Risk assessment and real-world outcomes in chronic thromboembolic pulmonary hypertension: insights from a UK pulmonary hypertension referral service.

OBJECTIVES: This study was conducted to evaluate the ability of risk assessment to predict healthcare resource utilisation (HCRU), costs, treatments, health-related quality of life (HRQoL) and survival in patients diagnosed with chronic thromboembolic pulmonary hypertension (CTEPH). DESIGN: Retrospective observational study. SETTING: Pulmonary hypertension referral centre in the UK. PARTICIPANTS: Adults diagnosed with CTEPH between 1 January 2012 and 30 June 2019 were included. Cohorts were retrospectively defined for operated patients (received pulmonary endarterectomy (PEA)) and not operated; further subgroups were defined based on risk score (low, intermediate or high risk for 1-year mortality) at diagnosis. PRIMARY AND SECONDARY OUTCOME MEASURES: Demographics, clinical characteristics, comorbidities, treatment patterns, HRQoL, HCRU, costs and survival outcomes were analysed. RESULTS: Overall, 683 patients were analysed (268 (39%) operated; 415 (61%) not operated). Most patients in the operated and not-operated cohorts were intermediate risk (63%; 53%) or high risk (23%; 31%) at diagnosis. Intermediate-risk and high-risk patients had higher HCRU and costs than low-risk patients. Outpatient and accident and emergency visits were lower postdiagnosis for both cohorts and all risk groups versus prediagnosis. HRQoL scores noticeably improved in the operated cohort post-PEA, and less so in the not-operated cohort at 6-18 months postdiagnosis. Survival at 5 years was 83% (operated) and 49% (not operated) and was lower for intermediate-risk and high-risk patients compared with low-risk patients. CONCLUSIONS: Findings from this study support that risk assessment at diagnosis is prognostic for mortality in patients with CTEPH. Low-risk patients have better survival and HRQoL and lower HCRU and costs compared with intermediate-risk and high-risk patients.

Design of an ultra-low mode volume piezo-optomechanical quantum transducer.

Coherent transduction of quantum states from the microwave to the optical domain can play a key role in quantum networking and distributed quantum computing. We present the design of a piezo-optomechanical device formed in a hybrid lithium niobate on silicon platform, that is suitable for microwave-to-optical quantum transduction. Our design is based on acoustic hybridization of an ultra-low mode volume piezoacoustic cavity with an optomechanical crystal cavity. The strong piezoelectric nature of lithium niobate allows us to mediate transduction via an acoustic mode which only minimally interacts with the lithium niobate, and is predominantly silicon-like, with very low electrical and acoustic loss. We estimate that this transducer can realize an intrinsic conversion efficiency of up to 35% with <0.5 added noise quanta when resonantly coupled to a superconducting transmon qubit and operated in pulsed mode at 10 kHz repetition rate. The performance improvement gained in such hybrid lithium niobate-silicon transducers make them suitable for heralded entanglement of qubits between superconducting quantum processors connected by optical fiber links.

Healthcare resource utilization and quality of life in patients with sarcoidosis-associated pulmonary hypertension.

A retrospective, observational cohort study was conducted to generate real-world evidence in adult patients diagnosed with sarcoidosis-associated pulmonary hypertension (SAPH) at a referral center in England between 2012 and 2019. Data from the referral center electronic medical record database were linked to the National Health Service Hospital Episode Statistics database to collect and analyze patient demographics, clinical characteristics, comorbidities, treatment patterns, health-related quality of life (HRQoL; assessed using the EmPHasis-10 questionnaire), healthcare resource utilization (HCRU), costs, and survival. Sixty-two patients with SAPH were identified. At diagnosis, 84% were in WHO functional class III and presented with significant pulmonary hemodynamic impairment. Cardiovascular and respiratory comorbidities were commonly reported prediagnosis. Median EmPHasis-10 score at diagnosis was 34, indicative of poor HRQoL. In the 1st year after diagnosis, median (Q1, Q3) per-patient HCRU was 1 (0, 2) all-cause inpatient hospitalizations; 3 (2, 4) same-day hospitalizations; and 9 (6, 11) outpatient consultations. In 24 patients who were hospitalized longer than 1 day in the 1st year after diagnosis, the median duration of hospitalization was 4 days. With a median follow-up of 1.8 years, the median overall survival was 2.9 years. In this cohort of patients with SAPH, poor HRQoL and high HCRU were observed following diagnosis. To our knowledge, this is the first study to report on HRQoL and HCRU in patients with SAPH. More research is needed on treatment options for this population with high unmet needs.

