Germ line variant GFI1-36N affects DNA repair and sensitizes AML cells to DNA damage and repair therapy.

ABSTRACT: Growth factor independence 1 (GFI1) is a DNA-binding transcription factor and a key regulator of hematopoiesis. GFI1-36N is a germ line variant, causing a change of serine (S) to asparagine (N) at position 36. We previously reported that the GFI1-36N allele has a prevalence of 10% to 15% among patients with acute myeloid leukemia (AML) and 5% to 7% among healthy Caucasians and promotes the development of this disease. Using a multiomics approach, we show here that GFI1-36N expression is associated with increased frequencies of chromosomal aberrations, mutational burden, and mutational signatures in both murine and human AML and impedes homologous recombination (HR)-directed DNA repair in leukemic cells. GFI1-36N exhibits impaired binding to N-Myc downstream-regulated gene 1 (Ndrg1) regulatory elements, causing decreased NDRG1 levels, which leads to a reduction of O6-methylguanine-DNA-methyltransferase (MGMT) expression levels, as illustrated by both transcriptome and proteome analyses. Targeting MGMT via temozolomide, a DNA alkylating drug, and HR via olaparib, a poly-ADP ribose polymerase 1 inhibitor, caused synthetic lethality in human and murine AML samples expressing GFI1-36N, whereas the effects were insignificant in nonmalignant GFI1-36S or GFI1-36N cells. In addition, mice that received transplantation with GFI1-36N leukemic cells treated with a combination of temozolomide and olaparib had significantly longer AML-free survival than mice that received transplantation with GFI1-36S leukemic cells. This suggests that reduced MGMT expression leaves GFI1-36N leukemic cells particularly vulnerable to DNA damage initiating chemotherapeutics. Our data provide critical insights into novel options to treat patients with AML carrying the GFI1-36N variant.

Peposertib, a DNA-PK Inhibitor, Enhances the Anti-Tumor Efficacy of Topoisomerase II Inhibitors in Triple-Negative Breast Cancer Models.

Triple-negative breast cancer (TNBC) remains the most lethal subtype of breast cancer, characterized by poor response rates to current chemotherapies and a lack of additional effective treatment options. While approximately 30% of patients respond well to anthracycline- and taxane-based standard-of-care chemotherapy regimens, the majority of patients experience limited improvements in clinical outcomes, highlighting the critical need for strategies to enhance the effectiveness of anthracycline/taxane-based chemotherapy in TNBC. In this study, we report on the potential of a DNA-PK inhibitor, peposertib, to improve the effectiveness of topoisomerase II (TOPO II) inhibitors, particularly anthracyclines, in TNBC. Our in vitro studies demonstrate the synergistic antiproliferative activity of peposertib in combination with doxorubicin, epirubicin and etoposide in multiple TNBC cell lines. Downstream analysis revealed the induction of ATM-dependent compensatory signaling and p53 pathway activation under combination treatment. These in vitro findings were substantiated by pronounced anti-tumor effects observed in mice bearing subcutaneously implanted tumors. We established a well-tolerated preclinical treatment regimen combining peposertib with pegylated liposomal doxorubicin (PLD) and demonstrated strong anti-tumor efficacy in cell-line-derived and patient-derived TNBC xenograft models in vivo. Taken together, our findings provide evidence that co-treatment with peposertib has the potential to enhance the efficacy of anthracycline/TOPO II-based chemotherapies, and it provides a promising strategy to improve treatment outcomes for TNBC patients.

Retrospective evaluation of the oral brush biopsy in daily dental routine - an effective way of early cancer detection.

