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Purpose: The aim of this cross-sectional study was to investigate the psychosocial burdens of patients with ovarian cancer during the COVID-19 pandemic., Methods: Ovarian cancer patients answered a quantitative survey assessing their resilience (BRS) and quality of life (FACT-G7) as well as clinical (first- vs. ≥ second-line treatment), demographic (age < 65 vs. ≥ 65 years) and COVID-19 pandemic-related psychosocial impairment, i.e. anxiety (GAD7); depression (PHQ2); global physical, mental, and social health (PROMIS items). Analyses of variance were applied to compare psychological impairment between patients on first- vs. ≥ second-line treatment and between patients aged < vs. ≥ 65 years at start of treatment. Multiple linear regression analyses were performed to evaluate predictors of patients' resilience and quality of life based on demographic, clinical, and psychosocial variables., Results: Most of the 93 patients rated their physical and mental health, and satisfaction with social activities as good. Eighty-seven (91.4%) were somewhat or very concerned about the pandemic. Patients on first-line therapy reported a better quality of life (p = 0.03) and better general health (p = 0.014) than those on at least second-line therapy. Patients < 65 years old reported significantly more concern about the pandemic than older patients (p = 0.008). Predictors of resilience were severity of anxiety (GAD-7) and mental health. Predictors of quality of life were general health, severity of depression (PHQ-2), and type of therapy., Conclusions: Patients in first line of treatment and younger patients could benefit from support in coping with pandemic-related burdens, meaning that attention should be paid to potential psychological distress, which should be treated alongside the cancer., Competing Interests: Declarations. Conflict of interests: BS reports consulting fees from MedConcept, ClinSol, Olympus. Payment or honoraria for lectures from GSK, AstraZeneca, Roche, MSD, Eisai, Daiichi Sankyo. She receives support for attending meetings and/or travel from Daiichi Sankyo, GSK, Roche, AstraZeneca. She participates on a Data Safety Monitoring Board or Advisory Board for GSK, AstraZeneca, Roche, MSD, Eisai, Daiichi Sankyo. Leadership or fiduciary role in other board, society, committee or advocacy group is performed for „Deutsche Gesellschaft für Gynäkologie und Geburtshilfe“ e. V. (DGGG), FIGO, „Wehrmedizinischer Beirat “, „Fakultätsrat UKE“, „Arzneimittelkommission UKE“. BL reports research funding (no personal honoraria) from the German Research Foundation, the German Federal Ministry of Education and Research, the German Innovation Committee at the Joint Federal Committee, the European Commission’s Horizon 2020 Framework Programme, the European Joint Programme for Rare Diseases (EJP), the Ministry of Science, Research, and Equality of the Free and Hanseatic City of Hamburg, Germany, and the Foundation Psychosomatics of Spinal Diseases, Stuttgart, Germany. He has received remunerations for several scientific book articles from various book publishers, from the Norddeutscher Rundfunk (NDR) for interviews in medical knowledge programmes on public television, and as a committee member at Aarhus University, Denmark. He received travel funds from the European Association of Psychosomatic Medicine (EAPM) and accommodation and meals from the Societatea de Medicina Biopsyhosociala, Romania, for a presentation at the EAPM Academy at the Conferința Națională de Psihosomatică, Cluj-Napoca, Romania, Oct 2023. He was a board member of the European Association of Psychosomatic Medicine (EAPM) (unpaid) until 2022. AT reports grants or contracts from „DFG: TO908/3–1“ and „DFG: TO908/2–1“. AW reports grants or contracts from „Werner Otto Stiftung research funding“ (no personal honoraria) and payment or honoraria for lectures from „Lindauer Psychotherapietage remunerations“. She participates on European Association of Psychosomatic Medicine Treasurer (unpaid). GO reports payment or honoraria for lectures from Astra Zeneca, Pfizer, Daiichi Sankyo, Novartis, Amgen, MSD and Gliead Science. Support for meetings and travel recived from Daiichi Sankyo, Astra Zeneca, MSD, Amgen and Gliead Science. She participates on a Data Savety Monitorin Board or Advisory Board from Amgen, Pfiser, MSD, Novartis and Daiichi Sankyo. LS, AH, JT, GA and DL: The authors declare that they have no conflict of interest. Ethical approval and consent to participate: The study was performed in accordance with the Declaration of Helsinki and after the positive approval of the local ethical committee: Ethics Committee of the Hamburg Medical Association (PV7348). Consent to participate: Informed consent was obtained from all individual participants included in the study., (© 2024. The Author(s).)

Fibromyalgia syndrome (FMS) is a chronic disorder characterized by widespread musculoskeletal pain, fatigue and tenderness and closely associated with high levels of stress. FMS is therefore often considered a stress-related disease. A comparative study was conducted with 99 individuals diagnosed with FMS and a control group of 50 pain-free individuals. Stress indicators were classified into three categories: perceived stress assessed using the Perceived Stress Scale, and daily average salivary cortisol and hair cortisol concentrations as indicators of acute and chronic stress levels related to the hypothalamic-pituitary-adrenal axis. Analysis of variance and covariance were used to identify group differences and the influence of covariates age, sex, and body mass index. Correlational analyses further elucidated the relationship between stress indicators and clinical symptoms. Participants with FMS reported significantly higher perceived stress levels than controls (p < .001, η p 2  = 0.3), which were positively correlated with symptom burden (r = .41, p < .001). In contrast, there were no significant differences in the endocrinological stress indicators salivary and hair cortisol between the groups (p > .05), nor were these indicators associated with clinical symptoms. The study highlights the central role of perceived stress in FMS, whereas endocrinological indicators did not differentiate FMS from controls. This finding calls for a nuanced approach to clinical assessment and therapeutic interventions tailored to patients with FMS, emphasizing the management of perceived stressors., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Rationale and Objectives: The prognostic role of computed tomography (CT)-defined skeletal muscle features in COVID-19 is still under investigation. The aim of the present study was to evaluate the prognostic role of CT-defined skeletal muscle area and density in patients with COVID-19 in a multicenter setting., Materials and Methods: This retrospective study is a part of the German multicenter project RACOON (Radiological Cooperative Network of the COVID-19 pandemic). The acquired sample included 1379 patients, 389 (28.2%) women and 990 (71.8%) men. In each case, chest CT was analyzed and pectoralis muscle area and density were calculated. Data were analyzed by means of descriptive statistics. Group differences were calculated using the Mann-Whitney-U test and Fisher's exact test. Univariable and multivariable logistic regression analyses were performed., Results: The 30-day mortality was 17.9%. Using median values as thresholds, low pectoralis muscle density (LPMD) was a strong and independent predictor of 30-day mortality, HR=2.97, 95%-CI: 1.52-5.80, p=0.001. Also in male patients, LPMD predicted independently 30-day mortality, HR=2.96, 95%-CI: 1.42-6.18, p=0.004. In female patients, the analyzed pectoralis muscle parameters did not predict 30-day mortality. For patients under 60 years of age, LPMD was strongly associated with 30-day mortality, HR=2.72, 95%-CI: 1.17;6.30, p=0.019. For patients over 60 years of age, pectoralis muscle parameters could not predict 30-day mortality., Conclusion: In male patients with COVID-19, low pectoralis muscle density is strongly associated with 30-day mortality and can be used for risk stratification. In female patients with COVID-19, pectoralis muscle parameters cannot predict 30-day mortality., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background Context: Spondylodiscitis management presents significant clinical challenges, particularly in critically ill patients, where the risks and benefits of surgical intervention must be carefully balanced. The optimal timing of surgery in this context remains a subject of debate., Purpose: This study aims to evaluate the effectiveness of early surgery versus delayed surgery or conservative management in critically ill patients with de novo pyogenic spondylodiscitis., Study Design/setting: This is an international, multicenter retrospective cohort study involving 24 centers, primarily in Europe., Patient Sample: The study included 192 critically ill patients (65.63% male) with a median age of 69 years, all severely affected by pyogenic spondylodiscitis characterized by an initial CRP level >200 mg/l or the presence of two out of four Systemic Inflammatory Response Syndrome criteria upon admission., Outcome Measures: The primary outcome was 30-day mortality. Secondary outcomes included length of ICU stay, length of hospital stay, and relapse rates of spondylodiscitis., Methods: Patients were divided into three groups: early surgery (within three days of admission), delayed surgery (after three days of admission), and conservative therapy. Propensity score matching and multivariate regression analyses were performed to adjust for baseline differences and assess the impact of treatment modalities on mortality and other clinical outcomes., Results: Delayed surgery was associated with significantly lower 30-day mortality (4.05%) compared to early surgery (27.85%) and conservative therapy (27.78%) (p<.001). Delayed surgery also resulted in shorter hospital stays (42.76 days) compared to conservative therapy (55.53 days) and early surgery (26.33 days) (p<.001), and shorter ICU stays (4.52 days) compared to conservative therapy (16.48 days) and early surgery (7.92 days) (p<.001). The optimal window for surgery, minimizing mortality, was identified as ten to fourteen days post-admission (p=.02). Risk factors for increased mortality included age (p<.05), multiple organ failure (p<.05), and vertebral body destruction (p<.05), whereas delayed surgery (p<.05) and the presence of an epidural abscess were associated with reduced mortality (p<.05)., Conclusions: Delayed surgery, optimally between 10 to 14 days post-admission, was associated with lower mortality in critically ill spondylodiscitis patients. These findings highlight the potential benefits of considering surgical timing to improve patient outcomes., Competing Interests: Declaration of Competing Interest One or more of the authors declare financial or professional relationships on ICMJE-TSJ disclosure forms., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Worldwide, valvular heart disease (VHD) is a common cause of hospitalization for acute heart failure. In acute heart failure caused by VHD, symptoms result from rapid haemodynamic changes and subsequent decline in cardiac function, and if left untreated, leads to acute decompensation and cardiogenic shock. Current evidence remains scarce and recommendations regarding the management of acute heart failure caused by VHD are lacking in most recent international guidelines. Herein, we review the management of acute heart failure caused by VHD with a focus on transcatheter therapies and describe currently available evidence based on a systematic literature search on the following valve pathologies: (i) aortic stenosis, (ii) aortic regurgitation, (iii) mitral regurgitation, and (iv) mitral stenosis. Articles reporting outcomes following urgent or emergent valve intervention in the setting of cardiogenic shock or acute heart failure were considered. After screening a total of 2234 articles, 76 published between 1994 and 2023 were included in subsequent analysis. Based on available evidence, proposed treatment algorithms to guide optimal management of acute heart failure caused by VHD were created. As the number of patients presenting with acute heart failure caused by VHD continues to rise and outcomes following transcatheter valve interventions continue to improve, it is inevitable that minimally invasive options will play an increasingly important role in the acute setting, especially given these patients are at an increased operative risk. This review aims to present an organized approach to the complex management and interventional treatment of patients with acute heart failure caused by VHD., (© 2024 European Society of Cardiology.)

