Common diseases such as endometriosis (ED), Alzheimer's disease (AD) and multiple sclerosis (MS) account for a significant proportion of the health care burden in many countries. Genome-wide ...association studies (GWASs) for these diseases have identified a number of individual genetic variants contributing to the risk of those diseases. However, the effect size for most variants is small and collectively the known variants explain only a small proportion of the estimated heritability. We used a linear mixed model to fit all single nucleotide polymorphisms (SNPs) simultaneously, and estimated genetic variances on the liability scale using SNPs from GWASs in unrelated individuals for these three diseases. For each of the three diseases, case and control samples were not all genotyped in the same laboratory. We demonstrate that a careful analysis can obtain robust estimates, but also that insufficient quality control (QC) of SNPs can lead to spurious results and that too stringent QC is likely to remove real genetic signals. Our estimates show that common SNPs on commercially available genotyping chips capture significant variation contributing to liability for all three diseases. The estimated proportion of total variation tagged by all SNPs was 0.26 (SE 0.04) for ED, 0.24 (SE 0.03) for AD and 0.30 (SE 0.03) for MS. Further, we partitioned the genetic variance explained into five categories by a minor allele frequency (MAF), by chromosomes and gene annotation. We provide strong evidence that a substantial proportion of variation in liability is explained by common SNPs, and thereby give insights into the genetic architecture of the diseases.
Understanding the origins and evolution of synapses may provide insight into species diversity and the organization of the brain. Using comparative proteomics and genomics, we examined the evolution ...of the postsynaptic density (PSD) and membrane-associated guanylate kinase (MAGUK)-associated signaling complexes (MASCs) that underlie learning and memory. PSD and MASC orthologs found in yeast carry out basic cellular functions to regulate protein synthesis and structural plasticity. We observed marked changes in signaling complexity at the yeast-metazoan and invertebrate-vertebrate boundaries, with an expansion of key synaptic components, notably receptors, adhesion/cytoskeletal proteins and scaffold proteins. A proteomic comparison of Drosophila and mouse MASCs revealed species-specific adaptation with greater signaling complexity in mouse. Although synaptic components were conserved amongst diverse vertebrate species, mapping mRNA and protein expression in the mouse brain showed that vertebrate-specific components preferentially contributed to differences between brain regions. We propose that the evolution of synapse complexity around a core proto-synapse has contributed to invertebrate-vertebrate differences and to brain specialization.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Buruli ulcer (BU), caused by Mycobacterium ulcerans, is increasing in incidence in Victoria, Australia. To improve understanding of disease transmission, we aimed to map the location of BU lesions on ...the human body.
Using notification data and clinical records review, we conducted a retrospective observational study of patients diagnosed with BU in Victoria from 1998-2015. We created electronic density maps of lesion locations using spatial analysis software and compared lesion distribution by age, gender, presence of multiple lesions and month of infection.
We examined 579 patients with 649 lesions; 32 (5.5%) patients had multiple lesions. Lesions were predominantly located on lower (70.0%) and upper (27.1%) limbs, and showed a non-random distribution with strong predilection for the ankles, elbows and calves. When stratified by gender, upper limb lesions were more common (OR 1·97, 95% CI 1·38-2·82, p<0·001) while lower limb lesions were less common in men than in women (OR 0·48, 95% CI 0·34-0·68, p<0·001). Patients aged ≥ 65 years (OR 3·13, 95% CI 1·52-6·43, p = 0·001) and those with a lesion on the ankle (OR 2·49, 95% CI 1·14-5·43, p = 0·02) were more likely to have multiple lesions. Most infections (71.3%) were likely acquired in the warmer 6 months of the year.
Comparison with published work in Cameroon, Africa, showed similar lesion distribution and suggests the mode of M. ulcerans transmission may be the same across the globe. Our findings also aid clinical diagnosis and provide quantitative background information for further research investigating disease transmission.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Endometriosis is a heritable hormone-dependent gynecological disorder, associated with severe pelvic pain and reduced fertility; however, its molecular mechanisms remain largely unknown. Here we ...perform a meta-analysis of 11 genome-wide association case-control data sets, totalling 17,045 endometriosis cases and 191,596 controls. In addition to replicating previously reported loci, we identify five novel loci significantly associated with endometriosis risk (P<5 × 10
), implicating genes involved in sex steroid hormone pathways (FN1, CCDC170, ESR1, SYNE1 and FSHB). Conditional analysis identified five secondary association signals, including two at the ESR1 locus, resulting in 19 independent single nucleotide polymorphisms (SNPs) robustly associated with endometriosis, which together explain up to 5.19% of variance in endometriosis. These results highlight novel variants in or near specific genes with important roles in sex steroid hormone signalling and function, and offer unique opportunities for more targeted functional research efforts.
