Disease progression in Plasmodium knowlesi malaria is linked to variation in invasion gene family members.

Emerging pathogens undermine initiatives to control the global health impact of infectious diseases. Zoonotic malaria is no exception. Plasmodium knowlesi, a malaria parasite of Southeast Asian macaques, has entered the human population. P. knowlesi, like Plasmodium falciparum, can reach high parasitaemia in human infections, and the World Health Organization guidelines for severe malaria list hyperparasitaemia among the measures of severe malaria in both infections. Not all patients with P. knowlesi infections develop hyperparasitaemia, and it is important to determine why. Between isolate variability in erythrocyte invasion, efficiency seems key. Here we investigate the idea that particular alleles of two P. knowlesi erythrocyte invasion genes, P. knowlesi normocyte binding protein Pknbpxa and Pknbpxb, influence parasitaemia and human disease progression. Pknbpxa and Pknbpxb reference DNA sequences were generated from five geographically and temporally distinct P. knowlesi patient isolates. Polymorphic regions of each gene (approximately 800 bp) were identified by haplotyping 147 patient isolates at each locus. Parasitaemia in the study cohort was associated with markers of disease severity including liver and renal dysfunction, haemoglobin, platelets and lactate, (r = ≥ 0.34, p =  <0.0001 for all). Seventy-five and 51 Pknbpxa and Pknbpxb haplotypes were resolved in 138 (94%) and 134 (92%) patient isolates respectively. The haplotypes formed twelve Pknbpxa and two Pknbpxb allelic groups. Patients infected with parasites with particular Pknbpxa and Pknbpxb alleles within the groups had significantly higher parasitaemia and other markers of disease severity. Our study strongly suggests that P. knowlesi invasion gene variants contribute to parasite virulence. We focused on two invasion genes, and we anticipate that additional virulent loci will be identified in pathogen genome-wide studies. The multiple sustained entries of this diverse pathogen into the human population must give cause for concern to malaria elimination strategists in the Southeast Asian region

Survey of pickup ion signatures in the vicinity of Titan using CAPS/IMS

Pickup ion detection at Titan is challenging because ion cyclotron waves are rarely detected in the vicinity of the moon. In this work, signatures left by freshly produced pickup heavy ions (m/q ∼ 16 to m/q ∼ 28) as detected in the plasma data by the Cassini Plasma Spectrometer/Ion Mass Spectrometer (CAPS/IMS) instrument on board Cassini are analyzed. In order to discern whether these correspond to ions of exospheric origin, one of the flybys during which the reported signatures were observed is investigated in detail. For this purpose, ion composition data from time-of-flight measurements and test particle simulations to constrain the ions' origin are used. After being validated, the detection method is applied to all the flybys for which the CAPS/IMS instrument gathered valid data, constraining the region around the moon where the signatures are observed. The results reveal an escape region located in the anti-Saturn direction as expected from the nominal corotation electric field direction. These findings provide new constraints for the area of freshly produced pickup ion escape, giving an approximate escape rate of inline image ions· s−1

Plasmodium knowlesi Genome Sequences from Clinical Isolates Reveal Extensive Genomic Dimorphism.

Plasmodium knowlesi is a newly described zoonosis that causes malaria in the human population that can be severe and fatal. The study of P. knowlesi parasites from human clinical isolates is relatively new and, in order to obtain maximum information from patient sample collections, we explored the possibility of generating P. knowlesi genome sequences from archived clinical isolates. Our patient sample collection consisted of frozen whole blood samples that contained excessive human DNA contamination and, in that form, were not suitable for parasite genome sequencing. We developed a method to reduce the amount of human DNA in the thawed blood samples in preparation for high throughput parasite genome sequencing using Illumina HiSeq and MiSeq sequencing platforms. Seven of fifteen samples processed had sufficiently pure P. knowlesi DNA for whole genome sequencing. The reads were mapped to the P. knowlesi H strain reference genome and an average mapping of 90% was obtained. Genes with low coverage were removed leaving 4623 genes for subsequent analyses. Previously we identified a DNA sequence dimorphism on a small fragment of the P. knowlesi normocyte binding protein xa gene on chromosome 14. We used the genome data to assemble full-length Pknbpxa sequences and discovered that the dimorphism extended along the gene. An in-house algorithm was developed to detect SNP sites co-associating with the dimorphism. More than half of the P. knowlesi genome was dimorphic, involving genes on all chromosomes and suggesting that two distinct types of P. knowlesi infect the human population in Sarawak, Malaysian Borneo. We use P. knowlesi clinical samples to demonstrate that Plasmodium DNA from archived patient samples can produce high quality genome data. We show that analyses, of even small numbers of difficult clinical malaria isolates, can generate comprehensive genomic information that will improve our understanding of malaria parasite diversity and pathobiology

