International Scoring System Research Articles

Phase I Results of a Multicenter Clinical Trial Combining Guadecitabine, a DNA Methyltransferase Inhibitor, with Atezolizumab, an Immune Checkpoint Inhibitor, in Patients with Relapsed or Refractory Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia

Background: There are no FDA-approved therapies for patients with myelodysplastic syndrome (MDS) in whom hypomethylating agents (HMAs) fail, and mechanisms of resistance are not well-characterized. Preclinical and clinical data suggest that some myeloblasts express PDL-1 and that HMAs can induce expression of PD-1 on T cells, which may result in resistance through immune tolerance. We hypothesized that the addition of the PDL1-inhibitor atezolizumab to guadecitabine, a next generation HMA which has a longer in vivo exposure time, would induce or restore HMA sensitivity in patients with relapsed or refractory (R/R) MDS. Overlapping toxicities were not expected given atezolizumab is not myelosuppressive and guadecitabine does not appear to induce autoimmune or inflammatory conditions.Methods: We are conducting a phase I/II, multicenter clinical trial for adult patients with R/R, intermediate (3+) or high-risk MDS by the revised international scoring system, including chronic myelomonocytic leukemia (CMML). A 3x3 dose escalation design for guadecitabine was used for Phase I, beginning with 30 mg/m2 (Dose level -1) days 1-5 along with a fixed dose of atezolizumab 840mg IV days 8 and 22 of a 28-day cycle. The plan was to escalate to the recommended dose of guadecitabine, 60mg/m2 (Dose Level 1) if no dose limiting toxicities (DLTs) were identified during Dose Level -1. If ≥2/6 DLTs were observed during the Dose Level 1, de-escalation to 45mg/m2 (Dose Level -1.5) would occur. The primary endpoint of phase I was safety and tolerability of the combination. Overall survival (OS) from the on-study date and overall response rates (ORR), based on the 2006 Modified IWG Response Criteria for MDS, were secondary endpoints.Results: Nine patients (5M, 4F, median age 73) with intermediate or higher risk were treated during phase I. Three patients were treated at Dose Level -1 and sustained no DLTs. Similarly, no DLTs were observed among 6 patients treated at Dose Level 1. There were 17 grade 3 or 4 events considered possibly or probably related to the study treatments, the most common of which were: neutropenia (4), thrombocytopenia (4), and leukopenia (4). The median number of treatment cycles was 5 and the treatment duration for each patient is illustrated in Figure 1. Two patients achieved hematologic improvement (HI) and 1 patient achieved CR. Two patients died after coming off of the study (at 4.5 and 9 months respectively) and the median OS has not been reached.Discussion: The combination of guadecitabine at the recommended dose of 60mg/m2 D1-D5 along with atezolizumab 840mg IV d8, 22 was found to be safe with an acceptable toxicity profile in patients with R/R MDS. The ORR was 33% and a phase II study is ongoing. [Display omitted] DisclosuresKropf:Celegene: Consultancy; Takeda: Consultancy. Grønbæk:Otsuka Pharma: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen Pharma: Membership on an entity's Board of Directors or advisory committees.

Histological validation of the automated caries detection system (ACDS) in classifying occlusal caries with the ICDAS II system in vitro.

To compare the diagnostic performance of the automated caries detection system (ACDS) for the detection and diagnosis of occlusal caries with the histological appearance of the lesions. Eighteen posterior permanent teeth were used, out of which 40 sections were made and 53 areas were evaluated. Teeth with hypoplastic and/or hypomineralised areas or sealants on the occlusal surfaces were excluded from the study. The teeth that were used for this study were a subgroup of the teeth used in the study that introduced ACDS system. This subgroup consisted of teeth having in their occlusal surfaces early carious lesions classified as international caries detection and scoring system (ICDAS) 0, 1, 2 and 3 after clinical examination by the examiners. Histological preparations were classified by experienced examiners based on the Ekstrand, Ricketts and Kidd (ERK) system and for the respective occlusal surfaces by the ACDS system based on ICDAS II system. There were two threshold limits considered as carious in either system ICDAS ≥ 2 or ≥ 3 and ERK index ≥ 2 or ≥ 3 and all possible combinations were analysed. Statistical methods of weighted version of kappa coefficient, Kendall's tau-b correlation coefficient and p-values using the Fisher's exact method were used at the confidence level of 0.05. Intra-examiner kappa coefficient agreement was 0.87 and 0.89 while the inter-examiner for the two trials were 0.87 and 0.92. The ICDAS3-ERK3 combination between the ACDS and histological sections presented the best agreement with kappa coefficient 0.76, agreement 92.5%, sensitivity 100% and specificity 91.1%. ICDAS3-ERK3 combination between the optical examination of the examiners compared to the histological preparations showed kappa coefficient 0.87, agreement 96.2%, sensitivity 100%, Specificity 95.6%. The evidence supports the view that ACDS classification of occlusal surfaces based on the ICDAS system are comparable with classification to that of an examiner and with the histology of the lesion. The use of ACDS has the distinct advantage though of removing the subjectivity of the examiner since it performs the classification without any intervention by him.

