Predictors of Aneurysm Obliteration in Patients Treated with the WEB Device: Results of a Multicenter Retrospective Study.

BACKGROUND AND PURPOSE: Despite the numerous studies evaluating the occlusion rates of aneurysms following WEB embolization, there are limited studies identifying predictors of occlusion. Our purpose was to identify predictors of aneurysm occlusion and the need for retreatment. MATERIALS AND METHODS: This is a review of a prospectively maintained database across 30 academic institutions. We included patients with previously untreated cerebral aneurysms embolized using the WEB who had available intraprocedural data and long-term follow-up. RESULTS: We studied 763 patients with a mean age of 59.9 (SD, 11.7) years. Complete aneurysm occlusion was observed in 212/726 (29.2%) cases, and contrast stasis was observed in 485/537 (90.3%) of nonoccluded aneurysms. At the final follow-up, complete occlusion was achieved in 497/763 (65.1%) patients, and retreatment was required for 56/763 (7.3%) patients. On multivariable analysis, history of smoking, maximal aneurysm diameter, and the presence of an aneurysm wall branch were negative predictors of complete occlusion (OR, 0.5, 0.8, and 0.4, respectively). Maximal aneurysm diameter, the presence of an aneurysm wall branch, posterior circulation location, and male sex increase the chances of retreatment (OR, 1.2, 3.8, 3.0, and 2.3 respectively). Intraprocedural occlusion resulted in a 3-fold increase in the long-term occlusion rate and a 5-fold decrease in the retreatment rate (P < .001), offering a specificity of 87% and a positive predictive value of 85% for long-term occlusion. CONCLUSIONS: Intraprocedural occlusion can be used to predict the chance of long-term aneurysm occlusion and the need for retreatment after embolization with a WEB device. Smoking, aneurysm size, and the presence of an aneurysm wall branch are associated with decreased chances of successful treatment.

Population-based approaches for reducing stroke risk: an update on their success and the challenges ahead.

INTRODUCTION: Stroke is a significant public health challenge as it is the second most common cause of death and the third leading cause of disability globally. Additionally, stroke incidence and the number of stroke deaths have been rising. Efforts to prevent stroke have been made, including high-risk approaches where patients are screened for cardiovascular risk factors, and population-based approaches which attempt to reduce stroke rates by improving overall population health. AREAS COVERED: We summarize studies of population-based approaches to stroke prevention involving greater than 1,000 participants identified on a PubMed database search. Based on these programs, challenges of population-based stroke prevention programs are discussed and potential keys to success are highlighted. EXPERT OPINION: Population-based stroke prevention programs face challenges including cost and interest of the public and certain stakeholders. Additionally, secular trends for improvement in risk factors and catastrophic adverse environmental circumstances add to the complexity of analyzing program success. Factors leading to successful programs include validated digital solutions for self-monitoring of risks, backing by global policy and legislation, flexibility to the needs of the population, intersectoral programs, community engagement, information dissemination back to the populations, and high-risk screening to develop a complementary combination approach to stroke prevention.

SGLT2 Inhibitor Therapy in Patients With Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Transthyretin cardiomyopathy (ATTR-CM) was an exclusion criterion in randomized clinical trials of sodium-glucose cotransporter 2 inhibitors (SGLT2i). OBJECTIVES: This study sought to assess the effectiveness and tolerability of SGLT2i in patients with ATTR-CM. METHODS: Data of 2,356 consecutive ATTR-CM patients (2014-2022) were analyzed: 260 (11%) received SGLT2i. After comparing the groups according to the treatment, 14 variables were significantly different-age and N-terminal pro-B-type natriuretic peptide were included in the model. A propensity score reflecting the likelihood of being treated with SGLT2i for each patient was determined using 16 variables. RESULTS: The study comprised 220 patients treated with SGLT2i (age 77 ± 2 years; 82.3% wild-type ATTR-CM; left ventricular ejection fraction 45.8% ± 11%) and 220 propensity-matched control individuals. Adequacy of matching was verified (standardized differences: <0.10 between groups). Discontinuation rate for SGLT2i was 4.5%; at 12 months, SGLT2i treatment was associated with less worsening of NYHA functional class, N-terminal pro-B-type natriuretic peptide, estimated glomerular filtration rate, and fewer new initiations of loop diuretic agent therapy. Over 28 months (Q1-Q3: 18-45 months), SGLT2i therapy was associated with lower all-cause mortality (HR: 0.57; 95% CI: 0.37-0.89; P = 0.010), cardiovascular mortality (HR: 0.41; 95% CI: 0.24-0.71; P < 0.001), heart failure (HF) hospitalization (HR: 0.57; 95% CI: 0.36-0.91; P = 0.014), and the composite outcome of cardiovascular mortality and HF hospitalization (HR: 0.57; 95% CI: 0.38-0.84; P = 0.003). CONCLUSIONS: SGLT2i treatment in ATTR-CM patients was well tolerated and associated with favorable effects on HF symptoms, renal function, and diuretic agent requirement over time. SGLT2i treatment was associated with reduced risk of HF hospitalization and cardiovascular and all-cause mortality, regardless of the ejection fraction, despite the effect size being likely overestimated. In the absence of randomized trials, these data may inform clinicians regarding the use of SGLT2i in patients with ATTR-CM.

