Growth hormone replacement in adults with growth hormone deficiency: assessment of current knowledge

The recent availability of recombinant human growth hormone (GH) has led to intense investigation of the consequences of adult GH deficiency (GHD) and the effects of GH replacement. These studies have led to the identification of a characteristic syndrome of GHD consisting of decreased mood and well-being, with alterations in body composition and substrate metabolism. In both placebo-controlled and open studies, GH replacement therapy has consistently been shown to reverse or correct these features. Whether long-term GH replacement will result in a reduction of osteoporotic fractures, cardiovascular morbidity and mortality is not yet known. To date, no permanent serious adverse effects have been associated with GH replacement in GHD, and although currently expensive, it is anticipated that GH replacement will become routine in the treatment of the severely hypopituitary adult.

Digital Systems for Open Access to Formal and Informal Learning

Today, Digital Systems and Services for Technology Supported Learning and Education are recognized as the key drivers to transform the way that individuals, groups and organizations “learn” and the way to “assess learning” in 21st Century. These transformations influence: Objectives - moving from acquiring new “knowledge” to developing new and relevant “competences”; Methods – moving from “classroom” based teaching to “context-aware” personalized learning; and Assessment – moving from “life-long” degrees and certifications to “on-demand” and “in-context” accreditation of qualifications. Within this context, promoting Open Access to Formal and Informal Learning, is currently a key issue in the public discourse and the global dialogue on Education, including Massive Open Online Courses (MOOCs) and Flipped School Classrooms. This volume on Digital Systems for Open Access to Formal and Informal Learning contributes to the international dialogue between researchers, technologists, practitioners and policy makers in Technology Supported Education and Learning. It addresses emerging issues related with both theory and practice, as well as, methods and technologies that can support Open Access to Formal and Informal Learning. In the twenty chapters contributed by international experts who are actively shaping the future of Educational Technology around the world, topics such as: - The evolution of University Open Courses in Transforming Learning - Supporting Open Access to Teaching and Learning of People with Disabilities - Assessing Student Learning in Online Courses - Digital Game-based Learning for School Education - Open Access to Virtual and Remote Labs for STEM Education - Teachers’ and Schools’ ICT Competence Profiling - Web-Based Education and Innovative Leadership in a K-12 International School Setting are presented. An in-depth blueprint of the promise, potential, and imminent future of the field, Digital Systems for Open Access to Formal and Informal Learning is necessary reading for researchers and practitioners, as well as, undergraduate and postgraduate students, in educational technology.

Identifying Distinct Quitting Trajectories after an Unassisted Smoking Cessation Attempt: An Ecological Momentary Assessment Study

Objectives: This study aimed at identifying distinct quitting trajectories over 29 days after an unassisted smoking ces- sation attempt by ecological momentary assessment (EMA). In order to validate these trajectories we tested if they predict smoking frequency up to six months later. Methods: EMA via mobile phones was used to collect real time data on smoking (yes/no) after an unassisted quit attempt over 29 days. Smoking frequency one, three and six months after the quit attempt was assessed with online questionnaires. Latent class growth modeling was used to analyze the data of 230 self-quitters. Results: Four different quitting trajectories emerged: quitter (43.9%), late quitter (11.3%), returner (17%) and persistent smoker (27.8%). The quitting trajectories predicted smoking frequency one, three and six months after the quit attempt (all p < 0.001). Conclusions: Outcome after a smoking cessation attempt is better described by four distinct trajectories instead of a binary variable for abstinence or relapse. In line with the relapse model by Marlatt and Gordon, late quitter may have learned how to cope with lapses during one month after the quitting attempt. This group would have been allocated to the relapse group in traditional outcome studies.

