Regulated necrosis and failed repair in cisplatin-induced chronic kidney disease

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Patients with end-stage renal disease have poor outcomes after endovascular abdominal aortic aneurysm repair

Objective

Although endovascular repair of abdominal aortic aneurysms (AAAs) has been demonstrated to have favorable outcomes, not all cohorts of patients with AAA fare equally well. Our goal was to investigate perioperative and 1-year outcomes in patients with end-stage renal disease (ESRD) on dialysis, who have traditionally fared worse after vascular interventions, to assess how ESRD affects outcomes in a large modern cohort of endovascular aneurysm repair (EVAR) patients.

Health Care Utilization After Ventricular Tachycardia Ablation: A Propensity Score-Matched Cohort Study

Background

Catheter ablation of ventricular tachycardia (VT) can reduce the burden of ventricular arrhythmia (VA) but its effect on health care utilization and costs after such therapy is poorly known. We sought to compare the rates of cardiovascular (CV)-related hospitalizations, survival, and health care costs in patients with recurrent VT treated either with VT ablation or with medical therapy.

Transmissible vaccines whose dissemination rates vary through time,with applications to wildlife

Transmission is a potential property of live viral vaccines that remains largely unexploited but may lie within the realm of many engineering designs. While likely unacceptable for vaccines of humans, transmission may be highly desirable for vaccines of wildlife, both to protect natural populations and also to limit zoonotic transmissions into humans. Defying intuition, transmission alone does not guarantee that a vaccine will perform well: the benefit of transmission over no transmission depends on and increases with the basic reproductive number of the vaccine, $R_0$. The $R_0$ of an infectious agent in a homogeneous population is typically considered to be a fixed number, but some evidence suggests that dissemination of transmissible vaccines may change through time. One obvious possibility is that transmission will be greater from hosts directly vaccinated than from hosts who acquire the vaccine passively, but other types of change might also accrue. Whenever transmission changes over time, the $R_0$ estimated from directly vaccinated hosts will not reflect the vaccine’s long term impact. As there is no theory on the consequences of changing transmission rates for a vaccine, we derive conditions for a transmissible vaccine with varying transmission rates to protect a population from pathogen invasion. Being the first in the transmission chain, the $R_0$ from directly vaccinated hosts has a larger effect than those from later steps in the chain. This mathematical property reveals that a transmissible vaccine with low long term transmission may nonetheless realize a big impact if early transmission is high. Furthermore, there may be ways to artificially elevate early transmission, thereby achieving high herd immunity from transmission while ensuring that the vaccine will ultimately die out.     

Sex bias of females in survival from cancer and infections. Is X the answer?

Major differences in survival of men and women from infectious diseases and cancers have been highlighted by death rates from COVID-19 infections. In cancer, attention has been focussed on differences in gene expression from X chromosomes in men and women with a preponderance of genes involved in immune responses being expressed in women. Important findings have been that some of the genes are important epigenetic regulators that play fundamental roles in immune responses.Subject terms: Cancer epigenetics, Oncology

