Confirmatory analysis of the 13-MD and ranking of its meta-dimensions and items.

Background: The 13-MD is a new generic instrument developed to measure general health-related quality of life (GHRQoL). This instrument considers all aspects of health (i.e., physical, mental, and social) in a balanced way. A previous study led to minor changes in the original version of the 13-MD. The objective of this study was to confirm the validity of the modified 13-MD. Methods: Validity was assessed with recent data from the general population of Quebec, Canada. The meta-dimensions and items composing the 13-MD were also subjected to a ranking procedure, which allowed to determine the most important aspects for respondents. Results: A total of 1337 French-speaking participants were recruited with 1099 completing the 13-MD for validation purposes and 1084 completing the ranking procedure. The 13-MD showed very satisfactory results and confirmed to be a valid instrument. The ranking of the meta-dimensions revealed that "Well-being" received the most points, followed by "Sleep and energy" and "Body functioning." Conclusion: These results will be very useful in the continuous improvement of the 13-MD, ultimately leading to the valuation stage (i.e., development of a value set).

Perinatal Outcomes Following Intravenous Iron for Treatment of Iron Deficiency With and Without Anemia.

OBJECTIVE: To determine maternal and neonatal outcomes in individuals with iron deficiency receiving antepartum intravenous (IV) iron supplementation, stratified by the degree of anemia. STUDY DESIGN: Retrospective cohort study of iron-deficient pregnant patients who received at least one IV infusion of iron (iron sucrose, low molecular weight iron dextran [LMWID], or ferric carboxymaltose) during their pregnancy from January 1, 2011 through June 16, 2022. Our primary outcomes included both neonatal composite morbidity and maternal composite morbidity in the context of maternal anemia. RESULTS: Patients who received LMWID had fewer infusion visits, received higher total doses of iron and had a more substantial correction of hemoglobin compared to those who received iron sucrose (p < 0.01). Maternal anemia at the time of admission was not associated with neonatal composite morbidity. However, there was a significant association between anemia status and maternal composite outcome (p = 0.05). Anemia at time of delivery was associated with the likelihood of requiring a blood transfusion (p = 0.01). CONCLUSION: This study reinforces previous findings emphasizing the adverse effects of iron deficiency on maternal health and the role of IV iron in reducing these risks.

Integrated epigenomic exposure signature discovery.

Aim: The epigenome influences gene regulation and phenotypes in response to exposures. Epigenome assessment can determine exposure history aiding in diagnosis.Materials & methods: Here we developed and implemented a machine learning algorithm, the exposure signature discovery algorithm (ESDA), to identify the most important features present in multiple epigenomic and transcriptomic datasets to produce an integrated exposure signature (ES).Results: Signatures were developed for seven exposures including Staphylococcus aureus, human immunodeficiency virus, SARS-CoV-2, influenza A (H3N2) virus and Bacillus anthracis vaccinations. ESs differed in the assays and features selected and predictive value.Conclusion: Integrated ESs can potentially be utilized for diagnosis or forensic attribution. The ESDA identifies the most distinguishing features enabling diagnostic panel development for future precision health deployment.

This article introduces ESDA, a new analytic tool for integrating multiple data types to identify the most distinguishing features following an exposure. Using the ESDA, we were able to identify signatures of infectious diseases. The results of the study indicate that integration of multiple types of large datasets can be used to identify distinguishing features for infectious diseases. Understanding the changes from different exposures will enable development of diagnostic tests for infectious diseases that target responses from the patient. Using the ESDA, we will be able to build a database of human response signatures to different infections and simplify diagnostic testing in the future.

Bridging the gap: Multi-omics profiling of brain tissue in Alzheimer's disease and older controls in multi-ethnic populations.

