Citations

Abstract Background Current oncological treatments improved survival but also increased awareness of cardiovascular side-effects following cancer therapy. Anthracyclines are a class of highly effective chemotherapeutics, yet their use is regularly complicated by anthracycline-induced cardiotoxicity (AIC). The advent of induced pluripotent stem cell-derived cardiac myocytes (iPSC-CMs) offers the potential for disease modeling and prediction of genetic cardiomyopathies. Purpose We aim to use iPSC-CMs to assess susceptibility to cardiotoxicity induced by anti-cancer treatments on an individual patient level. Furthermore, the assay could be exploited to unravel cellular processes and pathways involved in AIC. Methods Five heart transplant patients following AIC and five anthracycline treated patients without AIC were included in our study. We reprogrammed patient-derived lymphocytes from both groups toward iPSCs using Sendai Virus; afterwards, patient derived iPSCs were differentiated into CM-like cells. Cytotoxicity following chemotherapy exposure was assessed using flow cytometry (FC), in which iPSC-CM-specific cells were first selected based on the expression of signal-regulatory protein alpha (SIRPA) surface marker; thereafter the percentage of apoptotic versus viable cells following doxorubicin exposure was quantitatively assessed. Ultrastructural changes were evaluated using electron microscopy (EM) images, comparing doxorubicin treated and untreated iPSC-CMs. Reactive Oxygen Species (ROS) generation following doxorubicin exposure was assessed using a luciferin precursor-based plate reader assay (ROS-GLO) and FC. Furthermore, whole genome sequencing (WGS) was performed and variants were filtered based on allele frequency, pathogenicity using HumVar trained variant effect predictors and presence in patients versus controls. Results The cytotoxic effect of increasing concentrations of doxorubicin was quantifiable using FC on SIRPA positive iPSC-CMs (Figure 1 panel A). On the ultrastructural level, doxorubicin treated iPSC-CMs manifested darker and more condensed mitochondria as seen with EM (Figure 1 panel B). Increased ROS production was observed following doxorubicin exposure as assessed using ROS-GLO plate reader assay and FC (Figure 1 panel C). We used iPSC-CMs of transplant patients and matched controls to assess inter-individual susceptibility to anthracycline-induced cardiotoxicity. Included patient profiles can be found in Figure 2 panel A. There was a higher rate of cell death at any concentration of doxorubicin in patients with proven AIC as opposed to controls (Figure 2 panel B). WGS analysis showed 2 pathogenic variants in the PRAMEF6 gene present in cases and not in controls (Figure 3 panel C). Conclusion iPSC-CMs represent a robust disease model to study cancer therapy-induced cardiotoxicity. Furthermore, iPSC-CMs allow to study inter-individual differences in susceptibility to cancer therapy-induced cardiotoxicity.Mechanism of AICSusceptibility to AIC

Biodegradable and all-natural gelatin-based nanoemulsions encapsulate and stabilize antifungal essential oils to provide efficient penetration and eradication of drug-resistant fungal biofilms without resistance generation.

Objectives To assess the effects of percutaneous nephrolithotomy (PCNL) vs retrograde intrarenal surgery (RIRS) for the treatment of renal stones in adults. Methods We performed a comprehensive search of the Cochrane Library, MEDLINE, Embase, three other databases, trials registries, other sources of the grey literature, and conference proceedings up to 23 March 2023. We applied no restrictions on publication language or status. Screening, data extraction, risk‐of‐bias assessment, and certainty of evidence (CoE) rating using the Grading of Recommendations Assessment, Development and Evaluations (GRADE) approach were done in duplicate by two independent reviewers. This co‐publication focuses on the primary outcomes of this review only. Results We included 42 trials that met the inclusion criteria. Stone‐free rate (SFR): PCNL may improve SFRs (risk ratio [RR] 1.13, 95% confidence interval [CI] 1.08–1.18; I 2 = 71%; 39 studies, 4088 participants; low CoE). Major complications: PCNL probably has little to no effect on major complications (RR 0.86, 95% CI 0.59–1.25; I 2 = 15%; 34 studies, 3649; participants; moderate CoE) compared to RIRS. Need for secondary interventions: PCNL may reduce the need for secondary interventions (RR 0.31, 95% CI 0.17–0.55; I 2 = 61%; 21 studies, 2005 participants; low CoE) compared to RIRS. Conclusion Despite shortcomings in most studies that lowered our certainty in the estimates of effect to mostly very low or low, we found that PCNL may improve SFRs and reduce the need for secondary interventions while not impacting major complications. Ureteric stricture rates may be similar compared to RIRS. We expect the findings of this review to be helpful for shared decision‐making about management choices for individuals with renal stones.

