Diffusion Brazing of Ti-6Al-4V and Stainless Steel 316L Using AgCuZn Filler Metal

In the present study, vacuum brazing was applied to join Ti-6Al-4V and stainless steel using AgCuZn filler metal. The bonds were characterized by scanning electron microscopy, energy dispersive spectroscopy and X-ray diffraction analysis. Mechanical strengths of the joints were evaluated by the shear test and microhardness. It has been shown that shear strength decreased with increasing the brazing temperature and time. The wettability of the filler alloy was increased by enhancing the wetting test temperature. By increasing the brazing temperature various intermetallic compounds were formed in the bond area. These intermetallic compounds were mainly a combination of CuTi and Fe-Cu-Ti. The shear test results verified the influence of the bonding temperature on the strength of the joints based on the formation of different intermetallics in the bond zone. The fracture analysis also revealed different fracture footpath and morphology for different brazing temperatures

Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration

BACKGROUND & AIMS: Excess liver iron content is common and is linked to hepatic and extrahepatic disease risk. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. METHODS: First, we performed a genome-wide association study (GWAS) in 8,289 individuals in UK Biobank with MRI quantified liver iron, and validated our findings in an independent cohort (n=1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 29 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 anthropometric traits and diseases. RESULTS: We identified three independent genetic variants (rs1800562 (C282Y) and rs1799945 (H63D) in HFE and rs855791 (V736A) in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p < 5x10-8). The two HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. CONCLUSION: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases. LAY SUMMARY: Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and heart disease. We find that three genetic variants are linked to increased risk of developing higher liver iron content. We show that the same genetic variants are linked to higher risk of many diseases, but they may also be associated with some health advantages. Finally, we use genetic variants associated with waist-to-hip ratio as a tool to show that central obesity is causally associated with increased liver iron content

Comparison of Clinician Suspicion Versus a Clinical Prediction Rule in Identifying Children at Risk for Intra‐abdominal Injuries After Blunt Torso Trauma

ObjectivesEmergency department (ED) identification and radiographic evaluation of children with intra‐abdominal injuries who need acute intervention can be challenging. To date, it is unclear if a clinical prediction rule is superior to unstructured clinician judgment in identifying these children. The objective of this study was to compare the test characteristics of clinician suspicion with a derived clinical prediction rule to identify children at risk of intra‐abdominal injuries undergoing acute intervention following blunt torso trauma.MethodsThis was a planned subanalysis of a prospective, multicenter observational study of children (50% prior to knowledge of abdominal computed tomography (CT) scanning (if performed). Intra‐abdominal injuries undergoing acute intervention were defined by a therapeutic laparotomy, angiographic embolization, blood transfusion for abdominal hemorrhage, or intravenous fluid administration for 2 or more days in those with pancreatic or gastrointestinal injuries. Patients were considered to be positive for clinician suspicion if suspicion was documented as ≥1%. Suspicion ≥ 1% was compared to the presence of any variable in the prediction rule for identifying children with intra‐abdominal injuries undergoing acute intervention.ResultsClinicians recorded their suspicion in 11,919 (99%) of 12,044 patients enrolled in the parent study. Intra‐abdominal injuries undergoing acute intervention were diagnosed in 203 (2%) patients. Abdominal CT scans were obtained in the ED in 2,302 of the 2,667 (86%, 95% confidence interval [CI] = 85% to 88%) enrolled patients with clinician suspicion ≥1% and in 3,016 of the 9,252 (33%, 95% CI = 32% to 34%) patients with clinician suspicion  50% previamente a conocer la tomografía computarizada (TC) abdominal (si fue realizada). La LIA con necesidad de intervención urgente se definió como laparotomía terapéutica, embolización angiográfica, transfusión de sangre por hemorragia intrabdominal o administración de fluidos intravenosos durante 2 o más días en aquéllos con lesiones pancreáticas o gastrointestinales. Los pacientes se consideraron positivos para la sospecha clínica si la sospecha se documentó como ≥1%. La sospecha > 1% se comparó con la presencia de cualquier variable en la regla de predicción para la identificación de niños con LIA con necesidad de una intervención urgente.ResultadosLos clínicos documentaron su sospecha en 11.919 (99%) de los 12.044 pacientes incluidos en el estudio original. La LIA con necesidad de intervención urgente se diagnosticó en 203 (2%) pacientes. Las TC abdominales se obtuvieron en el SU en 2.302 de los 2.667 pacientes (86%, IC95% = 85% a 88%) incluidos con sospecha clínica ≥1%; y en 3.016 de los 9.252 pacientes (33%, IC95% = 32% a 34%) con sospecha clínica < 1%. La sensibilidad de la regla de predicción para LIA con necesidad de intervención aguda fue mayor que la sospecha clínica ≥1% (197 de 203, 97,0%, IC95% = 93,7% a 98,9%, frente a 168 de 203, 82,8%, IC95% = 76,9% a 87,7%, respectivamente; diferencia de 14,2%, IC95% = 8,6% a 20,0%). La especificidad de la regla de predicción, sin embargo, fue menor que la sospecha clínica (4,979 de los 11.716, 42,5%, IC95% = 41,6% a 43,4%, frente a 9,217 de los 11.716, 78,7%, IC95% = 77,9% a 79,4%, respectivamente; diferencia de –36,2%, IC95% = –37,3% a –35,0%). Treinta y cinco de los pacientes con sospecha clínica < 1% (0,4%, IC95% = 0,3% a 0,5%) tuvieron LIA con necesidad de intervención urgente.ConclusionesLa regla de predicción clínica derivada tuvo una sensibilidad mayor de forma significativa, pero menor especificidad que la sospecha clínica para la identificación de niños con necesidad de una intervención urgente. La mayor especificidad de la sospecha clínica, sin embargo, no se tradujo en la práctica clínica, ya que los clínicos obtuvieron más frecuentemente TC abdominales en los pacientes que consideraron de muy bajo riesgo. Si se validase, esta regla de predicción puede ayudar en la toma de decisiones clínicas sobre el uso de TC abdominal en los niños con traumatismo torácico cerrado.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/113736/1/acem12739.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/113736/2/acem12739_am.pd