Development of flow cytometry-based Zika virus detection assay.

Standard assays based on ELISA and RT-PCR have been widely used to detect flaviviral infections, including the Zika virus (Zika). Despite their simple, unique, and sensitive features, RT-PCR and ELISA-based assays cannot meet the requirements of high-throughput screening of bulk samples during an outbreak. Several research groups around the world are working on the development of rapid, multiplex, and sensitive assays to overcome the limitations of standard assays used in viral detection. Recent advances in flow cytometry have led to remarkable progress in its use as a basic analysis tool in laboratories. Here, we used the advantages of flow cytometry to develop a Zika detection assay using recombinant Zika envelope (E) protein. The E protein-based flow cytometry assay was able to detect anti-Zika E antibodies from Zika-infected patients, Zika-infected mice, and mice immunized with recombinant Zika E protein. We report the development of the first flow cytometry-based diagnostic assay that can be used for Zika detection. Its rapid turnaround time and ability to detect antibodies from Zika-infected patients can be used to improve the diagnostic accuracy of Zika detection. Keywords: Flavivirus; Zika virus; E protein; NS-1 protein; flow cytometry; ELISA; RT-PCR.

Examining the role of nickel and NiTi nanoparticles promoting inflammation and angiogenesis.

Nickel titanium (NiTi, or Nitinol) alloy is used in several biomedical applications, including cardiac, peripheral vascular, and fallopian tube stents. There are significant biocompatibility issues of metallic implants to nickel ions and nano-/micro-sized alloy particles. Our laboratories have recently shown that microscale CoCr wear particles from metal-on-metal hips crosslink with the innate immune signaling Toll-like receptor 4 (TLR4), prompting downstream signaling that results in interleukin (IL)-1ß and IL-8 gene expression. In vivo, NiTi alloy can also generate wear particles on the nanoscale (NP) that have thus far not been studied for their potential to induce inflammation and angiogenesis that can, in turn, contribute to implant (e.g. stent) failure. Earlier studies by others demonstrated that nickel could induce contact hypersensitivity by crosslinking the human, but not the mouse, TLR4. In the present work, it is demonstrated that NiCl2 ions and NiTi nanoparticles induce pro-inflammatory and pro-angiogenic cytokine/chemokine expression in human endothelial and monocyte cell lines in vitro. These observations prompt concerns about potential mechanisms for stent failure. The data here showed a direct correlation between intracellular uptake of Ni2+ and generation of reactive oxygen species. To determine a role for nickel and NiTi nanoparticles in inducing angiogenesis in vivo, 1-cm silicone angioreactors were implanted subcutaneously into athymic (T-cell-deficient) nude mice. The angioreactors contained Matrigel (a gelatinous protein mixture that resembles extracellular matrix) in addition to one of the following: PBS (negative control), VEGF/FGF-2 (positive control), NiCl2, or NiTi NP. The implantation of angioreactors represents a potential tool for quantification of angiogenic potentials of medical device-derived particles and ions in vivo. By this approach, NiTi NP were found to be markedly angiogenic, while Ni2+ was less-so. The angioreactors may provide a powerful tool to examine if debris shed from medical devices may promote untoward biological effects.

Cyanidin and delphinidin restore colon physiology in high fat diet-fed mice: Involvement of TLR-4 and redox-regulated signaling.

