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Objective: The small bowel is affected in up to 50% of systemic sclerosis (SSc) patients, and some patients experience severe complications. Our aim was to use specific statistical methods to compare demographic and clinical features of SSc patients with and without abnormal small bowel to better characterize patients at risk for this complication., Methods: SSc patients with gastrointestinal symptoms were prospectively enrolled and underwent a scintigraphy-based whole gut transit (WGT) study. A cross-sectional analysis was performed comparing clinical features between patients with and without abnormal small bowel transit by WGT. Univariate logistic regression models and multivariable models were used to examine the relationship between clinical features and abnormal small bowel transit., Results: Of 130 patients enrolled in this study, 22 had abnormal small bowel transit. SSc patients with abnormal small bowel transit were more likely to be male [Odds Ratio(OR)=3.70, Confidence Interval(CI) 1.07-12.50, p= 0.038], and have more severe cardiac involvement (OR = 3.98, CI 1.10-14.38, p= 0.035), while they were less likely to have sicca symptoms (OR = 0.30, CI 0.10-0.94, p= 0.039). In multivariable analyses, sicca symptoms (OR = 0.28, CI 0.08-0.96, p= 0.043) remained negatively associated with abnormal small bowel transit. Additionally, SSc patients with abnormal small bowel transit had higher mortality than patients with normal small bowel transit [Hazard ratio(HR)=4.57, CI 1.58-13.24, p= 0.005]., Conclusions: These findings suggest that patients with abnormal small bowel transit in SSc are more likely to be male, have more severe cardiac involvement, higher mortality, and less sicca symptoms. Recognizing this patient subgroup is essential for risk stratification and optimizing clinical care., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Patients with autonomic dysfunction, or dysautonomia, often report discoloration of their dependent extremities, which is thought to be from venous pooling or acrocyanosis. A subset of patients with systemic sclerosis (SSc) are affected by dysautonomia but may be challenging to identify. We sought to determine whether patients with SSc who report discoloration in their feet have a higher burden of autonomic symptoms, including orthostatic, gastrointestinal (GI), urinary, secretomotor, and pupillomotor., Methods: 167 patients with SSc completed the COMPASS-31 survey, which queries whether the patient experiences discoloration of the feet or hands. We compared the COMPASS-31 subdomain scores between SSc patients with and without foot discoloration. 79 patients with postural orthostatic tachycardia syndrome (POTS) also completed the COMPASS-31 questionnaire for comparison., Results: We found that extremity discoloration is common in POTS and more often affects the feet, whereas in SSc the hands are more frequently involved. 62% of SSc patients report colour changes in their feet. These patients are more likely to have other autonomic symptoms, including orthostatic (11.7 ± 10.6 vs 8.6 ± 9.9, p= 0.06), GI (11.3 ± 4.3 vs 8.8 ± 4.3, p= 0.0003), urinary (1.4 ± 1.5 vs 0.8 ± 1.3, p= 0.002) and secretomotor (7.0 ± 3.8 vs 5.9 ± 3.8, p= 0.06) symptoms. These associations persist in a multivariable model after adjusting for potential confounders., Conclusion: Dependent extremity discoloration is common in dysautonomia. Patients with SSc who report colour changes in their feet are more likely to report other symptoms of autonomic dysfunction., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Systemic sclerosis (SSc) is heterogeneous in its clinical presentation. Common manifestations cluster together, defining unique subgroups. This investigation aims to characterize gastrointestinal (GI) phenotypes and determine whether they can be distinguished by temporal progression., Methods: We examine a well-established SSc patient cohort with a modified Medsger GI severity score measured over time to determine heterogeneity in disease progression. Growth mixture models estimate each patient's phenotype and disease severity trajectory over time. We compare the characteristics of estimated phenotypes using non-parametric statistics and linear and logistic regression to compare patient characteristics between phenotypes while adjusting for disease duration., Results: We examined 2696 SSc patients with at least two Medsger GI scores, identifying four unique phenotypes. The most common phenotype (n = 2325) ("Stable") had an average score of 1 that was consistent over time. Two phenotypes were progressive ["Early Progressive" (n = 142) and "Late Progressive" (n = 115)] with an initial average score of 1. The Early Progressive group increased initially and stabilized, and the Late Progressive group worsened slowly over time. A fourth phenotype ["Early Severe GI"; (n = 114)] had an initial average Medsger GI score just below 3 with high mortality and improving GI severity over time., Conclusions: Clinically distinct GI phenotypes exist among patients with SSc. These phenotypes are not only distinguished by GI and extra-intestinal SSc clinical complications, but they are also temporally distinct. Distinct autoantibody profiles are associated strongly with more severe GI disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Dynamic prediction of causal effects under different treatment regimens is an essential problem in precision medicine. It is challenging because the actual mechanisms of treatment assignment and effects are unknown in observational studies. We propose a multivariate generalized linear mixed-effects model and a Bayesian g-computation algorithm to calculate the posterior distribution of subgroup-specific intervention benefits of dynamic treatment regimes. Unmeasured time-invariant factors are included as subject-specific random effects in the assumed joint distribution of outcomes, time-varying confounders, and treatment assignments. We identify a sequential ignorability assumption conditional on treatment assignment heterogeneity, that is, analogous to balancing the latent treatment preference due to unmeasured time-invariant factors. We present a simulation study to assess the proposed method's performance. The method is applied to observational clinical data to investigate the efficacy of continuously using mycophenolate in different subgroups of scleroderma patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Biometric Society.)

