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A Novel Giant Magnetoresistance-Enabled Multiplex Polymerase Chain Reaction Assay for the Diagnosis of Invasive Fungal Infection
No full textBACKGROUND: Despite advances in clinical microbiology, the diagnosis of invasive fungal infections remains challenging. Giant magnetoresistance (GMR) is a novel technology that enables the detection of trace amounts of cell-free DNA (cfDNA). We evaluated a high-multiplex molecular diagnostic assay coupled with GMR-enabled lab-on-a-chip technology that can detect 18 different fungal species.
METHODS: Analytical performance was evaluated in spiked plasma samples. After amplification, cfDNA was digested. Residual single-stranded DNA was flowed over a GMR sensor that was surface-coated with probes specific to different fungal species. After hybridization, magnetic beads bound to the probe complexes produced a GMR signal that was detected by the sensors. Clinical performance was determined using residual serum samples collected before the initiation of antifungal treatment from 20 patients with infection.
RESULTS: The limit of detection of the assay ranged from 5 to 50 copies per polymerase chain reaction (PCR) reaction. Nonspecific signals were not observed in the spiked samples. Fungal cfDNA was detected in 80% of patients with invasive candidiasis (3/4 with candidemia, 5/6 with invasive candidiasis without candidemia), all 3 cases of invasive pulmonary aspergillosis, and all 3 cases of disseminated histoplasmosis. cfDNA was not detected in 2 patients with cryptococcosis (both had negative blood cultures) and 2 patients with Pneumocystis pneumonia.
CONCLUSIONS: We developed a novel GMR-enabled multiplex PCR assay detecting fungal pathogens that have been prioritized for public health action. Clinical sensitivity was highest in cases of presumed angioinvasion and dissemination. This technology has the potential for use in the clinical microbiology laboratory setting
Interim Estimates of 2024-2025 COVID-19 Vaccine Effectiveness Among Adults Aged ≥18 Years - VISION and IVY Networks, September 2024-January 2025
No full textCOVID-19 vaccination averted approximately 68,000 hospitalizations during the 2023-24 respiratory season. In June 2024, CDC and the Advisory Committee on Immunization Practices (ACIP) recommended that all persons aged ≥6 months receive a 2024-2025 COVID-19 vaccine, which targets Omicron JN.1 and JN.1-derived sublineages. Interim effectiveness of 2024-2025 COVID-19 vaccines was estimated against COVID-19-associated emergency department (ED) or urgent care (UC) visits during September 2024-January 2025 among adults aged ≥18 years in one CDC-funded vaccine effectiveness (VE) network, against COVID-19-associated hospitalization in immunocompetent adults aged ≥65 years in two networks, and against COVID-19-associated hospitalization among adults aged ≥65 years with immunocompromising conditions in one network. Among adults aged ≥18 years, VE against COVID-19-associated ED/UC visits was 33% (95% CI = 28%-38%) during the first 7-119 days after vaccination. Among immunocompetent adults aged ≥65 years from two CDC networks, VE estimates against COVID-19-associated hospitalization were 45% (95% CI = 36%-53%) and 46% (95% CI = 26%-60%) during the first 7-119 days after vaccination. Among adults aged ≥65 years with immunocompromising conditions in one network, VE was 40% (95% CI = 21%-54%) during the first 7-119 days after vaccination. These findings demonstrate that vaccination with a 2024-2025 COVID-19 vaccine dose provides additional protection against COVID-19-associated ED/UC encounters and hospitalizations compared with not receiving a 2024-2025 dose and support current CDC and ACIP recommendations that all persons aged ≥6 months receive a 2024-2025 COVID-19 vaccine dose
Adaptive treatment workflow and dosimetric evaluation of intracranial fractionated stereotactic radiosurgery on a low-field magnetic resonance-linear accelerator
No full textBACKGROUND AND PURPOSE: Online adaptive radiotherapy for fractionated intracranial stereotactic radiosurgery (FSRS) on a magnetic resonance linear accelerator (MR-L) has the potential to allow for real-time adjustments of anatomical changes during radiotherapy treatment. This study investigates the dosimetric improvements of an online-adaptive MR-L workflow and validates the dosimetry utilizing an MR-visible phantom.