Consumption of high fat diets (HFD) mimics a modern or "Western style" diet pattern and can impair intestinal barrier integrity, leading to endotoxemia and associated unhealthy conditions. This study investigated if supplementation with an anthocyanin (cyanidin and delphinidin glucosides)-rich extract (CDRE) could revert or mitigate HFD-induced alterations of colonic physiology in part through the regulation of Toll-Like Receptor 4 (TLR-4)- and redox-regulated signaling. C57BL/6J male mice were fed for 4 weeks with a control or an HFD. Then, mice were divided in four groups fed either control or HFD, or these diets supplemented with CDRE for the subsequent 4 weeks. After 8 weeks on the HFD we observed in the colon: i) disruption of tight junction structure and function; ii) increased TLR-4 expression; iii) increased NADPH oxidase NOX1 expression, and iv) activation of redox-sensitive and TLR-4-triggered pathways, i.e. NF-κB, ERK1/2, JNK1/2, PI3K/Akt. All these events were prevented or reverted by CDRE supplementation. Supporting the relevance of CDRE-mediated downregulation of TLR-4 on its colon beneficial effect; in vitro (Caco-2 cell monolayers), cyanidin, delphinidin and their metabolites protocatechuic and gallic acid, mitigated lipopolysaccharide (LPS)-induced monolayer permeabilization by restoring tight junction structure and dynamics and preventing lipid/protein oxidation. The CDRE also mitigated HFD-mediated alterations in parameters of goblet cell differentiation and function, including the downregulation of markers of goblet cell differentiation (Klf4), and intestinal mucosa healing (Tff3). Results show that a short-term supplementation with cyanidin and delphinidin, protect from HFD-induced alterations in colon physiology in part through the modulation of TLR-4- and redox-regulated signaling.

Validation of Artificial Intelligence Cardiac MRI Measurements: Relationship to Heart Catheterization and Mortality Prediction.

Background Cardiac MRI measurements have diagnostic and prognostic value in the evaluation of cardiopulmonary disease. Artificial intelligence approaches to automate cardiac MRI segmentation are emerging but require clinical testing. Purpose To develop and evaluate a deep learning tool for quantitative evaluation of cardiac MRI functional studies and assess its use for prognosis in patients suspected of having pulmonary hypertension. Materials and Methods A retrospective multicenter and multivendor data set was used to develop a deep learning-based cardiac MRI contouring model using a cohort of patients suspected of having cardiopulmonary disease from multiple pathologic causes. Correlation with same-day right heart catheterization (RHC) and scan-rescan repeatability was assessed in prospectively recruited participants. Prognostic impact was assessed using Cox proportional hazard regression analysis of 3487 patients from the ASPIRE (Assessing the Severity of Pulmonary Hypertension In a Pulmonary Hypertension Referral Centre) registry, including a subset of 920 patients with pulmonary arterial hypertension. The generalizability of the automatic assessment was evaluated in 40 multivendor studies from 32 centers. Results The training data set included 539 patients (mean age, 54 years ± 20 [SD]; 315 women). Automatic cardiac MRI measurements were better correlated with RHC parameters than were manual measurements, including left ventricular stroke volume (r = 0.72 vs 0.68; P = .03). Interstudy repeatability of cardiac MRI measurements was high for all automatic measurements (intraclass correlation coefficient range, 0.79-0.99) and similarly repeatable to manual measurements (all paired t test P > .05). Automated right ventricle and left ventricle cardiac MRI measurements were associated with mortality in patients suspected of having pulmonary hypertension. Conclusion An automatic cardiac MRI measurement approach was developed and tested in a large cohort of patients, including a broad spectrum of right ventricular and left ventricular conditions, with internal and external testing. Fully automatic cardiac MRI assessment correlated strongly with invasive hemodynamics, had prognostic value, were highly repeatable, and showed excellent generalizability. Clinical trial registration no. NCT03841344 Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Ambale-Venkatesh and Lima in this issue. An earlier incorrect version appeared online. This article was corrected on June 27, 2022.

Targeting glycoprotein VI to disrupt platelet-mediated tumor cell extravasation.

