Miracle-dz/UniFAR-FTUs huggingface dataset:
Shortening the timeline of pediatric phase I trials: the rolling six design.

PURPOSE To shorten the study conduct timeline of pediatric phase I oncology trials by employing a novel trial design. METHODS A comparison of the traditional 3 + 3 patients per cohort, phase I trial design with a novel, rolling six design was performed by using discrete event simulation. The rolling six design allows for accrual of two to six patients concurrently onto a dose level based on the number of patients currently enrolled and evaluable, the number experiencing dose-limiting toxicity (DLT), and the number still at risk of developing a DLT. Clinical trial simulations (n = 1,000) were based on historical data and were performed using SAS 9.1. 3 (SAS Institute, Cary, NC). Study timelines and patient numbers were determined for each design, and safety was assessed as a function of the number of DLTs observed. RESULTS In twelve completed historical studies, the median time to study completion was 452 days (range, 220 to 606 days); number of evaluable participants enrolled was 22 (range, 11 to 33), and DLTs occurring per study was three (range, 0 to 5). In 1,000 study simulations, in which the average time to new patient accrual was 10 days, the average +/- standard deviation (SD) time to study completion was 294 +/- 75 days for the rolling six design versus 350 +/- 84 days for the 3 + 3 design, whereas the number of DLTs per study was the same (average +/- SD, 3.3 +/- 1.1 v 3.2 +/- 1.1 for the rolling six and 3 + 3 designs, respectively). CONCLUSION The rolling six design may significantly decrease the duration of pediatric phase I studies without increasing the risk of toxicity. The design will be tested prospectively in upcoming Children's Oncology Group phase I trials.
Effect of metformin and spironolactone therapy on OGTT in patients with polycystic ovarian syndrome – a retrospective analysis

Background: Metformin (an insulin sensitizer) and spironolactone (an antiandrogen) are both used for treatment of polycystic ovary syndrome. We analyzed the effect of 6 months of therapy with these drugs on body weight and glucose tolerance. Results: This was a retrospective analysis of polycystic ovarian syndrome (PCOS) cases on treatment. There were 88 patients with PCOS-42 were on metformin 1 g daily and 46 were taking spironolactone 50–75 mg daily. 21 of 42 had abnormal glucose tolerance (AGT) in the metformin group and 13 of 46 had AGT in the spironolactone group. Patients on metformin reported a greater reduction in body weight, whereas there was no change in body weight with spironolactone therapy (67.6–63.7 versus 59.6–59.2 kg). There was a significant reduction in the 1 and 2 h glucose and insulin levels with metformin therapy in those with AGT. However, fasting glucose increased in those with normal glucose tolerance. There was no change in either body weight or insulin levels with spironolactone. But, there was a significant reduction in both the 0 and 2 h glucose with spironolactone also in those with AGT. Conclusion: Spironolactone and metformin had similar effect in reducing the glucose levels in PCOS patients with AGT. PCOS patients with normal glucose tolerance had higher fasting plasma glucose at the end of 6 months of metformin therapy inspite of weight reduction.
Systemic Oxygen-Free Radical Production in Iron-Loaded Mice

Although iron is an essential element for normal cell metabolism, in excess quantities it is highly cytotoxic and lethal. In fact, acute iron poisoning is a leading cause of overdose mortality in young children. Hereditary hemochromatosis, a disorder of iron metabolism, is currently the most prevalent genetic disorder in the world, which results in organ failure and premature mortality. Hence, an enhanced understanding of its pathogenesis is critical for providing safe and effective nursing care to affected individuals and their families. Although the exact mechanism of iron’s toxicity is not known, it was hypothesized that chronic iron loading would result in increased tissue (heart, liver, and spleen) concentrations of iron and increased free radical production in a murine model (n = 20). Our results show that chronic iron loading results in highly significant dose-dependent increases in tissue concentrations of iron and systemic free radical generation (p < 0.001).
Wafer-Scale Microtensile Testing of Thin Films

