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Since phasor measurement units (PMUs) are increasingly installed in power systems, many research works have investigated the optimal PMU placement (OPP) problem with the sake of maximizing observability over the power grid, while minimizing the cost of purchasing PMUs. However, there are still some practical challenges that have not been considered in the previous research studies, and are needed to be addressed for a real wide-area measurement system (WAMS) implementation. In this paper, a comprehensive OPP model is proposed which employs a set of basic and novel constraints for a WAMS design. In this regard, the line-wise observability concept is proposed for the first time to consider the requirements of observability for a range of WAMS-based applications such as restoration management, model validation of power system components, and dynamic line rating (DLR) monitoring. In addition, observability constraints for multi-transmission system operator (multi-TSO) power systems that are operated by different legal entities are provided, which can considerably affect the OPP result. The proposed model is formulated based on a mixed-integer linear programming (MILP) formulation which enables the optimization problem to be solved easily and effectively by existing commercial optimization tools, without any need for linearization. The performance of the proposed OPP model is first verified through simulation results on an 86-bus real power system. Then, simulations are applied to IEEE 118-bus and 300-bus test systems, to certify the performance of the proposed model in comparison with other OPPs in the literature.

Summary Background Systemic sclerosis-associated interstitial lung disease (ILD) carries a high mortality risk; expert guidance is required to aid early recognition and treatment. We aimed to develop the first expert consensus and define an algorithm for the identification and management of the condition through application of well established methods. Methods Evidence-based consensus statements for systemic sclerosis-associated ILD management were established for six domains (ie, risk factors, screening, diagnosis and severity assessment, treatment initiation and options, disease progression, and treatment escalation) using a modified Delphi process based on a systematic literature analysis. A panel of 27 Europe-based pulmonologists, rheumatologists, and internists with expertise in systemic sclerosis-associated ILD participated in three rounds of online surveys, a face-to-face discussion, and a WebEx meeting, followed by two supplemental Delphi rounds, to establish consensus and define a management algorithm. Consensus was considered achieved if at least 80% of panellists indicated agreement or disagreement. Findings Between July 1, 2018, and Aug 27, 2019, consensus agreement was reached for 52 primary statements and six supplemental statements across six domains of management, and an algorithm was defined for clinical practice use. The agreed statements most important for clinical use included: all patients with systemic sclerosis should be screened for systemic sclerosis-associated ILD using high-resolution CT; high-resolution CT is the primary tool for diagnosing ILD in systemic sclerosis; pulmonary function tests support screening and diagnosis; systemic sclerosis-associated ILD severity should be measured with more than one indicator; it is appropriate to treat all severe cases; no pharmacological treatment is an option for some patients; follow-up assessments enable identification of disease progression; progression pace, alongside disease severity, drives decisions to escalate treatment. Interpretation Through a robust modified Delphi process developed by a diverse panel of experts, the first evidence-based consensus statements were established on guidance for the identification and medical management of systemic sclerosis-associated ILD. Funding An unrestricted grant from Boehringer Ingelheim International.

This systematic review summarises current evidence to help guide treatment decisions for patients with systemic sclerosis (SSc)-associated interstitial lung disease (ILD). A systematic search of the literature (January 2012 to April 2018), including grey literature (searched between 1992 and 2011), was conducted using multiple electronic databases. Guidelines, meta-analyses, randomised controlled trials and observational studies reporting on risk stratification, screening, diagnosis, treatment and management outcomes for patients with SSc-ILD were included. A quality assessment of the included evidence was undertaken.In total, 2464 publications were identified and 280 included. Multiple independent risk factors for ILD in patients with SSc were identified, including older age, male sex and baseline pulmonary function. High-resolution computed tomography (HRCT) has been used for characterising ILD in patients with SSc, and pulmonary function tests are a key adjunctive component in the diagnostic and monitoring pathway. The clinical value of biomarkers relating to SSc-ILD diagnosis or assessment for disease progression is unknown at present. Immunosuppressive therapy (monotherapy or combined therapy) is the current standard of care for SSc-ILD; long-term evidence for effective and safe treatment of SSc-ILD is limited.Identification of patients at risk for SSc-ILD remains challenging. HRCT and pulmonary function tests are key to diagnosing and monitoring for disease progression. Although immunosuppressive therapy is considered current first-line treatment, it is partly associated with adverse effects and long-term follow-up evidence is limited. Novel therapies and biomarkers should be further explored in well-controlled clinical studies.

