A Pilot Observational Study Evaluating the Diagnostic Capacity of Rotational Thromboelastometry in Periprosthetic Joint Infections.

BACKGROUND: Periprosthetic joint infections (PJIs) are associated with altered hemostatic dynamics; therefore, coagulation laboratory methods such as rotational thromboelastometry (ROTEM) may be valuable in their diagnosis. The aim of this study was to evaluate the diagnostic role of ROTEM in PJI. METHODS: A diagnostic study was conducted including 65 patients who underwent revision total hip arthroplasty or total knee arthroplasty due to PJI (30 patients) or aseptic loosening (35 patients). Preoperative laboratory evaluation included conventional coagulation studies, inflammatory markers, and ROTEM analysis. These parameters were compared between patients with PJI and patients with aseptic loosening. RESULTS: Several ROTEM parameters differed in the patients with PJI, indicating a higher coagulation potential associated with PJI. Specifically, the development of PJI was associated with higher EXTEM maximum clot firmness (MCF) (odds ratio [OR], 1.12 [95% confidence interval (CI), 1.04 to 1.20]; p = 0.001). Among the ROTEM parameters, EXTEM MCF was found to have the highest diagnostic accuracy for PJI (area under the receiver operating characteristic curve, 0.850; sensitivity, 76.6%; specificity, 91.4%), which was comparable with C-reactive protein (CRP) (p = 0.22) and erythrocyte sedimentation rate (ESR) (p = 0.65), but higher than D-dimer (p = 0.037). Moreover, the combined diagnostic accuracy of elevated EXTEM MCF and CRP was improved compared with CRP alone (p = 0.019). CONCLUSIONS: Our results indicate that ROTEM analysis might be helpful for the detection of the hemostatic derangements that are associated with the development of PJI. However, because of the small size of this pilot study, further research is needed to investigate the value of incorporating viscoelastic studies in diagnostic scores for PJI. LEVEL OF EVIDENCE: Diagnostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Pre- and Postoperative Exercise Effectiveness in Mobility, Hemostatic Balance, and Prognostic Biomarkers in Hip Fracture Patients: A Study Protocol for a Randomized Controlled Trial.

Hip fractures are a major health concern, particularly for older adults, as they can reduce life quality, mobility loss, and even death. Current evidence reveals that early intervention is recommended for endurance in patients with hip fractures. To our knowledge, preoperative exercise intervention in patients with hip fractures remains poorly researched, and no study has yet applied aerobic exercise preoperatively. This study aims to investigate the short-term benefits of a supervised preoperative aerobic moderate-intensity interval training (MIIT) program and the added effect of an 8-week postoperative MIIT aerobic exercise program with a portable upper extremity cycle ergometer. The work-to-recovery ratio will be 1-to-1, consisting of 120 s for each bout and four and eight rounds for the pre- and postoperative programs, respectively. The preoperative program will be delivered twice a day. A parallel group, single-blinded, randomized controlled trial (RCT) was planned to be conducted with 58 patients each in the intervention and control groups. This study has two primary purposes. First, to study the effect of a preoperative aerobic exercise program with a portable upper extremity cycle ergometer on immediate postoperative mobility. Second, to investigate the additional effect of an 8-week postoperative aerobic exercise program with a portable upper extremity cycle ergometer on the walking distance at eight weeks after surgery. This study also has several secondary objectives, such as ameliorating surgical and keeping hemostatic balance throughout exercise. This study may expand our knowledge of preoperative exercise effectiveness in hip fracture patients and enhance the current literature about early intervention benefits.

Fibrinolysis shutdown and elevated D-dimer levels have high prognostic capacity for postoperative thromboembolic complications in patients with bone tumors.

Surgical resection of malignant bone tumors is associated with a high risk of venous thromboembolism (VTE). The purpose of this study was to evaluate the association between rotational thromboelastometry (ROTEM) parameters and VTE following oncologic resections, and to evaluate their prognostic capacity for this complication. A prospective observational study was conducted including 113 patients who underwent surgical resection of malignant bone tumors. ROTEM analysis and conventional coagulation studies were performed preoperatively and on the 2nd postoperative day, while patients were followed for the development of VTE. Logistic regression was used to assess the association between ROTEM parameters and occurrence of VTE. The area under the receiver operating characteristic curve (AUC), sensitivity and specificity were calculated as measures of discrimination and predictive accuracy. Fourteen patients (12.4%) developed symptomatic VTE. Development of VTE was associated with shortened INTEM CFT (Odds Ratio [OR] 0.90, 95% Confidence Interval [CI] 0.84 - 0.96, p = 0.004), higher INTEM A10 (OR 1.21, 95% CI 1.07 - 1.36, p = 0.002), higher INTEM MCF (OR 1.22, 95% CI 1.08 - 1.37, p = 0.001) and higher INTEM LI60 (OR 2.10, 95% CI 1.38 - 3.21, p = 0.001). An INTEM LI60 value indicative of fibrinolysis shutdown (≥ 98%) had the best predictive accuracy for VTE (AUC = 0.887, 95% CI 0.824 - 0.951, sensitivity = 100%, specificity = 67.0%), higher than that of D-dimer levels (p = 0.028). ROTEM parameters were promising predictors of symptomatic VTE. Fibrinolysis shutdown as reflected by ROTEM LI60 and high D-dimer levels can aid the identification of high-risk patients. Future studies should evaluate whether the addition of ROTEM findings to an expanded risk-assessing model can improve the predictive capacity and provide better guidance in thromboprophylaxis.

