In order to identify pathogenic correlates of refractory rheumatoid arthritis (RA), antibodies against anti-cyclic citrullinated protein (ACPAs) were investigated in RA patients in whom the dysregulated immune system had been ablated by high-dose chemotherapy (HDC) and autologous haematopoietic stem cell transplantation (HSCT). Six patients with refractory RA were extensively characterized in terms of levels of total immunoglobulins, RA-specific autoantibodies (ACPAs and rheumatoid factor) and antibodies against rubella, tetanus toxoid (TT) and phosphorylcholine before and after HDC plus HSCT. Additionally, the avidity of ACPAs was measured before and after treatment and compared with the avidity of TT antibodies following repeated immunizations. Synovial biopsies were obtained by arthroscopy before HDC plus HSCT, and analyzed by immunohistochemistry. In the three patients with clinically long-lasting responses to HDC plus HSCT (median 423 days), significant reductions in ACPA-IgG levels after therapy were observed (median level dropped from 215 to 34 arbitrary units/ml; P = 0.05). In contrast, stable ACPA-IgG levels were observed in three patients who relapsed shortly after HDC plus HSCT (median of 67 days). Clinical responders had ACPA-IgG of lower avidity (r = 0.75; P = 0.08) and higher degree of inflammation histologically (r = 0.73; P = 0.09). Relapse (after 38 to 530 days) in all patients was preceded by rising levels of low avidity ACPA-IgG (after 30 to 388 days), in contrast to the stable titres of high avidity TT antibodies. In conclusion, humoral autoimmune responses were differentially modulated by immunoablative therapy in patients with synovial inflammation and low avidity ACPA-IgG autoantibodies as compared with patients with high levels of high avidity ACPA-IgG. The distinct clinical disease course after immunoablative therapy based on levels and avidity of ACPA-IgG indicates that refractory RA is not a single disease entity.
Rheumatoid arthritis (RA) is a systemic, chronic and progressive disease that requires long-term immunosuppressive treatment, in which disease-modifying antirheumatic drugs (DMARDs) play a central role. However, several studies have shown that failure rates with conventional DMARD therapy can reach 75% over a follow-up period of 5 years [1–3]. High-dose chemotherapy (HDC) followed by autologous haematopoietic stem cell transplantation (HSCT) is employed in the treatment of patients with refractory autoimmune diseases, including systemic lupus erythematosus (SLE), systemic sclerosis and RA . However, clinical efficacy of HDC plus HSCT varies between different autoimmune diseases. A recent review of the European Group for Blood and Marrow Transplantation/European League Against Rheumatism registry for autologous HSCT in autoimmune disease  showed that sustained improvements were common in patients with systemic sclerosis and systemic lupus erythematosus, whereas in RA temporary improvements with subsequently relapsing disease was the most common clinical course. Although the therapeutic mechanism of HDC plus HSCT is conceptually similar for all autoimmune diseases, it is currently unclear why HDC plus HSCT exhibited inferior efficacy in RA.
A common finding in autoimmune diseases is activation of autoreactive B lymphocytes, resulting in the formation of disease-specific autoantibodies [6, 7]. Although the contribution of autoantibodies to the pathogenesis of autoimmune diseases is still unclear, many studies have demonstrated that the presence of autoantibodies has diagnostic significance [8–10] and is associated with worse disease outcome [11–14]. In RA the presence of IgM rheumatoid factor (RF) and anti-cyclic citrullinated protein antibody (ACPA)-IgG can be demonstrated years before the clinical onset of RA , indicating that humoral autoimmunity had been elicited before the development of overt autoimmune disease. Additionally, their presence was associated with disease progression  and the levels of ACPA-IgG predicted responsiveness to antirheumatic drugs . However, the precise mechanisms underlying the humoral autoimmune response in RA patients are still poorly defined . The majority of studies on ACPA-IgG have investigated ACPA-IgG responses at a time when overt autoimmune disease was already established. In these studies, treatment with conventional immunosuppressive drugs or biological agents did not result in the elimination of circulating autoantibodies . The latter finding has been attributed to the persistence of autoreactive, memory T and B lymphocytes, the existence of long-lived autoreactive plasma cells [20, 21], or repeated activation and differentiation of new autoreactive lymphocytes [22, 23].
The present study exploited the profound anti-inflammatory, anti-proliferative, and immunoablative effects of HDC plus HSCT [24, 25] to investigate whether humoral autoimmune responses to ACPAs can be abrogated in refractory RA and whether relapses are accompanied by newly generated autoimmune responses.
Six patients with severe RA treated with HDC plus HSCT were included in the study. From the original study cohort of 14 patients , eight patients were treated and extensively followed up at Leiden University Medical Center. The present study involves the six patients who were seropositive for RF-IgM as well as ACPA-IgG, and for whom extensive clinical data and experimental data were available. All patients had an established diagnosis of RA based on American College of Rheumatology criteria  with progressive erosive disease, including large joint involvement, and were refractory to combination therapy with DMARDs and, in four patients, with tumour necrosis factor (TNF)-blocking agents. Heparinized whole blood was collected and peripheral blood mononuclear cells were isolated by density gradient centrifugation over Ficoll-amidotrizoate (Leiden University Medical Center, Leiden, The Netherlands) and frozen in liquid nitrogen until analysis. Peripheral blood mononuclear cells were collected every 3 months after treatment. Serum was collected and stored at -20°C every month during the first year after treatment and every 3 months during the second year after treatment. The protocol was approved by the Leiden University Medical Center Ethics Committee and all patients provided written informed consent.
RA disease activity was assessed by the Disease Activity Score for 44 joints (DAS44) . To correlate the results of immunological monitoring with individual disease courses, patients' clinical follow up was split in four consecutive periods, marked by the date of HSCT and by the first symptoms of relapse after HSCT. Thus, four distinct periods were defined: before HSCT, after HSCT ('nadir'), DMARD-free period after HSCT ('DMARD-free') and after clinical relapse after transplantation ('relapse'). Relapse was independently assessed by two rheumatologists and necessitated reinstitution of conventional antirheumatic treatment.
Synovial tissue specimens were obtained during arthroscopy, which was performed before treatment on clinically affected knees, as described previously . At each procedure 16 to 20 pieces of synovial tissue were collected using 2.0 mm grasping forceps (Storz, Tuttlingen, Germany) and embedded in paraffin until analysis. Paraffin-embedded, serial sections were stained with the following antibodies: rabbit anti-huCD3 (clone-SP7; Neomarkers, Fremont, CA, USA), mouse anti-huCD79a (clone-JCD117; Dako, Glostrup, Denmark), mouse anti-huCD20cy (clone-L26; Dako), mouse anti-human Ki-67 (clone-MIB-1; Dako), mouse anti-huCD68 (clone-KP1; Dako) and mouse anti-huCD138 (clone B-B4, Serotec, Dusseldorf, Germany). Sections were de-paraffinized by xylol, ethanol and demi-water, followed by antigen retrieval via 10 minutes of incubation of sections in boiling 1 mmol/l EDTA or 10 mmol/l citrate buffer. After washing in demi-water and phosphate-buffered saline, the appropriate titrated amount of antibody was added and incubated for 60 minutes at room temperature. Thereafter, sections were incubated with Mouse Envision or Rabbit Envision conjugate (Dako) for 30 minutes. The colouring reaction was completed with DAB substrate (Dako). Counterstaining was performed with haematoxylin. Sections were covered with Micromount mounting medium (Surgipath, Peterborough, UK).
Stained sections were coded and randomly analyzed. All areas of each biopsy section were scored blindly by two independent observers. Stained sections were scored semi-quantitatively from 0 to 4 (1 = lowest and 4 = highest level of expression) . The scoring system was calibrated for each marker separately. Inflammation scores (ranging from 0 to 16) were determined by the sum of four components: thickness score for synovial lining (as scored by the number of cells constituting the synovial lining) and semiquantitative scores (ranging from 0 to 4) for polymorphonuclear cells, lymphocytes and plasma cells . Differences between observers were resolved by mutual agreement.
Serial serum samples were analyzed for levels of total immunoglobulins, RA-specific autoantibodies and physiological antibodies. Total serum IgG and IgM levels were measured by immunoturbidimetry using the COBAS-Integra 400/700/800 (Roche Diagnostics, Indianapolis, IA, USA), in accordance with the manufacturer's guidelines.
A commercial ELISA was used to measure serum antibodies against cyclic citrullinated peptides (Immunoscan RA, mark 2; Euro-Diagnostica, Arnhem, The Netherlands), in accordance with the manufacturer's instructions. Consistent with the international literature, we use the general term 'ACPA-IgG' to refer to the entire family of autoantibodies to citrullinated proteins of the IgG isotype. Serum RF-IgM was measured using a standardized ELISA . Serum levels of rubella of the IgG isotype (RL-IgG) were measured using the MEIA, Axsym® System (Abbott Diagnostics, Abbott Park, IL, USA), in accordance with the manufacturer's recommendations. RL-IgG levels were considered positive when they were equal to or above 10 IU/ml. Serum levels of anti-phosphorylcholine of the IgM isotype (PC-IgM) were measured using ELISA, as described previously . Dilutions of a serum pool, obtained from 200 healthy volunteers, were used as standard, which was arbitrarily set at 100 units/ml of PC-IgM antibodies. Results were related to this standard and expressed as arbitrary units (AU)/ml.
Patients were given repeated immunizations with tetanus toxoid (TT), which was part of the DTPol vaccine (National Institute of Public Health and Environmental Protection, Bilthoven, The Netherlands), containing diphtheria toxoid, tetanus toxoid (five flocculation units), and inactivated poliovirus types 1, 2 and 3. Patients were boosted at 3, 4 and 5 months after HDC plus HSCT when leucocyte counts had normalized. During the period of immunizations, two patients (patients 4 and 5) had restarted DMARD treatment because of a relapse of RA. Serum was collected before each immunization and approximately 1 month after the last immunization and stored at -20°C.
Avidity of ACPA-IgG and TT-IgG was measured by a modified elution ELISA, as previously described . Briefly, dilutions of serum samples were allowed to interact with cyclic citrullinated peptide or TT coated in the wells of microtitre plates. After 1 hour incubation of 100 μl of diluted serum samples per well, ELISA plates were washed. Thereafter, wells were incubated with 150 μl of a variable molarity (range 0.5 to 6.0 mol/l) of the chaotropic agent sodium thiocyanate (NaSCN; Merck, Darmstadt, Germany) for 15 minutes at room temperature. After vigorous washing, conjugate and colour reactions were performed according to the corresponding ELISA described above. The relative avidity index was defined as the molarity of NaSCN at which 50% of the amount of IgG antibodies bound to the coated antigen in the absence of NaSCN had been eluted from the antigen.
Levels of autoantibodies, antibodies and immunohistochemical scores within patients were compared with their corresponding pre-transplantation values by using the nonparametric Wilcoxon signed rank test. Correlations between synovial inflammation and ACPA-IgG level and ACPA-IgG avidity, as well as correlations between ACPA-IgG levels and C-reactive protein levels were tested using linear regression analysis. Tests were considered significant at P ≤ 0.05.
As summarized in Table 1, all patients had persistent RA with a median disease duration of 12 years (range 7 to 20 years) and were positive for RF-IgM and ACPA-IgG, with a pre-transplantation median RF-IgM level of 836 IU/ml (range 61 to 1,796 IU/ml) and ACPA-IgG level of 484 AU/ml (range 94 to 1,584 AU/ml). All patients were heterozygous for shared epitope alleles. Patients had high disease activity before transplantation, as indicated by a median DAS44 score of 5.31 (range 4.58 to 7.24). After treatment with HDC plus HSCT all patients exhibited an improvement in clinical disease activity, with a lowest median DAS44 of score 1.95 (range 0.89 to 3.80). Importantly, in two patients (patients 4 and 6) the DAS44 score did not decrease to below 2.4 (cut-off for active disease according to European League Against Rheumatism response criteria ). The improvements in DAS44 score were temporary, and patients were off DMARD therapy for a median duration of 174 days (range 60 to 738 days). At the time of relapse, when DMARDs were reinstituted, the median DAS44 score was 3.91 (range 2.62 to 5.16).
ESR, erythrocyte sedimentation rate; DAS44, Disease Activity Score of 44 joints; DMARD, disease-modifying antirheumatic drug.
Although clinical responses to HDC plus HSCT were heterogeneous, immunoablative therapy resulted consistently in complete depletion of circulating B and T lymphocytes, and in significant reductions of synovial inflammation (data previously reported ). To investigate whether clinical responses were associated with eradication of autoantibodies, we analyzed the influence of immunoablative therapy on the levels of ACPA-IgG and RF-IgM in comparison with antibody levels against control antigens, respectively RL-IgG and PC-IgM (selected because of the high prevalence of seropositivity in the Dutch population), and the total IgG and total IgM levels (Figure 1).
Effects of immunoablative therapy. Shown are the effects of immunoablative therapy on rheumatoid arthritis (RA)-specific autoantibody responses, physiological antibody responses and total immunoglobulin levels. The individual disease course of patients was split in four consecutive time periods: before immunoablative therapy ('pre-TX'), the lowest antibody level after immunoablative therapy ('nadir'), the period after immunoablative therapy without disease-modifying antirheumatic drug (DMARD) therapy ('DMARD free'), and the time of overt clinical flare of synovitis ('relapse'). Because the duration of the DMARD-free period varied for each patient (see Table 1), the presented levels are a mean of all observations during that period. Each symbol corresponds to a different patient. (a) Titers of antibodies against anti-cyclic citrullinated protein (ACPA)-IgG. The cut-off for ACPA-IgG is 25 arbitrary units (AU)/ml. In patient 1 a long-lasting undetectable level of ACPA-IgG was observed after high-dose chemotherapy plus haematopoietic stem cell transplantation. Levels below the detection limit were arbitrarily assigned a value of 4 AU/mL to optimize the graphical representation. (b) Titres of rubella of the IgG isotype (RL-IgG). (c) Titres of total circulating IgG. (d) Titres of rheumatoid factor (RF)-IgM.(e) Titres of anti-phosphorylcholine of the IgM isotype (PC-IgM). (f) Titres of total circulating IgM.
