Gastroesophageal Junction and Pylorus Distensibility Before and After Sleeve Gastrectomy-pilot Study with EndoFlipTM.

Sleeve gastrectomy (SG) is the most frequently performed bariatric surgical intervention worldwide. Gastroesophageal reflux disease (GERD) is frequently observed after SG and is a relevant clinical problem. This prospective study investigated the gastroesophageal junction (GEJ) and pyloric sphincter by impedance planimetry (EndoFlipTM) and their association with GERD at a tertiary university hospital center. Between January and December 2018, patients undergoing routine laparoscopic SG had pre-, intra-, and postoperative assessments of the GEJ and pyloric sphincter by EndoFlipTM. The distensibility index (DI) was measured at different volumes and correlated with GERD (in accordance with the Lyon consensus guidelines). Nine patients were included (median age 48 years, preoperative BMI 45.1 kg/m2, 55.6% female). GERD (de novo or stable) was observed in 44.4% of patients one year postoperatively. At a 40-ml filling volume, DI increased significantly pre- vs. post-SG of the GEJ (1.4 mm2/mmHg [IQR 1.1-2.6] vs. 2.9 mm2/mmHg [2.6-5.3], p VALUE=0.046) and of the pylorus (6.0 mm2/mmHg [4.1-10.7] vs. 13.1 mm2/mmHg [7.6-19.2], p VALUE=0.046). Patients with postoperative de novo or stable GERD had a significantly increased preoperative DI at 40 ml of the GEJ (2.6 mm2/mmHg [1.9-3.5] vs. 0.5 mm2/mmHg [0.5-1.1], p VALUE=0.031). There was no significant difference in DI at 40 mL filling in the preoperative pylorus and postoperative GEJ or pylorus. In this prospective study, the DI of the GEJ and the pylorus significantly increased after SG. Postoperative GERD was associated with a significantly higher preoperative DI of the GEJ but not of the pylorus

Immunogenicity of High-Dose vs. MF59-adjuvanted vs. Standard Influenza Vaccine in Solid Organ Transplant Recipients: The STOP-FLU trial.

BACKGROUND The immunogenicity of the standard influenza vaccine is reduced in solid-organ transplant (SOT) recipients, so that new vaccination strategies are needed in this population. METHODS Adult SOT recipients from nine transplant clinics in Switzerland and Spain were enrolled if they were >3 months after transplantation. High, with stratification by organ and time from transplant. The primary outcome was vaccine response rate, defined as a ≥4-fold increase of hemagglutination-inhibition titers to at least one vaccine strain at 28 days post-vaccination. Secondary outcomes included PCR-confirmed influenza and vaccine reactogenicity. RESULTS 619 patients were randomized, 616 received the assigned vaccines, and 598 had serum available for analysis of the primary endpoint (standard, n=198; MF59-adjuvanted, n=205; high-dose, n=195 patients). Vaccine response rates were 42% (84/198) in the standard vaccine group, 60% (122/205) in the MF59-adjuvanted vaccine group, and 66% (129/195) in the high-dose vaccine group (difference in intervention vaccines vs. standard vaccine, 0.20 [97.5% CI 0.12-1]; p<0.001; difference in high-dose vs. standard vaccine, 0.24 [95% CI 0.16-1]; p<0.001; difference in MF59-adjuvanted vs. standard vaccine, 0.17 [97.5% CI 0.08-1]; p<0.001). Influenza occurred in 6% the standard, 5% in the MF59-adjuvanted, and 7% in the high-dose vaccine groups. Vaccine-related adverse events occurred more frequently in the intervention vaccine groups, but most of the events were mild. CONCLUSIONS In SOT recipients, use of an MF59-adjuvanted or a high-dose influenza vaccine was safe and resulted in a higher vaccine response rate. TRIAL REGISTRATION Clinicaltrials.gov NCT03699839

Patient-derived xenografts and organoids model therapy response in prostate cancer.

Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe an androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbors BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modeled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds

Epidemiology, clinical features and management of autoimmune hepatitis in Switzerland: a retrospective and prospective cohort study

