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OBJECTIVE Response to immunosuppression is highly variable in systemic sclerosis (SSc)-related interstitial lung disease (ILD). This study was undertaken to determine whether a composite serum interferon (IFN)-inducible protein score exhibits predictive significance for the response to immunosuppression in SSc-ILD. METHODS Serum samples collected in the Scleroderma Lung Study II, a randomized controlled trial of mycophenolate mofetil (MMF) versus cyclophosphamide (CYC), were examined. Results were validated in an independent observational cohort receiving active treatment. A composite score of 6 IFN-inducible proteins IFNγ-inducible 10-kd protein, monokine induced by IFNγ, monocyte chemotactic protein 2, β2 -microglobulin, tumor necrosis factor receptor type II, and macrophage inflammatory protein 3β) was calculated, and its predictive significance for longitudinal forced vital capacity percent predicted measurements was evaluated. RESULTS Higher baseline IFN-inducible protein score predicted better response over 3 to 12 months in the MMF arm (point estimate = 0.41, P = 0.001) and CYC arm (point estimate = 0.91, P = 0.009). In contrast, higher baseline C-reactive protein (CRP) levels were predictive of a worse ILD course in both treatment arms. The predictive significance of the IFN-inducible protein score and CRP levels remained after adjustment for baseline demographic and clinical predictors. During the second year of treatment, in which patients in the CYC arm were switched to placebo, a higher IFN-inducible protein score at 12 months showed a trend toward predicting a worse ILD course (point estimate = -0.61, P = 0.068), while it remained predictive of better response to active immunosuppression in the MMF arm (point estimate = 0.28, P = 0.029). The predictive significance of baseline IFN-inducible protein score was replicated in the independent cohort (rs = 0.43, P = 0.028). CONCLUSION A higher IFN-inducible protein score in SSc-ILD is predictive of better response to immunosuppression and could potentially be used to identify patients who may derive the most benefit from MMF or CYC.

OBJECTIVE Interstitial lung disease (ILD) is the leading cause of death in patients with systemic sclerosis (SSc). Although pulmonary function tests (PFTs) are commonly used to screen for ILD in patients with SSc, studies have shown that they lack sensitivity for the detection of ILD in general SSc cohorts. This study was undertaken to assess the performance characteristics of PFTs for the detection of ILD in patients with early diffuse cutaneous SSc (dcSSc), a population at high risk for the development of ILD. METHODS We performed a retrospective cohort study of patients enrolled in the Prospective Registry of Early Systemic Sclerosis at 11 sites in the US between April 2012 and January 2019. Patients were included if they underwent spirometry and high-resolution computed tomography (HRCT) of the chest. We calculated the performance characteristics of PFTs for the detection of ILD on HRCT. RESULTS The study included 212 patients, 54% of whom had radiographic ILD. For the detection of ILD on HRCT imaging, a forced vital capacity (FVC)

Hidradenitis suppurativa (HS) is a chronic, recurrent, inflammatory disease of apocrine gland-bearing skin which affects approximately 1–4% of the population. The disease is more common in women and patients of African American descent and approximately one-third of patients report a family history. Obesity and smoking are known risk factors, but associations with other immune disorders, especially inflammatory bowel disease, are also recognized. The pathogenesis of HS is poorly understood and host innate or adaptive immune response, defective keratinocyte function, and the microbial environment in the hair follicle and apocrine gland have all been postulated to play a role in disease activity. While surgical interventions can be helpful to reduce disease burden, there is a high recurrence rate. Increasingly, data supports targeted immune therapy for HS, and longitudinal studies suggest benefit from these agents, both when used alone and as an adjunct to surgical treatments. The purpose of this review is to outline the current data supporting use of targeted immune therapy in HS management.