Introduction: Patients with pulmonary embolism (PE) experience impaired functional ability and reduced quality of life long after discharge from the hospital. However, there are no structured follow-up programmes in Denmark for these patients, and there is considerable variation in practice patterns of post-PE management. No studies have investigated the effectiveness of structured follow-up care models in patients with PE. This study aims to investigate the effect and cost-effectiveness of a structured integrated post-pulmonary embolism follow-up care model (Attend-PE) compared with usual care. The Attend-PE model outlines a structured approach for in-hospital follow-up, involving group-based patient education, individual consultations and systematic use of patient-reported outcome measures to assess the patient's physical and psychological well-being., Methods and Analysis: The study is conducted in Denmark, where the healthcare system is tax-funded and services are freely available for all citizens, with an expected inclusion of 2000 patients in total. A pre-post-intervention study design is used to compare outcomes in the post-implementation cohort with the pre-implementation cohort. The co-primary outcomes are (1) health-related quality of life (patient-reported outcome, PRO) and (2) adherence to medical treatment (register-based data). Secondary outcomes include PROs on disability, treatment satisfaction, self-management, anxiety, depression and work productivity, and register-based outcomes, including recurrent PE, bleeding, mortality and healthcare use. Register-based data will be assessed at baseline (date of PE event), 6 and 12 months, while PRO-data will be assessed at 6 and 12 months after the PE event. The health economic evaluation of the Attend-PE model will include a cost-effectiveness analysis and a cost-utility analysis., Ethics and Dissemination: The project will be conducted by the Declaration of Helsinki. In accordance with the Danish Act on Health Research Ethics §14, the study is exempt from approval. The use of survey responses in research (in anonymous form) is, however, contingent on participants' consent, and the invitation letter therefore included information about the purpose of the study and participants' rights to withdraw consent at any time, and that completion of the questionnaire is considered as consent to their survey data to be included in research.Study findings will be disseminated in scientific peer-reviewed journals, at national and international conferences, and for staff and decision-makers at participating hospitals and patients and relatives via the Danish Heart Association., Trial Registration Number: Clinicaltrials.gov NCT06037096., Competing Interests: Competing interests: AAH has received research grants from The Danish Heart Foundation and The Novo Nordisk Foundation, consulting fees from Bayer and The Bristol-Myers Squibb-Pfizer Alliance, and speaker bureaus from Bayer, The Bristol-Myers Squibb-Pfizer Alliance. NR has given talks about pulmonary embolism and physical rehabilitation on postgraduate courses for nurses and physicians within thrombosis and participated in development and production of patient information material on the same subject, both sponsored by Bayer and Bristol-Myers Squibb-Pfizer Alliance. ELG has received speaker honoraria or consultancy fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Novo Nordisk, Organon and Lundbeck Pharma. He is investigator in clinical trials sponsored by AstraZeneca, Idorsia and Bayer has received unrestricted research grants from Boehringer Ingelheim. SFL has no conflicts of interest to declare. SPJ has received consultancy fees from Bristol-Myers Squibb and Pfizer and has worked on institutional grants from Bristol-Myers Squibb, Pfizer and Novo Nordisk., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Initial clinical trials with drugs targeting epigenetic modulators - such as bromodomain and extraterminal protein (BET) inhibitors - demonstrate modest results in acute myeloid leukemia (AML). A major reason for this involves an increased transcriptional plasticity within AML, which allows cells to escape the therapeutic pressure. In this study, we investigated immediate epigenetic and transcriptional responses following BET inhibition and could demonstrate that BET inhibitor-mediated release of BRD4 from chromatin is accompanied by an acute compensatory feedback that attenuates down-regulation, or even increases expression, of specific transcriptional modules. This adaptation is marked at key AML maintenance genes and is mediated by p300, suggesting a rational therapeutic opportunity to improve outcomes by combining BET- and p300- inhibition. p300 activity is required during all steps of resistance adaptation, however, the specific transcriptional programs that p300 regulates to induce resistance to BET inhibition differ in part between AML subtypes. As a consequence, in some AMLs the requirement for p300 is highest during earlier stages of resistance to BET inhibition, where p300 regulates transitional transcriptional patterns that allow leukemia-homeostatic adjustments. In other AMLs, p300 shapes a linear resistance to BET inhibition and remains crucial throughout all stages of the evolution of resistance. Altogether, our study elucidates the mechanisms that underlie an "acute" state of resistance to BET inhibition, achieved through p300 activity, and how these mechanisms remodel to mediate "chronic" resistance. Importantly, our data also suggest that sequential treatment with BET- and p300-inhibition may prevent resistance development, thereby improving outcomes., (Copyright © 2024 American Society of Hematology.)

Background: Pulmonary arterial hypertension (PAH) is a severe complication among adult patients with congenital heart disease (ACHD). This study presents real-world data on risk stratification, pharmacotherapy and survival rates in PAH-ACHD., Methods: Data from PAH-ACHD patients were analyzed using The Hellenic Pulmonary Hypertension Registry (HOPE), spanning eight specialized centers between 2015 and 2023. Patients were categorized into low, intermediate, and high-risk groups using the ESC/ERS three-strata model to assess 1-year mortality risk., Results: A total of 93 PAH-ACHD patients were included (median age 38.5 years, 60.2 % women). Most patients had an atrial septal defect (37.6 %) or a ventricular septal defect (35.5 %), with 11.8 % presenting with complex ACHD. Eisenmenger syndrome was present in 35.5 % of patients. The proportion of low-risk patients nearly doubled from first to last assessment (24.7 % vs. 40.9 %, p = 0.001). Initially, 52.7 % of patients were on PAH monotherapy, with a subsequent shift towards combination therapy (73.1 %) during follow-up. Over a median follow-up of 5.9 years, 29 patients (31.1 %) died, with 1- and 5-year survival rates of 95.5 % and 81.9 %, respectively. Compared to the high-risk group, low- and intermediate-risk patients exhibited a 70 % and 50 % lower hazard of death, respectively. The lowest survival rates were observed in patients with Eisenmenger physiology., Conclusion: Survival prospects were favorable for the non-high risk patients in this nationwide cohort of PAH-ACHD patients. The observed shift towards combination therapy use may have contributed to the improvement in 1-year ESC mortality risk, underscoring the importance of timely combination therapy with PAH drugs., Competing Interests: Declaration of competing interest Dr. A. Arvanitaki has received travel grants from MSD. Dr. Eftychia Demerouti received honorarium and consultation fees from Actelion Pharmaceuticals-Janssen Hellas, MSD Merck Hellas, Elpen and Galenica. Dr. A. Frogoudaki has received travel grants from Boehringer, ELPEN, Genesis Pharma and Pfizer. Dr. I. Tsangaris has received fees for lectures and/or consultations from Actelion, Bayer, ELPEN, GSK, Janssen, MSD, Pfizer and United Therapeutics. Dr. K. Naka reports lecture fees from Amgen, Astra, Bayer, BMS, Boehringer Ingelheim, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, Sanofi, Servier. Athanasios Manginas reports consultation fees from Astra Zeneca, Bayer, Elpen, Janssen, MSD and Novartis. Dr. Giannakoulas has received fees for lectures and/or consultations from Actelion/Janssen, Bayer, Boehringer Ingelheim, ELPEN Pharmaceuticals, Ferrer/Galenica, GlaxoSmithKline, Gossamer-Bio, Merck Sharp and Dohme, Pfizer, Lilly, and United Therapeutics. The rest of the authors report no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background and Aims: The optimal antithrombotic therapy in patients with device-detected atrial fibrillation (DDAF) is unknown. Concomitant vascular disease can modify the benefits and risks of anticoagulation., Methods: These pre-specified analyses of the NOAH-AFNET 6 (n = 2534 patients) and ARTESiA (n = 4012 patients) trials compared anticoagulation with no anticoagulation in patients with DDAF with or without vascular disease, defined as prior stroke/transient ischaemic attack, coronary or peripheral artery disease. Efficacy outcomes were the primary outcomes of both trials, a composite of stroke, systemic arterial embolism (SE), myocardial infarction, pulmonary embolism or cardiovascular death, and stroke or SE. Safety outcomes were major bleeding or major bleeding and death., Results: In patients with vascular disease (NOAH-AFNET 6, 56%; ARTESiA, 46%), stroke, myocardial infarction, systemic or pulmonary embolism, or cardiovascular death occurred at 3.9%/patient-year with and 5.0%/patient-year without anticoagulation (NOAH-AFNET 6), and 3.2%/patient-year with and 4.4%/patient-year without anticoagulation (ARTESiA). Without vascular disease, outcomes were equal with and without anticoagulation (NOAH-AFNET 6, 2.7%/patient-year; ARTESiA, 2.3%/patient-year in both randomized groups). Meta-analysis found consistent results across both trials (I2heterogeneity = 6%) with a trend for interaction with randomized therapy (pinteraction = .08). Stroke/SE behaved similarly. Anticoagulation equally increased major bleeding in vascular disease patients [edoxaban, 2.1%/patient-year; no anticoagulation, 1.3%/patient-year; apixaban, 1.7%/patient-years; no anticoagulation, 1.1%/patient-year; incidence rate ratio 1.55 (1.10-2.20)] and without vascular disease [edoxaban, 2.2%/patient-year; no anticoagulation, 0.6%/patient-year; apixaban, 1.4%/patient-year; no anticoagulation, 1.1%/patient-year; incidence rate ratio 1.93 (0.72-5.20)]., Conclusions: Patients with DDAF and vascular disease are at higher risk of stroke and cardiovascular events and may derive a greater benefit from anticoagulation than patients with DDAF without vascular disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: The gold standard in obstructive sleep apnea (OSA) diagnostics is nocturnal full-night polysomnography (PSG). Due to high costs and high time effort portable respiratory polygraphy (PG or home sleep apnea testing-HSAT) has been developed. In contrast to PG the PSG gains relevant further information concerning sleep stages, arousals and leg movements. However, the role of PG in the diagnostic of OSA remains largely undefined. The aim of this study was to investigate the difference of PG- and PSG- related metrics in OSA, to understand if there is a difference in PG and PSG-based treatment decision and show up the time between performed PG and PSG., Patients and Methods: 99 consecutive patients with existing outpatient performed PG and followed PSG in our tertiary care otorhinolaryngology department between February 2020 and December 2023 were retrospectively assessed. All patients were treatment-naive at the time of consultation. The time between performed outpatient PG and PSG was calculated. Furthermore, clinical baseline parameter and PG as well as PSG data were evaluated. All data were then blinded presented with relevant comorbid diseases to two experts in sleep medicine in our tertiary care centre to decide whether PAP therapy was indicated or not., Results: Mean AHI was significantly higher in PSG (32.32 ± 22.78/h) compared to PG (22.60 ± 15.12/h) (p<0.001). Mean duration between performed PG and PSG was 194.99 ± 131.96 days (range between 37 and 842 days). Only in two patients PAP-therapy was indicated with PG results but not with PSG results. Only in one case PAP-therapy was not indicated with PG results but with PSG results., Conclusion: These data suggest initiating OSA therapy based on PG results for patients with at least moderate OSA on PG, followed by a confirming PSG and a control PSG under treatment to avoid unnecessary prolongation of treatment start., Competing Interests: Prof. Dr. Haralampos Gouveris reports grants from Inspire Medical Systems, Inc., outside the submitted work. The authors have no other conflict of interest to declare., (© 2024 Pordzik et al.)

Unlabelled: The EyeMatics project, embedded as a clinical use case in Germany's Medical Informatics Initiative, is a large digital health initiative in ophthalmology. The objective is to improve the understanding of the treatment effects of intravitreal injections, the most frequent procedure to treat eye diseases. To achieve this, valuable patient data will be meaningfully integrated and visualized from different IT systems and hospital sites. EyeMatics emphasizes a governance framework that actively involves patient representatives, strictly implements interoperability standards, and employs artificial intelligence methods to extract biomarkers from tabular and clinical data as well as raw retinal scans. In this perspective paper, we delineate the strategies for user-centered implementation and health care-based evaluation in a multisite observational technology study., (© Julian Varghese, Alexander Schuster, Broder Poschkamp, Kemal Yildirim, Johannes Oehm, Philipp Berens, Sarah Müller, Julius Gervelmeyer, Lisa Koch, Katja Hoffmann, Martin Sedlmayr, Vinodh Kakkassery, Oliver Kohlbacher, David Merle, Karl Ulrich Bartz-Schmidt, Marius Ueffing, Dana Stahl, Torsten Leddig, Martin Bialke, Christopher Hampf, Wolfgang Hoffmann, Sebastian Berthe, Dagmar Waltemath, Peter Walter, Myriam Lipprandt, Rainer Röhrig, Jens Julian Storp, Julian Alexander Zimmermann, Lea Holtrup, Tobias Brix, Andreas Stahl, Nicole Eter. Originally published in JMIR Medical Informatics (https://medinform.jmir.org).)