Background A major concern for SLE clinical trials is the possibility that some patients who technically meet entry criteria may not have active disease. Antinuclear antibody (ANA) is known to lack specificity for SLE, permitting inclusion of inappropriate patients. Typically, ANA≥1:80 and/or positive anti-double stranded DNA (DNA) are required screening elements, but lately other autoantibody variables have been utilized. Objectives To examine serologic features that promote entry of active SLE patients into trials while supporting reasonable recruitment rates. Methods Serologic features of 1411 individual subjects who had full laboratory data at screening (N=783) and/or baseline (N=1019) in 4 phase 2 multicenter SLE trials were examined. Complement levels, percent of patients with low C3 or C4, and elevated DNA were used as markers of active disease. Serological profiles consistent with active SLE were tested on screened population for effects on potential screen failure rates. Results Of 1019 patients who qualified for the studies (baseline population), 399 (39.2%) were positive for DNA and 670 (65.8%) had anti-Extractable Nuclear Antibodies (ENA). Patients with positive DNA or ENA (even in absence of DNA) had lower complement levels and were more likely to have low C3/C4. (Table 1) In patients at screening, higher titers of ANA were associated with lower complement levels and higher rates of patients with low C3/C4 and elevated DNA. ENA impacted complement levels even in the absence of ANA. Compared to traditional entry criteria (ANA≥1:80 and/or DNA), patients defined by positive DNA or ENA or ANA≥1:640 had significantly lower complement levels and greater rates of low C3/C4, suggesting a more active patient population. (Table 1) Compared to a 22.5% screen failure rate with the typical requirement for ANA≥1:80 or DNA, testing DNA or ENA or low C3/C4 as entry criteria resulted in 30.7% exclusion. Adding high titer (≥1:640) ANA as an additional optional criterion would decrease the screen failure to 25.7%. (Table 2) Conclusion The following entry criteria may help increase the likelihood that trial subjects have active SLE: ANA≥1:640, or DNA, or ENA, or low C3 or C4. To the extent that a modest loss of recruitment increases the probability of entering true, active SLE patients, these alternative constructs should be considered in future SLE trials. Disclosure of Interests: Ewa Olech Grant/research support from: Bristol Myers Squibb, Eduard van Rijen: None declared, Alexander Kant: None declared, Ali Ashrafzadeh Employee of: Employee of IQVIA, Joan T Merrill Grant/research support from: Genentech, UCB, GSK, EMD Serono, Pfizer, Celgene, Exagen, Bristol Myers Squibb, Medimmune/Astra Zeneca, Lilly, Amgen, Xencor, Neovacs, Consultant for: Genentech, UCB, GSK, EMD Serono, Pfizer, RemeGen, Celgene, Exagen, Bristol Myers Squibb, Medimmune/Astra Zeneca, Lilly, Immupharma, Amgen, Janssen, Sanofi, Neovacs, Anthera, Speakers bureau: UCB, GSK, EMD Serono, Bristol Myers Squibb, Medimmune/Astra Zeneca, Janssen

