Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial

BACKGROUND: Prostate cancer might have high radiation-fraction sensitivity that would give a therapeutic advantage to hypofractionated treatment. We present a pre-planned analysis of the efficacy and side-effects of a randomised trial comparing conventional and hypofractionated radiotherapy after 5 years follow-up.

METHODS: CHHiP is a randomised, phase 3, non-inferiority trial that recruited men with localised prostate cancer (pT1b-T3aN0M0). Patients were randomly assigned (1:1:1) to conventional (74 Gy delivered in 37 fractions over 7·4 weeks) or one of two hypofractionated schedules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3·8 weeks) all delivered with intensity-modulated techniques. Most patients were given radiotherapy with 3-6 months of neoadjuvant and concurrent androgen suppression. Randomisation was by computer-generated random permuted blocks, stratified by National Comprehensive Cancer Network (NCCN) risk group and radiotherapy treatment centre, and treatment allocation was not masked. The primary endpoint was time to biochemical or clinical failure; the critical hazard ratio (HR) for non-inferiority was 1·208. Analysis was by intention to treat. Long-term follow-up continues. The CHHiP trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN97182923.

FINDINGS: Between Oct 18, 2002, and June 17, 2011, 3216 men were enrolled from 71 centres and randomly assigned (74 Gy group, 1065 patients; 60 Gy group, 1074 patients; 57 Gy group, 1077 patients). Median follow-up was 62·4 months (IQR 53·9-77·0). The proportion of patients who were biochemical or clinical failure free at 5 years was 88·3% (95% CI 86·0-90·2) in the 74 Gy group, 90·6% (88·5-92·3) in the 60 Gy group, and 85·9% (83·4-88·0) in the 57 Gy group. 60 Gy was non-inferior to 74 Gy (HR 0·84 [90% CI 0·68-1·03], pNI=0·0018) but non-inferiority could not be claimed for 57 Gy compared with 74 Gy (HR 1·20 [0·99-1·46], pNI=0·48). Long-term side-effects were similar in the hypofractionated groups compared with the conventional group. There were no significant differences in either the proportion or cumulative incidence of side-effects 5 years after treatment using three clinician-reported as well as patient-reported outcome measures. The estimated cumulative 5 year incidence of Radiation Therapy Oncology Group (RTOG) grade 2 or worse bowel and bladder adverse events was 13·7% (111 events) and 9·1% (66 events) in the 74 Gy group, 11·9% (105 events) and 11·7% (88 events) in the 60 Gy group, 11·3% (95 events) and 6·6% (57 events) in the 57 Gy group, respectively. No treatment-related deaths were reported.

INTERPRETATION: Hypofractionated radiotherapy using 60 Gy in 20 fractions is non-inferior to conventional fractionation using 74 Gy in 37 fractions and is recommended as a new standard of care for external-beam radiotherapy of localised prostate cancer.

FUNDING: Cancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network.

Safety and Efficacy of Oral Fexofenadine in Children with Seasonal Allergic Rhinitis - a Pooled Analysis of Three Studies

Allergic rhinitis is one of the most common clinical conditions in children; however, data regarding the safety of antihistamines in children with seasonal allergic rhinitis are limiting. To evaluate the safety and efficacy of fexofenadine in children with seasonal allergic rhinitis, data were pooled from three, double-blind, randomized, placebo-controlled, parallel-group, 2-week trials in children (6-11 year) with seasonal allergic rhinitis. All studies assessed fexofenadine HCl 30 mg b.i.d.; two studies included fexofenadine HCl at 15 and 60 mg b.i.d. Patients (and investigators) reported any adverse events during the trial. Physical examinations, including measurements of vital signs and laboratory tests, were performed. Efficacy assessments (total symptom score and individual symptom scores) were evaluated. Exposure to fexofenadine HCl 30 mg b.i.d. and to any fexofenadine dose exceeded 10,000 and 17,000 patient days, respectively. Incidences of adverse events, and discontinuations because of adverse events, were low and similar across treatment groups. In the placebo group, 24.4% of subjects reported adverse events compared with 24.1% for fexofenadine HCl 30 mg b.i.d., and 28.4% for all fexofenadine-treated groups. The most common adverse event overall was headache (4.3% placebo; 5.8% fexofenadine HCl 30 mg b.i.d.; and 7.2% any fexofenadine doses). Treatment-related adverse events were similar across treatment groups with no sedative effects. Fexofenadine HCl 30 mg b.i.d. was significantly superior to placebo in reducing the total symptom score and all individual seasonal allergic rhinitis symptoms, including nasal congestion (p < 0.05). Fexofenadine, at doses of up to 60 mg b.i.d., is safe and non-sedating, and fexofenadine HCl 30 mg b.i.d. effectively reduces all seasonal allergic rhinitis symptoms in children aged 6-11 years.

