How to improve drug dosing for patients with renal impairment in primary care - a cluster-randomized controlled trial

Background: Patients with chronic kidney disease (CKD) are at increased risk for inappropriate or potentially harmful prescribing. The aim of this study was to examine whether a multifaceted intervention including the use of a software programme for the estimation of creatinine clearance and recommendation of individual dosage requirements may improve correct dosage adjustment of relevant medications for patients with CKD in primary care. Methods: A cluster-randomized controlled trial was conducted between January and December 2007 in small primary care practices in Germany. Practices were randomly allocated to intervention or control groups. In each practice, we included patients with known CKD and elderly patients (>=70 years) suffering from hypertension. The practices in the intervention group received interactive training and were provided a software programme to assist with individual dose adjustment. The control group performed usual care. Data were collected at baseline and at 6 months. The outcome measures, analyzed across individual patients, included prescriptions exceeding recommended maximum daily doses, with the primary outcome being prescriptions exceeding recommended standard daily doses by 30% or more. Results: Data from 44 general practitioners and 404 patients are included. The intervention was effective in reducing prescriptions exceeding the maximum daily dose per patients, with a trend in reducing prescriptions exceeding the standard daily dose by more than 30%. Conclusions: A multifaceted intervention including the use of a software program effectively reduced inappropriately high doses of renally excreted medications in patients with CKD in the setting of small primary care practices

Extending the host range of Listeria monocytogenes by rational protein design

SummaryIn causing disease, pathogens outmaneuver host defenses through a dedicated arsenal of virulence determinants that specifically bind or modify individual host molecules. This dedication limits the intruder to a defined range of hosts. Newly emerging diseases mostly involve existing pathogens whose arsenal has been altered to allow them to infect previously inaccessible hosts. We have emulated this chance occurrence by extending the host range accessible to the human pathogen Listeria monocytogenes by the intestinal route to include the mouse. Analyzing the recognition complex of the listerial invasion protein InlA and its human receptor E-cadherin, we postulated and verified amino acid substitutions in InlA to increase its affinity for E-cadherin. Two single substitutions increase binding affinity by four orders of magnitude and extend binding specificity to include formerly incompatible murine E-cadherin. By rationally adapting a single protein, we thus create a versatile murine model of human listeriosis

Trehalose promotes atherosclerosis regression in female mice

IntroductionAtherosclerosis is a chronic inflammatory disease caused by the deposition of lipids within the artery wall. During atherogenesis, efficient autophagy is needed to facilitate efferocytosis and cholesterol efflux, limit inflammation and lipid droplet buildup, and eliminate defective mitochondria and protein aggregates. Central to the regulation of autophagy is the transcription factor EB (TFEB), which coordinates the expression of lysosomal biogenesis and autophagy genes. In recent years, trehalose has been shown to promote TFEB activation and protect against atherogenesis. Here, we sought to investigate the role of autophagy activation during atherosclerosis regression.Methods and resultsAtherosclerosis was established in C57BL/6N mice by injecting AAV-PCSK9 and 16 weeks of Western diet feeding, followed by switching to a chow diet to induce atherosclerosis regression. During the regression period, mice were either injected with trehalose concomitant with trehalose supplementation in their drinking water or injected with saline for 6 weeks. Female mice receiving trehalose had reduced atherosclerosis burden, as evidenced by reduced plaque lipid content, macrophage numbers and IL-1β content in parallel with increased plaque collagen deposition, which was not observed in their male counterparts. In addition, trehalose-treated female mice had lower levels of circulating leukocytes, including inflammatory monocytes and CD4+ T cells. Lastly, we found that autophagy flux in male mice was basally higher than in female mice during atherosclerosis progression.ConclusionsOur data demonstrate a sex-specific effect of trehalose in atherosclerosis regression, whereby trehalose reduced lipid content, inflammation, and increased collagen content in female mice but not in male mice. Furthermore, we discovered inherent differences in the autophagy flux capacities between the sexes: female mice exhibited lower plaque autophagy than males, which rendered the female mice more responsive to atherosclerosis regression. Our work highlights the importance of understanding sex differences in atherosclerosis to personalize the development of future therapies to treat cardiovascular diseases

