Developing technologies to assess vascular ageing: a roadmap from VascAgeNet.

Vascular ageing is the deterioration of arterial structure and function which occurs naturally with age, and which can be accelerated with disease. Measurements of vascular ageing are emerging as markers of cardiovascular risk, with potential applications in disease diagnosis and prognosis, and for guiding treatments. However, vascular ageing is not yet routinely assessed in clinical practice. A key step towards this is the development of technologies to assess vascular ageing. In this Roadmap, experts discuss several aspects of this process, including: measurement technologies; the development pipeline; clinical applications; and future research directions. The Roadmap summarises the state of the art, outlines the major challenges to overcome, and identifies potential future research directions to address these challenges.

Postoperative Extremity Tomosynthesis-A Superimposition-Free Alternative to Standard Radiography?

RATIONALE AND OBJECTIVES: This study investigates the performance of tomosynthesis in the presence of osteosynthetic implants, aiming to overcome superimposition-induced limitations in conventional radiograms. MATERIALS AND METHODS: After surgical fracture induction and subsequent osteosynthesis, 8 cadaveric fracture models (wrist, metacarpus, ankle, metatarsus) were scanned with the prototypical tomosynthesis mode of a multiuse x-ray system. Tomosynthesis protocols at 60, 80, and 116 kV (sweep angle 10°, 13 FPS) were compared with standard radiograms. Five radiologists independently rated diagnostic assessability based on an equidistant 7-point scale focusing on fracture delineation, intra-articular screw placement, and implant positioning. The intraclass correlation coefficient (ICC) was calculated to analyze interrater agreement. RESULTS: Radiation dose in radiography was 0.48 ± 0.26 dGy·cm2 versus 0.12 ± 0.01, 0.36 ± 0.02, and 1.95 ± 0.11 dGy·cm2 for tomosynthesis scans at 60, 80, and 116 kV. Delineation of fracture lines was superior for 80/116 kV tomosynthesis compared with radiograms (P ≤ 0.003). Assessability of intra-articular screw placement was deemed favorable for all tomosynthesis protocols (P ≤ 0.004), whereas superiority for evaluation of implant positioning could not be ascertained (all P's ≥ 0.599). Diagnostic confidence was higher for 80/116 kV tomosynthesis versus radiograms and 60 kV tomosynthesis (P ≤ 0.002). Interrater agreement was good for fracture delineation (ICC, 0.803; 95% confidence interval [CI], 0.598-0.904), intra-articular screw placement (ICC, 0.802; 95% CI, 0.599-0.903), implant positioning (ICC, 0.855; 95% CI, 0.729-0.926), and diagnostic confidence (ICC, 0.842; 95% CI, 0.556-0.934). CONCLUSIONS: In the postoperative workup of extremity fractures, tomosynthesis allows for superior assessment of fracture lines and intra-articular screw positioning with greater diagnostic confidence at radiation doses comparable to conventional radiograms.

[Interdisciplinary, collaborative D-A-CH (Germany, Austria and Switzerland) consensus statement concerning the diagnostic and treatment of myalgic encephalomyelitis/chronic fatigue syndrome]. / Interdisziplinäres, kollaboratives D-A-CH Konsensus-Statement zur Diagnostik und Behandlung von Myalgischer Enzephalomyelitis/Chronischem Fatigue-Syndrom.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe, chronic multisystemic disease which, depending on its severity, can lead to considerable physical and cognitive impairment, loss of ability to work and the need for nursing care including artificial nutrition and, in very severe cases, even death.The aim of this D-A-CH (Germany, Austria, Switzerland) consensus statement is 1) to summarize the current state of knowledge on ME/CFS, 2) to highlight the Canadian Consensus Criteria (CCC) as clinical criteria for diagnostics with a focus on the leading symptom post-exertional malaise (PEM) and 3) to provide an overview of current options and possible future developments, particularly with regard to diagnostics and therapy. The D-A-CH consensus statement is intended to support physicians, therapists and valuer in diagnosing patients with suspected ME/CFS by means of adequate anamnesis and clinical-physical examinations as well as the recommended clinical CCC, using the questionnaires and other examination methods presented. The overview of the two pillars of therapy for ME/CFS, pacing and symptom-relieving therapy options, is intended not only to provide orientation for physicians and therapists, but also to support decision-makers from healthcare policy and insurance companies in determining which therapy options should already be reimbursable by them at this point in time for the indication ME/CFS.

