Littérature scientifique sur le sujet « Art. 52 c. 4 c.p »

To date, there have been no studies examining the role of hepatitis B virus (HBV) genotypes on the response to lamivudine therapy and the development of YMDD mutations. The present study aimed at determining any differences in the antiviral response and risk of YMDD mutations between lamivudine-treated patients with HBV genotype B and genotype C. Eighty-two patients receiving lamivudine were recruited. HBV genotypes at baseline and YMDD mutations at week 52 were determined by line probe assays (LiPA). HBV DNA levels were determined by the Cobas Amplicor HBV Monitor Test. Seventeen (20.7%) and sixty-four (78%) patients had single genotypes of B and C, respectively. At both week 24 and 52 there were no differences in the median reduction of HBV DNA levels (median 4 logs drop), the median reduction of alanine aminotransferase (ALT) levels, and the proportion with normalization of ALT [8/8 (100%) vs 26/37 (70.3%), P=0.19] between patients with genotypes B and C. The rate of HBeAg seroconversion [3/17 (17.6%) vs 6/64 (9.4%), P=0.39] and the chance of YMDD mutation development [3/17 (17.6%) vs 12/64 (18.8%), P=1.0] at week 52 were also similar between patients with genotype B and C, respectively. In conclusion, there was no difference in the antiviral response and the rate of development of YMDD mutations in Chinese patients with genotype B and C after 1 year of lamivudine. Determination of HBV genotypes before lamivudine therapy was probably not an important pre-treatment investigation to predict antiviral responses in Chinese patients.

Objective. To analyze the course of chronic hepatitis C (CHC) and efficacy of its treatment in children with HIV infection. Patients and methods. This study included 29 children aged 12 to 17 years (mean age 15.1 ± 0.2 years) with perinatal HIV infection and CHC. HIV stages were distributed as follows: stage 4A in 24 individuals (82.8%), stage 4B in 4 individuals (13.8%), and stage 4B in 1 individual (3.4%). All 29 patients received antiretroviral therapy. The distribution of children by HCV genotypes was as follows: 1a in one child (3.4%), 1b in 12 children (41.4%), and 3a in 16 children (55.2%). Antiviral therapy for CHC included glecaprevir/pibrentasvir (3 tablets; 100 mg + 40 mg) once a day for 56 days. Data analysis was performed using the Statistica for Windows software (version 10.0). Results. The mean HCV RNA level was 595,666 ± 34,734 IU/mL (range: 1,100–3,863,025 IU/mL). After 4, 8, or 12 weeks of antiviral therapy for HCV, HCV RNA clearance was achieved in all study participants (p = 0.01). Before treatment initiation, mean CD4+ count was 738 ± 34 cells/μL (above 500 cells/μL), which indicated the absence of immunodeficiency in the group analyzed. Successful antiviral therapy for HCV (sustained virologic response at week 12; SVR 12) also resulted in increase of the CD4+ lymphocytes level, which was considered as a positive effect of glecaprevir/pibrentasvir (p = 0.15). We observed significant differences in the level of liver enzymes (ALT and AST) (p = 0.01) between samples collected before antiviral therapy initiation and those collected during treatment, as well as 12 weeks after its completion (SVR12). All children demonstrated good tolerance of glecaprevir/pibrentasvir; none of them had adverse events, complaints, or clinical/laboratory changes. Conclusion. Thus, all children with HIV infection and CHC achieved SVR12 after the 8-week course of antiviral therapy with glecaprevir/pibrentasvir regardless of HCV genotype. Clinical manifestations (hepatosplenomegaly in 62.1%; asthenovegetative syndrome in 31.0%) were eliminated after 8 weeks of therapy. Laboratory manifestations (hepatic cytolysis (AST/ALT)) were normalized after 4 weeks of therapy. Antiviral treatment for HCV resulted in some increase in the level of CD4+ lymphocytes. We observed no adverse events caused by glecaprevir/pibrentasvir (neither clinical symptoms nor changes in complete blood count or liver function tests), which confirms the safety of this treatment regimen. Key words: antiretroviral therapy, HIV infection, children, direct-acting antivirals, chronic hepatitis C

Abstract Deferasirox is an oral iron chelator approved for the management of iron overload in thalassemia major (TM). However, there are some concerns for its effect on renal function. Cystatin C (Cys-C) is a cysteine protease inhibitor, which is considered as a sensitive marker of GFR. Inflammation process has been recently implicated in TM pathophysiology. The aim of this study was to evaluate the effect of deferasirox on renal function and inflammatory cytokines in 52 TM patients. Deferasirox was administered at a dose between 10–30 mg/kg/day for a 12-month period. Serum Cys-C, serum creatinine (Cr), clearance of Cr (Ccr), albuminuria and inflammatory cytokines including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), IL-1α, IL-1β, IL-4, IL-10 and transforming growth factor (TGF)-β1 and β2, were measured at baseline and then after 6 and 12 months post-deferasirox therapy. Standard hematology and biochemistry was evaluated monthly. Serum Cys-C was measured using a latex particle-enhanced nephelometric immunoassay (Dade Behring, Liederbach, Germany). Serum levels of the above cytokines were determined using ELISA (R&D Systems, Minneapolis, MN, USA, for ILs, and Diaclone, Bensancon, France for TNF-α, TGF-β1 and TGF-β2). Ten healthy blood donors were also evaluated as control group. At baseline, TM patients had elevated values of Cys-C (p<0.0001) compared with controls. Specifically, 21/52 patients (40%) had higher Cys-C values than the upper normal limit according to manufacturer (0.95 mg/L), while no patient had increased levels of serum Cr (>1.4 mg/dl) and only 6 (11.5%) had low Ccr (<80 ml/min). Before deferasirox administration, TM patients had also increased levels of IL-6 (p=0.008), IL-1α (p=0.015), TGF-β2 (p=0.017), IL-10 (0.021), IL-4 (p=0.039), and a borderline increase of TNF-α (p=0.05) compared with controls (Table). Serum levels of Cys-C correlated strongly with Cr (r=0.657, p<0.0001), and Ccr (r=−0.625, p<0.0001) but also with IL-6 (r=0.441, r<0.001) and proteinuria (r=0.261, p=0.037). Il-1a correlated with Hb (r=−0.417, p<0.001) and IL-4 (r=0.474, p<0.001), while IL-6 correlated with TNF-α (r=0.37, p<0.01). After 6 and 12 months of therapy, deferasirox produced a dramatic reduction of ferritin, SGOT and SGPT compared with baseline values (p<0.0001), but concomitantly we observed an increase of Cys-C and Ccr during the same period (p<0.0001). In particular at the end of the study 32/52 patients (61.5%) had increased Cys-C values, while 10 (19.2%) had low Ccr and only one high serum Cr. Interestingly serum levels of TNF-α reduced post-deferasirox administration (p=0.01), while the levels of all other cytokines remained unchanged during therapy (Table). Our study suggests that deferasirox is an effective chelator in TM. However, its effect on renal function is not insignificant and needs further investigation. Inflammatory cytokines seem to have a role in the pathogenesis of TM but further studies are needed to fully elucidate this role as well as the effect of deferasirox, if any, on inflammation. Table 1. Characteristics of patients & controls (mean values ± SD) Parameters Controls (n=10) Patients-baseline values (n=52) p-value (patients vs. controls) Patients-12-month values p-value patients (baseline vs. 12 m) Age(years) 40.8±11.7 39.5±10.9 0.782 Gender(Male/Female) 4/6 22/30 0.346 Hb(g/dL) 14.8±2.6 8.8±1.4 <0.0001 8.7±1.5 AST(U/L) 29.3±10.1 46.7±23.9 <0.0001 35.5±19.2 <0.0001 ALT(U/L) 23.8±12.5 50.7±28.6 <0.0001 34.3±22.1 <0.0001 Ferritin(μg/L) 88±34.2 2355±1380 <0.0001 1516±1320 <0.0001 Serum Creatinine (mg/dL) 0.8±0.1 0.7±0.1 0.823 0.8±0.2 0.001 Creatinine Clearance (ml/min/1.732) 125.2±22.7 126.5±29.9 0.227 117.0±31.1 0.005 Proteinuria(mg/24h) 55.4±28.2 322.9±461.6 <0.0001 323.4±417.0 0.976 Cystatin-C (mg/L) 0.76±0.11 0.93±0.26 <0.0001 1.12±0.37 <0.0001 Inflammatory Cytokines IL-1α (pg/mL) 0.08±0.19 0.65±0.80 0.015 1.06±1.13 0.114 IL-1β (pg/mL) 2.30±2.54 1.68±2.37 0.475 2.05±2.82 0.571 IL-4 (pg/mL) ND 0.78±1.83 0.039 0.28±0.59 0.167 IL-6 (pg/mL) 0.09±0.21 2.50±4.42 0.008 3.00±7.51 0.752 TNF-α (pg/mL) 1.13±2.05 3.85±7.48 0.05 0.46±1.40 0.015 TGF-β1 (ng/mL) 87.1±21.7 107.5±53.6 0.180 112.1±74.0 0.678 TGF-β2 (pg/mL) 5.62±10.5 19.5±26.4 0.017 15.8±29.7 0.318

SARS-CoV-2 infection may precede and cause various autoimmune and inflammatory diseases, including multisystem inflammatory syndrome in children (MIS-C). Therefore, we aimed to observe the clinical presentation and laboratory, instrumental and other constellations in children with MIS-C, including liver involvement. We present the outcomes from a single-center prospective observational study in which 89 children was included (60 with proven COVID-19, 10 symptomatic with confirmed COVID-19 contact and 19 diagnosed with MIS-C). Laboratory, instrumental, immunological, and clinical investigations were performed. Only 12% (n = 4) from the COVID-19 group (except the ICU cases), we found elevated AST and/or ALT (up to 100). All of the children with elevated transaminase were overweight or obese, presenting along with moderate COVID-19 pneumonia. The majority of children with MIS-C showed typical laboratory constellations with higher levels of IL-6 (120.36 ± 35.56 ng/mL). About half of the children in the MIS-C group (52%, n = 11) showed elevated transaminases. Eleven children (57.9%) presented with abdominal pain, eight (42.1%) with ascites, two (10.5%) with hepatosplenomegaly, and four (21.1%) with symptoms such as diarrhea. Mesenteric lymphadenitis was observed more often in patients with elevated LDH (327.83 ± 159.39, p = 0.077). Ascites was associated with lymphopenia (0.86 ± 0.80, p = 0.029) and elevated LDH. Hepato-splenomegaly was also more frequent in children with lymphopenia (0.5 ± 0.14, p = 0.039), higher troponin (402.00 ± 101.23, p = 0.004) and low ESR. Diarrhea was more frequent in patients with lower CRP (9.00 ± 3.44 vs. 22.25 ± 2.58, p = 0.04), and higher AST and ALT (469.00 ± 349.59 vs. and 286.67 ± 174.91, respectively, p = 0.010), and D-dimer (4516.66 ± 715.83, p = 0.001). Our data suggest that the liver can also be involved in MIS-C, presenting with typical laboratory and instrumental outcomes.