This paper reports on the mechanical characterization of thin films using the microtensile technique performed for the first time at the wafer scale. Multiple test structures are processed and sequentially measured on the same silicon substrate, thus eliminating delicate handling of individual samples. The current layout uses 26 test structures evenly distributed over a 4-in wafer, each of them carrying a microtensile specimen that bridges the gap between the fixed and movable parts of the micromachined wafer. A fully automated high-throughput setup makes possible the fast acquisition of data with statistical relevance for the reliable extraction of material properties. The technique was successfully applied to micrometer- and submicrometer-thick films. Two brittle materials, namely, polycrystalline silicon (poly-Si) obtained by low-pressure chemical vapor deposition and silicon nitride (SiNx) produced by plasma-enhanced chemical vapor deposition, and a ductile material, i.e., evaporated aluminum (Al), were characterized. The extraction of the Young's modulus E, tensile strength sigmau, mean tensile strength sigmatildeu, and Weibull modulus m is demonstrated. Young's moduli thus obtained for the poly-Si, SiNx, and Al films were 156.3plusmn 2.6, 112.2plusmn3.5, and 62.5plusmn 2.5 GPa, respectively. The SiNx layers, which have a mean tensile strength sigmatildeu of 2.084-0.177 +0.169 GPa and m=5.9-1.6 +1.8, are the strongest from the fracture point of view when compared to poly-Si with sigmatildeu=1.382-0.026 +0.023 GPa and m=17.3-3.2 +3.5 and Al with sigmatildeu=0.347plusmn0. 013 GPa. In each case, the best estimate of the mean and the corresponding 90% confidence interval were evaluated using maximum likelihood estimation and the likelihood ratio method, respectively, on the basis of Gaussian and Weibull statistics.
Liposomal doxorubicin: antitumor activity and unique toxicities during two complementary phase I studies.

PURPOSE The purpose of our studies was to define the maximal-tolerated dose of liposomal doxorubicin (DOX-SL; Liposome Technology Inc, Menlo Park, CA), a doxorubicin formulation of polyethyleneglycol-coated liposomes, characterize the toxicities associated with this formulation, and evaluate any indication of antitumor activity within a phase I setting. PATIENTS AND METHODS Two separate phase I studies were conducted following the initial human pharmacokinetic testing at one of the sites (Hadassah). The starting dose of 20 mg/m2 at the University of Southern California was just below the dose without toxicity in the pharmacokinetic study. At Hadassah, the phase I starting dose was just above their earlier safe single doses, 60 mg/m2. Both studies involved cohorts of at least three patients and redosing every 3 to 4 weeks. To determine the recommended dose for phase II trials, an additional level of 50 mg/m2 every 3 weeks was explored, and the level of 60 mg/m2 every 4 weeks was expanded. RESULTS A total of 56 patients receiving 281 courses of DOX-SL was accrued and evaluated for toxicity. Hand-foot (H-F) syndrome and stomatitis are the two main dose-limiting factors of DOX-SL. Stomatitis was dose-limiting for high single doses of DOX-SL greater than 70 mg/m2. Skin toxicity manifested primarily as H-F syndrome was dose-limiting for repetitive dosing, but acceptable at either 50 mg/m2 every 3 weeks or 60 mg/m2 every 4 weeks. Attenuation of acute subjective symptoms and lack of alopecia were generally observed. Patients with carcinomas of the breast, ovary, prostate, and head and neck were among those showing objective antitumor responses or improvement based, in part, on blood levels of tumor markers. CONCLUSION The toxicity profile of DOX-SL differs prominently from that of the free drug administered by bolus or rapid infusion and with some differences, resembles that of prolonged continuous infusion. This finding, as well as the antitumor activity observed, supports wide phase II testing of DOX-SL in solid tumors.
Breast cancer in young women after treatment for Hodgkin's disease during childhood or adolescence--an observational study with up to 33-year follow-up.