Objectives: The objective of this study was to determine baseline risk factors for requiring immunosuppression and having persistent arthritis in patients with immune checkpoint inhibitor-induced inflammatory arthritis (ICI-inflammatory arthritis)., Methods: Participants were adults with rheumatologist diagnosed ICI-inflammatory arthritis. The primary outcome was requirement of conventional synthetic (cs) or biologic (b) DMARDs; other outcomes were persistence of inflammatory arthritis >6 months after ICI cessation and requirement of CSs. Logistic regression models evaluated associations between clinical features and primary and secondary outcomes, with adjustment for potential confounders, as appropriate., Results: One hundred and twenty-six patients with ICI-inflammatory arthritis were included; 53 patients (42%) required a csDMARD/bDMARD. In the univariate logistic regression analysis, higher clinical disease activity index (CDAI), tenosynovitis, longer symptom duration before first rheumatology visit and longer ICI duration were significantly associated with a higher likelihood of requiring DMARDs; in addition, there was a trend towards those treated with prior chemotherapy being less likely to need DMARDs. After adjustment, tenosynovitis, longer symptom duration and higher CDAI remained associated with requiring DMARDs, while those with prior chemotherapy were significantly less likely to require DMARDs. Combination anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein-4)/PD-1 (Programmed cell death protein-1) therapy and CS use at baseline were associated with a higher risk of persistent inflammatory arthritis., Conclusion: Higher levels of disease activity, tenosynovitis and longer symptom duration prior to rheumatology referral were associated with requiring DMARDs for ICI-inflammatory arthritis, while those treated previously with chemotherapy were less likely to require additional immunosuppression. The presence of risk factors for severe disease at baseline may indicate a role for higher initial CS dose, earlier rheumatology referral, and adoption of immunosuppression beyond CSs to improve outcomes., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: Assessment of construct validity and reliability of a novel patient-reported outcome (PRO) instrument for assessing the severity and impact of RP in SSc., Methods: An international multicentre study validation study of the 27-item Assessment of Systemic Sclerosis-Associated Raynaud's Phenomenon (ASRAP) and 10-item short-form (ASRAP-SF) questionnaires. The relationship between ASRAP questionnaires and demographics, clinical phenotype and legacy instruments for assessing SSc-RP severity, disability and pain was assessed. Repeatability was evaluated at 1 week. Anchor-based statements of health status facilitated assessment of ASRAP thresholds of meaning., Results: A total of 420 SSc subjects were enrolled. There was good correlation between ASRAP (and ASRAP-SF) with RP visual analogue scale (VAS) and Scleroderma Health Assessment Questionnaire RP VAS (rho range 0.648-0.727, P < 0.001). Correlation with diary-based assessment of SSc-RP attack frequency and duration was lower (rho range 0.258-0.504, P < 0.001). ASRAP questionnaires had good correlation with instruments for assessing disability, hand function, pain and global health assessment (rho range 0.427-0.575, P < 0.001). Significantly higher ASRAP scores were identified in smokers, patients with active digital ulceration (DU), previous history of DU and calcinosis (P < 0.05 for all comparisons). There was excellent repeatability at 1 week among patients with stable SSc-RP symptoms (intra-class coefficients of 0.891 and 0.848, P < 0.001). Patient-acceptable symptom state thresholds for ASRAP and ASRAP-SF were 45.34 and 45.77, respectively. A preliminary Minimally Important Clinical Difference threshold of 4.17 (95% CI 0.53, 7.81, P = 0.029) was estimated., Conclusion: ASRAP and ASRAP-SF questionnaires are valid and reliable novel PRO instruments for assessing the severity and impact of SSc-RP., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Ectopic calcification (calcinosis) is a common complication of SSc, but a subset of SSc patients has a heavy burden of calcinosis. We examined whether there are unique risk factors for a heavy burden of calcinosis, as compared with a light burden or no calcinosis., Methods: We reviewed the medical records of all patients in the Johns Hopkins Scleroderma Center Research Registry with calcinosis to quantify calcinosis burden using pre-specified definitions. We performed latent class analysis to identify SSc phenotypic classes. We used multinomial logistic regression to determine whether latent phenotypic classes and autoantibodies were independent