Neutrophil-specific expression of JAK2-V617F or CALRmut induces distinct inflammatory profiles in myeloproliferative neoplasia.

BACKGROUND: Neutrophils play a crucial role in inflammation and in the increased thrombotic risk in myeloproliferative neoplasms (MPNs). We have investigated how neutrophil-specific expression of JAK2-V617F or CALRdel re-programs the functions of neutrophils. METHODS: Ly6G-Cre JAK2-V617F and Ly6G-Cre CALRdel mice were generated. MPN parameters as blood counts, splenomegaly and bone marrow histology were compared to wild-type mice. Megakaryocyte differentiation was investigated using lineage-negative bone marrow cells upon in vitro incubation with TPO/IL-1ß. Cytokine concentrations in serum of mice were determined by Mouse Cytokine Array. IL-1α expression in various hematopoietic cell populations was determined by intracellular FACS analysis. RNA-seq to analyse gene expression of inflammatory cytokines was performed in isolated neutrophils from JAK2-V617F and CALR-mutated mice and patients. Bioenergetics of neutrophils were recorded on a Seahorse extracellular flux analyzer. Cell motility of neutrophils was monitored in vitro (time lapse microscopy), and in vivo (two-photon microscopy) upon creating an inflammatory environment. Cell adhesion to integrins, E-selectin and P-selection was investigated in-vitro. Statistical analysis was carried out using GraphPad Prism. Data are shown as mean ± SEM. Unpaired, two-tailed t-tests were applied. RESULTS: Strikingly, neutrophil-specific expression of JAK2-V617F, but not CALRdel, was sufficient to induce pro-inflammatory cytokines including IL-1 in serum of mice. RNA-seq analysis in neutrophils from JAK2-V617F mice and patients revealed a distinct inflammatory chemokine signature which was not expressed in CALR-mutant neutrophils. In addition, IL-1 response genes were significantly enriched in neutrophils of JAK2-V617F patients as compared to CALR-mutant patients. Thus, JAK2-V617F positive neutrophils, but not CALR-mutant neutrophils, are pathogenic drivers of inflammation in MPN. In line with this, expression of JAK2-V617F or CALRdel elicited a significant difference in the metabolic phenotype of neutrophils, suggesting a stronger inflammatory activity of JAK2-V617F cells. Furthermore, JAK2-V617F, but not CALRdel, induced a VLA4 integrin-mediated adhesive phenotype in neutrophils. This resulted in reduced neutrophil migration in vitro and in an inflamed vessel. This mechanism may contribute to the increased thrombotic risk of JAK2-V617F patients compared to CALR-mutant individuals. CONCLUSIONS: Taken together, our findings highlight genotype-specific differences in MPN-neutrophils that have implications for the differential pathophysiology of JAK2-V617F versus CALR-mutant disease.

Does Matrilineality Reduce Gender Inequality in Environmental and Social Impact Assessment (ESIA) Public Participation? Some Evidence from Malawi.

This paper reports on Environmental and Social Impact Assessment (ESIA) public participation in Malawi with a focus on the role of women from matrilineal and patrilineal marriage systems. Six rural ESIA projects are explored of which three are in areas of patrilineal and three are in areas of matrilineal systems. Participation space was found to be consistently dominated by men, with no obvious differences between both systems. The key reasons are likely to be lower educational and social status of women in rural areas throughout the country. This is associated with a number of challenges, including chronic poverty and food insecurity. Affirmative action is needed to achieve a better representation of women in ESIA processes.

Assessment of quantitative microflow Vascular Index in testicular cancer.

