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Abstract Background Personalized modeling is a promising tool to improve abdominal aortic aneurysm (AAA) rupture risk assessment. Computed tomography (CT) and quantitative flow (Q-flow) magnetic resonance imaging (MRI) are widely regarded as the gold standard for acquiring patient-specific geometry and velocity profiles, respectively. However, their frequent utilization is hindered by various drawbacks. Ultrasound is used extensively in current clinical practice and offers a safe, rapid and cost-effective method to acquire patient-specific geometries and velocity profiles. This study aims to extract and validate patient-specific velocity profiles from Doppler ultrasound and to examine the impact of the velocity profiles on computed hemodynamics. Methods Pulsed-wave Doppler (PWD) and color Doppler (CD) data were successfully obtained for six volunteers and seven patients and employed to extract the flow pulse and velocity profile over the cross-section, respectively. The US flow pulses and velocity profiles as well as generic Womersley profiles were compared to the MRI velocities and flows. Additionally, CFD simulations were performed to examine the combined impact of the velocity profile and flow pulse. Results Large discrepancies were found between the US and MRI velocity profiles over the cross-sections, with differences for US in the same range as for the Womersley profile. Differences in flow pulses revealed that US generally performs best in terms of maximum flow, forward flow and ratios between forward and backward flow, whereas it often overestimates the backward flow. Both spatial patterns and magnitude of the computed hemodynamics were considerably affected by the prescribed velocity boundary conditions. Larger errors and smaller differences between the US and generic CFD cases were observed for patients compared to volunteers. Conclusion These results show that it is feasible to acquire the patient-specific flow pulse from PWD data, provided that the PWD acquisition could be performed proximal to the aneurysm region, and resulted in a triphasic flow pattern. However, obtaining the patient-specific velocity profile over the cross-section using CD data is not reliable. For the volunteers, utilizing the US flow profile instead of the generic flow profile generally resulted in improved performance, whereas this was the case in more than half of the cases for the patients.

Objective: To explore the current state of knowledge and evidence about peer support for various disadvantaged groups; to identify the strengths, weaknesses, opportunities, and threats of peer support to critically reflect on peer support within health and social services. Methods: A rapid scoping review was conducted according to Arksey and O’Malley’s framework, aiming to identify eligible studies in PubMed, APA PsychInfo, Education Resources Information Center, Cochrane Library, Academic Search Premier, ScienceDirect, Directory of Open Access Journals, ResearchGate, WorldCat, and Google Scholar. According to Rodgers’ concept analysis steps and the SWOT model, data was reported using thematic synthesis. Results: Forty-five studies were included, describing a variety of peer support initiatives among groups of young migrants and unsupervised minors, young adults with autism, people with (mental) health problems, foster/shelter families, vulnerable pregnant women, people outside the labour force, older adults, and homeless people. The strength of peer support is its positive effect on the quality of life among vulnerable people. The weakness is represented by peers both being too involved and focused on personal interest or by peers lacking expertise and knowledge. Opportunities for peer support are mutual learning, the anticipated long-term effects, and the potential to facilitate social inclusion. Culture, language barriers, drop-out rates, securing sustainability, and peers’ lack of time and commitment are regarded as threats to peer support. Conclusion: Although peer support offers good outcomes for various groups of vulnerable people, the weaknesses and threats need to be considered to provide and proliferate peer support.

