Deletion of Hsd11b1 suppresses caloric restriction-induced bone marrow adiposity in male but not female mice.

Bone marrow adipose tissue (BMAT) comprises >10% of total adipose mass in healthy humans. It increases in diverse conditions, including ageing, obesity, osteoporosis, glucocorticoid therapy, and notably, during caloric restriction (CR). BMAT potentially influences skeletal, metabolic, and immune functions, but the mechanisms of BMAT expansion remain poorly understood. Our hypothesis is that, during CR, excessive glucocorticoid activity drives BMAT expansion. The enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) amplifies glucocorticoid activity by catalysing intracellular regeneration of active glucocorticoids from inert 11-keto forms. Mice lacking 11ß-HSD1 resist metabolic dysregulation and bone loss during exogenous glucocorticoid excess; thus, we hypothesised that 11ß-HSD1 knockout mice would also resist excessive glucocorticoid action during CR, thereby restrining BMAT expansion and bone loss. To test this, we first confirmed that 11ß-HSD1 is expressed in mouse and human bone marrow. We then investigated the effects of CR in male and female control and 11ß-HSD1 knockout mice from 9 to 15 weeks of age. CR increased Hsd11b1 mRNA in adipose tissue and bone marrow. Deletion of Hsd11b1 did not alter bone or BMAT characteristics in mice fed a control diet and had little effect on tibial bone microarchitecture during CR. Notably, Hsd11b1 deletion attenuated the CR-induced increases in BMAT and prevented increases in bone marrow corticosterone in males but not females. This was not associated with suppression of glucocorticoid target genes in bone marrow. Instead, knockout males had increased progesterone in plasma and bone marrow. Together, our findings show that knockout of 11ß-HSD1 prevents CR-induced BMAT expansion in a sex-specific manner and highlights progesterone as a potential new regulator of bone marrow adiposity.

Consensus statement on the interhospital transfer of patients with acute aortic syndrome: TRAVERSING Delphi study.

BACKGROUND: Standardisation of referral pathways and the transfer of patients with acute aortic syndromes (AAS) to regional centres are recommended by NHS England in the Acute Aortic Dissection Toolkit. The aim of the Transfer of Thoracic Aortic Vascular Emergencies to Regional Specialist INstitutes Group study was to establish an interdisciplinary consensus on the interhospital transfer of patients with AAS to specialist high-volume aortic centres. METHODS: Consensus on the key aspects of interhospital transfer of patients with AAS was established using the Delphi method, in line with Conducting and Reporting of Delphi Studies guidelines. A national patient charity for aortic dissection was involved in the design of the Delphi study. Vascular and cardiothoracic surgeons, emergency physicians, interventional radiologists, cardiologists, intensivists and anaesthetists in the United Kingdom were invited to participate via their respective professional societies. RESULTS: Three consecutive rounds of an electronic Delphi survey were completed by 212, 101 and 58 respondents, respectively. Using predefined consensus criteria, 60 out of 117 (51%) statements from the survey were included in the consensus statement. The study concluded that patients can be taken directly to a specialist aortic centre if they have typical symptoms of AAS on the background of known aortic disease or previous aortic intervention. Accepted patients should be transferred in a category 2 ambulance (response time <18 min), ideally accompanied by transfer-trained personnel or Adult Critical Care Transfer Services. A clear plan should be agreed in case of a cardiac arrest occurring during the transfer. Patients should reach the aortic centre within 4 hours of the initial referral from their local hospital. CONCLUSIONS: This consensus statement is the first set of national interdisciplinary recommendations on the interhospital transfer of patients with AAS. Its implementation is likely to contribute to safer and more standardised emergency referral pathways to regional high-volume specialist aortic units.

Autocrine IL-6 drives cell and extracellular matrix anisotropy in scar fibroblasts.

