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Long-term follow-up of patients with anti-cyclic citrullinated peptide antibody-positive connective tissue disease: a retrospective observational study including information on the HLA-DRB1 allele and citrullination dependency
Takeshi Iwasaki1 na1,
Shuichiro Nakabo1 na1,
Chikashi Terao2,3,4,
Kosaku Murakami1,
Ran Nakashima1,
Motomu Hashimoto5,
Yoshitaka Imura6,
Naoichiro Yukawa7,
Hajime Yoshifuji1,
Yasuo Miura8,
Kimiko Yurugi8,
Taira Maekawa8,
Myrthe A. M. van Delft9,
Leendert A. Trouw9,10,
Takao Fujii1,11,
Tsuneyo Mimori1,12 &
Koichiro Ohmura ORCID: orcid.org/0000-0003-2927-91591
The anti-cyclic citrullinated peptide (CCP) antibody is a diagnostic biomarker of rheumatoid arthritis (RA). However, some non-RA connective tissue disease (CTD) patients also test positive for the anti-CCP antibody and, thus, may ultimately develop RA. We retrospectively investigated whether anti-CCP-positive non-RA CTD patients developed RA and attempted to identify factors that may differentiate RA-overlapping CTD from pure CTD.
In total, 842 CTD patients with a primary diagnosis that was not RA were selected from our CTD database as of December 2012. Anti-CCP antibody titers were obtained from a retrospective chart review or measured using stored sera. RA was diagnosed according to the 1987 revised American College of Rheumatology classification criteria. Thirty-three anti-CCP-positive non-RA CTD patients were retrospectively followed up for the development of RA. Bone erosions on the hands and feet were assessed by X-ray. Citrullination dependency was evaluated by an in-house ELISA, the HLA-DRB1 allele was typed, and the results obtained were then compared between RA-overlapping and non-RA anti-CCP-positive CTD patients.
Two out of 33 anti-CCP-positive CTD patients (6.1%) developed RA during a mean follow-up period of 8.9 years. X-rays were examined in 27 out of the 33 patients, and only one (3.7%) showed bone erosions. The frequency of the HLA-DRB1 shared epitope (SE) and anti-CCP antibody titers were both significantly higher in anti-CCP-positive RA-overlapping CTD patients than in anti-CCP-positive non-RA CTD patients, while no significant differences were observed in citrullination dependency.
Anti-CCP-positive non-RA CTD patients rarely developed RA. HLA-DRB1 SE and anti-CCP antibody titers may facilitate the differentiation of RA-overlapping CTD from anti-CCP-positive non-RA CTD.
The anti-cyclic citrullinated peptide (CCP) antibody is a widely used diagnostic biomarker of rheumatoid arthritis (RA). Despite its high specificity, previous studies reported that 5–10% of non-RA connective tissue disease (CTD) patients tested positive for the anti-CCP antibody [1, 2]. These patients may develop RA in the future because the emergence of anti-citrullinated protein antibodies (ACPA), including the anti-CCP antibody, precedes the onset of RA [3,4,5,6]. However, limited information is currently available on the long-term outcomes of anti-CCP-positive non-RA CTD patients.
ACPA-positive RA is strongly associated with certain HLA-DRB1 alleles that carry specific amino acid sequences, the so-called shared epitope (SE) [7,8,9,10,11]. However, ACPA-positive healthy subjects, which account for 1–2% of the population [12, 13], do not have higher frequency of HLA-DRB1 SE [13]. Therefore, SE has potential as a genetic marker to distinguish RA from non-RA in the ACPA-positive population.
The existence of the anti-CCP antibody in non-RA patients, such as those with autoimmune hepatitis [14], tuberculosis [15], and systemic lupus erythematosus (SLE) [16], is not dependent on citrullination. The anti-CCP-positive sera of patients may also react with cyclic arginine peptides (CAP), in which the citrulline residues of CCP peptides are substituted with arginine residues.
Therefore, we retrospectively investigated whether anti-CCP antibody-positive non-RA CTD patients developed RA and clarified whether HLA-DRB1 SE and the citrullination dependency of the anti-CCP antibody are predictive factors for RA.
Patients and clinical information
Eight hundred and forty-two CTD patients were selected from the CTD database in our division as of December 2012. Diagnoses were based on the clinical judgments of individual physicians. Clinical judgments were based on the following classification criteria: the American College of Rheumatology (ACR) 1997 criteria [17] or the new Systemic Lupus International Collaborating Clinics (SLICC) 2012 classification criteria [18] for SLE, the ACR 2012 classification criteria [19] for primary Sjögren's syndrome (pSS), the ACR 1980 classification criteria [20] for systemic sclerosis, the Bohan and Peter diagnostic criteria [21] for polymyositis/dermatomyositis, the Kasukawa's criteria for mixed connective tissue disease (MCTD) [22], the Yamaguchi criteria for adult-onset Still's disease (AOSD) [23], and the Assessment in SpondyloArthritis international Society (ASAS) classification criteria for spondyloarthritis [24]. To assess the reliability of the diagnosis, we evaluated all SLE patients by chart review and found that all patients fulfilled the ACR 1997 or SLICC 2012 criteria. Since some patients in the database were diagnosed with overlapping RA, the attending physicians of patients diagnosed with RA completed a questionnaire survey in January 2020 to confirm whether their patients fulfilled the 1987 revised American College of Rheumatology (ACR) criteria for the classification of RA [25]. In the present study, we used the 1987 ACR criteria, not the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria [26], because the latter are not applicable to patients with symptoms that may be attributed to another disease, including CTD, and also include the anti-CCP antibody. X-rays of the hands and feet were taken in January 2020 to establish whether anti-CCP-positive non-RA CTD patients had developed bone erosions. Regarding anti-CCP-positive non-RA CTD patients who dropped out of the follow-up and RA-overlapped patients, we retrospectively evaluated X-rays of their hands and feet, which had been taken after the anti-CCP antibody became positive. To assess whether anti-CCP-positive CTD patients had suffered from arthritis during this time frame, the attending physicians of patients completed a questionnaire survey in September 2020. Smoking status of anti-CCP antibody-positive patients was obtained by chart review in September 2020.
The sera of patients were collected and stored with written informed consent at various time points in the follow-up period. The follow-up length of each patient was defined as the period from the day when serum was collected or the anti-CCP antibody test was ordered in the clinic to the last visit before January 2020 (see Supplementary Figure 1, Additional file 1). All data were analyzed anonymously.
Measurement of anti-CCP antibody titers and citrullination dependency
Anti-CCP antibody titers were obtained from a retrospective chart review for 445 patients or were measured using the stored sera of 397 patients. In both cases, anti-CCP antibody titers were assessed using a second-generation enzyme-linked immunosorbent assay (ELISA) kit (MESACUP-2 test CCP; MEDICAL & BIOLOGICAL LABORATORIES, Nagoya, Japan). The reference range in this kit is less than 4.5 U/mL, with a level of 100 and higher being calculated as 100 because the upper limit measured in old cases was 100. To investigate whether the anti-CCP antibody became negative over time, we obtained the latest anti-CCP antibody titer in January 2020 from the medical records of 64 anti-CCP-positive CTD patients whose anti-CCP antibody titers had been measured.
Citrullination dependency was evaluated using an in-house ELISA at the Leiden University Medical Center, as described previously [27]. CAP, the arginine version of CCP (the citrulline residues of CCP were converted to arginine), and CCP were coated on the same plate, and reactivities against CAP and CCP were compared. The dependency on citrullination was evaluated by subtracting absorbance values of anti-CAP from that of anti-CCP. A sample was considered to be citrullination-dependent when the anti-CCP antibody titer was higher than the cut-off (25 arbitrary U/mL) and the absorbance values at 415 nm value for CCP was ≥ 0.1 higher than that for CAP [28].
Genotyping of the HLA-DRB1 allele
The HLA-DRB1 allele was typed using the WAKFlow system (Wakunaga Pharmaceutical, Akitakata, Japan) and the following were classified as HLA-DRB1 SE: *01:01, *01:02, *04:01, *04:04, *04:05, *04:08, *04:10, *04:13, *04:16, *10:01, *13:03, *14:02, and *14:06, as reported previously [29].
All statistical analyses were conducted using R version 3.6.3. In comparisons of characteristics between anti-CCP-positive non-RA CTD patients and RA-overlapping CTD patients, the Mann-Whitney U test was used for continuous variables and Fisher's exact test for categorical variables. The Mann-Whitney U test was used to analyze absorbance difference between anti-CCP and anti-CAP patients. Significant threshold was set to p = 0.05.
A flow chart of the present study is shown in Fig. 1. We screened 842 CTD patients whose primary diagnosis was not RA in our database. Anti-CCP antibody titers were measured based on the discretion of physicians or when serum or plasma was stored regardless of joint symptoms. CTD onset times were available for 64 out of 72 patients (groups 1,2, and 3 in Fig. 1), and the mean CTD duration period at anti-CCP testing was 10.1 ± 9.4 years. Sixty-two patients were diagnosed with RA-overlapping CTD before the anti-CCP test was performed. Thirty-nine out of the 62 RA-overlapping CTD patients tested positive for the anti-CCP antibody (62.9%). On the other hand, 33 out of 780 non-RA CTD patients (4.2%) tested positive for the anti-CCP antibody. The diagnoses of the 780 non-RA CTD patients and prevalence of the anti-CCP antibody in each disease are shown in Table 1. The prevalence of the anti-CCP antibody was consistent with previous findings [2, 14, 30], except for a larger number of anti-CCP-positive patients with polymyositis/dermatomyositis than in a previous study conducted in a Western country [2].
Flow chart of the classification of patients with connective tissue disease (CTD). CTD patients were classified based on the diagnosis of rheumatoid arthritis (RA), anti- cyclic citrullinated peptide (CCP) antibody positivity, and clinical characteristics. Group 1 consists of patients who fulfilled the 1987 revised American College of Rheumatology (ACR) criteria of RA before the anti-CCP antibody test was performed, group 2 consists of patients who fulfilled the 1987 ACR criteria in the follow-up period, and group 3 consists of patients never fulfilled the 1987 ACR criteria. X-rays of the hands and feet were taken for all patients in groups 1 and 2, and in 25 out of 31 patients in group 3. An asterisk denotes the accuracy of the diagnosis was reconfirmed by a questionnaire completed by each attending physician, which asked whether the patient fulfilled the 1987 revised ACR criteria for the classification of RA
Table 1 Enrolled non-RA CTD patients and the prevalence of the anti-CCP antibody
We also investigated whether the 33 patients with anti-CCP-positive CTD subsequently developed RA by asking each attending physician to confirm their fulfillment of the 1987 revised ACR criteria over time. During the mean follow-up period of 8.9 years, only 2 out of 33 patients fulfilled the 1987 revised ACR criteria (Fig. 1). X-rays of the hands and feet were taken for 27 out of the 33 anti-CCP-positive CTD patients, and only one showed bone erosions (Fig. 1).
We compared the clinical characteristics of 41 anti-CCP-positive RA-overlapping CTD patients (groups 1 and 2 in Fig. 1) and 31 anti-CCP-positive non-RA CTD patients (group 3 in Fig. 1). Prevalence of arthritis in anti-CCP-positive non-RA CTD patients is shown in Supplementary Table 1, Additional file 2. The possession of HLA-DRB1 SE was also compared between 22 non-RA CTD patients and 32 RA-overlapping CTD patients. As shown in Table 2, the incidence of arthritis, prevalence of rheumatoid factor (RF), titer of the anti-CCP antibody, and usage of disease-modifying antirheumatic drugs (DMARDs) were all significantly lower in non-RA CTD patients. The anti-CCP antibody becoming negative over time was more frequently observed in non-RA CTD patients than in RA-overlapping CTD patients, although there was no statistical difference. Bone erosion was not observed in non-RA CTD patients but was frequently detected in RA-overlapping CTD patients (70.7%). The prevalence of HLA-DRB1 SE was significantly higher in RA-overlapping CTD patients (p = 0.01). The prevalence of HLA-DRB1 SE in RA-overlapping CTD and non-RA CTD patients was similar to that in ACPA-positive RA patients and healthy subjects in a previous study, respectively [11]. The odds ratio (OR) of developing RA for SE possession was 4.3 (95% CI 1.20–17.5). We also calculated the OR of developing RA for SE possession in patients with any smoking history ("past smokers" + "current smokers", n = 9) to account for any confounding effects of smoking on RA. As a result, we found significant effect on developing RA (OR Inf (95% CI 0.7-Inf), p value 0.048). Overall, RF positivity, the possession of SE, and anti-CCP titers were higher in RA-overlapping CTD patients than in non-RA CTD patients.