Association of Preserved Ratio Impaired Spirometry (PRISm) with Arterial Stiffness.

RATIONALE: Preserved ratio impaired spirometry (PRISm) is a recently recognized spirometric pattern defined by forced expiratory volume in 1 second (FEV1) / Forced vital capacity ratio ≥0.70 and FEV1 <80% of reference. For unclear reasons, PRISm is associated with increased cardiovascular (CV) morbidity and mortality. Arterial stiffness is a major mechanism of CV disease, which can be measured by carotid-femoral pulse wave velocity (cfPWV). OBJECTIVES: We explored the hypothesis that cfPWV would be increased in individuals with PRISm and airflow limitation (AL). METHODS: We measured forced spirometry, lung volumes by body plethysmography, and cfPWV in 9,466 subjects recruited from the general population in the Austrian cross-sectional LEAD study, and tested the association of arterial stiffness with PRISm and AL by multivariable linear regression analysis. Individuals aged 18 years and under as well as those with missing cfPWV or co-variates were excluded from further analysis. RESULTS: Individuals with PRISm (n = 431, 4.6%) were of similar age to those with normal spirometry (n = 8136, 85.9%) and significantly younger than those with AL (n = 899, 9.5%). Arterial hypertension, diabetes mellitus, coronary artery disease, heart failure and peripheral arterial occlusive disease were significantly more common in individuals with PRISm compared to normal lung function and similar to those with AL. There was a significant association between PRISm and arterial stiffness on bivariate linear regression analysis (crude model; ß = 0.038; 95% CI, 0.016 - 0.058), which persisted after robust adjustment for clinical confounders upon multivariable analysis (final model; ß = 0.017; 95% CI, 0.001 - 0.032). CfPWV was significantly higher in individuals with PRISm irrespective of the presence of established CV disease or pulmonary restriction. AL also showed a significant association with arterial stiffness on multivariable linear regression analysis (final model; 95% CI, ß = 0.025, 0.009 - 0.042). CONCLUSIONS: Arterial stiffness measured by cfPWV is increased in individuals with PRISm independent from CV disease and risk factors. The pathobiological mechanisms underlying this association deserve further research.

Time from diagnosis to treatment has no impact on survival in newly diagnosed acute myeloid leukemia treated with venetoclax-based regimens.

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

Pixelated High-Q Metasurfaces for in Situ Biospectroscopy and Artificial Intelligence-Enabled Classification of Lipid Membrane Photoswitching Dynamics.

Nanophotonic devices excel at confining light into intense hot spots of electromagnetic near fields, creating exceptional opportunities for light-matter coupling and surface-enhanced sensing. Recently, all-dielectric metasurfaces with ultrasharp resonances enabled by photonic bound states in the continuum (BICs) have unlocked additional functionalities for surface-enhanced biospectroscopy by precisely targeting and reading out the molecular absorption signatures of diverse molecular systems. However, BIC-driven molecular spectroscopy has so far focused on end point measurements in dry conditions, neglecting the crucial interaction dynamics of biological systems. Here, we combine the advantages of pixelated all-dielectric metasurfaces with deep learning-enabled feature extraction and prediction to realize an integrated optofluidic platform for time-resolved in situ biospectroscopy. Our approach harnesses high-Q metasurfaces specifically designed for operation in a lossy aqueous environment together with advanced spectral sampling techniques to temporally resolve the dynamic behavior of photoswitchable lipid membranes. Enabled by a software convolutional neural network, we further demonstrate the real-time classification of the characteristic cis and trans membrane conformations with 98% accuracy. Our synergistic sensing platform incorporating metasurfaces, optofluidics, and deep learning reveals exciting possibilities for studying multimolecular biological systems, ranging from the behavior of transmembrane proteins to the dynamic processes associated with cellular communication.

