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Objective: To investigate the effect of salvia miltiorrhiza polyphenolic acid combined with salvia miltiorrhiza ligustrazine injection on cognitive function in patients with cerebral infarction. Methods: 60 patients with cerebral infarction from December 2017 to December 2019 were randomly divided into control group (n = 30) and observation group (n = 30) by random number table method. The control group was treated with salvia miltiorrhiza ligustrazine injection, and the observation group was treated with salvia miltiorrhiza polyphenolic acid on the basis of the control group. After 4-week treatment, the effect of the patients was evaluated, and the hemorheological level, cognitive function and drug safety of the two groups were compared. Results: The levels of high blood and low shear viscosity, high whole blood and plasma viscosity in the observation group were lower than those in the control group 4 weeks after treatment (P0.05). Conclusion: The combination of salvia miltiorrhiza polyphenolic acid and salvia miltiorrhiza ligustrazine injection can improve the hemorheology of patients with cerebral infarction. It is helpful to improve the cognitive function of patients. The drug is safe and worthy of being popularized.

Aim: The lncRNA growth arrest-special 5 ( GAS5) is a critical tumor suppressor lncRNA, and its expression level has been found to be decreased in many types of cancers. So GAS5 polymorphisms are also likely to influence predisposition to many types of malignant diseases. Nevertheless, the relationships between GAS5 polymorphisms and cancer are still controversial. Thus, the authors designed this meta-analysis to get a more statistically reliable conclusion. Methods: The authors searched PubMed, Embase, and Web of Science for eligible studies. A total of 12 eligible studies involving 8693 cancer cases and 10,805 controls were pooled and analyzed in this meta-analysis. Results: Among GAS5 polymorphisms, only GAS5 rs145204276 insertion/deletion polymorphism could be analyzed in a meta-analysis with regard to predisposition to cancer since no any other GAS5 polymorphisms were explored by at least two individual genetic association studies. All eligible studies were found to be of Asian origin. Although the overall pooled meta-analysis results did not show any significant associations between rs145204276 insertion/deletion polymorphism and a predisposition to cancer, rs145204276 insertion/deletion polymorphism was demonstrated to be significantly associated with a predisposition to gastric cancer (dominant comparison: PConclusions: This meta-analysis demonstrated that GAS5 rs145204276 insertion/deletion polymorphism was associated with a predisposition to gastric cancer in Asians. Nevertheless, considering that this positive finding was only based on three eligible studies from the same area, future studies with larger sample sizes in other populations are still warranted to test the robustness of our findings.

Background: Acute coronary syndrome (ACS) is a group of clinical syndromes caused by thrombosis caused by rupture of coronary atherosclerotic plaque or erosion ulcer, resulting in complete or incomplete occlusion of blood vessels. ACS is the most common cardiovascular critical disease. Although with the development of coronary intervention technology, the incidence of major adverse cardiovascular events (MACE) is still high. In China, traditional Chinese medicine (TCM) has been widely used in the adjuvant treatment of ACS to improve the symptoms and prognosis. Danhong injection (DHI) and Naoxintong capsule (NXTC) may improve the prognosis of patients with ACS, but the evidence-based evidence is still insufficient. The main purpose of this study was to evaluate the efficacy and safety of DHI combined with NXTC in the treatment of ACS.Methods/design:This is a randomized, placebo-controlled clinical trial.1752 patients with ACS undergoing percutaneous coronary intervention (PCI) will be randomly assigned to receive DHI combined with NXTC or placebo at the ratio of 1:1. The course of treatment was 12 weeks. All participants received conventional treatment. The main outcome measure was the 12-months incidence of MACEs. Adverse events (AE) will also be evaluated.Discussion:This trial is a well designed study according to principles and regulations issued by the China food and Drug Administration (CFDA). The results will provide high-quality evidence for the efficacy and safety of DHI combined with NXTC in the treatment of ACS. The results of this study can provide clinicians with evidence-based recommendations for treatment of ACS.Trial registration：Chinese Clinical Trial Registry(http://www.chictr.org.cn/index.aspx), ChiCTR-IOR-14005693.Registered on November 12,2014.

