A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis

BACKGROUND: Systemic sclerosis (SSc) is a multi-organ autoimmune disease characterized by skin fibrosis. Internal organ involvement is heterogeneous. It is unknown whether disease mechanisms are common across all involved affected tissues or if each manifestation has a distinct underlying pathology. METHODS: We used consensus clustering to compare gene expression profiles of biopsies from four SSc-affected tissues (skin, lung, esophagus, and peripheral blood) from patients with SSc, and the related conditions pulmonary fibrosis (PF) and pulmonary arterial hypertension, and derived a consensus disease-associate signature across all tissues. We used this signature to query tissue-specific functional genomic networks. We performed novel network analyses to contrast the skin and lung microenvironments and to assess the functional role of the inflammatory and fibrotic genes in each organ. Lastly, we tested the expression of macrophage activation state-associated gene sets for enrichment in skin and lung using a Wilcoxon rank sum test. RESULTS: We identified a common pathogenic gene expression signature-an immune-fibrotic axis-indicative of pro-fibrotic macrophages (MØs) in multiple tissues (skin, lung, esophagus, and peripheral blood mononuclear cells) affected by SSc. While the co-expression of these genes is common to all tissues, the functional consequences of this upregulation differ by organ. We used this disease-associated signature to query tissue-specific functional genomic networks to identify common and tissue-specific pathologies of SSc and related conditions. In contrast to skin, in the lung-specific functional network we identify a distinct lung-resident MØ signature associated with lipid stimulation and alternative activation. In keeping with our network results, we find distinct MØ alternative activation transcriptional programs in SSc-associated PF lung and in the skin of patients with an "inflammatory" SSc gene expression signature. CONCLUSIONS: Our results suggest that the innate immune system is central to SSc disease processes but that subtle distinctions exist between tissues. Our approach provides a framework for examining molecular signatures of disease in fibrosis and autoimmune diseases and for leveraging publicly available data to understand common and tissue-specific disease processes in complex human diseases

Use of imaging for pre- and post-operative characterisation of ventral hernia: systematic review

OBJECTIVE: Complex ventral hernia repair is performed increasingly, exacerbated by the obesity epidemic. Imaging can characterise hernia morphology and diagnose recurrence. By systematic review we investigated the extent to which studies employ imaging. METHODS: The PubMed database was searched for studies of ventral hernia repair January 1995 to March 2016. Hernias of all size were eligible. Independent reviewers screened articles and extracted data from selected studies related to study design, use of pre- and post-operative hernia imaging, and the proportion of subjects imaged. The review was registered: PROSPERO CRD42016043071. RESULTS: 15,771 records were identified initially. 174 full-texts were examined and 158 ultimately included in the systematic review (31 randomised-controlled-trials; 32 cohort studies; 95 retrospective cohort studies). 31,874 subjects were reported overall. Only 19 (12%) studies employed pre-operative imaging for hernia characterisation and 46 (29%) post-operatively [equating to 511 (2%) of all preoperative subjects and 1123 (4%) post-operative]. Furthermore, most studies employing imaging did not do so in all subjects: Just six (4%) of the 158 studies used imaging in all subjects preoperatively and just 4 (3%) postoperatively, i.e. imaging was usually applied to a proportion of patients only. Moreover, the exact proportion was frequently not specified. Studies using imaging frequently stated that "imaging", "radiography" or "radiology" was used but did not specify the modality precisely nor the proportion of subjects imaged. CONCLUSION: Despite the ability to characterise ventral hernia morphology and recurrence with precision, most indexed studies do not employ imaging. Where imaging is used, data are often reported incompletely. Advances in knowledge: (1) This systematic review is the first to focus on the use of imaging in surgical studies of ventral hernia repair. (2) Studies of ventral hernia repair rarely use imaging, either to characterise hernias preoperatively or to diagnose recurrence, despite the latter being the primary outcome of most studies. (3) Failure to use imaging will result in incomplete hernia characterisation and underestimate recurrence rates in studies of surgical repair