A BAYESIAN APPROACH TO DOSE-RESPONSE ASSESSMENT AND DRUG-DRUG INTERACTION ANALYSIS: APPLICATION TO IN VITRO STUDIES

The considerable search for synergistic agents in cancer research is motivated by the therapeutic benefits achieved by combining anti-cancer agents. Synergistic agents make it possible to reduce dosage while maintaining or enhancing a desired effect. Other favorable outcomes of synergistic agents include reduction in toxicity and minimizing or delaying drug resistance. Dose-response assessment and drug-drug interaction analysis play an important part in the drug discovery process, however analysis are often poorly done. This dissertation is an effort to notably improve dose-response assessment and drug-drug interaction analysis. The most commonly used method in published analysis is the Median-Effect Principle/Combination Index method (Chou and Talalay, 1984). The Median-Effect Principle/Combination Index method leads to inefficiency by ignoring important sources of variation inherent in dose-response data and discarding data points that do not fit the Median-Effect Principle. Previous work has shown that the conventional method yields a high rate of false positives (Boik, Boik, Newman, 2008; Hennessey, Rosner, Bast, Chen, 2010) and, in some cases, low power to detect synergy. There is a great need for improving the current methodology. We developed a Bayesian framework for dose-response modeling and drug-drug interaction analysis. First, we developed a hierarchical meta-regression dose-response model that accounts for various sources of variation and uncertainty and allows one to incorporate knowledge from prior studies into the current analysis, thus offering a more efficient and reliable inference. Second, in the case that parametric dose-response models do not fit the data, we developed a practical and flexible nonparametric regression method for meta-analysis of independently repeated dose-response experiments. Third, and lastly, we developed a method, based on Loewe additivity that allows one to quantitatively assess interaction between two agents combined at a fixed dose ratio. The proposed method makes a comprehensive and honest account of uncertainty within drug interaction assessment. Extensive simulation studies show that the novel methodology improves the screening process of effective/synergistic agents and reduces the incidence of type I error. We consider an ovarian cancer cell line study that investigates the combined effect of DNA methylation inhibitors and histone deacetylation inhibitors in human ovarian cancer cell lines. The hypothesis is that the combination of DNA methylation inhibitors and histone deacetylation inhibitors will enhance antiproliferative activity in human ovarian cancer cell lines compared to treatment with each inhibitor alone. By applying the proposed Bayesian methodology, in vitro synergy was declared for DNA methylation inhibitor, 5-AZA-2'-deoxycytidine combined with one histone deacetylation inhibitor, suberoylanilide hydroxamic acid or trichostatin A in the cell lines HEY and SKOV3. This suggests potential new epigenetic therapies in cell growth inhibition of ovarian cancer cells.

An assessment of obesity and hyperphagia in individuals with Smith-Magenis syndrome

Smith-Magenis syndrome (SMS;OMIM# 182290) is a multiple congenital anomalies and mental retardation syndrome caused by a 3.7- Mb deletion on chromosome 17p11.2 or a mutation in the RAI1 gene. Although the majority of the SMS phenotype has been well described, limited studies are available describing growth patterns in SMS. There is some evidence that individuals with SMS develop obesity. Thus, this study aims to characterize the growth and potential influence of hyperphagia in a cohort of individuals with SMS. A retrospective chart review was conducted of 78 individuals with SMS through Baylor College of Medicine (BCM) at Texas Children¡¯s Hospital (TCH.) All documented height and weight measurements were abstracted and Z-scores (SD units) for height-for-age, length-for-age and BMI-for-age were calculated. Mail-out questionnaires were provided to the corresponding parents of the cohort to assess for the presence of hyperphagia through a validated hyperphagia questionnaire (HQ). Analysis of this data demonstrates that by the age ¡Ý 20 years males with SMS have mean BMI¡¯s in the 85th-90th percentile corresponding to an overweight BMI, and females with SMS had mean BMI¡¯s in the 95th -97th percentile corresponding to an obese BMI. Parents indicated that hyperphagia is present in individuals with SMS as 76% of parent¡¯s report having to lock food away from their child. Females¡¯ age ¡Ý 20 years of age had the highest mean behavior, drive and severity scores as well as the highest BMI. Thus, this study concludes that it appears overweight and obesity, as well as hyperphagia, are present in this cohort of SMS individuals. The results of this study will hopefully enable parents and caregivers of children with SMS to take preventative measures in order to control food related behaviors present in their children as well as to prevent overweight and obesity and the associated negative health consequences.