ObjectivesDetermine global skin transcriptome patterns of early diffuse systemic sclerosis (SSc) and how they differ from later disease.MethodsSkin biopsy RNA from 48 patients in the Prospective Registry for Early Systemic Sclerosis (PRESS) cohort (mean disease duration 1.3 years) and 33 matched healthy controls was examined by next-generation RNA sequencing. Data were analysed for cell type-specific signatures and compared with similarly obtained data from 55 previously biopsied patients in Genetics versus Environment in Scleroderma Outcomes Study cohort with longer disease duration (mean 7.4 years) and their matched controls. Correlations with histological features and clinical course were also evaluated.ResultsSSc patients in PRESS had a high prevalence of M2 (96%) and M1 (94%) macrophage and CD8 T cell (65%), CD4 T cell (60%) and B cell (69%) signatures. Immunohistochemical staining of immune cell markers correlated with the gene expression-based immune cell signatures. The prevalence of immune cell signatures in early diffuse SSc patients was higher than in patients with longer disease duration. In the multivariable model, adaptive immune cell signatures were significantly associated with shorter disease duration, while fibroblast and macrophage cell type signatures were associated with higher modified Rodnan Skin Score (mRSS). Immune cell signatures also correlated with skin thickness progression rate prior to biopsy, but did not predict subsequent mRSS progression.ConclusionsSkin in early diffuse SSc has prominent innate and adaptive immune cell signatures. As a prominently affected end organ, these signatures reflect the preceding rate of disease progression. These findings could have implications in understanding SSc pathogenesis and clinical trial design.