Response rates to second-line treatment with daratumumab bortezomib dexamethasone (DVD) in relapsed/refractory light chain amyloidosis (AL) after initial Bortezomib-based regime.

Bortezomib is regularly used as frontline therapy for systemic AL amyloidosis. We assess the efficacy of second-line daratumumab-bortezomib-dexamethasone (DVD) in AL amyloidosis in bortezomib-exposed patients. A total of 116 patients treated with second-line DVD were identified from a prospective observational study of newly diagnosed AL amyloidosis (ALchemy). DVD was initiated in both the relapsed setting or where there was an inadequate response defined as very good partial response (VGPR) or VGPR with organ progression/lack of organ improvement. A complete response (CR)/VGPR to second-line DVD was achieved in 81 (69.8%) patients. A CR/VGPR was achieved in 67 (79.7%) in those who achieved a VGPR/CR to first line versus 14/32 (43.8%) in those who did not. Where DVD was initiated due to an inadequate response to first line (vs. at relapse), the median event-free survival (EFS) was 18 vs. 34 months (p = 0.002). If a CR/VGPR was achieved to DVD, the 2-year EFS was still lower in those with prior inadequate response 54% vs. 66% (p = 0.062). DVD is an efficacious second-line treatment in systemic AL amyloidosis in a bortezomib-exposed population. However, the response to DVD is poorer in those with an inadequate response to first-line bortezomib.

Multimodal Neurologic Monitoring in Patients Undergoing Extracorporeal Membrane Oxygenation.

Introduction Extracorporeal membrane oxygenation (ECMO) is associated with a high rate of neurologic complications. Multimodal neurologic monitoring (MNM) has the potential for early detection and intervention. We examined the safety and feasibility of noninvasive MNM during ECMO. We hypothesized that survivors and non-survivors would have meaningful differences in transcranial Doppler (TCD) sonography and electroencephalographic (EEG) characteristics, which we aimed to identify. We also investigated adverse neurologic events and attempted to identify differences in EEG and TCD characteristics among patients based on the type of ECMO and the occurrence of these events. Material and methods We performed an observational study on all patients undergoing ECMO at Baylor St. Luke's Medical Center's critical care unit in Houston, Texas, United States, from January 2017 to February 2019. All patients underwent a noninvasive MNM protocol. Results NM was completed in 75% of patients; all patients received at least one component of the monitoring protocol. No adverse events were noted, showing the feasibility and safety of the protocol. The 60.4% of patients who did not survive tended to be older, had lower ejection fractions, and had lower median right middle cerebral artery (MCA) pulsatility and resistivity indexes. Patients undergoing venoarterial (VA)-ECMO had lower median left and right MCA velocities and lower right Lindegaard ratios than patients who underwent venovenous-ECMO. In VA-ECMO patients, EEG less often showed sleep architecture, while other findings were similar between groups. Adverse neurologic events occurred in 24.7% of patients, all undergoing VA-ECMO. Acute ischemic stroke occurred in 22% of patients, intraparenchymal hemorrhage in 4.9%, hypoxic-ischemic encephalopathy in 3.7%, subarachnoid hemorrhage in 2.5%, and subdural hematoma in 1.2%. Conclusion Our results suggest that MNM is safe and feasible for patients undergoing ECMO. Certain EEG and TCD findings could aid in the early detection of neurologic deterioration. MNM may not just be used in monitoring patients undergoing ECMO but also in prognostication and aiding clinical decision-making.

