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X-rays can penetrate deeply into biological cells and thus allow for examination of their internal structures with high spatial resolution. In this study, X-ray phase-contrast imaging and tomography is combined with an X-ray-compatible optical stretcher and microfluidic sample delivery. Using this setup, individual cells can be kept in suspension while they are examined with the X-ray beam at a synchrotron. From the recorded holograms, 2D phase shift images that are proportional to the projected local electron density of the investigated cell can be calculated. From the tomographic reconstruction of multiple such projections the 3D electron density can be obtained. The cells can thus be studied in a hydrated or even living state, thus avoiding artifacts from freezing, drying or embedding, and can in principle also be subjected to different sample environments or mechanical strains. This combination of techniques is applied to living as well as fixed and stained NIH3T3 mouse fibroblasts and the effect of the beam energy on the phase shifts is investigated. Furthermore, a 3D algebraic reconstruction scheme and a dedicated mathematical description is used to follow the motion of the trapped cells in the optical stretcher for multiple rotations.

Background: Many hospitalized patients decline in functional status after discharge, but functional decline in emergency admissions with hypoxemia is unknown. The primary aim of this study was to study functional outcomes as a clinical endpoint in a cohort of patients with acute hypoxemia. Methods: A multicenter prospective observational study was conducted in patients with new-onset hypoxemia emergently admitted to two respiratory departments at a university hospital and an academic teaching hospital. Using the WHO scale, the patients’ functional status 4 weeks before admission and at hospital discharge was assessed. The type and duration of oxygen therapy, hospital length of stay and survival and risk of hypercapnic failure were recorded. Results: A total of 151 patients with a median age of 74 were included. Two-thirds declined in functional status by at least one grade at discharge. A good functional status (OR 4.849 (95% CI 2.209–10.647)) and progressive cancer (OR 6.079 (1.197–30.881)) were more associated with functional decline. Most patients were treated with conventional oxygen therapy (n = 95, 62%). The rates of in-hospital mortality and need for intubation were both 8%. Conclusions: Patients with acute hypoxemia in the emergency room have a poorer functional status after hospital discharge. This decline may be of multifactorial origin.

Abstract Clinical research relies on high-quality patient data, however, obtaining big data sets is costly and access to existing data is often hindered by privacy and regulatory concerns. Synthetic data generation holds the promise of effectively bypassing these boundaries allowing for simplified data accessibility and the prospect of synthetic control cohorts. We employed two different methodologies of generative artificial intelligence – CTAB-GAN+ and normalizing flows (NFlow) – to synthesize patient data derived from 1606 patients with acute myeloid leukemia, a heterogeneous hematological malignancy, that were treated within four multicenter clinical trials. Both generative models accurately captured distributions of demographic, laboratory, molecular and cytogenetic variables, as well as patient outcomes yielding high performance scores regarding fidelity and usability of both synthetic cohorts (n = 1606 each). Survival analysis demonstrated close resemblance of survival curves between original and synthetic cohorts. Inter-variable relationships were preserved in univariable outcome analysis enabling explorative analysis in our synthetic data. Additionally, training sample privacy is safeguarded mitigating possible patient re-identification, which we quantified using Hamming distances. We provide not only a proof-of-concept for synthetic data generation in multimodal clinical data for rare diseases, but also full public access to synthetic data sets to foster further research.

Abstract Common mental disorders among young people are rising globally. Current university-based interventions are inadequate to address the need for evidence-based interventions. We investigated the effectiveness and implementation of Step-by-Step (SbS), a WHO digital intervention to address depression, among Chinese university students with depressive symptoms. In this paper, we report a type 1 hybrid effectiveness-implementation randomized controlled trial conducted between September 2021 and September 2022. The control condition was enhanced treatment as usual (ETAU, psychoeducation). The primary outcome was improvement in depression symptoms. Secondary outcomes were improvements in psychological well-being, anxiety symptoms, and self-identified psychosocial problems. Effectiveness of the intervention was evaluated using generalized linear mixed models. Implementation outcomes were evaluated by thematic analysis of participant interviews. A total of 371 participants were enrolled to two treatment conditions in a 1:1 ratio. SbS resulted in a greater reduction in depressive symptoms at posttreatment (p = 0.004, Hedges’ g = 0.35), but no significant difference between SbS and ETAU was observed at three-month follow-up (p = 0.179, Hedges’ g = 0.16). The treatment effect was larger among those who adhered to the treatment (Hedges’ gs = 0.59 and 0.30). Subjective well-being also improved for SbS at both time points (Hedges’ gs = 0.31 and 0.30). In addition, SbS resulted in more improvement in anxiety symptoms at posttreatment (p = 0.029, Hedges’ g = 0.26), but not at three-month follow-up (p = 0.265, Hedges’ g = 0.13). The qualitative results demonstrated that the intervention was well-implemented as a self-help mental health service, with minimal support from peer supporters. In conclusion, Step-by-Step, a digital intervention developed by WHO, was effective in reducing depressive symptoms in the short term and improving psychological well-being in a longer term. The sustained effect on depression needs further investigation. Improving uptake and engagement in the program is needed for its scale-up implementation as a university-based mental health service for Chinese young adults. Trial registration: ChiCTR2100050214.