Background Abatacept (ABA) is a recombinant fusion protein including extracellular domain of human CTLA4 and hinge– CH2–CH3 of the Fc domain of human IgG. Objectives This phase 2 trial assessed the safety and efficacy of ABA 125 mg subcutaneous (SC) versus placebo SC given every week on skin fibrosis using the modified Rodnan skin score (mRSS) in diffuse cutaneous SSc (dcSSc; clinicaltrials.gov NCT02161406). Methods A 12-month, investigator-initiated, multicenter double-blind, randomized placebo-controlled trial was conducted between September 2014 and February 2018 at 27 US, Canadian and UK sites. Eligible subjects were randomized in a 1:1 ratio to either ABA or matching placebo, stratified by duration of dcSSc (≤18 vs >18 to ≤36 months). Key inclusion criteria included dcSSc with disease duration of ≤ 36 months (defined as first non−Raynaud phenomenon) and mRSS ≥ 10 and ≤ 35 units for disease duration of ≤ 18 months and mRSS ≥ 15 and ≤ 45 units with evidence of active disease for disease duration of >18-36 months. Escape therapy was allowed at 6 months for worsening SSc. Primary outcomes include safety and change in mRSS over 12 months (ΔmRSS). Secondary endpoints include ΔFVC%, ΔHAQ-DI, Δpatient and Δphysician global assessment, and ACR CRISS1 (composite measure in dcSSc). The primary endpoint of ΔmRSS was assessed using a linear mixed model (see Table) with primary end point data censored after initiation of escape therapy. Results 88 subjects were randomized (44/group) and formed the mITT group; 34 (77%) and 35 (80%) completed the 12-month double-blind treatment period in ABA and placebo groups, respectively. At baseline, the mean age was 49 years, 75% were female, mean disease duration was 1.59 years, 60% had disease duration ≤ 18 months, mRSS was 22.4, mean FVC% was 84.3%, and mean HAQ-DI was 1.0. Compliance with both drugs was >98%. ABA was well tolerated with comparable adverse events (AEs), serious AEs, and AEs of special interest (e.g., infections and malignancies) between treatments. There were 3 deaths during the treatment— 2 in ABA (both scleroderma renal crisis-days 11 and 46) and 1 in placebo (sudden cardiac arrest- day 310). The primary endpoint showed an adjusted mean improvement of mRSS of -6.24 in ABA vs. -4.49 in placebo, p= 0.28 (Table). The secondary outcome measures were statistically significant and clinically meaningful (HAQ-DI and physician global assessment) or showed numerical results favoring ABA (Table). A larger proportion of placebo subjects required escape immunosuppressive therapy vs. ABA (36% vs. 16%, p=0.03). Estimates are from a linear mixed model with treatment group, month (3, 6, and 12), treatment x month interaction, duration of dcSSc (≤18 vs >18 to ≤36 months), and baseline outcome measure as fixed effects and participant as a random effect (except for ACR CRISS). For ACR CRISS, treatment differences were assessed by the non-parametric Van Elteren test. Multiple imputation was used for ACR CRISS analysis. Conclusion In patients with early dcSSc, ABA was well tolerated, but ΔmRSS was not statistically significant. Secondary outcome measures showed evidence in favor of ABA, including greater requirement of escape therapy in the placebo group. mRSS showed large variability, despite recruiting an early dcSSc population. References [1] Khanna D, et al. Arthritis Rheumatol2016, 68:299-311 Acknowledgement Project was supported by NIH/NIAID Clinical ACE grant (5UM1AI110557-05) and an investigator-initiated grant by Bristol-Myers Squibb. Disclosure of Interests Dinesh Khanna Shareholder of: Eicos Sciences, Inc, Grant/research support from: Bayer, BMS, Pfizer, Horizon, Consultant for: Actelion Acceleron, Arena, Bayer, BI, BMS, CSL Behring, Corbus, Cytori, GSK, Genentech/Roche, Galapagos, Employee of: Elcos Sciences, Inc, Cathie Spino: None declared, Erica Bush: None declared, Sindhu Johnson: None declared, Lorinda Chung Grant/research support from: United Therapeutics, Consultant for: Reata, Bristol Meyers Squibb, Boehringer Ingelheim, Mitsubishi Tanabe, Eicos, Christopher Denton Grant/research support from: GlaxoSmithKline, Inventiva, CSF Behring, Consultant for: Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Bayer, Jerry Molitor Grant/research support from: Pfizer, Consultant for: Boehringer Ingelheim, Amgen, Viginia Steen Consultant for: CSL Behring, Corbus and Bayer, Paid instructor for: Advisory Board: CSL Behring, Roach, Bayer and Reata, Robert Lafyatis Grant/research support from: Kiniksa, Elpidera, Regeneron, PRISM biolab, Consultant for: Sanofi, Genentech, Formation, Biocon, Bristol Meyers Squibb, Merck, Robert Simms: None declared, Suzanne Kafaja: None declared, Tracy Frech: None declared, Vivian Hsu: None declared, Robin Domsic Consultant for: Eicos Sciences Inc/Civi Biopharma and Boehringer-Ingelheim., Janet Pope Consultant for: Eli Lilly and Company, Jessica Gordon Grant/research support from: Corbus Pharmaceuticals Cumberland Pharmaceuticals, Maureen Mayes Grant/research support from: Maureen Mayes is a clinical trial investigator for Boehringer-Ingelheim; Galapagos, Reata, Sanofi, Merck-Serono, Consultant for: Maureen Mayes is a member of scientific advisory boards for Galapagos NV (Pharma), Boehringer-Ingelheim, Mitsubishi-Tanabe, Astellas: Grant Review Board for Actelion., Speakers bureau: Maureen Mayes received personal fees for being a conference speaker on the use of autoantibodies in connective tissue diseases for Medtelligence, Elena Schiopu Grant/research support from: Bristol Meyers Squibb and Bayer, Amber Young: None declared, Nora Sandorfi: None declared, Jane Park: None declared, Faye Hant: None declared, Elana Bernstein Grant/research support from: I have an investigator-initiated research grant from the Pfizer ASPIRE Rheumatology Program., Consultant for: I am the medical monitor for SLS III, which is sponsored by Genentech, Soumya Chatterjee: None declared, Flavia Castelino Consultant for: Genentech, Boehringer, Ali Ajam Consultant for: Focus Point Global, Yannick Allanore Grant/research support from: Inventiva, F Hoffman La-Roche, Sanofi, BMS, Pfizer, Consultant for: Actelion, Bayer, BMS, Boehringer, Roche, Sanofi, Marco Matucci-Cerinic Grant/research support from: Actelion, MSD, Pfizer, BMS, Chemomab, Sanipedia, Speakers bureau: Actelion, BMS; MSD, Janssen, Oliver Distler Grant/research support from: Prof. Distler received research funding from Actelion, Bayer, Boehringer Ingelheim and Mitsubishi Tanabe to investigate potential treatments of scleroderma and its complications, Consultant for: Prof. Distler has/had consultancy relationship within the last 3 years with Actelion, AnaMar, Bayer, Boehringer Ingelheim, ChemomAb, espeRare foundation, Genentech/Roche, GSK, Inventiva, Italfarmaco, iQvia, Lilly, medac, MedImmune, Mitsubishi Tanabe Pharma, Pharmacyclics, Novartis, Pfizer, Sanofi, Serodapharm and UCB in the area of potential treatments of scleroderma and its complications. In addition, he had/has consultancy relationship within the last 3 years with A. Menarini, Amgen, Abbvie, GSK, Mepha, MSD, Pfizer and UCB in the field of arthritides and related disorders, Ora Gewurz-Singer: None declared, David Fox Grant/research support from: Regeneron, Gilead, Seattle Genetics, Consultant for: Grant reviewer for Pfizer, Daniel Furst Grant/research support from: F. Hoffmann-La Roche, Genentech