Acute and chronic methylphenidate dose-response assessment on three adolescent male rat strains.

Methylphenidate (MPD), commonly known as Ritalin, is the most frequently prescribed drug to treat children and adults with attention deficit hyperactivity disorder (ADHD). Adolescence is a period of development involving numerous neuroplasticities throughout the central nervous system (CNS). Exposure to a psychostimulant such as MPD during this crucial period of neurodevelopment may cause transient or permanent changes in the CNS. Genetic variability may also influence these differences. Thus, the objective of the present study was to determine whether acute and chronic administration of MPD (0.6, 2.5, or 10.0mg/kg, i.p.) elicit effects among adolescent WKY, SHR, and SD rats and to compare whether there were strain differences. An automated, computerized, open-field activity monitoring system was used to study the dose-response characteristics of acute and repeated MPD administration throughout the 11-day experimental protocol. Results showed that all three adolescent rat groups exhibited dose-response characteristics following acute and chronic MPD administration, as well as strain differences. These strain differences depended on the MPD dose and locomotor index. Chronic treatment of MPD in these animals did not elicit behavioral sensitization, a phenomenon described in adult rats that is characterized by the progressive augmentation of the locomotor response to repeated administration of the drug. These results suggest that the animal's age at time of drug treatment and strain/genetic variability play a crucial role in the acute and chronic effect of MPD and in the development of behavioral sensitization.

Assessment of Collimator Jaw Optimization in Reducing Normal Tissue Irradiation with Intensity Modulated Radiation Therapy

Purpose: To evaluate normal tissue dose reduction in step-and-shoot intensity-modulated radiation therapy (IMRT) on the Varian 2100 platform by tracking the multileaf collimator (MLC) apertures with the accelerator jaws. Methods: Clinical radiation treatment plans for 10 thoracic, 3 pediatric and 3 head and neck patients were converted to plans with the jaws tracking each segment’s MLC apertures. Each segment was then renormalized to account for the change in collimator scatter to obtain target coverage within 1% of that in the original plan. The new plans were compared to the original plans in a commercial radiation treatment planning system (TPS). Reduction in normal tissue dose was evaluated in the new plan by using the parameters V5, V10, and V20 in the cumulative dose-volume histogram for the following structures: total lung minus GTV (gross target volume), heart, esophagus, spinal cord, liver, parotids, and brainstem. In order to validate the accuracy of our beam model, MLC transmission measurements were made and compared to those predicted by the TPS. Results: The greatest change between the original plan and new plan occurred at lower dose levels. The reduction in V20 was never more than 6.3% and was typically less than 1% for all patients. The reduction in V5 was 16.7% maximum and was typically less than 3% for all patients. The variation in normal tissue dose reduction was not predictable, and we found no clear parameters that indicated which patients would benefit most from jaw tracking. Our TPS model of MLC transmission agreed with measurements with absolute transmission differences of less than 0.1 % and thus uncertainties in the model did not contribute significantly to the uncertainty in the dose determination. Conclusion: The amount of dose reduction achieved by collimating the jaws around each MLC aperture in step-and-shoot IMRT does not appear to be clinically significant.