In three patients (patients 1 to 3) pre-transplantation levels of ACPA-IgG (median 215 AU/ml, range 94 to 401 AU/ml) were nearly completely eradicated after HDC plus HSCT (nadir median 34 AU/ml, range <20 to 77 AU/ml; P = 0.05). In one of these patients (patient 2) ACPA-IgG remained undetectable for the duration of follow up (757 days; Figure 1a). These decreases contrasted with the stable levels of the RL-IgG control antibody in all patients (median pre-transplantation level 114 IU/ml [range 16 to 1,430 IU/ml] versus median nadir level 63 IU/ml [range 10 to 494 IU/ml], P = 0.63; Figure 1b). Immunoablative therapy also resulted in significant reductions in both RF-IgM levels (median pre-transplantation level 1,125 IU/ml [range 500 to 1,796 IU/ml] versus median nadir level 344 IU/ml [range 19 to 1,210 IU/ml, P = 0.043; Figure 1d) and PC-IgM levels (median pre-transplantation level 109 AU/ml [range 19 to 340 AU/ml] and median nadir level 41 AU/ml [range 19 to 132 AU/ml, P = 0.043; Figure 1e) in the entire cohort. Importantly, serum levels of total IgM and IgG were also affected by HDC plus HSCT, notably IgM (Figure 1c,f). In individual patients, the relative reduction in RF-IgM paralleled the relative reduction in total IgM (median correlation coefficient 0.78, range 0.34 0.95), whereas the relative reduction in ACPA-IgG was only weakly correlated with the relative reductions in total IgG levels (median correlation coefficient 0.33, range 0.08 to 0.81; P = 0.07), which is indicative of nonselective depletion of RF-IgM.
In the patients exhibiting a significant drop in ACPA-IgG (patients 1 to 3) we observed a more pronounced decrease in DAS44 scores (0.89 to 1.95 versus 1.82 to 3.80; P = 0.27) and more DMARD-free days (163 to 738 days versus 60 to 184 days, P = 0.12) after HDC plus HSCT as compared with the three patients with stable ACPA-IgG levels (patients 4 to 6; Table 1). Therefore, we explored the possibility that persisting synovial inflammation, as a putative source of ACPA-IgG production, was associated with high and stable ACPA-IgG levels.
Cross-sectional analysis of pre-transplantation synovial tissue specimens revealed a heterogeneous degree of inflammation involving various cell types (Figure 2a). Unexpectedly, a high degree of synovial inflammation was correlated with relatively low ACPA-IgG levels (r = 0.73, P = 0.09) and relatively low avidity of ACPA-IgG (r = 0.75, P = 0.08; Figure 2b). These findings were corroborated by the observation that, throughout the complete study period, ACPA-IgG levels were strongly correlated with serum C-reactive protein levels in the three patients (patients 1 to 3) whose ACPA-IgG levels were nearly completely eradicated after immunoablative therapy ('ACPA responders': r = 0.56, P < 0.001; Figure 2c). The latter was not the case for the three patients (patients 4 to 6) whose ACPA-IgG remained relatively stable after immunoablative therapy ('ACPA nonresponders': r = 0.027, P = 0.86; Figure 2d). Taken together, these data indicated that inflammation in synovium corresponded with ACPA-IgG autoantibodies of low avidity, reflecting an 'immature' autoimmune response. Moreover, ACPA-IgG levels in serum were not exclusively derived from plasma cells in inflamed synovium, because patients with low synovial inflammation had high circulating levels of ACPA-IgG with relatively high avidity.
Associations between synovial inflammation and circulating ACPA-IgG autoantibodies. (a) Semiquantitative scores of individual patients before immunoablative therapy, scoring synovial infiltration for CD68 expression (macrophages), CD138 expression (plasma cells), CD20 expression, CD79a expression (B cells), CD3 expression (T-cells), Ki-67 expression (proliferation marker) and total inflammation. (b) Correlation of synovial inflammation scores with serum levels of antibodies against anti-cyclic citrullinated protein (ACPA)-IgG (open symbols) and avidity of ACPA-IgG (closed symbols) before immunoablative treatment. Each symbol corresponds to a distinct patient. (c) Correlation of serum levels of ACPA-IgG with C-reactive protein (CRP) levels (r = 0.56, P < 0.001) during complete follow up in the three patients whose ACPA-IgG levels are susceptible to immunoablative therapy ('ACPA responders'). (d) Correlation of serum levels of ACPA-IgG with CRP levels (r = 0.027, P = 0.86) during complete follow up in the three patients whose ACPA-IgG levels remained stable after immunoablative therapy ('ACPA nonresponders'). AU, arbitrary units; NaSCN, sodium thiocyanate.
Clinical relapses, which occurred between 38 and 530 days after HDC plus HSCT, were preceded by a rise in ACPA-IgG (30 to 217 days) and RF-IgM levels (30 to 388 days), respectively (P = 0.028 and P = 0.043). To study the reactivation of humoral autoimmunity after immunoablative therapy, we analyzed the avidity of reappearing ACPA-IgG autoantibodies by dichotomizing patients according to their pre-transplantation ACPA-IgG level and corresponding reduction after immunoablative therapy ('ACPA responders' and 'ACPA nonresponders'; Figure 3a,b).
Regeneration after immunoablative therapy of ACPA-IgG autoantibodies with low avidity. (a) Low avidity of antibodies against anti-cyclic citrullinated protein (ACPA)-IgG (solid lines) before and after immunoablative therapy when autoimmunity is reactivated with rising levels of ACPA-IgG (dotted lines) in the three 'ACPA responders'. Levels below the detection limit were arbitrarily assigned a value of 4 arbitrary units (AU)/ml to optimize the graphical representation. Thick lines represent mean values. (b) Avidity of ACPA-IgG (solid lines) before and after immunoablative therapy in the three 'ACPA nonresponders', in whom, despite relatively stable ACPA-IgG levels (dotted lines), reactivation of autoimmunity was accompanied by the avidity maturation of ACPA-IgG autoantibodies. Thick lines represent mean values. (c) Avidity of tetanus toxoid (TT)-IgG (solid lines) before and after immunoablative therapy in four patients. Increasing levels of TT-IgG (dotted lines) after repeated TT immunizations (see Materials and methods) were accompanied by stably high avidity of TT-IgG, indicative of an intact humoral recall response despite immunoablative therapy. Thick lines represent mean values. DMARD, disease-modifying antirheumatic drug; NaSCN, sodium thiocyanate.
In the ACPA responders the decline in ACPA-IgG levels after treatment and the rise preceding clinical relapse were associated with only minor changes in the avidity of ACPA-IgG autoantibodies, which remained relatively low. However, in the ACPA nonresponders the avidity of ACPA-IgG exhibited a clear reduction (pre-transplantation median 1.04 M [range 0.69 to 2.91 M] versus median nadir after HDC plus HSCT 0.69 M [range 0.14 to 1.11 M]), reflecting low avidity ACPA-IgG autoantibodies after immunoablative therapy. Overall, the avidity of ACPA-IgG autoantibodies detectable after HDC plus HSCT in both ACPA responders and nonresponders consistently exhibited a decrease after HDC plus HSCT (median 0.27 M, range 0.14 to 1.11 M) as compared with the avidity before transplantation (median 0.69, range 0.39 to 2.91 M). Thereafter, despite relatively stable levels of ACPA-IgG toward the time of relapse of RA, avidity maturation was observed in the ACPA nonresponders, with a median of 1.12 M (range 1.12 to 3.60 M).
Collectively, these data indicate that clinically overt flares of synovitis after HDC plus HSCT were preceded by the re-emergence of low avidity ACPA-IgG autoantibodies, which is indicative of a newly generated autoimmune response. Additionally, during progression toward disease relapse after HDC plus HSCT, avidity of ACPA-IgG autoantibodies returned to pre-transplantation values.
In general, humoral immunity to recall antigens depends on activation of long-lasting memory B cells and plasma cells producing high avidity antibodies. This contrasted with our findings of ACPA-IgG autoantibodies, raising the question of whether immunoablative therapy resulted in the eradication of humoral memory. Therefore, we analyzed the effects of immunoablative therapy on memory responses before and after repeated immunizations with the recall antigen TT.
As expected, the avidity of TT-IgG antibodies before transplantation was high (median 3.10 M, range 2.70 to 3.30 M). In four out of six patients, serum levels of TT-IgG increased following repeated immunizations after HDC plus HSCT, but the avidity remained high (median after first boost 3.0 M, range 2.70 to 3.30 M; after second boost 3.05 M, range 2.80 to 3.30 M; after third boost 3.0 M, range 2.60 to 3.30 M; Figure 3c). These data indicate that matured immune responses against a recall antigen remained intact despite immunoablative therapy, indicating a clear discrepancy between the humoral immunity against recall antigens and citrullinated autoantigens.
The aim of the present study was to investigate whether humoral autoimmune responses in six refractory RA patients, whose dysregulated immune system was ablated by HDC plus HSCT, underpinned their clinical responses. We showed that reductions in ACPA-IgG levels were associated with clinically prolonged responses to immunoablative therapy. The susceptibility of ACPA-IgG to immunoablative therapy was associated with a high degree of synovial inflammation before treatment and presence of ACPA-IgG autoantibodies of low avidity. Importantly, overt clinical relapse in all six patients was preceded by the reactivation of ACPA-IgG autoimmunity, which consisted of low avidity antibodies indicative of a newly generated ACPA-IgG response in these patients. The latter occurred despite the observation that humoral immunity against recall antigens (rubella and TT) remained unaffected by immunoablative therapy.
Previous studies have reported that avidity of autoantibodies, namely RF, anti-cardiolipin and anti-double stranded DNA autoantibodies, can also vary between patients [36, 37]. The present study is the first to show that circulating ACPA-IgG autoantibodies in RA patients differ in avidity. These differences were not reflected in DAS44 scores, number or distribution of swollen and tender joints, or concentrations of inflammatory markers (Table 1). We did observe a striking correlation at baseline between the level of ACPA-IgG and their avidity, although this correlation between level and avidity was not observed after immunoablative therapy, indicating that this finding was probably serendipidous. More importantly, we demonstrated that in one group of patients (patients 1 to 3; ACPA responders) the presence of low avidity ACPA-IgG autoantibodies was associated with a high degree of synovial inflammation, suggesting that production of low avidity ACPA-IgG was derived from plasma cells in inflamed synovium. This was further supported by the finding that ACPA-IgG levels correlated well with C-reactive protein levels in these patients and were effectively reduced by immunoablative therapy. In contrast, clinical nonresponders had high serum levels of ACPA-IgG with relatively high avidity and a low degree of synovial inflammation, suggesting that ACPA-IgG in these patients (patients 4 to 6) was mainly produced by plasma cells from bone marrow or other secondary lymphoid organs. Together, these data suggest that ACPA-IgG levels in serum reflect production at different sites (for example, inflamed synovium or bone marrow). Further studies are needed to investigate whether ACPA-IgG autoantibodies of high avidity are indeed produced by bone marrow derived plasma cells or whether other mechanisms are responsible for the differences in avidity of ACPA autoantibodies, for instance consumption of high avidity ACPA-IgG autoantibodies at sites of synovial inflammation.
By exploiting the antiproliferative and immunoablative properties of HDC plus HSCT, the present study was able to identify two different phenotypes of refractory RA patients on the basis of the level and avidity of circulating ACPA-IgG autoantibodies. As a consequence, high serum levels of ACPA-IgG with high avidity in RA patients can account for the seemingly paradoxical reports that high serum levels of ACPA-IgG predicted unresponsiveness to TNF-blocking therapy  and, at the same time, that decreases in ACPA-IgG levels are associated with response to TNF-blocking therapy [16, 38]. It is tempting to speculate that the presence of high avidity ACPA-IgG autoantibodies is characteristic of a category of RA patients who are refractory or less responsive to immunosuppressive treatment. In view of this hypothesis, it is noteworthy that one patient, with low avidity ACPA-IgG autoantibodies before transplantation, exhibited a long-lasting absence of detectable ACPA-IgG levels after HDC plus HSCT. One previous study  reported eradication of serum ACPA-IgG in eight patients with early RA receiving conventional antirheumatic treatment. To our knowledge, however, the present study is the first to show eradication of ACPA-IgG autoantibodies in refractory, persistent RA (disease duration 7 years) that simultaneously resulted in complete remission (lowest DAS44 score 0.89), with discontinuation of antirheumatic treatment for more than 1.5 years.
Another important observation was the discrepancy between the humoral immune responses against recall antigens and citrullinated autoantigens. The present study convincingly demonstrated that the ability to mount a recall response against TT remained intact after immunoablative therapy. The latter was not the case for the response to citrullinated antigens, as indicated by the nearly complete eradication of ACPA-IgG autoantibodies in the ACPA responder group after HDC plus HSCT, and by the decrease in ACPA-IgG avidity in the ACPA nonresponder group, despite relatively stable levels of serum ACPA-IgG. The latter strongly suggested that in the ACPA nonresponder group, during the short DMARD-free period after transplantation, a relapse of RA-related synovial inflammation was heralded by a newly generated ACPA immune response. However, our data could not discriminate between ablation by HDC plus HSCT of autoreactive memory in the ACPA nonresponder group and nonexistence of autoreactive memory B cells.
This study demonstrated an association in individual RA patients between clinical response and susceptibility of ACPA-IgG autoantibodies to immunoablative therapy. Response to HDC plus HSCT was associated with the presence of low avidity ACPA-IgG autoantibodies and histological features of active synovitis. Additionally, clinical relapse after HDC plus HSCT was preceded by the emergence of low avidity ACPA-IgG autoantibodies, indicative of a newly generated autoimmune response during synovial inflammation. These data give novel insight into the humoral autoimmune response in RA.
We thank Dr JK Sont of the Department of Medical Decision Making for his advice on the statistical analyses.
Financial support for this study was obtained from the Dutch Arthritis Association (NR 99-1-301). The work of YKO Teng was supported by an Agiko grant from The Netherlands Organization for Scientific Research.
YKOT contributed to the acquisition of data, analysis and interpretation of data, and preparation of the manuscript. RJV contributed to the design of the study and acquisition of the data. KNV contributed to the acquisition of data. GWND contributed to the acquisition of data. IMB contributed to the acquisition and analysis of data. MJDvT contributed to the interpretation of data. CMJ-vZ contributed to the acquisition, analysis and interpretation of the data. REMT contributed to the interpretation of the data. TWJH contributed to interpretation of data. JMvL contributed to the design of the study, acquisition, analysis and interpretation of the data, and preparation of the manuscript.


