Methods : The study group consisted of 186 patients with acute

Methods : The study group consisted of 186 patients with acute Sapitinib clinical trial NSAP compared to 147 patients with AA initially treated during 1985-1986. Medical history, social background, quality of life and abdominal symptoms were assessed with standardized questionnaires in both groups during 2006-2009. The patients who continued to have abdominal symptoms were invited to a check-up visit. Results : During 1985-6, the NSAP group had more previous

abdominal symptoms and operations than the AA group. Some 29% of patients with NSAP and 11% of patients with AA had still abdominal symptoms at long-term check-up (p smaller than 0.0001). Chronic abdominal pain (38 vs 17) and peptic ulcer disease (18 vs 2) occurred more often in the NSAP group than in the controls, respectively (p = 0.001). After five years of follow-up, 11 patients in the NSAP group and 6 patients in the AA group had died (ns). During the twenty years of follow-up, mortality was higher (46/22, 25/15%) in the patients with NSAP than in controls (p = 0.013). Ischaemic heart disease was the leading cause of death in both click here groups (18 NSAP vs 5 AA, p = 0.017). The quality of life scores were comparable in both study groups. Conclusion : Over 70% of NSAP- and almost 90% of AA-patients were free of symptoms after 20 years of follow-up. Mortality was higher and various

alimentary track diseases were more frequent in patients with NSAP than in AA.”
“Thyroid cancer is the most common endocrine cancer, but its key oncogenic drivers remain undefined. In this study we identified the TYRO3 and AXL receptor tyrosine kinases as transcriptional targets of the chemokine CXCL12/SDF-1 in CXCR4-expressing thyroid cancer cells. Both receptors were

constitutively expressed in thyroid cancer cell lines but not normal thyroid cells. AXL displayed high levels of tyrosine phosphorylation in most cancer cell lines due to constitutive expression of its ligand GAS6. In human thyroid carcinoma specimens, but not in normal thyroid tissues, AXL and GAS6 were often coexpressed. In cell lines expressing both receptors and ligand, blocking each receptor or ligand dramatically selleck chemicals affected cell viability and decreased resistance to apoptotic stimuli. Stimulation of GAS6-negative cancer cells with GAS6 increased their proliferation and survival. Similarly, siRNA-mediated silencing of AXL inhibited cancer cell viability, invasiveness, and growth of tumor xenografts in nude mice. Our findings suggest that a TYRO3/AXL-GAS6 autocrine circuit sustains the malignant features of thyroid cancer cells and that targeting the circuit could offer a novel therapeutic approach in this cancer. Cancer Res; 71(5); 1792-804. (c) 2011 AACR.”
“Diamond offers unique material advantages for the realization of micro-and nanomechanical resonators because of its high Young’s modulus, compatibility with harsh environments and superior thermal properties.

Western blot analyses further showed that cAkt3 promoted signific

Western blot analyses further showed that cAkt3 promoted significantly higher levels of phosphorylated Akt and phosphorylated mTOR than cAkt1. The mTOR inhibitor rapamycin blocked the protective effects of both cAkt1 and cAkt3. In conclusion, Akt isoforms are differentially regulated after stroke and Akt3 offers stronger protection than cAkt1 by maintaining Akt levels and promoting mTOR activity.”
“Symbioses between cool season grasses and fungi of the family Clavicipitaceae Bucladesine are an integral component of both natural and agricultural ecosystems.

An excellent experimental model is the association between the biotrophic fungus Epichloe festucae and Lolium perenne (perennial ryegrass). The fungal partner produces a suite of secondary metabolites that protect the host from various biotic and abiotic stresses. The plant host provides a source of nutrients and a mechanism of dissemination via seed transmission. Crucial mechanisms that maintain a stable mutualistic see more association include signaling through the stress activated MAP kinase pathway and production of reactive oxygen species by the fungal NADPH oxidase