BACKGROUND AND AIMS: The Swiss Autoimmune Hepatitis Cohort Study is a nationwide registry, initiated in 2017, that collects retrospective and prospective clinical data and biological samples from patients of all ages with autoimmune hepatitis treated at Swiss hepatology centres. Here, we report the analysis of the first 5 years of registry data. RESULTS: A total of 291 patients with autoimmune hepatitis have been enrolled, 30 of whom were diagnosed before 18 years of age and composed the paediatric cohort. Paediatric cohort: median age at diagnosis 12.5 years (range 1–17, interquartile range (IQR) 8–15), 16 (53%) girls, 6 (32%) with type 2 autoimmune hepatitis, 8 (27%) with autoimmune sclerosing cholangitis, 1 with primary biliary cholangitis variant syndrome, 4 (15%) with inflammatory bowel disease and 10 (41%) with advanced liver fibrosis at diagnosis. Adult cohort: median age at diagnosis 54 years (range 42–64, IQR 18–81), 185 (71%) women, 51 (20%) with primary biliary cholangitis variant syndrome, 22 (8%) with primary sclerosing cholangitis variant syndrome, 9 (4%) with inflammatory bowel disease and 66 (32%) with advanced liver fibrosis at diagnosis. The median follow-up time for the entire cohort was 5.2 years (IQR 3–9.3 years). Treatment in children: 29 (97%) children were initially treated with corticosteroids, 28 of whom received combination treatment with azathioprine. Budesonide was used in four children, all in combination with azathioprine. Mycophenolate mofetil was used in five children, all of whom had previously received corticosteroids and thiopurine. Treatment in adults (data available for 228 patients): 219 (96%) were treated with corticosteroids, mostly in combination with azathioprine. Predniso(lo)ne was the corticosteroid used in three-quarters of patients; the other patients received budesonide. A total of 78 (33%) patients received mycophenolate mofetil, 62 of whom had previously been treated with azathioprine. Complete biochemical response was achieved in 13 of 19 (68%) children and 137 of 182 (75%) adults with available follow-up data. All children were alive at the last follow-up, and none had undergone liver transplantation. Five (2%) adults underwent liver transplantation, two of whom had a fulminant presentation. Four (2%) adults with autoimmune hepatitis died (two from liver-associated causes). CONCLUSION: Patients with autoimmune hepatitis in Switzerland had clinical features similar to those in other cohorts. The proportion of patients diagnosed with primary biliary cholangitis variant syndrome was higher than expected. Autoimmune hepatitis was managed according to guidelines, except for the use of budesonide in a small proportion of paediatric patients. The outcomes were excellent, but the findings must be confirmed over a longer follow-up period

Repenser le management des ressources humaines et des relations de travail

Botulinum neurotoxin A (BoNT/A) belongs to the most dangerous class of bioweapons. Despite this, BoNT/A is used to treat a wide range of common medical conditions such as migraines and a variety of ocular motility and movement disorders. BoNT/A is probably best known for its use as an antiwrinkle agent in cosmetic applications (including Botox and Dysport). BoNT/A application causes long-lasting flaccid paralysis of muscles through inhibiting the release of the neurotransmitter acetylcholine by cleaving synaptosomal-associated protein 25 (SNAP-25) within presynaptic nerve terminals. Two types of BoNT/A receptor have been identified, both of which are required for BoNT/A toxicity and are therefore likely to cooperate with each other: gangliosides and members of the synaptic vesicle glycoprotein 2 (SV2) family, which are putative transporter proteins that are predicted to have 12 transmembrane domains, associate with the receptor-binding domain of the toxin. Recently, fibroblast growth factor receptor 3 (FGFR3) has also been reported to be a potential BoNT/A receptor. In SV2 proteins, the BoNT/A-binding site has been mapped to the luminal domain, but the molecular details of the interaction between BoNT/A and SV2 are unknown. Here we determined the high-resolution crystal structure of the BoNT/A receptor-binding domain (BoNT/A-RBD) in complex with the SV2C luminal domain (SV2C-LD). SV2C-LD consists of a right-handed, quadrilateral β-helix that associates with BoNT/A-RBD mainly through backbone-to-backbone interactions at open β-strand edges, in a manner that resembles the inter-strand interactions in amyloid structures. Competition experiments identified a peptide that inhibits the formation of the complex. Our findings provide a strong platform for the development of novel antitoxin agents and for the rational design of BoNT/A variants with improved therapeutic properties

Preventive strategies against cytomegalovirus and incidence of α-herpesvirus infections in olid-organ transplant recipients: A nationwide cohort study.