5537 Background: p38 mitogen-activated protein kinase (MAPK) regulates cytokine production in the tumor microenvironment and enables therapeutic resistance of cancer cells. Ralimetinib (R) is a selective small-molecule inhibitor of p38α and p38β MAPKs. Methods: Main inclusion criteria: ≥18 y; recurrent platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal, cancer after first-line treatment. Phase (Ph)1b was to determine the recommended Ph2 dose (RP2D) of R administered 12-hourly (Q12H) on Days 1-10 (21-day cycle [Q21D]) in combination with gemcitabine (G: 1000 mg/m2 on Days 3 and 10) and carboplatin (C: AUC 4 on Day 3) for 6 cycles. In Ph2, patients (pts) were randomized double-blind, 1:1 to RP2D R+GC or placebo (P)+GC, for 6 cycles, followed by R 300 mg Q12H or P on Days 1-14, Q28D until disease progression. The stratified log-rank test compared progression-free survival (PFS; primary endpoint) between treatment groups in Ph2, at a 1-sided α level of 0.2. ClinicalTrials.gov, NCT01663857. Results: 118 pts received ≥1 dose of R or P (safety population); 8 in Ph1b and 110 in Ph2 (R+GC N = 58; P+GC N = 52). The RP2D for R in combination with GC was 200 mg Q12H. The study met its primary objective (median PFS: R+GC 10.3 mo vs P+GC 7.9 mo; HR = 0.773, 2-sided p = 0.246). The secondary objectives of median overall survival (R+GC 29.2 mo vs P+GC 25.1 mo; HR = 0.827, p = 0.469) or overall response rate (R+GC 46.6% vs P+GC 46.2%; p = 0.967) were not statistically significant, and 32.4% vs 25.0% of pts had normalized CA125 at the end of cycle 6. Most pts (safety population) experienced ≥1 Grade 3/4 treatment-emergent adverse event (TEAE: R+GC 63/66 [95.5%]; P+GC 48/52 [92.3%]). Decreased neutrophil count (60.6% vs 76.9%), platelet count (43.9% vs 38.5%), and white blood cell count, (30.3% vs 26.9%), anemia (22.7% vs 25.0%), and increased alanine aminotransferase (ALT) (19.7% vs 3.8%) were the Grade 3/4 TEAEs in ≥10% of pts in the R+GC and P+GC arms, respectively. Conclusions: Addition of ralimetinib to GC resulted in modest improvements in PFS. Grade 3/4 elevated ALT was more common in the ralimetinib arm. Clinical trial information: NCT01663857.

128 Background: We have recently completed accrual of 63 patients (pts) to our study combining lenalidomide (L), with bevacizumab (B), docetaxel (D), and prednisone (P) (ART-P). Due to the lack of improved survival and the increased toxicity of anti-angiogenic docetaxel combinations in the MAINSAIL and CALGB 90410 trials we attempted to contrast and compare our studies with the failed phase III trials. Methods: Among the first 52 pts on the ART-P, 3 received L 15 mg daily, 3 had 20 mg daily, and the rest had 25 mg daily for 14 days of every 21−day cycle (C). We later enrolled 11 more pts at L 15 mg. All pts received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and enoxaparin daily throughout each C. Pegfilgrastim was given on day 2. Patients on CALGB 90410 received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and on MAINSAIL received D 75 mg/m2, L 25 mg daily for 14 days of every 21−day cycle with daily P. Patients on CALGB 90410 and MAINSAIL did not receive enoxaparin or pegfilgrastim prophylactically. Results: Median number of Cs in ART-P was 16 (3−38). PFS was 22 months and median OS has not been reached. Pts with measurable disease had 1 CR and 25 PR (86.7% RR). Two patients (3%) had deep vein thromboses. Of 1,219 cycles given, 14 cycles were complicated by febrile neutropenia (FN) (1.1%). There were no treatment related deaths. In comparison, median number of Cs in MAINSAIL L+DP arm was 6, with a PFS of 45 weeks and an OS of 77 weeks. Thirty-four pts (6.5%) developed pulmonary emboli and there were 2 deaths due to toxicity in the experimental arm. Nearly 12% of Cs were complicated by FN. In the experimental arm of CALGB 90410 trial, median OS was 22.6 months with median PFS of 9.9 months. Median number of Cs was 8, and 19 pts developed thromboses/emboli (3.6%). In addition, 7% of patients developed FN and treatment related deaths were reported at 4%. Conclusions: The use of supportive care allows the ART-P combination to be given for more cycles than were given in MAINSAIL and CALGB 90401 potentiating a longer PFS, RR and possibly OS with an improved toxicity profile. This data demonstrates the potential importance of supportive measures and is hypothesis generating for future combination studies. Clinical trial information: NCT00942578.

e16017 Background: We have completed accrual of 63 patients (pts) to our study combining lenalidomide (L), with bevacizumab (B), docetaxel (D), and prednisone (P) (ART-P) in mCRPC. Due to the lack of improved survival and the increased toxicity of anti-angiogenic docetaxel combinations in the MAINSAIL and CALGB 90401 trials, we attempted to compare and contrast our studies with these failed phase III trials. Methods: Among the first 52 pts on ART-P, 3 received L 15 mg daily, 3 received 20 mg daily, and the others received 25 mg daily for 14 days of every 21−day cycle (C). We then enrolled 11 pts at L 15 mg. All pts received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and enoxaparin daily. Pegfilgrastim was given on day 2. Patients on CALGB 90401 received D 75 mg/m2 and B 15 mg/kg on day 1, with P 10 mg. On MAINSAIL, pts received D 75 mg/m2, L 25 mg daily for 14 days of every 21−day cycle with daily P. Patients on CALGB 90401 and MAINSAIL did not receive enoxaparin or pegfilgrastim prophylactically. Results: The median number of Cs on ART-P is 18 (1-52). Median PFS is 19.1 months. Twenty-seven pts had a PR, and one pt with measurable disease had a CR. Two patients (3%) had deep vein thromboses. Of 1,334 Cs given, 14 cycles were complicated by febrile neutropenia (FN) (1%). There were no treatment related deaths. In comparison, median number of Cs in MAINSAIL L+DP arm was 6, with a PFS of 45 weeks and an OS of 77 weeks. Thirty-four pts (6.5%) developed pulmonary emboli and there were 2 deaths due to toxicity in the experimental arm. Nearly 12% of Cs were complicated by FN. In the experimental arm of CALGB 90401 trial, median OS was 22.6 months with median PFS of 9.9 months. The median number of Cs were 8 and 19 pts developed thrombosis/emboli (3.6%). In addition, 37 patients developed FN and treatment related deaths were reported at 4%. Conclusions: The use of supportive care allowed longer treatment duration with the ART-P combination as compared to D+L (MAINSAIL) and D+B (CALGB 90401), potentiating a longer PFS, RR and possibly OS with an improved safety profile. This data demonstrates the potential importance of supportive measures and is hypothesis generating for future combination studies. Clinical trial information: NCT00942578.

BackgroundBelimumab (BEL) is approved for the treatment of active autoantibody-positive systemic lupus erythematosus (SLE).1 Four Phase 3 studies have consistently demonstrated greater SLE Responder Index (SRI) response rates with BEL vs placebo (PBO).2-5 This robust dataset allows for additional exploration of the onset of efficacy of BEL and response rates by patient (pt) characteristics.ObjectivesTo perform a post hoc analysis evaluating the effect of BEL on SRI-4 response across a large, pooled population and pt subgroups.MethodsThe Belimumab Summary of Lupus Efficacy (Be-SLE) integrated analysis evaluated data from adults with SLE from 5 double-blind, PBO-controlled BEL trials: BLISS-76, BLISS-52, BLISS-NEA, BLISS-SC, and EMBRACE.2-6 Pts were randomised to BEL (monthly intravenous 10 mg/kg or weekly subcutaneous 200 mg) or PBO, plus standard therapy. Data were collected every 4 weeks (wks) from baseline (BL) to Wk 52. The SRI-4 response rate (a composite measure that includes ≥4-point reduction in Safety of Estrogens in Lupus Erythematosus National Assessment - SLE Disease Activity Index [SELENA-SLEDAI] score, stable Physician Global Assessment [PGA] increase of <0.3, and no new British Isles Lupus Assessment Group [BILAG] 1A/2B organ domain scores) by visit and time to first SRI-4 response maintained through Wk 52 were determined for both treatment groups. SRI-4 response rates at Wk 52 were evaluated by BL characteristic subgroups: SELENA-SLEDAI score; SLE International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) score; disease duration; biomarker levels (anti-dsDNA, complement [C]3/C4); glucocorticoid (GC), immunosuppressant (IS), and antimalarial (AM) use.ResultsOverall, 3086 pts were included (BEL, n=1869; PBO, n=1217). Most were female (94.4%); mean (standard deviation [SD]) age was 37.0 (11.6) years. Mean (SD) SLE duration was 6.4 (6.4) years.At Wk 52, in the overall population, significantly more BEL vs PBO pts were SRI-4 responders (Figure 1). A significantly greater proportion of SRI-4 responders was observed with BEL vs PBO as early as Wk 8 (38.4% vs 33.3%; odds ratio, OR [95% confidence interval, CI] 1.25 [1.07, 1.46]; p=0.0060), which continued to increase to Wk 52 (54.8% vs 41.6%; OR [95% CI] 1.70 [1.46, 1.98]; p<0.0001). At Wk 52, more BEL vs PBO pts had a 4-point reduction in SELENA-SLEDAI (56.3% vs 43.1%; OR [95% CI] 1.71 [1.47, 2.00]; p<0.0001), no worsening in PGA (76.6% vs 67.9%; OR [95% CI] 1.52 [1.28, 1.79]; p<0.0001), and no new BILAG 1A/2B organ domain scores (77.1% vs 69.4%; OR [95% CI] 1.47 [1.25, 1.74]; p<0.0001). Pts on BEL were 52% more likely to experience an SRI-4 response that was maintained through Wk 52 (hazard ratio, HR [95% CI] 1.52 [1.36, 1.69]; p<0.0001).Figure 1.SRI-4 response at Wk 52 in the overall population and by BL characteristic subgroups.*OR (95% CI) and p-value are from a logistic regression model for BEL vs PBO comparison with covariates of treatment group, study and BL SELENA-SLEDAI score (≤9 vs ≥10)SRI-4 response rates were significantly higher with BEL vs PBO in most subgroups, with the highest response rates observed in pts with SELENA-SLEDAI score of ≥10, low C3 and/or C4 + anti-dsDNA ≥30 IU/ml, and low C3 and/or C4 at BL (Figure 1).ConclusionSignificantly more pts receiving BEL had SRI-4 response rates that occurred from Wk 8 and were maintained through Wk 52 compared with pts receiving PBO. The efficacy of BEL was consistent across multiple pt subgroups, with higher response rates in pts with SELENA-SLEDAI scores of ≥10, low C3 and/or C4 + anti-dsDNA ≥30 IU/ml and low C3 and/or C4 at BL. These results further substantiate the benefits of BEL in the treatment of adults with SLE.References[1]GlaxoSmithKline. Benlysta US prescribing information. 2021[2]Furie R, et al. Arthritis Rheumatol 2011;63(12):3918–30[3]Navarra SV, et al. Lancet 2011;377(9767):721–31[4]Stohl W, et al. Arthritis Rheum 2017;69(5):1016–27[5]Zhang F, et al. Ann Rheum Dis 2018;77(3):355–63[6] Ginzler E, et al. Arthritis Rheum 2021; doi: 10.1002/art.41900AcknowledgementsThis analysis was funded by GlaxoSmithKline (GSK). Medical writing support was provided by Lulu Hill, MPharmacol, Fishawack Indicia Ltd. UK, part of Fishawack Health, and was funded by GSK.Disclosure of InterestsMichelle A Petri Consultant of: GSK, Grant/research support from: GSK, George Bertsias Speakers bureau: Pfizer, Aenorasis, UCB, Novartis, Lilly, SOBI, Consultant of: Novartis, GSK, AstraZeneca, Grant/research support from: GSK, Pfizer, Mark Daniels Shareholder of: GSK, Employee of: GSK, Norma Lynn Fox Shareholder of: GSK, Employee of: GSK, Bevra H. Hahn Consultant of: UCB, GSK, Anne Hammer Shareholder of: GSK, Employee of: GSK, Julia Harris Shareholder of: GSK, Employee of: GSK, Holly Quasny Shareholder of: GSK, Employee of: GSK, Chiara Tani Speakers bureau: GSK, AstraZeneca, Anca Askanase Consultant of: AstraZeneca, Aurinia Pharmaceuticals Inc., Amgen, AbbVie Inc., BMS, GSK, Grant/research support from: AstraZeneca, Eli Lilly and Company, GSK, Idorsia Pharmaceuticals Ltd, Janssen Pharmaceuticals, Pfizer