(Nox) complex. Disruption of components of the Nox complex (NoxA, NoxR and RacA), or the stress-activated MAP kinase (SakA), leads to a breakdown in this finely balanced association, resulting in pathogenic infection instead of mutualism. Hosts infected with fungi lacking a functional Nox complex, or the stress-activated MAP kinase, display a stunted phenotype and undergo premature senescence, GDC-0973 in vivo while the fungus switches from restricted to proliferative growth. To gain insight into the mechanisms that underlie these physiological changes, high throughput mRNA sequencing has been used to analyze the transcriptomes of both host and symbiont in wild-type and a mutant association. In the Delta sakA mutant association, a dramatic up-regulation of fungal hydrolases and transporters was observed, changes consistent

with a switch from restricted symbiotic to proliferative pathogenic growth. Analysis of the plant transcriptome revealed dramatic changes in expression of host genes involved in pathogen defense, transposon activation and hormone biosynthesis and response. This review highlights how finely tuned grass-endophyte associations are, and how interfering with the signaling pathways involved in maintenance of these associations can trigger a change from mutualistic to pathogenic interaction. (C) 2010 Elsevier Ireland Ltd. All rights reserved.”
“An increasing number of Australian slaughter plants were found not to meet the Meat Standards Australia (MSA) pH-temperature window, due to high rigor temperatures, particularly at plants where grain-fed animals were slaughtered. Hence, the red meat processing industry in Australia supported a research program focused on resolving this issue, as carcasses that do not meet the MSA pH-temperature window are excluded from MSA grading.

We conclude that rotational thromboelastometry/thromboelastograph

We conclude that rotational thromboelastometry/thromboelastography analysis plays a critical role in the management of traumatic bleeding and helps us provide more aggressive and targeted therapy for coagulopathy both in the acute FG-4592 clinical trial and later phases of treatment of severe bleeding.”
“In 1973, Germany’s first museum of the history of medicine was founded in the former

anatomical theatre of Ingolstadt University. Today, the baroque building with its beautiful medical garden is one of the attractions of the old city of Ingolstadt. The paper gives a round tour through the permanent exhibition, the medical technology wing and the herbal garden. The emphasis is put on those objects and plants which have a connection to the history of urology, from a “ladies urinal” to the world’s first ESWL apparatus.”
“A rewritable phase-change optical disk providing a large capacity

of 100 Gbyte on a 120mm disk was first demonstrated using the multilayer Bluray Disc (TM) (BD-XL) format. The doubled capacity of this optical disk compared with that of a conventional dual-layer disk was achieved firstly by stacking triple recording layers and secondly by increasing the recording capacity per layer from 25 to 33.4 Gbyte at 33.6%. The high transmittances of 50% (middle layer) and 60% (front layer) were achieved by thinning a Ge-Sb-Te phase-change film to 7.5 and 6 nm and also by thinning a Ag-alloy film to 9 and 7 nm, respectively. An additional TiO2-based film formed Roscovitine solubility dmso on the Ag-alloy film was effective in improving the transmittance at 3%, compared with the structure using a conventional TiO2 film. Furthermore, a transmittance-balanced structure was adopted for these layers in order to stabilize

the recording-reading properties. To improve cyclability, ZrO2-Cr2O3-based interface films were provided on both sides of the phase-change film for the middle and front layers. The increase in recording capacity per layer was achieved by reducing the minimum mark length from 0.149 to 0.112 mu m. Since the optical changes degrade with the reductions in the mark lengths and thicknesses of the Ge-Sb-Te and Ag-alloy films, a phase-change material with a GeTe-rich composition on a GeTe-Sb2Te3 pseudo-binary line was adopted for every layer FG-4592 molecular weight to compensate it. It was confirmed that the sample disk successfully satisfies all the requirements of the BD-XL format. (C) 2011 The Japan Society of Applied Physics”
“Gymnosperm root protophloem is not well understood. There is a question as to whether root protophloem cells mature as phloem parenchyma, or as sieve elements, or if within the protophloem there is an anatomical and evolutionary gradient having characteristics of both cell types. This question is relevant to understanding anatomical and physiological mechanisms that supply nutrients to the root tip.

This finding prompted us to clone the isolate for full-length gen

This finding prompted us to clone the isolate for full-length genome sequencing and molecular characterization as the prototype strain of p38 MAPK inhibitor CAV-9 is known to