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Improved Silicon-Substrate LEDs Address High Solid-State Lighting Costs
Posted date: April 17, 2017 In: Electronics News Updates | Tags: led high solid state
The dominant technology for today's high-brightness LEDs is gallium nitride (GaN) on sapphire or silicon carbide (SiC) substrates. These materials are popular because the resultant LEDs are bright, efficient, and last a long time. However, the chips are tough to manufacture and package into useable devices, multiplying the cost of end products that use them as light engines. Although prices have plummeted in recent years, LED lighting is still considerably more expensive to purchase than traditional alternatives. This initial expense is cited as a major factor slowing the acceptance of solid-state lighting (SSL).
A pioneering group of manufacturers has worked hard to reduce the cost of high-power LEDs by replacing the sapphire or SiC substrate with silicon (Si), the material routinely used to manufacture most electronic chips ("ICs"). The key benefit is a very-low-cost supply of wafers and the opportunity to use depreciated 8-inch wafer fabs for LED manufacture. Combined, those concepts enable a dramatic reduction in LED prices, overcoming consumer objections.
Initially, technical challenges limited the performance of GaN-on-Si LEDs, making them unattractive for mainstream lighting. Now, some manufacturers, notably Toshiba, have introduced a new generation of these LEDs with vastly improved performance at a very competitive price, making them a viable alternative to conventional devices in many applications.
This article reviews the development of silicon-substrate LEDs and describes the latest generation of commercial devices.
Pushing down the cost of LEDs
Though it's taken many years and millions of dollars of R&D funding, modern LEDs are a cost-effective alternative to traditional light sources such as incandescent bulbs, fluorescent tubes, and halogen lamps for mainstream lighting when factors such as initial purchase price, energy consumption, and lifetime are taken into consideration to determine "cost of ownership."
A recent report1 by analysts McKinsey & Company concluded that by 2016 (depending on how quickly the price of LEDs continues to fall) the payback on an LED fixture (due to lower running costs and longer life) will offset the initial higher purchase price compared to a compact fluorescent lamp (CFL) between 1.7 and 3.9 years. The corresponding calculation in 2011 yielded a figure of around 14 years. Payback time of LED bulb vs. CFL bulb in the residential segment (dark line represents base case, lighter line represents faster LED price erosion). (Courtesy of McKinsey & Company)
Unfortunately, the same report concluded that, despite the market share of LEDs in lighting applications climbing to around 45 percent in 2015, "the price premium on LED lighting products still remains high, and the initial purchase price represents a significant barrier to decision makers when considering an initial investment in general lighting applications."
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This reticence is perhaps not surprising when considering that an LED lamp replacement such as Philips' 100 W (incandescent) equivalent PAR38 LED bulb retails at $22 compared with $12 for the same company's 100 W equivalent T2 Twister CFL and $6 for a 100 W equivalent EcoSmart halogen bulb.
A key element of the cost of LED bulbs is the LED chips themselves. Each LED bulb typically comprises an array of six, eight, or ten LED chips, each of which is manufactured from exotic materials in a complex wafer-fabrication process and then expensively packaged in a three- or four-step assembly operation. Replacing both the material and manufacturing costs with cheaper alternatives would dramatically reduce the initial purchase price of LEDs, encouraging more rapid adoption.
The silicon alternative
The electronics revolution has been built on silicon; a stable, cheap, plentiful semiconductor that's easy to grow into crystals, slice into wafers, and subject to CMOS processes to turn each wafer into thousands of ICs. In addition, a huge investment has been made in fabs to mass-produce such chips, driving down the cost per unit to mere cents.
Recently, chip manufacturers have moved to a more efficient wafer-fabrication process that uses 12-inch (300 mm) wafers as raw material, replacing the older 8-inch (200 mm) slices. As a result, there is an excess of 8-inch capacity around the world which some suggest could be turned to LED manufacturing, dramatically cutting the price of the end products.
The majority of contemporary LEDs are constructed from a combination of GaN, which features a band gap suitable for emitting photons in the visible part of the spectrum, on a sapphire substrate. GaN thin films are grown by a process known as epitaxy, which builds up the LED's active regions by depositing successive layers on the substrate. One drawback is a mismatch between the crystal lattice spacing (the unit distance between individual atoms in the crystal structure) of GaN and the sapphire substrate which results in microscopic flaws in the active region. These flaws, also known as threading dislocations, compromise both LED luminosity and lifetime.
READ Thermal Conductivity: What is it and Why You Should Care
SiC has a crystal structure that is much more closely matched to GaN than sapphire, reducing the defect density, and improving efficacy and longevity by at least one and sometimes two orders of magnitude. (See the TechZone article "Material and Manufacturing Improvements Enhance LED Efficiency.")
Sapphire and SiC are not only expensive to produce but are also difficult to reliably manufacture on wafers larger than 4 inches (100 mm) in diameter. Besides being much cheaper and easier to work with, 8-inch silicon wafers take only slightly longer to process than wafers measuring 4 inches. The end result is that factories can quadruple production (the surface area of an 8-inch wafer is four times that of a 4-inch one (Figure 2), while at the same time slashing material and processing costs.
However, switching to silicon as a substrate for LEDs presents formidable technical challenges. Chief among these is the fact that silicon's crystal structure is an even worse mismatch with GaN than sapphire. To make matters worse, silicon has a very different coefficient of thermal expansion to GaN. These two factors lead to severe tensile stresses being incorporated into the wafers during fabrication that result in microcracking as the wafer cools. Cracked LEDs function poorly, if at all. Worse yet, silicon is a very good absorber of the photons that should escape and contribute to the luminosity of the LED. As a result, light extraction from early GaN-on-Si LEDs was a quarter to a third of that from comparable devices built on sapphire (see the TechZone article "Will Silicon Substrates Push LED Lighting Into the Mainstream?")
A few pioneering companies have persevered with their development programs, and while GaN-on-Si LEDs still lag the luminosity, efficacy, and long life of GaN-on-sapphire or on-SiC LEDs, the devices on today's lab benches don't suffer from the poor performance of earlier devices and can be made at a fraction of the cost of conventional LEDs.
Second-generation silicon
As conventional LEDs have steadily improved (at the same time reducing the number of LEDs required to match the output of single incandescent or fluorescent bulbs) a new market opened up for "mid-range" LEDs. Mid-range chips cannot match the performance of today's high-end devices, but instead offer reasonable performance (for example, providing luminosity and longevity equivalent to the top spec chip of two or three years ago) at a budget price (see the TechZone article "Mid-Power LEDs Offer Less Expensive Alternative for Lighting Applications").
READ 2048 on Arduino
The growth of the mid-range market has opened up an opportunity for GaN-on-Si chips. The performance of today's silicon-substrate LEDs can easily match that of mid-range GaN-on-sapphire or on-SiC while undercutting the latter's price.
Toshiba (which originally worked in a joint venture with Bridgelux but later bought out its partner's share in the venture) is one of the commercial frontrunners in the supply of GaN-on-Si LEDs.
Toshiba is understandably coy about how it has solved the technical difficulties of lattice- and thermal- mismatch between GaN and Si and has made few public pronouncements, but before being bought out, Bridgelux did reveal that the "tensile strain problem was solved using a proprietary buffer layer (between the GaN and the silicon)."
Further information about Toshiba's research is available in scientific papers. One example2 published in February 2006 describes how Toshiba researchers suppressed the crack generation that typically plagues GaN epitaxy on silicon by employing "cubic SiC" as intermediate layers. Cubic SiC has a lattice constant about half way between GaN and silicon, helping to relieve the stresses that would otherwise build up and cause cracking between abutted layers of GaN and silicon.
The researchers reported that a 1 µm layer of SiC on top of a conventional 8-inch silicon wafer was sufficient to suppress cracking in the active GaN layer. While slightly more expensive than depositing GaN onto "naked" silicon, the process is still much less expensive than fabricating sapphire or SiC wafers because it is still founded on the inexpensive silicon manufacturing processes.
Toshiba also claims its GaN-on-Si process lends itself to the production of large "volume-emitting" single-LED chips directly from the wafer without the need to go through the traditional LED assembly process (Figure 3). The advantages of this technique are greater cost savings and single LEDs which could compete with increasingly popular Chip-on-Board (CoB) arrays – products that comprise multiple conventional LEDs pre-assembled into a single unit (see the TechZone article "The Rise of Chip-on-Board LED Modules").
For more detail: Improved Silicon-Substrate LEDs Address High Solid-State Lighting Costs
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redpajama_set_name: RedPajamaCommonCrawl


