Type 2 diabetes mellitus (T2DM) represents a significant risk factor for cardiovascular disease, particularly heart failure with preserved ejection fraction (HFpEF). HFpEF predominantly affects elderly individuals and women, and is characterized by dysfunctions associated with metabolic, inflammatory, and oxidative stress pathways. Despite HFpEF being the most prevalent heart failure phenotype in patients with T2DM, its underlying pathophysiological mechanisms remain inadequately elucidated. This study aims to investigate the effects of diabetes mellitus on myocardial inflammation, oxidative stress, and protein quality control (PQC) mechanisms in HFpEF, with particular emphasis on insulin signaling, autophagy, and chaperone-mediated stress responses. We conducted an analysis of left ventricular myocardial tissue from HFpEF patients, both with and without diabetes, employing a range of molecular, biochemical, and functional assays. The passive stiffness of cardiomyocytes (Fpassive) was assessed in demembranated cardiomyocytes before and after implementing treatments aimed at reducing inflammation (IL-6 inhibition), oxidative stress (Mito-TEMPO), and enhancing PQC (HSP27, HSP70). Inflammatory markers (NF-κB, IL-6, TNF-α, ICAM-1, VCAM-1, NLRP3), oxidative stress markers (ROS, GSH/GSSG ratio, lipid peroxidation), and components of signaling pathways (PI3K/AKT/mTOR, AMPK, MAPK, and PKG) were evaluated using western blotting, immunofluorescence, and ELISA techniques. Hearts from diabetic HFpEF patients exhibited significantly heightened inflammation, characterized by the upregulation of NF-κB, IL-6, and the NLRP3 inflammasome. This increase in inflammation was accompanied by elevated oxidative stress, diminished nitric oxide (NO) bioavailability, and impaired activation of the NO-sGC-cGMP-PKG signaling pathway. Notably, dysregulation of insulin signaling was observed, as indicated by decreased AKT phosphorylation and impaired autophagy regulation mediated by AMPK and mTOR. Additionally, PQC dysfunction was evidenced by reduced expression levels of HSP27 and HSP70, which correlated with increased cardiomyocyte passive stiffness. Targeted therapeutic interventions effectively reduced Fpassive, with IL-6 inhibition, Mito-TEMPO, and HSP administration leading to improvements in cardiomyocyte mechanical properties. The findings of this study elucidate a mechanistic relationship among diabetes, inflammation, oxidative stress, and PQC impairment in the context of HFpEF. Therapeutic strategies that target these dysregulated pathways, including IL-6 inhibition, mitochondrial antioxidants, and chaperone-mediated protection, may enhance myocardial function in HFpEF patients with T2DM. Addressing these molecular dysfunctions could facilitate the development of novel interventions specifically tailored to the diabetic HFpEF population.

INTRODUCTION:Whipple's disease (WD) is a rare and infectious condition leading to multi-organ impairment caused by Tropheryma whipplei (TW), a ubiquitously occurring bacterium. TW can be detected in tissues by histological detection of PAS ("periodic acid-ship reaction")-positive macrophages and by polymerase-chain-reaction (PCR). Clinically, WD is often characterized by diarrhea, abdominal pain, and weight loss. These symptoms are also typical for a flare in Crohn's disease (CD) and, therefore, can lead to fatal misdiagnosis and wrong treatment by using biologics (e.g., anti-TNF-α).CASE REPORT:We here report a young male patient with pre-existing CD. The patient's symptoms were misinterpreted as a flare of CD and illustrate the multifaceted nature of WD. After intensifying immunosuppressive therapy, the patient developed therapy-refractory diarrhea with several opportunistic infections with a final, fatal outcome.CONCLUSION:Patients with inflammatory bowel disease (IBD) are not only at risk from infectious complications known with clostridium difficile or cytomegalovirus (CMV); infection with WD should also be ruled out by endoscopy and biopsy before the escalation of the immunosuppressive regime.

