Hepatic Sarcoidosis Found Incidentally in a Patient Presenting With Recurrent Clostridium difficile Infections.

A 50-year-old female who presented to our hospital for recurrent diarrhea was found to have worsening aminotransferase and alkaline phosphatase levels. Workup revealed lymphadenopathy and hepatomegaly prompting a biopsy of the liver and axillary lymph node, confirming a diagnosis of hepatic sarcoidosis. Our patient later developed cutaneous sarcoidosis. She is currently asymptomatic and is followed by gastroenterology, pulmonary, and dermatology. Recognition of extrapulmonary manifestations of sarcoidosis is important for proper management of patients. Treatment often requires a multidisciplinary approach when more than one organ system is involved.

A Machine Learning Algorithm Improves the Diagnostic Accuracy of the Histologic Component of Antibody Mediated Rejection (AMR-H) in Cardiac Transplant Endomyocardial Biopsies.

BACKGROUND: Pathologic antibody mediated rejection (pAMR) remains a major driver of graft failure in cardiac transplant patients. The endomyocardial biopsy remains the primary diagnostic tool but presents with challenges, particularly in distinguishing the histologic component (pAMR-H) defined by 1) intravascular macrophage accumulation in capillaries and 2) activated endothelial cells that expand the cytoplasm to narrow or occlude the vascular lumen. Frequently, pAMR-H is difficult to distinguish from acute cellular rejection (ACR) and healing injury. With the advent of digital slide scanning and advances in machine deep learning, artificial intelligence technology is widely under investigation in the areas of oncologic pathology, but in its infancy in transplant pathology. For the first time, we determined if a machine learning algorithm could distinguish pAMR-H from normal myocardium, healing injury and ACR. MATERIALS AND METHODS: A total of 4,212 annotations (1,053 regions of normal, 1,053 pAMR-H, 1,053 healing injury and 1,053 ACR) were completed from 300 hematoxylin and eosin slides scanned using a Leica Aperio GT450 digital whole slide scanner at 40X magnification. All regions of pAMR-H were annotated from patients confirmed with a previous diagnosis of pAMR2 (>50% positive C4d immunofluorescence and/or >10% CD68 positive intravascular macrophages). Annotations were imported into a Python 3.7 development environment using the OpenSlide™ package and a convolutional neural network approach utilizing transfer learning was performed. RESULTS: The machine learning algorithm showed 98% overall validation accuracy and pAMR-H was correctly distinguished from specific categories with the following accuracies: normal myocardium (99.2%), healing injury (99.5%) and ACR (99.5%). CONCLUSION: Our novel deep learning algorithm can reach acceptable, and possibly surpass, performance of current diagnostic standards of identifying pAMR-H. Such a tool may serve as an adjunct diagnostic aid for improving the pathologist's accuracy and reproducibility, especially in difficult cases with high inter-observer variability. This is one of the first studies that provides evidence that an artificial intelligence machine learning algorithm can be trained and validated to diagnose pAMR-H in cardiac transplant patients. Ongoing studies include multi-institutional verification testing to ensure generalizability.

Light at the end of the tunnel: bridging the gap from the duodenum to the jejunum.

Video 1Video describing the case, procedure, and outcomes.

Inequalities in neighbourhood features within children's 20-minute neighbourhoods and variation in time spent locally, measured using GPS.

