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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.
Objectives
We investigated whether pathway-specific PRS were significant predictors of LOAD case/control status.
Methods
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.
Results
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.
Conclusions
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.
Preemergence applications of atrazine [2-chloro-4-(ethylamino)-6-(isopropylamino)-s-triazine], chloramben (3-amino-2,5-dichlorobenzoic acid), fluometuron [1,1-dimethyl-3-(α,α,α-trifluro-m-tolyl)urea], propachlor (3-chloro-N-isopropylacetanilide), and trifluralin (α,α,α-trifluro-2,6-dinitro-N,N-dipropyl-p-toluidine) were compared in 10 North Carolina soils and the relationship of activity to soil physical and chemical properties appraised. Oats (Avena sativa L. ‘Carolee’) were used as the indicator plant in bioassays under greenhouse conditions. Fifteen soil properties were measured and correlated with herbicide I50 (50% fresh weight inhibition) values. Organic matter was the soil variable most highly correlated with herbicide phytotoxicity. There was an inverse relationship between herbicide water solubility and inactivation by organic matter. Volume weight determinations and water holding capacity values (0.1 bar) provided relatively good estimates of soil organic matter contents, but were not as highly related to herbicide activity as organic matter content.
In June 2014 Public Health England confirmed a case of Legionnaires' disease (LD) in a neonate following birth at home in a hired birthing pool incorporating a heater and a recirculation pump which had been filled in advance of labour. The case triggered a public health investigation and a microbiological survey of an additional ten heated birthing pools hired or recently hired to the general public across England. The birthing pool used by the parent of the confirmed case was identified as the source of the neonate's infection following detection of Legionella pneumophila ST48 in both patient and environmental samples. Legionella species were detected by quantitative polymerase chain reaction but not culture in a further three pools together with other opportunistic pathogens identified by culture and matrix-assisted laser desorption ionization–time of flight (MALDI–ToF) mass spectrometry. A Patient Safety Alert from NHS England and Public Health England was issued stating that heated birthing pools filled in advance of labour should not be used for home births. This recommendation remains in place. This investigation in conjunction with other recent reports has highlighted a lack of awareness regarding the microbiological safety of heated birthing pools and their potential to be a source of LD and other opportunistic infections. Furthermore, the investigation raised important considerations with regards to microbiological sampling and testing in such incidents. Public health authorities and clinicians should consider LD in the differential diagnosis of severe respiratory infection in neonates within 14 days of a water birth.
Prehospital first responders historically have treated hypoglycemia in the field with an IV bolus of 50 mL of 50% dextrose solution (D50). The California Contra Costa County Emergency Medical Services (EMS) system recently adopted a protocol of IV 10% dextrose solution (D10), due to frequent shortages and relatively high cost of D50. The feasibility, safety, and efficacy of this approach are reported using the experience of this EMS system.
Methods
Over the course of 18 weeks, paramedics treated 239 hypoglycemic patients with D10 and recorded patient demographics and clinical outcomes. Of these, 203 patients were treated with 100 mL of D10 initially upon EMS arrival, and full data on response to treatment was available on 164 of the 203 patients. The 164 patients’ capillary glucose response to initial infusion of 100 mL of D10 was calculated and a linear regression line fit between elapsed time and difference between initial and repeat glucose values. Feasibility, safety, and the need for repeat glucose infusions were examined.
Results
The study cohort included 102 men and 62 women with a median age of 68 years. The median initial field blood glucose was 38 mg/dL, with a subsequent blood glucose median of 98 mg/dL. The median time to second glucose testing was eight minutes after beginning the 100 mL D10 infusion. Of 164 patients, 29 (18%) required an additional dose of IV D10 solution due to persistent or recurrent hypoglycemia, and one patient required a third dose. There were no reported adverse events or deaths related to D10 administration. Linear regression analysis of elapsed time and difference between initial and repeat glucose values showed near-zero correlation.
