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Owing to the natural evolution of a disease, several events often arise after a first treatment for the same subject. For example, patients with a primary invasive breast cancer and treated with breast conserving surgery may experience breast cancer recurrences, metastases or death. A certain proportion of subjects in the population who are not expected to experience the events of interest are considered to be ‘cured’ or non-susceptible. To model correlated failure time data incorporating a surviving fraction, we compare several forms of cure rate frailty models. In the first model already proposed non-susceptible patients are those who are not expected to experience the event of interest over a sufficiently long period of time. The other proposed models account for the possibility of cure after each event. We illustrate the cure frailty models with two data sets. First to analyse time-dependent prognostic factors associated with breast cancer recurrences, metastases, new primary malignancy and death. Second to analyse successive rehospitalizations of patients diagnosed with colorectal cancer. Estimates were obtained by maximization of likelihood using SAS proc NLMIXED for a piecewise constant hazards model. As opposed to the simple frailty model, the proposed methods demonstrate great potential in modelling multivariate survival data with long-term survivors (‘cured’ individuals). [ABSTRACT FROM AUTHOR]

Background: Genome-wide association studies have identified determinants of chronic obstructive pulmonary disease, asthma, and lung function level; however, none have addressed decline in lung function. Objective: We conducted the first genome-wide association study on the age-related decrease in FEV1 and its ratio to forced vital capacity (FVC) stratified a priori by asthma status. Methods: Discovery cohorts included adults of European ancestry (1,441 asthmatic and 2,677 nonasthmatic participants: the Epidemiological Study on the Genetics and Environment of Asthma, the Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults, and the European Community Respiratory Health Survey). The associations of FEV1 and FEV1/FVC ratio decrease with 2.5 million single nucleotide polymorphisms (SNPs) were estimated. Thirty loci were followed up by in silico replication (1,160 asthmatic and 10,858 nonasthmatic participants: Atherosclerosis Risk in Communities, the Framingham Heart Study, the British 1958 Birth Cohort, and the Dutch Asthma Study). Results: Main signals identified differed between asthmatic and nonasthmatic participants. None of the SNPs reached genome-wide significance. The association between the height-related gene DLEU7 and FEV1 decrease suggested for nonasthmatic participants in the discovery phase was replicated (discovery, P = 4.8 × 10−6; replication, P = .03), and additional sensitivity analyses point to a relation to growth. The top ranking signal, TUSC3, which is associated with FEV1/FVC ratio decrease in asthmatic participants (P = 5.3 × 10−8), did not replicate. SNPs previously associated with cross-sectional lung function were not prominently associated with decline. Conclusions: Genetic heterogeneity of lung function might be extensive. Our results suggest that genetic determinants of longitudinal and cross-sectional lung function differ and vary by asthma status. [Copyright &y& Elsevier]

Transient receptor potential cation channels of the vanilloid subfamily (TRPV) participate in the generation of Ca2+ signals at different locations of the respiratory system, thereby controlling its correct functioning. TRPV1 expression and activity appear to be altered under pathophysiological conditions such as chronic cough and airway hypersensitivity, whereas TRPV4 single nucleotide polymorphisms (SNP) are associated with chronic obstructive pulmonary disease. However, to date, there is no information about the genetic impact of either TRPV1 or TRPV4 on asthma pathophysiology. We now report on the association of two functional SNPs, TRPVI-I585V and TRPV4-P1 with childhood asthma. Both SNPs were genotyped in a population of 470 controls without respiratory symptoms and 301 asthmatics. Although none of the SNPs modified the risk of suffering from asthma, carriers of the TRPV1-ISBSV genetic variant showed a lower risk of current wheezing (odds ratio = 0.51; p = 0.01), a characteristic of active asthma, or cough (odds ratio = 0.57; p = 0.02). Functional analysis of TRPV1-1585V, using the Ca2+-sensitive dye fura-2 to measure intracellular [Ca2+] concentrations, revealed a decreased channel activity in response to two typical TRPV1 stimuli, heat and capsaicin. On the other hand, TRPV4-P19S, despite its loss-of-channel function, showed no significant association with asthma or the presence of wheezing. Our data suggest that genetically determined level of TRPV1 activity is relevant for asthma pathophysiology. [ABSTRACT FROM AUTHOR]