LncRNA-CIR promotes articular cartilage degeneration in osteoarthritis by regulating autophagy

Osteoarthritis (OA) is a common joint disease that is regarded as a local inflammatory response caused by joint instability and accompanied by the progressive degeneration of articular cartilage. However, the molecular mechanisms involved in the maintenance of articular cartilage remain a subject of debate and research. This study aims to analyze the roles of long noncoding RNA (lncRNA)CIR and autophagy in cartilages and determine their overall contribution to the degradation of extracellular matrix. Patients with OA possessed high levels of lncRNA-CIR and MMP3 and low level of COL2A1. The levels of autophagy-related proteins, including LC3BI/II and beclin-1, increased from 12 h to 48 h. The use of si-lncRNA-CIR reversed the trend compared with that in the OA group. The negative effect of lncRNA-CIR was assessed in vivo by establishing a model of surgically induced OA. Moreover, si-lncRNA-CIR-treated joints exhibited fewer OA changes than saline-treated joints. Results were confirmed by histopathological grading of the models by using the Osteoarthritis Research Society International Scoring System and the outcomes of immunohistochemistry for LC3B-II and MMP-3. Overall, lncRNA-CIR played a negative role in the OA process by activating autophagy.

Development, Validation, and Comparative Assessment of an International Scoring System to Determine Risk of Upper Gastrointestinal Bleeding

The Glasgow-Blatchford score (GBS) and pre-endoscopy Rockall score (pRS) are used in determining prognoses of patients with acute upper gastrointestinal bleeding, but neither predicts outcomes of patients with a high level of accuracy. A scoring system is needed to identify patients at risk of adverse outcomes and patients at low risk of harm. We pooled data from 5 data sets in Canada, the United Kingdom, and Australia on 12,711 patients with acute upper gastrointestinal bleeding. The GBS and pRS were calculated for each patient. We performed multivariable logistic regression modeling of data from 10,639 cases to develop the new scoring system Canada - United Kingdom - Adelaide (CANUKA). We performed area under the receiver operating characteristic analyses to test the ability of CANUKA to identify patients who died or had rebleeding within 30 days, surgical or radiologic intervention to control bleeding, need for therapeutic endoscopy, and transfusion-a poor outcome was defined as 1 or more of these outcomes. Patients at low risk of a poor outcome (safe for management as an outpatient) were identified based on lack of transfusion, rebleeding, therapeutic endoscopy, interventional radiology or surgery, or death. We validated in 2072 patients from a separate cohort compiled from 2 datasets. In the development data set there was no difference between GBS and pRS in identifying patients who died without 30 days of bleeding (area under the receiver operating characteristic curve [AUROC], 0.67; 95% CI, 0.62-0.72 for GBS; AUROC, 0.70; 95% CI, 0.66-0.74 for pRS; P=.21). The GBS was superior to the pRS in identifying patients with rebleeding, hemostatic interventions, and transfusions. In the validation data set, CANUKA had higher accuracy than the GBS in identifying patients who died within 30 days of bleeding (AUROC, 0.77 vs 0.74; P=.047), but there was no significant difference in the accuracy of these scoring systems in identifying patients who required hemostatic intervention. The GBS more accurately identified patients who required therapeutic endoscopy (AUROC, 0.78; 95% CI, 0.76-0.81 for GBS; AUROC, 0.77; 95% CI, 0.74-0.79 for CANUKA; P= .47). For patients classified as low-risk patients by CANUKA (score ≤1), 96.3% were safely discharged, whereas 16 patients with a GBS ≤1 had an adverse outcome (a 95.3% probability of safe discharge). In an international validation analysis of the GBS and pRS for patients with acute upper gastrointestinal bleeding, we found the GBS to more accurately identify those who later required hemostatic interventions and transfusions; the scoring systems identified 30-day mortality or rebleeding with equal levels of accuracy. We developed a scoring system (CANUKA) that had similar performance to the GBS in predicting patient outcomes and it more accurately identifies patients at low risk for adverse outcomes.

The Influence of Concomitant Disorders on Disease Severity of Familial Mediterranean Fever in Children.