ObjectiveT cells play a key role in the pathogenesis of early systemic sclerosis. This study was undertaken to assess the safety and efficacy of abatacept in patients with diffuse cutaneous systemic sclerosis (dcSSc).MethodsIn this 12-month, randomized, double-blind, placebo-controlled trial, participants were randomized 1:1 to receive either subcutaneous abatacept 125 mg or matching placebo, stratified by duration of dcSSc. Escape therapy was allowed at 6 months for worsening disease. The coprimary end points were change in the modified Rodnan skin thickness score (MRSS) compared to baseline and safety over 12 months. Differences in longitudinal outcomes were assessed according to treatment using linear mixed models, with outcomes censored after initiation of escape therapy. Skin tissue obtained from participants at baseline was classified into intrinsic gene expression subsets.ResultsAmong 88 participants, the adjusted mean change in the MRSS at 12 months was -6.24 units for those receiving abatacept and -4.49 units for those receiving placebo, with an adjusted mean treatment difference of -1.75 units (P = 0.28). Outcomes for 2 secondary measures (Health Assessment Questionnaire disability index and a composite measure) were clinically and statistically significantly better with abatacept. The proportion of subjects in whom escape therapy was needed was higher in the placebo group relative to the abatacept group (36% versus 16%). In the inflammatory and normal-like skin gene expression subsets, decline in the MRSS over 12 months was clinically and significantly greater in the abatacept group versus the placebo group (P < 0.001 and P = 0.03, respectively). In the abatacept group, adverse events occurred in 35 participants versus 40 participants in the placebo group, including 2 deaths and 1 death, respectively.ConclusionIn this phase II trial, abatacept was well-tolerated, but change in the MRSS was not statistically significant. Secondary outcome measures, including gene expression subsets, showed evidence in support of abatacept. These data should be confirmed in a phase III trial.

International audience; The ro-vibrational transitions of NaH are crucially needed for the control of photo-association processes resulting from its formation and for accurately modeling the NaH abundance in space. In this work, we constructed new PESs of the NaH-He system. The potentials were computed at the CCSD(T)-F12/ cc-pVTZ level of theory. Each of the PESs presents two local minima. From these PESs, we calculated rotational cross sections of NaH induced by collision with He using the close coupling approach. These cross sections were then averaged at low temperature to obtain the collisional rates. The propensity rules favorite odd j transitions. The collisional rates presented in this paper may be crucial for the astrophysical community. The three dimensional PES can be used later to compute ro-vibrational quenching rate coefficients to interpret the NaH collisional interaction with laser-cooled atoms.