cause only minimal damage to insulin-producing fl-cells. Based on capsid-coding sequence comparisons, the isolate turned out to be echovirus 11 (E-1 1). Phylogenetic analyses demonstrated that E-1 1 /D207 was closely related to a specific subgroup B of E-1 1 strains known to cause uveitis. To study further antigenic properties of isolate E-1 1 /D207 and uveitis-causing E-1 1 strains, neutralization experiments were carried out with CAV-9- and E-1 1 -specific antisera. Unlike the prototype strains, the isolate E-1 1 /D207 and uveitis-causing E-1 1 strains were well neutralized with both CAV-9- and E-1 1 specific antisera. Attempts to identify recombination Selleck FDA-approved Drug Library of the capsid coding sequences as a reason for double-reactivity using the Simplot analysis failed to reveal major transferred motifs. However, pepticle scanning technique was able to identify antigenic regions of capsid proteins of E-11 1 /D207 as well as regions cross-reacting with an antiserurn raised to CAV-9. Thus, double

specificity of E- 11 /D207 seems to be a real characteristic shared by the phylogenetically closely related virus strains in the genetic subgroup B of E-1 1.”
“The mammalian target of rapamycin (mTOR) assembles into two distinct multi-protein complexes called mTORC1 and mTORC2. Whereas mTORC1 is known to regulate cell and organismal growth, the role of mTORC2 is less understood. We describe two mouse lines that are devoid of the mTORC2 component rictor

in the entire central nervous system or in Purkinje cells. In both lines neurons were smaller and their morphology and function were strongly affected. The phenotypes were accompanied by loss of activation of Akt, PKC, and SGK1 without effects on mTORC1 activity. The striking decrease in the activation and expression of several PKC isoforms, the subsequent loss of activation of GAP-43 and MARCKS, and the established role of PKCs in spinocerebellar ataxia and in shaping the actin cytoskeleton strongly suggest that the morphological deficits observed AZD8931 purchase in rictor-deficient neurons are mediated by PKCs. Together our experiments show that mTORC2 has a particularly important role in the brain and that it affects size, morphology, and function of neurons.”
“The present work was aimed at evaluating the “in vitro” efficacy of different concentrations of thymol on engorged nymphs and females of Rhipicephalus sanguineus. The nymphs were separated in seven groups and immersed in different concentrations of thymol (0.25%, 0.5%, 1.0%, 1.5%, and 2.0%) for 5 min. A control group was established (water + dimethylsulfoxide) together with a positive control group (Amitraz*), and mortality was evaluated after 15 days.

This phenomenon is altered in the fetoplacental vasculature, whic

This phenomenon is altered in the fetoplacental vasculature, which could be crucial for understanding GDM deleterious effects in fetal growth and development. (C) 2013 Elsevier Ltd. All rights reserved.”
“This study aimed at elucidating the influence of food matrix on the release of antioxidant activity from five plant foods (apple, spinach, walnut, red bean, and whole wheat). To this purpose a protocol based on sequential Ruboxistaurin enzymatic digestion was adopted. The total antioxidant capacity (TAC) of both solubilized and insoluble materials was measured at each step. Results showed that the overall TAC obtained by enzyme treatments was usually higher than that obtained by chemical

extraction-based methods. In apple most of the TAC was released C59 research buy upon water washing and after pepsin treatment, whereas in spinach, beans, and whole wheat the TAC released by

treatments with bacterial enzymes was prominent. Walnut had the highest TAC value, which was mainly released after pancreatin treatment. Therefore, the enzyme treatment is fundamental to estimate the overall potential TAC of foods having a high amount of polyphenols bound to dietary fiber or entrapped in the food matrix.”
“The functional unit of the mammalian metanephric kidney is the nephron: a complex tubular structure dedicated to blood filtration and maintenance of several important physiological functions. Nephrons are assembled from a nephron-restricted pool of mesenchymal progenitors over an extensive developmental see more period that is completed prior to (human), or shortly after (mouse), birth. An appropriate balance in the expansion and commitment of nephron progenitors to nephron formation is essential for normal kidney function. Too few nephrons increase risk of kidney disease later in life while the failure of normal progenitor

differentiation in Wilm’s tumor patients leads to massive growth of a nephroblast population often necessitating surgical removal of the kidney. An inductive process within the metanephric mesenchyme leads to the formation of a pretubular aggregate which transitions into an epithelial renal vesicle: the precursor for nephron assembly. Growth, morphogenesis and patterning transform this simple cyst-like structure into a highly elongated mature nephron with distinct cell types positioned along a proximal (glomerular) to distal (connecting segment) axis of functional organization. This review discusses our current understanding of the specification, maintenance and commitment of nephron progenitors, and the regulatory processes that transform the renal vesicle into a nephron. (C) 2014 Elsevier Ltd. All rights reserved.”
“The latent membrane protein-1 (LMP-1) is essential for Epstein-Barr virus (EBV)-induced nasal natural killer/T-cell lymphoma (NKTL). The aim of the present study was to evaluate the role of LMP-1 in NKTL.