Genetic diagnostic testing of 325 pulmonary arterial hypertension (PAH) patients using a PAH specific gene panel including 18 known PAH genes revealed mutations in 23 %. Further PAH candidate genes were sequenced in the remaining patients exposing two SMAD5 variants, which were clinically and functionally characterized. We first recorded familial cosegregation and clinical parameters. Functional tests were performed following transient over-expression of the two SMAD5 variants in pulmonary artery smooth muscle cells (PAMSCs). Expression of these variants was confirmed by qPCR, Sanger sequencing and Western blotting. Cell viability was evaluated using cell counting kit 8, cell proliferation by BrdU and apoptosis by annexin V assay. Both SMAD5 missense variants were absent in healthy controls and predicted to be pathogenic. The variant c.1175T>C p.(Leu392Pro) was identified in a heritable PAH patient and her healthy son. The mother had died of suspected PAH aged 42. Expression of this variant in PAMSCs led to significantly higher cell viability due to higher proliferation in comparison to SMAD5 wild type cells. The second variant c.277T>A p.(Trp93Arg) was identified in a patient with congenital heart disease associated PAH with a surgically repaired ventricle septal defect. Its expression led to significant lower cell viability due to increased apoptosis in comparison to wild type SMAD5 cells. Taking into account familial aggregation, clinical findings and functional evidence both variants could be classified as likely pathogenic. This is the first description of SMAD5 as a potential novel PAH gene for genetic diagnostic testing., (Copyright 2024 The Author(s).)

Venous thromboembolism (VT) is a frequent (annual incidence of 1 to 2 per 1,000) and potentially life-threatening (case-fatality rate up to 10%) disease. VT is associated with serious short-term and long-term complications including a recurrence rate of approximately 20% within five years. Anticoagulant therapy, the mainstay of VT treatment, drastically reduces the risk of early VT recurrence, but it exposes patients to a substantial risk of bleeding. We analysed the genomic architecture of VT recurrence using data from 6,571 patients across eight cohorts, 1,816 of whom experienced recurrence, with a particular focus on the clinical manifestation of the type of first VT event. Through genome-wide association studies (GWAS), we identified three loci significantly associated (P<5×10 -8 ) with VT recurrence in the general VT population: GPR149/MME , L3MBTL4 , and THSD7B . Protein Quantitative Trait Locus and Mendelian Randomization analyses further identified elevated plasma levels of coagulation factor XI and GOLM2 as risk factors for recurrence, while decreased levels of PCSK9 and pro-IL16 were linked to reduced VT recurrence risk. Subgroup analyses revealed 18 loci associated with VT recurrence, with notable differences between pulmonary embolism (PE) and deep vein thrombosis (DVT). For example, the exonic variant SLC4A1 p.Glu40Lys was significantly associated with recurrence in PE patients (Hazard Ratio (HR)=3.23, P=9.7×10 -12 ) but showed no effect in DVT (HR=1.00, P=0.98). These findings emphasize the role of specific genetic loci and protein pathways in influencing VT recurrence and provide valuable insights into potential therapeutic targets. Further research is needed to clarify the biological mechanisms driving these associations., Competing Interests: Disclosures The authors have no conflict of interest to declare.

Radiopharmaceutical therapies (RPTs) based on fibroblast activation protein (FAP) and FAP inhibitors (FAPIs) are a new option for progressive metastatic cancer in patients pretreated multiple times. To date, published in-human data refer to initial experiences with β-emitting 90 Y- and 177 Lu-based RPT. However, the short tumor retention time of FAPI ligands is considered a major limitation of FAPI RPT. Therefore, fractionated FAPI RPT with 213 Bi, an α-emitter with a half-life of 46 min, appears to be a promising FAPI RPT regimen. Here, we report on our initial experiences with regard to the feasibility, tolerability, and response of fractionated 213 Bi-FAPI-46 RPT. Methods: Six patients (4 women and 2 men) with progressive metastatic solid tumors (3 colon cancer, 1 anal cancer, 1 breast cancer, and 1 prostate cancer) aged 16-77 y were treated with a mean of 1,609 MBq of 213 Bi-FAPI-46, fractionated into 53 single applications (range, 5-12 RPT applications per patient; mean, 8.8 applications) over a period of up to 107 h per patient. Of the 6 patients, 4 patients received adjuvant treatment with pembrolizumab. 18 F-FDG (4 patients) and 68 Ga-FAPI-46 (5 patients) PET/CT scans were performed before and after RPT. PET images were assessed visually and by calculating total lesion glycolysis and total lesion FAPI. Results: RPT with 213 Bi-FAPI-46 was well tolerated without adverse side effects. In terms of visual response assessment, there was 1 partial response (16.7%), 1 patient with stable disease (16.7%), and 4 patients with progressive disease (66.7%). Concordantly, total lesion glycolysis and total lesion FAPI were decreased in the responding patient (not applicable and -24.3%, respectively), slightly decreased in the patient with stable disease (-10.6% and -5.9%, respectively), and increased in the 4 patients with progression (mean, +104.4% and +321.3%, respectively). Conclusion: Fractionated FAPI RPT with the short-half-life α-emitter 213 Bi-FAPI-46 is a promising approach that matches the pharmacokinetics of FAPI-46 better than the 177 Lu- or 90 Y-labeled compounds. In this pilot project, fractionated RPT with 213 Bi-FAPI-46 showed good clinical tolerability and even led to regressive or stable disease in the short term in 2 of 6 patients. Further studies with larger patient cohorts are required to evaluate the actual efficacy and long-term effects of this variant of FAPI RPT., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

This study examines the roles of platelet collagen receptors glycoprotein VI (GPVI), α2β1, and the GPIb-IX-V complex in platelet activation and thrombus formation on various collagen sources from different species. Type I collagens standardly used in haematology testing, i.e. collagen type I derived from equine tendon (HORM) and rat tail collagen were evaluated. Moreover, acid soluble collagen from human umbilical cord was tested. To inhibit platelet-collagen interactions, combinations of monoclonal antibodies 6B4 and 6F1, targeting GPIbα and α2β1, respectively, were used, along with the therapeutic collagen receptor GPVI antibody glenzocimab. Our findings reveal distinct dependencies on these receptors: platelet aggregation of washed platelets to HORM collagen relied on both α2β1 and GPVI, to acid soluble collagen mainly on GPVI, and to rat tail collagen solely on α2β1, respectively. In whole blood perfusion assays under non-coagulating conditions, the acid soluble collagen surface triggered a more homogenous platelet adhesion when compared to the HORM collagen surface, whilst platelet adhesion on rat tail collagen varied considerably. The GPIb-IX-V complex was shown to play a key role in initial platelet adhesion and activation across all collagen surfaces at a shear rate of 1600 s -1 . At 1600 s -1 , inhibiting platelet α2β1 interaction with collagen by 6F1 antibody did not affect platelet thrombus formation on acid soluble collagen, while it did reduce platelet surface coverage and P-selectin expression on HORM collagen without changing the overall thrombus morphology or contraction. Inhibiting GPVI interaction with collagen significantly reduced all thrombus parameters and abolished PS exposure and P-selectin expression on all three collagen surfaces, at both 1600 s -1 and 150 s -1 . Interestingly, upon investigating combined inhibition of GPIb and α2β1, an additive inhibitor effect of 6F1 was observed on P-selectin expression and PS-exposure on acid soluble collagen but not HORM collagen at 1600s -1 , suggesting that the acid soluble collagen is well suited to study reinforcing functions of collagen receptors. Overall, this study highlights the potential advantages of using alternative collagen surfaces beyond the conventional HORM collagen to detect nuanced collagen receptor dependencies, which may prove valuable in evaluating anti-platelet medication., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Judith Cosemans reports financial support was provided by Netherlands Organization for Health Research and Development. Judith Cosemans reports financial support was provided by European Commission Marie Sklodowska-Curie Actions. Judith Cosemans reports financial support was provided by British Heart Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In patients with compensated advanced chronic liver disease (cACLD), risk of clinically significant portal hypertension (CSPH) can be estimated by applying non-invasive tests such as liver stiffness measurement (LSM), platelet count, and, in some cases, BMI. We aimed to assess the diagnostic utility of spleen stiffness measurement (SSM) at 100 Hz as a standalone non-invasive test for CSPH and to evaluate its incremental value compared with the ANTICIPATE±NASH model in patients with cACLD., Methods: For this modelling study, patients were recruited from 16 expert centres in Europe. Patients who underwent characterisation by hepatic venous pressure gradient (HVPG) and non-invasive tests (ie, LSM, platelet count, and SSM at 100 Hz) at one of the participating centres between Jan 1, 2020, and Dec 31, 2023, were considered for inclusion. Only patients aged 18 years or older with Child-Pugh class A cACLD, shown by LSM 10 kPa or more or F3 or F4 fibrosis on liver histology, were included. The overall cohort was split into the derivation cohort (patients recruited between Jan 1, 2020, and Dec 31, 2022) and the temporal validation cohort (patients recruited between Jan 1, 2023, and Dec 31, 2023). The ANTICIPATE±NASH model was applied to assess individual CSPH probability and SSM was investigated as a standalone non-invasive test for CPSH; in combination with platelet count and BMI; and in a full model of SSM, LSM, platelet count, and BMI (ie, the Non-Invasive CSPH Estimated Risk [NICER] model). All models were binary logistic regression models. The primary outcome was CSPH. We evaluated the discriminative utility of the models by calculating the area under the receiver operating characteristics curve (AUC) and creating calibration plots and calibration of intercept, slope, and integrated calibration index., Findings: 407 patients with cACLD were included, 202 (50%) in the derivation cohort and 205 (50%) in the validation cohort. Median age was 60·0 years (IQR 55·0-66·8); 275 (68%) of 407 patients were male and 132 (32%) were female. 164 (40%) of 407 patients had metabolic dysfunction-associated steatotic liver disease (MASLD), 133 (33%) had MASLD with increased alcohol intake or alcohol-related liver disease, 75 (18%) had viral hepatitis (61 [81%] of whom had sustained virologic response of hepatitis C virus or suppression of hepatitis B virus DNA), and 35 (9%) had other chronic liver diseases. 241 (59%) patients had CSPH. Median SSM was 45·0 kPa (32·1-65·4) and LSM was 21·4 kPa (14·1-31·6). SSM and LSM had similar AUCs for prediction of CSPH in the derivation cohort (0·779 [95% CI 0·717-0·842] vs 0·781 [0·718-0·844]; p=0·97) and in the validation cohort (0·830 [0·772-0·887] vs 0·804 [0·743-0·864]; p=0·50). The SSM-based model comprising platelet count and BMI had a similar AUC as the ANTICIPATE±NASH model in both the derivation cohort (0·849 [0·794-0·903] vs 0·849 [0·794-0·903]; p=0·999) and in the validation cohort (0·873 [0·819-0·922] vs 0·863 [0·810-0·916]; p=0·75). The NICER model had a significantly higher AUC for prediction of CSPH than the ANTICIPATE±NASH model in the derivation cohort (0·889 [0·843-0·934] vs 0·849 [0·794-0·903]; p=0·022) and in the validation cohort (0·906 [0·864-0·946] vs 0·863 [0·810-0·916]; p=0·012)., Interpretation: The addition of SSM to LSM, BMI, and platelet count outperformed the ANTICIPATE±NASH model for CSPH risk stratification in our cohort of contemporary patients with cACLD. SSM improves the non-invasive diagnosis of CSPH, supporting its implementation into clinical practice., Funding: Echosens., Competing Interests: Declaration of interests MJ has been a speaker and consultant for Gilead. FT has been a speaker for W L Gore & Associates. LT has been a speaker, consultant, or advisory board member for AbbVie, Eisai, Gilead, Janssen, and W L Gore & Associates and has received travel support from AbbVie, Janssen, Roche, and Gilead. WJK has been a speaker for the panNASH initiative; has received travel grants from Ipsen and Norgine; and is a co-inventor and patent holder for the use of lipopigment imaging for disease (filed by Massachusetts General Hospital and Massachusetts Institute of Technology; US 20190307390). AC has been a speaker and consultant for Jazz Pharmaceuticals. BM received grants and research support from Abbott, Fujirebio, Ewimed, and Roche and personal fees from Abbott, AbbVie, BMS, Janssen, Luvos, Merck, MSD, Roche, Fujirebio, Norgine, Gilead, and Astellas. WL has been a consultant for Cook Medical, Boston Scientific, CSL Behring, and MRM Health. JP has been a speaker, consultant, or advisory board member for AbbVie, Gilead, Advanz, MSD, Roche, AstraZeneca, Eisai, Orphalan, and Sobi. JMS has been a consultant and advisory board member for AbbVie; has received honoraria from Apollo Endoscopy, Boehringer Ingelheim, Gilead, Advanz Sciences, Intercept Pharmaceuticals, Ipsen, Inventiva Pharma, Madrigal Pharmaceuticals, MSD, Northsea Therapeutics, Novartis, Novo Nordisk, Pfizer, Roche, AstraZeneca, Eisai, OrphalanSanofi, and Siemens Healthineers; has received research funding from Boehringer Ingelheim and Siemens Healthcare; has received speaker honoraria from Boehringer Ingelheim, Echosens, MedPublico, Novo Nordisk, Madrigal Pharmaceuticals, and Histoindex; and holds stockholder options in AGED diagnostics and Sobi JHepta Bio. AB has been a speaker or consultant for Boehringer Ingelheim, GE HealthCare, Hologic, and W L Gore & Associates. VC has been a speaker, consultant, or advisory board member for Advanz, Ipsen, AbbVie, Echosens, Gilead, and Roche and has received grants and research support from Advanz and MSD. SF has been a speaker or consultant for W L Gore & Associates, Cook Medical, and Echosens and has received grants and research support from W L Gore & Associates and Cook Medical. FS has been a speaker or consultant for W L Gore & Associates, Cook Medical, and Echosens and has received grants and research support from W L Gore & Associates and Cook Medical. BP has been a speaker for AbbVie and Echosens. AAl has received fellowship funding from United European Gastroenterology. P-ER has received research funding from Terrafirma and has been a speaker or consultant for Abbelight, AbbVie, Hemostod, Mursla, Genfit, Boehringer Ingelheim, and Tillots Pharma. JCG is an advisory board member for W L Gore & Associates and Cook and has received grant support from Mallinckrodt, CSL Vifor, and AstraZeneca. JIF has been a speaker for Grifols and has received travel support from Gilead. TR has been a speaker, consultant, or advisory board member for AbbVie, Bayer, Boehringer Ingelheim, Gilead, Intercept, MSD, Siemens, and W L Gore & Associates; has received grants and research support from AbbVie, Boehringer Ingelheim, Gilead, Intercept, MSD, Myr Pharmaceuticals, Pliant, Philips, Siemens, and W L Gore & Associates; and has received travel support from AbbVie, Boehringer Ingelheim, Gilead, and Roche. MM received a research grant from Echosens for the coordination of this study; has been a speaker, consultant, or advisory board member for AbbVie, Echosens, Gilead, Ipsen, and W L Gore & Associates and has received travel support from AbbVie and Gilead. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Metabolic syndrome (MetS) induces a systemic inflammatory state which can lead to cardiomyopathy, manifesting clinically as heart failure (HF) with preserved ejection fraction (HFpEF). MetS components are intricately linked to the pathophysiologic processes of myocardial remodeling. Increased sympathetic nervous system activity, which is noted as an upstream factor of MetS, has been linked to adverse myocardial structural changes. Since renal denervation and vagus nerve stimulation have a sympathoinhibitory effect, attention has been paid to the cardioprotective effects of autonomic neuromodulation. In this review, the pathophysiology underlying the relationship between MetS and HF is elucidated, and the evidence regarding autonomic neuromodulation in HFpEF is summarized., Competing Interests: Compliance with ethical standards. Conflict of interest: The authors declared no competing interests., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Donor-transmitted malignancy is a rare and often fatal complication of organ transplantation. We report a case of a 55-year old male kidney transplant recipient who was diagnosed with stage-IV donor-transmitted melanoma 5 months after transplantation with metastases in the liver, spleen, lung, and brain. Immunosuppression was discontinued, and encorafenib and binimetinib, inhibitors of a serine/threonine B-Raf proto-oncogene (BRAF) and mitogen-activated protein kinase kinase (MEK) respectively, were started. Severe rejection ensued and necessitated the start of hemodialysis as well as urgent graft nephrectomy. However, the tumor progressed and BRAF/MEK inhibition was replaced by immune-checkpoint inhibition with ipilimumab and nivolumab. When this also failed to slow disease progression and seizures occurred, therapy with encorafenib and binimetinib was reinstated. Afterwards, most of the metastases remained stable. The patient has now survived for more than 4 years in good general health, which is an exceptionally long survival with donor-transmitted, metastasized melanoma., Competing Interests: Declaration of competing interest The authors have no conflicts of interest regarding this manuscript., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Due to a lack of time and staff, informed consent (IC) in clinical practice often lacks clarity, comprehensibility and scope of information. Digital media offer great potential to enhance IC. Aim of this study is to evaluate the effectiveness of multimedia-supported compared to traditional paper-based IC., Methods: In the randomized, controlled, three-arm DICon (Digital Informed Consent for urological surgery) study 70 patients with an indication for prostate biopsy were randomized 1:1:1 to receive traditional paper-based IC vs. multimedia-supported information before IC vs. multimedia-supported information during IC. Patient satisfaction, anxiety and information gain were measured by validated questionnaires 2 weeks and directly before the procedure and time efficiency was recorded. Statistical analysis was performed using Kruskal-Wallis and Dunn's test (one-way ANOVA) and two-way ANOVA (with bonferroni post-test)., Results: Multimedia information prior to the consultation saved 32.9% time compared to paper-based (5.3 min. vs. 9.5 min; p < 0.05) and 60.4% time compared to shared multimedia information (5.3 min. vs. 13.9 min.; p < 0.001), with no difference in satisfaction (62.6 vs. 62.7 vs. 68.6 of max. 80; p = 0.07), anxiety (8 vs. 8.1 vs. 7 of max. 16; p = 0.35), or information gain (6.5 vs. 5.7 vs. 6.7 of max. 10; p = 0.23). Results on satisfaction (56.6 vs. 62.6 vs. 66; p = 0.06), anxiety (7.2 vs. 7.2 vs. 6.8; p = 0.84), and information gain (7 vs. 6.4 vs. 5.9; p = 0.43) remained stable over time., Conclusions: Multimedia-supported IC prior to consultation provided improved time efficiency (33% gain) compared to traditional paper-based IC, with comparable satisfaction, anxiety and information gain. Multimedia-supported information materials should therefore be used more frequently in patient education., (© 2023. The Author(s).)