Abstract The biologic effects of erythropoietin (EPO) are mediated by its cellular receptor EPOR, a member of the cytokine receptor superfamily. EPOR expression in non-hematopoietic cells is associated with novel biologic effects for EPO in diverse organ systems. We recently demonstrated functional EPOR expression in adult rat cardiac myocytes and found that recombinant EPO exerts a rapid cardioprotective effect during ischemia-reperfusion injury of the isolated, perfused heart. Here we investigated the mechanisms of the cardioprotective effect of EPO using Langendorff-perfused rat hearts while left-ventricular-developed pressure (LVDP) was measured continuously to assess contractile function. Hearts were treated directly with EPO in the presence or absence of inhibitors of specific signal transduction pathways prior to normothermic global ischemia followed by reperfusion. Post-ischemic recovery of contractile function was determined by measuring LVDP at the end of reperfusion and expressed as a percentage of the baseline pre-treatment measurement. We investigated EPO-mediated activation of signal transduction pathways in the isolated, perfused heart and observed phosphorylation of p44/p42 MAP kinases ERK 1/2 (Thr202/Tyr204) and protein kinase B/Akt (Ser473), a downstream target of the phosphatidylinositol 3-kinase (PI3K) signaling pathway. Furthermore, EPO treatment of the isolated, perfused heart was associated with translocation of protein kinase C (PKC) ε and δ isoforms to the membrane fraction. We investigated the role of specific signaling pathways in EPO-mediated cardioprotection by employing inhibitors targeting PI3K, PKC and MAP kinase kinase (MEK1). PI3K inhibitors LY294002 and wortmannin attenuated EPO-induced phosphorylation of Akt but had no effect on EPO-mediated cardioprotection. MEK1 inhibitor U0126 had no effect on EPO-mediated cardioprotection. The PKC catalytic inhibitor chelerythrine (chel) significantly inhibited EPO-mediated improvement in post-ischemic recovery of LVDP (figure 1). Hearts pre-treated with EPO exhibited significantly improved post-ischemic recovery of LVDP compared to control hearts (mean±SE: 72±3 in EPO-treated versus 35±3% in control hearts, P<0.05 by ANOVA and Bonferroni post-hoc test, n=10 experiments each group) and the protective effect of EPO was significantly inhibited in chel-treated hearts (52±4% in EPO+chel versus 72±3% in EPO-treated hearts, P<0.05, n=10). As a control, treatment of the hearts with chelerythrine alone had no significant effect on LVDP (49±4%) compared to control hearts. These data demonstrate that EPO-mediated activation of the PKC signaling pathway is required for the cardioprotective effect of EPO during ischemia-reperfusion injury. Figure Figure

Since the early days of the semiconductor industry, defect control has been key to the successful development of devices and circuits. It requires a thorough understanding of their formation and the impact on the electrical material parameters. This has only been possible by the invention of powerful structural, chemical and electrical characterization tools, with the device itself perhaps as the most sensitive probe. This evolution was paralleled by the development of ab initio calculation methods, based on Density Functional Theory and more recently, also TCAD tools allowing more and more refined modelling of the impact of defects on the electrical characteristics of devices. The implementation of other materials than Si and SiO2 in CMOS through the hetero-epitaxial growth on a silicon substrate for example, has renewed the interest in defect engineering during the last two decades, leading to single-defect analysis methods like Random Telegraph Noise (RTN) [1] or novel growth schemes like Aspect Ratio Trapping (ART) [2] for the removal of extended defects from the device active regions. In this presentation, some state-of-the-art analysis techniques will be highlighted, including Deep Level Transient Spectroscopy (DLTS) [3], Generation-Recombination (GR) noise and RTN spectroscopy [1,4] and p-n diode lifetime analysis [5]. These methods will be applied to several case studies. As shown in Fig. 1, threading extended defects impact the recombination lifetime of lowly-doped n-type In0.47Ga0.53As starting from a density of a few 107 cm-2. Likewise, it will be demonstrated that the GR noise observed in GaN-on-Si MOSHEMTs (Fig. 2) most likely originates from threading dislocations [6]. It is concluded that when hetero-epitaxial layers can be grown with a sufficiently low defect density, their impact will be more on the variability of the electrical parameters rather than on the effective values. In addition, the position of the defect with respect to strategic nodes like a p-n junction or depletion region largely determines its electrical impact, as has been validated by TCAD simulations. References [1] E. Simoen and C. Claeys, “Random Telegraph Signals in Semiconductor Devices”, The Institute of Physics, Bristol, UK (2016). [2] J. Z. Li et al., Appl. Phys. Lett., 91, p. 021114 (2007). [3] E. Simoen, J. Lauwaert and H. Vrielinck, Semiconductors and Semimetals, Eds. L. Romano, V. Privitera and C. Jagadish, 91, pp. 205-250, Elsevier 2015. [4] D. Boudier et al., Solid-St. Electron., 128, pp. 102-108 (2017). [5] Po-Chun (Brent) Hsu et al., J. Phys. D: Appl. Phys., 52, p. 485102 (2019). [6] K. Takakura et al., IEEE Trans. Electron Devices, 67, pp. 3062-3068 (2020). Figure 1

L’elaborato tratta il delicato tema della legittima difesa esercitata nel domicilio, che è stato oggetto di due riforme negli ultimi quindici anni – prima nel 2006, poi nel 2019 –, suscitando diffuse critiche e contrastanti pareri in ordine alla sua esatta portata. La grande attenzione pubblica per l’istituto e i due interventi legislativi hanno stimolato l’interesse e il desiderio di approfondire l’origine, la ratio e l’evoluzione della scriminante di cui all’art. 52 c.p. Lo scopo della presente indagine è duplice: da una parte, si è cercato di comprendere le esigenze sottostanti alle riforme e, più in generale, il fondamento del bisogno così ben radicato nella società contemporanea di una differenziazione di trattamento per le aggressioni perpetrate all’interno dell’abitazione; dall’altra, invece, partendo dallo studio della disciplina attualmente in vigore e dell’applicazione concreta della medesima ad opera della giurisprudenza, si è provato a trovare un equilibrio più soddisfacente tra le esigenze diffuse e il rispetto della Carta costituzionale e della Convenzione europea dei diritti dell’uomo, in sintesi una “contro-riforma sostenibile”. La tesi si articola in tre parti, di cui la prima è dedicata all’analisi storico-comparatistica della causa di giustificazione. In particolare, lo studio ripercorre le origini dell’istituto a partire dal diritto romano sino ai giorni nostri, cercando di evidenziare i precedenti storici atti a spiegare l’attuale predisposizione di una figura speciale di legittima difesa a beneficio di colui che sia aggredito in luoghi privati in ordine ai quali vanti uno ius excludendi alios nei confronti dell’aggressore. La ricerca storica è affiancata da un’indagine comparatistica, anch’essa impostata in prospettiva storica, che allarga lo sguardo alle scelte compiute in argomento dai principali ordinamenti europei – segnatamente quello francese e inglese –, nonché dal sistema federale statunitense. La seconda parte della tesi ha ad oggetto il diritto interno vigente; in particolare l’elaborato affronta prima la legge n. 59 del 13 febbraio 2006 e poi la legge n. 36 del 26 aprile 2019, ossia le riforme che hanno conferito rilievo alla figura speciale della legittima difesa domiciliare. A tal fine, si considera tanto il contesto politico criminale che ne ha segnato l’origine, quanto il contenuto delle riforme alla luce della giurisprudenza di legittimità; è stato infatti svolto uno studio su tutte le pronunce emesse dalla Corte di Cassazione in materia di legittima difesa domiciliare dal 1° gennaio 2000 sino al 1° gennaio 2021. Grazie a tale ricerca è emerso da una parte come la prima riforma risulti sostanzialmente priva di ricadute concrete e, dall’altra, come il secondo intervento legislativo, ove non sottoposto a un’interpretazione correttiva alla luce delle direttrici costituzionali e convenzionali europee, sia pericoloso per la tenuta del sistema. Lungo tale direttrice, l’indagine si sofferma in particolare sul ruolo che dovrebbero assumere il requisito della necessità e le presunzioni normative di legittimità della reazione. Con riferimento al caso dell’eccesso, poi, si prospettano i criteri rilevatori del grave turbamento e delle condizioni di minorata difesa a cui si ricollegano effetti scusanti. La terza ed ultima parte dell’elaborato, infine, tratta l’istituto in una prospettiva de iure condendo; nello specifico, prendendo le mosse dai risultati raggiunti attraverso l’indagine realizzata, si è provato ad avanzare una proposta di risistemazione della causa di giustificazione che si articola in tre passaggi, idealmente collegati tra loro. Secondo tale ipotesi di lavoro, l’art. 52 c.p. guadagnerebbe in razionalità ed efficacia se, anzitutto, fossero eliminati i commi disciplinanti la legittima difesa domiciliare attualmente in vigore; inoltre, alla disposizione di cui al c. 1 dell’art. 52 c.p. dovrebbe affiancarsi una scusante legata allo stato di turbamento emotivo vissuto dall’aggredito, applicabile alla fattispecie generale per i casi di eccesso e di errore sulla legittima difesa; infine, si potrebbe prevedere una presunzione iuris tantum di pericolo attuale per la sola incolumità dei presenti in caso di aggressione perpetrata all’interno del domicilio e dell’esercizio commerciale. La compresenza di tali proposte modificative sembrerebbe in grado di conferire un rinnovato equilibrio alla causa di giustificazione, da una parte dando voce e riconoscimento alle istanze diffuse, dall’altra rispettando i principi e i valori di cui la Costituzione e la Convezione europea dei diritti dell’uomo sono espressione, dall’altra ancora imprimendo una spinta contraria rispetto all’attuale tendenza antistatalista, se non addirittura anticostituzionale, di cui le due recenti riforme in materia si sono rese portavoce.
The thesis deals with the delicate issue of self defence exercised in the home, which has been the subject of two reforms in the last fifteen years – first in 2006, then in 2019 –, arousing widespread criticism and conflicting opinions regarding its exact scope. The great public attention for the institute and the two legislative interventions have stimulated the interest and the desire to investigate the origin, the ratio and the evolution of the justification regulated by art. 52 c.p. The purpose of this survey is twofold: on the one hand, an attempt has been made to understand the needs underlying the reforms and, more generally, the foundation of the need so well rooted in contemporary society for a differentiation of treatment for attacks perpetrated inside the house; on the other hand, starting from the study of the discipline currently in force and the concrete application of the same by jurisprudence, an attempt has been made to find a more satisfactory balance between the widespread needs and compliance with the Constitutional Charter and the European Convention of human rights, in short a "sustainable counter-reform". The thesis is divided into three parts, of which the first is dedicated to the historical-comparative analysis of the justification. In particular, the study traces the origins of the institute starting from Roman law up to the present day, trying to highlight the historical precedents capable of explaining the current predisposition of a special figure of self defence in favour of anyone who is attacked in private places, where individuals boasts an ius excludendi alios against the aggressor. The historical research is accompanied by a comparative survey, also set in a historical perspective, which broadens the gaze to the choices made on the subject by the main European systems – notably the French and English ones –, as well as by the US federal system. The second part of the thesis concerns the internal law in force; in particular, the paper first deals with law no. 59 of 13 February 2006 and then the law n. 36 of 26 April 2019, i.e. the reforms that have given prominence to the special figure of home self defence. To this end, both the criminal political context that marked its origin and the content of the reforms in the light of the jurisprudence of legitimacy are considered; in fact, a study was carried out on all the rulings issued by the Court of Cassation regarding home self defence from 1 January 2000 until 1 January 2021. Thanks to this research, it emerged on the one hand how the first reform is substantially devoid of concrete repercussions and, on the other hand, how the second legislative intervention, if not subjected to a corrective interpretation in the light of constitutional and conventional guidelines, is dangerous for system tightness. Along this line, the investigation focuses in particular on the role that the requirement of necessity and the normative presumptions of legitimacy of the reaction should assume. With reference to the case of excess, then, are presented the criteria for detecting the serious disturbance and the conditions of impaired defence to which excuse effects are linked. Finally, the third and last part of the paper deals with the institution from a de iure condendo perspective; specifically, starting from the results achieved through the survey carried out, an attempt was made to put forward a proposal for reorganization of the justification which is divided into three steps, ideally connected to each other. According to this working hypothesis, art. 52 c.p. would gain rationality and effectiveness if, first of all, the paragraphs governing home self defence currently in force were eliminated; furthermore, beside the provision referred to art. 52 c. 1 c.p., there should be an excuse linked to the state of emotional disturbance experienced by the attacked, applicable in cases of excess and error in self defence; finally, an iuris tantum presumption of current danger could be envisaged for the sole safety of those present in the event of aggression perpetrated within the home and business. The coexistence of these amending proposals would seem capable of giving a renewed balance to the justification, first of all giving voice and recognition to the widespread requests, furthermore respecting the principles and values of which the Constitution and the European Convention of human rights are an expression, and lastly still giving a push contrary to the current anti-statist tendency, if not even anti-constitutional, of which the two recent reforms on the subject have become spokesmen.

