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Insights into the genetic basis of human disease are helping to address some of the key challenges in new drug development including the very high rates of failure. Here we review the recent history of an emerging, genomics-assisted approach to pharmaceutical research and development, and its relationship to Mendelian randomization (MR), a well-established analytical approach to causal inference. We demonstrate how human genomic data linked to pharmaceutically relevant phenotypes can be used for (1) drug target identification (mapping relevant drug targets to diseases), (2) drug target validation (inferring the likely effects of drug target perturbation), (3) evaluation of the effectiveness and specificity of compound-target engagement (inferring the extent to which the effects of a compound are exclusive to the target and distinguishing between on-target and off-target compound effects), and (4) the selection of end points in clinical trials (the diseases or conditions to be evaluated as trial outcomes). We show how genomics can help identify indication expansion opportunities for licensed drugs and repurposing of compounds developed to clinical phase that proved safe but ineffective for the original intended indication. We outline statistical and biological considerations in using MR for drug target validation (drug target MR) and discuss the obstacles and challenges for scaled applications of these genomics-based approaches.

One of the defining narratives of the COVID-19 pandemic has been the acceptance and distribution of vaccine.Compare the outcomes of COVID-19 positive vaccinated and unvaccinated stroke patients.This is a single-center retrospective study of COVID-19-vaccinated and unvaccinated stroke patients between April 2020 and March 2022. All patients presenting with stroke regardless of treatment modalities were included. NIHSS was used to assess stroke severity. The primary outcome was functional capacity of the patients at discharge.The study cohort comprised 203 COVID-19 positive stroke patients divided into 139 unvaccinated and 64 fully vaccinated patients. At discharge, the mRS score was significantly lower in the vaccinated cohort (3[1-4] vs 4[2-5], OR=0.508, p=0.011). At 3 months of follow-up, the median mRS score was comparable between both cohorts.Although vaccination did not show any significant difference in stroke patient outcomes on follow-up, vaccines were associated with lower rates of morbidity and mortality at discharge among stroke patients during the pandemic.

Oil-in-water (O/W) microemulsions typically feature a low viscosity and exhibit the ordinary viscosity reduction as a function of temperature. However, for certain applications avoiding or even reverting the temperature trend might be required. This can be conceived by adding thermoresponsive (TR) block copolymers that induce network formation as temperature rises. Accordingly, various ME–polymer mixtures were studied for which three different block copolymer architectures of BAB*, B2AB*, and B(AB*)2 type were employed. Here, “B” represents a permanently hydrophobic, “A” a permanently hydrophilic, and “B*” a TR block. For the TR-block, three different poly(acrylamide)s, namely poly(N-n-propylacrylamide) (pNPAm), poly(N,N-diethylacrylamide) (pDEAm), and poly(N-isopropylacrylamide) (pNiPAm), were used, which all exhibit a lower critical solution temperature (LCST). For a well selected ME concentration, these block copolymers lead to a viscosity enhancement with rising temperature. At a polymer concentration of about 22 g L-1, the most pronounced enhancement was observed for the pNPAm-based systems with factors up to 3, 5, and 8 for BAB*, B2AB*, and B(AB*)2, respectively. This phenomenon is caused by the formation of a transitory network mediated by TR-blocks, as evidenced by the direct correlation between the attraction strength and the viscosity enhancement. For applications requiring a high hydrophobic payload, which is attained via microemulsion droplets, this kind of tailored temperature-dependent viscosity control of surfactant systems should therefore be advantageous.

ZusammenfassungDer Konsum von Missbrauchsabbildungen hat sich im Hellfeld in den letzten Jahren immer wieder verdoppelt. Dieses erhöhte Fallaufkommen stellt Polizei, Bewährungshilfe und forensische Therapeuten vor eine Vielzahl neuer Herausforderungen. In diesem Beitrag sollen daher aktuelle theoretische Modelle und empirische Erkenntnisse dargestellt werden, um Praktiker in ihrer täglichen Arbeit zu unterstützen. Im Einzelnen sollen das Ausmaß der Problematik und ätiologische Erklärungsmodelle dargestellt werden. Darauffolgend werden empirische Erkenntnisse zu Konsumenten von Missbrauchsabbildungen aufgeführt und diese mit Tätern, die zusätzlich auch Hands-On-Delikte begehen, verglichen. Ferner wird die Problematik von „Crossover“-Tätern diskutiert. Abschließend werden Ansätze vorgestellt, um Fälle in der polizeilichen Ermittlungsarbeit zu priorisieren sowie um das Rückfallrisiko von Konsumenten von Missbrauchsabbildungen vorherzusagen.

