Personalising Neoadjuvant Chemotherapy for Locally Advanced Colon Cancer: Protocols for the International Phase III FOxTROT2 and FOxTROT3 Randomised-Controlled Trials

Aim FOxTROT1 established a new standard of care for managing locally advanced colon cancer (CC) with neoadjuvant chemotherapy (NAC). Six weeks of neoadjuvant oxaliplatin and fluoropyrimidine (OxFp) chemotherapy was associated with greater 2-year disease-free survival (DFS) when compared to proceeding straight to surgery (STS). There is now a need to refine the use of NAC and identify those most likely to benefit. FOxTROT2 will investigate NAC in older adults and those with frailty. FOxTROT3 will assess whether intensified triplet NAC provides additional benefits over OxFp. Methods FOxTROT2 and FOxTROT3 are international, open-label, phase III randomised-controlled trials. Eligible patients will be identified by the multidisciplinary team. Patient age, frailty and comorbidities will be considered to guide trial entry. Participants will be randomised 2:1 to the intervention or control arm: six weeks of dose-adapted neoadjuvant OxFp vs. STS in FOxTROT2 and six weeks of neoadjuvant modified oxaliplatin, 5FU and irinotecan (mFOLFOXIRI) vs. OxFp in FOxTROT3. The primary endpoint in FOxTROT2 is 3-year DFS. In FOxTROT3, tumour regression grade and 3-year DFS are co-primary endpoints. Discussion FOxTROT2 and FOxTROT3 will establish the FOxTROT platform, a key part of our long-term strategy to develop neoadjuvant treatments for CC. FOxTROT2 will investigate NAC in a population under-represented in FOxTROT1 and wider research. FOxTROT3 will assess whether it is possible to induce greater early tumour responses and whether this translates to superior long-term outcomes. Looking ahead, the FOxTROT platform will facilitate further trial comparisons and extensive translational research to optimise the use of NAC in CC

Advances in prevention and therapy of neonatal dairy calf diarrhoea : a systematical review with emphasis on colostrum management and fluid therapy

Neonatal calf diarrhoea remains the most common cause of morbidity and mortality in preweaned dairy calves worldwide. This complex disease can be triggered by both infectious and non-infectious causes. The four most important enteropathogens leading to neonatal dairy calf diarrhoea are Escherichia coli, rota-and coronavirus, and Cryptosporidium parvum. Besides treating diarrhoeic neonatal dairy calves, the veterinarian is the most obvious person to advise the dairy farmer on prevention and treatment of this disease. This review deals with prevention and treatment of neonatal dairy calf diarrhoea focusing on the importance of a good colostrum management and a correct fluid therapy

Do smallholder farmer-led seed systems have the capacity to supply good-quality, fungal-free sorghum seed?

Local seed systems that are developed, managed and maintained by farmers are a fundamental practice in smallholder crop production, supporting more than 80% of farmers in sub-Saharan Africa and feeding more than 70% of its population. The resilience of such systems is under threat from poverty, climate change, drought, increased pests and diseases, over-promotion of modern crop varieties, change of lifestyles and restrictive seed policies. The system continues to be maligned as having inferior quality, yet few studies support this assertion. This study aims to fll this research gap by evaluating 60 sorghum seed samples collected from smallholder farmers in Uzumba-MarambaPfungwe and Chimanimani districts of Zimbabwe. We investigated the efect of farmer-led seed management practices (e.g. seed acquisition and seed storage practices) on farm-derived sorghum seed quality (moisture, germination and fungal incidences). We found farmers using diverse seed sources and seed storage practices. Seeds were typically of good quality in that their storage moisture content was low, their germination was high, and fungal incidences were low. Seed sourced from local markets, non-governmental organizations and other farmers had germination and moisture standards that met the sorghum certifcation standards in Zimbabwe. However, few samples obtained from the relatives and government failed to meet the germination and/or moisture certifcation standards. We detected low incidences of fungi (Aspergillus favus, Aspergillus niger, Curvularia lunata, Fusarium sp. and Penicillium sp.) in sorghum seed samples tested and in particular Fusarium sp., which is the most economic important fungus in sorghum production. We conclude that farmer-led seed systems have the capacity to supply seeds of good quality and recommend that such systems should be recognized and promoted to meet the ever-evolving needs of smallholder farmers in sub-Saharan Africa

