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Single nucleotide polymorphisms (SNPs) contribute small increases in risk for late-onset Alzheimer's disease (LOAD). LOAD SNPs cluster around genes with similar biological functions (pathways). Polygenic risk scores (PRS) aggregate the effect of SNPs genome-wide. However, this approach has not been widely used for SNPs within specific pathways.
We investigated whether pathway-specific PRS were significant predictors of LOAD case/control status.
We mapped SNPs to genes within 8 pathways implicated in LOAD. For our polygenic analysis, the discovery sample comprised 13,831 LOAD cases and 29,877 controls. LOAD risk alleles for SNPs in our 8 pathways were identified at a P-value threshold of 0.5. Pathway-specific PRS were calculated in a target sample of 3332 cases and 9832 controls. The genetic data were pruned with R2 > 0.2 while retaining the SNPs most significantly associated with AD. We tested whether pathway-specific PRS were associated with LOAD using logistic regression, adjusting for age, sex, country, and principal components. We report the proportion of variance in liability explained by each pathway.
The most strongly associated pathways were the immune response (NSNPs = 9304, = 5.63 × 10−19, R2 = 0.04) and hemostasis (NSNPs = 7832, P = 5.47 × 10−7, R2 = 0.015). Regulation of endocytosis, hematopoietic cell lineage, cholesterol transport, clathrin and protein folding were also significantly associated but accounted for less than 1% of the variance. With APOE excluded, all pathways remained significant except proteasome-ubiquitin activity and protein folding.
Genetic risk for LOAD can be split into contributions from different biological pathways. These offer a means to explore disease mechanisms and to stratify patients.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Breakthrough Listen is a 10-yr initiative to search for signatures of technologies created by extraterrestrial civilisations at radio and optical wavelengths. Here, we detail the digital data recording system deployed for Breakthrough Listen observations at the 64-m aperture CSIRO Parkes Telescope in New South Wales, Australia. The recording system currently implements two modes: a dual-polarisation, 1.125-GHz bandwidth mode for single-beam observations, and a 26-input, 308-MHz bandwidth mode for the 21-cm multibeam receiver. The system is also designed to support a 3-GHz single-beam mode for the forthcoming Parkes ultra-wideband feed. In this paper, we present details of the system architecture, provide an overview of hardware and software, and present initial performance results.
Introduction: Early recognition of sepsis can improve patient outcomes yet recognition by paramedics is poor and research evaluating the use of prehospital screening tools is limited. Our objective was to evaluate the predictive validity of the Regional Paramedic Program for Eastern Ontario (RPPEO) prehospital sepsis notification tool to identify patients with sepsis and to describe and compare the characteristics of patients with an emergency department (ED) diagnosis of sepsis that are transported by paramedics. The RPPEO prehospital sepsis notification tool is comprised of 3 criteria: current infection, fever &/or history of fever and 2 or more signs of hypoperfusion (eg. SBP<90, HR 100, RR24, altered LOA). Methods: We performed a review of ambulance call records and in-hospital records over two 5-month periods between November 2014 February 2016. We enrolled a convenience sample of patients, assessed by primary and advanced care paramedics (ACPs), with a documented history of fever &/or documented fever of 38.3°C (101°F) that were transported to hospital. In-hospital management and outcomes were obtained and descriptive, t-tests, and chi-square analyses performed where appropriate. The RPPEO prehospital sepsis notification tool was compared to an ED diagnosis of sepsis. The predictive validity of the RPPEO tool was calculated (sensitivity, specificity, NPV, PPV). Results: 236 adult patients met the inclusion criteria with the following characteristics: mean age 65.2 yrs [range 18-101], male 48.7%, history of sepsis 2.1%, on antibiotics 23.3%, lowest mean systolic BP 125.9, treated by ACP 58.9%, prehospital temperature documented 32.6%. 34 (14.4%) had an ED diagnosis of sepsis. Patients with an ED diagnosis of sepsis, compared to those that did not, had a lower prehospital systolic BP (114.9 vs 127.8, p=0.003) and were more likely to have a prehospital shock index >1 (50.0% vs 21.4%, p=0.001). 44 (18.6%) patients met the RPPEO sepsis notification tool and of these, 27.3% (12/44) had an ED diagnosis of sepsis. We calculated the following predictive values of the RPPEO tool: sensitivity 35.3%, specificity 84.2%, NPV 88.5%, PPV 27.3%. Conclusion: The RPPEO prehospital sepsis notification tool demonstrated modest diagnostic accuracy. Further research is needed to improve accuracy and evaluate the impact on patient outcomes.