Natural Adeno-Associated Virus Serotypes and Engineered Adeno-Associated Virus Capsid Variants: Tropism Differences and Mechanistic Insights.

Today, adeno-associated virus (AAV)-based vectors are arguably the most promising in vivo gene delivery vehicles for durable therapeutic gene expression. Advances in molecular engineering, high-throughput screening platforms, and computational techniques have resulted in a toolbox of capsid variants with enhanced performance over parental serotypes. Despite their considerable promise and emerging clinical success, there are still obstacles hindering their broader use, including limited transduction capabilities, tissue/cell type-specific tropism and penetration into tissues through anatomical barriers, off-target tissue biodistribution, intracellular degradation, immune recognition, and a lack of translatability from preclinical models to clinical settings. Here, we first describe the transduction mechanisms of natural AAV serotypes and explore the current understanding of the systemic and cellular hurdles to efficient transduction. We then outline progress in developing designer AAV capsid variants, highlighting the seminal discoveries of variants which can transduce the central nervous system upon systemic administration, and, to a lesser extent, discuss the targeting of the peripheral nervous system, eye, ear, lung, liver, heart, and skeletal muscle, emphasizing their tissue and cell specificity and translational promise. In particular, we dive deeper into the molecular mechanisms behind their enhanced properties, with a focus on their engagement with host cell receptors previously inaccessible to natural AAV serotypes. Finally, we summarize the main findings of our review and discuss future directions.

Tomosynthesis of the Appendicular Skeleton on a Twin Robotic X-ray System: A Cadaveric Fracture Study.

RATIONALE AND OBJECTIVES: Aiming to offset image quality limitations in radiographs due to superimposition, this study investigates the diagnostic potential of appendicular skeleton tomosynthesis. MATERIALS AND METHODS: Eight cadaveric extremities (four hands and feet) were examined employing the prototypical tomosynthesis mode of a twin robotic X-ray scanner. 12 protocols with varying sweep angles (10, 20 vs. 40°), frame rates (13 vs. 26 fps), and tube voltages (60 vs. 80 kV) were compared to radiographs. Four radiologists separately evaluated cortical and trabecular bone visualization and fracture patterns. Interreader reliability was assessed based on the intraclass correlation coefficient (ICC). RESULTS: Radiation dose in radiography was 0.59 ± 0.20 dGy * cm2 versus 0.11 ± 0.00 to 2.46 ± 0.17 dGy * cm2 for tomosynthesis. Cortical bone display was inferior for radiographs compared to 40° and 20° tomosynthesis. Best results were ascertained for the 80 kV/40°/26 fps protocol. Trabecular bone depiction was also superior in tomosynthesis (p ≤ 0.009) and best with the 80 kV/10°/26 fps setting. Interreader reliability was moderate for cortical bone display (ICC 0.521, 95% confidence interval 0.356-0.641) and good for trabecular bone (0.759, 0.697-0.810). Diagnostic accuracy for articular involvement and multifragment situations was higher in tomosynthesis (93.8-100%/92.2-100%) vs. radiography (85.9%/82.8%.). Diagnostic confidence was also better in tomosynthesis (p ≤ 0.003). CONCLUSION: Compared to radiography, tomosynthesis allows for superior assessability of cortical and trabecular bone and fracture morphology, especially at high framerates. Operating on a multipurpose X-ray system, tomosynthesis of the appendicular skeleton can be performed without additional scanner hardware.

Innovative in vivo rat model for global cerebral hypoxia: a new approach to investigate therapeutic and preventive drugs.

