Systematic review: Investigating the prognostic performance of four non‐invasive tests in alcohol‐related liver disease

BACKGROUND/AIMS: Mortality of Alcohol-related-Liver-Disease (ArLD) is increasing, and liver fibrosis stage is the best mortality predictor. Non-invasive-tests (NIT) are increasingly used to detect fibrosis, but their value as prognostic tests in chronic liver disease (CLD), and in particular in ArLD is less well recognized. We aimed to describe the prognostic performance of four widely used NITs (FIB4, ELF test, FibroScan and FibroTest) in ArLD. METHODS: Applying systematic-review methodology, four databases were searched from inception to May 2020. Inclusion/exclusion criteria were applied to search using MeSH terms and keywords. First and second reviewers independently screened results, extracted data and performed risk-of-bias assessment using Quality-In-Prognostic-Studies (QUIPS) tool. RESULTS: Searches produced 25,088 articles. After initial screening, 1,020 articles were reviewed independently by both reviewers. Eleven articles remained after screening for eligibility: one on ELF, four on FibroScan, four on FIB4, one on FIB4+FibroScan and one on FibroTest+FIB4. Area-Under-Receiving-Operator-Characteristics-curves (AUROCS) for outcome-prediction ranged from: 0.65-0.76 for FibroScan, 0.64-0.83 for FIB4, 0.69-0.79 for FibroTest and 0.72-0.85 for ELF. Studies scored low-moderate risk of bias for most domains, but high-risk in confounding/statistical reporting domains. The results were heterogeneous for outcomes and reporting, making pooling of data unfeasible. CONCLUSIONS: This systematic-review returned eleven papers, six of which were conference-abstracts and one unpublished manuscript. Whilst the heterogeneity of studies precluded direct comparisons of NITs, each NIT performed well in individual studies in predicting prognosis in ArLD (AUROCs >0.7 in each NIT category), and may add value to prognostication in clinical practice

Uncovering unsuspected advanced liver fibrosis in patients referred to alcohol nurse specialists using the ELF test

BBackground and aims: Alcohol use disorders (AUD) cause 7.2% of UK hospital admissions/year. Most are not managed by hepatologists and liver disease may be missed. We used the Enhanced Liver Fibrosis (ELF) test to investigate prevalence and associations of occult advanced liver fibrosis in AUD patients not known to have liver fibrosis. / Methods: Liver fibrosis was assessed using ELF in prospective patients referred to the Royal Free Hospital Alcohol Specialist Nurse (November 2018–December 2019). Known cases of liver disease were excluded. Patient demographics, blood tests, imaging data and alcohol histories recorded. Advanced fibrosis was categorised as ELF ≥ 10.5. / Results: The study included 99 patients (69% male, mean age 53.1 ± 14.4) with median alcohol intake 140 units/week (IQR 80.9–280), and a mean duration of harmful drinking of 15 years (IQR 10–27.5). The commonest reason for admission was symptomatic alcohol withdrawal (36%). The median ELF score was 9.62, range 6.87–13.78. An ELF score ≥ 10.5 was recorded in 28/99 (29%) patients, of whom 28.6% had normal liver tests. Within previous 5-years, 76% had attended A&E without assessment of liver disease. The ELF score was not associated with recent alcohol intake (p = 0.081), or inflammation (p = 0.574). / Conclusion: Over a quarter of patients with AUD had previously undetected advanced liver fibrosis assessed by ELF testing. ELF was not associated with liver inflammation or recent alcohol intake. The majority had recent missed opportunities for investigating liver disease. We recommend clinicians use non-invasive tests to assess liver fibrosis in patients admitted to hospital with AUD

Is there scope to improve the selection of patients with alcohol-related liver disease for referral to secondary care? A retrospective analysis of primary care referrals to a UK liver centre, incorporating simple blood tests