The Utility of NATEM Assay in Predicting Bleeding Risk in Critically Ill Neonates.

We aimed to investigate the hemostatic status of diseased neonates using nonactivated rotational thromboelastometry (ROTEM) assay (NATEM) assay and, in addition, to evaluate the discriminative power of NATEM parameters in predicting the risk of bleeding in critically ill neonates and compare it to that of EXTEM (extrinsically activated ROTEM) parameters. This cohort study included 158 consecutive, critically ill neonates with presumed sepsis, perinatal hypoxia, or respiratory distress syndrome. The EXTEM and NATEM assays were performed on the first day of disease onset. The neonatal bleeding assessment tool was used to record and assess clinical bleeding events on the day of ROTEM analysis. Several EXTEM and NATEM ROTEM parameters differed between neonates with and without clinical bleeding events, indicating a hypo-coagulable state in neonates with clinical bleeding. NATEM parameters had comparable predictive performance for clinical bleeding events with EXTEM parameters for clotting time, clot formation time (CFT), A10 (clot amplitude at 10minutes), maximum clot firmness, lysis index at 60minutes, and maximum clot elasticity (p>0.05). However, NATEM A20, A30, and α angle demonstrated better predictive ability than EXTEM A20, A30, and α angle, respectively (p<0.05). A NATEM CFT value ≥147seconds presented 95.2% sensitivity (95% confidence interval [CI]: 76.1-99.8%) and 65.6% specificity (95% CI: 57.1-73.5%) to detect neonates with clinical bleeding, while a NATEM A10 value ≤42mm had 80.8% sensitivity (95% CI: 71.8-85.9%) and 76.0% specificity (95% CI: 52.8-91.7%) to detect neonates with clinical bleeding events. The NATEM assay has shown remarkable sensitivity in predicting bleeding in critically ill neonates, exceeding EXTEM performance in some selected parameters. The incorporation of NATEM test parameters in predictive models for neonatal hemorrhage seems promising.

Rotational Thromboelastometry Predicts Transfusion Requirements in Total Joint Arthroplasties.

The frequency of red blood cell (RBC) transfusions is high in total joint arthroplasties, and the hemorrhagic risk is associated with both surgery- and patient-related factors. This study aims to assess the ability of rotational thromboelastometry (ROTEM) to identify patients at high risk for transfusion and excessive bleeding. A prospective observational study was conducted including 206 patients who underwent total knee or hip arthroplasties. Assessment of the coagulation status was performed preoperatively and immediately postoperatively using ROTEM analysis and conventional coagulation tests. The number of RBC transfusions and the postoperative hemoglobin drop were recorded. ROTEM findings were compared between transfused and nontransfused patients, and also between patients with and without excessive bleeding. Higher values of postoperative FIBTEM maximum clot firmness (MCF) were associated with lower risks of transfusion (odds ration [OR]: 0.66, 95% confidence interval [CI]: 0.57-0.78, p<0.001) and excessive bleeding (OR: 0.58, 95% CI: 0.36-0.94, p=0.028). A postoperative FIBTEM MCF value ≤10mm had 80.1% (95% CI: 73.1-85.9%) sensitivity with 75.5% (95% CI: 60.4-87.1%) specificity to predict transfusion requirements, and 70.5% (95% CI: 63.6-76.8%) sensitivity with 88.8% (95% CI: 51.7-99.7%) specificity to predict excessive bleeding. The estimated average probability of transfusion in patients with FIBTEM MCF values of 0 to 4mm is 86.3%. ROTEM assay demonstrated high predictive ability for transfusion and excessive bleeding. Identification of patients at risk for transfusion could allow blood banks to ensure adequate blood supply, while also more intense blood-salvaging strategies could be implemented in these patients.

