Computationally Efficient IMplicit Training Strategy for UNrolled NEtworks (IMUNNE): A preliminary analysis using accelerated real-time cardiac cine MRI.

OBJECTIVE: Highly-undersampled, dynamic MRI reconstruction, particularly in multi-coil scenarios, is a challenging inverse problem. Unrolled networks achieve state-of-the-art performance in MRI reconstruction but suffer from long training times and extensive GPU memory cost. METHODS: In this work, we propose a novel training strategy for IMplicit UNrolled NEtworks (IMUNNE) for highly-undersampled, multi-coil dynamic MRI reconstruction. It formulates the MRI reconstruction problem as an implicit fixed-point equation and leverages gradient approximation for backpropagation, enabling training of deep architectures with fixed memory cost. This study represents the first application of implicit network theory in the context of real-time cine MRI. The proposed method is evaluated using a prospectively undersampled, real-time cine dataset using radial k-space sampling, comprising balanced steady-state free precession (b-SSFP) readouts. Experiments include a hyperparameter search, head-to-head comparisons with a complex U-Net (CU-Net) and an alternating unrolled network (Alt-UN), and an analysis of robustness under noise perturbations; peak signal-to-noise ratio, structural similarity index, normalized root mean-square error, spatio-temporal entropic difference, and a blur metric were used. RESULTS: IMUNNE produced significantly and slightly better image quality compared to CU-Net and Alt-UN, respectively. Compared with Alt-UN, IMUNNE significantly reduced training and inference times, making it a promising approach for highly-accelerated, multi-coil real-time cine MRI reconstruction. CONCLUSION: IMUNNE strategy successfully applies unrolled networks to image reconstruction of highly-accelerated, real-time radial cine MRI. SIGNIFICANCE: Implicit training enables rapid, high-quality, and cost-effective CMR exams by reducing training and inference times and lowering memory cost associated with advanced reconstruction methods.

Exploring the Esterase Catalytic Activity of Minimalist Heptapeptide Amyloid Fibers.

This paper investigates the esterase activity of minimalist amyloid fibers composed of short seven-residue peptides, IHIHIHI (IH7) and IHIHIQI (IH7Q), with a particular focus on the role of the sixth residue position within the peptide sequence. Through computational simulations and analyses, we explore the molecular mechanisms underlying catalysis in these amyloid-based enzymes. Contrary to initial hypotheses, our study reveals that the twist angle of the fiber, and thus the catalytic site's environment, is not notably affected by the sixth residue. Instead, the sixth residue interacts with the p-nitrophenylacetate (pNPA) substrate, particularly through its -NO2 group, potentially enhancing catalysis. Quantum mechanics/molecular mechanics (QM/MM) simulations of the reaction mechanism suggest that the polarizing effect of glutamine enhances catalytic activity by forming a stabilizing network of hydrogen bonds with pNPA, leading to lower energy barriers and a more exergonic reaction. Our findings provide valuable insights into the intricate interplay between peptide sequence, structural arrangement, and catalytic function in amyloid-based enzymes, offering potentially valuable information for the design and optimization of biomimetic catalysts.

Incidence of anastomotic leakage using powered circular staplers versus manual circular staplers for left colorectal anastomosis: a cost-effectiveness analysis.

BACKGROUND: Colorectal anastomotic leakage causes severe consequences for patients and healthcare system as it will lead to increased consumption of hospital resources and costs. Technological improvements in anastomotic devices could reduce the incidence of leakage and its economic impact. The aim of the present study was to assess if the use of a new powered circular stapler is cost-effective. METHOD: This observational study included patients undergoing left-sided circular stapled colorectal anastomosis between January 2018 and December 2021. Propensity score matching was carried out to create two comparable groups depending on whether the anastomosis was performed using a manual or powered circular device. The rate of anastomotic leakage, its severity, the consumption of hospital resources, and its cost were the main outcome measures. A cost-effectiveness analysis comparing the powered circular stapler versus manual circular staplers was performed. RESULTS: A total of 330 patients were included in the study, 165 in each group. Anastomotic leakage rates were significantly different (p = 0.012): 22 patients (13.3%) in the manual group versus 8 patients (4.8%) in the powered group. The effectiveness of the powered stapler and manual stapler was 98.27% and 93.69%, respectively. The average cost per patient in the powered group was €6238.38, compared with €9700.12 in the manual group. The incremental cost-effectiveness ratio was - €74,915.28 per patient without anastomotic complications. CONCLUSION: The incremental cost of powered circular stapler compared with manual devices was offset by the savings from lowered incidence and cost of management of anastomotic leaks.

Systematic review of machine-learning models in orthopaedic trauma.

