Overdiagnosis and overtreatment of breast cancer: Estimates of overdiagnosis from two trials of mammographic screening for breast cancer

Randomised controlled trials have shown that the policy of mammographic screening confers a substantial and significant reduction in breast cancer mortality. This has often been accompanied, however, by an increase in breast cancer incidence, particularly during the early years of a screening programme, which has led to concerns about overdiagnosis, that is to say, the diagnosis of disease that, if left undetected and therefore untreated, would not become symptomatic. We used incidence data from two randomised controlled trials of mammographic screening, the Swedish Two-county Trial and the Gothenburg Trial, to establish the timing and magnitude of any excess incidence of invasive disease and ductal carcinoma in situ (DCIS) in the study groups, to ascertain whether the excess incidence of DCIS reported early in a screening trial is balanced by a later deficit in invasive disease and provide explicit estimates of the rate of 'real' and non-progressive 'overdiagnosed' tumours from the study groups of the trials. We used a multistate model for overdiagnosis and used Markov Chain Monte Carlo methods to estimate the parameters. After taking into account the effect of lead time, we estimated that less than 5% of cases diagnosed at prevalence screen and less than 1% of cases diagnosed at incidence screens are being overdiagnosed. Overall, we estimate overdiagnosis to be around 1% of all cases diagnosed in screened populations. These estimates are, however, subject to considerable uncertainty. Our results suggest that overdiagnosis in mammography screening is a minor phenomenon, but further studies with very large numbers are required for more precise estimation

Screening and brief interventions for hazardous and harmful alcohol use in primary care: a cluster randomised controlled trial protocol

A large number of randomised controlled trials in health settings have consistently reported positive effects of brief intervention in terms of reductions in alcohol use. However,although alcohol misuse is common amongst offenders, there is limited evidence of alcohol brief interventions in the criminal justice field. This factorial pragmatic cluster randomised controlledtrial with Offender Managers (OMs) as the unit of randomisation will evaluate the effectiveness and cost-effectiveness of different models of screening to identify hazardous and harmful drinkers in probation and different intensities of brief intervention to reduce excessive drinking in probation clients. Ninety-six OMs from 9 probation areas across 3 English regions (the NorthEast Region (n = 4) and London and the South East Regions (n = 5)) will be recruited. OMs will berandomly allocated to one of three intervention conditions: a client information leaflet control condition (n = 32 OMs); 5-minute simple structured advice (n = 32 OMs) and 20-minute brieflifestyle counselling delivered by an Alcohol Health Worker (n = 32 OMs). Randomisation will be stratified by probation area. To test the relative effectiveness of different screening methods all OMs will be randomised to either the Modified Single Item Screening Questionnaire (M-SASQ) orthe Fast Alcohol Screening Test (FAST). There will be a minimum of 480 clients recruited into the trial. There will be an intention to treat analysis of study outcomes at 6 and 12 months postintervention. Analysis will include client measures (screening result, weekly alcohol consumption,alcohol-related problems, re-offending, public service use and quality of life) and implementation measures from OMs (the extent of screening and brief intervention beyond the minimum recruitment threshold will provide data on acceptability and feasibility of different models of brief intervention). We will also examine the practitioner and organisational factors associated with successful implementation.The trial will evaluate the impact of screening and brief alcohol intervention in routine probation work and therefore its findings will be highly relevant to probation teams and thus the criminal justice system in the UK

Optimised Anaesthesia to Reduce Post Operative Cognitive Decline (POCD) in Older Patients Undergoing Elective Surgery, a Randomised Controlled Trial