text:
BEST PRACTICES FOR DEVELOPING EFFECTIVE TRAINING DEVICES FOR PULMONARY HEALTHCARE
Citation: Reynolds J, "Best Practices and Considerations in Developing Effective Training Devices for the Pulmonary Healthcare Market ". ONdrugDelivery Magazine, Issue 96 (Apr 2019), pp 28-30.
Joe Reynolds discusses the current state of pulmonary drug delivery device trainers, including their value to patients, the complexities of modern design and the stringent requirements on ensuring their quality.
Over the years, many industry stakeholders and pharmaceutical manufacturers have come to realise the importance of patient training and the role it has on promoting healthy outcomes and effective disease management. Many studies suggest that without proper training during the onboarding process (the first 30 to 90 days of treatment) patients are more likely to drop off from their prescribed therapy or incorrectly use drug delivery devices, including metered dose inhalers (MDIs), dry powder inhalers (DPIs), nebulisers and other forms of self-administration.
Designed primarily for at-home use, pulmonary drug delivery is an effective route of administration for localised and systemic uptake of pharmaceutical products. As a result, pulmonary administration is often a viable alternative to more invasive routes, with future growth potential across new therapeutic areas. These products are frequently marketed as combination therapies, consisting of API and a drug delivery device. When properly used by patients, these devices are effective in delivering a prescribed dose to the lungs. However, user errors can result in injuries, partial delivery and suboptimal therapeutic outcomes for patients.
"93% of patients prescribed an MDI failed to use their devices properly, with more than half missing three or more of the required use steps"
According to a study conducted by the University of Texas Medical Branch at Galveston (UTMB),1 93% of patients prescribed an MDI failed to use their devices properly, with more than half missing three or more of the required use steps (Table 1). The most common mistakes were failure to prime, exhaling and co-ordinating actuation with the necessary timing, force and duration of inhalation.
Step Description Risk of Error
1 Prepare device Low
2 Remove mouthpiece Low
3 Inspect the mouth piece for obstructions High
4 Prepare dose Medium
5 Exhale, away from the device High
6 Place device in mouth Medium
7 Actuate dose High
8 Inhale with the appropriate force, duration & sequence High
9 Hold breath (as specified in IFU) Medium
10 Repeat dose as prescribed Medium
11 Clean and store device as prescribed Medium
Table 1: Required use steps for MDIs and risk of error.
As an addition to standard instructions for use (IFU) and package inserts, healthcare providers are often expected to onboard patients and provide access to training and education. While these training strategies can be very effective, research suggests that there is often a great deal of variability and inconsistency in the effectiveness of such training and in patients' ability to retain the information and apply it to the successful use of their delivery system.
"82% of users said they would feel most confident with a training device that detects errors. Additionally, 76% of users prefer some form of error detection to aid in overcoming anxiety about administering treatment."
Further research has shown that many patients are looking for increased access to education and support for self-administration. A study conducted by Noble surveyed patients and examined the impact that device training solutions had on patients using an MDI. The study examined five different training solutions, ranging from standard IFU to smart error correcting training, in an effort to better understand how training technology can reduce device errors. 82% of users said they would feel most confident with a training device that detects errors. Additionally, 76% of users said they would prefer some form of error detection to aid in overcoming anxiety about administering treatment. For example, one device that was tested included IFU and would whistle if used incorrectly.
To address the common gaps in patient onboarding, training devices are often used to create consistent experiences for patients through the use of novel technologies and mechanisms that fully simulate the mechanical aspects of the drug delivery experience. While these devices appear to be fairly simple at first glance, numerous design and engineering challenges must be addressed in order to successfully develop authentic training devices and other onboarding solutions.
INTERNAL DESIGN AND TECHNOLOGY OF TRAINING DEVICES
Engineering training devices for manufacturability and repeatability is a delicate balance. Fully understanding device development and mechanical design is one of the first steps in engineering robust training device solutions. The exterior of the device should emulate the real drug delivery device as closely as possible, so that patients become familiar with key features and physical characteristics, such as the look, feel and weight of their commercial delivery devices. The interior design of training devices also need to be meticulously engineered in order to provide a proper training experience. To accomplish this, human factors must be taken into consideration throughout the design process to ensure that training devices align with the physical, cognitive and emotional needs of users.
In addition to understanding user needs, Noble has analysed a variety of on-market delivery systems to understand their handling requirements and critical functions.
Though in some cases mechanisms similar to commercial devices are used, groundup mechanical design is usually employed to integrate all necessary functions into a resettable and reusable training device. This means that the training device will look the same as the real thing on the outside, however, it will be vastly different internally.
Once human and environmental factors have been taken into consideration, design inputs can be documented and prioritised to mitigate user errors and maximise the value to pulmonary drug delivery device training. When looking at the case for pulmonary smart training devices, they are designed to monitor patient behaviours and provide corrective feedback during the early stages of the learning process. While there are many variables that influence the deposition of pulmonary therapeutics, including timing, force, volume and muscle memory, trainers should be developed to support patients in establishing motor and muscle skills, along with the appropriate level of force required to use their inhaler effectively.
How the patient interfaces with the delivery device plays an important role in drug deposition and achieving full absorption. When designing a device it's important to understand the sequence of steps patients go through and the risk of error associated with each (Table 1).
EXTERNAL DESIGN OF THE TRAINING DEVICE
As mentioned previously, external details are also crucial to the design and engineering process. Characteristics of the inhaler, such as the overall shape, mouthpiece, dose indicators and size and shape of the canister, are all accurately matched to the real device so that patients are able to familiarise themselves with its look and feel. However, this is a complex task, due to the fact that the interior of a training device contains additional mechanisms which allow the device to be used multiple times.
"One of the most seemingly simple design requirements is to make the device look like the real product externally, which presents its own set of challenges."
One of the most seemingly simple design requirements is to make the device look like the real product externally, which presents its own set of challenges. For example, if the trainer looks exactly like the real device one may mistakenly use a trainer in an emergency or vice-versa. This is typically addressed with optimised packaging, labelling and graphical training instructions. Trainers usually have large labels which read "Trainer, This Device Contains No Drug". In every other regard, the trainer appears exactly the same, in terms of size, shape, textures and Pantone-matched colour schemes (or complimentary colours to denote that it is a trainer).
Other considerations that must be prioritised include ancillary training features like augmented auditory and/or video-based training instructions. Many of the trainers currently in development include some form of collateral training, such as talking packaging, sensor-based error-correction, smart device application or a combination of these features.
Quality design standards are paramount when designing training devices, in order to ensure that every patient has a consistent and accurate training experience. Noble conducts rigorous device testing, taking into consideration each brand's specified requirements. One of the keys to success is utilising optimised standard operating procedures (SOPs) and standard inspection procedures (SIPs) in the assembly process at the factory. Many manual and semi-automated tests and inspections are integrated throughout the process to verify that targets will be met on the final assembly stage, reducing scrap rate and ensuring a high quality product.
"Critical functions, such as activation forces and the auditory feedback of calibrated whistles, are tested at several points during design, development and manufacturing."
Critical functions, such as activation forces and the auditory feedback of calibrated whistles, are tested at several points during design, development and manufacturing. During pilot runs, many other tests are also performed to evaluate that the device functions as intended and conforms to specifications and other design inputs. Some of these include environmental, accelerated ageing/life, shipping, drop-testing and materials compliance. Though not a formally regulated device category, Noble treats the design and manufacturing of trainers much like a regulated product to ensure the highest final quality product.
As training technology becomes more prevalent in the pharmaceutical industry, the engineering and capabilities of these devices will continue to advance, creating a more complex and intricate engineering process. These advancements are necessary, as they will allow patients to become more confident in their treatments, overcome treatment barriers and ultimately lead healthier lives.
In order for training devices to work efficiently, it is necessary that devices are tested with stringent standards. Patients need to familiarise themselves with the device in order to learn and anticipate the steps necessary for proper drug administration. This requires training devices to replicate the ergonomics, interaction and injection time of the actual device accurately.
In today's market, a growing number of patients are being prescribed self-administered treatments. Pharmaceutical companies that prioritise the patient experience, using training technology to help these patients properly onboard to therapy will continue to benefit through competitive advantages and the value they create within the industry.
Bonds RS, Asawa A, Ghazi AI, "Misuse of medical devices: a persistent problem in self-management of asthma and allergic disease". Ann Allergy, Asthma Immunol, 2015, Vol 114(1), pp 74–76.
AUTOMATING UNDER UNCERTAINTY – GOOD PRACTICES
A RE-USABLE CONNECTED AUTOINJECTOR CUSTOMISED FOR THE COMPANION® SAFETY SYRINGE SYSTEM
Joe Reynolds
Senior Manager, Strategy & Patient Insights
Noble, an Aptar Pharma company, supplies onboarding and training devices, such as mechanical and smart, error correcting autoinjectors, prefilled syringes, on-body injectors, inhalers, angle aid tools, auditory packaging and other multisensory solutions, to pharma and biotech clients.
You may also like reading...
GUILLAUME BROUET, APTAR PHARMA
Guillaume Brouet talks with ONdrugDelivery Magazine about how Aptar Pharma uses its device development expertise and infrastructure to provide its pharmaceutical company customers a comprehensive services offering around device development, global regulatory approval and commercialisation.
CONNECTED DEVICES – MEDICATION DELIVERY JUST GOT PERSONAL
Thierry Decock and Hadrien Gremillet explore how the obstacles to the adoption of connectivity can be overcome and how connected devices can deliver truly patient-centric care that will clearly improve adherence rates, whilst demonstrating a clear cost benefit to the pharmaceutical partner.
DRY POWDER INHALERS: TOWARDS EFFECTIVE, AFFORDABLE, SUSTAINABLE RESPIRATORY HEALTHCARE
João Ventura Fernandes and Peter Villax look at the trends shaping the development of dry powder inhalers, highlighting the need for a shift in industrial strategy towards effective, globally affordable, sustainable devices.


