The goal of this study was to determine the predictive value of cardiac T2* magnetic resonance for heart failure and arrhythmia in thalassemia major.
We analyzed cardiac and liver T2* magnetic ...resonance and serum ferritin in 652 thalassemia major patients from 21 UK centers with 1442 magnetic resonance scans. The relative risk for heart failure with cardiac T2* values <10 ms (compared with >10 ms) was 160 (95% confidence interval, 39 to 653). Heart failure occurred in 47% of patients within 1 year of a cardiac T2* <6 ms with a relative risk of 270 (95% confidence interval, 64 to 1129). The area under the receiver-operating characteristic curve for predicting heart failure was significantly greater for cardiac T2* (0.948) than for liver T2* (0.589; P<0.001) or serum ferritin (0.629; P<0.001). Cardiac T2* was <10 ms in 98% of scans in patients who developed heart failure. The relative risk for arrhythmia with cardiac T2* values <20 ms (compared with >20 ms) was 4.6 (95% confidence interval, 2.66 to 7.95). Arrhythmia occurred in 14% of patients within 1 year of a cardiac T2* of <6 ms. The area under the receiver-operating characteristic curve for predicting arrhythmia was significantly greater for cardiac T2* (0.747) than for liver T2* (0.514; P<0.001) or serum ferritin (0.518; P<0.001). The cardiac T2* was <20 ms in 83% of scans in patients who developed arrhythmia.
Cardiac T2* magnetic resonance identifies patients at high risk of heart failure and arrhythmia from myocardial siderosis in thalassemia major and is superior to serum ferritin and liver iron. Using cardiac T2* for the early identification and treatment of patients at risk is a logical means of reducing the high burden of cardiac mortality in myocardial siderosis. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00520559.
Chip-based quantum key distribution Sibson, P; Erven, C; Godfrey, M ...
Nature communications,
02/2017, Letnik:
8, Številka:
1
Journal Article
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Improvement in secure transmission of information is an urgent need for governments, corporations and individuals. Quantum key distribution (QKD) promises security based on the laws of physics and ...has rapidly grown from proof-of-concept to robust demonstrations and deployment of commercial systems. Despite these advances, QKD has not been widely adopted, and large-scale deployment will likely require chip-based devices for improved performance, miniaturization and enhanced functionality. Here we report low error rate, GHz clocked QKD operation of an indium phosphide transmitter chip and a silicon oxynitride receiver chip-monolithically integrated devices using components and manufacturing processes from the telecommunications industry. We use the reconfigurability of these devices to demonstrate three prominent QKD protocols-BB84, Coherent One Way and Differential Phase Shift-with performance comparable to state-of-the-art. These devices, when combined with integrated single photon detectors, pave the way for successfully integrating QKD into future telecommunications networks.
Tight junctions (TJs) regulate the paracellular movement of ions, macromolecules and immune cells across epithelia. Zonula occludens (ZO)-1 is a multi-domain polypeptide required for the assembly of ...TJs. MDCK II cells lacking ZO-1, and its homolog ZO-2, have three distinct phenotypes: reduced localization of occludin and some claudins to the TJs, increased epithelial permeability, and expansion of the apical actomyosin contractile array found at the apical junction complex (AJC). However, it is unclear exactly which ZO-1 binding domains are required to coordinate these activities. We addressed this question by examining the ability of ZO-1 domain-deletion transgenes to reverse the effects of ZO depletion. We found that the SH3 domain and the U5 motif are required to recruit ZO-1 to the AJC and that localization is a prerequisite for normal TJ and cytoskeletal organization. The PDZ2 domain is not required for localization of ZO-1 to the AJC, but is necessary to establish the characteristic continuous circumferential band of ZO-1, occludin and claudin-2. PDZ2 is also required to establish normal permeability, but is not required for normal cytoskeletal organization. Finally, our results demonstrate that PDZ1 is crucial for the normal organization of both the TJ and the AJC cytoskeleton. Our results establish that ZO-1 acts as a true scaffolding protein and that the coordinated activity of multiple domains is required for normal TJ structure and function.