Background The study determined the one year incidence of post operative cognitive decline (POCD) and evaluated the effectiveness of an intra-operative anaesthetic intervention in reducing post-operative cognitive impairment in older adults (over 60 years of age) undergoing elective orthopaedic or abdominal surgery. Methods and Trial Design The design was a prospective cohort study with a nested randomised, controlled intervention trial, using intra-operative BiSpectral index and cerebral oxygen saturation monitoring to enable optimisation of anaesthesia depth and cerebral oxygen saturation in older adults undergoing surgery. Results In the 52 week prospective cohort study (192 surgical patients and 138 controls), mild (?2 = 17.9 p<0.0001), moderate (?2 = 7.8 p = 0.005) and severe (?2 = 5.1 p = 0.02) POCD were all significantly higher after 52 weeks in the surgical patients than among the age matched controls. In the nested RCT, 81 patients were randomized, 73 contributing to the data analysis (34 intervention, 39 control). In the intervention group mild POCD was significantly reduced at 1, 12 and 52 weeks (Fisher’s Exact Test p = 0.018, ?2 = 5.1 p = 0.02 and ?2 = 5.9 p = 0.015), and moderate POCD was reduced at 1 and 52 weeks (?2 = 4.4 p = 0·037 and ?2 = 5.4 p = 0.02). In addition there was significant improvement in reaction time at all time-points (Vigilance Reaction Time MWU Z = ?2.1 p = 0.03, MWU Z = ?2.7 p = 0.004, MWU Z = ?3.0 p = 0.005), in MMSE at one and 52 weeks (MWU Z = ?2.9 p = 0.003, MWU Z = ?3.3 p = 0.001), and in executive function at 12 and 52 weeks (Trail Making MWU Z = ?2.4 p = .0.018, MWU Z = ?2.4 p = 0.019). Conclusion POCD is common and persistent in older adults following surgery. The results of the nested RCT indicate the potential benefits of intra-operative monitoring of anaesthetic depth and cerebral oxygenation as a pragmatic intervention to reduce post-operative cognitive impairment

Detailed analysis of X chromosome inactivation in a 49,XXXXX pentasomy

<p>Abstract</p> <p>Background</p> <p>Pentasomy X (49,XXXXX) has been associated with a severe clinical condition, presumably resulting from failure or disruption of X chromosome inactivation. Here we report that some human X chromosomes from a patient with 49,XXXXX pentasomy were functionally active following isolation in inter-specific (human-rodent) cell hybrids. A comparison with cytogenetic and molecular findings provided evidence that more than one active X chromosome was likely to be present in the cells of this patient, accounting for her abnormal phenotype.</p> <p>Results</p> <p>5-bromodeoxyuridine (BrdU)-pulsed cultures showed different patterns among late replicating X chromosomes suggesting that their replication was asynchronic and likely to result in irregular inactivation. Genotyping of the proband and her mother identified four maternal and one paternal X chromosomes in the proband. It also identified the paternal X chromosome haplotype (P), indicating that origin of this X pentasomy resulted from two maternal, meiotic non-disjunctions. Analysis of the <it>HUMANDREC </it>region of the androgen receptor (<it>AR</it>) gene in the patient's mother showed a skewed inactivation pattern, while a similar analysis in the proband showed an active paternal X chromosome and preferentially inactivated X chromosomes carrying the 173 <it>AR </it>allele. Analyses of 33 cell hybrid cell lines selected in medium containing hypoxanthine, aminopterin and thymidine (HAT) allowed for the identification of three maternal X haplotypes (M1, M2 and MR) and showed that X chromosomes with the M1, M2 and P haplotypes were functionally active. In 27 cell hybrids in which more than one X haplotype were detected, analysis of X inactivation patterns provided evidence of preferential inactivation.</p> <p>Conclusion</p> <p>Our findings indicated that 12% of X chromosomes with the M1 haplotype, 43.5% of X chromosomes with the M2 haplotype, and 100% of the paternal X chromosome (with the P haplotype) were likely to be functionally active in the proband's cells, a finding indicating that disruption of X inactivation was associated to her severe phenotype.</p

Origins of Spatial Working Memory Deficits in Schizophrenia: An Event-Related fMRI and Near-Infrared Spectroscopy Study