One of the striking features of the coronavirus disease 2019 (COVID-19) outbreak has been the higher death rates in men even though the infection rates seem similar between men and women.¹ Similar findings were reported from Wuhan where men had 2.4 times the death rate of women² and in New York where press releases stated twice the death rate of men compared with women.³ Although men had higher rates of comorbidities, these differences were not considered sufficient to explain the higher death rates and other explanations have been sort. Women are considered to have stronger immune responses against infective diseases and a higher rate of autoimmune diseases, so this has questioned whether the lower death rate may have an immune basis.A sex bias is not only seen in infections, but also in cancers where a strong sex bias in survival from cancer is well documented.^4,5 For example, women in Australia have approximately half the death rates from melanoma as males.⁶ A number of explanations have been proposed to account for these major differences in melanoma, such as higher sun exposure in males⁷ and higher mutation rates⁸ in melanoma from males. When stringent statistical analyses are carried out, however, female sex remains as the major contributor to longer survival.⁴Melanoma is not the only cancer to show improved survival in females and previous researchers have asked whether this may be due to differences in the sex chromosomes between male and females. In a mammoth study, Dunford and colleagues examined information in The Cancer Genome Atlas (TCGA) from 21 different tumour types from 4100 cancers.⁵ They found that 6 out of 783 X chromosome genes had loss-of-function mutations with tumour-suppressive function in males but not in females. There were no similar differences in 18,055 non-X autosomal genes. Importantly, four of the six genes were known epigenetic regulators, such as KDM6A (lysine-specific demethylase 6A), KDM5C (lysine-specific demethylase 5C), ATRX (Alpha thalassaemia/mental retardation syndrome X-linked) and DDX3X (DEAD-box helicase 3 X-linked).⁵These findings point to important differences in X chromosomes between the sexes. The Y chromosome codes mainly for genes that determine male sex, but X chromosomes are quite large and code for >800 genes many of which are involved in immune responses.⁹ To equalise the number of genes between the sexes, one of the X chromosomes in females undergoes inactivation (Xi) of its genes.¹⁰ The silencing process is, however, not perfect and between 10 and 20% of the genes on the X may be expressed in females depending on the tissue involved. It is probably of significance that failure to silence genes may be particularly high in activated lymphocytes.¹¹ As a result of this phenomenon, females have double expression of many genes involved in immune responses compared with males. Biologists have speculated that this is an evolutionary mechanism to protect the species by enhancing immune responses in females against harmful infections.Analysis of data in the TCGA on 458 melanoma patients revealed that KDM6A expression was strongly related to improved survival from melanoma in female patients. ATRX had prognostic significance in both sexes. Analysis of another series of 678 patients with earlier melanoma referred to as the Leeds Melanoma Cohort confirmed the association with KDM6A expression and also identified KDM5C and DDX3X as being related to improved survival.¹² Immune responses are known to be critical in survival from melanoma and the TCGA analysis allowed us to link high KDM6A to components of the immune system considered important in killing of melanoma. This was particularly so in the production of interferon γ in female patients which is a key cytokine needed by the immune system to kill cancer cells. Gene set analysis also showed downregulation of Myc and other oncogenic pathways that may have contributed to the improvement in survival.¹²These data add to a number of studies implicating KDM6A in immune responses against viral infections and in autoimmune diseases.¹³ At a molecular level, KDM6A is known to have an opposing role to EZH2 (enhancer of Zeste homologue 2) in the PRC2 complex in methylation of Lys 27 on H3 histone. This role may explain some of the effects of KDM6A on the immune system in that we previously reported that EZH2 was associated with the repression of several genes associated with antigen presentation and chemokines involved in T cell responses.¹⁴Although these studies are compelling in linking KDM6A to immune responses, it is still questionable whether it has a role in immune responses against COVID-19. If this was the case, we would expect that women being treated for severe COVID-19 infections in intensive care would have lower KDM6A expression than those with infections not requiring such care.¹⁵ We examined the RNA-seq data from blood samples of 102 COVID-19 patients. This included 38 women and 64 men, where 17 women and 34 men were admitted to intensive care unit. The analysis of KDM6A levels in the women showed that treatment in intensive care unit was associated with higher KDM6A expression ({"type":"entrez-geo","attrs":{"text":"GSE157103","term_id":"157103"}}GSE157103,¹⁵ data not shown). Although this was unexpected, it may indicate that KDM6A expression was linked to stronger responses causing higher inflammation in organs such as the lungs. No differences in KDM6A levels were detected in men irrespective of whether they were admitted to intensive care or not.Female patients with bi-allelic expression of KDM6A may induce the expression of interferon γ pathways which enhance anti-tumour immunity by recruiting immune modulatory cells (Fig. 1). These results point to the need for a better understanding of the role of X-linked genes in immune responses and whether EZH2-mediated suppression of immune modulatory genes have a role in infections as well as in cancer. In cancers and infections that have worst outcomes in males versus females, one approach might be to target (inhibit) the EZH2 epigenetic regulator that opposes KDM6A (Fig. 1). Another option may be to increase levels of KDM6A by administration of oestrogens. Oestrogen α receptors are expressed in practically all lymphocytes and were shown to physically interact with KDM6A to create a permissive chromatin state on endoplasmic reticulum (ER) targets such as C-X-C chemokine motif receptor 4.¹⁶ It was transactivated by ER to form a feed-forward loop. Administration of 17β-oestradiol has been suggested by others as treatment for COVID-19 infections.¹⁷Open in a separate windowFig. 1Proposed model of sex-biased role of the X-linked KDM6A gene in promoting immunity.Males harbour one X chromosome with no functional Y chromosome homologue. Hence, mutation in the X-linked epigenetic modifier KDM6A with tumour-suppressive or immunomodulatory role will probably lead to cancer or infection in males. Immune-related genes will be repressed by EZH2-mediated H3K27me3 deposition resulting in low KDM6A protein and immune evasion in male patients. In females, with two X chromosome, [one active (Xa) and one inactive (Xi)], a single mutation (m) in KDM6A is less likely to develop cancer or infections since another functional allele escapes X inactivation. Cells with high KDM6A level would be expected to demethylate H3K27me3 resulting in activation of the interferon γ pathway resulting in inactivation of natural killer (NK), dendritic or cytotoxic T cells to induce anti-tumour immunity and adaptive immunity against virus-infected cells.These studies have therefore raised many questions that require more detailed study to identify how the powerful survival benefits of the X-linked epigenetic regulators might be used to improve the therapeutic outcome in patients.     