Differences in adjustment by child developmental stage among caregivers of children with disorders of sex development

<p>Abstract</p> <p>Background</p> <p>The current study sought to compare levels of overprotection and parenting stress reported by caregivers of children with disorders of sex development at four different developmental stages.</p> <p>Methods</p> <p>Caregivers (<it>N </it>= 59) of children with disorders of sex development were recruited from specialty clinics and were asked to complete the Parent Protection Scale and Parenting Stress Index/Short Form as measures of overprotective behaviors and parenting stress, respectively.</p> <p>Results</p> <p>Analyses of covariance (ANCOVAs) were conducted to examine differences between caregiver report of overprotection and parenting stress. Results revealed that caregivers of infants and toddlers exhibited more overprotective behaviors than caregivers of children in the other age groups. Further, caregivers of adolescents experienced significantly more parenting stress than caregivers of school-age children, and this effect was driven by personal distress and problematic parent-child interactions, rather than having a difficult child.</p> <p>Conclusions</p> <p>These results suggest that caregivers of children with disorders of sex development may have different psychosocial needs based upon their child's developmental stage and based upon the disorder-related challenges that are most salient at that developmental stage.</p

Screening for data clustering in multicenter studies: the residual intraclass correlation

status: publishe

Functional diversity of mesograzers in an eelgrass-epiphyte system

Historically, small invertebrate grazers in marine plant communities have been considered to be a relatively homogeneous group in their impact on ecosystem processes. However, recent studies propose that species composition is an important agent in determining grazer effects. We used four mesocosm experiments to test the biomass-specific and density-dependent effects of common mesograzers in temperate regions (Littorina littorea, Rissoa membranacea, Idotea baltica and Gammarus oceanicus) on epiphyte and eelgrass biomass and productivity. Mesograzer species identity strongly influenced epiphyte accumulation and eelgrass growth, where Rissoa was the most efficient mesograzer (per biomass) and Gammarus had the weakest impact. Density-dependent effects varied considerably among species. Both gastropod species reduced epiphyte accumulation in direct proportion to their density, and Littorina had the strongest negative effect on epiphyte biomass. The impact of Idotea seemed to level off to a threshold value and Gammarus had no density-dependent effect on epiphyte accumulation at all. Rissoa and Idotea increased eelgrass productivity in accordance with their effect on epiphyte accumulation, whereas Littorina showed a less positive effect than could be expected by its strong impact on epiphyte biomass. Gammarus had no significant impact on eelgrass growth. Our results show that the different functional traits of superficially similar mesograzers can have important consequences for ecosystem processes in macrophyte systems

Improvements in access to malaria treatment in Tanzania after switch to artemisinin combination therapy and the introduction of accredited drug dispensing outlets - a provider perspective

BACKGROUND\ud \ud To improve access to treatment in the private retail sector a new class of outlets known as accredited drug dispensing outlets (ADDO) was created in Tanzania. Tanzania changed its first-line treatment for malaria from sulphadoxine-pyrimethamine (SP) to artemether-lumefantrine (ALu) in 2007. Subsidized ALu was made available in both health facilities and ADDOs. The effect of these interventions on access to malaria treatment was studied in rural Tanzania.\ud \ud METHODS\ud \ud The study was carried out in the villages of Kilombero and Ulanga Demographic Surveillance System (DSS) and in Ifakara town. Data collection consisted of: 1) yearly censuses of shops selling drugs; 2) collection of monthly data on availability of anti-malarials in public health facilities; and 3) retail audits to measure anti-malarial sales volumes in all public, mission and private outlets. The data were complemented with DSS population data.\ud \ud RESULTS\ud \ud Between 2004 and 2008 access to malaria treatment greatly improved and the number of anti-malarial treatment doses dispensed increased by 78%. Particular improvements were observed in the availability (from 0.24 shops per 1,000 people in 2004 to 0.39 in 2008) and accessibility (from 71% of households within 5 km of a shop in 2004 to 87% in 2008) of drug shops. Despite no improvements in affordability this resulted in an increase of the market share from 49% of anti-malarial sales 2005 to 59% in 2008. The change of treatment policy from SP to ALu led to severe stock-outs of SP in health facilities in the months leading up to the introduction of ALu (only 40% months in stock), but these were compensated by the wide availability of SP in shops. After the introduction of ALu stock levels of the drug were relatively high in public health facilities (over 80% months in stock), but the drug could only be found in 30% of drug shops and in no general shops. This resulted in a low overall utilization of the drug (19% of all anti-malarial sales)\ud \ud CONCLUSIONS\ud \ud The public health and private retail sector are important complementary sources of treatment in rural Tanzania. Ensuring the availability of ALu in the private retail sector is important for its successful uptake