Conclusions
In addition to practical reasons of cost and availability, theoretical risks of using 50 mL of D50 in the out-of-hospital setting include extravasation injury, direct toxic effects of hypertonic dextrose, and potential neurotoxic effects of hyperglycemia. The results of one local EMS system over an 18-week period demonstrate the feasibility, safety, and efficacy of using 100 mL of D10 as an alternative. Additionally, the linear regression line of repeat glucose measurements suggests that there may be little or no short-term decay in blood glucose values after D10 administration.
KieferMV, HernHG, AlterHJ, BargerJB. Dextrose 10% in the Treatment of Out-of-Hospital Hypoglycemia. Prehosp Disaster Med. 2014;29(2):1-5.
Post-traumatic stress disorder (PTSD) in response to the World Trade Center (WTC) disaster of 11 September 2001 (9/11) is one of the most prevalent and persistent health conditions among both professional (e.g. police) and non-traditional (e.g. construction worker) WTC responders, even several years after 9/11. However, little is known about the dimensionality and natural course of WTC-related PTSD symptomatology in these populations.
Method
Data were analysed from 10 835 WTC responders, including 4035 police and 6800 non-traditional responders who were evaluated as part of the WTC Health Program, a clinic network in the New York area established by the National Institute for Occupational Safety and Health. Confirmatory factor analyses (CFAs) were used to evaluate structural models of PTSD symptom dimensionality; and autoregressive cross-lagged (ARCL) panel regressions were used to examine the prospective interrelationships among PTSD symptom clusters at 3, 6 and 8 years after 9/11.
Results
CFAs suggested that five stable symptom clusters best represent PTSD symptom dimensionality in both police and non-traditional WTC responders. This five-factor model was also invariant over time with respect to factor loadings and structural parameters, thereby demonstrating its longitudinal stability. ARCL panel regression analyses revealed that hyperarousal symptoms had a prominent role in predicting other symptom clusters of PTSD, with anxious arousal symptoms primarily driving re-experiencing symptoms, and dysphoric arousal symptoms primarily driving emotional numbing symptoms over time.
Conclusions
Results of this study suggest that disaster-related PTSD symptomatology in WTC responders is best represented by five symptom dimensions. Anxious arousal symptoms, which are characterized by hypervigilance and exaggerated startle, may primarily drive re-experiencing symptoms, while dysphoric arousal symptoms, which are characterized by sleep disturbance, irritability/anger and concentration difficulties, may primarily drive emotional numbing symptoms over time. These results underscore the importance of assessment, monitoring and early intervention of hyperarousal symptoms in WTC and other disaster responders.
Longitudinal symptoms of post-traumatic stress disorder (PTSD) are often characterized by heterogeneous trajectories, which may have unique pre-, peri- and post-trauma risk and protective factors. To date, however, no study has evaluated the nature and determinants of predominant trajectories of PTSD symptoms in World Trade Center (WTC) responders.
Method
A total of 10835 WTC responders, including 4035 professional police responders and 6800 non-traditional responders (e.g. construction workers) who participated in the WTC Health Program (WTC-HP), were evaluated an average of 3, 6 and 8 years after the WTC attacks.
Results
Among police responders, longitudinal PTSD symptoms were best characterized by four classes, with the majority (77.8%) in a resistant/resilient trajectory and the remainder exhibiting chronic (5.3%), recovering (8.4%) or delayed-onset (8.5%) symptom trajectories. Among non-traditional responders, a six-class solution was optimal, with fewer responders in a resistant/resilient trajectory (58.0%) and the remainder exhibiting recovering (12.3%), severe chronic (9.5%), subsyndromal increasing (7.3%), delayed-onset (6.7%) and moderate chronic (6.2%) trajectories. Prior psychiatric history, Hispanic ethnicity, severity of WTC exposure and WTC-related medical conditions were most strongly associated with symptomatic trajectories of PTSD symptoms in both groups of responders, whereas greater education and family and work support while working at the WTC site were protective against several of these trajectories.
Conclusions
Trajectories of PTSD symptoms in WTC responders are heterogeneous and associated uniquely with pre-, peri- and post-trauma risk and protective factors. Police responders were more likely than non-traditional responders to exhibit a resistant/resilient trajectory. These results underscore the importance of prevention, screening and treatment efforts that target high-risk disaster responders, particularly those with prior psychiatric history, high levels of trauma exposure and work-related medical morbidities.