The chromosome bands 15q24.1-15q24.3 contain a complex region with numerous segmental duplications that predispose to regional microduplications and microdeletions, both of which have been linked to intellectual disability, speech delay and autistic features. The region may also harbour common inversion polymorphisms whose functional and phenotypic manifestations are unknown. Using single nucleotide polymorphism (SNP) data, we detected four large contiguous haplotype-genotypes at 15q24 with Mendelian inheritance in 2,562 trios, African origin, high population stratification and reduced recombination rates. Although the haplotype-genotypes have been most likely generated by decreased or absent recombination among them, we could not confirm that they were the product of inversion polymorphisms in the region. One of the blocks was composed of three haplotype-genotypes (N1a, N1b and N2), which significantly correlated with intelligence quotient (IQ) in 2,735 children of European ancestry from three independent population cohorts. Homozygosity for N2 was associated with lower verbal IQ (2.4-point loss, p-value = 0.01), while homozygosity for N1b was associated with 3.2-point loss in non-verbal IQ (p-value = 0.0006). The three alleles strongly correlated with expression levels of MAN2C1 and SNUPN in blood and brain. Homozygosity for N2 correlated with over-expression of MAN2C1 over many brain areas but the occipital cortex where N1b homozygous highly under-expressed. Our population-based analyses suggest that MAN2C1 may contribute to the verbal difficulties observed in microduplications and to the intellectual disability of microdeletion syndromes, whose characteristic dosage increment and removal may affect different brain areas.

The importance of maintaining data privacy and complying with regulatory requirements is highlighted especially when sharing omic data between different research centers. This challenge is even more pronounced in the scenario where a multi-center effort for collaborative omics studies is necessary. OmicSHIELD is introduced as an open-source tool aimed at overcoming these challenges by enabling privacy-protected federated analysis of sensitive omic data. In order to ensure this, multiple security mechanisms have been included in the software. This innovative tool is capable of managing a wide range of omic data analyses specifically tailored to biomedical research. These include genome and epigenome wide association studies and differential gene expression analyses. OmicSHIELD is designed to support both meta- and mega-analysis, so that it offers a wide range of capabilities for different analysis designs. We present a series of use cases illustrating some examples of how the software addresses real-world analyses of omic data. Author summary: OmicSHIELD revolutionizes the way researchers can engage with federated omics data, providing a secure framework for conducting different omic data analyses. This innovative platform allows data to stay in their original repositories, thus eliminating data transfer—a crucial feature in an era where data privacy regulations are becoming increasingly stringent. By leveraging advanced techniques like differential privacy, OmicSHIELD aims to mitigate disclosure risks associated with analysis of omics data, while still enabling accurate collaborative research. The platform is highly flexible, supporting processing and analysis of multiple omic data formats. This makes it a useful tool for researchers looking to perform complex analyses across multiple datasets. OmicSHIELD includes active disclosure control checks and the ability to compute a wide range of analytical methods useful to obtain insights from omic data. By prioritizing both analytical power and data privacy, OmicSHIELD addresses the most pressing challenges in omics research today, making it easier for scientists to unlock new insights while maintaining high ethical standards. [ABSTRACT FROM AUTHOR]

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified 10 novel risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with novel secondary signals at 4 of these). Notably, the new loci include candidate genes with roles in regulation of innate host defenses and T-cell function, underscoring the important contribution of (auto-)immune mechanisms to atopic dermatitis pathogenesis.

Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10−6) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; β = 0.046, SE = 0.008, P = 2.46 × 10−8, explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10−4) and adult height (N = 127 513; P = 1.45 × 10−5). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.

Background The literature supporting ventral hernia management is growing; however, it is unclear whether the quality of work is improving. We hypothesize that the quality of clinical ventral hernia research has improved over the past 2.5 decades. Methods A review of MEDLINE, Scopus, and Cochrane databases was conducted for all ventral hernia studies from January 1, 1980 to May 1, 2015. Relevant abstracts were assigned a level according to the Oxford Center for Evidence-Based Medicine. Reviews, and meta-analyses were graded using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Checklist and randomized controlled trials (RCTs) using the Consolidated Standards of Reporting Trials (CONSORT) checklist. Studies that did not fulfill at least 70% of the elements for the PRISMA (19/27) or CONSORT (26/37) checklists were considered to contain substantial methodological flaws. Results Of 12,431 citations, 1336 met criteria for quality evaluation. Level 1 studies were sparse ( n = 104, 7.8%), and most were level 2 or 3 ( n = 463, 34.7%) or 4 ( n = 769, 57.6%). Of the level 1 studies, 37 (35.6%) were RCTs, 61(58.7%) were reviews and/or meta-analyses, and 6 (5.8%) were consensus statements. Most RCTs and reviews and/or meta-analyses contained substantial methodological flaws (75.7%, 75.8%). Critical areas of weakness in RCTs were explaining losses and exclusions after randomization and/or allocation and reporting determination of sample size. For reviews and/or meta-analyses, areas of weakness were presenting an electronic search strategy and providing an assessment of risk of bias before pooling data. Linear regressions of PRISMA and CONSORT scores demonstrated improvement over time (PRISMA slope 0.95, R 2 = 0.24; CONSORT slope 0.34, R 2 = 0.08). Conclusions Although the quality of literature guiding ventral hernia management has improved over time, there is room for improvement. [ABSTRACT FROM AUTHOR]