The Development and Implementation of an Anthropomorphic Head Phantom for the Assessment of Proton Therapy Treatment Procedures

Proton therapy has become an increasingly more common method of radiation therapy, with the dose sparing to distal tissue making it an appealing option, particularly for treatment of brain tumors. This study sought to develop a head phantom for the Radiological Physics Center (RPC), the first to be used for credentialing of institutions wishing to participate in clinical trials involving brain tumor treatment of proton therapy. It was hypothesized that a head phantom could be created for the evaluation of proton therapy treatment procedures (treatment simulation, planning, and delivery) to assure agreement between the measured dose and calculated dose within ±5%/3mm with a reproducibility of ±3%. The relative stopping power (RSP) and Hounsfield Units (HU) were measured for potential phantom materials and a human skull was cast in tissue-equivalent Alderson material (RLSP 1.00, HU 16) with anatomical airways and a cylindrical hole for imaging and dosimetry inserts drilled into the phantom material. Two treatment plans, proton passive scattering and proton spot scanning, were created. Thermoluminescent dosimeters (TLDs) and film were loaded into the phantom dosimetry insert. Each treatment plan was delivered three separate times. Each treatment plan passed our 5%/3mm criteria, with a reproducibility of ±3%. The hypothesis was accepted and the phantom was found to be suitable for remote audits of proton therapy treatment facilities.

Food Volume Computation for Self Dietary Assessment Applications

There is great demand for easily-accessible, user-friendly dietary self-management applications. Yet accurate, fully-automatic estimation of nutritional intake using computer vision methods remains an open research problem. One key element of this problem is the volume estimation, which can be computed from 3D models obtained using multi-view geometry. The paper presents a computational system for volume estimation based on the processing of two meal images. A 3D model of the served meal is reconstructed using the acquired images and the volume is computed from the shape. The algorithm was tested on food models (dummy foods) with known volume and on real served food. Volume accuracy was in the order of 90 %, while the total execution time was below 15 seconds per image pair. The proposed system combines simple and computational affordable methods for 3D reconstruction, remained stable throughout the experiments, operates in near real time, and places minimum constraints on users.

Open issues in transcatheter aortic valve implantation. Part 1: patient selection and treatment strategy for transcatheter aortic valve implantation.

An exponential increase in the use of transcatheter aortic valve implantation (TAVI) in patients with severe aortic stenosis has been witnessed over the recent years. The current article reviews different areas of uncertainty related to patient selection. The use and limitations of risk scores are addressed, followed by an extensive discussion on the value of three-dimensional imaging for prosthesis sizing and the assessment of complex valve anatomy such as degenerated bicuspid valves. The uncertainty about valvular stenosis severity in patients with a mismatch between the transvalvular gradient and the aortic valve area, and how integrated use of echocardiography and computed tomographic imaging may help, is also addressed. Finally, patients referred for TAVI may have concomitant mitral regurgitation and/or coronary artery disease and the management of these patients is discussed.

Perioperative use of crystalloids in patients undergoing open radical cystectomy: balanced Ringer's maleate versus a glucose 5%/potassium-based balanced solution: study protocol for a randomized controlled trial

BACKGROUND The optimal crystalloid solution to use perioperatively in patients undergoing open radical cystectomy remains unclear. Many of the fluids used for intravenous hydration contain supraphysiologic concentrations of chloride, which can induce hyperchloremia and metabolic acidosis, resulting in renal vasoconstriction and decreased renal function. In addition, patients receiving less fluid and less sodium show faster recovery of gastrointestinal (GI) function after colonic surgery. METHODS AND DESIGN This is an investigator-initiated, single-center, randomized, controlled, parallel group trial with assessor-blinded outcome assessment, in the Department of Urology, University Hospital Bern, Switzerland. The study will involve 44 patients with bladder cancer scheduled for radical cystectomy and urinary diversion. The primary outcome is the duration between the end of surgery and the return of the GI function (first defecation). Secondary outcomes are fluid balance (body weight difference postoperatively versus preoperatively) and the incidence of kidney function disorders according to the Risk-Injury-Failure-Loss-End Stage Renal Disease (RIFLE classification). An equal number of patients are allocated to receive Ringerfundin® solution or a glucose/potassium-based balanced crystalloid solution as baseline infusion during the entire time that intravenous administration of fluid is necessary during the perioperative period. The randomized crystalloid solution is infused at a rate of 1 ml/kg/h until the bladder has been removed, followed by 3 ml/kg/h until the end of surgery. Postoperative hydration is identical in both groups and consists of 1,500 ml of the randomized crystalloid solution per 24 hours. Postoperative patient care is identical in both groups; patients are allowed to drink clear fluids immediately after surgery, and liquid diet is started on postoperative day 1, as well as active mobilization and the use of chewing gum. Body weight is measured daily in the morning. Time of first flatus and first defecation are recorded. DISCUSSION This trial assesses the benefits and harms of two different balanced crystalloid solutions for perioperative fluid management in patients undergoing open radical cystectomy with urinary diversion, with regard to return of GI function and effects on postoperative renal function. TRIAL REGISTRATION Current Controlled Trials ISRCTN32976792 (registered on November 21 2013).