Table 2 Comparison of characteristics between anti-CCP-positive non-RA CTD patients and RA-overlapping CTD patients
The positive predictive value (PPV) of anti-CCP antibody for erosive arthritis was calculated in each disease subset (n = 65, groups 1, 2, and 3 with X-ray images in Fig. 1) (Table 3). PPV was low in SLE, pSS, and polymyositis/dermatomyositis. However, a large proportion of systemic sclerosis patients with the anti-CCP antibody developed erosive arthritis.
Table 3 Positive predictive value (PPV) of the anti-CCP antibody for erosive arthritis in each disease
We also investigated the citrullination dependency of anti-CCP test results because anti-CCP antibodies may react with the non-citrullinated part of CCP peptides, which have been reported in several diseases, such as SLE [16], autoimmune hepatitis [14], and tuberculosis [15]. These antibodies react with CAP, which is the arginine version of CCP (the citrulline residues of CCP were replaced by arginine). We simultaneously assessed anti-CAP and anti-CCP in 60 serum samples (33 RA-overlapping CTD and 27 non-RA CTD) and compared their reactivities. Although all 60 samples tested positive for the anti-CCP antibody using a commercial ELISA kit, 5 out of 33 RA-overlapping CTD and 6 out of 27 non-RA CTD serum samples tested negative using our in-house CCP ELISA. Therefore, we excluded anti-CCP-negative samples and examined citrullination dependency. Twenty-seven out of 28 RA-overlapping CTD patients (96%) and 18 out of 21 (85.7%) non-RA CTD patients were citrullination-dependent (Fig. 2a). There were no significant differences between the two groups (p = 0.15). Sensitivity/specificity of citrullination dependency for predicting RA development in the population of anti-CCP positive patients with arthritis (n = 39) was 96%/18%, and PPV/negative predictive value (NPV) of that was 75%/67%. In addition, we calculated the association of citrullination dependency with erosive disease. However, we could not find any significant association of citrullination dependency with erosive disease (OR = 4.4 (95% CI 0.3–244), p value = 0.3). We also analyzed citrullination dependency by mixing all anti-CCP-positive RA-overlapping CTD and non-RA CTD serum samples together and stratifying them by HLA-DR SE possession. Citrullination dependency was more common in patients with SE, although it was not statistically significant (p = 0.11) (Fig. 2b).
Anti-cyclic citrullinated peptide (CCP) antibody and anti-cyclic arginine peptide (CAP) antibody titers. a Comparison of citrullination dependency between rheumatoid arthritis (RA)-overlapping connective tissue diseases (CTD) and non-RA CTD patients. The reactivities to CAP and CCP of sera from RA-overlapping CTD patients and non-RA CTD patients were measured by an in-house ELISA and absorbance values at 415 nm, and the absorbance values of anti-CAP antibodies were subtracted from those of anti-CCP antibodies for each patient. b A similar analysis was performed by stratifying all samples for which HLA data were available based on positivity for the HLA-DR shared epitope (SE). Horizontal dashed lines in a and b represent the cut-off level (= 0.1) of citrullination dependency
The present results revealed that anti-CCP-positive non-RA CTD patients rarely developed RA. The 1987 revised ACR criteria were used to diagnose RA; therefore, the potential effect of anti-CCP positivity on the RA or non-RA classification was excluded. Furthermore, our observation period, 8.9 years, was sufficiently long to assess the outcomes of the anti-CCP-positive population because the median period during which an anti-CCP-positive population developed RA was previously reported to be 4.5 years [4]. Ryu et al. suggested that pSS patients who test positive for the anti-CCP antibody subsequently develop RA [31]. However, the target population in the present study was pSS patients who were cross-sectionally evaluated, and RA-overlapping CTD patients were not excluded when anti-CCP antibody titers were measured. Furthermore, the 2010 ACR/EULAR criteria were used to diagnose RA [26]. Therefore, the discrepancy with the present results may be explained by differences in the target population and diagnostic criteria. One of the limitations of the present study is that information on when the anti-CCP antibody became positive was not obtained for 39 anti-CCP-positive RA-overlapping CTD patients (group 1 in Fig. 1). Since the emergence of the anti-CCP antibody may have preceded the onset of RA in these patients, anti-CCP-positive non-RA CTD patients may be more susceptible to developing RA than indicated by the present results. Despite this limitation, PPV for developing RA in non-RA CTD patients (2/33, 6.1%) was markedly lower than that in healthy individuals (82–96%) [3, 4] and similar to the incidence of RA complications in CTD patients in the present study ((group 1 and group 2)/group 0 in Fig. 1, 7.6%). Therefore, the clinical significance of the presence of the anti-CCP antibody in non-RA CTD patients remains unclear.
Limitations of our study also include the following points: (1) There is a possibility that treatment for CTD suppressed RA development in anti-CCP positive patients although there were significantly less patients who had taken DMARDs compared with RA overlapping CTD (Table 2). (2) We evaluated only anti-CCP-positive patients and did not re-evaluate the serology of anti-CCP negative CTD patients, some of whom may have newly developed anti-CCP antibody. Therefore, in this study, we cannot compare characteristics between anti-CCP positive and negative population, nor evaluate the utility of anti-CCP antibody in terms of NPV.
When we compared clinical, serological, and genetic features between non-RA CTD and RA-overlapping CTD patients, we found not only the presence of joint symptoms, bone erosion, and RF, which were all included in the 1987 revised ACR criteria [25], but also a higher anti-CCP titer and more prevalent HLA-DRB1 SE in RA-overlapping CTD patients (Table 2). Although we considered an anti-CCP titer ≥ 100 to be 100, the relationship between the anti-CCP antibody titer and the risk of developing RA is supported by patients with a high ACPA level having a high score in the 2010 ACR/EULAR classification criteria of RA [26] as well as a high anti-CCP antibody titer being more strongly associated with RA in the general population [32]. The relationship between SE and the overlap of RA in the anti-CCP-positive CTD population is consistent with previous findings showing that SE plays a crucial role in identifying which ACPA-positive patients will ultimately develop arthritis [33]. Based on these findings, a higher anti-CCP antibody titer and the presence of SE appear to be important factors in the development of RA, not only in the general population, but also in the anti-CCP-positive CTD population.
Previous studies reported that 4–10% of non-RA CTD patients tested positive for the anti-CCP antibody [1, 2], which is consistent with the present results. Due to a higher positive rate than that in the general population (1–2%) [12, 13], potential differences in autoantigens between RA-overlapping CTD patients and non-RA CTD patients may be a source of concern. In the present study, we focused on differences in the citrullination dependency of the anti-CCP antibody. Previous studies detected the anti-CCP antibody in patients with autoimmune hepatitis [34] and tuberculosis [35]; however, the epitope of this antibody was not the citrulline residue and sera reacted with the arginine version of CCP, namely, CAP [14, 15]. We speculated that the anti-CCP antibody in non-RA CTD patients was not "genuine" ACPA, but a citrullination-independent antibody. However, we found citrullination dependency was not associated with the risk of developing RA. This might be partly due to strict criterion of threshold of citrullination dependency (absorbance difference between anti-CAP and anti-CCP 0.1) for low absorbance level samples. However, absorbance difference between anti-CAP and anti-CCP was slightly larger in the RA-overlapping group (Fig. 2a). Further studies on auto-antigens of the anti-CCP antibodies in non-RA CTD patients are warranted.
The present results revealed that anti-CCP-positive non-RA CTD patients rarely developed RA. RF positivity, HLA-DRB1 SE possession, and anti-CCP antibody titers may facilitate the differentiation of anti-CCP-positive RA-overlapping CTD from anti-CCP-positive non-RA CTD.
The datasets generated and/or analyzed in the present study are available from the corresponding author upon reasonable request.
CCP:
Cyclic citrullinated peptide
CTD:
SE:
Shared epitope
ACPA:
Anti-citrullinated protein antibodies
ACR:
EULAR:
European League Against Rheumatism
ELISA:
Enzyme-linked immunosorbent assay
Cyclic arginine peptides
Disease-modifying antirheumatic drugs
PPV:
Positive predictive value
NPV:
Negative predictive value
pSS:
Primary Sjögren's syndrome
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We thank all the attending physicians who substantially contributed to the acquisition of data. We appreciate Dr. Xinghao Wang for the critical reading of the manuscript.
The present study was supported in part by JSPS KAKENHI (grant no. 26460649).
Takeshi Iwasaki and Shuichiro Nakabo contributed equally to this work.
Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, Japan
Takeshi Iwasaki, Shuichiro Nakabo, Kosaku Murakami, Ran Nakashima, Hajime Yoshifuji, Takao Fujii, Tsuneyo Mimori & Koichiro Ohmura
Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
Chikashi Terao
Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan
The Department of Applied Genetics, The School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
Department of Advanced Medicine for Rheumatic Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Motomu Hashimoto
Department of Clinical Immunology and Rheumatology, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan
Yoshitaka Imura
Yukawa Clinic, Wakayama, Japan
Naoichiro Yukawa
Department of Transfusion Medicine & Cell Therapy, Kyoto University Hospital, Kyoto, Japan
Yasuo Miura, Kimiko Yurugi & Taira Maekawa
Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
Myrthe A. M. van Delft & Leendert A. Trouw
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
Leendert A. Trouw
Department of Clinical Immunology and Rheumatology, Wakayama Medical University, Wakayama, Japan
Takao Fujii
Ijinkai Takeda General Hospital, Kyoto, Japan
Tsuneyo Mimori
Takeshi Iwasaki
Shuichiro Nakabo
Kosaku Murakami
Ran Nakashima
Hajime Yoshifuji
Yasuo Miura
Kimiko Yurugi
Taira Maekawa
Myrthe A. M. van Delft
Koichiro Ohmura
TI, SN, and KO conceived the study design. TI and SN analyzed the data. TI, SN, and KO wrote the main manuscript. TI and SN measured anti-CCP antibody titers by ELISA. MAMvd and LAT evaluated citrullination dependency by ELISA. CT, KM, RN, MH, YI, NY, HY, YM, KY, TM, TF, TMi, and KO contributed to the collection of samples and/or data. All authors approved the final manuscript.
Correspondence to Koichiro Ohmura.
The present study was performed in accordance with the Helsinki Declaration and was approved by Kyoto University Graduate School and Faculty of Medicine Ethics Committee (approval numbers: E458 and R1540).
M Hashimoto: Received a research and/or speaker fee from Bristol-Myers, Eisai, Eli Lilly, and Tanabe-Mitsubishi. He belongs to the department that is financially supported by five pharmaceutical companies (Mitsubishi-Tanabe Pharma Corp., Chugai Pharmaceutical Co., Ltd., Ayumi Pharmaceutical Corp., Asahi-Kasei Pharma Corp., and UCB Japan Co., Ltd.).
T Fujii: Received speaking fees and/or honoraria from Abbvie, Astellas, Asahi-kasei, Chugai, Eli Lilly, Eisai, Janssen, Kissei, Mitsubishi-Tanabe, Ono, Pfizer, Sanofi, Taisho Toyama, Takeda, and UCB, and has received research grants from AbbVie, Ayumi, Asahi-kasei, Astellas, Chugai, Daiichi-Sankyo, Eli Lilly, Eisai, Kissei, Mitsubishi-Tanabe, Pfizer, Nippon-Kayaku, Ono, Takeda, and UCB.
K Ohmura: Received research grants and/or speaker's fees from Abbvie, Actelion, Asahikasei Pharma, Astellas, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, GSK, Janssen, JB, Mitsubishi Tanabe, Nippon Kayaku, Nippon Shinyaku, Novartis, Sanofi, and Takeda.
Additional file 1: Supplementary Figure 1.
Description of the definition of the follow-up length. (PPTX 45 kb)
Additional file 2: Supplementary Table 1.
Prevalence of arthritis in anti-CCP-positive non-RA CTD patients. (PPTX 48 kb)
Iwasaki, T., Nakabo, S., Terao, C. et al. Long-term follow-up of patients with anti-cyclic citrullinated peptide antibody-positive connective tissue disease: a retrospective observational study including information on the HLA-DRB1 allele and citrullination dependency. Arthritis Res Ther 22, 248 (2020). https://doi.org/10.1186/s13075-020-02351-4
Anti-cyclic citrullinated peptide antibody


