The 5T mouse multiple myeloma model: absence of c-myc oncogene rearrangement in early transplant generations.

Consistent chromosomal translocations involving the c-myc cellular oncogene and one of the three immunoglobin loci are typical for human Burkitt's lymphoma, induced mouse plasmacytoma (MPC) and spontaneously arising rat immunocytoma (RIC). Another plasma cell malignancy, multiple myeloma (MM), arising spontaneously in the ageing C57BL/KaLwRij mice, was investigated in order to see whether the MM cells contain c-myc abnormalities of the MPC or RIC type. Rearrangement of the c-myc oncogene was found in the bone marrow cells only in 5T2 MM transplantation line in a mouse of the 24th generation and in none of the seven other MM of the 5T series which were of earlier generations. Since the mouse 5T MM resembles the human MM very closely, including the absence of consistent structural c-myc oncogene abnormalities, it can serve as a useful experimental model for studies on the aetiopathogenesis of this disease

Duloxetine in OsteoArthritis (DOA) study: study protocol of a pragmatic open-label randomised controlled trial assessing the effect of preoperative pain treatment on postoperative outcome after total hip or knee arthroplasty

Introduction Residual pain is a major factor in patient dissatisfaction following total hip arthroplasty or total knee arthroplasty (THA/TKA). The proportion of patients with unfavourable long-term residual pain is high, ranging from 7% to 34%. There are studies indicating that a preoperative degree of central sensitisation (CS) is associated with poorer postoperative outcomes and residual pain. It is thus hypothesised that preoperative treatment of CS could enhance postoperative outcomes. Duloxetine has been shown to be effective for several chronic pain syndromes, including knee osteoarthritis (OA), in which CS is most likely one of the underlying pain mechanisms. This study aims to evaluate the postoperative effects of preoperative screening and targeted duloxetine treatment of CS on residual pain compared with care-as-usual. Methods and analysis This multicentre, pragmatic, prospective, open-label, randomised controlled trial includes patients with idiopathic hip/knee OA who are on a waiting list for primary THA/TKA. Patients at risk for CS will be randomly allocated to the preoperative duloxetine treatment programme group or the care-as-usual control group. The primary end point is the degree of postoperative pain 6 months after THA/TKA. Secondary end points at multiple time points up to 12 months postoperatively are: pain, neuropathic pain-like symptoms, (pain) sensitisation, pain catastrophising, joint-associated problems, physical activity, health-related quality of life, depressive and anxiety symptoms, and perceived improvement. Data will be analysed on an intention-to-treat basis. Ethics and dissemination The study is approved by the local Medical Ethics Committee (METc 2014/087) and will be conducted according to the principles of the Declaration of Helsinki (64th, 2013) and the Good Clinical Practice standard (GCP), and in compliance with the Medical Research Involving Human Subjects Act (WMO)

Management of prolonged first stage of labour in a low-resource setting: lessons learnt from rural Malawi

Background Caesarean sections without medical indication cause substantial maternal and perinatal ill-health, particularly in low-income countries where surgery is often less safe. In presence of adequate labour monitoring and by appropriate use of evidence-based interventions for prolonged first stage of labour, unnecessary caesarean sections can be avoided. We aim to describe the incidence of prolonged first stage of labour and the use of amniotomy and augmentation with oxytocin in a low-resource setting in Malawi. Methods Retrospective analysis of medical records and partographs of all women who gave birth in 2015 and 2016 in a rural mission hospital in Malawi. Primary outcomes were incidence of prolonged first stage of labour based on partograph tracings, caesarean section indications and utilization of amniotomy and oxytocin augmentation. Results Out of 3246 women who gave birth in the study period, 178 (5.2%) crossed the action line in the first stage of labour, of whom 21 (11.8%) received oxytocin to augment labour. In total, 645 women gave birth by caesarean section, of whom 241 (37.4%) with an indication 'prolonged first stage of labour'. Only 113 (46.9%) of them crossed the action line and in 71/241 (29.5%) membranes were still intact at the start of caesarean section. Excluding the 60 women with prior caesarean sections, 14/181 (7.7%) received oxytocin prior to caesarean section for augmentation of labour. Conclusion The diagnosis prolonged first stage of labour was often made without being evident from labour tracings and two basic obstetric interventions to prevent caesarean section, amniotomy and labour augmentation with oxytocin, were underused.Perioperative Medicine: Efficacy, Safety and Outcome (Anesthesiology/Intensive Care

Compensating errors in inversions for subglacial bed roughness: same steady state, different dynamic response

