Influence of Obesity on the Efficacy and Toxicity of Patients Undergoing Autologous Hematopoietic Cell Transplantation for Lymphoma.

Hematopoietic cell transplantation requires higher doses of chemotherapy, and practices of adjusting the weight because of concerns of organ toxicity are common. This retrospective analysis of 239 adult recipients of autologous hematopoietic cell transplantation for lymphoma assessed the effect of obesity on transplantation outcomes. BACKGROUND: Prior data evaluating the impact of obesity in autologous hematopoietic cell transplantation (AHCT) for lymphomas have provided differing results when assessing overall (OS) and progression-free survival (PFS). Impact on survival outcomes have been described, but direct comparison of discrete toxicities is lacking. PATIENTS AND METHODS: We retrospectively compared outcomes with patients divided between 3 groups: nonobese patients (n = 129), obese patients dosed on adjusted body weight (AdjBW) (n = 32), and obese patients dosed on total body weight (TBW) (n = 78). RESULTS: In multivariate analysis of OS with the nonobese group as the comparator, outcomes trended worse in obese patients dosed on AdjBW (HR 1.22, 95% CI 0.52-2.85) but were improved in obese patients dosed on TBW (HR 0.19, 95% CI 0.04-0.85, P = .012). PFS of obese patients dosed on AdjBW vs. the nonobese group was comparable (HR 1.19, 95% CI 0.63-2.24), but improved in obese patients dosed on TBW (HR 0.45, 95% CI 0.23-0.89, P = .021). Notably, no differences were noted between groups in gastrointestinal, infectious, renal, or hepatic toxicities. CONCLUSION: In summary, our data suggest that recipients of AHCT for lymphoma should be dosed on TBW to maximize curative outcomes with no apparent increase in toxicities.

Catheter Ablation versus Advanced Therapy for Patients with Severe Heart Failure and Ventricular Electrical Storm.

BACKGROUND: Current data on outcomes of an initial strategy of catheter ablation versus advanced therapy in patients with severe HF and ES are limited. OBJECTIVE: To evaluate the outcomes of ventricular tachycardia (VT) ablation versus left ventricular assist device (LVAD) or heart transplantation (HT) in patients with severe heart failure (HF) and ventricular electric storm (ES). METHODS: Patients with severe HF and ES who underwent VT ablation, LVAD, or HT between 2012 and 2022 at our medical center were reviewed. Severe HF was defined as ejection fraction ≤ 35% or presence of severe restrictive, valvular or genetic cardiomyopathy. We assessed in-hospital adverse events and one-year outcomes between the two groups. RESULTS: Of 73 patients, 43 underwent VT ablation and 30 received advanced therapy (21 HT and 9 LVAD). One-year survival was similar (76.7% vs 86.7%, log-rank p = 0.308). However, 10 patients (23.3%) in the ablation group underwent HT during follow up. After multivariable analysis, UNOS status 1 or 2 by VT criteria (HR 5.52, 95% CI: 1.27-24.12; p = 0.023) and early VT recurrence (HR 5.67, 95% CI: 1.68-19.09; p = 0.005) were associated with HT or mortality in patients who underwent VT ablation. CONCLUSION: Patients with severe HF and ES who underwent VT ablation had similar overall survival as patients who directly proceeded with advanced therapy, although rates of HT were high during follow up. Predictors of HT or mortality after catheter ablation include UNOS status 1 or 2 by VT criteria and early VT recurrence.

Sleep disruption in patients with active and treated endogenous Cushing's syndrome.