OBJECTIVES: Twenty per cent of people with alcohol use disorders develop advanced fibrosis and warrant referral to secondary care. Improving outcomes in alcohol-related liver disease (ArLD) relies on its earlier detection in primary care with non-invasive tests (NIT). We aimed to determine the proportion of alcohol-related referrals who were diagnosed with advanced fibrosis in secondary care, the prevalence of both alcohol and fatty liver disease ('BAFLD') and the potential impact of NIT on referral stratification. DESIGN/SETTING: Retrospective analysis of all general practitioner-referrals with suspected ArLD/non-alcoholic fatty liver disease (NAFLD) to a UK hepatology-centre between January 2015 and January 2018. PARTICIPANTS: Of 2944 new referrals, 762 (mean age 55.5±13.53 years) met inclusion criteria: 531 NAFLD and 231 ArLD, of which 147 (64%) could be reclassified as 'BAFLD'. PRIMARY OUTCOME MEASURE: Proportion of referrals with suspected ArLD/NAFLD with advanced fibrosis as assessed by tertiary centre hepatologists using combinations of FibroScan, imaging, examination and blood tests and liver histology, where indicated. SECONDARY OUTCOME MEASURES: Included impact of body mass index/alcohol consumption on the odds of a diagnosis of advanced fibrosis, and performance of NIT in predicting advanced fibrosis in planned post-hoc analysis of referrals. RESULTS: Among ArLD referrals 147/229 (64.2%) had no evidence of advanced fibrosis and were judged 'unnecessary'. Advanced fibrosis was observed in men drinking ≥50 units per week (U/w) (OR 2.74, 95% CI 1.51 to 5, p=0.001) and ≥35 U/w in women (OR 5.11, 95% CI 1.31 to 20.03, p=0.019). Drinking >14 U/w doubled the likelihood of advanced fibrosis in overweight/obesity (OR 2.11; 95% CI 1.44 to 3.09; p<0.001). Use of fibrosis 4 score could halve unnecessary referrals (OR 0.50; 95% CI 0.32 to 0.79, p=0.003) with false-negative rate of 22%, but was rarely used. CONCLUSIONS: The majority of referrals with suspected ArLD were deemed unnecessary. NIT could improve identification of liver damage in ArLD, BAFLD and NAFLD in primary care. Anecdotal thresholds for harmful drinking (35 U/w in women and 50 U/w in men) were validated. The impact of alcohol on NAFLD highlights the importance of multi-causality in chronic liver disease

Eyespot variation and field temperature in the Meadow Brown butterfly

This is the final version. Available on open access from Wiley via the DOI in this record. Data availability statement: Data and R codes are available at FigShare 10.6084/m9.figshare.22759490.Since the classic work of E.B. Ford, explanations for eyespot variation in the Meadow Brown butterfly have focused on the role of genetic polymorphism. The potential role of thermal plasticity in this classic example of natural selection has therefore been overlooked. Here, we use large daily field collections of butterflies from three sites, over multiple years, to examine whether field temperature is correlated with eyespot variation, using the same presence/absence scoring as Ford. We show that higher developmental temperature in the field leads to the disappearance of the spots visible while the butterfly is at rest, explaining the historical observation that hindwing spotting declines across the season. Strikingly, females developing at 11°C have a median of six spots and those developing at 15°C only have three. In contrast, the large forewing eyespot is always present and scales with forewing length. Furthermore, in contrast to the smaller spots, the size of the large forewing spot is best explained by calendar date (days since 1st March) rather than the temperature at pupation. As this large forewing spot is involved in startling predators and/or sexual selection, its constant presence is therefore likely required for defence, whereas the disappearance of the smaller spots over the season may help with female crypsis. We model annual total spot variation with phenological data from the UK and derive predictions as to how spot patterns will continue to change, predicting that female spotting will decrease year on year as our climate warms.Biotechnology & Biological Sciences Research Council (BBSRC

Atmospheric methane variability: Centennial-scale signals in the Last Glacial Period

In order to understand atmospheric methane (CH$_{4}$) biogeochemistry now and in the future, we must apprehend its natural variability, without anthropogenic influence. Samples of ancient air trapped within ice cores provide the means to do this. Here we analyze the ultrahigh-resolution CH$_{4}$ record of the West Antarctic Ice Sheet Divide ice core 67.2–9.8 ka and find novel, atmospheric CH$_{4}$ variability at centennial time scales throughout the record. This signal is characterized by recurrence intervals within a broad 80–500 year range, but we find that age-scale uncertainties complicate the possible isolation of any periodic frequency. Lower signal amplitudes in the Last Glacial relative to the Holocene may be related to incongruent effects of firn-based signal smoothing processes. Within interstadial and stadial periods, the peak-to-peak signal amplitudes vary in proportion to the underlying millennial-scale oscillations in CH$_{4}$ concentration—the relative amplitude change is constant. We propose that the centennial CH$_{4}$ signal is related to tropical climate variability that influences predominantly low-latitude wetland CH$_{4}$ emissions.This study was funded by the U.S. National Science Foundation (NSF) grants 0944552, 1142041, and 0968391 to E.J.B. and 0839093 and 1142166 to J.R.M. A European Union Horizon 2020 Marie Curie Individual Fellowship (grant 58120, SEADOG) provided partial support for R.H.R. This work also benefitted from funding to X.F. from the French RPD COCLICO ANR program (ANR-10-RPDOC-002-01), the INSU/LEFE project IceChrono, and the Ars Cuttoli foundation and additionally from the UK Natural Environment Research Council (NERC) grant NE/P009271/1 awarded to L.C.S. Grateful thanks to B. Tournadre for help in Fletcher Promontory ice core analysis. The authors appreciate the support of the WAIS Divide Science Coordination Office at the Desert Research Institute, Reno, NV, USA, and University of New Hampshire, USA, for the collection and distribution of the WD ice core (NSF grants 0230396, 0440817, 0944348, and 0944266). We are grateful to all participants in the field effort led by K. Taylor. The NSF Office of Polar Programs also funded the Ice Drilling Program Office and Ice Drilling Design and Operations group, the National Ice Core Laboratory, Raytheon Polar Services, and the 109th New York Air National Guard

