Efficient and Effective Testing of Automotive Software Product Lines

Within the automotive industry, the clients’ high demand for individually customized products results in a growing number of product variants. In order to control the complexity of developing these variants, a product line approach is used that supports reuse of the common set of assets (e.g. requirements, software code, and test cases). The naive approach to assure quality of the variants derived from the product line would be to individually test each variant. However, due to the large number of variants it is virtually impossible to test all variants in detail and still release the product line on time. In this paper, we propose a new test approach based on requirements coverage and variant properties coverage (i.e. feature coverage) that leads to effective but also efficient test coverage of all variants of the product line. A set of variants is selected that is 1) as small as possible, 2) covers all requirements of the product line, and 3) covers all features of the product line. This small set of variants is then tested in detail. Reducing the number of tested variants allows for deeper testing and thus finding more defects. Because of the coverage achieved by the variant set, the quality of all other variants can be inferred from the test results. Finding the optimal set of variants in itself is a very hard problem, i.e. in an industry setting with huge numbers of possible variants it is practicably infeasible to strive for the optimum. Therefore, we developed two approaches which are not guaranteed to find the optimal set but get very near to it in little time. First, a greedy algorithm was created which produced very good results in very little time in all case studies. For example, for a system with one million variants a set of eight representing variants was selected within seconds. Second, a simulated annealing approach was evaluated in order to check for further potential of improvement. However, the case studies showed that the greedy algorithm is the better choice for practical results

Fat: Quality, or Quantity? What Matters Most for the Progression of Metabolic Associated Fatty Liver Disease (MAFLD)

Fibrosi; Obesitat; Àcid palmític (AP)Fibrosis; Obesidad; Ácido palmítico (AP)Fibrosis; Obesity; Palmitic acid (PA)Objectives: Lately, many countries have restricted or even banned transfat, and palm oil has become a preferred replacement for food manufacturers. Whether palm oil is potentially an unhealthy food mainly due to its high content of saturated Palmitic Acid (PA) is a matter of debate. The aim of this study was to test whether qualitative aspects of diet such as levels of PA and the fat source are risk factors for Metabolic Syndrome (MS) and Metabolic Associated Fatty Liver Disease (MAFLD). Methods: C57BL/6 male mice were fed for 14 weeks with three types of Western diet (WD): 1. LP-WD—low concentration of PA (main fat source—corn and soybean oils); 2. HP-WD—high concentration of PA (main fat source—palm oil); 3. HP-Trans-WD—high concentration of PA (mainly transfat). Results: All types of WD caused weight gain, adipocyte enlargement, hepatomegaly, lipid metabolism alterations, and steatohepatitis. Feeding with HP diets led to more prominent obesity, hypercholesterolemia, stronger hepatic injury, and fibrosis. Only the feeding with HP-Trans-WD resulted in glucose intolerance and elevation of serum transaminases. Brief withdrawal of WDs reversed MS and signs of MAFLD. However, mild hepatic inflammation was still detectable in HP groups. Conclusions: HP and HP-Trans-WD play a crucial role in the genesis of MS and MAFLD.This work was supported by the MINECO Retos SAF2016-78711, SAF2017-87919-R, PID2020-117827RB-IOO, PID2020-117941RB-IOO, EXOHEP-CM S2017/BMD-3727, NanoLiver-CM Y2018/NMT-4949, AMMF 2018/117, COST Action CA17112 and UCM-25/2019, German Research Foundation (SFB/TRR57/P04, SFB 1382-403224013/A02). F.J.C. and Y.A.N. are Ramón y Cajal Researchers RYC-2014-15242 and RYC-2015-17438. F.J.C. is a Gilead Liver Research Scholar. The research group belongs to the validated Research Groups Ref. 970935 ¨Liver Pathophysiology¨, 920631 ¨Lymphocyte immunobiology¨, 920361 “Inmunogenética e6937 inmunología de las mucosas” and IBL-6 (imas12-associated). O.E.-V. is supported by Beca FPI (associated with MINECO SAF2017-87919R), C.-S.G. by Atracción de Talento 2019-T1/BMD-1331 and R.B.-U. by Contratos predoctorales de personal investigador en formación UCM-Banco Santander (CT63/19). F.G. is a Chinese Scholarship Council (CSC) fellow. T.B. is supported by the German Research Foundation SFB 1382-403224013/B07, and P.A. by Ayudas para apoyar grupos de investigación del sistema Universitario Vasco (IT971-16) and MCIU/AEI/FEDER, UE (RTI2018-095134-B-100)