PURPOSE: Ultrasound (US) is the primary imaging modality when a testicular tumor is suspected. Superb microvascular imaging (SMI) is a novel, highly sensitive Doppler technique that allows quantification of flow signals by determination of the Vascular Index (VI). The aim of the present study is to investigate the diagnostic significance of the SMI-derived VI in normal testicular tissue and testicular cancer. METHODS: This retrospective analysis included patients who underwent testicular US in our department from 2018 to 2022. Inclusion criteria were: i) sufficient image quality of the stored images, ii) US with standardized SMI-default setting (colour gain of 44 ± 5), iii) patient age ≥ 18 years, and iv) normal testicular findings or testicular tumor with histopathological workup. US examinations were performed as part of clinical routine using a high-end ultrasound system (Aplio i800/i900, Canon Medical Systems Corporation, Tochigi, Japan). Statistical analysis included Chi-square test and Mann-Whitney U tests and receiver operating characteristic (ROC) curve analysis. RESULTS: A total of 62 patients (31 each with normal findings and testicular tumors) were included. The VI differed statistically significantly (p < 0.001) between normal testis (median 2.5 %) and testicular tumors (median 17.4 %). Like vascular patterns (p < 0.001), the VI (p = 0.030) was shown to distinguish seminomas (median 14.8 %), non-seminomas (median 17.6 %) and lymphomas (median 34.5 %). CONCLUSIONS: In conclusion, our study has shown the VI to be a quantitative tool that can add information for differentiating testicular tumor entities. While further confirmation in larger study populations is desirable, our results suggest that the VI may be a useful quantitative parameter.

[Syncopes - differential diagnoses and treatment]. / Synkopen ­ Differenzialdiagnosen und Behandlungsmöglichkeiten.

Syncope is a sudden loss of consciousness (transient loss of consciousness, TLOC) caused by a lack of cerebral perfusion that resolves spontaneously and completely after a short period of time 1. With a lifetime prevalence of 40% and constituting about 1% of all emergency department admissions, syncope is a common and medically relevant problem 2 3. The underlying causes of syncope are diverse and associated with significantly different prognoses. A structured approach is essential to identify high-risk patients and ensure appropriate treatment. This article aims at providing an overview of the current recommendations for the diagnosis and treatment of syncope.

Activated rate-response is associated with increased mortality risk in cardiac device carriers with acute heart failure.

AIMS: This study investigated whether an activated R-mode in patients carrying a cardiac implantable electronic device (CIED) is associated with worse prognosis during and after an episode of acutely decompensated heart failure (AHF). METHODS: Six hundred and twenty-three patients participating in an ongoing prospective cohort study that phenotypes and follows patients admitted for AHF were studied. We compared CIED carriers with activated R-mode stimulation (CIED-R) to CIED carriers not in R-mode (CIED-0) and patients without CIEDs (no-CIED). The independent impact of R-mode activation on 12-month all-cause death was examined using uni- and multivariable Cox proportional hazards regression taking into account potential confounders, and hazard ratios (HR) with their 95% confidence intervals (CI) were reported. RESULTS: Mean heart rate on admission was lower in CIED-R (n = 37, 16% women) vs. CIED-0 (n = 64, 23% women) or no-CIED (n = 511, 43% women): 70 bpm vs. 80 bpm or 82 bpm; both p<0.001. In-hospital mortality was similar across groups, but age- and sex-adjusted all-cause 12-month mortality risk was differentially affected by R-mode activation; CIED-R vs. CIED-0: HR 2.44, 95%CI 1.25-4.74; CIED-R vs. no-CIED: HR 2.61, 95%CI 1.59-4.29. These effects persisted after multivariable adjustment for potential confounders. Within CIED-R, mortality risk was similar in patients with pacemakers vs. ICDs and in subgroups with left ventricular ejection fraction (LVEF) <50% vs. ≥50%. CONCLUSION: In patients admitted with AHF, R-mode stimulation was associated with a significantly increased 12-month mortality risk. Our findings shed new light on "admission heart rate" as a potentially treatable target in AHF. Our data are compatible with the concept that chronotropic incompetence contributes to an adverse outcome in these patients and may not be adequately treated through accelerometer-based R-mode stimulation.

Multiparametric Characterization of the DSL-6A/C1 Pancreatic Cancer Model in Rats.

The DSL-6A/C1 murine pancreatic ductal adenocarcinoma (PDAC) tumor model was established in Lewis rats and characterized through a comprehensive multiparametric analysis to compare it to other preclinical tumor models and explore potential diagnostic and therapeutical targets. DSL-6A/C1 tumors were histologically analyzed to elucidate PDAC features. The tumor microenvironment was studied for immune cell prevalence. Multiparametric MRI and PET imaging were utilized to characterize tumors, and 68Ga-FAPI-46-targeting cancer-associated fibroblasts (CAFs), were used to validate the histological findings. The histology confirmed typical PDAC characteristics, such as malformed pancreatic ductal malignant cells and CAFs. Distinct immune landscapes were identified, revealing an increased presence of CD8+ T cells and a decreased CD4+ T cell fraction within the tumor microenvironment. PET imaging with 68Ga-FAPI tracers exhibited strong tracer uptake in tumor tissues. The MRI parameters indicated increasing intralesional necrosis over time and elevated contrast media uptake in vital tumor areas. We have demonstrated that the DSL-6A/C1 tumor model, particularly due to its high tumorigenicity, tumor size, and 68Ga-FAPI-46 sensitivity, is a suitable alternative to established small animal models for many forms of preclinical analyses and therapeutic studies of PDAC.