The impact of maternal smoking during pregnancy on hemostatic profile of neonates using thromboelastometry (ROTEM). A pilot observational study.

INTRODUCTION: In adults, the negative effect of smoking on hemostasis has been well established. Contrarily, data regarding the hemostatic status of neonates exposed to tobacco during pregnancy are limited. This study aimed to investigate the influence of antenatal tobacco exposure on the hemostatic profile of neonates using Thromboelastometry (ROTEM). METHODS: This observational study included 92 healthy full-term neonates born in the maternity department of our hospital over a 5-year period. The neonates were categorized in 2 groups: neonates born to mothers who reported smoking during the entire pregnancy and neonates born to non-smoking mothers. Neonates were matched 1:1 with regards to gestational age, delivery mode, and gender. ROTEM EXTEM assay was performed on the 2nd-3rd day of life and clotting time (CT); clot formation time (CFT); clot amplitude recorded at 10 and 30 min (A10, A30); a angle (ao); maximum clot firmness (MCF, mm); lysis index at 30 and 60 min (LI30, LI60, %); maximum clot elasticity (MCE), were measured. RESULTS: Neonates with antenatal exposure to tobacco had shorter CT (p < 0.001) and CFT (p = 0.035), higher A10 (p = 0.043), A30 (p = 0.028) and MCE (p = 0.028) compared to those not exposed to tobacco during pregnancy. The multivariable regression analysis adjusted for gestational age, gender, birth weight and delivery mode showed that maternal tobacco use during pregnancy is associated with an accelerated activation of coagulation in neonates expressed by shorter EXTEM CT values (coefficient: -8.68, 95%,CI: -13.51--3.85, p = 0.001) while no association was found with the remaining ROTEM parameters. DISCUSSION: Smoking during pregnancy results in a hypercoagulable profile of neonates, expressed by shorter ROTEM CT. Antenatal exposure to tobacco appears to be an aggravating factor for the hemostatic status of neonates.

The Hypercoagulable Profile of Patients with Bone Tumors: A Pilot Observational Study Using Rotational Thromboelastometry.

Introduction: A detailed evaluation of the malignancy-associated coagulopathy (MAC) in surgical patients with bone tumors may allow for more effective thromboprophylactic measures. The purpose of this study was to assess the perioperative hemostatic changes in patients with bone tumors, using rotational thromboelastometry (ROTEM). Methods: An observational study was performed, including 50 patients with bone tumors who underwent oncologic resection and 30 healthy controls, matched for age and gender. The preoperative and postoperative laboratory evaluation of coagulation in both groups included conventional coagulation tests and a ROTEM analysis. The results of the conventional coagulation tests and the ROTEM analysis were compared between the two groups. Results: The results of the conventional coagulation tests were comparable between the tumor patients and the healthy controls. However, compared to the healthy adults, the tumor patients had lower CT (p < 0.001) and CFT (p < 0.001) values suggesting a rapid induction of the coagulation cascade, elevated A10 (p < 0.001) and MCF (p < 0.001) values indicating a higher clot strength and platelet activation, and elevated LI60 (p < 0.001) values indicating hypofibrinolysis in patients with bone tumors. The multiple linear regression analysis (controlling for potential confounding factors) confirmed the independent association of bone tumors with these hemostatic changes. Conclusions: Our results support the advantageous use of a ROTEM in patients with bone tumors over conventional coagulation tests because the qualitative changes in the hemostatic profile of these patients that can be detected by a ROTEM analysis cannot be identified by conventional tests. The ROTEM results indicate that the hypercoagulable state in patients with bone tumors is caused by the malignancy-associated activation of the coagulation cascade, platelet activation, and hypofibrinolysis.

Aspergillus spp. osteoarticular infections: an updated systematic review on the diagnosis, treatment and outcomes of 186 confirmed cases.