Introduction: Severe acute global cerebral hypoxia can lead to significant disability in humans. Although different animal models have been described to study hypoxia, there is no endogenous model that considers hypoxia and its effect on the brain as an independent factor. Thus, we developed a minimally invasive rat model, which is based on the non-depolarizing muscle blocking agent rocuronium in anesthetized animals. This drug causes respiratory insufficiency by paralysis of the striated muscles. Methods: In this study, 14 rats underwent 12 min of hypoxemia with an oxygen saturation of approximately 60% measured by pulse oximetry; thereafter, animals obtained sugammadex to antagonize rocuronium immediately. Results: Compared to controls (14 rats, anesthesia only), hypoxic animals demonstrated significant morphological alterations in the hippocampus (cell decrease in the CA 1 region) and the cerebellum (Purkinje cell decrease), as well as significant changes in hypoxia markers in blood (Hif2α, Il1ß, Tgf1ß, Tnfα, S100b, cspg2, neuron-specific enolase), hippocampus (Il1ß, Tnfα, S100b, cspg2, NSE), and cerebellum (Hif1α, Tnfα, S100b, cspg2, NSE). Effects were more pronounced in females than in males. Discussion: Consequently, this model is suitable to induce hypoxemia with consecutive global cerebral hypoxia. As significant morphological and biochemical changes were proven, it can be used to investigate therapeutic and preventive drugs for global cerebral hypoxia.

Assessment and Management of Patients with Obesity and Hypertension in European Society of Hypertension Excellence Centres. A survey from the ESH Working Group on Diabetes and Metabolic Risk Factors.

BACKGROUND: Healthcare providers are faced with an increasing number of patients with obesity and arterial hypertension. Preventing obesity-associated hypertension and appropriately managing patients with established disease are both important. Hence, the aim of our study was to evaluate the clinical care of patients with obesity and hypertension among ESH Excellence Centres (ECs). METHODS: We conducted a cross-sectional, international 30-item survey through e-mails. RESULTS: In total, 70 representatives of ECs participated (78% men) with 66% of them practicing medicine for more than 30 years and working in well-equipped clinics. Most were internists (41%) and cardiologists (37%) and 73% reported training on the management of obese patients with hypertension. A majority weigh their patients (77%) and evaluate patients for sleep disorders (93%). However, only 47% spend more than 5min to advise for lifestyle modification in general, 59% for weight loss, 56% for salt intake and 64% for exercise. Finally, a minority of participants ask patients if they like their body (6%) or about previous attempts to lose weight (28%), evaluate 24h urinary sodium excretion rate (22%) and provide written (15%) or personalized (10%) dietary advices. If the patient suffers also from type 2 diabetes mellitus, 66% switch treatment to GLP1 receptor agonists and 60% to SGLT2 inhibitors. CONCLUSION: Most clinicians in ESH ECs are well educated regarding obesity-associated hypertension, and clinics are sufficiently equipped to manage these patients, as well. However, several deficits were reported regarding efforts to address and implement obesity specific aspects and interventions to improve care in patients with obesity and hypertension.

Hypertension and obesity still remain two of the main cardiovascular risk factors worldwide.There is a need to lower the incidence of obesity-induced hypertension, and to focus on practical guidelines for the evaluation and management of patients with obesity and hypertension.This is a web-based survey to understand the current clinical practices in assessing/managing patients with obesity and hypertension in ESH Excellence Centres.Most clinicians in ESH ECs are well educated regarding obesity-associated hypertension.Clinics are sufficiently equipped to manage these patients.Several deficits were reported regarding efforts to address and implement obesity specific aspects and interventions to improve care in patients with obesity and hypertension.

Feasibility of bone marrow edema detection using dual-energy cone-beam computed tomography.