Intra- and interreader reproducibility of PI-RADSv2: A multireader study

Background: The Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) has been in use since 2015; while interreader reproducibility has been studied, there has been a paucity of studies investigating the intrareader reproducibility of PI-RADSv2. Purpose: To evaluate both intra- and interreader reproducibility of PI-RADSv2 in the assessment of intraprostatic lesions using multiparametric magnetic resonance imaging (mpMRI). Study Type: Retrospective. Population/Subjects: In all, 102 consecutive biopsy-naïve patients who underwent prostate MRI and subsequent MR/transrectal ultrasonography (MR/TRUS)-guided biopsy. Field Strength/Sequences: Prostate mpMRI at 3T using endorectal with phased array surface coils (TW MRI, DW MRI with ADC maps and b2000 DW MRI, DCE MRI). Assessment: Previously detected and biopsied lesions were scored by four readers from four different institutions using PI-RADSv2. Readers scored lesions during two readout rounds with a 4-week washout period. Statistical Tests: Kappa (κ) statistics and specific agreement (Po) were calculated to quantify intra- and interreader reproducibility of PI-RADSv2 scoring. Lesion measurement agreement was calculated using the intraclass correlation coefficient (ICC). Results: Overall intrareader reproducibility was moderate to substantial (κ = 0.43–0.67, Po = 0.60–0.77), while overall interreader reproducibility was poor to moderate (κ = 0.24, Po = 46). Readers with more experience showed greater interreader reproducibility than readers with intermediate experience in the whole prostate (P = 0.026) and peripheral zone (P = 0.002). Sequence-specific interreader agreement for all readers was similar to the overall PI-RADSv2 score, with κ = 0.24, 0.24, and 0.23 and Po = 0.47, 0.44, and 0.54 in T2-weighted, diffusion-weighted imaging (DWI), and dynamic contrast-enhanced (DCE), respectively. Overall intrareader and interreader ICC for lesion measurement was 0.82 and 0.71, respectively. Data Conclusion: PI-RADSv2 provides moderate intrareader reproducibility, poor interreader reproducibility, and moderate interreader lesion measurement reproducibility. These findings suggest a need for more standardized reader training in prostate MRI. Level of Evidence: 2. Technical Efficacy: Stage 2

Development of policies and practices of social responsibility in Portuguese companies: implications of the SA8000 standard

Series: Management and Industrial EngineeringThis study aims to explore the implications of the SA8000 standard in the implementation of Corporate Social Responsibility (CSR) policies and practices in Portuguese companies. Although this is not a recent issue, it is a subject that has motivated a growing interest on the part of the business and academic community. CSR should be seen as a new business management model, which includes universal human values as well as ethical decisions that ensure the satisfaction of the interests and needs of all stakeholders and the community in general. Regarding the empirical aspect of this research, a qualitative approach was followed through the application of a semi-structured interview to certified and not certified companies by SA8000 standard, in order to understand possible disparities with regard to the implementation of CSR policies and practices. Although the certification is the guarantee of the commitment of the companies with the CSR, the truth is that this is seen by the companies as a form of differentiation in the market. In general terms, it can be concluded that the policies and practices of CSR do not differ in relation to certification, which means that all companies have the possibility of making a difference by being socially responsible.Delfina Gomes acknowledges that this study was conducted at the Research Center in Political Science (UID/CPO/0758/2019), University of Minho/University of Évora, and was supported by the Portuguese Foundation for Science and Technology and the Portuguese Ministry of Education and Science through national funds

Assessment of the Variability in Influenza A(H1N1) Vaccine Effectiveness Estimates Dependent on Outcome and Methodological Approach