Background: Acute respiratory distress syndrome (ARDS) is an increasingly common acute respiratory failure that seriously threaten people's health. ARDS has a case fatality rate of up to 40%. ARDS is a serious threat to the life safety of patients and the quality of life, causing a huge economic burden to individuals, families and society. ARDS has become a large worldwide public health problem. Prone position ventilation (PPV) is an important auxiliary treatment for ARDS, which could improve oxygenation. However, PPV could cause Pressure injuries (PI) and other complications easily. We found that 45° PPV could reduce the incidence of PI, but lack of robust Evidence-based medicine evidence proving its efficacy. Therefore, we designed a randomized controlled trial to evaluate the efficacy of 45° PPV in the treatment of ARDS. Methods: A total of 268 patients will be randomly assigned to the control group and the test group (n = 134 each) in a ratio of 1:1. The treatment period is 7 days. The primary outcome measure will be the incidence of PI. The secondary outcomes will include APACHE II score, Braden Scale score, heart rate, systolic blood pressure, diastolic blood pressure, central venous pressure, mean arterial pressure, pH of arterial blood, oxygenation index, oxygen partial pressure, and carbon dioxide partial pressure. The evaluation will be performed at baseline, 1 hour, 12 hour, 48 hour, 5days, 7days after PPPV. Results: This study is helpful to evaluate the efficacy of 45° PPV in the treatment of ARDS. Conclusion: 45° PPV may reduce the incidence of PI and improve oxygenation in patients with ARDS, which has important value in practical application Trial registration: ChiCTR2000040436, registration time: November 28, 2020.

Supplemental Digital Content is available in the text, Background: H-type hypertension is a kind of cardiovascular disease that threatens human life and health seriously. Banxia Baizhu Tianma Tang (BBTT) has been used widely for H-type hypertension while its effective evidence is not clear. Hence, we provide a systematic review protocol to evaluate the efficacy and safety of BBTT in the treatment of H-type hypertension. Methods: Nine databases including Cochrane Library, PubMed, EMBASE, WOS, Medline, CNKI, WangFang, CBM, and VIP will be searched from their inception to October 2019. All randomized controlled trials (RCTs) of BBTT for H-type hypertension will be included. The language is limited to Chinese and English. The primary outcome measure will be the major adverse cardiac and cerebral events (MACCE). The entire process will include study selection, data extraction, assessment of bias risk, data synthesis. Data analysis will be performed using RevMan V.5.3.5 (The Cochrane Collaboration, Oxford, UK). Results: This study will evaluate the efficacy and safety of BBTT in the treatment of H-type hypertension from several aspects, including MACCE, blood pressure (BP), blood lipids, inflammation indicators and homocysteine (Hcy). Conclusion: This systematic review will provide evidence for determining whether or not BBTT is an effective and safe intervention for H-type hypertension. PROSPERO registration number: PROSPERO CRD 42019131491.

Additional file 1: Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Checklist: recommended items to address in a clinical trial protocol and related documents.

Supplemental material, Supplementary_material for LncRNA growth arrest-special 5 polymorphisms and predisposition to cancer: A meta-analysis by Hairong Cai, Wenyan Xu and Xian Zhang in The International Journal of Biological Markers

Background: Coronary microvascular disease (CMVD) refers to cardiovascular diseases with normal coronary angiography but evidence of myocardial ischemia or microcirculation lesions, often presenting as angina pectoris attack. Coronary artery of microtubules dysfunction is one of the pathogenesis of coronary heart disease,but the occurrence and development and the current of CMVD intervention therapy remains to be further researched.Chinese traditional medicine (TCM)has advantages in the treatment of cardiovascular diseases, therefore, this article describes an ongoing randomized controlled clinical trial, based on the theory of TCM, for the purpose of evaluating the efficacy and safety of Guhong injection ,a Chinese patent medicine,compared with placebo in patients suffering from CMVD. Methods/design: This is a multicenter, randomized, parallel arm, open-label, double-blind, placebo-controlled clinical trial. A total of 260 eligible patients will be allocated and randomly assigned, in a ratio of 1:1, to either the experimental group or the control group. The treatment course is 10 consecutive days, with a 8-week follow-up. The primary outcome is the frequency of angina attacks, Secondary outcomes include myocardial metabolites, ecg changes, quantitative score of TCM syndromes, inflammatory response and endothelial function indicators. Discussion: This trial is strictly designed in accordance with principles and regulations issued by the China Food and Drug Administration (CFDA). The results will provide high quality evidence on the efficacy and safety of Guhong injection in the treatment of CMVD. Trial registration: Chinese Clinical Trials Registry, ChiCTR1900022902. Registered on 27 April 2019. Keywords: Guhong injection, Coronary microvascular disease, randomized controlled trial, inflammatory response,endothelial function