Activated platelets coat circulating tumor cells, protecting them from shear stress in the blood stream and promoting their evasion from immune surveillance. Platelets promote tumor cell dissemination to distant organs by releasing transforming growth factor-ß1 (TGF-ß1) into the tumor microenvironment, which induces phenotypic changes to the epithelial-mesenchymal transition. This process facilitates tumor cell transendothelial extravasation and formation of early metastatic niches. Development of antiplatelet agents that interrupt the platelet-tumor cell axis but do not interfere with physiological hemostatic mechanisms is critical. The glycoprotein VI (GPVI), a member of the immunoreceptor family that is co-expressed with the fragment crystallizable (Fc) receptor γ-chain, is exclusively expressed in platelets and megakaryocytes, and blocking the receptor or genetic deficiency has minimal impact on bleeding. Tumor cell-expressed galectin-3, which contains a collagen-like peptide domain, binds to platelet GPVI-dimers, and the receptor-ligand activates platelets to form a protective heteroaggregate coat around tumor cells. This review highlights the potential of targeting the GPVI/FcR γ-chain complex to inhibit platelet activation by galectin-3 expressing tumor cells, disrupting the platelet-tumor cell amplification loop while maintaining the function of platelets in hemostasis.

A randomized placebo-controlled cross-over study on the effects of anthocyanins on inflammatory and metabolic responses to a high-fat meal in healthy subjects.

This study investigated the effects of supplementation with a cyanidin- and delphinidin-rich extract (CDRE) on the postprandial dysmetabolism, inflammation, and redox and insulin signaling, triggered by the consumption of a high fat meal (HFM) in healthy individuals. Participants (n = 25) consumed a 1026-kcal HFM simultaneously with either the CDRE providing 320.4 mg of anthocyanins (90% cyanidin and delphinidin) or placebo. Diets were randomly assigned in a double blind, placebo-controlled crossover design. Blood was collected prior to (fasted, time 0), and for 5 h after meal consumption; plasma, serum, and peripheral blood mononuclear cells (PBMC) were isolated. AC metabolites were detected in serum as early as 30 min after CDRE consumption. The CDRE mitigated HFM-induced endotoxemia, reducing increases in plasma LPS and LPS-binding protein. The CDRE also reduced other events associated with HFM-triggered postprandial dysmetabolism including: i) plasma glucose and triglyceride increases; ii) TNFα and NOX4 upregulation in PBMC; and iii) JNK1/2 activation in PBMC. The CDRE did not significantly affect HFM-mediated increases in plasma insulin, GLP-1, GLP-2, GIP, and LDL- and HDL-cholesterol, and IKK phosphorylation in PBMC. In summary, dietary AC, i.e. cyanidin and delphinidin, exerted beneficial actions against unhealthy diets by modulating the associated postprandial dysmetabolism, endotoxemia, alterations of glycemia and lipidemia, and redox and insulin signaling.

Supplementation with cyanidin and delphinidin mitigates high fat diet-induced endotoxemia and associated liver inflammation in mice.

Consumption of high fat diets (HFD) and the associated metabolic endotoxemia can initiate liver inflammation and lipid deposition that with time can progress to non-alcoholic fatty liver disease (NAFLD). We previously observed that 14 weeks supplementation with the anthocyanidins cyanidin and delphinidin mitigated HFD-induced metabolic endotoxemia and liver insulin resistance, steatosis, inflammation and oxidative stress. This work investigated if a 4-week supplementation of mice with a cyanidin- and delphinidin-rich extract (CDRE) could mitigate or reverse HFD (60% calories from lard fat)-induced liver steatosis and inflammation. After a first 4-weeks period on the HFD, mice showed increased endotoxemia and activation of liver proinflammatory signaling cascades. Supplementation with CDRE between weeks 4 and 8 did not mitigate liver steatosis or the altered lipid and glucose plasma levels. However, CDRE supplementation reverted HFD-induced metabolic endotoxemia, in parallel with the mitigation of the overexpression of hepatic TLR2 and TLR4, and of the activation of: (i) NF-κB, (ii) AP-1 and upstream mitogen-activated kinases p38 and ERK1/2, and (iii) HIF-1. Thus, even a short-term consumption of cyanidin and delphinidin could help mitigate the adverse consequences, i.e. metabolic endotoxemia and associated liver inflammation, triggered by the regular consumption of diets rich in fat.

Correlation between targeted RNAseq signature of breast cancer CTCs and onset of bone-only metastases.