BACKGROUND: Dual-energy (DE) detection of bone marrow edema (BME) would be a valuable new diagnostic capability for the emerging orthopedic cone-beam computed tomography (CBCT) systems. However, this imaging task is inherently challenging because of the narrow energy separation between water (edematous fluid) and fat (health yellow marrow), requiring precise artifact correction and dedicated material decomposition approaches. PURPOSE: We investigate the feasibility of BME assessment using kV-switching DE CBCT with a comprehensive CBCT artifact correction framework and a two-stage projection- and image-domain three-material decomposition algorithm. METHODS: DE CBCT projections of quantitative BME phantoms (water containers 100-165 mm in size with inserts presenting various degrees of edema) and an animal cadaver model of BME were acquired on a CBCT test bench emulating the standard wrist imaging configuration of a Multitom Rax twin robotic x-ray system. The slow kV-switching scan protocol involved a 60 kV low energy (LE) beam and a 120 kV high energy (HE) beam switched every 0.5° over a 200° angular span. The DE CBCT data preprocessing and artifact correction framework consisted of (i) projection interpolation onto matched LE and HE projections views, (ii) lag and glare deconvolutions, and (iii) efficient Monte Carlo (MC)-based scatter correction. Virtual non-calcium (VNCa) images for BME detection were then generated by projection-domain decomposition into an Aluminium (Al) and polyethylene basis set (to remove beam hardening) followed by three-material image-domain decomposition into water, Ca, and fat. Feasibility of BME detection was quantified in terms of VNCa image contrast and receiver operating characteristic (ROC) curves. Robustness to object size, position in the field of view (FOV) and beam collimation (varied 20-160 mm) was investigated. RESULTS: The MC-based scatter correction delivered > 69% reduction of cupping artifacts for moderate to wide collimations (> 80 mm beam width), which was essential to achieve accurate DE material decomposition. In a forearm-sized object, a 20% increase in water concentration (edema) of a trabecular bone-mimicking mixture presented as ∼15 HU VNCa contrast using 80-160 mm beam collimations. The variability with respect to object position in the FOV was modest (< 15% coefficient of variation). The areas under the ROC curve were > 0.9. A femur-sized object presented a somewhat more challenging task, resulting in increased sensitivity to object positioning at 160 mm collimation. In animal cadaver specimens, areas of VNCa enhancement consistent with BME were observed in DE CBCT images in regions of MRI-confirmed edema. CONCLUSION: Our results indicate that the proposed artifact correction and material decomposition pipeline can overcome the challenges of scatter and limited spectral separation to achieve relatively accurate and sensitive BME detection in DE CBCT. This study provides an important baseline for clinical translation of musculoskeletal DE CBCT to quantitative, point-of-care bone health assessment.

Sizing and mending of appendicular muscle mass for hydration during the 12-lead electrocardiogram: True incidence of sarcopenia in heart failure.

BACKGROUND: Our aim was to develop and evaluate a method for the measurement of muscle mass during the 12-channel electrocardiogram (ECG), to determine the incidence of sarcopenia in patients with overhydration and to correct it for congestion. METHODS: A 12-channel ECG that simultaneously provided multifrequency segmental impedance data was used to measure total body water (TBW), extracellular water (ECW), ECW/TBW ratio and appendicular muscle mass (AppMM), validated by whole-body dual-energy X-ray absorptiometry. The mean ECW/TBW ratio was 0.24 ± 0.018 (SD) and 0.25 ± 0.016 for young (age range 20-25 years) healthy males (n = 77) and females (n = 88), respectively. The deviation of the ECW/TBW ratio from this mean was used to correct AppMM for excess ECW ('dry AppMM') in 869 healthy controls and in 765 patients with chronic heart failure (CHF) New York Heart Association classes II-IV. The association of AppMM and dry AppMM with grip strength was also examined in 443 controls and patients. RESULTS: With increasing N-terminal pro-brain natriuretic peptide (NT-proBNP), a continuous decline of AppMM indices is observed, which is more pronounced for dry AppMM indices (for males with NT-proBNP < 125 pg/mL: AppMM index mean = 8.4 ± 1.05, AppMM index dry mean = 8.0 ± 1.46 [n = 201, P < 0.001]; for females with NT-proBNP < 150 pg/mL: AppMM index mean = 6.4 ± 1.0, AppMM index dry mean = 5.8 ± 1.18 [n = 198, P < 0.001]; for males with NT-proBNP > 1000 pg/mL: AppMM index mean = 7.6 ± 0.98, AppMM index dry mean = 6.2 ± 1.11 [n = 137, P < 0.001]; and for females with NT-proBNP > 1000 pg/mL: AppMM index mean = 5.9 ± 0.96, AppMM index dry mean = 4.8 ± 0.94 [n = 109, P < 0.001]). The correlation between AppMM and upper-body AppMM and grip strength (r-value) increased from 0.79 to 0.83 (P < 0.001) and from 0.80 to 0.84 (P < 0.001), respectively, after correction (n = 443). The decline of AppMM with age after correction for ECW is much steeper than appreciated, especially in males: In patients with CHF and sarcopenia, the incidence of sarcopenia may be up to 30% higher after correction for ECW excess according to the European (62% vs. 57%, for males, and 43% vs. 31%, for females) and Foundation for the National Institutes of Health (FNIH) (56% vs. 46%, for males, and 54% vs. 38%, for females) consensus guidelines. CONCLUSIONS: The incidence of sarcopenia in CHF as defined by the European Working Group on Sarcopenia and FNIH consensus may be up to 30% higher after correction for ECW excess. This correction improves the correlation between muscle mass and strength. The presented technology will facilitate, on a large scale, screening for sarcopenia, help identify mechanisms and improve understanding of clinical outcomes.