Expansion of the National Amyloidosis Centre staging system to detect early mortality in transthyretin cardiac amyloidosis.

AIMS: Transthyretin cardiac amyloidosis (ATTR-CA) is stratified into prognostic categories using the National Amyloidosis Centre (NAC) staging system. The aims of this study were to further expand the existing NAC staging system to incorporate an additional disease stage that would identify patients at high risk of early mortality. METHODS AND RESULTS: The traditional NAC staging system (stage 1: N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≤3000 ng/L and estimated glomerular filtration rate [eGFR] ≥45 ml/min; stage 3: NT-proBNP >3000 ng/L and eGFR <45 ml/min; stage 2: remainder) was expanded by the introduction of a new stage 4 (defined as NT-proBNP ≥10 000 ng/L irrespective of eGFR) and studied in 2042 patients. The optimal NT-proBNP cut-point was established using time-dependent receiver operating characteristic curves in the subgroup of patients with NAC stage 3 disease. Mortality at 1 year according to NAC stage was 2.3% (n = 20/886) for stage 1, 8.8% (n = 62/706) for stage 2, 10.4% (n = 28/270) for stage 3, and 30.6% (n = 55/180) for stage 4 (log-rank p < 0.001). After adjustment for age, mortality hazard for stage 4 was >15-fold higher than that of stage 1 (hazard ratio [HR] 15.5; 95% confidence interval [CI] 9.3-26.1) and >3-fold higher than that of stage 3 (HR 3.4; 95% CI 2.2-5.4). The increased risk of early mortality was consistent across the different genotypes and subclasses of patients based on the severity of heart failure symptoms and echocardiographic parameters. CONCLUSIONS: The proposed modification of the NAC staging system identifies patients with ATTR-CA at a high risk of early mortality, who may benefit from a more intensive treatment strategy, and who are most likely to experience an event early in the course of a clinical trial.

Prognostic Value of a 6-Minute Walk Test in Patients With Transthyretin Cardiac Amyloidosis.

BACKGROUND: The 6-minute walk test (6MWT) represents a comprehensive functional assessment that is commonly used in patients with heart failure; however, data are lacking in patients with transthyretin cardiac amyloidosis (ATTR-CA). OBJECTIVES: This study aimed to assess the prognostic importance of the 6MWT in patients with ATTR-CA. METHODS: A retrospective analysis of patients diagnosed with ATTR-CA at the National Amyloidosis Centre who underwent a baseline 6MWT between 2011 and 2023 identified 2,141 patients, of whom 1,118 had follow-up at 1 year. RESULTS: The median baseline 6MWT distance was 347 m (Q1-Q3: 250-428 m) and analysis by quartiles demonstrated an increased death rate with each distance reduction (deaths per 100 person-years: 6.3 vs 9.2 vs 13.6 vs 19.0; log-rank P < 0.001). A 6MWT distance of <350 m was associated with a 2.2-fold higher risk of mortality (HR: 2.15; 95% CI: 1.85-2.50; P < 0.001), with a similar increased risk across National Amyloidosis Centre disease stages (P for interaction = 0.761) and genotypes (P for interaction = 0.172). An absolute (reduction of >35 m) and relative worsening (reduction of >5%) of 6MWT at 1 year was associated with an increased risk of mortality (HR: 1.80; 95% CI: 1.51-2.15; P < 0.001 and HR: 1.89; 95% CI: 1.59-2.24; P < 0.001, respectively), which was similar across the aforementioned subgroups. When combined with established measures of disease progression (N-terminal pro-B-type natriuretic peptide progression and outpatient diuretic intensification), each incremental increase in progression markers was associated with an increased death rate (deaths per 100 person-years: 7.6 vs 13.9 vs 22.4 vs 32.9; log-rank P < 0.001). CONCLUSIONS: The baseline 6MWT distance can refine risk stratification beyond traditional prognosticators. A worsening 6MWT distance can stratify disease progression and, when combined with established markers, identifies patients at the highest risk of mortality.

Association of preprocedural antiplatelet use with decreased thromboembolic complications for intracranial aneurysms undergoing intrasaccular flow disruption.