Exploring the short-term and maintained effects of strategic instruction on the writing of 4th grade students: should strategies be focused on the process?

p.1769-1790The principal aim of strategy-focused instruction is to teach students strategies to control their writing processes and achieve quality writing. For this purpose, nine 4th grade Elementary School classes from three diferent schools (N=215) were randomly allocated to two forms of strategy-focused program called cognitive selfregulation instruction (CSRI). The full-CSRI (experimental condition 1, n=72) taught students a strategic approach to set appropriate product goals along with planning strategies. However, in the brief-CSRI (experimental condition 2, n=69), the direct teaching of planning procedures was removed. These two experimental conditions were compared with a control condition (n=74). We used a pre-test/posttest design and we also collected a maintenance writing performance 7 months after the intervention. Writing performance was holistically evaluated through readerbased measures made up of aspects related to structure, coherence, and quality. Only the full-CSRI condition wrote better compare–contrast texts than the control group in both the short term and at the maintenance timepoint. The study discusses the efects of the intervention on each measure and whether or not it is necessary to train process strategiesS

In Vivo Evaluation of Cervical Stiffness Evolution during Induced Ripening Using Shear Wave Elastography, Histology and 2 Photon Excitation Microscopy: Insight from an Animal Model

Prematurity affects 11% of the births and is the main cause of infant mortality. On the opposite case, the failure of induction of parturition in the case of delayed spontaneous birth is associated with fetal suffering. Both conditions are associated with precocious and/or delayed cervical ripening. Quantitative and objective information about the temporal evolution of the cervical ripening may provide a complementary method to identify cases at risk of preterm delivery and to assess the likelihood of successful induction of labour. In this study, the cervical stiffness was measured in vivo in pregnant sheep by using Shear Wave Elastography (SWE). This technique assesses the stiffness of tissue through the measurement of shear waves speed (SWS). In the present study, 9 pregnant ewes were used. Cervical ripening was induced at 127 days of pregnancy (term: 145 days) by dexamethasone injection in 5 animals, while 4 animals were used as control. Elastographic images of the cervix were obtained by two independent operators every 4 hours during 24 hours after injection to monitor the cervical maturation induced by the dexamethasone. Based on the measurements of SWS during vaginal ultrasound examination, the stiffness in the second ring of the cervix was quantified over a circular region of interest of 5 mm diameter. SWS was found to decrease significantly in the first 4–8 hours after dexamethasone compared to controls, which was associated with cervical ripening induced by dexamethasone (from 1.779 m/s ± 0.548 m/s, p < 0.0005, to 1.291 m/s ± 0.516 m/s, p < 0.000). Consequently a drop in the cervical elasticity was quantified too (from 9.5 kPa ± 0.9 kPa, p < 0.0005, to 5.0 kPa ± 0.8 kPa, p < 0.000). Moreover, SWE measurements were highly reproducible between both operators at all times. Cervical ripening induced by dexamethasone was confirmed by the significant increase in maternal plasma Prostaglandin E2 (PGE2), as evidenced by the assay of its metabolite PGEM. Histological analyses and two-photon excitation microscopy, combining both Second Harmonic Generation (SHG) and Two-photon Fluorescence microscopy (2PF) contrasts, were used to investigate, at the microscopic scale, the structure of cervical tissue. Results show that both collagen and 2PF-active fibrillar structures could be closely related to the mechanical properties of cervical tissue that are perceptible in elastography. In conclusion, SWE may be a valuable method to objectively quantify the cervical stiffness and as a complementary diagnostic tool for preterm birth and for labour induction success