Broadband acoustic characterization of backscattering from a rough stratification interface.

Broadband acoustic analysis of scattering from sharp density gradients in the water column generally treat the interfaces as smooth surfaces. However, these interfaces may exhibit roughness owing to external water column forcing and local convective processes. In this work we extend broadband backscatter analysis methods to consider interface roughness by drawing upon methods developed for sea surface and seabed acoustic backscattering. The one-dimensional acoustic model from Weidner and Weber [J. Acoust. Soc. Am. 150(6), 4353-4361 (2021)], which predicts a decay in the reflected wave amplitude from stratification interfaces with increasing frequency, was expanded for surface applications. The expanded model was used to analyze the scattered pressure field from interfaces over a range of surface roughness magnitudes. Analysis of model results indicate that stratification interface roughness, quantified by the root-mean-squared interface slope angle and root-mean-squared height of the interface, modifies the model-predicted frequency-dependent backscattering. A broadband acoustic inversion procedure to remotely measure the magnitude of the vertical extent of stratification gradients and the corresponding sound speed perturbation was defined. The broadband inversion method was tested on data collected in the Baltic Sea with well-documented, strong salinity-driven stratification.

Genetic Characterization of Primary Mediastinal B-Cell Lymphoma: Pathogenesis and Patient Outcomes.

PURPOSE: Primary mediastinal large B-cell lymphoma (PMBCL) is a rare aggressive lymphoma predominantly affecting young female patients. Large-scale genomic investigations and genetic markers for risk stratification are lacking. PATIENTS AND METHODS: To elucidate the full spectrum of genomic alterations, samples from 340 patients with previously untreated PMBCL were investigated by whole-genome (n = 20), whole-exome (n = 78), and targeted (n = 308) sequencing. Statistically significant prognostic variables were identified using a multivariable Cox regression model and confirmed by L1/L2 regularized regressions. RESULTS: Whole-genome sequencing revealed a commonly disrupted p53 pathway with nonredundant somatic structural variations (SVs) in TP53-related genes (TP63, TP73, and WWOX) and identified novel SVs facilitating immune evasion (DOCK8 and CD83). Integration of mutation and copy-number data expanded the repertoire of known PMBCL alterations (eg, ARID1A, P2RY8, and PLXNC1) with a previously unrecognized role for epigenetic/chromatin modifiers. Multivariable analysis identified six genetic lesions with significant prognostic impact. CD58 mutations (31%) showed the strongest association with worse PFS (hazard ratio [HR], 2.52 [95% CI, 1.50 to 4.21]; P < .001) and overall survival (HR, 2.33 [95% CI, 1.14 to 4.76]; P = .02). IPI high-risk patients with mutated CD58 demonstrated a particularly poor prognosis, with 5-year PFS and OS rates of 41% and 58%, respectively. The adverse prognostic significance of the CD58 mutation status was predominantly observed in patients treated with nonintensified regimens, indicating that dose intensification may, to some extent, mitigate the impact of this high-risk marker. By contrast, DUSP2-mutated patients (24%) displayed durable responses (PFS: HR, 0.2 [95% CI, 0.07 to 0.55]; P = .002) and prolonged OS (HR, 0.11 [95% CI, 0.01 to 0.78]; P = .028). Upon CHOP-like treatment, these patients had very favorable outcome, with 5-year PFS and OS rates of 93% and 98%, respectively. CONCLUSION: This large-scale genomic characterization of PMBCL identified novel treatment targets and genetic lesions for refined risk stratification. DUSP2 and CD58 mutation analyses may guide treatment decisions between rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab.

