Effect of RANKL on Lower Depressive Symptoms In Hemodialysis Patients.

Depression and osteoporosis are common diseases in dialysis patients. In addition, patients with osteoporosis are more susceptible to depression. Contrary to previous anti-osteoporosis agents, denosumab and romosozumab could be used in dialysis patients and have similar action mechanisms for blocking RANKL. RANKL causes bone resorption after binding RANKL, but binding with OPG leads to suppress of bone resorption. In recent mice study, inhibition of RANKL with denosumab improved depressive-like phenotype. Besides, it was found that OPG was associated with depression. Therefore, this study aimed to investigate the association of depressive symptoms with RANKL and OPG in hemodialysis patients. We conducted a cross-sectional study with a total of 172 hemodialysis patients. The participants were measured for plasma RANKL, OPG, MMP-2, and MMP-9 levels. Logistic regression analysis was performed to evaluate the effect of RANKL and OPG on the presence of depressive symptoms. The depressive symptoms were observed in 90 (52.3%) subjects. RANKL tertile 3 had negative association with BDI score (ß - 4.527, 95% CI - 8.310 to - 0.743) in univariate analysis, and this association persisted even after multivariate adjustments (ß - 5.603, 95% CI - 9.715 to -1.491) in linear regression. In logistic regression between RANKL tertiles and depressive symptoms, RANKL tertile 3 had significantly lower unadjusted OR (0.40, 95% CI 0.19-0.86), and multivariate-adjusted OR (0.31, 95% CI 0.12-0.82) for depressive symptoms. OPG was not significantly associated with depressive symptoms. Higher plasma RANKL concentrations were significantly associated with lower depressive symptoms in HD patients.Trial registration WHO registry, No. KCT0003281, date: January 12, 2017.

Understanding the Korean Dialysis Cohort for Mineral, Vascular Calcification, and Fracture (ORCHESTRA) Study: Design, Method, and Baseline Characteristics.

INTRODUCTION: End-stage renal disease (ESRD) is a growing disease worldwide, including Korea. This is an important condition that affects patient outcome. To provide optimal management for mineral disturbance, vascular calcification, and bone disease in ESRD patients, the Korean dialysis cohort for mineral, vascular calcification, and fracture (ORCHESTRA) study was conducted by enrolling Korean dialysis patients. METHODS: Sixteen university-affiliated hospitals and one Veterans' Health Service Medical Center participated in this study. This prospective cohort study enrolled approximately 900 consecutive patients on dialysis between May 2019 and January 2021. Enrolled subjects were evaluated at baseline for demographic information, laboratory tests, radiologic imaging, and bone mineral densitometry (BMD) scans. After enrollment, regular assessments of the patients were performed, and their biospecimens were collected according to the study protocol. The primary outcomes were the occurrence of major adverse cardiovascular events, invasive treatment for peripheral artery disease, and osteoporotic fractures. The secondary outcomes were hospitalization for cerebrovascular disease or progression of abdominal aortic calcification. Participants will be assessed for up to 3 years to determine whether primary or secondary outcomes occur. RESULTS: Between May 2019 and January 2021, all participating centers recruited 900 consecutive dialysis patients, including 786 undergoing hemodialysis (HD) and 114 undergoing peritoneal dialysis (PD). The mean age of the subjects was 60.4 ± 12.3 years. Males accounted for 57.7% of the total population. The mean dialysis vintage was 6.1 ± 6.0 years. The HD group was significantly older, had a longer dialysis vintage, and more comorbidities. Overall, the severity of vascular calcification was higher and the level of BMD was lower in the HD group than in the PD group. CONCLUSION: This nationwide, multicenter, prospective cohort study focused on chronic kidney disease-mineral and bone disorder and aimed to provide clinical evidence to establish optimal treatment guidelines for Asian dialysis patients.

Comparison of Modified Shock Index and Shock Index for Predicting Massive Transfusion in Women with Primary Postpartum Hemorrhage: A Retrospective Study.

