A simple two-stage design for quantitative responses with application to a study in diabetic neuropathic pain

Two-stage designs offer substantial advantages for early phase II studies. The interim analysis following the first stage allows the study to he stopped for futility, or more positively, it might lead to early progression to the trials needed for late phase H and phase III. If the study is to continue to its second stage, then there is an opportunity for a revision of the total sample size. Two-stage designs have been implemented widely in oncology studies in which there is a single treatment arm and patient responses are binary. In this paper the case of two-arm comparative studies in which responses are quantitative is considered. This setting is common in therapeutic areas other than oncology. It will be assumed that observations are normally distributed, but that there is some doubt concerning their standard deviation, motivating the need for sample size review. The work reported has been motivated by a study in diabetic neuropathic pain, and the development of the design for that trial is described in detail. Copyright (C) 2008 John Wiley & Sons, Ltd.

A systematic review of controlled trials of interventions to prevent childhood obesity and overweight: realistic synthesis of the evidence

Background: Preventing childhood overweight and obesity has become a major public health issue in developed and developing countries. Systematic reviews of this topic have not provided practice-relevant guidance because of the generally low quality of research and the heterogeneity of reported effectiveness. Aim: To present practice-relevant guidance on interventions to reduce at least one measure of adiposity in child populations that do or do not contain overweight or obese children. Design: Systematic review of eligible randomized, controlled trials or controlled trials using a novel approach to synthesizing the trial results through application of descriptive epidemiological and realistic evaluation concepts. Eligible trials involved at least 30 participants, lasted at least 12 weeks and involved non-clinical child populations. Results: Twenty-eight eligible trials were identified to 30 April 2006. Eleven trials were effective and 17 were ineffective in reducing adiposity. Blind to outcome, the main factor distinguishing effective from ineffective trials was the provision of moderate to vigorous aerobic physical activity in the former on a relatively 'compulsory' rather than 'voluntary' basis. Conclusions: By using a novel approach to synthesizing trials, a decisive role for the 'compulsory' provision of aerobic physical activity has been demonstrated. Further research is required to identify how such activity can be sustained and transformed into a personally chosen behaviour by children and over the life course. (C) 2007 The Royal Institute of Public Health. Published by Elsevier Ltd. All rights reserved.

Geoarchaeological investigations of midden-formation processes in the early to late Neolithic levels at Catalhoyuk, Turkey ca. 8550-8370 cal BP.

Anthropogenic midden deposits are remarkably well preserved at the Neolithic settlement of atalhöyük and provide significant archaeological information on the types and nature of activities occurring at the site. To decipher their complex stratigraphy and to investigate formation processes, a combination of geoarchaeological techniques was used. Deposits were investigated from the early ceramic to late Neolithic levels, targeting continuous sequences to examine high resolution and broader scale changes in deposition. Thin-section micromorphology combined with targeted phytolith and geochemical analyses indicates they are composed of a diverse range of ashes and other charred and siliceous plant materials, with inputs of decayed plants and organic matter, fecal waste, and sedimentary aggregates, each with diverse depositional pathways. Activities identified include in situ burning, with a range of different fuel types that may be associated with different activities. The complexity and heterogeneity of the midden deposits, and thus the necessity of employing an integrated microstratigraphic approach is demonstrated, as a prerequisite for cultural and palaeoenvironmental reconstructions.

Predicting early data revisions to US GDP and the effects of releases on equity markets

The effects of data uncertainty on real-time decision-making can be reduced by predicting early revisions to US GDP growth. We show that survey forecasts efficiently anticipate the first-revised estimate of GDP, but that forecasting models incorporating monthly economic indicators and daily equity returns provide superior forecasts of the second-revised estimate. We consider the implications of these findings for analyses of the impact of surprises in GDP revision announcements on equity markets, and for analyses of the impact of anticipated future revisions on announcement-day returns.

