Clinicopathological factors influencing outcome in metastatic colorectal cancer patients treated with fluoropyrimidine and bevacizumab maintenance treatment vs observation: an individual patient data meta-analysis of two phase 3 trials

BACKGROUND: The CAIRO3 and AIO 0207 trials demonstrated the efficacy of fluoropyrimidine plus bevacizumab (FP+Bev) maintenance treatment in metastatic colorectal cancer (mCRC) patients. In this individual patient data meta-analysis with updated follow-up, we aim to provide more precise estimates of treatment effects and to identify subgroups that benefit most from maintenance treatment or observation. METHODS: In 871 patients, randomised to FP+Bev maintenance treatment or observation, we investigated whether treatment effect was modified by sex, age, performance status, response to induction treatment, primary tumour location, number of metastatic sites, disease stage and primary tumour resection, serum LDH, platelet count, CEA, and RAS/BRAF mutation status. Primary end point was time to second progression after reintroduction of the induction regimen (PFS2). Secondary end points were first progression-free survival (PFS1) and overall survival (OS). RESULTS: At a median follow-up of 68.5 months (IQR 54.6-87.0 months), maintenance treatment was more effective compared with observation in PFS1 (HR 0.40(95% CI 0.34-0.47)) and PFS2 (HR 0.70(0.60-0.81)). No subgroups were identified that did not benefit from maintenance treatment in PFS1 and PFS2; no clinically relevant subgroup effects were observed. Regarding OS, pooled results were not significant (HR 0.91(0.78-1.05)), and the trials showed marked heterogeneity in overall treatment effect and subgroup effects. CONCLUSIONS: FP+Bev maintenance treatment is effective in all patients, regardless of the investigated subgroups.info:eu-repo/semantics/publishedVersio

Cardiovascular disease in a cohort exposed to the 1940-45 Channel Islands occupation

BACKGROUND To clarify the nature of the relationship between food deprivation/undernutrition during pre- and postnatal development and cardiovascular disease (CVD) in later life, this study examined the relationship between birth weight (as a marker of prenatal nutrition) and the incidence of hospital admissions for CVD from 1997–2005 amongst 873 Guernsey islanders (born in 1923–1937), 225 of whom had been exposed to food deprivation as children, adolescents or young adults (i.e. postnatal undernutrition) during the 1940–45 German occupation of the Channel Islands, and 648 of whom had left or been evacuated from the islands before the occupation began. METHODS Three sets of Cox regression models were used to investigate (A) the relationship between birth weight and CVD, (B) the relationship between postnatal exposure to the occupation and CVD and (C) any interaction between birth weight, postnatal exposure to the occupation and CVD. These models also tested for any interactions between birth weight and sex, and postnatal exposure to the occupation and parish of residence at birth (as a marker of parish residence during the occupation and related variation in the severity of food deprivation). RESULTS The first set of models (A) found no relationship between birth weight and CVD even after adjustment for potential confounders (hazard ratio (HR) per kg increase in birth weight: 1.12; 95% confidence intervals (CI): 0.70 – 1.78), and there was no significant interaction between birth weight and sex (p = 0.60). The second set of models (B) found a significant relationship between postnatal exposure to the occupation and CVD after adjustment for potential confounders (HR for exposed vs. unexposed group: 2.52; 95% CI: 1.54 – 4.13), as well as a significant interaction between postnatal exposure to the occupation and parish of residence at birth (p = 0.01), such that those born in urban parishes (where food deprivation was worst) had a greater HR for CVD than those born in rural parishes. The third model (C) found no interaction between birth weight and exposure to the occupation (p = 0.43). CONCLUSION These findings suggest that the levels of postnatal undernutrition experienced by children, adolescents and young adults exposed to food deprivation during the 1940–45 occupation of the Channel Islands were a more important determinant of CVD in later life than the levels of prenatal undernutrition experienced in utero prior to the occupatio

