Genital Dysplasia and Immunosuppression: Why Organ-Specific Therapy Is Important

Background Young patients with Crohn's disease (CD) show a high prevalence of human papillomavirus (HPV) which is the main cause of high-grade squamous intraepithelial lesions (HSIL). A major complication for patients undergoing immunocompromising therapy is the development of genital dysplasia. Methods We report the case of a 32-year-old patient with recurrent genital dysplasia under long-term therapy for CD with a focus on different drug-related, immunosuppressive mechanisms. Results Gynecological examination and biopsy revealed high-grade vulvar intraepithelial neoplasia (VIN) positive for HPV 16 treated with laser vaporization. Due to the combination of HPV positivity, intraoperative multilocularity, and CD, follow-up examinations were performed every 6 months. One year later, the patient showed a VIN at a new location and additionally, a cervical intraepithelial neoplasia (CIN), which were surgically treated. Catch-up HPV vaccination was applied accessorily. After the switch from a TNF-α blocker to vedolizumab, which acts as a gut-selective anti-integrin, the subsequent PAP smear, vulvoscopy, and colposcopy showed no more evidence of dysplasia. Conclusions This case report highlights that gut-selective immunosuppression with vedolizumab might be favorable in young HPV-positive patients due to a good side effect profile. Regular screening and HPV vaccination are a mainstay of dysplasia prevention and control. The risk for HPV-associated dysplasia in immunosuppressed patients is highly dependent on the choice of immunosuppressive therapy

Magnetization transfer for the assessment of bowel fibrosis in patients with Crohn's disease: initial experience

Object: To assess the feasibility of magnetization transfer (MT) imaging of the bowel wall in patients with Crohn's disease (CD), and to evaluate its utility for the detection of intestinal fibrosis. Materials and methods: In this prospective study, 31 patients (age 39.0±13.2years) with CD were examined in a 1.5T MR scanner. To establish a standard of reference, two independent readers classified the patients in different disease states using standard MR enterography, available clinical data and histological findings. In addition to the standard protocol, a 2D gradient-echo sequence (TR/TE 32ms/2.17ms; flip angle 25°) with/without 1,100Hz off-resonance prepulse was applied. MT ratios (MTR) of the small bowel wall were computed off-line on a pixel-by-pixel basis. Results: The MT sequences acquired images of sufficient quality and spatial resolution for the evaluation of the small bowel wall without detrimental motion artefacts. In normal bowel wall segments, an intermediate MTR of 25.4±3.4% was measured. The MTR was significantly increased in bowel wall segments with fibrotic scarring (35.3±4.0%, p<0.0001). In segments with acute inflammation, the mean MTR was slightly smaller (22.9±2.2%). Conclusion: MT imaging of the small bowel wall is feasible in humans with sufficient image quality and may help with the identification of fibrotic scarring in patients with C

Nasopharyngeal Microbiota in Infants With Acute Otitis Media

Background. Interspecies interactions of the nasopharyngeal microbiota are likely to be involved in the pathogenesis of acute otitis media (AOM). Capturing the breadth of microbial interactions requires a detailed description of the microbiota during health and AOM. Methods. The nasopharyngeal microbiota of 163 infants with (n = 153) or without (n = 10) AOM was characterized using nasopharyngeal swabs and multiplexed pyrosequencing of 16S rRNA. Nasopharyngeal swab specimens were collected during 4 winter seasons from 2004 through 2010 for infants with AOM and during 2010 for controls. Results. Fifty-eight bacterial families were identified, of which Moraxellaceae, Streptococcaceae, and Pasteurellaceae were the most frequent. Commensal families were less prevalent in infants with AOM than in controls. In infants with AOM, prior exposure to antimicrobials and administration of the heptavalent conjugated pneumococcal polysaccharide vaccine (PCV7) were also associated with reduced prevalence of distinct commensal families (Streptococcaceae and Corynebacteriaceae). In addition, antimicrobial exposure increased the prevalence of Enterobacteriaceae and the abundance of Pasteurellaceae. Other factors, such as age, sex, day care, and a history of recurrent AOM, did not influence the microbiota. Conclusions. Infants' nasopharyngeal microbiota undergoes significant changes during AOM and after exposure to antimicrobials and PCV7, which is mainly attributable to reduced prevalence of commensal bacterial familie

Genetic variations in bile acid homeostasis are not overrepresented in alcoholic cirrhosis compared to patients with heavy alcohol abuse and absent liver disease