Abnormal prefrontal functioning plays a central role in the working memory (WM) deficits of schizophrenic patients, but the nature of the relationship between WM and prefrontal activation remains undetermined. Using two functional neuroimaging methods, we investigated the neural correlates of remembering and forgetting in schizophrenic and healthy participants. We focused on the brain activation during WM maintenance phase with event-related functional magnetic resonance imaging (fMRI). We also examined oxygenated hemoglobin changes in relation to memory performance with the near-infrared spectroscopy (NIRS) using the same spatial WM task. Distinct types of correct and error trials were segregated for analysis. fMRI data indicated that prefrontal activation was increased during WM maintenance on correct trials in both schizophrenic and healthy subjects. However, a significant difference was observed in the functional asymmetry of frontal activation pattern. Healthy subjects showed increased activation in the right frontal, temporal and cingulate regions. Schizophrenic patients showed greater activation compared with control subjects in left frontal, temporal and parietal regions as well as in right frontal regions. We also observed increased ‘false memory’ errors in schizophrenic patients, associated with increased prefrontal activation and resembling the activation pattern observed on the correct trials. NIRS data replicated the fMRI results. Thus, increased frontal activity was correlated with the accuracy of WM in both healthy control and schizophrenic participants. The major difference between the two groups concerned functional asymmetry; healthy subjects recruited right frontal regions during spatial WM maintenance whereas schizophrenic subjects recruited a wider network in both hemispheres to achieve the same level of memory performance. Increased “false memory” errors and accompanying bilateral prefrontal activation in schizophrenia suggest that the etiology of memory errors must be considered when comparing group performances. Finally, the concordance of fMRI and NIRS data supports NIRS as an alternative functional neuroimaging method for psychiatric research

The BraveNet prospective observational study on integrative medicine treatment approaches for pain

BACKGROUND: Chronic pain affects nearly 116 million American adults at an estimated cost of up to $635 billion annually and is the No. 1 condition for which patients seek care at integrative medicine clinics. In our Study on Integrative Medicine Treatment Approaches for Pain (SIMTAP), we observed the impact of an integrative approach on chronic pain and a number of other related patient-reported outcome measures. METHODS: Our prospective, non-randomized, open-label observational evaluation was conducted over six months, at nine clinical sites. Participants received a non-standardized, personalized, multimodal approach to chronic pain. Validated instruments for pain (severity and interference levels), quality of life, mood, stress, sleep, fatigue, sense of control, overall well-being, and work productivity were completed at baseline and at six, 12, and 24 weeks. Blood was collected at baseline and week 12 for analysis of high-sensitivity C-reactive protein and 25-hydroxyvitamin D levels. Repeated-measures analysis was performed on data to assess change from baseline at 24 weeks. RESULTS: Of 409 participants initially enrolled, 252 completed all follow-up visits during the 6 month evaluation. Participants were predominantly white (81%) and female (73%), with a mean age of 49.1 years (15.44) and an average of 8.0 (9.26) years of chronic pain. At baseline, 52% of patients reported symptoms consistent with depression. At 24 weeks, significantly decreased pain severity (−23%) and interference (−28%) were seen. Significant improvements in mood, stress, quality of life, fatigue, sleep and well-being were also observed. Mean 25-hydroxyvitamin D levels increased from 33.4 (17.05) ng/mL at baseline to 39.6 (16.68) ng/mL at week 12. CONCLUSIONS: Among participants completing an integrative medicine program for chronic pain, significant improvements were seen in pain as well as other relevant patient-reported outcome measures. TRIAL REGISTRATION: ClinicalTrials.gov, NCT0118634

The study of women, infant feeding and type 2 diabetes after GDM pregnancy and growth of their offspring (SWIFT Offspring study): prospective design, methodology and baseline characteristics

Abstract Background Breastfeeding is associated with reduced risk of becoming overweight or obese later in life. Breastfed babies grow more slowly during infancy than formula-fed babies. Among offspring exposed in utero to maternal glucose intolerance, prospective data on growth during infancy have been unavailable. Thus, scientific evidence is insufficient to conclude that breastfeeding reduces the risk of obesity among the offspring of diabetic mothers (ODM). To address this gap, we devised the Study of Women, Infant Feeding and Type 2 Diabetes after GDM Pregnancy and Growth of their Offspring, also known as the SWIFT Offspring Study. This prospective, longitudinal study recruited mother-infant pairs from the SWIFT Study, a prospective study of women with recent gestational diabetes mellitus (GDM). The goal of the SWIFT Offspring Study is to determine whether breastfeeding intensity and duration, compared with formula feeding, are related to slower growth of GDM offspring during the first year life. This article details the study design, participant eligibility, data collection, and methodologies. We also describe the baseline characteristics of the GDM mother-infant pairs. Methods The study enrolled 466 mother-infant pairs among GDM deliveries in northern California from 2009–2011. Participants attended three in-person study exams at 6–9 weeks, 6 months and 12 months after delivery for infant anthropometry (head circumference, body weight, length, abdominal circumference and skinfold thicknesses), as well as maternal anthropometry (body weight, waist circumference and percent body fat). Mothers also completed questionnaires on health and lifestyle behaviors, including infant diet, sleep and temperament. Breastfeeding intensity and duration were assessed via several sources (diaries, telephone interviews, monthly mailings and in-person exams) from birth through the first year of life. Pregnancy course, clinical perinatal and newborn outcomes were obtained from health plan electronic medical records. Infant saliva samples were collected and stored for genetics studies. Discussion This large, racially and ethnically diverse cohort of GDM offspring will enable evaluation of the relationship of infant feeding to growth during infancy independent of perinatal characteristics, sociodemographics and other risk factors. The longitudinal design provides the first quantitative measures of breastfeeding intensity and duration among GDM offspring during early life