INTRODUCTION: Multi-omics studies in Alzheimer's disease (AD) revealed many potential disease pathways and therapeutic targets. Despite their promise of precision medicine, these studies lacked Black Americans (BA) and Latin Americans (LA), who are disproportionately affected by AD. METHODS: To bridge this gap, Accelerating Medicines Partnership in Alzheimer's Disease (AMP-AD) expanded brain multi-omics profiling to multi-ethnic donors. RESULTS: We generated multi-omics data and curated and harmonized phenotypic data from BA (n = 306), LA (n = 326), or BA and LA (n = 4) brain donors plus non-Hispanic White (n = 252) and other (n = 20) ethnic groups, to establish a foundational dataset enriched for BA and LA participants. This study describes the data available to the research community, including transcriptome from three brain regions, whole genome sequence, and proteome measures. DISCUSSION: The inclusion of traditionally underrepresented groups in multi-omics studies is essential to discovering the full spectrum of precision medicine targets that will be pertinent to all populations affected with AD. HIGHLIGHTS: Accelerating Medicines Partnership in Alzheimer's Disease Diversity Initiative led brain tissue profiling in multi-ethnic populations. Brain multi-omics data is generated from Black American, Latin American, and non-Hispanic White donors. RNA, whole genome sequencing and tandem mass tag proteomicsis completed and shared. Multiple brain regions including caudate, temporal and dorsolateral prefrontal cortex were profiled.

Lack of Evidence for Vaccine-Associated Enhanced Disease From COVID-19 Vaccines Among Adults in the Vaccine Safety Datalink.

PURPOSE: Vaccine-associated enhanced disease (VAED) is a theoretical concern with new vaccines, although trials of authorized vaccines against SARS-CoV-2 have not identified markers for VAED. The purpose of this study was to detect any signals for VAED among adults vaccinated against coronavirus disease 2019 (COVID-19). METHODS: In this cross-sectional study, we assessed COVID-19 severity as a proxy for VAED among 400 adults hospitalized for COVID-19 from March through October 2021 at eight US healthcare systems. Primary outcomes were admission to an intensive care unit (ICU) and severe illness (score ≥6 on the World Health Organization [WHO] Clinical Progression Scale). We compared the risk of outcomes among those who had completed a COVID-19 vaccine primary series versus those who were unvaccinated. We incorporated inverse propensity weights for vaccination status in a doubly robust regression model to estimate the causal average treatment effect. RESULTS: The causal risk ratio in vaccinated versus unvaccinated was 0.36 (95% confidence interval [CI], 0.15-0.94) for ICU admission and 0.46 (95% CI, 0.25-0.76) for severe illness. CONCLUSION: Among hospitalized patients, reduced disease severity in those vaccinated against COVID-19 supports the absence of VAED.

Oncogenic pathway signatures predict the risk of progression and recurrence in well-differentiated pancreatic neuroendocrine tumors.

BACKGROUND: Pancreatic neuroendocrine tumors (pNETs) are genomically diverse tumors. The management of newly diagnosed well-differentiated pNETs is limited by a lack of sensitivity of existing biomarkers for prognostication. Our goal was to investigate the potential utility of genetic markers as a predictor of progression-free survival (PFS) and recurrence-free survival (RFS). METHODS: Whole-exome sequencing of resected well-differentiated, low and intermediate-grade (G1 and G2) pNETs and normal adjacent tissue from patients who underwent resection from 2005 to 2015 was performed. Genetic alterations were classified using pan-genomic and oncogenic pathway classifications. Additional samples with genetic and clinicopathologic data available were obtained from the publicly available International Cancer Genome Consortium (ICGC) database and included in the analysis. The prognostic relevance of these genomic signatures on PFS and RFS was analyzed. RESULTS: Thirty-one patients who underwent resection for pNET were identified. Genomic analysis of mutational, copy number, cytogenetic, and complex phenomena revealed similar patterns to prior studies of pNETs with relatively few somatic gene mutations but numerous instances of copy number changes. Analysis of genomic and clinicopathologic outcomes using the combined data from our study as well as the ICGC pNET cohort (n = 124 patients) revealed that the recurrent pattern of whole chromosome loss (RPCL) and metastatic disease were independently associated with disease progression. When evaluating patients with local disease at the time of resection, RPCL and alterations in the TGFß oncogenic pathway were independently associated with the risk of recurrence. CONCLUSIONS: Well-differentiated pNETs are genomically diverse tumors. Pathway signatures may be prognostic for predicting disease progression and recurrence.