Three essays on investment in human capital in Canada

Cette thèse examine l’investissement en capital humain au Canada en s’intéressant à la contribution de l’aide financière aux études, aux effets de la fiscalité, à la rentabilité de l’investissement en éducation postsécondaire et à la redistribution des revenus. Elle est subdivisée en cinq chapitres. Le premier chapitre présente une révue chronologique des études microéconomiques sur l’investissement en capital humain. Il présente également une synthèse des études canadiennes sur l’investissement en capital humain en insistant sur les limites portant essentiellement sur la non prise en compte de l’hétérogénéité des systèmes de prêts et bourses et des systèmes fiscaux à travers les provinces canadiennes et la faible analyse de la répartition des coûts et bénéfices de l’investissement en éducation au Canada. Le second chapitre présente la méthodologie de mesure des rendements de l’éducation et des gains issus des investissements en éducation. Il décrit les données utilisées et les résultats des régressions économetriques. Finalement, le chapitre présente SIMAID, un calculateur d’aide financière aux études élaboré pour les objectifs dans cette thèse et qui permet d’estimer le montant de l’aide financière devant être attribuée à chaque étudiant en fonction de ses caractéristiques personnelles et de celles de sa famille. Dans sa première section, le troisième chapitre présente les rendements sociaux, privés et publics de l’éducation et montre que les rendements de l’éducation varient selon les provinces, les filières de formation, le genre et les cohortes d’année de naissance et décroient avec le niveau d’éducation. Dans sa seconde section, le chapitre montre que l’aide financière aux études accroît le rendement des études du baccalauréat de 24.3% et 9.5% respectivement au Québec et en Ontario. Finalement, le chapitre indique qu’un changement du système d’aide financière aux études de Québec par celui de l’Ontario entraîne une baisse de 11.9% du rendement des études au baccalauréat alors qu’un changement du système fiscal québécois par celui ontarien entraine une hausse du rendement du baccalauréat de 4.5%. L’effet combiné du changement des systèmes d’aide financière et fiscal est une baisse du rendement du baccalauréat de 7.4%. Le quatrième chapitre fournit une décomposition comptable détaillée des gains sociaux, privés et publics des investissements en éducation. Le gain social de l’investissement au baccalauréat est de $738 384 au Québec et de $685 437 en Ontario. Ce gain varie selon les filières de formation avec un niveau minimal pour les études humanitaires et un niveau maximal pour les études en ingénierie. Le chapitre montre également que la répartition des bénéfices et des coûts de l’investissement en éducation entre les individus et le gouvernement est plus équitable en Ontario qu’à Québec. En effet, un individu qui investit à Québec supporte 51.6% du coût total et engrange 64.8% des gains alors que le même individu supporterait 62.9% des coûts sociaux et engrangerait 62.2% des gains en Ontario. Finalement, le cinquième chapitre présente et analyse les effets rédistributifs des transferts et des taxes suite à un investissement en éducation. Il examine aussi si l’aide financière aux études est effectivement allouée aux personnes les plus pauvres. L’argument selon lequel l’aide financière est destinée aux plus pauvres est rejeté en analysant la distribution du revenu permanent. En effet, il ressort que 79% des personnes bénéficiant de l’aide financière aux études se trouvent dans le cinquième quintile de la distribution des revenus permanents. Le chapitre montre également que l’investissement en éducation impacte positivement les effets rédistributifs en 2006, 2001 et 1996 et négativement en 1991 et 2011. L’impact est également perceptible sur les composantes de l’effet rédistributif. Toutefois, la sensibilité de l’impact au taux d’actualisation dépend de l’indice utilisé dans l’analyse.