BACKGROUND The treatment of Hodgkin's disease (HD; also called Hodgkin's lymphoma) in children and adolescents with radiotherapy and chemotherapy leads to high survival rates but has a number of late effects. The most serious one is the development of a secondary malignant tumor, usually in the field that was irradiated. In women, breast cancer can arise in this way. METHOD Data on the occurrence of secondary breast cancer (sBC) were collected from 590 women who were treated in five consecutive pediatric HD treatment studies in the years 1978-1995 and then re-evaluated in a late follow-up study after a median interval of 17.8 years (maximum, 33.7 years). Information was obtained from 1999 onward by written inquiry to the participants and their treating physicians. The cumulative incidence of sBC was calculated by the Gooley method. RESULTS By July 2012, sBC had been diagnosed in 26 of 590 female HD patients; the breast cancer was in the irradiated field in 25 of these 26 patients. Their age at the time of treatment for HD was 9.9 to 16.2 years (the pubertal phase), and sBC was discovered with a median latency of 20.7 years after HD treatment (shortest latency, 14.3 years) and at a median age of 35.3 years (youngest age, 26.8 years). The radiation dose to the supradiaphragmatic fields ranged from 20 to 45 Gy. The cumulative incidence for sBC 30 years after treatment for HD was 19% (95% confidence interval, 12% to 29%). For women aged 25 to 45 in this series, the frequency of breast cancer was 24 times as high as in the corresponding normal population. CONCLUSION Women who were treated for HD in childhood or adolescence have an increased risk of developing breast cancer as young adults. The risk is associated with prior radiotherapy and with the age at which it was administered (the pubertal phase). Because of these findings, a structured breast cancer screening project for this high-risk group has been initiated in collaboration with the German Consortium for Hereditary Breast and Ovarian Cancer (Deutsches Konsortium für familiären Brust- und Eierstockkrebs).
Cutting Edge: Activation of Virus-Specific CD4 T Cells throughout γ-Herpesvirus Latency

CD4 T cells are essential for immune control of γ-herpesvirus latency. We previously identified a murine MHC class II-restricted epitope in γ-herpesvirus-68 gp150 (gp15067–83I-Ab) that elicits CD4 T cells that are maintained throughout long-term infection. However, it is unknown whether naive cells can be recruited into the antiviral CD4 T cell pool during latency. In this study, we generate a mouse transgenic for a gp150-specific TCR and show epitope-specific activation of transgenic CD4 T cells during acute and latent infections. Furthermore, although only dendritic cells can stimulate virus-specific CD8 T cells during latency, we show that both dendritic cells and B cells stimulate transgenic CD4 T cells. These studies demonstrate that naive CD4 T cells specific for a viral glycoprotein can be stimulated throughout infection, even during quiescent latency, suggesting that CD4 T cell memory is maintained in part by the continual recruitment of naive cells.
Novel dipeptide prodrugs of acyclovir for ocular herpes infections: Bioreversion, antiviral activity and transport across rabbit cornea

Purpose. A series of dipeptide prodrugs of antiviral nucleoside acyclovir (ACV) were designed to target the oligopeptide transporter on the cornea with an aim of improving the ocular bioavailability and therapeutic activity of ACV. Methods. Aqueous stability, ocular bioreversion kinetics in various tissues, in vitro antiviral activity, cell proliferation assay and corneal transport characteristics of the dipeptide prodrugs were studied. Results. ACV dipeptide prodrugs were found to be more stable at pH 5.6 in comparison to L-Val-ACV, an amino acid prodrug of ACV. The prodrugs exhibited higher solubility than ACV. Val-Val-ACV and Val-Tyr-ACV were found to have excellent antiviral activity against herpes simplex virus-1 (HSV-1). All the dipeptide prodrugs exhibited lower cytotoxicity as compared to currently approved anti-HSV agent, trifluorothymidine (TFT). Transport of [ 3 H] Val-ACV was inhibited significantly in the presence of the dipeptide prodrugs of ACV. Corneal permeabilities of all the ACV dipeptide prodrugs were observed to be higher than ACV possibly due to recognition of the prodrugs by the oligopeptide transporter on the cornea. Conclusions. The dipeptide prodrugs were found to be more permeable than the parent drug, ACV. More permeable, less cytotoxic ACV dipeptide prodrugs exhibited excellent chemical stability and antiviral activity against herpes simplex virus thereby rendering these lead compounds promising drug candidates against herpes virus infections.
H/sub /spl infin// output feedback control of discrete-time fuzzy systems with application to chaos control

This paper presents an observer based H/sub /spl infin// output feedback synthesis method for discrete time fuzzy dynamic systems based on a piecewise Lyapunov function. The basic idea of the approach is to design an observer based piecewise linear output feedback control law to guarantee the global stability with H/sub /spl infin// performance of the resulting closed-loop fuzzy control systems. It is shown that the controller parameters can be obtained by solving a set of linear matrix inequalities (LMIs) that are numerically feasible with commercially available software. Application to control chaotic systems is given to illustrate the effectiveness and advantages of the proposed method.
Metabolic indices, energy and macronutrient intake according to weight status in a rural sample of 17-year-old adolescents.