OBJECTIVE Stent-assisted coil (SAC) embolization has been the mainstay endovascular treatment for bifurcation aneurysms. The recent introduction of the Woven EndoBridge (WEB) device has presented an alternative endovascular treatment modality for these aneurysms. Direct comparisons of outcomes between these two modalities are limited in the literature. Here, the authors compared the outcomes of bifurcation aneurysms treated with SAC and WEB devices. METHODS This retrospective single-center study comprised 148 bifurcation aneurysms that were treated endovascularly with SAC or WEB devices between 2011 and 2019. The primary outcome was complete occlusion of the aneurysm at 6 months on catheter angiography. RESULTS The SAC and WEB cohorts comprised 85 and 63 aneurysms, respectively. The baseline characteristics were well balanced after inverse probability weight (IPW) adjustment, except for smoking status. The 6-month complete occlusion rate was higher in the WEB cohort than the SAC cohort (67.4% vs 40.6%; unadjusted OR [95% CI] 3.014 [1.385–6.563], p = 0.005). However, this difference in complete occlusion rates did not remain significant after IPW adjustment and multiple imputations. The neck remnant rate was lower in the WEB cohort than the SAC cohort (20% vs 50%; OR [95% CI] 0.250 [0.107–0.584], p = 0.001), and this difference remained significant after IPW adjustment (OR [95% CI] 0.304 [0.116–0.795], p = 0.015) and multiple imputations. CONCLUSIONS Use of SAC and WEB demonstrated comparable 6-month complete occlusion rates for bifurcation aneurysms. WEB appeared to be associated with a lower rate of neck remnant at 6 and 12 months compared with SAC. WEB was also associated with fewer complications and decreased retreatment rates compared with SAC.

PURPOSE This study aimed to evaluate the safety and outcome of image-guided embolization for treating arteriovenous malformations (AVMs) of the hand using ethylene-vinyl alcohol copolymer (EVOH). METHODS A retrospective, multicenter cohort of 15 patients with AVMs of the hand treated with 35 imageguided embolotherapies using EVOH was investigated. Clinical history, symptomatology, and imaging findings were assessed to evaluate clinical outcome (symptom-free, partial relief of pain, no improvement of pain, and clinical progression despite embolization), lesion devascularization (total, 100%; near-total, 90%-99%; substantial, 70%-90%; partial, 30%-70%; and failure, 0%-30%), and peri- and postprocedural complication rates (major complications classified according to CIRSE guidelines). Substratification analysis was performed with respect to the involvement of different anatomical compartments and the injected volume of the embolic agent. RESULTS Patients were treated for pain (93.3%), skin ulceration (46.7%), and local bleeding (33.3%). The mean number of embolotherapies was 2.3 (±1.1) in 3 patients, a planned surgical resection was conducted after embolization. Clinical outcome after a median follow-up of 18 months revealed an overall response of 11/15 patients (73.3%). Imaging at last follow-up revealed 70%- 99% reduced vascularization in 12/15 patients (80%) including 2 patients (13.3%) with a neartotal devascularization of 90%-99%. Peri- and postprocedural complications occurred in 8.5% and 31.5%, respectively, including 17.1% major complications, in 1 case requiring a previously unplanned resection. Involvement of the finger was associated with increased rates of persistent symptoms compared to the other groups (P=.049). No significant difference between the embolic agent volume injected and complication rates was found (P=.372). CONCLUSION Image-guided embolization using EVOH-based liquid embolic agents is effective for treating AVMs of the hand in the mid-term.