risk factors for calcinosis burden., Results: Of all patients, 29.4% (997/3388) had calcinosis, and 13.5% (130/963) of those with calcinosis had a heavy burden. The latent phenotypic class with predominantly diffuse skin disease and higher disease severity (characterized by pulmonary hypertension, interstitial lung disease, cardiomyopathy, severe RP, gastrointestinal involvement, renal crisis, myopathy and/or tendon friction rubs) was associated with an increased risk of both a heavy burden [odds ratio (OR) 6.92, 95% CI 3.66, 13.08; P < 0.001] and a light burden (OR 2.88, 95% CI 2.11, 3.95; P < 0.001) of calcinosis compared with the phenotypic class with predominantly limited skin disease. Autoantibodies to PM/Scl were strongly associated with a heavy burden of calcinosis (OR 17.31, 95% CI 7.72, 38.81; P < 0.001) and to a lesser degree a light burden of calcinosis (OR 3.59, 95% CI 1.84, 7.00; P < 0.001)., Conclusions: Calcinosis burden is associated with cumulative SSc-related tissue damage. Independent of disease severity, autoantibodies to PM/Scl are also associated with a heavy burden of calcinosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: SSc is associated with increased health-care resource utilization and economic burden. The Collaborative National Quality and Efficacy Registry (CONQUER) is a US-based collaborative that collects longitudinal follow-up data on SSc patients with <5 years of disease duration enrolled at scleroderma centres in the USA. The objective of this study was to investigate the relationship between gastrointestinal tract symptoms and self-reported resource utilization in CONQUER participants., Methods: CONQUER participants who had completed a baseline and 12-month Gastrointestinal Tract Questionnaire (GIT 2.0) and a Resource Utilization Questionnaire (RUQ) were included in this analysis. Patients were categorized by total GIT 2.0 severity: none-to-mild (0-0.49); moderate (0.50-1.00), and severe-to-very severe (1.01-3.00). Clinical features and medication exposures were examined in each of these categories. The 12-month RUQ responses were summarized by GIT 2.0 score categories at 12 months., Results: Among the 211 CONQUER participants who met the inclusion criteria, most (64%) had mild GIT symptoms, 26% had moderate symptoms, and 10% severe GIT symptoms at 12 months. The categorization of GIT total severity score by RUQ showed that more upper endoscopy procedures and inpatient hospitalization occurred in the CONQUER participants with severe GIT symptoms. These patients with severe GIT symptoms also reported the use of more adaptive equipment., Conclusion: This report from the CONQUER cohort suggests that severe GIT symptoms result in more resource utilization. It is especially important to understand resource utilization in early disease cohorts when disease activity, rather than damage, primarily contributes to health-related costs of SSc., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To define the clinical phenotype of SSc patients with antibodies against Sjogren's syndrome (SS)/scleroderma autoantigen 1 (SSSCA1), and to examine the association between these antibodies and cancer in SSc patients., Methods: We conducted a case-control study using data from 209 patients with SSc and cancer, and 205 SSc patients without cancer. All were randomly selected from the Johns Hopkins Scleroderma Center Research Registry. Antibodies against SSSCA1 were assayed by immunoprecipitation of 35S-methionine-labelled protein generated by in vitro transcription and translation. We performed logistic regression analysis to examine the relationship between anti-SSSCA1 antibodies and cancer., Results: Among the 414 study patients, 31 (7%) were anti-SSSCA1 antibody positive. Antibody-positive patients were more likely to have severe RP, a lower minimum ejection fraction, a trend towards more severe heart involvement and a lower baseline diffusing capacity of the lungs for carbon monoxide percent predicted than anti-SSSCA1-negative patients. Patients with cancer were significantly more likely to be anti-SSSCA1 positive compared with those without cancer [22/209 (11%) vs 9/205 (4%), respectively; P = 0.018]. Among patients with cancer, there was a trend towards longer cancer-SSc interval in anti-SSSCA1-positive patients compared with anti-SSSCA1-negative patients. Patients with anti-SSSCA1 antibodies had an increased adjusted risk of cancer (odds ratio 2.46, 95% CI 1.06, 5.70) compared with anti-SSSCA1-negative patients., Conclusions: These data suggest anti-SSSCA1 antibody status may be of utility as a cancer biomarker in SSc. Anti-SSSCA1-positive patients with SSc may be more likely to have severe Raynaud's and cardiac involvement., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