Aims: Machine-learning (ML) prediction models in orthopaedic trauma hold great promise in assisting clinicians in various tasks, such as personalized risk stratification. However, an overview of current applications and critical appraisal to peer-reviewed guidelines is lacking. The objectives of this study are to 1) provide an overview of current ML prediction models in orthopaedic trauma; 2) evaluate the completeness of reporting following the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) statement; and 3) assess the risk of bias following the Prediction model Risk Of Bias Assessment Tool (PROBAST) tool. Methods: A systematic search screening 3,252 studies identified 45 ML-based prediction models in orthopaedic trauma up to January 2023. The TRIPOD statement assessed transparent reporting and the PROBAST tool the risk of bias. Results: A total of 40 studies reported on training and internal validation; four studies performed both development and external validation, and one study performed only external validation. The most commonly reported outcomes were mortality (33%, 15/45) and length of hospital stay (9%, 4/45), and the majority of prediction models were developed in the hip fracture population (60%, 27/45). The overall median completeness for the TRIPOD statement was 62% (interquartile range 30 to 81%). The overall risk of bias in the PROBAST tool was low in 24% (11/45), high in 69% (31/45), and unclear in 7% (3/45) of the studies. High risk of bias was mainly due to analysis domain concerns including small datasets with low number of outcomes, complete-case analysis in case of missing data, and no reporting of performance measures. Conclusion: The results of this study showed that despite a myriad of potential clinically useful applications, a substantial part of ML studies in orthopaedic trauma lack transparent reporting, and are at high risk of bias. These problems must be resolved by following established guidelines to instil confidence in ML models among patients and clinicians. Otherwise, there will remain a sizeable gap between the development of ML prediction models and their clinical application in our day-to-day orthopaedic trauma practice.

Systematic review of motivational interventions to improve adherence to medication in patients with hypertension and meta-analysis / Revisión sistemática de intervenciones motivacionales para mejorar la adherencia a la medicación en pacientes con hipertensión y metanálisis

Introduction: Antihypertensive medication non-adherence is an important cause of poor control in hypertension. The role of motivational interventions to increase antihypertensive medication adherence remains unclear. Objective: To systematically review RCTs of motivational interventions for improving medication adherence in hypertension. Methods: EMBASE and Pubmed were searched from inception to February 2019 for RCTs of motivational interventions for improving medication adherence in hypertension vs. usual care. Inclusion criteria: RCTs with motivational intervention to improve medication adherence in adults with hypertension. A blinded review was conducted by 2 reviewers. Disagreements were resolved by consensus/a third reviewer. Data extraction and quality appraisal was performed using the risk of bias tool from cochrane collaboration. The meta-analyses of blood pressure control used random-effects models to report mean difference and 95% CIs. Primary outcome was medication adherence and second outcome was blood pressure control. Results: The search methodology yielded 10 studies comprising 1171 participants. Medication adherence improved significantly in 5 studies. We could not perform pool analysis for this outcome due to different measurements of medication adherence. Seven trials reported significant results regarding blood pressure control. On pooled analysis, motivational interventions were not significantly associated with a systolic blood pressure (mean difference, −0.06; 95% CI, −0.05 to 0.18; p=0.63; I2=0.0%) or diastolic blood pressure (mean difference, −0.11; 95% CI, −0.10 to 0.31; p=0.28; I2=23.8%) decrease or blood pressure control. (AU)

Introducción: La falta de adherencia a la terapia farmacológica es una de las principales razones del descontrol de la hipertensión arterial. Se desconoce el papel de las intervenciones motivacionales en el aumento de la adherencia. Objetivo: Realizar una revisión sistemática de ensayos clínicos aleatorizados (ECA) dirigidos a mejorar la adherencia a la medicación en hipertensión arterial. Métodos: Se buscaron ECA de intervenciones motivacionales vs. atención habitual en las bases de datos Embase y PubMed desde su inicio hasta febrero de 2019. Criterios de inclusión: ECA de intervenciones motivacionales para aumentar la adherencia a la terapia con medicamentos en adultos con hipertensión. Dos revisores realizaron una revisión ciega y sus desacuerdos se resolvieron por consenso/por un tercer revisor. La extracción de datos y la evaluación de la calidad se realizaron mediante la herramienta Cochrane de evaluación del riesgo de sesgo. El metaanálisis del control de la presión arterial utilizó modelos de efectos aleatorios para informar la diferencia en las medias y los intervalos de confianza de 95% (IC 95%). El outcome primario fue la adherencia a la medicación y el secundario fue el control de la presión arterial. Resultados: Se obtuvieron 10 estudios con 1.171 participantes. La adherencia mejoró significativamente en cinco estudios. No fue posible realizar un análisis agrupado de la adherencia debido al uso de diferentes medidas de cumplimiento. Siete estudios mostraron una diferencia significativa en el control de la presión arterial. En el análisis conjunto, las intervenciones motivacionales no se asociaron a una disminución significativa de la presión arterial sistólica (diferencia de medias, -0,06; IC 95%, -0,05-0,18; p=0,63; I2=0%) o de la presión arterial diastólica (diferencia de medias, -0,11; IC 95%, -0,10-0,31; p=0,28; I2=23,8%) o a mejora en control de la misma.(AU)