Aspergillus spp. osteoarticular infections are destructive opportunistic infections, while there is no clear consensus on their management. The purpose of this review is to investigate the current literature regarding Aspergillus spp. osteoarticular infections. An electronic search of the PubMed and Scopus databases was conducted considering studies that assessed osteoarticular infections from Aspergillus spp. We included only studies with biopsy proven documentation of positive cultures or histological findings for Aspergillus spp., and those with essential information for each case such as the anatomical location of the infection, the type of treatment (conservative, surgical, combination), the antifungal therapy, and the outcome. Overall, 148 studies from 1965 to 2021 including 186 patients were included in the review. One hundred and seven (57.5%) patients underwent surgical debridement in addition to antifungal therapy, while 79 (42.7%) patients were treated only conservatively. Complete infection resolution was reported in 107 (57.5%) patients, while partial resolution in 29 (15.5%) patients. Surgical debridement resulted in higher complete infection resolution rate compared to only antifungal therapy (70.0% vs. 40.5%, P < 0.001), while complete resolution rate was similar for antifungal monotherapy and combination/sequential therapy (58.3% vs. 54.5%; P = 0.76). Last, complete resolution rate was also similar for monotherapy with amphotericin B (58.1%) and voriconazole (58.6%; P = 0.95). The results of this study indicate that antifungal monotherapy has similar efficacy with combination/sequential therapy, while voriconazole has similar efficacy with amphotericin B. Moreover, surgical debridement of the infected focus results in better outcomes in terms of infection eradication compared to conservative treatment. LAY SUMMARY: Antifungal monotherapy has similar efficacy with combination/sequential therapy, and voriconazole has similar efficacy with amphotericin B for the treatment of Aspergillus spp. osteoarticular infections, while surgical debridement of the infected focus improves the infection eradication rate.

The Safety and Efficacy of Tranexamic Acid in Oncology Patients Undergoing Endoprosthetic Reconstruction and a ROTEM-Based Evaluation of Their Hemostatic Profile: A Pilot Study.

BACKGROUND: An endoprosthetic reconstruction in musculoskeletal oncology patients is associated with significant blood loss. The purpose of this study is to evaluate the safety and efficacy of tranexamic acid (TXA) for these patients and to assess any changes in their hemostatic profile using rotational thromboelastometry (ROTEM). METHODS: A retrospective observational study was performed including 61 patients with primary or metastatic bone tumors who underwent surgery. Group A (n = 30) received both intravenous and local TXA whereas Group B (n = 31) was the control group. The primary outcomes were perioperative blood loss and blood unit transfusions and the secondary outcomes included the incidence of thromboembolic complications and a change in blood coagulability as reflected by ROTEM parameters. RESULTS: The median difference in blood loss between the two groups was 548.5 mL, indicating a 29.2% reduction in the 72 h blood loss following TXA administration (p < 0.001). TXA also led to a reduced transfusion of 1 red blood cell (RBC) unit per patient (p < 0.001). The two groups had similar rates of thromboembolic complications (p = 0.99). The antifibrinolytic properties of TXA were confirmed by the significantly higher INTEM, FIBTEM and EXTEM LI60 (p < 0.001, p = 0.005 and p < 0.001, respectively) values in the TXA group. CONCLUSION: Tranexamic acid was associated with a significant reduction in perioperative blood loss and transfusion requirements without a complete shutdown of the fibrinolysis. Larger studies are warranted to assess the frequency of these outcomes in musculoskeletal oncology patients.

Rotational Thromboelastometry Findings Are Associated with Symptomatic Venous Thromboembolic Complications after Hip Fracture Surgery.