Poly(dimethylsiloxane) (PDMS)-based nanocomposites have attracted increasing attention due to their inherent outstanding properties. Nevertheless, the realization of high levels of dispersion of nanosilicas in PDMS represents a challenge arising from the poor compatibility between the two components. Herein, we explore the use of ionic interactions located at the interface between silica and a PDMS matrix by combining anionic sulfonate-functionalized silica and cationic ammonium-functionalized PDMS. A library of ionic PDMS nanocomposites was synthesized and characterized to highlight the impact of charge location, density, and molecular weight of ionic PDMS polymers on the dispersion of nanosilicas and the resulting mechanical reinforcement. The use of reversible ionic interactions at the interface of nanoparticles–polymer matrix enables the healing of scratches applied to the surface of the nanocomposites. Molecular dynamics simulations were used to estimate the survival probability of ionic cross-links between nanoparticles and the polymer matrix, revealing a dependence on polymer charge density., MRS Bulletin, 47 (12), ISSN:0883-7694, ISSN:1938-1425

IMPORTANCE: Cholesteryl ester transfer protein inhibition (CETP) has been shown to increase levels of high-density lipoprotein cholesterol (HDL-C) and reduce levels of low-density lipoprotein cholesterol (LDL-C). Current LDL-C target attainment is low, and novel phase 3 trials are underway to investigate whether CETP inhibitors result in reduction of cardiovascular disease risk in high-risk patients who may be treated with PCSK9-inhibiting agents. OBJECTIVE: To explore the associations of combined reduction of CETP and PCSK9 concentrations with risk of coronary artery disease (CAD) and other clinical and safety outcomes. DESIGN, SETTING, AND PARTICIPANTS: Two-sample 2 × 2 factorial Mendelian randomization study in a general population sample that includes data for UK Biobank participants of European ancestry. EXPOSURES: Separate genetic scores were constructed for CETP and PCSK9 plasma protein concentrations, which were combined to determine the associations of combined genetically reduced CETP and PCSK9 concentrations with disease. MAIN OUTCOMES AND MEASURES: Blood lipid and lipoprotein concentrations, blood pressure, CAD, age-related macular degeneration, type 2 diabetes, any stroke and ischemic stroke, Alzheimer disease, vascular dementia, heart failure, atrial fibrillation, chronic kidney disease, asthma, and multiple sclerosis. RESULTS: Data for 425 354 UKB participants were included; the median (IQR) age was 59 years (51-64), and 229 399 (53.9%) were female. The associations of lower CETP and lower PCSK9 concentrations with CAD are similar when scaled per 10-mg/dL reduction in LDL-C concentrations (CETP: odds ratio [OR], 0.74; 95% CI, 0.67 to 0.81; PCSK9: OR, 0.75; 95% CI, 0.71 to 0.79). Combined exposure to lower CETP and PCSK9 concentrations was associated with an additive magnitude with lipids and all outcomes, and we did not observe any nonadditive interactions, most notably for LDL-C (CETP: effect size, -1.11 mg/dL; 95% CI, -1.40 to -0.82; PCSK9: effect size, -2.13 mg/dL; 95% CI, -2.43 to -1.84; combined: effect size, -3.47 mg/dL; 95% CI, -3.76 to -3.18; P = .34 for interaction) and CAD (CETP: OR, 0.96; 95% CI, 0.94 to 1.00; PCSK9: OR, 0.94; 95% CI, 0.91 to 0.97; combined: OR, 0.90; 95% CI, 0.87 to 0.93; P = .83 for interaction). In addition, when corrected for multiple testing, lower CETP concentrations were associated with increased age-related macular degeneration (OR, 1.11; 95% CI, 1.04 to 1.19). CONCLUSIONS AND RELEVANCE: Our results suggest that joint inhibition of CETP and PCSK9 has additive effects on lipid traits and disease risk, including a lower risk of CAD. Further research may explore whether a combination of CETP- and PCSK9-related therapeutics can benefit high-risk patients who are unable to reach treatment targets with existing options.