Unveiling the signaling network of FLT3-ITD AML improves drug sensitivity prediction.

Currently, the identification of patient-specific therapies in cancer is mainly informed by personalized genomic analysis. In the setting of acute myeloid leukemia (AML), patient-drug treatment matching fails in a subset of patients harboring atypical internal tandem duplications (ITDs) in the tyrosine kinase domain of the FLT3 gene. To address this unmet medical need, here we develop a systems-based strategy that integrates multiparametric analysis of crucial signaling pathways, and patient-specific genomic and transcriptomic data with a prior knowledge signaling network using a Boolean-based formalism. By this approach, we derive personalized predictive models describing the signaling landscape of AML FLT3-ITD positive cell lines and patients. These models enable us to derive mechanistic insight into drug resistance mechanisms and suggest novel opportunities for combinatorial treatments. Interestingly, our analysis reveals that the JNK kinase pathway plays a crucial role in the tyrosine kinase inhibitor response of FLT3-ITD cells through cell cycle regulation. Finally, our work shows that patient-specific logic models have the potential to inform precision medicine approaches.

Impact of FAPI-46/dual-tracer PET/CT imaging on radiotherapeutic management in esophageal cancer.

BACKGROUND: Fibroblast activation protein (FAP) is expressed in the tumor microenvironment (TME) of various cancers. In our analysis, we describe the impact of dual-tracer imaging with Gallium-68-radiolabeled inhibitors of FAP (FAPI-46-PET/CT) and fluorodeoxy-D-glucose (FDG-PET/CT) on the radiotherapeutic management of primary esophageal cancer (EC). METHODS: 32 patients with EC, who are scheduled for chemoradiation, received FDG and FAPI-46 PET/CT on the same day (dual-tracer protocol, 71%) or on two separate days (29%) We compared functional tumor volumes (FTVs), gross tumor volumes (GTVs) and tumor stages before and after PET-imaging. Changes in treatment were categorized as "minor" (adaption of radiation field) or "major" (change of treatment regimen). Immunohistochemistry (IHC) staining for FAP was performed in all patients with available tissue. RESULTS: Primary tumor was detected in all FAPI-46/dual-tracer scans and in 30/32 (93%) of FDG scans. Compared to the initial staging CT scan, 12/32 patients (38%) were upstaged in nodal status after the combination of FDG and FAPI-46 PET scans. Two lymph node metastases were only visible in FAPI-46/dual-tracer. New distant metastasis was observed in 2/32 (6%) patients following FAPI-4 -PET/CT. Our findings led to larger RT fields ("minor change") in 5/32 patients (16%) and changed treatment regimen ("major change") in 3/32 patients after FAPI-46/dual-tracer PET/CT. GTVs were larger in FAPI-46/dual-tracer scans compared to FDG-PET/CT (mean 99.0 vs. 80.3 ml, respectively (p < 0.001)) with similar results for nuclear medical FTVs. IHC revealed heterogenous FAP-expression in all specimens (mean H-score: 36.3 (SD 24.6)) without correlation between FAP expression in IHC and FAPI tracer uptake in PET/CT. CONCLUSION: We report first data on the use of PET with FAPI-46 for patients with EC, who are scheduled to receive RT. Tumor uptake was high and not depending on FAP expression in TME. Further, FAPI-46/dual-tracer PET had relevant impact on management in this setting. Our data calls for prospective evaluation of FAPI-46/dual-tracer PET to improve clinical outcomes of EC.

Activating mutations in JAK2 and CALR differentially affect intracellular calcium flux in store operated calcium entry.