Computed Tomography With Intravenous Contrast Alone: The Role of Intra‐abdominal Fat on the Ability to Visualize the Normal Appendix in Children

Background Computed tomography ( CT ) with enteric contrast is frequently used to evaluate children with suspected appendicitis. The use of CT with intravenous ( IV ) contrast alone ( CT IV ) may be sufficient, however, particularly in patients with adequate intra‐abdominal fat ( IAF ). Objectives The authors aimed 1) to determine the ability of radiologists to visualize the normal (nondiseased) appendix with CT IV in children and to assess whether IAF adequacy affects this ability and 2) to assess the association between IAF adequacy and patient characteristics. Methods This was a retrospective 16‐center study using a preexisting database of abdominal CT scans. Children 3 to 18 years who had CT IV scan and measured weights and for whom appendectomy history was known from medical record review were included. The sample was chosen based on age to yield a sample with and without adequate IAF . Radiologists at each center reread their site's CT IV scans to assess appendix visualization and IAF adequacy. IAF was categorized as “adequate” if there was any amount of fat completely surrounding the cecum and “inadequate” if otherwise. Results A total of 280 patients were included, with mean age of 10.6 years (range = 3.1 to 17.9 years). All 280 had no history of prior appendectomy; therefore, each patient had a presumed normal appendix. A total of 102 patients (36.4%) had adequate IAF . The proportion of normal appendices visualized with CT IV was 72.9% (95% confidence interval [ CI ] = 67.2% to 78.0%); the proportions were 89% (95% CI  = 81.5% to 94.5%) and 63% (95% CI  = 56.0% to 70.6%) in those with and without adequate IAF (95% CI for difference of proportions = 16% to 36%). Greater weight and older age were strongly associated with IAF adequacy (p < 0.001), with weight appearing to be a stronger predictor, particularly in females. Although statistically associated, there was noted overlap in the weights and ages of those with and without adequate IAF . Conclusions Protocols using CT with IV contrast alone to visualize the appendix can reasonably include weight, age, or both as considerations for determining when this approach is appropriate. However, although IAF will more frequently be adequate in older, heavier patients, highly accurate prediction of IAF adequacy appears challenging solely based on age and weight. Resumen Tomografía Computarizada Únicamente con Contraste Intravenoso: El Papel de la Grasa Intrabadominal en la Capacidad para Visualizar el Apéndice Normal en los Niños Introduction La tomografía computarizada ( TC ) con contraste entérico es usada frecuentemente para evaluar a los niños con sospecha de apendicitis. El uso de la TC únicamente con contraste intravenoso ( TC IV ) puede ser suficiente, especialmente en pacientes con adecuada grasa intrabdominal ( GIA ). Objetivos 1) Determinar la capacidad de los radiólogos para visualizar el apéndice normal (sin enfermedad) con TC IV en niños, y valorar si la cantidad de GIA afecta a esta capacidad; y 2) valorar la asociación entre la idoneidad de la GIA y las características del paciente. Metodología Estudio retrospectivo de 16 hospitales que utilizó una base de datos prexistente de TC abdominales. Se incluyó a los niños entre 3 y 18 años que tenían una TC IV , una medida del peso e historia de apendectomía conocida por la revisión de la historia clínica. La muestra se eligió en base a la edad con el fin de conseguir una muestra con y sin GIA adecuada. Los radiólogos de cada centro releyeron las TC IV de sus centros para