This paper examines relationships between rainfall-runoff, catchment connectivity, antecedent moisture conditions and fertiliser application with nitrate-N and total phosphorus (TP) fluxes in an arable headwater catchment over three hydrological years (2012-2014). Annual precipitation totals did not vary substantially between years, yet the timing of rainfall strongly influenced runoff generation and subsequent nitrate-N and TP fluxes. The greatest nitrate-N (>250 kg N day(-1)) and TP (>10 kg TP day(-1)) fluxes only occurred when shallow groundwater was within 0.6m of the ground surface and runoff coefficients were greater than 0.1. These thresholds were reached less frequently in 2012 due to drought recovery resulting in lower annual nitrate-N (7.4 kg N ha(-1)) and TP (0.12 kg P ha(-1)) fluxes in comparison with 2013 (15.1 kg N ha(-1); 0.21 kg P ha(-1)). The wet winter of 2013 with elevated shallow groundwater levels led to more frequent activation of sub-surface pathways and tile drain flow. Throughout the period, dry antecedent conditions had a temporary effect in elevating TP loads. Evidence of TP source exhaustion after consecutive storm events can be attributed to the repeated depletion of temporarily connected critical source areas to the river network via impermeable road surfaces. Fertiliser application varied considerably across three years due to differences in crop rotation between farms, with annual N and P fertiliser inputs varying by up to 21% and 41%, respectively. Proportional reductions in annual riverine nitrate-N and TP loadings were not observed at the sub-catchment outlet as loadings were largely influenced by annual runoff. Nitrate loadings were slightly higher during fertiliser application, but there was little relationship between P fertiliser application and riverine TP load. These data indicate that this intensive arable catchment may be in a state of biogeochemical stationarity, whereby legacy stores of nutrients buffer against changes in contemporary nutrient inputs.

Objective.We sought to identify predictors of mortality and cardiopulmonary hospitalizations in patients at risk for pulmonary hypertension (PH) and enrolled in PHAROS, a prospective cohort study to investigate the natural history of PH in systemic sclerosis (SSc).Methods.The at-risk population for PH was defined by the following entry criteria: echocardiogram systolic pulmonary arterial pressure > 40 mmHg, or DLCO < 55% predicted or ratio of % forced vital capacity/%DLCO > 1.6, measured by pulmonary function testing. Baseline clinical measures were evaluated as predictors of hospitalization and death between 2005 and 2014. Cox proportional hazards models were censored at date of PH onset or latest study visit and adjusted for age, sex, race, and disease duration.Results.Of the 236 at-risk subjects who were followed for a median of 4 years (range 0.4–8.5 yrs), 35 developed PH after entering PHAROS (reclassified as PH group). In the at-risk group, higher mortality was strongly associated with male sex, low %DLCO, exercise oxygen desaturation, anemia, abnormal dyspnea scores, and baseline pericardial effusion. Risks for cardiopulmonary hospitalization were associated with increased dyspnea and pericardial effusions, although PH patients with DLCO < 50% had the highest risk of cardiopulmonary hospitalizations.Conclusion.Risk factors for poor outcome in patients with SSc who are at risk for PH were similar to others with SSc-PH and SSc-pulmonary arterial hypertension, including male sex, DLCO < 50%, exercise oxygen desaturation, and pericardial effusions. This group should undergo right heart catheterization and receive appropriate intervention if PH is confirmed.

Background Pulmonary arterial hypertension (PAH) is a leading cause of death in patients with systemic sclerosis (SSc). The purpose of this study was to assess long-term outcomes in patients with SSc-PAH. Methods Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma is a prospective registry of patients with SSc at high risk for or with incident pulmonary hypertension from right heart catheterization. Incident World Health Organization group I PAH patients were analyzed. Kaplan-Meier survival curves were generated for the overall cohort and those who died of PAH. Multivariate Cox regression models identified predictors of mortality. Results Survival in 160 patients with incident SSc-PAH at 1, 3, 5, and 8 years was 95%, 75%, 63%, and 49%, respectively. PAH accounted for 52% of all deaths. When restricted to deaths from PAH, respective survival rates were 97%, 83%, 76%, and 76%, with 93% of PAH-related deaths occurring within 4 years of diagnosis. Men (hazard ratio [HR], 3.11; 95% CI, 1.38-6.98), diffuse disease (HR, 2.12; 95% CI, 1.13-3.93), systolic pulmonary artery pressure (PAP) on ECG (HR, 1.06 95% CI, 1.01-1.11), mean PAP on right heart catheterization (HR, 1.03; 95% CI, 1.001-1.07), 6-min walk distance (HR, 0.92; 95% CI, 0.86-0.99), and diffusing capacity for carbon monoxide (HR, 0.65; 95% CI, 0.46-0.92) significantly affected survival on multivariate analysis. Conclusions Overall survival in PHAROS was higher than other SSc-PAH cohorts. PAH accounted for more than one-half of deaths and primarily within the first few years after PAH diagnosis. Optimization of treatment for those at greatest risk of early PAH-related death is crucial.