A high-resolution map of direct and indirect connectivity of erosion risk areas to surface waters in Switzerland: A risk assessment tool for planning and policy-making

Off-site effects of soil erosion are becoming increasingly important, particularly the pollution of surface waters. In order to develop environmentally efficient and cost effective mitigation options it is essential to identify areas that bear both a high erosion risk and high connectivity to surface waters. This paper introduces a simple risk assessment tool that allows the delineation of potential critical source areas (CSA) of sediment input into surface waters concerning the agricultural areas of Switzerland. The basis are the erosion risk map with a 2 m resolution (ERM2) and the drainage network, which is extended by drained roads, farm tracks, and slope depressions. The probability of hydrological and sedimentological connectivity is assessed by combining soil erosion risk and extended drainage network with flow distance calculation. A GIS-environment with multiple-flow accumulation algorithms is used for routing runoff generation and flow pathways. The result is a high resolution connectivity map of the agricultural area of Switzerland (888,050 ha). Fifty-five percent of the computed agricultural area is potentially connected with surface waters, 45% is not connected. Surprisingly, the larger part of 34% (62% of the connected area) is indirectly connected with surface waters through drained roads, and only 21% are directly connected. The reason is the topographic complexity and patchiness of the landscape due to a dense road and drainage network. A total of 24% of the connected area and 13% of the computed agricultural area, respectively, are rated with a high connectivity probability. On these CSA an adapted land use is recommended, supported by vegetated buffer strips preventing sediment load. Even areas that are far away from open water bodies can be indirectly connected and need to be included in planning of mitigation measures. Thus, the connectivity map presented is an important decision-making tool for policy-makers and extension services. The map is published on the web and thus available for application.

Endoscopic and Open Release Similarly Safe for the Treatment of Carpal Tunnel Syndrome. A Systematic Review and Meta-Analysis.

BACKGROUND The Endoscopic Release of Carpal Tunnel Syndrome (ECTR) is a minimal invasive approach for the treatment of Carpal Tunnel Syndrome. There is scepticism regarding the safety of this technique, based on the assumption that this is a rather "blind" procedure and on the high number of severe complications that have been reported in the literature. PURPOSE To evaluate whether there is evidence supporting a higher risk after ECTR in comparison to the conventional open release. METHODS We searched MEDLINE (January 1966 to November 2013), EMBASE (January 1980 to November 2013), the Cochrane Neuromuscular Disease Group Specialized Register (November 2013) and CENTRAL (2013, issue 11 in The Cochrane Library). We hand-searched reference lists of included studies. We included all randomized or quasi-randomized controlled trials (e.g. study using alternation, date of birth, or case record number) that compare any ECTR with any OCTR technique. Safety was assessed by the incidence of major, minor and total number of complications, recurrences, and re-operations.The total time needed before return to work or to return to daily activities was also assessed. We synthesized data using a random-effects meta-analysis in STATA. We conducted a sensitivity analysis for rare events using binomial likelihood. We judged the conclusiveness of meta-analysis calculating the conditional power of meta-analysis. CONCLUSIONS ECTR is associated with less time off work or with daily activities. The assessment of major complications, reoperations and recurrence of symptoms does not favor either of the interventions. There is an uncertain advantage of ECTR with respect to total minor complications (more transient paresthesia but fewer skin-related complications). Future studies are unlikely to alter these findings because of the rarity of the outcome. The effect of a learning curve might be responsible for reduced recurrences and reoperations with ECTR in studies that are more recent, although formal statistical analysis failed to provide evidence for such an association. LEVEL OF EVIDENCE I.

