Circulando hacia la seguridad del paciente: realidad y deseo

ObjectiveTo evaluate differences between the need and degree of implementation of safe practices recommended for patient safety and to check the usefulness of traffic sign iconicity to promote their implementation. MethodThe study was developed in two stages: 1) review of safe practices recommended by different organizations and 2) a survey to assess the perceptions for the need and implementation of them and the usefulness of signs to improve their implementation. The sample consisted of professionals from Spain and Latin America working in healthcare settings and in the academic field related to patient safety. Results365 questionnaires were collected. All safe practices included were considered necessary (mean and lower limit of confidence interval over 3 out of 5 points). However, in six of the patient safety practices evaluated the implementation was considered insufficient: illegible handwriting, medication reconciliation, standardization of communication systems, early warning systems, procedures performed or equipment used only by trained people, and compliance with patient preferences at the end of life. Improve compliance of with hand hygiene and barrier precautions to prevent infections, ensure the correct identification of patients and the use of checklists are the four practices in which more than 75% of respondents found a high degree of consensus on the usefulness of traffic sings to broaden their use. ConclusionThe differences between perceived need and actual implementation in some safe practices indicate areas for improvement in patient safety. With this aim, the common language and the iconicity of traffic signs could constitute a simple instrument to improve compliance with safe practices for patient safety.

Nalfurafine hydrochloride for refractory pruritus in peritoneal dialysis patients: a phase III, multi-institutional, non-controlled, open-label trial

BackgroundNalfurafine hydrochloride (“nalfurafine”), the world’s first selective oral κ-receptor agonist for improving pruritus, is approved in Japan for the treatment of pruritus resistant to existing treatments in hemodialysis (HD) or chronic liver disease patients. Peritoneal dialysis (PD) patients, like HD patients, suffer from end-stage renal disease (ESRD) and some experience refractory pruritus.MethodsWe investigated the efficacy and safety of nalfurafine in 37 ESRD patients who underwent PD and had refractory pruritus. Nalfurafine was given once daily for 4 weeks at 2.5 μg in weeks 1 and 2 of the treatment period and at 5 μg in weeks 3 and 4. The primary endpoint was visual analog scale (VAS) changes for pruritus (i.e., the value upon rising or before sleep in week 2, whichever larger).ResultsThe mean VAS change from baseline in week 2 of the treatment period was 24.93 mm [18.67, 31.19] (the point estimate of the mean [90% confidence interval (CI)]); the lower limit of CI exceeded the point estimate of the mean VAS change (15.24 mm) of the placebo group at the evaluation point (week 2) in a preceding confirmatory trial suggesting that had demonstrated nalfurafine efficacy for refractory pruritus in HD patients. The observed VAS change was comparable to that of the 2.5-μg group (week 2) in the preceding confirmatory trial, demonstrating that nalfurafine is as effective for treating pruritus in PD patients as in HD patients. Nalfurafine 5 μg was associated with a mean VAS change of 32.13 mm at week 4, i.e., the full length of the trial treatment period suggesting efficacy at the dose of 5 μg. The incidence of adverse drug reactions (ADR) was 45.9% (1/37 patients) with no serious ADRs observed. ADRs occurring in ≥ 5% of patients included insomnia (13.5%), increased blood prolactin (13.5%), somnolence (8.1%), lower blood testosterone free (8.1%), and vomiting (5.4%), all of which were mild.ConclusionsThis trial demonstrated the efficacy and safety of nalfurafine against refractory pruritus in PD, suggesting clinical benefit for treating pruritus in PD patients.Trial registrationJapan Pharmaceutical Information Center, JapicCTI-142565

A Randomized, Open-Label, Multicenter, Dose Escalation Study of HQK-1001 (2,2-Dimethylbutyrate, Sodium Salt) in Sickle Cell Disease