Changing perspectives on the internationalization of R&D and innovation by multinational enterprises: a review of the literature

Internationalization of R&D and innovation by Multinational Enterprises (MNEs) has undergone a gradual and comprehensive change in perspective over the past 50 years. From sporadic works in the late 1950s and in the 1960s, it became a systematically analysed topic in the 1970s, starting with pioneering reports and “foundation texts”. Our review unfolds the theoretical and empirical evolution of the literature from dyadic interpretations of centralization versus decentralization of R&D by MNEs to more comprehensive frameworks, wherein established MNEs from Advanced Economies still play a pivotal role, but new players and places also emerge in the global generation and diffusion of knowledge. Hence views of R&D internationalization increasingly rely on concepts, ideas and methods from IB and other related disciplines such as industrial organization, international economics and economic geography. Two main findings are highlighted. First, scholarly research pays an increasing attention to the network-like characteristics of international R&D activities. Second, different streams of literature have emphasized the role of location- specific factors in R&D internationalization. The increasing emphasis on these aspects has created new research opportunities in some key areas, including inter alia: cross-border knowledge sourcing strategies, changes in the geography of R&D and innovation, and the international fragmentation of production and R&D activities

Closing yield gaps in maize production in Southeast Asia through site-specific nutrient management

Rising incomes and changing dietary requirements are swiftly transforming maize (Zea mays L) in Southeast Asia from a food staple into an important industrial commodity. Increased maize production is required to meet rising demands, but additional production should come from the sustainable intensification of existing farmlands to minimize the undesirable effects of agriculture on the environment. We hypothesize that maize yields, profit, and N use efficiencies can be significantly increased through site-specific nutrient management (SSNM), thereby reducing yield gaps in the region. Through a combined approach of simulation modeling and on-farm research in at least 65 sites in 13 major maize-producing domains across Indonesia, Vietnam and the Philippines from 2004 to 2008, we were able to (a) quantify maize yield gaps and yield responses to fertilizer application, (b) evaluate the agronomic and economic performance of SSNM, and (c) evaluate the incremental profitability of SSNM in various production and grain and fertilizer price scenarios. The average exploitable yield gap between the attainable yield and current farmers’ yield in Southeast Asia was about 0.9 t ha−1. Yield responses to fertilizer application across the region followed the order N > >P > K. Yield response to N was higher in irrigated sites than in rainfed sites (6 t ha−1 versus 2 t ha−1), while P and K fertilizer responses were similar across production systems (<2 t ha−1). Yield with SSNM was 1.0 t ha−1 (+13%) higher than the current farmers’ fertilizer practice (FFP) measured in the same cropping seasons. Yield increases were associated with a 10% decrease in the average N rate, but with increased application of K at sites where the previous K rates were low. Average N use efficiency increased by 42%, mainly by adjusting the rates and timing of N application to the stages of crop development. Across all sites and seasons, profitability increased by US$167 ha−1 per crop, which was equivalent to15$100 ha−1 season) were greatest in highly favorable rainfed environments; less favorable rainfed areas were vulnerable to unfavorable market prices. We conclude that SSNM has the potential to close existing yield gaps in the maize production systems of Southeast Asia by improving yield, nutrient use efficiency, and profitability