OBJECTIVES: Oral brush biopsies are a well researched index for early detection of oral cancer in specialised centers. But the performance of the exfoliative biopsy is not yet researched in daily dental routine. METHODS: Private dentists and private oral surgeons in Germany took brush biopsies out of 814 suspicious lesions from 670 patients using the Orcellex brush while regular dental appointments. The analyses of the biopsies were performed by the Cytological Laboratory of Bonn (CLB) using liquid-based cytology. RESULTS: The final results were 74 oral squamous cell carcinomas and one verrucous carcinoma, histological proven, 232 cases of leukoplakia, 242 cases of lichen planus, 17 cases of erythroplakia, 259 cases of benign inflammatory, traumatic or hyperplastic oral lesions. The sensitivity for the detection of cancer cells using brush biopsy archived 100%, the specificity for the detection of non-neoplastic cells was 86.5%. The positive predictive value was 43.1%, the negative predicative value was at 100%. CONCLUSION: The oral brush biopsy seems to be a sufficient tool for early cancer detection in private dental offices. CLINICAL RELEVANCE: Generally, practicing dentists do not see various oral squamous cell carcinomas in their careers, so the experience in identifying oral squamous cell carcinomas as such is very low. The brush biopsy might help them in cases of doubt to prevent tumors from expansive growth.

Prognostic value of lymph node involvement in oral squamous cell carcinoma.

OBJECTIVES: Different parameters have been identified in patients with oral squamous cell carcinomas (OSCC) that have a serious impact on survival, including residual tumour and extracapsular spread. Moreover, other factors, including the lymph node ratio (LNR) and lymph node yield (LNY), have been suggested as prognostic markers. MATERIAL AND METHODS: This retrospective study included patients diagnosed with OSCC and cervical lymph node metastases during the years 2010-2020. Patients' records were evaluated regarding lymph node status, final therapy regime, tumour recurrence, time to death, tumour association with death, disease-free survival (DSF), and overall survival (OS). RESULTS: In 242 patients with a mean age of 63.57 ± 11.24 years, treated either by selective neck dissection (SND; n = 70) or by modified radical neck dissection (MRND; n = 172), 5772 lymph nodes were detected. The LNR and LNY were identified as independent risk factors in OS and DFS. The optimal cut-off point for the LNY was ≥ 17 lymph nodes in the SND and ≥ 27 lymph nodes in the MRND group. The metastatic lymph node clearance (MLNC) was established as a score to relate the LNR and LNY to the extent of lymph node removal. Survival analysis showed statistically significant differences among score levels. CONCLUSIONS: As information about the extent of nodal dissection is excluded from LNR and LNY, we propose the use of a new scoring system comprising individual cut-off values for LNY and LNR with regard to the extent of neck dissection. CLINICAL RELEVANCE: MLNC might help to identify high-risk OSCC patients with metastatic lymph nodes.

A cross-sectional survey study on the nutrition patterns of patients with peripheral artery disease.

Background: Even though nutrition was demonstrated to have an impact on chronic atherosclerotic disease, there is a paucity of corresponding recommendations for patients with peripheral artery disease (PAD). A Mediterranean Diet based on daily intake of fruits and vegetables with high fibre, vegetable oil, and unsalted nuts including fish several times a week may have protective effects. This cross-sectional survey aimed to determine nutritional patterns amongst inpatients with PAD. Methods: All inpatients with symptomatic PAD who underwent revascularisation at a single centre between 1st May 2018 and 31st December 2021 were asked to fill out a questionnaire on nutritional intake. An 8-item frequency rating scale (from never to three times a day) was used for 15 food groups. For 11 of them, an adapted Mediterranean Diet score was calculated using the answers. The descriptive results were stratified by sex and disease stage (intermittent claudication vs. chronic limb-threatening ischaemia). Results: A total of 319 patients (31.7% female, 69.4 years in mean) were included. Thereof, 71.8% reported they did never receive any nutritional information considering their PAD disease. The mean adapted Mediterranean Diet score was 2.7 points (of maximum 11) with most patients not achieving the recommended servings per week for fruits (1.6%), vegetables (1.0%), and unsalted nuts (12.2%). The intake of cereals was sufficient (43.3%). When compared with men, women consumed more fruits and less meat. Conclusions: This survey demonstrated that although healthy nutrition may have a positive impact on patients with PAD, the education and adherence to a Mediterranean Diet was inappropriate. Nutritional patterns should be more focused in future PAD studies to derive specific recommendations and nutritional programmes as well as patient education in clinical practice.