Background Regional differences have been identified as potential confounders of SLE clinical trial results. Recently, no difference between treatment and placebo was observed in the US lupus patients when a significant treatment effect was observed in Europe1. Objectives To compare SLE serologic features/markers of active disease between different geographic regions in recent multinational clinical trials. Methods Laboratory data of 1005 subjects from four global randomized SLE clinical trials at baseline were examined. Mean/median C3 and C4 complement levels, prevalence of low C3 or C4 (Low C3/C4), positive anti-double stranded DNA (DNA), anti-Extractable Nuclear Antibodies (ENA), and high-titer Antinuclear Antibody (ANA≥1:640) in North America (NA) patients were compared to Asia (AS), Latin America (LA), Africa (AF), Western Europe (WE), and Eastern Europe (EE) Results NA patients were significantly older than patients in LA, AF, or AS but not WE or EE. Not surprisingly, they also had higher complement levels and the lowest rates of low C3/C4, DNA, ENA, and ANA ≥1:640. Our data confirm that age is an important factor in the prevalence of low complement and autoantibodies. However, there remained a marked difference in serologic activity between NA and EE, despite being close in age. Asian patients were the youngest, had the lowest complement levels and the highest rate of ENA & DNA consistent with high disease activity. Low complement, but not DNA, was relatively common in Europe. LA patients, like Asians, had high rates of serologic activity but less incidence of low C3/C4, suggesting that this population may have intrinsic disease severity without being as acutely active. Conclusion SLE patients entering studies from North America are strikingly less likely to have markers of active disease than other regions, raising concerns for their suitability for trials. This appears to be associated, at least in part, with age, although more aggressive treatments cannot be ruled out. Asian subjects have the greatest prevalence of autoantibodies and low complement. Latin American patients have high prevalence of ANA≥1:640 and other autoantibodies, but less evidence of low complements. These findings may help to explain regional differences in treatment/placebo responses and emphasize the importance of geographical stratification and improved methods to screen out patients unsuitable for SLE trials. Reference [1] www.immupharma.co.uk Disclosure of Interests Ewa Olech Grant/research support from: Bristol Myers Squibb, Eduard van Rijen: None declared, Ali Ashrafzadeh Employee of: Employee of IQVIA, Alexander Kant: None declared, Joan T Merrill Grant/research support from: Genentech, UCB, GSK, EMD Serono, Pfizer, Celgene, Exagen, Bristol Myers Squibb, Medimmune/Astra Zeneca, Lilly, Amgen, Xencor, Neovacs, Consultant for: Genentech, UCB, GSK, EMD Serono, Pfizer, RemeGen, Celgene, Exagen, Bristol Myers Squibb, Medimmune/Astra Zeneca, Lilly, Immupharma, Amgen, Janssen, Sanofi, Neovacs, Anthera, Speakers bureau: UCB, GSK, EMD Serono, Bristol Myers Squibb, Medimmune/Astra Zeneca, Janssen