The DEAP-3600 experiment is searching for weakly interacting massive particles dark matter with a 3.3 ×103kg single phase liquid argon (LAr) target, located 2.1 km underground at SNOLAB. The ...experimental signature of dark matter interactions is kilo electron volt–scale Ar40 nuclear recoils producing 128 nm LAr scintillation photons observed by photomultiplier tubes. The largest backgrounds in DEAP-3600 are electronic recoils (ERs) induced by β and γ rays originating from internal and external radioactivity in the detector material. A background model of the ER interactions in DEAP-3600 was developed and is described in this work. The model is based on several components which are expected from radioisotopes in the LAr, from ex situ material assay measurements, and from dedicated independent in situ analyses. This prior information is used in a Bayesian fit of the ER components to a 247.2 d dataset to model the radioactivity in the surrounding detector materials. Pulse-shape discrimination separates ER and NR events. However, detailed knowledge of the ER background and activity of detector components sets valuable constraints on NR backgrounds including neutrons and alphas. In addition, the activity of Ar42 in LAr in DEAP-3600 is determined by measuring the daughter decay of K42. This cosmogenically activated trace isotope is a relevant background at higher energies for other rare event searches using atmospheric argon, e.g., DarkSide-20k, GERDA, or LEGEND. The specific activity of Ar42 in the atmosphere is found to be 40.4±5.9 μBq/kg of argon.
The DEAP-3600 detector searches for the scintillation signal from dark matter particles scattering on a 3.3 tonne liquid argon target. The largest background comes from
39
Ar
beta decays and is ...suppressed using pulse-shape discrimination (PSD). We use two types of PSD estimator: the prompt-fraction, which considers the fraction of the scintillation signal in a narrow and a wide time window around the event peak, and the log-likelihood-ratio, which compares the observed photon arrival times to a signal and a background model. We furthermore use two algorithms to determine the number of photons detected at a given time: (1) simply dividing the charge of each PMT pulse by the mean single-photoelectron charge, and (2) a likelihood analysis that considers the probability to detect a certain number of photons at a given time, based on a model for the scintillation pulse shape and for afterpulsing in the light detectors. The prompt-fraction performs approximately as well as the log-likelihood-ratio PSD algorithm if the photon detection times are not biased by detector effects. We explain this result using a model for the information carried by scintillation photons as a function of the time when they are detected.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Infection control measures are effective for nosocomial COVID-19 prevention but bear substantial health-economic costs, motivating their “de-escalation” in settings at low risk of SARS-CoV-2 ...transmission. Yet consequences of de-escalation are difficult to predict, particularly in light of novel variants and heterogeneous population immunity.
To estimate how infection control measure de-escalation influences nosocomial COVID-19 risk.
An individual-based transmission model was used to simulate SARS-CoV-2 outbreaks and control measure de-escalation in a French long-term care hospital with multi-modal control measures in place (testing and isolation, universal masking, single-occupant rooms). Estimates of COVID-19 case fatality rates (CFRs) from reported outbreaks were used to quantify excess COVID-19 mortality due to de-escalation.
In a population fully susceptible to infection, de-escalating both universal masking and single rooms resulted in hospital-wide outbreaks of 114 (95% CI: 103–125) excess infections, compared with five (three to seven) excess infections when de-escalating only universal masking or 15 (11–18) when de-escalating only single rooms. When de-escalating both measures and applying CFRs from the first wave of COVID-19, excess patient mortality ranged from 1.57 (1.41–1.71) to 9.66 (8.73–10.57) excess deaths/1000 patient-days. By contrast, when applying CFRs from subsequent pandemic waves and assuming susceptibility to infection among 40–60% of individuals, excess mortality ranged from 0 (0–0) to 0.92 (0.77–1.07) excess deaths/1000 patient-days.