BACKGROUND The modified shock index (MSI) is calculated as the ratio of heart rate (HR) to mean arterial pressure (MAP) and has been used to predict the need for massive transfusion (MT) in trauma patients. This retrospective study from a single center aimed to compare the MSI with the traditional shock index (SI) to predict the need for MT in 612 women diagnosed with primary postpartum hemorrhage (PPH) at the Emergency Department (ED) between January 2004 and August 2023. MATERIAL AND METHODS The patients were divided into the MT group and the non-MT group. The predictive power of MSI and SI was compared using the areas under the receiver operating characteristic curve (AUC). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value were calculated. RESULTS Out of 612 patients, 105 (17.2%) required MT. The MT group had higher median values than the non-MT group for MSI (1.58 vs 1.07, P<0.001) and SI (1.22 vs 0.80, P<0.001). The AUC for MSI, with a value of 0.811 (95% confidence interval [CI], 0.778-0.841), did not demonstrate a significant difference compared to the AUC for SI, which was 0.829 (95% CI, 0.797-0.858) (P=0.066). The optimal cutoff values for MSI and SI were 1.34 and 1.07, respectively. The specificity and PPV for MT were 77.1% and 40.2% for MSI, and 83.2% and 45.9% for SI. CONCLUSIONS Both MSI and SI were effective in predicting MT in patients with primary PPH. However, MSI did not demonstrate superior performance to SI.

The Impact of Obesity on Kidney Disease: Observational Cohort Study Analyzing 14,492 Kidney Biopsy Cases.

BACKGROUND: The obesity epidemic is associated with the emergence of new kidney diseases including obesity-related glomerulopathy (ORG) and metabolic syndrome-associated disorders. However, the effects of obesity on prevalence and outcome of biopsy-proven kidney disease are not well known. METHODS: We analyzed 14,492 kidney biopsies in 18 hospitals from 1979 to 2018 in Korea. Obesity was defined as a body mass index value of ≥ 30 kg/m². RESULTS: The most common disease was IgA nephropathy (IgAN) in both obese and non-obese participants (33.7% vs. 38.9%). Obesity was associated with a higher risk of focal segmental glomerulosclerosis (FSGS) and hypertensive nephropathy (HT-N) (odds ratio [OR], 1.72, 95% confidence interval [CI], 1.37-2.17; OR, 1.96, 95% CI, 1.21-3.19) and a lower risk of IgAN (OR, 0.74, 95% CI, 0.62-0.88). During the median follow up of 93.1 ± 88.7 months, obesity increased the risk of end-stage kidney disease (ESKD) in patients with IgAN (relative risk [RR], 1.49, 95% CI, 1.01-2.20) and lupus nephritis (LN) (RR, 3.43, 95% CI, 1.36-8.67). Of 947 obese individuals, ORG was detected in 298 (31.5%), and 230 participants had other kidney diseases, most commonly, IgAN (40.9%) followed by diabetic nephropathy (15.2%). Participants with ORG, when combined with other renal diseases, showed higher risks for developing ESKD compared to those with ORG alone (RR, 2.48, 95% CI, 1.09-5.64). CONCLUSION: Obesity is associated with an increased risk of FSGS and HT-N, and also increase the ESKD risk in IgAN and LN patients. ORG in obese participants may have favorable renal outcomes if it occurs alone without any other renal disease.

Automated radiolabeling and handling of 177 Lu- and 225 Ac-PSMA-617 using a robotic pipettor.

While automated modules for F-18 and C-11 radiosyntheses are standardized with features such as multiple reactors, vacuum connection and semi-preparative HPLC, labeling and processing of compounds with radiometals such as Zr-89, Lu-177 and Ac-225 often do not require complex manipulations and are frequently performed manually by a radiochemist. These procedures typically involve transferring solutions to and from vials using pipettes followed by heating of the reaction mixture, and do not require all the features found in most commercial automated synthesis units marketed as F-18 or C-11 modules. Here we present an efficient automated method for performing radiosyntheses involving radiometals by adapting a commercially available robotic pipettor originally developed for high-throughput processing of biological samples. While a robotic pipettor is less costly than a radiosynthesis module, it holds many similar advantages over manual radiosynthesis such as minimization of operator error, lower operator exposure rates, and abbreviated synthesis times, among others. To demonstrate the feasibility of using the OpenTrons OT-2 robotic pipettor to perform automated radiosyntheses, we radiolabeled and formulated 177 Lu-PSMA-617 and 225 Ac-PSMA-617 on the system. The OT-2 was then used to help streamline the quality control process for both products, further minimizing manual handling by and exposure to the radiochemist.

Performance analysis considering endpoints for three accelerated diagnostic protocols for chest pain.

