Identifying the genes that influence levels of pro-inflammatory molecules can help to elucidate the mechanisms underlying this process. We first conducted a two-stage genome-wide association scan ...(GWAS) for the key inflammatory biomarkers Interleukin-6 (IL-6), the general measure of inflammation erythrocyte sedimentation rate (ESR), monocyte chemotactic protein-1 (MCP-1), and high-sensitivity C-reactive protein (hsCRP) in a large cohort of individuals from the founder population of Sardinia. By analysing 731,213 autosomal or X chromosome SNPs and an additional ∼1.9 million imputed variants in 4,694 individuals, we identified several SNPs associated with the selected quantitative trait loci (QTLs) and replicated all the top signals in an independent sample of 1,392 individuals from the same population. Next, to increase power to detect and resolve associations, we further genotyped the whole cohort (6,145 individuals) for 293,875 variants included on the ImmunoChip and MetaboChip custom arrays. Overall, our combined approach led to the identification of 9 genome-wide significant novel independent signals-5 of which were identified only with the custom arrays-and provided confirmatory evidence for an additional 7. Novel signals include: for IL-6, in the ABO gene (rs657152, p = 2.13×10(-29)); for ESR, at the HBB (rs4910472, p = 2.31×10(-11)) and UCN119B/SPPL3 (rs11829037, p = 8.91×10(-10)) loci; for MCP-1, near its receptor CCR2 (rs17141006, p = 7.53×10(-13)) and in CADM3 (rs3026968, p = 7.63×10(-13)); for hsCRP, within the CRP gene (rs3093077, p = 5.73×10(-21)), near DARC (rs3845624, p = 1.43×10(-10)), UNC119B/SPPL3 (rs11829037, p = 1.50×10(-14)), and ICOSLG/AIRE (rs113459440, p = 1.54×10(-08)) loci. Confirmatory evidence was found for IL-6 in the IL-6R gene (rs4129267); for ESR at CR1 (rs12567990) and TMEM57 (rs10903129); for MCP-1 at DARC (rs12075); and for hsCRP at CRP (rs1205), HNF1A (rs225918), and APOC-I (rs4420638). Our results improve the current knowledge of genetic variants underlying inflammation and provide novel clues for the understanding of the molecular mechanisms regulating this complex process.
In this work, the possible use of quantum annealers for the optimization of multi-tower systems is studied. These systems are constituted by multiple solar towers and a set of mirrors (heliostats) ...reflecting the incident sun radiation toward a receiver on top of a tower of choice. The optimization consists in choosing on which tower each of the heliostats should focus the reflected radiation in order to optimize the global collected energy and, therefore, is inherently discrete. In this work, we formulated it in Quadratic Unconstrained Binary Optimization (QUBO) form and solved it with the use of quantum annealers. Results are shown for systems ranging from 2 to 9 towers and from tenths to thousands of heliostats. It is demonstrated that quantum annealers, used in hybrid mode, are effective in finding good solutions. The results are compared with the ones obtained with classical annealers showing comparable performances.
•Optimization of heliostat targeting to a tower of choice in multi-tower systems.•Adiabatic quantum computing optimization of solar fields.•Real time multi-tower solar field optimization.•Practical advantage of quantum annealers in multi-tower optimization.
In the past decade, quantum computing has undergone rapid evolution, capturing the increasing interest of the scientific community, industry, and governments. This enthusiasm has resulted in ...ambitious growth plans which stimulate the development of more efficient quantum computing devices and programming environments. The easy accessibility of quantum platforms in the cloud has attracted individuals to explore quantum computing, prompting a comprehensive analysis and assessment of quantum device's behavior. The extensive benchmarking presented in this study involved all free available quantum computing devices within the IBM Quantum Platform. These devices are employed to execute tens of thousands of quantum program executions, with the objective of evaluating quantum computer behavior and performance over time and under different optimization options. Special emphasis has been placed on analyzing the transpile operation and the depth of generated quantum circuits. The machine analysis tests are conducted using Quantum Computing Run Assistant (QCRA), a versatile software tool specifically designed to streamline the effortless distribution of quantum programs across a range of quantum computing platforms. This software not only streamlines the optimization of benchmarking processes but also simplifies the assessment of different configurations and result quality through the collection of advanced job metadata.