No standard definition exists for surveillance and characterization of the epidemiology of bloodstream infections (BSIs) after cardiac catheterization (CC) procedures. We proposed a novel case definition and determined the epidemiology and risk factors of BSIs after CC procedure using this new definition.
NASA's NuSTAR observatory is the first focusing hard X-ray telescope. Launched in June 2012, NuSTAR is sensitive in the 3–79 keV range with unprecedented ~17″ FWHM angular resolution above 12 keV, a result of its multilayer-coated optics and 10-m focal length. With its large effective area (900 cm2 at 10 keV), NuSTAR has point-source sensitivity ~100 times better than previous hard X-ray telescopes. Here we describe NuSTAR and its planned work on rotation-powered pulsars and magnetars during its nominal 2-yr baseline mission that has just commenced.
Insurance accounting has for many years proved a challenging topic for standard setters, preparers and users, often described as a “black box”. Will recent developments, in particular the July 2010 Insurance Contracts Exposure Draft, herald a new era?
This paper reviews these developments, setting out key issues and implications. It concentrates on issues relevant to life insurers, although much of the content is also relevant to non-life insurers.
The paper compares certain IFRS and Solvency II developments, recognising that UK insurers face challenges in implementing new financial and regulatory reporting requirements in similar timeframes. The paper considers resulting external disclosure requirements and a possible future role for supplementary information.
Preliminary evidence suggests that consumption of Porphyridium cruentum (PC) biomass results in hypocholesterolaemic effects; however, mechanisms responsible have not been elucidated. The aim of the present study was to determine whether PC biomass lowers circulating cholesterol concentrations, dose dependently, in hamsters fed hypercholesterolaemic diets for 28 d and determine whether cholesterol biosynthesis is affected. Biomass added to diets at 2·5, 5 and 10 % resulted in 14, 38 and 53 % reductions (P < 0·001) in total plasma cholesterol, respectively, compared with a control diet. Similarly, non-HDL-cholesterol concentrations in the 5 and 10 % PC groups were reduced (P < 0·001) 28 and 45 %, respectively, v. controls. These effects were unrelated to cholesterol fractional synthesis rate (FSR), as this did not differ between either treatment or control animals. PC consumption had no effect on food intake, plasma glucose concentrations or energy expenditure, but percentage of body fat was lower (P < 0·001) in the 5 and 10 % PC groups compared with controls. These data show that PC reduces total plasma cholesterol and non-HDL-cholesterol when incorporated into the diet at levels as low as 2·5 %. The mechanism of action for this reduction may be related to increased excretion since food intakes and cholesterol FSR were not reduced in the animals receiving the PC. In conclusion, the use of PC biomass reduces circulating cholesterol, dose dependently, in hypercholesterolaemic hamsters but not via reductions in cholesterol FSR. There is potential for the use of this biomass as a functional ingredient to aid in the management of blood cholesterol concentrations.
The membrane-filter assay, GM1-ELISA, and DNA-DNA hybridization assay, were used to detect enterotoxigenic Escherichia coli (ETEC) in samples of water, weaning food, food preparation surface swabs, fingerprints of mothers, and the fingerprints and stools of children under 5 years of age, in 20 households in a Malaysian village. Weaning food and environmental samples were frequently contaminated by faecal coliforms, including ETEC. The membrane-filter assay detected and enumerated faecal coliforms and LT-ETEC in all types of water and weaning food samples. Highest concentrations of faecal coliforms and LT-ETEC were found in weaning food, followed by well-water, stored water and stored drinking water. The GM1-ELISA detected LT-ETEC in weaning food, food preparation surfaces, fingerprints and stool samples. The DNA-DNA hybridization assay detected a larger proportion of STa2-ETEC than the other toxotypes, either singly or in combination. All the assays in combination detected the presence of ETEC in all types of samples on at least one occasion in each household. It was not possible to classify households as consistently more or less contaminated with ETEC. On individual occasions it was possible to show a significant association of the presence of LT-ETEC between the fingerprints of children and their stools, fingerprints of mothers and children, and weaning food and the stools of the child consuming the food.