Biomarkers of hepatocellular synthesis in patients with decompensated cirrhosis

Abstract Background and aim Since hepatocytes produce majority of serum proteins, patients with cirrhosis display substantial alterations in the serum proteome. The aim of the current study was to characterize these changes and to study the prognostic utility of hepatocellular proteins available in routine clinical testing. Methods Sera from 29 healthy controls and 43 patients with cirrhosis were subjected to untargeted proteomic analysis. Unsupervised hierarchical clustering was performed with Perseus software and R . Ingenuity pathway analysis (IPA) suggested upstream regulators that were validated in liver tissues. The behavior and prognostic usefulness of selected biomarkers was investigated in 61 controls and 285 subjects with decompensated cirrhosis. Results Proteomics uncovered 65 and 16 hepatocellular serum proteins that are significantly downregulated or upregulated in patients with cirrhosis vs. controls. Hierarchical clustering revealed two main clusters and six sub-clusters. IPA identified HNF4α and IL-6 as the two major upstream regulators that were confirmed by hepatic gene expression analyses. Among pseudocholinesterase, transferrin, transthyretin, albumin, and apolipoprotein AI (Apo-AI), Apo-AI was the best predictor of 90-days transplant-free survival (AUROC 0.678; p  = 0.0001) and remained an independent predictor in multivariable Cox independently of the presence of acute-on-chronic liver failure. Conclusion Our study reveals cirrhosis-associated changes in hepatocellular serum proteins and underlying transcription factors. Serum apolipoprotein AI may constitute a useful prognostic adjunct in patients with decompensated cirrhosis. Graphical abstrac

Painful sex (dyspareunia) in women: prevalence and associated factors in a British population probability survey.

ObjectiveTo estimate the prevalence of painful sex among women in Britain, and to explore associated sexual, relationship and health factors that should be considered in assessment.DesignMulti-stage, clustered and stratified population probability sample survey, using computer-assisted self-interview. Sample frame was the British Postcode Address File.SettingParticipants interviewed at home between 2010 and 2012.SampleA total of 15 162 adults aged 16-74 years (8869 women). Data reported from 6669 sexually active women.MethodsAge-adjusted logistic regressions to examine associations between painful sex and indicators of sexual, relational, mental and physical health.Main outcome measurePhysical pain as a result of sex for ≥3 months in the past year, plus measures of symptom severity.ResultsPainful sex was reported by 7.5% (95% CI 6.7-8.3) of sexually active women, of whom one-quarter experienced symptoms very often or always, for ≥6 months, and causing distress. Reporting painful sex was strongly associated with other sexual function problems, notably vaginal dryness (age adjusted odds ratio 7.9; 6.17-10.12), anxiety about sex (6.34; 4.76-8.46) and lacking enjoyment in sex (6.12; 4.81-7.79). It was associated with sexual relationship factors [such as not sharing same level of interest in sex (2.56; 1.97-3.33)], as well as with adverse experiences such as non-volitional sex (2.17; 1.68-2.80). Associations were also found with measures of psychological and physical health, including depressive symptoms (1.68; 1.28-2.21).ConclusionPainful sex is reported by a sizeable minority of women in Britain. Health professionals should be supported to undertake holistic assessment and treatment which takes account of the sexual, relationship and health context of symptoms.Tweetable abstractPainful sex-reported by 7.5% of women in Britain-is linked to poorer sexual, physical, relational and mental health