Fibrosis is associated with dramatic changes in extracellular matrix (ECM) architecture of unknown etiology. Here we exploit keloid scars as a paradigm to understand fibrotic ECM organization. We reveal that keloid patient fibroblasts uniquely produce a globally aligned ECM network in 2-D culture as observed in scar tissue. ECM anisotropy develops after rapid initiation of a fibroblast supracellular actin network, suggesting that cell alignment initiates ECM patterning. Keloid fibroblasts produce elevated levels of IL-6, and autocrine IL-6 production is both necessary and sufficient to induce cell and ECM alignment, as evidenced by ligand stimulation of normal dermal fibroblasts and treatment of keloid fibroblasts with the function blocking IL-6 receptor monoclonal antibody, tocilizumab. Downstream of IL-6, supracellular organization of keloid fibroblasts is controlled by activation of cell-cell adhesion. Adhesion formation inhibits contact-induced cellular overlap leading to nematic organization of cells and an alignment of focal adhesions. Keloid fibroblasts placed on isotropic ECM align the pre-existing matrix, suggesting that focal adhesion alignment leads to active anisotropic remodeling. These results show that IL-6-induced fibroblast cooperativity can control the development of a nematic ECM, highlighting both IL-6 signaling and cell-cell adhesions as potential therapeutic targets to inhibit this common feature of fibrosis.

Infection, nutritional status, and body composition: Associations at birth and 6 months postnatally in Soweto, South Africa.

INTRODUCTION: The impact of infection on infant nutritional status, body size, and growth is well documented. However, research into the impact of infection on infant body composition is limited. Greater understanding is, therefore, needed on the effects of infection in early life. METHODS: Associations between a composite morbidity index consisting of the sum of the cumulative tallies for a range of symptoms representing infection and morbidity in the infants and nutritional status (height-for-age (HAZ), and weight-for-height (WHZ)), and body composition (fat-free mass (FFM), fat mass (FM), fat-free mass index (FFMI), and fat mass index (FMI)) at 6 months of age were investigated using hierarchical regression analysis. RESULTS: The sample comprised data between birth and 6 months postnatally, of 156 infants who were a priori born healthy in Soweto, South Africa. Morbidity, over the cumulative period of birth to 6 months, was associated with lower FMI (ß = -1.77) and lower FM (ß = -0.61), and conversely with higher FFM (ß = 0.94), in infants at 6 months. No associations were found between the morbidity index and FFMI, HAZ, and WHZ. Increased birthweight was associated with a higher FFM (ß = 0.66), HAZ (ß = 1.14), and WHZ (ß = 0.87). Finally, safely managed sanitation facilities, representative of reduced environmental exposure to fecal-oral transmission pathways were associated with a higher HAZ (ß = 1.21). DISCUSSION: Reduction in FMI and FM and exposure to inflammatory cytokines associated with mounting an immune response could alter phenotypic trajectories during to this period of plasticity. From a public health perspective, these results imply that it is important to intensify efforts to prevent infection in infants in the first 6 months postnatally, and that these efforts should concentrate on access to safely managed sanitation facilities.

Balance and Cognition in Male Collegiate Lacrosse Players.

Concussion screening among collegiate lacrosse athletes is a major safety priority. Although attention has been directed at concussion management following injury, less is known about the association between cognition and balance during preseason screening. The purpose of the study was to assess the relationship between balance and neurocognition among collegiate male lacrosse players and to examine predictive determinants of postural stability. Participants included a convenience sample of 49 male collegiate Division 3 lacrosse players who completed a demographic survey and performed the immediate postconcussion test (ImPACT) and instrumented Sensory Organization Test (SOT). There was a significant association between balance SOT performance and both verbal memory (r = .59, p < .01) and visual motor speed scores (r = .43, p < .05). Significant correlations between verbal memory and SOT Conditions 2, 5, and 6 were also noted (all p < .05). Verbal memory predicted 33% of the variance in the SOT composite balance score (p < .001). Our results indicate a significant relationship exists between postural stability and both verbal memory and visual processing speed among collegiate male lacrosse players and supports vestibulocortical associations. Findings warrant ongoing performance and executive function tracking and can serve as a conduit for integrated sensorimotor and dual-task training.

Single-cell analysis of senescent epithelia reveals targetable mechanisms promoting fibrosis.