Usual clinical practice for early supported discharge after stroke with continued rehabilitation at home : an observational comparative study

Introduction: Based on randomised controlled trials, evidence exists that early supported discharge (ESD) from the hospital with continued rehabilitation at home has beneficial effects after stroke; however, the effects of ESD service in regular clinical practice have not been investigated. The purpose of the current study was to compare ESD service with conventional rehabilitation in terms of patient outcomes, caregiver burden at 3 and 12 months and the use and costs of healthcare during the first year after stroke. Material and methods: This study was a subgroup analysis of a longitudinal observational study of patients who received care in the stroke unit at Karolinska University Hospital in Sweden. Patients who met the inclusion criteria for ESD in previous experimental studies were included. The patients were referred to available rehabilitation services at discharge, and comparisons between those who received ESD service (the ESD group, n = 40) and those who received conventional rehabilitation (the NoESD group, n = 110) were performed with regard to independence in activities of daily living (ADL), the frequency of social activities, life satisfaction, and caregiver burden and the use and costs of healthcare during the first year after stroke. Results: At 3 and 12 months, no differences were observed with regard to patient outcomes; however, ESD was associated with a lower caregiver burden (p = 0.01) at 12 months. The initial length of stay (LOS) at the hospital was 8 days for the ESD group and 15 days for the NoESD group (p = 0.02). The median number of outpatient rehabilitation contacts was 20.5 for the ESD group (81% constituting ESD service) and 3 for the NoESD group (p<0.001). There was no difference between the groups with regard to overall healthcare costs. Conclusions: ESD service in usual clinical practice renders similar health benefits as conventional rehabilitation but a different pattern of resource use and with released capacity in acute stroke care.

An Agent-Based Approach to Real-Time Patient Identification for Clinical Trials

Patient recruitment for clinical trials is expensive and has been a significant challenge, with many trials not achieving their recruitment goals. One method that shows promise for improving recruitment is the use of interactive prompts that inform practitioners of patient eligibility for clinical trials during consultation. This paper presents the ePCRN-IDEA recruitment system, which utilises an agent-based infrastructure to enable real-time recruitment of patients. In essence, whenever patients enter a clinic, the system compares their details against eligibility criteria, which define the requirements of active clinical trials. If a patient is found to be eligible, a prompt is raised to notify the user. In this way, it becomes possible for recruitment to take place quickly in a cost effective manner, whilst maintaining patient trust through the involvement of their own health care practitioner.

The Cool Little Kids randomised controlled trial population-level early prevention for anxiety disorders

Background: The World Health Organization predicts that by 2030 internalising problems (e.g. depression and anxiety) will be second only to HIV/AIDS in international burden of disease. Internalising problems affect 1 in 7 school aged children, impacting on peer relations, school engagement, and later mental health, relationships and employment. The development of early childhood prevention for internalising problems is in its infancy. The current study follows two successful ‘efficacy’ trials of a parenting group intervention to reduce internalising disorders in temperamentally inhibited preschool children. Cool Little Kids is a population-level randomised trial to determine the impacts of systematically screening preschoolers for inhibition then offering a parenting group intervention, on child internalising problems and economic costs at school entry.
Methods/Design: This randomised trial will be conducted within the preschool service system, attended by more than 95% of Australian children in the year before starting school. In early 2011, preschool services in four local government areas in Melbourne, Australia, will distribute the screening tool. The ≈16% (n≈500) with temperamental inhibition will enter the trial. Intervention parents will be offered Cool Little Kids, a 6-session group program in the local community, focusing on ways to develop their child’s bravery skills by reducing overprotective parenting interactions. Outcomes one and two years post-baseline will comprise child internalising diagnoses and symptoms, parenting interactions, and parent wellbeing. An economic evaluation (costconsequences framework) will compare incremental differences in costs of the intervention versus control children to incremental differences in outcomes, from a societal perspective. Analyses will use the intention-to-treat principle, using logistic and linear regression models (binary and continuous outcomes respectively) to compare outcomes between the trial arms.
Discussion: This trial addresses gaps for internalising problems identified in the 2004 World Health Organization Prevention of Mental Disorders report. If effective and cost-effective, the intervention could readily be applied at a population level. Governments consider mental health to be a priority, enhancing the likelihood that an effective early prevention program would be adopted in Australia and internationally.