Background: Esophageal strictures following esophageal atresia repair are a source of significant morbidity. To test new therapeutic approaches, we designed a piglet model of esophageal stricture by resecting variable lengths of esophagus with subsequent re-anastomosis. This study describes the model and validates its physiologic impact by blinded analysis of the weight gains of the piglets., Methods: A total of 24 two-week old Pietrain piglets had esophageal resections performed, ranging from 0 to 5 cm, with the goal of inducing postoperative esophageal strictures. Postoperative body-weights were evaluated by repeated analysis of variance followed by pairwise group-comparisons based on estimated marginal means. In addition, body weight was modeled by linear-mixed model regression. Different resection lengths were compared. The esophagi were evaluated postmortem for stricture., Results: Of 24 operated piglets, 23 reached the endpoint, and 90% developed an esophageal stricture that was radiologically visible in a contrast study, as well as appreciable macroscopically in the necropsy. We found differences in pre- and postoperative body weights for all piglets (F (1, 18) = 298.54, p < 0.001), but no differences between resection lengths (F (4, 18) = 0.36, p = 0.837)., Conclusion: Our model of postoperative esophageal stricture offers the opportunity to investigate potential treatments for strictures associated with esophageal atresia, since it reliably induces strictures and results in minimal loss of animals. The similar body weight gain in all groups indicates that stricture is mainly the result of esophageal resection and re-anastomosis, regardless of the length of the resected segment., (© 2024 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.)

Background: The clinical relevance of cardiac troponin (cTn) elevation in takotsubo syndrome (TTS) remains uncertain. The present study sought to investigate the role of cardiac troponin (cTn) elevations in mortality prediction of patients with Takotsubo syndrome (TTS)., Methods: Patients enrolled in the International Takotsubo (InterTAK) Registry from January 2011 to February 2020 with available data on peak cTn levels were included in the analysis. Peak cTn levels during the index hospitalization were used to define clinically relevant myocardial injury. The threshold at which clinically relevant myocardial injury drives mortality at 1 year was identified using restricted cubic spline analysis., Results: Out of 2'938 patients, 222 (7.6%) patients died during 1-year follow-up. A more than 28.8-fold increase of cTn above the upper reference limit was identified as threshold for clinically relevant myocardial injury. The presence of clinically relevant myocardial injury was significantly associated with an increased risk of mortality at 5 years (adjusted HR 1.58, 95% CI 1.18-2.12, p =.002). Clinically relevant myocardial injury was related to an increased 5-year mortality risk in patients with apical TTS (adjusted HR 1.57, 95% CI 1.21-2.03, p =.001), in presence of physical stressors (adjusted HR 1.60, 95% CI 1.22-2.11, p =.001), and in absence of emotional stressors (adjusted HR 1.49, 95% CI, 1.17-1.89, p =.001)., Conclusion: This study for the first time determined a troponin threshold for the identification of TTS patients at excess risk of mortality. These findings advance risk stratification in TTS and assist in identifying patients in need for close monitoring and follow-up., (© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Objectives: The seroprevalence of antibodies against Cytomegalovirus (CMV) is an established poor prognostic factor for patients receiving an allogeneic stem cell transplantation. However, the impact of CMV serology on outcome after autologous stem cell transplantation remains unknown., Methods: Here, we analyzed the CMV immunoglobulin (Ig) serology of 446 newly-diagnosed multiple myeloma (MM) patients of the GMMG-MM5 phase III trial with a median follow-up of 58 months., Results: CMV IgG and IgM positivity was seen in 51% and 6% of the patients, respectively. In multivariate analysis CMV IgG and CMV IgM serology show an age-depending effect for PFS. We identified positive CMV IgG/positive CMV IgM serology as an age-depending beneficial factor on PFS., Discussion: Younger patients with a positive CMV IgG/positive CMV IgM serology experienced a favorable effect on PFS, whereas a positive CMV IgG/positive CMV IgM serology at older age has a disadvantageous effect on PFS.

This study investigates the role of positive cognitive reappraisal (PCR) flexibility and variability in mental health in response to real-life stressors among college students. We employed ecological momentary assessment and intervention through ReApp, a mobile app designed to train and promote PCR. We analyzed data from the intervention group of a randomized controlled trial with a total of 100 participants who used ReApp for three weeks. Stressors due to health problems, uncomfortable environment (e.g., rainy weather, crowded buses, etc.), and lack of time were reported most frequently. Stressors related to the war in Ukraine, fear of the future, exams, and COVID-19 were reported as the most severe. To reappraise these stressors, the participants used mostly acceptance and problem-solving tactics. A key finding is the role of emotional demand-dependent PCR flexibility in mental health. Specifically, the flexible adaptation of PCR tactics in response to stressor severity was associated with a more substantial decline in perceived stress over the study period among participants reporting low tendency to use PCR at the study's baseline (β = - 0.963, p = .016, Cohen's f = 0.26). In contrast, stressor domain-dependent flexibility and contextually independent between-tactic variability had no moderating effect on stress, depression, and anxiety symptoms. This study contributes to the field of emotion regulation flexibility by highlighting the adaptive role of emotional demand-dependent PCR flexibility in mental well-being among young adults navigating real-life stressors and underscores the importance of tailoring interventions based on the emotional demands of stressors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Basal cell carcinoma is the most common malignant tumor in the fair-skinned population and its incidence continues to rise. An update of the S2k guideline with the participation of all specialist societies familiar with the clinical picture and previous literature research is of great importance for the quality of care for affected patients. In addition to epidemiology, diagnostics and histology are discussed. After risk stratification, therapy is divided into topical, systemic and radiation therapy. Surgical removal remains the treatment of first choice in most cases. The approval of anti-PD1 inhibitors for locally advanced and metastatic tumors has opened up a new option in second-line therapy (after hedgehog inhibitors)., (© 2024 The Author(s). Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Cationic, core-crosslinked nanogel particles are prepared from synthetic biodegradable materials. These fully hydrophilic nanogels offer superior customizability compared to common lipid nanoparticles, thereby circumventing intrinsic immune stimulatory properties. Electrostatic loading allows for complexation of nucleic acids including the immune stimulatory Toll-like receptor 9 (TLR9) agonistCpG-ODN (cytidine-phosphate-guanosine oligodeoxynucleotide). Only when complexed inside nanogels, one can control CpG-ODN's biodistribution, prevent systemic toxicity, and increase bioavailability at target locations. Nanogels are prepared from cyclic aliphatic carbonate monomers with reactive pentafluorophenyl (PFP) esters. First, block copolymers are acquired via cationic ring opening polymerization (CROP) onto polyethylene glycol (PEG). Upon self-assembly in ethanol, the micelles' core is cationically core-crosslinked, and the resulting fully hydrophilic particles exhibit sizes of ≈20 nm, also upon loading with CpG-ODN. In vitro, they promote intracellular delivery devoid of carrier-related toxicities, while retaining the immune stimulatory properties of the TLR agonist cargo. In vivo, the nanogels reduce systemic liver immune responses and remain near the injection site. Additionally, delivery into cDC1 (conventional dentritic cells type 1) antigen-presenting cells, which are highly relevant for antitumoral T-cell immune responses, is confirmed. Altogether, cationic, core-crosslinked polycarbonate nanogels show promise for nucleic acid delivery, showcasing controlled immunostimulatory cargo delivery and an enhanced hydrolytic biodegradability profile, highly valuable for cancer immunotherapy., (© 2024 The Author(s). Small published by Wiley‐VCH GmbH.)