Abstract Background Refugee populations have an increased risk for mental disorders, such as depression, anxiety, and posttraumatic stress disorders. Comorbidity is common. At the same time, refugees face multiple barriers to accessing mental health treatment. Only a minority of them receive adequate help. The planned trial evaluates a low-threshold, transdiagnostic Internet-based treatment. The trial aims at establishing its efficacy and cost-effectiveness compared with no treatment. Methods N = 131 treatment-seeking Arabic- or Farsi-speaking patients, meeting diagnostic criteria for a depressive, anxiety, and/or posttraumatic stress disorder will be randomized to either the intervention or the waitlist control group. The intervention group receives an Internet-based treatment with weekly written guidance provided by Arabic- or Farsi-speaking professionals. The treatment is based on the Common Elements Treatment Approach (CETA), is tailored to the individual patient, and takes 6–16 weeks. The control group will wait for 3 months and then receive the Internet-based treatment. Discussion The planned trial will result in an estimate of the efficacy of a low-threshold and scalable treatment option for the most common mental disorders in refugees. Trial registration German Registry for Clinical Trials DRKS00024154. Registered on February 1, 2021.

[Background] An online self-help programme for the treatment of depression called Hap-pas-Hapi was tested among Albanian-speaking immigrants in Switzerland and Germany, and two different levels of cultural adaptation were compared. Despite a massive recruitment effort, an insufficient number of participants could be recruited, and the drop-out rate was over 90%. [Aims] We conducted a qualitative study to better understand the reasons for the non-use of Hap-pas-Hapi. [Method] Eleven interviews were conducted with 17 Albanian-speaking participants aged 19-59. Participants were recruited for the purpose of this study and were not participants from the trial. They went through the recruitment material and the Hap-pas-Hapi introduction module, commented on the graphic design, usability, content, and shared their views about mental health and self-help. [Results] Participants criticised the lack of a “design system” (i.e., a clearly identifiable and consistent graphic design) on social media for Hap-pas-Hapi, and the recruitment messages were unclear. The programme itself was perceived to be important and helpful for the community at large, but most participants said that they would not use it for themselves. The younger generation would have preferred an application in German or French, while the older generation did not see a benefit in using an online self-help programme to manage their psychological distress. Negative beliefs about mental disorders and psychological interventions were perceived to be common in this target group. [Discussion] A professional recruitment strategy, a more careful selection of the target population (e.g., age groups) and different kinds of adaptations might have resulted in a better acceptance of the intervention. At the same time, anti-stigma campaigns and psychoeducation are needed to enhance treatment motivation.

[Background] Research on cultural adaptation of psychological interventions indicates that a higher level of adaptation is associated with a higher effect size of the intervention. However, direct comparisons of different levels of adaptations are scarce. [Aims] This study used a smartphone-based self-help programme called Step-by-Step (Albanian: Hap-pas-Hapi) for the treatment of psychological distress among Albanian-speaking immigrants in Switzerland and Germany. Two levels of cultural adaptation (i.e., surface vs. deep structure adaptation) were compared. We hypothesised that the deep structure adaptation would enhance the acceptance and efficacy of the intervention. [Method] We conducted a two-arm, single-blind randomised controlled trial. Inclusion criteria were good command of the Albanian language, age above 18, and elevated psychological distress (Kessler Psychological Distress Scale score above 15). Primary outcome measures were the total score of the Hopkins Symptom Checklist and the number of participants who completed at least three (out of five) sessions. Secondary outcomes were global functioning, well-being, post-traumatic stress, and self-defined problems. [Results] Two-hundred-twenty-two participants were included, of which 18 (8%) completed the post-assessments. The number of participants who completed the third session was equal in both conditions, with N = 5 (5%) and N = 6 (6%) respectively. [Discussion] Drop-out rates were high in both conditions, and no group difference was found regarding the acceptance of the intervention. The high drop-out rate stands in contrast with other trials testing Step-by-Step. Future research should examine cultural factors impacting recruitment strategies, as insights could help to reduce participant drop-out rates in clinical trials.