Abstract Background Shotgun and targeted metagenomic sequencing have been shown in separate studies to be potentially useful for culture-free pathogen identification in blood and/or plasma of patients with infective endocarditis (IE). However, the 2 approaches have not been directly compared. The aim of this study was to compare shotgun metagenomic sequencing with targeted metagenomic sequencing (tMGS) for organism identification in blood or plasma of patients with IE. Methods Patients with possible or definite IE were prospectively enrolled from October 2020 to July 2021. Shotgun metagenomic sequencing was performed with the Karius test, which uses microbial cell-free DNA (mcfDNA) sequencing to detect, identify, and quantitate DNA-based pathogens in plasma. tMGS was performed using a 16S ribosomal RNA (rRNA) polymerase chain reaction assay targeting the V1 to V3 regions of the 16S rRNA gene. Results were compared using the McNemar test of paired proportions. Results Samples from 34 patients were investigated. The Karius test was positive in 24/34 (71%), including 3/6 (50%) with blood culture–negative endocarditis (BCNE), which was not significantly different from the positivity rate of tMGS (P = .41). Results of the Karius test were concordant with tMGS in 75% of cases. The Karius test detected 2 cases of methicillin-resistant Staphylococcus aureus among the 7 S. aureus detections, in accordance with results of phenotypic susceptibility testing. The combination of blood cultures, the Karius test, and tMGS found a potential causative pathogen in 33/34 (97%), including 5/6 with BCNE. Conclusions The Karius test and tMGS yielded comparable detection rates; however, beyond organism identification, the Karius test generated potentially useful antibiotic resistance data.

339 Background: Limited health insurance literacy (HIL) has been linked to problems paying medical bills or delaying care among patients with cancer. In this study, we describe the prevalence and correlates of HIL in a cohort of cancer patients measured using a ten-question HIL quiz developed by the Kaiser Family Foundation. Methods: We examined HIL in 393 adult patients (aged >18 years) receiving cancer treatment in two ambulatory infusion centers, Mayo Clinic in Phoenix, Arizona (12/2019 to 2/2020 and 8/2020 to 10/2020) and University of Mississippi Medical Center in Jackson, Mississippi (9/2020 to 1/2021). HIL was categorized as low, moderate, or high based on the total number of correct answers: 0-4 (low), 5-6 (moderate), and 7-10 (high). Descriptive statistics characterized the sample and chi-square statistics compared HIL by sociodemographic factors. Results: Most patients understood basic insurance terms, such as premiums and deductibles (Table). However, fewer patients answered questions correctly about provider networks (46.1%), formularies (48.6%), and calculating out-of-pocket (OOP) spending (16.8%). 53 (13.5%), 69 (17.6%), and 271 (69.0%) patients had low, moderate, and high HIL scores, respectively. Lower HIL was more common among patients of younger age (<65 years: 17.8%, 65+ years: 8.7%), lower educational attainment (less than college: 23.2%; college or higher: 4.4%), and lower household income (<$4999: 21.1%, $5000+: 6.1%) (all p-values<0.05). Conclusions: Although HIL in our cohort of cancer patients was relatively high - 69% answered at least 7 questions correctly - there were gaps in understanding of provider networks, formularies, and calculation of OOP spending. Efforts to improve HIL and help with navigation of health insurance plans may be required, especially for socioeconomically vulnerable patients.[Table: see text]