CONTEXT: The hypothalamic-pituitary-adrenal axis is a critical regulator of circadian rhythm in humans. Impaired sleep adversely affects metabolic, emotional, and cognitive health. OBJECTIVE: To characterize sleep disturbances in patients with active and treated Cushing's syndrome (CS), and identify factors associated with impaired sleep in treated patients. DESIGN: Single-center cross-sectional study. METHODS: Patients with pituitary or adrenal CS enrolled in an observational study completed Nottingham Health Profile (NHP), CushingQoL, and Hospital Anxiety and Depression assessments. Cross-sectional analysis was conducted including patients with active and treated disease. RESULTS: 113 (94 female) patients with CS were included, 104 pituitary and 9 adrenal, with mean age at diagnosis of 43.9 ± 13.4 years. Mean and maximum duration of follow up was 5.1 and 23 years. Mean NHP sleep score was lower (i.e., improved) in patients with treated vs. active disease (29.6 ± 30.2 vs. 51.9 ± 30.9, p = 0.0005), as was CushingQoL sleep score (p = 0.015), but 41.5% of patients with treated disease stated they often or always had trouble sleeping. The proportion of treated vs. active patients taking medication for sleep, mood, or pain was not different. Neither NHP nor CushingQoL pain scores were lower in treated vs. active patients (p = 0.39 and 0.53). In patients with treated CS, anxiety and depression correlated with worse sleep scores. CONCLUSIONS: Patients with treated CS report improved sleep quality compared to those with active disease, but almost half of treated patients still report sleep challenges. The need for sleep medications, reported by one third of patients, was not different after CS treatment. Ongoing mood disturbances may play a role in persistent sleep disruption. Further work should focus on determinants of sleep impairments in treated CS patients.

Isatuximab for Delayed Red Cell Engraftment after Allogeneic Hematopoietic Cell Transplantation.

Isatuximab is an IgG1κ-derived monoclonal antibody against CD38 approved for the treatment of adult patients with multiple myeloma. Here we describe the successful treatment of a therapy-refractory pure red cell aplasia case following ABO-mismatched allogeneic stem cell transplantation with isatuximab. Our patient was a 75-year-old female with acute myeloid leukemia who received an HLA-B antigen mismatched, unrelated peripheral blood stem cell transplant with a major ABO incompatibility (blood group A+ in the donor and blood group O+ in the recipient). The patient developed persistent red cell aplasia and anti-A antibodies for more than 500 days from transplant. She received therapy with rituximab, bortezomib, prednisone, and darbepoetin alfa with partial to no response. After repeated insurance denials for daratumumab, isatuximab was obtained from the manufacturer through their CareASSIST program. Following the completion of 2 cycles of isatuximab (8 doses), significant and sustained red cell recovery was observed.

Coronary Artery Calcium Density and Risk of Cardiovascular Events: A Systematic Review and Meta-Analysis.

BACKGROUND: There is increasing evidence that coronary artery calcium (CAC) density is inversely associated with plaque vulnerability and atherosclerotic cardiovascular disease risk. OBJECTIVES: A systematic review and meta-analysis were performed to examine the predictive value of CAC density for future cardiovascular events in asymptomatic individuals undergoing noncontrast CAC scoring computed tomography. METHODS: Electronic databases were searched for studies reporting CAC density and subsequent cardiovascular disease (CVD) or coronary heart disease (CHD) events. Two independent reviewers performed data extraction. Random-effects models were used to estimate pooled HRs and 95% CIs. Subgroup analyses were performed with studies stratified by CVD vs CHD events and by statin use. RESULTS: Of 5,029 citations, 5 studies with 6 cohorts met inclusion criteria. In total, 1,309 (6.1%) cardiovascular events occurred in 21,346 participants with median follow-up ranging from 5.2 to 16.7 years. Higher CAC density was inversely associated with risk of cardiovascular events following adjustment for clinical risk factors and CAC volume (HR: 0.80 per SD of density [95% CI: 0.72-0.89]; P < 0.01; I2 = 0%). There was no significant difference in the pooled HRs for CVD vs CHD events (HR: 0.80 per SD [95% CI: 0.71-0.90] vs 0.74 per SD [95% CI: 0.59-0.94] respectively; P = 0.59). The protective association between CAC density and event risk persisted among statin-naive patients (HR: 0.79 per SD [95% CI: 0.70-0.89]; P < 0.01) but not statin-treated patients (HR: 0.97 per SD [95% CI: 0.77-1.22]; P = 0.78); the test for interaction indicated no significant between-group differences (P = 0.12). CONCLUSIONS: Higher CAC density is associated with a lower risk of cardiovascular events when adjusted for risk factors and CAC volume. Future work may expand the contribution of CAC density in CAC scoring, and enhance its role in CVD risk assessment, treatment, and prevention.