Live-cell imaging of RNA Pol II and elongation factors distinguishes competing mechanisms of transcription regulation.

RNA polymerase II (RNA Pol II)-mediated transcription is a critical, highly regulated process aided by protein complexes at distinct steps. Here, to investigate RNA Pol II and transcription-factor-binding and dissociation dynamics, we generated endogenous photoactivatable-GFP (PA-GFP) and HaloTag knockins using CRISPR-Cas9, allowing us to track a population of molecules at the induced Hsp70 loci in Drosophila melanogaster polytene chromosomes. We found that early in the heat-shock response, little RNA Pol II and DRB sensitivity-inducing factor (DSIF) are reused for iterative rounds of transcription. Surprisingly, although PAF1 and Spt6 are found throughout the gene body by chromatin immunoprecipitation (ChIP) assays, they show markedly different binding behaviors. Additionally, we found that PAF1 and Spt6 are only recruited after positive transcription elongation factor (P-TEFb)-mediated phosphorylation and RNA Pol II promoter-proximal pause escape. Finally, we observed that PAF1 may be expendable for transcription of highly expressed genes where nucleosome density is low. Thus, our live-cell imaging data provide key constraints to mechanistic models of transcription regulation.

Cost-effectiveness of HCC Surveillance Strategies in Patients With Compensated Liver Cirrhosis in the United Kingdom.

OBJECTIVES: This study aimed to evaluate the cost-effectiveness (CE) of four hepatocellular carcinoma (HCC) surveillance strategies in the UK, the GAAD algorithm, which combines gender (biological sex) and age with Elecsys® biomarker assays, alpha-fetoprotein (AFP) and protein induced by vitamin K absence-II (PIVKA-II), ultrasound (US), US+AFP and GAAD+US. METHODS: A de novo micro-simulation state-transition Markov model was developed in Microsoft Excel® from the perspective of the UK National Health Service to calculate life years, quality-adjusted life-years (QALYs), costs, incremental CE ratios, and net monetary benefits. Parameters were sourced from peer-reviewed published literature, national guidelines, and public cost databases. Sensitivity and scenario analyses were performed to evaluate the impact of parameter and structural uncertainty on the results. RESULTS: In a simulated cohort of 100,000 patients, discounted costs and QALYs per patient were £8,663 and 6·066 for US, £9,095 and 6·076 for US+AFP, £8,719 and 6·078 for GAAD alone, and £9,114 and 6·086 for GAAD+US. At a CE threshold of £20,000/QALY, GAAD was the most cost-effective strategy; however, although most costly, GAAD+US was the most clinically effective. Sensitivity and scenario analyses indicated that HCC incidence along with costs associated with diagnostic performance influence CE. CONCLUSION: Considering the cost of US and low incidence of HCC in the UK, this study suggests that GAAD alone or in combination with US are cost-effective surveillance strategies compared with US and US+AFP. Whilst GAAD+US showed the highest QALY increase, GAAD alone is considered preferable regarding CE; however, better performance estimates for GAAD+US are needed to confirm.

Association between APOE genotypes and metabolic syndrome in a middle aged and elderly Urban South Indian population.

