Academic literature on the topic 'S-step CG method'

Abstract The study investigates effectiveness of selected credit related macro prudential instruments in reducing the correlation between economic and credit growth in European emerging countries between 2000 and 2017. Two GMM (Generalized Method of Moments) estimators are used to empirically investigate the validity of tightening policy actions. Although greater attention to MMPs is found in both European regions the study finds some differences as well. On the level of full sample, the findings confirm our expectation about effectiveness of the selected credit related macroprudential instruments in reducing credit growth. More specifically, the European transition countries proved to be more successful in using macroprudential tools in curbing credit growth than European post-transition countries. It is confirmed that all three employed credit related macroprudential instruments play a key role in curbing credit growth in the expansive stage of business cycle in the European transition countries. It means that a lower economic growth leads to lower effects of credit related macroprudential instruments on credit growth. However, empirical evidence from European post-transition countries shows mixed results followed by the lack of robustness of economic results, but with expected theoretical sign. In fact, introduction of CG limits and FC limits reduce the correlation between GDP growth and credit growth only in one step S-GMM estimator, while a variable of caps on debt-to-income ratio (DTI) not.

Abstract Abstract 3815 Background: The activity of DNA methyltransferase inhibitor (DNMTI) monotherapy is suboptimal for most patients (pts) with myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML). DNMTI combinations studied to date have not convincingly produced higher response rates compared to DNMTI monotherapy, although time to response appears to be improved in some studies. We combined decitabine (DAC) with tretinoin (ATRA), an RAR ligand which can recruit histone acetyltransferases to gene regulatory regions, as a means to upregulate gene expression, and to induce apoptosis or differentiation, as is seen in in vitro studies of non-M3 AML. Our previous phase 1 study established 65 mg/m2/day of ATRA as the MTD (headache was DLT at 85 mg/m2/d) when given on days 10–19 following standard dose decitabine (20 mg/m2/d), given on days 1–5 of a 28-day cycle (Klimek VM, et al. Leuk Res, 2011;35:S70-S). Materials and Methods: MDS pts with any FAB or WHO subtype were enrolled if they had an IPSS score ≥ 0.5, were ineligible for allogeneic stem cell transplant (AlloSCT) at study entry, and had adequate hepatic and renal function. Prior DAC or 5-azacytidine (5-aza) responders who then progressed off treatment, and pts whose MDS progressed on 5-aza were eligible. Pts received up to 10 cycles of DAC (given on days 1–5) and tretinoin (65 mg/m2/d on days 10–19 of a 28-day cycle), allowing for delays due to infection or to allow count recovery as deemed necessary by the treating physician. Those with an ongoing response after 10 cycles continued DAC alone off-study. The primary endpoint is efficacy, assessed after even-numbered cycles using the 2006 Modified International Working Group MDS response criteria. Kaplan-Meier methodology was used to estimate duration of best response due to the censoring for patients undergoing AlloSCT. Results: 36 eligible pts (27M, 9F; median age 66, range 45–84 yrs) were enrolled in the phase 2 cohort as of 6/2012. FAB/WHO subtypes included: RA/RCMD, n=3 (8%); RARS/RCMD-RARS, n=1 (3%); RAEB/RAEB-1 & 2, n= 24 (67%); RAEBt/AML, n= 6 (17%); CMML/CMML-1, n=2 (6%). IPSS risk categories included: Int-1, n=5 (14%); Int-2, n=16 (44%); High Risk, n=11 (31%), and pts with ≥ Int-1 (n=3) or ≥ Int-2 (n=1) risk disease who could not be definitively classified using the IPSS. Most pts (n=20) had IPSS poor risk cytogenetics (CG), 11 had IPSS good risk CG (all with normal karyotype), 3 had intermediate risk CG, and CG results were unknown in 2 pts. 15/36 (42%) had therapy-related disease (t-MDS/AML), all with IPSS poor risk CG and either IPSS Int-2 (n=9) or High Risk (n=6) disease. Marrow blasts were ≥ 5% in 26/36 pts: (5–10%, n=13; 11–20%, n=13; 21–30%, n=6). Prior MDS therapy included lenalidomide (n=2), thalidomide (n=1), 5-aza (n=3), DAC (n=1), and lintuzumab (n=1). Pts received a median of 4 cycles of therapy (range, 1–10), and started therapy 0.6–180 months (median, 1.42 months) from the time of diagnosis. Two pts were classified as treatment failures since they died during the first cycle of therapy. One pt with CMML-1 at baseline progressed to AML during the screening period, and was deemed ineligible. Two pts on study have not yet had a full response assessment. Best responses in the evaluable intent to treat cohort (n=33) include: CR, n=7 (21%); PR, n=1 (3%); mCR, n=3 (9%); mCR+HI, n=3 (9 %); HI alone, n=3 (9 %); Stable disease, n=10 (30%); Disease progression, n= 3 (9%). The composite CR rate (CR+mCR±HI) was 39% (13/33), and the overall response rate (CR+PR+mCR±HI+HI) is 51% (17/33). Median time from diagnosis to start of therapy for responders was 1.7 months (range, 0.8–180). The ORR for the 13 t-MDS/AML pts was 46% (6/13), including 5 pts with monosomy 17 and/or p53 loss by FISH. The median time to initial response and best response is 1.1 months and 2.3 months, respectively. The median response duration is 7.8 months, incorporating the 7 pts censored at the time they came off study to undergo AlloSCT. Conclusions: DAC/ATRA is active in IPSS Int-2 and High Risk MDS and in t-MDS/AML, which is characterized by poor risk cytogenetics and an increased frequency of p53 or chromosome 17p loss. Although our interim ORR appears similar to DAC and 5-aza monotherapy trials, our results were achieved in a higher risk cohort, and the CR rate is equal to or greater than some earlier monotherapy studies with a shorter median time to response. Ongoing and planned correlative studies may define pre-treatment biomarkers for response. Disclosures: Off Label Use: Tretinoin.