RECENT reconnaissance surveys in south-west Persia have brought to our notice many examples of enigmatical structures preserved in massive limestones beautifully exposed in the naked mountains of that region. Application of many hypotheses involving faulting and thrusting proved impossible to satisfy the facts we had observed. We were at length forced to explain some of the structures we encountered as being produced by collapse of great sheets of limestone after removal of their original supporting cover accompanied by unsticking from their basement. Gravity alone provided the motive force. Simple folds, erosion, a shaly substratum, and gravity have induced massive beds of limestone to behave in an entirely unexpected manner. Examples are described below with sketches.
This paper provides one of the first assessments of the burden of both the public health investigation and the economic costs associated with an apparent outbreak of Legionnaires' disease (LD) in South East London. In addition to epidemiological, microbiological and environmental investigations, we collected data on the staff time and resources committed by the 11 main organizations responsible for managing the outbreak. Of the overall estimated costs of £455 856, only 14% (£64 264) was spent on investigation and control of the outbreak compared with 86% (£391 592) spent on the hospital treatment of the patients. The time and money spent on public health services in this investigation appear to represent good value for money considering the potential costs of a major outbreak, including the high case-fatality rate in LD generally and the high health-care costs. Further research is needed to determine optimum strategies for the cost-effective use of health system resources in investigations of LD. Whether the threshold for investigation of cases should be based on observed incidence rates or the cost-effectiveness of investigations, or both, should be debated further.
Eight cases of Legionnaires' disease were identified among the 215 German passengers after a cruise to the Nordic Sea in August 2003. An unmatched case-control study was conducted to identify risk factors and the source of infection. In total, eight passengers fulfilled the case definition, one of these died. Forty-two passengers served as controls. The attack rate was 4%. The mean age was 60 years for cases and 62 years for controls. Prolonged exposure to the spa pool seemed to be a risk factor of infection (OR 4·85, P=0·09). Legionella pneumophila serogroup 1, monoclonal antibody (mAb) subgroup ‘Knoxville’ was isolated from clinical and environmental samples. DNA sequence-based typing revealed that these isolates were indistinguishable from each other. The investigation showed the importance of an interdisciplinary approach of microbiology and epidemiology as not all sites on the ship that tested positive for L. pneumophila actually posed a relevant risk for the passengers.
Pr doped YBa2Cu3O7-d targets with composition Y1-xPrxBa2Cu3O7-d where × = 0.0001, 0.001, 0.01, and 0.1 were prepared from oxide powders and were used to deposit thin films by pulsed laser deposition using conditions previously optimized for pure YBa2Cu3O7-d. The Pr dopant was found to be dispersed throughout the film by secondary ion mass spectrometry and found to have an increased density of nanoparticles on the surface. The pinning force of the doped samples was found to decrease with increasing concentration of Pr; however, at 0.01% concentration the doped film displayed a significant enhancement over pure YBa2Cu3O7-d for nearly the full range of 0 – 9 T.
Poorly defined cohorts and weak study designs have hampered cross-cultural comparisons of course and outcome in schizophrenia.
Aims
To describe long-term outcome in 18 diverse treated incidence and prevalence cohorts. To compare mortality, 15- and 25-year illness trajectory and the predictive strength of selected baseline and short-term course variables.
Method
Historic prospective study. Standardised assessments of course and outcome.
Results
About 75% traced. About 50% of surviving cases had favourable outcomes, but there was marked heterogeneity across geographic centres. In regression models, early (2-year) course patterns were the strongest predictor of 15-year outcome, but recovery varied by location; 16% of early unremitting cases achieved late-phase recovery.
Conclusions
A significant proportion of treated incident cases of schizophrenia achieve favourable long-term outcome. Sociocultural conditions appear to modify long-term course. Early intervention programmes focused on social as well as pharmacological treatments may realise longer-term gains.