OBJECTIVE: This study was conducted to investigate the impact of antiplatelet administration in the periprocedural period on the occurrence of thromboembolic complications (TECs) in patients undergoing treatment using the Woven EndoBridge (WEB) device for intracranial wide-necked bifurcation aneurysms. The primary objective was to assess whether the use of antiplatelets in the pre- and postprocedural phases reduces the likelihood of developing TECs, considering various covariates. METHODS: A retrospective multicenter observational study was conducted within the WorldWideWEB Consortium and comprised 38 academic centers with endovascular treatment capabilities. Univariable and multivariable logistic regression analyses were performed to determine the association between antiplatelet use and TECs, adjusting for covariates. Missing predictor data were addressed using multiple imputation. RESULTS: The study comprised two cohorts: one addressing general thromboembolic events and consisting of 1412 patients, among whom 103 experienced TECs, and another focusing on symptomatic thromboembolic events and comprising 1395 patients, of whom 50 experienced symptomatic TECs. Preprocedural antiplatelet use was associated with a reduced likelihood of overall TECs (OR 0.32, 95% CI 0.19-0.53, p < 0.001) and symptomatic TECs (OR 0.49, 95% CI 0.25-0.95, p = 0.036), whereas postprocedural antiplatelet use showed no significant association with TECs. The study also revealed additional predictors of TECs, including stent use (overall: OR 4.96, 95% CI 2.38-10.3, p < 0.001; symptomatic: OR 3.24, 95% CI 1.26-8.36, p = 0.015), WEB single-layer sphere (SLS) type (overall: OR 0.18, 95% CI 0.04-0.74, p = 0.017), and posterior circulation aneurysm location (symptomatic: OR 18.43, 95% CI 1.48-230, p = 0.024). CONCLUSIONS: The findings of this study suggest that the preprocedural administration of antiplatelets is associated with a reduced likelihood of TECs in patients undergoing treatment with the WEB device for wide-necked bifurcation aneurysms. However, postprocedural antiplatelet use did not show a significant impact on TEC occurrence.

An Enhanced Agile V-Model: Conformance to regulatory bodies and experiences from model's adoption to medical device development.

Context: Medical devices fall under the broad topic encompass everything from basic hardware to integrated software systems. The integration of software into hardware devices is not simple due to requirements of regional regulatory bodies. Therefore, medical businesses need to oversee not only the creation of devices but also the observance of guidelines and standards established by regulatory bodies. While plan-driven methodologies prevented software from evolving or changing, agile methodologies have inherent characteristics of insufficient planning and documentation. Objectives: The objective of our research is to propose a suitable process model for medical device development, keeping in mind the regulatory requirements. Methods: First, based on the detailed analysis of literature and McHughs proposed model, we suggested the Enhanced Agile V-Model (EAV), which combines plan-driven and agile approaches. Second, we mapped the proposed model to the MDEVSPICE framework to confirm that it adhered to the rules outlined in the standard IEC62304. Finally, the proposed model is evaluated through implication to case study of wave therapeutic medical device. Results: The support of both agile and waterfall approach in EAV model helps in accommodating new requirements in the medical devices and the proposed systems engineering approach helps in hardware and software integration. The mapping of the EAV model to the MDEVSPICE shows complete compliance. Moreover, the implication of the proposed model has been clearly shown statistically and successfully implemented in our case study. Further, device usability and efficiency metrics showed confidence of P < 0.05 and for device safety and efficiency, we conducted an experiment which shows significant improvement in selected parameters. Conclusion: The proposed model shows conformance to regulatory standards, and successfully implemented in development of wave therapeutic device. However, its applicability to more compact and straightforward medical products is unknown and can be determined by using this model to analyze the performance of other medical products.

Mutations at the conserved N-Terminal of the human Rhinovirus capsid gene VP4, and their impact on the immune response.