Background: The treatment of large-sized bone defects remains a major challenge in trauma and orthopaedic surgery. Although there are many treatment options, there is still no clear guidance on surgical management, and the influence of defect size on radiological and clinical outcome remains unclear due to the small number of affected patients. The aim of the present study was to determine the influence of defect size on the outcome of atrophic and infected nonunions of the tibia or the femur based on the diamond concept in order to provide recommendations for treatment guidance. Patients and Methods: All medical records, surgical reports, laboratory data and radiological images of patients treated surgically for atrophic or infected nonunions of the lower limbs (femur or tibia) between 1 January 2010 and 31 December 2020 were examined. Patients with proximal, diaphyseal or distal nonunions of the femur or tibia who were surgically treated at our institution according to the “diamond concept” and attended our standardised follow-up program were included in a database. Surgical treatment was performed as a one- or two-step procedure, depending on the type of nonunion. Patients with a segmental bone defect ≥5 cm were matched with patients suffering a bone defect <5 cm based on five established criteria. According to our inclusion and exclusion criteria, 70 patients with a bone defect ≥5 cm were suitable for analysis. Two groups were formed by matching: the study group (bone defect ≥5 cm; n = 39) and control group (bone defect <5 cm; n = 39). The study was approved by the local ethics committee (S-262/2017). Results: The mean defect size was 7.13 cm in the study and 2.09 cm in the control group. The chi-square test showed equal consolidation rates between the groups (SG: 53.8%; CG: 66.7%). However, the Kaplan–Meier curve and log-rank test showed a significant difference regarding the mean duration until consolidation was achieved, with an average of 15.95 months in the study and 9.24 months in the control group (α = 0.05, p = 0.001). Linear regression showed a significant increase in consolidation duration with increasing defect size (R2 = 0.121, p = 0.021). Logistic regression modelling showed a significant negative correlation between consolidation rate and revision performance, as well as an increasing number of revisions, prior surgeries and total number of surgeries performed on the limb. Clinical outcomes showed equal full weight bearing of the lower extremity after 5.54 months in the study vs. 4.86 months in the control group (p = 0.267). Conclusion: Surprisingly, defect size does not seem to have a significant effect on the consolidation rate and should not be seen as a risk factor. However, for the treatment of large-sized nonunions, the follow-up period should be prolonged up to 24 months, due to the extended time until consolidation will be achieved. This period should also pass before a premature revision with new bone augmentation is performed. In addition, it should be kept in mind that as the number of previous surgeries and revisions increases, the prospects for consolidation decrease and a change in therapeutic approach may be required.

Abstract BACKGROUND Endocrine therapies (ETs) that target estrogen receptor (ER) activity and/or estrogen synthesis are the mainstay of ER+ breast cancer (BC) treatment. Despite best management, ≤20% of patients (pts) with ER+/HER2– early BC (eBC) develop resistance (in some cases due to acquisition of tumor mutations in ESR1 that can drive estrogen-independent transcription and proliferation) and still have high recurrence rates on standard ETs. New treatment alternatives for ER+/HER2– eBC are needed to reduce risk of recurrence and improve survival, tolerability, quality of life, and adherence. Giredestrant, a highly potent, nonsteroidal oral selective ER antagonist and degrader (SERD), achieves robust ER occupancy and is active against tumors that retain ER-sensitivity or have ESR1 mutation(s). It has been demonstrated to be more potent in vitro and achieves higher ER occupancy in vivo than fulvestrant, the only currently approved SERD. Early-phase clinical studies have demonstrated that single-agent giredestrant (30 mg daily) has promising clinical and pharmacodynamic activity and is well tolerated in the ER+/HER2– eBC and metastatic BC settings. TRIAL DESIGN This is a phase III, global, randomized, open-label, multicenter study evaluating efficacy and safety of adjuvant giredestrant vs physician’s choice of adjuvant ET (PCET) in pts with medium- and high-risk stage I–III histologically confirmed ER+/HER2– eBC. Pts are randomized 1:1 to oral 30 mg daily giredestrant or PCET (tamoxifen, anastrozole, letrozole, or exemestane, given according to prescribing information). Stratification factors are risk (medium vs high, based on anatomic [tumor size, nodal status] and biologic features [grade, Ki67, gene signatures if available]); geographic region (US/Canada/Western Europe vs Asia-Pacific vs rest of the world); prior chemotherapy (no vs yes); and menopausal status (pre-/perimenopausal vs postmenopausal). Beginning on Day 1 of Cycle 1, pts will be treated with giredestrant or PCET for ≥5 years. Continuing PCET after 5 years is at discretion of the investigator and per local standard of care. ELIGIBILITY Female/male pts with medium-/high-risk stage I–III ER+/HER2– eBC; prior curative surgery; completion of (neo)adjuvant chemotherapy (if administered) and/or surgery &lt; 12 months prior to enrollment; no prior ET (≤4 weeks of [neo]adjuvant ET is allowed). For men and pre-/perimenopausal women, a luteinizing hormone-releasing hormone agonist will be given per local prescribing information (mandatory for pts in the giredestrant arm). AIMS Primary endpoint: Invasive disease-free survival (IDFS). Secondary endpoints: Overall survival; IDFS (STEEP definition, including second non-primary BC); disease-free survival; distant recurrence-free survival; locoregional recurrence-free interval; safety; pharmacokinetics; pt-reported outcomes. In addition, this study aims to improve health equity in research and expand clinical trial access. The study will also use/develop digital healthcare solutions, which will enable better understanding of pts’ needs and their adherence to ET. STATISTICAL METHODS The primary endpoint analysis will use a stratified log-rank test at an overall 0.05 significance level (two-sided). An interim analysis and a futility analysis are planned, and an independent data monitoring committee will be in place. ACCRUAL 1018/4100 pts have been recruited globally. CONTACT INFORMATION For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only). Clinicaltrials.gov number NCT04961996. AB, PS and CG contributed equally. This abstract was originally presented at SABCS 2021 (OT2-11-09). a&gt;Disclosure(s): Peter Schmid, MD, PhD: Astellas Pharma: Contracted Research (Ongoing); AstraZeneca: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Honoraria (Ongoing); Bayer: Consulting Fees (e.g., advisory boards) (Ongoing), Honoraria (Ongoing); Boehringer Ingelheim: Consulting Fees (e.g., advisory