Estimation of Influenza vaccine effectiveness (VE) varies with study design, clinical outcome 10 considered and statistical methodology used. By estimating VE using differing outcomes and 11 statistical methods on the same cohort of individuals the variability in the estimates produced can 12 be better understood. The Pandemic Influenza Primary Care Reporting (PIPeR) cohort of approximately 193,000 individuals 14 was used to estimate pandemic VE in Scotland during season 2009-10. VE results for three 15 outcomes; influenza related consultations, virological confirmed influenza and death were 16 considered. Use of individualised records allowed all models to be adjusted for age, sex, 17 deprivation, risk status relating to chronic illnesses, seasonal vaccination status and a marker of the 18 individual’s propensity to consult. For the consultation and death outcomes, VE was calculated by 19 comparing consultation rates in the unvaccinated and vaccinated groups, adjusted for the listed 20 factors, using both Cox and Poisson regression models. For the consultation outcome, the 21 unvaccinated group was split into individuals before vaccination and those never vaccinated to allow 22 for potential differences in the health seeking behaviour of these groups. For the virology outcome 23 estimates were calculated using a generalised additive logistic regression model. All models were 24 adjusted for time. Vaccine effect was demonstrated for the influenza-like illness consultation outcome using the Cox 26 model (VE=49% 95% CI (19%, 67%)) with lower estimates from the model splitting the before and 27 never vaccinated groups (VE=34.2% with 95% CI (-0.5%, 58.9%)). Vaccine effect was also illustrated 28 for overall mortality (VE=40% (95% CI 18%, 56%)) and a virological confirmed subset of symptomatic 29 individuals (VE=60% (95% CI -38%, 89%))

Stellar Coronal and Wind Models: Impact on Exoplanets

Surface magnetism is believed to be the main driver of coronal heating and stellar wind acceleration. Coronae are believed to be formed by plasma confined in closed magnetic coronal loops of the stars, with winds mainly originating in open magnetic field line regions. In this Chapter, we review some basic properties of stellar coronae and winds and present some existing models. In the last part of this Chapter, we discuss the effects of coronal winds on exoplanets.Comment: Chapter published in the "Handbook of Exoplanets", Editors in Chief: Juan Antonio Belmonte and Hans Deeg, Section Editor: Nuccio Lanza. Springer Reference Work

Shorter leukocyte telomere length is associated with adverse COVID-19 outcomes: A cohort study in UK Biobank

Background Older age is the most powerful risk factor for adverse coronavirus disease-19 (COVID-19) outcomes. It is uncertain whether leucocyte telomere length (LTL), previously proposed as a marker of biological age, is also associated with COVID-19 outcomes. Methods We associated LTL values obtained from participants recruited into UK Biobank (UKB) during 2006–2010 with adverse COVID-19 outcomes recorded by 30 November 2020, defined as a composite of any of the following: hospital admission, need for critical care, respiratory support, or mortality. Using information on 130 LTL-associated genetic variants, we conducted exploratory Mendelian randomisation (MR) analyses in UKB to evaluate whether observational associations might reflect cause-and-effect relationships. Findings Of 6775 participants in UKB who tested positive for infection with SARS-CoV-2 in the community, there were 914 (13.5%) with adverse COVID-19 outcomes. The odds ratio (OR) for adverse COVID-19 outcomes was 1·17 (95% CI 1·05–1·30; P = 0·004) per 1-SD shorter usual LTL, after adjustment for age, sex and ethnicity. Similar ORs were observed in analyses that: adjusted for additional risk factors; disaggregated the composite outcome and reduced the scope for selection or collider bias. In MR analyses, the OR for adverse COVID-19 outcomes was directionally concordant but non-significant. Interpretation Shorter LTL is associated with higher risk of adverse COVID-19 outcomes, independent of several major risk factors for COVID-19 including age. Further data are needed to determine whether this association reflects causality. Funding UK Medical Research Council, Biotechnology and Biological Sciences Research Council and British Heart Foundation

On dynamic network entropy in cancer

The cellular phenotype is described by a complex network of molecular interactions. Elucidating network properties that distinguish disease from the healthy cellular state is therefore of critical importance for gaining systems-level insights into disease mechanisms and ultimately for developing improved therapies. By integrating gene expression data with a protein interaction network to induce a stochastic dynamics on the network, we here demonstrate that cancer cells are characterised by an increase in the dynamic network entropy, compared to cells of normal physiology. Using a fundamental relation between the macroscopic resilience of a dynamical system and the uncertainty (entropy) in the underlying microscopic processes, we argue that cancer cells will be more robust to random gene perturbations. In addition, we formally demonstrate that gene expression differences between normal and cancer tissue are anticorrelated with local dynamic entropy changes, thus providing a systemic link between gene expression changes at the nodes and their local network dynamics. In particular, we also find that genes which drive cell-proliferation in cancer cells and which often encode oncogenes are associated with reductions in the dynamic network entropy. In summary, our results support the view that the observed increased robustness of cancer cells to perturbation and therapy may be due to an increase in the dynamic network entropy that allows cells to adapt to the new cellular stresses. Conversely, genes that exhibit local flux entropy decreases in cancer may render cancer cells more susceptible to targeted intervention and may therefore represent promising drug targets.Comment: 10 pages, 3 figures, 4 tables. Submitte