Background Syrian refugees have a high burden of mental health symptoms and face challenges in accessing mental health and psychosocial support (MHPSS). This study assesses health system responsiveness (HSR) to the MHPSS needs of Syrian refugees, comparing countries in Europe and the Middle East to inform recommendations for strengthening MHPSS systems Methods A mixed-methods rapid appraisal methodology guided by an adapted WHO Health System Framework was used to assess HSR in eight countries (Egypt, Germany, Jordan, Lebanon, Netherlands, Sweden, Switzerland, and Türkiye). Quantitative and qualitative analysis of primary and secondary data was used. Data collection and analysis were performed iteratively by multiple researchers. Country reports were used for comparative analysis and synthesis. Results We found numerous constraints in HSR: i) Too few appropriate mental health providers and services; ii) Travel-related barriers impeding access to services, widening rural-urban inequalities in the distribution of mental health workers; iii) Cultural, language, and knowledge-related barriers to timely care likely caused by insufficient numbers of culturally sensitive providers, costs of professional interpreters, somatic presentations of distress by Syrian refugees, limited mental health awareness, and stigma associated to mental illness; iv) High out-of-pocket costs for psychological treatment and transportation to services reducing affordability, particularly in middle-income countries; v) Long waiting times for specialist mental health services; vi) Information gaps on the mental health needs of refugees and responsiveness of MHPSS systems in all countries. Six recommendations are provided to address these issues. Conclusions All eight host countries struggle to provide responsive MHPSS to Syrian refugees. Strengthening the mental health workforce (in terms of quantity, quality, diversity, and distribution) is urgently needed to enable Syrian refugees to receive culturally appropriate and timely care and improve mental health outcomes. Increased financial investment in mental health and improved health information systems are crucial.

BackgroundThere is evidence from meta-analyses and systematic reviews that digital mental health interventions for depression, anxiety, and stress-related disorders tend to be cost-effective. However, no such evidence exists for guided digital mental health care in low and middle-income countries (LMICs) facing humanitarian crises, where the needs are highest. Step-by-Step (SbS), a digital mental health intervention for depression, anxiety, and stress-related disorders, proved to be effective for Lebanese citizens and war-affected Syrians residing in Lebanon. Assessing the cost-effectiveness of SbS is crucial because Lebanon’s overstretched health care system must prioritize cost-effective treatment options in the face of continuing humanitarian and economic crises. ObjectiveThis study aims to assess the cost-effectiveness of SbS in a randomized comparison with enhanced usual care (EUC). MethodsThe cost-effectiveness analysis was conducted alongside a pragmatic randomized controlled trial in 2 parallel groups comparing SbS (n=614) with EUC (n=635). The primary outcome was cost (in US $ for the reference year 2019) per treatment response of depressive symptoms, defined as >50% reduction of depressive symptoms measured using the Patient Health Questionnaire (PHQ). The secondary outcome was cost per remission of depressive symptoms, defined as a PHQ score 75% probability to be cost-saving while gaining response or remission. ConclusionsTo our knowledge, this study is the first cost-effectiveness analysis based on a large randomized controlled trial (n=1249) of a guided digital mental health intervention in an LMIC. From the principal findings, 2 implications flowed, from the (1) health care perspective and (2) wider societal perspective. First, our findings suggest that SbS is associated with greater health benefits, albeit for higher costs than EUC. It is up to decision makers in health care to decide if they find the balance between additional health gains and additional health care costs acceptable. Second, as seen from the wider societal perspective, there is a substantial likelihood that SbS is not costing more than EUC but is associated with cost-savings as SBS participants become more productive, thus offsetting their health care costs. This finding may suggest to policy makers that it is in the interest of both population health and the wider Lebanese economy to implement SbS on a wide scale. In brief, SbS may offer a scalable, potentially cost-saving response to humanitarian emergencies in an LMIC. Trial RegistrationClinicalTrials.gov NCT03720769; https://clinicaltrials.gov/ct2/show/NCT03720769 International Registered Report Identifier (IRRID)RR2-10.2196/21585