BACKGROUND: Bone is the most frequent site of metastases from breast cancer (BC), but no biomarkers are yet available to predict skeletal dissemination. METHODS: We attempted to identify a gene signature correlated with bone metastasis (BM) onset in circulating tumour cells (CTCs), isolated by a DEPArray-based protocol from 40 metastatic BC patients and grouped according to metastasis sites, namely "BM" (bone-only), "ES" (extra-skeletal) or BM + ES (bone + extra-skeletal). RESULTS: A 134-gene panel was first validated through targeted RNA sequencing (RNAseq) on sub-clones of the MDA-MB-231 BC cell line with variable organotropism, which successfully shaped their clustering. The panel was then applied to CTC groups and, in particular, the "BM" vs "ES" CTC comparison revealed 31 differentially expressed genes, including MAF, CAPG, GIPC1 and IL1B, playing key prognostic roles in BC. CONCLUSION: Such evidence confirms that CTCs are suitable biological sources for organotropism investigation through targeted RNAseq and might deserve future applications in wide-scale prospective studies.

Sequen-C: A Multilevel Overview of Temporal Event Sequences.

Building a visual overview of temporal event sequences with an optimal level-of-detail (i.e. simplified but informative) is an ongoing challenge - expecting the user to zoom into every important aspect of the overview can lead to missing insights. We propose a technique to build a multilevel overview of event sequences, whose granularity can be transformed across sequence clusters (vertical level-of-detail) or longitudinally (horizontal level-of-detail), using hierarchical aggregation and a novel cluster data representation Align-Score-Simplify. By default, the overview shows an optimal number of sequence clusters obtained through the average silhouette width metric - then users are able to explore alternative optimal sequence clusterings. The vertical level-of-detail of the overview changes along with the number of clusters, whilst the horizontal level-of-detail refers to the level of summarization applied to each cluster representation. The proposed technique has been implemented into a visualization system called Sequence Cluster Explorer (Sequen-C) that allows multilevel and detail-on-demand exploration through three coordinated views, and the inspection of data attributes at cluster, unique sequence, and individual sequence level. We present two case studies using real-world datasets in the healthcare domain: CUREd and MIMIC-III; which demonstrate how the technique can aid users to obtain a summary of common and deviating pathways, and explore data attributes for selected patterns.

Glucosamine Supplementation Improves Physical Performance in Trained Mice.

INTRODUCTION: d-Glucosamine (GlcN) is one of the most widely consumed dietary supplements and complementary medicines in the world and has been traditionally used to attenuate osteoarthritis in humans. GlcN extends life span in different animal models. In humans, its supplementation has been strongly associated with decreased total mortality and improved vascular endothelial function. GlcN acts as a suppressor of inflammation, and by inhibiting glycolysis, it can activate the metabolism of stored fat and mitochondrial respiration. METHODS: The conventional human GlcN dose is 1500 mg·d-1, but extensive evidence indicates that much higher doses are well tolerated. GlcN is one of the supplements that has experienced a greater use in the last years in elite athletes mainly because of its potential chondroprotective effects that may promote cartilage health. However, the possibility of it being an ergogenic aid has not been explored. We aimed to study the potential beneficial effects of GlcN on mitochondrial content, physical performance, and oxidative stress in mice that were aerobically trained and supplemented with three different doses of glucosamine (250, 500, and 1000 mg·kg-1) for 6 wk. We measured exercise performance (grip strength, motor coordination, and running capacity) before and after the training period. Proteins involved in mitochondrial biogenesis (AMPK, PGC-1, NRF-1, SIRT-1, cytochrome c, citrate synthase), markers of oxidative stress (GSSG/GSH) or damage (malondialdehyde, carbonylated proteins), antioxidant enzymes (NRF-2, SOD1, SOD2, catalase, and PRDX6), and MAPKs (p38 and ERK1/2 were also determined in skeletal muscle. RESULTS AND CONCLUSIONS: Our results show that GlcN supplementation in aerobically trained mice, at doses equivalent to those conventionally used in humans, increases the protein levels of mitochondrial biogenesis markers, improves motor coordination, and may have a synergistic effect with exercise training on running distance.

Risk factors for SARS-CoV-2 seroprevalence following the first pandemic wave in UK healthcare workers in a large NHS Foundation Trust.