Developing an image-based grading scale for peripheral drusen to investigate associations of peripheral drusen type with age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of blindness. It is associated with peripheral drusen which has not been categorized. We investigated peripheral drusen to validate an image grading system and to understand possible associations between peripheral drusen and AMD. We collated clinical data, ultra-widefield (UWF) pseudocolor fundus images and Spectral-Domain Optical Coherence Tomography (SD-OCT) scans from consecutive retinal patients. SD-OCT scans were used to determine AMD stage. A masked retinal specialist recorded the types of peripheral drusen observed in UWF images. Eyes whose UWF images did not pass quality screening and those without AMD and peripheral drusen were excluded from the study. Statistical tests were utilized to determine the validity of our grading system and associations of peripheral drusen with AMD. A total of 481 eyes (283 subjects) were included in the study (mean age 73.1 ± 1.2years, 64.3% female). Interobserver and test-retest statistical analyses to evaluate the UWF image grading system resulted in Cohen's Kappa 0.649 (p < 0.001) and 0.922 (p < 0.001) respectively. A total of 284 (59.0%), 28 (5.8%), 15 (3.1%), 22 (4.6%), 4 (0.8%), 39 (8.1%), and 32 (6.7%) eyes had hard, soft, reticular, cuticular, atrophic, mixed drusen, and mixed drusen and atrophy respectively in at least one peripheral retinal quadrant. Hard peripheral drusen was significantly associated with the presence of AMD (p = 0.010). Peripheral drusen types were variably seen in retinal patients with and without AMD. We validated a peripheral drusen grading system and provided an image library to assist in the identification of peripheral drusen. Our study found an association between peripheral hard drusen and an AMD diagnosis but did not find a link between peripheral drusen and severity of AMD.

Evaluation of Retinal Arterial Occlusion and its Visual and Systemic Prognosis after Hyperbaric Oxygen Therapy.

PURPOSE: To evaluate the systemic and ocular outcomes of patients with branch retinal artery occlusion (BRAO) and central retinal artery occlusion (CRAO) after hyperbaric oxygen therapy (HBOT). METHODS: This is a single-institution study of 75 subjects diagnosed with BRAO (28, 37.3%) and CRAO (47, 62.7%) who visited the emergency department or stroke clinic. Twenty-seven (36%) subjects received HBOT on initial presentation (BRAO-14.3%, CRAO-48.9%). The primary outcome was the best corrective visual acuity (BCVA) change in non-HBOT and HBOT subjects. Secondary outcomes included subsequent development of an acute cerebrovascular accident (CVA)/stroke or neovascular glaucoma (NVG). RESULTS: Overall BCVA did not change from the initial presentation to the final timepoint (logMAR 1.5) in either the conservative management or HBOT cohorts for either BRAO subjects (non-HBOT-logMAR 0.4 vs. 0.6, p=0.658; HBOT-logMAR 0.1 vs. 0.4, p=0.207) or CRAO subjects (non-HBOT-logMAR 2.1 vs. 2.2, p=0.755; HBOT-logMAR 2.1 vs. 2.0, p=0.631). Seven (9.3%) subjects developed CVA (BRAO: non-HBOT-4.2% and HBOT-25.0%, p=0.207; CRAO: non-HBOT-16.7% and HBOT-4.3%, p=0.348) and five subjects (6.7%) developed NVG (BRAO: non-HBOT-4.2% and HBOT-0%, p=1.00; CRAO: non-HBOT-16.7% and HBOT-0%, p=0.109). CONCLUSIONS: Our findings suggest that HBOT does not significantly improve BCVA or mitigate the subsequent development of stroke and NVG in patients with RAOs.

Mating proximity blinds threat perception.

Romantic engagement can bias sensory perception. This 'love blindness' reflects a common behavioural principle across organisms: favouring pursuit of a coveted reward over potential risks1. In the case of animal courtship, such sensory biases may support reproductive success but can also expose individuals to danger, such as predation2,3. However, how neural networks balance the trade-off between risk and reward is unknown. Here we discover a dopamine-governed filter mechanism in male Drosophila that reduces threat perception as courtship progresses. We show that during early courtship stages, threat-activated visual neurons inhibit central courtship nodes via specific serotonergic neurons. This serotonergic inhibition prompts flies to abort courtship when they see imminent danger. However, as flies advance in the courtship process, the dopaminergic filter system reduces visual threat responses, shifting the balance from survival to mating. By recording neural activity from males as they approach mating, we demonstrate that progress in courtship is registered as dopaminergic activity levels ramping up. This dopamine signalling inhibits the visual threat detection pathway via Dop2R receptors, allowing male flies to focus on courtship when they are close to copulation. Thus, dopamine signalling biases sensory perception based on perceived goal proximity, to prioritize between competing behaviours.