Efficacy and safety of non-hormonal remedies for vaginal dryness: open, prospective, randomized trial

OBJECTIVES To prove non-inferiority of the first non-hormonal vaginal cream in Germany, Vagisan(®) Moisturising Cream (CREAM), compared to a non-hormonal vaginal gel (GEL) for vulvovaginal atrophy (VVA) symptom relief. METHOD This was a 12-week multicenter, open-label, prospective, randomized, two-period, cross-over phase-III trial. The primary endpoint was the cumulative VVA subjective symptom score of the respective treatment period. Secondary endpoints were assessment of single VVA subjective and objective symptoms, VVA objective symptom score, vaginal pH, safety parameters, overall assessment of efficacy, tolerability and evaluation of product properties. In total, 117 women were randomly allocated to either one of the two treatments, each administered for 4 weeks; 92 women were included in the per-protocol analysis (primary analysis). The main outcome measure was cumulative VVA subjective symptom score. RESULTS Regarding VVA symptom relief, results confirmed non-inferiority of CREAM compared to GEL and even indicated superiority of CREAM. Frequency and intensity of subjective symptoms and objective findings were clearly reduced, with CREAM showing better results compared to GEL. Mean VVA objective symptom score significantly decreased; improvement was significantly greater with CREAM. Vaginal pH decreased only following CREAM treatment. Tolerability was superior for CREAM: burning and itching, mostly rated as mild, occurred markedly less often with CREAM than with GEL. Overall satisfaction with treatment efficacy, tolerability and most product properties were rated significantly superior for CREAM. CONCLUSIONS Subjective and objective VVA symptoms were reliably and safely reduced by both non-hormonal topical products. However, efficacy and tolerability of CREAM were shown to be superior to GEL.

An international assessment of the comprehensibility of material safety data sheets (MSDSs)

Material Safety Data Sheets (MSDSs) are an integral component of occupational hazard communication systems. These documents are used to disseminate hazard information to workers on chemical substances. The primary purpose of this study was to investigate the comprehensibility of MSDSs by workers at an international level. ^ A total of 117 employees of a multi-national petrochemical company participated; thirty-nine (39) each in the United States, Canada and the United Kingdom. Overall participation rate of those approached to participate was 82%. These countries were selected as they each utilize one of the three major existing hazard communication systems for fixed workplaces. The systems are comprised of the Occupational Safety and Health Administration's Hazard Communication Standard in the United States, the Workplace Hazardous Materials Information System (WHMIS) in Canada, and the compilation of several European Union directives addressing classification, labeling of substances and preparations, and MSDSs in Europe. ^ A pretest posttest randomized study design was used, with the posttest being comparable to an open book test. The results of this research indicated that only about two-thirds of the information on the MSDSs was comprehended by the workers with a significant difference identified among study participants based on country comparisons. This data was fairly consistent with the results of previous MSDS comprehensibility studies conducted in the United States. There was no significant difference in the comprehension level among study participants when taking into account the international hazard communication standard that the MSDS complied with. Marginally, age, education level and experience level did not have a significant impact on the comprehension level. ^ Participants did find MSDSs to be satisfactory in providing the information needed to protect them regardless of their views on the readability and formatting of MSDSs. The health-related information was the least comprehended as less than half of it was comprehended on the basis of the responses. The findings from this research suggest that there is much work needed yet to make MSDSs more comprehensible on a global basis, particularly regarding health-related information. ^