Objective.To determine the inter/intraobserver reliability of the tender and swollen joint counts (TJC, SJC) and the modified Rodnan Skin Score (mRSS) in diffuse cutaneous systemic sclerosis (dcSSc) and to assess content validity of the TJC/SJC.Methods.Ten rheumatologists completed the SJC, TJC, and mRSS on 7 patients. Musculoskeletal ultrasound (MSUS) was performed.Results.Interobserver and intraobserver reliability for the TJC was 0.97 and 0.99, for the SJC was 0.24 and 0.71, and for the mRSS was 0.81 and 0.94, respectively. MSUS abnormalities did not correspond with SJC/TJC.Conclusion.We demonstrate excellent inter- and intraobserver reliability for the mRSS and TJC in dcSSc. However, the SJC and TJC did not correspond to MSUS.

Hidradenitis suppurativa (HS) is a chronic, recurrent, inflammatory disease of apocrine gland-bearing skin which affects approximately 1–4% of the population. The disease is more common in women and patients of African American descent and approximately one-third of patients report a family history. Obesity and smoking are known risk factors, but associations with other immune disorders, especially inflammatory bowel disease, are also recognized. The pathogenesis of HS is poorly understood and host innate or adaptive immune response, defective keratinocyte function, and the microbial environment in the hair follicle and apocrine gland have all been postulated to play a role in disease activity. While surgical interventions can be helpful to reduce disease burden, there is a high recurrence rate. Increasingly, data supports targeted immune therapy for HS, and longitudinal studies suggest benefit from these agents, both when used alone and as an adjunct to surgical treatments. The purpose of this review is to outline the current data supporting use of targeted immune therapy in HS management.

The origin of gold nuggets in placers is enigmatic as they can be mechanically separated from the primary vein deposit or can be of secondary origin, formed in the placer environment. Pb isotopes can be a valuable tracer as a match in the isotopic ratios between vein and placer gold will indicate that the placer nuggets are simply mechanically separated from the hydrothermal vein and unmodified by weathering. Reconnaissance elemental analyses revealed that vein and placer gold from the Rich Hill district, Arizona, contain up to thousands of ppm Pb and therefore both are suitable for Pb isotope analyses. We measured Pb isotopes in placer gold nuggets and compare the results to primary vein gold and sulfides and also gangue minerals and host rocks in the Rich Hill area. Primary vein gold and galena show similar Pb isotope ratios with 206Pb/204Pb ranging from 18.364 to 18.486, 207Pb/204Pb from 15.574 to 15.593, and 208Pb/204Pb from 37.150 to 37.359. This indicates that the ore metals were derived from a similar source during a hypogene hydrothermal event in the geologic past. Present-day Pb isotope compositions of local rocks in the area show distinct values compared to the primary vein mineralization. Age-corrected and modeled Pb isotope compositions for local magmatic rocks do not provide a clear picture for a possible hydrothermal ore metal source due to possible alteration processes and the long time elapsed since the mineralization event. The distinct present-day Pb isotopes in local lithological units, however, provide an excellent tracer for deciphering the origin of the placer gold. All the placer gold nuggets show very distinct Pb isotope compositions when compared to their respective hydrothermal vein source represented by the vein gold and galena. The placer gold Pb isotopes show very wide variations, with 206Pb/204Pb ranging from 17.985 to 20.057, 207Pb/204Pb from 15.494 to 15.749, and 208Pb/204Pb from 36.863 to 38.606. The placer nuggets follow the present-day Pb isotope trend observed in rocks and sediments in the area. In addition, the Pb isotopes in majority of the placer gold nuggets are far more radiogenic compared to the vein gold, sulfides, and even gangue minerals. This is indicating that a significant part, if not all, of the Pb in the placer gold was relatively recently acquired from the placer sediments. The observed distinct Pb isotope compositions between primary and placer samples suggest that gold undergoes significant chemical changes during the supergene stage. Considering a number of possible scenarios, the most plausible explanation for the observed present-day Pb isotope similarity between placer gold and local rocks is formation of a significant part of the total mass of these nuggets within the placer environment.