This study was to compare the short- and long-term outcomes of elderly versus middle-aged patients with localized renal cell carcinoma who had undergone laparoscopic radical nephrectomy.Between January 2012 and January 2018, a total of 54 patients aged 70 years and above with localized renal cell carcinoma (elderly group) underwent laparoscopic radical nephrectomy. The short- and long-term outcomes of these 54 patients were compared with those of 97 middle-aged patients (aged between 55 and 69 years; middle-aged group) who underwent laparoscopic radical nephrectomy due to localized renal cell carcinoma.The age, Charlson's comorbidity index, and American Society of Anesthesiologists (ASA) score were higher in the elderly group than in the middle-aged group. Other preoperative baseline data did not show any statistically significant differences. The differences in short-term outcomes, including operative time, intraoperative blood loss, transfer rate, postoperative 30-day complication rate and severity of complication, and pathological data were not statistically significant between the elderly and middle-aged groups. Long-term follow-up results showed that the tumor recurrence rates were similar in the two groups. Overall and disease-free survival rates were similar in the two groups. Multivariate analysis showed that age was not an independent predictor for overall and disease-free survival rates.Treatment with laparoscopic radical nephrectomy for elderly patients with localized renal cell carcinoma, could achieve short- and long-term outcomes, similar to those of middle-aged patients.

Objective Prostate cancer is a malignant tumour that poses a serious risk to human health. Epidemiological studies suggest that it may be associated with vitamin D receptor gene ( VDR) polymorphisms. Previous work investigated potential risks between Taq I (rs731236) and Bsm I (rs1544410) VDR polymorphisms with prostate cancer in humans; however, results are inconsistent. Methods We conducted a meta-analysis to retrieve genetic association analyses of rs731236 and rs1544410 polymorphisms with prostate cancer from studies published between 2006–2016. Pooled odds ratios with 95% confidence intervals were used to assess genetic associations, and heterogeneity was assessed by Q and I2statistics. Results Our findings suggest a significant association between rs731236 and prostate cancer risk in Asians and African Americans, but rs1544410 was not associated with prostate cancer under three genetic models. Conclusion Future studies including larger sample sizes and the analysis of gene functions are needed to help develop prostate cancer treatment.

Background: Coronary microvascular disease (CMVD) refers to cardiovascular diseases with normal coronary angiography but evidence of myocardial ischemia or microcirculation lesions, often presenting as angina pectoris attack. Coronary artery of microtubules dysfunction is one of the pathogenesis of coronary heart disease,but the occurrence and development and the current of CMVD intervention therapy remains to be further researched.Chinese traditional medicine (TCM)has advantages in the treatment of cardiovascular diseases, therefore, this article describes an ongoing randomized controlled clinical trial, based on the theory of TCM, for the purpose of evaluating the efficacy and safety of Guhong injection ,a Chinese patent medicine,compared with placebo in patients suffering from CMVD. Methods/design: This is a multicenter, randomized, parallel arm, open-label, double-blind, placebo-controlled clinical trial. A total of 260 eligible patients will be allocated and randomly assigned, in a ratio of 1:1, to either the experimental group or the control group. The treatment course is 10 consecutive days, with a 8-week follow-up. The primary outcome is the frequency of angina attacks, Secondary outcomes include myocardial metabolites, ecg changes, quantitative score of TCM syndromes, inflammatory response and endothelial function indicators. Discussion: This trial is strictly designed in accordance with principles and regulations issued by the China Food and Drug Administration (CFDA). The results will provide high quality evidence on the efficacy and safety of Guhong injection in the treatment of CMVD. Trial registration: Chinese Clinical Trials Registry, ChiCTR1900022902. Registered on 27 April 2019.