Progressive fibrosis and maladaptive organ repair result in significant morbidity and millions of premature deaths annually. Senescent cells accumulate with aging and after injury and are implicated in organ fibrosis, but the mechanisms by which senescence influences repair are poorly understood. Using 2 murine models of injury and repair, we show that obstructive injury generated senescent epithelia, which persisted after resolution of the original injury, promoted ongoing fibrosis, and impeded adaptive repair. Depletion of senescent cells with ABT-263 reduced fibrosis in reversed ureteric obstruction and after renal ischemia/reperfusion injury. We validated these findings in humans, showing that senescence and fibrosis persisted after relieved renal obstruction. We next characterized senescent epithelia in murine renal injury using single-cell RNA-Seq. We extended our classification to human kidney and liver disease and identified conserved profibrotic proteins, which we validated in vitro and in human disease. We demonstrated that increased levels of protein disulfide isomerase family A member 3 (PDIA3) augmented TGF-ß-mediated fibroblast activation. Inhibition of PDIA3 in vivo significantly reduced kidney fibrosis during ongoing renal injury and as such represented a new potential therapeutic pathway. Analysis of the signaling pathways of senescent epithelia connected senescence to organ fibrosis, permitting rational design of antifibrotic therapies.

An Exercise-Induced Metabolic Shield in Distant Organs Blocks Cancer Progression and Metastatic Dissemination.

Exercise prevents cancer incidence and recurrence, yet the underlying mechanism behind this relationship remains mostly unknown. Here we report that exercise induces the metabolic reprogramming of internal organs that increases nutrient demand and protects against metastatic colonization by limiting nutrient availability to the tumor, generating an exercise-induced metabolic shield. Proteomic and ex vivo metabolic capacity analyses of murine internal organs revealed that exercise induces catabolic processes, glucose uptake, mitochondrial activity, and GLUT expression. Proteomic analysis of routinely active human subject plasma demonstrated increased carbohydrate utilization following exercise. Epidemiologic data from a 20-year prospective study of a large human cohort of initially cancer-free participants revealed that exercise prior to cancer initiation had a modest impact on cancer incidence in low metastatic stages but significantly reduced the likelihood of highly metastatic cancer. In three models of melanoma in mice, exercise prior to cancer injection significantly protected against metastases in distant organs. The protective effects of exercise were dependent on mTOR activity, and inhibition of the mTOR pathway with rapamycin treatment ex vivo reversed the exercise-induced metabolic shield. Under limited glucose conditions, active stroma consumed significantly more glucose at the expense of the tumor. Collectively, these data suggest a clash between the metabolic plasticity of cancer and exercise-induced metabolic reprogramming of the stroma, raising an opportunity to block metastasis by challenging the metabolic needs of the tumor. SIGNIFICANCE: Exercise protects against cancer progression and metastasis by inducing a high nutrient demand in internal organs, indicating that reducing nutrient availability to tumor cells represents a potential strategy to prevent metastasis. See related commentary by Zerhouni and Piskounova, p. 4124.

CD8+ Tumor-Infiltrating Lymphocyte Abundance Is a Positive Prognostic Indicator in Nasopharyngeal Cancer.

PURPOSE: Tumor-infiltrating lymphocytes (TIL) are immune cell populations found within tumors, critical in the antigen-specific host immune response. In this study, we aimed to elucidate the prognostic significance of CD3+, CD4+, and CD8+ TILs in nasopharyngeal cancer (NPC). EXPERIMENTAL DESIGN: Immune cell infiltration was quantified in NPC samples (n = 50) using RNA-sequencing (RNA-seq) data based on rearranged T-cell receptor (TCR) reads and the Estimation of Stromal and Immune cells in malignant tumors using expression data (ESTIMATE) immune score tool. The differential abundances of TIL subset populations were also characterized through IHC staining of formalin-fixed, paraffin-embedded samples from a training cohort (n = 35), which was a subset of the RNA-seq cohort (n = 50). RESULTS: In the RNA-seq cohort, patients with higher rearranged TCR reads experienced superior 5- and 10-year overall survival (OS; P < 0.001), and disease-free survival (DFS; P < 0.001). Similarly, patients with higher ESTIMATE immune scores experienced superior 5- and 10-year OS (P = 0.024) and DFS (P = 0.007). In the training cohort, high abundances of CD8+ TILs were significantly associated with improved 5- and 10-year OS (P = 0.003) and DFS (P = 0.005). These findings were corroborated in an independent validation cohort (n = 84), and combined analysis of the training and validation cohorts [n = 119 (35+84)], which further demonstrated improved 5- and 10-year survival in terms of locoregional control (P < 0.001) and distant metastasis (P = 0.03). CONCLUSIONS: Taken together, our study highlights the prognostic value of CD8+ TILs in NPC, and the potential of future investigations into cellular-based immunotherapies employing CD8+ lymphocytes.