Traditional Gamma Knife radiosurgery (GKRS) of brain arteriovenous malformations (AVMs) using digital subtraction angiography (DSA) requires head immobilization using a stereotactic frame.We describe our protocol of frameless GKRS using DSA while maintaining high spatial resolution for precision.This study is a retrospective review of patients with unruptured AVMs who underwent frameless GKRS. Magnetic resonance imaging and 3-dimensional DSA were obtained without a stereotactic frame for all patients. The imaging studies were merged for contouring of the AVM nidus. During GKRS treatment, patients were immobilized using an individually molded thermoplastic mask.Thirty-one patients were included in the analysis. The median age is 45.0 years (interquartile range [IQR]: 28.0-55.0). The median nidus size is 3.0 cm (IQR: 2.0-3.4). One patient had a Spetzler-Martin grade I, 11 had a grade II, 11 had a grade III, 6 had a grade IV, and 2 had a grade V AVM. Eleven patients underwent preradiosurgical embolization, 3 patients had previous microsurgical resection and/or embolization, and 1 patient had prior radiosurgery. The median administered dose was 20 Gy (IQR: 18.0-21.0). All patients completed their treatment with the planned radiation dose without complications.This is the first study that integrates DSA in the treatment planning of brain AVMs using GKRS without utilizing a stereotactic head frame. Frameless GKRS provides numerous advantages over frame-based techniques including improved patient experience and the capability of fractionation and thus expanding the eligibility of more AVMs for radiosurgery, while maintaining high spatial resolution of the AVM using angiography data.

Opportunistic osteoporosis screening using multidetector CT-scans (MDCT) and convolutional neural network (CNN)-derived segmentations of the spine to generate volumetric bone mineral density (vBMD) bears the potential to improve incidental osteoporotic vertebral fracture (VF) prediction. However, the performance compared to the established manual opportunistic vBMD measures remains unclear. Hence, we investigated patients with a routine MDCT of the spine who had developed a new osteoporotic incidental VF and frequency matched to patients without incidental VFs as assessed on follow-up MDCT images after 1.5 years. Automated vBMD was generated using CNN-generated segmentation masks and asynchronous calibration. Additionally, manual vBMD was sampled by two radiologists. Automated vBMD measurements in patients with incidental VFs at 1.5-years follow-up (n = 53) were significantly lower compared to patients without incidental VFs (n = 104) (83.6 ± 29.4 mg/cm3 vs. 102.1 ± 27.7 mg/cm3, p < 0.001). This comparison was not significant for manually assessed vBMD (99.2 ± 37.6 mg/cm3 vs. 107.9 ± 33.9 mg/cm3, p = 0.30). When adjusting for age and sex, both automated and manual vBMD measurements were significantly associated with incidental VFs at 1.5-year follow-up, however, the associations were stronger for automated measurements (β = −0.32; 95% confidence interval (CI): −20.10, 4.35; p < 0.001) compared to manual measurements (β = −0.15; 95% CI: −11.16, 5.16; p < 0.03). In conclusion, automated opportunistic measurements are feasible and can be useful for bone mineral density assessment in clinical routine.

A new method for the preparation of polyaniline (PANI) films that have a 2D structure and can record high active mass loading (up to 30 mg cm−2) via acid-assisted polymerization in the presence of concentrated formic acid was developed. This new approach represents a simple reaction pathway that proceeds quickly at room temperature in quantitative isolated yield with the absence of any byproducts and leads to the formation of a stable suspension that can be stored for a prolonged time without sedimentation. The observed stability was explained by two factors: (a) the small size of the obtained rod-like particles (50 nm) and (b) the change of the surface of colloidal PANI particles to a positively charged form by protonation with concentrated formic acid. The films cast from the concentrated suspension were composed of amorphous PANI chains assembled into 2D structures with nanofibrillar morphology. Such PANI films demonstrated fast and efficient diffusion of the ions in liquid electrolyte and showed a pair of revisable oxidation and reduction peaks in cyclic voltammetry. Furthermore, owing to the high mass loading, specific morphology, and porosity, the synthesized polyaniline film was impregnated by a single-ion conducting polyelectrolyte-poly(LiMn-r-PEGMm) and characterized as a novel lightweight all-polymeric cathode material for solid-state Li batteries by cyclic voltammetry and electrochemical impedance spectroscopy techniques.