text:
Peuet Sague is a volcanic complex in the northwestern part of Sumatra, Indonesia. The name peuet sagoe in Acehnese means four square. The location of the volcanic complex is isolated that needs several journeys on foot from the nearest village to reach the mountain. There are four summits in the complex that all of them are located in the Sigli Regency, Aceh Province. One of the lava dome is called Mount Tutung and it has 70 metres (230 feet) diameter and 80 meters (262.5 feet) deep of an active crater.

Eruptive History
The first recorded eruption took place between 1918–1921. Due to its remoteness, the volcanic complex is infrequently visited. Little is known about its eruption history prior the 20th century.

In the morning of 26 April 1998, an ash eruption was spotted by a pilot of the Garuda Indonesia airline. The pilot saw the ash around 3 km (9,840 feet) altitude when he flew over 7 km (23,000 feet) altitude. The local Indonesia Air Force chief confirmed the eruption from a fighter pilot who also spotted fire and thick smoke from the nearby forest. This was actually the second eruption from the first one on 19 April 1998, but the first eruption was obscured by a thick smoke from forest fires. Officials from the Ministry of Mines and Energy reported a phreatic eruption. The active crater was near Mount Tutung,  west of the Peuet Sague's peak. Nobody was injured from this eruption because the nearest village is  west of the mountain.

Between 9 March 1999 until 24 May 1999, volcanic activity in the Peuet Sague complex increased. Local people heard explosion noises about 20 times per day. Tectonic events increased and an eruption emitted white-gray ash up until 200 metres (656 feet) height. A white plume was observed between 10–20 metres (30–65 feet) height. All activities were then diminished.

The 1999 activity was later discovered to be continued until late of December 2000, although at a decreased level. The activity monitoring at that time was stopped due to a malfunctioning seismograph. Plumes continued to rise in June up to heights of 20 metres. Rumbling was heard on 18 occasions, and plumes continued to rise through 14 June 1999. A renewed activity began on 25 December 2000 with three explosions. Ash was spread over a relatively large area. Reports of ashfall occurred on Geumpang, Lutung, Mane and Bangke villages, up to  away. A glowing lava flows at night was also reported. The 2000 eruption was estimated at scale 2 on Volcanic Explosivity Index.

See also

 List of volcanoes in Indonesia

References

Volcanoes of Sumatra
Mountains of Sumatra
Complex volcanoes
Landforms of Aceh

redpajama_set_name: RedPajamaWikipedia


T-Pain has been a huge influence on music since he came on the scene in 2005 with his debut album, Rappa Ternt Sanga. Though he's arguably always either started or contributed to most of the trends that become huge throughout hip-hop and other genres, it's sad to say that the reality is: Tallahassee Pain is often under-appreciated for his role throughout the scape of music.
With that being said, it's easy for someone like Pain to become discouraged, contributing so much to the world and not getting enough accolades thrown back at him. But it looks like he really isn't concerned with anything other people think about him, including whether or not fans think he's washed in 2018.
Whether or not you respect the fact that T-Pain is a LEGEND, one think people have to realize is that in the present, Pain is always tweeting out gold. The auto-tune gawd posted a video of his dancing on his driveway completely care-free, with his caption indicating the video as a response to people who comment on his current career.
This carefree joy is a total mood. Put some respect on T-Pain's name.