BACKGROUND: Calcium (Ca2+) signaling regulates various vital cellular functions, including integrin activation and cell migration. Store-operated calcium entry (SOCE) via calcium release-activated calcium (CRAC) channels represents a major pathway for Ca2+ influx from the extracellular space in multiple cell types. The impact of JAK2-V617F and CALR mutations which are disease initiating in myeloproliferative neoplasms (MPN) on SOCE, calcium flux from the endoplasmic reticulum (ER) to the cytosol, and related key signaling pathways in the presence or absence of erythropoietin (EPO) or thrombopoietin (TPO) is poorly understood. Thus, this study aimed to elucidate the effects of these mutations on the aforementioned calcium dynamics, in cellular models of MPN. METHODS: Intracellular Ca2+ levels were measured over a time frame of 0-1080 s in Fura-2 AM labeled myeloid progenitor 32D cells expressing various mutations (JAK2-WT/EpoR, JAK2-V617F/EpoR; CALR-WT/MPL, CALR-ins5/MPL, and del52/MPL). Basal Ca2+ concentrations were assessed from 0-108 s. Subsequently, cells were stimulated with EPO/TPO in Ca2+-free Ringer solution, measuring Ca2+ levels from 109-594 s (store depletion). Then, 2 mM of Ca2+ buffer resembling physiological concentrations was added to induce SOCE, and Ca2+ levels were measured from 595-1080 s. Fura-2 AM emission ratios (F340/380) were used to quantify the integrated Ca2+ signal. Statistical significance was assessed by unpaired Student's t-test or Mann-Whitney-U-test, one-way or two-way ANOVA followed by Tukey's multiple comparison test. RESULTS: Following EPO stimulation, the area under the curve (AUC) representing SOCE significantly increased in 32D-JAK2-V617F cells compared to JAK2-WT cells. In TPO-stimulated CALR cells, we observed elevated Ca2+ levels during store depletion and SOCE in CALR-WT cells compared to CALR-ins5 and del52 cells. Notably, upon stimulation, key components of the Ca2+ signaling pathways, including PLCγ-1 and IP3R, were differentially affected in these cell lines. Hyper-activated PLCγ-1 and IP3R were observed in JAK2-V617F but not in CALR mutated cells. Inhibition of calcium regulatory mechanisms suppressed cellular growth and induced apoptosis in JAK2-V617F cells. CONCLUSIONS: This report highlights the impact of JAK2 and CALR mutations on Ca2+ flux (store depletion and SOCE) in response to stimulation with EPO and TPO. The study shows that the JAK2-V617F mutation strongly alters the regulatory mechanism of EpoR/JAK2-dependent intracellular calcium balance, affecting baseline calcium levels, EPO-induced calcium entry, and PLCγ-1 signaling pathways. Our results reveal an important role of calcium flux in the homeostasis of JAK2-V617F positive cells.

Effects of antibiotics ceftriaxone and levofloxacin on the growth of Protophormia terraenovae (Diptera: Calliphoridae).

Protophormia terraenovae is a colonizer of decomposing bodies and is known to cause pre-mortem myiasis as the female flies lay eggs in uncleaned wounds. In this study the effects of different concentrations of antibiotics levofloxacin and ceftriaxone on maggot development, weight, length, and mortality were examined. The maggot length and weight were significantly increased by therapeutical doses of levofloxacin and ceftriaxone. The maggot development time was significantly decreased in every levofloxacin treatment compared to the control. The time to start pupation was significantly increased in the control compared to the antibiotic treatments. Levofloxacin significantly increased the survivability of the maggots. Every levofloxacin treatment significantly improved the rearing conditions for the maggots. Reaching the third instar was delayed by 24 h in the control compared to the Levo 3.57 treatment. The Pupation in the control was delayed by an average of 48 h compared to the Levo 3.57 treatment. The significantly reduced development time of the maggots in the antibiotic treatments might lead to an overestimation of the post-mortem interval and therefore an incorrect time of death determination. The improved rearing conditions may be an indication of the potential of a combined application of antibiotics and maggot therapy.

Efficacy and safety of everolimus plus exemestane in patients with hormone receptor-positive, HER-2-negative advanced breast cancer: Results from the open-label, multicentre, non-interventional BRAWO study.