Povoações, freguesias e vilas na Paraíba Colonial: Pombal e Sousa, 1697-1800

The towns presently named Pombal and Sousa, located in the hinterland of the State of Paraíba, Brazil, still keep vestiges of the colonization process they went through along the 18th and 19th centuries, when they both emerged as settlement nuclei in the extreme West of the then captaincy of Paraíba and attained the status of freguesia and vila in a later period. This research aims to comprehend the process of urban formation and development of the colonial urban nuclei of Pombal and Sousa as they became povoados (hamlets), freguesias (parishes) and vilas (small urban communities with a local government), according to territorial expansion policies implemented by the Portuguese government from 1697 to 1800. The choice of the two urban settlements for this survey lies in the fact that they were part of the great conquest and colonization program undertaken by the Portuguese Crown. Another aspect that was considered was the fact that those towns are the oldest urban nuclei of Paraíba s hinterland. They came into being as early as in the times of the colony, thus producing a favorable environment to the study of the changes that occurred in the captaincy s hinterland scenery resulting from the process of formation and development of the colonial urban space. Three fundamental categories of analysis were defined since they have a direct bearing upon the urban configuration of the two colonization nuclei: povoado, freguesia and vila. The three of them are related to civil and ecclesiastic jurisdictions. Field, documentation and bibliography surveys were undertaken in order to develop the study. They allowed for the finding of vestiges of the old, colonial urban structures and for the development of theoretical analysis based on present-day studies of issues relating to the colonial urban history. The study purposes were, therefore, to try to understand how the old urban nuclei of Pombal and Sousa fit in the territorial expansion policies undertaken by the Portuguese government; to relate the process of urban formation and development of such nuclei with the categories of analysis povoação-freguesia-vila by discussing the relations and influences they exert over one another and their territory, as well as to unveil, as much as possible, the configuration the urban spaces that were shaped along the 18th century

The Serido Group of NE Brazil, a late Neoproterozoic pre- to syn-collisional basin in West Gondwana: insights from SHRIMP U-Pb detrital zircon ages and Sm-Nd crustal residence (T-DM) ages

The Serido Group is a deformed and metamorphosed metasedimentary sequence that overlies early Paleoproterozoic to Archean basement of the Rio Grande do Norte domain in the Borborema Province of NE Brazil. The age of the Serido Group has been disputed over the past two decades, with preferred sedimentation ages being either Paleoproterozoic or Neoproterozoic. Most samples of the Serido Formation, the upper part of the Serido Group, have Sm-Nd T-DM ages between 1200 and 1600 Ma. Most samples of the Jucurutu Formation, the lower part of the Serido Group, have T-DM ages ranging from 1500 to 1600 Ma; some basal units have T-DM ages as old as 2600 Ma, reflecting proximal basement. Thus, based on Sm-Nd data, most, if not all, of the Serido Group was deposited after 1600 Ma and upper parts must be younger than 1200 Ma.Cathodoluminescence photos of detrital zircons show very small to no overgrowths produced during ca. 600 Ma Brasiliano deformation and metamorphism, so that SHRIMP and isotope dilution U-Pb ages must represent crystallization ages of the detrital zircons. Zircons from meta-arkose near the base of the Jucurutu Formation yield two groups of ages: ca. 2200 Ma and ca. 1800 Ma. In contrast, zircons from a metasedimentary gneiss higher in the Jucurutu Formation yield much younger ages, with clusters at ca. 1000 Ma and ca. 650 Ma. Zircons from metasedimentary and metatuffaceous units in the Serido Formation also yield ages primarily between 1000 and 650 Ma, with clusters at 950-1000, 800, 750, and 650 Ma. Thus, most, if not all, of the Serido Group must be younger than 650 Ma. Because these units were deformed and metamorphosed in the ca. 600 Ma Brasiliano fold belt during assembly of West Gondwana, deposition probably occurred ca. 610-650 Ma, soon after crystallization of the youngest population of zircons and before or during the onset of Brasiliano deformation.The Serido Group was deposited upon Paleoproterozoic basement in a basin receiving detritus from a variety of sources. The Jucurutu Formation includes some basal volcanic rocks and initially received detritus from proximal 2.2-2.0 Ga (Transamazonian) to late Paleoproterozoic (1.8-1.7 Ga) basement. Provenance for the upper Jucurutu Formation and all of the Serido Formation was dominated by more distal and younger sources ranging in age from 1000 to 650 Ma. We suggest that the Serido basin may have developed as the result of late Neoproterozoic extension of a pre-existing continental basement, with formation of small marine basins that were largely floored by cratonic basement (subjacent oceanic crust has not yet been found). Immature sediment was initially derived from surrounding land; as the basin evolved much of the detritus probably came from highlands to the south (present coordinates). Alternatively, if the Patos shear zone is a major terrane boundary, the basin may have formed as an early collisional foredeep associated with south-dipping subduction. In any case, within 30 million years the region was compressed, deformed, and metamorphosed during final assembly of West Gondwana and formation of the Brasiliano-Pan African fold belts. (C) 2003 Elsevier B.V. All rights reserved.