London is a big city so packed with history and culture that a week in town won't even make you scratch the surface. We found travel planning challenging, especially picking which one should we prioritize and not. Obviously, the major landmarks are on the list – Big Ben, London Eye, Tower Bridge and Houses of Parliament. I have only been to London twice and while I still don't find myself an authority to tell you where you should go, I came up with a little guide you might find helpful when building your itinerary. This is especially good for London first timers. Perhaps take one from each category and voila, itinerary (sort of) done!
TIP: Most of the places listed here are included when you get a London Pass!
The United Kingdom is home to one of the most successful monarchies in the world. Being the capital, it's not surprising that London has a couple of royal residences. While the Buckingham Palace where Her Majesty lives is not open for everyone year-round (except from July – October), most of the royal palaces are!
Hampton Court – Henry VIII's Tudor palace lets everyone in to his interesting life as a king. This is my favorite from all the palaces we visited, mainly because of its fabulous gardens. I loved every corner of the palace grounds, especially the chunky yew trees at the Great Fountain Garden. The Tudor palace among its interesting features like the Chocolate Kitchens and wine fountain at the Base Court, brings everyone to the life of Henry VIII and his (famous) marriages. Free entry with London Pass.
Tower of London – Once a royal residence and a prison, this castle steeped in history is a UNESCO World Heritage Site. Yeomen Warders wander within its walls – walls surrounding the Crown Jewels and home to ravens and ghosts of noble men who were executed back in the day (including Anne Boleyn). Free entry with London Pass.
The fact that most museums in London are free makes them an absolute must-do when in the city. There's almost a museum for everything in this city – from artifacts to paintings, fan to artillery, horse guards to gardens.
Victoria and Albert Museum– Ahh, my favorite museum in London! V&A is the biggest museum of arts and design in the world, so expect a lot of beautiful objects on display! Among my favorites are the Cast Courts, the jewelry section and theatre & performance collections. It has a mean gift shop as well!
British Museum – Elgin marbles, anyone? The Rosetta Stone? The British Museum has a rich collection of items from around the world. The most interesting gallery to me is that of the Middle East's which houses a number of impressive Mesopotamian artifacts, big and small. There's also a moai statue from Easter Island!
Apart from skyscrapers and age-old buildings, London has abundant open spaces, too. The vast parks and gardens are the lungs of the city, offering everyone a quick respite from the bustling city life. Everyone is invited to jog, walk their dog, go for a picnic or simply stroll and admire the secret pockets.
Kensington Gardens and Hyde Park – Located in Kensington and Westminster, these two parks are situated next to each other. Check out The Serpentine/The Long Water, the beautiful Diana, Princess of Wales memorial and the Italian Gardens.
Royal Botanic Gardens, Kew – Although this requires a £14 ticket (when purchased online, £15 onsite, free with London Pass), Kew Gardens is well worth a visit. It is a UNESCO World Heritage Site and houses variety of flora. See the Palm House, Pagoda and the Princess of Wales Conservatory.
To better understand the way of life of a city, a visit to the market/s is a must! London has a plethora of markets for everyone. Whether you're an antique collector, a fashionista or a foodie, there's one for you! We love every market in London we visited – one could not go wrong which one you pick to check out.
Borough Market – It's a heaven for foodies! Stall upon stall of gourmet ingredients, fresh produce, organic products and awesome cooking.
Camden Markets – Camden Town has about 6 markets making it one lively, colorful and quirky shopping community. If you're keen to see everything, half a day isn't enough!
With lots of iconic buildings/structures, a view of the London skyline is always a lovely visual treat. You can choose between climbing the 311 steps of the Monument, hopping on the London Eye, riding the Emirates Air Line cable car, going to the top of Tower Bridge or paying a hefty amount to get to The Shard.
Sky Garden – Well, my pockets like the sound of the word F-R-E-E so I booked a visit to Sky Garden in 20 Fernchurch! With a ticket in one hand and an ID (passport, driving license or bank card – I showed my credit card after forgetting my passport in the hotel!) on the other, show up on your schedule and enjoy the mesmerizing 360-view of the city.
There's no other perfect way to cap a long day of exploring than seeing a world-class performance in West End! Take your pick with the number of plays and musicals available. Score cheap theatre tickets (at almost half the price!) in TKTS at Leicester Square!
Les Miserables – The longest running musical in West End. I don't know where in the world you're from if you haven't heard of Les Mis! It retains the original revolving stage, so see it while they haven't change the sets to the new ones.
The Phantom of the Opera – The second longest running and my ultimate, super, absolute favorite (lol) musical in the world! The classic love story (kind of) of an opera singer and the phantom (of course) with lots of thrilling and exciting special effects!
While I agree that exploring by foot is one of the best ways to see the city, I'd say you're missing a lot if you dare not try London's extensive public transportation.
London Underground – The complex Tube map might be daunting to look at first but you'll be surprised at how easy your travel will be. Figuring your way to your destination by changing tube lines is a wonderful experience itself.
Red Double-Decker Bus – The iconic bus is a cheaper alternative to roam around the city. Sitting on the upper deck affords amazing street views!
The capital is home to many churches with outstanding architectural beauty. Most of these were built in 1700s as a number of churches have been devastated by the Great Fire of London in 1666.
St. Paul's Cathedral – This is one of London's well-known landmarks. For a time, it was the tallest structure to ever grace the city's skyline. There is an entrance fee of £16 (when bought online, £18 on site), otherwise attend a service to get in for free.
Westminster Abbey – The Gothic cathedral witnessed generations upon generations of royal coronations, weddings and burials. The magnificent interiors are very photogenic but unfortunately, no cameras are allowed inside. It's also a UNESCO World Heritage Site. Free entry with London Pass.
London is a favorite setting for movies whatever genre may it be. If you're a cinephilia or a geek/fan of a particular film, it's a nice experience to be in the place where your favorite scenes where shot.
Harry Potter – Who doesn't know The Boy Who Lived? There are a lot of spots in London where the franchise was filmed – Millennium Bridge, Leadenhall Market, King's Cross, just to name a few. If you're a super fan, check out the Warner Bros studio and see the awesome sets!
Notting Hill – "I'm just a girl standing in front of a boy asking him to love her." Julia Roberts' Anna Scott in the movie, Notting Hill, made this line famous. The iconic blue door and the Travel Book Company, the bookshop in Portobello Road (though not a bookshop IRL) still stand in the same spot today!
Pubs – Pubs or public houses serve traditional local cuisine such as the infamous fish and chips, pies, bangers and mash and… booze!


text:
Rotational Seismology Workshop of February 2006
Open-File Report 2007-1145
By: John R. Evans, A. Cochard, Vladimir Graizer, Bor-Shouh Huang, Kenneth W. Hudnut, Charles R. Hutt, H. Igel, William H.K. Lee, Chun-Chi Liu, Eugeniusz Majewski, Robert Nigbor, Erdal Safak, William U. Savage, U. Schreiber, Roman Teisseyre, Mihailo Trifunac, J. Wassermann, and Chien-Fu Wu
https://doi.org/10.3133/ofr20071145
More information: USGS Index Page (html)
Introduction A successful workshop titled 'Measuring the Rotation Effects of Strong Ground Motion' was held simultaneously in Menlo Park and Pasadena via video conference on 16 February 2006. The purpose of the Workshop and this Report are to summarize existing data and theory and to explore future challenges for rotational seismology, including free-field strong motion, structural strong motion, and teleseismic motions. We also forged a consensus on the plan of work to be pursued by this international group in the near term. At this first workshop were 16 participants in Menlo Park, 13 in Pasadena, and a few on the telephone. It was organized by William H. K. Lee and John R. Evans and chaired by William U. Savage in Menlo Park and by Kenneth W. Hudnut in Pasadena. Its agenda is given in the Appendix. This workshop and efforts in Europe led to the creation of the International Working Group on Rotational Seismology (IWGoRS), an international volunteer group providing forums for exchange of ideas and data as well as hosting a series of Workshops and Special Sessions. IWGoRS created a Web site, backed by an FTP site, for distribution of materials related to rotational seismology. At present, the FTP site contains the 2006 Workshop agenda (also given in the Appendix below) and its PowerPoint presentations, as well as many papers (reasonable-only basis with permission of their authors), a comprehensive citations list, and related information. Eventually, the Web site will become the sole authoritative source for IWGoRS and shared information: http://www.rotational-seismology.org ftp://ehzftp.wr.usgs.gov/jrevans/IWGoRS_FTPsite/ With contributions from various authors during and after the 2006 Workshop, this Report proceeds from the theoretical bases for making rotational measurements (Graizer, Safak, Trifunac) through the available observations (Huang, Lee, Liu, Nigbor), proposed suites of measurements (Hudnut), a discussion of broadband teleseismic rotational seismology (Cochard, Igel, Schreiber, Teisseyre, Wassermann, Majewski), sensor-calibration issues (Evans, Hutt), and finally the summary and conclusions (Savage). As a direct result of the 2006 Workshop and the formation of IWGoRS, we held a special session at the Fall 2006 AGU meeting (convened by H. Igel, W.H.K. Lee, and M.I. Todorovska). Currently, the first formal Workshop of the IWGoRS is being organized by W.H.K. Lee, M. Celebi, and M. I. Todorovska with sponsorship by the USGS and assistance from many others; this First International Workshop on Rotational Seismology and Engineering Applications will be held in September 2007 at Menlo Park, California (http://pubs.usgs.gov/of/2007/1144/). The following summarizes presentations and discussions during and shortly after the informal Workshop of February 2006.
USGS Numbered Series
Open-File Report
10.3133/ofr20071145
Geological Survey (U.S.)
Earthquake Hazards Team
Online Only (Y/N)


text:
import os
import sys

import django
from django.conf import settings

DIRNAME = os.path.abspath(os.path.dirname(__file__))

sys.path.insert(0, os.getcwd())

settings.configure(
    DEBUG=True,
    DATABASES={
        'default': {
            'ENGINE': 'django.db.backends.sqlite3',
            'NAME': ':memory:',
        }
    },
    INSTALLED_APPS=(
        'lightpdf',
    ),
    MIDDLEWARE_CLASSES=(
        'django.middleware.common.CommonMiddleware',
        'django.middleware.csrf.CsrfViewMiddleware',
    ),
    MEDIA_ROOT=os.path.join(DIRNAME, 'media'),
    MEDIA_URL='/media/',
    STATIC_ROOT=os.path.join(DIRNAME, 'static'),
    STATIC_URL='/static/',
)

try:
    django.setup()
except AttributeError:
    pass  # Django < 1.7; okay to ignore

from django.test.runner import DiscoverRunner

test_runner = DiscoverRunner(verbosity=2)
failures = test_runner.run_tests(['lightpdf'])
if failures:
    sys.exit(1)