2024 Recommendations for Validation of Noninvasive Arterial Pulse Wave Velocity Measurement Devices.

BACKGROUND: Arterial stiffness, as measured by arterial pulse wave velocity (PWV), is an established biomarker for cardiovascular risk and target-organ damage in individuals with hypertension. With the emergence of new devices for assessing PWV, it has become evident that some of these devices yield results that display significant discrepancies compared with previous devices. This discrepancy underscores the importance of comprehensive validation procedures and the need for international recommendations. METHODS: A stepwise approach utilizing the modified Delphi technique, with the involvement of key scientific societies dedicated to arterial stiffness research worldwide, was adopted to formulate, through a multidisciplinary vision, a shared approach to the validation of noninvasive arterial PWV measurement devices. RESULTS: A set of recommendations has been developed, which aim to provide guidance to clinicians, researchers, and device manufacturers regarding the validation of new PWV measurement devices. The intention behind these recommendations is to ensure that the validation process can be conducted in a rigorous and consistent manner and to promote standardization and harmonization among PWV devices, thereby facilitating their widespread adoption in clinical practice. CONCLUSIONS: It is hoped that these recommendations will encourage both users and developers of PWV measurement devices to critically evaluate and validate their technologies, ultimately leading to improved consistency and comparability of results. This, in turn, will enhance the clinical utility of PWV as a valuable tool for assessing arterial stiffness and informing cardiovascular risk stratification and management in individuals with hypertension.

Upright Tomosynthesis of the Lumbar Spine.

RATIONALE AND OBJECTIVES: This experimental study investigates the potential of lumbar spine tomosynthesis to offset the traditional limitations of radiographic and computed tomography imaging, that is, superimposition of anatomy and disregard of physiological load-bearing. MATERIALS AND METHODS: A gantry-free twin robotic scanner was used to obtain lateral radiographs and tomosyntheses of the lumbar spine under weight-bearing conditions in eight body donors. Tomosynthesis protocols varied in terms of sweep angle (20 versus 40°), scan time (2.4 versus 4.8 seconds), and framerate (16 versus 30 fps). Image quality and vertebral endplate assessability were evaluated by five radiologists with 4-8 years of skeletal imaging experience. Aiming to identify potential diagnostic deterioration near the scan volume margins, readers additionally determined the craniocaudal extent of clinically acceptable image quality. RESULTS: Tomosynthesis scans effectuated a substantial dose reduction compared to standard radiographs (3.8 ± 0.2 to 15.4 ± 0.8 dGy*cm2 versus 77.7 ± 34.8 dGy*cm2; p ≤ 0.021). Diagnostic image quality and endplate assessability were deemed highest for the 30 fps wide-angle tomosynthesis protocol with good to excellent interrater reliability (intraclass correlation coefficients: 0.846 and 0.946). Accordingly, the craniocaudal extent of acceptable image quality was substantially larger compared to radiography (26.9 versus 18.9 cm; p < 0.001), whereas no significant difference was ascertained for the tomosynthesis protocols with 16 fps (15.3-22.1 cm; all p ≥ 0.058). CONCLUSION: Combining minimal radiation dose with superimposition-free visualization, 30 fps wide-angle tomosynthesis superseded radiography in all evaluated aspects. With superior diagnostic assessability despite significant dose reduction, load-bearing tomosynthesis appears promising as an alternative for first-line lumbar spine imaging in the future.

Octreotide improves human lymphatic fluid transport a translational trial.