This study aims to describe the effects of concomitant disorders on the course of familial Mediterranean fever (FMF) and the relevance of genotype on these associations. Files of 494 FMF patients (257 males, 237 females; mean age 12.8±1.94 years; range 1.6 to 23 years) were retrospectively examined. Age of diagnosis, sex, MEditerrenean FeVer mutations, colchicine dosage, disease severity score and concomitant diseases in FMF course were recorded. FMF diagnoses were based on Tel-Hashomer criteria and disease severity was determined by international severity scoring system for FMF. Patients were divided into two groups as M694V positives and M694V negatives. We compared the groups in terms of accompanying illnesses, MEditerrenean FeVer mutations, and disease severity scores among five concomitant diseases: juvenile idiopathic arthritis (JIA), asthma, Henoch- Schonlein purpura, periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome, and others. The mean age at diagnosis was 8.7±1.9 years. Eighty-five patients (17.2%) had accompanying diseases including JIA, asthma, periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome, and Henoch-Schonlein purpura. Mean disease severity scores were 2.4±1.1 in patients with only FMF and 3.0±1.5 in patients with concomitant disorders (p=0.001). Patients with concomitant JIA showed the highest severity scores (4.3±1.6). A statistically significant difference was found with one-way analysis of variance. Our findings indicate that concomitant diseases, particularly JIA, influence FMF severity. Therefore, it may be beneficial to focus on diagnosis and treatment of comorbid inflammatory diseases, which may worsen the course of FMF.

Validation of a western scoring system on large asian Series of outcomes following elective laparoscopic cholecystectomy; A value driven outcome based analysis

Laparoscopic cholecystectomy is one of the most commonly performed general surgical procedures worldwide. We aim to validate an international scoring system (CLOC score), in predicting day surgery in a large tertiary Asian hospital. Subsequently, using a Value Driven Outcomes (VDO) based analysis of the results; we describe an algorithm of quality patient care.A retrospective study of a prospectively held database in a large tertiary hospital was undertaken between April 2015 and April 2017. All patients with complete data who underwent elective cholecystectomy in the study time frame were included. Each patient was assigned a CLOC score and divided into two groups - discharged within 24hrs and more than 24hrsOver 1000 patients underwent laparoscopic cholecystectomy with 619 included in this study with complete data. The CLOC score was an independent predictor of length of stay less or more than 24 hours (score = 8.1 versus 9.3 respectively; p< 0.0001). An AUC on an ROC curve of the CLOC predicting day surgery was 0.7. At a cut off of CLOC=8 or more the sensitivity and specificity of this prediction was 67% and 60% respectively. Using a cut off 8, we noted a significant difference in cost of care. Using a score previously validated in a western population to predict conversion to open cholecystectomy, we describe in this retrospective analysis, its use in predicting day surgery. An interplay of logistic regression and VDO analysis has resulted in a management algorithm that will help streamline care in this common general surgical procedure.

Is age associated with disease severity and compliance to treatment in children with familial Mediterranean fever?

Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease in the world. The disease characteristics may vary in different age groups. In this study, we aimed to compare disease characteristics and treatment compliance according to the age of pediatric FMF patients. This is a single-center, cross-sectional study. Between August and October 2016, patients who were diagnosed with FMF, participated to the study. 378 pediatric FMF patients were enrolled in the study. Among those, age at symptom onset was ≤ 5years in 69%, 6-11years in 26% and ≥ 12years in 5%. Patients older than 12years old at symptom onset, had significantly less frequent fever attacks than the patients from other age groups. Patients younger than 5years old at symptom onset had significantly higher international severity scoring system for FMF (ISSF) than other patients. And M694V homozygosity was significantly more frequent in patients with younger age at symptom onset. Patients younger than 5years old were using their drugs more regularly than the other age groups (p = 0.002). Drug compliance was 90.5% in patients ≤ 5 years, 64.4% in patients 6-11 years, 58.3% in patients ≥ 12years. The disease characteristics of FMF may differ between patients with different age at symptom onset. Younger age at disease onset seems to be related with more severe course; thus these patients should be followed-up more closely. In addition, treatment compliance which is critical for prevention of amyloidosis in FMF should be questioned especially in adolescent patients.

Prognostic significance of bone marrow abnormalities in the appendicular skeleton of patients with multiple myeloma

AbstractWe aimed to determine the clinical and prognostic significance of medullary abnormalities detected by low-dose whole-body multidetector computed tomography (MDCT) in the appendicular skeleton (AS) of patients with newly diagnosed symptomatic multiple myeloma (MM). One hundred ninety-six patients underwent low-dose whole-body MDCT as an initial workup. Patients were categorized into 3 groups based on the medullary pattern of the AS: fatty (36.3%), focal (43.4%), and diffuse (20.4%). Medullary abnormalities were associated with Durie-Salmon and revised International Scoring System stage 3, creatinine levels >2.0 mg/dL, and the proportion of bone marrow plasma cells. The median follow-up was 35.4 months. Patients with fatty, focal, and diffuse patterns had a median survival of not reached, 56 months, and 38 months, respectively. Overall survival (OS) was associated with age, Durie-Salmon stage 3, creatinine levels >2.0 mg/dL, ineligibility for autologous stem cell transplantation, and focal and diffuse patterns on univariate analysis. Multivariate analysis showed that age and diffuse pattern (hazard ratio [HR], 1.92; 95% confidence interval [CI], 1.12-3.31; P = .018) were independent predictors of progression-free survival. Age and focal (HR, 2.51; 95% CI, 1.14-5.56; P = .023) and diffuse (HR, 4.12; 95% CI, 1.74-9.77; P = .001) patterns were also independent predictors of OS. The addition of marrow pattern to preexisting risk factors was associated with a net reclassification improvement for predicting OS (to 0.37, P = .015). Medullary abnormalities in the AS (detected by low-dose whole-body MDCT) are associated with a poor prognosis, independent of other clinical variables.