Rhinoviruses (RV) are the major cause of chronic obstructive pulmonary disease and are associated with exacerbation development as well as community-acquired pneumonia in children, leading to substantial morbidity, mortality, and hospital admission. Here we have examined how changes at the amino terminal of the conserved VP4 epitope of different RV serotypes may affect pulmonary cytokine and chemokine responses and disease severity. Samples positive for rhinovirus were used for genetic characterization, followed by profiling gene expression of pulmonary Th1 and Th2 cytokines/chemokines by RT-PCR arrays. Genetic sequencing and homology 3D modeling revealed changes at the amino terminal of the conserved viral protein 4 (VP4) epitope in the RV-A101 serotype, especially serine at several positions that are important for interactive binding with the host immune cells. We found dysregulation of pulmonary gene expression of Th1- and Th2-related cytokines and chemokines in RV-A 101 and RV-C 8 pneumonia patients. These findings might contribute to a better understanding of RV immunity and the potential mechanisms underlying the pathogenesis of severe RV infections, but further functional studies are needed to confirm the causal relationship.

Cardiopulmonary Exercise Testing in Evaluating Transthyretin Amyloidosis.

Importance: Cardiopulmonary exercise testing (CPET) has an established role in the assessment of patients with heart failure. However, data are lacking in patients with transthyretin (ATTR) amyloidosis. Objective: To use CPET to characterize the spectrum of functional phenotypes in patients with ATTR amyloidosis and assess their association with the cardiac amyloid burden as well as the association between CPET parameters and prognosis. Design, Setting and Participants: This single-center study evaluated patients diagnosed with ATTR amyloidosis from May 2019 to September 2022 who underwent CPET at the National Amyloidosis Centre. Of 1045 patients approached, 506 were included and completed the study. Patients were excluded if they had an absolute contraindication to CPET or declined participation. The mean (SD) follow-up period was 22.4 (11.6) months. Main Outcomes and Measures: Comparison of CPET parameters across disease phenotypes (ATTR with cardiomyopathy [ATTR-CM], polyneuropathy, or both [ATTR-mixed]), differences in CPET parameters based on degree of amyloid infiltration (as measured by cardiovascular magnetic resonance [CMR] with extracellular volume mapping), and association between CPET parameters and prognosis. Results: Among the 506 patients with ATTR amyloidosis included in this study, the mean (SD) age was 73.5 (10.2) years, and 457 participants (90.3%) were male. Impairment in functional capacity was highly prevalent. Functional impairment in ATTR-CM and ATTR-mixed phenotypes (peak mean [SD] oxygen consumption [VO2], 14.5 [4.3] mL/kg/min and 15.7 [6.2] mL/kg/min, respectively) was observed alongside impairment in the oxygen pulse, with ventilatory efficiency highest in ATTR-CM (mean [SD] ventilatory efficiency/volume of carbon dioxide expired slope, 38.1 [8.6]). Chronotropic incompetence and exercise oscillatory ventilation (EOV) were highly prevalent across all phenotypes, with both the prevalence and severity being higher than in heart failure from different etiologies. Worsening of amyloid burden on CMR was associated with decline in multiple CPET parameters, although chronotropic response and EOV remained abnormal irrespective of amyloid burden. On multivariable Cox regression analysis, peak VO2 and peak systolic blood pressure (SBP) were independently associated with prognosis (peak VO2: hazard ratio, 0.89 [95% CI, 0.81-0.99; P = .03]; peak SBP: hazard ratio, 0.98 [95% CI, 0.97-0.99; P < .001]). Conclusions and Relevance: In this study, ATTR amyloidosis was characterized by distinct patterns of functional impairment between all disease phenotypes. A high prevalence of chronotropic incompetence, EOV, and ventilatory inefficiency were characteristic of this population. CPET parameters were associated with amyloid burden by CMR and with peak VO2, and SBP, which have been shown to be independent predictors of mortality. These findings suggest that CPET may be useful in characterizing distinct patterns of functional impairment across the spectrum of amyloid infiltration and predicting outcomes, and potentially offers a more comprehensive method of evaluating functional capacity for future prospective studies.

Dual Layer vs Single Layer Woven EndoBridge Device in the Treatment of Intracranial Aneurysms: A Propensity Score-Matched Analysis.