Pelvic inflammatory disease (PID) and more specifically salpingitis (visually confirmed inflammation) is the primary cause of tubal factor infertility and is an important risk factor for ectopic pregnancy. The risk of these outcomes increases following repeated episodes of PID. We developed a homogenous discrete-time Markov model for the distribution of PID history in the UK. We used a Bayesian framework to fully propagate parameter uncertainty into the model outputs. We estimated the model parameters from routine data, prospective studies, and other sources. We estimated that for women aged 35–44 years, 33·6% and 16·1% have experienced at least one episode of PID and salpingitis, respectively (diagnosed or not) and 10·7% have experienced one salpingitis and no further PID episodes, 3·7% one salpingitis and one further PID episode, and 1·7% one salpingitis and ⩾2 further PID episodes. Results are consistent with numerous external data sources, but not all. Studies of the proportion of PID that is diagnosed, and the proportion of PIDs that are salpingitis together with the severity distribution in different diagnostic settings and of overlap between routine data sources of PID would be valuable.
The Darwin region in northern Australia has experienced rapid population growth in recent years, and with it, an increased incidence of melioidosis. Previous studies in Darwin have associated the environmental presence of Burkholderia pseudomallei, the causative agent of melioidosis, with anthropogenic land usage and proximity to animals. In our study, we estimated the occurrence of B. pseudomallei and Burkholderia spp. relatives in faecal matter of wildlife, livestock and domestic animals in the Darwin region. A total of 357 faecal samples were collected and bacteria isolated through culture and direct DNA extraction after enrichment in selective media. Identification of B. pseudomallei, B. ubonensis, and other Burkholderia spp. was carried out using TTS1, Bu550, and recA BUR3–BUR4 quantitative PCR assays, respectively. B. pseudomallei was detected in seven faecal samples from wallabies and a chicken. B. cepacia complex spp. and Pandoraea spp. were cultured from wallaby faecal samples, and B. cenocepacia and B. cepacia were also isolated from livestock animals. Various bacteria isolated in this study represent opportunistic human pathogens, raising the possibility that faecal shedding contributes to the expanding geographical distribution of not just B. pseudomallei but other Burkholderiaceae that can cause human disease.
Melioidosis is an infectious disease caused by Burkholderia pseudomallei, a bacterium endemic in Southeast Asia and northern Australia. In New Caledonia, sporadic cases were first described in 2005; since then, more cases have been identified. To improve our understanding of melioidosis epidemiology in New Caledonia, we compared the local cases and B. pseudomallei isolates with those from endemic areas. Nineteen melioidosis cases have been diagnosed in New Caledonia since 1999, mostly severe and with frequent bacteraemia, leading to three (16%) fatalities. All but one occurred in the North Province. Besides sporadic cases caused by non-clonal strains, we also identified a hotspot of transmission related to a clonal group of B. pseudomallei that is phylogenetically related to Australian strains.
High-redshift quasars are unique probes of the evolution of supermassive black holes and the intergalactic medium at the end of the epoch of reionization. We present the optical spectra of eight new z ~ 6 quasars selected from the Panoramic Survey Telescope & Rapid Response System 1 (Pan-STARRS1). Details of the selection strategy can be found in Bañados et al. (2014). With this work we increase the number of known quasars at z < 5.7 by more than 10%. The quasars discovered here span a large range of luminosities (19.6 ≤ zP1 ≤ 21.2) and are remarkably heterogeneous in their spectral features: half of them show bright emission lines whereas the other half show weak or no Lyα emission line. We find a larger fraction of weak–line emission quasars than in lower redshift studies, although still based on low number statistics, this may imply that the quasar population could be more diverse than previously thought.
Information on the incidence of Chlamydia trachomatis (CT) is essential for models of the effectiveness and cost-effectiveness of screening programmes. We developed two independent estimates of CT incidence in women in England: one based on an incidence study, with estimates ‘recalibrated’ to the general population using data on setting-specific relative risks, and allowing for clearance and re-infection during follow-up; the second based on UK prevalence data, and information on the duration of CT infection. The consistency of independent sources of data on incidence, prevalence and duration, validates estimates of these parameters. Pooled estimates of the annual incidence rate in women aged 16–24 and 16–44 years for 2001–2005 using all these data were 0·05 [95% credible interval (CrI) 0·035–0·071] and 0·021 (95% CrI 0·015–0·028), respectively. Although, the estimates apply to England, similar methods could be used in other countries. The methods could be extended to dynamic models to synthesize, and assess the consistency of data on contact and transmission rates.