INTRODUCTION: The modified accelerated diagnostic protocol (ADP) to assess patients with chest pain symptoms using troponin as the only biomarker (mADAPT), the History, ECG, Age, Risk factors, and Troponin (HEART) pathway, and the Emergency Department Assessment of Chest Pain Rule (EDACS)-ADP, are the three most well-known ADPs for patients with chest pain. These ADPs define major adverse cardiac event (MACE) as components of acute myocardial infarction, revascularization, and death; unstable angina is not included as an endpoint. METHODS: We performed a single-center prospective observational study comparing the performance of these 3 ADPs for patients with 30-day MACE with and without unstable angina. We hypothesized that these ADPs will have high sensitivities for MACE without unstable angina, a definition used for score derivation studies. However, when unstable angina is included in the MACE, their performances would be lower than the acceptable rate of >99% sensitivity. RESULTS: A total of 1,214 patients were included in the analysis. When unstable angina was not included in the endpoint, sensitivities for MACE were 99.1% (95% confidence interval [CI]: 96.7-99.9%), 99.5% (95% CI: 97.4-100%), and 100% (95% CI: 98.3-100%) for mADAPT, EDACS-ADP, and HEART pathway, respectively. The HEART pathway had the highest proportion of patients classified as low risk (39.2%, 95% CI: 35.8-42.9%), followed by EDACS-ADP (31.3%, 95% CI: 28.2-34.6%) and mADAPT (29.3%, 95% CI: 26.4-32.5%). However, when unstable angina was included in the MACE, sensitivities were 96.6% (95% CI: 94.4-98.1%) for mADAPT, 97.3% (95% CI: 95.3-98.6%) for EDACS-ADP, and 97.3% (95% CI: 95.3-98.6%) for the HEART pathway, respectively. There were 15 false-negative cases with mADAPT, and 12 false-negative cases each for EDACS-ADP and HEART pathway. CONCLUSION: All three ADPs-mADAPT, EDACS-ADP, and HEART pathway-were similarly accurate in their discriminatory performance for the risk stratification of ED patients presenting with possible ACS when unstable angina was not included in the endpoint. The HEART pathway showed the best combination of sensitivity and proportion of patients that can be classified as safe for early discharge. However, when unstable angina was added to the endpoint, all three ADPs did not show appropriate safety levels and their performances were lower than the acceptable risk of MACE.

Content Analysis of Feedback Journals for New Nurses From Preceptor Nurses Using Text Network Analysis.

This study aimed to identify keywords, core topic areas, and subthemes by analyzing feedback journals written by preceptor nurses to new nurses during the preceptorship period and to derive implications through word clustering. A total of 143 preceptor nurses' feedback journals for new nurses from March 2020 to January 2021 were converted into a database using Microsoft Office Excel. Text network analysis was performed using the NetMiner 4.4.3 program. After data preprocessing, simple frequency, degree centrality, closeness centrality, betweenness centrality, and community modularity were analyzed. In the feedback journals, the most central words were "study," "medication," "practice," "nursing," "method," "need," and "effort," whereas frustration, "new nurses" had low centrality. Five subthemes were derived: (1) learning necessity to strengthen new nurses' competency, (2) independence of new nurses, (3) emphasis on accuracy in nursing skills, (4) difficulties in understanding the nursing tasks expected of new nurses, and (5) basic competency of new nurses. The results of this study highlighted the experiences of new nurses and allowed for an assessment of journal feedback content provided by preceptor nurses. As such, the study provides basic data to develop a standardized education and competency empowerment program for preceptor nurses.

Capturing New Nurses' Experiences and Supporting Critical Thinking: Text Network Analysis of Critical Reflective Journals.

This study analyzed the contents of critical reflective journals written by new nurses during their orientations using a text network. This study aimed to find ways to reduce turnover and improve clinical field adaptability among new nurses. The authors analyzed the content of reflective journals written by 143 new nurses from March 2020 to January 2021. Text network analysis was performed using the NetMiner 4.4.3 program. After data preprocessing, frequency of occurrence, degree centrality, closeness centrality, betweenness centrality, and eigenvector community were analyzed. In total, 453 words were extracted and refined, and words with high simple frequency and centrality were "incompetence," "preparation," "explanation," "injection," "time," "examination," and "first try." "Medication" had the highest frequency of occurrence, and "incompetence" was the most important keyword in the centrality analysis. In addition, component analysis and eigenvector community analysis revealed three sub-theme groups: (1) basic nursing skills required for new nurses, (2) insufficient competency, and (3) explanation of nursing work. Significantly, this study is the first to use the text network method to analyze the subjective experiences of the critical reflective journals of new nurses. In conclusion, changes are needed to improve the education system for new nurses and promote efficient sharing of nursing tasks.