Intraperitoneal injection of thalidomide alleviates early osteoarthritis development by suppressing vascular endothelial growth factor expression in mice.

Vascular endothelial growth factor (VEGF) is expressed in articular cartilage and increases in expression levels have been associated with the progression of osteoarthritis (OA). Thalidomide is a drug that has been reported to inhibit angiogenesis and reduce VEGF production by downregulating VEGF expression. The objective of the present study was to determine whether intraperitoneal administration of thalidomide may attenuate early OA development in mice. Male C57BL/6 mice (10‑weeks‑old) were randomly assigned into the destabilization of the medial meniscus (Dmm) with thalidomide treatment (Dmm+Th), Dmm and Sham groups equally. An OA model was induced surgically in Dmm+Th and Dmm groups, and mice of the Dmm+Th group were subsequently treated with an intraperitoneal injection of thalidomide (200mg/kg/day). At 2 and 4weeks following surgery, the pathological alterations in cartilage samples were assessed qualitatively by hematoxylin and eosin staining and Safranin O/Fast green staining, and quantitatively by the Osteoarthritis Research Society International scoring system. The mRNA expression levels of matrix metalloproteinase‑13 (MMP‑13) and VEGF were measured by reverse transcription‑quantitative polymerase chain reaction. The protein expression levels of MMP‑13 and VEGF were detected by immunofluorescence and immunohistochemistry, respectively. The production of VEGF in serum was evaluated via an ELISA assay. Pathological scores were significantly higher in the Dmm and the Dmm+Th groups than those in the Sham group; however, the Dmm+Th group exhibited markedly less severe pathological changes compared with the Dmm group. Compared with the Sham group, the mRNA and protein expression levels of VEGF and MMP‑13 in the Dmm and the Dmm+Th groups were significantly increased. The Dmm+Th group exhibited significantly decreased expression levels of VEGF and MMP‑13, as well as significantly decreased serum VEGF concentration compared with the Dmm group. Thus, the results of the present study demonstrated that intraperitoneal administration of thalidomide may alleviate the development of early OA by suppressing VEGF expression in mice and may have potential as a novel therapy for the treatment of OA.

Models to predict length of stay in the Intensive Care Unit after coronary artery bypass grafting: a systematic review.

Intensive Care Units (ICU) length of stay (LoS) prediction models are used to compare different institutions and surgeons on their performance, and is useful as an efficiency indicator for quality control. There is little consensus about which prediction methods are most suitable to predict (ICU) length of stay. The aim of this study is to systematically review models for predicting ICU LoS after coronary artery bypass grafting and to assess the reporting and methodological quality of these models to apply them for benchmarking. A general search was conducted in Medline and Embase up to 31-12-2016. Three authors classified the papers for inclusion by reading their title, abstract and full text. All original papers describing development and/or validation of a prediction model for LoS in the ICU after CABG surgery were included. We used a checklist developed for critical appraisal and data extraction for systematic reviews of prediction modeling and extended it on handling specific patients subgroups. We also defined other items and scores to assess the methodological and reporting quality of the models. Of 5181 uniquely identified articles, fifteen studies were included of which twelve on development of new models and three on validation of existing models. All studies used linear or logistic regression as method for model development, and reported various performance measures based on the difference between predicted and observed ICU LoS. Most used a prospective (46.6%) or retrospective study design (40%). We found heterogeneity in patient inclusion/exclusion criteria; sample size; reported accuracy rates; and methods of candidate predictor selection. Most (60%) studies have not mentioned the handling of missing values and none compared the model outcome measure of survivors with non-survivors. For model development and validation studies respectively, the maximum reporting (methodological) scores were 66/78 and 62/62 (14/22 and 12/22). There are relatively few models for predicting ICU length of stay after CABG. Several aspects of methodological and reporting quality of studies in this field should be improved. There is a need for standardizing outcome and risk factor definitions in order to develop/validate a multi-institutional and international risk scoring system.