Cirrus is conventionally considered as cloud forming in the Earth's upper troposphere at temperatures somewhat below -40°C, composed of ice crystals and forming long, wispy trails. This characteristic shape, in the form of a curl of hair, results from evaporation in vertical shear of horizontal winds, and leads to its Latin name—originally proposed by Luke Howard in 1803. Here we address the nucleation, growth, and evaporation processes that influence the concentration and shape of individual particles and their role in specific atmospheric phenomena. To set the scene, figure 3.1 shows examples of such crystals collected by aircraft. In this chapter, we also address the radiation and dynamic environment in which crystals grow and subsequently evaporate. Crystal growth depends on the location of a crystal with respect to the cloud edge and the intervening cloud optical thickness; evaporation depends on larger scale processes as at fronts and cumulonimbus anvils and also at inversion interfaces where shear instability and resulting gravity waves produce significant effects over a range of scales. These effects lead to differing cloud radiative properties and ultimately control of the earth's radiation budget and overall climate (Liou 1986; Stephens et al. 1990; Liou and Takano 1994; Takano and Liou 1995; Mishchenko et al. 1996; Strauss et al. 1997; Macke et al. 1998). A growing crystal implies a supersaturated or supercooled environment with respect to the solid phase and can, in general, be considered as growth from either three-fold symmetry overlying a needle, (NASA DC-8,TOGA COARE,-48°C, deep tropical convection, 1993). The replica visually shows a uniformity of color in vertical illumination, indicating a thin crystal a few micrometers thick, uniform to ±0.05 μm. e. Replica of needles, small scalene and triangular three-fold symmetry plates, hexagonal plates, columns, and irregular crystals collected by D.L.R. Falcon in thin cirrus over the Alps, temperature -55°C, October 29,1992. (Courtesy Dr. P. Wendling.) f. Replica of crystals from the evaporating tip of a contrail formed 50 s earlier by the NASA 757 aircraft sampled from the NASA DC-8. Multiple trigonal symmetry crystals are present, with a 60° rotation (left side), along with hexagonal and scalene and triangle crystals, concentration 10/cm3. Clear sky environment over Kansas, temperature -52°C, 1840-1900Z, 4 May 1996.

For a review of a monograph by C. Wiles and P. Watts on applications of flow reactors in organic synthesis, see Org. Process. Res. Dev. 2011, 15, 947. For a review by Klavs S. Jensen of MIT of flow approaches, see Angew. Chem. Int. Ed. 2011, 50, 7502. Hans-René Bjørsvik of the University of Bergen described (Org. Process. Res. Dev. 2011, 15, 997) a multijet oscillating disc microreactor, and Andreas Schmid of the Technische Universität Dortmund (Adv. Synth. Catal. 2011, 353, 2511) and László Poppe of the Budapest University of Technology and Economics discussed (Adv. Synth. Catal. 2011, 353, 2481) continuous flow reactors for biotransformations. Gases are readily handled in a flow apparatus. S. Chandrasekhar of the Indian Institute of Chemical Technology, Hyderabad demonstrated (Tetrahedron Lett. 2011, 52, 3865) partial deuteration of 1 to 2, using D2O as the deuterium source. Peter H. Seeberger of the Max Planck Institute, Potsdam oxidized (Org. Lett. 2011, 13, 5008) 3 to 4 with singlet oxygen. Dong-Pyo Kim of Chungnam National University and Robert H. Grubbs of Caltech effected (Org. Lett. 2011, 13, 2398) ethenolysis of 5 to give 6 and 7. Takashi Takahashi of the Tokyo Institute of Technology showed (Chem. Commun. 2011, 47, 12661) that even phosgene could be handled in a flow system, using it to activate 8 for condensation with benzylamine to give 9. In the liquid phase, Stephen L. Buchwald of MIT prepared (Angew. Chem. Int. Ed. 2011, 50, 8900) 11 by the fluorination of 10. Jesús Alcázar of Janssen Pharmaceutical, Toledo, showed (Tetrahedron Lett. 2011, 52, 6058) that a nitrile 12 could be reduced in a flow system to the aldehyde 13. Mark York of CSIRO prepared (Tetrahedron Lett. 2011, 52, 6267) the furan 16 by condensation of 14 with 15. Floris P.J.T. Rutjes of Radboud University Nijmegen used (Org. Process Res. Dev. 2011, 15, 783) the careful controls of a flow reactor to optimize the exothermic combination of 17 with 18 to give 19. Professor Buchwald demonstrated (Angew. Chem. Int. Ed. 2011, 50, 10665) a flow protocol for the lithiation of 20 with in situ borylation and Pd-catalyzed coupling with 21 to give 22.

Xiangge Zhou of Sichuan University showed (Tetrahedron Lett. 2011, 52, 318) that even the monosubstituted alkene 1 was smoothly converted to the methyl ether 2 by catalytic FeCl3. Brian C. Goess of Furman University protected (J. Org. Chem. 2011, 76, 4132) the more reactive alkene of 3 as the 9-BBN adduct, allowing selective reduction of the less reactive alkene to give, after reoxidation, the monoreduced 4. Nobukazu Taniguchi of the Fukushima Medical University added (Synlett 2011, 1308) Na p-toluenesulfinate oxidatively to 1 to give the sulfone 5. Krishnacharya G. Akamanchi of the Indian Institute of Chemical Technology, Mumbai oxidized (Synlett 2011, 81) 1 directly to the bromo ketone 6. Osmium is used catalytically both to effect dihydroxylation, to prepare 8, and to mediate oxidative cleavage, as in the conversion of 7 to the dialdehyde 9. Ken-ichi Fujita of AIST Tsukuba devised (Tetrahedron Lett. 2011, 52, 3137) magnetically retrievable osmium nanoparticles that can be reused repeatedly for the dihydroxylation. B. Moon Kim of Seoul National University established (Tetrahedron Lett. 2011, 52, 1363) an extraction scheme that allowed the catalytic Os to be reused repeatedly for the oxidative cleavage. Maurizio Taddei of the Università di Siena showed (Synlett 2011, 199) that aqueous formaldehyde could be used in place of Co/H2 (syngas) for the formylation of 1 to 10. Hirohisa Ohmiya and Masaya Sawamura of Hokkaido University prepared (Org. Lett. 2011, 13, 1086) carboxylic acids (not illustrated) from alkenes using CO2. Joseph M. Ready of the University of Texas Southwestern Medical Center selectively arylated (Angew. Chem. Int. Ed. 2011, 50, 2111) the homoallylic alcohol 11 to give 12. Many reactions of alkenes are initiated by hydroboration, then conversion of the resulting alkyl borane. Hiroyuki Kusama of the Tokyo Institute of Technology photolyzed (J. Am. Chem. Soc. 2011, 133, 3716) 14 with 13 to give the ketone 15. William G. Ogilvie of the University of Ottawa added (Synlett 2011, 1113) the 9-BBN adduct from 1 to 16 to give 17. Professors Ohmiya and Sawamura effected (Org. Lett. 2011, 13, 482) a similar conjugate addition, not illustrated, of 9-BBN adducts to α,β-unsaturated acyl imidazoles.