boards) (Ongoing), Honoraria (Ongoing); Celgene: Consulting Fees (e.g., advisory boards) (Ongoing); Eisai: Consulting Fees (e.g., advisory boards) (Ongoing); F. Hoffmann-La Roche Ltd.: Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing); Genentech: Contracted Research (Ongoing); Medivation Inc.: Contracted Research (Ongoing); Merck: Consulting Fees (e.g., advisory boards) (Ongoing), Honoraria (Ongoing); Novartis: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Honoraria (Ongoing); OncoGenex: Contracted Research (Ongoing); Pfizer: Consulting Fees (e.g., advisory boards) (Ongoing), Honoraria (Ongoing); Puma Biotechnology: Consulting Fees (e.g., advisory boards) (Ongoing), Honoraria (Ongoing); Roche: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Honoraria (Ongoing) Charles E. Geyer Jr, MD, FACP: Abbvie: Contracted Research (Terminated, July 1, 2022), Writing assistance (Terminated, July 1, 2022); AstraZeneca: Contracted Research (Ongoing), Writing assistance (Ongoing); Daiichi/Sankyo: Contracted Research (Ongoing); Exact Sciences: Consulting Fees (e.g., advisory boards) (Ongoing); F. Hoffman-La Roche Ltd: Contracted Research (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche) (Ongoing); Genentech: Contracted Research (Ongoing), Writing assistance (Ongoing) Nadia Harbeck, MD, PhD: Amgen: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); AstraZeneca: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Daiichi Sankyo: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Eli Lilly: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Exact Sciences: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); MSD: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Novartis: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Pfizer: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Pierre Fabre: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Roche: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing); Sandoz: Consulting Fees (e.g., advisory boards) (Ongoing); Seagen: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); WSG: Ownership Interest (stocks, stock options, patent or other intellectual property or other ownership interest excluding diversified mutual funds) (Ongoing) Mothaffar Rimawi, MD: Daiichi Sankyo: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); F. Hoffmann-La Roche Ltd.: Contracted Research (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing); Genentech: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Macrogenics: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Pfizer: Contracted Research (Ongoing); Seattle Genetics: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing) Sara Hurvitz, MD, FACP: Ambrx: Contracted Research (Ongoing); Amgen: Contracted Research (Ongoing); Arvinas: Contracted Research (Ongoing); Astra Zeneca: Contracted Research (Ongoing); Bayer: Contracted Research (Ongoing); Cytomx: Contracted Research (Ongoing); Daiichi-Sankyo: Contracted Research (Ongoing); Dignitana: Contracted Research (Ongoing); Eli Lilly: Contracted Research (Ongoing); Genentech/Roche: Contracted Research (Ongoing); Gilead: Contracted Research (Ongoing); GSK: Contracted Research (Ongoing); Ideal Implant: Ownership Interest (stocks, stock options, patent or other intellectual property or other ownership interest excluding diversified mutual funds) (Ongoing); Immunomedics: Contracted Research (Ongoing); Macrogenics: Contracted Research (Ongoing); Novartis: Contracted Research (Ongoing); OBI Pharma: Contracted Research (Ongoing); Orinove: Contracted Research (Ongoing); Pfizer: Contracted Research (Ongoing); Phoenix Molecular Designs, Ltd.: Contracted Research (Ongoing); Pieris: Contracted Research (Ongoing); PUMA: Contracted Research (Ongoing); Radius: Contracted Research (Ongoing); Sanofi: Contracted Research (Ongoing); Seattle Genetics/Seagen: Contracted Research (Ongoing); Zymeworks: Contracted Research (Ongoing) Miguel Martín, MD, PhD: AstraZeneca: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Daiichi Sankyo: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); F. Hoffmann-La Roche: Third-party writing assistance for this abstract, furnished by Eleanor Porteous, MSc, of Health Interactions, was provided by Roche (Ongoing); Genentech/Roche: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing); Gilead: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Lilly/ImClone: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing), Honoraria (Ongoing); Novartis: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing), Honoraria (Ongoing); Pfizer: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing), Honoraria (Ongoing); Pierre Fabre: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing), Honoraria (Ongoing); Seagen: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing), Honoraria (Ongoing) Sherene Loi, MBBS (Hons), PhD, FRACP, FAHMS, GAICD: Aduro Biotech, Inc.: Consulting Fees (e.g., advisory boards) (Ongoing); Akamara Therapeutics: Uncompensated scientific advisory board member (Ongoing); AstraZeneca: Consulting Fees (e.g., advisory boards) (Ongoing), Uncompensated consultant (Ongoing); BMS: Uncompensated consultant (Ongoing); Breast Cancer Research Foundation, New York: Supported by the Breast Cancer Research Foundation, New York (Ongoing); G1 Therapeutics: Consulting Fees (e.g., advisory boards) (Ongoing); GlaxoSmithKline: Consulting Fees (e.g., advisory boards) (Ongoing); Merck: Uncompensated consultant (Ongoing); National Breast Cancer Foundation of Australia Endowed Chair: Supported by the National Breast Cancer Foundation of Australia Endowed Chair (Ongoing); Novartis: Consulting Fees (e.g., advisory boards) (Ongoing), Uncompensated consultant (Ongoing); Roche-Genentech: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing), Uncompensated consultant (Ongoing); Seattle Genetics: Uncompensated consultant (Ongoing); Silverback Therapeutics: Consulting Fees (e.g., advisory boards) (Ongoing) Shigehira Saji, MD, PhD: Astra Zeneca: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Bayer: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Boerhringer-ingelheim: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Breast International Group: Executive board member (Ongoing); Chugai: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Daiichi Sankyo: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Eisai: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Eli Lilly: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); F. Hoffmann-La Roche Ltd.: Contracted Research (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing); Japan Breast Cancer Research Group: Executive board member (Ongoing); Japanese Breast Cancer Society: Executive board member (Ongoing); Japanese Society of Medical Oncology: Executive board member (Ongoing); Kyowa Kirin: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); MSD: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Nihonkayaku: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Novartis: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Ono: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Pfizer: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Taiho: Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Takeda: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing) Kyung