Vertical transmission of SARS-CoV-2 from mother to fetus is widely accepted. Whereas most infected neonates present with mild symptoms or are asymptomatic, respiratory distress syndrome (RDS) and abnormal lung images are significantly more frequent in COVID-19 positive neonates than in non-infected newborns. Fatality is rare and discordant meta-analyses of case reports and series relating perinatal maternal COVID-19 status to neonatal disease severity complicate their extrapolation as prognostic indicators. A larger database of detailed case reports from more extreme cases will be required to establish therapeutic guidelines and allow informed decision making. Here we report an unusual case of a 28 weeks' gestation infant with perinatally acquired SARS-CoV-2, who developed severe protracted respiratory failure. Despite intensive care from birth with first line anti-viral and anti-inflammatory therapy, respiratory failure persisted, and death ensued at 5 months. Lung histopathology showed severe diffuse bronchopneumonia, and heart and lung immunohistochemistry confirmed macrophage infiltration, platelet activation and neutrophil extracellular trap formation consistent with late multisystem inflammation. To our knowledge, this is the first report of SARS CoV-2 pulmonary hyperinflammation in a preterm newborn with fatal outcome.

We demonstrate a simple connection between dictionary methods for time series classification, which involve extracting and counting symbolic patterns in time series, and methods based on transforming input time series using convolutional kernels, namely ROCKET and its variants. We show that by adjusting a single hyperparameter it is possible to move by degrees between models resembling dictionary methods and models resembling ROCKET. We present HYDRA, a simple, fast, and accurate dictionary method for time series classification using competing convolutional kernels, combining key aspects of both ROCKET and conventional dictionary methods. HYDRA is faster and more accurate than the most accurate existing dictionary methods, and can be combined with ROCKET and its variants to further improve the accuracy of these methods., 27 pages, 18 figures

Background: Clinical guidelines recommend regular screening for arrhythmogenic right ventricular cardiomyopathy (ARVC) to monitor at-risk relatives, resulting in a significant burden on clinical resources. Prioritizing relatives on their probability of developing definite ARVC may provide more efficient patient care. Objectives: The aim of this study was to determine the predictors and probability of ARVC development over time among at-risk relatives. Methods: A total of 136 relatives (46% men, median age 25.5 years [IQR: 15.8-44.4 years]) from the Netherlands Arrhythmogenic Cardiomyopathy Registry without definite ARVC by 2010 task force criteria were included. Phenotype was ascertained using electrocardiography, Holter monitoring, and cardiac imaging. Subjects were divided into groups with “possible ARVC” (only genetic or familial predisposition) and “borderline ARVC” (1 minor task force criterion plus genetic or familial predisposition). Cox regression was performed to determine predictors and multistate modeling to assess the probability of ARVC development. Results were replicated in an unrelated Italian cohort (57% men, median age 37.0 years [IQR: 25.4-50.4 years]). Results: At baseline, 93 subjects (68%) had possible ARVC, and 43 (32%) had borderline ARVC. Follow-up was available for 123 relatives (90%). After 8.1 years (IQR: 4.2-11.4 years), 41 (33%) had developed definite ARVC. Independent of baseline phenotype, symptomatic subjects (P = 0.014) and those 20 to 30 years of age (P = 0.002) had a higher hazard of developing definite ARVC. Furthermore, patients with borderline ARVC had a higher probability of developing definite ARVC compared with those with possible ARVC (1-year probability 13% vs 0.6%, 3-year probability 35% vs 5%; P < 0.01). External replication showed comparable results (P > 0.05). Conclusions: Symptomatic relatives, those 20 to 30 years of age, and those with borderline ARVC have a higher probability of developing definite ARVC. These patients may benefit from more frequent follow-up, while others may be monitored less often.