“Background: Epidemiologic

evidence regarding the


“Background: Epidemiologic

evidence regarding the background factors of childhood infections in Japan is scarce. The aim of the present study was therefore to investigate the rates and associated factors of hospitalization for lower respiratory tract infections (LRTI) and gastrointestinal infections (GII) among children with birthweight >= 2500 g and >= 37 weeks of gestational age.\n\nMethod: The data for the study were collected at 18-month health selleck kinase inhibitor checkups in one city in Japan. The community database included information on the main outcome (past hospitalization) and 16 host, environmental, and parenting factors. The Kaplan-Meier method and log-rank test were used to determine sex differences signaling pathway in hospital admission for infection, and the Cox regression model to analyze sex-specific factors associated with the hospitalization.\n\nResults: The proportion of children who were admitted to hospital before their 18-month checkup was 7.1% for LRTI and 2.2% for GII.

Hospital admission for LRTI among boys was higher than girls. Multivariate analysis indicated the following LRTI-associated factors: child-care attendance (hazard ratio [HR] = 1.97) and three or more adults living together (HR = 2.63) for boys; and child-care attendance (HR = 4.30) and two or more children living together (HR = 4.57) for girls. GII-associated factors were maternal age <25 years (HR = 3.45) for boys, and hand washing by caregivers after lavatory use and diaper changing (HR = 6.93) for girls.\n\nConclusions: One out of 11 children was hospitalized because

of LRTI or GII during their first 18 months, which was associated with a biologic factor (sex), environmental factors (child-care attendance and family size), and parenting practices (shorter duration of exclusive breast-feeding and caregivers’ unfavorable hygiene practices).”
“This article provides an update to the published instructor’s notes for the Core Curriculum tutorial presented annually at the Drug Information Association medical communications https://www.selleckchem.com/products/ag-881.html workshop. The original publication has become the foundation for training individuals new to industry-based drug information practice. This update to the Core Curriculum publication describes the evolving role of medical communications professionals, highlighting changes from the original publication that impact the core role of a medical communications professional as well as describing new activities.\n\nMedical communications departments play a role throughout a product’s development and life cycle. They serve both external customers and internal business partners with various services.

Seventy-eight patients with simple cataract were randomized t

\n\nSeventy-eight patients with simple cataract were randomized to receive either the BioVue 3 HSM hydrophilic acrylic IOL (Ophthalmic

Innovations International, Ontario, CA, USA) (n = 38) or the Sensar AR40e hydrophobic acrylic IOL (AMO, Santa Ana, CA, USA) (n = 40). Another 99 patients with complicated cataract received either the BioVue 3 (n = 49) or the Sensar AR40e IOL (n = 50). Twelve months after surgery, POCOman software was used to analyze digital retroillumination photographs of the PCO.\n\nIn the simple cataract group, the respective PCO areas, expressed as a percentage and PCO severity scores at 12 months were this website 6.12% and 0.081 in the BioVue 3 group and 5.91% and 0.075 in the Sensar AR40e group. There was no statistically significant difference in the PCO area or the PCO severity score between the two IOLs (P = 0.631, P = 0.495, respectively). find more In the complicated cataract group, the respective PCO areas and PCO severity scores were 35.80% and 0.181 in

the BioVue 3 group and 27.17% and 0.110 in the Sensar AR40e group. There was no statistically significant difference between the two IOLs (P = 0.147, P = 0.162).\n\nThere was no difference in the degree or severity of PCO between the HSM hydrophilic acrylic IOL and the hydrophobic acrylic IOL groups.”
“Although in previous studies were examined the ultrasonic reflection behaviors at a nano-air gap using a relatively