Global ocean heat content in the Last Interglacial

The Last Interglacial (129-116 ka) represents one of the warmest climate intervals of the last 800,000 years and the most recent time when sea level was meters higher than today. However, the timing and magnitude of peak warmth varies between reconstructions, and the relative importance of individual sources contributing to elevated sea level (mass gain versus seawater expansion) during the Last Interglacial remains uncertain. Here we present the first mean ocean temperature record for this interval from noble gas measurements in ice cores and constrain the thermal expansion contribution to sea level. Mean ocean temperature reaches its maximum value of 1.1±0.3°C warmer-than-modern at the end of the penultimate deglaciation at 129 ka, resulting in 0.7±0.3m of elevated sea level, relative to present. However, this maximum in ocean heat content is a transient feature; mean ocean temperature decreases in the first several thousand years of the interglacial and achieves a stable, comparable-to-modern value by ~127 ka. The synchroneity of the peak in mean ocean temperature with proxy records of abrupt transitions in oceanic and atmospheric circulation suggests that the mean ocean temperature maximum is related to the accumulation of heat in the ocean interior during the preceding period of reduced overturning circulation

Pulmonary talc granulomatosis mimicking malignant disease 30 years after last exposure: a case report

<p>Abstract</p> <p>Introduction</p> <p>Pulmonary talc granulomatosis is a rare disorder characterized by the development of foreign body granuloma secondary to talc exposure. Previous case reports have documented the illness in current intravenous drug users who inject medications intended for oral use. We present a rare case of the disease in a patient with a distant history of heroin abuse who presented initially with history and imaging findings highly suggestive of malignancy.</p> <p>Case presentation</p> <p>A 53-year-old man reported a 4-month history of increasing dyspnea and weight loss. He had a long history of smoking and admission chest X-ray revealed a density in the right hemithorax. Computed tomography confirmed a probable mass with further speculated opacities in both lung fields suspicious for malignant spread. Biopsies obtained using endobronchial ultrasound-guided aspiration returned negative for malignancy and showed bronchial epithelial cells with foreign body giant cell reaction and polarizable birefringent talc crystals.</p> <p>Conclusion</p> <p>This case demonstrates a rare presentation of talc granulomatosis three decades after the last likely exposure. The history and imaging findings in a chronic smoker were initially strongly suggestive of malignant disease, and we recommend that talc-induced lung disease is considered in any patient with multiple scattered pulmonary lesions and a history of intravenous drug use. Confirmation of the disease by biopsy is essential, but unfortunately there are few successful proven management options for patients with worsening disease.</p

Improving survey methods in sero-epidemiological studies of injecting drug users: a case example of two cross sectional surveys in Serbia and Montenegro