Subglacial bed roughness is one of the main factors controlling the rate of future Antarctic ice-sheet retreat and also one of the most uncertain. A common technique to constrain the bed roughness using ice-sheet models is basal inversion, tuning the roughness to reproduce the observed present-day ice-sheet geometry and/or surface velocity. However, many other factors affecting ice-sheet evolution, such as the englacial temperature and viscosity, the surface and basal mass balance, and the subglacial topography, also contain substantial uncertainties. Using a basal inversion technique intrinsically causes any errors in these other quantities to lead to compensating errors in the inverted bed roughness. Using a set of idealised-geometry experiments, we quantify these compensating errors and investigate their effect on the dynamic response of the ice sheet to a prescribed forcing. We find that relatively small errors in ice viscosity and subglacial topography require substantial compensating errors in the bed roughness in order to produce the same steady-state ice sheet, obscuring the realistic spatial variability in the bed roughness. When subjected to a retreat-inducing forcing, we find that these different parameter combinations, which per definition of the inversion procedure result in the same steady-state geometry, lead to a rate of ice volume loss that can differ by as much as a factor of 2. This implies that ice-sheet models that use basal inversion to initialise their model state can still display a substantial model bias despite having an initial state which is close to the observations.</p

Glucocorticoid receptor mRNA levels are selectively decreased in neutrophils of children with sepsis

Objective: Corticosteroids are used in sepsis treatment to benefit outcome. However, discussion remains on which patients will benefit from treatment. Inter-individual variations in cortisol sensitivity, mediated through the glucocorticoid receptor, might play a role in the observed differences. Our aim was to study changes in mRNA levels of three glucocorticoid receptor splice variants in neutrophils of children with sepsis. Patients and design: Twenty-three children admitted to the pediatric intensive care unit with sepsis or septic shock were included. Neutrophils were isolated at days 0, 3 and 7, and after recovery (>3 months). mRNA levels of the glucocorticoid receptor splice variants GR-α (determining most of the cortisol effect), GR-P (increasing GR-α effect) and GR-β (inhibitor of GR-α) were measured quantitatively. Main results: Neutrophils from sepsis patients showed decreased levels of glucocorticoid receptor mRNA of the GR-α and GR-P splice variants on day 0 compared to after recovery. GR-α and GR-P mRNA levels showed a gradual recovery on days 3 and 7 and normalized after recovery. GR-β mRNA levels did not change significantly during sepsis. GR expression was negatively correlated to interleukin-6 (a measure of disease severity, r = -0.60, P = 0.009). Conclusions: Children with sepsis or septic shock showed a transient depression of glucocorticoid receptor mRNA in their neutrophils. This feature may represent a tissue-specific adaptation during sepsis leading to increased cortisol resistance of neutrophils. Our study adds to understanding the mechanism of cortisol sensitivity in immune cells. Future treatment strategies, aiming at timing and tissue specific regulation of glucocorticoids, might benefit patients with sepsis or septic shock

A Case Study in the Future Challenges in Electricity Grid Infrastructure

The generation by renewables and the loading by electrical vehicle charging imposes severe challenges in the redesign of today’s power supply systems. Indeed, accommodating these emerging power sources and sinks requires traditional power systems to evolve from rigid centralized unidirectional architectures to intelligent decentralized entities allowing a bidirectional power flow. In the case study proposed by ENDINET, we investigate how the penetration of solar panels and of battery charging stations on large scale affects the voltage quality and loss level in a distribution network servicing a residential area in Eindhoven, NL. In our case study we take the average household load during summer and winter into account and consider both a radial and meshed topology of the network. Our study results for both topologies considered in a quantification of the levels of penetration and a strategy for electrical vehicle loading strategy that meet the voltage and loss requirements in the network

Facilitating livelihoods diversification through flood-based land restoration in pastoral systems of Afar, Ethiopia

The pastoral systems of Eastern Africa have been affected by the alternated incidence of recurrent drought and flood for the last decades, aggravating poverty and local conflicts. We have introduced an innovation to convert floods to productive use using water spreading weirs (WSW) as an entry point to capture and spread the torrential flood emerging in the neighbouring highlands into rangelands and crop fields of low-lying pastoral systems in Afar, Ethiopia. The productivity and landscape feature have changed from an abandoned field to a productive landscape within 3 years of intervention. The flood patterns and sediment loads created at least four different crop management zones and productivity levels. Based on moisture and nutrient regimes, we developed land suitability maps for integrating crops and forages fitting to specific niches. The outcome was a fast recovery of landscapes, with 150% biomass yield increment, increased access to dry season feed and food. These positive outcomes could be attributed to the proper design of weirs, joint planning and execution between pastoralists, researchers and development agents, identification and availing best-fitting varieties for each management zone and developing simple GIS-based parcel level maps to guide development agents and pastoralists. The major ‘agents’ were community leaders (‘Kedoh Abbobati’) who keenly debated potential benefits and drawbacks of innovations, enforced customary rules and byelaw and suggested changes in approaches and choices of interventions. In general, an innovation system approach helped to create local confidence, attract attention of government institutions and helped local actors to identify investment areas, develop implementation strategies to increase productivity, define changes as it occurs and minimize conflicts between competing communities. However, the risk of de facto use of a plot of communal land translating into long-term occupation and ownership may be impacting a communal territory and social cohesion that was subject to other collective choice customary rules