Abstract Aims To study the impact of heart failure with preserved ejection fraction (HFpEF) vs. aortic stenosis (AS) lesion severity on left ventricular (LV) hypertrophy, diastolic dysfunction, left atrial (LA) dysfunction, haemodynamics, and exercise capacity. Methods and results Patients (n = 206) with at least moderate AS (aortic valve area ≤0.85 cm/m2) and discordant symptoms underwent cardiopulmonary exercise testing with simultaneous echocardiography. The population was stratified according to the probability of underlying HFpEF by the heavy, hypertension, atrial fibrillation, pulmonary hypertension, elder, filling pressure (H2FPEF) score [0–5 (AS/HFpEF−) vs. 6–9 points (AS/HFpEF+)] and AS severity (Moderate vs. Severe). Mean age was 73 ± 10 years with 40% women. Twenty-eight patients had Severe AS/HFpEF+ (14%), 111 Severe AS/HFpEF− (54%), 13 Moderate AS/HFpEF+ (6%), and 54 Moderate AS/HFpEF− (26%). AS/HFpEF+ vs. AS/HFpEF− patients, irrespective of AS severity, had a lower LV global longitudinal strain, impaired diastolic function, reduced LV compliance, and more pronounced LA dysfunction. The pulmonary arterial pressure–cardiac output slope was significantly higher in AS/HFpEF+ vs. AS/HFpEF− (5.4 ± 3.1 vs. 3.9 ± 2.2 mmHg/L/min, respectively; P = 0.003), mainly driven by impaired cardiac output and chronotropic reserve, with signs of right ventricular pulmonary arterial uncoupling. AS/HFpEF+ vs. AS/HFpEF− was associated with a lower peak aerobic capacity (11.5 ± 3.7 vs. 15.9 ± 5.9 mL/min/kg, respectively; P &lt; 0.0001) but did not differ between Moderate and Severe AS (14.7 ± 5.5 vs. 15.2 ± 5.9 mL/min/kg, respectively; P = 0.6). Conclusion A high H2FPEF score is associated with a reduced exercise capacity and adverse haemodynamics in patients with moderate to severe AS. Both exercise performance and haemodynamics correspond better with intrinsic cardiac dysfunction than AS severity.

Abstract The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs.

ImportanceIncreased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors.ObjectiveTo estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes.Design, Setting, and ParticipantsThis cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).Main Outcome and MeasuresThe main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH.ResultsData from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [P = .002]; ADNI: t = −5.6 [P &amp;lt; .001]; HABS: t = −2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P &amp;lt; .001]; ADNI: t = 9.1 [P &amp;lt; .001]; HABS: t = 5.4 [P &amp;lt; .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P &amp;lt; .001).Conclusions and RelevanceThe findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

Abstract Clinical research networks conduct important studies that would not otherwise be performed by other entities. In the case of the Antibacterial Resistance Leadership Group (ARLG), such studies include diagnostic studies using master protocols, controlled phage intervention trials, and studies that evaluate treatment strategies or dynamic interventions, such as sequences of empiric and definitive therapies. However, the value of a clinical research network lies not only in the results from these important studies but in the creation of new approaches derived from collaborative thinking, carefully examining and defining the most important research questions for clinical practice, recognizing and addressing common but suboptimal approaches, and anticipating that the standard approaches of today may be insufficient for tomorrow. This results in the development and implementation of new methodologies and tools for the design, conduct, analyses, and reporting of research studies. These new methodologies directly impact the studies conducted within the network and have a broad and long-lasting impact on the field, enhancing the scientific value and efficiency of generations of research studies. This article describes innovations from the ARLG in diagnostic studies, observational studies, and clinical trials evaluating interventions for the prevention and treatment of antibiotic-resistant bacterial infections.

AbstractDeveloping and implementing the scientific agenda of the Antibacterial Resistance Leadership Group (ARLG) by soliciting input and proposals, transforming concepts into clinical trials, conducting those trials, and translating trial data analyses into actionable information for infectious disease clinical practice is the collective role of the Scientific Leadership Center, Clinical Operations Center, Statistical and Data Management Center, and Laboratory Center of the ARLG. These activities include shepherding concept proposal applications through peer review; identifying, qualifying, training, and overseeing clinical trials sites; recommending, developing, performing, and evaluating laboratory assays in support of clinical trials; and designing and performing data collection and statistical analyses. This article describes key components involved in realizing the ARLG scientific agenda through the activities of the ARLG centers.