text:
Ex-NBCU TV chief to lead Primary Wave
Former NBCUniversal Television chairman Jeff Gaspin has signed on as president of US indie producer Primary Wave Entertainment. As part of the deal, Primary Wave has acquired Gaspin Media, which is behind series such as A&E's Fit to Fat to Fit and ABC's To Tell the Truth. Gaspin had overseen the NBCU Television Entertainment business, […]
NBCU boss: NBC trails rivals by $1bn but opportunity knocks
The president and CEO of NBCUniversal has taken the unusual step of publicly admitting his network trails its broadcast rivals in profitability terms by as much as US$1 billion a year. Speaking at the Merill Lynch 2013 Media, Communications and Entertainment Conference, Burke (left) said that though NBC's new shows were showing much promise, "the […]
CBS: Amazon, int'l sales key to Under the Dome profits
The streaming deal CBS scored with Amazon in February and international sales were key to pushing the broadcast network's summer breakout hit Under the Dome into profit, its CEO has revealed. Les Moonves described the Stephen King-penned sci-fi series as a "brand new form of entertainment" for US summer broadcasting and claimed it would "bring […]
Comcast cable channels grow as NBC toils
NBCUniversal's cable channels business grew revenues by 4.6% in the first quarter of this year, but revenues at US broadcast network NBC tumbled nearly 20%. The cable unit – which houses channels including USA Network, Bravo and Syfy – saw revenues for the three months to March 31, 2013, reach US$2.25 billion compared with US$2.12 […]
Comcast to take full control of NBC Universal
US cable and media giant Comcast is to acquire the 49% of NBC Universal that it does not already own from General Electric for US$16.7 billion. Comcast said it would take full control of NBC Universal at the time of its original acquisition deal, which was completed in 2011, but had seven years in which […]