BackgroundGlaucoma stands as a prominent global cause of irreversible blindness and the primary treatment approach involves reducing intraocular pressure (IOP). However, around one-third of patients exhibit disease progression despite effective IOP reduction. Microvascular endothelial function, chronic inflammation, and oxidative stress are known to affect retinal neuronal networks and have been associated with disease severity and progression. Exercise training has the potential to counteract these mechanisms as add-on treatment to usual care.AimsThe HIT-GLAUCOMA study will investigate the effects of a 6-month high-intensity interval training (HIIT) on intermediate endpoints such as local retinal microvascular and systemic large artery function, inflammation, and oxidative stress as well as clinical endpoints such as visual field indices, optic nerve rim assessment, retinal nerve fiber layer thickness, IOP, number of eye drops, vision-related quality of life and ocular surface disease symptomatology.MethodsThe study is a multi-center randomized controlled clinical trial in patients with both normal tension and high-tension primary open angle glaucoma. Across two study centers, 128 patients will be enrolled and randomized on a 1:1 basis into an exercise intervention group and a usual care control group. The primary microvascular endpoints are retinal arteriolar and venular flicker light-induced dilation at 6 months. The primary endpoint in the systemic circulation is brachial artery flow-mediated dilation at 6 months.Anticipated resultsWe hypothesize that exercise therapy will improve retinal microvascular function and thus ocular blood flow in patients with glaucoma. As clinical outcomes, we will investigate the effect of exercise on visual field indices, optic nerve rim assessment, retinal nerve fiber layer thickness, IOP, number of eye drops, vision-related quality of life and ocular surface disease symptomatology.DiscussionHIT-GLAUCOMA is a blueprint trial design to study the effect of exercise training on neurodegenerative and cardiovascular diseases. Importantly, patients are also expected to benefit from improvements in general health and cardiovascular co-morbidities. If proven effective, exercise may offer a new add-on treatment strategy to slow glaucoma progression.Clinical Trial Registration NumberThe trial is registered at Clinicaltrials.gov under the identifier NCT06058598 and is currently in the recruitment stage.

In newly diagnosed acute myeloid leukemia, immediate initiation of treatment is standard of care. However, deferral of antileukemic therapy may be indicated to assess comorbidities or pre-therapeutic risk factors. We explored the impact of time from diagnosis to treatment on outcomes in newly diagnosed acute myeloid leukemia undergoing venetoclax-based therapy in two distinct cohorts. By querying the Study Alliance Leukemia database and the global health network TriNetX, we identified 138 and 717 patients respectively with an average age of 76 and 72 years who received venetoclax-based firstline therapy. When comparing patients who started treatment earlier or later than 10 days after initial diagnosis, no significant difference in median overall survival was observed - neither in the SAL cohort (7.7 vs. 9.6 months, p=.42) nor in the TriNetX cohort (7.5 vs. 7.2 months, p=.41). Similarly, severe infections, bleeding, and thromboembolic events were equally observed between early and later treatments, both in the overall patient groups and specific subgroups (age ≥75 years or leukocytes ≥20x109/L). This retrospective analysis indicates that delaying the start of venetoclax-based therapy in newly diagnosed acute myeloid leukemia might be a safe option for selected patients, provided that close clinical monitoring is performed.

