Dialyzer Performance During Hemodialysis Without Systemic Anticoagulation Using a Heparin-Grafted Dialyzer Combined With a Citrate-Enriched Dialysate: Results of the Randomized Crossover Noninferiority EvoCit Study.

RATIONALE & OBJECTIVE: The EvoCit study was designed to evaluate performance of a heparin-grafted dialyzer during hemodialysis with and without systemic anticoagulation. STUDY DESIGN: Randomized, crossover, noninferiority trial. Noninferiority was defined as a difference of≤10% for the primary outcome. SETTING & PARTICIPANTS: Single hemodialysis center; 26 prevalent patients treated with 617 hemodialysis sessions. INTERVENTIONS: Hemodialysis using a heparin-grafted dialyzer combined with a 1.0mmol/L citrate-enriched dialysate ("EvoCit") without systemic anticoagulation compared with hemodialysis performed with a heparin-grafted dialyzer with systemic heparin ("EvoHep"). Patients were randomly allocated to a first period of 4 weeks and crossed over to the alternative strategy for a second period of 4 weeks. OUTCOMES: The primary end point was the difference in Kt/Vurea between EvoCit and EvoHep. Secondary end points were urea reduction ratio, middle molecule removal, treatment time, thrombin generation, and reduction in dialyzer blood compartment volume. RESULTS: The estimated difference in Kt/Vurea between EvoCit and EvoHep was-0.03 (95% CI, -0.06 to-0.007), establishing noninferiority with mean Kt/Vurea of 1.47±0.05 (SE) for EvoCit and 1.50±0.05 for EvoHep. Noninferiority was also established for reduction ratios of urea and ß2-microglobulin. Premature discontinuation of dialysis was required for 4.2% of sessions among 6 patients during EvoCit and no sessions during EvoHep. Effective treatment time was 236±5 minutes for EvoCit and 238±1 minutes for EvoHep. Thrombin generation was increased and there was greater reduction in dialyzer blood compartment volume after treatments with EvoCit compared with EvoHep. LIMITATIONS: The effects of avoiding systemic anticoagulation on clinical outcomes were not evaluated. CONCLUSIONS: EvoCit is noninferior to EvoHep with respect to solute clearance but results in a greater number of shortened treatments, more membrane clotting, and greater thrombin generation TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT03887468.

Leptomeningeal metastasis in a marginal zone lymphoma, presenting as a delirium: case report.

BACKGROUND: Hematologic malignancies can spread to the central nervous system (CNS), either as focal lesions or as leptomeningeal disease. Marginal zone lymphoma (MZL) is a low-grade non-Hodgkin lymphoma and generally presents as an indolent disease. This case report illustrates an unexpected diagnosis of leptomeningeal metastasis in an MZL, presenting as a delirium without B symptoms, pronounced hematologic progression or abnormalities on cerebral imaging. CASE PRESENTATION: An 80-year-old patient with a medical history of monoclonal B-cell lymphocytosis (MBL) with a clone indicative for an MZL, presented to the emergency and the geriatric departments with a recent cognitive deterioration and behavioral changes. MMSE score was 18/30. After excluding the most common etiologies through classical work-up including a normal head magnetic resonance imaging, a lumbar puncture was performed. In the cerebrospinal fluid an elevated protein level and increased lymphocyte count were identified, whereas beta-amyloid and tau protein levels were normal. Immunophenotyping of the lymphocytes confirmed CNS invasion by the MZL clone. Staging revealed mild splenomegaly. Prednisolone, intrathecal and systemic chemotherapy were initiated, leading to quick cognitive improvement with a final MMSE score of 28/30. CONCLUSIONS: To the best of our knowledge a delirium in an older patient due to leptomeningeal disease in MZL has never been described. To date, rare reports of CNS invasion by MZL describe focal intracranial lesions. After exclusion of common etiologies, physicians should remain vigilant when confronted with a patient with history of MBL presenting neurological symptoms. This case illustrates the importance of low threshold for lumbar punctures in this population, also for those patients with normal imaging studies.