This study provides an extensive benchmark of Noisy Intermediate‐Scale Quantum (NISQ) devices, assessing behavior and performance with thousands of runs. Emphasizing transpile operations and circuit depth, it explores the correlation between final result fidelity and quantum circuit depth, comparing results over time for specific quantum machines. Quantum Computing Run Assistant (QCRA) optimizes benchmark processes across various configurations.
A quantum‐enhanced implementation of the binary inversion method for gravity data acquisition is discussed. The subsurface structure of a single density anomaly with an assigned density contrast is ...calculated by using a D‐Wave adiabatic quantum computer. In particular, an iterative heuristic based on quantum annealing that recovers a sharp shape of the subsurface anomaly is developed. Such a task is accomplished by collecting partial images obtained by quantum annealing processes for optimal Lagrange penalty coefficients. The results are compared with those obtained according to the same cost function minimized via genetic algorithms by conventional hardware on a realistic 2D dataset. The outcomes of this work are promising as the reconstructed model is obtained in tenths of iterations instead of the hundreds required in conventional methods. Moreover, for the part of the computation that resides in the quantum processing unit, the computational cost of the single quantum annealing descent is constant with respect to the number of degrees of freedom of the subsurface grid. The implemented method is likely to reveal its full potential on forthcoming quantum annealing devices, outperforming existing techniques.
The gravity inversion method is used to map the subsurface density distributions starting from surface measurements. The article investigates a quantum‐enhanced binary inversion formulation, addressing a novel application of quantum annealing to geophysics. The algorithm is tested in two different realistic use cases. When non‐convexity of the associated optimization problem prevails, a hybrid classical‐quantum approach provides an improved subsurface reconstruction.
Primary biliary cirrhosis（PBC）,which is characterised by progressive destruction of intrahepatic bile ducts,is not a rare disease since both prevalence and incidence are increasing during the last ...years mainly due to the improvement of case finding strategies.The prognosis of the disease has improved due to both the recognition of earlier and indolent cases,and to the wide use of ursodeoxycholic acid（UDCA）.New indicators of prognosis are available that will be useful especially for the growing number of patients with less severe disease.Most patients are asymptomatic at presentation.Pruritus may represent the most distressing symptom and,when UDCA is ineffective,cholestyramine represents the mainstay of treatment.Complications of long-standing cholestasis may be clinically relevant only in very advanced stages.Available data on the effects of UDCA on clinically relevant end points clearly indicate that the drug is able to slow but not to halt the progression of the disease while,in advanced stages,the only therapeutic option remains liver transplantation.
ObjectivesTo analyse the prevalence of CECR1 mutations in patients diagnosed with early onset livedo reticularis and/or haemorrhagic/ischaemic strokes in the context of inflammation or polyarteritis ...nodosa (PAN). Forty-eight patients from 43 families were included in the study.MethodsDirect sequencing of CECR1 was performed by Sanger analysis. Adenosine deaminase 2 (ADA2) enzymatic activity was analysed in monocyte isolated from patients and healthy controls incubated with adenosine and with or without an ADA1 inhibitor.ResultsBiallelic homozygous or compound heterozygous CECR1 mutations were detected in 15/48 patients. A heterozygous disease-associated mutation (p.G47V) was observed in two affected brothers. The mean age of onset of the genetically positive patients was 24 months (6 months to 7 years). Ten patients displayed one or more cerebral strokes during their disease course. Low immunoglobulin levels were detected in six patients. Thalidomide and anti-TNF (tumour necrosis factor) blockers were the most effective drugs. Patients without CECR1 mutations had a later age at disease onset, a lower prevalence of neurological and skin manifestations; one of these patients displayed all the clinical features of adenosine deaminase 2deficiency (DADA2) and a defective enzymatic activity suggesting the presence of a missed mutation or a synthesis defect.ConclusionsDADA2 accounts for paediatric patients diagnosed with PAN-like disease and strokes and might explain an unrecognised condition in patients followed by adult rheumatologist. Timely diagnosis and treatment with anti-TNF agents are crucial for the prevention of severe complications of the disease. Functional assay to measure ADA2 activity should complement genetic testing in patients with non-confirming genotypes.
Purpose
The aim of this prospective multicenter study was to compare antibiotic therapy and appendectomy as treatment for patients with uncomplicated appendicitis confirmed by ultrasound and/or ...computed tomography.
Methods
The study was conducted from January 2017 to January 2018. Data regarding all patients discharged from the participating centers with a diagnosis of uncomplicated appendicitis were collected prospectively.