There has been a growing interest in policies that encourage local living by promoting accessible and walkable communities, such as the 20-minute neighbourhood concept. Despite the widespread adoption of this policy in cities worldwide, little research has been conducted on the characteristics of children's 20-minute neighbourhoods and their association with time spent locally. This study aimed to explore the features of Scottish children's 20-minute neighbourhoods by analysing an 800-meter road and path network buffer surrounding 687 children's homes. Based on existing literature, the study identified key features associated with children's time spent locally and the 20-minute neighbourhood policy. The study then examined variations in these features by socioeconomic status, urbanicity, and gender. The findings revealed significant inequalities in the presence of health-benefiting (e.g., green spaces, recreational facilities, healthy food outlets) and health-harming (e.g., major roads, unhealthy commodity retailers) environments within children's 20-minute neighbourhoods. Children from more deprived areas had access to more of both types of environments. The study also found that having a school within a 20-minute neighbourhood was associated with an increased amount of time spent locally (IRR 1.62, 95% CI 1.5 to 1.8, p<0.001). The study suggests that the 20-minute neighbourhood policy should extend beyond mere access to local amenities and prioritise creating healthy 20-minute neighbourhoods, particularly in socioeconomically deprived areas. The research highlights the importance of promoting equal access to quality local environments, which can contribute to improved health and well-being outcomes for children.

Patterns in and predictors of stream and river macroinvertebrate genera and fish species richness across the conterminous USA.

Both native and non-native taxa richness patterns are useful for evaluating areas of greatest conservation concern. To determine those patterns, we analyzed fish and macroinvertebrate taxa richness data obtained at 3475 sites collected by the USEPA's National Rivers and Streams Assessment. We also determined which natural and anthropogenic variables best explained patterns in regional richness. Macroinvertebrate and fish richness increased with the number of sites sampled per region. Therefore, we determined residual taxa richness from the deviation of observed richness from predicted richness given the number of sites per region. Regional richness markedly exceeded average site richness for both macroinvertebrates and fish. Predictors of macroinvertebrate-genus and fish-species residual-regional richness differed. Air temperature was an important predictor in both cases but was positive for fish and negative for macroinvertebrates. Both natural and land use variables were significant predictors of regional richness. This study is the first to determine mean site and regional richness of both fish and aquatic macroinvertebrates across the conterminous USA, and the key anthropogenic drivers of regional richness. Thus, it offers important insights into regional USA biodiversity hotspots.

Understanding the effects of phosphorus on diatom richness in rivers and streams using taxon-environment relationships.

Changes in phosphorus concentrations affect periphytic diatom composition in streams, yet we rarely observe strong relationships between diatom richness and phosphorus. In contrast, changes in conductivity are strongly associated with differences in both diatom composition and richness. We hypothesised that we could better understand the mechanisms that control the phosphorus-richness relationship by examining relationships between phosphorus and the occurrence of individual diatom taxa, comparing these with relationships between conductivity and taxon occurrence, and documenting how niche breadths of taxa affect richness patterns. We estimated relationships between phosphorus and taxon occurrence using DNA metabarcoding data of diatoms collected from 1,811 sites distributed across the conterminous U.S.A. and contrasted patterns in these relationships with those between conductivity and taxon occurrence. The distribution of taxon optima for phosphorus was bimodal, with most optima located at either the maximum or minimum observed phosphorus concentration. The distribution of taxon optima for conductivity was unimodal. Niche breadths of taxa for phosphorus and for conductivity both generally increased with optimum values. The distribution of conductivity optima gave rise to a prominent hump-shaped relationship between richness and conductivity. The relationship between richness and phosphorus was also slightly hump-shaped, but this relationship would not be expected from the bimodal distribution of optima. Instead, we determined that broad niche breadths caused the hump-shaped relationship between richness and phosphorus. Our results highlight the nuanced effects that increased P loadings exert on diatom assemblages in rivers and streams and identify reasons that weak relationships between taxon richness and increased phosphorus have been observed. These findings allow us to better describe how excess phosphorus and subsets of taxa and their niche breadths contribute to patterns of taxa richness in diatom assemblages, and to improve the tools used to manage phosphorus pollution.

Triarylphosphine-Coordinated Bipyridyl Ru(II) Complexes Induce Mitochondrial Dysfunction.