Incidence and features of thrombosis in children with inherited antithrombin deficiency.

Pediatric thromboembolism (≤18 years) is very rare (0.07-0.14/10,000/year) but may be more prevalent in children with severe thrombophilia (protein C, protein S or antithrombin deficiency). The aim of this study was to define the prevalence and clinical characteristics of pediatric thrombosis in subjects with inherited antithrombin deficiency. Our observational retrospective multicentric study from two countries recruited 968 patients of any age from 441 unrelated families with genetically, biochemically and functionally characterized antithrombin deficiency. Seventy-three subjects (7.5%) developed thrombosis before 19 years of age. Two high-risk periods for thrombosis were identified: adolescence (12-18 years, n=49) with thrombus localization (lower limb deep venous thrombosis or pulmonary embolism) and triggering factors common to adults (oral contraceptives, surgery or pregnancy); and the neonatal period (<30 days, n=15) with idiopathic thrombosis at unusual sites. The clinical evaluation of pediatric thrombosis in subjects with antithrombin deficiency revealed: i) a high prevalence of cerebral sinovenous thrombosis (n=13, 17.8%), mainly at young age (8 neonates and 4 children <6 years); ii) severe outcome with fatality in six cases (3 neonates, two of them homozygous for p.Leu131Phe). The majority of subjects (76.7%) carried quantitative type I deficiency. This retrospective analysis includes the largest cohort of subjects with inherited antithrombin deficiency so far and provides strong evidence for an increased risk of pediatric thrombosis associated with this thrombophilia (300-fold compared with the general population: 0.41%/year vs 0.0014%/year, respectively). Our results support testing for antithrombin deficiency in children of affected families, particularly in case of type I deficiency.

Six weeks of strength endurance training decreases circulating senescence-prone T-lymphocytes in cytomegalovirus seropositive but not seronegative older women.

BACKGROUND: Ageing is associated with a decline in immune function termed immunosenescence. This process is characterized amongst others by less naive T-cells and more senescent phenotypes, which have been implicated in the pathogenesis of many age-related diseases. Thus far, reports regarding the long-term adaptation effects of exercise on T-cell phenotypes are scant and largely equivocal. These inconsistencies may be due to potential contributors to immunosenescence, particularly cytomegalovirus infection, which is considered a hallmark of T-cell senescence. Therefore, we sought to investigate the impact of cytomegalovirus serostatus on the distribution of peripheral T-cell subsets following long-term exercise in older women. METHODS: One hundred women (aged 65 years and above) were randomized to 3 times/weekly training at either intensive strength training (3 × 10 repetitions at 80% of one-repetition maximum, n = 31), strength endurance training (2 × 30 repetitions at 40% of one-repetition maximum, n = 33), or control (passive stretching exercise, n = 36) for 6 weeks. All training sessions were supervised by trained instructors to minimize the risk of injury and to ensure that the participants adhered to the training protocol throughout the entire range of motion. The T-cell percentages and absolute blood counts were determined before and after 6 weeks (24 h-48 h after the last training session) using flow cytometry and a haematology analyser. Cytomegalovirus antibodies were measured in serum using Architect iSystem and cytomegalovirus serostatus was balanced in the three intervention groups. C-reactive protein was measured using immunonephelometry. RESULTS: We report for the first time that 6 weeks of strength endurance training significantly decreased senescence-prone T-cells along with a small increase in the number of CD8- naive T-cells in blood. The absolute counts of senescent-like T-cells decreased by 44% (from 26.03 ± 35.27 to 14.66 ± 21.36 cells/µL, p < 0.01) and by 51% (from 6.55 ± 12.37 to 3.18 ± 6.83 cells/µL, p < 0.05) for the CD8+ and CD8- T-cell pools, respectively. Intriguingly, these changes were observed in cytomegalovirus seropositive, but not cytomegalovirus seronegative individuals. CONCLUSIONS: In conclusion, the present study shows that strength endurance training leads to a reduction in circulating senescence-prone T-cells in cytomegalovirus seropositive older women. It remains to be established if monitoring of peripheral senescence-prone T-cells may have utility as cellular biomarkers of immunosenescence.