BACKGROUND: We aimed to measure SARS-CoV-2 seroprevalence in a cohort of healthcare workers (HCWs) during the first UK wave of the COVID-19 pandemic, explore risk factors associated with infection, and investigate the impact of antibody titres on assay sensitivity. METHODS: HCWs at Sheffield Teaching Hospitals NHS Foundation Trust (STH) were prospectively enrolled and sampled at two time points. SARS-CoV-2 antibodies were tested using an in-house assay for IgG and IgA reactivity against Spike and Nucleoprotein (sensitivity 99·47%, specificity 99·56%). Data were analysed using three statistical models: a seroprevalence model, an antibody kinetics model, and a heterogeneous sensitivity model. FINDINGS: As of 12th June 2020, 24·4% (n=311/1275) HCWs were seropositive. Of these, 39·2% (n=122/311) were asymptomatic. The highest adjusted seroprevalence was measured in HCWs on the Acute Medical Unit (41·1%, 95% CrI 30·0-52·9) and in Physiotherapists and Occupational Therapists (39·2%, 95% CrI 24·4-56·5). Older age groups showed overall higher median antibody titres. Further modelling suggests that, for a serological assay with an overall sensitivity of 80%, antibody titres may be markedly affected by differences in age, with sensitivity estimates of 89% in those over 60 years but 61% in those ≤30 years. INTERPRETATION: HCWs in acute medical units working closely with COVID-19 patients were at highest risk of infection, though whether these are infections acquired from patients or other staff is unknown. Current serological assays may underestimate seroprevalence in younger age groups if validated using sera from older and/or more symptomatic individuals. RESEARCH IN CONTEXT: Evidence before this study: We searched PubMed for studies published up to March 6th 2021, using the terms "COVID", "SARS-CoV-2", "seroprevalence", and "healthcare workers", and in addition for articles of antibody titres in different age groups against coronaviruses using "coronavirus", "SARS-CoV-2, "antibody", "antibody tires", "COVID" and "age". We included studies that used serology to estimate prevalence in healthcare workers. SARS-CoV-2 seroprevalence has been shown to be greater in healthcare workers working on acute medical units or within domestic services. Antibody levels against seasonal coronaviruses, SARS-CoV and SARS-CoV-2 were found to be higher in older adults, and patients who were hospitalised.Added value of this study: In this healthcare worker seroprevalence modelling study at a large NHS foundation trust, we confirm that those working on acute medical units, COVID-19 "Red Zones" and within domestic services are most likely to be seropositive. Furthermore, we show that physiotherapists and occupational therapists have an increased risk of COVID-19 infection. We also confirm that antibody titres are greater in older individuals, even in the context of non-hospitalised cases. Importantly, we demonstrate that this can result in age-specific sensitivity in serological assays, where lower antibody titres in younger individuals results in lower assay sensitivity.Implications of all the available evidence: There are distinct occupational roles and locations in hospitals where the risk of COVID-19 infection to healthcare workers is greatest, and this knowledge should be used to prioritise infection prevention control and other measures to protect healthcare workers. Serological assays may have different sensitivity profiles across different age groups, especially if assay validation was undertaken using samples from older and/or hospitalised patients, who tend to have higher antibody titres. Future seroprevalence studies should consider adjusting for age-specific assay sensitivities to estimate true seroprevalence rates.

Risk factors for SARS-CoV-2 seroprevalence following the first pandemic wave in UK healthcare workers in a large NHS Foundation Trust.

Background: We aimed to measure SARS-CoV-2 seroprevalence in a cohort of healthcare workers (HCWs) during the first UK wave of the COVID-19 pandemic, explore risk factors associated with infection, and investigate the impact of antibody titres on assay sensitivity. Methods: HCWs at Sheffield Teaching Hospitals NHS Foundation Trust were prospectively enrolled and sampled at two time points. We developed an in-house ELISA for testing participant serum for SARS-CoV-2 IgG and IgA reactivity against Spike and Nucleoprotein. Data were analysed using three statistical models: a seroprevalence model, an antibody kinetics model, and a heterogeneous sensitivity model. Results: Our in-house assay had a sensitivity of 99·47% and specificity of 99·56%. We found that 24·4% (n=311/1275) of HCWs were seropositive as of 12th June 2020. Of these, 39·2% (n=122/311) were asymptomatic. The highest adjusted seroprevalence was measured in HCWs on the Acute Medical Unit (41·1%, 95% CrI 30·0-52·9) and in Physiotherapists and Occupational Therapists (39·2%, 95% CrI 24·4-56·5). Older age groups showed overall higher median antibody titres. Further modelling suggests that, for a serological assay with an overall sensitivity of 80%, antibody titres may be markedly affected by differences in age, with sensitivity estimates of 89% in those over 60 years but 61% in those ≤30 years. Conclusions:  HCWs in acute medical units and those working closely with COVID-19 patients were at highest risk of infection, though whether these are infections acquired from patients or other staff is unknown. Current serological assays may underestimate seroprevalence in younger age groups if validated using sera from older and/or more severe COVID-19 cases.