Hae Jung, MD, MS, PhD: AstraZeneca: Consulting Fees (e.g., advisory boards) (Ongoing); Celgene: Consulting Fees (e.g., advisory boards) (Ongoing); Daiichi-Sankyo: Consulting Fees (e.g., advisory boards) (Ongoing); Eisai: Consulting Fees (e.g., advisory boards) (Ongoing); Everest Medicine: Consulting Fees (e.g., advisory boards) (Ongoing); Merck: Consulting Fees (e.g., advisory boards) (Ongoing); MSD: Consulting Fees (e.g., advisory boards) (Ongoing); Novartis: Consulting Fees (e.g., advisory boards) (Ongoing); Pfizer: Consulting Fees (e.g., advisory boards) (Ongoing); Roche: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing); Takeda: Consulting Fees (e.g., advisory boards) (Ongoing) Gustavo Werutsky, MD, PhD: AstraZeneca: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Honoraria (Ongoing); Bayer: Contracted Research (Ongoing); Beigene: Contracted Research (Ongoing); Daiichi Sankyo: Consulting Fees (e.g., advisory boards) (Ongoing); Genentech/Roche: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); GSK: Contracted Research (Ongoing); Lilly: Contracted Research (Ongoing), Honoraria (Ongoing); MSD: Honoraria (Ongoing); Novartis: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Honoraria (Ongoing); Pfizer: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Honoraria (Ongoing); Sanofi: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); Seattle Genetics: Contracted Research (Ongoing) Daniil L. Stroyakovsky, MD: Roche: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing) Vanesa López-Valverde, PharmD, PhD: F. Hoffmann-La Roche Ltd.: Ownership Interest (stocks, stock options, patent or other intellectual property or other ownership interest excluding diversified mutual funds) (Ongoing), Salary (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing) Michael Davis, PsyD: F. Hoffmann-La Roche Ltd.: Ownership Interest (stocks, stock options, patent or other intellectual property or other ownership interest excluding diversified mutual funds) (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing); Genentech, Inc.: Salary (Ongoing) Tanja Badovinac Crnjevic, MD, PhD: F. Hoffmann-La Roche Ltd.: Ownership Interest (stocks, stock options, patent or other intellectual property or other ownership interest excluding diversified mutual funds) (Ongoing), Salary (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing) Pablo D. Perez-Moreno, MD: F. Hoffmann-La Roche Ltd.: Ownership Interest (stocks, stock options, patent or other intellectual property or other ownership interest excluding diversified mutual funds) (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing); Genentech, Inc.: Salary (Ongoing) Aditya Bardia, MD, MPH: AstraZeneca: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); BioTheranostics: Consulting Fees (e.g., advisory boards) (Ongoing); Daiichi Sankyo: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); Eli Lilly: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); Foundation Medicine: Consulting Fees (e.g., advisory boards) (Ongoing); Genentech/Roche: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); Immunomedics/Gilead: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); Merck: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); Novartis: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); Pfizer: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); Phillips: Consulting Fees (e.g., advisory boards) (Ongoing); Radius Health: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); Sanofi: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing) &lt;/a&gt; Citation Format: Peter Schmid, Charles E. Geyer Jr, Nadia Harbeck, Mothaffar Rimawi, Sara Hurvitz, Miguel Martín, Sherene Loi, Shigehira Saji, Kyung Hae Jung, Gustavo Werutsky, Daniil L. Stroyakovsky, Vanesa López-Valverde, Michael Davis, Tanja Badovinac Crnjevic, Pablo D. Perez-Moreno, Aditya Bardia. lidERA Breast Cancer: A phase III adjuvant study of giredestrant (GDC-9545) vs physician’s choice of endocrine therapy in patients with estrogen receptor+, HER2– early breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-03-02.

This work investigates a variant of the conjugate gradient (CG) method and embeds it into the context of high-order finite-element schemes with fast matrix-free operator evaluation and cheap preconditioners like the matrix diagonal. Relying on a data-dependency analysis and appropriate enumeration of degrees of freedom, we interleave the vector updates and inner products in a CG iteration with the matrix-vector product with only minor organizational overhead. As a result, around 90% of the vector entries of the three active vectors of the CG method are transferred from slow RAM memory exactly once per iteration, with all additional access hitting fast cache memory. Node-level performance analyses and scaling studies on up to 147k cores show that the CG method with the proposed performance optimizations is around two times faster than a standard CG solver as well as optimized pipelined CG and s-step CG methods for large sizes that exceed processor caches, and provides similar performance near the strong scaling limit.

Background: Myotendinous stiffness is related to the collagen content of the muscle and tendon, and can be estimated during running by changes in vertical stiffness (kvert) and the resulting modifications of the spatiotemporal parameters (on-off ground asymmetry and landing-takeoff asymmetry). Supplementation with amino acids found in collagen, such as proline, glycine, and hydroxyl proline, combined with ascorbic acid, improve collagen synthesis and potentially result in improved mechanical strength and stiffness. Objectives: To determine if hydrolyzed collagen (HC) supplementation increases kvert and improves the spatiotemporal parameters during running in recreational triathletes. Methods: Nine active males (weight; 68.4 ± 5.7 kg, height; 171.8 ± 5.4 cm, age; 32.5 ± 4.1 years; Vo2max; 53.15 ± 2.19 mL/kg/min) were randomly distributed into a collagen group (CollG, n = 5) and a control group (CG, n = 4). Participants were supplemented for 4 weeks with 15g HC (CollG) or 15g placebo (CG; maltodextrin), 3 times per week. One hour after supplementation, the participants of both groups were asked to perform four repetitions of short sprints to further stimulate collagen synthesis. The ground reaction forces were recorded during running at 4.44 m s-1, 5.55 m.s-1, and 6.66 m.s-1 for assessment of kvert and the spatiotemporal step parameters. Results: Both groups increased kvert with speed (4.44 - 6.66 m s-1) from 24.8 ± 2.7 to 53.7 ± 16.5 N/m and from 25.1 to 49.8 N/m in the CollG and CG, respectively (P < 0.0001); however, there were no differences between groups before and after the supplementation period. As a consequence, the spatiotemporal parameters of running were also similar between groups. Conclusions: Four weeks of HC supplementation does not improve the bouncing mechanism of running in recreational triathletes.