valorar la visualización del apéndice y la adecuación de la GIA . La GIA se clasificó como “adecuada” si había cualquier cantidad de grasa completamente alrededor del ciego e “inadecuada” si era de otra manera. Resultados Se incluyeron 280 pacientes, con una media de edad de 10,6 años (rango 3,1 a 17,9 años). Ninguno tenía historia previa de apendectomía; por lo tanto todos los pacientes tuvieron un apéndice presumiblemente normal. Ciento dos pacientes (36,4%) tuvieron GIA adecuada. El porcentaje de apéndices normales visualizados con TC IV fue de 72,9% ( IC 95% = 67,2% a 78,0%); la proporción fue 89% ( IC 95% = 81,5% a 94,5%), y 63% ( IC 95% = 56,0% a 70,6%) en aquéllos con y sin GIA adecuada ( IC 95% para la diferencia de proporciones = 16% a 36%). El mayor peso y la mayor edad se asociaron fuertemente con la adecuación de la GIA (p < 0,001), y el peso resultó ser el mayor factor predictivo, especialmente en mujeres. Aunque se asoció estadísticamente, se vio un solapamiento en los pesos y edades de aquéllos con y sin GIA adecuada. Conclusiones Los protocolos que usan la TC IV para visualizar el apéndice pueden razonablemente incluir el peso, la edad, o ambas como consideraciones para determinar cuándo esta aproximación es apropiada. Sin embargo, aunque la cantidad de GIA será frecuentemente más apropiada en los pacientes más mayores y de mayor peso, la predicción certera de adecuación de GIA es altamente desafiante si se basa sólo en la edad y el peso.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99695/1/acem12185.pd

Predicting and elucidating the etiology of fatty liver disease : A machine learning modeling and validation study in the IMI DIRECT cohorts

Background Non-alcoholic fatty liver disease (NAFLD) is highly prevalent and causes serious health complications in individuals with and without type 2 diabetes (T2D). Early diagnosis of NAFLD is important, as this can help prevent irreversible damage to the liver and, ultimately, hepatocellular carcinomas. We sought to expand etiological understanding and develop a diagnostic tool for NAFLD using machine learning. Methods and findings We utilized the baseline data from IMI DIRECT, a multicenter prospective cohort study of 3,029 European-ancestry adults recently diagnosed with T2D (n= 795) or at high risk of developing the disease (n= 2,234). Multi-omics (genetic, transcriptomic, proteomic, and metabolomic) and clinical (liver enzymes and other serological biomarkers, anthropometry, measures of beta-cell function, insulin sensitivity, and lifestyle) data comprised the key input variables. The models were trained on MRI-image-derived liver fat content (= 5%) available for 1,514 participants. We applied LASSO (least absolute shrinkage and selection operator) to select features from the different layers of omics data and random forest analysis to develop the models. The prediction models included clinical and omics variables separately or in combination. A model including all omics and clinical variables yielded a cross-validated receiver operating characteristic area under the curve (ROCAUC) of 0.84 (95% CI 0.82, 0.86;p = 5%) rather than a continuous one. Conclusions In this study, we developed several models with different combinations of clinical and omics data and identified biological features that appear to be associated with liver fat accumulation. In general, the clinical variables showed better prediction ability than the complex omics variables. However, the combination of omics and clinical variables yielded the highest accuracy. We have incorporated the developed clinical models into a web interface (see:) and made it available to the community.Peer reviewe