Although the causes of Parkinson's disease (PD) are thought to be primarily environmental, recent studies suggest that a number of genes influence susceptibility. Using targeted case recruitment and ...online survey instruments, we conducted the largest case-control genome-wide association study (GWAS) of PD based on a single collection of individuals to date (3,426 cases and 29,624 controls). We discovered two novel, genome-wide significant associations with PD-rs6812193 near SCARB2 (p = 7.6 × 10(-10), OR = 0.84) and rs11868035 near SREBF1/RAI1 (p = 5.6 × 10(-8), OR = 0.85)-both replicated in an independent cohort. We also replicated 20 previously discovered genetic associations (including LRRK2, GBA, SNCA, MAPT, GAK, and the HLA region), providing support for our novel study design. Relying on a recently proposed method based on genome-wide sharing estimates between distantly related individuals, we estimated the heritability of PD to be at least 0.27. Finally, using sparse regression techniques, we constructed predictive models that account for 6%-7% of the total variance in liability and that suggest the presence of true associations just beyond genome-wide significance, as confirmed through both internal and external cross-validation. These results indicate a substantial, but by no means total, contribution of genetics underlying susceptibility to both early-onset and late-onset PD, suggesting that, despite the novel associations discovered here and elsewhere, the majority of the genetic component for Parkinson's disease remains to be discovered.
Glioblastoma multiforme is a malignant intracranial neoplasm that constitutes a therapeutic challenge because of the associated high morbidity and mortality given the lack of effective approved ...medication and aggressive nature of the tumor. However, there has been extensive research recently to address the reasons implicated in the resistant nature of the tumor to pharmaceutical compounds, which have resulted in several clinical trials investigating promising treatment approaches.
We reviewed literature published since 2010 from PUBMED and several annual meeting abstracts through 15 September 2020. Selected articles included those relevant to topics of glioblastoma tumor biology, original basic research, clinical trials, seminal reviews, and meta-analyses. We provide a discussion based on the collected evidence regarding the challenging factors encountered during treatment, and we highlighted the relevant trials of novel therapies including immunotherapy and targeted medication.
Selected literature revealed four main factors implicated in the low efficacy encountered with investigational treatments which included: (1) blood-brain barrier; (2) immunosuppressive microenvironment; (3) genetic heterogeneity; (4) external factors related to previous systemic treatment that can modulate tumor microenvironment. Investigational therapies discussed in this review were classified as immunotherapy and targeted therapy. Immunotherapy included: (1) immune checkpoint inhibitors; (2) adoptive cell transfer therapy; (3) therapeutic vaccines; (4) oncolytic virus therapy. Targeted therapy included tyrosine kinase inhibitors and other receptor inhibitors. Finally, we provide our perspective on future directions in treatment of glioblastoma.
Despite the limited success in development of effective therapeutics in glioblastoma, many treatment approaches hold potential promise including immunotherapy and novel combinational drugs. Addressing the molecular landscape and resistant immunosuppressive nature of glioblastoma are imperative in further development of effective treatments.