Abstract Background Glucocorticoids are used for the treatment of autoimmune disorders; however, they can elicit several side effects such as osteoporosis. Several approaches can be made to treat glucocorticoid-induced osteoporosis, including the use of stem cells. However, the therapeutic effect of mesenchymal stem cells depends on its released factors, including extracellular vesicles. Extracellular vesicles have been recognized as important mediators of intercellular communication as they participate in many physiological processes. The present study was designed to investigate the effect of bone marrow mesenchymal stem cells derived extracellular vesicles on the structure of alveolar bone in rats with glucocorticoid-induced osteoporosis. Methods Thirty adult albino male rats were divided into 3 groups: control group (CG), glucocorticoid-induced osteoporosis (GOG) and extracellular vesicles treated group (ExTG). Rats in the GOG and ExTG groups were injected with methylprednisolone acetate (40 mg/kg) intramuscularly in the quadriceps muscle 3 times per week for three weeks in the early morning. Afterwards, the rats in GOG group received a single vehicle injection (PBS) while each rat in the ExTG group received a single injection of extracellular vesicles (400 μg/kg suspended in 0.2 ml PBS) in the tail vein. Rats were euthanized 1 month after injection. Mandibles were dissected and the molar segments were prepared for histological preparation, scanning electron microscopy (SEM), and energy dispersive x-ray (EDX). Results Histology and scanning electron microscopyof bone tissue showed alveolar bone loss and bone resorption in the GOG group. while in the ExTG group, alveolar bone demostrated normal bone architecture. EDX showed that calcium percentage in GOG group was lower than ExTG group,which showed no statistically significant difference from the control group. Conclusions Extracellular vesicles may be a promising treatment modality in the treatment of bone diseases and in bone regeneration. However, further research is needed before stating that extracellular vesicles s can be used to treat bone disorders especially when translating to humans.

Background: Reperfusion following ischemia can lead to more injuries than ischemia itself especially in diabetic patients. The aim of this study was to evaluate the effect of dexmedetomidine on ischemia-reperfusion injury (IRI) in rats with have hepatic IRI and diabetes mellitus. Methodology: Twenty-eight Wistar Albino rats were randomised into four groups as control (C), diabetic (DC), diabetic with hepatic ischemia-reperfusion injury (DIR), and diabetic but administered dexmedetomidine followed by hepatic IRI (DIRD) groups. Hepatic tissue samples were evaluated histopathologically by semiquantitative methods. Malondialdehyde (MDA), superoxide dismutase (SOD), glutathion s-transpherase (GST), and catalase (CAT) enzyme levels were investigated in liver and kidney tissues as oxidative state parameters. Results: In Group DIR; hepatocyte degeneration, sinusoidal dilatation, pycnotic nucleus, and necrotic cells were found to be more in rat hepatic tissue; while mononuclear cell infiltration was higher in the parenchyme. MDA levels were significantly lower; but SOD levels were significantly higher in Group DIRD with regard to Group DIR. In the IRI induced diabetic rats’ hepatic and nephrotic tissues MDA levels, showing oxidative injury, were found to be lower. SOD levels, showing early antioxidant activity, were higher. Conclusion: The enzymatic findings of our study together with the hepatic histopathology indicate that dexmedetomidine has a potential role to decrease IRI. Key words: Hepatic ischemia reperfusion injury; Diabetes mellitus; Dexmedetomidine; Rat; MDA; SOD Citation: Sezen SC, Işık B, Bilge M, Arslan M, Çomu FM, Öztürk L, Kesimci E, Kavutçu M. Effect of dexmedetomidine on ischemia-reperfusion injury of liver and kidney tissues in experimental diabetes and hepatic ischemia-reperfusion injury induced rats. Anaesth Pain & Intensive Care 2016;20(2):143-149 Received: 21 November 2015; Reviewed: 10, 24 December 2015, 9, 10 June 2016; Corrected: 12 December 2015; Accepted: 10 June 2016 INTRODUCTİON Perioperative acute tissue injury induced by ischemia-reperfusion is a comman clinical event caused by reduced blood supply to the tissue being compromised during major surgery. Ischemia leads to cellular injury by depleting cellular energy deposits and resulting in accumulation of toxic metabolites. The reperfusion of tissues that have remained in ischemic conditions causes even more damage.1 Furthermore hepatic ischemia-reperfusion injury (IRI) demonstrates a strong relationship with peri-operative acute kidney injury.2 The etiology of diabetic complications is strongly associated with increased oxidative stress (OS). Diabetic patients are known to have a high risk of developing OS or IRI which results with tissue failure.3 The most important role in ischemia and reperfusion is played by free oxygen radicals.1 In diabetes, characterized by hyperglycemia, even more free oxygen radicals are produced due to oxidation of glucose and glycosylation of proteins.3 The structures which are most sensitive to free oxygen radicals in the cells are membrane lipids, proteins, nucleic acids and deoxyribonucleic acids.1 It has been reported that endogenous antioxidant enzymes [superoxide dismutase (SOD), glutathion s-transpherase (GST), catalase (CAT)] play an important role to alleviate IRI.4-8 Also some pharmacological agents have certain effects on IRI.1 The anesthetic agents influence endogenous antioxidant systems and free oxygen radical formation.9-12 Dexmedetomidine is a selective α-2 adrenoceptor agonist agent. It has been described as a useful and safe adjunct in many clinical applications. It has been found that it may increase urine output by considerably redistributing cardiac output, inhibiting vasopressin secretion and maintaining renal blood flow and glomerular filtration. Previous studies demonstrated that dexmedetomidine provides protection against renal, focal cerebral, cardiac, testicular, and tourniquet-induced IRI.13-18 Arslan et al observed that dexmedetomidine protected against lipid peroxidation and cellular membrane alterations in hepatic IRI, when given before induction of ischemia.17 Si et al18 demonstrated that dexmedetomidine