Systematic Review of the Effectiveness of Advocacy Interventions for Adult Victims of Domestic Violence Within an Emergency Department Setting.

Advocacy interventions for survivors of domestic violence are well established and supported by evidence in some community and healthcare settings. Survivors of domestic violence identified in emergency departments have important differences, and it is not clear whether evidence can be applied to this population. We conducted an inclusive systematic review of controlled studies evaluating the effectiveness of advocacy workers for adult survivors identified in emergency departments. We identified five studies, all with substantial methodological flaws. The outcome measures were very varied. No study reported harm from advocacy. Most reported benefits from referrals to advocacy workers. Despite weak evidence, referral to advocacy workers for survivors of domestic violence is not harmful and offers benefits.

Hair Microbiome Diversity within and across Primate Species.

Primate hair and skin are substrates upon which social interactions occur and are host-pathogen interfaces. While human hair and skin microbiomes display body site specificity and immunological significance, little is known about the nonhuman primate (NHP) hair microbiome. Here, we collected hair samples (n = 158) from 8 body sites across 12 NHP species housed at three zoological institutions in the United States to examine the following: (1) the diversity and composition of the primate hair microbiome and (2) the factors predicting primate hair microbiome diversity and composition. If both environmental and evolutionary factors shape the microbiome, then we expect significant differences in microbiome diversity across host body sites, sexes, institutions, and species. We found our samples contained high abundances of gut-, respiratory-, and environment-associated microbiota. In addition, multiple factors predicted microbiome diversity and composition, although host species identity outweighed sex, body site, and institution as the strongest predictor. Our results suggest that hair microbial communities are affected by both evolutionary and environmental factors and are relatively similar across nonhuman primate body sites, which differs from the human condition. These findings have important implications for understanding the biology and conservation of wild and captive primates and the uniqueness of the human microbiome. IMPORTANCE We created the most comprehensive primate hair and skin data set to date, including data from 12 nonhuman primate species sampled from 8 body regions each. We find that the nonhuman primate hair microbiome is distinct from the human hair and skin microbiomes in that it is relatively uniform-as opposed to distinct-across body regions and is most abundant in gut-, environment-, and respiratory-associated microbiota rather than human skin-associated microbiota. Furthermore, we found that the nonhuman primate hair microbiome varies with host species identity, host sex, host environment, and host body site, with host species identity being the strongest predictor. This result demonstrates that nonhuman primate hair microbiome diversity varies with both evolutionary and environmental factors and within and across primate species. These findings have important implications for understanding the biology and conservation of wild and captive primates and the uniqueness of the human microbiome.

Macrophages in the kidney in health, injury and repair.

Macrophages are a key component of the renal mononuclear phagocyte system, playing a major role in defense against infection, renal injury and repair. Yolk sac macrophage precursors seed the early embryonic kidney and are important for renal development. Later, renal macrophages are derived from hematopoietic stem cells and in adult life, there is a significant contribution from circulating monocytes, which is enhanced in response to infection or injury. Macrophages are highly plastic and can alter their phenotype in response to cues from parenchymal renal cells. Danger-associated molecules released from injured kidney cells may activate macrophages toward a pro-inflammatory phenotype, mediating further recruitment of inflammatory cells, exacerbating renal injury and activating renal fibroblasts to promote scarring. In acute kidney injury, once the injury stimulus has abated, macrophages may adopt a more reparative phenotype, dampening the immune response and promoting repair of renal tissue. However, in chronic kidney disease ongoing activation of pro-inflammatory monocytes and persistence of reparative macrophages leads to glomerulosclerosis and tubulointerstitial fibrosis, the hallmarks of end-stage kidney disease. Several strategies to inhibit the recruitment, activation and secretory products of pro-inflammatory macrophages have proven beneficial in pre-clinical models and are now undergoing clinical trials in patients with kidney disease. In addition, macrophages may be utilized in cell therapy as a "Trojan Horse" to deliver targeted therapies to the kidney. Single-cell RNA sequencing has identified a previously unappreciated spectrum of macrophage phenotypes, which may be selectively present in injury or repair, and ongoing functional analyses of these subsets may identify more specific targets for therapeutic intervention.