Legislative changes during the 1960s–1970s granted user rights over wildlife to landowners in southern Africa, resulting in a shift from livestock farming to wildlife-based land uses. Few comprehensive assessments of such land uses on private land in southern Africa have been conducted and the associated benefits are not always acknowledged by politicians. Nonetheless, wildlife-based land uses are growing in prevalence on private land. In Namibia wildlife-based land use occurs over c. 287,000 km2. Employment is positively related to income from ecotourism and negatively related to income from livestock. While 87% of meat from livestock is exported ≥ 95% of venison from wildlife-based land uses remains within the country, contributing to food security. Wildlife populations are increasing with expansion of wildlife-based land uses, and private farms contain 21–33 times more wildlife than in protected areas. Because of the popularity of wildlife-based land uses among younger farmers, increasing tourist arrivals and projected impacts of climate change on livestock production, the economic output of wildlife-based land uses will probably soon exceed that of livestock. However, existing policies favour livestock production and are prejudiced against wildlife-based land uses by prohibiting reintroductions of buffalo Syncerus caffer, a key species for tourism and safari hunting, and through subsidies that artificially inflate the profitability of livestock production. Returns from wildlife-based land uses are also limited by the failure to reintroduce other charismatic species, failure to develop fully-integrated conservancies and to integrate black farmers sufficiently.
Salmonellosis is an internationally important disease of mammals and birds. Unique epidemics in New Zealand in the recent past include two Salmonella serovars: Salmonella enterica subsp. enterica serovar Typhimurium definitive type (DT) 160 (S. Typhimurium DT160) and S. Brandenburg. Although not a major threat internationally, in New Zealand S. Typhimurium DT160 has been the most common serovar isolated from humans, and continues to cause significant losses in wildlife. We have identified DNA differences between the first New Zealand isolate of S. Typhimurium DT160 and the genome-sequenced strain, S. Typhimurium LT2. All the differences could be accounted for in one cryptic phage ST64B, and one novel P22-like phage, ST160. The majority of the ST160 genome is almost identical to phage SE1 but has two regions not found in SE1 which are identical to the P22-like phage ST64T, suggesting that ST160 evolved from SE1 via two recombination events with ST64T. All of the New Zealand isolates of DT160 were identical indicating the clonal spread of this particular Salmonella. Some overseas isolates of S. Typhimurium DT160 differed from the New Zealand strain and contained SE1 phage rather than ST160. ST160 was also identified in New Zealand isolates of S. Typhimurium DT74 and S. Typhimurium RDNC-April06 and in S. Typhimurium DT160 isolates from the USA. The emergence of S. Typhimurium DT160 as a significant pathogen in New Zealand is postulated to have occurred due to the sensitivity of the Salmonella strains to the ST160 phage when S. Typhimurium DT160 first arrived.
In August 1988 an increase was noted in the number of cases of cryptosporidiosis identified by the microbiology laboratory at Doncaster Royal Infirmary. By 31 October, 67 cases had been reported. Preliminary investigations implicated the use of one of two swimming pools at a local sports centre and oocysts were identified in the pool water. Inspection of the pool revealed significant plumbing defects which had allowed ingress of sewage from the main sewer into the circulating pool water. Epidemiological investigation confirmed an association between head immersion and illness. The pools were closed when oocysts were identified in the water and extensive cleaning and repair work was undertaken. The pool water was retested for cryptosporidial oocysts and found to be negative before the pool re-opened.
This paper briefly describes the principle of operation and science goals of the AMANDA high energy neutrino telescope located at the South Pole, Antarctica. Results from an earlier phase of the telescope, called AMANDA-BIO, demonstrate both reliable operation and the broad astrophysical reach of this device, which includes searches for a variety of sources of ultrahigh energy neutrinos: generic point sources, Gamma-Ray Bursts and diffuse sources. The predicted sensitivity and angular resolution of the telescope were confirmed by studies of atmospheric muon and neutrino backgrounds. We also report on the status of the analysis from AMANDA-II, a larger version with far greater capabilities. At this stage of analysis, details of the ice properties and other systematic uncertainties of the AMANDA-II telescope are under study, but we have made progress toward critical science objectives. In particular, we present the first preliminary flux limits from AMANDA-II on the search for continuous emission from astrophysical point sources, and report on the search for correlated neutrino emission from Gamma Ray Bursts detected by BATSE before decommissioning in May 2000. During the next two years, we expect to exploit the full potential of AMANDA-II with the installation of a new data acquisition system that records full waveforms from the in-ice optical sensors.