A modernização da agricultura e as implicações nas relações de trabalho no campo: os trabalhadores volantes no município de Fernandópolis-SP

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Use of VEGFR-2 targeted microbubbles (BR55, Bracco imaging) for the early ultrasound evaluation of response to antiangiogenic treatment in a xenograft model of hepatocarcinoma

Aim: To evaluate the early response to treatment to an antiangiogenetic drug (sorafenib) in a heterotopic murine model of hepatocellular carcinoma (HCC) using ultrasonographic molecular imaging. Material and Methods: the xenographt model was established injecting a suspension of HuH7 cells subcutaneously in 19 nude mice. When tumors reached a mean diameter of 5-10 mm, they were divided in two groups (treatment and vehicle). The treatment group received sorafenib (62 mg/kg) by daily oral gavage for 14 days. Molecular imaging was performed using contrast enhanced ultrasound (CEUS), by injecting into the mouse venous circulation a suspension of VEGFR-2 targeted microbubbles (BR55, kind gift of Bracco Swiss, Geneve, Switzerland). Video clips were acquired for 6 minutes, then microbubbles (MBs) were destroyed by a high mechanical index (MI) impulse, and another minute was recorded to evaluate residual circulating MBs. The US protocol was repeated at day 0,+2,+4,+7, and +14 from the beginning of treatment administration. Video clips were analyzed using a dedicated software (Sonotumor, Bracco Swiss) to quantify the signal of the contrast agent. Time/intensity curves were obtained and the difference of the mean MBs signal before and after high MI impulse (Differential Targeted Enhancement-dTE) was calculated. dTE represents a numeric value in arbitrary units proportional to the amount of bound MBs. At day +14 mice were euthanized and the tumors analyzed for VEGFR-2, pERK, and CD31 tissue levels using western blot analysis. Results: dTE values decreased from day 0 to day +14 both in treatment and vehicle groups, and they were statistically higher in vehicle group than in treatment group at day +2, at day +7, and at day +14. With respect to the degree of tumor volume increase, measured as growth percentage delta (GPD), treatment group was divided in two sub-groups, non-responders (GPD>350%), and responders (GPD<200%). In the same way vehicle group was divided in slow growth group (GPD<400%), and fast growth group (GPD>900%). dTE values at day 0 (immediately before treatment start) were higher in non-responders than in responders group, with statistical difference at day 2. While dTE values were higher in the fast growth group than in the slow growth group only at day 0. A significant positive correlation was found between VEGFR-2 tissue levels and dTE values, confirming that level of BR55 tissue enhancement reflects the amount of tissue VEGF receptor. Conclusions: the present findings show that, at least in murine experimental models, CEUS with BR55 is feasable and appears to be a useful tool in the prediction of tumor growth and response to sorafenib treatment in xenograft HCC.

Chemotherapy alone versus chemotherapy plus radiotherapy for early stage Hodgkin lymphoma

Background Combined modality treatment (CMT) consisting of chemotherapy followed by localised radiotherapy is standard treatment for patients with early stage Hodgkin lymphoma (HL). However, due to long term adverse effects such as secondary malignancies, the role of radiotherapy has been questioned recently and some clinical study groups advocate chemotherapy only for this indication. Objectives We performed a systematic review with meta-analysis of randomised controlled trials (RCTs) comparing chemotherapy alone with CMT in patients with early stage Hodgkin lymphoma with respect to response rate, progression-free survival (alternatively tumour control) and overall survival (OS). Search methods We searched MEDLINE, EMBASE and CENTRAL as well as conference proceedings from January 1980 to November 2010 for randomised controlled trials comparing chemotherapy alone to the same chemotherapy regimen plus radiotherapy. Selection criteria Randomised controlled trials comparing chemotherapy alone with CMT in patients with early stage HL. Trials in which the chemotherapy differed between treatment arms were excluded. Trials with more than 20% of patients in advanced stage were also excluded. Data collection and analysis Effect measures used were hazard ratios (HR) for tumour control and OS as well as relative risks for response rates. Two review authors independently extracted data and assessed quality of trials. We contacted study authors to obtain missing information. Since none of the trials reported progression-free survival according to our definitions, all similar outcomes were evaluated as tumour control. Main results Five RCTs involving 1245 patients were included. The HR was 0.41 (95% confidence interval (CI) 0.25 to 0.66) for tumour control and 0.40 (95% CI 0.27 to 0.61) for OS for patients receiving CMT compared to chemotherapy alone. Complete response rates were similar between treatment groups. In sensitivity analyses another six trials were included that did not fulfil the inclusion criteria of our protocol but were considered relevant to the topic. These trials underlined the results of the main analysis. Authors' conclusions Adding radiotherapy to chemotherapy improves tumour control and overall survival in patients with early stage Hodgkin lymphoma.