Historical overview of spinal deformities in ancient Greece

Little is known about the history of spinal deformities in ancient Greece. The present study summarizes what we know today for diagnosis and management of spinal deformities in ancient Greece, mainly from the medical treatises of Hippocrates and Galen. Hippocrates, through accurate observation and logical reasoning was led to accurate conclusions firstly for the structure of the spine and secondly for its diseases. He introduced the terms kyphosis and scoliosis and wrote in depth about diagnosis and treatment of kyphosis and less about scoliosis. The innovation of the board, the application of axial traction and even the principle of trans-abdominal correction for correction of spinal deformities have their origin in Hippocrates. Galen, who lived nearly five centuries later impressively described scoliosis, lordosis and kyphosis, provided aetiologic implications and used the same principles with Hippocrates for their management, while his studies influenced medical practice on spinal deformities for more than 1500 years

Energy Restriction during Childhood and Early Adulthood and Ovarian Cancer Risk

Dietary energy restriction may protect against cancer. In parts of the Netherlands, mostly in larger cities, periods of chronically impaired nutrition and even severe famine (Hunger Winter 1944–1945) existed during the 1930s and World War II (1940–1945). We studied the association between energy restriction during childhood and early adulthood on the risk of ovarian cancer later in life. In 1986, the Netherlands Cohort Study was initiated. A self-administered questionnaire on dietary habits and other cancer risk factors was completed by 62,573 women aged 55–69 years at baseline. Follow-up for cancer was established by record linkage to the Netherlands Cancer Registry. After 16.3 years of follow-up, 364 invasive epithelial ovarian cancer cases and 2220 subcohort members (sampled from the total cohort directly after baseline) with complete information confounders were available for case-cohort analyses. In multivariable analysis, ovarian cancer risk was lower for participants with an unemployed father during the 1930s (Hazard Ratio (HR), 0.70; 95% Confidence Interval (CI), 0.47–1.06) compared to participants with an employed father as well as for participants living in a city during World War II (HR, 0.69; 95% CI, 0.54–0.90) compared to participants living in the country-side. Residence in a Western City during the famine (Hunger Winter) was not associated with a decreased risk. Our results show a relation between proxy variables for modest energy restriction over a longer period of time during childhood or early adulthood and a reduced ovarian cancer risk

Characterization of Protective Human CD4+CD25+ FOXP3+ Regulatory T Cells Generated with IL-2, TGF-β and Retinoic Acid

BACKGROUND: Protective CD4+CD25+ regulatory T cells bearing the Forkhead Foxp3 transcription factor can now be divided into three subsets: Endogenous thymus-derived cells, those induced in the periphery, and another subset induced ex-vivo with pharmacological amounts of IL-2 and TGF-β. Unfortunately, endogenous CD4+CD25+ regulatory T cells are unstable and can be converted to effector cells by pro-inflammatory cytokines. Although protective Foxp3+CD4+CD25+ cells resistant to proinflammatory cytokines have been generated in mice, in humans this result has been elusive. Our objective, therefore, was to induce human naïve CD4+ cells to become stable, functional CD25+ Foxp3+ regulatory cells that were also resistant to the inhibitory effects of proinflammatory cytokines. METHODOLOGY/PRINCIPAL FINDINGS: The addition of the vitamin A metabolite, all-trans retinoic acid (atRA) to human naïve CD4+ cells suboptimally activated with IL-2 and TGF-β enhanced and stabilized FOXP3 expression, and accelerated their maturation to protective regulatory T cells. AtRA, by itself, accelerated conversion of naïve to mature cells but did not induce FOXP3 or suppressive activity. The combination of atRA and TGF-β enabled CD4+CD45RA+ cells to express a phenotype and trafficking receptors similar to natural Tregs. AtRA/TGF-β-induced CD4+ regs were anergic and low producers of IL-2. They had potent in vitro suppressive activity and protected immunodeficient mice from a human-anti-mouse GVHD as well as expanded endogenous Tregs. However, treatment of endogenous Tregs with IL-1β and IL-6 decreased FOXP3 expression and diminished their protective effects in vivo while atRA-induced iTregs were resistant to these inhibitory effects. CONCLUSIONS/SIGNIFICANCE: We have developed a methodology that induces human CD4(+) cells to rapidly become stable, fully functional suppressor cells that are also resistant to proinflammatory cytokines. This methodology offers a practical novel strategy to treat human autoimmune diseases and prevent allograft rejection without the use of agents that kill cells or interfere with signaling pathways