treatment results in a partial but significant attenuation of renal demage induced by IRI through the inactivation of JAK/STAT signaling pathway in an in vivo model. The efficacy of the dexmedetomidine for IRI in diabetic patient is not resarched yet. The purpose of this experimental study was to evaluate the biochemical and histological effects of dexmedetomidine on hepatic IRI in diabetic rat’s hepatic and renal tissue. METHODOLOGY Animals and Experimental Protocol: This study was conducted in the Physiology Laboratory of Kirikkale University upon the consent of the Experimental Animals Ethics Committee of Kirikkale University. All of the procedures were performed according to the accepted standards of the Guide for the Care and Use of Laboratory Animals. In the study, 28 male Wistar Albino rats, weighing between 250 and 300 g, raised under the same environmental conditions, were used. The rats were kept under 20-21 oC at cycles of 12-hour daylight and 12-hour darkness and had free access to food until 2 hours before the anesthesia procedure. The animals were randomly separated into four groups, each containing 7 rats. Diabetes was induced by a single intraperitoneal injection of streptozotocin (Sigma Chemical, St. Louis, MO, USA) at a dose of 65 mg/kg body weight. The blood glucose levels were measured at 72 hrs following this injection. Rats were classified as diabetic if their fasting blood glucose (FBG) levels exceeded 250 mg/dl, and only animals with FBGs of > 250 mg/dl were included in the diabetic groups (dia­betes only, diabetes plus ischemia-reperfusion and diabetes plus dexmedetomidine-ischemia-reperfusion). The rats were kept alive 4 weeks after streptozotocin injection to allow development of chronic dia­betes before they were exposed to ischemia-reperfusion.(19) The rats were weighed before the study. Rats were anesthetized with intraperitoneal ketamine 100 mg/kg. The chest and abdomen were shaved and each animal was fixed in a supine position on the operating table. The abdomen was cleaned with 1% polyvinyl iodine and when dry, the operating field was covered with a sterile drape and median laparotomy was performed. There were four experimental groups (Group C (sham-control; n = 7), (Group DC (diabetes-sham-control; n = 7), Group DIR (diabetes-ischemia-reperfusion; n = 7), and Group DIRD (diabetes-ischemia-reperfusion-dexmedetomidine; n = 7). Sham operation was performed on the rats in Group C and Group DC. The sham operation consisted of mobilization of the hepatic pedicle only. The rats in this group were sacrificed 90 min after the procedure. Hepatic I/R injury was induced in Groups DIR and DIRD respectively with hepatic pedicle clamping using a vascular clamp as in the previous study of Arslan et al.(17) After an ischemic period of 45 min, the vascular clamp was removed. A reperfusion period was maintained for 45 min. In Group DIRD, dexmedetomidine hydrochloride 100 μg/kg, (Precedex 100 μg/2 ml, Abbott®, Abbott Laboratory, North Chicago, Illinois, USA) was administrated via intraperitoneal route 30 minutes before surgery. All the rats were given ketamine 100 mg/kg intraperitoneally and intracardiac blood samples were obtained. Preserving the tissue integrity by avoiding trauma, liver and renal biopsy samples were obtained. Biochemical Analysis: The liver and renal tissues were first washed with cold deionized water to discard blood contamination and then homogenized in a homogenizer. Measurements on cell contest require an initial preparation of the tissues. The preparation procedure may involve grinding of the tissue in a ground glass tissue blender using a rotor driven by a simple electric motor. The homogenizer as a tissue blender similar to the typical kitchen blender is used to emulsify and pulverize the tissue (Heidolph Instruments GMBH & CO KGDiax 900 Germany®) at 1000 U for about 3 min. After centrifugation at 10,000 g for about 60 min, the upper clear layer was taken. MDA levels were determined using the method of Van Ye et al,(20) based on the reaction of MDA with thiobarbituric acid (TBA). In the TBA test reaction, MDA and TBA react in acid pH to form a pink pigment with an absorption maximum at 532 nm. Arbitrary values obtained were compared with a series of standard solutions (1,1,3,3-tetraethoxypropane). Results were expressed as nmol/mg.protein. Part of the homogenate was extracted in ethanol/chloroform mixture (5/3 v/v) to discard the lipid fraction, which caused interferences in the activity measurements of T-SOD, CAT and GST activities. After centrifugation at 10.000 x g for 60 min, the upper clear layer was removed and used for the T-SOD, CAT, GST enzyme activity measurement by methods as described by Durak et al21, Aebi22 and Habig et al23 respectively. One unit of SOD activity was defined as the enzyme protein amount causing 50% inhibition in NBTH2 reduction rate and result were expressed in U/mg protein. The CAT activity method is based on the measurement of absorbance decrease due to H2O2 consumption at 240 nm. The GST activity method is based on the measurement of absorbance changes at 340 nm due to formation of GSH-CDNB complex. Histological determinations: Semiquantitative evaluation technique used by Abdel-Wahhab et al(24) was applied for interpreting the structural changes investigated in hepatic tissues of control and research groups. According to this, (-) (negative point) represents no structural change, while (+) (one positive point) represents mild, (++) (two positive points) medium and (+++) (three positive points) represents severe structural changes. Statistical analysis: The Statistical Package for the Social Sciences (SPSS, Chicago, IL, USA) 20.0 softwre was used for the statistical analysis. Variations in oxidative state parameters, and histopathological examination between study groups were assessed using the Kruskal-Wallis test. The Bonferroni-adjusted Mann-Whitney U-test was used after significant Kruskal-Wallis to determine which groups differed from the others. Results were expressed as mean ± standard deviation (Mean ± SD). Statistical significance was set at a p value < 0.05 for all analyses. RESULTS There was statistically significant difference observed between the groups with respect to findings from the histological changes in the rat liver tissue (hepatocyte degeneration, sinüsoidal dilatation, pycnotic nucleus, prenecrotic