Supplemental Digital Content is available in the text, Background: Essential hypertension is one of the most common chronic diseases worldwide, as well as a leading risk factor for cardiocerebrovascular diseases. Zhengan Xifeng Decoction (ZGXFD) has been widely used to treat essential hypertension, but there is no systematic review by assessing efficacy and safety of ZGXFD on essential hypertension. Therefore, we aim to perform systematic review and meta-analysis to evaluate the efficacy and safety of ZGXFD in the treatment of essential hypertension. Methods: This systematic review and meta-analysis will be performed by means of electronic databases, including EMBASE, Cochrane Center Registration Controlled trials (Cochrane Library), Web of Science (WOS), World Health Organization International Clinical Trials Registry Platform, PubMed, China Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), and Wan-fang database. The electronic databases will be searched from their inception to October 2018. This systemic review will include only published English and Chinese articles randomized controlled trials (RTCs) of ZGXFD on essential hypertension. The primary outcome is Efficacy and blood pressure (BP), blood lipid and adverse reactions will be accepted as secondary outcomes. All statistical analyses will be conducted using RevMan V.5.3.5 software. Results: This systematic review and meta-analysis will provide high-quality evidence from several aspects, including for efficacy, blood pressure, blood lipid and adverse effects to evaluate the efficacy and safety of ZGXFD on EHTN. Conclusion: This systematic review will determine whether or not ZGXFD is an effective intervention for essential hypertension.

Background Coronary heart disease (CHD) is the leading cause of morbidity and mortality worldwide. Guipi Decoction (GPD) is a classical traditional Chinese medication used to treat CHD. However, systematic review and meta-analysis regarding its efficacy and safety has not been systematically evaluated. The objective of this protocol is to determine the efficacy and safety of GPD in the treatment of CHD. Methods Randomized controlled trials evaluating the effectiveness and safety of GPD in the treatment of CHD will be retrieved from 8 electronic databases, including PubMed, EMBASE, Cochrane Library, Web of science, China National Knowledge Infrastructure Database, VIP Database, Wanfang Database and China Biology Medicine Database. Study selection, data collection, risk of bias assessment, and evaluation of the quality of evidence will be performed in order. Data will be analyzed by RevMan V.5.3.5 software. Results This study will evaluate the efficacy and safety of GPD in the treatment of CHD. Conclusion This systematic review will provide evidence for determining whether or not GPD is an effective and safe intervention for CHD. Prospero registration number PROSPERO CRD 42020156420.

Objective. This double-blind and randomized placebo-controlled trial evaluated the safety and efficacy of Danhong injection combined with Naoxintong capsule in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). Methods. ACS patients scheduled to undergo PCI (n=130) were equally and randomly apportioned to either a treatment or control group. After PCI, the treatment group received Danhong injection combined with Naoxintong capsule for 12 weeks, while the control group was given placebo. Both groups were otherwise treated with conventional secondary prevention of coronary artery disease. The groups were primarily evaluated for clinical efficacy and cardiovascular events. Evaluative indicators of safety included adverse events, platelet count, and liver, renal, and blood coagulation functions. Result. No cardiovascular events or adverse reactions were observed in either group. The treatment group demonstrated better signs of clinical efficacy, including left ventricular ejection fraction, higher nitric oxide levels, and lower levels of endothelin-1 (ET-1) and von Willebrand factor (VWF). Conclusion. ACS patients treated with Danhong injection combined with Naoxintong capsule after PCI demonstrated better improvement with regard to markers associated with atherosclerosis and adverse cardiovascular events, without apparent adverse effects. Thus, Danhong injection combined with Naoxintong capsule was safe and effective for treating ACS patients after PCI.