OBJECTIVES: Chylothorax is a complex condition and many different pharmacological agents have been tried as treatment. Octreotide is used off-label to treat chylothorax, but the efficacy of octreotide remains unclear. A decrease in lymph production is suggested as the mechanism. In this cross-over study, we explore the direct effect of octreotide on human lymphatic drainage. METHODS: Pre-clinical: the effect of octreotide on force generation was assessed during acute and prolonged drug incubation on human lymphatic vessels mounted in a myograph. Clinical: in a double-blinded, randomized, cross-over trial including 16 healthy adults, we administered either octreotide or saline as an intravenous infusion for 2.5 h. Near-infrared fluorescence imaging was used to examine spontaneous lymphatic contractions and lymph pressure in peripheral lymphatic vessels and plethysmography was performed to assess the capillary filtration rate, capillary filtration coefficient and isovolumetric pressures of the lower leg. RESULTS: Pre-clinical: human thoracic duct (n = 12) contraction rate was concentration-dependently stimulated by octreotide with a maximum effect at 10 and 100 nmol/l in the myograph chamber. Clinical: spontaneous lymphatic contractions and lymph pressure evaluated by near-infrared fluorescence did not differ between octreotide or placebo (P = 0.36). Plethysmography revealed similar capillary filtration coefficients (P = 0.057), but almost a doubling of the isovolumetric pressures (P = 0.005) during octreotide infusion. CONCLUSIONS: Octreotide stimulated lymphatic contractility in the pre-clinical setup but did not affect the spontaneous lymphatic contractions or lymph pressure in healthy individuals. Plethysmography revealed a doubling in the isovolumetric pressure. These results suggest that octreotide increases lymphatic drainage capacity in situations with high lymphatic afterload.

Development of local-power-free, remote α-particle detection using optical fibers.

We demonstrate the application of fluorescence optical fiber coupled to a telecom grade fiber as a sensor for alpha particles using alpha-specific ZnS(Ag) scintillation materials whose wavelength is down-shifted into a low-loss region of the telecom grade fiber transmission band. Telecom-grade fiber optics offer a solution for sensing alpha radiation in deep repositories and cask storage for radioactive materials due to the stability of SiO2 under normal environmental conditions and its relative radiation hardness at low radiation doses. Long-term nuclear waste storage facilities require sensors for the detection of leakage of radioactive materials that are maintenance-free, do not require power and can survive with no 'wear out' mechanisms for decades. By accomplishing the wavelength transformation, we maximize efficiencies in the detection of α-particles and signal transport and can detect alpha scintillation at distances on the order of >1 km with a sensor that is ~3% efficient and can be easily scaled as a sensor array. This paper describes the construction and testing of the sensor including manufacture of the controlled thickness films, verification of the wavelength shift from 450 to 620 nm and optimization of the sensitivity as a function of thickness. We also model the relative sensitivity of the film as a function of film thickness, and we demonstrate a signal-to-noise ratio of 10 at a range of greater than 1 km.

Laboratory-Based Correlative Soft X-ray and Fluorescence Microscopy in an Integrated Setup.

Correlative microscopy is a powerful technique that combines the advantages of multiple imaging modalities to achieve a comprehensive understanding of investigated samples. For example, fluorescence microscopy provides unique functional contrast by imaging only specifically labeled components, especially in biological samples. However, the achievable structural information on the sample in its full complexity is limited. Here, the intrinsic label-free carbon contrast of water window soft X-ray microscopy can complement fluorescence images in a correlative approach ultimately combining nanoscale structural resolution with functional contrast. However, soft X-ray microscopes are complex and elaborate, and are usually installed on large-scale synchrotron radiation sources due to the demanding photon flux requirements. Yet, with modern high-power lasers it has become possible to generate sufficient photon flux from laser-produced plasmas, thus enabling laboratory-based setups. Here, we present a compact table-top soft X-ray microscope with an integrated epifluorescence modality for "in situ" correlative imaging. Samples remain in place when switching between modalities, ensuring identical measurement conditions and avoiding sample alteration or destruction. We demonstrate our new method by multimodal images of several exemplary samples ranging from nanoparticles to various multicolor labeled cell types. A structural resolution of down to 50 nm was reached.