redpajama_set_name: RedPajamaCommonCrawl


text:
Observations on the Korea Crisis and Donald Trump
by Gary Leupp
Photo by Kamil Antosiewicz Monika Powalisz | CC BY 2.0
1) The North Korean (DPRK) leadership considers the development of nuclear weapons as vital to national security.
Why? There are 70,000 U.S. troops in Japan and South Korea, and Pyongyang is in Washington's nuclear cross hairs. B-52s over South Korea provide a "nuclear umbrella" (as the Pentagon puts it). The U.S.-led war of 1950-1953 (to prevent the reunification of the country under Pyongyang's leadership) resulted in the death of around three million civilians.
Washington's hostility has been unremitting. After signing the "Agreed Framework" with Pyongyang in Geneva, in August 1994—which called for North Korea to freeze and eventually eliminate its nuclear facilities, in exchange for two light water reactors financed through the Korean Peninsula Energy Development Organization (KEDO), a multinational consortium—Washington could have halted the program. But the Bush/Cheney administration, to the horror of South Korean President Kim Dae-jung, opposed his "Sunshine Policy" of rapprochement with North Korea and helped sabotage the agreement.
2) An ICBM that can strike the Aleutians can strike Vladivostok or Beijing. Look at a map. The Russians and Chinese are as concerned about the North Korean program as much as the Americans. Moscow and Beijing have proposed that the crisis be settled by an agreement by the U.S. and South Korea to suspend annual joint military exercises and the deployment of the THAAD anti-ballistic missile system (unpopular in South Korea itself), in return for a freeze of the DPRK nuclear program.
This is a reasonable proposal, made by Chinese President Xi Jinping and Russian President Vladimir Putin, whom we might call (in relation to Donald Trump) "respected world leaders."
3) The U.S. has rejected this proposal out of hand. It values the "Foal Eagle" joint military exercises in South Korea every year, some of the largest field exercises in the world, sometimes involving over 200,000 troops. (This rejection might not enhance global perceptions of the U.S. A recent PEW poll shows that only 49% of people around the world now see the U.S. favorably, down from 64% a few years ago.)
4) The U.S. is led by an unstable, impulsive president who said in January: "North Korea just stated that it is in the final stages of developing a nuclear weapon capable of reaching parts of the US. It won't happen!"
Pyongyang is now provoking him with this message: "Trump blustered early this year that the DPRK's final access to a nuclear weapon that can reach the US mainland will never happen. But the strategic weapons tests conducted by the DPRK clearly proved that the time of its ICBM test is not a long way off at all."
5) Trump has become a figure of ridicule on cable TV, is vastly unpopular, is weak politically, under pressure to display his manhood. He recalls how wildly popular his strikes on Syria and the dropping of that mega-bomb on Afghanistan were.
(Recall how Brian Williams was so moved he quoted a Leonard Cohen song about "the beauty of our weapons"). Liberal anchors declared that Trump "became president" in such moments. All that must have been gratifying to a man so insecure he used to pose as his own publicist (as "Marc Fisher") to boast about his sexual conquests to the tabloids.
6) Talking heads call for "more sanctions," which at this point means sanctioning Chinese banks that finance trade with North Korea and their associates, and pressuring China to stop buying DPRK coal. But sanctions famously do not work. The North Korean economy has apparently improved in recent years, despite them, and tourists in the country report lots of foreign consumer goods imported through China or perhaps a few other friendly countries (such as Malaysia or Cambodia). It might be politically necessary to announce a new "round" of sanctions to assure the U.S. public that something, anyway, is being done. And leave it at that.
7) But massive military preparations are being made for an attack on North Korea as we speak. George Friedman notes that on May 20, the USS Carl Vinson supercarrier and USS Ronald Reagan were both within striking distance of North Korea. "More than 100 F-16 aircraft are conducting daily exercises in the area, a tactic that foreshadowed the beginning of Desert Storm in 1991. F-35 aircraft have also been deployed to the area, and US government representatives are expected to brief Guam on civil defense, terrorism, and Korea on May 31".
Meanwhile U.S. Ambassador to the United Nations Nikki Haley tells the U.N. Security Council that North Korea's actions were "quickly closing off the possibility of a diplomatic solution" and that, "One of our capabilities lies with our considerable military forces. We will use them if we must, but we prefer not to have to go in that direction."
8) Trump is surrounded by military leaders who presumably want to avoid World War III. He has a good relationship with President Xi, and respects Vladimir Putin. Both of them will urge restraint, for obvious reasons.
9) But Trump will likely insist on the need to do something, and ask his generals for a list of options—from apocalyptic to merely symbolic—to vent his wrath and boost his ratings. This happened before the April 7 missile strike on the Syrian air base.
10) For insight into Trump's thinking, let us keep watching his 4:00 a.m. tweets.
More articles by:Gary Leupp
Gary Leupp is Professor of History at Tufts University, and holds a secondary appointment in the Department of Religion. He is the author of Servants, Shophands and Laborers in in the Cities of Tokugawa Japan; Male Colors: The Construction of Homosexuality in Tokugawa Japan; and Interracial Intimacy in Japan: Western Men and Japanese Women, 1543-1900. He is a contributor to Hopeless: Barack Obama and the Politics of Illusion, (AK Press). He can be reached at: gleupp@tufts.edu


text:
What Are The Three Parts Of A Comet?
Evelyn Vaz answered
Astronomy defines a comet as a relatively small extraterrestrial body that consists of a frozen mass, which revolves around the sun in an elliptical orbit. It is similar to an asteroid, but the main difference lies in the fact that the comet primarily comprises of ice and dust particles along with rocky material. Comets are the leftovers from the outer cold spaces in the solar system.
cometstarmoon
A comet consists of three parts – the nucleus, the coma and the tail. The nucleus is the centre, which is hard and dark, and made out of ice, gas and rock. The gas and the dust around the nucleus form the coma. The coma is visible to us, since the sun heats the nucleus, and the coma is nothing but the gas and dust surrounding the nucleus. The power of the sun pushes the dust and gas away from the nucleus, which appears to us as the tail of the comet.
The nucleus the coma and the tail
The three parts of a comet are the nucleus, coma, and tail.
jessie peeler commented
Hey where did you find the info?
The 3 main parts of a comet are the Nucleus, Coma, and the tail.
The Nucleus is the head of the comet, the Coma is the middle & the tail is the end of the comet.
The 3 parts of a comet are the necleus, the coma, and the 2 types of tails, the Dust Tail, and the Ion Tail.
James Wheeler answered
The nucleus, the dust tail, the ion tail.
makiel allbritton answered
Tails, coma, and nucleus.
Because of the the particles that is made of gas,dust,small bits of rocks.it has also parts that is composed of all of it
Nucleus/core, halo/coma, and tails
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I'm 18 and whenever i find a guy that i like or should i say fall for. They always hurt me either emotionly or physically. Why do they do this to people that don't deserve it?
I don't like lists or pop up reminders; please don't judge me. I don't know why this is but it is ok? So my question is...is there another way I can organize to make sure everything gets done? Please&Thanks :-)
Individuals Who Regularly Exercise Too Hard, Too Often Are Likely Candidates For A. Exercise Burnout. B. Cardio Coasting. C. Heart Attack Or Stroke. D. A Career In Fitness?


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Saguenay Lac-St-Jean is one of my favourite Quebec snowmobiling destinations. It's located a two-hour drive north of Quebec City on the four-lane Highway 175. Here, the Saguenay Lac-St-Jean region delivers consistent and reliable early, in season and late snow conditions for a great Quebec snowmobile vacation. So that's where we trailered when January rain and thaw made trail conditions and snow conditions sketchy elsewhere.
Nine guys participated in this Quebec snowmobile tour, a client appreciation ride hosted by Brent Murphy Insurance. Our mission was to snowmobile three different rides, staging from the same hotel each day. Preferably without repeating trails. This way, we didn't have to pack saddlebags. We could also decide where to point our snow machines each day, depending on snow conditions. And what the group felt like doing after breakfast each morning.
For this Quebec snowmobile tour, we chose Hotel La Saguenéenne in Chicoutimi as our staging site. With direct trail access, this full service lodging is centrally located in proximity to stores, restaurants and gas stations. It also provides plenty of parking for trucks and trailers, and several secure sled garages.
Amenities include indoor pool and hot tub, an on site restaurant/bar and comfortable beds. Tip: the easiest access gas station near the hotel is the Ultramar located about two klicks away along the access trail.
Day one was overcast and snowy. We snowmobiled a 230-kilometre, hill country loop east from Hotel La Saguenéenne on the fresh powder, covering Trans Quebec 83 and back on Regional Trail 383. With many other trail options available, we could have made the ride shorter at about 180 klicks or longer at about 320.
Day two dawned sunny, bright and perfect for sight seeing. So we decided to trailer across to Monts Valin on the north side of the Saguenay Fiord and stage from the parking lot at Valinouet ski area on Trans Quebec 93. We could certainly have snowmobiled there directly from the hotel. But that would have added about 100 kilometres total to our ride and meant having less time left to explore the famous Monts Valin area.
Monts Valin is popular for its massive snowfalls, unique mix of great trails and backcountry riding opportunities. And for the Five Summits – scenic lookouts best experienced on a clear day like this one when we could see to the far horizons.
We snowmobiled from Hotel La Saguenéenne on day three, heading west on Trans Quebec 83 and Regional Trail 367. Then we crossed the Saguenay Fiord on special snowmobile lanes added to road bridges. One even had its own set of traffic lights! From there, we hopped on a primo Trans Quebec 93 westbound to Sainte-Monique. Here we rode the equally remarkable Regional Trails 367 and 328 back. This journey was 244 kilometres. But once again could easily have been shortened or lengthened by taking other trail options.
Most of our group hadn't snowmobiled in Saguenay Lac-St-Jean before. The consensus was absolutely superlative. Not only was there abundant snow, smooth trails and good access to restaurants and fuel. But there was also an impressive variety of terrain and scenery. What's more, based on my previous visits there, I know we could have snowmobiled at least two more full days without much trail repetition.
So the next time you're looking for an outstanding Quebec snowmobiling destination, you're guaranteed to come home smiling when you choose Saguenay Lac-St-Jean. No wonder it's called Saguenay snowmobile paradise!