METHODS AND MATERIALS: Twenty-six cases previously treated with a conventional C-arm linear accelerator (CA-L) were replanned to determine optimal optimization constraints and objectives for achieving comparable MR-L plans. The optimization methodology was subsequently applied to simulate an online adaptive workflow on an MR phantom, incorporating target volumes from five previously treated patients that required offline adaptation. Plan quality and normal brain dose statistics were evaluated and compared to the offline adapted CA-L plans.
RESULTS: No significant difference was observed between the CA-L and MR-L target coverage. The normal brain dose for MR-L plans increased with target volume more rapidly than for CA-L plans. However, some outliers achieved equivalent normal brain doses, indicating potential benefits of MRIgRT for specific superficial volumes located in the frontal, occipital lobes, and cerebellum. End-to-end validation with simulated adaptive workflow on a MR phantom utilizing target volumes that previously required adaption showed acceptable difference of \u3c 2.5 % between measured and planned target dose.
CONCLUSION: The study shows promising results for an online adaptive workflow for the treatment of intracranial FSRS on a low-field MR-L
Efficacy and Safety of Zilucoplan in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial
No full textIMPORTANCE: The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression.
OBJECTIVE: To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS.
DESIGN, SETTING, AND PARTICIPANTS: Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens.
INTERVENTIONS: Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing.
MAIN OUTCOMES AND MEASURES: The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR; \u3c 1 indicating treatment benefit). The study included prespecified rules for early stopping for futility. Outcome analyses were performed in the full analysis set comparing the zilucoplan group with the total shared placebo group (n = 164).
RESULTS: Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority, 0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified.
CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04297683
Impact of developmental state, p53 status, and interferon signaling on glioblastoma cell response to radiation and temozolomide treatment
Get PDFGlioblastoma (GBM) tumors exhibit extensive genomic, epigenomic, and transcriptional diversity, with significant intratumoral heterogeneity, complicating standard treatment approaches involving radiation (RT) and the DNA-alkylating agent temozolomide (TMZ). In this study, we employed an integrative multi-omics approach, including targeted proteomics, transcriptomics, genomics, and DNA methylation profiling, to investigate the response of a representative panel of GBM patient-derived cancer stem cells (CSCs) to astrocytic differentiation and RT and TMZ treatments. Differentiated CSC progenies retained the expression of key stemness genes and survival pathways, while activating the BMP-Smad signaling pathway and upregulating extracellular matrix components. This was associated with increased resistance to TMZ, though not to RT, across all models. We identified TP53 status as a critical determinant of transcriptional response to both RT and TMZ, which was also modulated by the differentiation state and treatment modality in wildtype (wt) p53 GBM cells. Both mutant and wt p53 models exhibited significant activation of the DNA-damage associated interferon (IFN) response in CSCs and differentiated cells, implicating this pathway in the GBM response to therapy. We observed that activation of NF-κB was positively correlated with the levels of O-6-methylguanine-DNA methyltransferase (MGMT) protein, a direct DNA repair enzyme leading to TMZ resistance, regardless of MGMT promoter methylation status, further supporting the clinical potential for inhibition of NF-kB signaling in GBM treatment. Our integrative analysis of the impact of GBM cell developmental states, in the context of genomic and molecular diversity of patient-derived models, provides valuable insights for pre-clinical studies aimed at optimizing treatment strategies
Association of plasma metabolites and cardiac mitochondrial function with heart failure progression
No full textAIMS: Plasma metabolites are prognostic in heart failure with reduced ejection fraction (HFrEF), with citric acid cycle metabolites linked to ejection fraction (EF) changes. We investigated these mechanisms in a canine chronic HFrEF model. We tested associations between changes in plasma metabolites, left ventricular (LV) end-diastolic volume and cardiomyocyte mitochondrial function.
METHODS: Eighteen dogs underwent microembolization to induce moderate HFrEF (target LVEF 35%-40%). Plasma metabolites, LV size and mitochondrial function were assessed over 12 months.
RESULTS: Plasma metabolite heatmap showed acylcarnitine changes, with early alterations in organic acids and amino acids predicting later adverse LV remodelling. Using either baseline or change over time, 13 metabolites correlated with 12 month LV enlargement. This is mostly often at 3 months (11 of 13), notably C18:2 (r = -0.58, P = 0.003) and cardiac anaplerotic substrates like glutamine (r = -0.52, P = 0.009) and 3-HBA (r = -0.43, P = 0.035). Impaired cardiomyocyte mitochondrial function correlated with LV enlargement (max ATP synthesis 12.7 vs. 19.9 nmol/min/mg, P = 0.0036; ADP-stimulated respiration 224 vs. 308 nAtom O/min/mg protein; P = 0.0064). Plasma metabolites correlated with mitochondrial parameters at 12 month, particularly with MAX ATP: malate (r = -0.75, P \u3c 0.001), fumarate (r = -0.6, P = 0.008) and glutamine (r = 0.51, P = 0.031).