Increased serum bile salt levels have been associated to a single-nucleotide polymorphism in the bile salt export pump (BSEP; ABCB11) in several acquired cholestatic liver diseases but there is little evidence in alcoholic liver disease (ALD). Furthermore, a crosstalk between vitamin D and bile acid synthesis has recently been discovered. Whether this crosstalk has an influence on the course of ALD is unclear to date. Our aim was to analyse the role of genetic polymorphisms in BSEP and the vitamin D receptor gene (NR1I1) on the emergence of cirrhosis in patients with ALD. Therefore, 511 alcoholic patients (131 with cirrhosis and 380 without cirrhosis) underwent ABCB11 genotyping (rs2287622). Of these, 321 (131 with cirrhosis and 190 without cirrhosis) were also tested for NR1I1 polymorphisms (bat-haplotype: BsmI rs1544410, ApaI rs7975232 and TaqI rs731236). Frequencies of ABCB11 and NR1I1 genotypes and haplotypes were compared between alcoholic patients with and without cirrhosis and correlated to serum bile salt, bilirubin and aspartate aminotransferase levels in those with cirrhosis. Frequencies of ABCB11 and NR1I1 genotypes and haplotypes did not differ between the two subgroups and no significant association between genotypes/haplotypes and liver function tests could be determined for neither polymorphism. We conclude that ABCB11 and NR1I1 polymorphisms are obviously not associated with development of cirrhosis in patients with AL

Rückblick, Ausblick, Weitblick : Arbeitswelt 4.0 in der Schweizer MEM-Branche

Swissmem hat die ZHAW beauftragt, die Transformation der Arbeitswelt durch die Digitalisierung entlang der Wertschöpfungskette der Schweizer Geräte-, Maschinen- und Anlagenbauunternehmen zu untersuchen. Diese Arbeit soll das Bewusstsein der Firmen für die Transformation steigern, relevante Handlungsfelder aufzeigen und Denkanstösse für den Swissmem Verband geben. Diese Studie gliedert sich in drei Teile. Im ersten Teil werden die Auslöser für die Einführung von neuen Technologien mittels Literaturauswertung und deren Validierung mit Unternehmensbefragungen untersucht. Diese Technologien werden im zweiten Teil den einzelnen Prozessen der Wertschöpfungskette zugeordnet, und deren Einfluss auf die Arbeitswelt wird beschrieben. Im dritten Teil werden Zukunftsszenarien erarbeitet, um die Herausforderungen der Arbeitswelt 4.0 zu erfassen. Die Literaturrecherche und die Unternehmensbefragungen zeigen, dass Effizienz, Innovation und Komplexität Hauptauslöser für die Einführung von neuen Technologien waren. Bezüglich Technologie werden für industrielle Anwendungen die ERP-Systeme am meistens zitiert; die Sensortechnik ist ebenfalls weit verbreitet. Die am meisten thematisierten Industrie 4.0 Technologien, wie das «Industrial Internet of Things», «Künstliche Intelligenz», «Augmented Reality», sind bis jetzt in vielen Unternehmen wenig umgesetzt. Die durch Befragung von ausgewählten Leuchtturm-Unternehmen der MEM Industrie validierte Zuordnung der neuen Technologien auf die industriellen Anwendungen zeigt vier Haupttrends für die Arbeitswelt: 1. Verschiedene Anwendungen sind weiterhin auf Spezialisten angewiesen. 2. Dazu sind neue Fähigkeiten von Mitarbeitern erforderlich. 3. In manchen Anwendungen stellt sich die Frage, ob die für die Einführung von neuen Technologien benötigten Kompetenzen intern oder extern aufzubauen sind. 4. Ergänzend wird eine Rekrutierung von neuen Talenten erforderlich. Anhand der Literaturrecherche und den Unternehmensbefragungen sind die im Geräte-, Maschinen und Anlagenbau tätigen Schweizer Unternehmen in drei Gruppen (Weiter-Wie-Bisher, Kompression und Expansion) segmentiert, welche unterschiedliche Prioritäten in der Anwendung von neuen Technologien haben. Ausgehend von den «Fundamental Business Drivers», bzw. den internen und externen Hauptreibern der Schweizer MEM-Branche, werden künftig mögliche Entwicklungen in den Unternehmen erläutert. Die drei Unternehmensgruppen werden anhand von zwei Dimensionen, zeitlich (fünf Jahre Ausblick und zwanzig Jahre Weitblick) und kontextabhängig (z.B. offene Welthandel, oder steigende Handelsbarrieren) in Szenarien beschrieben. Expansive Unternehmen liefern konkrete Erkenntnisse und Empfehlungen. Diese Unternehmen haben einen starken Fokus auf Services und haben bereits neue Technologien wie IIoT, Datenanalytik und künstliche Intelligenz eingeführt. Zudem sind sie direkt in der Wertschöpfungskette der Kunden eingebunden und stiften dadurch Mehrwert durch datengetriebenen Dienstleistungen. Damit entstehen drei wesentliche Herausforderungen für eine erfolgreiche Gestaltung der zukünftigen Wertschöpfungskette: 1. Die Erarbeitung von Grundlagen für die Umsetzung der Technologien der Industrie 4.0, 2. die Stärkung der Fachkompetenzen der Mitarbeiter und 3. eine neue Denkweise der Unternehmensführung, die diese Veränderungen ermöglicht. Voraussetzungen für die Arbeitswelt 4.0 entlang der ganzen Wertschöpfungskette und die benötigten neuen Kompetenzen, z.B. in den Datenwissenschaften, sind erläutert. Abschliessend werden Empfehlungen an Swissmem zur Unterstützung des erfolgreichen Wandels im Kontext der Arbeitswelt 4.0 abgegeben

