Search

Background: BXQ-350 is a novel anti-neoplastic agent composed of saposin C (SapC) and phospholipid dioleoylphosphatidyl-serine sodium (DOPS) that selectively binds tumor cell phosphatidylserine (PS), inducing apoptosis. BXQ-350 has demonstrated preclinical antitumor effects in high-grade gliomas (HGG) and clinical activity in adult patients with recurrent HGG. Methods: A phase 1 study was conducted in pediatric patients with relapsed/refractory solid tumors, including recurrent brain tumors. Primary objectives were to characterize safety and determine maximum tolerated dose (MTD) and preliminary antitumor activity. Sequential dose cohorts were assessed up to 3.2 mg/kg using an accelerated titration design. Each cycle was 28 days; dosing occurred on days 1–5, 8, 10, 12, 15, and 22 of cycle 1, and day 1 of subsequent cycles, until disease progression or toxicity. Results: Nine patients, median age 10 years (range: 4–23), were enrolled. Seven patients (78%) had central nervous system (CNS) and two (22%) had non-CNS tumors. Eight patients completed cycle 1. No dose limiting toxicity (DLT) or BXQ-350-related serious adverse events (SAEs) were observed. Six patients experienced at least one adverse event (AE) considered possibly BXQ-350-related, most were grade ≤2. One patient with diffuse intrinsic pontine glioma experienced stable disease for 5 cycles. The study was terminated after part 1 to focus development on the frontline setting. Conclusion: No DLTs or BXQ-350-related SAEs were reported, and the maximal planned dose of 3.2 mg/kg IV was tolerable. Limited safety and efficacy data support continued BXQ-350 development in pediatric HGG; however, early discontinuations for progression suggest novel therapies be assessed at earlier disease stages.

ABSTRACTIn today’s industrialized society food consumption has changed immensely toward heightened red meat intake and use of artificial sweeteners instead of grains and vegetables or sugar, respectively. These dietary changes affect public health in general through an increased incidence of metabolic diseases like diabetes and obesity, with a further elevated risk for cardiorenal complications. Research shows that high red meat intake and artificial sweeteners ingestion can alter the microbial composition and further intestinal wall barrier permeability allowing increased transmission of uremic toxins like p-cresyl sulfate, indoxyl sulfate, trimethylamine n-oxide and phenylacetylglutamine into the blood stream causing an array of pathophysiological effects especially as a strain on the kidneys, since they are responsible for clearing out the toxins. In this review, we address how the burden of the Western diet affects the gut microbiome in altering the microbial composition and increasing the gut permeability for uremic toxins and the detrimental effects thereof on early vascular aging, the kidney per se and the blood-brain barrier, in addition to the potential implications for dietary changes/interventions to preserve the health issues related to chronic diseases in future.

Abstract Background Chronic kidney disease (CKD) is linked to an increased cardiovascular disease (CVD) burden. Albeit underappreciated, sex differences are evident in CKD with females being more prone to CKD development, but males progressing more rapidly to kidney failure (KF). Cardiovascular remodelling is a hallmark of CKD with increased arterial and valvular calcification contributing to CKD. However, little is known regarding sex differences in calcific cardiovascular remodelling in KF patients. Thus, we hypothesise that sex differences are present in coronary artery calcification (CAC) and aortic valve calcification (AVC) in patients with KF. Methods KF patients, males (n = 214) and females (n = 107), that had undergone computer tomography (CT) assessment for CAC and AVC were selected from three CKD cohorts. All patients underwent non-contrast multi-detector cardiac CT scanning, with CAC and AVC scoring based on the Agatston method. Baseline biochemical measurements were retrieved from cohort databases, including plasma analyses for inflammation markers (IL-6, TNF, hsCRP) and oxidative stress by skin autofluorescence measuring advanced glycation end-products (AGE), amongst other variables. Results Sex-disaggregated analyses revealed that CAC score was associated with age in both males and females (both p