It has long been known that the outcome of species interactions depends on the environmental context in which they occur. Climate change research has sparked a renewed interest in context-dependent species interactions because rapidly changing abiotic environments will cause species interactions to occur in novel contexts and researchers must incorporate this in their predictions of species' responses to climate change. Here, we argue that predicting how the environment will alter the outcome of species interactions requires an integrative biology approach that focuses on the traits, mechanisms, and processes that bridge disciplines such as physiology, biomechanics, ecology, and evolutionary biology. Specifically, we advocate for quantifying how species differ in their tolerance and performance to both environmental challenges independent of species interactions, and in interactions with other species as a function of the environment. Such an approach increases our understanding of the mechanisms underlying outcomes of species interactions across different environmental contexts. This understanding will help determine how the outcome of species interactions affects the relative abundance and distribution of the interacting species in nature. A general theme that emerges from this perspective is that species are unable to maintain high levels of performance across different environmental contexts because of trade-offs between physiological tolerance to environmental challenges and performance in species interactions. Thus, an integrative biology paradigm that focuses on the trade-offs across environments, the physiological mechanisms involved, and how the ecological context impacts the outcome of species interactions provides a stronger framework to understand why species interactions are context dependent., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology.)

Background: People with autoimmune or inflammatory conditions taking immunomodulatory/suppressive medications may have higher risk of novel coronavirus disease 2019 (COVID-19). Chronic disease care has also changed for many patients, with uncertain downstream consequences., Methods: We included participants with autoimmune or inflammatory conditions followed by specialists at Johns Hopkins. Participants completed periodic surveys querying comorbidities, disease-modifying medications, exposures, COVID-19 testing and outcomes, social behaviors, and disruptions to healthcare. We assessed whether COVID-19 risk is higher among those on immunomodulating or suppressive agents and characterized pandemic-associated changes to care and mental health., Results: In total, 265 (5.6%) developed COVID-19 over 9 months of follow-up (April-December 2020). Patient characteristics (age, race, comorbidity, medications) were associated with differences in social distancing behaviors during the pandemic. Glucocorticoid exposure was associated with higher odds of COVID-19 in models incorporating behavior and other potential confounders (odds ratio [OR]: 1.43; 95% confidence interval [CI]: 1.08, 1.89). Other medication classes were not associated with COVID-19 risk. Diabetes (OR: 1.72; 95% CI: 1.08, 2.73), cardiovascular disease (OR: 1.68; 95% CI: 1.24, 2.28), and kidney disease (OR: 1.76; 95% CI: 1.04, 2.97) were associated with higher odds of COVID-19. Of the 2156 reporting pre-pandemic utilization of infusion, mental health or rehabilitative services, 975 (45.2%) reported disruptions therein, which disproportionately affected individuals experiencing changes to employment or income., Conclusions: Glucocorticoid exposure may increase risk of COVID-19 in people with autoimmune or inflammatory conditions. Disruption to healthcare and related services was common. Those with pandemic-related reduced income may be most vulnerable to care disruptions., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Environmental temperature variation may play a significant role in the adaptive evolutionary divergence of ectotherm thermal performance curves (TPCs). However, divergence in TPCs may also be constrained due to various causes. Here, we measured TPCs for swimming velocity of temperate and tropical mayflies (Family: Baetidae ) and their stonefly predators (Family: Perlidae ) from different elevations. We predicted that differences in seasonal climatic regimes would drive divergence in TPCs between temperate and tropical species. Stable tropical temperatures should favor the evolution of "specialists" that perform well across a narrow range of temperatures. Seasonally, variable temperatures in temperate zones, however, should favor "generalists" that perform well across a broad range of temperatures. In phylogenetically paired comparisons of mayflies and stoneflies, swimming speed was generally unaffected by experimental temperature and did not differ among populations between latitudes, suggesting a maintenance of performance breadth across elevation and latitude. An exception was found between temperate and tropical mayflies at low elevation where climatic differences between latitudes are large. In addition, TPCs did not differ between mayflies and their stonefly predators, except at tropical low elevation. Our results indicate that divergence in TPCs may be constrained in aquatic insects except under the most different thermal regimes, perhaps because of trade-offs that reduce thermal sensitivity and increase performance breadth., (© The Author(s) (2020). Published by Oxford University Press on behalf of Editorial Office, Current Zoology.)

Non-degradability of conventional plastics, filling of landfill sites, raising water and land pollution and rapid depletion of fossil resources have raised the environmental issues and global concerns. The current demand and production of plastics is putting immense pressure on fossil resources, consuming about 6% of the global oil and is expected to grow up to 20%. The polyester-based biodegradable plastics (BPs) are considered as a remedy to the issue of plastics waste in the environment. BPs appear to manage the overflow of plastics by providing new means of waste management system and help in securing the non-renewable resources of nature. This review comprehensively presents the environmental burdens due to conventional plastics as well as production of polyester-based BPs as an alternative to conventional commodity plastics. The diversity of micro-organisms and their enzymes that degrade various polyester-based BPs (PLA, PCL, PHB/PHBV and PET) has also been described in detail. Moreover, the impact of plastics degradation products on soil ecology and ecosystem functions has critically been discussed. The report ends with special focus on future recommendations for the development of sustainable waste management strategies to control pollution due to plastics waste. SIGNIFICANCE AND IMPACT OF THE STUDY: Polyester-based BPs considered as a solution to current plastic waste problem as well as leading polymers in terms of biodegradability and sustainability has been critically discussed. The role of microorganisms and their enzymes involved in the biodegradation of these polymers and ecotoxicological impact of degradation products of BPs on soil microbial community and biogeochemical cycles has also been described. This report will provide an insight on the key research areas to bridge the gap for development of simulated systems as an effective and emerging strategy to divert the overflow of plastic in the environment as well as for the greener solution to the plastic waste management problems., (© 2020 The Society for Applied Microbiology.)

Aim: Escherichia coli is the conventional choice as the host strain for whole-cell bioreporter construction due to its well-understood genetics and well-established cloning protocols. However, for real-world environmental biosensing applications, it is often beneficial to use a bacterial strain derived directly from the environment under study to better ensure chemical target specificity and optimal response time. The aim of this study was to develop a whole-cell bioreporter for detection of bioavailable mercury by replacing E. coli with a wild-type bacterial host derived from a soil environment., Materials and Results: In this study, an Enterobacter cloacae strain isolated from soil derived from a municipal and electronic waste dumping site was engineered to serve as a bioluminescent bioreporter for mercury toxicity by linking its merR-like gene and promoter sequence to a reorganized luxABCDE gene cassette from Photorhabdus luminescens. This bioreporter, designated as E. cloacae DWH4 lux , detected mercury (HgCl 2 ) at a minimum concentration of 0·2 µg l -1 with a linear response profile being maintained between a range of 0·4-1600 µg l -1 (R 2  = 0·9604) with a peak bioluminescent response occurring within 1 h after exposure. No significant synergistic or antagonistic influences were observed on the bioluminescent response by other contaminating metal elements. Enterobacter cloacae DWH4 lux was also demonstrated to detect mercury effectively in artificially contaminated water sample with linear correlation (R 2  = 0·9623)., Conclusions: The results indicated that E. cloacae DWH4 lux could detect mercury in quantities below the US Environmental Protection Agency's permitted limit values (2 µg l -1 ). Hence, it is concluded that E. cloacae DWH4 lux has the potential to serve as an effective whole-cell bioreporter for the environmental monitoring of mercury contamination., Significance and Impact of the Study: This study provides new insight into the recruitment of mercury-tolerant bacterial hosts derived from environmental samples over the conventional lab-based E. coli host for the construction of mercury bioreporters. With improved response time and selectivity, the environmentally sourced bacteria can serve as an alternative host choice to improve biosensing technology in the near future., (© 2019 The Society for Applied Microbiology.)

