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Genome-wide association studies (GWAS) have successfully identified several loci associated with primary biliary cirrhosis (PBC) risk. Pathway analysis complements conventional GWAS analysis. We applied the recently developed linear combination test for pathways to datasets drawn from independent PBC GWAS in Italian and Canadian subjects. Of the Kyoto Encyclopedia of Genes and Genomes and BioCarta pathways tested, 25 pathways in the Italian dataset (449 cases, 940 controls) and 26 pathways in the Canadian dataset (530 cases, 398 controls) were associated with PBC susceptibility ( P <0.05). After correcting for multiple comparisons, only the eight most significant pathways in the Italian dataset had FDR <0.25 with tumor necrosis factor/stress-related signaling emerging as the top pathway ( P =7.38 × 10 −4 , FDR=0.18). Two pathways, phosphatidylinositol signaling and hedgehog signaling, were replicated in both datasets ( P <0.05), and subjected to two additional complementary pathway tests. Both pathway signals remained significant in the Italian dataset on modified gene set enrichment analysis ( P <0.05). In both GWAS, variants nominally associated with PBC were significantly overrepresented in the phosphatidylinositol pathway (Fisher exact P <0.05). These results point to established and novel pathway-level associations with inherited predisposition to PBC that, on further independent replication and functional validation, may provide fresh insights into PBC etiology.

The dynamical properties of periodic two-component phononic rods, whose elementary cells are generated adopting the Fibonacci substitution rules, are studied through the recently introduced method of the toroidal manifold. The method allows all band gaps and pass bands featuring the frequency spectrum to be represented in a compact form with a frequency-dependent flow line on the surface describing their ordered sequence. The flow lines on the torus can be either closed or open: in the former case, (i) the frequency spectrum is periodic and the elementary cell corresponds to a canonical configuration, (ii) the band gap density depends on the lengths of the two phases; in the latter, the flow lines cover ergodically the torus and the band gap density is independent of those lengths. It is then shown how the proposed compact description of the spectrum can be exploited (i) to find the widest band gap for a given configuration and (ii) to optimize the layout of the elementary cell in order to maximize the low-frequency band gap. The scaling property of the frequency spectrum, that is a distinctive feature of quasicrystalline-generated phononic media, is also confirmed by inspecting band-gap/pass-band regions on the torus for the elementary cells of different Fibonacci orders. This article is part of the theme issue ‘Modelling of dynamic phenomena and localization in structured media (part 2)’.

The dynamical properties of periodic two-component phononic rods, whose elementary cells are generated adopting the Fibonacci substitution rules, are studied through the recently introduced method of the toroidal manifold. The method allows all band gaps and pass bands featuring the frequency spectrum to be represented in a compact form with a frequency-dependent flow line on the surface describing their ordered sequence. The flow lines on the torus can be either closed or open: in the former case, (i) the frequency spectrum is periodic and the elementary cell corresponds to a canonical configuration, (ii) the band gap density depends on the lengths of the two phases; in the latter, the flow lines cover ergodically the torus and the band gap density is independent of those lengths. It is then shown how the proposed compact description of the spectrum can be exploited (i) to find the widest band gap for a given configuration and (ii) to optimize the layout of the elementary cell in order to maximize the low-frequency band gap. The scaling property of the frequency spectrum, that is a distinctive feature of quasicrystalline-generated phononic media, is also confirmed by inspecting band-gap/pass-band regions on the torus for the elementary cells of different Fibonacci orders. This article is part of the theme issue ‘Modelling of dynamic phenomena and localization in structured media (part 2)’.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects ( n =2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort ( n =3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC ( P combined <5 × 10 −8 ) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine–cytokine pathways, for which relevant therapies exist. Primary biliary cirrhosis is an autoimmune liver disease with poor therapeutic options. Here Cordell et al . a perform meta-analysis of European genome-wide association studies identifying six novel risk loci and a number of potential therapeutic pathways.