BACKGROUND: The Woven EndoBridge (WEB) devices have been used for treating wide neck bifurcation aneurysms (WNBAs) with several generational enhancements to improve clinical outcomes. The original device dual-layer (WEB DL) was replaced by a single-layer (WEB SL) device in 2013. This study aimed to compare the effectiveness and safety of these devices in managing intracranial aneurysms. METHODS: A multicenter cohort study was conducted, and data from 1,289 patients with intracranial aneurysms treated with either the WEB SL or WEB DL devices were retrospectively analyzed. Propensity score matching was utilized to balance the baseline characteristics between the two groups. Outcomes assessed included immediate occlusion rate, complete occlusion at last follow-up, retreatment rate, device compaction, and aneurysmal rupture. RESULTS: Before propensity score matching, patients treated with the WEB SL had a significantly higher rate of complete occlusion at the last follow-up and a lower rate of retreatment. After matching, there was no significant difference in immediate occlusion rate, retreatment rate, or device compaction between the WEB SL and DL groups. However, the SL group maintained a higher rate of complete occlusion at the final follow-up. Regression analysis showed that SL was associated with higher rates of complete occlusion (OR: 0.19; CI: 0.04 to 0.8, p = 0.029) and lower rates of retreatment (OR: 0.12; CI: 0 to 4.12, p = 0.23). CONCLUSION: The WEB SL and DL devices demonstrated similar performances in immediate occlusion rates and retreatment requirements for intracranial aneurysms. The SL device showed a higher rate of complete occlusion at the final follow-up.

Stratifying Disease Progression in Patients With Cardiac ATTR Amyloidosis.

BACKGROUND: Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive cardiomyopathy. The clinical course varies among individuals and there are no established measures to assess disease progression. OBJECTIVES: The goal of this study was to assess the prognostic importance of an increase in N-terminal pro-B-type natriuretic peptide (NT-proBNP) and outpatient diuretic intensification (ODI) as markers of disease progression in a large cohort of patients with ATTR-CA. METHODS: We evaluated landmark survival analysis based on worsening of NT-proBNP and requirement for ODI between time of diagnosis and a 1-year visit, and subsequent mortality in 2,275 patients with ATTR-CA from 7 specialist centers. The variables were developed in the National Amyloidosis Centre (NAC) cohort (n = 1,598) and validated in the external cohort from the remaining centers (n = 677). RESULTS: Between baseline and 1-year visits, 551 (34.5%) NAC patients and 204 (30.1%) patients in the external validation cohort experienced NT-proBNP progression (NT-proBNP increase >700 ng/L and >30%), which was associated with mortality (NAC cohort: HR: 1.82; 95% CI: 1.57-2.10; P < 0.001; validation cohort: HR: 1.75; 95% CI: 1.32-2.33; P < 0.001). At 1 year, 451 (28.2%) NAC patients and 301 (44.5%) patients in the external validation cohort experienced ODI, which was associated with mortality (NAC cohort: HR: 1.88; 95% CI: 1.62-2.18; P < 0.001; validation cohort: HR: 2.05; 95% CI: 1.53-2.74; P < 0.001). When compared with patients with a stable NT-proBNP and stable diuretic dose, a higher risk of mortality was observed in those experiencing either NT-proBNP progression or ODI (NAC cohort: HR: 1.93; 95% CI: 1.65-2.27; P < 0.001; validation cohort: HR: 1.94; 95% CI: 1.36-2.77; P < 0.001), and those experiencing both NT-proBNP progression and ODI (NAC cohort: HR: 2.98; 95% CI: 2.42-3.67; P < 0.001; validation cohort: HR: 3.23; 95% CI: 2.17-4.79; P < 0.001). CONCLUSIONS: NT-proBNP progression and ODI are frequent and consistently associated with an increased risk of mortality. Combining both variables produces a simple, universally applicable model that detects disease progression in ATTR-CA.

One model to unite them all: Personalized federated learning of multi-contrast MRI synthesis.

Curation of large, diverse MRI datasets via multi-institutional collaborations can help improve learning of generalizable synthesis models that reliably translate source- onto target-contrast images. To facilitate collaborations, federated learning (FL) adopts decentralized model training while mitigating privacy concerns by avoiding sharing of imaging data. However, conventional FL methods can be impaired by the inherent heterogeneity in the data distribution, with domain shifts evident within and across imaging sites. Here we introduce the first personalized FL method for MRI Synthesis (pFLSynth) that improves reliability against data heterogeneity via model specialization to individual sites and synthesis tasks (i.e., source-target contrasts). To do this, pFLSynth leverages an adversarial model equipped with novel personalization blocks that control the statistics of generated feature maps across the spatial/channel dimensions, given latent variables specific to sites and tasks. To further promote communication efficiency and site specialization, partial network aggregation is employed over later generator stages while earlier generator stages and the discriminator are trained locally. As such, pFLSynth enables multi-task training of multi-site synthesis models with high generalization performance across sites and tasks. Comprehensive experiments demonstrate the superior performance and reliability of pFLSynth in MRI synthesis against prior federated methods.