Genome-Wide and Abdominal MRI-Imaging Data Provides Evidence that a Genetically Determined Favourable Adiposity Phenotype is Characterized by Lower Ectopic Liver Fat and Lower Risk of Type 2 Diabetes, Heart Disease and Hypertension

Recent genetic studies have identified alleles associated with opposite effects on adiposity and risk of type 2 diabetes. We aimed to identify more of these variants and test the hypothesis that such favorable adiposity alleles are associated with higher subcutaneous fat and lower ectopic fat. We combined MRI data with genome-wide association studies of body fat percentage (%) and metabolic traits. We report 14 alleles, including 7 newly characterized alleles, associated with higher adiposity but a favorable metabolic profile. Consistent with previous studies, individuals carrying more favorable adiposity alleles had higher body fat % and higher BMI but lower risk of type 2 diabetes, heart disease, and hypertension. These individuals also had higher subcutaneous fat but lower liver fat and a lower visceral-to-subcutaneous adipose tissue ratio. Individual alleles associated with higher body fat % but lower liver fat and lower risk of type 2 diabetes included those in PPARG, GRB14, and IRS1, whereas the allele in ANKRD55 was paradoxically associated with higher visceral fat but lower risk of type 2 diabetes. Most identified favorable adiposity alleles are associated with higher subcutaneous and lower liver fat, a mechanism consistent with the beneficial effects of storing excess triglycerides in metabolically low-risk depots.</p

Pharmacogenomics of GLP-1 receptor agonists: a genome-wide analysis of observational data and large randomised controlled trials

Background: In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1 receptor agonists vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insight into drug action and provide biomarkers to inform clinical decision making. We therefore aimed to identify genetic variants associated with glycaemic response to GLP-1 receptor agonist treatment. Methods: In this genome-wide analysis we included adults (aged ≥18 years) with type 2 diabetes treated with GLP-1 receptor agonists with baseline HbA1c of 7% or more (53 mmol/mol) from four prospective observational cohorts (DIRECT, PRIBA, PROMASTER, and GoDARTS) and two randomised clinical trials (HARMONY phase 3 and AWARD). The primary endpoint was HbA1c reduction at 6 months after starting GLP-1 receptor agonists. We evaluated variants in GLP1R, then did a genome-wide association study and gene-based burden tests. Findings: 4571 adults were included in our analysis, of these, 3339 (73%) were White European, 449 (10%) Hispanic, 312 (7%) American Indian or Alaskan Native, and 471 (10%) were other, and around 2140 (47%) of the participants were women. Variation in HbA1c reduction with GLP-1 receptor agonists treatment was associated with rs6923761G→A (Gly168Ser) in the GLP1R (0·08% [95% CI 0·04–0·12] or 0·9 mmol/mol lower reduction in HbA1c per serine, p=6·0 × 10−5) and low frequency variants in ARRB1 (optimal sequence kernel association test p=6·7 × 10−8), largely driven by rs140226575G→A (Thr370Met; 0·25% [SE 0·06] or 2·7 mmol/mol [SE 0·7] greater HbA1c reduction per methionine, p=5·2 × 10−6). A similar effect size for the ARRB1 Thr370Met was seen in Hispanic and American Indian or Alaska Native populations who have a higher frequency of this variant (6–11%) than in White European populations. Combining these two genes identified 4% of the population who had a 30% greater reduction in HbA1c than the 9% of the population with the worse response. Interpretation: This genome-wide pharmacogenomic study of GLP-1 receptor agonists provides novel biological and clinical insights. Clinically, when genotype is routinely available at the point of prescribing, individuals with ARRB1 variants might benefit from earlier initiation of GLP-1 receptor agonists. Funding: Innovative Medicines Initiative and the Wellcome Trus