Clinical Significance of Myocardial Injury in Patients Hospitalized for COVID-19: A Prospective, Multicenter, Cohort Study.

BACKGROUND: Hospitalized COVID-19 patients with troponin elevation have a higher prevalence of cardiac abnormalities than control individuals. However, the progression and impact of myocardial injury on COVID-19 survivors remain unclear. OBJECTIVES: This study sought to evaluate myocardial injury in COVID-19 survivors with troponin elevation with baseline and follow-up imaging and to assess medium-term outcomes. METHODS: This was a prospective, longitudinal cohort study in 25 United Kingdom centers (June 2020 to March 2021). Hospitalized COVID-19 patients with myocardial injury underwent cardiac magnetic resonance (CMR) scans within 28 days and 6 months postdischarge. Outcomes were tracked for 12 months, with quality of life surveys (EuroQol-5 Dimension and 36-Item Short Form surveys) taken at discharge and 6 months. RESULTS: Of 342 participants (median age: 61.3 years; 71.1% male) with baseline CMR, 338 had a 12-month follow-up, 235 had a 6-month CMR, and 215 has baseline and follow-up quality of life surveys. Of 338 participants, within 12 months, 1.2% died; 1.8% had new myocardial infarction, acute coronary syndrome, or coronary revascularization; 0.8% had new myopericarditis; and 3.3% had other cardiovascular events requiring hospitalization. At 6 months, there was a minor improvement in left ventricular ejection fraction (1.8% ± 1.0%; P < 0.001), stable right ventricular ejection fraction (0.4% ± 0.8%; P = 0.50), no change in myocardial scar pattern or volume (P = 0.26), and no imaging evidence of continued myocardial inflammation. All pericardial effusions (26 of 26) resolved, and most pneumonitis resolved (95 of 101). EuroQol-5 Dimension scores indicated an overall improvement in quality of life (P < 0.001). CONCLUSIONS: Myocardial injury in severe hospitalized COVID-19 survivors is nonprogressive. Medium-term outcomes show a low incidence of major adverse cardiovascular events and improved quality of life. (COVID-19 Effects on the Heart; ISRCTN58667920).

Retinal structural changes after cessation of pentosan polysulfate sodium.

PURPOSE: To quantify baseline and longitudinal structural changes post-cessation in pentosan polysulfate sodium (PPS) retinopathy patients. METHODS: This is a retrospective cohort study. Retinal thickness and volume of choroidal and hyperreflective retinal pigment epithelium (RPE) excrescences were manually segmented from optical coherence tomography (OCT) volume scans. Baseline measurements were compared against age-matched controls. Longitudinal measurements were performed on patients with follow-up data. RESULTS: Twenty-four eyes of 13 patients were included. At baseline, the mean total retinal thickness was lower in the PPS retinopathy cohort than in age and sex-matched controls (269.1 µm vs. 290.2 µm, p = 0.006).The median (range) of follow-up was 18.6 (4.1 to 34.7) months, with the mean last follow-up of 35.2 months after cessation. During the follow-up period, the thickness of the retina decreased significantly by 11.3 µm (CI: 16.8, 5.8) (p<0.001), with an annual mean decrease of 6.70 µm. However, the mean hyperreflective RPE excrescence volume did not change significantly (p = 0.140) over the follow-up period. CONCLUSIONS: Following PPS discontinuation, although RPE excrescence volumes do not change significantly in volume, there continues to be a progressive long-term thinning of the retina which continues at a rate greater than that associated with normal aging. Consequently, long-term follow-up is suggested to monitor patients with PPS maculopathy.

Protocol and rationale of the Australian multicentre registry for serial cardiac computed tomography angiography (ARISTOCRAT): a prospective observational study of the natural history of pericoronary adipose tissue attenuation and radiomics.

