Laplace deconvolution and its application to Dynamic Contrast Enhanced imaging

In the present paper we consider the problem of Laplace deconvolution with noisy discrete observations. The study is motivated by Dynamic Contrast Enhanced imaging using a bolus of contrast agent, a procedure which allows considerable improvement in {evaluating} the quality of a vascular network and its permeability and is widely used in medical assessment of brain flows or cancerous tumors. Although the study is motivated by medical imaging application, we obtain a solution of a general problem of Laplace deconvolution based on noisy data which appears in many different contexts. We propose a new method for Laplace deconvolution which is based on expansions of the convolution kernel, the unknown function and the observed signal over Laguerre functions basis. The expansion results in a small system of linear equations with the matrix of the system being triangular and Toeplitz. The number $m$ of the terms in the expansion of the estimator is controlled via complexity penalty. The advantage of this methodology is that it leads to very fast computations, does not require exact knowledge of the kernel and produces no boundary effects due to extension at zero and cut-off at $T$. The technique leads to an estimator with the risk within a logarithmic factor of $m$ of the oracle risk under no assumptions on the model and within a constant factor of the oracle risk under mild assumptions. The methodology is illustrated by a finite sample simulation study which includes an example of the kernel obtained in the real life DCE experiments. Simulations confirm that the proposed technique is fast, efficient, accurate, usable from a practical point of view and competitive

Deconstructing maternal sensitivity: Predictive relations to mother-child attachment in home and laboratory settings

Despite the well-documented importance of parental sensitivity for child development, there is a lack of consensus regarding how best to assess it. We investigated the factor structure of maternal caregiving behavior as assessed at 12 months by the Maternal Behavior Q-Sort (Pederson, Moran, & Bento, 1999) with 274 mother-infant dyads. Subsequently, we examined associations between these empirically-derived dimensions and child attachment, assessed in the home and laboratory (final N = 157). Three dimensions of maternal behavior were identified, corresponding fairly closely to Ainsworth’s original scales. They were labeled Cooperation/Attunement, Positivity, and Accessibility/Availability. Only Cooperation/Attunement consistently predicted home-based attachment at 15 months and 2 years, and at comparable strength to the overall sensitivity score, suggesting that this construct may be central to sensitivity. At 18 months, compared to their primarily secure counterparts, different types of laboratory-assessed insecure attachment were associated with different patterns of maternal behavior. Mothers in avoidant relationships (n = 18) were low on Cooperation/Attunement and Accessibility/Availability, but fairly high on Positivity. Mothers of disorganized infants (n = 11) were Cooperative/Attuned but somewhat less Positive toward, and less Accessible/Available to, their infants. A multi-dimensional approach to parental behavior may facilitate the identification of parenting precursors of insecure parent-child relationships

Effect of tadalafil on blood flow, pain, and function in chronic cold Complex Regional Pain Syndrome: a randomized controlled trial

Background. This double-blind, randomized, controlled trial investigated the effect of the phosphodiesterase-5 inhibitor tadalafil on the microcirculation in patients with cold Complex Regional Pain Syndrome (CRPS) in one lower extremity. Methods. Twenty-four patients received 20 mg tadalafil or placebo daily for 12 weeks. The patients also participated in a physical therapy program. The primary outcome measure was temperature difference between the CRPS side and the contralateral side, determined by measuring the skin temperature with videothermography. Secondary outcomes were: pain measured on a Visual Analogue Scale, muscle force measured with a MicroFet 2 dynamometer, and level of activity measured with an Activity Monitor (AM) and walking tests. Results. At the end of the study period, the temperature asymmetry was not significantly reduced in the tadalafil group compared with the placebo group, but there was a significant and clinically relevant reduction of pain in the tadalafil group. Muscle force improved in both treatment groups and the AM revealed small, non-significant improvements in time spent standing, walking, and the number of short walking periods. Conclusion. Tadalafil may be a promising new treatment for patients that have chronic cold CRPS due to endothelial dysfunction, and deserves further investigation. Trial Registration. The registration number in the Dutch Trial Register is ISRCTN60226869