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text:
by David Carrico
Magdeburg, April 1635
Andrea Abati moved down the hallway with a light step. This was one of Marla Linder's lesson days, and he didn't want to be late.
Working with Marla was such a joy to him. As a gentilhuomo—or castrato, as he and those like him were more vulgarly known—his life in Italy had been one of performances mixed with adulation, a certain amount of scheming in the papal court, and frequent dalliances with ladies—often married—who enjoyed both his notoriety and the fact that an unanticipated pregnancy would never complicate their lives. In his early thirties, his voice fully mature and in the prime of his singing life, he had not yet begun to teach. But then he came to Magdeburg and met Marla Linder.
Andrea's friend, Maestro Giacomo Carissimi, called Marla's voice golden. Andrea thought that the maestro was guilty of an understatement. The young woman's voice surpassed his own in range, and was fully the equal of his in timbre. What she lacked was technique. And she awoke in him the hunger to teach, the desire to take a younger musician in hand as a gardener might take a sapling, to nurture the raw talent, help to shape it and grow it, until full maturity was reached. And as that hunger grew, Andrea's life began to change.
Il Prosperino, Andrea had been called in Italy. The name literally meant "The Prosperous One," but was usually meant to say "Little Prospero." It had actually been bestowed on him because in his early days in Rome he had been somewhat of a protégé to Prospero Orsi, an artist and fellow citizen of Norcia, Andrea's home. Some wit had said, "Look, here comes Prospero and his Prosperino," and the name had stuck. He hadn't minded—in truth, he had been a bit smug about it. The name was appropriate, because he had indeed prospered in almost every way.
If musical talent was the cornerstone of Andrea's fame in Rome, flamboyance had certainly been the keystone. Flamboyant speech, flamboyant dress, and definitely flamboyant liaisons with the ladies. Yet here in Germany, exposed to the music found in Grantville, the uptime instruments and works and harmonies, bit by bit the flamboyance began to drain from him. That alone had shocked him when he realized it was happening. But to find it replaced with a desire to teach, when he had always looked down on teaching as the refuge of those who either could not perform to his high standard or those who were past their prime, that had been an even greater shock. But before long, Il Prosperino had been replaced by Master Andrea.
Andrea smoothed a hand down the front of his short-waisted black velvet jacket, and grinned to himself. Of course, he had not given up all culture and appearances, but now it was somewhat different. Now he did not seek to shock or titillate or over-awe; he demonstrated instead . . . what was the French phrase Marla had told him . . . oh yes, savoir-faire. Andrea was now a "class act."
Marla had been his first student. He had many more students now, including several girls from the Duchess Elisabeth Sofie Secondary School for Girls. He enjoyed teaching every one of them, but Marla was still his favorite. He smiled. Her passion for the music may not have exceeded his own, but it was certainly equal to it.
Music wafted down the hall; piano, then flute. Marla must be practicing the flute piece for the concert as well. Andrea opened the door just a moment after the music stopped in mid-phrase.
"It still doesn't sound right." Marla sounded determined. Andrea smiled. Determination was a frequent state of mind for Marla.
"I think it sounds fine." Hermann Katzberg spoke from where he sat at the piano.
The Steinway grand that Marla had escorted to Magdeburg in late 1633 was still the reigning queen of keyboards in the city. It had somehow become the property of the Imperial and Royal Academy of Music in Magdeburg. Andrea still wasn't sure just how Master Carissimi, the head of the academy, had managed to bring that about, but he had. In addition, no less than three of the Bledsoe & Riebeck pianos, built with hardware salvaged from old up-time pianos, had made their way from Grantville to Magdeburg in the last two years. The academy had managed to acquire one of them, which was now the principal practice piano.
"It's not right," Marla insisted again.
"What's not right?" Andrea asked.
"This passage." She pointed to the music on the piano.
Andrea studied the passage in question, then straightened.
"Play it again."
Marla raised the flute, licked her lips, and nodded to Hermann. He began the accompaniment part; she entered moments later. Andrea listened attentively, but also observed Marla's physical actions.
At the end of the phrase, she stopped, making a face as if smelling something rancid. She turned to Andrea and waited.
"You are breathing in the wrong places. You don't have enough diaphragm support."
"But that's where my flute teacher told me to breath!"
Marla sounded somewhat offended. Andrea looked at her with his best Master Andrea frown. "Marla, breathing is breathing, whether you play a flute, a pennywhistle, one of those molto grande tubas, or sing. I know breathing. And I tell you, you are breathing in the wrong places."
He pulled a pencil from his jacket pocket, leaned over the music, and made two marks. "Breath here and here, and firm your diaphragm, just as if you were singing the high notes."
Her expression skeptical, Marla raised the flute and played the phrase again, Hermann following her lead. Andrea listened with head cocked to one side, nodding. She finished with a bit of a flourish, then gave her teacher a nod.
"You were right, Master Andrea. It does sound better that way."
"Don't sound so surprised," he growled. He was unable to keep the smile from his face as her skirling laughter filled the room. "As Franz would say, play it again to prove you know it."
Again the flute notes sounded; again he observed.
"Excellent!" Andrea applauded. "Now, can we begin the songs we are supposed to be rehearsing today?"
"Yes, Master Andrea."
Maestro Giacomo Carissimi, the head master of the Imperial and Royal Academy of Music in Magdeburg, settled into his seat next to his good friend, Girolamo Zenti, proprietor and master craftsman of the instrument crafting firm of the same name.
"Good evening, Girolamo."
"Good evening, Maestro."
Giacomo wanted to shake his head. Even though they had been friends for several years now, Girolamo would always speak to him with utmost respect in public. He started to chide his friend, but in the end just sighed and held his tongue. They had had this conversation before. He doubted that anything would change if they rehearsed it one more time. He looked at the programme instead.
Franz Sylwester, the dirigent—or conductor, as the Grantvillers would have it—had established a theme of "Songs Without Words" for tonight's concert, declaring that only up-time works would be performed. There were six works on the programme: three orchestral works, two voice solo works accompanied by the orchestra, and a flute solo accompanied by piano. Giacomo ordinarily would have attended most of the rehearsals, but his schedule of late had been so burdened that he had been forced to set that pleasure aside. As a consequence, he was truly looking forward to tonight's performance.
The orchestra had quietly been warming up for some time. Matthaüs Amsel, the concert master, now strode out to the front of the orchestra. He bowed to the polite applause from the audience, then proceeded to tune the orchestra. Once they were tuned to Matthaüs' satisfaction, he took his seat.
This was the first concert of the year for the Magdeburg Symphony Orchestra, and everyone who was anyone in Magdeburg was present. Giacomo had seen Hoch-Adel by the dozens when he entered, as well as members of the government and various influential members of the community. Even the Committees of Correspondence were represented . . . or at least he thought he had seen Gunther Achterhof in the back of the room. And of course, Mary Simpson and her coterie of ladies he had heard Marla refer to as the "music mafia" were present in full force.
Franz Sylwester strode through the side door and out to the podium, where he bowed to the audience. Giacomo watched as his friend stepped onto the podium, gathered the eyes of the orchestra, and raised his baton.
The soft flute opened over the ripple of the piano chords; Vaughan Williams' Fantasia on Greensleeves was begun. The strings came in singing the melody in the lower strings with a descant in the violins. So simple, yet so beautiful.
Giacomo would always have a fond spot in his heart for Ralph (pronounced "Rafe" for some unknown English reason) Vaughan Williams. Despite the fact that the man was a professed atheist, he had written some of the most beautiful hymns and songs Giacomo had ever heard. And his orchestral writing! Remembering the performance of Fantasia on a Theme by Thomas Tallis from last year's summer concert, Giacomo shivered.
This other fantasia, he had to admit, was much lighter, although still exhibiting Vaughan Williams' deft orchestrations and lush string sounds. He knew that Franz regretted having to substitute piano for the harp part, but there just had not been time to have craftsmen experiment in building a full concert pedal harp from the descriptions and pictures found in various books in Grantville.
Ah, here was the transition of the piece, where for contrast the composer brought in another air, another folk song from England entitled "Lovely Joan." Melodically darker, moving somewhat quicker, written in what was almost a driving style, until it grounded out into the solo flute line again, and returned to a final statement of the original theme. So light, so airy, almost as if it were sung instead of played. The violins lilted the final statement of the theme, and quietly decrescendoed to fade away.
The audience was rapt for a moment, then applause broke out. It was more than simply polite, but not as fulsome as Giacomo expected to hear later this evening. Franz took a bow, then left through the door.
In the resulting moment of quiet murmuring, Giacomo quickly perused the programme. Yes, his memory had not failed him. The flute solo Marla was to perform came next. Marla and Andrea had talked of little else for days, until they were both happy with both the notes and the musicianship.
And speaking—all right, thinking—of Marla, it was as if she had been summoned. She appeared in the side door, holding her silver flute as if it were a standard, and marched to stand in the curve of the grand piano which was placed in front of the orchestra. She bowed to acknowledge the substantial applause—it was no secret that she was the darling of the patrons of Magdeburg—as Hermann Katzberg settled himself at the keyboard. Marla nodded to Hermann. With a single chord from the piano she launched herself into what sounded as if it were a tour-de-force.
According to the programme, this was the Sonata "Undine" by Carl Reinecke, a composer who was not extremely well-known in the up-time. Marla said he had written some lovely pieces, and this sonata was apparently well known among flutists.
The first movement had a passionately stated theme that passed back and forth between the flute and the piano. The piano part was so lush it was almost made the work a duet. The tone darkened momentarily, flute and piano both working as if under a cloud, then returning to the lighter tonality.
The second movement was an allegretto in a most vivacious manner. Marla played incredibly rapid passages. Just as Giacomo began to worry about her ability to breathe, there was a brief interlude where the piano played solo, but all too soon the flute returned to recapitulate the original theme of the movement.
There was a very brief pause for a spurt of applause and a buzz of whispers in reaction to the bravura performance of the second movement. The audience hushed as Marla raised her flute again.
The third movement was aptly marked andante tranquillo. Tranquility was indeed its hallmark, and even more than the first movement this was a duet between the two instruments, calling back and forth to each other, then meeting to harmonize, then fading away.
The fourth movement was the most passionate of the work. You could hear the passion in the music, but you could also see it in Marla. That tall, almost regal figure in a white Empire gown—her favorite style—was bending and swaying—now slightly, now slowly, now deeper, now faster—in time with the music. Much as one of Frau Bitty's dancers would move in the dance on stage, so Marla moved in the dance of the music in the air. Even Hermann was caught up in it, hunching forward as his hands rushed up and down the keyboard in places, in others leaning back almost languidly.
The ending was a complete surprise, as all of the storm and passion seemed to fade away to a calm, almost placid theme, with both musicians playing lightly, lyrically, to a final soft chord.
Applause began as soon as Marla lowered her flute. She stood, smiling that brilliant smile that lit every corner of the room. After a moment, she bowed two or three times in response.
Giacomo could see that his friend was breathing deeply. Despite her apparent facility with the instrument, she had worked very hard to play this piece. To his perceptive eye, it showed.
Marla waved her hand to Hermann. He stood at the piano keyboard to take his bow. She bowed one final time, and together they left.
Once again there was a brief moment between the performances. Giacomo leaned over to his friend. He had no need to glance at the programme; he knew well what the next work was.
"Wake up, Girolamo."
"You slander me, maestro, if you think I would dare to doze off now."
The side door opened again. Their mutual friend Master Andrea Abati strode forth confidently—as if he could walk any other way—followed by Franz Sylwester. As Franz assumed the podium, Andrea bowed to the applause. The corners of Giacomo's mouth bent upwards in a smile. Despite his changes in outward appearance and demeanor during the last year or so, Andrea still bowed as if he were a king acknowledging the fealty and praise of his subjects. Some things might never change.
Andrea looked to Franz. The music began.
A vocalise, Giacomo remembered from the conversation with Marla when the concert programme was developed, was a vocal exercise sung on an open syllable. But when Marla or Mary Simpson said "the vocalise," they referred to a work by one of the greater composers of the up-time twentieth century, a Russian named Rachmaninoff. It was titled simply "Vocalise" and was on the programme tonight at Mary's personal request. In fact, it was the first piece chosen, thus determining the theme.
After two chords from the accompaniment, Andrea opened his mouth and the melody began. Within six notes of the beginning he had everyone's rapt attention. Quiet, contemplative, not quite mournful, the sound of his voice lifted quietly, ebbing and flowing.
Giacomo closed his eyes, listening to one of the two finest voices in Germany—in the known world, for that matter. Andrea's voice had always had that classic castrato silkiness, a timbre that just wasn't found in a woman's voice. Tonight, however, without words to get in the way, without the baroque ornamentation that pre-Ring of Fire music required, he was free to pour all of his art, all of his passion, all of his being into realizing a powerful melody. It was as if he was a living flute, equal to that which Marla had played early, but warm with life, fountaining song forth from his heart and soul.
To Giacomo, Andrea's pride had always been forgivable. To be able to sing with that voice—ah, what a gift.
He opened his eyes again and watched as Andrea sang, his hands before him, body and hands moving slowly as if in a dance. As Marla had done before him, the passion of the music flowed through Andrea as well. It could well have been a study for the ballet, watching the minimal movements of that tall slim figure clad in black velvet that nonetheless evoked so much in partnership with his voice.
Chills chased up and down Giacomo's spine as he listened to trills that were so fast they seemed indeed to be played on a flute. He seemed to float like an eagle, soaring higher and higher, riding currents of song until a final pinnacle was reached where for a timeless moment he seemed released from the bonds of earth.
After the barest of pauses, there was a slow descent to a final syllable that faded to infinity. Franz closed his hand—the orchestra stopped. Andrea was frozen in his final position. No one moved—it seemed that no one breathed. Giacomo watched as Andrea, timing by an internal clock, finally broke his position, which instantly triggered a massive applause from the audience. Hoch-Adel were on their feet, clapping as fervently as any of the burghers and guildsmen. Some of the stolid Germans were roaring as loudly as the excitable Italian standing to his right.
Andrea gave bow after bow, grinning widely. At length he stood to one side and waved to the orchestra. Franz stepped from the podium to give a bow. In turn, he gestured to his players. As one, they stood to receive their just acclaim.
Franz stepped forward once more. Joined by Andrea, they gave one more bow, then exited through the side door.
Giacomo and Girolamo dropped back into their seats.
"God and all his angels." Giacomo mopped his brow. "I am as limp as a wet rag, my friend."
"Not me, maestro," Girolamo declared. "I quiver like a bell that has just been sounded."
"Well, it is a good thing for both of us that we have reached the Intermissio. Perhaps we can regain our composure before they begin again."
"We had better," Girolamo intoned. "Marla has yet to sing. Mind you, I don't see how she could do better than Master Andrea. But by all that is holy, if she equals him, I will be in a state of grace for weeks."
Giacomo laughed. "I somehow doubt that the Holy Father would agree that hearing heavenly music will forgive your sins and pay your penance. Not that I disagree with your opinion of the quality."
"Well, he should. I think he would if he only heard what we will hear tonight."
"Enough! You border on sacrilege." Giacomo's smile belied his words. "If you would earn merit, go find me a glass of wine, for I am as dry and dusty as the Via Appia in high summer."
"At your command, maestro. Just see to it that you mention this to Saint Peter."
The intermission concluded just after Giacomo received his wine. Ushers walked through the throng waving gold and silver fans on high, signaling everyone to be seated.
Girolamo settled at his side with a sigh, and whispered, "When do we hear Marla sing?"
"Shhh. After the Pastorale. Minutes only."
Franz returned to the podium and took his bow. The orchestra began the performance of the Pastorale from Messiah, by Georg Friederich Händel. An international programme indeed, Giacomo thought, with works by an Englishman, a Russian and two Germans having been played, and works from a Frenchman and a German of Jewish descent yet to be heard. Hmmm, no Italian. How had that slipped by him? He'd have to have words with Franz about that, he thought with a smile, before returning his attention to the music.
The Händel piece was almost soothing. It came from a time not too far in advance of their own and by now should sound familiar to the audience, as it had received two other performances in the last ten months. It opened with a very formal stately theme, almost a processional, which came to a moment of pause, then entered into a fugal section that had a joyful feel to it. The various string sections passed themes back and forth with a verve and élan that was . . . refreshing, Giacomo decided. All too soon, the Pastorale was completed. There was reasonable applause from the audience, after which Franz left the room again.
Giacomo waited, knowing what to expect but still scarcely daring to breathe. Finally, Franz reentered from the side door, his wife Marla on his arm. The applause began the moment she was seen, and crested as he handed her off to stand before the audience alone. She bowed again, smiled that illuminating smile of hers, then stood expectantly. Giacomo sat immediately, going to so far as to lay a hand on Girolamo's arm to encourage him to sit also. The remaining audience caught on. Within moments the room was almost as still as a mausoleum. Marla looked to Franz. He caught the regal nod, and began.
It was Andrea's idea, actually. After agreeing to perform the Vocalise, he had insisted that Marla should sing also. Giacomo put it down to the master teacher being protective of his stellar student. Of course, when that student was as popular as Marla, not including her might have caused a riot. Passionate music lovers had done stranger things, he had learned from the history of the future.