Background: Transanal minimally invasive surgery (TAMIS) is an advanced local excision platform that helps overcome technical limitations and morbidity associated with other resection methods. Our goal was to review the indications and outcomes of TAMIS in a large series.Study Design: A review of a prospective database identified patients who underwent TAMIS from 2010 to 2014. Demographic, perioperative, short-term outcomes, and recurrence data were analyzed.Results: There were 75 patients with 76 lesions analyzed. Mean age was 64.0 years (SD 11.6 years) and mean BMI was 27.4 kg/m(2) (SD 4.7 kg/m(2)). Median American Society of Anesthesiologists (ASA) score was 2 (range 1 to 4). There were 59 benign (77.3%) and 17 malignant (22.7%) lesions: 6 pT0, 6 pT1, 4 pT2, and 1 pT3. Median lesion distance from the anal verge was 10 cm (range 6 to 16 cm). Mean operative time was 76.0 minutes (SD 36.1 minutes). Three patients had intraperitoneal entry; all were closed transanally, but 2 had temporary diverting ileostomies fashioned to ensure healing. Median length of stay was 1 day (range 0 to 6). One patient had a fragmented lesion (1.3%). Five patients had positive margins: 2 in palliative pT2 resections, and 3 in pT1, pT2, and gastrointestinal stromal tumor (GIST) patients. They were managed with radical resection (pT1 and pT2 lesions) and surveillance/medical oncology (GIST). Postoperatively, 3 patients had complications (bleeding, rectal stricture, and recto-vaginal fistula), and all were managed nonoperatively. After median follow-up of 39.5 months (range 10.5 to 65.3 months), 1 pT1 patient with negative margins developed a local recurrence and underwent salvage APR.Conclusions: Transanal minimally invasive surgery is a viable option for excision of benign or early stage rectal masses, with mid-term oncologic outcomes comparable to those of radical resection. Further, TAMIS minimizes the morbidity and can allow more patients to benefit from the minimally invasive approach. [ABSTRACT FROM AUTHOR]

• PIV single-phase measurements are analyzed for confined mixing. • Three parallel confined flows employed to investigate multi-regime mixing. • Physics are revealed with common traits to fundamental flow scenarios. • Multi-regime mixing is found to be superior relative to turbulent-turbulent mixing. The hydraulic single-phase mixing of three parallel rectangular channels is experimentally investigated at various Reynolds numbers (Re) and flow regime combinations. Particle Image Velocimetry results for seven mixing cases are presented and discussed with varying Re combinations ranging from 1,824 to 20,844. While all cases result in the same Re ratio of ∼0.69 between the inner and outer flows, two cases represent multi-regime mixing with the inner-outer regime pair of laminar-transitional and transitional-turbulent, while the other 5 cases are all characteristic of turbulent mixing with varying levels of turbulence. The outer channels initially share characteristics with a backward facing step. The center channel is found to initially behave like a slot jet, but then sees a significant increase in velocity decay. This inner flow velocity decay increased dramatically in the laminar-transitional mixing case, whose centerline velocity decay was ∼6 times larger than the decay in the turbulent mixing cases. Second order statistics revealed a consistent mixing layer thickness of ∼0.1 hydraulic diameters for all the cases but showed more intense shearing in the multi-regime mixing cases. The combined point and thereby the mixing layer length is determined using centerline velocity decay profiles, which show a much more aggressive mixing in multi-regime flows. Multi-regime mixing demonstrated superior characteristics relative to turbulent mixing due to a more dramatic velocity decay in the inner flow and a shorter mixing length. The contributions of this work include communicating the benefits of multi-regime mixing and providing detailed characterization efforts that can serve future efforts for validating computational models. This research also lays the groundwork for future studies aimed at achieving high levels of mixing without a severe penalty in pressure drop. [ABSTRACT FROM AUTHOR]