BACKGROUND: Venous thromboembolism is a common complication after hip fractures. However, there are no reliable laboratory assays to identify patients at risk for venous thromboembolic (VTE) events after major orthopaedic surgery. QUESTION/PURPOSES: (1) Are rotational thromboelastometry (ROTEM) findings associated with the presence or development of symptomatic VTE after hip fracture surgery? (2) Were any other patient factors associated with the presence or development of symptomatic VTE after hip fracture surgery? (3) Which ROTEM parameters were the most accurate in terms of detecting the association of hypercoagulability with symptomatic VTE? METHODS: This retrospective study was conducted over a 13-month period. In all, 354 patients with femoral neck and peritrochanteric fractures who underwent hip hemiarthoplasty or cephallomedullary nailing were assessed for eligibility. Of those, 99% (349 of 354) were considered eligible for the study, 1% (3 of 354) of patients were excluded due to coagulation disorders, and another 1% (2 of 354) were excluded because they died before the postoperative ROTEM analysis. An additional 4% (13 of 354) of patients were lost before the minimum study follow-up of 3 months, leaving 95% (336 of 354) for analysis. A ROTEM analysis was performed in all patients at the time of their hospital admission, within hours of the injury, and on the second postoperative day. The patients were monitored for the development of symptoms indicative of VTE, and the gold standard tests for diagnosing VTE, such as CT pulmonary angiography or vascular ultrasound, were selectively performed only in symptomatic patients and not routinely in all patients. Therefore, this study evaluates the association of ROTEM with only clinically evident VTE events and not with all VTE events. ROTEM results did not affect the clinical surveillance of the study group and the decision for further work up. To determine whether ROTEM findings were associated with the presence or development of symptomatic VTE, ROTEM parameters were compared between patients with and without symptomatic VTE. To establish whether any other patient factors were associated with the presence or development of symptomatic VTE after hip fracture surgery, clinical parameters and conventional laboratory values were also compared between patients with and without symptomatic VTE. Finally, to determine which ROTEM parameters were the most accurate in terms of detecting the association of hypercoagulability with symptomatic VTE, the area under the curve (AUC) for certain cut off values of ROTEM parameters was calculated. RESULTS: We found several abnormal ROTEM values to be associated with the presence or development of symptomatic VTE. The preoperative maximum clot firmness was higher in patients with clinically evident VTE than in patients without these complications (median [interquartile range] 70 mm [68 to 71] versus 65 mm [61 to 68]; p < 0.001). The preoperative clot formation time was lower in patients with clinically evident VTE than those without clinically evident VTE (median 61 seconds [58 to 65] versus 70 seconds [67 to 74]; p < 0.001), and also the postoperative clot formation time was lower in patients with clinically evident VTE than those without these complications (median 52 seconds [49 to 59] versus 62 seconds [57 to 68]; p < 0.001). Increased BMI was also associated with clinically evident VTE (odds ratio 1.26 [95% confidence interval 1.07 to 1.53]; p < 0.001). We found no differences between patients with and without clinically evident VTE in terms of age, sex, smoking status, comorbidities, and preoperative use of anticoagulants. Lastly, preoperative clot formation time demonstrated the best performance for detecting the association of hypercoagulability with symptomatic VTE (AUC 0.89 [95% CI 0.81 to 0.97]), with 81% (95% CI 48% to 97%) sensitivity and 86% (95% CI 81% to 89%) specificity for clot formation time ≤ 65 seconds. CONCLUSION: ROTEM's performance in this preliminary study was promising in terms of its association with symptomatic VTE. This study extended our earlier work by demonstrating that ROTEM has a high accuracy in detecting the level of hypercoagulability that is associated with symptomatic VTE. However, until its performance is validated in a study that applies a diagnostic gold standard (such as venography, duplex/Doppler, or chest CT) in all patients having ROTEM to confirm its performance, ROTEM should not be used as a regular part of clinical practice. LEVEL OF EVIDENCE: Level IV, diagnostic study.

The Brain-Gut Axis: Psychological Functioning and Inflammatory Bowel Diseases.

The brain-gut axis represents a complex bi-directional system comprising multiple interconnections between the neuroendocrine pathways, the autonomous nervous system and the gastrointestinal tract. Inflammatory bowel disease (IBD), comprising Crohn's disease and ulcerative colitis, is a chronic, relapsing-remitting inflammatory disorder of the gastrointestinal tract with a multifactorial etiology. Depression and anxiety are prevalent among patients with chronic disorders characterized by a strong immune component, such as diabetes mellitus, cancer, multiple sclerosis, rheumatoid arthritis and IBD. Although psychological problems are an important aspect of morbidity and of impaired quality of life in patients with IBD, depression and anxiety continue to be under-diagnosed. There is lack of evidence regarding the exact mechanisms by which depression, anxiety and cognitive dysfunction may occur in these patients, and whether psychological disorders are the result of disease activity or determinants of the IBD occurrence. In this comprehensive review, we summarize the role of the brain-gut axis in the psychological functioning of patients with IBD, and discuss current preclinical and clinical data on the topic and therapeutic strategies potentially useful for the clinical management of these patients. Personalized pathways of psychological supports are needed to improve the quality of life in patients with IBD.

Higher coagulation activity in hip fracture patients: A case-control study using rotational thromboelastometry.

INTRODUCTION: Trauma-induced coagulopathy has been extensively investigated in the multitrauma setting, but only sparsely following moderate orthopedic trauma. The purpose of this study was to evaluate changes in the hemostatic profile of patients with hip fractures, using rotational thromboelastometry (ROTEM). METHODS: 198 patients with hip fractures who underwent surgery were included in the study. A matched group of 52 healthy individuals was also enrolled. Demographics, conventional laboratory assays, and ROTEM parameters were recorded and compared between patients and healthy adults. The preoperative and postoperative ROTEM values of fractured patients were also compared. RESULTS: The conventional coagulation assays were similar for the 2 groups. However, several ROTEM parameters including EXTEM MCF (P < .001), EXTEM alpha angle (P < .001), INTEM MCF (P < .001), INTEM A10 (P < .001), and INTEM alpha angle (P < .001) significantly differed between the 2 groups indicating a higher coagulation potential following hip fractures. Also, fractured patients had significantly lower INTEM and EXTEM CT values (P = .008 and P = .012, respectively) and significantly lower INTEM and EXTEM CFT values (P < .001). Adjusted analysis for confounders further confirmed the direct relationship between hip fracture and higher coagulation activity. Last, INTEM CT and CFT significantly decreased (P = .008 and P < .001, respectively), while INTEM MCF, A10, and alpha angle significantly increased (P < .001) postoperatively, indicating that surgery further increases the coagulation potential. CONCLUSION: A higher coagulation activity following hip fractures and surgical treatment can be detected by ROTEM shortly after the injury, even when this is undetectable by conventional coagulation assays.