Somatization and psychological distress among women with vulvar vestibulitis syndrome

ObjectiveTo investigate the distribution of psychological characteristics and pain reporting among women with vulvar vestibulitis syndrome (VVS).MethodsIn this exploratory study, 109 women with VVS completed a battery of questionnaires to assess pain with intercourse and psychological characteristics (e.g. somatization, anxiety, distress). The distribution of these characteristics was compared, first with a conventional binary classification schema (primary and secondary) and subsequently with a 3â category schema (primary, latent primary, secondary).ResultsSeverity of pain with intercourse did not differ among the subgroups using either classification schema. Women with primary VVS consistently showed higher levels of somatization, anxiety, and distress compared with those with secondary VVS. Using a 3â tiered classification system, we found no difference between latent primary diagnosis and the other 2 groups (primary and secondary).ConclusionThis study highlights the critical need for research on subtype definition and the role of psychological factors in VVS.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135448/1/ijgo38.pd

Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease

Fibropolycystic liver disease is characterized by hyperproliferation of the biliary epithelium and the formation of multiple dilated cysts, a process associated with unfolded protein response (UPR). In the present study, we aimed to understand the mechanisms of cyst formation and UPR activation in hepatocytic c-Jun N-terminal kinase 1/2 (Jnk1/2) knockout mice. Floxed JNK1/2 (Jnkf/f) and Jnk∆hepa animals were sacrificed at different time points during progression of liver disease. Histological examination of specimens evidenced the presence of collagen fiber deposition, increased α-smooth muscle actin (αSMA), infiltration of CD45, CD11b and F4/80 cells and proinflammatory cytokines (Tnf, Tgfβ1) and liver injury (e.g., ALT, apoptosis and Ki67-positive cells) in Jnk∆hepa compared with Jnkf/f livers from 32 weeks of age. This was associated with activation of effectors of the UPR, including BiP/GRP78, CHOP and spliced XBP1. Tunicamycin (TM) challenge strongly induced ER stress and fibrosis in Jnk∆hepa animals compared with Jnkf/f littermates. Finally, thioacetamide (TAA) administration to Jnk∆hepa mice induced UPR activation, peribiliary fibrosis, liver injury and markers of biliary proliferation and cholangiocarcinoma (CCA). Orthoallografts of DEN/CCl4-treated Jnk∆hepa liver tissue triggered malignant CCA. Altogether, these results suggest that activation of the UPR in conjunction with fibrogenesis might trigger hepatic cystogenesis and early stages of CCA

An Experimental DUAL Model of Advanced Liver Damage

Individuals exhibiting an intermediate alcohol drinking pattern in conjunction with signs of metabolic risk present clinical features of both alcohol-associated and metabolic-associated fatty liver diseases. However, such combination remains an unexplored area of great interest, given the increasing number of patients affected. In the present study, we aimed to develop a preclinical DUAL (alcohol-associated liver disease plus metabolic-associated fatty liver disease) model in mice. C57BL/6 mice received 10% vol/vol alcohol in sweetened drinking water in combination with a Western diet for 10, 23, and 52 weeks (DUAL model). Animals fed with DUAL diet elicited a significant increase in body mass index accompanied by a pronounced hypertrophy of adipocytes, hypercholesterolemia, and hyperglycemia. Significant liver damage was characterized by elevated plasma alanine aminotransferase and lactate dehydrogenase levels, extensive hepatomegaly, hepatocyte enlargement, ballooning, steatosis, hepatic cell death, and compensatory proliferation. Notably, DUAL animals developed lobular inflammation and advanced hepatic fibrosis. Sequentially, bridging cirrhotic changes were frequently observed after 12 months. Bulk RNA-sequencing analysis indicated that dysregulated molecular pathways in DUAL mice were similar to those of patients with steatohepatitis. Conclusion: Our DUAL model is characterized by obesity, glucose intolerance, liver damage, prominent steatohepatitis and fibrosis, as well as inflammation and fibrosis in white adipose tissue. Altogether, the DUAL model mimics all histological, metabolic, and transcriptomic gene signatures of human advanced steatohepatitis, and therefore serves as a preclinical tool for the development of therapeutic targets.Supported by EXOHEP-CM (S2017/BMD-3727), Ramón y Cajal (RYC-2014-15242 and RYC-2015-17438), NanoLiver-CM (Y2018/NMT-4949), COST Action (CA17112), AMMF (2018/117), ERAB (EA 18/14), MINECO Retos (SAF2016-78711 and SAF2017-87919-R), and German Research Foundation (DFG NE 2128/2-1, SFB 1382-403224013/A02, and SFB/TRR57/P04). FJC is a Gilead Research Liver Scholar. The research group belongs to the validated Research group Ref. 970935 “Liver Pathophysiology”, 920631 “Lymphocyte immunology”, 920361 “Immunogenética e inmunología de las mucosas” and IBL-6 (imas12-associated). FG and KZ are Chinese Scholarship Council (CSC) fellows. O.E.-V is supported by Beca FPI (associated to MINECO SAF2017-87919R) and R.B.-U. by Contratos predoctorales de personal investigador en formación UCM-Banco Santander (CT63/19)

Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis

Background: Histologically assessed liver fibrosis stage has prognostic significance in patients with non-alcoholic fatty liver disease (NAFLD) and is accepted as a surrogate endpoint in clinical trials for non-cirrhotic NAFLD. Our aim was to compare the prognostic performance of non-invasive tests with liver histology in patients with NAFLD. Methods: This was an individual participant data meta-analysis of the prognostic performance of histologically assessed fibrosis stage (F0–4), liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE), fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) in patients with NAFLD. The literature was searched for a previously published systematic review on the diagnostic accuracy of imaging and simple non-invasive tests and updated to Jan 12, 2022 for this study. Studies were identified through PubMed/MEDLINE, EMBASE, and CENTRAL, and authors were contacted for individual participant data, including outcome data, with a minimum of 12 months of follow-up. The primary outcome was a composite endpoint of all-cause mortality, hepatocellular carcinoma, liver transplantation, or cirrhosis complications (ie, ascites, variceal bleeding, hepatic encephalopathy, or progression to a MELD score ≥15). We calculated aggregated survival curves for trichotomised groups and compared them using stratified log-rank tests (histology: F0–2 vs F3 vs F4; LSM: <10 vs 10 to <20 vs ≥20 kPa; FIB-4: <1·3 vs 1·3 to ≤2·67 vs >2·67; NFS: <–1·455 vs –1·455 to ≤0·676 vs >0·676), calculated areas under the time-dependent receiver operating characteristic curves (tAUC), and performed Cox proportional-hazards regression to adjust for confounding. This study was registered with PROSPERO, CRD42022312226. Findings: Of 65 eligible studies, we included data on 2518 patients with biopsy-proven NAFLD from 25 studies (1126 [44·7%] were female, median age was 54 years [IQR 44–63), and 1161 [46·1%] had type 2 diabetes). After a median follow-up of 57 months [IQR 33–91], the composite endpoint was observed in 145 (5·8%) patients. Stratified log-rank tests showed significant differences between the trichotomised patient groups (p<0·0001 for all comparisons). The tAUC at 5 years were 0·72 (95% CI 0·62–0·81) for histology, 0·76 (0·70–0·83) for LSM-VCTE, 0·74 (0·64–0·82) for FIB-4, and 0·70 (0·63–0·80) for NFS. All index tests were significant predictors of the primary outcome after adjustment for confounders in the Cox regression. Interpretation: Simple non-invasive tests performed as well as histologically assessed fibrosis in predicting clinical outcomes in patients with NAFLD and could be considered as alternatives to liver biopsy in some cases. Funding: Innovative Medicines Initiative 2 (*The LITMUS investigators