small optical Newton’s ring specimen and a commercial acoustic lens, the details of the quantitative ultrasonic behaviors at a nano-air gap have remained unqualified until now. Since the accuracy of estimating these behaviors is directly related to the accuracy of industrial ultrasonic crack sizing, we tried to measure more accurately quantitative ultrasonic behaviors at a nano-air gap in this study. For this purpose, a special highly focused acoustic lens was designed and fabricated and applied to a large optical Newton’s ring specimen to obtain 4-Hydroxytamoxifen price accurate and reliable experimental results. Comparisons between the experimental and the conventional small gap theoretical results for a nano-air gap were also carried out. As a result, ultrasonic transmission was found to begin to occur from 60-70nm air gaps in all the measurements. This finding was largely different from that based on the gap theory. Regarding the cause of this large difference between the experimental and theoretical results, we also examined the influence of the surface roughness of contact plates. (C) 2012 The Japan Society of Applied Physics”
“Retinopathy of prematurity (ROP) is one of the three leading causes of legal blindness in childhood in developed countries. Adequate screening is one of the most important steps towards successful treatment.

C We assess evidence for paleopathology to infer the biological

C. We assess evidence for paleopathology to infer the biological consequences

of climate change and socio-economic disruption in the post-urban period at Harappa, one of the largest urban centers in the Indus Civilization. Bioarchaeological evidence demonstrates the prevalence of infection and infectious disease increased through time. Furthermore, the risk for infection and disease was uneven among burial communities. Corresponding mortuary differences suggest that socially and economically marginalized communities were most vulnerable in the context of climate uncertainty at Harappa. Combined with prior evidence for increasing levels of interpersonal violence, our data support a growing pathology of power at Harappa after 2000 B. C. Observations of the intersection between climate change and social processes in proto-historic cities offer valuable lessons about vulnerability, insecurity, and the long-term consequences of short-term strategies for coping BMS 826476 HCl with climate change.”
“We evaluated pain frequency and severity in 339 women enrolled in the Women’s Interagency HIV Study (WIHS). Among these, 63% were 39 years

of age or younger, 17% were white, 54% African American, and 29% Momelotinib clinical trial Hispanic; 32% did not complete high school; 58% had a CD4 less than 200; 65% had clinical AIDS; 60% were on highly active antiretroviral therapy ( HAART); and 32% had a viral load of 50,000 or more. Data were collected between 1996 and 1998. Within the past 6 months 190 (56%) women experienced pain 6 or more days and 168 (50%) women indicated pain severity scores of 4 or 5 (5-point scale). Pain frequency

and pain severity were not associated with age, education, ethnicity, current therapy, or location of the WIHS site. Pain frequency and severity were related to lower CD4 count, higher depression, with a history and longer duration of smoking and use of marijuana. Severity was associated with a history of crack/cocaine or heroin use or with injection drug use as the transmission category. In the multivariate models, pain severity was related to CD4 count and depression and to current tobacco use but not to crack, cocaine, heroin, or marijuana use. Pain frequency was related AG 14699 to depression and to former tobacco, crack, cocaine, heroin, or marijuana use but not to current use. The long-term effects of tobacco use may be to increase pain experience but women may also smoke tobacco or use other substances to give mild pain relief. Pain is frequent and often severe among women with HIV requiring medical management.”
“Background : Cyclooxygenase-2 (COX-2) is an enzyme that promotes proliferation of tumor cells. HuR is a member of the family of embryonic lethal abnormal vision-like proteins. Recent studies show that cytoplasmic HuR stabilizes the mRNA of COX-2 and regulates the expression of COX-2. Moreover, cytoplasmic HuR expression is associated with a poorer prognosis for patients with some cancers.

Among children perceived to be at highest risk for pneumonia (&gt

Among children perceived to be at highest risk for pneumonia (>75% prediction), 30.6% (95% CI, 15.5%-45.6%) had definite pneumonia, and 52.8% (95% CI, 37.7%-70.3%) had probable or definite pneumonia.

Physicians’ estimates of the likelihood of pneumonia were positively correlated with the rate of definite (Spearman rho = 0.15, P < 0.001) and probable or definite radiographic pneumonia (Spearman rho = 0.19, P < 0.001).\n\nConclusions: With some overestimation, physicians’ assessment of the likelihood of pneumonia correlates well with radiographic diagnosis of pneumonia.”
“Porous titanium metal subjected to NaOH and heat treatments is useful QNZ manufacturer as a bone substitute as it shows high mechanical strength as well as osteoconductivity and osteoinductivity. However, the porous metal is liable to be