Djamaladdin G. Musaev and Huw M. L. Davies of Emory University effected (Chem. Sci. 2013, 4, 2844) enantioselective cyclopropanation of ethyl acrylate 2 with the α-diazo ester 1 to give 3 in high ee. Philippe Compain of the Université de Strasbourg used (J. Org. Chem. 2013, 78, 6751) SmI2 to cyclize 4 to the cyclobutanol 5. Jianrong (Steve) Zhou of Nanyang Technological University effected (Chem. Commun. 2013, 49, 11758) enantioselective Heck addition of 7 to the prochiral ester 6 to give the cyclopentene 8. Liu-Zhu Gong of USTC, Hefei added (Org. Lett. 2013, 15, 3958) the Rh enolate from the enantioselective ring expansion of the α-diazo ester 9 to the nitroalkene 10, to give 11 in high de. Stephen P. Fletcher of the University of Oxford set (Angew. Chem. Int. Ed. 2013, 52, 7995) the cyclic quaternary center of 14 by the enantioselective conjugate addition to 12 of the alkyl zirconocene derived from 13. Alexandre Alexakis of the University of Geneva reported (Chem. Eur. J. 2013, 19, 15226) high ee from the conjugate addition of alkenyl Al reagents (not illustrated) to 12. Paultheo von Zezschwitz of Philipps-Universität Marburg prepared (Adv. Synth. Catal. 2013, 355, 2651) the silyl enol ether 17 by trapping the intermediate from the conjugate addition of 16 to 15. Stefan Bräse of the Karlsruhe Institute of Technology effected (Eur. J. Org. Chem. 2013, 7110) conjugate addition to the prochiral dienone 18 to give the highly substi­tuted cyclohexenone 19. Ping Tian and Guo-Qiang Lin of the Shanghai Institute of Organic Chemistry cyclized (J. Am. Chem. Soc. 2013, 135, 11700) 20 to the kinetic, less stable epimer of the diketone 21. Rh-mediated intramolecular C–H insertion has been a powerful tool for the con­struction of cyclopentane derivatives. Douglass F. Taber of the University of Delaware found (J. Org. Chem. 2013, 78, 9772) that the Rh carbene derived from 22 was dis­criminating enough to target the more nucleophilic C–H bond, leading to the cyclohexanone 23. Kozo Shishido of the University of Tokushima observed (Org. Lett. 2013, 15, 3666) high diastereoselectivity in the intramolecular Heck cyclization of 24 to 25.

Akio Baba of Osaka University combined (Chem. Lett. 2013, 42, 1551) reduction of the acid 1 with subsequent condensation with the ketene silyl acetal 2 to directly give the coupled product 3. Song-Lin Zhang of Soochow University showed (Chem. Commun. 2013, 49, 10635) that the allyl Sm reagent 5 could be added to an aldehyde 4 under reducing conditions, leading to the alkene 6. In a related development, Patrick Perlmutter of Monash University reduced (Org. Lett. 2013, 15, 4327) the interme­diate lactol from addition of the alkyl lithium reagent 8 to the lactone 7, to give the alcohol 9. Yoshihiro Miyake, now at Nagoya University, and Yoshiaki Nishibayashi of the University of Tokyo added (Chem. Commun. 2013, 49, 7854) the benzyl radical from the decarboxylation of 10 to the acceptor 11 to give 12. Yasuharu Yoshimi of the University of Fukui (Tetrahedron Lett. 2013, 54, 4324) and Larry E. Overman of the University of California, Irvine (J. Am. Chem. Soc. 2013, 135, 15342) reported related results. David Milstein of the Weizmann Institute of Science developed (Angew. Chem. Int. Ed. 2013, 52, 14131) an Fe catalyst for the hydrogenation of an alkyne 13 to the E-alkene 14. Zhi-Xiang Yu of Peking University showed (Org. Lett. 2013, 15, 4634) that kinetic isomerization of the alkene 15 led selectively to the Z-alkene 16. Umasish Jama of Jadavpur University prepared (Eur. J. Org. Chem. 2013, 4823) the nitroalkene 18 by condensing nitromethane with the aldehyde 17. Vladimir A. D’yakonov of the Russian Academy of Sciences, Ufa described (Chem. Commun. 2013, 49, 8401; Tetrahedron 2013, 69, 8516) the remarkably selective coupling of the allene 19 with the allene 20 to give the Z,Z-diene 21. Sang-Hyeup Lee of the Catholic University of Daegu assembled (Synlett 2013, 24, 1953) the ketone 24 by coupling the alkynyl aluminum 23 with the nitrile 22. Jean-Marc Weibel and Patrick Pale of the Université de Strasbourg showed (Chem. Eur. J. 2013, 19, 8765) that the alkenyl nosylate (p-nitrobenzenesulfonate) 25 coupled smoothly with 26, leading to the enyne 27. Reinhold Zimmer and Hans-Ulrich Reissig of the Freie Universität Berlin described (Synthesis 2013, 45, 2752) similar results with alkenyl nonaflates.

Benjamin List at the Max-Planck-Institute in Mülheim reported (Angew. Chem. Int. Ed. 2013, 52, 3490) that the chiral phosphoric acid TRIP catalyzed the asymmet­ric SN2-type intramolecular etherification of 1 to produce tetrahydrofuran 2 with a selectivity factor of 82. The coupling of alkenol 3 with 4 to give the α-arylated tetra­hydropyran 5 via a method that combined gold catalysis and photoredox catalysis was disclosed (J. Am. Chem. Soc. 2013, 135, 5505) by Frank Glorius at Westfälische Wilhelms-Universität Münster. Mark Lautens at the University of Toronto reported (Org. Lett. 2013, 15, 1148) the conversion of cyclohexanedione 6 and phenylboronic acid to bicyclic ether 8 using rhodium catalysis in the presence of dienyl ligand 7. Propargylic ether 9 was found (Org. Lett. 2013, 15, 2926) by John P. Wolfe at the University of Michigan to undergo conversion to furanone 10 upon treatment with dibutylboron triflate and Hünig’s base followed by oxidation with hydrogen peroxide. Tomislav Rovis at Colorado State University demonstrated (Chem. Sci. 2013, 4, 1668) that the spirocyclic compound 13 could be prepared in enantioenriched form from 11 by a photoisomerization- coupled Stetter reaction using carbene catalyst 12. Antonio C. B. Burtoloso at the University of São Paulo reported (Org. Lett. 2013, 15, 2434) the conversion of ketone 14 to lactone 15 using samarium(II) iodide and methyl acrylate. The merger of diketone 16 and pyrone 17 in the presence of Amberlyst-15 to pro­duce (−)- tenuipyrone 18 was disclosed (Org. Lett. 2013, 15, 6) by Rongbiao Tong at the Hong Kong University of Science and Technology. Joanne E. Harvey at Victoria University of Wellington in New Zealand found (Org. Lett. 2013, 15, 2430) that tricy­clic ether 20 could be generated efficiently from dihydropyran 19 and pyrone 17 via a palladium-catalyzed double allylic alkylation cascade. Two rings and four stereocenters were generated in the construction of bicyclic ether 23 from dienol 21 and acetal 22 via a Lewis acid-mediated cascade, as reported (Org. Lett. 2013, 15, 2046) by Christine L. Willis at the University of Bristol.

The primary objective of this book has been to present a reasonably broad overview of the different classes of discrete-time dynamic models that have been proposed for empirical modeling, particularly in the process control literature. In its simplest form, the empirical modeling process consists of the following four steps: 1. Select a class C of model structures 2. Generate input/output data from the physical process P 3. Determine the model M ∊ C that best fits this dataset 4. Assess the general validity of the model M. The objective of this final chapter is to briefly examine these four modeling steps, with particular emphasis on the first since the choice of the model class C ultimately determines the utility of the empirical model, both with respect to the application (e.g., the difficulty of solving the resulting model-based control problem) and with respect to fidelity of approximation. Some of the basic issues of model structure selection are introduced in Sec. 8.1 and a more detailed treatment is given in Sec. 8.3, emphasizing connections with results presented in earlier chapters; in addition, the problem of model structure selection is an important component of the case studies presented in Secs. 8.2 and 8.5. The second step in this procedure—input sequence design—is discussed in some detail in Sec. 8.4 and is an important component of the second case study (Sec. 8.5). The literature associated with the parameter estimation problem—the third step in the empirical modeling process—is much too large to attempt to survey here, but a brief summary of some representative results is given in Sec. 8.1.1. Finally, the task of model validation often depends strongly on the details of the physical system being modelled and the ultimate application intended for the model. Consequently, detailed treatment of this topic also lies beyond the scope of this book but again, some representative results are discussed briefly in Sec. 8.1.3 and illustrated in the first case study (Sec. 8.2). Finally, Sec. 8.6 concludes both the chapter and the book with some philosophical observations on the problem of developing moderate-complexity, discrete-time dynamic models to approximate the behavior of high-complexity, continuous-time physical systems.

Michael J. Krische at the University of Texas at Austin developed (Angew. Chem. Int. Ed. 2013, 52, 4470) a total synthesis of cyanolide A 7 in only seven steps, a sequence so short it is shown here in its entirety. Diol 1 was subjected to enantioselective cat­alytic bisallylation under iridium catalysis to furnish 2 with very high levels of ste­reocontrol. Cross metathesis using ruthenium catalyst 3 first with ethyl vinyl ketone and then with ethylene resulted in the production of pyran 4. Glycosylation of 4 with phenylthioglycoside 5, stereoselective reduction of the ketone function, and oxidative cleavage of the olefin then furnished the carboxylic acid 6. Finally, dimerization of 6 with 2-methyl-6-nitrobenzoic anhydride (MBNA) yielded cyanolide A. Kathlyn A. Parker at Stony Brook University reported (J. Am. Chem. Soc. 2013, 135, 582) a tandem radical cyclization strategy for the total synthesis of bisabosqual A 11. The key substrate 9 was prepared in three steps from the diester 8. Treatment of 9 with tri-s-butylborane and TTMS in the presence of air induced the tandem 5-exo, 6-exo radical cyclization to produce the complete core 10 of the natural product as a mixture of diastereomers, which could be equilibrated. Some further redox maneu­vers then led to bisabosqual A. Richard P. Hsung at the University of Wisconsin, Madison disclosed (Org. Lett. 2013, 15, 3130) a very brief synthesis of iso-eriobrucinol A and related isomers using a unique cascade sequence. First, phloroglucinol 12 and citral 13 were condensed using piperidine and acetic anhydride. The product of this operation was the tetracy­clic cyclobutane 14, the result of an oxa-[3+3] annulation followed by a stepwise, cat­ionic [2+2] cycloaddition. Treatment of 14 with methyl propiolate in the presence of catalytic indium(III) chloride under microwave irradiation furnished iso-eriobrucinol A, as well as the isomeric natural product iso-eriobrucinol B. A concise approach to trichodermatide A 19 was developed (Angew. Chem. Int. Ed. 2013, 52, 3546) by Kou Hiroya at Musashino University. Aldehyde 16, which was syn­thesized from L-tartaric acid, was condensed with 1,3-cyclohexanedione in the presence of piperidine, resulting in diketone 17.