Heart transplantation in patients with anthracycline-induced cardiomyopathy / Trasplante cardiaco en pacientes con cardiotoxicidad inducida por antraciclinas

Abstract Objective: The objective of this study was to describe the clinical and imaging characteristics and the evolution of heart transplantation patients due to anthracycline-induced cardiomyopathy Methods: Patients with a diagnosis of ACM who received a heart transplantation in our institution in the period of November 2009-April 2021 were included. Clinical characteristics, pre-transplant studies, and clinical outcomes after transplantation were collected retrospectively from the electronic medical record. Results: A total of 11 patients were included in the study. The median age at the time of cancer diagnosis was 15 years (IQR 10-37 years), while the median age at the time of heart transplant was 56 years (IQR 39-62 years). Regarding post-transplant outcomes, three patients died in the post-operative period. One died 4 years after the intervention due to chronic rejection, while the other seven had a favorable evolution. No oncological relapse was observed with a median follow-up of 2.5 years (IQR 1.86-3.85 years). Conclusion: End-stage anthracycline-induced cardiomyopathy can occur many years after chemotherapy treatment, so close cardiovascular follow-up is extremely important. Heart transplantation is a treatment option after an exhaustive multidisciplinary evaluation, to minimize the risk of oncological relapse.

Resumen Objetivo: Describir las características clínicas, imagenológicas y la evolución de los pacientes trasplantados cardiacos por cardiotoxicidad inducida por antraciclinas. Métodos: Serie de casos descriptiva de pacientes consecutivos trasplantados cardiacos debido a cardiotoxicidad mediada por antraciclinas en el periodo de Noviembre de 2009 a Abril de 2021.Las características clínicas, los estudios complementarios pretrasplante y la información sobre la evolución posterior al trasplante fue recolectada de la historia clínica electrónica de forma retrospectiva. Resultados: Se incluyeron un total de 11 pacientes. La mediana de edad al diagnóstico de la patología oncológica fue de 15 años (RIC 10-37 años), mientras que la mediana de edad en la que recibieron el trasplante cardiaco fue de 56 años (RIC 39-62 años). Con respecto a la evolución posterior al trasplante, 3 pacientes murieron en el periodo del post operatorio inmediato. 1 paciente falleció a los 4 años del trasplante y los otros 7 pacientes tuvieron una evolución favorable. No se observó recaída oncológica en ningún paciente durante una mediana de seguimiento o de 2,5 años (RIC 1.86-3.85 años). Conclusión: La etapa final de la miocardiopatía inducida por antraciclinas puede ocurrir muchos años después del tratamiento con quimioterapia, por lo que es extremadamente importante un seguimiento cardiológico estricto. El trasplante cardiaco es una opción en este grupo de pacientes luego de una exhaustiva evaluación multidisciplinaria, con el fin de minimizar el riesgo de recaída oncológica.

Heart transplantation in patients with anthracycline-induced cardiomyopathy.

OBJECTIVE: The objective of this study was to describe the clinical and imaging characteristics and the evolution of heart transplantation patients due to anthracycline-induced cardiomyopathy. METHODS: Patients with a diagnosis of ACM who received a heart transplantation in our institution in the period of November 2009-April 2021 were included. Clinical characteristics, pre-transplant studies, and clinical outcomes after transplantation were collected retrospectively from the electronic medical record. RESULTS: A total of 11 patients were included in the study. The median age at the time of cancer diagnosis was 15 years (IQR 10-37 years), while the median age at the time of heart transplant was 56 years (IQR 39-62 years). Regarding post-transplant outcomes, three patients died in the post-operative period. One died 4 years after the intervention due to chronic rejection, while the other seven had a favorable evolution. No oncological relapse was observed with a median follow-up of 2.5 years (IQR 1.86-3.85 years). CONCLUSION: End-stage anthracycline-induced cardiomyopathy can occur many years after chemotherapy treatment, so close cardiovascular follow-up is extremely important. Heart transplantation is a treatment option after an exhaustive multidisciplinary evaluation, to minimize the risk of oncological relapse.