Placental energy metabolism: Evidence for a placental-maternal lactate-ketone trade in the human.

INTRODUCTION: Glucose from placenta is the predominant energy source for the fetus. Individual placentas exhibit a range of glucose handling from apparent net production to high consumption, presumably reflecting an ability of placenta to secure both own and fetal energy needs. A dependency of placenta on glucose as the main energy source could impede fetal supply. Placenta seems to release lactate to maternal side implying loss of energy. Whether placenta takes up ketones is unclear. Our main hypothesis was that the human placenta can release lactate to the maternal side but take up maternal ketones. METHODS: An in vivo study of term uncomplicated pregnancies including 56 women delivered by cesarean section. We measured uterine and umbilical blood flow by Doppler ultrasonography, combined with blood sampling from maternal radial artery, uterine vein, umbilical artery and vein. Lactate and ketones were determined by quantitative nuclear magnetic resonance. RESULTS: Placenta released lactate to the maternal side (median -36.65 µmol/min. Q1, Q3: 78.53, 13.29), p < 0.001), but not to the fetal side. A net uptake of maternal ketones was found (median (Q1, Q3): 59.12 (30.64, 131.46) µmol acetate equivalents/min, p < 0.001) which largely was metabolized by the uteroplacenta. The uptake of ketones was comparable in energy to the loss of lactate. DISCUSSION: Placenta may release lactate to the maternal side. The energy lost by lactate may be compensated by uptake of maternal ketones. This lactate-ketone trade could benefit both placenta and the fetus by providing lactate for maternal gluconeogenesis and ketones for uteroplacental oxidative energy production.

Multiorgan Dysfunction and Associated Prognosis in Transthyretin Cardiac Amyloidosis.

BACKGROUND: Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive and ultimately fatal cardiomyopathy. Biomarkers reflecting multiorgan dysfunction are of increasing importance in patients with heart failure; however, their significance in ATTR-CA remains largely unknown. The aims of this study were to characterize the multifaceted nature of ATTR-CA using blood biomarkers and assess the association between blood biomarkers and prognosis. METHODS AND RESULTS: This is a retrospective cohort study of 2566 consecutive patients diagnosed with ATTR-CA between 2007 and 2023. Anemia (39%), high urea (52%), hyperbilirubinemia (18%), increased alkaline phosphatase (16%), increased CRP (C-reactive protein; 27%), and increased troponin (98.2%) were common findings in the overall population, whereas hyponatremia (6%) and hypoalbuminemia (2%) were less common. These abnormalities were most common in patients with p.(V142I) hereditary ATTR-CA, and became more prevalent as the severity of cardiac disease increased. Multivariable Cox regression analysis demonstrated that anemia (hazard ratio [HR], 1.19 [95% CI, 1.04-1.37]; P=0.01), high urea (HR, 1.23 [95% CI, 1.04-1.45]; P=0.01), hyperbilirubinemia (HR, 1.32 [95% CI, 1.13-1.57; P=0.001), increased alkaline phosphatase (HR, 1.20 [95% CI, 1.01-1.42; P=0.04), hyponatremia (HR, 1.65 [95% CI, 1.28-2.11]; P<0.001), and troponin-T >56 ng/L (HR, 1.72 [95% CI, 1.46-2.03]; P<0.001) were all independently associated with mortality in the overall population. The association between biomarkers and mortality varied across the spectrum of genotypes and left ventricular ejection fraction, with anemia remining independently associated with mortality in p.(V142I) hereditary ATTR-CA (HR, 1.58 [95% CI, 1.17-2.12]; P=0.003) and in a subgroup of the overall population with a left ventricular ejection fraction ≤40% (HR, 1.39 [95% CI, 1.08-1.81]; P=0.01). CONCLUSIONS: Cardiac and noncardiac biomarker abnormalities were common and reflect the complex and multifaceted nature of ATTR-CA, with a wide range of biomarkers remaining independently associated with mortality. Clinical trials are needed to investigate whether biomarker abnormalities represent modifiable risk factors that if specifically targeted could improve outcomes.