Background: This study examines the association between apolipoprotein E (APOE) genotypes and metabolic syndrome (MetS) in an older urban population in South India, as part of the Tata Longitudinal Study on Aging. Methods: A total of 618 participants aged 45 and above were analyzed cross-sectionally for the association between APOE carrier status and MetS (based on both NCEP ATP III and Consensus criteria). Results: Despite the high prevalence of MetS observed in this cohort (51.62 % by NCEP-ATP III and 61.33 % by Consensus criteria), multivariable logistic regression revealed no significant association between APOE genotypes and MetS under both criteria. However, specific associations were noted in age and sex-stratified analyses; notably, E2 carriers under 60 showed 0.42-fold decreased odds (95%CI:0.20,0.89, p-value-0.023) for an increased waist circumference, and E4 carriers above 60 were at 1.85 times increased odds (95 % CI:1.04,3.28, p-value<0.05) for decreased HDL. Conclusion: These findings suggest that while APOE genotypes influence certain metabolic parameters, their impact on MetS may be limited in this urban setting, possibly overshadowed by environmental factors and lifestyle influences, which was highlighted by the differences seen in its sister rural cohort.

The source craters of the martian meteorites: Implications for the igneous evolution of Mars.

Approximately 200 meteorites come from ~10 impact events on the surface of Mars, yet their pre-ejection locations are largely unknown. Here, we combine the results of diverse sets of observations and modeling to constrain the source craters for several groups of martian meteorites. We compute that ejection-paired groups of meteorites are derived from lava flows within the top 26 m of the surface. We link ejection-paired groups to specific source craters and geologic units, providing context for these important samples, reconciling microscopic observations with remote sensing records, and demonstrating the potential to constrain the ages of their source geologic units. Furthermore, we show that there are craters that may have produced martian meteorites not represented in the world's meteorite collections that have yet to be discovered.

An infusible biologically active adhesive for chemotherapy-related heart failure in elderly rats.

Chemotherapy-induced cardiotoxicity with subsequent heart failure (HF) is a major cause of morbidity and mortality in cancer survivors worldwide. Chemotherapy-induced HF is exceptionally challenging as it generally manifests in patients who are typically not eligible for left ventricular device implantation or heart transplantation. To explore alternative treatment strategies for cancer survivors suffering from chemotherapy-induced HF, we developed a minimally invasive infusible cardiac stromal cell secretomes adhesive (MISA) that could be delivered locally through an endoscope-guided intrapericardial injection. To mimic the typical clinical presentation of chemotherapy-induced HF in elder patients, we established an aged rat model in which restrictive cardiomyopathy with sequential HF was induced via consecutive doxorubicin injections. In vitro, we prove that MISA not only enhanced cardiomyocytes proliferation potency and viability, but also inhibited their apoptosis. In vivo, we prove that MISA improved the ventricular contractility indexes and led to beneficial effects on histological and structural features of restrictive cardiomyopathy via promoting cardiomyocyte proliferation, angiogenesis, and mitochondrial respiration. Additionally, we also evaluated the safety and feasibility of MISA intrapericardial delivery in a healthy porcine model with an intact immune system. In general, our data indicates that MISA has a strong potential for translation into large animal models and ultimately clinical applications for chemotherapy-induced HF prior to the final option of heart transplantation.

Design and Development of a Powered Myoelectric Elbow Orthosis for Neuromuscular Injuries.