Timothy F. Jamison at MIT developed (Org. Lett. 2013, 15, 710) a metal-free continuous-flow hydrogenation of alkene 1 using the protected hydroxylamine reagent 2 in the presence of free hydroxylamine. The reduction of nitroindole 4 to the corresponding aniline 5 using in situ-generated iron oxide nanocrystals in continuous flow was reported (Angew. Chem. Int. Ed. 2012, 51, 10190) by C. Oliver Kappe at the University of Graz. A flow method for the MPV reduction of ketone 6 to alcohol 7 was disclosed (Org. Lett. 2013, 15, 2278) by Steven V. Ley at the University of Cambridge. Corey R.J. Stephenson, now at the University of Michigan, developed (Chem. Commun. 2013, 49, 4352) a flow deoxygenation of alcohol 8 to yield 9 using visible light photoredox catalysis. Stephen L. Buchwald at MIT demonstrated (J. Am. Chem. Soc. 2012, 134, 12466) that arylated acetaldehyde 11 could be generated from aminopyridine 10 by diazonium formation and subsequent Meerwein arylation of ethyl vinyl ether in flow. The team of Takahide Fukuyama and Ilhyong Ryu at Osaka Prefecture University showed (Org. Lett. 2013, 15, 2794) that p-iodoanisole (12) could be converted to amide 13 via low-pressure carbonylation using carbon monoxide generated from mixing formic and sulfuric acids. The continuous-flow Sonogashira coupling of alkyne 14 to produce 15 using a Pd-Cu dual reactor was developed (Org. Lett. 2013, 15, 65) by Chi-Lik Ken Lee at Singapore Polytechnic. A tandem Sonogashira/cycloisomerization procedure to convert bromopyridine 16 to aminoindolizine 18 in flow was realized (Adv. Synth. Cat. 2012, 354, 2373) by Keith James at Scripps, La Jolla. A procedure for the Pauson-Khand reaction of alkene 19 to produce the bicycle 20 in a photochemical microreactor was reported (Org. Lett. 2013, 15, 2398) by Jun-ichi Yoshida at Kyoto University. Kevin I. Booker-Milburn at the University of Bristol discovered (Angew. Chem. Int. Ed. 2013, 52, 1499) that irradiation of N-butenylpyrrole 21 in flow produced the rearranged tricycle 22. Professor Jamison described (Angew. Chem. Int. Ed. 2013, 52, 4251) a unique peptide coupling involving the photochemical rearrangement of nitrone 23 to the hindered dipeptide 24 in continuous flow.

In platelets exposed to chelating agents at 37°C and recalcified, aggregation to ADP, adrenaline, collagen and thrombin were either abolished or markedly reduced (1). This phenomenon has been suggested to be caused by disruption, by Ca2+ deprivation, of the fibrinogen receptor (glycoprotein lib Ilia complex) on the surface of the platelet (2). This effect was dependent on the exposure time of Ca2+ chelators and was reduced at lower temperatures. We have investigated the effect of exposure of human platelets to EGTA upon aggregation to a range of agonists at both 37 and 25°C. EGTA (5 mM) was incubated with citrated (12.9 mM) whole blood for either 0, 1, 5, 15 or 30 min. One minute following recalcification (5 mM CaCl2), full aggregation concentration-response curves were constructed to ADP and adrenaline (0.1 to 3 μM), PAF (3 to 100 nM), collagen (0.1 to 4 μg/ml) and U46619 (0.03 to 1 μM), using a platelet counting technique (3). At 25°C, EGTA produced little or no significant loss of sensitivity to any agonist. At 37°C marked rightward shifts of the ADP, adrenaline and PAF aggregation curves occurred which were related to the time of incubation with EGTA (e.g. ADP concentration ratios (CR) of 2.0 (0.8-4.8), 4.7 (2.1-10.7), › 186.6 (135.2-257.6) (95% confidence intervals n=4) obtained at 1, 5 and 15 min respectively). Following 30 min incubation aggregation to all three agonists was abolished (up to ADP 300 pM; adrenaline 100 μM; PAF 10 μM). In contrast, whilst collagen and U46619 concentration-effect curves were displaced to the right following 30 minutes exposure to EGTA (CR =13.6 (6.1-30.4) and 9.0 (4.3-18.7) respectively, n=4) full aggregation curves could still be established. Furthermore, a 60 min incubation with EGTA caused little further effect. Our findings suggest platelet agonists such as collagen and U46619, but not ADP, adrenaline and PAF, can evoke expression of a population of fibrinogen receptor sites involved in platelet aggregation that are inaccessible to EGTA.(1) Zucker, MB & Grant, RA (1978). Blood, 52, 505. (2)Shattil, SJ et al. (1985). Blood, 66, 92. (3) Lumley, P & Humphrey, PPA (1981). J. Pharm. Methods, 6, 153.

Reduced circulating platelet count sometimes to thrombocytopenic levels in man and normally severe thrombocytopenia in animals are well known features of acute Plasmodium falciparum or experimental P. bergei infections in these respective organisms. Suggested mechanism(s), disseminated intravascular coagulation or immune mediated mechanism, thought to be involved in these observations are disputed. Shortened platelet survival has been reported in man.We now present data on platelet survival and total platelet sialic acid concentration in P. bergei-infected Wistar rats. A total of 52 rats were used. For the platelet survival studies each of the 8 suckling test animals was infected by intraperi-toneal route with mouse-passaged P. bergei 4-5 days before inaction of Cr-labelled homologous rat platelets (50 μCi Na51 CrC4/rat) the platelets being obtained from adult Wistarrats. Blood samples were then collected 2 hr after the injection (zero hr sample) and subsequently at 17.0, 42.5 and 66 hr s.Platelet recovery and survival curves were determined on these samples. It was found dat fewer platelets (as % recovery) were obtained from each infected rat sample compared with control, the difference was significant in the 42.5 and 66 hr samples: 7.9 ± 8.1 (test) vs 41.4 ± 15.2% (C) for 42.5 hr and 2.8 ±4.1 (t) vs 26.8 ± 6.2% (C) for the 66 hr samples (p < 0.005 for each). For sialic acid determinations, 40 suckling Wistar rats (30 test, 10 control) were treated as for survival studies.At identical periods, blood was collected, washed platelets obtained, lysed and protein and total sialic acid determined by Lowry (1951) and Aminoff (1961) methods respectively. Total sialic acid of 7.02 ± 4.21 nM/mg protein at 42.5 hrs and 4.8 ± 2.14 at 66 hrs were significantly less than control value of 11.43 nm/mg protein and also showed a negative correlation (r = -0.95) with % parasitaemia.It is concluded that P. bergei infection causes a reduction in total platelet sialic acid with resultant significant shortening of the platelet life span.

With the continuous development of interactive technology, informatization has begun to integrate into people's life[1].Having been neglected in history, postpartum depression reminds us that we need to pay attention to maternal emotional needs and prenatal care[2]. In the current situation, it is worth researching the interactive products for prenatal emotional care. According to the survey, it is not difficult to find that some speech emotion and facial expression recognition technologies in artificial intelligence are developing Which have large potential for extensive use.[3,4]. Therefore, it is necessary and feasible to design prenatal emotional diagnosis tools for pregnant women. This study has designed a product to care for pregnant women by identifying their emotional needs through AI recognition technologies. Appropriate prenatal intervention is conducive to the prevention of postpartum depression[5,6] . The use of artificial intelligence recognition technology can provide an appropriate emotional care plan. This can reduce the difficulty of training medical personnel and the difficulty of relatives caring for pregnant women. Therefore, the risk of postpartum depression can be reduced. QUESTIONCollecting opinions and information from previous studies is an important reference for this study. Therefore, this study needs to solve the following problems.1) How to design an artificial intelligence product that can accurately diagnose the emotion of pregnant women?2) How to integrate AI facial emotion recognition technology?3) How to help nurses and their families take care of users more professionally and easily through the information database?4) How to adapt the emotional care program provided by interactive products to different pregnant women? Methods:the research methods of this study are as follows:1) Observing the working process of artificial midwives and psychologists to find Which part can be assisted by machines[7].2) To understand the emotional needs of pregnant women through interview.3) To brainstorm according to the real data collected before and research findings, and then design interactive products that can practically solve the emotional care problems of pregnant women.4) Through the experiment of AI emotion recognition technologies, the feasibility of emotion recognition is verified. CONCLUSIONS:With the continuous development of artificial intelligence, more and more artificial intelligence products have entered our life [1]. This study is aimed to help pregnant women prevent prenatal and postpartum depression and maintain their health through artificial intelligence interaction technologies. This study is exploring the solution under the help of artificial intelligence after studying the problem that prenatal and postpartum emotion are neglected. This design is still in the conceptual design stage, but it seems only a matter of time before this design is applied in the future[8]. REFERENCES:[1]. Lee H S , Lee J . Applying Artificial Intelligence in Physical Education and Future Perspectives. 2021.[2]. Beck C T . Postpartum depression: it isn't just the blues.[J]. American Journal of Nursing, 2006, 106(5):40-50.[3].Ramakrishnan S , Emary I M M E . Speech emotion recognition approaches in human computer interaction[J]. Telecommunication Systems, 2013, 52(3):OnLine-First.[4]. Samara A , Galway L , Bond R , et al. Affective state detection via facial expression analysis within a human–computer interaction context[J]. Journal of Ambient Intelligence & Humanized Computing, 2017.[5]. Clatworthy J . The effectiveness of antenatal interventions to prevent postnatal depression in high-risk women[J]. Journal of Affective Disorders, 2012, 137(1-3):25-34.[6]. Ju C H , Hye K J , Jae L J . Antenatal Cognitive-behavioral Therapy for Prevention of Postpartum Depression: A Pilot Study[J]. Yonsei Medical Journal, 2008, 49(4):553-.[7]. Fletcher A , Murphy M , Leahy-Warren P . Midwives' experiences of caring for women's emotional and mental well-being during pregnancy[J]. Journal of Clinical Nursing, 2021.[8]. Jin X , Liu C , Xu T , et al. Artificial intelligence biosensors: Challenges and prospects[J]. Biosensors & Bioelectronics, 2020, 165:112412.