Lymphoma-like monoclonal B cell lymphocytosis in a patient population: biology, natural evolution, and differences from CLL-like clones.

High-count monoclonal B cell lymphocytosis (MBL) with a chronic lymphocytic leukemia (CLL) phenotype is a well-known entity, featuring 1-4% annual risk of progression towards CLL requiring treatment. Lymphoma-like MBL (L-MBL), on the other hand, remains poorly defined and data regarding outcome are lacking. We retrospectively evaluated 33 L-MBL cases within our hospital population and compared them to 95 subjects with CLL-like MBL (C-MBL). Diagnoses of L-MBL were based on asymptomatic B cell clones with Matutes score < 3, B cells < 5.0 × 103/µl, and negative computerized tomography scans. We found that median B cell counts were considerably lower compared to C-MBL (0.6 vs 2.3 × 103/µl) and remained stable over time. Based on immunophenotyping and immunogenetic profiling, most L-MBL clones did not correspond to known lymphoma entities. A strikingly high occurrence of paraproteinemia (48%), hypogammaglobulinemia (45%), and biclonality (21%) was seen; these incidences being significantly higher than in C-MBL (17, 21, and 5%, respectively). Unrelated monoclonal gammopathy of undetermined significance was a frequent feature, as the light chain type of 5/12 paraproteins detected was different from the clonal surface immunoglobulin. After 46-month median follow-up, 2/24 patients (8%) had progressed towards indolent lymphoma requiring no treatment. In contrast, 41% of C-MBL cases evolved to CLL and 17% required treatment. We conclude that clinical L-MBL is characterized by pronounced immune dysregulation and very slow or absent progression, clearly separating it from its CLL-like counterpart.

Child-onset thrombotic thrombocytopenic purpura caused by p.R498C and p.G259PfsX133 mutations in ADAMTS13.

INTRODUCTION: Patients suffering from congenital thrombotic thrombocytopenic purpura (cTTP) have a deficiency in ADAMTS13 due to mutations in their ADAMTS13 gene. OBJECTIVE: The aim of this study was to determine ADAMTS13 parameters (activity, antigen, and mutations), to investigate if the propositus suffered from child-onset cTTP, and to study the in vitro effect of the ADAMTS13 mutations. METHODS: ADAMTS13 activity and antigen were determined using the FRETS VWF73 assay and ELISA and ADAMTS13 mutations via sequencing of the exons. Mutant proteins were expressed in Chinese hamster ovary cells, and their expression was studied using fluorescence microscopy and ELISA. Molecular modeling was used to evaluate the effect of the mutations on ADAMTS13 structure and stability. RESULTS: The propositus was diagnosed with cTTP at the age of 20. ADAMTS13 activity was below 10%, and 2 compound heterozygous mutations, the p.R498C point and the p.G259PfsX133 frameshift mutation, were identified. Expression of ADAMTS13 mutants revealed that the p.R498C and the p.G259PfsX133 mutation cause secretion and translation defects in vitro, respectively. Molecular modeling showed that the R498 intra-domain interactions are lacking in the p.R498C mutant, resulting in protein instability. CONCLUSION: The ADAMTS13 mutations result in a severe ADAMTS13 deficiency explaining the patient's phenotype.

Homozygous antithrombin deficiency in adolescents presenting with lower extremity thrombosis and renal complications: two case reports from Turkey.

We present 2 cases of lower extremity deep venous thrombosis in 2 gypsy adolescents from related families. The patients had low antithrombin activity levels and inherited homozygous antithrombin deficiency was confirmed by molecular analysis (Leu131Phe mutation). One patient had a history of nephrectomy at the age of 9 due to nonfunctioning kidney and 2 siblings died at 4 months of age. His mother had 3 fetal losses in the third trimester. The other propositus had an elder sister who suffered from postpartum deep vein thrombosis and pulmonary embolism. Heterozygous mutation was demonstrated in both parents.