Circulating cell-free DNA (cfDNA) has diverse applications in oncological, prenatal, toxicological, cardiovascular, and autoimmune diseases, diagnostics, and organ transplantation. In particular, mitochondrial cfDNA (mt-cfDNA) is associated with inflammation and linked to early vascular ageing (EVA) in end-stage kidney failure (ESKF), which could be a noninvasive marker for graft rejection and organ damage. Plasma samples from 44 ESKF patients, of whom half (n = 22) underwent either conservative therapy (non-HD) or hemodialysis (HD) before kidney transplantation (KT). These samples were analyzed at baseline and two years after KT. cfDNA was extracted from plasma and quantified using the fluorometric method. qPCR was used to quantify and differentiate the fractions of mt-cfDNA and nuclear cfDNA (nc-cfDNA). mt-cfDNA levels in KT patients decreased significantly from baseline to two years post-KT (p < 0.0268), while levels of total cfDNA and nc-cfDNA did not differ. Depending on therapy modality (HD vs. non-HD) before KT, total cfDNA levels were higher in HD patients at both baseline (p = 0.0133) and two years post-KT (p = 0.0421), while nc-cfDNA levels were higher in HD only at baseline (p = 0.0079). Males showed a nonsignificant trend of higher cfDNA levels. Patients with assessed vascular fibrosis (p = 0.0068), either alone or in combination with calcification plus fibrosis, showed reduced mt-cfDNA post-KT (p = 0.0195). Changes in mt-cfDNA levels suggests the impact of KT on the inflammatory state of ESKF, as evidenced via its correlation with high sensitivity C-reactive protein after KT. Further studies are warranted to assess if cfDNA could serve as a noninvasive method for monitoring the response to organ transplantation and even for amelioration of EVA status per se.

Abstract Kidney failure and associated uraemia have implications for the cardiovascular system, brain, and blood–brain barrier (BBB). We aim to examine BBB disruption, by assessing brain-derived neurotropic factor (BDNF), neuron-specific enolase (NSE) levels, and gut-blood barrier (GBB) disruption by trimethylamine N-oxide (TMAO), in chronic kidney disease (CKD) patients. Additionally, endothelial tight-junction protein expressions and modulation via TMAO were assessed. Serum from chronic kidney disease (CKD) female and male haemodialysis (HD) patients, and controls, were used to measure BDNF and NSE by enzyme-linked immunosorbent assays, and TMAO by mass spectrometry. Immunofluorescent staining of subcutaneous fat biopsies from kidney transplant recipients, and controls, were used to measure microvascular expression of tight-junction proteins (claudin-5, occludin, JAM-1), and control microvasculature for TMAO effects. HD patients versus controls, had significantly lower and higher serum levels of BDNF and NSE, respectively. In CKD biopsies versus controls, reduced expression of claudin-5, occludin, and JAM-1 were observed. Incubation with TMAO significantly decreased expression of all tight-junction proteins in the microvasculature. Uraemia affects BBB and GBB resulting in altered levels of circulating NSE, BDNF and TMAO, respectively, and it also reduces expression of tight-junction proteins that confer BBB maintenance. TMAO serves as a potential candidate to alter BBB integrity in CKD.

FDA approval of targeted therapies for lung cancer has significantly improved patient survival rates. Despite these improvements, barriers to timely access to biomarker information, such as nucleic acid input, still exist. Here, we report the analytical performance and concordance with next-generation sequencing (NGS) of a highly multiplexed research-use-only (RUO) panel using digital PCR (dPCR). The panel’s analytical sensitivity and reactivity were determined using contrived DNA and RNA mixes. The limit of blank was established by testing FFPE curls classified as negative by pathology. Concordance was established on 77 FFPE samples previously characterized using the Oncomine Precision Assay®, and any discordant results were resolved with Archer Fusionplex® and Variantplex® panels. The analytical sensitivity, reported as the estimated mutant allele fraction (MAF), for DNA targets ranged from 0.1 to 0.9%. For RNA targets (ALK, RET, ROS, NTRK 1/2/3 Fusions, and MET Exon 14 skipping alteration), the analytical sensitivity ranged from 23 to 101 detected counts with 5 ng of total RNA input. The population prevalence-based coverage ranged from 89.2% to 100.0% across targets and exceeded 99.0% in aggregate. The assay demonstrated >97% concordance with respect to the comparator method.

Abstract Background Sex differences are underappreciated in the current understanding of cardiovascular disease (CVD) in association with chronic kidney disease (CKD). A hallmark of CKD is vascular aging that is characterised, amongst others, by; systemic inflammation, microbiota disbalance, oxidative stress, and vascular calcification—features linked to atherosclerosis/arteriosclerosis development. Thus, it is the necessary to introduce novel biomarkers related to athero-/arteriosclerotic damage for better assessment of vascular ageing in patients CKD. However, little is known about the relationship between uraemia and novel CVD biomarkers, such as growth differentiation factor-15 (GDF-15), cartilage glycoprotein-39 (YKL-40) and matrix metalloproteinase-9 (MMP-9). Therefore, we hypothesise that there are sex-specific relationships between GDF-15, YKL-40, MMP-9 levels in end-stage kidney disease (ESKD) patients in relation to gut microbiota, vascular calcification, inflammation, comorbidities, and all-cause mortality. Methods ESKD patients, males (n = 151) and females (n = 79), not receiving renal replacement therapy were selected from two ongoing prospective ESKD cohorts. GDF-15, YKL-40 and MMP9 were analysed using enzyme-linked immunosorbent assay kits. Biomarker levels were analysed in the context of gut microbiota-derived trimethylamine N-oxide (TMAO), vascular calcification, inflammatory response, oxidative stress, comorbidities, and all-cause mortality. Results Increased GDF-15 correlated with higher TMAO in females only, and with higher coronary artery calcification and IL-6. In females, diabetes was associated with elevated GDF-15 and MMP-9, whilst males with diabetes only had elevated GDF-15. No associations were found between biomarkers and CVD comorbidity. Deceased males and females had higher GDF-15 concentrations (p = 0.01 and p