While cancer cells rely heavily upon glycolysis to meet their energetic needs, reducing the importance of mitochondrial oxidative respiration processes, more recent studies have shown that their mitochondria still play an active role in the bioenergetics of metastases. This feature, in combination with the regulatory role of mitochondria in cell death, has made this organelle an attractive anticancer target. Here, we report the synthesis and biological characterization of triarylphosphine-containing bipyridyl ruthenium (Ru(II)) compounds and found distinct differences as a function of the substituents on the bipyridine and phosphine ligands. 4,4'-Dimethylbipyridyl-substituted compound 3 exhibited especially high depolarizing capabilities, and this depolarization was selective for the mitochondrial membrane and occurred within minutes of treatment in cancer cells. The Ru(II) complex 3 exhibited an 8-fold increase in depolarized mitochondrial membranes, as determined by flow cytometry, which compares favorably to the 2-fold increase observed by carbonyl cyanide chlorophenylhydrazone (CCCP), a proton ionophore that shuttles protons across membranes, depositing them into the mitochondrial matrix. Fluorination of the triphenylphosphine ligand provided a scaffold that maintained potency against a range of cancer cells but avoided inducing toxicity in zebrafish embryos at higher concentrations, displaying the potential of these Ru(II) compounds for anticancer applications. This study provides essential information regarding the role of ancillary ligands for the anticancer activity of Ru(II) coordination compounds that induce mitochondrial dysfunction.

A blinded, placebo-controlled study on the clinical effects of vitamin E supplementation in dogs with osteoarthritis.

BACKGROUND: Vitamin E has a positive effect in the management of osteoarthritis in humans, and in a previous study of dogs. It has been suggested to decrease C-reactive protein concentrations and liver enzyme activities in humans and animals. OBJECTIVE: To assess the effect of vitamin E supplementation on lameness, pain, pain medication requirement, clinical pathology variables, and quality of life in large-breed dogs with naturally occurring osteoarthritis. ANIMALS: Fifty-seven client-owned dogs with naturally occurring osteoarthritis. METHODS: Dogs received either vitamin E or placebo for 90 days in a randomized, placebo-controlled, double-blinded, prospective clinical trial. Clinical lameness scores, pain medication requirements, and owner questionnaires were used to assess response to treatment every 30 days. Blood samples were collected at enrollment and at the end of the study period. RESULTS: Vitamin E administration did not improve pain, lameness, or quality of life as assessed by owners and veterinarians. Vitamin E supplementation did not decrease the requirement for rescue pain relief. No changes in clinical pathology variables were observed after 90 days of vitamin E supplementation. Body weight was negatively associated with the lameness scores and requirement for rescue pain relief. CONCLUSION: Vitamin E supplementation did not have any observable positive effects in dogs with naturally occurring osteoarthritis.

Recruited macrophages elicit atrial fibrillation.

Atrial fibrillation disrupts contraction of the atria, leading to stroke and heart failure. We deciphered how immune and stromal cells contribute to atrial fibrillation. Single-cell transcriptomes from human atria documented inflammatory monocyte and SPP1+ macrophage expansion in atrial fibrillation. Combining hypertension, obesity, and mitral valve regurgitation (HOMER) in mice elicited enlarged, fibrosed, and fibrillation-prone atria. Single-cell transcriptomes from HOMER mouse atria recapitulated cell composition and transcriptome changes observed in patients. Inhibiting monocyte migration reduced arrhythmia in Ccr2-∕- HOMER mice. Cell-cell interaction analysis identified SPP1 as a pleiotropic signal that promotes atrial fibrillation through cross-talk with local immune and stromal cells. Deleting Spp1 reduced atrial fibrillation in HOMER mice. These results identify SPP1+ macrophages as targets for immunotherapy in atrial fibrillation.

Impact of built environment change on all-cause and cause-specific mortality: a novel longitudinal method and study.