Objective: To evaluate the frequency of HLA class I and II alleles associated with traditional forms of inflammatory arthritis in patients with immune checkpoint inhibitor (ICI)-induced inflammatory arthritis as compared with population controls., Methods: High-resolution HLA typing was performed on 27 patients with ICI-induced inflammatory arthritis and 726 healthy controls. Genotyping at the shared epitope (SE) locus (HLA DRB1) was performed on 220 RA cases. Allele-positivity rates and frequency of having at least one SE allele were compared using Fisher's exact test between ICI-induced inflammatory arthritis and healthy controls. Frequency of having at least one SE allele was also compared between ICI-induced inflammatory arthritis and RA cases., Results: Twenty-six patients with ICI-induced inflammatory arthritis were of European descent, and one was African American. In those 26 patients, 16 (61.5%) had at least one SE allele, significantly different from healthy controls of European descent, in whom 299 (41.2%) had at least one SE allele (odds ratio 2.3, P = 0.04). The allele-positivity rate of DRB1*04: 05 was also higher in the ICI-induced inflammatory arthritis group. The ICI-induced inflammatory arthritis population and RA patients of European descent did not differ in frequency of having at least one SE allele, but ICI-induced inflammatory arthritis patients were more likely to be autoantibody-negative for RF and anti-CCP antibodies., Conclusion: Patients with ICI-induced inflammatory arthritis of European descent were more likely to have at least one SE allele than healthy controls. Further studies are needed to validate these findings and investigate whether a unique immunogenetic framework increases risk for different immune-related adverse events., (© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Autoimmune diseases are characterized by highly specific immune responses against molecules in self-tissues. Different autoimmune diseases are characterized by distinct immune responses, making autoantibodies useful for diagnosis and prediction. In many diseases, the targets of autoantibodies are incompletely defined. Although the technologies for autoantibody discovery have advanced dramatically over the past decade, each of these techniques generates hundreds of possibilities, which are onerous and expensive to validate. We set out to establish a method to greatly simplify autoantibody discovery, using a pre-filtering step to define subgroups with similar specificities based on migration of radiolabeled, immunoprecipitated proteins on sodium dodecyl sulfate (SDS) gels and autoradiography [Gel Electrophoresis and band detection on Autoradiograms (GEA)]. Human recognition of patterns is not optimal when the patterns are complex or scattered across many samples. Multiple sources of errors-including irrelevant intensity differences and warping of gels-have challenged automation of pattern discovery from autoradiograms.In this article, we address these limitations using a Bayesian hierarchical model with shrinkage priors for pattern alignment and spatial dewarping. The Bayesian model combines information from multiple gel sets and corrects spatial warping for coherent estimation of autoantibody signatures defined by presence or absence of a grid of landmark proteins. We show the pre-processing creates more clearly separated clusters and improves the accuracy of autoantibody subset detection via hierarchical clustering. Finally, we demonstrate the utility of the proposed methods with GEA data from scleroderma patients.

Aim: Thiss study was conducted to investigate the possible role of a compatible solute from radio-halophilic bacterium against desiccation and ultra-violet radiation-induced oxidative stress., Methods and Results: Nine different radio-resistant bacteria were isolated from desert soil, where strain WMA-LM19 was chosen for detailed studies on the basis of its high tolerance to ultraviolet radiation among all these isolates. Here, 16S rRNA gene sequencing indicated the bacterium was closely related to Stenotrophomonas sp. (KT008383). A bacterial milking strategy was applied for extraction of intracellular compatible solutes in 70% (v/v) ethanol, which were purified by High Performance Liquid Chromatography (HPLC). The compound was characterized as ectoine by 1 H and 13 C Nuclear Magnetic Resonance (NMR), and Mass Spectrometry (MS). Ectoine inhibited oxidative damage to proteins and lipids in comparison to the standard ascorbic acid. It also demonstrated more efficient prevention (54·80%) against lysis to erythrocytes membrane by surface active agents than lecithin. Furthermore, a high level of ectoine-mediated protection of bovine serum albumin against ionizing radiation (1 500-2 000Jm -2 ) was observed, as indicated by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) analysis., Conclusion: The results indicated that ectoine from Stenotrophomonas sp. WMA-LM19 can be used as a potential mitigator and radio-protective agent to overcome radiation- and salinity-mediated oxidative damages in extreme environment., Significance and Impact of the Study: Due to its anti-oxidant properties, ectoine from a radio-halophilic bacterium might be used in sunscreen formulation for protection against UV-induced oxidative stress., (© 2018 The Society for Applied Microbiology.)

It has long been recognized that populations and species occupying different environments vary in their thermal tolerance traits. However, far less attention has been given to the impact of different environments on the capacity for plastic adjustments in thermal sensitivity, i.e., acclimation ability. One hypothesis is that environments characterized by greater thermal variability and seasonality should favor the evolution of increased acclimation ability compared with environments that are aseasonal or thermally stable. Additionally, organisms under selection for high heat tolerance may experience a trade-off and lose acclimation ability. Few studies have tested these non-mutually exclusive hypotheses at both broad latitudinal and local elevation scales in phylogenetically paired taxa. Here, we measure short-term acclimation ability of the critical thermal maximum (CTMAX) in closely related temperate and tropical mayflies (Ephemeroptera) and stoneflies (Plecoptera) from mountain streams at different elevations. We found that stream temperature was a good predictor of acclimation ability in mayflies, but not in stoneflies. Specifically, tropical mayflies showed reduced acclimation ability compared with their temperate counterparts. High elevation tropical mayflies had greater acclimation ability than low elevation mayflies, which reflected the wider temperature variation experienced in high elevation streams. In contrast, temperate and tropical stoneflies exhibited similar acclimation responses. We found no evidence for a trade-off between heat tolerance and acclimation ability in either taxonomic order. The acclimation response in stoneflies may reflect their temperate origin or foraging mode. In combination with previous studies showing tropical taxa have narrower thermal breadths, these results demonstrate that many lower elevation tropical aquatic insects are more vulnerable to climate warming than their temperate relatives., (© The Author 2017. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.)