Osteochondral Interface Stiffening in Mandibular Condylar Osteoarthritis

Osteoarthritis (OA) of the temporomandibular joint (TMJ) is associated with dental biomechanics. A major change during OA progression is the ossification of the osteochondral interface. This study investigated the formation, radiological detectability, and mechanical property of the osteochondral interface at an early stage, the pathogenesis significance of which in OA progression is of clinical interest and remains elusive for the TMJ. Unilateral anterior crossbite (UAC) was performed on 6-wk-old rats as we previously reported. TMJs were harvested at 4, 12, and 20 wk. The progression of TMJ OA was evaluated using a modified Osteoarthritis Research Society International (OARSI) score system. Osteochondral interface was investigated by quantifying the thickness via von Kossa staining of histological slices and in vivo calcium deposition by calcein injection. Tissue ossification was imaged by micro–computed tomography (CT). Mechanical properties were measured at nanoscale using dynamic indentation. Time-dependent TMJ cartilage lesions were elicited by UAC treatment. Geometric change of the condyle head and increased value of the OARSI score were evident in UAC TMJs. At the osteochondral interface, there was not only enhanced deep-zone cartilage calcification but also calcium deposition at the osseous boundary. The thickness, density, and stiffness of the osteochondral interface were all significantly increased. The enhanced ossification of the osteochondral interface is a joint outcome of the aberrant deeper cartilage calcification at the superior region and promoted formation of subchondral cortical bone at the inferior region. The micro-CT detectable ossification from an early stage thus is of diagnostic significance. Although the environment of the cartilage and subchondral bone could be changed due to the stiffness of the interface, whether or not the stiffened interface would accelerate OA progress remains to be confirmed. With that evidence, the osteochondral interface could be a new diagnostic and therapeutic target of the mechanically initiated OA in the TMJ.

The Effect of 4-Week Training with Shoulder Kinesio-Taping on Shooting Accuracy of Young Archers

The aim of this research is to investigate the effects of exercises done by the kinesio-taping technique with 4-week on target shooting accuracy in young archers using olympic recurve bow. Eight athletes (3 females-5 males) (age: 15.63 ± 1.85 years) who competed in different ages and categories were voluntarily participated in the study, with the consent of their families. Athletes trained for 4 weeks through exercising deltoid muscles on the shoulders of grasp arm with a kinesiology tape before training by the help of a specialis. They performed 10 series of arrow shots consisting of three shots a standard olympic recurve bow according to the rules of saloon (18 meter distance) before and after the athletic training. Shooting scores were recorded according to the international scoring system. To determine the difference between the pre-test and post-test shot scores, the paired sample t-test and a correlation analysis between them was performed. The statistical significance (p) value was taken as <0.05. Statistically significant difference was found between pre-test and post-test values of average score of the shooters (p <0.05). This increase in post-test shooting scores in the archers shows that the kinesio-taping on shoulders positively affects the shooting accuracy during 4 weeks of trainings. The use of this method, which is thought to improve shooting accuracy of archers.

Isoimperatorin ameliorates osteoarthritis by downregulating the mammalian target of rapamycin C1 signaling pathway.

Osteoarthritis (OA) is the most common disease of the joints, and is characterized by the breakdown of cartilage and degradation of the extracellular matrix. OA causes a high level of patient suffering and incurs large societal costs; however, the current strategies for treating OA are restricted due to limited understanding of the underlying molecular and cellular mechanisms. In the present study, the beneficial effects of isoimperatorin (Iso) were investigated using an experimental mouse model of OA, and its mechanism of action on primary chondrocytes was elucidated. Destabilization of the medial meniscus was performed on 8‑week‑old male mice to induce OA in the knees. Iso (500mg/g/day) was intragastrically administered for 4weeks. Degeneration of articular cartilage was assessed by histology using the Osteoarthritis Research Society International scoring system. The expression of matrix metalloproteinase (MMP)13, Runt‑related transcription factor (Runx)2, type X collagen (Col X) and vascular endothelial growth factor (VEGF) in the knee joints was examined by immunohistochemistry. Invitro, murine primary chondrocytes were treated with various concentrations of Iso, followed by 10ng/ml interleukin‑1. The mRNA expression levels of MMP13, Runx2, Col X and VEGF were determined by reverse transcription‑quantitative polymerase chain reaction. The levels of autophagy and mammalian target of rapamycin (mTOR) signaling were determined by western blotting. Iso significantly ameliorated the severity of articular cartilage degradation in mice with experimental OA. The expression levels of MMP13, Runx2, Col X and VEGF were reduced in Iso‑treated mice. In murine primary chondrocytes, Iso also reduced MMP13, Runx2, Col X and VEGF expression, and activated autophagy by downregulating the mTOR complex1 (mTORC1) signaling pathway. Therefore, the results of the present study demonstrated that Iso ameliorates OA‑induced pathological alterations by delaying chondrocyte deterioration, activating autophagy and inhibiting mTORC1, which suggests that Iso may have therapeutic potential for attenuating articular cartilage degradation and treating OA.