Cytomegalovirus disease in inflammatory bowel disease: epidemiology and disease characteristics in a large single-centre experience

BACKGROUND Patients with inflammatory bowel disease (IBD) show an increased risk of developing cytomegalovirus (CMV) disease because of immunosuppressive medication and malnutrition. Here, we aimed to investigate the prevalence and clinical characteristics of CMV disease in our cohort of IBD patients. PATIENTS AND METHODS We carried out a retrospective analysis of 1023 IBD patients treated at our IBD clinic at the University Hospital Zurich between 2007 and 2014. CMV disease was defined as a positive immunohistochemistry for CMV and 14 patients were identified. RESULTS The prevalence of CMV disease in our IBD cohort was 1.37%. Twelve patients had ulcerative colitis and two had Crohn's disease with colonic involvement. All patients who developed CMV disease received immunosuppressive medication or, as in one case, had HIV infection. The most used immunosuppressive medications were steroids and azathioprine. The most common therapeutic strategy was the consecutive use of ganciclovir and valganciclovir. Ten patients recovered and two were treatment refractory; among these, one required colectomy and two had a relapse. CONCLUSION CMV disease may influence the clinical course of IBD. There is probably an association between CMV disease and IBD-specific medication. Risk factors, epidemiology and therapeutic strategy need to be further investigated

SELFIES and the future of molecular string representations

Artificial intelligence (AI) and machine learning (ML) are expanding in popularity for broad applications to challenging tasks in chemistry and materials science. Examples include the prediction of properties, the discovery of new reaction pathways, or the design of new molecules. The machine needs to read and write fluently in a chemical language for each of these tasks. Strings are a common tool to represent molecular graphs, and the most popular molecular string representation, Smiles, has powered cheminformatics since the late 1980s. However, in the context of AI and ML in chemistry, Smiles has several shortcomings—most pertinently, most combinations of symbols lead to invalid results with no valid chemical interpretation. To overcome this issue, a new language for molecules was introduced in 2020 that guarantees 100% robustness: SELF-referencing embedded string (Selfies). Selfies has since simplified and enabled numerous new applications in chemistry. In this perspective, we look to the future and discuss molecular string representations, along with their respective opportunities and challenges. We propose 16 concrete future projects for robust molecular representations. These involve the extension toward new chemical domains, exciting questions at the interface of AI and robust languages, and interpretability for both humans and machines. We hope that these proposals will inspire several follow-up works exploiting the full potential of molecular string representations for the future of AI in chemistry and materials science

Low allopurinol doses are sufficient to optimize azathioprine therapy in inflammatory bowel disease patients with inadequate thiopurine metabolite concentrations

Purpose: Recent studies in patients with inflammatory bowel diseases (IBD) on thiopurine therapy suggest that too low 6-thioguanine nucleotide concentrations (6-TGN) and too high methylmercaptopurine nucleotide concentrations (MMPN) can be reversed by a combination therapy of allopurinol and low-dose thiopurines. To date, however, optimal dosing has not been established. The aim of this study was to evaluate the minimal allopurinol doses necessary to achieve adequate 6-TGN concentrations in combination with low-dose azathioprine. Methods: A stepwise dose-escalation of allopurinol was performed in 11 azathioprine-pretreated IBD patients with inadequately low 6-TGN concentrations (5,000pmol/8 × 108 erythrocytes) and/or elevated liver enzymes (alanine aminotransferase and/or aspartate aminotransferase levels one- to threefold the upper limit of normal). Six patients were recruited into an open study, and five were treated in the context of an individualized therapeutic approach. Adverse effects, azathioprine metabolites, liver enzymes and whole blood counts were monitored two to three times per month. Results: Adequate 6-TGN concentrations were achieved with a combination of 25mg allopurinol and 50mg azathioprine in one patient and with 50mg allopurinol and 50mg azathioprine in nine patients. Median 6-TGN concentrations (range) were 336 (290-488) pmol/8 × 108 erythrocytes after an 8-week-long intake of the final dose combination. One patient dropped out due to nausea after the first intake. MMPN concentrations and liver enzymes normalized immediately in all affected patients. All patients finishing the dose-escalation regimen tolerated the treatment without toxicity. Conclusions: Combination therapy with only 50mg allopurinol and 50mg azathioprine daily is sufficient, efficacious and safe in most IBD patients with inadequate thiopurine metabolite concentrations to optimize azathioprine-based IBD therap