Objectives: To determine the prevalence and distribution of intracranial vessel occlusion identified on computed tomography (CT) or magnet resonance (MR) angiography and to explore its association with functional outcome in patients with atrial fibrillation (AF) and ischemic stroke., Methods: Multicenter cohort study enrolling consecutive patients with AF with imaging-confirmed ischemic stroke who underwent CT- or MR-angiography on admission (2014-2022). Multivariable regression was used to explore the association between intracranial vessel occlusion and poor functional outcome (modified Rankin Scale score 3-6) at 90 days., Results: The analysis included 10,164 patients (median age 81.5 years, 47.8% female, median National Institutes of Health Stroke Scale score on admission 6; 14.7% on a vitamin K antagonist [VKA], 27.5% on a direct oral anticoagulant [DOAC], 57.8% not receiving oral anticoagulation). Angiography showed intracranial vessel occlusion in 5,190 patients (51.1%), affecting the anterior cerebral circulation in 87.4%. Overall, 29.2% and 29.4% of patients received thrombolysis and mechanical thrombectomy, respectively. The proportion of patients with poor functional outcome at 90 days was 60.6% and 42.7% in those with and without vessel occlusion, respectively. In multivariable analyses, vessel occlusion was associated with poor functional outcome (adjusted odds ratio [aOR]: 1.95, 95% confidence interval [CI]: 1.71-2.22) with consistent results in subgroups according to oral anticoagulation use (VKA, aOR: 1.98, 95% CI: 1.40-2.80; DOAC, aOR: 2.35, 95% CI: 1.83-3.03; none, aOR: 1.76, 95% CI: 1.49-2.09)., Interpretation: Intracranial vessel occlusion is common in patients with AF with ischemic stroke, mainly affects the anterior circulation and is associated with poor functional outcome. ANN NEUROL 2024;96:1115-1123., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Cancer is a disease characterized by the acquisition of a multitude of unique traits. It has long been understood that cancer cells divert significantly from normal cell metabolism. The most obvious of metabolic changes is that cancer cells strongly rely on glucose conversion by aerobic glycolysis. In addition, they also regularly develop mechanisms to use lipids and fatty acids for their energy needs. Peroxisomes lie central to these adaptive changes of lipid metabolism. Peroxisomes are metabolic organelles that take part in over 50 enzymatic reactions crucial for cellular functioning. Thus, they are essential for an effective and comprehensive use of lipids' energy supplied to cells. Cancer cells display a substantial increase in the biogenesis of peroxisomes and an increased expression of proteins necessary for the enzymatic functions provided by peroxisomes. Moreover, the enzymatic conversion of FAs in peroxisomes is a significant source of reactive oxygen and nitrogen species (ROS/RNS) that strongly impact cancer malignancy. Important regulators in peroxisomal FA oxidation and ROS/RNS generation are the transcription factors of the peroxisome proliferator-activated receptor (PPAR) family. This review describes the metabolic changes in tumorigenesis and cancer progression influenced by peroxisomes. We will highlight the ambivalent role that peroxisomes and PPARs play in the different stages of tumor development and summarize our current understanding of how to capitalize on the comprehension of peroxisomal biology for cancer treatment., Competing Interests: Declaration of competing interest We declare: There are no conflicts of interests, for the article titled “Peroxisomes and PPARs: Emerging Roles as Master Regulators of Cancer Metabolism and Immunity”., (Copyright © 2024. Published by Elsevier GmbH.)

Defects in myelin homeostasis have been reported in many neuropathological conditions. Cannabinoid compounds have been shown to efficiently promote myelin regeneration in animal models of demyelination. However, it is still unknown whether this action relies mostly on a cell autonomous effect on oligodendroglial-lineage-NG2 cells. By using conditional genetic mouse models, here we found that cannabinoid CB 1 receptors located on NG2 cells are required for oligodendroglial differentiation and myelin regeneration after demyelination. Selective CB 1 receptor gene depletion in NG2 cells following toxin-induced demyelination disrupted oligodendrocyte regeneration and functional remyelination and exacerbated axonal damage. These deficits were rescued by pharmacological blockade of the RhoA/ROCK/Cofilin pathway. Conversely, tetrahydrocannabinol administration promoted oligodendrocyte regeneration and functional remyelination in wild-type but not Ng2-CB 1 -deficient mice. Overall, this study identifies CB 1 receptors as essential modulators of remyelination and support the therapeutic potential of cannabinoids for promoting remyelination in neurological disorders., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Acute pancreatitis (AP) and venous thromboembolism (VTE) remain common and potentially lethal disease entities. AP might be an important trigger of systemic inflammtion and may activate the coagulation system with increased VTE risk., Methods: The German nationwide inpatient sample was screened for patients admitted due to AP (ICD-code K85) 2005-2019. AP hospitalizations were stratified for VTE as well as risk-factors and the impact of VTE on in-hospital case-fatality rate were investigated., Results: Overall, 797,364 hospitalizations of patients due to AP (aged in median 56.0 [IQR 44.0-71.0] years), 39.2 % females) were detected in Germany 2005-2019. Incidence of VTE in hospitalized AP patients was 1764.8 per 100,000 hospitalizations (1.8 %) with highest VTE rate between 5th and 6th decade. Cancer (OR 1.656 [95 %CI 1.513-1.812], P < 0.001), any surgery (OR 4.063 [95 %CI 3.854-4.284], P < 0.001), and heart failure (OR 1.723 [95 %CI 1.619-1.833], P < 0.001) were independently associated with VTE occurrence. Case-fatality (8.8 % vs. 2.7 %, P < 0.001) was more than 3-fold higher in AP patients with than without VTE. VTE was associated with increased case-fatality in AP patients (OR 3.925 [95 %CI 3.684-4.181], P < 0.001)., Conclusions: VTE is a life-threatening event in hospitalized AP patients associated with an almost 4-fold increased case-fatality rate. Cancer, any surgery, thrombophilia and heart failure were important risk factors for occurrence of VTE in AP., Competing Interests: Declaration of competing interest KK, VS, ITF, VHS, MAO, TM report no conflict of interests. TM is PI of the DZHK (German Center for Cardiovascular Research), Partner Site Rhine-Main, Mainz, Germany. CEK reports having from Amarin Germany, Amgen GmbH, Bayer Vital, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Leo Pharma, MSD Sharp & Dohme, Novartis Pharma, Pfizer Pharma GmbH, Sanofi-Aventis GmbH. SK reports institutional grants and personal lecture/advisory fees from Bayer AG, Daiichi Sankyo, and Boston Scientific; institutional grants from Inari Medical; and personal lecture/advisory fees from MSD and Bristol Myers Squibb/Pfizer. TM reports no conflict of interests. LH received lecture/consultant fees from MSD, Boston Scientific, Johnson&Johnson and Inari Medical, outside the submitted work., (Copyright © 2024. Published by Elsevier Ltd.)