Background: Vascular inflammation plays a crucial role in the development of atherosclerosis and atherosclerotic plaque rupture resulting in acute coronary syndrome (ACS). Pericoronary adipose tissue (PCAT) attenuation quantified from routine coronary computed tomography angiography (CCTA) has emerged as a promising non-invasive imaging biomarker of coronary inflammation. However, a detailed understanding of the natural history of PCAT attenuation is required before it can be used as a surrogate endpoint in trials of novel therapies targeting coronary inflammation. This article aims to explore the natural history of PCAT attenuation and its association with changes in plaque characteristics. Methods: The Australian natuRal hISTOry of periCoronary adipose tissue attenuation, RAdiomics and plaque by computed Tomographic angiography (ARISTOCRAT) registry is a multi-centre observational registry enrolling patients undergoing clinically indicated serial CCTA in 9 centres across Australia. CCTA scan parameters will be matched across serial scans. Quantitative analysis of plaque and PCAT will be performed using semiautomated software. Discussion: The primary endpoint is to explore temporal changes in patient-level and lesion-level PCAT attenuation by CCTA and their associations with changes in plaque characteristics. Secondary endpoints include evaluating: (I) impact of statin therapy on PCAT attenuation and plaque characteristics; and (II) changes in PCAT attenuation and plaque characteristics in specific subgroups according to sex and risk factors. ARISTOCRAT will further our understanding of the natural history of PCAT attenuation and its association with changes in plaque characteristics. Trial Registration: This study has been prospectively registered with the Australia and New Zealand Clinical Trials Registry (ACTRN12621001018808).

The Next Frontier in Tuberculosis Investigation: Automated Whole Genome Sequencing for Mycobacterium tuberculosis Analysis.

A fully automated bacteria whole genome sequencing (WGS) assay was evaluated to characterize Mycobacterium tuberculosis (MTB) and non-tuberculosis Mycobacterium (NTM) clinical isolates. The results generated were highly reproducible, with 100% concordance in species and sub-lineage classification and 92% concordance between antimicrobial resistance (AMR) genotypic and phenotypic profiles. Using extracted deoxyribonucleic acid (DNA) from MTB clinical isolates as starting material, these findings demonstrate that a fully automated WGS assay, with a short turnaround time of 24.5 hours, provides timely and valuable insights into MTB outbreak investigation while providing reliable genotypic AMR profiling consistent with traditional antimicrobial susceptibility tests (AST). This study establishes a favorable proposition for the adoption of end-to-end fully automated WGS solutions for decentralized MTB diagnostics, thereby aiding in World Health Organization's (WHO) vision of tuberculosis eradication.

A Phase II Study Assessing Long-term Response to Ibrutinib Monotherapy in Recurrent or Refractory CNS Lymphoma.

PURPOSE: Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase. We previously reported the safety and short-term antitumor activity of ibrutinib in 20 patients with relapsed or refractory (r/r) primary central nervous system (CNS) lymphoma (PCNSL) or secondary CNS lymphoma (SCNSL). PATIENTS AND METHODS: We enrolled 26 additional patients with r/r PCNSL/SCNSL into the dose-expansion cohort of the trial into a combined cohort of 46 patients (31 with PCNSL and 15 with SCNSL). Patients received ibrutinib at 560 or 840 mg daily in the dose-escalation cohort and ibrutinib at 840 mg daily in the expansion cohort. The median follow-up was 49.9 and 62.1 months for patients with PCNSL and SCNSL, respectively. We sequenced DNA from available tumor biopsies and cerebrospinal fluid collected before and during ibrutinib therapy. RESULTS: Tumor responses were observed in 23/31 (74%) patients with PCNSL and 9/15 (60%) patients with SCNSL, including 12 complete responses in PCNSL and 7 in SCNSL. The median progression-free survival (PFS) for PCNSL was 4.5 months [95% confidence interval (CI), 2.8-9.2] with 1-year PFS at 23.7% (95% CI, 12.4%-45.1%). The median duration of response in the 23 PCNSL responders was 5.5 months. The median PFS in SCNSL was 5.3 months (95% CI, 1.3-14.5) with a median duration of response of 8.7 months for the 9 responders. Exploratory biomarker analysis suggests that mutations in TBL1XR1 may be associated with a long-term response to ibrutinib in PCNSL (P = 0.0075). Clearance of ctDNA from cerebrospinal fluid was associated with complete and long-term ibrutinib responses. CONCLUSIONS: Our study confirms single-agent activity of ibrutinib in r/r CNS lymphoma and identifies molecular determinants of response based on long-term follow-up.

Distributed Maritime Operations and the Medical Challenge: How a Medical Common Operating Picture Can Help Bridge the Gap.