Background Sepsis is the most common critical illness in the clinic, with a high incidence and mortality. Qingwen Baidu decoction (QWBDD) has been widely applied in the treatment of sepsis, however, there is no systematic review or meta-analysis of QWBDD in the treatment of sepsis. Hence, we provide a protocol of systematic review and meta-analysis to evaluate the efficacy and safety of QWBDD in the treatment of sepsis. Methods The databases including Cochrane Library, PubMed, Embase, Web of Science, Cochrane Clinical Trial Database, World Health Organization International Clinical Trial Registration Platform, CNKI, CBM, VIP, and WanFang Database will be searched from the time when the respective databases were established to January 2019. All randomized controlled trials (RTCs) published in Chinese and English assessing QWBDD for sepsis will be included. Continuity data are expressed as mean difference (MD) or standard mean difference (SMD), and dichotomous data is expressed as relative risk. Analyses will be performed by using RevMan V.5.3.5 software. Results This study will provide high-quality synthesis of current evidence of QWBDD in the treatment of sepsis from the following aspects, including 28-day mortality, mean arterial pressure (MAP), blood lactate, procalcitonin (PCT), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), hypersensitive C-reactive protein (hs-CRP), acute physiology and chronic health score (APACHE-II), intensive care unit stay, mean hospital stay, mechanical ventilation time, etc. CONCLUSION:: Our systematic review will provide evidence for judging whether QWBDD is an effective intervention for sepsis. Prospero registration number PROSPERO CRD 42019123078.

Background Chronic heart failure (CHF) is one of the most important cardiovascular diseases worldly, with high morbidity and mortality. Fuling Sini decoction (FSD) has been used in the management of CHF widely in China, while its effective evidence is not clear. A systematic review and meta-analysis to evaluate FSD for CHF is lacking. Hence, we propose a protocol for systematic evaluation of its efficacy and safety for CHF. Methods We will search the following electronic databases from inception to October 2018, including EMBASE, Cochrane Center Registration Controlled trials (Cochrane Library), PubMed, Medline, WHO International Clinical Trials Registry Platform, China Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), and Wan-fang database. Only randomized controlled trials (RCTs) of FSD alone or combined with other management for CHF will be included. Two independent reviewers will screen the literature and extract data according to the Cochrane Handbook method. The assessment of bias risk, data synthesis, subgroup analysis, and meta-analyses and finally meta-analysis will be performed by using RevMan V.5.3.5 software. Results This systematic review will provide high-quality evidence and may be the first to evaluate efficacy and safety of FSD in the treatment of CHF. Conclusion This systematic review will provide evidence for judging whether FSD is an effective management for CHF or not. Prospero registration number CRD 42018110210.

Background Unstable angina (UA) is a clinically common coronary heart disease. Zhishi xiebai guizhi decoction (ZXGD) has been widely used in the management of UA, although its effective evidence is not clear and there is no systematic review regarding its efficacy and safety. Therefore, we conduct this systematic review protocol to evaluate the efficacy and safety of ZXGD in the treatment of UA. Methods We will search the following electronic databases: Cochrane Library, Web of Science, PubMed, EBASE, Springer, WHO International Clinical Trial Registration Platform, China Biomedical Literature Database, China National Knowledge Infrastructure, Chinese Scientific Journal Database (VIP), and Wan-fang database from their inception to October 2018. Only randomized controlled trials (RCTs) published in English and Chinese will be included. Continuous data will be expressed as mean difference or standard mean difference, and dichotomous data relative as risk. Study selection, data extraction, and assessment with risk of bias and data analysis will be performed by two independent authors. RevMan software version 5.3 will be used for meta-analysis. Results This study will provide high-quality evidence of ZXGD in the treatment of UA from the following aspects, including clinical efficacy, blood lipids, Seattle angina scale, electrocardiogram improvement, ST-segment depression, left ventricular ejection fraction, angina duration, and adverse events. Conclusion This systematic review will provide a basis for judging whether ZXGD is an effective intervention for UA or not. Prospero registration number PROSPERO CRD 42018115528.

Supplemental Digital Content is available in the text, Background: Hyperlipidemia is one of the most common metabolic diseases worldwide, as well as a leading risk factor for cardio-cerebrovascular diseases. Banxia Baizhu Tianma decoction (BBTD) is widely used for the treatment of hyperlipidemia in China, however, systematic review and meta-analysis regarding its efficacy and safety is lacking. The aim of this protocol of systematic review is to evaluate the effectiveness and safety of BBTD in the treatment of hyperlipidemia. Methods: We will include the randomized controlled trials estimating the effectiveness and safety of BBTD in the treatment of hyperlipidemia. Data sources will include 5 English databases (PubMed, EMBASE, Cochrane Library, Web of Science, CINAHL) and 4 Chinese databases (CMB, CNKI, VIP, Wanfang database). The literature to be collected will be from the time when databases were established to September 2018. Efficacy will be accepted as the primary outcome, while blood lipid levels and adverse reactions as the secondary outcome. Study selection, data collection, risk of bias assessment, and evaluation of the quality of the evidence will be conducted by 2 × 2 different reviewers. Statistical syntheses will be conducted by using RevMan software V.5.3. Results: This study will provide a high-quality evidence for BBTD on the treatment of hyperlipidemia from efficacy, serum lipid levels, and adverse reactions. Conclusion: The result will provide a basis for judging whether BBTD is an effective intervention for the treatment of hyperlipidemia. PROSPERO registration number: PROSPERO CRD 42018081359.