Meijer Cadillac Mi- Cadillac /kdlk/, formally the Cadillac Motor Car Division, is a separation of the U.S.-based General Motors (GM) that markets luxury vehicles worldwide. Its primary markets are the joined States, Canada, and China, but Cadillac-branded vehicles are distributed in 34 supplementary markets worldwide. Historically, Cadillac automobiles have always held a area at the summit of the luxury arena within the united States. In 2017, Cadillac's U.S. sales were 156,440 vehicles and its global sales were 356,467 vehicles.
Cadillac is in the course of the oldest automobile brands in the world, second in the allied States unaided to fellow GM marque Buick. The unqualified was founded from the remnants of the Henry Ford Company in 1902. It was named after Antoine de la Mothe Cadillac, who founded Detroit, Michigan. The Cadillac crest is based upon his jacket of arms.
By the mature General Motors purchased the company in 1909, Cadillac had already time-honored itself as one of America's premier luxury carmakers. The total interchangeability of its accurateness parts had allowed it to lay the start for the ahead of its time growth production of automobiles. It was at the forefront of technological advances, introducing full electrical systems, the clashless reference book transmission and the steel roof. The brand developed three engines, later than its V8 atmosphere the conventional for the American automotive industry.
Cadillac was the first American car to win the Royal Automobile Club of the allied Kingdom's Dewar Trophy by successfully demonstrating the interchangeability of its component parts during a reliability test in 1908; this spawned the firm's slogan "Standard of the World". It won the trophy once again in 1912 for incorporating electric starting and lighting in a production automobile.
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I had a lot of fun making this game. My long suffering partner even enjoyed testing it and that is a first, she hates playing games. It is buggy but then aren't they all? If you like it then send me feedback etc.
Totally untested widows version. Let me know if it workd for you.