Background Interstitial lung disease in systemic sclerosis (SSc-ILD) occurs frequently and carries a high burden of morbidity and mortality. To date, there are no existing guidelines for screening, diagnosis and management of SSc-ILD that would aid early recognition and treatment and improve the care of these patients. Objectives To develop expert consensus recommendations for the identification and management of SSc-ILD. Methods Based on the results of a comprehensive systematic literature analysis conducted in line with NICE/CRD and IQWiG guidelines and PRISMA methodology, evidence-based statements on SSc-ILD risk, screening, diagnosis, treatment and follow-up were developed. A modified Delphi process was then used to establish consensus statements for the identification and management of SSc-ILD. Briefly, an expert panel of 27 European-based pulmonologists, rheumatologists and internists with experience in treating SSc-ILD was established. Between July and November 2018, the panel took part in 3 rounds of online surveys, a face-to-face discussion and a WebEx meeting to establish consensus-based recommendations for the management of SSc-ILD. Statements were categorised by topic: risk factors (including biomarkers); screening; diagnosis; assessment of severity; treatment initiation; treatment options; disease progression; treatment escalation; other management options. Panellists indicated their level of agreement with proposed statements on a scale of 1 (strong disagreement) to 7 (strong agreement), and consensus was considered achieved when ≥80% either disagreed (score of 1–3) or agreed (score of 5–7) with a statement. Based on panel feedback, statements that did not reach consensus were modified and re-voted in later rounds. Results At the close of the Delphi process, the panel agreed on the following: Risk factors: The presence of anti–topoisomerase I antibodies, male gender and diffuse cutaneous SSc all increase risk for ILD Screening: All SSc patients should undergo screening for ILD, using HRCT and lung function testing. Frequency of screening using HRCT should be guided by risk of developing ILD, in combination with clinical symptoms and lung function Diagnosis and assessment of severity: Use of HRCT to diagnose SSc–ILD and assess severity, with supporting findings from lung function testing and clinical assessment, is also recommended Treatment initiation and options: All patients with severe or progressive SSc–ILD should be considered for pharmacotherapy, with mycophenolate mofetil and cyclophosphamide recommended as treatments. Patients not receiving treatment should be followed closely for signs of disease progression Disease progression: Indicators of progression include sustained decline in lung function, worsening of clinical symptoms, and change in extent and/or pattern of fibrosis on HRCT Treatment escalation: Patients with inadequate treatment responses should be considered for treatment escalation. Suitability for lung transplant should be evaluated early, especially for patients diagnosed with advanced disease. Autologous haematopoietic stem cell transplant may be considered in carefully selected patients Conclusion These evidence-based expert consensus recommendations, developed using a modified Delphi process, provide important guidance for the identification and management of SSc-ILD. Acknowledgement Funding: Boehringer Ingelheim Disclosure of Interests Anna-Maria Hoffmann-Vold Grant/research support from: Received research funding or other remuneration from Boehringer Ingelheim, GSK, and Actelion, Consultant for: Received consulting fees or other remuneration from Boehringer Ingelheim, GSK, and Actelion, Speakers bureau: Actelion and Boehringer Ingelheim, Toby M Maher Shareholder of: Has stock options or bond holdings in a for-profit corporation in Apellis, Grant/research support from: Received funds from BI advisory board participation and conference travel. Received research funding and/or consulting fees or other remuneration from GSK, UCB, AstraZeneca, Roche, Bayer, Biogen Idec, Cipla, Prometic, and Sanumed, Consultant for: Toby Maher has received consultancy or speakers fees from Apellis, AstraZeneca, Bayer, Biogen Idec, Boehringer Ingelheim, Galapagos, GlaxoSmithKline RD and has received consultancy fees from Galecto, Edward E Philpot Employee of: Employee of IQVIA, Ali Ashrafzadeh Employee of: Employee of IQVIA, 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