Abstract 998 Fetal hemoglobin (Hb F) induction is an effective therapeutic strategy in SCD. Widespread use of hydroxyurea (HU), the only approved anti-switching agent, has been limited by patient concerns about tolerability, patient compliance, and long-term use of a cytotoxic agent. There is a need for alternative anti-switching agents that are not cytotoxic and with different mechanisms of action. HQK-1001, an orally bioavailable short-chain fatty acid, promotes Hb F synthesis and prolongs erythroid survival and proliferation in pre-clinical models. In an earlier placebo-controlled Phase I/II study in SCD, HQK-1001 at 10, 20, and 30 mg/kg/day for 12 weeks was well tolerated and resulted in dose-dependent increase in Hb F. This randomized, open-label, dose escalation study evaluated the safety, pharmacodynamics (PD) and pharmacokinetics (PK) of HQK-1001 given at higher doses and for longer duration (NCT01322269). Patients with SCD ≥ 12 years of age were randomized to receive HQK-1001 at 30, 40, or 50 mg/kg daily for 26 weeks. Enrollment at 50 mg/kg was opened after an interim review of safety data at the 2 lower doses. Patients were stratified by HU at enrollment, and those on HU had to be on a stable dose for ≥ 6 months. HQK-1001 was discontinued if the patient was transfused. Oral iron was given daily if baseline plasma ferritin was The median duration on study drug was 114 days (range, 8–192), with 27 patients (52%) having discontinued HQK-1001 prior to completing the planned 26 weeks of dosing, 12 due to a transfusion and 15 for other reasons including withdrawal of consent and adverse events (AEs). The most common drug-related AEs, nausea (44%), vomiting (29%), somnolence (25%), headache (17%) and upper abdominal pain (17%), were usually graded as mild or moderate. Oral iron may have exacerbated upper gastrointestinal (GI) AEs. Dose limiting toxicities identified at 40 and 50 mg/kg doses consisted of gastritis (n = 3), somnolence (n = 2), pancreatitis (n = 1) and increased AST (n = 1). The maximum tolerated dose was established as 30 mg/kg/day and the protocol was amended to dose all patients at 30 mg/kg/day and discontinue oral iron. To further improve GI tolerability, the protocol was then amended to switch all patients to 15 mg/kg twice a day. No new drug-related severe toxicities were reported after stopping oral iron and dosing all patients at 30 mg/kg/day. Peak plasma concentrations were dose proportional. Average half-lives ranged from 9.8 to 11.7 hours and were dose independent. Plasma concentrations at 30 mg/kg were in the range shown to induce Hb F and erythropoiesis in pre-clinical models. Plasma concentrations were Of the 21 patients receiving HQK-1001 alone, Hb F increased in 18 patients (86%), with a mean increase of 2% (range, −2% to +10%), total Hb increased by a mean of 0.5 g/dL (range, −0.7 to 2.4 g/dL), and reticulocytes increased by a mean of 4.1% (range, to −4% to +15%). In 31 patients receiving HQK-1001 + HU, Hb F increased in 25 patients (80%), with a mean increase of 2.7% (range, −3% to + 10%), total Hb increased by a mean of 0.75 g/dL (range, −1.2 to + 1.8 g/dL), and reticulocytes increased by a mean of 1.4% (range, −6% to +15%). Covariate analysis showed significant correlation between change in Hb F at peak value and baseline ferritin (positive correlation, p = 0.008) and TIBC (negative correlation, p This study demonstrated that HQK-1001 is well tolerated at 30 mg/kg/day. Plasma concentrations at this dose were in the range shown to induce Hb F and erythropoiesis in pre-clinical models. Hb F increased in most patients, both in HU and non-HU groups. HQK-1001 also increased erythropoiesis. Based on these positive results, a placebo-controlled Phase 2 study was launched to evaluate the PD, efficacy and safety of HQK-1001 at 15 mg/kg BID in SCD patients not currently treated with HU. Disclosures: Kutlar: HemaQuest Pharmaceuticals, Inc.: Research Funding. Reid: Haemaquest: Honoraria. Taher: Novartis: Research Funding, Speakers Bureau. Abboud: Novartis: Speakers Bureau; Pfizer: Research Funding; Sangart: Membership on an entity9s Board of Directors or advisory committees. Buchanan: HemaQuest Pharmacuetical, Inc.: Research Funding. Ataga: HemaQuest Pharmaceuticals, Inc: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding. White: HemaQuest: Consultancy. Johnson: HemaQuest Pharmaceuticals: Employment, Equity Ownership. Ghalie: HemaQuest Pharmaceuticals: Employment, Equity Ownership.