Gender Differences in Early Reading Strategies: a Comparison of Synthetic Phonics Only with a Mixed Approach to Teaching Reading to 4-5 Year-Old Children

A survey of primary schools in England found that girls outperform boys in English across all phases (Ofsted in Moving English forward. Ofsted, Manchester, 2012). The gender gap remains an on-going issue in England, especially for reading attainment. This paper presents evidence of gender differences in learning to read that emerged during the development of a reading scheme for 4- and 5-year-old children in which 372 children from Reception classes in sixteen schools participated in 12-month trials. There were three arms per trial: Intervention non-PD (non-phonically decodable text with mixed methods teaching); Intervention PD (phonically decodable text with mixed methods teaching); and a ‘business as usual’ control condition SP (synthetic phonics and decodable text). Assignment to Intervention condition was randomised. Standardised measures of word reading and comprehension were used. The research provides statistically significant evidence suggesting that boys learn more easily using a mix of whole-word and synthetic phonics approaches. In addition, the evidence indicates that boys learn to read more easily using the natural-style language of ‘real’ books including vocabulary which goes beyond their assumed decoding ability. At post-test, boys using the nonphonically decodable text with mixed methods (Intervention A) were 8 months ahead in reading comprehension compared to boys using a wholly synthetic phonics approach.

Three-trocar laparoscopic cholecistectomy in patient with situs viscerum inversus totalis. Case report and review of the literature

Situs viscerum inversus totalis is a rare defect with a genetic predisposition, which can present difficulties in the management of abdominal pathology, especially in laparoscopic surgery (mirror-image anatomy). We report the case of a 52-year-old female with situs viscerum inversus totalis, known from pediatric age, with a medical history of colic pain in the epigastrium radiating to the right abdominal quadrant. Laparoscopic cholecistectomy was safely performed with a three trocar technique. To the best of our knowledge this is the first time that laparoscopic cholecistectomy by three trocars was performed in a patient with situs viscerum inversus. We also review the relevant literature concerning this issue.

Three dimensional modeling of contaminants transportation (oil spill) in Caspian Sea

Nowadays, Caspian Sea is in focus of more attentions than past because of its individualistic as the biggest lake in the world and the existing of very large oil and gas resources within it. Very large scale of oil pollution caused by development of oil exploration and excavation activities not only make problem for coastal facilities but also make severe damage on environment. In the first stage of this research, the location and quality of oil resources in offshore and onshore have been determined and then affected depletion factors on oil spill such as evaporation, emulsification, dissolution, sedimentation and so on have been studied. In second stage, sea hydrodynamics model is offered and tested by determination of governing hydrodynamic equations on sea currents and on pollution transportation in sea surface and by finding out main parameters in these equations such as Coriolis, bottom friction, wind and etc. this model has been calculated by using cell vertex finite volume method in an unstructured mesh domain. According to checked model; sea currents of Caspian Sea in different seasons of the year have been determined and in final stage different scenarios of oil spill movement in Caspian sea on various conditions have been investigated by modeling of three dimensional oil spill movement on surface (affected by sea currents) and on depth (affected by buoyancy, drag and gravity forces) by applying main above mentioned depletion factors.

Three dimensional models of water flow in the Persian Gulf

Persian Gulf region is globally of great importance due to its economical and political reasons. The importance lies in oil sources and sea exports. Geophysical phenomena dominated in the water circulation affected this region is called Monsoon it stretches from African coasts to the half way of Red Seal affected all coasts of Persian Gulf and goes toward east to the Indian ocean. Other essential factors in the water circulation in this region are net evaporation (several meters in per year), high density and high salinity. In this article the effects of wind stress and evaporation in the water circulation in the region will be considered and model equations for wind forces, density, pressure, gradient, and bottom friction for Persian Gulf will be discussed.