A great combination of wines and cavas from the Penedès region with the best international jazz. ViJazz combines good drink with good music.
Enjoy the wines and cavas from the Penedès region while listening to worldwide maestros of jazz in the unbeatable setting of Vilafranca del Penedès' old town centre. Vijazz Penedès is a unique event that has made a place for itself on the yearly calendar of wine fairs. It consists of three days of wine culture combined with an international jazz festival.
The fields of the Sorres of Gavà have always grown asparagus. They cultivate a long, white, medium-sized variety with a fibrous texture. It is renowned for its slightly bitter taste, due to the characteristics of the soil of the Baix Llobregat, which is sandy and light, and due to the warm climate during the harvesting period. Try it out at the Asparagus Fair in Gavà, with more than 60 years of history!
This was born from the wish to bring back the historic Sentmenat Spring Town Festival, commonly known as the Snail Fair.
From the 18th century through to the 1980s, Sentmenat held a Spring Town Festival, popularly known as the Snail Fair. At that time, the carrying of the relics of the patron saint of Sentmenat, Sant Menna was celebrated. The council now wishes to bring back the tradition of the festival, while changing the reasons for it. Therefore, it will become known as the Snail Fair and this delicatessen will be its protagonist.
Calella hosts one of the most challenging events which only the best-prepared athletes will be able to tackle.
If you are brave enough to swim 1,900 metres, pedal 90 km and run for 21 km, you will be able to do so in a wonderful setting. You will test the water of the Mediterranean and trample the roads of the coastal mountain range, where you will be able to enjoy some unique places. You will also be able to share the race with athletes from all over the world, attracted by the prestige of this event, as well as the climate and the Mediterranean countryside.


text:
package azkaban.execapp;

import com.google.common.collect.ImmutableSet;
import java.util.Map;
import java.util.Set;
import org.junit.Assert;
import org.junit.Before;
import org.junit.Test;

public class FlowRampManagerTest {

    private FlowRampManager.RampDataModel rampDataModel;

    @Before
    public void setup() throws Exception {
        this.rampDataModel = new FlowRampManager.RampDataModel();
    }

    @Test
    public void test() {
        Assert.assertFalse(rampDataModel.hasUnsavedFinishedFlow());
        Assert.assertEquals(0, rampDataModel.getBeginFlowCount());
        Assert.assertEquals(0, rampDataModel.getEndFlowCount());

        rampDataModel.beginFlow(1, ImmutableSet.<String>builder().add("daliSpark").build());
        rampDataModel.beginFlow(2, ImmutableSet.<String>builder().add("daliSpark").build());
        rampDataModel.endFlow(1);
        rampDataModel.beginFlow(3, ImmutableSet.<String>builder().add("daliSpark").build());
        rampDataModel.beginFlow(4, ImmutableSet.<String>builder().add("daliSpark").build());
        rampDataModel.endFlow(3);
        Assert.assertTrue(rampDataModel.hasUnsavedFinishedFlow());
        Assert.assertEquals(4, rampDataModel.getBeginFlowCount());
        Assert.assertEquals(2, rampDataModel.getEndFlowCount());

        Map<Integer, Set<String>> executingFlows = rampDataModel.getExecutingFlows();
        Assert.assertEquals(2, executingFlows.size());
        Assert.assertFalse(executingFlows.containsKey(1));
        Assert.assertTrue(executingFlows.containsKey(2));
        Assert.assertFalse(executingFlows.containsKey(3));
        Assert.assertTrue(executingFlows.containsKey(4));

        rampDataModel.resetFlowCountAfterSave();
        Assert.assertFalse(rampDataModel.hasUnsavedFinishedFlow());
        Assert.assertEquals(2, rampDataModel.getBeginFlowCount());
        Assert.assertEquals(0, rampDataModel.getEndFlowCount());

        executingFlows = rampDataModel.getExecutingFlows();
        Assert.assertEquals(2, executingFlows.size());
        Assert.assertFalse(executingFlows.containsKey(1));
        Assert.assertTrue(executingFlows.containsKey(2));
        Assert.assertFalse(executingFlows.containsKey(3));
        Assert.assertTrue(executingFlows.containsKey(4));
    }
}

redpajama_set_name: RedPajamaGithub


text:
Boost� Educational Series
CraftStash
Education.com Workbooks
Ethnic Interest
Kits and Boxed Sets
Ixia Press
Occult and Esoteric Studies
My Adventures as a Spy
By: Robert Baden-Powell
Reg. Price � $5.95
Sale Price � $4.76
Written during the first years of World War I by a British military hero, this charming volume introduces the essentials of spycraft. Sir Robert Baden-Powell, founder of the Boy Scouts and storyteller extraordinaire, developed his spying skills in South Africa and conducted some of his most inspired work in the Balkans, where he worked undercover as a butterfly hunter. In brief, breezy chapters, he explains how to adopt disguises, hide messages, create diversions, escape capture, and perform other thrilling maneuvers.
"A good spy no matter which country he serves is of necessity a brave and valuable fellow," Baden-Powell declares. His attitude toward espionage as a sport, in which the players appreciate and honor each other, brings the emotional exhilaration of a well-played game to these tales of danger and adventure. This book will captivate anyone with an interest in spying and the history of espionage.
Reprint of the C. Arthur Pearson, Ltd., London, 1915 edition.
Author/Editor Robert Baden-Powell
Page Count 96
The River War: An Account of the Reconquest of the Sudan
The Story of the Malakand Field Force
Army Life in a Black Regiment
An Encyclopedia of Battles: Accounts of Over 1,560 Battles from 1479 B.C. to the Present
The Battles that Changed History
The Fifteen Decisive Battles of the World: From Marathon to Waterloo
Memoir of a Revolutionary Soldier: The Narrative of Joseph Plumb Martin
Napoleon's Military Maxims
On Guerrilla Warfare
Memoirs of a Revolutionist
Bushido: Samurai Ethics and the Soul of Japan
101 Great Samurai Prints


text:
Q: TSQL msdb.dbo.sp_send_dbmail - how to add email signature? Using MS SSMS v18.x, the code below emails a specific recipient with a custom subject & body.
How do I include the Outlook signature?
declare @body nvarchar (max) = 'Body goes here'
Execute msdb.dbo.sp_send_dbmail
@recipients = 'name@name.com',
@body=@body,
@body_format = 'HTML',
@subject='TEST Subject'

I can't find anything in the MS page nor any other Google results.