• Exposome studies suffer from low specificity and sensitivity when looking for causal predictors of an outcome. • Intermediary layer (eg methylome) information can help reducing exposome dimension. • We proposed an "oriented Meet-in-the-Middle" (oMITM) approach. • Simulations demonstrated that oMITM showed improved performance compared to current methods used. • oMITM is more robust to reverse causality than methods ignoring intermediary data. Challenges in the assessment of the health effects of the exposome, defined as encompassing all environmental exposures from the prenatal period onwards, include a possibly high rate of false positive signals. It might be overcome using data dimension reduction techniques. Data from the biological layers lying between the exposome and its possible health consequences, such as the methylome, may help reducing exposome dimension. We aimed to quantify the performances of approaches relying on the incorporation of an intermediary biological layer to relate the exposome and health, and compare them with agnostic approaches ignoring the intermediary layer. We performed a Monte-Carlo simulation, in which we generated realistic exposome and intermediary layer data by sampling with replacement real data from the Helix exposome project. We generated a Gaussian outcome assuming linear relationships between the three data layers, in 2381 scenarios under five different causal structures, including mediation and reverse causality. We tested 3 agnostic methods considering only the exposome and the health outcome: ExWAS (for Exposome-Wide Association study), DSA, LASSO; and 3 methods relying on an intermediary layer: two implementations of our new oriented Meet-in-the-Middle (oMITM) design, using ExWAS and DSA, and a mediation analysis using ExWAS. Methods' performances were assessed through their sensitivity and FDP (False-Discovery Proportion). The oMITM-based methods generally had lower FDP than the other approaches, possibly at a cost in terms of sensitivity; FDP was in particular lower under a structure of reverse causality and in some mediation scenarios. The oMITM–DSA implementation showed better performances than oMITM–ExWAS, especially in terms of FDP. Among the agnostic approaches, DSA showed the highest performance. Integrating information from intermediary biological layers can help lowering FDP in studies of the exposome health effects; in particular, oMITM seems less sensitive to reverse causality than agnostic exposome-health association studies. [ABSTRACT FROM AUTHOR]

BACKGROUND: The epigenetic effects of individual environmental toxicants in tobacco remain largely unexplored. Cadmium (Cd) has been associated with smoking-related health effects, and its concentration in tobacco smoke is higher in comparison with other metals. OBJECTIVES: We studied the association of Cd and smoking exposures with human blood DNA methylation (DNAm) profiles. We also evaluated the implication of findings to relevant methylation pathways and the potential contribution of Cd exposure from smoking to explain the association between smoking and site-specific DNAm. METHODS: We conducted an epigenome-wide association study of urine Cd and self-reported smoking (current and former vs. never, and cumulative smoking dose) with blood DNAm in 790,026 CpGs (methylation sites) measured with the Illumina Infinium Human MethylationEPIC (Illumina Inc.) platform in 2,325 adults 45–74 years of age who participated in the Strong Heart Study in 1989–1991. In a mediation analysis, we estimated the amount of change in DNAm associated with smoking that can be independently attributed to increases in urine Cd concentrations from smoking. We also conducted enrichment analyses and in silico protein–protein interaction networks to explore the biological relevance of the findings. RESULTS: At a false discovery rate (FDR)-corrected level of 0.05, we found 6 differentially methylated positions (DMPs) for Cd; 288 and 17, respectively, for current and former smoking status; and 77 for cigarette pack-years. Enrichment analyses of these DMPs displayed enrichment of 58 and 6 Gene Ontology and Kyoto Encyclopedia of Genes and Genomes gene sets, respectively, including biological pathways for cancer and cardiovascular disease. In in silico protein-to-protein networks, we observed key proteins in DNAm pathways directly and indirectly connected to Cd- and smokingDMPs. Among DMPs that were significant for both Cd and current smoking (annotated to PRSS23, AHRR, F2RL3, RARA, and 2q37.1), we found statistically significant contributions of Cd to smoking-related DNAm. CONCLUSIONS: Beyond replicating well-known smoking epigenetic signatures, we found novel DMPs related to smoking. Moreover, increases in smoking-related Cd exposure were associated with differential DNAm. Our integrative analysis supports a biological link for Cd and smoking-associated health effects, including the possibility that Cd is partly responsible for smoking toxicity through epigenetic changes. [ABSTRACT FROM AUTHOR]

Background: Financial interactions between industry and healthcare providers are reportable. Substantial discrepancies have been detected between industry and self-report of these conflicts of interest (COIs).Objective: Our aim was to determine if authors who fail to disclose reportable COI are more likely to publish findings that are favorable to industry than authors with no COI.Design: In this blinded, observational study of medical and surgical primary research articles in PubMed, 590 articles were reviewed.Main Measures: Reportable financial relationships between authors and industry were evaluated. COIs were considered to have relevance if they were associated with the product(s) mentioned by an article. Primary outcome was favorability, defined as an impression favorable to the product(s) discussed by an article and determined by 3 independent, blinded clinicians for each article. Primary analysis compared Incomplete Self-Disclosure to No COI. Two-level multivariable mixed-effects ordered logistic regression was used to assess factors associated with favorability.Key Results: A 69% discordance rate existed between industry and self-report in COI disclosure. When authors failed to disclose COI, their conclusions were more likely to favor industry partners than authors without COI (favorable ratings 73% versus 62%, RR 1.18, p = < 0.001). On univariate (any COI 74% versus no COI 62%, RR 1.11, p = < 0.001) and multivariable analyses, any COI was associated with favorability.Conclusions: All financial COIs (disclosed or undisclosed, relevant or not relevant, research or non-research) influence whether studies report findings favorable to industry sponsors. [ABSTRACT FROM AUTHOR]