Abstract Background Neuropsychiatric symptoms (NPS) are prevalent in the early clinical stages of Alzheimer’s disease (AD) according to proxy-based instruments. Little is known about which NPS clinicians report and whether their judgment aligns with proxy-based instruments. We used natural language processing (NLP) to classify NPS in electronic health records (EHRs) to estimate the reporting of NPS in symptomatic AD at the memory clinic according to clinicians. Next, we compared NPS as reported in EHRs and NPS reported by caregivers on the Neuropsychiatric Inventory (NPI). Methods Two academic memory clinic cohorts were used: the Amsterdam UMC (n = 3001) and the Erasmus MC (n = 646). Patients included in these cohorts had MCI, AD dementia, or mixed AD/VaD dementia. Ten trained clinicians annotated 13 types of NPS in a randomly selected training set of n = 500 EHRs from the Amsterdam UMC cohort and in a test set of n = 250 EHRs from the Erasmus MC cohort. For each NPS, a generalized linear classifier was trained and internally and externally validated. Prevalence estimates of NPS were adjusted for the imperfect sensitivity and specificity of each classifier. Intra-individual comparison of the NPS classified in EHRs and NPS reported on the NPI were conducted in a subsample (59%). Results Internal validation performance of the classifiers was excellent (AUC range: 0.81–0.91), but external validation performance decreased (AUC range: 0.51–0.93). NPS were prevalent in EHRs from the Amsterdam UMC, especially apathy (adjusted prevalence = 69.4%), anxiety (adjusted prevalence = 53.7%), aberrant motor behavior (adjusted prevalence = 47.5%), irritability (adjusted prevalence = 42.6%), and depression (adjusted prevalence = 38.5%). The ranking of NPS was similar for EHRs from the Erasmus MC, although not all classifiers obtained valid prevalence estimates due to low specificity. In both cohorts, there was minimal agreement between NPS classified in the EHRs and NPS reported on the NPI (all kappa coefficients

Abstract INTRODUCTION We investigated whether mortality in memory clinic patients changed due to coronavirus disease 2019 (COVID‐19) pandemic. METHODS We included patients from the Amsterdam Dementia Cohort: (1) n = 923 pandemic patients (baseline visit: 2017–2018, follow‐up: until 2021), and (2) n = 830 historical control patients (baseline visit: 2015–2016, follow‐up: until 2019). Groups were well‐balanced. We compared mortality during pandemic with historical control patients using Cox regression. Differences in cause of death between groups were explored using Fisher's exact test. RESULTS Pandemic patients had a higher risk of mortality than historical control patients (hazard ratio [HR] [95% confidence interval {CI}] = 1.34 [1.05–1.70]). Stratified for syndrome diagnosis, the effect remained significant in dementia patients (HR [95% CI] = 1.35 [1.03–1.78]). Excluding patients who died of COVID‐19‐infection, the higher mortality risk in pandemic patients attenuated (HR [95% CI] = 1.24 [0.97–1.58]). Only the difference in cause of death between pandemic patients and historical control patients for death to COVID‐19‐infection (p = 0.001) was observed. CONCLUSION Memory clinic patients had increased mortality risk during COVID‐19 compared to historical control patients, attributable to dementia patients. Highlights We investigated if mortality rates in memory clinic patients changed due to COVID‐19 pandemic. We included patients along the cognitive continuum, including SCD, MCI, and dementia. We used a well‐balanced historical control group. Memory clinic patients had higher risk for mortality during COVID‐19 lockdown. Our results indicate that excess mortality is mainly caused by death to COVID‐19 infection.

The Alliance Party played a minor role during the Northern Ireland conflict, but since Brexit it has become a significant political force, rallying voters disappointed by dominant parties or not identifying with the traditional divide between unionists and nationalists. Nonetheless, the Northern Irish institutional framework and the perspective of a referendum on Irish reunification constitute major obstacles for this party of the centre seeking to promote power-sharing in a deeply divided region.

Abstract Background During COVID-19 lockdown measures, memory clinic patients reported worries for faster cognitive decline, due to loss of structure and feelings of loneliness and depression. We aimed to investigate the impact of the COVID-19 lockdown on rate of cognitive decline in a mixed memory clinic population, compared to matched historical controls. Methods We included patients who visited Alzheimer Center Amsterdam 6 months to 1 week before the first Dutch COVID-19 lockdown, and had a second visit 1 year later, after this lockdown period (n = 113; 66 ± 7 years old; 30% female; n = 55 dementia, n = 31 mild cognitive impairment (MCI), n = 18 subjective cognitive decline (SCD), n = 9 postponed diagnosis). Historical controls (visit in 2016/2017 and second visit 1 year later (n = 640)) were matched 1:1 to lockdown patients by optimal Mahalanobis distance matching (both groups n = 113). Groups were well matched. Differences between lockdown patients and historical controls over time in Mini-Mental State Examination, Trail Making Test part A and B, Rey-Auditory Verbal Learning Test (RAVLT) immediate and delayed recall, and category fluency scores were analyzed using linear mixed effect models with random intercepts. We examined differences in rate of cognitive decline between whole groups, and after stratification in SCD, MCI, and dementia separately. Results Lockdown patients had a faster rate of memory decline compared to controls on both RAVLT immediate [B(SE) = − 2.62 (1.07), p = 0.015] and delayed recall [B(SE) = − 1.07 (0.34), p = 0.002]. Stratification by syndrome diagnosis showed that this effect was largely attributable to non-demented participants, as we observed faster memory decline during lockdown in SCD and MCI (RAVLT immediate [SCD: B(SE) = − 6.85 (2.97), p = 0.027; MCI: B(SE) = − 6.14 (1.78), p = 0.001] and delayed recall [SCD: B(SE) = − 2.45 (1.11), p = 0.035; MCI: B(SE) = − 1.50 (0.51), p = 0.005]), but not in dementia. Conclusion Memory clinic patients, specifically in pre-dementia stages, showed faster memory decline during COVID-19 lockdown, providing evidence that lockdown regulations had a deleterious effect on brain health. In individuals that may have been able to deal with accumulating, subclinical neuropathology under normal and structured circumstances, the additional stress of lockdown regulations may have acted as a “second hit,” resulting in less beneficial disease trajectory.