Five-year review of an international clinical research-training program

The exponential increase in clinical research has profoundly changed medical sciences. Evidence that has accumulated in the past three decades from clinical trials has led to the proposal that clinical care should not be based solely on clinical expertise and patient values, and should integrate robust data from systematic research. As a consequence, clinical research has become more complex and methods have become more rigorous, and evidence is usually not easily translated into clinical practice. Therefore, the instruction of clinical research methods for scientists and clinicians must adapt to this new reality. To address this challenge, a global distance-learning clinical research-training program was developed, based on collaborative learning, the pedagogical goal of which was to develop critical thinking skills in clinical research. We describe and analyze the challenges and possible solutions of this course after 5 years of experience (2008-2012) with this program. Through evaluation by students and faculty, we identified and reviewed the following challenges of our program: 1) student engagement and motivation, 2) impact of heterogeneous audience on learning, 3) learning in large groups, 4) enhancing group learning, 5) enhancing social presence, 6) dropouts, 7) quality control, and 8) course management. We discuss these issues and potential alternatives with regard to our research and background.

Three dimensional numerical simulation of thermohaline currents of the Persian Gulf

Observational data and a three dimensional numerical model (POM) are used to investigate the Persian Gulf outflow structure and its spreading pathway into the Oman Sea. The model is based on orthogonal curvilinear coordinate system in horizontal and train following coordinate (sigma coordinate) system in vertical. In the simulation, the horizontal diffusivity coefficients are calculated form Smogorinsky diffusivity formula and the eddy vertical diffusivities are obtained from a second turbulence closure model (namely Mellor-Yamada level 2.5 model of turbulence). The modeling area includes the east of the Persian Gulf, the Oman Sea and a part of the north-east of the Indian Ocean. In the model, the horizontal grid spacing was assumed to be about 3.5 km and the number of vertical levels was set to 32. The simulations show that the mean salinity of the PG outflow does not change substantially during the year and is about 39 psu, while its temperature exhibits seasonal variations. These lead to variations in outflow density in a way that is has its maximum density in late winter (March) and its minimum in mid-summer (August). At the entrance to the Oman Sea, the PG outflow turns to the right due to Coriolis Effect and falls down on the continental slope until it gains its equilibrium depth. The highest density of the outflow during March causes it to sink more into the deeper depths in contrast to that of August which the density is the lowest one. Hence, the neutral buoyancy depths of the outflow are about 500 m and 250 m for March and August respectively. Then, the outflow spreads in its equilibrium depths in the Oman Sea in vicinity of western and southern boundaries until it approach the Ras al Hamra Cape where the water depth suddenly begins to increase. Therefore, during March, the outflow that is deeper and wider relative to August, is more affected by the steep slope topography and as a result of vortex stretching mechanism and conservation of potential vorticity it separates from the lateral boundaries and finally forms an anti-cyclonic eddy in the Oman Sea. But during August the outflow moves as before in vicinity of lateral boundaries. In addition, the interaction of the PG outflow with tide in the Strait of Hormuz leads to intermittency in outflow movement into the Oman Sea and it could be the major reason for generations of Peddy (Peddies) in the Oman Sea.

The broad spectrum of bioactive properties of phenolic extracts: a prospective study in three different plants

Natural resources like plants are currently used all over developed and under developed countries of the world as traditional home remedies and are promising agents for drug discovery as they play crucial role in traditional medicine. The use of plants for medicinal purpose usually varies from country to country and region to region because their use depends on the history, culture, philosophy and personal attitudes of the users (Ahmad et al., 2015). The use of plants and plant products as drugs predates the written human history (Hayta et al., 2014). Plants are a very important resource for traditional drugs and around 80% of the population of the planet use plants for the treatment of many diseases and traditional herbal medicine accounts for 30-50% of the total medicinal consumption in China. In North America, Europe and other well-developed regions over 50% of the population have used traditional preparations at least once (Dos Santos Reinaldo et al., 2015). Medicinal plants have been used over years for multiple purposes, and have increasingly attract the interest of researchers in order to evaluate their contribution to health maintenance and disease’s prevention (Murray, 2004). Recently between 50,000 and 70,000 species of plants are known and are being used in the development of modern drugs. Plants were the main therapeutic agents used by humans from the 19th century, and their role in medicine is always topical (Hayta et al., 2014). The studies of medicinal plants are rapidly increasing due to the search for new active molecules, and to improve the production of plants or bioactive molecules for the pharmaceutical industries (Rates, 2001). Several studies have been reported, but numerous active compounds directly responsible for the observed bioactive properties remain unknown, while in other cases the mechanism of action is not fully understood. According to the WHO 25% of all modern medicines including both western and traditional medicine have been extracted from plants, while 75% of new drugs against infective diseases that have arrived between 1981 and 2002 originated from natural sources, it was reported that the world market for herbal medicines stood at over US $60 billion per year and is growing steadily (Bedoya et al., 2009). Traditional medicine has an important economic impact in the 21st century as it is used worldwide, taking advantage on the low cost, accessibility, flexibility and diversity of medicinal plants (Balunas & Kinghorn, 2005).