Comparison of the Simple Patient-Centric Atopic Dermatitis Scoring System PEST with SCORAD in Young Children Using a Ceramide Dominant Therapeutic Moisturizer.

INTRODUCTION: Patient eczema severity time (PEST) is a new atopic dermatitis (AD) scoring system based on patients' own perception of their disease. Conventional scales such as SCORing of atopic dermatitis (SCORAD) reflect the clinician's observations during the clinic visit. Instead, the PEST score captures eczema severity, relapse and recovery as experienced by the patient or caregiver on a daily basis, promoting patient engagement, compliance with treatment and improved outcomes. This study aims to determine the correlation between carer-assessed PEST and clinician-assessed SCORAD in paediatric AD patients after 12 weeks of treatment using a ceramide-dominant therapeutic moisturizer. METHODS: Prospective, open-label, observational, multi-centre study in which children with AD aged 6 months to 6 years were treated with a ceramide dominant therapeutic moisturizer twice daily for 12 weeks; 58 children with mild-to-moderate AD were included. Correlation between the 7-day averaged PEST and SCORAD scores for assessment of AD severity was measured within a general linear model. PEST and SCORAD were compared in week 4 and week 12. RESULTS: At week 12, a moderate correlation was found between the SCORAD and PEST scores (r = 0.51). The mean change in SCORAD and PEST scores from baseline to week 12 was -11.46 [95% confidence interval (CI) -14.99 to -7.92, p < 0.0001] and -1.33 (95% CI -0.71 to -0.10, p < 0.0001) respectively. PEST demonstrated greater responsiveness to change (33.3% of scale) compared to SCORAD (13.8% of scale). CONCLUSION: The PEST score correlates well with the SCORAD score and may have improved sensitivity when detecting changes in the severity of AD. The ceramide-dominant therapeutic moisturizer used was safe and effective in the management of AD in young children

Study protocol for a group randomized controlled trial of a classroom-based intervention aimed at preventing early risk factors for drug abuse: integrating effectiveness and implementation research

<p>Abstract</p> <p>Background</p> <p>While a number of preventive interventions delivered within schools have shown both short-term and long-term impact in epidemiologically based randomized field trials, programs are not often sustained with high-quality implementation over time. This study was designed to support two purposes. The first purpose was to test the effectiveness of a universal classroom-based intervention, the Whole Day First Grade Program (WD), aimed at two early antecedents to drug abuse and other problem behaviors, namely, aggressive, disruptive behavior and poor academic achievement. The second purpose--the focus of this paper--was to examine the utility of a multilevel structure to support high levels of implementation during the effectiveness trial, to sustain WD practices across additional years, and to train additional teachers in WD practices.</p> <p>Methods</p> <p>The WD intervention integrated three components, each previously tested separately: classroom behavior management; instruction, specifically reading; and family-classroom partnerships around behavior and learning. Teachers and students in 12 schools were randomly assigned to receive either the WD intervention or the standard first-grade program of the school system (SC). Three consecutive cohorts of first graders were randomized within schools to WD or SC classrooms and followed through the end of third grade to test the effectiveness of the WD intervention. Teacher practices were assessed over three years to examine the utility of the multilevel structure to support sustainability and scaling-up.</p> <p>Discussion</p> <p>The design employed in this trial appears to have considerable utility to provide data on WD effectiveness and to inform the field with regard to structures required to move evidence-based programs into practice.</p> <p>Trial Registration</p> <p><b>Clinical Trials Registration Number</b>: NCT00257088</p

Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis

Background Ultrasound (US) has largely replaced contrast venography as the definitive diagnostic test for deep vein thrombosis (DVT). We aimed to derive a definitive estimate of the diagnostic accuracy of US for clinically suspected DVT and identify study-level factors that might predict accuracy. Methods We undertook a systematic review, meta-analysis and meta-regression of diagnostic cohort studies that compared US to contrast venography in patients with suspected DVT. We searched Medline, EMBASE, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, Database of Reviews of Effectiveness, the ACP Journal Club, and citation lists (1966 to April 2004). Random effects meta-analysis was used to derive pooled estimates of sensitivity and specificity. Random effects meta-regression was used to identify study-level covariates that predicted diagnostic performance. Results We identified 100 cohorts comparing US to venography in patients with suspected DVT. Overall sensitivity for proximal DVT (95% confidence interval) was 94.2% (93.2 to 95.0), for distal DVT was 63.5% (59.8 to 67.0), and specificity was 93.8% (93.1 to 94.4). Duplex US had pooled sensitivity of 96.5% (95.1 to 97.6) for proximal DVT, 71.2% (64.6 to 77.2) for distal DVT and specificity of 94.0% (92.8 to 95.1). Triplex US had pooled sensitivity of 96.4% (94.4 to 97.1%) for proximal DVT, 75.2% (67.7 to 81.6) for distal DVT and specificity of 94.3% (92.5 to 95.8). Compression US alone had pooled sensitivity of 93.8 % (92.0 to 95.3%) for proximal DVT, 56.8% (49.0 to 66.4) for distal DVT and specificity of 97.8% (97.0 to 98.4). Sensitivity was higher in more recently published studies and in cohorts with higher prevalence of DVT and more proximal DVT, and was lower in cohorts that reported interpretation by a radiologist. Specificity was higher in cohorts that excluded patients with previous DVT. No studies were identified that compared repeat US to venography in all patients. Repeat US appears to have a positive yield of 1.3%, with 89% of these being confirmed by venography. Conclusion Combined colour-doppler US techniques have optimal sensitivity, while compression US has optimal specificity for DVT. However, all estimates are subject to substantial unexplained heterogeneity. The role of repeat scanning is very uncertain and based upon limited data

Overexpression of Hydroxynitrile Lyase in Cassava Roots Elevates Protein and Free Amino Acids while Reducing Residual Cyanogen Levels

Cassava is the major source of calories for more than 250 million Sub-Saharan Africans, however, it has the lowest protein-to-energy ratio of any major staple food crop in the world. A cassava-based diet provides less than 30% of the minimum daily requirement for protein. Moreover, both leaves and roots contain potentially toxic levels of cyanogenic glucosides. The major cyanogen in cassava is linamarin which is stored in the vacuole. Upon tissue disruption linamarin is deglycosylated by the apolplastic enzyme, linamarase, producing acetone cyanohydrin. Acetone cyanohydrin can spontaneously decompose at pHs >5.0 or temperatures >35°C, or is enzymatically broken down by hydroxynitrile lyase (HNL) to produce acetone and free cyanide which is then volatilized. Unlike leaves, cassava roots have little HNL activity. The lack of HNL activity in roots is associated with the accumulation of potentially toxic levels of acetone cyanohydrin in poorly processed roots. We hypothesized that the over-expression of HNL in cassava roots under the control of a root-specific, patatin promoter would not only accelerate cyanogenesis during food processing, resulting in a safer food product, but lead to increased root protein levels since HNL is sequestered in the cell wall. Transgenic lines expressing a patatin-driven HNL gene construct exhibited a 2–20 fold increase in relative HNL mRNA levels in roots when compared with wild type resulting in a threefold increase in total root protein in 7 month old plants. After food processing, HNL overexpressing lines had substantially reduced acetone cyanohydrin and cyanide levels in roots relative to wild-type roots. Furthermore, steady state linamarin levels in intact tissues were reduced by 80% in transgenic cassava roots. These results suggest that enhanced linamarin metabolism contributed to the elevated root protein levels