cell) determined by light microscopy according to semiquantitative evaluation techniques (p < 0.0001). In Group DIR, hepatocyte degeneration was significantly high compared to Group C, Group DC and Group DIRD (p < 0.0001, p < 0.0001, p = 0.002, respectively), (Table 1, Figure 1-4). Similarly, sinüsoidal dilatation was significantly higher in Group DIR (p < 0.0001, p = 0.004, p = 0.015, respectively). Although, pcynotic nucleus was decreased in Group DIRD, it did not make a significant difference in comparison to Group DIR (p = 0.053), (Table 1, Figure 1-4). The prenecrotic cells were significantly increased in Group DIR, with respect to Group C, Group DC and Group DIRD (p < 0.0001, p = 0.004, p < 0.0001, respectively), (Table 1, Figure 1-4). Table 1. The comparison of histological changes in rat hepatic tissue [Mean ± SD)] p**: Statistical significance was set at a p value < 0.05 for Kruskal-Wallis test *p < 0.05: When compared with Group DIR Figure 1: Light microscopic view of hepatic tissue of Group C (control). VC: vena centralis, *: sinusoids. ®: hepatocytes, k: Kupffer cells, G: glycogen granules, mc: minimal cellular changes, Hematoxilen & Eosin x 40 Figure 2: Light-microscopic view of hepatic tissue of Group DC (diabetes mellitus control) (G: Glycogen granules increased in number, (VC: vena centralis, *:sinusoids. ®:hepatocytes, k:Kupffer cells, G: glycogen granules, mc: minimal cellular changes; Hematoxylin & Eosin x 40) Figure 3: Light-microscopic view of hepatic tissue of Group DIR (Diabetes Mellitus and ischemia-reperfusion) (VC: vena centralis, (H) degenerative and hydrophic hepatocytes, (dej) vena centralis degeneration (centrolobar injury) (*): sinusoid dilatation. (←) pycnotic and hyperchromatic nuclei, MNL: mononuclear cell infiltration, (¯) congestion, K: Kupffer cell hyperplasia, (­) vacuolar degeneration (Hematoxylin & Eosin x 40) Figure 4: Light-microscopic view of hepatic tissue of Group DIRD (Diabetes Mellitus and ischemia-reperfusion together with dexmedetomidine applied group) (VC: vena centralis, (MNL) mononuclear cell infiltration, (dej) hydrophilic degeneration in hepatocytes around vena centralis, (conj) congestion, G: glycogen granules, (←) pycnotic and hyperchromatic nuclei, sinusoid dilatation (*) (Hematoxylin & Eosin x 40) Besides, in liver tissue parenchyma, MN cellular infiltration was a light microscopic finding; and showed significant changes among the groups (p < 0.0001). This was significantly higher in Group DIR, compared to Group C, DC, and DIRD (p < 0.0001, p=0.007, p = 0.007, respectively), (Table 1, Figure 1-4). The enzymatic activity of MDA, SOD and GST in hepatic tissues showed significant differences among the groups [(p = 0.019), (p = 0.034). (p = 0.008) respectively]. MDA enzyme activity was significantly incresed in Group DIR, according to Group C and Group DIRD (p = 0.011, p = 0.016, respectively), (Table 2). In Group DIR SOD enzyme activity was lower with respect to Group C and Group DIRD (p = 0.010, p = 0.038, respectively), (Table 2). The GST enzyme activity was significantly higher in Group DIR, when compared to Group C, DC and DIRD (p = 0.007, p = 0.038, p = 0.039, respectively), (Table 2). Table 2. Oxidative state parameters in rat hepatic tissue [Mean ± SD] p**: Statistical significance was set at a p value < 0.05 for Kruskal-Wallis test *p < 0.05: When compared with Group DIR The enzymatic activity of MDA, SOD in renal tissues, showed significant differences among the groups [(p < 0.0001), (p = 0.008) respectively ]. MDA enzyme activity was significantly incresed in Group DIR, according to Group C and Group DIRD (p < 0.0001, p < 0.0001, respectively). Also MDA enzyme activity level was significantly increased in Group DC, in comparison to Group C and Group DIRD (p = 0.003, p = 0.001, respectively), (Table 3). In Group DIR SOD enzyme activity was lower with respect to Group C and Group DIRD (p = 0.032, p = 0.013, respectively), (Table 3). The GST enzyme activity was significantly higher in Group DIR than the other three groups, however; CAT levels were similar among the groups (Table 3). Table 3: Oxidative state parameters in rat nephrotic tissue [Mean ± SD)] p**: Statistical significance was set at a p value < 0.05 for Kruskal-Wallis test *p < 0.05: When compared with Group DIR DISCUSSION In this study, we have reported the protective effect of dexmedetomidine in experimental hepatic and renal IRI model in the rat by investigating the MDA and SOD levels biochemically. Besides, hepatic histopathological findings also supported our report. Ischemic damage may occur with trauma, hemorrhagic shock, and some surgical interventions, mainly hepatic and renal resections. Reperfusion following ischemia results in even more injury than ischemia itself. IRI is an inflammatory response accompanied by free radical formation, leucocyte migration and activation, sinusoidal endothelial cellular damage, deteoriated microcirculation and coagulation and complement system activation.1 We also detected injury in hepatic and renal tissue caused by reperfusion following ischemia in liver. Experimental and clinical evidence indicates that OS is involved in both the pathogenesis and the complications of diabetes mellitus.25,26 Diabetes mellitus is a serious risk factor for the development of renal and cardiovascular disease. It is also related to fatty changes in the liver.27 Diabetes-related organ damage seems to be the result of multiple mechanisms. Diabetes has been associated with increased free radical reactions and oxidant tissue damage in STZ-induced diabetic rats and also in patients.26Oxidative stress has been implicated in the destruction of pancreatic β-cells28 and could largely contribute to the oxidant tissue damage associated with chronic hyperglycemia.29 A number of reports have shown that antioxidants can attenuate the complications of diabetes in patients30 and in experimental models.28,31 This study demonstrated that diabetes causes a tendency to increase the IRI. There is a lot of investigations related to the pharmacological agents or food supplements applied for decreasing OS and IRI. Antioxidant agents paly an important role in IRI by effecting antioxidant system or lessening the formation of ROS. It has been reported that anesthetic agents too, are effective in oxidative stress.1 During surgical interventions, it seems