contaminated with oxygen gas during the fabrication process and this incorporated oxygen could lead to adverse effects on the bioactivity and mechanical properties of the prepared porous body. In this study, oxygen contamination during fabrication of bioactive porous bodies was measured. It was selleck products found that the oxygen content of the titanium metal was increased from 0.08 to 0.23 mass% when the porous body was prepared from bar stock, and it further increased up to 0.51 mass% when it was subjected to NaOH and heat treatments. Despite this, the porous bodies subjected to NaOH and heat treatments formed apatite on their pore walls within I day in a simulated body fluid. This result was consistent with the apatite-forming ability of NaOH- and heat-treated titanium plates with different oxygen contents in the range of 0.05 to 0.30 mass%. The compressive strength of the porous body was increased about SB273005 10% by the NaOH and heat treatments. (C) 2009 Elsevier B.V. All rights reserved.”
“This study describes the anatomical and developmental aspects of muscular development from the early embryo to competent larval stage in the gastropod Ilyanassa obsoleta. Staining of F-actin revealed differential spatial and temporal patterns of several muscles. In

particular, two major muscles, the larval retractor and pedal retractor muscles originate independently and display distinct developmental patterns similar to observations in other gastropod species. Additionally, together with the larval retractor muscle, the accessory larval muscle developed in the embryo at the trochophore stage. Therefore, both these muscles develop prior to ontogenetic torsion. The pedal retractor muscle marked the most abundant growth in the mid veliger stage. Also during the middle stage, the metapodial retractor muscle and opercular retractor muscle grew concurrently with development of the foot. We show evidence that juvenile muscles, such as the buccal mass muscle and siphon muscle develop initially during the late veliger stage.

ROS can alter chromosomal DNA, leading to genomic instability, an

ROS can alter chromosomal DNA, leading to genomic instability, and may serve as signaling molecules that affect tumor cell proliferation, survival, metabolism, angiogenesis, and metastasis. Targeting Noxs and

their downstream signaling components may be a promising approach to pre-empting inflammation-related malignancies. Published by Elsevier Ireland Ltd.”
“Background: From 1998 to 2008, 1000 skeletally mature patients underwent, autologous chondrocyte implantation for an osteochondral defect of the knee. We evaluated the functional outcomes in 827 of 869 patients who had undergone autologous chondrocyte implantation with Chondron or periosteum (ACI-C/ACI-P) or matrix-assisted selleck kinase inhibitor chondrocyte implantation (MACI) and attempted to identify factors that influenced outcome. Methods: The age of the patient, the size and site of the osteochondral lesion, previous surgery, and the presence of early osteoarthritis were assessed for their influence on outcomes. Each factor was evaluated in a separate Cox proportional hazards model with use of hazard ratios (HRs), LY3023414 clinical trial with 95% confidence intervals (CIs), describing the likelihood of failure for that particular factor. Outcomes were assessed with use of the modified Cincinnati score, visual analog scale pain score, and Stanmore functional score. Results: The mean duration of follow-up was 6.2 years (range, two to twelve years). The mean age

selleck chemicals llc was thirty-four years (range, fourteen to fifty-six years), with 493 males and 334 females. The average size of the defect was 409 mm(2) (range, 64 to 2075 mm2). Four hundred and twenty-one procedures (51%) were performed on the medial femoral condyle; 109 (13%), on the lateral femoral condyle; 200 (24%), on the patella; and fifty (6%), on the trochlea. Kaplan-Meier survival analysis revealed that the unadjusted graft survival rate was 78.2% at five years and 50.7% and ten years for the entire cohort. No difference was

found between the survival rates of the ACI-C/ACI-P and MACI techniques (HR = 0.948, 95% CI = 0.738 to 1.219, p = 0.678). There was a significant postoperative improvement in the function and pain scores of all three outcome measures (p smaller than 0.002). Survivorship in the group with a previous cartilage regenerative procedure was inferior to that in patients with a previously untreated lesion, with failure five times more likely in the former group (HR = 4.718, standard error [SE] = 0.742, 95% CI = 3.466 to 6.420, p smaller than 0.001). Degenerative change in any compartment had a significant detrimental effect on survivorship, with survivorship worsening as the osteoarthritis grade increased (Grade 1: HR = 2.077, 95% Cl = 1.299 to 3.322, p = 0.002; Grade 2: HR = 3.450, 95% CI = 2.646 to 4.498, p smaller than 0.001; and Grade 3: HR = 3.820, 95% Cl = 2.185 to 6.677, p smaller than 0.001).