Guidance for the assessment and management of prostate cancer treatment-induced bone loss. A consensus position statement from an expert group.

CONTEXT AND OBJECTIVE: Incidence of prostate cancer (PC) is increasing, but androgen deprivation therapy (ADT) and other therapies are substantially improving survival. In this context, careful consideration of skeletal health is required to reduce the risk of treatment-related fragility fractures and their associated morbidity and mortality. This risk is currently not well-managed. ADT causes significant loss of bone mineral density (BMD). In the metastatic setting, systemic treatments (e.g. chemotherapy, abiraterone, enzalutamide) are used alongside ADT and may require concomitant glucocorticoids. Both ADT and glucocorticoids pose significant challenges to skeletal health in a population of patients already likely to have ongoing age-related bone loss and/or comorbid conditions. Current PC guidelines lack specific recommendations for optimising bone health. This guidance presents evidence for assessment and management of bone health in this population, with specific recommendations for clinical practitioners in day-to-day PC management. METHODS: Structured meetings of key opinion leaders were integrated with a systematic literature review. Input and endorsement was sought from patients, nursing representatives and specialist societies. SUMMARY OF GUIDANCE: All men starting or continuing long-term ADT should receive lifestyle advice regarding bone health. Calcium/vitamin D supplementation should be offered if required. Fracture risk should be calculated (using the FRAX® tool), with BMD assessment included where feasible. BMD should always be assessed where fracture risk calculated using FRAX® alone is close to the intervention threshold. Intervention should be provided if indicated by local or national guidelines e.g. UK National Osteoporosis Guideline Group (NOGG) thresholds. Men requiring bone protection therapy should be further assessed (e.g. renal function), with referral to specialist centres if available and offered appropriate treatment to reduce fracture risk. Those near to, but below an intervention threshold, and patients going on to additional systemic therapies (particularly those requiring glucocorticoids), should have FRAX® (including BMD) repeated after 12-18 months. PATIENT SUMMARY: Modern treatments for prostate cancer have led to significant improvements in survival and quality of life. However, some of these treatments may lead to weakening of patient's bones with risk of fracture and it is therefore important to monitor patients' bone health and provide bone protection where needed. This paper provides specific guidance to clinical teams, based on the most recent research evidence, to ensure optimal bone health in their patients.

Personal Medicine and Bone Metastases: Biomarkers, Micro-RNAs and Bone Metastases.

Bone metastasis is a major cause of morbidity within solid tumours of the breast, prostate, lung and kidney. Metastasis to the skeleton is associated with a wide range of complications including bone fractures, spinal cord compression, hypercalcaemia and increased bone pain. Improved treatments for bone metastasis, such as the use of anti-bone resorptive bisphosphonate agents, within post-menopausal women have improved disease-free survival; however, these treatments are not without side effects. There is thus a need for biomarkers, which will predict the risk of developing the spread to bone within these cancers. The application of molecular profiling techniques, together with animal model systems and engineered cell-lines has enabled the identification of a series of potential bone-metastasis biomarker molecules predictive of bone metastasis risk. Some of these biomarker candidates have been validated within patient-derived samples providing a step towards clinical utility. Recent developments in multiplex biomarker quantification now enable the simultaneous measurement of up to 96 micro-RNA/protein molecules in a spatially defined manner with single-cell resolution, thus enabling the characterisation of the key molecules active at the sites of pre-metastatic niche formation as well as tumour-stroma signalling. These technologies have considerable potential to inform biomarker discovery. Additionally, a potential future extension of these discoveries could also be the identification of novel drug targets within cancer spread to bone. This chapter summarises recent findings in biomarker discovery within the key bone metastatic cancers (breast, prostate, lung and renal cell carcinoma). Tissue-based and circulating blood-based biomarkers are discussed from the fields of genomics, epigenetic regulation (micro-RNAs) and protein/cell-signalling together with a discussion of the potential future development of these markers towards clinical development.