We assessed the impact of antiviral preventive strategies on the incidence of herpes-simplex virus (HSV) and varicella-zoster virus (VZV) infections in a nationwide cohort of transplant recipients. Risk factors for the development of HSV/VZV infection were assessed by Cox PH regression. We included 2781 patients (56% kidney, 20% liver, 10% lung, 7.3% heart, 6.7% others). Overall, 1264 (45%) patients received antiviral prophylaxis [(val)ganciclovir (n=1126) or (val)acyclovir (n=138)]. Incidences for HSV and VZV infections were 28.9 and 12.1 cases per 1000 person-years, respectively. Incidence of HSV/VZV infections at 1-year post-transplant was 4.6% (95% CI 3.5-5.8) in patients receiving antiviral prophylaxis vs. 12.3% (95% CI 10.7-14) in patients without prophylaxis; this was particularly observed for HSV infections: 3% (95% CI 2.2-4) vs. 9.8% (95% CI 8.4-11.4), respectively. A lower rate of HSV/VZV infections was also seen in donor or recipient CMV-positive patients receiving (val)ganciclovir prophylaxis as compared to a preemptive approach. Female gender (HR 1.663, p=0.001), HSV seropositivity (HR 5.198, p<0.001), previous episodes of rejection (HR 1.95, p=0.004), and use of a preemptive approach (HR 2.841, p=0.017) were significantly associated with a higher risk for HSV infection. While HSV/VZV infections were common after transplantation, antiviral prophylaxis significantly reduced symptomatic HSV infections. This article is protected by copyright. All rights reserved

Aspects of albendazole metabolism in western lowland gorillas (Gorilla gorilla gorilla) compared to humans and other species assessed by HPLC, LC-MS, and chiral electrokinetic chromatography

The benzimidazole anthelmintic drug albendazole becomes metabolized to chiral albendazole sulfoxide, albendazole sulfone, albendazole 2-aminosulfone, and other metabolites. High-performance liquid chromatography with UV absorbance and fluorescence detection, liquid chromatography with mass spectrometry, and chiral electrokinetic chromatography were used to analyze albendazole metabolites in extracts of western lowland gorilla (Gorilla gorilla gorilla) plasma of patients with alveolar echinococcosis and the data are compared to those obtained with human patient samples and to those reported for other species in the literature. The data revealed that the albendazole sulfoxide to albendazole sulfone concentration ratio in gorilla plasma is significantly smaller compared to that in samples of men, rats, dogs, and cattle. It is, however, similar to what was observed in sheep and goats. The (+)-albendazole sulfoxide to (−)-albendazole sulfoxide enantiomeric ratio in gorilla blood determined by chiral electrokinetic chromatography was found to be >1 which is comparable to what was observed in humans, dogs, sheep, goats, and cattle but different to mice and rats. Furthermore, the electrokinetic chromatography data suggest that small amounts of albendazole 2-aminosulfone may be present in plasma of gorillas and humans. The data gathered with the various separation-based assays illustrate the value of technology featuring different analyte separation and detection principles. This is the first account describing aspects of the albendazole metabolism in gorillas

Tractor Engines and Transmissions

Im Berichtsjahr wurden wieder mehrere neue Dieselmotoren vorgestellt, darunter auch 4-Zylinder in der 5-l-Hubraumklasse. Der Trend zu Verbrennungsmotoren für alternative Kraftstoffe hält weiter an und auffallend viele Hersteller stellten auf der Agritechnica Prototypen für Wasserstoff aus. Weichai Lovol präsentierte den Traktor P 7240 (180 kW) mit einem in China produzierten CVT-Getriebe, das auf Entwicklungen von VDS basiert. ZF stellte verschiedene Konzepte zur Elektrifizierung von Traktoren vor, darunter auch eine E-Hinterachse. ARGO brachte in den letzten zwei Jahren neue Lastschaltgetriebe auf den Markt, die anhand von Getriebeplänen besprochen werden. Aus einem anderen Beitrag wird ein Diagramm mit äquivalenten Motorschleppmomenten wiedergegeben. Die Methoden des „Model Based Systems Engineering“ (MBSE) gewinnen in der Landtechnik an Bedeutung. Sie ermöglichen die Erstellung von "digitalen Zwillingen" der physischen Produkte und damit kürzere Entwicklungszyklen.Several new diesel engines were presented again in the reporting year, including 4-cylinder engines in the 5 litre displacement class. The trend towards combustion engines for alternative fuels continues and a striking number of manufacturers exhibited prototypes for hydrogen at Agritechnica. Weichai Lovol presented the P 7240 tractor (180 kW) with a CVT transmission produced in China and based on developments from VDS. ZF presented various concepts for the electrification of tractors, including a rear axle with electric drive technology. ARGO has introduced new powershift transmissions in the past two years, which are discussed using transmission diagrams. Equivalent engine drag torques are reported from another publication by a diagram. The methods of "Model Based Systems Engineering" (MBSE) are becoming increasingly important in agricultural engineering. They enable the creation of "digital twins" of physical products and therefore shorter development cycles

Structural Basis of TBX5–DNA Recognition: The T-Box Domain in Its DNA-Bound and -Unbound Form

International audienc