The 2023 Belgian clinical guidance on anticoagulation management in hospitalized and ambulatory COVID-19 patients.

COVID-19 is associated with an increased risk for thrombotic complications. The trials investigating the optimal thromboprophylactic dose are performed in challenging times and seemingly produce conflicting evidence. The burdensome circumstances, divergent endpoints, and different analytical approaches hamper comparison and extrapolation of available evidence. Most importantly, clinicians should provide thromboprophylaxis in hospitalized COVID-19 patients while (re)assessing bleeding and thrombotic risk frequently. The COVID-19 Thromboprophylaxis Working Group of the BSTH updated its guidance document. It aims to summarize the available evidence critically and to guide clinicians in providing the best possible thromboprophylaxis.

Performance of Abbott Alinity hq hematology analyzer for automated cell counting of body fluids.

INTRODUCTION: Body fluid cell counting and differentiation provide essential information for diagnosis and monitoring of diverse pathologies. We evaluated the performance of the newly launched Abbott Alinity hq hematology analyzer for automated cell counting in body fluids and compared red blood cell (RBC) and total nucleated cell (TNC) counts with the Cell-Dyn Sapphire automated hematology analyzer. Differential counts were compared with microscopic differentiation on cytocentrifuged preparations. METHODS: Background concentration limits, limit of detection (LOD), linearity, imprecision, functional sensitivity and carryover were evaluated. For method comparison, we collected 172 body fluids (17 continuous ambulatory peritoneal dialysis fluids, 56 cerebrospinal fluids and 99 serous fluids). RESULTS: Background concentration limits were ≤1000 cells/µL for RBC counts and ≤3 cells/µL for TNC counts. The LOD was 1000 RBC/µL and 5 TNC/µL. Results from linear regression analysis revealed excellent linearity. Functional sensitivity was 3000 cells/µL for RBC counts and 50 cells/µL for TNC counts. Carryover was 0.6% and 0.1% for TNC and RBC, respectively. The Alinity hq shows good clinical performance. CONCLUSION: We demonstrated comparable performance for body fluid cell counting between the Alinity hq analyzer and the Cell-Dyn Sapphire. The Alinity hq can be very useful as a screening tool for body fluid cell counting.

Belgian clinical guidance on anticoagulation management in hospitalised and ambulatory patients with COVID-19.

OBJECTIVES: COVID-19 predisposes patients to thrombotic disease. The aim of this guidance document is to provide Belgian health-care workers with recommendations on anticoagulation management in COVID-19 positive patients. METHODS: These recommendations were based on current knowledge and a limited level of evidence. RESULTS: We formulated recommendations for the prophylaxis and treatment of COVID-related venous thromboembolism in ambulatory and hospitalised patients, as well as recommendations for the use of antithrombotic drugs in patients with prior indication for anticoagulation who develop COVID-19. CONCLUSIONS: These recommendations represent an easy-to-use practical guidance that can be implemented in every Belgian hospital and be used by primary care physicians and gynaecologists. Of note, they are likely to evolve with increased knowledge of the disease and availability of data from ongoing clinical trials.

Molecular Dissection of Structural Variations Involved in Antithrombin Deficiency.

Inherited antithrombin deficiency, the most severe form of thrombophilia, is predominantly caused by variants in SERPINC1. Few causal structural variants have been described, usually detected by multiplex ligation-dependent probe amplification or cytogenetic arrays, which only define the gain or loss and the approximate size and location. This study has done a complete dissection of the structural variants affecting SERPINC1 of 39 unrelated patients with antithrombin deficiency using multiplex ligation-dependent probe amplification, comparative genome hybridization array, long-range PCR, and whole genome nanopore sequencing. Structural variants, in all cases only affecting one allele, were deleterious and caused a severe type I deficiency. Most defects were deletions affecting exons of SERPINC1 (82.1%), but the whole cohort was heterogeneous, as tandem duplications, deletion of introns, or retrotransposon insertions were also detected. Their size was also variable, ranging from 193 bp to 8 Mb, and in 54% of the cases involved neighboring genes. All but two structural variants had repetitive elements and/or microhomologies in their breakpoints, suggesting a common mechanism of formation. This study also suggested regions recurrently involved in structural variants causing antithrombin deficiency and found three structural variants with a founder effect: the insertion of a retrotransposon, duplication of exon 6, and a 20-gene deletion. Finally, nanopore sequencing was determined to be the most appropriate method to identify and characterize all structural variants at nucleotide level, independently of their size or type.