Cardio-pulmonary diseases, which were once regarded as a man's illness, have been one of the leading causes of morbidity and mortality for both men and women in many countries in recent years. Both gender and sex influence the functional and structural changes in the human body and therefore play an important role in disease clinical manifestation, treatment choice, and/or response to treatment and prognosis of health outcomes. The gender dimension integrates sex and gender analysis in health sciences and medical research, however, it is still relatively overlooked suggesting the need for empowerment in the medical research community. Latest advances in the field of cardiovascular research have provided supportive evidence that the application of biological variables of sex has led to the understanding that heart disease in females may have different pathophysiology compared to males, particularly in younger adults. It has also resulted in new diagnostic techniques and a better understanding of symptomatology, while gender analysis has informed more appropriate risk stratification and prevention strategies. The existing knowledge in the pulmonary field shows the higher prevalence of pulmonary disorders among females, however, the role of gender as a socio-cultural construct has yet to be explored for the implementation of targeted interventions. The purpose of this review is to introduce the concept of gender dimension and its importance for the cardiopulmonary continuum with a focus on shared pathophysiology and disease presentation in addition to interrelation with chronic kidney disease. The review presents basic knowledge of what gender dimension means, and the application of sex and gender aspects in cardiovascular medicine with a specific focus on early pulmonary development, pulmonary hypertension, and chronic obstructive pulmonary disease (COPD). Early vascular aging and inflammation have been presented as a potential pathophysiological link, with further interactions between the cardiopulmonary continuum and chronic kidney disease. Finally, implications for potential future research have been provided to increase the impact of gender dimension on research excellence that would add value to everybody, foster toward precision medicine and ultimately improve human health.

Category: Trauma Introduction/Purpose: Currently there is minimal focus on traumatic lower extremity amputations due to their relatively low incidence, but they often come with a higher morbidity and mortality than its upper extremity counterparts. The purpose of this study was to evaluate the incidence and trends of lower extremity amputations in the United States over a ten-year period. Methods: The National Electronic Injury Surveillance System (NEISS), was used for evaluation of lower extremity amputations that presented to the United States emergency departments. The overall incidence rate of lower extremity amputations within the United States was calculated as per 100,000 persons. After grouping mechanisms of injury, the data were stratified by both age groups and gender. Chi-square tests were used for direct comparisons of proportions. The five most common mechanisms were ranked for each age group and the most common overall age group for lower extremity amputations were determined using descriptive statistics. Trends for injury incidence and hospital admissions were evaluated using linear regression and Pearson correlation with Bonferroni correction. Results: From 2008 to 2017, 393 patients were reported to have sustained lower extremity amputations via the NIESS database with an estimated 11,475 patients sustaining a lower extremity amputation over the past ten years and an incidence of 2.2/100,000 person-years. The incidence of lower extremity amputations is highest in those less than five years old. Lawnmower incidents are the most common mechanism of injury in all age groups. Conclusion: Due to the high morbidity and mortality associated with these injuries, it is prudent to follow the trends in lower extremity amputations.