Radiosynthesis and Early Evaluation of a Positron Emission Tomography Imaging Probe [18F]AGAL Targeting Alpha-Galactosidase A Enzyme for Fabry Disease.

Success of gene therapy relies on the durable expression and activity of transgene in target tissues. In vivo molecular imaging approaches using positron emission tomography (PET) can non-invasively measure magnitude, location, and durability of transgene expression via direct transgene or indirect reporter gene imaging in target tissues, providing the most proximal PK/PD biomarker for gene therapy trials. Herein, we report the radiosynthesis of a novel PET tracer [18F]AGAL, targeting alpha galactosidase A (α-GAL), a lysosomal enzyme deficient in Fabry disease, and evaluation of its selectivity, specificity, and pharmacokinetic properties in vitro. [18F]AGAL was synthesized via a Cu-catalyzed click reaction between fluorinated pentyne and an aziridine-based galactopyranose precursor with a high yield of 110 mCi, high radiochemical purity of >97% and molar activity of 6 Ci/µmol. The fluorinated AGAL probe showed high α-GAL affinity with IC50 of 30 nM, high pharmacological selectivity (≥50% inhibition on >160 proteins), and suitable pharmacokinetic properties (moderate to low clearance and stability in plasma across species). In vivo [18F]AGAL PET imaging in mice showed high uptake in peripheral organs with rapid renal clearance. These promising results encourage further development of this PET tracer for in vivo imaging of α-GAL expression in target tissues affected by Fabry disease.

Augmented-Medication CardioPulmonary Resuscitation Trials in out-of-hospital cardiac arrest: a pilot randomized controlled trial.

BACKGROUND: Previously conducted physician-centered trials on the usefulness of vasopressin have yielded negative results; thus, patient-oriented trials have been warranted. We hypothesize that Augmented-Medication CardioPulmonary Resuscitation could be helpful for selected patients with out-of-hospital cardiac arrest (OHCA). METHODS: This is a double-blind, single-center, randomized, placebo-controlled trial conducted in the emergency department in a tertiary, university-affiliated hospital in Seoul, Korea. A total of 148 adults with non-traumatic OHCA who had initial diastolic blood pressure (DBP) < 20 mm Hg via invasive arterial monitoring during the early cardiac compression period were randomly assigned to two groups. Patients received a dose of 40 IU of vasopressin or placebo with initial epinephrine. The primary endpoint was a sustained return of spontaneous circulation. Secondary endpoints were survival discharge, and neurologic outcomes at discharge. RESULTS: Of the 180 included patients, 32 were excluded, and 148 were enrolled in the trial. A sustained return of spontaneous circulation was achieved by 27 patients (36.5%) in the vasopressin group and 24 patients (32.4%) in the control group (risk difference, 4.1%; P = .60). Survival discharge and good neurologic outcomes did not differ between groups. The trial group had significantly higher median DBPs during resuscitation than the control group (16.0 vs. 14.5 mm Hg, P < 0.01). There was no difference in end-tidal carbon dioxide, acidosis, and lactate levels at baseline, 10 min, and end-time. CONCLUSION: Among patients with refractory vasodilatory shock in OHCA, administration of vasopressin, compared with placebo, did not significantly increase the likelihood of return of spontaneous circulation.

Risk stratification for clinical severity of pulmonary embolism in patients with cancer: a narrative review and MASCC clinical guidance for daily care.

Pulmonary embolism (PE) is a leading cause of morbidity and mortality in patients with cancer. The clinical presentation and outcomes of PE range from an acute life-threatening condition requiring intensive care to a mild symptomatic condition associated with favorable outcomes and potentially candidate for early hospital discharge. The wide clinical spectrum of PE has led to the development of risk stratification models aimed at the triage of patients in emergency care departments and optimizing the utilization of health care resources. Incidental or unsuspected PE (UPE), detected during routine staging computed tomography scans, make up a significant proportion of this cohort among the oncology population. The present narrative review is aimed at examining the currently available PE risk assessment models developed for the general population and for patients with cancer including UPE. We include general recommendations for the daily care of patients with cancer-related PE and hypothesize on the factors that would potentially favor hospitalization with early discharge or ambulatory management in this setting.