The increasing advance of the new technologies applied in the retail market, make it common to sell products without the personal contact between seller and buyer, being the registration and payment of the products made in electronic equipment of self-checkout. The large-scale use of these devices forces the consumer to participate in the service process, which was previously done through interaction with the company's employees. The user of the self-checkout system thus performs all the steps of the purchase, from weighing the products, registering them and making the payment. This is seen as a partial employee, whose participation or performance in providing services can be used by the company to improve the quality of its operations (KELLEY, et al 1993). However this participation does not always satisfy the user, and may cause negative experiences related to usability failures. This article presents the results of the evaluation by the users of the self-checkout system. The data were collected in Portugal through a questionnaire to 400 users. The study analyzes the degree of satisfaction regarding the quality and usability of the system, the degree of motivation for its adoption, as well as the profile of the users. Analysis of the sample data reveals that users have basic or higher education and use new technologies very often. They also have a high domain of the system and an easy learning of its use. The reason for using self-checkout instead of the traditional checkout is mainly due to "queues at checkout with operator" and "at the small volume of products". In general, the sample reveals a high degree of satisfaction with the service and with quality, however, in comparative terms, self-checkout is not considered better than operator checkout. The evaluation of the interaction with the self-checkout was classified according to twenty-six attributes of the system. The analysis identifies five groups with similar characteristics, of which two have low scores. "Cancellation of registered articles", "search for articles without a bar code", "manual registration", "bagging area", "error messages", "weight sensor" and “invoice request "are seven critical attributes of the system. The results indicate that the usability analysis oriented to the self-checkout service can be determinant for the user-system interaction. The implications of empirical findings are discussed together with guidelines for future research.Keywords: Interaction Design, Self service, Self-checkout, User evaluation, UsabilityReferencias ABRAHÃO, J., et al (2013). Ergonomia e Usabilidade. 1ª Edição. São Paulo: Blucher. ALEXANDRE, J. W. C., et al (2013). Análise do número de categorias da escala de Likert aplicada à gestão pela qualidade total através da teoria da resposta ao item. In: XXIII Encontro Nacional de Engenharia de Produção, Ouro Preto. BOOTH, P. (2014). An Introduction to Human-Computer Interaction (Psychology Revivals). London Taylor and Francis. CASTRO, D., ATKINSON, R., EZELL, J., (2010). Embracing the Self-Service Economy, Information Technology and Innovation Foundation. Available at SSRN: http://dx.doi.org/10.2139/ssrn.1590982 CHANG, L.A. (1994). A psychometric evaluation of 4-point and 6-point Likert-type scale in relation to reliability and validity. Applied Psychological Measurement. v. 18, n. 2, p. 05-15. DABHOLKAR, P. A. (1996). Consumer Evaluations of New Technology-based Self-service Options: An Investigation of Alternative Models of Service Quality. International Journal of Research in Marketing, Vol. 13, pp. 29-51. DABHOLKAR, P. A., BAGOZZI, R. P. (2002). An Attitudinal Model of Technology-based Selfservice: Moderating Effects of Consumer Traits and Situational Factors. Journal of the Academy of Marketing Science, Vol. 30 (3), pp. 184-201. DABHOLKAR, P. A., BOBBITT, L. M. &amp; LEE, E. (2003). Understanding Consumer Motivation and Behavior related to Self-scanning in Retailing. International Journal of Service Industry Management, Vol. 14 (1), pp. 59-95. DIX, A. et al (2004). Human-Computer Interaction. Third edition. Pearson/Prentice-Hall. New York. FERNANDES, F. et al, (2015). Do Ensaio à Investigação – Textos Breves Sobre a Investigação, Bernabé Hernandis, Carmen Lloret e Francisco Sanmartín (Editores), Oficina de Acción Internacional - Universidade Politécnica de Valência Edições ESAD.cr/IPL, Leiria. HELANDER, M., LANDAUER, T., PRABHU, P. (1997). Handbook of Human – Computer Interaction. North–Holland: Elsevier. KALLWEIT, K., SPREER, P. &amp; TOPOROWSKI, W. (2014). Why do Customers use Self-service Information Technologies in Retail? The Mediating Effect of Perceived Service Quality. Journal of Retailing and Consumer Services, Vol. 21, pp. 268-276. KELLEY SW, HOFFMAN KD, DAVIS MA. (1993). A typology of retail failures and recoveries. J Retailing. 69(4):429 – 52.

Studies suggest that dogs preferentially choose fat as their major dietary energy source (59-63% of the total metabolisable energy (ME) content of the diet). However, high fat diets have been linked to the development of pancreatitis in dogs. This study investigated several biomarkers associated with pancreatitis in dogs fed either a high fat (HF; Protein: Fat: Carbohydrate content; 35%:63%:2% ME; n= 10 dogs) or high carbohydrate (HC; Protein: Fat: Carbohydrate content; 17%:32%:51% ME) diet.A high fat meal tolerance test (MTT) was undertaken on dogs (n=20) at baseline consuming a commercial dry food diet (Protein: Fat: Carbohydrate content; 23%:25%:52% on an ME basis) and then again after 8 weeks consuming either a HF (n=10) or HC (n=10) diet. Briefly, after an overnight fast, dogs were fed a single meal containing 100% of their daily requirements (P: F: C content; 35%:63%:2% ME). Each dog was then blood sampled 1, 2, 3, 4, 5, 6, 12, and 24 hours post-prandially. Samples were analysed for plasma triglycerides and markers of pancreatitis (i.e., pancreatic lipase, endotoxin, C-reactive protein, Interleukin 1-alpha, Interleukin 6 and Tumour necrosis factor-alpha). The postprandial peak plasma concentration of triglycerides (Cmax) were higher (p less than 0.001) at baseline, compared to after feeding of the either the HC or HF diets for 8 weeks. This suggests dietary components such as moisture level, specific ingredients, level of diet processing, and possibly apparent nutrient digestibility were potential factors driving this response. There was no effect of feeding either HF or HC diets on Cmax values (P >0.05) during the final MTT. This study suggests that feeding a HF diet for 8 weeks does not elevate blood markers associated with pancreatitis, with the serum biochemistry and complete blood count indicating the dogs remained clinically healthy.

Abstract The paper investigates matrix-free high-order implementation of finite element discretization with p-multigrid preconditioning for the compressible Neo-Hookean hyperelasticity problem at finite strain on unstructured 3D meshes in parallel. We consider two formulations for the matrix-free action of the Jacobian in Neo-Hookean hyperelasticity: (i) working in the reference configuration to define the second Piola-Kirchhoff tensor as a function of the Green-Lagrange strain S(E) (or equivalently, the right Cauchy-Green tensor C = I+2E), and (ii) working in the current configuration to define the Kirchhoff stress in terms of the left Cauchy-Green tensor τ(b). The proposed efficient algorithm utilizes the Portable, Extensible Toolkit for Scientific Computation (PETSc), along with the libCEED library for efficient compiler optimized tensor-product-basis computation to demonstrate an efficient nonlinear solution algorithm. We utilize p-multigrid preconditioning on the high-order problem with algebraic multigrid (AMG) on the assembled linear Q1 coarse grid operator. In contrast to classical geometric multigrid, also known as h-multigrid, each level in p-multigrid is related to a different approximation polynomial order p, instead of the element size h. A Chebyshev polynomial smoother is used on each multigrid level. AMG is then applied to the assembled Q1 (trilinear hexahedral elements), which allows low storage that can be efficiently used to accelerate convergence to a solution. For the compressible Neo-Hookean hyperelastic constitutive model we exploit the stored energy density function to compute the stored elastic energy density of the Neo-Hookean material as it relates to the deformation gradient. Based on our formulation, we consider four different algorithms each with different storage strategies. Algorithms 1 and 3 are implemented in the reference and current configurations respectively and store ∇Xξ, det(∇ξX), and ∇Xu. Algorithm 2 in the reference configuration stores, ∇Xξ, det(∇ξX), ∇Xu, C−1, and λ log (J). Algorithm 4, in the current configuration, stores det(∇ξX), ∇xξ, τ, and μ – λ log(J). x refers to the current coordinates, X to the reference coordinates, and ξ to the natural coordinates. We perform 3D bending simulations of a tube composed of aluminum (modulus of elasticity E = 69 GPa, Poisson’s ratio v = 0.3) using unstructured meshes and polynomials of order p = 1 through p = 4 under mesh refinement. We explore accuracy-time-cost tradeoffs for the prediction of strain energy across the range of polynomial degrees and Jacobian representations. In all cases, Algorithm 4 using the current configuration formulation outperforms the other three algorithms and requires less storage. Similar simulations for large deformation compressible Neo-Hookean hyperelasticity as applied to the same aluminum material are conducted with ABAQUS, a commercial finite element software package which is a state-of-the-art engineering software package for finite element simulations involving large deformation. The best results from the proposed implementations and ABAQUS are compared in the case of p = 2 on an Intel system with @2.4 GHz and 128 GB RAM. Algorithm 4 outperforms ABAQUS for polynomial degree p = 2.

The 2014 Edition of ASME B31.3, Process Piping [1], introduced significant changes to the post weld heat treatment (PWHT) requirements for P-No. 1 carbon steel materials. In particular, PWHT is no longer a mandatory requirement for any wall thickness provided that multi-pass welding is employed for wall thicknesses greater than 5 mm (3/16 of an inch) and a minimum preheat of 95°C (200°F) is implemented for wall thicknesses greater than 25 mm (1 inch). Detailed fracture mechanics analyses have shown that the lack of a mandatory PWHT requirement for thicker P-No. 1 components may result in a significant increase in risk for brittle fracture failures due to near-yield level weld residual stresses. Given the concern throughout the pressure vessel and piping community regarding potential brittle fracture failures, this updated PWHT guidance is examined. Impact testing requirements and exemption curves were introduced in the 1987 Addenda [2] of ASME Section VIII Division 1 (VIII-1) [3] in Paragraph UCS-66 and extended into ASME Section VIII Division 2 (VIII-2) [4]. During the VIII-2 rewrite in 2007 [5], the available technical and historical basis for the UCS-66 exemption curves was examined and improved to reflect modern fracture mechanics standards. The result of that effort was a systematic approach that can be modified for particular geometries and assumed flaws, if desired. The method used the most modern, fracture mechanics approach for welds in API 579-1/ASME FFS-1, Fitness-For-Service, (API 579) [6] based on the failure assessment diagram (FAD). As a result of explicitly accounting for weld residual stress, two separate sets of exemption curves are provided in VIII-2 [4]; one set for as-welded components and another set for PWHT components. In this paper, a similar approach is summarized to generate exemption curves by establishing newer as-welded and PWHT curves using the Fracture Toughness Master Curve (Master Curve) as documented in upcoming Welding Research Council (WRC) Bulletin 562 [7]. The increased propensity for brittle fracture in as-welded components versus PWHT components is clearly highlighted using this approach. The Master Curve, in conjunction with the elastic-plastic fracture mechanics employed in API 579 [6] provides a means to develop exemptions curves anchored in state-of-the-art fracture toughness technology that can be directly tied to different reference flaw sizes. Additionally, commentary on the appropriateness of the current ASME B31.3 [1] PWHT requirements is offered and the effectiveness of using weld preheat in lieu of PWHT as permitted in the National Board Inspection Code (NBIC) [8] is examined using simplified computational weld analysis.