Introduction: Small cell transformation (SCT) is a typical mechanism of adaptive resistance to third generation epidermal growth factor receptor inhibitors (EGFRi) which have become the standard of care for EGFR-driven non-small cell lung cancer (EGFR+ NSCLC). Little is known about the optimal management of SCT patients. This study aimed to compare outcomes under platinum/etoposide chemotherapy alone (chemo) or in combination with EGFR inhibitors (EGFRi+chemo) or immune checkpoint inhibitors (ICI+chemo). In addition, DLL3 expression was explored as potential novel therapeutic target., Methods: We conducted a retrospective study on patients with EGFR+ NSCLC and SCT treated at 19 centers in Europe and the United States. A total of 47 patients were included of whom 17 received chemo, 20 ICI+chemo, and 10 EGFRi+chemo. We analyzed DLL3 expression by immunohistochemistry., Results: In the entire cohort, median overall survival (OS) from start of first SCT therapy was 11 months (95 % confidence interval [95 %CI] 9.1-12.9) and median progression-free survival (PFS) was 5 months (95 %CI 4.2-5.8). Median PFS was similar in all three groups (chemo and ICI+chemo 4 months, EGFRi+chemo 6 months), and 12-months PFS was 12 % (95 %CI 2 %-31 %), 13 % (95 %CI 0 %-43 %), and 0 % for ICI+chemo, EGFRi+chemo, and chemo, respectively. Median OS in the ICI+chemo group was 13 months (95 %CI 5.5-20.5) compared to 10 months (95 %CI 7.6-12.4) with chemo and EGFRi+chemo (95 %CI 8.1-11.9), respectively. Before and after SCT, 0 % and 93 % of tumors were DLL3-positive., Conclusions: Our results suggest that ICI+chemo and DLL3-targeting agents are worth further exploration in EGFR+ NSCLC undergoing SCT., Presented Elsewhere: Part of this work has been presented at ESMO annual meeting in Madrid, Spain in October 2023 (Poster 1336 P)., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Allgäuer, M received speaker fees from Boehringer Ingelheim. Alt, J received speaker fees and/or honoraria for advisory boards by Astra Zeneca, Pfizer, Daichii Sankyo, Roche, Amgen, MSD, Novartis, Janssen, Boehringer Ingelheim, Merck, BMS. Aust, DEA received honoraria from Roche, Astra Zeneca, MSD, Pfizer, Novartis. Christopoulos. P received research funding from Roche, Amgen, Boehringer Ingelheim, Takeda, Merck, AstraZeneca, and Novartis, honoraria from Roche, Takeda, Gilead, AstraZeneca, Merck, Thermo Fisher, Janssen, Pfizer, and Novartis, travel support from AstraZeneca, Pfizer, Janssen, Merck, Gilead, Daiichi Sankyo, Takeda, Novartis, Eli Lilly and compensation for advisory roles for Pfizer, Chugai, Boehringer Ingelheim, Takeda, Janssen, Novartis, astraZeneca, MSD, Roche. Griesinger, F received speaker fees and/or honoraria for advisory boards from AstraZeneca, Boehringer, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Ariad, Abbvie, Tesaro/GSK, Siemens, Tesaro, Amgen, Sanofi, Daiichi-Sankyo, Beigene. Grohé, C received honoraria from AstraZeneca, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, and Roche, and has had consulting or advisory roles with Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Novartis, and Roche. Hochmair, M received honoraria from AstraZeneca, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, and Roche, and has had consulting or advisory roles with Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Novartis, and Roche. Illini, O received speaker fees and/or honoraria for advisory boards from Boehringer Ingelheim, Eli Lilly, Johnson & Johnson, Menarini, Merck Sharp & Dohme, Pfizer, and Roche and received research grants from Amgen and AstraZeneca outside of the submitted study. Jöhrens, K received compensation for advisory roles for BMS, GSK, Merck Sharp & Dohme, honoraria from AstraZeneca, Agilent, Boehringer Ingelheim, and DSO, and serves as medical advisor for QuIP. Kauffmann-Guerrero received speaker fees and/or honoraria for advisory boards from AstraZeneca, Boehringer Ingelheim, BMS, Lilly, MSD, Novartis, Pfizer, Roche, Takeda. Kirfel, J received speaker fees and/or honoraria for advisory boards, from AstraZeneca, Bristol-Myers Squibb, Novartis, Pfizer and Roche. König, D received a personal grant from Geistlich-Stucki-Stiftung, consulting fees from AstraZeneca, Merck, MSD, Novartis, PharmaMar, honoraria for presentations from Amgen, BMS, Mirati, Sanofi, Swiss Oncology in Motion, support for attending meetings from Amgen, Roche, Sanofi, honoraria for advisory boards from AstraZeneca, BMS, Merck, MSD, PharmaMar, Roche. Michels, S received research grants from Novartis and Pfizer, personal fees from Eli Lilly, Janssen, and Astra Zeneca as well as support for attending meetings and/or travel from Eli Lilly, and Janssen. Overbeck, T received speaker fees and/or honoraria for advisory boards by AstraZeneca, BMS, Boehringer-Ingelheim, Eli Lilly, Janssen-Cilag, Merck, MSD, Novartis, Roche, Takeda, Tesaro/GSK, Lilly, Roche, travel reimbursement by AstraZeneca, Boehringer-Ingelheim, Janssen-Cilag, Lilly, and Roche. Rohde, G received personal fees from Astra Zeneca, Atriva, Boehringer Ingelheim, GSK, Insmed, MSD, Sanofi, Novartis and Pfizer for consultancy during advisory board meetings and personal fees from Astra Zeneca, Berlin Chemie, BMS, Boehringer Ingelheim, Chiesi, Essex Pharma, Grifols, GSK, Insmed, MSD, Roche, Sanofi, Solvay, Takeda, Novartis, Pfizer and Vertex for lectures. Rothschild, S received honoraria (institutional) from, Roche, AstraZeneca, BMS, Boheringer Ingelheim, MSD Oncology, Novartis, Amgen, Lilly, Eisai, Merck serono, Pfizer, Takeda, Bayer, Janssen Oncology, Otsuka, PharmaMar, and Sanofi, compensation for advisory roles for AstraZeneca, Boerhinger Ingelheim, BMS, Pfizer, Eisai, Eli Lilly, Merck Serono, MSD Oncology, Novartis, Roche Pharma AG, Takeda, Amgen, Otsuka, PharmaMar, serves for the speakers bureau of Roche Pharma AG, Sanodi/Aventis, Amgen, AstraZeneca, Takeda, received research funding from Abbvie, BMS, AstraZeneca, Boerhinger Ingelheim, Merck Serono, Roche Pharma AG, and travel support, accomodation, expenses from Sanofi, Roche Pharma AG, BMS, MSD Oncology, AstraZeneca, Takeda, Boehringer Ingelheim, Amgen. He serves at the Federal Drug Comission of the Federal Office of Public Health and the Swiss Group for Clinical Cancer Research (SAKK). Saalfeld, F received research funding from Roche, consultancy fees from Boehringer Ingelheim, honoraria for lectures from AstraZeneca, Janssen, Takeda, Pfizer, Novartis, Thieme, and GWT-TUD, travel support from Janssen and Eli Lilly, and compensation for advisory meetings with BMS, Pfizer, AstraZeneca, Janssen, MSD, and Roche. Stenzinger, A received research grants from Bayer, BMS, Chugai, Incyte, and MSD, and compensation for advisory boards/speaker’s bureau: Agilent, Aignostics, Amgen, Astellas, Astra Zeneca, Bayer, BMS, Eli Lilly, Illumina, Incyte, Janssen, MSD, Novartis, Pfizer, Qlucore, QuiP, Roche, Sanofi, Seagen, Servier, Takeda, Thermo Fisher. Syrigos, K received honoraria for advisory boards from Merck Sharp & Dohme, AstraZeneca, BMS Amgen. Thomas, M received research funding (institution) from AstraZeneca, BMS, Merck, Roche, Takeda, speaker fees and/or honoraria for advisory boards by Amgen, AstraZeneca, Beigene, BMS, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Janssen Oncology, Lilly, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, Takeda. Veluswamy, R served on advisory boards for Bristol-Myers Squibb, Astrazeneca, Merck, Boehringer Ingelheim, Merus, Novocure, Regeneron, BerGenBio, and Serna Bio, on unbranded speaker’s bureau of Astrazeneca and EMD Serono, received consulting honorarium from Beigene, received research funding from Bristol-Myers Squibb, Onconova, Astrazeneca, Boehringer Ingelheim, Lung Cancer Research Foundation, Stand Up 2 Cancer. Wenzel, C received speaker fees from Astra Zeneca. Wermke, M received honorary from Lilly, Boehringer-Ingelheim, SYNLAB, Janssen, Merck Serono, GWT, Amgen, Novartis, Pfizer, BMS and has/had paid consulting or advisory positions for BMS, Novartis, Lilly, Boehringer-Ingelheim, ISA Pharmaceuticals, Amgen, Immatics, Bayer, ImCheck, AstraZeneca, Tacalyx, Regeneron, Daiichi, Zymeworks, PharmaMar. He receive research funding (instution) from Roche and travel support from Pfizer, BMS, AstraZeneca, Amgen, Gemoab, Sanofi-Aventis, Merck Serono, Immatics, Janssen, Iovance, Daiichi-Sankyo. Wesseler, C received speaker fees and/or honoraria for advisory boards from Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Pfizer, Roche, MSD, Novartis, Takeda, AstraZeneca, Chugai, BMS. Wiesweg, M received honoraria and Advisory Role: Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Janssen, Novartis, Pfizer, Roche, Takeda, and travel costs from Amgen, Janssen, Daiichi Sankyo, and research funding from Bristol-Myers Squibb, Takeda. Klimova, A, Kulhvay, J, Möller, J, Pelusi, N, Rasokat, A, Schubart, C, Schütz, M, Wang, A, and Vathiotis, J have nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To examine the impact of deep learning-augmented contrast enhancement on image quality and diagnostic accuracy of poorly contrasted CT angiography in patients with suspected stroke., Methods: This retrospective single-centre study included 102 consecutive patients who underwent CT imaging for suspected stroke between 01/2021 and 12/2022, including whole brain volume perfusion CT (VPCT) and, specifically, a poorly contrasted CT angiography (defined as < 350HU in the proximal MCA). CT angiography imaging data was reconstructed using i.) an iterative reconstruction kernel (conventional CTA, c-CTA) as well as ii.) an iodine-based contrast boosting deep learning model (Deep Learning-enhanced CTA, DLe-CTA). For quantitative analysis, the slope, contrast-to-noise ratio (CNR), and signal-to-noise ratio (SNR) were determined. Qualitative image analysis was conducted by three readers, rating image quality and vessel-specific parameters on a 4-point Likert scale. Readers evaluated both datasets for cerebral vessel occlusion presence. VPCT served as the reference standard for calculating sensitivity and specificity., Results: 102 patients were evaluated (mean age 69 ± 13 years; 70 men). DLe-CTA outperformed c-CTA in quantitative (all items p < 0.001) and qualitative image analysis (all items p < 0.05). VPCT revealed 58/102 patients with vascular occlusion. DLe-CTA resulted in significantly higher sensitivity compared to c-CTA (p < 0.001); (all readers put together: c-CTA: 142/174 [81.6 %; 95 % CI: 75.0 %-87.1 %] vs. DLe-CTA 163/174 [94 %; 95 % CI: 89.0 %-96.8 %]). One false positive finding occurred on DLe-CTA (specificity 1/132) [99.2 %; 95 % CI: 95.9 %-100 %]., Conclusions: Deep learning-augmented contrast enhancement improves the image quality and increases the sensitivity of detection vessel occlusions in poorly contrasted CTA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: In cases of atrophy in the maxillary posterior region, characterized by reduced vertical bone volume, implant placement becomes challenging. Augmentation procedures like sinus lifts are often needed to address insufficient bone volume. This study aims to explore if alveolar ridge preservation, using a bovine bone substitute and a porcine collagen membrane, significantly decreases the need for sinus lifts compared to natural wound healing after tooth extraction., Materials and Methods: In this comparative clinical study, 40 patients requiring a total of 53 extractions were assigned to one of the following groups: a test group with bovine bone substitute material (Straumann® XenoFlex) and a porcine collagen membrane (Jason® membrane), or a control group with spontaneous socket healing. After 6 months, digital volume tomography was performed for implant planning., Results: For seven patients from the control group (n = 22 extracted sites) sinus lift augmentations were performed while only four sinus lift procedures were performed in the test group (n = 31 extracted sites), indicating a higher need for sinus augmentation procedures in the control group, however not statistically different on a p value of 0.05 (p = 0.168). In the control group, the mean value of the radiographically measured bone height (mesial and distal) was 11.13 ± 2.12 mm preoperatively before tooth extraction, while it was 11.3 ± 2.17 mm postoperatively after implant placement. In contrast, the mean value in the test group was 11.78 ± 3.09 mm preoperatively and 11.92 ± 2.79 mm postoperatively. Statistical analysis revealed no significant difference between the two groups (odds ratio 0.32; 95% CI: 0.08, 1.26; p = 0.951). The implant survival rate in the control group was 100%, compared to 96.77% in the test group., Conclusion: Within the limits of this study, the use of bovine bone substitute and a porcine resorbable membrane after tooth extraction in the posterior maxilla seems to reduce the need for sinus augmentation in comparison to spontaneous healing although the difference was not statistically significant. Additionally, the Alveolar Ridge Preservation in the test group made external sinus floor elevation unnecessary compared to the control group. The change in radiographically measured bone height pre- and postoperatively showed no significant difference between the two groups., (© 2024 The Author(s). Clinical Implant Dentistry and Related Research published by Wiley Periodicals LLC.)

Background: Idiopathic normal pressure hydrocephalus (iNPH) is a reversible cause of dementia, typically treated with shunt surgery, although outcomes vary. Artificial intelligence (AI) advancements could improve predictions of shunt response (SR) by analyzing extensive datasets., Methods: We conducted a systematic review to assess AI's effectiveness in predicting SR in iNPH. Studies using AI or machine learning algorithms for SR prediction were identified through searches in MEDLINE, Embase, and Web of Science up to September 2023, adhering to Synthesis Without Meta-Analysis reporting guidelines., Results: Of 3541 studies identified, 33 were assessed for eligibility, and 8 involving 479 patients were included. Study sample sizes varied from 28 to 132 patients. Common data inputs included imaging/radiomics (62.5%) and demographics (37.5%), with Support Vector Machine being the most frequently used machine learning algorithm (87.5%). Two studies compared multiple algorithms. Only 4 studies reported the Area Under the Curve values, which ranged between 0.80 and 0.94. The results highlighted inconsistency in outcome measures, data heterogeneity, and potential biases in the models used., Conclusions: While AI shows promise for improving iNPH management, there is a need for standardized data and extensive validation of AI models to enhance their clinical utility. Future research should aim to develop robust and generalizable AI models for more effective diagnosis and management of iNPH., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Polyphosphates play a crucial role in various biological processes, such as blood coagulation, energy homeostasis, and cellular stress response. However, their isolation, detection, and quantification present significant challenges. These difficulties arise primarily from their solubility, low concentration in mammals, and structural similarity to other ubiquitous biopolymers. This review provides an overview of the current understanding of polyphosphates in mammals, including their proposed functions and tissue distribution. It also examines key isolation techniques, such as chromatography and precipitation, alongside detection methods, such as colorimetric assays and enzymatic digestion. The strengths and limitations of these methods are discussed, as well as the challenges in preserving polyphosphate integrity. Recent advancements in isolation and detection are also highlighted, offering a comprehensive perspective essential for advancing polyphosphate research., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: The presence of multiple localizations (ML) in glioblastoma is rare and associated with perceived poor prognosis. The aim of this study is to evaluate the impact of a multimodal treatment on progression-free survival (PFS) and overall survival (OS) in ML glioblastoma., Methods: Patients presenting with CNS WHO grade 4 glioblastoma with ML to 2 major German Departments of Neurosurgery between January 1st, 2008, to December 31st, 2020 were included in this study. Primary outcome parameters were extent of resection (EOR) using the 2021 RANO criteria, progression free- and overall survival., Results: A total of 483 patients with newly diagnosed glioblastoma (CNS WHO grade 4) were assessed. 134 patients presented with ML (72 multifocal (MF), 62 multicentric (MC)). The median PFS and OS did not differ among MC and MF glioblastomas. The EOR was a significant predictor of PFS and OS in ML glioblastoma. complete-, near total-, and subtotal resection significantly prolonged PFS (p < 0.0001) and OS (p < 0.0001) compared to biopsy alone. Standard radiotherapy (p = 0.045) and hypofractionated (p < 0.0001) radiotherapy and adjuvant treatment (Stupp protocol) prolonged PFS (p = 0.0012) and OS (p < 0.0001). In multivariate analysis Karnfosky performance score, EOR, and concomitant adjuvant treatment remained significant factors influencing OS. Propensity score matching of patients with ML and solitary lesion tumors showed similar PFS and OS (p = 0.08)., Conclusion: The presented data suggests that glioblastomas with multiple lesions treated with multimodal therapy equal survival rates compared to patients with solitary lesion tumors can be achieved. The results reflect the importance of an equally aggressive maximal treatment effort in this particular and often marginalized group of patients., Competing Interests: Declarations. Ethical approval: The ethics committee of Rhineland-Palatinate, Germany, reviewed and approved this study (No: 2020-15140-retrospektiv). Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Competing Interests: Competing interests: The authors declare no competing interests.