Lifestyle-related phenotypes have been shown to be heritable and associated with DNA methylation. We aimed to investigate whether genetic predisposition to tobacco smoking, alcohol consumption, and higher body mass index (BMI) moderates the effect of these phenotypes on blood DNA methylation. We calculated polygenic scores (PGS) to quantify genetic predisposition to these phenotypes using training (N = 7,431) and validation (N = 4,307) samples. Using paired genetic-methylation data (N = 4,307), gene–environment interactions (i.e., PGS × lifestyle) were assessed using linear mixed-effects models with outcomes: 1) methylation at sites found to be strongly associated with smoking (1,061 CpGs), alcohol consumption (459 CpGs), and BMI (85 CpGs) and 2) two epigenetic ageing measures, PhenoAge and GrimAge. In the validation sample, PGS explained ~1.4% (P = 1 × 10(−14)), ~0.6% (P = 2 × 10(−7)), and ~8.7% (P = 7 × 10(−87)) of variance in smoking initiation, alcohol consumption, and BMI, respectively. Nominally significant interaction effects (P

Past research shows there are significant barriers for creating long lasting products. In this paper we examine, the distinct collaborative barriers design consultancies face when striving to design long-lasting products for client firms. Data is collected through case studies (four months of observations and interviews) from three projects. Through the study we find indications, that the value chain intricacies, provide distinct interfirm barriers for creating long lasting products. These barriers include vision clashes, misalignment in the aspired manufacturing quality and price position.

Recent work presented a framework for space-time-resolved neurophysiological process imaging that augments existing electromagnetic source imaging techniques. In particular, a nonlinear Analytic Kalman filter (AKF) has been developed to efficiently infer the states and parameters of neural mass models believed to underlie the generation of electromagnetic source currents. Unfortunately, as the initialization determines the performance of the Kalman filter, and the ground truth is typically unavailable for initialization, this framework might produce suboptimal results unless significant effort is spent on tuning the initialization. Notably, the relation between the initialization and overall filter performance is only given implicitly and is expensive to evaluate; implying that conventional optimization techniques, e.g. gradient or sampling based, are inapplicable. To address this problem, a novel efficient framework based on blackbox optimization has been developed to find the optimal initialization by reducing the signal prediction error. Multiple state-of-the-art optimization methods were compared and distinctively, Gaussian process optimization decreased the objective function by 82.1% and parameter estimation error by 62.5% on average with the simulation data compared to no optimization applied. The framework took only 1.6[Formula: see text]h and reduced the objective function by an average of 13.2% on 3.75[Formula: see text]min 4714-source channel magnetoencephalography data. This yields an improved method of neurophysiological process imaging that can be used to uncover complex underpinnings of brain dynamics.

Dysfunction of either the right or left ventricle can lead to heart failure (HF) and subsequent morbidity and mortality. We performed a genome-wide association study (GWAS) of 16 cardiac magnetic resonance (CMR) imaging measurements of biventricular function and structure. Cis- Mendelian randomization (MR) was used to identify plasma proteins associating with CMR traits as well as with any of the following cardiac outcomes: HF, non-ischemic cardiomyopathy, dilated cardiomyopathy (DCM), atrial fibrillation, or coronary heart disease. In total, 33 plasma proteins were prioritized, including repurposing candidates for DCM and/or HF: IL18R (providing indirect evidence for IL18), I17RA, GPC5, LAMC2, PA2GA, CD33, and SLAF7. In addition, 13 of the 25 druggable proteins (52%; 95% confidence interval, 0.31 to 0.72) could be mapped to compounds with known oncological indications or side effects. These findings provide leads to facilitate drug development for cardiac disease and suggest that cardiotoxicities of several cancer treatments might represent mechanism-based adverse effects.

In this short note, we derive a new bias adjusted maximum likelihood estimate for the shape parameter of the Weibull distribution with complete data and type I censored data. The proposed estimate of the shape parameter is significantly less biased and more efficient than the corresponding maximum likelihood estimate, while being simple to compute using existing maximum likelihood software procedures.