Effects of electronic cigarette on platelet and vascular function after four months of use.

We examined the effects of electronic cigarette on platelet and vascular function after 4 months of use compared to tobacco smoking. Forty smokers without cardiovascular disease were randomized to smoke either conventional cigarettes or an electronic cigarette (nicotine concentration of 12 mg/ml). At baseline and after four months, we measured a) platelet function by Platelet Function Analyzer PFA-100 and Light Transmission Aggregometry, b) pulse wave velocity, c) plasma malondialdehyde levels as oxidative stress index and d) the exhaled CO level. After 4 months, continuation of conventional cigarette smoking further impaired platelet function compared to vaping as assessed by PFA (mean increase 27.1 vs 11.6 s, p for interaction = 0.048) and by LTA (decline 24.1 vs 9.4%, p for interaction = 0.045). Conversely, compared to smoking, vaping resulted in greater reduction of exhaled CO (6.9 ppm vs 2.6, p for interaction < 0.001), improvement of PWV (decrease of 0.8 m/s vs increase of 0.8 m/s, p for interaction = 0.020) and reduction of MDA (reduction 0.13 vs increase 0.19 nmol/L, p for interaction = 0.035). Switching to electronic cigarette for 4 months has a neutral effect on platelet function while it reduces arterial stiffness and oxidative stress compared to tobacco smoking.

ß-Amyloid and mitochondrial-derived peptide-c are additive predictors of adverse outcome to high-on-treatment platelet reactivity in type 2 diabetics with revascularized coronary artery disease.

BACKGROUND AND AIMS: Increased ß-amyloid and decreased mitochondrial-derived peptide (MOTS-c), are reported in diabetes. We investigated their additive value to high on-clopidogrel platelet reactivity (HPR) for adverse outcome in type 2 diabetics after recent revascularization. PATIENTS AND METHODS: In 121 type II diabetics, treated with clopidogrel and aspirin, (93 males, mean age 67.2 years) we measured: (a) maximum platelet aggregation to adenosine diphosphate (ADP) by light transmission aggregometry (LTAmax), (b) malondialdehyde (MDA), as oxidative stress marker, (c) MOTS-c, (d) ß-amyloid blood levels. Cardiac death and acute coronary syndromes (MACE) were recorded during 2 years of follow-up. RESULTS: Out of 121 patients, 32 showed HPR (LTAmax > 48%,). At baseline, HPR was associated with ß-amyloid > 51 pg/ml (p = 0.006) after adjusting clinical variables, HbA1c, MOTS-c, MDA and medication. During follow-up, 22 patients suffered a MACE. HPR, ß-amyloid > 51 pg/ml and MOTS-c < 167 ng/ml were predictors of MACE (relative risk 3.1, 3.5 and 3.8 respectively, p < 0.05) after adjusting for confounders and medication. There was significant interaction between HPR and ß-amyloid or MOTS-c for the prediction of MACE (p < 0.05). Patients with HPR and ß-amyloid > 51 mg/dl or HPR and MOTS-c concentration < 167 ng/ml had a fourfold higher risk for MACE than patients without these predictors (relative risk 4.694 and 4.447 respectively p < 0.01). The above results were confirmed in an external validation cohort of 90 patients with diabetes and CAD. CONCLUSIONS: Increased ß-amyloid or low MOTS-c are additive predictors to high on-clopidogrel platelet reactivity for adverse outcome in diabetics with CAD during 2-years follow-up. Clinical Trial Registration-URL: https://www.clinicaltrials.gov. Unique identifier: NCT04027712.

Platelet to lymphocyte and neutrophil to lymphocyte ratio as predictive indices of endometrial carcinoma: Findings from a retrospective series of patients and meta-analysis.