Evaluation of Immuno-Rolling Circle Amplification for Multiplex Detection and Profiling of Antigen-Specific Antibody Isotypes.

Antibody characterization is essential for understanding the immune system and development of diagnostics and therapeutics. Current technologies are mainly focusing on the detection of antigen-specific immunoglobulin G (IgG) using bulk singleplex measurements, which lack information on other isotypes and specificity of individual antibodies. Digital immunoassays based on nucleic acid amplification have demonstrated superior performance by allowing the detection of single molecules in a multiplex and sensitive manner. In this study, we demonstrate for the first time an immuno-rolling circle amplification (immuno-RCA) assay for the multiplex detection of three antigen-specific antibody isotypes (IgG, IgA, and IgM) and its integration with microengraving. To validate this approach, we used the autoimmune disease immune-mediated thrombotic thrombocytopenic purpura (iTTP) as the model disease with anti-ADAMTS13 autoantibodies as the diagnostic target molecules. To identify the anti-ADAMTS13 autoantibody isotypes, we designed a pool of three unique antibody-oligonucleotide conjugates for identification and subsequent amplification and visualization via RCA. To validate this approach, we first confirmed an assay specificity of >88% and a low limit of detection of 0.3 ng/mL in the spiked buffer. Subsequently, we performed a dilution series of an iTTP plasma sample for the multiplex detection of the three isotypes with higher sensitivity compared to an enzyme-linked immunosorbent assay. Finally, we demonstrated single-cell analysis of human B cells and hybridoma cells for the detection of secreted antibodies using microengraving and achieved a detection of 23.3 pg/mL secreted antibodies per hour. This approach could help to improve the understanding of antibody isotype distributions and their roles in various diseases.

Padlock Probe Assay for Detection and Subtyping of Seasonal Influenza.

BACKGROUND: Influenza remains a constant threat worldwide, and WHO estimates that it affects 5% to 15% of the global population each season, with an associated 3 to 5 million severe cases and up to 500000 deaths. To limit the morbidity and the economic burden of influenza, improved diagnostic assays are needed. METHODS: We developed a multiplexed assay for the detection and subtyping of seasonal influenza based on padlock probes and rolling circle amplification. The assay simultaneously targets all 8 genome segments of the 4 circulating influenza variants-A(H1N1), A(H3N2), B/Yamagata, and B/Victoria-and was combined with a prototype cartridge for inexpensive digital quantification. Characterized virus isolates and patient nasopharyngeal swabs were used for assay design and analytical validation. The diagnostic performance was assessed by blinded testing of 50 clinical samples analyzed in parallel with a commercial influenza assay, Simplexa™ Flu A/B & RSV Direct. RESULTS: The assay had a detection limit of 18 viral RNA copies and achieved 100% analytical and clinical specificity for differential detection and subtyping of seasonal circulating influenza variants. The diagnostic sensitivity on the 50 clinical samples was 77.5% for detecting influenza and up to 73% for subtyping seasonal variants. CONCLUSIONS: We have presented a proof-of-concept padlock probe assay combined with an inexpensive digital readout for the detection and subtyping of seasonal influenza strains A and B. The demonstrated high specificity and multiplexing capability, together with the digital quantification, established the assay as a promising diagnostic tool for seasonal influenza.

Status quo of interprofessional education for midwifery and medical students in Germany, Austria, and Switzerland.

Objectives: The care of women and their families around childbirth requires effective interprofessional collaboration of the midwifery and medical profession. Given the academisation of midwifery, early interaction between students of midwifery and medicine is both necessary and feasible. As there is a lack of comprehensive data on interprofessional education (IPE) for midwifery and medical students at higher education institutions in Germany, Austria, and Switzerland (DACH region), the aim was to identify existing IPE activities, and their curricular determination. Methods: The exploratory study was conducted in the DACH region over three months (Dec. 2022-Feb. 2023). Higher education institutions offering midwifery science and/or medicine were invited to participate in a web-based survey. The questionnaire focused on the structure and curricular implementation of IPE courses, on cooperation, financial support and more. Results: A total of 58 out of 96 invited institutions (60%) participated in the survey, of which 34 (59%) offered IPE. Eighteen institutions (19%) offered 32 IPE courses for midwifery and medical students through cooperation within faculty (n=8) and between faculties (n=10). Notably, most of these IPE courses (60%) were integrated into the required curriculum of both study programmes. Most IPE courses were offered without financial support (71%). Conclusion: The current status quo highlighted the existence of numerous IPE offers for midwifery and medical students in the DACH region that warrant further curricular integration of proven and well-established best practice examples to further enhance these initiatives.