Black beans and red kidney beans induce positive postprandial vascular responses in healthy adults: A pilot randomized cross-over study

Background and aimsConsuming pulses (dry beans, dry peas, chickpeas, lentils) over several weeks can improve vascular function and decrease cardiovascular disease risk; however, it is unknown whether pulses can modulate postprandial vascular responses. The objective of this study was to compare different bean varieties (black, navy, pinto, red kidney) and white rice for their acute postprandial effects on vascular and metabolic responses in healthy individuals.Methods and resultsThe study was designed as a single-blinded, randomized crossover trial with a minimum 6 days between consumption of the food articles. Vascular tone (primary endpoint), haemodynamics and serum biochemistry (secondary endpoints) were measured in 8 healthy adults before and at 1, 2, and 6 h after eating ¾ cup of beans or rice. Blood pressure and pulse wave velocity (PWV) were lower at 2 h following red kidney bean and pinto bean consumption compared to rice and navy bean, respectively (p < 0.05). There was greater vasorelaxation 6 h following consumption of darker-coloured beans, as shown by decreased vascular tone: PWV was lower after consuming black bean compared to pinto bean, augmentation pressure was lower after consuming black bean compared to rice and pinto bean, and wave reflection magnitude was lower after consuming red kidney bean and black bean compared to rice, navy bean, and pinto bean (p < 0.05). LDL-cholesterol concentrations were lower 6 h after black bean consumption compared to rice (p < 0.05).ConclusionOverall, red kidney and black beans, the darker-coloured beans, elicited a positive effect on the tensile properties of blood vessels, and this acute response may provide insight for how pulses modify vascular function.     

The mutational landscape of melanoma brain metastases presenting as the first visceral site of recurrence

Brain metastases are a major cause of melanoma-related mortality and morbidity. We undertook whole-exome sequencing of 50 tumours from patients undergoing surgical resection of brain metastases presenting as the first site of visceral disease spread and validated our findings in an independent dataset of 18 patients. Brain metastases had a similar driver mutational landscape to cutaneous melanomas in TCGA. However, KRAS was the most significantly enriched driver gene, with 4/50 (8%) of brain metastases harbouring non-synonymous mutations. Hotspot KRAS mutations were mutually exclusive from BRAF^V600, NRAS and HRAS mutations and were associated with a reduced overall survival from the resection of brain metastases (HR 10.01, p = 0.001). Mutations in KRAS were clonal and concordant with extracranial disease, suggesting that these mutations are likely present within the primary. Our analyses suggest that KRAS mutations could help identify patients with primary melanoma at higher risk of brain metastases who may benefit from more intensive, protracted surveillance.Subject terms: CNS cancer, Metastasis, Melanoma, Tumour biomarkers, Cancer     