The de-escalation of bundled COVID-19 control measures may facilitate widespread nosocomial SARS-CoV-2 transmission. However, excess mortality is probably limited in populations at least moderately immune to infection and given CFRs resembling those estimated during the ‘post-vaccine’ era.
Patients with hepatic and pulmonary metastases from colorectal cancer (CRC) may benefit from aggressive surgical therapy. We examined the longterm outcomes of patients who underwent both lung and ...liver resections for colorectal metastases over a 10-year period.
Four hundred twenty-three hepatectomies were performed for metastatic CRC between 1992 and 2002 at two university-affiliated hospitals. Patients who underwent both lung and liver resections for metastatic CRC were studied. Demographic, perioperative, and survival data were evaluated by retrospective chart review. Disease-free survival (DFS) and overall survival (OS) were evaluated by Kaplan-Meier analysis and survival curves were compared using the log-rank test.
Thirty-nine patients underwent both lung and liver resections for metastatic CRC. Eleven patients (28%) underwent staged liver and lung metastasectomy from synchronously identified metastases. Twenty-eight patients (72%) underwent sequential metastasectomy because of recurrent disease. The median disease-free and overall survivals after initial metastasectomy were 19.8 and 87months, respectively. Serial metastasectomy was common in this patient population. The mean number of metastasectomies performed was 2.6 per patient (range 1 to 4). There was no difference in overall survival for patients with synchronous versus metachronous presentation of liver and lung metastases (p
=
0.45). The site of first recurrence after initial metastasectomy was, most commonly, the lung (n
=
19, 49%), followed by the liver (n
=
8, 21%). Nineteen patients (49%) underwent subsequent resections for recurrences. Seven patients (18%) underwent 2 or more liver resections for recurrent disease, and 12 (31%) underwent multiple lung resections.
An aggressive multidisciplinary surgical approach should be undertaken for recurrent CRC metastases. In selected patients, serial metastasectomy for recurrent metastatic disease is safe and results in excellent longterm survival after CRC resection.
We report on the first axion search results from the Cryogenic Dark Matter Search (CDMS) experiment at the Soudan Underground Laboratory. An energy threshold of 2 keV for electron-recoil events ...allows a search for possible solar axion conversion into photons or local galactic axion conversion into electrons in the germanium crystal detectors. The solar axion search sets an upper limit on the Primakov coupling g(agammagamma) of 2.4x10(-9) GeV-1 at the 95% confidence level for an axion mass less than 0.1 keV/c2. This limit benefits from the first precise measurement of the absolute crystal plane orientations in this type of experiment. The galactic axion search analysis sets a world-leading experimental upper limit on the axioelectric coupling g(aee) of 1.4x10(-12) at the 90% confidence level for an axion mass of 2.5 keV/c2.
Metal-related artifacts from spine instrumentation can obscure relevant anatomy and pathology. We evaluated the ability of CT images reconstructed with and without iterative metal artifact reduction ...to visualize critical anatomic structures in postoperative spines and assessed the potential for implementation into clinical practice.
We archived CT projection data in patients with instrumented spinal fusion. CT images were reconstructed by using weighted filtered back-projection and iterative metal artifact reduction. Two neuroradiologists evaluated images in the region of spinal hardware and assigned a score for the visualization of critical anatomic structures by using soft-tissue and bone windows (critical structures totally obscured, n = 0; anatomic recognition with high diagnostic confidence, n = 5). Using bone windows, we measured the length of the most pronounced linear artifacts. For each patient, neuroradiologists made recommendations regarding the optimal use of iterative metal artifact reduction and its impact on diagnostic confidence.
Sixty-eight patients met the inclusion criteria. Visualization of critical soft-tissue anatomic structures was significantly improved by using iterative metal artifact reduction compared with weighted filtered back-projection (median, 1 ± 1.5 versus 3 ± 1.3, P < .001), with improvement in the worst visualized anatomic structure in 88% (60/68) of patients. There was not significant improvement in visualization of critical osseous structures. Linear metal artifacts were reduced from 29 to 11 mm (P < .001). In 87% of patients, neuroradiologists recommended reconstructing iterative metal artifact reduction images instead of weighted filtered back-projection images, with definite improvement in diagnostic confidence in 32% (22/68).
Iterative metal artifact reduction improves visualization of critical soft-tissue structures in patients with spinal hardware. Routine generation of these images in addition to routine weighted filtered back-projection is recommended.
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