RESUMO A abordagem sistêmica é um processo interdisciplinar, cujo princípio primordial é compreender a interdependência recíproca e relações de todas as áreas e da necessidade de sua integração, permitindo maior aproximação entre os seus limites de estudo. Nesse contexto o olhar sistêmico, da ergonomia, sobretudo no que se refere à segurança, ao conforto e à eficácia de uso, de funcionalidade e de operacionalidade dos objetos, considerando todos os produtos ou sistemas de produtos, como sistema de uso, desde os mais simples aos mais complexos ou sistêmicos, tem como objetivo adequá-los aos seres humanos, tendo em vista as atividades e tarefas exercidas por eles. No que se refere ao design funcional, os conhecimentos da ergonomia, nessa visão sistêmica, relativos à sua metodologia de projeto, são absolutamente necessários, e a sua aplicação aponta a melhor adequação dos produtos aos seus usuários. Como é o caso do vestuário feminino funcional, sobretudo no que se refere a proteção das mamas, que são peças convencionais que necessitam de um correto dimensionamento e especificação dos tecidos e de outros materiais. É um tipo de vestuário que apresenta funcionalidade diversa, como para a proteção física, o aumento do volume da mama, enchimento no bojo de pano, de água, de óleo, estruturado com arame, etc.; para amamentação (sutiã que se abre na frente, em parte ou totalmente); para o design inclusivo (pessoas com deficiência e mobilidade reduzida, no caso de mamas com prótese ou órtese) facilitando com fechamentos e aberturas colocadas em peças de roupas difíceis de manusear, roupas confortáveis e fáceis de vestir. São peças usadas por pessoas com biótipos e percentis antropométricos variáveis e com características corporais que mudam significativamente nas passagens para a adolescência, idade adulta e idosa. As mudanças corporais apresentam diferenças significativas em termos de volume das mamas, nas quais as soluções ergonômicas por uma abordagem sistêmicas que se evidencia mais para a complexidade de uso, são as mais necessárias em termos de atributos como, segurança, conforto, comodidade corporal, facilidade do vestir, funcionalidade, além da estética. Esta pesquisa, embora exploratória e descritiva, não isenta de desafios, tem por objetivo, por meio de dados e informações ergonômicas sistêmicas contribuir com o design funcional, de modo a oferecer subsídios para a confecção de roupas funcionais ou tecnologia vestível, com os atributos citados, respeitando a diversidade e inclusão das pessoas em todas as fases de sua vida, atendendo assim os princípios formais do design. Palavra-chave: Abordagem sistêmica, Ergonomia, Design funcional. REFERENCIAS AROS, Kammiri Corinaldesi. Elicitação do processo projetual do Núcleo de Abordagem Sistêmica do Design da Universidade Federal de Santa Catarina. Orientador: Luiz Fernando Gonçalves de Figueiredo – Florianópolis, SC, 2016. BERTALANFFY, Ludwig V. Teoria geral dos sistemas: fundamentos, desenvolvimento e aplicações. 3. ed. Petrópolis, RJ: Vozes, 2008. BEST, Kathryn. Fundamentos de gestão do design. Porto Alegre: Bookman, 2012. 208 p. CHIAVENATO, I. Gestão de pessoas. 3ª ed. Rio de Janeiro: Elsevier, 2010. CORRÊA, Vanderlei Moraes; BOLETTI, Rosane Rosner. Ergonomia: fundamentos e aplicações. Bookman Editora, 2015.MERINO, Eugenio. Fundamentos da ergonomia. 2011. Disponível em: &lt;https://moodle.ufsc.br/pluginfile.php/2034406/mod_resource/content/1/Ergo_Fundamentos.pdf&gt;. Acesso em: 24 Mar 2017. DIAS E. C. Condições de vida, trabalho, saúde e doença dos trabalhadores rurais no Brasil. In: Pinheiro TMM, organizador. Saúde do trabalhador rural –RENAST. Brasília: Ministério da Saúde; 2006.p. 1-27. GIL, A. C. Como elaborar projetos de pesquisa. 4. ed. São Paulo: Atlas, 2010. GOMES FILHO, J. Ergonomia do objeto: sistema técnico de leitura ergonômica. São Paulo: Escrituras Editora, 2003. GUIMARÃES, L. B. M. (ed). Ergonomia de Processo. Porto Alegre, v.2, PPGE/UFRGS, 2000. IIDA, I. Ergonomia: projeto e produção. 2ª ed rev. e ampl. – São Paulo: Edgard Blucher, 2005. MANZINI, Ezio. Design para inovação social e sustentabilidade: comunidades criativas, organizações colaborativas e novas redes projetuais. Rio de Janeiro: E-Papers, 2008, 104p. MARCONI, M. A.; Lakatos, E. M. Fundamentos de metodologia científica. São Paulo: Atlas, 2007. Pandarum, R., Yu, W., and Hunter, L., 2011. 3-D breast anthropometry of plus-sized women in South Africa. Ergonomics, 54(9), 866–875. McGhee, D.E., Steele, J.R., and Munro, B.J., 2008. Sports bra fitness. Wollongong (NSW): Breast Research Australia. McGhee, D.E., Steele, J.R., and Munro, B.J., 2010. Education improves bra knowledge and fit, and level of breast support in adolescent female athletes: a cluster-randomised trial. Journal of Physiotherapy, 56, 19–24. Pechter, E.A., 1998. A new method for determining bra size and predicting postaugmentation breast size. Plastic and Reconstructive Surgery, 102 (4), 1259–1265. RICHARDSON, R. J. Pesquisa social: métodos e técnicas. 3 ed. São Paulo: Atlas, 2008. RIO, R. P. DO; PIRES, L. Ergonomia: fundamentos da prática ergonômica, 3ª Ed., Editora LTr, 2001. SANTOS, N. ET AL. Antropotecnologia: A Ergonomia dos sistemas de Produção. Curitiba: Gênesis, 1997. VASCONCELLOS, Maria José Esteves de. Pensamento sistêmico: O novo paradigma da ciência. 10ª ed. Campinas, SP: Papirus, 2013. WEERDMEESTER, J. D. e B. Ergonomia Prática. São Paulo: Edgard Blucher, 2001. WHITE, J.; SCURR, J. Evaluation of professional bra fitting criteria for bra selection and fitting in the UK. Ergonomics, 1–8. 2012. WHITE, J.;SCURR, J.; SMITH, N. The effect of breast support on kinetics during overground running performance. Ergonomics, Taylor &amp; Francis. 52 (4), 492–498. 2009.

Considered repositories of objects(Cuno 2009), museums have been analysed through the object-oriented policies they mainly focus on. Three main purposes are often mentioned: preservation, dissemination of knowledge and access to tradition. Beyond these informative and cultural-laden functions, museums have also been labeled as theatres of power, the emphasis lying on nation-oriented policies. According to Michael F. Brown (2009: 148), the outcome of this moral standing of the nation-state is a mobilizing public sentiment in favour of the state power. We consider that the constant flow of national and international exhibitions or events that could be hosted in museums has a twofold consequence: on the one hand, a cultural dynamics due to the permanent contact with unknown objects, and on the other hand, some visibility strategies in order to attract visitors. This latter effect actually embodies a shift within the perception of museums from entities of knowledge towards leisure environments. Within this context where the concept of edutainment(Eschach 2007) seems to prevail in the non-formal way of acquiring new knowledge, contemporary virtual museums display visual information without regard to geographic location (Dahmen, Sarraf, 2009). They play ?a central role in making culture accessible to the mass audience(Carrazzino, Bergamasco 2010) by using new technologies and novel interaction paradigms. Our study will aim at analyzing the way in which civilization was e-framed in the virtual project ?A History of the World in 100 Objects, run by BBC Radio 4 and the British Museum in 2010. The British Museum won the 2011 Art Fund Prize for this innovative platform whose main content was created by the contributors (the museums and the members of the public). The chairman of the panel of judges, Michael Portillo, noted that the judges were impressed that the project used digital media in ground-breaking and novel ways to interact with audiences. The two theoretical frameworks used in our analysis are framing theories and critical discourse analysis. ?Schemata of interpretation? (Goffman 1974), frames are used by individuals to make sense of information or an occurrence, providing principles for the organization of social reality? (Hertog & McLeod 2001). Considered cultural structures with central ideas and more peripheral concepts and a set of relations that vary in strength and kind among them? (Hertog, McLeod 2001, p.141), frames rely on the selection of some aspects of a perceived reality which are made more salient in a communicating text or e-text. We will interpret this virtual museum as a hypertext which ?makes possible the assembly, retrieval, display and manipulation? (Kok 2004) of objects belonging to different cultures. The structural analysis of the virtual museum as a hypertext will focus on three orders of abstraction (Kok 2004): item, lexia, and cluster. Dividing civilization into 20 periods of time, from making us human (2,000,000 - 9000 BC) up to the world of our making (1914 - 2010 AD), the creators of the digital museum used 100 objects to make sense of the cultural realities which dominated our civilization. The History of the World in 100 Objects used images of these objects which can be considered ?as ideological and as power-laden as word (Jewitt 2008). Closely related to identities, ideologies embed those elements which provide a group legitimation, identification and cohesion. In our analysis of the 100 virtual objects framing e-civilization we will use the six categories which supply the structure of ideologies in the critical discourse analysis framework (van Dijk 2000: 69): membership, activities, goals, values/norms, position (group-relations), resources. The research questions will focus on the content of this digital museum: (1) the types of objects belonging to the 20 periods of e-civilization; (2) the salience of countries of origin for the 100 objects; (3) the salience of social practices framed in the non-formal teaching of e-civilization/culture; and on the visitors? response: (1) the types of attitudes expressed in the forum comments; (2) the types of messages visitors decoded from the analysis of the objects; (3) the (creative) value of such e-resources. References Brown, M.F. (2009). Exhibiting indigenous heritage in the age of cultural property. J.Cuno (Ed.). Whose culture? The promise of museums and the debate over antiquities (pp. 145-164), Princeton, Oxford: Princeton University Press. Carrazzino, M., Bergamasco, M. (2010). Beyond virtual museums: Experiencing immersive virtual reality in real museums. Journal of Cultural Heritage, 11, 452-458. Cuno, J. (2009) (Ed.). Whose culture? The promise of museums and the debate over antiquities (pp. 145-164), Princeton, Oxford: Princeton University Press. Dahmen, N. S., & Sarraf, S. (2009, May 22). Edward Hopper goes to the net: Media aesthetics and visitor analytics of an online art museum exhibition. Visual Communication Studies, Annual Conference of the International Communication Association, Chicago, IL. Eshach, H. (2007). Bridging in-school and out-of-school learning: formal, non-formal, and informal education . Journal of Science Education and Technology, 16 (2), 171-190. Goffman, E. (1974). Frame analysis: An essay on the organization of experience. Cambridge, MA: Harvard University Press. Hertog, J.K., & McLeod, D. M. (2001). A multiperspectival approach to framing analysis: A field guide. In S.D. Reese, O.H. Gandy, & A.E. Grant (Eds.), Framing public life: Perspective on media and our understanding of the social world (pp. 139-162). Mahwah, NJ: Lawrence Erlbaum Associates. Jewitt, C. (2008). Multimodality and literacy in school classrooms. Review of Research in Education, 32 (1), 241-267. Kok, K.C.A. (2004). Multisemiotic mediation in hypetext. In Kay L. O?Halloren (Ed.), Multimodal discourse analysis. Systemic functional perspectives (pp. 131-159), London: Continuum. van Dijk, T. A. (2000). Ideology ? a multidisciplinary approach. London, Thousand Oaks, New Delhi: Sage.