SURVEILLANCE OF HOSPITAL ACQUIRED INFECTIONS IN A MEDICAL INTENSIVE CARE UNIT

Introduction: Hospitalized patients are at risk to develop sepsis from infections due to colonized intravenous lines, surgical wounds, and/or bedsores. Multidrug resistant Acinetobacter commonly colonizes patients in the intensive care unit (ICU) and can cause serious infections. The APACHE II severity score has shown a good calibration and discriminatory value across a wide range of disease processes, and remains the most commonly used international severity scoring system worldwide. Aim of work: to evaluate the patients having different types of hospital-acquired infections in the medical ICU, especially infections caused by multidrug resistant organisms (as Acinetobacter spp.), in a specific period of time, applying the APACHE II scoring system of severity. Materials and methods: The study included 148 patients from the medical ICU in Cairo University Hospital. Routine laboratory investigations were done together with chest X-rays, ECG, abdominal ultrasound and bacterial cultures,and APACHE II scores were calculated for all patients. Results: We found that the mostcommon cause of death in ICU patients in our study was sepsis (48% of all deaths). Most frequently reported isolated organisms were Klebsiella spp. (24.4%), E-coli (21.8%), and Acinetobacter spp. (17.1%). There was a meaningful association between observed mortality rates in patients in ICU and their APACHE II score evaluation, so APACHEII score had a strong positive correlation with actual mortality rate. Conclusion: Sepsis was the cause of high mortality rates in medical ICU, and the most important step in the prevention and control of infection in the ICU is continuous application of effective infection control measures.

Usefulness of Multiparametric Ultrasound for Evaluating Structural Abnormality of Transplanted Kidney: Can We Predict Histologic Abnormality on Renal Biopsy in Advance?

The purpose of this study was to investigate the associations between microscopic abnormalities of transplanted kidneys and sonography-based imaging biomarkers, including elasticity, venous impedance index, arterial resistive index, and size. Between 2011 and 2015, 159 recipients underwent sonography and biopsy of a transplanted kidney at our institution; 104 adult patients were included in this study. The maximal longitudinal length on gray-scale images, arterial resistive index, and venous impedance index on Doppler images and shear wave velocity on acoustic radiation force impulse imaging or Young modulus on supersonic shear imaging were measured before biopsy. The Banff criteria (2009 update), an international standardized classification and scoring system for renal allograft pathology, were used to evaluate the biopsy samples. Sonography parameters and clinical variables were analyzed with individual and summed Banff scores. Spearman rank correlation coefficients and ordinal logistic regression showed no association between sonography parameters and summed Banff scores. Only the interval between transplant and biopsy was significantly associated with summed Banff scores (p < 0.05). Univariate logistic regression analysis with individual Banff scores showed associations of one Banff feature with arterial resistive index, three with venous impedance index, and six with interval between transplant and biopsy (p < 0.05). Sonoelastography parameters were not associated with any individual Banff score. Neither sonoelastography parameter was associated with any histopathologic change of renal allografts. Although arterial resistive index and venous impedance index were related to a few individual Banff scores, length of time between transplant and biopsy showed stronger correlation than any imaging biomarkers with renal allograft deterioration.

Novel panel of protein biomarkers to predict response to bortezomib-containing induction regimens in multiple myeloma patients

BackgroundMultiple myeloma (MM) is a complex heterogeneous disease. Various risk stratification models have been recommended including cytogenetic and FISH analysis to identify high-risk patients who may benefit from novel treatments, but such facilities are not widely available. The International Scoring System (ISS) using beta-2-microglobulin and albumin remains a widely used prognostic scoring system in many clinical practices; however it is not useful in predicting response to treatment in MM. The aim of this study is to identify clinically useful biomarkers to predict response to treatment containing bortezomib. Methods17 MM patient serum samples (9 responders/8 non-responders) were used for the discovery phase (label-free mass spectrometry) and an additional 20 MM patient serum samples were used for the ELISA-based validation phase (14 responders/6 non-responders). ResultsCLU and ANG mean levels were higher in the responders group, while Complement C1q had lower concentrations. The combination of all standard biomarkers (albumin, beta-2-microglobulin (ß2M), paraprotein and kappa/lambda (K/L) ratio) had an AUC value of 0.71 with 65% correct classification, while an overall combination of new candidate protein biomarkers with standard biomarkers had an AUC value of 0.89 with 85.3% correct classification. ConclusionsA combination of new and standard biomarkers consisting of CLU, ANG, C1Q, albumin, ß2M, paraprotein and K/L ratio may have potential as a novel panel of biomarkers to predict MM response to treatment containing bortezomib. General significanceUse of this biomarker panel could facilitate a more personalized therapy approach and to minimize unnecessary side effects from ineffective drugs.