Association study of cholesterol-related genes in Alzheimer's disease

Alzheimer's disease (AD) is a genetically complex disorder, and several genes related to cholesterol metabolism have been reported to contribute to AD risk. To identify further AD susceptibility genes, we have screened genes that map to chromosomal regions with high logarithm of the odds scores for AD in full genome scans and are related to cholesterol metabolism. In a European screening sample of 115 sporadic AD patients and 191 healthy control subjects, we analyzed single nucleotide polymorphisms in 28 cholesterol-related genes for association with AD. The genes HMGCS2, FDPS, RAFTLIN, ACAD8, NPC2, and ABCG1 were associated with AD at a significance level of P ≤ 0.05 in this sample. Replication trials in five independent European samples detected associations of variants within HMGCS2, FDPS, NPC2, or ABCG1 with AD in some samples (P = 0.05 to P = 0.005). We did not identify a marker that was significantly associated with AD in the pooled sample (n = 2864). Stratification of this sample revealed an APOE-dependent association of HMGCS2 with AD (P = 0.004). We conclude that genetic variants investigated in this study may be associated with a moderate modification of the risk for AD in some sample

Understanding the effectiveness of government interventions against the resurgence of COVID-19 in Europe.

Funder: European and Developing Countries Clinical Trials Partnership (EDCTP); doi: https://doi.org/10.13039/501100001713Funder: MRC Centre for Global Infectious Disease Analysis (MR/R015600/1), jointly funded by the U.K. Medical Research Council (MRC) and the U.K. Foreign, Commonwealth and Development Office (FCDO), under the MRC/FCDO Concordat agreement. Community Jameel. The UK Research and Innovation (MR/V038109/1), the Academy of Medical Sciences Springboard Award (SBF004/1080), The MRC (MR/R015600/1), The BMGF (OPP1197730), Imperial College Healthcare NHS Trust- BRC Funding (RDA02), The Novo Nordisk Young Investigator Award (NNF20OC0059309) and The NIHR Health Protection Research Unit in Modelling Methodology. S. Bhatt thanks Microsoft AI for Health and Amazon AWS for computational credits.Funder: EA FundsFunder: University of Oxford (Oxford University); doi: https://doi.org/10.13039/501100000769Funder: DeepMindFunder: OpenPhilanthropyFunder: UKRI Centre for Doctoral Training in Interactive Artificial Intelligence (EP/S022937/1)Funder: Augustinus Fonden (Augustinus Foundation); doi: https://doi.org/10.13039/501100004954Funder: Knud Højgaards Fond (Knud Højgaard Fund); doi: https://doi.org/10.13039/501100009938Funder: Kai Lange og Gunhild Kai Langes Fond (Kai Lange and Gunhild Kai Lange Foundation); doi: https://doi.org/10.13039/501100008206Funder: Aage og Johanne Louis-Hansens Fond (Aage and Johanne Louis-Hansen Foundation); doi: https://doi.org/10.13039/501100010344Funder: William Demant FoundationFunder: Boehringer Ingelheim Fonds (Stiftung für medizinische Grundlagenforschung); doi: https://doi.org/10.13039/501100001645Funder: Imperial College COVID-19 Research FundFunder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289European governments use non-pharmaceutical interventions (NPIs) to control resurging waves of COVID-19. However, they only have outdated estimates for how effective individual NPIs were in the first wave. We estimate the effectiveness of 17 NPIs in Europe's second wave from subnational case and death data by introducing a flexible hierarchical Bayesian transmission model and collecting the largest dataset of NPI implementation dates across Europe. Business closures, educational institution closures, and gathering bans reduced transmission, but reduced it less than they did in the first wave. This difference is likely due to organisational safety measures and individual protective behaviours-such as distancing-which made various areas of public life safer and thereby reduced the effect of closing them. Specifically, we find smaller effects for closing educational institutions, suggesting that stringent safety measures made schools safer compared to the first wave. Second-wave estimates outperform previous estimates at predicting transmission in Europe's third wave

Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

The risk of germline copy number variants (CNVs) in BRCA1 and BRCA2 pathogenic variant carriers in breast cancer is assessed, with CNVs overlapping SULT1A1 decreasing breast cancer risk in BRCA1 carriers.The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.Peer reviewe

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development