INTRODUCTION: Recovering from neuromuscular injuries or conditions can be a challenging journey that involves complex surgeries and extensive physical rehabilitation. During this process, individuals often rely on orthotic devices to support and enable movement of the affected limb. However, users have criticized current commercially available powered orthotic devices for their bulky and heavy design. To address these limitations, we developed a novel powered myoelectric elbow orthosis. MATERIALS AND METHODS: The orthosis incorporates 3 mechanisms: a solenoid brake, a Bowden cable-powered constant torque elbow mechanism, and an extension limiter. The device controller and battery are in a backpack to reduce the weight on the affected arm. We performed extensive calculations and testing to ensure that the orthosis could withstand at least 15 Nm of elbow torque. We developed a custom software effectively control the orthosis, enhancing its usability and functionality. A certified orthotist fitted a subject who had undergone a gracilis free functioning muscle transfer surgery with the device. We studied the subject under Mayo clinic IRB no. 20-006849 and obtained objective measurements to assess the orthosis's impact on upper extremity functionality during daily activities. RESULTS: The results are promising since the orthosis significantly improved elbow flexion range of motion by 40° and reduced compensatory movements at the shoulder (humerothoracic joint) by 50°. Additionally, the subject was able to perform tasks which were not possible before, such as carrying a basket with weights, highlighting the enhanced functionality provided by the orthosis. CONCLUSION: In brief, by addressing the limitations of existing devices, this novel powered myoelectric elbow orthosis offers individuals with neuromuscular injuries/conditions improved quality of life. Further research will expand the patient population and control mechanisms.

Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). METHOD: In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. RESULTS: Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10-3) in PSP. CONCLUSIONS: Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

A Perioperative Quality Improvement Program for Cesarean Delivery in Ethiopia: A Stepped-Wedge Cluster Randomized Clinical Trial.

Importance: Infections and complications following cesarean delivery are a significant source of maternal mortality in Ethiopia. Objective: To study the effectiveness of a program to strengthen compliance with perioperative standards and reduce postoperative complications following cesarean delivery. Design, Setting, and Participants: This stepped-wedge cluster randomized clinical trial included patients undergoing cesarean delivery from August 24, 2021, to January 31, 2023, at 9 hospitals organized into 5 clusters in Ethiopia. Intervention: Clean Cut, a multimodal surgical quality improvement program that includes process-mapping 6 perioperative standards and creating site-specific, systems-level improvements. The control period was the period before implementation of the intervention. Main Outcomes and Measures: The primary end point was surgical site infection rate, and secondary end points were maternal mortality and perinatal mortality and a composite outcome of infections and both mortality outcomes. All were assessed at 30 days postoperatively in the intervention and control groups, adjusting for clustering and demographics. Compliance with standards and the relationship between compliance and outcomes were also compared between the 2 arms. Results: Among 9755 women undergoing cesarean delivery, 5099 deliveries (52.3%) occurred during the control period (2722 emergency cases [53.4%]) and 4656 (47.7%) during the intervention period (2346 emergency cases [50.4%]). Mean (SD) patient age was 27.04 (0.05) years. Thirty-day follow-up was completed for 5153 patients (52.8%). No significant reduction in infection rates was detected after the intervention (OR, 0.84; 95% CI, 0.55-1.27; P = .40). Intraoperative infection prevention standards improved significantly in the intervention arm vs control arm for compliance with at least 5 of the 6 standards (odds ratio [OR], 2.95; 95% CI, 2.40-3.62; P < .001). Regardless of trial arm, high compliance was associated with reduced odds of maternal (OR, 0.32; 95% CI, 0.11-0.93; P = .04) and perinatal (OR, 0.64; 95% CI, 0.47-0.89; P = .008) mortality. Conclusions and Relevance: In this stepped-wedge cluster randomized clinical trial of patients undergoing cesarean delivery, no significant reductions in surgical site infections were observed. However, compliance with perioperative standards improved following the intervention. Trial Registration: ClinicalTrials.gov Identifier: NCT04812522; Pan-African Clinical Trials Registry Identifier: PACTR202108717887402.

Efficacy and safety of teclistamab in patients with relapsed/refractory multiple myeloma after BCMA-targeting therapies.