Catheter-related thrombosis (CRT) in patients with solid tumors: a narrative review and clinical guidance for daily care.

Central venous access devices (CVADs) including central venous catheters and peripherally inserted central catheters (PICCs) are essential in the treatment of cancer. Catheter-related thrombosis (CRT) is the most frequent non-infectious complication associated with the use of central lines. The development of CRT may cause to delays in oncologic treatment and increase morbidity leading to potentially life-threatening complications. Several local and systemic risk factors are associated with the development of CRT and should be taken into account to prevent CRT by standardizing appropriate catheter placement and maintenance. The use of primary pharmacological thromboprophylaxis in order to avoid CRT is not routinely recommended, although it can be considered in selected cases. Recommendations for the management of established CRT are based on the extrapolation of anticoagulation for lower limb venous thrombosis. The present review summarizes the current evidence and recommendations for the prevention and management of CRT and identifies areas that require further research.

Waist-hip ratio measured by bioelectrical impedance analysis as a valuable predictor of chronic kidney disease development.

Obesity is a major health problem worldwide and is associated with chronic kidney disease (CKD). Body mass index (BMI) is a common method of diagnosing obesity, but there are concerns about its accuracy and ability to measure body composition. This study evaluated the risk of CKD development in a middle-aged population in association with various body composition metrics. From a prospective cohort of 10,030 middle-aged adults, we enrolled 6727 for whom baseline and follow-up data were available. We collected data pertaining to participants' BMI, manually measured waist-hip ratio (WHR), and various measurements of bioelectrical impedance analysis (BIA), including total body fat content, muscle content, and calculated WHR, and classified the participants into quintiles accordingly. CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 in follow-up laboratory tests. While an increase in BMI, WHR, and total body fat were associated with an elevated risk of CKD, an increase in total body muscle decreased the risk. Among the body composition metrics, WHR measured by BIA had the highest predictive value for CKD (C-statistics: 0.615). In addition, participants who were "healthy overweight, (defined as low WHR but high BMI), exhibited a 62% lower risk of developing CKD compared to those with "normal-weight obesity," (defined as high WHR despite a normal BMI). In conclusion, we suggest that central obesity measured by BIA is a more accurate indicator than BMI for predicting the development of CKD.

The Roles and Associated Mechanisms of Adipokines in Development of Metabolic Syndrome.

Metabolic syndrome is a cluster of metabolic indicators that increase the risk of diabetes and cardiovascular diseases. Visceral obesity and factors derived from altered adipose tissue, adipokines, play critical roles in the development of metabolic syndrome. Although the adipokines leptin and adiponectin improve insulin sensitivity, others contribute to the development of glucose intolerance, including visfatin, fetuin-A, resistin, and plasminogen activator inhibitor-1 (PAI-1). Leptin and adiponectin increase fatty acid oxidation, prevent foam cell formation, and improve lipid metabolism, while visfatin, fetuin-A, PAI-1, and resistin have pro-atherogenic properties. In this review, we briefly summarize the role of various adipokines in the development of metabolic syndrome, focusing on glucose homeostasis and lipid metabolism.

Homologous Structural, Chemical, and Biological Behavior of Sc and Lu Complexes of the Picaga Bifunctional Chelator: Toward Development of Matched Theranostic Pairs for Radiopharmaceutical Applications.

The radioactive isotopes scandium-44/47 and lutetium-177 are gaining relevance for radioimaging and radiotherapy, resulting in a surge of studies on their coordination chemistry and subsequent applications. Although the trivalent ions of these elements are considered close homologues, dissimilar chemical behavior is observed when they are complexed by large ligand architectures due to discrepancies between Lu(III) and Sc(III) ions with respect to size, chemical hardness, and Lewis acidity. Here, we demonstrate that Lu and Sc complexes of 1,4-bis(methoxycarbonyl)-7-[(6-carboxypyridin-2-yl)methyl]-1,4,7-triazacyclononane (H3mpatcn) and its corresponding bioconjugate picaga-DUPA can be employed to promote analogous structural features and, subsequently, biological properties for coordination complexes of these ions. The close homology was evidenced using potentiometric methods, computational modeling, variable temperature mass spectrometry, and pair distribution function analysis of X-ray scattering data. Radiochemical labeling, in vitro stability, and biodistribution studies with Sc-47 and Lu-177 indicate that the 7-coordinate ligand environment of the bifunctional picaga ligand is compatible with biological applications and the future investigation of ß-emitting, picaga-chelated Sc and Lu isotopes for radiotherapy.