Prevalence and characterization of Salmonella spp. in three shellfish-harvesting areas in France

Shellfish farming is an important economic activity in the Brittany and Normandy regions. However, a part of the production sites corresponds to relatively sensitive areas where the presence of faecal microorganisms is a major concern for shellfish and constitutes a possible health risk. Indeed, shellfish bioaccumulates in their tissues pathogenic contaminants present in water and can cause food-borne diseases such as salmonellosis. During a two-year study, we evaluated the presence of faecal indicators, measured the prevalence of Salmonella spp., isolated and characterized Salmonella spp. from three French shellfish-harvesting areas (shellfish and sediment) and their watersheds (from river water samples).

Early consumption of liquids different to breast milk in Mexican infants under 1 year: results of the probabilistic National Health and Nutrition Survey 2012

Introduction: Studies on infant dietary intake do not generally focus on the types of liquids consumed. Objective: To document by age and breastfeeding status, the types of liquids present in the diet of Mexican children under 1 year of age (< 1 y) who participated in the National Health and Nutrition Survey 2012 (ENSANUT-2012). Methods: Analysis of the infant < 1 y feeding practices from the ENSANUT-2012 survey in non-breastfed (non-BF) and breastfed (BF) infants by status quo for the consumption of liquids grouped in: water, formula, fortified LICONSA milk, nutritive liquids (NL; thin cereal-based gruel with water or milk and coffee with milk) and non-nutritive liquids (non-NL) as sugared water, water-based drinks, tea, beans or chicken broth, aguamiel and coffee. In this infants < 1 y we analyzed the not grouped consumption of liquids in the first three days of life (newborns) from the mother's recall. Percentage and confidence intervals (95% CI) were calculated adjusting for survey design. Statistical differences were analyzed by Z test. Results: We observed a high consumption of human milk followed by formula (56.7%) and water (51.1%) in infants under 6 months of age (< 6 mo). The proportion of non-BF infants consuming non-NL was higher than for BF infants (p < 0.05). More than 60% of older infants (6 mo and < 1 y) consumed formula and were non-BF. In newborns formula consumption was predominant, followed by tea or infusion and water. Conclusions: Non-breast milk liquids are present undesirably in Mexican infants' diet and non-NL are consumed earlier than NL, revealing inadequate early dietary practices.

The Comparison of Under-Five-Children’s Nutrition Status Among Ethnic Groups in North of Iran, 1998 - 2013; Results of a Three Stages Cross-Sectional Study

Background: Despite improvements in child health, malnutrition still remains one of the main public health challenges in Iran. Objectives: The aim of this study was to compare under nutrition among under-five children with regard to ethnicity in rural area in north Iran. Patients and Methods: In three cross-sectional studies 7575 subjects in three time-periods including 2339 children in 1998, 2749 in 2004, and 2487 in 2013, were evaluated. All under-five-children in 20 out of 118 villages were chosen by random sampling and assessed. Under nutrition was defined as underweight, stunting and wasting lower than -2 SD (Z < -2 SD). Results: Generally, stunting was declined 17.1% and underweight and wasting were increased 0.9% and 1%, respectively during 15 years (1998 - 2013). Underweight increased 0.5% in Fars-natives and 3.2% in Turkmans and it was decreased 0.9% in Sistanis. Statistical difference in Turkman children among the three stages of the study was significant (P = 0.001). Stunting has decreased 28.7% in Fars-natives and 35.1% in Sistanis, it was increased 9.3% in Turkman group. Statistical differences among three stages in inter-ethnic groups were significant (P = 0.001 for all). Compared the group with good economic status, the odds ratio was 1.831 in poor economic group (P = 0.001). The risk of under nutrition in Sistanis was 1.754 times more than in Fars-natives (P = 0.001). Conclusions: Under nutrition remains one of the main health problems in under-five-year children in north Iran being more common in Sistani children. Stunting in Sistani children deeply decreased while in Turkman children slightly increased during the 15-year period study. Poor economic status is a risk factor for under nutrition in this area.