INTRODUCTION With adolescent health a priority on the WHO agenda, research into the diet, weight status and metabolic profile of adolescents is indicated. The present study aimed to assess the diet and metabolic parameters of a rural sample of adolescents. METHODS One hundred adolescents (17 years of age) were recruited from schools in Nea Madytos, Thessaloniki, Greece. Two previous-day food recalls were collected for each participant, and weight, height, waist circumference, serum lipids and fasting glucose levels were measured. The prevalence of underweight/overweight, central obesity, dyslipidemia and impaired fasting glucose (IFG) were calculated. RESULTS Overweight was present in half the boys (51.2%) and one-fifth of the girls (21.3%). In the total sample 7.1% were underweight and another 7.1% were diagnosed with central obesity. Boys had an increased risk of abdominal obesity (OR:1.405, CI:0.7-2.8), IFG (OR:1.200, CI:0.3-4.9) and elevated triglycerides (OR:1.514, CI:1.0-2.4) and serum cholesterol levels (OR:1.806, CI:1.1-3.1). Central obesity increased the chances of IFG (OR:8.000, CI:1.6-39.1) and doubled the prevalence of dyslipidemia (OR:2.190, CI:0.5-9.1). Under-reporting of energy was found among overweight participants and was further verified by an inverse relationship between BMI and the ratio of energy intake to energy expenditure. Adolescents identified a dietary pattern high in fats in lieu of protein. CONCLUSIONS Irrespectively of their weight status, teenagers consume a high fat diet; therefore, dietary counseling, as a means of preventive medicine, should be applied to all weight categories. In addition, the prevalence of obesity in a rural sample of adolescents appears to be higher compared with the whole of Greece.
New attempt using labio‐vestibular flap technique to manage circumcised women with Rokitansky syndrome

Objective. To assess the efficacy of the labio‐vestibular flap technique in managing circumcised women with Rokitansky syndrome and in correcting the sexuality defects caused by the anomaly present and by female circumcision. Design. A prospective, comparative, clinical study. Setting. Kasr El Aini School of Medicine, Cairo University, Egypt. Patients. Thirty‐four circumcised patients with Rokitansky syndrome were divided into 2 groups; Group 1 consisted of 22 cases treated with the labio‐vestibular flap technique, and Group 2 consisted of 12 cases treated with McIndoe's technique. Main outcome measures. Pre and postoperative clinical assessment of the newly formed vagina and sexuality. The new flap is formed of the remaining parts of the labia minora and the adjoining parts of the vestibule, and is used to cover the posterior and lateral walls. Meanwhile, the anterior wall is covered by the epithelium of the original blind vaginal pouch. The modified Kasr El Aini sexual assessment sheet assesses sexuality. Results. Rokitansky syndrome could be classified into 4 clinical types according to the degree of development of the uterus. The labio‐vestibular technique was simple and not associated with any graft rejection, hair growth or contraction of the reformed tract. Dyspareunia and marital failure were less significantly recorded in the labio‐vestibular technique than in McIndoe's technique. But, the most significant results were the improvement in sexuality, in addition to restoration of genital continuation, menstruation and fertility in some cases. Conclusion. The labio‐vestibular flab technique is the most simple and most suitable line of treatment for circumcised cases with Rokitansky syndrome. In these cases, the technique achieved good results in correcting sexual defects after circumcision.
Diagnostic and predictive performance and standardized threshold of traditional biomarkers for drug‐induced liver injury in rats