Impact of water consumption on renal function in the general population: a cross-sectional analysis of KNHANES data (2008-2017).

BACKGROUND: The renoprotective effect of water intake remains unclear. We aimed to investigate the relationship between water intake and renal impairment in the Korean general population, focusing on individual differences in body fluid distribution and risk of chronic dehydration. METHODS: We conducted a cross-sectional analysis of the 2008-2017 Korea National Health and Nutrition Examination Survey (KNHANES). Adult participants who had body weight and serum creatinine data and had answered 24-h recall nutritional survey were included. Four water intake groups were defined by daily total water intake per body weight: lowest (< 20 mL/kg/day), low-moderate (20-29.9 mL/kg/day), high-moderate (30-49.9 mL/kg/day), and highest (≥ 50 mL/kg/day). We assessed the risk of renal impairment (estimated glomerular filtration rate ≤ 60 mL/min/1.73 m2) according to water intake. RESULTS: In total of 50,113 participants, 3.9% had renal impairment. The risk of renal impairment gradually decreased as water intake increased. After adjustment of sodium intake, the trend of renoprotective effect was remained in low-moderate and high-moderate water intake group compared to low intake group, whereas no significant impact was observed with the highest water intake due to concurrent intake of high sodium. In subgroup analysis, the renoprotective effect of water intake was significant in the participants with elderly, male and daily sodium intake over 2 g/day. CONCLUSIONS: High daily water intake is renoprotective. Our data may provide an important basis for determining the amount of water intake needed to prevent renal impairment, considering variations in body weight, body composition and risk of chronic dehydration.

Associations between Cell-Free Mitochondrial DNA and Inflammation, and Their Clinical Implications for Patients on Hemodialysis: A Prospective Multicenter Cohort Study.

BACKGROUND: Cell-free mitochondrial DNA (cf-mtDNA) has recently been in the spotlight as an endogenously produced danger molecule that can potentially elicit inflammation. However, its clinical and prognostic implications are uncertain in patients undergoing hemodialysis. METHODS: We examined the association of baseline cf-mtDNA categorized as tertiles with health-related quality of life (HRQOL), inflammatory cytokines, and mortality in a multicenter prospective cohort of 334 patients on hemodialysis. To better understand cf-mtDNA-mediated inflammation, we measured cytokine production after in vitro stimulation of bone marrow-derived macrophages (BMDMs) with mtDNA. RESULTS: The higher cf-mtDNA tertile had a longer dialysis vintage, a greater comorbidity burden, and increased levels of inflammatory markers, including high-sensitivity-C-reactive protein, tumor necrosis factor-alpha, CXCL16, and osteoprotegerin. In particular, mtDNA augmented inflammatory cytokine release from BMDMs by lipopolysaccharide, the levels of which are reported to be increased in hemodialysis patients. Although the patients with higher levels of cf-mtDNA generally had lower (poorer) scores for HRQOL, cf-mtDNA was not associated with all-cause mortality in hemodialysis patients. CONCLUSION: cf-mtDNA was correlated with poor clinical status and modestly associated with impaired quality of life in patients on hemodialysis. In proinflammatory milieu in end-stage renal disease, these associations may be attributed to the boosting effects of cf-mtDNA on inflammation.

Comparison of the CAD consortium and updated Diamond-Forrester scores for predicting obstructive coronary artery disease.