This work explores the challenges of delivering medical care in the geographically dispersed and resource-constrained environment of Distributed Maritime Operations (DMO) and Expeditionary Advanced Base Operations (EABO). Traditional medical planning approaches may struggle to adapt to the vast operational space, extended evacuation times, and limited medical force present in these scenarios. The concept of a Medical Common Operating Picture (COP) emerges as a potential solution. By providing a shared view of the medical situation across the theater, encompassing logistics, personnel, and patient data, a medical COP has the potential to facilitate medical command and control (MED C2) in DMO/EABO. The implementation of a medical COP has the potential to optimize resource allocation, enhance situational awareness, streamline medical evacuation, and reduce healthcare provider moral injury in large-scale combat operations. A medical COP will allow medical planners to make informed decisions on triage, resupply, and evacuation, ensuring the best use of limited medical resources. This is done by leveraging a comprehensive understanding of the medical landscape, enabling informed clinical and operational decision-making by humanitarian and combat personnel respectively. A fully realized medical COP system will enable a dynamic theater evacuation policy, balancing the conflicting needs of patient care at higher echelons with the operational expediency of returning servicemembers to their operational units, thereby maximizing evacuation effectiveness. It will further enable medical personnel to perform dynamic casualty triage based on operational realities, mitigating potential ethical dilemmas. Implementing such a medical COP system will require overcoming communication limitations to facilitate data exchange and potentially integrating clinical decision support tools for real-time data analysis and recommendations. It will also require the rapid adoption of modernized operational medicine documentation solutions by medical assets within the operational forces. Ultimately, this work suggests that a medical COP has the potential to bridge the gap between traditional medical planning and the unique demands of DMO/EABO, ultimately optimizing casualty care, maximizing resource efficiency, and preserving the fighting force.

Sensory encoding and memory in the mushroom body: signals, noise, and variability.

To survive in changing environments, animals need to learn to associate specific sensory stimuli with positive or negative valence. How do they form stimulus-specific memories to distinguish between positively/negatively associated stimuli and other irrelevant stimuli? Solving this task is one of the functions of the mushroom body, the associative memory center in insect brains. Here we summarize recent work on sensory encoding and memory in the Drosophila mushroom body, highlighting general principles such as pattern separation, sparse coding, noise and variability, coincidence detection, and spatially localized neuromodulation, and placing the mushroom body in comparative perspective with mammalian memory systems.

Ultrasensitive quantification of PD-L1+ extracellular vesicles in melanoma patient plasma using a parallelized high throughput droplet digital assay.

The expression of programmed death-ligand 1 (PD-L1) on extracellular vesicles (EVs) is an emerging biomarker for cancer, and has gained particular interest for its role mediating immunotherapy. However, precise quantification of PD-L1+ EVs in clinical samples remains challenging due to their sparse concentration and the enormity of the number of background EVs in human plasma, limiting applicability of conventional approaches. In this study, we develop a high-throughput droplet-based extracellular vesicle analysis (DEVA) assay for ultrasensitive quantification of EVs in plasma that are dual positive for both PD-L1 and tetraspanin (CD81) known to be expressed on EVs. We achieve a performance that significantly surpasses conventional approaches, demonstrating 360× enhancement in the limit of detection (LOD) and a 750× improvement in the limit of quantitation (LOQ) compared to conventional plate enzyme-linked immunoassay (ELISA). Underlying this performance is DEVA's high throughput analysis of individual EVs one at a time and the high specificity to targeted EVs versus background. We achieve a 0.006% false positive rate per droplet by leveraging avidity effects that arise from EVs having multiple copies of their target ligands on their surface. We use parallelized optofluidics to rapidly process 10 million droplets per minute, ∼100× greater than conventional approaches. A validation study on a cohort of 14 patients with melanoma confirms DEVA's ability to match conventional ELISA measurements with reduced plasma sample volume and without the need for prior EV purification. This proof-of-concept study demonstrates DEVA's potential for clinical utility to enhance prognosis as well as guide treatment for cancer.

Variation of computed tomography-derived extracellular volume fraction and the impact of protocol parameters: A systematic review and meta-analysis.