Background: Clinical practice guidelines (CPGs) are widely used to inform the development of protocols for clinical management. Previous work has demonstrated that the quality of CPGs varies widely. This systematic review aimed to determine the quality of CPGs in kidney transplantation in the UK., Methods: CPGs in kidney transplantation published between 2010 and 2017 were identified through searches of MEDLINE, NHS NICE Evidence, and websites of relevant UK societies. Using the Appraisal of Guidelines for Research and Evaluation (AGREE) II tool, three appraisers rated the quality of CPGs across six domains, the overall quality of each CPG, and whether it should be recommended for future use. Domain scores were calculated, and inter-rater reliability using the intraclass correlation coefficient (ICC) was reported., Results: Thirteen CPGs met the inclusion criteria. The domain 'clarity of presentation' scored highest, followed closely by 'scope and purpose'. The poorest scoring domains were 'applicability' and 'editorial independence'. Editorial independence also had the widest range of scores. Of the 13 CPGs, one was not recommended for future use, seven were recommended for use with modifications, and five for future use with no need for modification. Mean overall CPG quality was 5 (range 3-6) of a maximum score of 7, and mean inter-rater reliability was substantial with an ICC of 0·71., Conclusion: UK CPGs scored satisfactorily, although with wide variation in how well each domain scored both within and across CPGs. The quality of UK CPGs can still be improved.

Objectives: Hyalinizing clear cell carcinoma (HCCC) is common in head and neck sites but extremely rare in the lung. This case report describes an HCCC in the lung of a 54-year-old female patient., Methods: We summarize the histomorphologic, immunophenotypic, and molecular features for our and three previously reported HCCCs of the lung with emphasis on potential diagnostic pitfalls., Results: Sections of a well-circumscribed 3.5-cm lung mass were characterized by a bronchocentric tumor growing in sheets, nests, and cords in a background of hyalinized stroma. Tumor cell appearance was clear to eosinophilic, lacking significant pleomorphism or mitotic activity. By immunohistochemistry, the tumor cells were strongly positive with antibodies to pan-keratin, p63, and CK5/6 while negative for CK7, CK20, thyroid transcription factor 1, napsin A, chromogranin, and synaptophysin. Next-generation sequencing demonstrated an EWSR1-ATF1 fusion transcript., Conclusions: Awareness of key morphologic features of pulmonary HCCC is crucial for the recognition of this rare entity in the lung. Ancillary studies, including immunohistochemistry and molecular testing, are essential for the distinction from its mimics., (© American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article.

A poly(ε-caprolactone) (PCL)-degrading bacterium designated as strain MRL-AN1 was isolated from soil. The bacterium was identified as Brevundimonas sp. strain MRL-AN1 through biochemical tests and 16S rRNA gene sequencing. Scanning electron microscopy and Fourier transform infrared spectroscopy results confirmed the degradation of PCL by strain MRL-AN1. An extracellular PCL depolymerase was purified to homogeneity by column chromatography and molecular weight was estimated to be approximately 63.49 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. PCL depolymerase could degrade not only PCL but also other aliphatic polyesters. The enzyme was stable at wide range of temperature (20-45°C) and pH (5-9) as well as stable in the presence of various metal ions, surfactants and organic solvents. Phenylmethylsulfonyl fluoride inhibited enzyme activity that indicates this enzyme belongs to the serine hydrolase family. It is concluded from the results that the enzymes from strain MRL-AN1 might be applied in the process of biochemical monomer recycling in the polyester-contaminated environments., (© FEMS 2014. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: We questioned whether the use of p16(INK4a) immunohistochemistry in endocervical curettage (ECC) specimens would improve the detection of high-grade squamous intraepithelial lesions (HSIL) in a high-risk patient population., Methods: Papanicolaou test results were retrieved in 58 consecutive ECC specimens that were previously diagnosed as no histopathologic abnormality in patients with antecedent HSIL or atypical squamous cells, cannot exclude HSIL. An H&E recut and immunohistochemistry for p16(INK4a) were performed on all cases., Results: HSIL were found in 18 (31%) ECC specimens originally interpreted as negative. Of these 18 cases, three had moderate-sized fragments of ectocervical epithelium with HSIL seen on the recut H&E with concurrent positivity for p16(INK4a). Fourteen cases had rare to occasional clusters of atypical cells with strong immunoreactivity for p16(INK4a). A single case showed a medium-sized fragment of HSIL on the p16(INK4a)-stained section., Conclusions: The use of recuts and adjunct p16(INK4a) should be considered when evaluating ECC specimens in high-risk patient populations.