Clinical predictors of all-cause mortality in patients presenting to specialist heart failure clinic with raised NT-proBNP and no heart failure.

AIMS: Clinical outcomes for patients suspected of having heart failure (HF) who do not meet the diagnostic criteria of any type of HF by echocardiography remain unknown. The aim of this study was to investigate the clinical predictors of all-cause mortality in patients with suspected HF, a raised N-terminal pro-b-type natriuretic peptide (NTproBNP) and who do not meet the diagnostic criteria of any type of HF by echocardiography. METHODS AND RESULTS: Relevant data were taken from the Sheffield HEArt Failure (SHEAF) registry (222349P4). The inclusion criteria were presence of symptoms raising suspicion of HF, NTproBNP > 400 pg/mL, and preserved left ventricular function. Exclusion criteria were any type of HF by echocardiography. The outcome was defined as all-cause mortality. Cox proportional-hazards regression model was used to investigate the association between the survival time of patients and clinical variables; 1031 patients were identified with NTproBNP > 400 pg/mL but who did not have echocardiographic evidence of HF. All-cause mortality was 21.5% (222 deaths) over the mean follow-up (FU) period of 6 ± 2 years. NTproBNP was similar in patients who were alive or dead (P = 0.96). However, age (HR 1, P < 0.01), chronic kidney disease (CKD, HR 1.2, P < 0.01), chronic pulmonary obstructive disease (COPD, HR 1.6, P < 0.01), dementia (HR 5.9, P < 0.01), male gender (HR 1.4, P < 0.01), first-degree atrioventricular block (HR 2.1, P < 0.01), left axis deviation (HR 1.6, P = 0.04), and diabetes (HR 1.4, P = 0.03) were associated with all-cause mortality. In multivariate regression, age, gender, CKD stage, COPD, and dementia were independently associated with mortality. In patients with NTproBNP > 627 pg/mL, NYHA class predicted death (II, 19.6%; III, 27.4%; IV, 66.7%; P < 0.01). CONCLUSIONS: Patients with no HF on echocardiography but raised NTproBNP suffer excess mortality particularly in the presence of certain clinical variables. Age, male gender, worsening CKD stage, presence of COPD, and dementia are independently associated with all-cause mortality in these patients. An NTproBNP > 627 pg/mL coupled with NYHA class could identify patients at greatest risk of death.

Particulate Matter Decreases Intestinal Barrier-Associated Proteins Levels in 3D Human Intestinal Model.

(1) Background: The gastrointestinal tract (GI) tract is one of the main organs exposed to particulate matter (PM) directly through ingestion of contaminated food or indirectly through inhalation. Previous studies have investigated the effects of chronic PM exposure on intestinal epithelia in vitro using Caco-2 cells and in vivo using mice. In this study, we hypothesized that chronic PM exposure would increase epithelial permeability and decrease barrier function due to altered redox homeostasis, which alters levels and/or localization of barrier-associated proteins in human three-dimensional (3D) intestinal tissues. (2) Methods: Transepithelial electrical resistance (TEER) in tissues exposed to 50, 100, 150, 250, and 500 µg/cm2 of PM for 1 week and 2 weeks was analyzed. Levels and localization of tight junction proteins zonula occludens protein 1 (ZO-1) and claudin-1 and desmosome-associated desmocollin were analyzed using immunofluorescence. As a marker of oxidative stress, levels of 4-hydroxy-nonenal (4HNE) adducts were measured. (3) Results: No differences in TEER measurements were observed between exposed and un-exposed tissues. However, increased levels of 4HNE adducts in exposed tissues were observed. Additionally, decreased levels of ZO-1, claudin-1, and desmocollin were demonstrated. (4) Conclusion: These data suggest that chronic PM exposure results in an increase of oxidative stress; modified levels of barrier-associated proteins could possibly link to GI tract inflammatory conditions.