BACKGROUND: Public health research increasingly acknowledges the influence of built environments (BE) on health; however, it is uncertain how BE change is associated with better population health and whether BE change can help narrow health inequalities. This knowledge gap is partly due to a lack of suitable longitudinal BE data in most countries. We devised a method to quantify BE change longitudinally and explored associations with mortality. The method is replicable in any nation that captures BE vector map data. METHODS: Ordnance Survey data were used to categorise small areas as having no change, loss or gain, in buildings, roads, and woodland between 2015 and 2019. We examined individual mortality records for 2012-2015 and 2016-2019, using negative binomial regression to explore associations between BE change and all-cause and cause-specific mortality, adjusting for income deprivation. RESULTS: BE change varied significantly by deprivation and urbanicity. Change in the BE and change in mortality were not related, however, areas that went on to experience BE change had different baseline mortality rates compared with those that did not. For example, areas that gained infrastructure already had lower mortality rates. CONCLUSION: We provide new methodology to quantify BE change over time across a nation. Findings provide insight into the health of areas that do/do not experience change, prompting critical perspectives on cross-sectional studies of associations between BE and health. Methods and findings applied internationally could explore the context of BE change and its potential to improve health in areas most in need beyond the UK.

A monoadduct generating Ru(ii) complex induces ribosome biogenesis stress and is a molecular mimic of phenanthriplatin.

Ruthenium complexes are often investigated as potential replacements for platinum-based chemotherapeutics in hopes of identifying systems with improved tolerability in vivo and reduced susceptibility to cellular resistance mechanisms. Inspired by phenanthriplatin, a non-traditional platinum agent that contains only one labile ligand, monofunctional ruthenium polypyridyl agents have been developed, but until now, few demonstrated promising anticancer activity. Here we introduce a potent new scaffold, based on [Ru(tpy)(dip)Cl]Cl (tpy = 2,2':6',2''-terpyridine and dip = 4,7-diphenyl-1,10-phenanthroline) in pursuit of effective Ru(ii)-based monofunctional agents. Notably, the extension of the terpyridine at the 4' position with an aromatic ring resulted in a molecule that was cytotoxic in several cancer cell lines with sub-micromolar IC50 values, induced ribosome biogenesis stress, and exhibited minimal zebrafish embryo toxicity. This study demonstrates the successful design of a Ru(ii) agent that mimics many of the biological effects and phenotypes seen with phenanthriplatin, despite numerous differences in both the ligands and metal center structure.

Effects of Mineralocorticoid Receptor Blockade and Statins on Kidney Injury Marker 1 (KIM-1) in Female Rats Receiving L-NAME and Angiotensin II.

Kidney injury molecule-1 (KIM-1) is a biomarker of renal injury and a predictor of cardiovascular disease. Aldosterone, via activation of the mineralocorticoid receptor, is linked to cardiac and renal injury. However, the impact of mineralocorticoid receptor activation and blockade on KIM-1 is uncertain. We investigated whether renal KIM-1 is increased in a cardiorenal injury model induced by L-NAME/ANG II, and whether mineralocorticoid receptor blockade prevents the increase in KIM-1. Since statin use is associated with lower aldosterone, we also investigated whether administering eiSther a lipophilic statin (simvastatin) or a hydrophilic statin (pravastatin) prevents the increase in renal KIM-1. Female Wistar rats (8-10 week old), consuming a high salt diet (1.6% Na+), were randomized to the following conditions for 14 days: control; L-NAME (0.2 mg/mL in drinking water)/ANG II (225 ug/kg/day on days 12-14); L-NAME/ANG II + eplerenone (100 mg/kg/day p.o.); L-NAME/ANG II + pravastatin (20 mg/kg/day p.o.); L-NAME/ANG II + simvastatin (20 mg/kg/day p.o.). Groups treated with L-NAME/ANG II had significantly higher blood pressure, plasma and urine aldosterone, cardiac injury/stroke composite score, and renal KIM-1 than the control group. Both eplerenone and simvastatin reduced 24-h urinary KIM-1 (p = 0.0046, p = 0.031, respectively) and renal KIM-1 immunostaining (p = 0.004, p = 0.037, respectively). Eplerenone also reduced renal KIM-1 mRNA expression (p = 0.012) and cardiac injury/stroke composite score (p = 0.04). Pravastatin did not affect these damage markers. The 24-h urinary KIM-1, renal KIM-1 immunostaining, and renal KIM-1 mRNA expression correlated with cardiac injury/stroke composite score (p < 0.0001, Spearman ranked correlation = 0.69, 0.66, 0.59, respectively). In conclusion, L-NAME/ANG II increases renal KIM-1 and both eplerenone and simvastatin blunt this increase in renal KIM-1.