Systemic sclerosis is a complex connective tissue disease with high morbidity and mortality. The scleroderma patient with rapidly progressive skin disease and joint contractures is one of the most challenging a clinician will face. It is important to recognize that such patients also may be at increased risk of severe internal organ involvement. The timing for institution of therapies is important and may lead to improved outcomes if undertaken early. With the evolving therapeutic landscape, there is the promise for treatments that may prove to be effective in the treatment of diffuse cutaneous systemic sclerosis. This chapter highlights a systemic sclerosis patient with rapidly progressive skin disease and considerations for therapies.

Purpose: A small number of recent studies have linked daily cycles in stream turbidity to nocturnal bioturbation by aquatic fauna, principally crayfish, and demonstrated this process can significantly impact upon water quality under baseflow conditions. Adding to this limited body of research, we use high-resolution water quality monitoring data to investigate evidence of diel turbidity cycles in a lowland, headwater stream with a known signal crayfish (Pacifastacus leniusculus) population and explore a range of potential causal mechanisms. Materials and methods: Automatic bankside monitoring stations measured turbidity and other water quality parameters at 30-min resolution at three locations on the River Blackwater, Norfolk, UK during 2013. Specifically, we focused on two 20-day periods of baseflow conditions during January and April 2013 which displayed turbidity trends typical of winter and spring seasons, respectively. The turbidity time-series, which were smoothed with 6.5 hour Savitzky-Golay filters to highlight diel trends, were correlated against temperature, stage, dissolved oxygen and pH to assess the importance of abiotic influences on turbidity. Turbidity was also calibrated against suspended particulate matter (SPM) over a wide range of values via linear regression. Results and discussion: Pronounced diel turbidity cycles were found at two of the three sites under baseflow conditions during April. Spring night-time turbidity values consistently peaked between 21:00 and 04:00 with values increasing by ~10 nephelometric turbidity units (NTU) compared with the lowest recorded daytime values which occurred between 10:00 and 14:00. This translated into statistically significant increases in median midnight SPM concentration of up to 76% compared with midday, with night-time (18:00 – 05:30) SPM loads also up to 30% higher than that recorded during the daytime (06:00 – 17:30). Relating turbidity to other water quality parameters exhibiting diel cycles revealed there to be neither any correlation that might indicate a causal link, nor any obvious mechanistic connections to explain the temporal turbidity trends. Diel turbidity cycles were less prominent at all sites during the winter. Conclusions: Considering the seasonality and timing of elevated turbidity, visual observations of crayfish activity, and an absence of mechanistic connections with other water quality parameters, the results presented here are consistent with the hypothesis that nocturnal bioturbation is responsible for generating diel turbidity cycles under baseflow conditions in headwater streams. However, further research in a variety of fluvial environments is required to better assess the spatial extent, importance and causal mechanisms of this phenomenon.