OBJETIVO: Describir las características clínicas, imagenológicas y la evolución de los pacientes trasplantados cardiacos por cardiotoxicidad inducida por antraciclinas. MÉTODOS: Serie de casos descriptiva de pacientes consecutivos trasplantados cardiacos debido a cardiotoxicidad mediada por antraciclinas en el periodo de Noviembre de 2009 a Abril de 2021.Las características clínicas, los estudios complementarios pretrasplante y la información sobre la evolución posterior al trasplante fue recolectada de la historia clínica electrónica de forma retrospectiva. RESULTADOS: Se incluyeron un total de 11 pacientes. La mediana de edad al diagnóstico de la patología oncológica fue de 15 años (RIC 10-37 años), mientras que la mediana de edad en la que recibieron el trasplante cardiaco fue de 56 años (RIC 39-62 años). Con respecto a la evolución posterior al trasplante, 3 pacientes murieron en el periodo del post operatorio inmediato. 1 paciente falleció a los 4 años del trasplante y los otros 7 pacientes tuvieron una evolución favorable. No se observó recaída oncológica en ningún paciente durante una mediana de seguimiento o de 2,5 años (RIC 1.86-3.85 años). CONCLUSIÓN: La etapa final de la miocardiopatía inducida por antraciclinas puede ocurrir muchos años después del tratamiento con quimioterapia, por lo que es extremadamente importante un seguimiento cardiológico estricto. El trasplante cardiaco es una opción en este grupo de pacientes luego de una exhaustiva evaluación multidisciplinaria, con el fin de minimizar el riesgo de recaída oncológica.

Sequencing paired tumor DNA and white blood cells improves circulating tumor DNA tracking and detects pathogenic germline variants in localized colon cancer.

BACKGROUND: In the setting of localized colon cancer (CC), circulating tumor DNA (ctDNA) monitoring in plasma has shown potential for detecting minimal residual disease (MRD) and predicting a higher risk of recurrence. With the tumor-only sequencing approach, however, germline variants may be misidentified as somatic variations, precluding the possibility of tracking in up to 11% of patients due to a lack of known somatic mutations. In this study, we assess the potential value of adding white blood cells (WBCs) to tumor tissue sequencing to enhance the accuracy of sequencing results. PATIENTS AND METHODS: A total of 148 patients diagnosed with localized CC were prospectively recruited at the Hospital Clínico Universitario in Valencia (Spain). Employing a custom 29-gene panel, sequencing was conducted on tumor tissue, plasma and corresponding WBCs. Droplet digital PCR and amplicon-based NGS were performed on plasma samples post-surgery to track MRD. Oncogenic somatic variants were identified by annotating with COSMIC, OncoKB and an internal repository of pathogenic mutations database. A variant prioritization analysis, mainly characterized by the match of oncogenic mutations with the evidence levels defined in OncoKB, was carried out to select specific targeted therapies. RESULTS: Utilizing paired tumor and WBCs sequencing, we identified somatic mutations in all patients (100%) within our cohort, compared to 89% using only tumor tissue. Consequently, the top 10 most frequently mutated genes for plasma monitoring were altered. The sequencing of WBCs identified 9% of patients with pathogenic mutations in the germline, with APC and TP53 being the most frequently mutated genes. Additionally, mutations in genes related to clonal hematopoiesis of indeterminate potential were detected in 27% of the cohort, with TP53, KRAS, and KMT2C being the most frequently altered genes. There were no observed differences in the sensitivity of monitoring MRD using ddPCR or amplicon-based NGS (p = 1). Ultimately, 41% of the patients harbored potentially targetable alterations at diagnosis. CONCLUSION: The germline testing method not only enhanced sequencing results and raised the proportion of patients eligible for plasma monitoring, but also uncovered the existence of pathogenic germline variations, thereby aiding in the identification of patients at a higher risk of hereditary cancer syndromes.

Granulin loss of function in human mature brain organoids implicates astrocytes in TDP-43 pathology.

Loss of function (LoF) of TAR-DNA binding protein 43 (TDP-43) and mis-localization, together with TDP-43-positive and hyperphosphorylated inclusions, are found in post-mortem tissue of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, including those carrying LoF variants in the progranulin gene (GRN). Modeling TDP-43 pathology has been challenging in vivo and in vitro. We present a three-dimensional induced pluripotent stem cell (iPSC)-derived paradigm-mature brain organoids (mbOrg)-composed of cortical-like-astrocytes (iA) and neurons. When devoid of GRN, mbOrgs spontaneously recapitulate TDP-43 mis-localization, hyperphosphorylation, and LoF phenotypes. Mixing and matching genotypes in mbOrgs showed that GRN-/- iA are drivers for TDP-43 pathology. Finally, we rescued TDP-43 LoF by adding exogenous progranulin, demonstrating a link between TDP-43 LoF and progranulin expression. In conclusion, we present an iPSC-derived platform that shows striking features of human TDP-43 proteinopathy and provides a tool for the mechanistic modeling of TDP-43 pathology and patient-tailored therapeutic screening for FTD and ALS.