Analysis of Stroke Detection during the COVID-19 Pandemic Using Natural Language Processing of Radiology Reports

BACKGROUND AND PURPOSE:The coronavirus disease 2019 (COVID-19) pandemic has led to decreases in neuroimaging volume. Our aim was to quantify the change in acute or subacute ischemic strokes detected on CT or MR imaging during the pandemic using natural language processing of radiology reports.MATERIALS AND METHODS:We retrospectively analyzed 32,555 radiology reports from brain CTs and MRIs from a comprehensive stroke center, performed from March 1 to April 30 each year from 2017 to 2020, involving 20,414 unique patients. To detect acute or subacute ischemic stroke in free-text reports, we trained a random forest natural language processing classifier using 1987 randomly sampled radiology reports with manual annotation. Natural language processing classifier generalizability was evaluated using 1974 imaging reports from an external dataset.RESULTS:The natural language processing classifier achieved a 5-fold cross-validation classification accuracy of 0.97 and an F1 score of 0.74, with a slight underestimation (−5%) of actual numbers of acute or subacute ischemic strokes in cross-validation. Importantly, cross-validation performance stratified by year was similar. Applying the classifier to the complete study cohort, we found an estimated 24% decrease in patients with acute or subacute ischemic strokes reported on CT or MR imaging from March to April 2020 compared with the average from those months in 2017–2019. Among patients with stroke-related order indications, the estimated proportion who underwent neuroimaging with acute or subacute ischemic stroke detection significantly increased from 16% during 2017–2019 to 21% in 2020 (P = .01). The natural language processing classifier performed worse on external data.CONCLUSIONS:Acute or subacute ischemic stroke cases detected by neuroimaging decreased during the COVID-19 pandemic, though a higher proportion of studies ordered for stroke were positive for acute or subacute ischemic strokes. Natural language processing approaches can help automatically track acute or subacute ischemic stroke numbers for epidemiologic studies, though local classifier training is important due to radiologist reporting style differences.

There is much concern regarding the impact of the coronavirus disease 2019 (COVID-19) pandemic on the quality of stroke care, including issues with hospital capacity, clinical resource re-allocation, and the safety of patients and clinicians.^1,2 Previous reports have shown that there have been substantial decreases in stroke neuroimaging volume during the pandemic.^3,4 In addition, acute ischemic infarcts have been found on neuroimaging studies in many hospitalized patients with COVID-19, though the causal relationship is unclear.^5,6 Studies like these and other epidemiologic analyses usually rely on the creation of manually curated databases, in which identification of cases can be time-consuming and difficult to update in real-time. One way to facilitate such research is to use natural language processing (NLP), which has shown utility for automated analysis of radiology report data.⁷ NLP algorithms have been developed previously for the classification of neuroradiology reports for the presence of ischemic stroke findings and acute ischemic stroke subtypes.^8,9 Thus, NLP has the potential to facilitate COVID-19 research.In this study, we developed an NLP machine learning model that classifies radiology reports for the presence or absence of acute or subacute ischemic stroke (ASIS), as opposed to chronic stroke. We used this model to quantify the change in ASIS detected on all CT or MR imaging studies performed at a large comprehensive stroke center during the COVID-19 pandemic in the United States. We also evaluated NLP model generalizability and different training strategies using a sample of radiology reports from a second stroke center.     