The PINE study: rationale and design of a randomised comparison of epidural injection of local anaesthetics and steroids versus care-as-usual to prevent postherpetic neuralgia in the elderly [ISRCTN32866390]

BACKGROUND: Postherpetic neuralgia (PHN) is by far the most common complication of herpes zoster (HZ) and one of the most intractable pain disorders. Since PHN is seen most often in the elderly, the number of patients with this disorder is expected to increase in our ageing society. PHN may last for months to years and has a high impact on the quality of life. The results of PHN treatment are rather disappointing. Epidural injection of local anaesthetics and steroids in the acute phase of HZ is a promising therapy for the prevention of PHN. Since randomised trials on the effectiveness of this intervention are lacking, the PINE (Prevention by epidural Injection of postherpetic Neuralgia in the Elderly) study was set up. The PINE study compares the effectiveness and cost-effectiveness of a single epidural injection of local anaesthetics and steroids during the acute phase of HZ with that of care-as-usual (i.e. antivirals and analgesics) in preventing PHN in elderly patients. METHODS / DESIGN: The PINE study is an open, multicenter clinical trial in which 550 elderly (age ≥ 50 yr.) patients who consult their general practitioner in the acute phase of HZ (rash < 7 days) are randomised to one of the treatment groups. The primary clinical endpoint is the presence of HZ-related pain one month after the onset of the rash. Secondary endpoints include duration and severity of pain, re-interventions aiming to treat the existing pain, side effects, quality of life, and cost-effectiveness. CONCLUSION: The PINE study is aimed to quantify the (cost-) effectiveness of a single epidural injection during the acute phase of HZ on the prevention of PHN

Association of Longer Leukocyte Telomere Length With Cardiac Size, Function, and Heart Failure.

IMPORTANCE: Longer leukocyte telomere length (LTL) is associated with a lower risk of adverse cardiovascular outcomes. The extent to which variation in LTL is associated with intermediary cardiovascular phenotypes is unclear. OBJECTIVE: To evaluate the associations between LTL and a diverse set of cardiovascular imaging phenotypes. DESIGN, SETTING, AND PARTICIPANTS: This is a population-based cross-sectional study of UK Biobank participants recruited from 2006 to 2010. LTL was measured using a quantitative polymerase chain reaction method. Cardiovascular measurements were derived from cardiovascular magnetic resonance using machine learning. The median (IQR) duration of follow-up was 12.0 (11.3-12.7) years. The associations of LTL with imaging measurements and incident heart failure (HF) were evaluated by multivariable regression models. Genetic associations between LTL and significantly associated traits were investigated by mendelian randomization. Data were analyzed from January to May 2023. EXPOSURE: LTL. MAIN OUTCOMES AND MEASURES: Cardiovascular imaging traits and HF. RESULTS: Of 40 459 included participants, 19 529 (48.3%) were men, and the mean (SD) age was 55.1 (7.6) years. Longer LTL was independently associated with a pattern of positive cardiac remodeling (higher left ventricular mass, larger global ventricular size and volume, and higher ventricular and atrial stroke volumes) and a lower risk of incident HF (LTL fourth quartile vs first quartile: hazard ratio, 0.86; 95% CI, 0.81-0.91; P = 1.8 × 10-6). Mendelian randomization analysis suggested a potential causal association between LTL and left ventricular mass, global ventricular volume, and left ventricular stroke volume. CONCLUSIONS AND RELEVANCE: In this cross-sectional study, longer LTL was associated with a larger heart with better cardiac function in middle age, which could potentially explain the observed lower risk of incident HF