Cost-effectiveness of stereotactic large-core needle biopsy for nonpalpable breast lesions compared to open-breast biopsy

This paper demonstrates that the introduction of large-core needle biopsy (LCNB) replacing needle-localised breast biopsy (NLBB) for nonpalpable (screen-detected) breast lesions could result in substantial cost savings at the expense of a possible slight increase in breast cancer mortality. The cost-effectiveness of LCNB and NLBB was estimated using a microsimulation model. The sensitivity of LCNB (0.97) and resource use and costs of LCNB and NLBB were derived from a multicentre consecutive cohort study among 973 women who consented in getting LCNB and NLBB, if LCNB was negative. Sensitivity analyses were performed. Replacing NLBB with LCNB would result in approximately six more breast cancer deaths per year (in a target population of 2.1 million women), or in 1000 extra life-years lost from breast cancer (effect over 100 years). The total costs of management of breast cancer (3% discounted) are estimated at £4676 million with NLBB; introducing LCNB would save £13 million. The incremental cost-effectiveness ratio of continued NLBB vs LCNB would be £12 482 per additional life-year gained (3% discounted); incremental costs range from £-21 687 (low threshold for breast biopsy) to £74 378 (high sensitivity of LCNB)

Reduction of Severe Acute Maternal Morbidity and Maternal Mortality in Thyolo District, Malawi: The Impact of Obstetric Audit

BACKGROUND: Critical incident audit and feedback are recommended interventions to improve the quality of obstetric care. To evaluate the effect of audit at district level in Thyolo, Malawi, we assessed the incidence of facility-based severe maternal complications (severe acute maternal morbidity (SAMM) and maternal mortality) during two years of audit and feedback. METHODOLOGY/PRINCIPAL FINDINGS: Between September 2007 and September 2009, we included all cases of maternal mortality and SAMM that occurred in Thyolo District Hospital, the main referral facility in the area, using validated disease-specific criteria. During two- to three-weekly audit sessions, health workers and managers identified substandard care factors. Resulting recommendations were implemented and followed up. Feedback was given during subsequent sessions. A linear regression analysis was performed on facility-based severe maternal complications. During the two-year study period, 386 women were included: 46 died and 340 sustained SAMM, giving a case fatality rate of 11.9%. Forty-five cases out of the 386 inclusions were audited in plenary with hospital staff. There was a reduction of 3.1 women with severe maternal complications per 1000 deliveries in the district health facilities, from 13.5 per 1000 deliveries in the beginning to 10.4 per 1000 deliveries at the end of the study period. The incidence of uterine rupture and major obstetric hemorrhage reduced considerably (from 3.5 to 0.2 and from 5.9 to 2.6 per 1000 facility deliveries respectively). CONCLUSIONS: Our findings indicate that audit and feedback have the potential to reduce serious maternal complications including maternal mortality. Complications like major hemorrhage and uterine rupture that require relatively straightforward intrapartum emergency management are easier to reduce than those which require uptake of improved antenatal care (eclampsia) or timely intravenous medication or HIV-treatment (peripartum infections)

A Case Study in the Future Challenges in Electricity Grid Infrastructure

The generation by renewables and the loading by electrical vehicle charging imposes severe challenges in the redesign of today’s power supply systems. Indeed, accommodating these emerging power sources and sinks requires traditional power systems to evolve from rigid centralized unidirectional architectures to intelligent decentralized entities allowing a bidirectional power flow. In the case study proposed by ENDINET, we investigate how the penetration of solar panels and of battery charging stations on large scale affects the voltage quality and loss level in a distribution network servicing a residential area in Eindhoven, NL. In our case study we take the average household load during summer and winter into account and consider both a radial and meshed topology of the network. Our study results for both topologies considered in a quantification of the levels of penetration and a strategy for electrical vehicle loading strategy that meet the voltage and loss requirements in the network