Background: We have developed a genome-wide association study analysis method called DEPTH (DEPendency of association on the number of Top Hits) to identify genomic regions potentially associated with disease by considering overlapping groups of contiguous markers (e.g., SNPs) across the genome. DEPTH is a machine learning algorithm for feature ranking of ultra-high dimensional datasets, built from well-established statistical tools such as bootstrapping, penalized regression, and decision trees. Unlike marginal regression, which considers each SNP individually, the key idea behind DEPTH is to rank groups of SNPs in terms of their joint strength of association with the outcome. Our aim was to compare the performance of DEPTH with that of standard logistic regression analysis.Methods: We selected 1,854 prostate cancer cases and 1,894 controls from the UK for whom 541,129 SNPs were measured using the Illumina Infinium HumanHap550 array. Confirmation was sought using 4,152 cases and 2,874 controls, ascertained from the UK and Australia, for whom 211,155 SNPs were measured using the iCOGS Illumina Infinium array.Results: From the DEPTH analysis, we identified 14 regions associated with prostate cancer risk that had been reported previously, five of which would not have been identified by conventional logistic regression. We also identified 112 novel putative susceptibility regions.Conclusions: DEPTH can reveal new risk-associated regions that would not have been identified using a conventional logistic regression analysis of individual SNPs.Impact: This study demonstrates that the DEPTH algorithm could identify additional genetic susceptibility regions that merit further investigation. Cancer Epidemiol Biomarkers Prev; 25(12); 1619–24. ©2016 AACR.

List of the previously identified 100 independent prostate cancer susceptibility SNPs.

Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 single-nucleotide polymorphisms (SNP) among a discovery set of 3,523 EOBC incident cases and 2,702 population control women ages ≤ 51 years. The SNPs with smallest P values were examined in a replication set of 3,470 EOBC cases and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P values to obtain a gene-based P value. We examined the gene with smallest P value for replication in 1,145 breast cancer cases and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P < 4 × 10−8) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P < 6 × 10−4) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P < 0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genome-wide gene-based threshold of 2.5 × 10−6. In conclusion, EOBC and LOBC seem to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer. Cancer Epidemiol Biomarkers Prev; 23(4); 658–69. ©2014 AACR.

Table S2: Odds ratio and 95% confidence limits for cancers associated with variants with pleiotropic associations. Figure S1: Flowchart showing analysis steps. Figure S2. Manhattan plots by chromosome for individual cancer sites. Figure S3. Results for rs11571833. Figure S4: Conditional QQ-plots.

Compelling evidence points to immune cell infiltration as a critical component of successful immunotherapy. However, there are currently no clinically available, noninvasive methods capable of evaluating immune contexture prior to or during immunotherapy. In this study, we evaluate a T-cell–specific PET agent, [18F]F-AraG, as an imaging biomarker predictive of response to checkpoint inhibitor therapy. We determined the specificity of the tracer for activated T cells in vitro and in a virally induced model of rhabdomyosarcoma. Of all immune cells tested, activated human CD8+ effector cells showed the highest accumulation of [18F]F-AraG. Isolation of lymphocytes from the rhabdomyosarcoma tumors showed that more than 80% of the intratumoral signal came from accumulation of [18F]F-AraG in immune cells, primarily CD8+ and CD4+. Longitudinal monitoring of MC38 tumor-bearing mice undergoing anti-PD-1 treatment revealed differences in signal between PD-1 and isotype antibody–treated mice early into treatment. The differences in [18F]F-AraG signal were also apparent between responders and nonresponders to anti-PD-1 therapy. Importantly, we found that the signal in the tumor-draining lymph nodes provides key information about response to anti-PD-1 therapy. Overall, [18F]F-AraG has potential to serve as a much needed immunomonitoring clinical tool for timely evaluation of immunotherapy.Significance:These findings reveal differences in T-cell activation between responders and nonresponders early into anti-PD-1 treatment, which may impact many facets of immuno-oncology, including patient selection, management, and development of novel combinatorial approaches.

Plot of the first two principal components for the 7,920 participants in the iCOGS dataset.

Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103–14. ©2016 AACR.

Technical details of the DEPTH procedure.