Background:Randomized controlled trials in Systemic Lupus (SLE) have shown disappointing results for decades. Key challenges may include the heterogenous population coupled with high placebo response rates.Objectives:To evaluate trends in SLE study metrics over time and explore associations between primary endpoint failure and response in placebo/standard of care arms.Methods:Data from Phase II or III trials which enrolled ≥ 100 patients with SLE and reported SRI-4 and/or BICLA responses after a minimum of 24 weeks were included in the analysis. Sample size, recruitment rates, regional patient distributions, and results in placebo arms (at 24-36 weeks or 48-52 weeks) were examined according to the start date of each study in order to determine trends over time. Placebo group SRI-4 response rates in studies that met their primary endpoint were compared with those that did not.Results:Twenty-seven (14 phase II and 13 phase III) studies met the search criteria. Eleven of them met their primary endpoints. The study start dates ranged from Dec 2006 to Jan 2017. Mean/median total subject numbers were 461/349. Mean/median placebo subjects’ age at baseline were 39.9/39.2 and SLEDAI: 10.6/10.6. Mean/median placebo SRI-4 responses at Week 24-36 were 47.2%/45.8% and 42.8%/43% at Week 48-52. For BICLA, the rates were 40.3%/37.2% at Week 24-36 and 33.2%/33.5% at Week 48-52.As expected, lower placebo response was found in trials that met primary endpoints vs studies that did not (p=0.005). Total subject numbers and recruitment rates decreased over time while placebo SRI-4 response rates increased overall (Figure). However, there has been a greater range of placebo responses in more recent trials. Similar trends were observed in BICLA responses at Week 24-36 and 48-52, and in a corticosteroid reduction endpoint (percent of patients with reduction in steroid dose by ≥25% and to ≤7.5 mg/day prednisone/equivalent) at Week 48-52. Enrollment of patients from North America decreased while proportions of Eastern Europeans increased over time (Figure).Conclusion:High placebo response rates pose a continuing challenge in SLE studies and are associated with primary endpoint failures.Clinical trial metrics have been changing over time, with declining size and recruitment rates, possibly due to competition from increasing numbers of studies.These trends should be considered while designing and conducting future trials. Attention to site training and data quality may be particularly important to control high placebo rates, especially as trial sizes decrease.Figure.Disclosure of Interests:Ewa Olech Grant/research support from: BMS, Consultant of: Abbvie, Amgen, Remegen, Employee of: IQVIA, Speakers bureau: Abbvie, Amgen, Merck, Pfizer, UCB, Eduard van Rijen Employee of: IQVIA, Faizi Hussain Employee of: IQVIA, Gregory Dennis Employee of: IQVIA, Ali Ashrafzadeh Employee of: IQVIA, Joan T Merrill Grant/research support from: Xencor, Bristol Myers Squibb, Glaxo Smith Kline, Consultant of: Xencor, Abbvie, UCB, Glaxo Smith Kline, EMD Serono, Astellas, Remegen, Celgene/Bristol Myers Squibb, Exagen, Astra Zeneca, Amgen, Jannsen, Servier, ILTOO, Daitchi Sankyo, Lilly, Paid instructor for: Abbvie, Bristol Myers Squibb

The fertility of zebu cattle (Bos indicus) is higher than that of the European purebred (Bos taurus) and crossbred (Bos taurus × Bos indicus) cattle in tropical areas. To identify proteins related to the higher thermo-tolerance and fertility of Zebu cattle, this study was undertaken to identify differences in sperm proteome between the high fertile Malaysian indigenous zebu cattle (Kedah Kelantan) and the sub-fertile crossbred cattle (Mafriwal). Frozen semen from three high performance bulls from each breed were processed to obtain live and pure sperm. Sperm proteins were then extracted, and two-dimensional gel electrophoresis performed to compare proteome profiles. Gel image analysis identified protein spots of interest which were then identified by liquid chromatography mass spectrometry quadrupole time-of-flight (LC MS/MS Q-TOF). STRING network analysis predicted interactions between at least 20 of the identified proteins. Among the identified proteins, a number of motility and energy related proteins were present in greater abundance in Kedah Kelantan. Sperm motility evaluation by Computer Assisted Semen Analysis (CASA) confirmed significantly higher motility in Kedah Kelantan. While results from this study do identify proteins that may be responsible for the higher fertility of Kedah Kelantan, functional characterization of these proteins is warranted to reinforce our understanding of their roles in sperm fertility.

Infertility is an important aspect of human and animal reproduction and still presents with much etiological ambiguity. As fifty percent of infertility is related to the male partner, molecular investigations on sperm and seminal plasma can lead to new knowledge on male infertility. Several comparisons between fertile and infertile human and other species sperm proteome have shown the existence of potential fertility markers. These proteins have been categorized into energy related, structural and other functional proteins which play a major role in sperm motility, capacitation and sperm-oocyte binding. The data from these studies show the impact of sperm proteome studies on identifying different valuable markers for fertility screening. In this article, we review recent development in unraveling sperm fertility related proteins.