redpajama_set_name: RedPajamaGithub


text:
Woody Allen's MAGIC IN THE MOONLIGHT Unfortunately Doesn't Cast a Spell on Its Audience
I've never really liked the saying, "You're only as good as your last film." The fact that it disqualifies past great performances and films to solely determine all talent from one movie is, well, unfair. And, might I add, super lame. But it sprang to mine after I watched Woody Allen's latest, MAGIC IN THE MOONLIGHT. The prolific filmmaker follows up last year's fantastic Blue Jasmine with a lackluster movie that's unfortunately not as enchanting as it sounds.
After taking us on a whimsical trip through the City of Light three years ago in Midnight in Paris, Allen brings us back to France on a more pertinent mission--to determine whether the sixth sense is actually real and, if not, dismantle the notion once and for all. Well, we watch Colin Firth do it anyway. The actor plays Stanley, a renowned 1920s English magician who is brought to France by an old friend and colleague, Howard (Simon McBurney), to disprove a popular psychic (Emma Stone). Why? Because Houdini-like Stanley is ironically not a believer in actual magic or telekinesis, and if anyone could prove Sophie (Stone) to be a hack, it's him.
Already not a very interesting premise right from its start. But, like many Allen films, it's not so much the premise that draws you to the film but how engaging its character is written--down to each quirk. That's what's missing here in this film: there's just nothing very special about any of these characters. In fact, there's nothing throughout most the film to keep you invested it. It's pedestrian to the point of being bland (and I hate that I've become one of those writers that use the word "pedestrian," but it's the best way to describe it). Almost as if he realizes that the film has to be more than about a magician trying to out-trick a trickster, Allen folds MAGIC IN THE MOONLIGHT into a predictable, cringe-worthy romance that develops between Stanley and Sophie. What makes it uncomfortable to watch is the fact that Firth and Stone have zero chemistry together, especially for a romance. Their age differences (28 years, to be exact) aside, Firth and Stone are two very different styles of actors, neither of whom are particularly suitable for the roles they're playing here. (Casting directors continue to place Stone in roles that fall way outside her range, only utilizing her "It" girl appeal and not her actual strengths; Firth is just such a deliberate actor that to play a character that's so frivolous is an odd fit for him).
What may most attract moviegoers is MAGIC IN THE MOONLIGHT's portrait, albeit a sloppy one, of a man so consumed by his own desire to be clever that it is love that plays the ultimate trick on him: making him see that not everything comes down to what does and doesn't make sense to him. But does he believe in magic? Is Allen suggesting that love is magic? Perhaps, but this is not a particularly refreshing story for fans of Allen's work or even film fans at all. Frankly, it goes stale after the first twenty minutes, after you've realized exactly where it's going and how it will get there. Which makes it a chore to watch. It's far too amateur, especially from someone like Allen who's been making films for almost fifty years.
MAGIC IN THE MOONLIGHT just seems more like notes on a scribble pad, not an actual film. Despite its decent cast (Marcia Gay Harden is in it for a moment, playing Sophie's stern mother, along with Jacki Weaver and Eileen Atkins, who's the film's true delight), charming score and cinematography, it just left me really hollow, scratching my head. Allen is better than this.
Rating: D+ (* out of *****)
MAGIC IN THE MOONLIGHT is in select theaters July 25th. Watch the trailer:
Labels: Colin Firth, emma stone, Magic in the Moonlight, Marcia Gay Harden, Reviews, woody allen
I had a feeling after seeing the trailer that this was going to be the case. It's sad, but Allen has this track record of one hit, one miss. So, his next film should be great.