BACKGROUND: Little is known about the prevalence of HIV or HCV in injecting drug users (IDUs) in Serbia and Montenegro. We measured prevalence of antibodies to HIV (anti-HIV) and hepatitis C virus (anti-HCV), and risk factors for anti-HCV, in community-recruited IDUs in Belgrade and Podgorica, and determined the performance of a parallel rapid HIV testing algorithm. METHODS: Respondent driven sampling and audio-computer assisted survey interviewing (ACASI) methods were employed. Dried blood spots were collected for unlinked anonymous antibody testing. Belgrade IDUs were offered voluntary confidential rapid HIV testing using a parallel testing algorithm, the performance of which was compared with standard laboratory tests. Predictors of anti-HCV positivity and the diagnostic accuracy of the rapid HIV test algorithm were calculated. RESULTS: Overall population prevalence of anti-HIV and anti-HCV in IDUs were 3% and 63% respectively in Belgrade (n = 433) and 0% and 22% in Podgorica (n = 328). Around a quarter of IDUs in each city had injected with used needles and syringes in the last four weeks. In both cities anti-HCV positivity was associated with increasing number of years injecting (eg Belgrade adjusted odds ratio (AOR) 5.6 (95% CI 3.2-9.7) and Podgorica AOR 2.5 (1.3-5.1) for >or= 10 years v 0-4 years), daily injecting (Belgrade AOR 1.6 (1.0-2.7), Podgorica AOR 2.1 (1.3-5.1)), and having ever shared used needles/syringes (Belgrade AOR 2.3 (1.0-5.4), Podgorica AOR 1.9 (1.4-2.6)). Half (47%) of Belgrade participants accepted rapid HIV testing, and there was complete concordance between rapid test results and subsequent confirmatory laboratory tests (sensitivity 100% (95%CI 59%-100%), specificity 100% (95%CI 98%-100%)). CONCLUSION: The combination of community recruitment, ACASI, rapid testing and a linked diagnostic accuracy study provide enhanced methods for conducting blood borne virus sero-prevalence studies in IDUs. The relatively high uptake of rapid testing suggests that introducing this method in community settings could increase the number of people tested in high risk populations. The high prevalence of HCV and relatively high prevalence of injecting risk behaviour indicate that further HIV transmission is likely in IDUs in both cities. Urgent scale up of HIV prevention interventions is needed

Location of Immunization and Interferon-γ Are Central to Induction of Salivary Gland Dysfunction in Ro60 Peptide Immunized Model of Sjögren's Syndrome

INTRODUCTION: Anti-Ro antibodies can be found in the serum of the majority of patients with Sjögren's syndrome (SS). Immunization with a 60-kDa Ro peptide has been shown to induce SS-like symptoms in mice. The aim of this study was to investigate factors involved in salivary gland (SG) dysfunction after immunization and to test whether the induction of SS could be improved. METHODS: Ro60 peptide immunization was tested in Balb/c mice, multiple antigenic peptide (MAP)-Ro60 and Pertussis toxin (PTX) were tested in SJL/J mice. In addition, two injection sites were compared in these two strains: the abdominal area and the tailbase. Each group of mice was tested for a loss of SG function, SG lymphocytic infiltration, anti-Ro and anti-La antibody formation, and cytokine production in cultured cells or homogenized SG extracts. RESULTS: Ro60 peptide immunization in the abdominal area of female Balb/c mice led to impaired SG function, which corresponded with increased Th1 cytokines (IFN-γ and IL-12) systemically and locally in the SG. Moreover, changing the immunization conditions to MAP-Ro60 in the abdominal area, and to lesser extend in the tailbase, also led to impaired SG function in SJL/J mice. As was seen in the Balb/c mice, increased IFN-γ in the SG draining lymph nodes accompanied the SG dysfunction. However, no correlation was observed with anti-MAP-Ro60 antibody titers, and there was no additional effect on disease onset or severity. CONCLUSIONS: Effective induction of salivary gland dysfunction after Ro60 peptide immunization depended on the site of injection. Disease induction was not affected by changing the immunization conditions. However, of interest is that the mechanism of action of Ro60 peptide immunization appears to involve an increase in Th1 cytokines, resulting in the induction of SG dysfunction

Sea ice and pollution-modulated changes in Greenland ice core methanesulfonate and bromine

Reconstruction of past changes in Arctic sea ice extent may be critical for understanding its future evolution. Methanesulfonate (MSA) and bromine concentrations preserved in ice cores have both been proposed as indicators of past sea ice conditions. In this study, two ice cores from central and north-eastern Greenland were analysed at sub-annual resolution for MSA (CH$_3$SO$_3$H) and bromine, covering the time period 1750–2010. We examine correlations between ice core MSA and the HadISST1 ICE sea ice dataset and consult back trajectories to infer the likely source regions. A strong correlation between the low-frequency MSA and bromine records during pre-industrial times indicates that both chemical species are likely linked to processes occurring on or near sea ice in the same source regions. The positive correlation between ice core MSA and bromine persists until the mid-20th century, when the acidity of Greenland ice begins to increase markedly due to increased fossil fuel emissions. After that time, MSA levels decrease as a result of declining sea ice extent but bromine levels increase. We consider several possible explanations and ultimately suggest that increased acidity, specifically nitric acid, of snow on sea ice stimulates the release of reactive Br from sea ice, resulting in increased transport and deposition on the Greenland ice sheet.This research was funded by the National Science Foundation, grant numbers 1023672 and 1204176