FACS analyses, expression of transporters and kinases in immune cells, tumor growth.

PDF file - 197K, Table S1. Discovery set study populations. Table S2. Distribution of discovery set subjects by site, case-control status and chip. Table S3. Discovery set quality control summary. Table S4. SNPs with score-based P-values < 4 X 10-8 among 58016 SNPs for which Plink aborted the logistic regressions. Table S5. Replication set study populations. Table S6. Distribution of replication set subjects by site, case-control status and

Funding sources, acknowledgements, consortia involved in study and bioinformatics tools used

Variants selected for replication

The latent structure of individual difference constructs is a core concern in psychological science. Understanding latent structure has wide-ranging implications for measurement practices, statistical modelling choices, clinical/applied practice, and research examining etiology and causation. Most constructs in psychological science tend towards dimensional latent structure and can be accurately characterised as continua. One exception to this general rule is human sexual attraction. Within this area of psychological science, the status of sexual preference for children over adults is contested, with different studies suggesting varying latent structures. Using a large sample of males living in the community (N = 8,776), the current research aims to provide a robust evaluation of the latent structure of sexual maturity interests. Evidence for a three-taxa latent structure was confirmed in the sample. This study demonstrates human sexual maturity preference is populated with categorical constructs and has wide-ranging implications for future research in this area.

BackgroundTinnitus affects 10 to 15 percent of the population, but its underlying causes are not yet fully understood. Hearing loss has been established as the most important risk factor. Ageing is also known to accompany increased prevalence, however, the risk is normally seen as a consequence of (age-related) hearing loss. Whether ageing per se is a risk factor has not yet been established. We specifically focused on the effect of ageing and the relationship between age, hearing loss and tinnitus.MethodsWe used two samples for our analyses. The first, exploratory analyses, comprised 2249 Austrian individuals. The second included data from 16008 people, drawn from a publicly available dataset (NHANES). We used logistic regressions to investigate the effect of age on tinnitus.FindingsIn both samples, ageing per se was found to be a significant predictor of tinnitus. In the more decisive NHANES sample, an interaction effect was observed as well. Odds ratio analyses show that per unit increase of hearing loss the odds of reporting tinnitus is higher in older people (1.06 vs 1.03).InterpretationExpanding previous findings of hearing loss as the main risk factor for tinnitus, we established ageing as a risk factor in its own right. Underlying mechanisms remain unclear, and this work calls for urgent research efforts to link biological ageing processes, hearing loss and tinnitus. We therefore suggest a novel working hypothesis that integrates these aspects from an ageing brain viewpoint.FundingAustrian Research Promotion Agency (FFG; BRIDGE 1 project “SmartCIs,” 871232) and Land Salzburg (“Hidden Hearing Loss”, 20204-WISS/225/288/4-2021).

Healthy human skin is constantly exposed to sterile and microbial agents. The skin immune system plays an important role in immune surveillance between tolerance and immune activation. This is mainly mediated by neutrophils, macrophages and most importantly lymphocytes. Keratinocytes, which form the outer skin barrier (epidermis) are also critical for cutaneous homeostasis. Being a non-professional immune cell, recognition of danger signals in keratinocytes is mediated by innate immune receptors (pattern recognition receptors, PRR). While Toll-like receptors are located on the cell membrane or the endosomes, nucleotide-binding domain and leucine-rich repeat containing gene family receptors (NLR) are intracellular PRRs. Some of these, once activated, trigger the formation of inflammasomes. Inflammasomes are multiprotein complexes and serve as platforms that mediate the release of innate cytokines after successful recognition, thereby attracting immune cells. Moreover, they mediate the pro-inflammatory cell death pyroptosis. Best characterized is the NLRP3 inflammasome. The function of inflammasomes differs significantly between different cell types (keratinocytes versus immune cells) and between different species (human versus mouse). In recent years, great progress has been made in deciphering the activation mechanisms. Dysregulation of inflammasomes can lead to diseases with varying degrees of severity. Here we focus on the structure, function, and associated pathologies of the NLRP1 inflammasome, which is the most relevant inflammasome in keratinocytes.