Seafarers' attitudes and chances to improve the nutrition on merchant ships from the crews' and cooks' perspective.

BACKGROUND: Seafarers' diets are often high in fat, sugar and calories, thus contributing to an increased risk of obesity, metabolic syndrome and cardiovascular disease. The multitude of obstacles to healthy eating in the on-board environment on merchant ships makes it essential to find new approaches for health promotion. This study explored seafarers' attitudes, the status quo of support measures and chances to improve nutrition on merchant ships from the perspective of crews and cooks. METHODS: In the course of the EU-funded project "e-healthy ship", European and Southeast Asian seafarers (N = 810) and ship cooks (N = 62) were examined by using two questionnaires on 68 ships of two German shipping companies. RESULTS: Almost all seafarers (98.8%) considered a healthy diet important for their well-being and the majority of seafarers reported being open-minded about changing their eating habits (88.4%). However, European seafarers were less likely to respond that they are willing to eat less meat [OR 0.11; 95%CI (0.07-0.17); p < .001], more vegetables [OR 0.10; 95%CI (0.02-0.49); p = .005] and more fruits [OR 0.11; 95%CI (0.02-0.61); p = .011] than their Southeast Asian colleagues. On the one hand, 82.3% of the ship cooks reported having taken part in at least one cooking course organized by their employer (1: 33.9%, 2: 25.8%, 3: 14.5%, 4 or more: 8.1%), on the other hand, slightly above half stated that the last of these courses had taken place more than 2 years ago. Furthermore, the ship cooks showed a positive attitude towards the use of a tablet-based digital platform that supports the ship cooks in daily and complex tasks (> 85% agreement). CONCLUSIONS: To improve nutrition on board merchant ships, various parameters need to be adjusted, such as ensuring a demand-oriented food supply on board or supporting seafarers' healthy food choices through target group-specific nutrition education. Ship cooks would be able to play a crucial role if they receive support. The development of a tablet-based digital platform that supports the ship cooks in their daily tasks, offers training and empowers them to implement health-promoting measures themselves seems to be an accepted and promising approach.

Oncological Outcome of Node-Positive Oral Squamous Cell Carcinomas Treated With Selective and Comprehensive Neck Dissection.

Selective neck dissection (SND) is the treatment of choice in patients with oral squamous cell carcinomas (OSCCs) and clinically node-negative necks (cN0). The treatment of patients with positive-staged necks (cN+) includes SND as well as comprehensive neck dissection (CND). The clear benefit of one or the other remains under debate. We aim to address this lack of clarity by analysing patients with OSCC staged with clinically node-positive necks, treated with either CND or SND using a level-by-level approach. This retrospective study included patients diagnosed with OSCC with clinically (cN+) and pathologically (pN+) positive cervical lymph nodes (LNs) with clear neck level categorization during the years 2010-2019. In total, 74 patients were analysed. Cox regression analysis found no significance for the type of ND being an independent risk factor, neither for overall survival (OS) nor for disease-free survival (DFS). Regional recurrence of CND cases (5.77%) was comparable to SND cases (9.09%). For OS, extracapsular spread (ECS) and male sex were identified as independent risk factors with poorer outcome. pT-stage and ECS were found to be independent risk factors for DFS. The results of this study suggest that both CND and SND may be viable treatment options for certain patients with OSCC pN+.

Resection status and margin control in intraoperative frozen sectioning analysis of oral squamous cell carcinoma.