BACKGROUND: Cardiac computed tomography quantification of extracellular volume fraction (CT-ECV) is an emerging biomarker of myocardial fibrosis which has demonstrated high reproducibility, diagnostic and prognostic utility. However, there has been wide variation in the CT-ECV protocol in the literature and useful disease cut-offs are yet to be established. The objectives of this meta-analysis were to describe mean CT-ECV estimates and to estimate the effect of CT-ECV protocol parameters on between-study variation. METHODS: We conducted a meta-analysis of studies assessing CT-ECV in healthy and diseased participants. We used meta-analytic methods to pool estimates of CT-ECV and performed meta-regression to identify the contribution of protocol parameters to CT-ECV heterogeneity. RESULTS: Thirteen studies had a total of 248 healthy participants who underwent CT-ECV assessment. Studies of healthy participants had high variation in CT-ECV protocol parameters. The pooled estimate of CT-ECV in healthy participants was 27.6% (95%CI 25.7%-29.4%) with significant heterogeneity (I2 â€‹= â€‹93%) compared to 50.2% (95%CI 46.2%-54.2%) in amyloidosis, 31.2% (28.5%-33.8%) in severe aortic stenosis and 36.9% (31.6%-42.3%) in non-ischaemic dilated cardiomyopathies. Meta-regression revealed that CT protocol parameters account for approximately 25% of the heterogeneity in CT-ECV estimates. CONCLUSION: CT-ECV estimates for healthy individuals vary widely in the literature and there is significant overlap with estimates in cardiac disease. One quarter of this heterogeneity is explained by differences in CT-ECV protocol parameters. Standardization of CT-ECV protocols is necessary for widespread implementation of CT-ECV assessment for diagnosis and prognosis.

Genome-wide loss of heterozygosity predicts aggressive, treatment-refractory behavior in pituitary neuroendocrine tumors.

Pituitary neuroendocrine tumors (PitNETs) exhibiting aggressive, treatment-refractory behavior are the rare subset that progress after surgery, conventional medical therapies, and an initial course of radiation and are characterized by unrelenting growth and/or metastatic dissemination. Two groups of patients with PitNETs were sequenced: a prospective group of patients (n = 66) who consented to sequencing prior to surgery and a retrospective group (n = 26) comprised of aggressive/higher risk PitNETs. A higher mutational burden and fraction of loss of heterozygosity (LOH) was found in the aggressive, treatment-refractory PitNETs compared to the benign tumors (p = 1.3 × 10-10 and p = 8.5 × 10-9, respectively). Within the corticotroph lineage, a characteristic pattern of recurrent chromosomal LOH in 12 specific chromosomes was associated with treatment-refractoriness (occurring in 11 of 14 treatment-refractory versus 1 of 14 benign corticotroph PitNETs, p = 1.7 × 10-4). Across the cohort, a higher fraction of LOH was identified in tumors with TP53 mutations (p = 3.3 × 10-8). A machine learning approach identified loss of heterozygosity as the most predictive variable for aggressive, treatment-refractory behavior, outperforming the most common gene-level alteration, TP53, with an accuracy of 0.88 (95% CI: 0.70-0.96). Aggressive, treatment-refractory PitNETs are characterized by significant aneuploidy due to widespread chromosomal LOH, most prominently in the corticotroph tumors. This LOH predicts treatment-refractoriness with high accuracy and represents a novel biomarker for this poorly defined PitNET category.

Application of Quantitative Assessment of Coronary Atherosclerosis by Coronary Computed Tomographic Angiography.

Coronary computed tomography angiography (CCTA) has emerged as a pivotal tool for diagnosing and risk-stratifying patients with suspected coronary artery disease (CAD). Recent advancements in image analysis and artificial intelligence (AI) techniques have enabled the comprehensive quantitative analysis of coronary atherosclerosis. Fully quantitative assessments of coronary stenosis and lumen attenuation have improved the accuracy of assessing stenosis severity and predicting hemodynamically significant lesions. In addition to stenosis evaluation, quantitative plaque analysis plays a crucial role in predicting and monitoring CAD progression. Studies have demonstrated that the quantitative assessment of plaque subtypes based on CT attenuation provides a nuanced understanding of plaque characteristics and their association with cardiovascular events. Quantitative analysis of serial CCTA scans offers a unique perspective on the impact of medical therapies on plaque modification. However, challenges such as time-intensive analyses and variability in software platforms still need to be addressed for broader clinical implementation. The paradigm of CCTA has shifted towards comprehensive quantitative plaque analysis facilitated by technological advancements. As these methods continue to evolve, their integration into routine clinical practice has the potential to enhance risk assessment and guide individualized patient management. This article reviews the evolving landscape of quantitative plaque analysis in CCTA and explores its applications and limitations.