Proteome analysis of the human hair remains challenging due to the poor solubility of hair proteins and the difficulty in their extraction. In the present study, we have developed a rapid extraction protocol for hair shaft protein using alkaline-based buffer. The new protocol accelerated the procedure by reducing the extraction time from at least a day to less than two hours and showed a protein recovery of 47.3 ± 3.72%. Further analyses of the extracted protein sample through sodium dodecyl sulfate polyacrylamide gel electrophoresis and Quadrupole-time-of-flight mass spectrometry analysis unveiled a total of 60 proteins, including 25 that were not previously reported. Identification of these proteins is anticipated to be crucial in helping to understand the molecular basis of hair for potential applications in the future.

Heavily glycosylated mucin glycopeptides such as CA 27.29 and CA 15–3 are currently being used as biomarkers for detection and monitoring of breast cancer. However, they are not well detected at the early stages of the cancer. In the present study, perchloric acid (PCA) was used to enhance detection of mucin-type O-glycosylated proteins in the serum in an attempt to identify new biomarkers for early stage breast cancer. Sensitivity and specificity of an earlier developed sandwich enzyme-linked lectin assay were significantly improved with the use of serum PCA isolates. When a pilot case-control study was performed using the serum PCA isolates of normal participants (n = 105) and patients with stage 0 (n = 31) and stage I (n = 48) breast cancer, higher levels of total O-glycosylated proteins in sera of both groups of early stage breast cancer patients compared to the normal control women were demonstrated. Further analysis by gel-based proteomics detected significant inverse altered abundance of proteoglycan 4 and plasma protease C1 inhibitor in both the early stages of breast cancer patients compared to the controls. Our data suggests that the ratio of serum proteoglycan 4 to protease C1 inhibitor may be used for screening of early breast cancer although this requires further validation in clinically representative populations.

The Chikungunya virus (CHIKV) is an arthropod borne virus. In the last 50 years, it has been the cause of numerous outbreaks in tropical and temperate regions, worldwide. There is limited understanding regarding the underlying molecular mechanisms involved in CHIKV replication and how the virus interacts with its host. In the present study, comparative proteomics was used to identify secreted host proteins that changed in abundance in response to early CHIKV infection. Two-dimensional gel electrophoresis was used to analyse and compare the secretome profiles of WRL-68 cells infected with CHIKV against mock control WRL-68 cells. The analysis identified 25 regulated proteins in CHIKV infected cells. STRING network analysis was then used to predict biological processes that may be affected by these proteins. The processes predicted to be affected include signal transduction, cellular component and extracellular matrix (ECM) organization, regulation of cytokine stimulus and immune response. These results provide an initial view of CHIKV may affect the secretome of infected cells during early infection. The results presented here will compliment earlier results from the study of late host response. However, functional characterization will be necessary to further enhance our understanding of the roles played by these proteins in the early stages of CHIKV infection in humans.

Objective To determine the efficacy and safety of ocrelizumab (OCR) with methotrexate (MTX) in MTX-naive rheumatoid arthritis (RA) patients. Methods In a randomised, double-blind, controlled trial, patients received placebo+MTX (MTX; n=210), OCR 200 mg×2+MTX (OCR 200; n=200) or OCR 500 mg×2+MTX (OCR 500; n=203). OCR/placebo (two intravenous infusions) was given on days 1 and 15, with fixed re-treatment scheduled at weeks 24/26, 52/54 and 76/78. Due to early termination of OCR dosing, there was no formal primary end point analysis (change from baseline in modified total Sharp score (ΔmTSS) at week 104). Analyses are reported for week 52 outcomes. Results At week 52, treatment with OCR+MTX compared with MTX alone reduced progression of joint damage (mean (SD) change in ΔmTSS: OCR 200, 0.66 (4.51); OCR 500, 0.27 (2.91); MTX alone, 1.59 (4.82); p=0.001 and p=0.003, respectively vs MTX alone) and improved clinical signs and symptoms (American College of Rheumatology 20 response: OCR 200, 73.0%; OCR 500, 71.0%; MTX alone, 57.5%; p