Flat H Frangible Joint Evolution

Space vehicle staging and separation events require pyrotechnic devices. They are single-use mechanisms that cannot be tested, nor can failure-tolerant performance be demonstrated in actual flight articles prior to flight use. This necessitates the implementation of a robust design and test approach coupled with a fully redundant, failure-tolerant explosive mechanism to ensure that the system functions even in the event of a single failure. Historically, NASA has followed the single failure-tolerant (SFT) design philosophy for all human-rated spacecraft, including the Space Shuttle Program. Following the end of this program, aerospace companies proposed building the next generation human-rated vehicles with off-the-shelf, non-redundant, zero-failure-tolerant (ZFT) separation systems. Currently, spacecraft and launch vehicle providers for both the Orion and Commercial Crew Programs (CCPs) plan to deviate from the heritage safety approach and NASA's SFT human rating requirements. Both programs' partners have base-lined ZFT frangible joints for vehicle staging and fairing separation. These joints are commercially available from pyrotechnic vendors. Non-human-rated missions have flown them numerous times. The joints are relatively easy to integrate structurally within the spacecraft. In addition, the separation event is debris free, and the resultant pyro shock is lower than that of other design solutions. It is, however, a serious deficiency to lack failure tolerance. When used for critical applications on human-rated vehicles, a single failure could potentially lead to loss of crew (LOC) or loss of mission (LOM)). The Engineering and Safety & Mission Assurance directorates within the NASA Johnson Space Center took action to address this safety issue by initiating a project to develop a fully redundant, SFT frangible joint design, known as the Flat H. Critical to the ability to retrofit on launch vehicles being developed, the SFT mechanisms must fit within the same three-dimensional envelope as current designs as well as meet structural loads requirements. There is increased mass associated with the redundant design, and the goal is to minimize the weight impact as much as possible. These requirements presented significant challenges, both technically and financially; these challenges will be explored in this paper. Perhaps greater than the technical issues confronted during this design process, were the financial considerations. These were a significant part of the story of this design and development plan. Insufficient financial and labor resources were formidable barriers to completing this project. Nevertheless, JSC personnel successfully conducted several test series at JSC with very useful results. The many lessons learned drove design improvements, performance efficiency, and increased functional reliability. This paper examines the significant technical and financial challenges that these requirements posed to the project team. It discusses the evolution of the SFT frangible joint design, including optimization, testing, and successful partnering of the Johnson Space Center (JSC) engineering and JSC safety organizations, to enhance the flight safety margin for America's next generation of human-rated space vehicles

Flat H Redundant Frangible Joint

No abstract availabl

A 1300-year microfaunal record from the Beaufort Sea shelf indicates exceptional climate-related environmental changes over the last two centuries

<p>The environments of Arctic Ocean nearshore areas experience high intra- and inter-annual variability, making it difficult to evaluate the impact of anthropogenic warming. However, a sediment record from the southern Canadian Beaufort Sea allowed us to reconstruct the impacts of climate and environmental changes over the last 1300 years along the northern Yukon coast, Canada. The coring site (PG2303; 69.513°N, 138.895°W; water depth 32 m) is located in the Herschel Basin, where high sedimentation rates (0.1–0.5 cm a−1) allowed analyses at sub-centennial to decadal resolutions. Benthic foraminiferal, ostracod, and tintinnid assemblages, as well as the stable isotope composition of the foraminifera Elphidium clavatum and Cassidulina reniforme were used as paleoclimatic and ecological indicators, while the age model was based on the combined radiometric data of 14C, 210Pb and 137Cs. From ca 700 to 1050 CE, our data suggest penetration of offshore shelf-break waters inferred by the dominance of C. reniforme followed by the relatively abundant Triloculina trihedra in the foraminiferal assemblages as both species are associated with stable saline conditions. Afterwards, the occurrence of ostracods Kotoracythere arctoborealis and Normanicythere leioderma suggests influx of Pacific-sourced waters until ca. 1150 CE. From ∼1150–1650 CE, persistent frigid waters, limited sediment supply, and low abundances of microfossils suggest cold conditions with pervasive annual sea-ice cover that may have restricted upwelling of oceanic waters. After ∼1800 CE, the co-occurrence of Tintinnopsis fimbriata and bacterial/complex organic carbon feeder foraminifera (Quinqueloculina stalkeri, Textularia earlandi and Stetsonia horvathi), suggest an increased influence of freshwater rich in particulate organic matter, which may be related to the spreading of the Mackenzie River plume and/or increased coastal permafrost erosion during longer ice-free seasons. Based on these proxy data, the shift at ∼1800 CE marks the onset of regional warming, which further intensified after ∼1955 CE, likely in response to the anthropogenic forcing.</p&gt