Proteomic differences among patients with heart failure taking furosemide or torsemide.

BACKGROUND: Loop diuretics are commonly used for patients with heart failure (HF) but it remains unknown if one loop diuretic is clinically superior. HYPOTHESIS: Biomarkers and proteomics provide insight to how different loop diuretics may differentially affect outcomes. METHODS: Blood and urine were collected from outpatients with HF who were taking torsemide or furosemide for >30 days. Differences were assessed in cardiac, renal, and inflammatory biomarkers and soluble protein panels using the Olink Cardiovascular III and inflammation panels. RESULTS: Of 78 subjects, 55 (71%) were treated with furosemide and 23 (29%) with torsemide, and 25 provided a urine sample (15 treated with furosemide, 10 with torsemide). Patients taking torsemide were older (68 vs 64 years) with a lower mean eGFR (46 vs 54 ml/min/1.73 m2 ), a higher proportion were women (39% vs 24%) and Black (43% vs 27%). In plasma, levels of hs-cTnT, NT-proBNP, and hsCRP were not significantly different between groups. In urine, there were significant differences in urinary albumin, ß-2M, and NGAL, with higher levels in the torsemide-treated patients. Of 184 proteins testing in Olink panels, in plasma, 156 (85%) were higher in patients taking torsemide but none were significantly different after correcting for false discovery. CONCLUSIONS: We show differences in urinary biomarkers but few differences in plasma biomarkers among HF patients on different loop diuretics. Olink technology can detect differences in plasma protein levels from multiple biologic domains. These findings raise the importance of defining differences in mechanisms of action of each diuretic in an appropriately powered study.

A functionally impaired missense variant identified in French Canadian families implicates FANCI as a candidate ovarian cancer-predisposing gene.

BACKGROUND: Familial ovarian cancer (OC) cases not harbouring pathogenic variants in either of the BRCA1 and BRCA2 OC-predisposing genes, which function in homologous recombination (HR) of DNA, could involve pathogenic variants in other DNA repair pathway genes. METHODS: Whole exome sequencing was used to identify rare variants in HR genes in a BRCA1 and BRCA2 pathogenic variant negative OC family of French Canadian (FC) ancestry, a population exhibiting genetic drift. OC cases and cancer-free individuals from FC and non-FC populations were investigated for carrier frequency of FANCI c.1813C>T; p.L605F, the top-ranking candidate. Gene and protein expression were investigated in cancer cell lines and tissue microarrays, respectively. RESULTS: In FC subjects, c.1813C>T was more common in familial (7.1%, 3/42) than sporadic (1.6%, 7/439) OC cases (P = 0.048). Carriers were detected in 2.5% (74/2950) of cancer-free females though female/male carriers were more likely to have a first-degree relative with OC (121/5249, 2.3%; Spearman correlation = 0.037; P = 0.011), suggesting a role in risk. Many of the cancer-free females had host factors known to reduce risk to OC which could influence cancer risk in this population. There was an increased carrier frequency of FANCI c.1813C>T in BRCA1 and BRCA2 pathogenic variant negative OC families, when including the discovery family, compared to cancer-free females (3/23, 13%; OR = 5.8; 95%CI = 1.7-19; P = 0.005). In non-FC subjects, 10 candidate FANCI variants were identified in 4.1% (21/516) of Australian OC cases negative for pathogenic variants in BRCA1 and BRCA2, including 10 carriers of FANCI c.1813C>T. Candidate variants were significantly more common in familial OC than in sporadic OC (P = 0.04). Localization of FANCD2, part of the FANCI-FANCD2 (ID2) binding complex in the Fanconi anaemia (FA) pathway, to sites of induced DNA damage was severely impeded in cells expressing the p.L605F isoform. This isoform was expressed at a reduced level, destabilized by DNA damaging agent treatment in both HeLa and OC cell lines, and exhibited sensitivity to cisplatin but not to a poly (ADP-ribose) polymerase inhibitor. By tissue microarray analyses, FANCI protein was consistently expressed in fallopian tube epithelial cells and only expressed at low-to-moderate levels in 88% (83/94) of OC samples. CONCLUSIONS: This is the first study to describe candidate OC variants in FANCI, a member of the ID2 complex of the FA DNA repair pathway. Our data suggest that pathogenic FANCI variants may modify OC risk in cancer families.