Is spatial exposure to heritage associated with visits to heritage and to mental health? A cross-sectional study using data from the UK Household Longitudinal Study (UKHLS).

OBJECTIVES: Existing research highlights the beneficial nature of heritage engagement for mental health, but engagement varies geographically and socially, and few studies explore spatial exposure (ie, geographic availability) to heritage and heritage visits. Our research questions were 'does spatial exposure to heritage vary by area income deprivation?', 'is spatial exposure to heritage linked to visiting heritage?' and 'is spatial exposure to heritage linked to mental health?'. Additionally, we explored whether local heritage is associated with mental health regardless of the presence of green space. DESIGN: Data were collected from January 2014 to June 2015 via the UK Household Longitudinal Study (UKHLS) wave 5. Our study is cross-sectional. SETTING: UKHLS data were either collected via face-to-face interview or online questionnaire. PARTICIPANTS: 30 431 adults (16+ years) (13 676 males, 16 755 females). Participants geocoded to Lower Super Output Area (LSOA) 'neighbourhood' and 'English Index of Multiple Deprivation' 2015 income score. MAIN EXPOSURES/OUTCOME MEASURES: LSOA-level heritage exposure and green space exposure (ie, population and area densities); heritage site visit in the past year (outcome, binary: no, yes); mental distress (outcome, General Health Questionnaire-12, binary: less distressed 0-3, more distressed 4+). RESULTS: Heritage varied by deprivation, the most deprived areas (income quintile (Q)1: 1.8) had fewer sites per 1000 population than the least deprived (Q5: 11.1) (p<0.01). Compared with those with no LSOA-level heritage, those with heritage exposure were more likely to have visited a heritage site in the past year (OR: 1.12 (95% CI 1.03 to 1.22)) (p<0.01). Among those with heritage exposure, visitors to heritage had a lower predicted probability of distress (0.171 (95% CI 0.162 to 0.179)) than non-visitors (0.238 (95% CI 0.225 to 0.252)) (p<0.001). CONCLUSIONS: Our research contributes to evidence for the well-being benefits of heritage and is highly relevant to the government's levelling-up heritage strategy. Our findings can feed into schemes to tackle inequality in heritage exposure to improve both heritage engagement and mental health.

Exploring the influence of local alcohol availability on drinking norms and practices: A qualitative scoping review.

INTRODUCTION: High alcohol availability is related to increased alcohol consumption and harms. Existing quantitative research provides potential explanations for this relationship but there is little understanding of how people experience local alcohol availability. This is the first review to synthesise qualitative research exploring the relationship between alcohol availability and other factors in local alcohol environments. METHODS: The scoping review includes qualitative studies exploring community-level alcohol availability and other factors, facilitating the purchase and consumption of alcohol. We included studies focusing on children and adolescents as well as adults. Study findings were brought together using thematic analysis and the socio-environmental context model, which explains how certain environments may facilitate drinking. RESULTS: The review includes 34 articles. The majority of studies were conducted since 2012. Most studies were conducted in the United Kingdom, Australia and South Africa. The physical availability of alcohol and proximity to local amenities and temporal aspects, like late night opening hours, may be linked to social factors, such as normalisation of drinking and permissive drinking environments. The review highlights the importance of social and cultural factors in shaping interactions with local alcohol environments. DISCUSSION AND CONCLUSION: This qualitative scoping review advances understanding of the pathways linking alcohol availability and alcohol harms by showing that availability, accessibility and visibility of alcohol may contribute towards permissive drinking environments. Further research is needed to better understand how people experience alcohol availability in their local environment and how this can inform alcohol control policies.

Synthesis and photobiological evaluation of Ru(II) complexes with expanded chelate polypyridyl ligands.