BACKGROUND:Coronavirus disease 2019 (COVID-19) cases in Germany, as in most other places in Europe or worldwide, are still highly prevalent. Vaccination rates currently remain low, putting cancer patients at a continued risk of infection with SARS-CoV-2, while prevalence of SARS-CoV-2 antibodies among cancer patients in Germany remains essentially unknown.METHODS:Between August 2020 and February 2021, patients admitted to our hospital were prospectively enrolled in our COVID-19 biobank. Collected sera were analyzed for SARS-CoV-2-IgM/IgG using Elecsys Anti-SARS-CoV-2 assay.RESULTS:One hundred and ten patients with cancer were included in this study. With 71 (65%) patients, most had active cancer treatment, mainly chemotherapy (56%). The most frequent diagnosis was gastrointestinal cancer (54%) with pancreatic cancer being the most common cancer type (24%). Hematologic malignancies were present in 21 patients (17%). Among the cancer patients first diagnosed during the pandemic, the rate of palliative treatment situations tended to be higher (76% vs. 67%, p = 0.17). A history of SARS-CoV-2 infection was documented in 15 (14%) patients; however, SARS-CoV-2 antibodies were detected in 10 (67%) patients only. Of the patients without a history of SARS-CoV-2 infection, none displayed SARS-CoV-2 antibodies.CONCLUSION:In the present single-center experience, a low serological prevalence of SARS-CoV-2 antibodies among cancer patients even after SARS-CoV-2 infection was found. The results support continued strict preventive measures as well as efforts toward faster vaccination, due to a low immunity level in the population.

e18603 Background: Cancer patients (pts) were among the first to receive vaccination against SARS-CoV-2 (vac). However, their attitude towards as well as experience with vac remain unclear. Methods: Between 04-11/2021 cancer pts at our university cancer center completed a baseline (BL) and follow-up (FU) questionnaire (Q) containing multiple choice questions and ten eleven-level Likert items ranging from 1 (“totally disagree”) to 11 (“totally agree”). Data was analyzed using Student’s t-test or Chi-square test. Results: 219 pts (43% female) completed BLQ (110 FUQ). Mean age was 64 (24-87) years. 82% had solid tumors, 93% were on active therapy (80% chemotherapy). 4% had history of COVID-19. 78% had already received at least one vac at BL, mainly BNT162b2 (91%) or ChAdOx1-S (8%). Only 1% refused vac. Most pts completely agreed to “definitely get vaccinated” (82%) and completely disagreed with “vac is dispensable due to COVID-19 being no serious threat” (82%; more dissent among men, p = 0.037) or “being against vaccination in general” (81%). Self-assessment as member of a risk group (p = 0.03) and fear of COVID-19 (p = 0.002) were more common among women. Every third patient (31%) completely agreed to “being afraid of COVID-19”, every second thinks “SARS-CoV-2 infection would be very dangerous” (56%). Only 41% expressed “complete confidence in the vaccine being safe” and 37% “not being afraid of side effects”. Fear of side effects (SE) was more common among women (p = 0.0016), pts with solid tumors (p = 0.05), with GI tumors (p < 0.0001) and below mean age (p = 0.006). The latter expressed less “confidence in the vaccine being safe” (p = 0.0029). At FUQ, most pts (91%) reported their vac to be well tolerated, 44% reported no SE, especially men (p = 0.001) and pts above age average (p = 0.002). Most common SE was local pain at injection site (36%), which was more frequent among women (p = 0.002), younger pts (p = 0.024) and pts with solid tumors (p = 0.04). Other common SE included fatigue (18%) and myalgia (8%). No thromboembolic events occurred. Only 3 pts had their therapy postponed due to SE. Almost all pts felt retrospectively sufficiently informed about vac and possible SE (94%), would have it again (88%) and agree to get it yearly, if recommended (78%). After vac, pts felt safe meeting friends or family (91%) or shopping (62%). Vacation (32%), work (22%), public transport (21%) or sports (19%) were considered less safe (less frequent among men, p < 0.05). Most pts (70%) did not feel that the COVID-19 pandemic negatively influenced their treatment and regarded the hospitals protective measures as adequate (91%). Conclusions: Willingness to get vac is high among cancer pts and vac is well tolerated in this sensitive cohort. However, concerns about vac safety remain an issue. Those as well as gender differences need to be addressed to increase vac rates and tolerability. The present results may help identify pts that benefit from more detailed pre-vac consultation.

Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease of the skin and mucous membranes. This disease typically affects the elderly and presents with itch and localized or, most frequently, generalized bullous lesions. A subset of patients only develops excoriations, prurigo‐like lesions, and eczematous and/or urticarial erythematous lesions. The disease, which is significantly associated with neurological disorders, has high morbidity and severely impacts the quality of life.

A celebration of the life and accomplishments of internationally known mathematician Doctor Hans-Jürgen Engelbert, who passed away on May 23, 2021.