Teclistamab is a B­cell maturation antigen (BCMA)-directed bispecific antibody approved for the treatment of patients with triple-class exposed relapsed/refractory multiple myeloma. In the phase 1/2 MajesTEC-1 study, a cohort of patients who had prior BCMA-targeted therapy (antibody-drug conjugate [ADC] or CAR-T cell therapy) were enrolled to explore teclistamab in patients previously exposed to anti-BCMA treatment. At median follow-up of 28.0 months (range, 0.7-31.1), 40 patients with prior BCMA-targeted therapy had received subcutaneous 1.5 mg/kg weekly teclistamab. Median prior lines of treatment were 6 (range, 3-14). Prior anti-BCMA therapy included ADC (n = 29), CAR-T (n = 15), or both (n = 4). Overall response rate was 52.5%; 47.5% of patients achieved very good partial response or better and 30.0% achieved complete response or better. Median duration of response was 14.8 months, median progression-free survival was 4.5 months, and median overall survival was 15.5 months. The most common treatment-emergent adverse events (TEAEs) were neutropenia, infections, cytokine release syndrome, and anemia; cytopenias and infections were the most common grade ≥3 TEAEs. Infections occurred in 28 (70.0%) patients (n = 13 [32.5%] maximum grade 3/4; n = 4 [10%] grade 5). Prior to starting teclistamab, baseline BCMA expression and immune characteristics were unaffected by prior anti-BCMA treatment. The MajesTEC-1 trial cohort C results demonstrate favorable efficacy and safety of teclistamab in patients with heavily pretreated RRMM and prior anti-BCMA treatment. NCT03145181; NCT04557098.

An Orthogonal T7 Replisome for Continuous Hypermutation and Accelerated Evolution in E. coli.

Systems that perform continuous hypermutation of designated genes without compromising the integrity of the host genome can dramatically accelerate the evolution of new or enhanced protein functions. We describe an orthogonal DNA replication system in E. coli based on the controlled expression of the replisome of bacteriophage T7. The system replicates circular plasmids that enable high transformation efficiencies and seamless integration into standard molecular biology workflows. Engineering of T7 DNA polymerase yielded variant proteins with mutation rates of 1.7 × 10 -5 substitutions per base in vivo - 100,000-fold above the genomic mutation rate. Continuous evolution using the mutagenic T7 replisome was demonstrated by expanding the substrate scope of TEM-1 ß-lactamase and increase activity 1,000-fold against clinically relevant monobactam and cephalosporin antibiotics in less than one week.

PCD-CT enables contrast media reduction in abdominal imaging compared to an individualized kV-adapted contrast media injection protocol on EID-CT.

OBJECTIVES: This study aims to demonstrate reduced iodine contrast media (CM) in routine abdominal CT scans in portal venous phase (PVP) using a photon-counting detector CT (PCD-CT) compared to total body weight (TBW) and kV-adapted CM injection protocols on a state-of-the-art energy-integrating detector CT (EID-CT) while maintaining sufficient image quality (IQ). MATERIALS AND METHODS: Consecutive contrast-enhanced abdominal PVP CT scans from an EID-CT (Nov 2022-March 2024) and a PCD-CT (Sep 2023-Dec 2023) were compared. CM parameters (total iodine load (TIL), iodine delivery rate (IDR) and dosing factor (DF)) were reported. An individualized acquisition and CM injection protocol based on TBW and kV was applied for the EID-CT and a TBW adapted CM injection protocol was used for the PCD-CT. Objective IQ was evaluated with mean attenuation (Hounsfield Units, HU), signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR)). Subjective IQ was assessed via a 5-point Likert scale by 2 expert readers based on diagnostic confidence. RESULTS: Based on 91 EID-CT scans and 102 PCD-CT scans a TIL reduction of 20.1 % was observed for PCD-CT. PCD-CT demonstrated significantly higher SNR (9.9 ± 1.7 vs. 9.1 ± 1.8, p < 0.001) and CNR (5.1 ± 1.7 vs. 4.3 ± 1.3, p < 0.001) compared to EID-CT. Subjective IQ assessment showed that all scans had sufficient diagnostic IQ. CONCLUSIONS: PCD-CT allows for CM reduction while providing higher SNR and CNR compared to EID-CT, using clinical individualized scan and CM injection protocols.