The effect of having a physician in the triage area on the rate of patients leaving without being seen: A quality improvement initiative at King Fahad Specialist hospital.

OBJECTIVES: To evaluate the effect of the presence of a physician in the triage area on the number of patients who leave without being seen (LWBS) and some of the factors affecting emergency department (ED) crowding. METHODS: This was a pre-post study carried out at King Fahad Specialist Hospital, Dammam, Saudi Arabia. The 3-month study, consisting of 7826 patients, was split into pre-physician and post-physician periods. Variables compared across these periods were the number of LWBS patients, length of hospital stay, time to physician, and time to disposition decision. Statistical analysis was carried out using R version 4.3.0. RESULTS: Our results showed that the presence of a triage physician significantly decreased the number of LWBS patients (p<0.001) and the time taken to encounter an ED physician (p<0.001). However, it did not have any significant impact on the length of hospital stay (p=0.5) or time to disposition decision (p=0.9). CONCLUSION: The appointment of a triage physician has streamlined patient flow and decreased LWBS rates in the ED, demonstrating the need for more thorough research in this area.

AMPK-mTORC1 pathway mediates hepatic IGFBP-1 phosphorylation in glucose deprivation: a potential molecular mechanism of hypoglycemia-induced impaired fetal growth.

Mechanisms underlying limitations in glucose supply that restrict fetal growth are not well established. IGF-1 is an important regulator of fetal growth and IGF-1 bioavailability is markedly inhibited by IGFBP-1 especially when the binding protein is hyperphosphorylated. We hypothesized that the AMPK-mTORC1 pathway increases IGFBP-1 phosphorylation in response to glucose deprivation. Glucose deprivation in HepG2 cells activated AMPK and TSC2, inhibited mTORC1 and increased IGFBP-1 secretion and site-specific phosphorylation. Glucose deprivation also decreased IGF-1 bioavailability and IGF-dependent activation of IGF-1R. AICAR (an AMPK activator) activated TSC2, inhibited mTORC1, and increased IGFBP-1 secretion/phosphorylation. Further, siRNA silencing of either AMPK or TSC2 prevented mTORC1 inhibition and IGFBP-1 secretion and phosphorylation in glucose deprivation. Our data suggest that the increase in IGFBP-1 phosphorylation in response to glucose deprivation is mediated by the activation of AMPK/TSC2 and inhibition of mTORC1, providing a possible mechanistic link between glucose deprivation and restricted fetal growth.

Complete responses in AL amyloidosis are unequal: the impact of free light chain mass spectrometry in AL amyloidosis.

ABSTRACT: Amyloidogenic serum free light chains (sFLCs) drive disease progression in AL amyloidosis. Matrix-assisted laser desorption/ionization time of flight mass spectrometry-based FLC assay (FLC-MS) has greater sensitivity than conventional sFLC assays allowing for the detection of serological residual disease. We report the utility of FLC-MS in a large series of patients with AL amyloidosis assessing the impact of FLC-MS negativity after treatment on overall survival (OS) and organ response rates. Serum samples were analyzed using FLC-MS at diagnosis and at 6 and 12 months after treatment. The impact of FLC-MS negativity over standard hematologic responses on survival and organ response was assessed. A total of 487 patients were included; 290 (59%) and 349 (71.5%) had cardiac and renal involvement, respectively. There was 100% concordance between the light chain (LC) fibril type and LC isotype identified by FLC-MS. At 6 and 12 months, 81 (16.6%) and 101 (20.7%) were FLC-MS negative. Of those achieving a conventional hematologic complete response (CR) at 6 and 12 months, 45 (27.7%) and 64 (39%) were FLC-MS negative. At 12 months, median OS for CR + FLC-MS negative was not reached vs 108 months in CR + FLC-MS positive (P = .024). At 12 months, 70% of patients with FLC-MS negativity (vs 50% FLC-MS positive) achieved a cardiac response (P = .015). In a multivariate analysis, FLC-MS negativity at 12 months was an independent predictor of better outcomes. FLC-MS can detect persistent monoclonal light chains in a significant proportion of patients in a conventional hematologic CR. FLC-MS assessment promises to be a new standard for response assessment in AL amyloidosis.