Summary Background Multiple system atrophy is a rare, fatal neurodegenerative disorder with symptoms of autonomic failure plus parkinsonism, cerebellar ataxia, or both. We report results of the first ...prospective natural history study of multiple system atrophy in the USA, and the effects of phenotype and autonomic failure on prognosis. Methods We recruited participants with probable multiple system atrophy—of either the parkinsonism subtype (MSA-P) or the cerebellar ataxia subtype (MSA-C)—at 12 neurology centres in the USA specialising in movement or autonomic disorders. We followed up patients every 6 months for 5 years and assessed them with the Unified Multiple System Atrophy Rating Scale part I (UMSARS I; a functional score of symptoms and ability to undertake activities of daily living), UMSARS II (neurological motor evaluation), and the Composite Autonomic Symptoms Scale (COMPASS)-select (a measure of autonomic symptoms and autonomic functional status). We assessed potential predictors of outcome. We used Cox proportional hazards models to calculate univariate hazard ratios for shorter survival using age at disease onset as a continuous variable and sex, clinical phenotype, and early development of neurological and autonomic manifestations as categorical variables. Findings We recruited 175 participants. Mean age at study entry was 63·4 years (SD 8·6). Median survival from symptom onset was 9·8 years (95% CI 8·8–10·7) and median survival from enrolment was 1·8 years (0·9–2·7). Participants with severe symptomatic autonomic failure (symptomatic orthostatic hypotension, urinary incontinence, or both) at diagnosis (n=62) had a worse prognosis than those without severe disease (n=113; median survival 8·0 years, 95% CI 6·5–9·5 vs 10·3 years, 9·3–11·4; p=0·021). At baseline, patients with MSA-P (n=126) and MSA-C (n=49) had much the same symptoms and functional status: mean UMSARS I 25·2 (SD 8·08) versus 24·6 (8·34; p=0·835); mean UMSARS II 26·4 (8·8) versus 25·4 (10·5; p=0·764); COMPASS-select 43·5 (18·7) versus 42·8 (19·6; p=0·835). Progression over 5 years, assessed by change in UMSARS I, UMSARS II, and COMPASS-select, was modest. Interpretation Probable multiple system atrophy is a late-stage disease with short survival. The natural histories of MSA-P and MSA-C are similar and severe symptomatic autonomic failure at diagnosis is associated with worse prognosis. Funding US National Institutes of Health, Mayo Clinic, and Kathy Shih Memorial Foundation.
Large-scale integrated quantum photonic technologies will require on-chip integration of identical photon sources with reconfigurable waveguide circuits. Relatively complex quantum circuits have been ...demonstrated already, but few studies acknowledge the pressing need to integrate photon sources and waveguide circuits together on-chip. A key step towards such large-scale quantum technologies is the integration of just two individual photon sources within a waveguide circuit, and the demonstration of high-visibility quantum interference between them. Here, we report a silicon-on-insulator device that combines two four-wave mixing sources in an interferometer with a reconfigurable phase shifter. We configured the device to create and manipulate two-colour (non-degenerate) or same-colour (degenerate) path-entangled or path-unentangled photon pairs. We observed up to 100.0 ± 0.4% visibility quantum interference on-chip, and up to 95 ± 4% off-chip. Our device removes the need for external photon sources, provides a path to increasing the complexity of quantum photonic circuits and is a first step towards fully integrated quantum technologies.
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Weighted Quantile Sum (WQS) regression is a method commonly used in environmental epidemiology to assess the impact of chemical mixtures in relation to a health outcome of interest. ...Data are partitioned into a single training and test set to reduce sample-specific chemical weights. However, in typical epidemiology sample sizes, this may produce unstable chemical weights and WQS index estimates, and investigators may resort to training and testing on the same data. To solve this problem, we propose repeated holdout validation whereby data are randomly partitioned 100 times, producing a distribution of validated results. Taking the mean as the final estimate, confidence estimates may also be calculated for inference. Further, this method helps characterize the variability in chemical weights, aiding in the identification of chemicals of concern. This is important since it may direct future research into specific chemicals.
Using data from 718 mother-child pairs in the Swedish Environmental Longitudinal, Mother and Child, Asthma and Allergy (SELMA) study, we assessed the association between prenatal exposure to 26 endocrine disrupting chemicals and child Intelligence Quotient (IQ). Results using a single partition were unstable, varying by random seed. The WQS index estimate was significant when all data was used (e.g. no partition) (β = −2.2 CI = −3.43, −0.98), but attenuated and nonsignificant using repeated holdout validation (β = −0.82 CI = −2.11, 0.45). When implementing WQS in epidemiologic studies with limited sample sizes, repeated holdout validation is a viable alternative to using a single, or no partitioning. Repeated holdout can both stabilize results and help characterize the uncertainty in identifying chemicals of concern, while maintaining some of the the rigor of holdout validation.
•Repeated holdout validation improves the stability of WQS estimates in finite study samples•Uncertainty in identifying toxic chemicals of concern is acknowledged and characterized
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