Seropositivity of COVID-19 among asymptomatic healthcare workers: A multi-site prospective cohort study from Northern Virginia, United States.

BACKGROUND: Because of their direct patient contact, healthcare workers (HCW) face an unprecedented risk of exposure to COVID-19. The aim of this study was to examine incidence of COVID-19 disease among asymptomatic HCW and community participants in Northern Virginia during 6 months of follow-up. METHODS: This is a prospective cohort study that enrolled healthy HCW and residents who never had a symptomatic COVID-19 infection prior to enrolment from the community in Northern Virginia from April to November 2020. All participants were invited to enrol in study, and they were followed at 2-, and 6-months intervals. Participants were evaluated by commercial chemiluminescence SARS-CoV-2 serology assays as part of regional health system and public health surveillance program to monitor the spread of COVID-19 disease. FINDINGS: Of a total of 1,819 asymptomatic HCW enrolled, 1,473 (96%) had data at two-months interval, and 1,323 (73%) participants had data at 6-months interval. At baseline, 21 (1.15%) were found to have prior COVID-19 exposure. At two-months interval, COVID-19 rate was 2.8% and at six months follow-up, the overall incidence rate increased to 4.8%, but was as high as 7.9% among those who belong to the youngest age group (20-29 years). Seroconversion rates in HCW were comparable to the seropositive rates in the Northern Virginia community. The overall incidence of COVID-19 in the community was 4.5%, but the estimate was higher among Hispanic ethnicity (incidence rate = 15.3%) potentially reflecting different socio-economic factors among the community participants and the HCW group. Using cross-sectional logistic regression and spatio-temporal mixed effects models, significant factors that influence the transmission rate among HCW include age, race/ethnicity, resident ZIP-code, and household exposure, but not direct patient contact. INTERPRETATION: In Northern Virginia, the seropositive rate of COVID-19 disease among HCW was comparable to that in the community.

Slow Transcription of the 99a/let-7c/125b-2 Cluster Results in Differential MiRNA Expression and Promotes Melanoma Phenotypic Plasticity.

Almost half of the human microRNAs (miRNAs) are encoded in clusters. Although transcribed as a single unit, the levels of individual mature miRNAs often differ. The mechanisms underlying differential biogenesis of clustered miRNAs and the resulting physiological implications are mostly unknown. In this study, we report that the melanoma master transcription regulator MITF regulates the differential expression of the 99a/let-7c/125b-2 cluster by altering the distribution of RNA polymerase II along the cluster. We discovered that MITF interacts with TRIM28, a known inhibitor of RNA polymerase II transcription elongation, at the mIR-let-7c region, resulting in the pausing of RNA polymerase II activity and causing an elevation in mIR-let-7c expression; low levels of RNA polymerase II occupation over miR-99a and miR-125b-2 regions decreases their biogenesis. Furthermore, we showed that this differential expression affects the phenotypic state of melanoma cells. RNA-sequencing analysis of proliferative melanoma cells that express miR-99a and miR-125b mimics revealed a transcriptomic shift toward an invasive phenotype. Conversely, expression of a mIR-let-7c mimic in invasive melanoma cells induced a shift to a more proliferative state. We confirmed direct target genes of these miRNAs, including FGFR3, BAP1, Bcl2, TGFBR1, and CDKN1A. Our study demonstrates an MITF-governed biogenesis mechanism that results in differential expression of clustered 99a/let-7c/125b-2 miRNAs that control melanoma progression.

Editor's Choice - A Comparison of Computed Tomography Angiography and Colour Duplex Ultrasound Surveillance Post Infrarenal Endovascular Aortic Aneurysm Repair: Financial Implications and Impact of Different International Surveillance Guidelines.