rational to get benefit from anesthetic agents in prevention of OS caused by IRI instead of using other agents. It has been declared that; dexmedetomidine; as an α-2 agonist with sedative, hypnotic properties; is important in prevention of renal, focal, cerebral, cardiac, testicular and tourniquet-induced IRI.13-18 On the other hand Bostankolu et al. concluded that dexmedetomidine did not have an additional protective role for tournique induced IRI during routine general anesthesia.32 In this study; we have shown that dexmedetomidine has a reducing effect in IRI in diabetic rats. Some biochemical tests and histopathological evaluations are applied for bringing up oxidative stress and IRI in the tissues. Reactive oxygen species (ROS) that appear with reperfusion injury damage cellular structures through the process of the lipid peroxidation of cellular membranes and yield toxic metabolites such as MDA.33 As an important intermidiate product in lipid peroxidation, MDA is used as a sensitive marker of IRI.34 ROS-induced tissue injury is triggered by various defense mechanisms.35 The first defence mechanisms include the antioxidant enzymes of SOD, CAT, and GPx. These endogenous antioxidants are the first lines of defence against oxidative stres and act by scavenging potentially damaging free radical moieties.36 There is a balance between ROS and the scavenging capacity of antioxidant enzymes.1-8 In this study, for evaluation of oxidative damage and antioxidant activity, MDS, SOD, GST and CAT levels were determined in liver and kidney tissues. MDA levels in hepatic and renal tissues were higher in Group DIR compared to Group C and Group DIRD. GST levels were higher in Group DIR compared to all the other three groups. When the groups were arranged from highest to lowest order, with respect to CAT levels, the order was; Group DIR, Group DIRD, Group DC and Group C. However, the difference was not significant. The acute phase reactant MDA, as a marker of OS, was found to be high in Group DIR and low in Group DIRD. This could be interpreted as the presence of protective effect of dexmedetomidine in IRI. IRI developing in splanchnic area causes injury also in the other organs.35 Leithead et al showed that clinically significant hepatic IRI demonstrates a strong relationship with peri-operative acute kidney injury.2 In our experimental research that showed correlation to that of research by Leithead et al. After hepatic IRI in diabetic rats renal OS marker MDA levels were significantly more in Group DIR than Group DIRD. In our study, we observed histopathological changes in the ischemic liver tissue and alterations in the level of MDA, SOD, GST and CAT levels which are OS markers. Histopathological changes of the liver tissues are hepatocyt degeneration, sinusoidal dilatation, nuclear picnosis, celluler necrosis, mononuclear cell infiltrationat paranchimal tissue. These histopathological injury scores were significantly lower in the Group DIRD than those in group DIR. LIMITATION Study limitation is there was no negative control group, as this type of surgical intervention is not possible in rats without anesthesia. CONCLUSION The enzymatic findings of our study together with the hepatic histopathology indicate that dexmedetomidine has a potential role to decrease ischemia-reperfusion injury. Conflict of interest and funding: The authors have not received any funding or benefits from industry or elsewhere to conduct this study. 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Many high performance computing applications in computational fluid dynamics, electromagnetics etc. need to solve a linear system of equations $Ax=b$. For linear systems where $A$ is generally large and sparse, Krylov Subspace methods (KSMs) are used. In this thesis, we propose communication overlapping KSMs. We start with the Conjugate Gradient (CG) method, which is used when $A$ is sparse symmetric positive definite. Recent variants of CG include a Pipelined CG (PIPECG) method which overlaps the allreduce in CG with independent computations i.e., one Preconditioner (PC) and one Sparse Matrix Vector Product (SPMV). As we move towards the exascale era, the time for global synchronization and communication in allreduce increases with the large number of cores available in the exascale systems, and the allreduce time becomes the performance bottleneck which leads to poor scalability of CG. Therefore, it becomes necessary to reduce the number of allreduces in CG and adequately overlap the larger allreduce time with more independent computations than the independent computations provided by PIPECG. Towards this goal, we have developed PIPECG-OATI (PIPECG-One Allreduce per Two Iterations) which reduces the number of allreduces from three per iteration to one per two iterations and overlaps it with two PCs and two SPMVs. For better scalability with more overlapping, we also developed the Pipelined s-step CG method which reduces the number of allreduces to one per s iterations and overlaps it with s PCs and s SPMVs. We compared our methods with state-of-art CG variants on a variety of platforms and demonstrated that our method gives 2.15x - 3x speedup over the existing methods. We have also generalized our research with parallelization of CG on multi-node CPU systems in two dimensions. Firstly, we have developed communication overlapping variants of KSMs other than CG, including Conjugate Residual (CR), Minimum Residual (MINRES) and BiConjugate Gradient Stabilised (BiCGStab) methods for matrices with different properties. The pipelined variants give up to 1.9x, 2.5x and 2x speedup over the state-of-the-art MINRES, CR and BiCGStab methods respectively. Secondly, we developed communication overlapping CG variants for GPU accelerated nodes, where we proposed and implemented three hybrid CPU-GPU execution strategies for the PIPECG method. The first two strategies achieve task parallelism and the last method achieves data parallelism. Our experiments on GPUs showed that our methods give 1.45x - 3x average speedup over existing CPU and GPU-based implementations. The third method gives up to 6.8x speedup for problems that cannot be fit in GPU memory. We also implemented GPU related optimizations for the PIPECG-OATI method and show performance improvements over other GPU implementations of PCG and PIPECG on multiple nodes with multiple GPUs.