PURPOSE: Intraoperative frozen section analysis (IFSA) is a well-established procedure for determining the intraoperative soft tissue resection status in patients with oral squamous cell carcinoma (OSCC). Margin status is a major predictor of the patient´s outcome, histologically free margins of ≥ 5 mm are demanded. This study evaluates the accuracy of IFSA, the impact of margin status and the impact of intraoperative margin revision on disease-free survival (DFS) and overall survival (OS). METHODS: This retrospective study included 213 patients with OSCC. IFSA results were compared with definitive histopathological reports, Kaplan-Meier analysis was performed. Cut-off values were calculated for resection margins considering known risk factors. RESULTS: IFSA showed positive margins in 8 cases (3.8%). Kaplan-Meier analysis revealed no significant differences for OS or DFS if R0-status was achieved by initial resection or immediate re-resection. Final histopathological evaluation revealed false-positive IFSA in 3/8 cases (37.5%) and false-negative IFSA in 1/205 cases (0.5%). Sensitivity was 83.3% and specificity was 98.6%. Analysis of optimal cut-off values showed no general need for larger resection margins in patients with risk factors. Cut-off values were slightly higher for patients with the risk factor alcohol consumption (7 mm for OS and DFS) or pN + ECS- disease (7 mm for DFS). Optimal cut-off values for tumour-margin-distance were around 6 mm. CONCLUSION: IFSA provides a valuable assessment method for intraoperative soft tissue resection margins. Risk factors seemingly do not significantly influence the extent of tumour resection.

Sex-Specific Dietary Patterns and Social Behaviour in Low-Risk Individuals.

Dietary and social behaviour are non-medical factors that influence health outcomes. Non-communicable diseases are related to dietary patterns. To date, little is known about how social behaviour is associated with health-related dietary patterns, and, in particular, we lack information about the role of sex within this possible relation. Our cross-sectional study investigated associations between dietary patterns and social behaviour including personality traits (self-control, risk taking), political preferences (conservative, liberal, ecological, social) and altruism (willingness to donate, club membership, time discounting) in men and women. We performed sex-specific correlation analyses to investigate relationships between dietary patterns based on self-reported protocols from the Mediterranean Diet Adherence Screener (MEDAS) and the validated Healthy Eating Index (HEI) from the EPIC Study and a self-reported social behaviour questionnaire. In linear regression models, we analysed associations between dietary and social behaviour patterns. Sex differences were measured by interaction analysis for each social behaviour item. The study sample consisted of N = 102 low-risk individuals. The median age of the study participants was 62.4 (25th/75th percentile 53.6, 69.1) years, and 26.5% were women. Analyses showed that a lower HEI score was correlated with a higher BMI in both women and men. MEDAS and HEI showed a positive correlation with each other in men. In men, a higher MEDAS showed a positive correlation when they estimated their ability as high, with the same for self-control and preference for ecological politics and MEDAS. A weak negative correlation has been shown between men with a preference for conservative politics and MEDAS. HEI showed a positive significant correlation with age in men. Male participants without club membership scored significantly higher in the HEI compared to non-members. A negative correlation was shown for time discounting in men. Linear regression models showed positive associations between preferences for ecological-oriented politics and nutrition for both HEI and MEDAS. No sex interactions were observed. We faced a few limitations, such as a small sample size, particularly for women, and a limited age spectrum in a European cohort. However, assuming that individuals with a preference for ecological-oriented politics act ecologically responsibly, our findings indicate that ecological behaviour in low-risk individuals might determine, at least in part, a healthy diet. Furthermore, we observed dietary patterns such as higher alcohol consumption in men or higher intake of butter, margarine and cream in women that indicate that women and men may have different needs for nutritional improvement. Thus, further investigations are needed to better understand how social behaviour affects nutrition, which could help to improve health. Our findings have the potential to inform researchers and practitioners who investigate the nature of the relationship between social behaviour and dietary patterns to implement strategies to create first-stage changes in health behaviour for individuals with a low cardiovascular risk profile.