Coronary-artery bypass surgery in patients with ischemic cardiomyopathy

BACKGROUND The survival benefit of a strategy of coronary-artery bypass grafting (CABG) added to guideline-directed medical therapy, as compared with medical therapy alone, in patients with coronary artery disease, heart failure, and severe left ventricular systolic dysfunction remains unclear. METHODS From July 2002 to May 2007, a total of 1212 patients with an ejection fraction of 35% or less and coronary artery disease amenable to CABG were randomly assigned to undergo CABG plus medical therapy (CABG group, 610 patients) or medical therapy alone (medical-therapy group, 602 patients). The primary outcome was death from any cause. Major secondary outcomes included death from cardiovascular causes and death from any cause or hospitalization for cardiovascular causes. The median duration of follow-up, including the current extended-follow-up study, was 9.8 years. RESULTS A primary outcome event occurred in 359 patients (58.9%) in the CABG group and in 398 patients (66.1%) in the medical-therapy group (hazard ratio with CABG vs. medical therapy, 0.84; 95% confidence interval [CI], 0.73 to 0.97; P=0.02 by log-rank test). A total of 247 patients (40.5%) in the CABG group and 297 patients (49.3%) in the medical-therapy group died from cardiovascular causes (hazard ratio, 0.79; 95% CI, 0.66 to 0.93; P=0.006 by log-rank test). Death from any cause or hospitalization for cardiovascular causes occurred in 467 patients (76.6%) in the CABG group and in 524 patients (87.0%) in the medical-therapy group (hazard ratio, 0.72; 95% CI, 0.64 to 0.82; P&lt;0.001 by log-rank test). CONCLUSIONS In a cohort of patients with ischemic cardiomyopathy, the rates of death from any cause, death from cardiovascular causes, and death from any cause or hospitalization for cardiovascular causes were significantly lower over 10 years among patients who underwent CABG in addition to receiving medical therapy than among those who received medical therapy alone. (Funded by the National Institutes of Health; STICH [and STICHES] ClinicalTrials.gov number, NCT00023595.

Continuity or change in business representation in Britain? An assessment of the Heseltine initiatives of the 1990s

Britain has a fragmented, overlapping, and underresourced system of business representation. Attempts at reform, however, have proved difficult and largely unsuccessful. A coherent and logical system is relevant, in terms of both an effective dialogue between government and business, and the promotion of competitiveness and productivity. Through interviews and archival evidence, I look at how government has attempted to reform business associations. The main focus is the Heseltine initiatives of the 1990s: I outline the various initiatives taken, reveal the extent to which policy represented continuity or change, and consider whether the initiatives were effective. I show that they had a degree of success but that they would have made greater impact if they had been sustained over a longer period of time. A consideration of the historical context, moreover, suggests there may be limits to the role of government intervention in business association reform

A probabilistic analysis of argument cogency

This paper offers a probabilistic treatment of the conditions for argument cogency as endorsed in informal logic: acceptability, relevance, and sufficiency. Treating a natural language argument as a reason-claim-complex, our analysis identifies content features of defeasible argument on which the RSA conditions depend, namely: change in the commitment to the reason, the reason’s sensitivity and selectivity to the claim, one’s prior commitment to the claim, and the contextually determined thresholds of acceptability for reasons and for claims. Results contrast with, and may indeed serve to correct, the informal understanding and applications of the RSA criteria concerning their conceptual dependence, their function as update-thresholds, and their status as obligatory rather than permissive norms, but also show how these formal and informal normative approachs can in fact align

On the Interface Formation Model for Dynamic Triple Lines

This paper revisits the theory of Y. Shikhmurzaev on forming interfaces as a continuum thermodynamical model for dynamic triple lines. We start with the derivation of the balances for mass, momentum, energy and entropy in a three-phase fluid system with full interfacial physics, including a brief review of the relevant transport theorems on interfaces and triple lines. Employing the entropy principle in the form given in [Bothe & Dreyer, Acta Mechanica, doi:10.1007/s00707-014-1275-1] but extended to this more general case, we arrive at the entropy production and perform a linear closure, except for a nonlinear closure for the sorption processes. Specialized to the isothermal case, we obtain a thermodynamically consistent mathematical model for dynamic triple lines and show that the total available energy is a strict Lyapunov function for this system

Preliminary results of a feasibility study of the use of information technology for identification of suspected colorectal cancer in primary care: the CREDIBLE study