Background The contribution of droplet-contaminated surfaces for virus transmission has been discussed controversially in the context of the current Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic. Importantly, the risk of fomite-based transmission has not been systematically addressed. Methods We initiated this single-center observational study to evaluate whether hospitalized COVID-19 patients can contaminate stainless steel carriers by coughing or intensive moistening with saliva and to assess the risk of SARS-CoV-2 transmission upon detection of viral loads and infectious virus in cell culture. Fifteen hospitalized patients with a high baseline viral load (CT value ≤ 25) shortly after admission were included. We documented clinical and laboratory parameters and used patient samples to perform virus culture, quantitative PCR and virus sequencing. Results Nasopharyngeal and oropharyngeal swabs of all patients were positive for viral RNA on the day of the study. Infectious SARS-CoV-2 could be isolated from 6 patient swabs (46.2 %). While after coughing, no infectious virus could be recovered, intensive moistening with saliva resulted in successful viral recovery from steel carriers of 5 patients (38.5 %). Conclusions Transmission of infectious SARS-CoV-2 via fomites is possible upon extensive moistening, but unlikely to occur in real-life scenarios and from droplet-contaminated fomites.

BACKGROUND:The contribution of droplet-contaminated surfaces for virus transmission has been discussed controversially in the context of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic. More importantly, the risk of fomite-based transmission has not been systematically addressed. Therefore, the aim of this study was to evaluate whether confirmed hospitalized coronavirus disease 2019 (COVID-19) patients can contaminate stainless steel carriers by coughing or intensive moistening with saliva and to assess the risk of SARS-CoV-2 transmission upon detection of viral loads and infectious virus in cell culture.METHODS:We initiated a single-center observational study including 15 COVID-19 patients with a high baseline viral load (cycle threshold value ≤25). We documented clinical and laboratory parameters and used patient samples to perform virus culture, quantitative polymerase chain reaction, and virus sequencing.RESULTS:Nasopharyngeal and oropharyngeal swabs of all patients were positive for viral ribonucleic acid on the day of the study. Infectious SARS-CoV-2 could be isolated from 6 patient swabs (46.2%). After coughing, no infectious virus could be recovered, however, intensive moistening with saliva resulted in successful viral recovery from steel carriers of 5 patients (38.5%).CONCLUSIONS:Transmission of infectious SARS-CoV-2 via fomites is possible upon extensive moistening, but it is unlikely to occur in real-life scenarios and from droplet-contaminated fomites.

With the emergence of novel Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Variants of Concern (VOCs), vaccination studies that elucidate the efficiency and effectiveness of a vaccination campaign are critical to assess the durability and the protective immunity provided by vaccines. SARS-CoV-2 vaccines have been found to induce robust humoral and cell-mediated immunity in individuals vaccinated with homologous vaccination regimens. Recent studies also suggest improved immune response against SARS-CoV-2 when heterologous vaccination strategies are employed. Yet, few data exist on the extent to which heterologous prime-boost-boost vaccinations with two different vaccine platforms have an impact on the T cell-mediated immune responses with a special emphasis on the currently dominantly circulating Omicron strain. In this study, we collected serum and peripheral blood mononuclear cells (PBMCs) from 57 study participants of median 35-year old’s working in the health care field, who have received different vaccination regimens. Neutralization assays revealed robust but decreased neutralization of Omicron VOC, including BA.1 and BA.4/5, compared to WT SARS-CoV-2 in all vaccine groups and increased WT SARS-CoV-2 binding and neutralizing antibodies titers in homologous mRNA prime-boost-boost study participants. By investigating cytokine production, we found that homologous and heterologous prime-boost-boost-vaccination induces a robust cytokine response of CD4+ and CD8+ T cells. Collectively, our results indicate robust humoral and T cell mediated immunity against Omicron in homologous and heterologous prime-boost-boost vaccinated study participants, which might serve as a guide for policy decisions.