Developing an international scoring system for a consensus-based social cognition measure: MSCEIT-managing emotions

Measures of social cognition are increasingly being applied to psychopathology, including studies of schizophrenia and other psychotic disorders. Tests of social cognition present unique challenges for international adaptations. The Mayer-Salovey-Caruso Emotional Intelligence Test, Managing Emotions Branch (MSCEIT-ME) is a commonly-used social cognition test that involves the evaluation of social scenarios presented in vignettes. This paper presents evaluations of translations of this test in six different languages based on representative samples from the relevant countries. The goal was to identify items from the MSCEIT-ME that show different response patterns across countries using indices of discrepancy and content validity criteria. An international version of the MSCEIT-ME scoring was developed that excludes items that showed undesirable properties across countries. We then confirmed that this new version had better performance (i.e. less discrepancy across regions) in international samples than the version based on the original norms. Additionally, it provides scores that are comparable to ratings based on local norms. This paper shows that it is possible to adapt complex social cognitive tasks so they can provide valid data across different cultural contexts.

Anti-inflammatory and anti-osteoarthritis effects of tectorigenin.

ABSTRACTOsteoarthritis (OA) is a common and dynamic disease of the joints, including the articular cartilage, underlying bones and synovium. In particular, OA is considered as the degeneration of the cartilage. Tectorigenin (Tec) is known to affect many biological processes; however, its effects on articular chondrocytes remain unclear. This study aimed to assess the effects of Tec on articular cartilage. In vitro, Tec inhibited the expression levels of type X collagen, cyclooxigenase-2, matrix metalloproteinase (MMP)-3 and MMP-13, but enhanced the expression of Runx1, type II collagen and aggrecan in the presence of IL-1β. Meanwhile, Tec inhibited apoptosis through the Bax/Bcl-2/caspase-3 pathway, upregulating p-Bad, downregulating the Bax/Bcl-2 ratio, and activating caspase-3 compared with IL-1β treatment only. Moreover, this process was partially regulated by NF-κB P65. In vivo, the chondroprotective effects of Tec were assessed by establishing a model of surgically induced OA. Tec-treated joints exhibited fewer osteoarthritic changes than saline-treated joints. Meanwhile, 1.5 μg/kg Tec treatment produced a greater protective effect than 0.75 μg/kg Tec. The Osteoarthritis Research Society International (OARSI) scoring system, employed to assess histopathological grading of the models, as well immunohistochemistry for Aggrecan Neoepitope and MMP-3, further confirmed the results. In conclusion, this study showed that Tec plays a chondroprotective role in the OA process by preventing articular cartilage degeneration and chondrocyte apoptosis via the NF-κB P65 pathway.

Prognosis of Myelodysplastic Syndromes (MDS) in Patients in the Age of 80 Years and Older: Data from the Regular Care MDS Registry in Germany

▪The international prognosis scoring system (IPSS) and the revised-IPSS were generated with data from 816 and 7,019 patients (pts) from academic centers with a median age of 69 and 71 years (y) respectively. As the median age of pts with MDS receiving care in Germany is 74.9 y and around a quarter of pts are older than 80 y, the aim was to evaluate the meaning of the IPSS and additional risk factors in the older population group.Methods: Pts with written informed consent could be included in the online-registry. Pts were eligible if a bone marrow examination had been performed and if basic data and the quarterly course of the disease were documented. Statistical analysis: Depending on the distributions of each variable frequency tables, means (SD), medians were calculated overall and stratified by age classes. Corresponding overall tests were performed (Chi-square, Kruskal-Wallis). Time dependent survival probabilities from MDS diagnosis were estimated by Kaplan Meier curves (compared using log rank test). Multiple Cox regression models were used to investigate associations between mortality risk and baseline risk factors. Variable selection was performed in the subpopulation of elderly pts based on univariate models and models including all prespecified variables (IPSS, sex, transfusion dependent at diagnosis (Tx at d), primary or secondary MDS, comorbidities). Mortality of pts subgroups was compared and age-sex-standardized with the German population 2013 as given in the Human Mortality Database (www.mortality.org, University of California Berkeley, Max Planck Institute for Demographic Research). Standardized mortality rates (SMR) and 95%-confidence intervals were estimated.Results: Between July 2009 and March 2016 (81 months) 2,118 pts from 90 institutions, mainly outpatient practices, were documented. The median age of the 843 (39.8%) female and 1,275 (60.2%) male pts was 74.9y (min-max: 26.5 - 94.2). 631 patients were excluded from analysis due to missing IPSS risk. The duration of observation, frequencies of IPSS, Tx at d, and the Charlson comorbidity index (CCI) are given in the table.Increased age and IPSS risk were significantly associated with the risk of death. An additional interaction between age and IPSS risk was significant (p=0.0198, Cox model, lower IPSS risk in increased age).In the subgroup of elderly patients (n=332, 147 died) after variable selection, IPSS, gender and Tx at d (22 missings) were significantly associated with the risk of death. Furthermore, even in the low risk group an elevated risk was estimated (SMR 1.773) compared to the normal population in the same age class. SMRs increase with higher IPSS risk.Analysis of comorbidities using CCI showed no significant association with mortality in the low risk group of the elderly patients (n=121, 44 died). Because of low sample sizes in the CCI subgroups the power is small, but even the survival curves did not show a clear trend (p= 0.497).Conclusion: IPSS risk and age are significantly associated with the risk of death. In elderly pts associated risk factors were IPSS, male gender and transfusion at diagnosis. Even the diagnosis of low risk MDS has a negative impact on life expectancy.Supported by an unrestricted grant from Celgene and Novartis. [Display omitted] [Display omitted] [Display omitted] DisclosuresSteinmetz:Vifor: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau. Haastert:X-Med: Honoraria. Tesch:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Schmitz:Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Amgen: Speakers Bureau.