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969.035(6)(a) (a) The state has the burden of going forward and proving by clear and convincing evidence that the defendant committed an offense specified under sub. (2) (a), or that the defendant committed or attempted to commit a violent crime subsequent to a prior conviction for a violent crime.
969.035(6)(b) (b) The state has the burden of going forward and proving by clear and convincing evidence that available conditions of release will not adequately protect members of the community from serious bodily harm or prevent the intimidation of witnesses.
969.035(6)(c) (c) The evidence shall be presented in open court with the right of confrontation, right to call witnesses, right to cross-examination and right to representation by counsel. The rules of evidence applicable in criminal trials govern the admissibility of evidence at the hearing.
969.035(6)(d) (d) The court may exclude witnesses until they are called to testify, may direct that persons who are expected to be called as witnesses be kept separate until called and may prevent them from communicating with one another until they have been examined.
969.035(6)(e) (e) Testimony of the defendant given shall not be admissible on the issue of guilt in any other judicial proceeding, but the testimony shall be admissible in perjury proceedings and for impeachment purposes in any subsequent proceeding.
969.035(7) (7) If the court does not make the findings under sub. (6) (a) and (b) and the defendant is otherwise eligible, the defendant shall be released from custody with or without conditions in accordance with s. 969.03.
969.035(8) (8) If the court makes the findings under sub. (6) (a) and (b), the court may deny bail to the defendant for an additional period not to exceed 60 days following the hearing. If the time period passes and the defendant is otherwise eligible, he or she shall be released from custody with or without conditions in accordance with s. 969.03.
969.035(9) (9) In computing the 10-day periods under sub. (5) and the 60-day period under sub. (8), the court shall omit any period of time found by the court to result from a delay caused by the defendant or a continuance granted which was initiated by the defendant. Delay is caused by the defendant only if the delay is expressly requested by the defendant.
969.035(10) (10) The defendant may petition the court to be released from custody with or without conditions in accordance with s. 969.03 at any time.
969.035(11) (11) A person who has been detained under this section is entitled to placement of his or her case on an expedited trial calendar and his or her trial shall be given priority.
969.035 History History: 1981 c. 183; 1987 a. 90; 1987 a. 332 ss. 58, 64; 1987 a. 399, 403; 1993 a. 227, 441, 491; 1997 a. 295; 2005 a. 277.
969.04 969.04 Surety may satisfy default. Any surety may, after default, pay to the clerk of the court the amount for which the surety was bound, or such lesser sum as the court, after notice and hearing, may direct, and thereupon be discharged.
969.05 969.05 Endorsement of bail upon warrants.
969.05(1)(1) In misdemeanor actions, the judge who issues a warrant may endorse upon the warrant the amount of bail.
969.05(2) (2) The amount and method of posting bail may be endorsed upon felony warrants.
969.05 History History: 1981 c. 183.
969.065 969.065 Judicial conference; bail alternatives. The judicial conference shall develop guidelines for cash bail for persons accused of misdemeanors which the supreme court shall adopt by rule. The guidelines shall relate primarily to individuals. The guidelines may be revised from time to time under this section.
969.065 History History: 1981 c. 183.
969.065 Annotation The constitutionality of this section is upheld. Demmith v. Wisconsin Judicial Conference, 166 Wis. 2d 649, 480 N.W.2d 502 (1992).
969.07 969.07 Taking of bail by law enforcement officer. When bail has been set for a particular defendant, any law enforcement officer may take bail in accordance with s. 969.02 and release the defendant to appear in accordance with the conditions of the appearance bond. Bail shall not be required of a defendant who has been cited for commission of a misdemeanor in accordance with s. 968.085. The law enforcement officer shall give a receipt to the defendant for the bail so taken and within a reasonable time deposit the bail with the clerk of court before whom the defendant is to appear. Bail taken by a law enforcement officer may be taken only at a sheriff's office or police station. The receipts shall be numbered serially and shall be in triplicate, one copy for the defendant, one copy to be filed with the clerk and one copy to be filed with the police or sheriff's department which takes the bail. This section does not require the release of a defendant from custody when an officer is of the opinion that the defendant is not in a fit condition to care for his or her own safety or would constitute, because of his or her physical condition, a danger to the safety of others. If a defendant is not released under this section, s. 970.01 shall apply.
969.07 History History: 1981 c. 183; 1983 a. 433.
969.07 AnnotationOfficers may validly deny bail to a misdemeanant under this section. 75 Atty. Gen. 209.
969.07 Annotation Law enforcement officers may be authorized by court rule to accept surety bonds for, or, under specified circumstances, 10 percent cash deposits of, the amount listed in a misdemeanor bail schedule when an accused cannot be promptly taken before a judge for bail determination. However, such rules may not afford officers discretion as to the amount or form of bail an accused individual must post. 63 Atty. Gen. 241.
969.07 Annotation Neither a county nor a county sheriff possesses statutory authority to use county funds to establish a revolving bail fund for the purpose of making loans to persons allowing them to post bail for certain kinds of offenses for which they are booked into the county jail. OAG 1-09.
969.08 969.08 Grant, reduction, increase or revocation of conditions of release.
969.08(1)(1) Upon petition by the state or the defendant, the court before which the action is pending may increase or reduce the amount of bail or may alter other conditions of release or the bail bond or grant bail if it has been previously revoked. Except as provided in sub. (5), a defendant for whom conditions of release are imposed and who after 72 hours from the time of initial appearance before a judge continues to be detained in custody as a result of the defendant's inability to meet the conditions of release, upon application, is entitled to have the conditions reviewed by the judge of the court before whom the action against the defendant is pending. Unless the conditions of release are amended and the defendant is thereupon released, the judge shall set forth on the record the reasons for requiring the continuation of the conditions imposed. A defendant who is ordered released on a condition which requires that he or she return to custody after specified hours, upon application, is entitled to a review by the judge of the court before whom the action is pending. Unless the requirement is removed and the defendant thereupon released on another condition, the judge shall set forth on the record the reasons for continuing the requirement.
969.08(2) (2) Violation of the conditions of release or the bail bond constitutes grounds for the court to increase the amount of bail or otherwise alter the conditions of release or, if the alleged violation is the commission of a serious crime, revoke release under this section.
969.08(3) (3) Reasonable notice of petition under sub. (1) by the defendant shall be given to the state.
969.08(4) (4) Reasonable notice of petition under sub. (1) by the state shall be given to the defendant, except as provided in sub. (5).
969.08(5)(a)(a) A court shall proceed under par. (b) if the district attorney alleges to the court and provides the court with documents as follows:
969.08(5)(a)1. 1. Alleges that the defendant is released on conditions for the alleged commission of a serious crime;
969.08(5)(a)2. 2. Alleges that the defendant has violated the conditions of release by having committed a serious crime; and
969.08(5)(a)3. 3. Provides a copy of the complaint charging the commission of the serious crime specified in subd. 2.
969.08(5)(b) (b)
969.08(5)(b)1.1. If the court determines that the state has complied with par. (a), the court may issue a warrant commanding any law enforcement officer to bring the defendant without unnecessary delay before the court. When the defendant is brought before the court, he or she shall be given a copy of the documents specified in par. (a) and informed of his or her rights under s. 970.02 (1) and (6). The court may hold the defendant in custody and suspend the previously imposed conditions of release pending a hearing on the alleged breach. The hearing under this paragraph and the preliminary examination under s. 970.03, if required, shall be a combined hearing, with the court making the separate findings required under this paragraph and s. 970.03 at the conclusion of the combined hearing. The hearing shall be commenced within 7 days from the date the defendant is taken into custody. The defendant may not be held without setting conditions of release for more than 7 days unless a hearing is held and the findings required by this paragraph are established.
969.08(5)(b)2. 2. At a hearing on the alleged violation the state has the burden of going forward and proving by clear and convincing evidence that the violation occurred while the defendant was on conditional release. The evidence shall be presented in open court with the right of confrontation, right to call witnesses, right of cross-examination and right to representation by counsel. The rules of evidence applicable in criminal trials govern the admissibility of evidence at the hearing.
969.08(5)(b)3. 3. Upon a finding by the court that the state has established by clear and convincing evidence that the defendant has committed a serious crime while on conditional release, the court may revoke the release of the defendant and hold the defendant for trial without setting conditions of release. No reference may be made during the trial of the offense to the court's finding in the hearing. No reference may be made in the trial to any testimony of the defendant at the hearing, except if the testimony is used for impeachment purposes. If the court does not find that the state has established by clear and convincing evidence that the defendant has committed a serious crime while on conditional release, the defendant shall be released on bail or other conditions deemed appropriate by the court.
969.08(5)(b)4. 4. If the release of any defendant is revoked under subd. 3., the defendant may demand and shall be entitled to be brought to trial on the offense with respect to which he or she was formerly released on conditions within 60 days after the date on which he or she appeared before the court under subd. 1. If the defendant is not brought to trial within the 60-day period he or she shall not be held longer without setting conditions of release and shall be released on bail or other conditions deemed appropriate by the court. In computing the 60-day period, the court shall omit any period of delay if the court finds that the delay results from a continuance granted at the exclusive request of the defendant.
969.08(5)(b)5. 5. The defendant may petition the court for reinstatement of conditions of release if any of the circumstances authorizing the revocation of release is altered. The altered conditions include, but are not limited to, the facts that the original complaint is dismissed, the defendant is found not guilty of that offense or the defendant is found guilty of a crime which is not a serious crime.
969.08(6) (6) If the judge before whom the action is pending, in which a person was released on conditions, is not available, any other circuit judge of the county may act under this section.
969.08(7) (7) If a person is charged with the commission of a serious crime in a county other than the county in which the person was released on conditions, the district attorney and court may proceed under sub. (6) and certify the findings to the circuit court for the county in which the person was released on conditions. That circuit court shall make the release revocation decision based on the certified findings.
969.08(8) (8) Information stated in, or offered in connection with, any order entered under this chapter setting bail or other conditions of release need not conform to the rules of evidence, except as provided under sub. (5) (b) 2. or s. 901.05.
969.08(9) (9) This section does not limit any other authority of a court to revoke the release of a defendant.
969.08(9m) (9m) A person who has had bail revoked under this section is entitled to placement of his or her case on an expedited trial calendar and his or her trial shall be given priority.
969.08(10) (10) In this section:
969.08(10)(a) (a) "Commission of a serious crime" includes a solicitation, conspiracy or attempt, under s. 948.35, 1999 stats., or s. 939.30, 939.31, or 939.32, to commit a serious crime.
969.08(10)(b) (b) "Serious crime" means any crime specified in s. 943.23 (1m), 1999 stats., or s. 943.23 (1r), 1999 stats., or s. 346.62 (4), 940.01, 940.02, 940.03, 940.05, 940.06, 940.08, 940.09, 940.10, 940.19 (5), 940.195 (5), 940.20, 940.201, 940.203, 940.21, 940.225 (1) to (3), 940.23, 940.24, 940.25, 940.29, 940.295 (3) (b) 1g., 1m., 1r., 2. or 3., 940.302 (2), 940.31, 941.20 (2) or (3), 941.26, 941.30, 941.327, 943.01 (2) (c), 943.011, 943.013, 943.02, 943.03, 943.04, 943.06, 943.10, 943.23 (1g), 943.30, 943.32, 943.81, 943.82, 943.83, 943.85, 943.86, 943.87, 943.88, 943.89, 943.90, 946.01, 946.02, 946.43, 947.015, 948.02 (1) or (2), 948.025, 948.03, 948.04, 948.05, 948.051, 948.06, 948.07, 948.085, or 948.30 or, if the victim is a financial institution, as defined in s. 943.80 (2), a crime under s. 943.84 (1) or (2).
969.08 History History: 1971 c. 298; 1977 c. 449; 1979 c. 112; 1981 c. 183; 1985 a. 293 s. 3; 1987 a. 90, 332, 399, 403; 1991 a. 153, 269; 1993 a. 50, 92, 94, 227, 441, 445, 491; 1997 a. 143, 180, 295; 1999 a. 32; 2001 a. 109; 2005 a. 212, 277; 2007 a. 97, 116.
969.09 969.09 Conditions of bond.
969.09(1)(1) If a defendant is admitted to bail before sentencing the conditions of the bond shall include, without limitation, the requirements that the defendant will appear in the court having jurisdiction on a day certain and thereafter as ordered until discharged on final order of the court and that the defendant will submit to the orders and process of the court.
969.09(2) (2) If the defendant is admitted to bail upon appeal, the conditions of the bond shall be that the defendant will duly prosecute the defendant's appeal, that the defendant will appear at such time and place as the court directs, and that if the judgment is affirmed or reversed and remanded for a new trial or further proceedings upon notice after remittitur, the defendant will surrender to the sheriff of the county in which the defendant was tried.
969.09(3) (3) A defendant shall receive a copy of the bond which the defendant executes pursuant to this chapter.
969.09 History History: 1993 a. 486; 1995 a. 225.
969.09 Annotation A petition for a writ of habeas corpus properly named the state department with custody of probationers, rather than the sheriff, as the respondent if the petitioner was released on bail pending appeal. Dreske v. DHSS, 483 F. Supp. 783 (1980).
969.10 969.10 Notice of change of address. A person who has been released on bail or other conditions shall give written notice to the clerk of any change in his or her address within 48 hours after the change. This requirement shall be printed on all bonds.
969.11 969.11 Release upon arrest in another county.
969.11(1)(1) If the defendant is arrested in a county other than the county in which the offense was committed, he or she shall, without unreasonable delay, either be brought before a judge of the county in which arrested for the purpose of setting bail or other conditions of release or be returned to the county in which the offense was committed. The judge shall release him or her on conditions imposed in accordance with this chapter to appear before a court in the county in which the offense was committed at a specified time and place.
969.11(2) (2) If the defendant is released on bail or other conditions pursuant to sub. (1), the judge shall make a record of the proceedings and shall certify his or her minutes thereof and shall forward the bond and bail to the court before whom the defendant is bound to appear.
969.12 969.12 Sureties.
969.12(1)(1) Every surety under this chapter, except a surety under s. 345.61, shall be a resident of the state.
969.12(2) (2) A surety under this chapter shall be a natural person, except a surety under s. 345.61. No surety under this chapter may be compensated for acting as such a surety.
969.12(3) (3) A court may require a surety to justify by sworn affidavit that the surety is worth the amount specified in the bond exclusive of property exempt from execution. The surety shall provide such evidence of financial responsibility as the judge requires. The court may at any time examine the sufficiency of the bail in such manner as it deems proper, and in all cases the state may challenge the sufficiency of the surety.
969.12 History History: 1979 c. 34; 1993 a. 486.
969.13 969.13 Forfeiture.
969.13(1)(1) If the conditions of the bond are not complied with, the court having jurisdiction over the defendant in the criminal action shall enter an order declaring the bail to be forfeited.
969.13(2) (2) This order may be set aside upon such conditions as the court imposes if it appears that justice does not require the enforcement of the forfeiture.
969.13(3) (3) By entering into a bond, the defendant and sureties submit to the jurisdiction of the court for the purposes of liability on the bond and irrevocably appoint the clerk as their agent upon whom any papers affecting their bond liability may be served. Their liability may be enforced without the necessity of an independent action.
969.13(4) (4) Notice of the order of forfeiture under sub. (1) shall be mailed forthwith by the clerk to the defendant and the defendant's sureties at their last addresses. If the defendant does not appear and surrender to the court within 30 days from the date of the forfeiture and within such period the defendant or the defendant's sureties do not satisfy the court that appearance and surrender by the defendant at the time scheduled for the defendant's appearance was impossible and without the defendant's fault, the court shall upon motion of the district attorney enter judgment for the state against the defendant and any surety for the amount of the bail and costs of the court proceeding. Proceeds of the judgment shall be paid to the county treasurer. The motion and such notice of motion as the court prescribes may be served on the clerk who shall forthwith mail copies to the defendant and the defendant's sureties at their last addresses.
969.13(5)(a)(a) A cash deposit made with the clerk pursuant to this chapter shall be applied first to the payment of any recompense determined under par. (b) and then, if the recompense is paid in full, to the payment of costs. If any amount of such deposit remains after the payment of costs, it shall be applied to payment of the judgment of forfeiture. The person making the cash deposit shall be given written notice of the requirements of this paragraph.
969.13(5)(b) (b) The court shall determine a recompense amount for any victim, or if the victim is deceased, for his or her estate, of the crime for which the bond was entered into unless the court finds substantial reason not to do so and states the reason on the record. The court shall determine the recompense amount in the same manner as the court would have determined the restitution amount under s. 973.20 (2), (3), (4), (4m), (5), and (7) had the person been convicted.
969.13 History History: 1971 c. 298; 1993 a. 486; 2005 a. 447.
969.13 Annotation Forfeiture proceedings are a part of an underlying criminal case. State v. Givens, 88 Wis. 2d 457, 276 N.W.2d 790 (1979).
969.13 Annotation The trial court abused its discretion in refusing to modify an order under sub. (2) when partial remission of a bond was appropriate. State v. Ascencio, 92 Wis. 2d 822, 285 N.W.2d 910 (Ct. App. 1979).
969.13 Annotation Forfeiture proceedings are civil in nature; appeals are governed by s. 808.04. State v. Wickstrom, 134 Wis. 2d 158, 396 N.W.2d 188 (1986).
969.13 Annotation Sub. (1) mandates bail forfeiture for any bond condition violation. State v. Badzmierowski, 171 Wis. 2d 260, 490 N.W.2d 784 (Ct. App. 1992).
969.13 Annotation A circuit court has discretion to enter a judgment on an order forfeiting bail absent a motion by the district attorney when the defendant appears within 30 days of the forfeiture. State v. Achterberg, 201 Wis. 2d 291, 548 N.W.2d 515 (1996), 94-3360.
969.13 Annotation The trial court's decision under sub. (2) requires the exercise of discretion. Refusing all requests for the return of bail money is not an exercise of discretion. The standard "that justice requires" cannot be parlayed into an all-inclusive list, but is essentially an appeal to the conscience of the court. Melone v. State, 2001 WI App 13, 240 Wis. 2d 451, 623 N.W.2d 179, 00-0969.
969.13 Annotation Forfeited cash bond may not be used to pay restitution to a victim of the crime. 68 Atty. Gen. 71.
969.14 969.14 Surrender of principal by surety.
969.14(1)(1) When the sureties desire to be discharged from the obligations of their bond, they may arrest the principal and deliver the principal to the sheriff of the county in which the action against the principal is pending.
969.14(2) (2) The sureties shall, at the time of surrendering the principal, deliver to the sheriff a certified copy of the original warrant and of the order admitting the principal to bail and of the bond thereon; such delivery of these documents shall be sufficient authority for the sheriff to receive and retain the principal until the principal is otherwise bailed or discharged.
969.14(3) (3) Upon the delivery of the principal as provided herein, the sureties may apply to the court for an order discharging them from liability as sureties; and upon satisfactory proof being made that this section has been complied with the court shall make an order discharging them from liability.
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