Background: The role of educational facilities including schools and universities in the SARS-CoV-2 pandemic is heavily debated. Specifically, the risk of infection in student dormitories has not been studied. Methods: This cohort study monitors students living in dormitories in Bochum, Germany, throughout the winter term 2020/2021. Over the course of 4 months, participants were tested repeatedly for SARS-CoV-2 infection using RT-PCR from gargle samples and serological testing. An online questionnaire identified individual COVID-19-related risk factors.Findings: In total, 810 (46·5% female) students participated. Of these, 590 (72·8%) students participated in the final visit with serological follow up. The cross-sectional antibody prevalence was n=23 (2·8%) in November 2020 and n=29 (4·9%) in February 2021. Of 2,513 gargle samples analysed, 19 (0·8%) tested positive for SARS-CoV-2, corresponding to a total of 14 (2·4%) infections detected within the study period. All gargle samples available of cases with present infection were positive. The person-time incidence rate was 112·7 (95% CI: 54·11 – 207·2) per 100,000 person weeks. The expected incidence was calculated at 2·74% (RKI). This results in a standardized incidence ratio of 0·9 (95% CI 0·51-1·46, p=0·69). One possible infection cluster was detected by phylogenetic analysis (viral genome sequencing).Interpretation: Based on the results of the present study, students living in student dormitories do not appear to be major drivers of SARS-CoV-2 infections when appropriate measures are used. RT-PCR from gargle samples is a patient-friendly and scalable surveillance tool for the detection of SARS-CoV-2 infections.Funding Information: German Federal Ministry of Education and Research (BMBF).Declaration of Interests: The authors have no conflict of interest to disclose.Ethics Approval Statement: All participants provided written informed consent. The present study was approved by the Ethical Committee of the Medical Faculty, RuhrUniversity of Bochum (registration number: 20-7074).

ZusammenfassungEs wird über eine 15-jährige Patientin mit chronischen Bauchschmerzen, Übelkeit, stuhlig riechendem Aufstoßen und Durchfällen nach dem Trinken berichtet. Endoskopisch wurden 3 gastrokolische Fisteln entdeckt. Weder laborchemisch noch histologisch ergab sich ein Hinweis auf das Vorliegen eines M. Crohn oder anderer Grunderkrankungen. Histologisch fanden sich in Schleimhautbiopsaten der größten Fistel Zeichen einer geringgradigen chronischen und floriden Gastritis. Nach Therapiebeginn mit Omeprazol kam es zur deutlichen Beschwerdebesserung. Alle Fisteln wurden in einer laparoskopischen Operation mithilfe eines Staplers durchtrennt.

This article reports the case of a 15-year-old female patient who presented with chronic abdominal pain, nausea, eructation (burping) smelling of feces and sudden diarrhea after ingestion of fluids. After years of persisting symptoms a diagnosis of three benign gastrocolic fistulas could be established by gastroscopy and colonoscopy. Mucosal samples were taken from the largest fistula where the size enabled a successful biopsy. No features suggestive of Crohn's disease or other underlying inflammatory diseases were identified by laboratory investigations or histological findings. Histological investigations revealed signs of a mild chronic and acute antral and corpus gastritis. Pharmacological treatment with the proton pump inhibitor (PPI) omeprazol resulted in a significant improvement of symptoms. Subsequently, laparoscopic closure of all fistulas using the stapling system was carried out. This treatment modality resulted in the successful recovery of the patient.

The role of educational facilities, including schools and universities, in the SARS-CoV-2 pandemic is heavily debated. Specifically, the risk of infection in student dormitories has not been studied. This cohort study monitored students living in dormitories in Bochum, Germany, throughout the winter term of 2020/2021. Over the course of four months, participants were tested repeatedly for SARS-CoV-2 infections using RT-PCR from gargle samples and serological testing. An online questionnaire identified individual risk factors. A total of 810 (46.5% female) students participated. Of these, 590 (72.8%) students participated in the final visit. The cross-sectional antibody prevalence was n = 23 (2.8%) in November 2020 and n = 29 (4.9%) in February 2021. Of 2513 gargle samples analyzed, 19 (0.8%) tested positive for SARS-CoV-2, corresponding to 14 (2.4%) infections detected within the study period. Gargle samples available of cases with confirmed present infection were always positive. The person-time incidence rate was 112.7 (95% CI: 54.11–207.2) per 100,000 person weeks. The standardized incidence ratio was 0.9 (95% CI 0.51–1.46, p = 0.69). In conclusion, students living in student dormitories do not appear to be major drivers of SARS-CoV-2 infections. RT-PCR from gargle samples is a patient-friendly and scalable surveillance tool for detection of SARS-CoV-2 infections.

Data on SARS-CoV-2 detection in lesional skin is controversial.1-8 We report a PCR-proven COVID-19 patient with a chilblain-like SARS-CoV-2 positive skin lesion. An 80-year-old woman presented to the emergency department at the End of March 2020. She reported an onset of fever (38.4 C°) several days before admission, along with cough and shortness of breath. RT-PCR from a nasopharyngeal swab was positive for SARS-CoV-2. An X-ray showed evidence for right-sided pneumonic infiltrates.