CONCLUSIONS: In canine HFrEF, plasma acylcarnitines, citric acid cycle or anaplerotic metabolites predicted adverse LV remodelling. LV enlargement correlated with reduced cardiomyocyte mitochondrial function, which in turn was also associated with increased citric acid cycle metabolites. Together, these data suggest impaired cardiac energetic function drives plasma metabolite associations in HFrEF progression
Design and rationale for the clinical investigation of a novel, magnetically levitated left ventricular assist device for the treatment of refractory heart failure
No full textBACKGROUND: Contemporary durable left ventricular assist devices (LVAD) have established current benchmarks for patient outcomes, but introduction of more novel technology is lacking. The BrioVAD System (BrioHealth Solutions, Burlington, MA) is an innovative, fully magnetically levitated pump intended to provide short-term (ST) and long-term (LT) mechanical circulatory support.
METHODS: The Investigation of a Novel, MagNetically Levitated VAD for the Treatment of RefractOry Left Ventricular HeArT FailurE Clinical Trial (INNOVATE) is designed to evaluate safety and efficacy of the BrioVAD by demonstrating non-inferiority to the HeartMate 3 (HM3; Abbott Labs, Chicago, IL). INNOVATE is a multi-center, prospective, non-blinded, randomized (2 BrioVAD: 1 HM3), controlled, non-inferiority study designed as a staged pivotal study with a pre-defined safety phase. Exclusion criteria are designed to enroll a patient population that aligns with contemporary clinical practice. Primary endpoints include a composite of survival to transplant, cardiac recovery, or 6 months (ST) or 24 months (LT) of LVAD support free from debilitating stroke (modified Rankin Scale \u3e 3), or reoperation to replace the pump. A powered secondary outcome evaluates days spent in hospital, skilled nursing facility, or inpatient rehabilitation.
RESULTS: INNOVATE study screening and enrollment began in 2024. Completed enrollment of the safety cohort (n = 45) is projected in early 2025. Completion of the ST cohort (n = 237) and LT cohort (n = 402) is projected for 2026 and 2027, respectively.
CONCLUSIONS: INNOVATE represents a contemporary clinical trial design evaluating unique design features of the BrioVAD System with the expectation to improve patient outcomes
Left atrial veno-arterial extracorporeal membrane oxygenation as a bridge to surgical or percutaneous closure of post-myocardial infarction ventriculoseptal defects: a case series
No full textBACKGROUND: Post-myocardial infarct (MI) ventricular septal defect (VSD) is a rare and severe complication of an acute MI with high mortality rate. The use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) as a bridge to surgical or percutaneous repair in cardiogenic shock secondary to post-MI-VSD has been published, but is limited to small case series primarily utilizing surgical ECMO, with the main drawback of potentially increasing afterload and left ventricle pressure, further worsening VSD shunting. Left-atrial VA-ECMO (LAVA-ECMO) can potentially absolve this concern given that it utilizes bi-atrial drainage through a trans-septal fenestrated cannula.
CASE SUMMARY: Five patients were included in this series, all with VSD secondary to MI, and all managed with LAVA-ECMO as a bridge to repair. Average age was 62 ± 4.2 years, body mass index of 29.4 ± 4.5 kg/m(2), and left ventricular ejection fraction of 46.6 ± 13.8%. Haemodynamics monitoring pre- and post-LAVA-ECMO demonstrated improvement in right atrial, right ventricular, pulmonary, left atrial, and left ventricular pressures (Figure 1). Average time to repair was 7.4 ± 3.9 days. All five patients survived to repair, with four undergoing surgical and one undergoing percutaneous closure. Four out of five patients were decannulated successfully.