Age is a major risk-factor for atrial fibrillation (AF) and associated hospitalisations. With increasing emphasis on rhythm control, pulmonary vein isolation (PVI) is often suggested, even to elderly patients (≥ 75 years of age). Efficacy of PVI aiming at rhythm control is limited in persistent AF. Pacemaker implantation with atrioventricular node (AVN) ablation may represent a reasonable alternative, with the aim of controlling symptoms and improving quality of life in elderly patients. In this investigator-initiated, randomised, multicentre trial, we test the hypothesis that pacemaker implantation and AVN ablation provides superior symptom control over PVI in elderly patients with symptomatic persistent AF, without any increase in adverse event profile. In the ABLATE Versus PACE (NCT04906668) prospective open-label superiority trial, 196 elderly patients with normal ejection fraction and symptomatic persistent AF despite guideline-indicated medical therapy will be randomised to either cryoballoon PVI (ABLATE) or dual-chamber pacemaker implantation with subsequent AVN ablation (PACE), and followed for a minimum of 12 months. The primary efficacy outcome is a composite end point of rehospitalisation for atrial arrhythmia or cardiac decompensation/heart failure, (outpatient) electrical cardioversion, or upgrade to cardiac resynchronisation therapy owing to worsening of left ventricular ejection fraction to ≤ 35%. Secondary end points include death from any cause, stroke, quality of life, and procedure-related complications. Sample size is designed to achieve 80% power for the primary end point (2-tailed alpha of 5%). ABLATE Versus PACE will determine whether pacemaker implantation and AVN ablation can improve symptom-control in elderly patients with persistent AF over PVI without increasing safety end points., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Smoking is one of the leading causes of chronic non-communicable diseases and a significant risk factor for cardiovascular and respiratory diseases. While global tobacco consumption has decreased over the past two decades, the use of e‑cigarettes and water pipes (shisha) has surged at an alarming rate, particularly among younger individuals. E‑cigarettes do not offer a completely risk-free alternative to traditional cigarettes, as the vast array of flavors and ease of use contribute to a growing number of dependent users. Furthermore, they are not necessarily effective in overcoming nicotine addiction. This contribution provides an overview of the cardiovascular health impacts associated with shisha smoking and e‑cigarette vaping, with a particular emphasis on the detrimental effects on endothelial function. The harmful biological effects of the toxic substances in these products, especially oxidative stress and inflammatory responses, are also discussed. Finally, the current state of recommendations, legal regulations, and commercial advertising are summarized., Competing Interests: Declarations. Conflict of interest: T. Münzel, M. Kuntic, P. Stamm and A. Daiber declare that they have no competing interests. For this article no studies with human participants or animals were performed by any of the authors. All studies mentioned were in accordance with the ethical standards indicated in each case as far as this is overseen by the authors., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Internal tandem duplications in the FMS-like tyrosine kinase-3 (FLT3-ITD) are common mutations in acute myeloid leukemia (AML). Proteolysis-targeting chimeras (PROTACs) that induce proteasomal degradation of mutated FLT3 emerge as innovative pharmacological approach. Molecular mechanisms that control targeted proteolysis beyond the ubiquitin-proteasome-system are undefined and PROTACs are the only known type of FLT3 degraders. We report that the von-Hippel-Lindau ubiquitin-ligase based FLT3 PROTAC MA49 (melotinib-49) and the FLT3 hydrophobic tagging molecule MA50 (halotinib-50) reduce endoplasmic reticulum-associated, oncogenic FLT3-ITD but spare FLT3. Nanomolar doses of MA49 and MA50 induce apoptosis of human leukemic cell lines and primary AML blasts with FLT3-ITD (p < 0.05-0.0001), but not of primary hematopoietic stem cells and differentiated immune cells, FLT3 wild-type cells, retinal cells, and c-KIT-dependent cells. In vivo activity of MA49 against FLT3-ITD-positive leukemia cells is verified in a Danio rerio model. The degrader-induced loss of FLT3-ITD involves the pro-apoptotic BH3-only protein BIM and a previously unidentified degrader-induced depletion of protein-folding chaperones. The expression levels of HSP90 and HSP110 correlate with reduced AML patient survival (p < 0.1) and HSP90, HSP110, and BIM are linked to the expression of FLT3 in primary AML cells (p < 0.01). HSP90 suppresses degrader-induced FLT3-ITD elimination and thereby establishes a mechanistically defined feed-back circuit., Competing Interests: Competing interests: OHK declares the patents WO2019/034538, WO2016020369A1, and WO/2004/027418, and paid advisory work for the BASF Ludwigshafen, Germany. WO2019/034538 (Synthesis, Pharmacology and use of New and Selective FMS-like tyrosine kinase 3 (FLT3) FLT3 Inhibitors) covers substance classes that are discussed in this work. The substances that are covered in these patents are not the same that are shown in the submitted manuscript. The BASF has not influenced our study, and its products are not discussed in the manuscript. Thus, there are no direct competing interests. All other authors declare that they have no conflict of interest. Ethics: Peripheral blood and bone marrow samples were obtained from AML patients with written informed consent in accordance with the Declaration of Helsinki under ethical approval REC: 17/LO/1566. Institutional Review Board Statement Zebrafish husbandry (permit number 35-9185.64/BH Hassel) and experiments (permit number 35-9185.81/G-126/15) were performed according to local animal welfare standards (Tierschutzgesetz §11, Abs. 1, No. 1) and in accordance with European Union animal welfare guidelines (EU Directive 2010/63/EU). All applicable national and institutional guidelines for the care and use of zebrafish were followed. C57BL/6 mice were bred and maintained in the Central Animal Facility of the Johannes Gutenberg-University Mainz under specific pathogen-free conditions on a standard diet according to the guidelines of the regional animal care committee. The “Principles of Laboratory Animal Care” (NIH publication no. 85-23, revised 1985) were followed. Mice at 12 weeks of age were sacrificed for organ retrieval according to § 4(3) TierSchG., (© 2024. The Author(s).)

Background: The liver-heart axis potentially influences the risk of mortality in patients with heart failure. We aimed to identify the clinical utility of the fibrosis-4 (FIB-4) index in patients with heart failure for predicting mortality in the context of metabolic dysfunction-associated steatotic liver disease (MASLD)., Methods: Patients with heart failure and a subsample of healthy participants were enrolled in the MyoVasc study (NCT04064450) and followed for nine years. Participants with excessive alcohol consumption were excluded. The Fatty Liver Index (FLI) and FIB-4 index were used to classify MASLD and hepatic fibrosis, respectively. Data were adjusted for potential confounders. The primary endpoint was all-cause mortality., Findings: 2726 participants, including 172 healthy individuals, were included in the study. The participants had a mean age of 64.4 ± 11.2 years and a median FIB-4 index of 1.59 (interquartile range [1.17; 2.17]). There were 532 deaths. The FIB-4 index was predictive for all-cause mortality (hazard ratio (HR) 1.341, 95% confidence interval (CI) [1.273; 1.412], p < 0.0001). The HRs and 95% CIs for the FIB-4 index in FLI categories were 1.597 [1.256; 2.031] (p = 0.00013, FLI <30), 1.802 [1.519; 2.138] (p < 0.0001, FLI 30-60), and 1.292 [1.215; 1.374] (p < 0.0001, FLI ≥60). The interaction term for the FIB-4 index with FLI ≥60 (reference FLI <30) was HR 0.774 [0.617; 0.972] (p = 0.027), indicating a smaller impact of the FIB-4 index in FLI ≥60 than in FLI <30 (HR 1.664 [1.333; 2.077], p < 0.0001). Multivariable linear regressions revealed relevant independent relationships between the FIB-4 index and N-terminal pro-B-type natriuretic peptide, systolic dysfunction, diastolic dysfunction and left ventricular hypertrophy in participants with a FLI below 60., Interpretation: In patients with heart failure, the FIB-4 index predicts all-cause mortality and relates to cardiac functional and structural changes, especially in those without MASLD., Funding: Johannes Gutenberg-University Mainz., Competing Interests: J.B. reports outside the submitted work research funding from Colgate-Palmolive. J.P. reports personal fees from Bayer AG, Daiichi-Sankyo, and Sanofi-Aventis. He is an employee of Boehringer Ingelheim International GmbH, but was not employed at the time of conception and design of the study and during analysis and interpretation of data. M.B. reports research support from the Deutsche Forschungsgemeinschaft, speakers honoraria from Abbott, Amgen, Astra Zeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Cytokinetics, Medtronic, Novartis, Servier, and Vifor. He is or was part of the advisory board for Amgen, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, Pfizer, ReCor, Servier, and Vifor. P.S.W reports outside the submitted work: consulting fees from Astra Zeneca, research grants from Bayer AG, research grants, consulting and lecturing fees from Bayer Health Care, lecturing fees from Bristol Myers Squibb, grants and consulting fees from Boehringer Ingelheim, grants, consulting and lecturing fees from Daiichi Sankyo Europe, consulting fees and non-financial support from Diasorin, non-financial support from I.E.M., grants and consulting fees from Novartis Pharma, lecturing fees from Pfizer Pharma, non-financial grants from Philips Medical Systems, and grants and consulting fees from Sanofi-Aventis. J.M.S. has acted as Consultant to Apollo Endosurgery, Albireo Pharma Inc, Bayer, Boehringer Ingelheim, Gilead Sciences, GSK, Intercept Pharmaceuticals, Ipsen, Inventiva Pharma, Madrigal, MSD, Northsea Therapeutics, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, Siemens Healthineers; has received research funding from Gilead Sciences, Boehringer Ingelheim, Siemens Healthcare GmbH and Speaker Honorarium from Boehringer Ingelheim, Echosens, MedPublico GmbH, Novo Nordisk, Madrigal Pharmaceuticals. A.G. reports no potential conflict of interest., (© 2024 The Author(s).)

The long-term consequences of cancer and its therapy on the patients' immune system years after cancer-free survival remain poorly understood. Here, we present an in-depth characterization of the bone marrow immune ecosystem of multiple myeloma long-term survivors, from initial diagnosis up to 17 years following a single therapy line and cancer-free survival. Using comparative single-cell analyses combined with molecular, genomic, and functional approaches, we demonstrate that multiple myeloma long-term survivors exhibit pronounced alterations in their bone marrow microenvironment associated with impaired immunity. These immunological alterations were frequently linked to an inflammatory immune circuit fueled by the long-term persistence or resurgence of residual myeloma cells. Notably, even in the complete absence of any detectable residual disease for decades, sustained changes in the immune system were observed, suggesting an irreversible 'immunological scarring' caused by the initial exposure to the cancer and therapy. Collectively, our study provides key insights into the molecular and cellular bone marrow ecosystem of long-term survivors of multiple myeloma, revealing both reversible and irreversible alterations in the immune compartment., Competing Interests: Competing interests: C.M.-T. received research funding from Bioline RX and Pfizer. M.B. has served as a consultant for Takeda and Novartis; received research funding from Novartis and travel support from Celgene, Amgen, and Janssen. H.G. received funding from the International Myeloma Foundation – Black Swan and the Dietmar-Hopp-Foundation. The other authors declare no competing interests related to this study., (© 2024. The Author(s).)