The Clinical and Biological Effects of Expression of Dedicator of Cytokinesis 1 (DOCK1) in Myelodysplastic Syndrome

Background: DOCK1 is an archetype member of the CDM (CED-5, Dock180, Myoblast city) superfamily of guanine nucleotide exchange factors and functions as an RAC activator.DOCK1 is involved in diverse biological processes including cytoskeleton rearrangement, cell motility and phagocytosis. Expression of DOCK1 is ubiquitous except in hematopoietic cells. Several studies highlighted the functional implications of DOCK1 in migratory and invasive properties of cancer cells, yet the roles of DOCK1 in hematological malignancies are not known.Materials and Methods: In this study, we focused on myelodysplastic syndrome (MDS) according to the diagnostic criteria of 2008 WHO classification, a clinically heterogeneous myeloid cancer whose pathogenesis remains enigmatic. We employed Affymetrix Human Transcriptome Array 2.0 to quantify the global expression patterns of the marrow mononuclear cells (MNC) in 243 newly diagnosed MDS patient recruited in the National Taiwan University Hospital (NTUH). We specifically analyzed the clinical, genetic, and prognostic significance of DOCK1 expression in various stages of MDS.Results: Our data showed that higher expression of DOCK1 conferred an unfavorable prognosis in MDS patients. Increased expression levels of DOCK1 was associated with higher-risk MDS defined by either revised international scoring system (IPSS-R) or WHO classification. Notably, DOCK1 expression levels in lower-risk MDS such as RA, RARS, RCMD, RCMD-RS, in which the marrow blast percentages were not increased, were still significantly higher than normal marrow (Figure 1), implying that the higher DOCK1 expression was independent of blast numbers in the samples, at least in these subgroups of patients. Among the 51 patients documented with leukemic transformation, 36 patients (70.6%) had higher DOCK1 expression compared with 70 out of 168 patients (41.7%) without transformation (P < 0.001). Regarding the genetic alterations, mutations in RUNX1, EZH2, SETBP1, ZRSR2, ASXL1 and TP53 were more frequently seen in the patients with higher DOCK1 expression, whilst SF3B1 mutation showed the contrary pattern. Remarkably, we demonstrated step-wise decreasing DOCK1 expression in the marrow MNC from higher-risk MDS, lower-risk MDS, to normal marrow, suggesting an impact of DOCK1 in pathogenesis in MDS. With a median follow up of 37.4 months, higher expression of DOCK1 was associated with shorter overall survival (OS) (median 13.7 months vs. 69.9 months) and shorter interval to leukemic transformation (median 23.6 months vs. not reached) after a follow up of 20.0 months (both P < 0.001) (Figure 3A and 3B). Independent analysis of DOCK1 expression showed higher level in the very poor cytogenetic subgroup in MDS (P < 0.001). In the multivariate analysis, higher DOCK1 expression proved to be a strong unfavorable prognostic factor for OS and leukemic transformation (P = 0.005 and P = 0.001, respectively) independent of other unfavorable factors including age, karyotype, and mutations of ASXL1, RUNX1, EZH2 and TP53.Conclusion: To our knowledge, our study is the first to show the clinical, genetic, prognostic, and biological association of DOCK1 expression in MDS patients. The step-wise increasing expression levels of DOCK1 in MNC from normal marrow, lower-risk MDS to higher-risk MDS patients highlight the hitherto unappreciated role of DOCK1 in the pathogenesis of MDS. Further studies on large and prospective cohorts are necessary to confirm our observations. Animal studies are needed to elucidate the in vivo roles of DOCK1 in MDS. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.