In this article, the authors attempt to determine the retention rate and benefits of Painless Punctal Plug F(TM) placed in patients diagnosed with dry eye. This is a prospective, observational cohort study. Forty patients diagnosed with dry eye underwent Painless Punctal Plug F placement in the inferior puncta (80 puncta) in a private clinic from January 2010 to July 2012. Patients were then followed up monthly for seven months taking note of plug retention, spontaneous plug loss, and complications. Retention rates of patients with mean age of 58.6 years were 100% after one month, 98.75% after two months, 96.25% after three months, 95% after four months, 93.75% after five months, and 92.5% after seven months. In the 80 plugs, three plugs underwent spontaneous punctal plug loss and three plugs were removed due to local discomfort. In total, 74 out of 80 plugs remained intact after seven months of follow-up. Kaplan-Meier analysis showed that there was propensity for spontaneous punctal plug loss or plug removal in the Sjogren group as compared to the non-Sjogren group. No complications were noted such as epiphora, local inflammatory reaction, nor canalicular pyogenic granuloma except for local discomfort. This study showed that Painless Punctal Plug F has a high retention rate with the following benefits, it has one-size, fitted for small to medium puncta; extended round end which made prior dilation unnecessary and once inserted, the soft round bulb fits snugly inside the punctum preventing plug loss.

Glucocorticoids, proton pump inhibitors, selective serotonin reuptake inhibitors (SSRIs), certain antiepileptic drugs, and aromatase inhibitors have significant adverse effects on bone. Healthcare providers should monitor the bone health of patients on these agents, supplement their intake of calcium and vitamin D, encourage weight-bearing exercise, and initiate osteoporosis-prevention treatment as indicated.

Previous studies have shown that the transforming growth factor (TGF)β/Alk1/Smad1 signaling pathway is constitutively activated in a subset of systemic sclerosis (SSc) fibroblasts and this pathway is a critical regulator of CCN2 gene expression. Caveolin-1 (cav-1), an integral membrane protein and the main component of caveolae, has also been implicated in SSc pathogenesis. This study was undertaken to evaluate the role of caveolin-1 in Smad1 signaling and CCN2 expression in healthy and SSc dermal fibroblasts. We show that a significant subset of SSc dermal fibroblasts has up-regulated cav-1 expression in vitro, and that cav-1 up-regulation correlates with constitutive Smad1 phosphorylation. In addition, basal levels of phospho-Smad1 were down-regulated after inhibition of cav-1 in SSc dermal fibroblasts. Caveolin-1 formed a protein complex with Alk1 in dermal fibroblasts, and this association was enhanced by TGFβ. By using siRNA against cav-1 and adenoviral cav-1 overexpression we demonstrate that activation of Smad1 in response to TGFβ requires cav-1 and that cav-1 is sufficient for Smad-1 phosphorylation. We also show that cav-1 is a positive regulator of CCN2 gene expression, and that it is required for the basal and TGFβ-induced CCN2 levels. In conclusion, this study has revealed an important role of cav-1 in mediating TGFβ/Smad1 signaling and CCN2 gene expression in healthy and SSc dermal fibroblasts.

In the UK agriculture is by far the largest source of nitrous oxide (N(2)O) emissions. Direct N(2)O emissions as a result of nitrogen (N) application to soils have been well documented in the UK, whereas indirect emissions produced in surface waters and groundwaters from leached N are much less understood with limited data to support IPCC emission factors. Indirect emissions were studied in surface waters in the Upper Thurne, a lowland drained arable catchment in eastern England. All surface waters were found to have dissolved N(2)O concentrations above that expected if in equilibrium with ambient concentrations, demonstrating all surface waters were acting as a source of N(2)O. The drainage channels represented 86% of the total indirect N(2)O flux, followed by wetland areas, 11%, and the river, 3%. The dense drainage network was found to have the highest dissolved N(2)O concentrations of all the water bodies studied with a combined N(2)O flux of 16 kg N(2)O-N per day in March 2007. Such indirect fluxes are comparable to direct fluxes per hectare and represent a significant proportion of the total N(2)O flux for this catchment. Separate emission factors were established for the three different surface water types within the same catchment, suggesting that the one emission factor used in the Intergovernmental Panel on Climate Change (IPCC) methodology for predicting all indirect N(2)O emissions is inappropriate.