BRAWO, a real-world study, assessed the efficacy, quality of life (QoL) and safety of EVE + EXE in postmenopausal women with HR+/HER2- advanced breast cancer (ABC) in routine clinical practice. Postmenopausal women with HR+/HER2-ABC with recurrence or progression after a NSAI were included. Primary Observation parameters included the evaluation of the effectiveness of EVE + EXE. A multivariate-analysis using Cox proportional hazard model was built to identify predictors of progression. Overall, 2100 patients were enrolled (August 2012-December 2017); 2074 were evaluable for efficacy and safety analyses. Majority of patients (60.6%) received EVE + EXE as first (28.7%) or second-line (31.9%) therapy. Visceral metastases were present in 54.1% patients. Median progression-free survival (mPFS) reported as 6.6 months (95%CI: 6.3-7.0). Multivariate-analysis in a subset of patients (n = 1837) found higher body mass index (BMI) and non-visceral metastases to be independent predictors of favorable PFS. Patients with a BMI of 20 to <25 had a mPFS of 6.0 (95%CI: 5.4-6.4) and those with a BMI ≥30 had mPFS of 8.5 (95%CI: 6.9-9.9). 41.2% patients achieved stable disease and 7.3% partial response. No major changes were observed QoL; 86.4% patients received stomatitis prophylaxis and 41.4% experienced EVE related AEs of stomatitis, mainly low grade. AEs occurred in 91.2% of patients, of which stomatitis (42.6%) and fatigue (19.8%) were most frequent. The BRAWO study provides real-world evidence of efficacy and safety of EVE + EXE in patients with HR+, HER2- ABC. A high BMI and the absence of visceral metastases were independent predictors of PFS in this cohort of patients.

Sunitinib for Metastatic Renal Cell Carcinoma: Real-World Data from the STAR-TOR Registry and Detailed Literature Review.

INTRODUCTION: We evaluated the effectiveness and safety profile of the tyrosine kinase inhibitor sunitinib in patients with advanced or metastatic renal cell carcinoma (a/mRCC) in a real-world setting. METHODS: We analyzed data of adult a/mRCC patients treated with sunitinib. Data were derived from the German non-interventional post-approval multicenter STAR-TOR registry (NCT00700258). Progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated using descriptive statistics and survival analyses for the entire cohort and patient subgroups. RESULTS: A total of 116 study sites recruited 702 patients treated with sunitinib (73.1% male; median age 68.0 years; median Karnofsky index 90%) between November 2010 and May 2020. The most frequent histological subtype was clear cell RCC (81.6%). Sunitinib was administered as first-line treatment in 83.5%, as second line in 11.7%, and as third line or beyond in 4.8% of the patients. Drug-related AEs and serious AEs were reported in 66.3% and 13.9% of the patients, respectively (most common AE: gastrointestinal disorders; 39.7% of all patients). CONCLUSIONS: This study adds further real-world evidence of the persisting relevance of sunitinib for patients with a/mRCC who cannot receive or tolerate immune checkpoint inhibitors. The study population includes a high proportion of patients with unfavorable MSKCC poor-risk score, but shows still good PFS and OS results, while the drug demonstrates a favorable safety profile. The STAR-TOR registry is also registered in the database of US library of medicine (NCT00700258).

The Quality in Acute Stroke Care (QASC) global scale-up using a cascading facilitation framework: a qualitative process evaluation.