DNA-Dependent Protein Kinase Inhibitor Peposertib Potentiates the Cytotoxicity of Topoisomerase II Inhibitors in Synovial Sarcoma Models.

Synovial sarcoma is a rare and highly aggressive subtype of soft tissue sarcoma. The clinical challenge posed by advanced or metastatic synovial sarcoma, marked by limited treatment options and suboptimal outcomes, necessitates innovative approaches. The topoisomerase II (Topo II) inhibitor doxorubicin has remained the cornerstone systemic treatment for decades, and there is pressing need for improved therapeutic strategies for these patients. This study highlights the potential to enhance the cytotoxic effects of doxorubicin within well-characterized synovial sarcoma cell lines using the potent and selective DNA-PK inhibitor, peposertib. In vitro investigations unveil a p53-mediated synergistic anti-tumor effect when combining doxorubicin with peposertib. The in vitro findings were substantiated by pronounced anti-tumor effects in mice bearing subcutaneously implanted tumors. A well-tolerated regimen for the combined application was established using both pegylated liposomal doxorubicin (PLD) and unmodified doxorubicin. Notably, the combination of PLD and peposertib displayed enhanced anti-tumor efficacy compared to unmodified doxorubicin at equivalent doses, suggesting an improved therapeutic window-a critical consideration for clinical translation. Efficacy studies in two patient-derived xenograft models of synovial sarcoma, accurately reflecting human metastatic disease, further validate the potential of this combined therapy. These findings align with previous evidence showcasing the synergy between DNA-PK inhibition and Topo II inhibitors in diverse tumor models, including breast and ovarian cancers. Our study extends the potential utility of combined therapy to synovial sarcoma.

Oncologic Outcome in Advanced Oral Squamous Cell Carcinoma After Refusal of Recommended Adjuvant Therapy.

Importance: Clinicians may be confronted with patients refusing recommended adjuvant therapy (AT) after the primary resection of an advanced oral squamous cell carcinoma (OSCC). However, for this tumor entity, data are lacking regarding the oncological outcomes and associated factors after refusal of AT. Objective: To evaluate the difference in survival and disease recurrence for patients with and without recommended AT after resection of advanced OSCC. Design, Setting, and Participants: In this single-center retrospective matched cohort study, patients with advanced OSCC who refused recommended AT between January 2010 and December 2021 were matched 1:1 according to Union for International Cancer Control tumor staging with patients who completed AT. Exposures: Patients with advanced OSCC who refused or completed recommended AT between 2010 and 2021. Main Outcomes and Measures: The primary outcome of this study was the comparison of overall survival (OS) and recurrence-free survival (RFS) between the 2 study groups. Results: A total of 82 patients (mean [SD] age at time of surgery, 68.0 [11.3] years; 38 [46.3%] female, 44 [53.7%] male) with and without AT (41 per study group) were included in the analysis. Patients refusing AT developed more frequent disease recurrence than patients who completed AT (61.0% vs 26.8%; difference, 34.2%; odds ratio, 4.26; 95% CI, 1.68-10.84). In addition, patients who refused AT presented with lower 2-year OS (72.7% vs 88.6%; difference, 15.9%; 95% CI, 8.6%-40.6%) and much lower 2-year RFS (39.1% vs 74.2%; difference, 35.1%; 95% CI, 0.2%-70.5%). In the patient cohort who rejected AT, a worse OS was associated with female sex (48.6% vs 90.5%; difference, 41.9%; 95% CI, 0.6%-84.4%), pT1-2 category (57.1% vs 92.3%; difference, 35.2%; 95% CI, 3.3%-73.6%), and pN1 or higher category (61.2% vs 82.6%; difference, 21.4%; 95% CI, 14.1%-56.8%). Lower RFS was associated with female sex (37.9% vs 90.9%; difference, 53.0%; 95% CI, 8.0%-97.9%), advanced T category (pT3-4, 35.3% vs 80.0%; difference, 44.7%; 95% CI, 6.4%-95.3%), lymph node yield of 20 or greater (31.4% vs 80.6%; difference, 49.2%; 95% CI, 4.9%-93.4%), and lymph node ratio of less than 4.6% (36.6% vs 84.4%; difference, 47.8%; 95% CI, 1.8%-93.1%). Conclusions and Relevance: In this cohort study of patients with advanced OSCC, refusal of AT was associated with worse oncological outcomes. The prevalence of disease recurrence during follow-up was 34% higher in patients who refused AT than in patients who completed AT. The results from this study may assist clinicians in guiding patients who are considering refusal of or withdrawal from AT.