DA (D-blood group of Palm and Agouti, also known as Dark Agouti) and F344 (Fischer) are two inbred rat strains with differences in several phenotypes, including susceptibility to autoimmune disease models and inflammatory responses. While these strains have been extensively studied, little information is available about the DA and F344 genomes, as only the Brown Norway (BN) and spontaneously hypertensive rat strains have been sequenced to date. Here we report the sequencing of the DA and F344 genomes using next-generation Illumina paired-end read technology and the first de novo assembly of a rat genome. DA and F344 were sequenced with an average depth of 32-fold, covered 98.9% of the BN reference genome, and included 97.97% of known rat ESTs. New sequences could be assigned to 59 million positions with previously unknown data in the BN reference genome. Differences between DA, F344, and BN included 19 million positions in novel scaffolds, 4.09 million single nucleotide polymorphisms (SNPs) (including 1.37 million new SNPs), 458,224 short insertions and deletions, and 58,174 structural variants. Genetic differences between DA, F344, and BN, including high-impact SNPs and short insertions and deletions affecting >2500 genes, are likely to account for most of the phenotypic variation between these strains. The new DA and F344 genome sequencing data should facilitate gene discovery efforts in rat models of human disease.

To assess the diagnostic accuracy of histopatho-logic and cytopathologic examination (HCE) of Aspergillus species (spp), we performed an 11-year retrospective review to correlate surgical/cytology cases with a diagnosis of Aspergillus spp with their concurrent fungal culture results. Diagnostic accuracy was defined as the percentage of cases with culture-proven Aspergillus spp divided by the number of cases diagnosed as Aspergillus spp on HCE that had growth on fungal culture. Ninety surgical/cytology cases with concurrent fungal culture were reviewed, 58 of which grew a fungal organism. Of these 58 cases, 45 grew an Aspergillus spp, whereas 13 grew an organism other than Aspergillus spp, including both common (Scedosporium, Fusarium, and Paecilomyces spp) and uncommon mimickers (Trichosporon loubieri), resulting in a diagnostic accuracy of 78%. The low diagnostic accuracy indicates that several fungal organisms can morphologically mimic Aspergillus spp and can only be distinguished by fungal culture and DNA sequencing.

This study compares the use of immunohistochemistry (IHC) for diagnosing carcinoma in private practice and commercial settings with use in a single academic center. H&E-stained slides and IHC stains, when present, of recently diagnosed carcinomas (n = 200) from patients referred to our institution for treatment were reviewed by a resident and mid-and senior-level pathologists. Diagnostic agreement between academic and referral pathologists was 98%; the former group used IHC stains in 11% and the latter in 26% of cases (P < .0001). Pathologists from commercial laboratories (12% of referrals) used IHC in 38% of cases, whereas private/hospital-based community laboratories (86% of referrals) used them in 24%. The average number of stains ordered per case was similar among all groups. We suggest that the use of IHC may reflect both the degree of experience of the pathologist and the pathology practice setting.

The effects of increased amounts of progesterone on the endometrium, including such features as eosinophilic cytoplasmic metaplasia, glandular atrophy, and decidualized stroma, are well-known among surgical pathologists. These changes are typically seen as secondary effects of pregnancy or exogenous hormone therapy for birth control purposes or abnormal bleeding. Treatment with progesterone has become a viable alternative to hysterectomy in some patients with complex atypical hyperplasia (CAH) and well-differentiated endometrial carcinoma (WDC), especially those who are poor surgical candidates or those wishing to preserve fertility. To date, only 1 study has specifically examined the effects of progestin therapy on patients with a previous diagnosis of CAH or WDC. That study proposed a classification scheme for the assessment of treated CAH and WDC. The authors concluded that after 6 months of treatment, endometrial biopsy findings of persistent cytologic atypia and architectural abnormalities were associated with treatment failure. This current study aims to assess the previously proposed criteria in a cohort of 30 patients (18 with a diagnosis of CAH and 12 with a diagnosis of WDC), and determine the usefulness of these criteria in clinical practice. Our study confirms that cytologic atypia after 6 months of therapy is strongly associated with treatment failure, and should be an indication to pursue definitive surgical treatment in these patients.

Context: Trophoblast-derived human chorionic gonadotropin (hCG) promotes corpus luteum progesterone (P4) production, and wide ranges of serum P4 levels are noted in various pregnancy outcomes, despite similar hCG concentrations. There are five unique biologically active hCG variants in human pregnancy urine, and previous studies of P4 production in response to hCG have used only preparations containing all isoforms. Understanding exactly which hCG variant is primarily responsible for stimulating corpus luteum steroidogenesis may have great clinical and diagnostic implications, including in the setting of ectopic pregnancy., Objective: Our objective was to delineate the role of the standard and hyperglycosylated (H)-hCG isoforms in stimulating P4 production by luteinized granulosa cells., Design and Setting: Cell culture, ELISA, and fluorometric-based protein assays were done at Duke University Medical Center., Patients: Patients were anonymous oocyte donors., Intervention: Cultured luteinized granulosa cells were treated with 0.25, 0.5, and 1.0 ng/ml total hCG, which contains all isoforms, purified standard hCG (37.1 kDa), and purified H-hCG (42.8 kDa)., Main Outcome Measure: P4 produced per total cellular protein (nanograms per microgram) was measured via ELISA and fluorometric protein determination kits., Results: Both total hCG (P = 0.0003) and purified standard hCG (P < 0.0001) stimulated a dose-dependent increase in P4 production. Purified H-hCG did not change the P4 produced per total cellular protein response (P value not significant)., Conclusions: Standard hCG stimulated P4 production by cultured granulosa cells and likely supports corpus luteum function via interactions with the LH/hCG receptor. In contrast, H-hCG did not increase P4 production, which indicates a nonsteroidogenic role for this protein during early gestation.