BackgroundObesity is a risk factor for ventral hernia development and affects up to 60% of patients undergoing ventral hernia repair. It is also associated with a higher rate of surgical site occurrences and an increased risk of recurrence after ventral hernia repair, but data is lacking on the differences between obesity classes.MethodsBetween 2008 and 2018, 322 patients with obesity underwent laparoscopic ventral hernia repair in our department: class I n = 231 (72%), II n = 55 (17%), III n = 36 (11%). We compared short and long-term outcomes between the three classes.ResultsPatients with class III obesity had a longer median length of hospital stay compared to I and II (5 days versus 4 days in the other groups, p = 0.0006), but without differences in postoperative complications or surgical site occurrences. After a median follow up of 49 months, there were no significant differences in the incidence of seroma, recurrence, chronic pain, pseudorecurrence and port-site hernia. At multivariate analysis, risk factors for recurrence were presence of a lateral defect and previous hernia repair; risk factors for seroma were immunosuppression, defect > 15 cm and more than one previous hernia repair; the only risk factor for postoperative complications was chronic obstructive pulmonary disease.ConclusionClass III obesity is associated with longer length of hospital stay after laparoscopic ventral hernia repair, but without differences in postoperative complications and long-term outcomes compared with class I and class II obesity.

Michael Seldin and colleagues report a genome-wide association study and meta-analyses for primary biliary cirrhosis. They identify three loci newly associated with susceptibility to this autoimmune liver disease. A genome-wide association screen for primary biliary cirrhosis risk alleles was performed in an Italian cohort. The results from the Italian cohort replicated IL12A and IL12RB associations, and a combined meta-analysis using a Canadian dataset identified newly associated loci at SPIB ( P = 7.9 × 10 −11 , odds ratio (OR) = 1.46), IRF5 - TNPO3 ( P = 2.8 × 10 −10 , OR = 1.63) and 17q12-21 ( P = 1.7 × 10 −10 , OR = 1.38).

The stromal vascular cell fraction (SVF) of visceral and subcutaneous adipose tissue (VAT and SAT) has increasingly come into focus in stem cell research, since these compartments represent a rich source of multipotent adipose-derived stem cells (ASCs). ASCs exhibit a self-renewal potential and differentiation capacity. Our aim was to study the different expression of the embryonic stem cell markers NANOG (homeobox protein NANOG), SOX2 (SRY (sex determining region Y)-box 2) and OCT4 (octamer-binding transcription factor 4) and to evaluate if there exists a hierarchal role in this network in ASCs derived from both SAT and VAT. ASCs were isolated from SAT and VAT biopsies of 72 consenting patients (23 men, 47 women; age 45 ± 10; BMI between 25 ± 5 and 30 ± 5 range) undergoing elective open-abdominal surgery. Sphere-forming capability was evaluated by plating cells in low adhesion plastic. Stem cell markers CD90, CD105, CD29, CD31, CD45 and CD146 were analyzed by flow cytometry, and the stem cell transcription factors NANOG, SOX2 and OCT4 were detected by immunoblotting and real-time PCR. NANOG, SOX2 and OCT4 interplay was explored by gene silencing. ASCs from VAT and SAT confirmed their mesenchymal stem cell (MSC) phenotype expressing the specific MSC markers CD90, CD105, NANOG, SOX2 and OCT4. NANOG silencing induced a significant OCT4 (70 ± 0.05%) and SOX2 (75 ± 0.03%) downregulation, whereas SOX2 silencing did not affect NANOG gene expression. Adipose tissue is an important source of MSC, and siRNA experiments endorse a hierarchical role of NANOG in the complex transcription network that regulates pluripotency.

PurposeProphylactic mesh placement has been proposed to reduce the high occurrence of parastomal hernia (PSH) after stoma formation.MethodsThis is an observational study comparing two cohorts of patients: a mesh prophylaxis group (who received mesh prevention since introduction at our Institution) and a no mesh prophylaxis group (retrospectively selected from our historical series). Same exclusion criteria were applied for both groups. The study was conducted at a tertiary referral center for colorectal surgery. 43 patients were operated with mesh prophylaxis between May 2015 and may 2019. 45 patients underwent end-colostomy formation without prophylaxis between April 2011 and April 2015. The primary outcome measure was PSH development at 12-month follow up.ResultsDemographic variables and risk factors for PSH were comparable between the two groups. There was no difference between the two cohorts in terms of operative time and main early postoperative outcomes. 37 patients completed the 12-month follow up in each group. PSH occurrence after 12-months was 11% in the mesh prophylaxis group and 54% in the no mesh prophylaxis group (p < 0.0001). There were no differences in long-term complications. 5% of patients who received mesh prophylaxis underwent emergency surgery for bowel occlusion at 7 and 10 months after surgery, with partial or complete mesh removal. At multivariate analysis, mesh prophylaxis was a protective factor for PSH development at 12 months (p < 0.0001).ConclusionsProphylactic intraperitoneal mesh placement appears to be effective in preventing PSH.