BACKGROUND: Variation in hospital stroke care is problematic. The Quality in Acute Stroke (QASC) Australia trial demonstrated reductions in death and disability through supported implementation of nurse-led, evidence-based protocols to manage fever, hyperglycaemia (sugar) and swallowing (FeSS Protocols) following stroke. Subsequently, a pre-test/post-test study was conducted in acute stroke wards in 64 hospitals in 17 European countries to evaluate upscale of the FeSS Protocols. Implementation across countries was underpinned by a cascading facilitation framework of multi-stakeholder support involving academic partners and a not-for-profit health organisation, the Angels Initiative (the industry partner), that operates to promote evidence-based treatments in stroke centres. .We report here an a priori qualitative process evaluation undertaken to identify factors that influenced international implementation of the FeSS Protocols using a cascading facilitation framework. METHODS: The sampling frame for interviews was: (1) Executives/Steering Committee members, consisting of academics, the Angels Initiative and senior project team, (2) Angel Team leaders (managers of Angel Consultants), (3) Angel Consultants (responsible for assisting facilitation of FeSS Protocols into multiple hospitals) and (4) Country Co-ordinators (senior stroke nurses with country and hospital-level responsibilities for facilitating the introduction of the FeSS Protocols). A semi-structured interview elicited participant views on the factorsthat influenced engagement of stakeholders with the project and preparation for and implementation of the FeSS Protocol upscale. Interviews were recorded, transcribed verbatim and analysed inductively within NVivo. RESULTS: Individual (n = 13) and three group interviews (3 participants in each group) were undertaken. Three main themes with sub-themes were identified that represented key factors influencing upscale: (1) readiness for change (sub-themes: negotiating expectations; intervention feasible and acceptable; shared goal of evidence-based stroke management); (2) roles and relationships (sub-themes: defining and establishing roles; harnessing nurse champions) and (3) managing multiple changes (sub-themes: accommodating and responding to variation; more than clinical change; multi-layered communication framework). CONCLUSION: A cascading facilitation model involving a partnership between evidence producers (academic partners), knowledge brokers (industry partner, Angels Initiative) and evidence adopters (stroke clinicians) overcame multiple challenges involved in international evidence translation. Capacity to manage, negotiate and adapt to multi-level changes and strategic engagement of different stakeholders supported adoption of nurse-initiated stroke protocols within Europe. This model has promise for other large-scale evidence translation programs.

Dual-tracer PET/CT protocol with [18F]FDG and [68Ga]Ga-FAPI-46 outperforms single-tracer PET/CT with [18F]FDG in different cancer types, resulting in larger functional and gross tumor volume.

PURPOSE: Fibroblast activation protein (FAP) detected by positron-emission tomography (PET) using fibroblast activation protein inhibitor (FAPI) appears to be a promising target for cancer imaging, staging, and therapy, providing added value and strength as a complement to [18F]fluorodeoxyglucose (FDG) in cancer imaging. We recently introduced a combined single-session/dual-tracer protocol with [18F]FDG and [68Ga]Ga-FAPI for cancer imaging and staging. Malignant tissue visualization and target-to-background uptake ratios (TBRs) as well as functional tumor volume (FTV) and gross tumor volume (GTV) were assessed in the present study with single-tracer [18F]FDG PET/computed tomography (CT) and with dual-tracer [18F]FDG&[68Ga]Ga-FAPI-46 PET/CT. METHODS: A total of 19 patients with head and neck and gastrointestinal cancers received initial [18F]FDG-PET/CT followed by dual-tracer PET/CT after additional injection of [68Ga]Ga-FAPI-46 during the same medical appointment (on average 13.9 ± 12.3 min after injection of [18F]FDG). Two readers visually compared detection rate of malignant tissue, TBR, FTV, and GTV for tumor and metastatic tissue in single- and dual-tracer PET/CT. RESULTS: The diagnostic performance of dual-tracer compared to single-tracer PET/CT was equal in 13 patients and superior in 6 patients. The mean TBRs of tumors and metastases in dual-tracer PET/CTs were mostly higher compared to single-tracer PET/CT using maximal count rates (CRmax). GTV and FTV were significantly larger when measured on dual-tracer compared to single-tracer PET/CT. CONCLUSION: Dual-tracer PET/CT with [18F]FDG and [68Ga]Ga-FAPI-46 showed better visualization due to a generally higher TBR and larger FTV and GTV compared to [18F]FDG-PET/CT in several tumor entities, suggesting that [68Ga]Ga-FAPI-46 provides added value in pretherapeutic staging.

Intra- and Interobserver Study Investigating the Adapted EFSUMB Bosniak Cyst Categorization Proposed for Contrast-Enhanced Ultrasound (CEUS) in 2020.