Gaining Insight into Teaching: A Phenomenological Exploration of the Lived Experience of the Teachers of the Year

What qualities, skills, and knowledge produce quality teachers? Many stake-holders in education argue that teacher quality should be measured by student achievement. This qualitative study shows that good teachers are multi-dimensional; their effectiveness cannot be represented by students’ test scores alone. The purpose of this phenomenological study was to gain a deeper understanding of quality in teaching by examining the lived experiences of 10 winners or finalists of the Teacher of the Year (ToY) Award. Phenomenology describes individuals’ daily experiences of phenomena, examines how these experiences are structured, and focuses analysis on the perspectives of the persons having the experience (Moustakas, 1994). This inquiry asked two questions: (a) How is teaching experienced by recognized as outstanding Teachers of the Year? and (b) How do ToYs feelings and perceptions about being good teachers provide insight, if any, about concepts such as pedagogical tact, teacher selfhood, and professional dispositions? Ten participants formed the purposive sample; the major data collection tool was semi-structured interviews (Patton, 1990; Seidman, 2006). Sixty to 90-minute interviews were conducted with each participant. Data also included the participants’ ToY application essays. Data analysis included a three-phase process: description, reduction, interpretation. Findings revealed that the ToYs are dedicated, hard-working individuals. They exhibit behaviors, such as working beyond the school day, engaging in lifelong learning, and assisting colleagues to improve their practice. Working as teachers is their life’s compass, guiding and wrapping them into meaningful and purposeful lives. Pedagogical tact, teacher selfhood, and professional dispositions were shown to be relevant, offering important insights into good teaching. Results indicate that for these ToYs, good teaching is experienced by getting through to students using effective and moral means; they are emotionally open, have a sense of the sacred, and they operate from a sense of intentionality. The essence of the ToYs teaching experience was their being properly engaged in their craft, embodying logical, psychological, and moral realms. Findings challenge current teacher effectiveness process-product orthodoxy which makes a causal connection between effective teaching and student test scores, and which assumes that effective teaching arises solely from and because of the actions of the teacher.

Circulation of canine viruses in free-ranging Italian wolves (Canis lupus italicus) from three Italian regions

In this study, the duodenum, spleen, tongue, and lungs were sampled from 56 Italian wolves who died between 2017 and 2020. The aim of the study was to evaluate the presence and spread of DNA and RNA viruses in the wolf population examined, relating the virological results to: year of sampling, region of origin, sex, age, season, genetic determination of the species, nutritional conditions, causes of death, matrices examined. In addition, the presence or absence of co-infections was evaluated. Through molecular methods, the presence of genomic DNA of three important DNA viruses was investigated, i.e.: Canine Parvovirus type 2 (CPV-2), Canine Adenovirus type 1 (CAdV-1), Canine Adenovirus type 2 (CAdV-2). Furthermore, the presence of genomic RNA of the important RNA viruses, Canine Enteric Coronavirus (CCoV) and Canine Distemper Virus (CDV), was also investigated. The results showed that the virus with the highest prevalence in the wolf population studied was CPV-2, found in 78.6% of subjects (44/56). The prevalence of CAdV was 17.9% (10/56), in particular CAdV-1 (12.5% - 7/56) and CAdV-2 (5.4% - 3/56). The results of the molecular investigations in RT-PCR of the two RNA viruses (CCoV and CDV) did not give positive results in the study population. In this study it was observed that the majority of wolves that resulted positive were in good nutritional conditions, thus excluding a direct cause of death from CPV-2, CAdV-1, and CAdV- 2 infections. Moreover, the prevalence obtained in this study suggests that, during the years here studied, the circulation of CAdV-1 and CAdV-2 in Italian wolves of the three sampled regions was sporadic, proving consistent with sporadic and short-lived introductions of the virus in these populations. However, the situation for CPV-2 is different as there was a circulation that suggests a pattern of continuous and lasting endemic exposure over time.