Youth at Risk: Part 1, 2012 Massachusetts Family Impact Seminar

The youth of Massachusetts are of primary concern to legislators and citizens. This briefing report features three essays by experts – Lisa Jones, Ramon Borges-Mendez, and Janis Wolak – who focus on three aspects of youth wellbeing: youth victimization and other indicators of psychological health, youth unemployment, and online sexual predators of youth. Although youth well-being is of primary concern, the worrisome stories about crimes against children that regularly fill the media have unfortunately obscured some more positive news from statistical reports on these same issues. Child victimizations of various types – i.e., child sexual abuse, witnessing domestic violence, child physical abuse, sexual assaults of teenagers, physical assaults and robberies of teenagers, and homicides of teenagers – have been declining nationwide and in Massachusetts since the early 1990s, in some cases declining dramatically.

Jackson County Heifer Development Project Summary

The heifer development project was a five year project conducted on the site of the former Jackson County Farm north of Andrew, Iowa, for four years and on an area producer’s farm for the fifth year. Heifers arrived around December 1 each year and the average number of heifers each year was 43 with a low of 37 and high of 47. After a 30+ day warm-up period the heifers were put on a 112-day test from early January to late April. They were fed a shelled corn and legume-grass hay ration consisting of between 13% and 14% crude protein and a range of .44 to .58 megacal/pound of NEg over the five years. During the 112-day test heifers gained 1.86, 1.78, 1.5, 1.63 and 2.2 pounds per day, respectively, for years 1992 through 1996. The actual average breeding weight was less than the target weight in three years by 5, 12 and 22 pounds and exceeded the target weight in two year by 17 and 28 pounds. Estrus synchronization used a combination of MGA feeding and Lutalyse injection. Heifers were heat detected and bred 12 hours later for a three-day period. On the fourth day, all heifers not bred were mass inseminated. Heifers then ran with the cleanup bull for 58 days. The average synchronization response rate during the project was 79%. The overall pregnancy rates based on September pregnancy averaged 92%. The five year average total cost per head for heifer development was $286.18 or about $.85 per day. Feed and pasture costs averaged 61% of the total costs.

Jackson County Heifer Development Project Update

The heifer development project took place the past four years on the site of the former Jackson County Farm north of Andrew, Iowa. Heifers arrived around December 1 with 38 heifers delivered for 1992, 44 for 1993, 46 for 1994, and 47 for 1995. After a 30+ day warm-up period, the heifers were put on a 112-day test from early January to late April. They were fed a shelled corn and legume-grass hay ration consisting of between 13% and 14% crude protein and .48, .58, .44, and .54 megacal/pound of NEg respectively for the years 1992 - 1995. During the 112-day test heifers gained 1.86, 1.78, 1.5, and 1.63 pounds per day respectively for years 1992 through 1995. The 1995 heifers averaged 853 pounds at breeding (22 pounds under target weight). This compares with previous years in which the breeding weight was less than target weight in two years by 5 and 12 pounds and exceeded the target weight in one year by 17 pounds. Estrus synchronization used a combination of MGA feeding and Lutalyse injection. Heifers were heatdetected and bred 12 hours later for a three-day period. On the fourth day, all heifers not bred were mass inseminated. Heifers then ran with the cleanup bull for 58 days. The synchronization response rate in 1995 was 83%, which compares with the three year previous average of 77%. The overall pregnancy rates based on September pregnancy exams were 94.6% in 1992, 93% in 1993, 91% in 1994, and 91.5% in 1995. Development costs for the 326 days in 1995 totaled $269.14 per heifer. This compares with the average of $286. 92 for the three previous years. The four-year average total cost per head for heifer development was $282.48, or about $.84 per day. Feed and pasture costs represented 58% of the total costs, or $.49 per day.