Sleep Architecture and Sleep-Related Breathing Disorders of Seafarers on Board Merchant Ships: A Polysomnographic Pilot Field Study on the High Seas.

As seafarers are assumed to have an increased risk profile for sleep-related breathing disorders, this cross-sectional observational study measured (a) the feasibility and quality of polysomnography (PSG) on board merchant ships, (b) sleep macro- and microarchitecture, (c) sleep-related breathing disorders, such as obstructive sleep apnea (OSA), using the apnea-hypopnea index (AHI), and (d) subjective and objective sleepiness using the Epworth Sleepiness Scale (ESS) and pupillometry. Measurements were carried out on two container ships and a bulk carrier. A total of 19 out of 73 male seafarers participated. The PSG's signal qualities and impedances were comparable to those in a sleep laboratory without unusual artifacts. Compared to the normal population, seafarers had a lower total sleep time, a shift of deep sleep phases in favor of light sleep phases as well as an increased arousal index. Additionally, 73.7% of the seafarers were diagnosed with at least mild OSA (AHI ≥ 5) and 15.8% with severe OSA (AHI ≥ 30). In general, seafarers slept in the supine position with a remarkable frequency of breathing cessations. A total of 61.1% of the seafarers had increased subjective daytime sleepiness (ESS > 5). Pupillometry results for objective sleepiness revealed a mean relative pupillary unrest index (rPUI) of 1.2 (SD 0.7) in both occupational groups. In addition, significantly poorer objective sleep quality was found among the watchkeepers. A need for action with regard to poor sleep quality and daytime sleepiness of seafarers on board is indicated. A slightly increased prevalence of OSA among seafarers is likely.

Exploration of Seafarers' Mobile Proficiency as a Prerequisite for Possible Health App-based Health Promotion on Board.

Numerous health hazards characterize the profession of a seafarer. The job-specific environment may affect the crews' well-being and mental health. The options for health promotion are limited, as seafarers are isolated for long periods and are a difficult-to-reach collective. A digital app-based health management system might offer a promising approach in this regard. This study aims to identify seafarers' technical competencies as a prerequisite for possible health app-based health promotion. A total of 976 seafarers (response rate 75.1%) on 65 ships of a Hamburg shipping company completed the standardized questionnaire MDPQ-16 (Mobile Device Proficiency Questionnaire) that assesses the IT competence in 8 different sub-scales. The results were stratified in respect to occupational groups aboard as well as compared to a reference collective ashore. The seafarers had an MDPQ-16 sum-score of 4.40 (SD 0.84), scoring 0.21 points higher than the land-based reference collective. Significant differences were observed between the ratings and officers in almost every sub-scale and item of the MDPQ-16. The highest sum-score was held by the nautical officers with 4.71. Greater differences between officers and ratings were observed in sub-scales related to rather complex tasks. The seafarers demonstrated a high level of IT proficiency, even surpassing the land-based sample, suggesting that their technical competence is adequate for app-based health promotion. In view of the higher scores of officers, the selection of health apps has to be tailored to the seafarers' different levels of mobile competence in order to maximize the improvement in mental health and well-being. Further research is needed to determine seafarers' needs and interests.

Management of the Contralateral Neck in Unilateral Node-Positive Oral Squamous Cell Carcinoma.