redpajama_set_name: RedPajamaStackExchange


text:
Decision made: Graham Potter and Brighton make significant loan call on international midfielder ahead of Crystal Palace, Chelsea and Leicester
Another attacking injury boost for Patrick Vieira and Crystal Palace ahead of Brighton
Brighton football star arrest: Police issue update on investigation into alleged sexual assault
The Brighton and Hove Albion player arrested on suspicion of sexual assault at a seafront night club will remain on bail for at least another month.
By Sam Morton
Wednesday, 3rd November 2021, 10:01 am
The player in his 20s and another man in his 40s — who both cannot be named for legal reasons — were arrested in the early hours of Wednesday, October 6 after a woman reported being sexually assaulted.
The incident is alleged to have taken place at a seafront nightclub in Brighton.
The pair, from Brighton, were initially released on conditional bail by Sussex Police until November 3 but this has now been extended.
Brighton and Hove Albion FC
In a statement today (Wednesday, November 3), a spokesperson for Sussex Police said: "The bail date for both individuals has been extended to Monday, December 6 while investigations continue. No further information is available at this time."
Click here to see what Brighton and Hove Albion Football Club said after the arrests were made and why the pair cannot be named.
Have you read?: Memory of ardent Brighton and Hove Albion supporter will live on through touching memorial


Facebook is an incredible advertising platform. With specific targeting, a sensible budget, and beautiful creative, the world is the limit! We're here with some handy ad specs if you're starting out (or just need a quick reference).
First off, the tried and true photo ad. Putting your message right in the middle of the user's feed is a great way to get their attention.
Video ads are doing extremely well on Facebook these days. Facebook gets over 8 billion video views per day.
Upload the highest resolution video possible within the 4gb file cap.
Recommended resolution is greater than 1080 x 1080.
Canvas ads are a full screen, elegant way to get across a message on mobile. Canvas ads do particularly well with video.
So you've got the info you need to make a great ad, so how do you prep the image? There are two incredibly easy tools that even non-designers can use to create an effective ad image. Both are web-based.
Canva: Canva has a lot of premade templates that are ready for your branding. You can alter an existing ad image template on Canva and be up and running in just minutes.
RelayThat: a bit pricey, but RelayThat is great for A/B testing ad creative. Just set your colors, fonts, and upload an image. RelayThat populates those assets into several options you can choose for your ad. It only takes a few seconds to get a great image.
Drawing from both agency and in-house experience, Jordan Digital Marketing understands the struggles on both sides fo the table. Founded in 2016, JDM is an independent agency focused on clients promoting marketplace platforms, subscription based products, and B2B services.


text:
'Alex was not a drug taker. She just wanted to try it'
Alex Ross-King was an "alcohol girl", a friend said.
by Derrick Krusche
ONE of Central Coast teenager Alex Ross-King's closest friends says she was not a drug taker and was an "alcohol girl" before her sudden death after a dance rave.
It is understood Ms Ross-King purchased drugs in Terrigal before going to the FOMO festival in Parramatta on a "party bus" she and her friends had hired.
It is believed the 19-year-old took at least two MDMA capsules or pills before entering the festival where she died on Saturday night.
A close friend of Ms Ross-King, who did not wish to be identified, said she was not into drugs.
"I was really close with her and she never took drugs," the friend said.
"I just knew she never took drugs, she was always an alcohol girl, she'd have it all under control and was happy to just drink."
Alex Ross-King took a party bus to the FOMO music festival.
The friend said it could have been the nature of the FOMO festival that caused her to change her normal practice. "I think maybe the festival, maybe she just wanted to try it," she said.
The friend said the fact Ms Ross-King was not a big drug user only made the situation sadder.
"She's gone off and done something so small and it's taken her life," she said.
Another friend said Ms Ross-King was not a big drug user but sometimes indulged when "partying".
Alex Ross-King took at least two MDMA capsules or pills before entering the festival. Picture: David Swift.
"(It was) young people partying, it's not addiction, it's just being young and having fun."
Ms Ross-King had been living in Lisarow and working at a butcher shop run by her family. She had recently finished high school and was planning to travel after she had saved money.
The friend, who went to school with Ms Ross-King, said drug use was common with those aged in their late teens to early 20s on the Central Coast.
"MDMA - a lot of caps and pills," she said. "A bit of cocaine."
She said her friend was not addicted.
Premium Content Newman's radical call to stop drug deaths
Premium Content Pills: To test or not to test?
One-word lie we keep telling about drugs
Dead teen's final moments revealed
Premium Content 'Popular' drug OD victim remembered at funeral
drug death
fomo festival
drug death editors picks fomo festival


text:
Like Ludwig van Beethoven, Johann Christian Heinrich Rinck (1770-1846) also celebrated his 250th birthday in 2020. As a composer, organ virtuoso, author of an organ school and expert in the service of Grand Duke Ludwig I of Hesse-Darmstadt, he was one of the outstanding figures in the history of church music in the 19th century. Professor Gerhard Gnann and his students play selected works by the composer on the Dreymann organ in St. Ignaz Church in Mainz, built in 1837. At the transition from late classical to romanticism, they bring out the fine nuances of the timbres of the organ, which was restored from the ground up in 2015-2018.
Label: COVIELLO CLASSICS
Works For Organ (2pk)
Artist: Rinck


text:
From the Land of Broken Dreams
February 18, 2015 § 1 Comment
I've posted here, here, here, here, and here about the unfortunate guardianship of Demon B. McClinton, who inherited more than $3 million dollars from his mother, who died in 1999. The guardianship was closed in 2006, but reopened later to investigate abuses in the case.
What the guardian ad litem discovered was that Demon's guardian and others had pilfered the account to near-extinction. The attorney, Michael J. Brown, was jailed until he could either account for the missing millions, or until he could replace them. He ultimately could do neither.
Disenchanted with the chancellor's ruling finding him in contempt, Mr. Brown appealed. You can read how the COA disposed of his appeal in In re: Guardianship of Demon B. McClinton: Michael J. Brown v. Thomas A. McClinton, decided by the COA February 3, 2015. To put it in blunt terms, his appeal was for naught.
You can read the COA's opinion by Judge Roberts for yourself. The point I am intending to drive home here is that there are serious professional, financial, legal, and even criminal repercussions awaiting lawyers who ignore or flout their duties in fiduciary matters. Read the Uniform Chancery Court Rules, Part 6, for yourself. Or, simply consider what happened to Mr. Brown. His mishandling of this guardianship is a textbook example of how not to represent a fiduciary.
Oh, and lest you are chafing at the lawyer being saddled with the blame, check out what the court did to the guardian and his friends who benefited financially at the ward's expense.
Sadly, however, as the opinion points out, there may be nothing that Mr. McClendon can recover from the malefactors. Whatever his dreams were for the comfortable estate that his mother left him will not be realized. There may be actions available against Mr. Brown's malpractice carrier and the fiduciary's bonding company. I don't know that for a fact, but even if he pursues, those avenues, it's doubtful that Mr. McClendon will ever recoup his losses.
Let's not overlook the wreckage that Mr. Brown left in his wake. There is a legal practice destroyed and a reputation annihilated. The toll on his family, I am sure, has been devastating. All because he let a guardianship get out of control.
Tagged: guiardianhips
§ One Response to From the Land of Broken Dreams
Mismanagement of a Guardianship Morphed into a Crime | The Better Chancery Practice Blog says:
[…] and embezzled more than $1.2 million of guardianship funds. It's a sordid tale that you can review at this post, which includes links to several others. Brown's conduct also attracted an indictment in Rankin County Circuit […]
« Reprise: It does not Pay to Get on the Wrong Side of the Clerks
When an Estate is Unnecessary »
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Categories: Ethics, Guardianship, Professionalism


A good-looking stiff stirs up the city: The ACROS Urban Pedal!
A good-looking stiff stirs up the city!
At the end of the day we identify as mountain and road bikers – but let's not fool ourselves: On the way to the supermarket, the ice cream shop or the playground with the kids, we usually ride our city bike – like an unglamorous stiff. And even though nowadays city bikes and e-bikes (did we just say e-bikes?!) are thought through and fully equipped, they are usually missing the perfect fitting pedal.
That's why we developed the ACROS Urban pedal with a CNC machined aluminium body. Our pedal brings cheap looking plastic pedals, on which you have grip only when you stepped into a chewing gum, to an end – once and for all. The timeless design of the ACROS Urban pedal fits perfectly to modern e-bikes as well as city bikes with either a futuristic or retro design. Who said that being a stiff couldn't be stylish?
The new pedal takes up the functionality and design language of the well-tried and tested ACROS A-FLAT-pedal series and applies it to city life. On the inside, we integrated our reliable and popular technology known from our mountain bike pedals: The combination of extra-long slide bearings and stainless steel industrial ball-bearings guarantees great durability and flexibility. Replaceable grip tape from the specialist 3M™ offers superior grip on the pedal body without straining the shoe too much. The ACROS Urban pedal is compatible with all common toe straps and conforms to the road traffic regulations (StVO) thanks to the integrated reflectors. If needed, the reflectors can be replaced by neutral pin plates that are included in the delivery.