Traditional biomarkers such as alanine and aspartate aminotransferase (ALT, AST) and total bilirubin (TBIL) have been widely used for detecting drug‐induced liver injury (DILI). Although the Food and Drug Administration (FDA) proposed standardized thresholds for human as Hy's law, those for animals have not been determined, and predictability of these biomarkers for future onset of hepatic lesions remains unclear. In this study, we investigated these diagnostic and predictive performance of 10 traditional biomarkers for liver injury by receiver‐operating characteristic (ROC) curve, using a free‐access database where 142 hepatotoxic or non‐hepatotoxic compounds were administrated to male rats (n = 5253). Standardization of each biomarker value was achieved by calculating the ratio to control mean value, and the thresholds were determined under the condition of permitting 5% false positive. Of these 10 biomarkers, AST showed the best diagnostic performance. Furthermore, ALT and TBIL also showed high performance under the situation of hepatocellular necrosis and bile duct injury, respectively. Additionally, the availability of the diagnostic thresholds in difference testing facility was confirmed by the application of these thresholds to in‐house prepared dataset. Meanwhile, incorrect diagnosis by the thresholds was also observed. Regarding prediction, all 10 biomarkers showed insufficient performance for future onset of hepatic lesions. In conclusion, the standardized diagnostic thresholds enable consistent evaluation of traditional biomarkers among different facilities, whereas it was suggested that novel biomarker is required for more accurate diagnosis and prediction of DILI. Copyright © 2014 John Wiley & Sons, Ltd.
Computation of real structured singular value by Stability Feeler

The real structured singular value μ is effective for robust stability analysis of systems with structured uncertainty. Several methods for obtaining upper bounds of μ have been proposed. However, it is difficult to obtain the true value of μ. In this paper we propose a calculation method for real structured singular value μ by Stability Feeler, which is a new robust stability analysis tool proposed by the authors. While we need to obtain stability intervals of multiple parameters for real μ-analysis, it is possible by using Stability Feeler and the bisection method. Linearization is also needed for real μ-analysis by Stability Feeler. The conservativeness of the result, however, can be reduced by using a region splitting and expanding method. A numerical example shows that the proposed method can give an upper bound and a lower bound of μ, which almost coincide with the true value of μ. The conservativeness of the obtained result is less than the previous ones. The authors believe that this method can generally give the results, which almost coincide with the true value of μ if region splitting is done by sufficiently small splitting rate.
Our current approach to root cause analysis: is it contributing to our failure to improve patient safety?

Background Despite over a decade of efforts to reduce the adverse event rate in healthcare, the rate has remained relatively unchanged. Root cause analysis (RCA) is a process used by hospitals in an attempt to reduce adverse event rates; however, the outputs of this process have not been well studied in healthcare. This study aimed to examine the types of solutions proposed in RCAs over an 8-year period at a major academic medical institution. Methods All state-reportable adverse events were gathered, and those for which an RCA was performed were analysed. A consensus rating process was used to determine a severity rating for each case. A qualitative approach was used to categorise the types of solutions proposed by the RCA team in each case and descriptive statistics were calculated. Results 302 RCAs were reviewed. The most common event types involved a procedure complication, followed by cardiopulmonary arrest, neurological deficit and retained foreign body. In 106 RCAs, solutions were proposed. A large proportion (38.7%) of RCAs with solutions proposed involved a patient death. Of the 731 proposed solutions, the most common solution types were training (20%), process change (19.6%) and policy reinforcement (15.2%). We found that multiple event types were repeated in the study period, despite repeated RCAs. Conclusions This study found that the most commonly proposed solutions were weaker actions, which were less likely to decrease event recurrence. These findings support recent attempts to improve the RCA process and to develop guidance for the creation of effective and sustainable solutions to be used by RCA teams.
Textless Speech-to-Speech Translation on Real Data

We present a textless speech-to-speech translation (S2ST) system that can translate speech from one language into another language and can be built without the need of any text data. Different from existing work in the literature, we tackle the challenge in modeling multi-speaker target speech and train the systems with real-world S2ST data. The key to our approach is a self-supervised unit-based speech normalization technique, which finetunes a pre-trained speech encoder with paired audios from multiple speakers and a single reference speaker to reduce the variations due to accents, while preserving the lexical content. With only 10 minutes of paired data for speech normalization, we obtain on average 3.2 BLEU gain when training the S2ST model on the VoxPopuli S2ST dataset, compared to a baseline trained on un-normalized speech target. We also incorporate automatically mined S2ST data and show an additional 2.0 BLEU gain. To our knowledge, we are the first to establish a textless S2ST technique that can be trained with real-world data and works for multiple language pairs.