Retinofugal projections in the lepidosirenid lungfishes

Autoradiographic and silver methods indicate that the African and South American lungfishes, Protopterus and Lepidosiren , lack ipsilateral retinal projections. Contralaterally, the retina projects to the preoptic nucleus of the hypothalamus, to four discrete areas located in the lateral neuropil of the thalamus, to a superficial pretectal neuropil, to the upper half of the tectal neuropil, and to a laterally situated basal optic neuropil located in the rostral tegmentum. The overall pattern of the primary retinofugal projections is markedly similar to that of amphibians which suggests that lungfishes may be more closely related to amphibians than to actinopterygian fishes. Neotenic trends in both lepidosirenid lungfishes and urodeles may be expressions of parallelism, hence Latimeria and Neoceratodus must be examined to resolve this phylogenetic problem. A 300-fold range in the size of the eye, indicated by the number of ganglion cells present, occurs among lungfishes, salamanders and frogs. This variation may have implications for recognizing the morphological expression of selection operating on the visual systems of lepidosirenids and amphibians.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50000/1/901740402_ftp.pd

Water-loss dehydration and aging

This review defines water-loss and salt-loss dehydration. For older people serum osmolality appears the most appropriate gold standard for diagnosis of water-loss dehydration, but clear signs of early dehydration have not been developed. In older adults, lower muscle mass, reduced kidney function, physical and cognitive disabilities, blunted thirst, and polypharmacy all increase dehydration risk. Cross-sectional studies suggest a water-loss dehydration prevalence of 20-30% in this population. Water-loss dehydration is associated with higher mortality, morbidity and disability in older people, but evidence is still needed that this relationship is causal. There are a variety of ways we may be able to help older people reduce their risk of dehydration by recognising that they are not drinking enough, and being helped to drink more. Strategies to increase fluid intake in residential care homes include identifying and overcoming individual and institutional barriers to drinking, such as being worried about not reaching the toilet in time, physical inability to make or to reach drinks, and reduced social drinking and drinking pleasure. Research needs are discussed, some of which will be addressed by the FP7-funded NU-AGE (New dietary strategies addressing the specific needs of elderly population for a healthy ageing in Europe) trial

Does offering an incentive payment improve recruitment to clinical trials and increase the proportion of socially deprived and elderly participants?

BACKGROUND: Patient recruitment into clinical trials is a major challenge, and the elderly, socially deprived and those with multiple comorbidities are often underrepresented. The idea of paying patients an incentive to participate in research is controversial, and evidence is needed to evaluate this as a recruitment strategy. METHOD: In this study, we sought to assess the impact on clinical trial recruitment of a £100 incentive payment and whether the offer of this payment attracted more elderly and socially deprived patients. A total of 1,015 potential patients for five clinical trials (SCOT, FAST and PATHWAY 1, 2 and 3) were randomised to receive either a standard trial invitation letter or a trial invitation letter containing an incentive offer of £100. To receive payment, patients had to attend a screening visit and consent to be screened (that is, sign a consent form). To maintain equality, eventually all patients who signed a consent form were paid £100. RESULTS: The £100 incentive offer increased positive response to the first invitation letter from 24.7% to 31.6%, an increase of 6.9% (P < 0.05). The incentive offer increased the number of patients signing a consent form by 5.1% (P < 0.05). The mean age of patients who responded positively to the invitation letter was 66.5 ± 8.7 years, whereas those who responded negatively were significantly older, with a mean age of 68.9 ± 9.0 years. The incentive offer did not influence the age of patients responding. The incentive offer did not improve response in the most socially deprived areas, and the response from patients in these areas was significantly lower overall. CONCLUSION: A £100 incentive payment offer led to small but significant improvements in both patient response to a clinical trial invitation letter and in the number of patients who consented to be screened. The incentive payment did not attract elderly or more socially deprived patients. TRIAL REGISTRATIONS: Standard care versus Celecoxib Outcome Trial (SCOT) (ClinicalTrials.gov identifier: NCT00447759). Febuxostat versus Allopurinol Streamlined Trial (FAST) (EudraCT number: 2011-001883-23). Prevention and Treatment of Hypertension with Algorithm Guided Therapy (British Heart Foundation funded trials) (PATHWAY) 1: Monotherapy versus dual therapy for initiating treatment (EudraCT number: 2008-007749-29). PATHWAY 2: Optimal treatment of drug-resistant hypertension (EudraCT number: 2008-007149-30). PATHWAY 3: Comparison of single and combination diuretics in low-renin hypertension (EudraCT number: 2009-010068-41). ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13063-015-0582-8) contains supplementary material, which is available to authorized users