Esophageal dysmotility is common in patients with Barrett's esophagus. Previously we have reported deterioration of esophageal motility after photodynamic therapy (PDT) in a heterogeneous group of patients with esophageal carcinoma. This prospective study in consecutive patients describes changes in motility noted after endoscopic ablation. Forty-seven patients referred to our institution for endoscopic ablation for Barrett's high grade dysplasia or mucosal carcinoma between August 2001 and May 2003 were prospectively evaluated with esophageal manometry before and after porfimer sodium PDT. Six patients did not complete the study. Manometry results were classified as normal, diffuse esophageal spasm, ineffective esophageal motility, or aperistalsis. Abnormal esophageal motility was found in 14 of 47 (30%) patients at study entry ([diffuse esophageal spasm] DES-3, [ineffective esophageal motility] IEM-7, Aperistalsis-4). After PDT, 11 of 41 patients with paired studies experienced a change in manometric diagnosis. Three patients had an improvement in motility, seven a worsening and one changed diagnosis, but did not particularly worsen or improve. No patient developed new aperistalsis. Therefore, abnormal motility was present in 19 of 41 (46%) patients after PDT (DES-2, IEM-14, Aperistalsis-3). There was a statistically significant (P = 0.016) relationship with longer segment Barrett's esophagus and deterioration of function. Baseline abnormalities in motility can occur in patients with Barrett's high-grade dysplasia or mucosal carcinoma. Changes in esophageal function also may occur following photodynamic therapy, but usually are not clinically significant. Worsening in function was more likely to occur in patients with longer segment Barrett's esophagus.

An mRNA transcript contains many potential antisense oligodeoxynucleotide target sites. Identification of the most efficacious targets remains an important and challenging problem. Building on separate work that revealed a strong correlation between the inclusion of short sequence motifs and the activity level of an oligo, we have developed a predictive artificial neural network system for mapping tetranucleotide motif content to antisense oligo activity. Trained for high-specificity prediction, the system has been cross-validated against a database of 348 oligos from the literature and a larger proprietary database of 908 oligos. In cross- validation tests the system identified effective oligos (i.e. oligos capable of reducing target mRNA expression to <25% that of the control) with 53% accuracy, in contrast to the <10% success rates commonly reported for trial-and-error oligo selection, suggesting a possible 5-fold reduction in the in vivo screening required to find an active oligo. We have implemented a web interface to a trained neural network. Given an RNA transcript as input, the system identifies the most likely oligo targets and provides estimates of the probabilities that oligos targeted against these sites will be effective.

Motivation: In an effort to identify potential programmed frameshift sites by statistical analysis, we explore the hypothesis that selective pressure would have rendered such sites underabundant and underrepresented in protein-coding sequences. We developed a computer program to compare the frequencies of k-length subsequences of nucleotides with the frequencies predicted by a zero order Markov chain determined by the codon bias of the same set of sequences. The program was used to calculate and evaluate the distribution of 7-base oligonucleotides in the 6000+ putative protein-coding sequences of S. cerevisiae preliminary to the laboratory testing of the most highly underrepresented oligos for frameshifting efficiency., Results: Among the most significant results is the finding that the heptanucleotides CUU-AGG-C and CUU-AGU-U, sites of the programmed +1 translational frameshifts required for the production in yeast of actin filament-binding protein ABP140 and telomerase subunit EST3, respectively, rank among the least represented of phase I heptanucleotides in the coding sequences of S. cerevisiae. Laboratory experiments demonstrated that other underrepresented heptanucleotides identified by the program, for example GGU-CAG-A, are also prone to significant translational frameshifting, suggesting the possibility that genes containing other underrepresented heptamers may also encode transframe products., Availability: The program is available for download from http://www.gesteland.genetics.utah.edu/freqAnalysis, Supplementary Information: Complete results from the analysis of S. cerevisiae are available on http://www.gesteland.genetics.utah.edu/freqAnalysis

In man, nimesulide selectively inhibits cyclooxygenase-2 (COX-2) with little effect on haemostatic function or gastric prostaglandin formation. It causes significantly less gastrointestinal injury than naproxen, but has anti-inflammatory efficacy similar to that of naproxen and other currently available non-steroidal anti-inflammatory drugs. Naproxen suppressed arachidonic-acid-mediated platelet aggregation, reduced serum thromboxane B2 levels by 98% throughout the treatment period and reduced gastric mucosal prostaglandins (PGE2 and 6-keto-PGF1alpha) production by an average of 80%. This contrasts with nimesulide: platelet aggregation was not significantly affected, thromboxane B2 levels were only 29% lower and the gastric mucosal prostaglandins were inhibited in the order of approximately 20%. During the treatment period, both nimesulide and naproxen significantly inhibited COX-2-dependent PGE2 synthesis in the whole blood; however, naproxen had a lesser effect than nimesulide.

Seventeen cases of invasive aspergillosis occurring since 1987 in apparently immunologically normal hosts have been reviewed: 9 of invasive sinus aspergillosis, 2 of isolated brain abscesses, 3 of pneumonia (1 in a patient who developed mediastinitis), 2 of lymph node aspergillosis, and 1 of osteomyelitis of the foot. Two of the 9 patients with sinus aspergillosis died; the rest were stable up to March 1993. They responded initially to combined surgical and medical therapy. Both patients with brain abscesses survived following surgery, but one had neurological sequelae. Both patients with pneumonia were well following therapy with amphotericin B; one also received itraconazole. The patient with mediastinitis died, but this disease was diagnosed late. The patients with lymph node involvement were lost to follow-up, as was the patient with osteomyelitis. Invasive aspergillosis may be common in Pakistan. Greater awareness would allow earlier diagnosis and therapy, thereby improving the outcome.