Recent advances in melanoma therapy have significantly improved the prognosis of metastasized melanoma. However, large therapeutic gaps remain that need to be closed by new strategies. Antiapoptotic Bcl-2 proteins critically contribute to apoptosis deficiency and therapy resistance. They can be targeted by BH3 mimetics, small molecule antagonists that mimic the Bcl-2 homology domain 3 (BH3) of proapoptotic BH3-only proteins. By applying in vitro experiments, we aimed to obtain an overview of the possible suitability of BH3 mimetics for future melanoma therapy. Thus, we investigated the effects of ABT-737 and ABT-263, which target Bcl-2, Bcl-xL and Bcl-w as well as the Bcl-2-selective ABT-199 and the Mcl-1-selective S63845, in a panel of four BRAF-mutated and BRAF-WT melanoma cell lines. None of the inhibitors showed significant effectiveness when used alone; however, combination of S63845 with each one of the three ABTs almost completely abolished melanoma cell survival and induced apoptosis in up to 50–90% of the cells. Special emphasis was placed here on the understanding of the downstream pathways involved, which may allow improved applications of these strategies. Thus, cell death induction was correlated with caspase activation, loss of mitochondrial membrane potential, phosphorylation of histone H2AX, and ROS production. Caspase dependency was demonstrated by a caspase inhibitor, which blocked all effects. Upregulation of Mcl-1, induced by S63845 itself, as reported previously, was blocked by the combinations. Indeed, Mcl-1, as well as XIAP (X-linked inhibitor of apoptosis), were strongly downregulated by combination treatments. These findings demonstrate that melanoma cells can be efficiently targeted by BH3 mimetics, but the right combinations have to be selected. The observed pronounced activation of apoptosis pathways demonstrates the decisive role of apoptosis in the loss of cell viability by BH3 mimetics.

Adrian Gillissen,1 Tonja Kochanek,1 Michaela Zupanic,2 Jan P Ehlers1 1Institute for Didactics and Educational Research in Health Care, Department of Medicine, Faculty of Health, Witten/Herdecke University, Witten, Germany; 2Interprofessional and Collaborative Didactics in Medicine- and Health professions, Department of Medicine, Faculty of Health, Witten/Herdecke University, Witten, GermanyCorrespondence: Adrian Gillissen, Institute for Didactics and Educational Research in Health Care, Department of Medicine, Faculty of Health, Witten/Herdecke University, Alfred-Herrhausen-Straße 50, Witten, 58455, Germany, Email adrian.gillissen@uni-wh.deBackground and Objectives: The aim of this study was to investigate in the millennium medical student generation the influence of the curriculum (problem-based curriculum [PBC] vs science-based curriculum [SBC]), gender and semester level on medical students’ motives to study medicine, their attitudes toward their career and in this regard their view about their study condition in university.Methods: Semi-structured qualitative interviews with 28 medical students were performed and analyzed using Mayring’s content analysis. Based on these results, a quantitative questionnaire for a nationwide survey was developed using a mixed-method-approach and send to most medical faculties in Germany. Data from n=1053 students entered statistical analysis.Results: Humanistic ideals prevailed in the choice to enter medical school and to become a physician. PBC students were found to be significantly (p< 0.001) more idealistic and patient oriented, and they regard their curriculum more competitive than SBC-students (p< 0.001). A balanced work and family life is essential for all students but particularly important for the PBC – group, male and undergraduate students. The majority of students wanted to work with patients and omitted patient-distant line of work. Undergraduate SBC-students saw their studies as old-fashioned citing lack of patient contact (p< 0.001 compared to PBC), which eased in the graduate study part.Conclusion: This study found major differences in student’s perceptions depending on curriculum type. PBC-students were more idealistic, and humanistic ideals prevailed in comparison to SBC. For both, close patient contact is essential in their training. Particularly for female students, lifestyle factors and a balanced work-life-integration outweigh career ambitiousness. This study offers an important insight to policy makers and educators to understand the motivation and perceptions of the millennial student generation regarding their studies and future career plans, which should be considered in educational policies.Keywords: medical students, career expectations, perceptions