Abstract Background IL‐17A and TNF synergistically promote inflammation and tumorigenesis. Their interplay and impact on ovarian carcinoma (OC) progression are, however, poorly understood. We addressed this question focusing on mesothelial cells, whose interaction with tumor cells is known to play a pivotal role in transcoelomic metastasis formation. Methods Flow‐cytometry and immunohistochemistry experiments were employed to identify cellular sources of IL‐17A and TNF. Changes in transcriptomes and secretomes were determined by bulk and single cell RNA sequencing as well as affinity proteomics. Functional consequences were investigated by microscopic analyses and tumor cell adhesion assays. Potential clinical implications were assessed by immunohistochemistry and survival analyses. Results We identified Th17 cells as the main population of IL‐17A‐ and TNF producers in ascites and detected their accumulation in early omental metastases. Both IL‐17A and its receptor subunit IL‐17RC were associated with short survival of OC patients, pointing to a role in clinical progression. IL‐17A and TNF synergistically induced the reprogramming of mesothelial cells towards a pro‐inflammatory mesenchymal phenotype, concomitantly with a loss of tight junctions and an impairment of mesothelial monolayer integrity, thereby promoting cancer cell adhesion. IL‐17A and TNF synergistically induced the Th17‐promoting cytokines IL‐6 and IL‐1β as well as the Th17‐attracting chemokine CCL20 in mesothelial cells, indicating a reciprocal crosstalk that potentiates the tumor‐promoting role of Th17 cells in OC. Conclusions Our findings reveal a novel function for Th17 cells in the OC microenvironment, which entails the IL‐17A/TNF‐mediated induction of mesothelial‐mesenchymal transition, disruption of mesothelial layer integrity and consequently promotion of OC cell adhesion. These effects are potentiated by a positive feedback loop between mesothelial and Th17 cells. Together with the observed clinical associations and accumulation of Th17 cells in omental micrometastases, our observations point to a potential role in early metastases formation and thus to new therapeutic options.

Abstract Background Refugees are at high risk for developing mental illnesses. Due to language and cultural barriers, there is need for specifically adapted therapeutic procedures for refugees in inpatient mental health care settings. Internet-based applications in refugee mother tongues have the potential to improve the outcomes of mental health care for this vulnerable population. The key research question of the present implementation study is whether the newly developed “blended ALMAMAR” app for Arabic and Farsi speaking refugees in Germany is used and accepted by patients and professionals in routine inpatient mental health care (blended care). Methods We present the design of an observational, prospective multicenter implementation study in eight psychiatric hospitals. We plan to recruit 100 Farsi or Arabic speaking refugees receiving in-patient treatment due to depression, anxiety disorder, posttraumatic stress disorder or substance use disorders. These patients will get access to the “blended ALMAMAR” app during their inpatient stay in a blended-care approach. We will assess the usage (e.g., duration and frequency of use of the app) as well as subjective acceptability and usability of the intervention. To identify sociodemographic and clinical factors associated with “blended ALMAMAR” usage, we will also perform clinical and questionnaire assessments. Discussion The newly developed “blended ALMAMAR” app may help to close communication gaps for the hard-to reach and vulnerable group of refugees in inpatient mental health care. It is the first blended-care intervention that addresses severely mentally ill refugees in an inpatient psychiatric setting in Germany. Trial registration The trial was registered in the German Clinical Trials Register on November 11, 2021 (DRKS00025972) and adapted on November 14, 2023.

Abstract Background The use of CT images for attenuation correction of myocardial perfusion imaging with single photon emission computer tomography (SPECT) increases diagnostic confidence. However, acquiring a CT image registered to a SPECT image is often not possible because most scanners are SPECT-only. It is possible to approximate attenuation maps using deep learning, but this has not yet been shown to work for a SPECT scanner with an IQ $$\varvec{\cdot {}}$$ · SPECT collimator. This study investigates whether it is possible to approximate attenuation maps from non-attenuation-corrected (nAC) reconstructions acquired with a SPECT scanner equipped with an IQ $$\varvec{\cdot {}}$$ · SPECT collimator. Methods Attenuation maps and reconstructions were acquired retrospectively for 150 studies. A U–Net was trained to predict attenuation maps from nAC reconstructions using the conditional generative adversarial network framework. Predicted attenuation maps are compared to real attenuation maps using the normalized mean absolute error (NMAE). Attenuation-corrected reconstructions were computed, and the resulting polar maps were compared by pixel and by average perfusion per segment using the absolute percent error (APE). The training and evaluation code is available at https://gitlab.ub.uni-bielefeld.de/thuxohl/mu-map . Results Predicted attenuation maps are similar to real attenuation maps, achieving an NMAE of 0.020±0.007. The same is true for polar maps generated from reconstructions with predicted attenuation maps compared to CT-based attenuation maps. Their pixel-wise absolute distance is 3.095±3.199, and the segment-wise APE is 1.155±0.769. Conclusions It is feasible to approximate attenuation maps from nAC reconstructions acquired by a scanner with an IQ $$\varvec{\cdot {}}$$ · SPECT collimator using deep learning.