OBJECTIVE: Current guidelines recommend the use of the updated Diamond-Forrester (DF) method and Coronary Artery Disease (CAD) Consortium models to assess the pretest probability of obstructive CAD. The present study aimed to compare the performance of these models among patients with chest pain evaluated in an emergency department (ED). METHODS: We compared three scores (DF, CAD consortium basic, and clinical) among 1247 consecutive patients with chest pain who underwent coronary computed tomographic angiography (CTA). Invasive angiography was performed to confirm the stenosis for those who showed obstructive CAD on CTA, if clinically indicated. Primary outcome was the presence of obstructive CAD (≧50% stenosis). RESULTS: Overall, 426 (34.2%) patients were diagnosed with obstructive CAD. The expected prevalence of CAD was underestimated by the CAD consortium clinical model (23.4%) and overestimated by the DF model (53.1%). For the prediction of obstructive CAD, the CAD consortium clinical model had superior area under the receiver-operating curve (0.754), followed by the CAD consortium basic (0.736), and finally, the DF model (0.718). Whereas the CAD consortium models more accurately classified patients without any CAD or nonobstructive CAD as low-risk patients, the DF model more accurately classified high-risk patients with obstructive CAD. The net reclassification improvement of CAD consortium basic and clinical models were 24.7% and 27.9%, respectively. CONCLUSIONS: Compared with the DF model, the CAD consortium clinical model appears to improve the prediction of low-risk patients with <15% probability of having obstructive CAD. However, this model needs caution when using in high-risk population.

Site-Specific 89Zr- and 111In-Radiolabeling and In Vivo Evaluation of Glycan-free Antibodies by Azide-Alkyne Cycloaddition with a Non-natural Amino Acid.

Antibody-drug conjugates (ADCs) are a class of targeted therapeutics consisting of a monoclonal antibody coupled to a cytotoxic payload. Various bioconjugation methods for producing site-specific ADCs have been reported recently, in efforts to improve immunoreactivity and pharmacokinetics and minimize batch variance-potential issues associated with first-generation ADCs prepared via stochastic peptide coupling of lysines or reduced cysteines. Recently, cell-free protein synthesis of antibodies incorporating para-azidomethyl phenylalanine (pAMF) at specific locations within the protein sequence has emerged as a means to generate antibody-drug conjugates with strictly defined drug-antibody-ratio, leading to ADCs with markedly improved stability, activity, and specificity. The incorporation of pAMF enables the conjugation of payloads functionalized for strain-promoted azide-alkyne cycloaddition. Here, we introduce two dibenzylcyclooctyne-functionalized bifunctional chelators that enable the incorporation of radioisotopes for positron emission tomography with 89Zr (t1/2 = 78.4 h, ß+ = 395 keV (22%), γ = 897 keV) or single photon emission computed tomography with 111In (t1/2 = 67.3 h, γ = 171 keV (91%), 245 keV (94%)) under physiologically compatible conditions. We show that the corresponding radiolabeled conjugates with site-specifically functionalized antibodies targeting HER2 are amenable to targeted molecular imaging of HER2+ expressing tumor xenografts in mice and exhibit a favorable biodistribution profile in comparison with conventional, glycosylated antibody conjugates generated by stochastic bioconjugation.

Accuracy of the Ottawa score in risk stratification of recurrent venous thromboembolism in patients with cancer-associated venous thromboembolism: a systematic review and meta-analysis.

In patients with cancer-associated venous thromboembolism, knowledge of the estimated rate of recurrent events is important for clinical decision-making regarding anticoagulant therapy. The Ottawa score is a clinical prediction rule designed for this purpose, stratifying patients according to their risk of recurrent venous thromboembolism during the first six months of anticoagulation. We conducted a systematic review and meta-analysis of studies validating either the Ottawa score in its original or modified versions. Two investigators independently reviewed the relevant articles published from 1st June 2012 to 15th December 2018 and indexed in MEDLINE and EMBASE. Nine eligible studies were identified; these included a total of 14,963 patients. The original score classified 49.3% of the patients as high-risk, with a sensitivity of 0.7 [95% confidence interval (CI): 0.6-0.8], a 6-month pooled rate of recurrent venous thromboembolism of 18.6% (95%CI: 13.9-23.9). In the low-risk group, the recurrence rate was 7.4% (95%CI: 3.4-12.5). The modified score classified 19.8% of the patients as low-risk, with a sensitivity of 0.9 (95%CI: 0.4-1.0) and a 6-month pooled rate of recurrent venous thromboembolism of 2.2% (95%CI: 1.6-2.9). In the high-risk group, recurrence rate was 10.2% (95%CI: 6.4-14.6). Limitations of our analysis included type and dosing of anticoagulant therapy. We conclude that new therapeutic strategies are needed in patients at high risk for recurrent cancer-associated venous thromboembolism. Low-risk patients, as per the modified score, could be good candidates for oral anticoagulation. (This systematic review was registered with the International Prospective Registry of Systematic Reviews as: PROSPERO CRD42018099506).