This is the final version of the article. Available from Cancer Research UK/Nature Publishing Group via the DOI in this record.BACKGROUND: We report the findings of a feasibility study using information technology to search electronic primary care records and to identify patients with possible colorectal cancer. METHODS: An algorithm to flag up patients meeting National Institute for Health and Care Excellence (NICE) urgent referral criteria for suspected colorectal cancer was developed and incorporated into clinical audit software. This periodically flagged up such patients aged 60 to 79 years. General practitioners (GPs) reviewed flagged-up patients and decided on further clinical management. We report the numbers of patients identified and the numbers that GPs judged to need further review, investigations or referral to secondary care and the final diagnoses. RESULTS: Between January 2012 and March 2014, 19,580 records of patients aged 60 to 79 years were searched in 20 UK general practices, flagging up 809 patients who met urgent referral criteria. The majority of the patients had microcytic anaemia (236 (29%)) or rectal bleeding (205 (25%)). A total of 274 (34%) patients needed further clinical review of their records; 199 (73%) of these were invited for GP consultation, and 116 attended, of whom 42 were referred to secondary care. Colon cancer was diagnosed in 10 out of 809 (1.2%) flagged-up patients and polyps in a further 28 out of 809 (3.5%). CONCLUSIONS: It is technically possible to identify patients with colorectal cancer by searching electronic patient records.We acknowledge the General Practitioners, practice nurses, practice managers and administrative staff who supported this study, our trial co-ordinator Marie Crook, Anthony Ingold who was one of our patient representatives and MSDi for their support in developing the software algorithm. We also acknowledge the support of the National Institute for Health Research Clinical Research Network. This study was funded by the National Awareness and Early Diagnosis Initiative (NAEDI). TM is partly funded by the National Institute for Health Research (NIHR) through the Collaborations for Leadership in Applied Health Research and Care for the West Midlands (CLAHRC-WM) programme

Building social capital through breastfeeding peer support: Insights from an evaluation of a voluntary breastfeeding peer support service in North-West England

Background: Peer support is reported to be a key method to help build social capital in communities. To date there are no studies that describe how this can be achieved through a breastfeeding peer support service. In this paper we present findings from an evaluation of a voluntary model of breastfeeding peer support in North-West England to describe how the service was operationalized and embedded into the community. This study was undertaken from May, 2012 to May, 2013. Methods: Interviews (group or individual) were held with 87 participants: 24 breastfeeding women, 13 peer supporters and 50 health and community professionals. The data contained within 23 monthly monitoring reports (January, 2011 to February 2013) compiled by the voluntary peer support service were also extracted and analysed. Results: Thematic analysis was undertaken using social capital concepts as a theoretical lens. Key findings were identified to resonate with ’bonding’, ‘bridging’ and ‘linking’ forms of social capital. These insights illuminate how the peer support service facilitates ‘bonds’ with its members, and within and between women who access the service; how the service ‘bridges’ with individuals from different interests and backgrounds, and how ‘links’ were forged with those in authority to gain access and reach to women and to promote a breastfeeding culture. Some of the tensions highlighted within the social capital literature were also identified. Conclusions: Horizontal and vertical relationships forged between the peer support service and community members enabled peer support to be embedded into care pathways, helped to promote positive attitudes to breastfeeding and to disseminate knowledge and maximise reach for breastfeeding support across the community. Further effort to engage with those of different ethnic backgrounds and to resolve tensions between peer supporters and health professionals is warranted

Antenatal breast expression in women with diabetes: outcomes from a retrospective cohort study

Background: Women with diabetes are sometimes advised to express breast milk antenatally to prepare for breastfeeding and to store colostrum for infant feeding in preventing or treating hypoglycaemia after the birth. The acceptability, risks and benefits of this practice have not been evaluated. This was aimed to investigate the pattern of antenatal breast expression uptake and its relationship with birth outcomes in women with diabetes. Methods: This was part of a two year retrospective cohort study of pregnant women with diabetes (type 1, 2 and gestational diabetes) who gave birth during 2001–2003 in Derby Hospitals NHS Foundation Trust (n = 94). The information on the practice of antenatal breastfeeding expression and birth outcomes was collected via self-administered questionnaires and by examining maternity records. Results: Thirty-seven percent of women (35/94) recalled that they were advised to express antenatally and 17% did (16/94). The mean gestational age at birth for women who hand-expressed was lower than that for those who did not (mean difference (MD) (95% confidence intervals (CI)): -1.2 (−2.4 to 0.04), p = 0.06). A higher proportion of babies from the antenatal expression group were admitted to special care baby units (SCBU) (MD (95% CI): 21% (−3.9 to 46.3). Conclusions: Less than half the women who stated that they were advised to express, did so. There seems to be an indication that antenatal breast milk expression and lower gestational age at birth are associated. The trend of a higher rate of SCBU admission for babies from the breast milk expression group compared to those who did not express antenatally is of concern. An appropriately-powered randomised controlled trial is needed to determine the safety of this practice and its acceptability to women and health professionals before it can be recommended for implementation in practice. Keywords: Diabetes, Antenatal, Breast milk expression, Retrospective, Gestational age, Cohort, Gestation</p