BACKGROUND: The purpose of the present study is to present new data concerning the diagnostic efficacy of neutrophil to lymphocyte (NLR) and platelet to lymphocyte (PLR) ratios in detecting endometrial carcinoma and to summarize the existing knowledge by accumulating all the available data in the existing literature. MATERIALS AND METHODS: We retrospectively identified patients with evidence of endometrial pathology (vaginal bleeding or increased endometrial thickness) that undergone dilatation and curettage. For the meta-analysis we used the Medline, Scopus, Clinicaltrials.gov, EMBASE, Cochrane Central Register of Controlled Trials CENTRAL and Google Scholar databases to identify relevant articles in the field. RESULTS: In our retrospective series we identified 106 women with endometrioid endometrial carcinoma and 72 controls. PLR and NLR values were comparable among the two groups (p>.05). Eleven studies were included in the present systematic review with a total of 4168 patients. The meta-analysis included 1013 patients. PLR values were not significantly different among the two groups. On the other hand, NLR was significantly raised among patients with endometrial carcinoma (MD 0.73, 95% CI 0.01, 1.45). CONCLUSION: The findings of our meta-analysis support that NLR values are significantly elevated in patients with endometrial cancer compared to controls. Moreover, there seem to be evidence to support that both PLR and NLR values increase in patients with advanced stage disease, including positive lymph nodes, lymphovascular space involvement and distant metastases. Future studies are needed in this field to reach firm conclusions and these should specifically target patients with advanced stage disease.

Angiopoietin-2 Levels as Predictors of Outcome in Mechanically Ventilated Patients with Acute Respiratory Distress Syndrome.

Pulmonary endothelium dysfunction is a key characteristic of ARDS. The aim of this study was to investigate endothelium-derived markers, such as angiopoietin-2 (Ang-2) and endothelial cell-specific molecule-1 (endocan), at the vascular and alveolar compartments as outcome predictors in ARDS. Fifty-three consecutive ARDS patients were studied. The primary outcome was 28-day mortality. Secondary endpoints were days of unassisted ventilation and days with organ failure other than ARDS, during the 28-day study period. Nonsurvivors presented higher lung injury scores and epithelial lining fluid (ELF) Ang-2 levels compared to survivors, with no significant differences in plasma Ang-2, endocan, and protein C concentrations between the two groups. In logistic regression analysis, ELF Ang-2 levels > 705 pg/ml were the only independent variable for 28-day mortality among the previous four. Plasma endocan values > 13 ng/pg were the only parameter predictive against days of unassisted ventilation during the 28-day study period. Finally, lung injury score > 2.25 and ELF Ang-2 levels > 705 pg/ml were associated with increased number of days with organ failure, other than ARDS. Our findings suggest that Ang-2 levels are increased in the alveolar compartment of ARDS patients, and this may be associated both with increased mortality and organ failure besides lung.

Intravenous Versus Oral Iron for the Treatment of Anemia in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Anemia is the most prevalent extraintestinal complication of inflammatory bowel disease (IBD). Our aim was to evaluate the comparative efficacy and harm of intravenous (IV) versus oral iron supplementation for correcting anemia in adult IBD patients.We conducted a systematic review and meta-analysis to integrate evidence from randomized controlled trials having enrolled adults with IBD, and comparing IV versus oral iron (head-to-head) for correcting iron-deficiency anemia. Medline, Embase, Scopus, and the Web of Science database were searched through July 2015. The Cochrane Central Register of Controlled Trials, the WHO International Clinical Trials Registry Platform, the ClinicalTrials.gov, and international conference proceedings were also investigated. Two reviewers independently abstracted study data and outcomes, and rated each trial's risk-of-bias. Pooled odds ratio (OR) estimates with their 95% CIs were calculated using fixed- and random-effects models.Five eligible studies, including 694 IBD patients, were identified. In meta-analysis, IV iron demonstrated a higher efficacy in achieving a hemoglobin rise of ≥2.0 g/dL as compared to oral iron (OR: 1.57, 95% CI: 1.13, 2.18). Treatment discontinuation rates, due to adverse events or intolerance, were lower in the IV iron groups (OR: 0.27, 95% CI: 0.13, 0.59). Similarly, the occurrence of gastrointestinal adverse events was consistently lower in the IV iron groups. On the contrary, serious adverse events (SAEs) were more frequently reported among patients receiving IV iron preparations (OR: 4.57, 95% CI: 1.11, 18.8); however, the majority of the reported SAEs were judged as unrelated or unlikely to be related to the study medication. We found no evidence of publication bias, or between-study heterogeneity, across all analyses. Risk of bias was high across primary studies, because patients and personnel were not blinded to the intervention.IV iron appears to be more effective and better tolerated than oral iron for the treatment of IBD-associated anemia.

The role of procalcitonin and IL-6 in discriminating between septic and non-septic causes of ALI/ARDS: a prospective observational study.