Results
Of the 318 patients enrolled in the study, 27.4% underwent antibiotic-first therapy, and 72.6% underwent appendectomy. The matched group was composed of 87 patients in both study arms. Of the 87 patients available of 1-year follow-up in the antibiotic-first group, 64 (73.6%) did not require appendectomy. The complication-free treatment success in the antibiotic-first group was 64.4%. A statistically significant higher complication-free treatment success was found in the appendectomy group: 81.8% in the pre-matching sample and 83.9% in the post-matching sample. Patients in the antibiotic-first group reported lower VAS scores compared to those treated with an appendectomy, both at discharge (2.0 ± 1.7 vs 3.6 ± 2.3) and at 30-day follow-up (0.3 ± 0.6 vs 2.1 ± 1.7). The mean of the days of absence from work was higher in the appendectomy group (
β
0.63; 95% CI 0.08–1.18).
Conclusion
Although laparoscopic appendectomy remains the gold standard of treatment for uncomplicated appendicitis, conservative treatment with antibiotics is a safe option in most cases. Approximately 65% of patients treated with antibiotics are symptom-free at 1 year, without increased risk of adverse events should symptoms recur, and better outcomes in terms of less pain and shorter period of absence from work compared to patients undergoing an appendectomy.
Trial registration
Clinicaltrials.gov
identifier (NCT number): NCT03080103
Abstract Background About 40% of clopidogrel-treated patients display high platelet reactivity (HPR). Alternative treatments of HPR patients, identified by platelet function tests, failed to improve ...their clinical outcomes in large randomized clinical trials. A more appealing alternative would be to identify HPR patients a priori , based on the presence/absence of demographic, clinical and genetic factors that affect PR. Due to the complexity and multiplicity of these factors, traditional statistical methods (TSMs) fail to identify a priori HPR patients accurately. The objective was to test whether Artificial Neural Networks (ANNs) or other Machine Learning Systems (MLSs), which use algorithms to extract model-like ‘structure’ information from a given set of data, accurately predict platelet reactivity (PR) in clopidogrel-treated patients. Methods A complete set of fifty-nine demographic, clinical, genetic data was available of 603 patients with acute coronary syndromes enrolled in the prospective GEPRESS study, which showed that HPR after 1 month of clopidogrel treatment independently predicted adverse cardiovascular events in patients with Syntax Score > 14. Data were analysed by MLSs and TSMs. ANNs identified more variables associated PR at 1 month, compared to TSMs. Results ANNs overall accuracy in predicting PR, although superior to other MLSs was 63% (95% CI 59–66). PR phenotype changed in both directions in 35% of patients across the 3 time points tested (before PCI, at hospital discharge and at 1 month). Conclusions Despite their ability to analyse very complex non-linear phenomena, ANNs or MLS were unable to predict PR accurately, likely because PR is a highly unstable phenotype.
Acute appendicitis (AA) is among the most common causes of acute abdominal pain. Diagnosis of AA is still challenging and some controversies on its management are still present among different ...settings and practice patterns worldwide. In July 2015, the World Society of Emergency Surgery (WSES) organized in Jerusalem the first consensus conference on the diagnosis and treatment of AA in adult patients with the intention of producing evidence-based guidelines. An updated consensus conference took place in Nijemegen in June 2019 and the guidelines have now been updated in order to provide evidence-based statements and recommendations in keeping with varying clinical practice: use of clinical scores and imaging in diagnosing AA, indications and timing for surgery, use of non-operative management and antibiotics, laparoscopy and surgical techniques, intra-operative scoring, and peri-operative antibiotic therapy.
This executive manuscript summarizes the WSES guidelines for the diagnosis and treatment of AA. Literature search has been updated up to 2019 and statements and recommendations have been developed according to the GRADE methodology. The statements were voted, eventually modified, and finally approved by the participants to the consensus conference and by the board of co-authors, using a Delphi methodology for voting whenever there was controversy on a statement or a recommendation. Several tables highlighting the research topics and questions, search syntaxes, and the statements and the WSES evidence-based recommendations are provided. Finally, two different practical clinical algorithms are provided in the form of a flow chart for both adults and pediatric (< 16 years old) patients.
The 2020 WSES guidelines on AA aim to provide updated evidence-based statements and recommendations on each of the following topics: (1) diagnosis, (2) non-operative management for uncomplicated AA, (3) timing of appendectomy and in-hospital delay, (4) surgical treatment, (5) intra-operative grading of AA, (6) ,management of perforated AA with phlegmon or abscess, and (7) peri-operative antibiotic therapy.
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