The German version of the Child Perceptions Questionnaire (CPQ-G11-14): translation process, reliability, and validity in the general population

The aims of this study were to develop a German version of the Child Perceptions Questionnaire (CPQ11-14, a measure of oral health-related quality of life in 11-14-year-old children) and to assess the instrument's reliability and validity in German children ages 11-14. The English original version of the CPQ11-14 questionnaire was translated into German (CPQ-G11-14) by a forward-backward translation method. Reliability was investigated in 1,061 subjects aged 11-14 years from a regional sample (Wernigerode, Saxonia-Anhalt, Germany) who were recruited during the annual dental public health examination. The subjects completed the CPQ-G11-14 and were clinically examined for the presence of dental caries, plaque accumulation, and malocclusion. In the reliability assessment, questionnaire summary score test-retest reliability was excellent (intraclass correlation coefficient, 95% confidence interval (CI) = 0.83, 0.73-0.94) and internal consistency was satisfactory (Cronbach's alpha, lower limit of CI = 0.87, 0.86). Validity of the CPQ-G11-14 questionnaire was supported by correlations with global ratings of oral health and overall well-being that were moderate in magnitude and met expectations (r = 0.35; 95% CI, 0.30-0.40 and r = 0.30; 95% CI, 0.24-0.35, respectively). In conclusion, the German version of the CPQ11-14 was reliable and valid in a general population of 11-14-year-old German children.

Prognostic Value of Magnetic Resonance Imaging in Post-Resuscitation Encephalopathy

Prediction of the prognosis of comatose survivors after cardiopulmonary arrest (CPA), so-called post-resuscitation encephalopathy (PRE), relies on neurological examination findings. Early laboratory indicators of poor prognosis (vegetative state/death) are not sensitive enough. We analyzed the results of magnetic resonance (MR) imaging with fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging (DWI) in 22 consecutive patients with PRE. Clinical details such as arrest place and anoxia time along with neurological examination findings including items of Glasgow coma scale (GCS) and the Full Outline of UnResponsiveness (FOUR) score were determined. Receiver Operator Characteristics (ROC) curves were produced to determine prognostic yield of the parameters studied. Prognosis was classified as 'poor' (Glasgow-Pittsburg Cerebral Performance -CPC-score 4 or 5) in 16 and 'better' (CPC score 1-3) in 6 patients. The lower limit of confidence interval (CI) of the area under the curve (AUC) of the ROC was higher than 0.5 for visual, motor and total scores of GCS and FOUR score. Presence of a lesion pattern of multilobar, or diffuse, cortical involvement, termed as "extensive cortical lesion pattern" in MR imaging was a very good predictor of poor prognosis with an AUC of ROC of 0,937. Sensitivity of GCS motor part score and MR was 87.5% (95% CI: 61.6%-92.6%). Motor part of the FOUR score has a slightly lower sensitivity (68.7% with 95% CI from 41.4% to 88.9%). Incorporating of MR to the motor scores (either GCS or FOUR score) improved sensitivity to 100 % (95% CI: 79.2%-100%). AUC of the ROC was 1.000 (95%CI: 0.844-1.000) for the combination of MR and GCS motor score. This study provides the preliminary evidence that MRI, when used in conjunction with a neurological examination, may have potential in terms of predicting outcome in patients with PRE.

A Note on an Input Control Model of a Predictive Regression Interval

A well-known problem of prediction in linear regression models is to find a confidence interval for the random value of the dependent variable when the values of the independent variables are given. Such a situation may arise in economic quality control models when the independent variables are costly inputs and the dependent variable is some measure of quality or production. In such a circumstance, an important control objective may be to find values for the inputs that will maximize the lower limit of the prediction confidence interval for a fixed budget, or alternatively, to minimize the cost of the inputs for a fixed lower limit of the confidence interval. In this paper, we shall show that global optima can be found using known algorithms. The special case of simple linear regression is discussed and an illustrative example is provided.