INTRODUCTION: In lateralized oral squamous cell carcinoma (OSCC) with ipsilateral cervical lymph node metastasis (CLNM), the surgical management of the unsuspicious contralateral neck remains a matter of debate. The aim of this study was to analyze this cohort and to compare the outcomes of patients with and without contralateral elective neck dissection (END). MATERIAL AND METHODS: A retrospective analysis of patients with lateralized OSCC, ipsilateral CLNM (pN+) and contralateral cN0-stage was performed. Patients were divided into two groups according to the surgical management of the contralateral neck: I: END; and II: no END performed. Adjuvant radiotherapy was applied bilaterally in both groups according to individual risk. RESULTS: A total of 65 patients (group I: 16 (24.6%); group II: 49 (75.4%)) with a median follow-up of 28 months were included. Initially, there was no case of contralateral CLNM after surgery. During follow-up, 6 (9.2%) patients presented with recurrent CLNM. In 5 of these cases (7.7%), the contralateral neck (group I: 3/16 (18.8%); group II: 2/49 (4.1%)) was affected. Increased ipsilateral lymph node ratio was associated with contralateral CLNM (p = 0.07). END of the contralateral side showed no significant benefit regarding OS (p = 0.59) and RFS (p = 0.19). CONCLUSIONS: Overall, the risk for occult contralateral CLNM in patients with lateralized OSCC ipsilateral CLNM is low. Our data suggest that END should not be performed routinely in this cohort. Risk-adapted radiotherapy of the contralateral neck alone seems to be sufficient from the oncological point of view.

Mediterranean Diet and Atrial Fibrillation: Lessons Learned from the AFHRI Case-Control Study.

A relationship between lifestyle, diet, and atrial fibrillation (AF) remains unclear. Except for alcohol consumption, AF guidelines do not differentiate specific advice for this rhythm disorder. The aim of this study was to investigate the association between adherence to healthy dietary patterns and the presence of AF, among 104 low risk participants from the 1:1 matched case-control AFHRI (Atrial Fibrillation in High-Risk Individuals) study. Dietary data were obtained using a three-day food record. Adapted German versions of the validated 14-item Mediterranean Diet Adherence Screener (MEDAS) and the validated eight-item Healthy Eating Index (HEI) from the Epic Study served as the basis for data derivation. The median age of the study participants was 63.0 years, 73.1% were men. In multivariable adjusted binary logistic regression analyses, we found inverse associations between both dietary indices (MEDAS: Median = 3, HEI: Median = 54.9) and the presence of AF (odds ratio for MEDAS: 0.65, 95% confidence interval (CI): 0.47-0.91, odds ratio for HEI: 0.60, 95% CI 0.39-0.95). Further clinical studies are needed to confirm the extent to which high quality dietary patterns such as a Mediterranean diet influence the onset and natural history of AF, in order to provide dietary counselling.

Presence of the GFI1-36N single nucleotide polymorphism enhances the response of MLL-AF9 leukemic cells to CDK4/6 inhibition.

The zinc finger protein Growth Factor Independence 1 (GFI1) acts as a transcriptional repressor regulating differentiation of myeloid and lymphoid cells. A single nucleotide polymorphism of GFI1, GFI1-36N, has a prevalence of 7% in healthy Caucasians and 15% in acute myeloid leukemia (AML) patients, hence most probably predisposing to AML. One reason for this is that GFI1-36N differs from the wildtype form GFI1-36S regarding its ability to induce epigenetic changes resulting in a derepression of oncogenes. Using proteomics, immunofluorescence, and immunoblotting we have now gained evidence that murine GFI1-36N leukemic cells exhibit a higher protein level of the pro-proliferative protein arginine N-methyltransferase 5 (PRMT5) as well as increased levels of the cell cycle propagating cyclin-dependent kinases 4 (CDK4) and 6 (CDK6) leading to a faster proliferation of GFI1-36N leukemic cells in vitro. As a therapeutic approach, we subsequently treated leukemic GFI1-36S and GFI1-36N cells with the CDK4/6 inhibitor palbociclib and observed that GFI1-36N leukemic cells were more susceptible to this treatment. The findings suggest that presence of the GFI1-36N variant increases proliferation of leukemic cells and could possibly be a marker for a specific subset of AML patients sensitive to CDK4/6 inhibitors such as palbociclib.