DISCUSSION: This case series reports the successful use of LAVA-ECMO as a bridge to MI-VSD repair in patients with cardiogenic shock. Left-atrial VA-ECMO serves as a convenient approach to managing patients with MI-VSD related cardiogenic shock as it is implanted percutaneously, and can be done at the time of shock diagnosis, during right heart catheterization by trained interventionists
Clinical Profile and Treatment Patterns in Individuals with Type 2 Diabetes and Chronic Kidney Disease Who Initiate a GLP-1 Receptor Agonist: A Multinational Cohort Study
No full textINTRODUCTION: Novel therapies are emerging for the prevention of chronic kidney disease (CKD) progression in patients with type 2 diabetes (T2D). Within the FOUNTAIN platform (NCT05526157; EUPAS48148), this real-world study aimed to characterize cohorts of adults with CKD and T2D starting therapy with a glucagon-like peptide-1 receptor agonist (GLP-1 RA) in Europe, Japan, and the United States (US) during 2012-2021.
METHODS: This multinational, multicohort study was conducted in five data sources: the Danish National Health Registers (DNHR) (Denmark), PHARMO Data Network (PHARMO) (The Netherlands), Valencia Health System Integrated Database (VID) (Spain), Japan Chronic Kidney Disease Database Extension (J-CKD-DB-Ex) (Japan), and Optum\u27s de-identified Clinformatics® Data Mart Database (CDM) (US). Eligible patients had T2D (defined by data source-specific algorithms) and CKD (based on diagnosis codes, estimated glomerular filtration rate values, and/or urine albumin-to-creatinine ratio) and initiated an GLP-1 RA during 2012-2021. Baseline demographic, lifestyle, and clinical characteristics were analyzed, and treatment patterns were described.
RESULTS: Study cohorts included 18,929 GLP-1 RA initiators in DNHR; 476 in PHARMO; 11,798 in VID; 329 in J-CKD-DB-Ex; and 70,158 in CDM. Across cohorts, mean age ranged from 66.1 years in J-CKD-DB-Ex to 67.9 years in CDM, and between 46.6% (PHARMO) and 59.6% (J-CKD-DB-Ex) of patients were men. There was a steady increase in GLP-1 RA initiators from 2012 (when 1.6-4.8% of GLP-1 RA initiators started therapy) to 2019 (when 19.8-31.5% started therapy). The median duration of initial treatment with a GLP-1 RA ranged from 2.3 months (PHARMO) to 12.4 months (VID). At 1-year follow-up, between 52% (CDM) and 78% (DNHR) of patients were receiving treatment. Findings suggested that GLP-1 RA use was independent of CKD severity.
CONCLUSIONS: During 2012-2021, GLP-1 RA use steadily increased across multinational cohorts of patients with T2D and CKD, and persistence with treatment was high. GLP-1 use was independent of CKD severity
Racial Diversity and Co-Mutational Analysis of Biologically Relevant Alterations in EGFR Mutant Lung Cancers
No full textBACKGROUND: EGFR alterations have significant therapeutic implications in lung cancer (LCa), yet their prevalence and co-mutational patterns in African American populations remain understudied. This study analyzes EGFR-mutant LCa across races using the Tempus database.
METHODS: De-identified records sequenced via Tempus xT assay, (595 to 648 gene DNA panel) were included if they had ≥ 1 pathogenic EGFR mutation (short variants (SVs), copy number amplifications (CNAs), or fusions). Race was determined based on recorded clinical records. Co-mutations were restricted to genes with ≥ 5% frequency in at least 1 race. Statistical analyses were performed using chi-squared tests with Bonferroni or false discovery rate adjustments for multiple testing.
RESULTS: Among 17,482 LCa samples, EGFR alterations occurred in 8.9% of CA, 7.6% of BAA, 39% of API, 15% of other races, and 12% of unknown races. Exon 19 deletions (P = .017) and L858R mutations (P \u3c .001) varied by race, with higher L858R frequency in CA compared to BAA (P = .034) and in API compared to CA (P = .006). EGFR copy number variants (CNVs) were highest in BAA (P \u3c .001). TP53 alterations occurred at a higher frequency in patients with a history of smoking, those with high tumor mutational burden (TMB), and high PD-L1. KMT2C co-mutations were significantly more common in BAA (13%) compared to CA (3%) and API (4%) (q = 0.003). Similarly, GLI1 co-mutations were most frequent in BAA (5.8%) compared to 1.5% in CA and 0% in API patients (q = 0.025).
CONCLUSIONS: EGFR mutation subtypes and co-mutations differ by race. KMT2C may influence TMB and immunotherapy response, while GLI1 is linked to TKI resistance. TP53 alterations were more commen in smokers, and patients with high PDL-1 and TMB, highlighting additional factors that drive tumors with these alterations