Can MRI differentiate between atypical cartilaginous tumors and high-grade chondrosarcoma? A systematic review

Background and purpose — Adequate staging of chondroid tumors at diagnosis is important as it determines both treatment and outcome. This systematic review provides an overview of MRI criteria used to differentiate between atypical cartilaginous tumors (ACT) and high-grade chondrosarcoma (HGCS).Patients and methods — For this systematic review PubMed and Embase were searched, from inception of the databases to July 12, 2018. All original articles describing MRI characteristics of pathologically proven primary central chondrosarcoma and ACT were included. A quality appraisal of the included papers was performed. Data on MRI characteristics and histological grade were extracted by 2 reviewers. Meta-analysis was performed if possible. The study is registered with PROSPERO, CRD42018067959.Results — Our search identified 2,132 unique records, of which 14 studies were included. 239 ACT and 140 HGCS were identified. The quality assessment showed great variability in consensus criteria used for both pathologic and radiologic diagnosis. Due to substantial heterogeneity we refrained from pooling the results in a meta-analysis and reported non-statistical syntheses. Loss of entrapped fatty marrow, cortical breakthrough, and extraosseous soft tissue expansion appeared to be present more often in HGCS compared with ACT.Interpretation — This systematic review provides an overview of MRI characteristics used to differentiate between ACT and HGCS. Future studies are needed to develop and assess more reliable imaging methods and/or features to differentiate ACT from HGCS.

The incidence of chondrosarcoma of bone appears to have been increasing during the last decade and is now reported to be the most common primary malignant bone tumor in several countries (Thorkildsen et al. 2018, van Praag et al. 2018). Conventional chondrosarcoma is the most common subtype of chondrosarcoma. Other subtypes of chondrosarcoma (e.g., juxtacortical, mesenchymal, or secondary chondrosarcoma) are rare and show different radiologic appearance and clinical behavior (Bindiganavile et al. 2015).Conventional chondrosarcoma is classified into the histological grades 1 (currently known as atypical cartilaginous tumor [ACT]), 2, and 3. The metastatic potential, and therefore the disease-specific survival, correlates with the histological grade (Fletcher et al. 2013, Laitinen et al. 2018, Thorkildsen et al. 2018). ACTs rarely metastasize and are therefore reclassified as an intermediate type of tumor, not a malignancy (Fletcher et al. 2013). Due to the increase in patients undergoing MRI examinations for joint-related complaints, the incidental detection of ACT has increased substantially (van Praag et al. 2018).With the increasing incidence of ACT, clear radiologic criteria to differentiate ACT from high-grade chondrosarcoma (i.e., grades 2 and 3) become more and more important. Adequate staging of chondroid tumors at diagnosis is important as it determines both treatment and prognosis. High-grade chondrosarcomas behave aggressively. Between 10% and 30% of grade 2 and about 70% of grade 3 chondrosarcomas metastasize (Evans et al. 1977). Hence, high-grade chondrosarcoma (HGCS) requires wide en bloc resection with free surgical margins. In contrast, ACTs are intermediate tumors and can be treated either with intralesional curettage and local adjuvant or nonoperatively with regular follow-up when located in the long bones (Deckers et al. 2016).Due to the heterogenous composition of chondroid tumors, diagnostic biopsy is unreliable in assessing the genuine histological grade and malignant potential of chondrosarcomas (Laitinen et al. 2018). Therefore, physicians need to rely on imaging and clinical findings (e.g., pain is more common in HGCS) to differentiate ACT from HGCS. Imaging evaluation of cartilaginous and other bone tumors is generally based on multimodal assessment including at least conventional radiography and MRI (Nascimento et al. 2014).During the most recent decades research has focused mainly on differentiating enchondroma from chondrosarcoma (Choi et al. 2013, Douis et al. 2014, Crim et al. 2015, Lisson et al. 2018). New insights have shown that both enchondroma and ACT located in the long bones can be observed without treatment (Deckers et al. 2016, Sampath Kumar et al. 2016, Chung et al. 2018). These insights make the differentiation between ACT and HGCS clinically relevant. Currently, literature on differentiating ACT from HGCS is sparse and clear radiologic criteria are lacking. Therefore, we performed a systematic review to provide an overview of MRI characteristics used to date to differentiate between ACT and HGCS.