Abstract Enhanced expression of anti-apoptotic B-cell lymphoma 2 (BCL-2) protein is frequent in cancer. Targeting of BCL-2 with the specific inhibitor ABT-199 (Venetoclax) has significant clinical activity in malignant diseases such as chronic lymphocytic leukemia and multiple myeloma. The small molecule drug ABT-199 mimics the pro-apoptotic BCL-2 homology domain 3 of BH3-only proteins and blocks the hydrophobic BC-groove in BCL-2. We have previously shown that ABT-199 synergizes with the proteasome inhibitor (PI) bortezomib in soft tissue sarcoma derived cells and cell lines to induce apoptosis. Synergistic apoptosis induction relies on the pore-forming effector BAX and expression of the pro-apoptotic BH3-only protein NOXA. Bortezomib augments expression of NOXA by blocking its proteasomal degradation. Interestingly, shown here for the first time, expression of NOXA is strongly enhanced by ABT-199 induced integrated stress response (ISR). ISR transcription factors ATF3 & ATF4 mediate transactivation of the BH3-only protein NOXA which specifically inhibits the anti-apoptotic MCL-1. Thus, NOXA potentiates the efficacy of the BCL-2 inhibitor ABT-199 by simultaneous inhibition of MCL-1. Hence, ABT-199 has a double impact by directly blocking anti-apoptotic BCL-2 and inhibiting MCL-1 via transactivated NOXA. By preventing degradation of NOXA PIs synergize with ABT-199. Synergism of ABT-199 and PIs therefore occurs on several, previously unexpected levels. This finding should prompt clinical evaluation of combinatorial regimens in further malignancies.

Review of Reconciling Ireland: Fifty Years of Anglo-Irish Agreements, by Richard Humphreys (ed.) (Newbridge: Irish Academic Press, 2021), 474 pp., ISBN: 9781 788551571, €35 (hardback)

Abstract Background Photodynamic therapy with a photosensitizer such as protoporphyrin-IX, a light sensitive metabolite of heme synthesis, is a highly selective treatment for various carcinomas. In previous studies, we found a significant down regulation of the relevant enzyme ferrochelatase in gastrointestinal carcinomas leading to an accumulation of protoporphyrin-IX within the tumor cells. Recent studies showed that a novel anti-cancer drug, Alectinib, an orally available, highly selective, potent second-generation inhibitor of anaplastic lymphoma tyrosinkinase binds to ferrochelatase. Therefore, we were interested to see whether Alectinib treatment might lead to an accumulation of protoporphyrin IX. Methods Tumor cells of different origin were cultured, treated with LED-light and Alectinib. Results were gained by flow cytometry, immunohistochemistry and western blotting. Apoptosis was determined by flow cytometric analysis of Annexin V-FITC stained cells. In addition, cells were counterstained with propidium iodide to distinguish early apoptotic cells and late apoptotic/necrotic cells. Results Here, we report that photodynamic treatment of tumor cell lines of different origin in combination with Alectinib increased protoporphyrin-IX specific fluorescence and concomitantly cell death. Conclusions The usage of Alectinib could be another step for enhancing the effectiveness of photodynamic therapy. Further experiments will show whether photodynamic therapy in combination with Alectinib could be a new strategy for the treatment of e.g. peritoneal disseminated carcinomas.