BACKGROUND: To investigate the inter- and intraobserver variability in comparison to an expert gold standard of the new and modified renal cyst Bosniak classification proposed for contrast-enhanced ultrasound findings (CEUS) by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) in 2020. MATERIALS AND METHODS: 84 CEUS examinations for the evaluation of renal cysts were evaluated retrospectively by six readers with different levels of ultrasound expertise using the modified Bosniak classification proposed for CEUS. All cases were anonymized, and each case was rated twice in randomized order. The consensus reading of two experts served as the gold standard, to which all other readers were compared. Statistical analysis was performed using Cohen's weighted kappa tests, where appropriate. RESULTS: Intraobserver variability showed substantial to almost perfect agreement (lowest kappa κ=0.74; highest kappa κ=0.94), with expert level observers achieving the best results. Comparison to the gold standard was almost perfect for experts (highest kappa κ=0.95) and lower for beginner and intermediate level readers still achieving mostly substantial agreement (lowest kappa κ=0.59). Confidence of rating was highest for Bosniak classes I and IV and lowest for classes IIF and III. CONCLUSION: Categorization of cystic renal lesions based on the Bosniak classification proposed by the EFSUMB in 2020 showed very good reproducibility. While even less experienced observers achieved mostly substantial agreement, training remains a major factor for better diagnostic performance.

Clinical Applicability of Ultrasound Shear Wave Elastography in Patients under Hypoglossal Nerve Stimulation Therapy.

Relationship between stiffness of genioglossi (GG) and geniohyoidei (GH) muscles under electric hypoglossal nerve stimulation therapy (HNS) in relation to success of therapy was investigated with additional special focus on tongue movement. PATIENTS AND METHODS: Clinical and sleep laboratory parameters of a cohort of 18 patients with known shear wave velocity (SWV) data of the ipsilateral and contralateral musculi GG and GH (sGG, sGH and nGG, nGH) before and under HNS therapy were analyzed. The SWV was already determined using the ultrasonic shear wave elastography (US-SWE) technique. RESULTS: Median Epworth Sleepiness Scale (ESS) was 8 (IQR 12), median baseline Apnoe-Hypopnoe Index (AHI) 31.65 (IQR 25.1), median AHI under HNS therapy 16.3 (IQR 20.03). Therapy success: 9/18 patients (AHI during therapy < 15/h). There was no significant difference in SWV (sGG, sGH, nGG and nGH) between therapy responders and non-responders during therapy. Also, no difference could be seen with respect to the difference and increase in SWV values without and with stimulation. Examination of SWV values (sGG, sGH, nGG, nGH during stimulation, difference of SWV values stimulation - no stimulation, increase factor of SWV) revealed a significant negative correlation between the AHI under therapy and the measured SWV of the musculus GH of the contralateral side during stimulation (-0.622, p = 0.006). Patients with bilateral protrusion of the tongue differed regarding to therapy success in increase in SWV in sGG (p = 0.032). Tongue protrusion to contralateral: A significant difference between patients with AHI during therapy < 15/h in SWV values at sGG without stimulation (p = 0.021) was seen, with also a correlation to the current AHI under therapy (p = 0.047) and the change factor of the AHI (p = 0.015). CONCLUSION: Stiffness of the target muscle does not appear to be an isolated measure of the success of HNS therapy. This observation may have implications for future decision-making processes in the process of titrating electrical therapy parameters. But the technique of US-SWE may be useful for future research of the neurophysiology of the tongue and OSA phenotyping.

Impact of pulmonary valve replacement on ventricular function and cardiac events in patients with tetralogy of Fallot. A retrospective cohort study.

INTRODUCTION AND OBJECTIVES: Our aim was to assess the impact of prosthetic pulmonary valve replacement (PVR) in patients with repaired tetralogy of Fallot (rTOF) on changes in biventricular volumes and function and on adverse cardiac events. METHODS: Adults with rTOF were identified from the SACHER-registry. Data from serial cardiac magnetic resonance imaging, echocardiography, exercise capacity and n-terminal pro b-type natriuretic peptide (NT-proBNP) were collected. The primary endpoint was right ventricular ejection fraction (RVEF) as measured by cardiac magnetic resonance. Secondary endpoints were biventricular volumes, left ventricular ejection fraction, exercise capacity and NT-proBNP levels, and time to adverse cardiac outcomes (atrial and ventricular arrhythmia, endocarditis). Associations between previous PVR and longitudinal changes in functional outcomes and time to adverse cardiac outcomes were analyzed using linear mixed-effects models and Cox proportional hazards models, respectively. RESULTS: A total of 308 patients (153 with and 155 without PVR) with 887 study visits were analyzed. Previous PVR was not significantly associated with changes in RVEF (CE, -1.33; 95%CI, -5.87 to 3.21; P=.566). Previous PVR was associated with lower right ventricular end-diastolic volume but had no significant effect on left ventricular ejection fraction, exercise capacity, or NT-proBNP-levels. Previous PVR was associated with an increased hazard of atrial arrhythmias (HR, 2.09; 95%CI, 1.17-3.72; P=.012) and infective endocarditis (HR, 12.72; 95%CI, 4.69-34.49; P<.0001) but not with an increased hazard of sustained ventricular arrhythmias (HR, 0.64; 95%CI, 0.18-2.27; P=.490). CONCLUSIONS: Previous PVR was not significantly associated with changes in RVEF but was associated with an increased risk of atrial arrhythmias and infective endocarditis.