Photoreactive Ru(II) complexes capable of ejecting ligands have been used extensively for photocaging applications and for the creation of "photocisplatin" reagents. The incorporation of distortion into the structure of the coordination complex lowers the energy of dissociative excited states, increasing the yield of the photosubstitution reaction. While steric clash between ligands induced by adding substituents at the coordinating face of the ligand has been extensively utilized, a lesser known, more subtle approach is to distort the coordination sphere by altering the chelate ring size. Here a systematic study was performed to alter metal-ligand bond lengths, angles, and to cause intraligand distortion by introducing a "linker" atom or group between two pyridine rings. The synthesis, photochemistry, and photobiology of five Ru(II) complexes containing CH2, NH, O, and S-linked dipyridine ligands was investigated. All systems where stable in the dark, and three of the five were photochemically active in buffer. While a clear periodic trend was not observed, this study lays the foundation for the creation of photoactive systems utilizing an alternative type of distortion to facilitate photosubstitution reactions.

Systematic dissection, preservation, and multiomics in whole human and bovine hearts.

OBJECTIVES: We sought to develop a rigorous, systematic protocol for the dissection and preservation of human hearts for biobanking that expands previous success in postmortem transcriptomics to multiomics from paired tissue. BACKGROUND: Existing cardiac biobanks consist largely of biopsy tissue or explanted hearts in select diseases and are insufficient for correlating whole organ phenotype with clinical data. METHODS: We demonstrate optimal conditions for multiomics interrogation (ribonucleic acid (RNA) sequencing, untargeted metabolomics) in hearts by evaluating the effect of technical variables (storage solution, temperature) and simulated postmortem interval (PMI) on RNA and metabolite stability. We used bovine (n=3) and human (n=2) hearts fixed in PAXgene or snap-frozen with liquid nitrogen. RESULTS: Using a paired Wald test, only two of the genes assessed were differentially expressed between left ventricular samples from bovine hearts stored in PAXgene at 0 and 12 hours PMI (FDR q<0.05). We obtained similar findings in human left ventricular samples, suggesting stability of RNA transcripts at PMIs up to 12 hours. Different library preparation methods (mRNA poly-A capture vs. rRNA depletion) resulted in similar quality metrics with both library preparations achieving >95% of reads properly aligning to the reference genomes across all PMIs for bovine and human hearts. PMI had no effect on RNA Integrity Number or quantity of RNA recovered at the time points evaluated. Of the metabolites identified (855 total) using untargeted metabolomics of human left ventricular tissue, 503 metabolites remained stable across PMIs (0, 4, 8, 12 hours). Most metabolic pathways retained several stable metabolites. CONCLUSIONS: Our data demonstrate a technically rigorous, reproducible protocol that will enhance cardiac biobanking practices and facilitate novel insights into human CVD. CONDENSED ABSTRACT: Cardiovascular disease (CVD) is the leading cause of mortality worldwide. Current biobanking practices insufficiently capture both the diverse array of phenotypes present in CVDs and the spatial heterogeneity across cardiac tissue sites. We have developed a rigorous and systematic protocol for the dissection and preservation of human cardiac biospecimens to enhance the availability of whole organ tissue for multiple applications. When combined with longitudinal clinical phenotyping, our protocol will enable multiomics in hearts to deepen our understanding of CVDs.

Severe triple vessel disease secondary to IgG4-related coronary periarteritis.

BACKGROUND: Immunoglobulin G4-related disease is a rare systemic inflammatory disease that can lead to vascular manifestations such as periarteritis. CASE PRESENTATION: A 41-year-old man with stress angina was referred for coronary bypass surgery due to triple vessel coronary disease. CONCLUSIONS: Operative findings revealed significant adhesions and dense peri-coronary and periaortic thickening, also involving the left internal mammary artery. The IgG4-associated disease was confirmed by aortic pathology. The stress angina subsequently improved with the initiation of treatment with prednisone and rituximab.