BACKGROUND: The aim was to evaluate the clinical usefulness of a single plasma and bronchoalveolar lavage fluid (BALF) PCT and IL-6 measurement in discriminating septic from non-septic causes of acute respiratory distress syndrome (ARDS) and forecasting clinical outcomes. METHODS: One hundred patients were enrolled within 48 h of ALI/ARDS recognition. Demographic, clinical data, severity indices were recorded and PCT and IL-6 concentrations were measured in plasma and BALF. RESULTS: Plasma PCT and IL-6 values were significantly higher in septic compared to non-septic individuals (p=0.001 and 0.0005, respectively), while there were no differences in their respective BALF values. As far as identification of septic vs. non-septic ARDS is concerned, the comparison of the areas under the curves favored PCT vs. IL-6 [0.88, (95% CI 0.81-0.95) vs. 0.71, (95% CI 0.60-0.81); χ(2)=9.04, p=0.003]. A plasma PCT level of 0.815 ng/mL was associated with 74.1% sensitivity and 97.6% specificity in identifying septic ARDS cases; this corresponded to a diagnostic odds ratio value of 116. Linear regression multivariable analysis disclosed a significant relation of plasma PCT with SOFA score in septic ARDS patients (p<0.001), while neither BALF PCT nor IL-6 levels were associated with clinical outcome. CONCLUSIONS: Early plasma - but not BALF - PCT concentrations can discriminate between septic and non-septic ARDS causes and are associated with the severity of multiple organ dysfunction syndrome in septic ARDS patients. However, neither plasma or BALF IL-6 levels nor BALF PCT levels carry any prognostic potential. A single plasma PCT value higher than 0.815 ng/mL makes a non-septic cause of ARDS highly unlikely.

Angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism and circulating ACE levels are not associated with outcome in critically ill septic patients.

BACKGROUND: In critically ill patients independent studies have shown contradictory findings regarding the prognostic significance of the D/D genotype of the I/D angiotensin converting enzyme (ACE) polymorphism. The study aim was to evaluate the effect of both ACE I/D polymorphism and ACE serum levels on the clinical outcomes of critically ill septic patients. METHODS: This study recruited 186 Caucasian patients with sepsis, severe sepsis or septic shock. Epidemiological, clinical data, co-morbidities and severity scores were recorded. Measurements of serum ACE activity and genotyping for ACE I/D polymorphism were carried out. Primary outcomes were the 28- and the 90-day mortality; secondary outcomes included the number of days without renal or cardiovascular failure and ventilation-free days over the 28-day period following study enrolment. RESULTS: Neither 28- nor 90-day mortality were associated with ACE I/D polymorphism (p=0.59 and 0.34, respectively) or circulating ACE levels (p=0.17 and 0.25, respectively). Similarly, ACE polymorphism and levels were not related to ventilation-free days (p=0.14 and 0.25, respectively), days without cardiovascular failure (p=0.14 and 0.81, respectively) and days without renal failure (p=0.64 and 0.27, respectively). CONCLUSIONS: Neither ACE I/D polymorphism nor serum ACE levels seem to be significant prognostic factors of clinical outcomes in septic, critically ill patients.

Direct evidence for normalization of platelet function resulting from platelet count reduction in essential thrombocythemia.

Essential thrombocythemia is characterized by persistent elevation and functional disturbances of platelets. Both the platelet function analyzer-100 (PFA-100) collagen-epinephrine (CEPI) cartridge and aggregometry with epinephrine are considered sensitive and valid methods in detecting abnormal platelet function in essential thrombocythemia. We attempted to confirm that restoration of abnormal platelet function results from platelet count reduction in essential thrombocythemia, by using these two methods. Thirty-nine essential thrombocythemia patients were divided into two groups on the basis of their platelet count. Group A participants (n = 20) exhibited platelet counts greater than 500 × 10/l, whereas group B participants (n = 19) had platelet counts below this limit. Hematological parameters, plasma von Willebrand factor (vWF) antigen and activity levels were assessed. Platelet function was analyzed by the PFA-100 and light transmission aggregometry with epinephrine, collagen, and ADP. The point mutation JAK2 V617F was identified and its effect on platelet function tests was also investigated. By using logistic regression analysis, white blood cell count, vWF activity level, and the measurements of aggregation in response to epinephrine were significantly different between the two groups. Epinephrine-induced aggregation retained the statistical significance in the multivariable procedure (P : 0.002). PFA-100 CEPI closure times were lower - but not statistically significant - in group B. Neither the JAK2 V617F positivity nor different cytoreductive treatments had any influence on ex-vivo platelet function tests. Our findings demonstrate normalization of platelet function resulting from platelet count reduction in essential thrombocythemia and reinforce the concept of lowering platelet counts in these patients.