OBJECTIVE: Use of colour duplex ultrasound (CDUS) and computed tomography angiography (CTA) for infrarenal endovascular aortic aneurysm repair (EVAR) surveillance differs in internationally published guidelines. This study aimed firstly to compare CDUS detection of significant sac abnormalities with CTA. Secondly, a sensitivity analysis was conducted to compare financial estimates of the, predominantly CDUS based, local and Society of Vascular Surgery (SVS) protocols, the risk stratified European Society of Vascular Surgery (ESVS) protocol, and the CTA based National Institute of Health and Care Excellence (NICE) protocol. METHODS: Agreement between CDUS and CTA was assessed for detection of significant sac abnormalities. Surveillance protocols were extrapolated from published guidelines and applied to infrarenal EVAR patients active on local surveillance at a large, single centre. Surveillance intensity was dependent on presence of endoleak and subsequent risk of treatment failure in accordance with surveillance recommendations. Estimates for each surveillance protocol were inclusive of a range of published incidences of endoleak, contrast associated acute kidney injury (AKI), and excess hospital bed days, and estimated for a hypothetical five year surveillance period. RESULTS: The kappa coefficient between CDUS and CTA for detecting sac abnormalities was 0.68. Maximum five year surveillance cost estimates for the 289 active EVAR patients were £272 359 for SVS, £230 708 for ESVS, £643 802 for NICE, and £266 777 for local protocols, or £1 270, £1 076, £3 003, and £1 244 per patient. Differences in endoleak incidence accounted for a 1.1 to 1.4 fold increase in costs. AKI incidence accounted for a 3.3 to 6.2 fold increase in costs. CONCLUSION: A combined CTA and CDUS EVAR surveillance protocol, with CTA reserved for early seal assessment and confirmatory purposes, provides an economical approach without compromising detection of sac abnormalities. AKI, as opposed to direct imaging costs, accounted for the largest differences in surveillance cost estimates.

Keloid tissue analysis discredits a role for myofibroblasts in disease pathogenesis.

Myofibroblasts, renowned for their contractility and extracellular matrix production, are widely considered the key effector cells for nearly all scars resulting from tissue repair processes, ranging from normal scars to extreme fibrosis. For example, it is often assumed that myofibroblasts underpin the characteristics of keloid scars, which are debilitating pathological skin scars lacking effective treatments because of a poor understanding of the disease mechanisms. Here, we present primary and published transcriptional and histological evidence that myofibroblasts are not consistently present in primary keloid lesions, and when alpha-smooth muscle actin (αSMA)-positive cells are detected, they are not greater in number or expressing more αSMA than in normal or hypertrophic scars. In conclusion, keloid scars do not appear to require αSMA-positive myofibroblasts; continuing to consider keloids on a quantitative spectrum with normal or hypertrophic scars, with αSMA serving as a biomarker of disease severity, is hindering advancement of understanding and therapy development.

Carbonyl reductase 1 amplifies glucocorticoid action in adipose tissue and impairs glucose tolerance in lean mice.

OBJECTIVE: Carbonyl reductase 1 (Cbr1), a recently discovered contributor to tissue glucocorticoid metabolism converting corticosterone to 20ß-dihydrocorticosterone (20ß-DHB), is upregulated in adipose tissue of obese humans and mice and may contribute to cardiometabolic complications of obesity. This study tested the hypothesis that Cbr1-mediated glucocorticoid metabolism influences glucocorticoid and mineralocorticoid receptor activation in adipose tissue and impacts glucose homeostasis in lean and obese states. METHODS: The actions of 20ß-DHB on corticosteroid receptors in adipose tissue were investigated first using a combination of in silico, in vitro, and transcriptomic techniques and then in vivo administration in combination with receptor antagonists. Mice lacking one Cbr1 allele and mice overexpressing Cbr1 in their adipose tissue underwent metabolic phenotyping before and after induction of obesity with high-fat feeding. RESULTS: 20ß-DHB activated both the glucocorticoid and mineralocorticoid receptor in adipose tissue and systemic administration to wild-type mice induced glucose intolerance, an effect that was ameliorated by both glucocorticoid and mineralocorticoid receptor antagonism. Cbr1 haploinsufficient lean male mice had lower fasting glucose and improved glucose tolerance compared with littermate controls, a difference that was abolished by administration of 20ß-DHB and absent in female mice with higher baseline adipose 20ß-DHB concentrations than male mice. Conversely, overexpression of Cbr1 in adipose tissue resulted in worsened glucose tolerance and higher fasting glucose in lean male and female mice. However, neither Cbr1 haploinsfficiency nor adipose overexpression affected glucose dyshomeostasis induced by high-fat feeding. CONCLUSIONS: Carbonyl reductase 1 is a novel regulator of glucocorticoid and mineralocorticoid receptor activation in adipose tissue that influences glucose homeostasis in lean mice.