The spatial switching retardation and heterogeneity of fatigue in lead zirconate titanate ceramics were investigated using quasi-static d33 measurements. The variation of d33 values was measured on the samples with different fatigue states and different reverse switching pulses. Experimental results indicated that the switching retardation exists in the different fatigue stages and increases with increasing cycle number. The d33 measurements exhibit a strongly heterogeneous behavior of fatigue. This fatigue heterogeneity weakened in the seriously fatigued samples.

OBJECTIVE To investigate the diagnostic value of modified prostate specific antigen (PSA) parameters in the diagnosis of prostate cancer (PCA) when the serum PSA is in a grey zone of 4~10 ng/mL. METHODS The results of serum PSA determinations of the patients receiving a transrectal ultrasound- guided multiphase prostatic biopsy, were retrospectively analyzed. In the 88 patients with a serum PSA value of 4-10 ng/mL, the final diagnosis of PCA was made in 21, and that of benign pros tate hyperplasia (BPH) in 67 patients. The percentage of the free-serum PSA ([FPSA]/total-serum PSA [TPSA], F/T), PSA density (PSAD) and the sensitivity and specificity of the new PSA modified parameter (F/T)/PSAD in diagnosing PCA, within a set threshold value, was compared. RESULTS In the 88 patients with serum PSA in the grey zone of 4.0-10.0 ng/ml, there was no significant difference in comparing the TPSA between the 21 PCA patients and 67 BPH patients ( P > 0.05). However, there was a significant difference in the value of modified PSA parameters, such as F/T, PSAD and (F/T)/PSAD, between the PCA and the BPH groups ( P 0.05), whereas an overt predominance was present in the specificity of (F/T)/PSAD for PCA diagnosis ( P < 0.05). CONCLUSION In the serum PSA grey zone of 4-10 ng/mL, a modified PSA parameter can improve the PCA diagnostic accuracy rate. With a considerably high sensitivity, application of the (F/T)/PSAD may effectively enhance the diagnostic specificity, which is superior to the F/T and PSAD, and can be expected to be one of the new indices derived from the PSA.

The face-shear ( d36) mode may be the most practical shear mode in piezoelectrics, while theoretically this mode cannot appear in piezoelectric ceramics because of its transversally isotropic symmetry. Recently, we realized piezoelectric coefficient d36 up to 206pC/N in soft PbZr1-xTixO3 (PZT) ceramics via ferroelastic domain engineering [H. C. Miao and F. X. Li, Appl. Phys. Lett. 107, 122902 (2015)]. In this work, we further realized the face-shear mode in both hard and soft PZT ceramics including PZT-4 (hard), PZT-51(soft), and PZT-5H (soft) and investigated the electric properties systematically. The resonance methods are derived to measure the d36 coefficients using both square patches and narrow bar samples, and the obtained values are consistent with that measured by a modified d33 meter previously. For all samples, the pure d36 mode can only appear near the resonance frequency, and the coupled d36-d31 mode dominates off resonance. It is found that both the piezoelectric coefficient d36 and the elec...

(Chemical Equation Presented) Butterfly clusters: Hydrogenation of a cationic iridium complex with the sterically bulky N-ligand tetrahydroquinoline (thq) leads to the formation of two distinct tetrameric polyhydrides (see scheme; Ir green, N blue, P purple), which differ by exchanging one thq ligand for hydride. Both complexes have butterfly structures, with similar core geometries, but markedly different hinge angles (40.8° for 1 and 9.1° for 2). © 2009 Wiley-VCH Verlag GmbH and Co. KGaA.