Background: Reliable, noninvasive tools to diagnose at-risk metabolic dysfunction-associated steatohepatitis (MASH) are urgently needed to improve management. We developed a risk stratification score incorporating proteomics-derived serum markers with clinical variables to identify high-risk patients with MASH (NAFLD activity score >4 and fibrosis score >2)., Methods: In this 3-phase proteomic study of biopsy-proven metabolic dysfunction-associated steatotic fatty liver disease, we first developed a multi-protein predictor for discriminating NAFLD activity score >4 based on SOMAscan proteomics quantifying 1305 serum proteins from 57 US patients. Four key predictor proteins were verified by ELISA in the expanded US cohort (N = 168) and enhanced by adding clinical variables to create the 9-feature MASH Dx score, which predicted MASH and also high-risk MASH (F2+). The MASH Dx score was validated in 2 independent, external cohorts from Germany (N = 139) and Brazil (N = 177)., Results: The discovery phase identified a 6-protein classifier that achieved an AUC of 0.93 for identifying MASH. Significant elevation of 4 proteins (THBS2, GDF15, SELE, and IGFBP7) was verified by ELISA in the expanded discovery and independently in the 2 external cohorts. MASH Dx score incorporated these proteins with established MASH risk factors (age, body mass index, ALT, diabetes, and hypertension) to achieve good discrimination between MASH and metabolic dysfunction-associated steatotic fatty liver disease without MASH (AUC: 0.87-discovery; 0.83-pooled external validation cohorts), with similar performance when evaluating high-risk MASH F2-4 (vs. MASH F0-1 and metabolic dysfunction-associated steatotic fatty liver disease without MASH)., Conclusions: The MASH Dx score offers the first reliable noninvasive approach combining novel, biologically plausible ELISA-based fibrosis markers and clinical parameters to detect high-risk MASH in patient cohorts from the United States, Brazil, and Europe., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: Pulmonary lymphangiomatosis (PL) is an ultrarare disease characterized by diffuse infiltration of the lung, pleura and/or mediastinum by abnormal lymphatic proliferation. Consented diagnostic or treatment approaches are not established. We therefore aimed to collect data on diagnostics and treatments in a cohort of patients with PL from a tertiary center for rare lung diseases., Methods: Clinical, radiological and outcome data from PL patients were collected retrospectively., Results: 12 patients were diagnosed between 1996 and 2022 in our center. PL was diagnosed more commonly in female (58%), never smokers (75%) and younger patients (mean age 42 years). Main clinical symptoms comprised haem- and chyloptysis (58%) and dyspnea on exertion (83%). Pulmonary function was mostly restrictive (mean VC 59%) with impaired DLCO (mean 65%). Radiological assessment mainly showed mediastinal involvement (83%), and pleural effusion (67%), pleural thickening (67%) and bronchial wall thickening (67%) while interstitial changes were rare. Diagnosis was confirmed by surgical or transbronchial cryobiopsy. 8 patients were treated with sirolimus, 3 of these combined with a surgical intervention and in one case surgical intervention was necessary 9 months after initiation of sirolimus. Clinical and radiological improvement was demonstrated for all patients treated with sirolimus. 1 patient received a lung transplant due disease progression. Survival rates were 90% after a mean follow up of at least 3 months., Conclusion: This case series illustrates the variability of the clinical presentation of PL. Among our patients, those treated with sirolimus showed significant clinical, functional and radiological improvement. However, further investigation is needed to understand the pathogenesis of lymphangiomatosis in order to establish therapeutic approaches., Competing Interests: Declarations. Ethics approval and consent to participate: In accordance with declaration of Helsinki the studies involving human participants were reviewed and approved by the EC committee of the medical faculty of the University of Heidelberg, Germany. Consent for publication: The ethics committee of the University of Heidelberg approved this retrospective study (S-318/2013). Due to the retrospective nature of this analysis and according to the vote of the ethics committee, written informed consent could not be obtained by the patients but patient records/information were anonymized. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background/Objectives : Buffered local anesthetics are suggested to enhance patient comfort and anesthetic efficacy during dental procedures. However, their advantages over non-buffered solutions in maxillary third molar extractions remain under-investigated. This prospective, randomized, double-blind, split-mouth study aimed to compare the efficacy of buffered versus non-buffered 4% articaine in terms of pain, anesthetic onset, and the duration of anesthesia during maxillary third molar extractions. Methods : Each participant randomly received two buccal infiltrations on two single appointments to extract maxillary third molars: one with 4% articaine buffered with sodium bicarbonate and the other with non-buffered 4% articaine. Pain during injection, post-extraction pain, onset time, and the duration of anesthesia were assessed using a visual analog scale (VAS; 0-10). Results : Fifty adult participants (23 males and 27 females) with a mean age of 21.6 years were included in the study. Buffered 4% articaine significantly reduced injection pain (mean VAS: 3.12 ± 1.36 vs. 4.2 ± 0.3, p = 0.0001) and post-extraction pain (mean VAS: 4.4 ± 1.75 vs. 5.76 ± 1.78, p = 0.0002) compared to non-buffered articaine. Additionally, buffered articaine demonstrated a faster onset of anesthesia (mean time (seconds): 85.92 ± 27.37 vs. 126.86 ± 33.15, p < 0.0001) and a longer duration of anesthesia (mean duration (minutes): 70.4 ± 13.64 vs. 51.4 ± 7.2, p < 0.0001). Regarding gender's factor, the comparisons revealed no statistically significant differences ( p < 0.05) in pain perception between males and females for either injection pain or post-extraction pain. Conclusions : Buffered 4% articaine provides superior anesthetic efficacy compared to non-buffered 4% articaine, enhancing patient comfort by reducing pain, accelerating onset, and prolonging the duration of anesthesia during maxillary third molar extractions.

Objective: B-cell-depletion via CD20 antibodies is a safe and effective treatment for active relapsing multiple sclerosis (RMS). Both ocrelizumab (OCR) and ofatumumab (OFA) have demonstrated efficacy in randomized controlled trials and are approved for treatment of RMS, yet nothing is known on their comparative effectiveness, especially in the real-world setting., Methods: This prospective cohort study includes patients that were started on either OCR or OFA between September 2021 and December 2023. Patients were followed until June 2024 and recruited at 3 large tertiary centers in Germany (Duesseldorf, Essen, and Giessen). Propensity-score-matching was used to address baseline imbalances among patients. Clinical relapses, presence of new or enlarging MRI lesions and 6-month confirmed disability worsening were evaluated. Non-inferiority of OFA compared to OCR was evaluated through comparison of Kaplan-Meier-estimates., Results: A total of 1,138 patients were initially enrolled in the cohort. Following patient selection and propensity-score-matching, 544 OCR and 417 OFA patients were included in the final analysis. In our primary analysis, OFA was non-inferior to OCR in terms of relapses, disability progression, and accrual of MRI lesions. Subgroup analyses confirmed findings in previously naïve and platform-treated patients. Potential differences between OFA and OCR were seen in patients switching from S1P receptor modulators or natalizumab., Conclusion: We here provide comparative data on the effectiveness of OCR and OFA in patients with active RMS. OFA was non-inferior to OCR in the overall cohort. Potential differences observed in patients switching from S1P receptor modulators or natalizumab require further validation. ANN NEUROL 2024., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Several methods have been described for treating deep Cairo Class RT1 recessions. Most involve relieving incisions, which cause scar tissue formation or use a tunneled approach. This report introduces a modified technique for treating a single deep recession beyond the mucogingival margin. The approach uses a laterally closed coronally advanced flap (LCAF) without relieving incisions, combined with a subepithelial connective tissue graft and enamel matrix derivative., Methods: A 28-year-old woman was referred to our periodontal practice for the treatment of a progressive deep Cairo Class I recession with hypersensitivity and limited access to hygiene measures. The root coverage procedure was performed using a modified LCAF, combined with a connective tissue graft from the palate and enamel matrix derivative. The case was followed for 6 months., Results: The healing process was uneventful. Six months after surgery, the root surfaces remained completely covered. Hypersensitivity resolved entirely, and there was only a slight formation of visible scar tissue., Conclusions: This modified technique of an LCAF is a feasible and effective method for treating single deep RT1 recessions. By avoiding visible relieving incisions, scar tissue formation is minimized. The preparation of an LCAF allows for adequate coronal advancement., Key Points: As far as our knowledge, this is the first description of a laterally closed coronally advanced flap (LCAF) combining the advantage of a minimalized scarring root coverage with a simplified coronally advancement for recessions exceeding the mucogingival junction. This modified technique combines the advantages of a lateral closing with a CAF for covering deep class RT1 recessions. Meticulous handling of the delicate pedicles combined with a coronal advancement of at least 2 mm beyond the cemento-enamel junction is the key factor for the successful adaption of this technique., Plain Language Summary: Deep gum recessions originating from traumatic hygiene measures can cause hypersensitivity and limit patients´ access to oral hygiene. Especially in deep recessions, the common surgical techniques have shortcomings due to a post-surgical lack of keratinized gingiva or visible scar tissue formation. This case study shows the treatment of a 28-year-old woman´s deep recession on a mandibular front tooth introducing a modified surgical technique for covering deep gum recessions exceeding the area of the keratinized gingiva (so-called deep Cairo RT1 recessions). This new technique uses a "laterally closed coronally advanced flap" (LCAF), which combines a curtain-similar lateral closing of the flap pedicles with a coronal advancement to cover the recession without making cuts that can lead to scars. It is combined with a tissue graft from the patient's palate and a special protein to regenerate the periodontium. Six months after surgery, complete root coverage was achieved without remaining hypersensitivity and with restored access for oral hygiene measures. Minimal visible scar tissue formed. This case study demonstrates that the LCAF is a feasible technique for covering single deep gum recessions exceeding the keratinized area of the gingiva., (© 2024 American Academy of Periodontology.)

Objectives: This retrospective study aimed to evaluate the clinical outcomes associated with zygomatic implant (ZI) rehabilitation in partially atrophic edentulous maxillae over a mean follow-up period of more than 10.3 years., Methods: All consecutive patients underwent ZI rehabilitation between 1999 and 2020, with a minimum follow-up period of 3 years. The primary outcome was the implant survaival rate. Secondary outcomes included the prosthesis success rate, complications, and Oral Health-Related Quality of Life., Results: Of the 21 patients, treated with 27 ZIs and 48 conventional implants (CIs), 9 (42.9%) were females. The mean follow-up was 10.3 ± 5.7 years (range 3.2-23.4). ZI and CI survival rates were 100% and 97.9%, respectively, with one CI that failed. Eleven patients received 12 CIs placed in the pterygoid and tuberosity region. Most of the implants (81.33%) were immediately loaded, with 17 patients (80.9%) receiving 21 acrylic bridges. Of the total of 26 definitive prosthesis, the success rate was 96.1%. Local inflammation (n = 2) and soft tissue recession (n = 1) were reported as complications, occurring at a mean follow-up of 4.5 and 3.2 years, respectively. The mean score of the OHIP-14 questionnaire was 1.19 ± 1.99., Conclusions: Unilateral ZI rehabilitation was a predictable option for patients with partially atrophic edentulous maxilla who have experienced previous graft or implant failures, or who require immediate loading. Splinting the ZI with CI for restoration appeared to be essential in unilateral ZI treatment. Complications were infrequent and could be managed effectively, with patient-reported outcomes indicating normalization in quality of life., (© 2024 The Author(s). Clinical Oral Implants Research published by John Wiley & Sons Ltd.)