Category: Ankle; Bunion Introduction/Purpose: Peripheral nerve blocks have become an integral part of orthopedic surgery to assist with postoperative pain. However, 40% of patients who undergo a peripheral nerve block will experience rebound pain, which in turn, long-acting narcotics may be able to block. Unfortunately, this rebound pain can cancel out the potential benefits of decreased opioid medication use. Therefore, this study seeks to compare the difference in patient reported pain scores in those patients whom received long-acting opioid pain medication and those who did not. Methods: This is a retrospective review of patient-reported pain scores for 96 patients who underwent a peripheral nerve block for outpatient foot and ankle surgery. 48 patients either received three days of long-acting opioids or did not. Each patient was asked to fill out and return a pain diary as well as fill out a pain catastrophizing survey (PCS) at their postoperative appointment. The pain diary discussed their Visual Analogue Scale pain scores, amount of pain medication, and time they took the medicine. This data was then collected and compared via paired student t-tests for evaluation of significance. Results: Pain diaries were completed by 69 patients (72%). There were no significant differences between those comorbidities, types of procedures, age, or BMI between the groups. Mean postoperative pain scores did not differ between patients that did and did not receive postoperative extended release opioid medications (p = 0.226). Mean opioid consumption did not differ between groups (p = 0.945). There were no correlations between daily reported pain scores or the postoperative day with the highest pain score for those who received long acting opioid pain medication versus those who did not (r=0.336, p=0.550). Conclusion: Rebound pain is a difficult potential side effect of peripheral nerve blocks that currently does not have a preventative measure. This study was an attempted effort to help eliminate rebound pain, but there did not appear to be a significant benefit to adding long-acting opioid pain medication in addition to the peripheral nerve block and short-acting pain medication

Introduction The emergency department (ED) presents a challenging task-management environment to emergency medicine (EM) trainees. However, equipping residents with a tool to improve task switching (generically known as multitasking) could have positive impacts on patient care and physician emotional state. We designed a task-management tool and educational curriculum with the goal of improving emergency medicine resident task-switching ability. Methods The task-management tool uses the acronym SPRINT: (1) stabilize critical patients, (2) perform procedures, (3) rack (see new patients in the chart rack), (4) in or out (reassess and disposition), (5) type it up (chart completion). These tasks and their order were decided on by two seasoned clinicians based on their years of experience in the ED. The SPRINT tool was taught to EM residents through a 1-hour curriculum consisting of an introductory video, a classroom-based workshop with multimedia didactics, and team learning with a card game simulating the use of the SPRINT tool on a shift. Residents were surveyed to evaluate their task-management confidence and perceived effectiveness of the curriculum. Results A total of 34 EM residents participated in this training on the SPRINT tool. There was an improvement in resident confidence in task management, and residents reporting having a strategy for task prioritization 8 weeks after the workshop. Discussion The SPRINT curriculum provides EM residents with a tool to manage the complex task-management environment of the ED. Further research in task-management education should focus on patient-oriented outcomes among physicians who have received this training.

Understanding the molecular mechanisms that regulate secondary cell death after acute central nervous system (CNS) injury is critical for the development of effective neuroprotective drugs. Previous research has shown that neurotoxic processes including excitotoxicity, oxidative stress and neuroinflammation can cause secondary cell death. Nevertheless, clinical trials targeting these processes have been largely unsuccessful, suggesting that the signalling pathways underlying secondary cell death remain incompletely understood. Due to their suitability for live imaging and their amenability to genetic and pharmacological manipulation, larval zebrafish provide an ideal platform for studying the regulation of secondary cell death in vivo. Here, we use RNA-seq gene expression profiling and compound screening to identify signalling pathways that regulate secondary cell death after acute neural injury in larval zebrafish. RNA-seq analysis of genes upregulated in cephalic mpeg1+ macrophage-lineage cells isolated from mpeg1:GFP transgenic larvae after neural injury suggested an involvement of cytokine and polyamine signalling in secondary cell death. Furthermore, screening a library of FDA approved compounds indicated roles for GABA, serotonin and dopamine signalling. Overall, our results highlight multiple signalling pathways that regulate secondary cell death in vivo, and thus provide a starting point for the development of novel neuroprotective treatments for patients with CNS injury. This article has an associated First Person interview with the two first authors of the paper.

Abstract Background People with type 2 diabetes (T2D) have impaired exercise capacity, even in the absence of complications, which is predictive of their increased cardiovascular mortality. Cardiovascular dysfunction is one potential cause of this exercise defect. Acute infusion of vitamin C has been separately shown to improve diastolic and endothelial function in prior studies. We hypothesized that acute vitamin C infusion would improve exercise capacity and that these improvements would be associated with improved cardiovascular function. Methods Adults with T2D (n = 31, 7 female, 24 male, body mass index (BMI): 31.5 ± 0.8 kg/m2) and BMI-similar healthy adults (n = 21, 11 female, 10 male, BMI: 30.4 ± 0.7 kg/m2) completed two randomly ordered visits: IV infusion of vitamin C (7.5 g) and a volume-matched saline infusion. During each visit peak oxygen uptake (VO2peak), brachial artery flow mediated dilation (FMD), reactive hyperemia (RH; plethysmography), and cardiac echocardiography were measured. General linear mixed models were utilized to assess the differences in all study variables. Results Acute vitamin C infusion improved diastolic function, assessed by lateral and septal E:E’ (P