Shear Wave Elastography for Assessing Liver Stiffness in HCV-Infected Kidney Transplant Recipients after Direct-Acting Antiviral Treatment: A Comparative Study with Magnetic Resonance Elastography.

Hepatitis C virus (HCV) infection can lead to hepatic fibrosis. The advent of direct-acting antivirals (DAAs) has substantially improved sustained virological response (SVR) rates. In this context, kidney transplant recipients (KTRs) are of particular interest due to their higher HCV infection rates and uncertain renal excretion and bioavailability of DAAs. We investigated liver stiffness after DAA treatment in 15 HCV-infected KTRs using ultrasound shear wave elastography (SWE) in comparison with magnetic resonance elastography (MRE). KTRs were treated with DAAs (daclatasvir and sofosbuvir) for three months and underwent SWE at baseline, end of therapy (EOT), and 3 (EOT+3) and 12 months (EOT+12) after EOT. Fourteen patients achieved SVR12. Shear wave speed (SWS)-as a surrogate parameter for tissue stiffness-was substantially lower at all three post-therapeutic timepoints compared with baseline (EOT: -0.42 m/s, p < 0.01; CI = -0.75--0.09, EOT+3: -0.43 m/s, p < 0.01; CI = -0.75--0.11, and EOT+12: -0.52 m/s, p < 0.001; CI = -0.84--0.19), suggesting liver regeneration after viral eradication and end of inflammation. Baseline SWS correlated positively with histopathological fibrosis scores (r = 0.48; CI = -0.11-0.85). Longitudinal results correlated moderately with APRI (r = 0.41; CI = 0.12-0.64) but not with FIB-4 scores (r = 0.12; CI = -0.19-0.41). Although higher on average, SWE-derived measurements correlated strongly with MRE (r = 0.64). In conclusion, SWE is suitable for non-invasive therapy monitoring in KTRs with HCV infection.

Implementing stroke care in a lower-middle-income country: results and recommendations based on an implementation study within the Nepal Stroke Project.

Background: Globally, the majority of strokes affect people residing in lower- and lower-middle-income countries (LMICs), but translating evidence-based knowledge into clinical practice in regions with limited healthcare resources remains challenging. As an LMIC in South Asia, stroke care has remained a healthcare problem previously unaddressed at a national scale in Nepal. The Nepal Stroke Project (NSP) aims to improve acute stroke care in the tertiary healthcare sector of Nepal. We hereby describe the methods applied and analyze the barriers and facilitators of the NSP after 18 months. Methods: The NSP follows a four-tier strategy: (1) quality improvement by training healthcare professionals in tertiary care centers; (2) implementation of in-hospital stroke surveillance and quality monitoring system; (3) raising public awareness of strokes; and (4) collaborating with political stakeholders to facilitate public funding for stroke care. We performed a qualitative, iterative analysis of observational data to analyze the output indicators and identify best practices. Results: Both offline and online initiatives were undertaken to address quality improvement and public awareness. More than 1,000 healthcare professionals across nine tertiary care hospitals attended 26 stroke-related workshops conducted by Nepalese and international stroke experts. Monthly webinars were organized, and chat groups were made for better networking and cross-institutional case sharing. Social media-based public awareness campaigns reached more than 3 million individuals. Moreover, live events and other mass media campaigns were instituted. For quality monitoring, the Registry of Stroke Care Quality (RES-Q) was introduced. Collaboration with stakeholders (both national and international) has been initiated. Discussion: We identified six actions that may support the development of tertiary care centers into essential stroke centers in a resource-limited setting. We believe that our experiences will contribute to the body of knowledge on translating evidence into practice in LMICs, although the impact of our results must be verified with process indicators of stroke care.