Potential increase in radiation-induced DNA double-strand breaks with higher doses of iodine contrast during coronary CT angiography.

PURPOSE: To investigate the contrast media iodine dose dependency of radiation-induced DNA double-strand breaks (DSBs) during a coronary computed tomography angiography (CCTA) scan. METHODS: This prospective patient study was approved by the ethical committee. Between November 2018 and July 2019, 50 patients (31 males and 19 females, mean age 64 years) were included in the study, 45 CCTA and five noncontrast-enhanced (NCE) cardiac computed tomography (CT) patients. A single-heartbeat scan protocol with a patient-tailored contrast media injection protocol was used, administering a patient-specific iodine dose. DNA double-strand breaks were quantified using a γH2AX foci assay on peripheral blood lymphocytes. The net amount of γH2AX/cell was normalized to the individual patient CT dose by the size-specific dose estimate (SSDE). Correlation between the administered and blood-iodine dose and the SSDE normalized amount of DNA DSBs was investigated using a Pearson correlation test. RESULTS: CCTA patients were scanned with a mean CTDIvol of 10.6 ± 5.6 mGy, corresponding to a mean SSDE of 11.3 ± 5.3 mGy while the NCE cardiac CT patients were scanned with a mean CTDIvol of 6.00 ± 1.8 mGy, corresponding to a mean SSDE of 6.6 ± 2.7 mGy. The administered iodine dose ranged from 16.5 to 34.0 gI in the CCTA patients, resulting in a blood-iodine dose range from 5.1 to 15.0 gI in the exposed blood volume. A significant linear relationship (r = 0.79, p-value < 0.001) was observed between the blood iodine dose and SSDE normalized radiation-induced DNA DSBs. A similar significant linear relationship (r = 0.62, p-value < 0.001) was observed between the administered iodine dose and SSDE normalized radiation-induced DNA DSBs. CONCLUSIONS: This study shows that contrast media iodine dose increases the level of radiation-induced DNA DSBs in peripheral blood lymphocytes in a linear dose-dependent manner with CCTA. Importantly, the level of DNA DSBs can be reduced by lowering the administered iodine dose.

Antithrombin p.Thr147Ala: The First Founder Mutation in People of African Origin Responsible for Inherited Antithrombin Deficiency.

BACKGROUND: Hereditary antithrombin deficiency is a rare autosomal-dominant disorder predisposing to recurrent venous thromboembolism (VTE). To date, only two founder mutations have been described. OBJECTIVES: We investigated the antithrombin p.Thr147Ala variant, found in 12 patients of African origin. This variant is known as rs2227606 with minor allele frequency of 0.5% in Africans and absent in Europeans. A possible founder effect was investigated. METHODS: Phenotypical characterization was established through immunological and functional methods, both under basal and stress conditions. Recombinant antithrombin molecules were constructed by site-directed mutagenesis and expressed in HEK-293T cells. Secreted antithrombin was purified and functionally characterized. Structural modeling was performed to predict the impact of the mutation on protein structure. A novel nanopore sequencing approach was used for haplotype investigation. RESULTS: Ten patients experienced VTE, stroke, or obstetric complications. Antithrombin antigen levels and anti-IIa activity were normal or slightly reduced while anti-Xa activity was reduced with only one commercial assay. On crossed immunoelectrophoresis, an increase of antithrombin fractions with reduced heparin affinity was observed under high ionic strength conditions but not under physiological conditions. The recombinant p.Thr147Ala protein displayed a reduced anti-Xa activity. Structural modeling revealed that residue Thr147 forms three hydrogen bonds that are abolished when mutated to alanine. The investigated patients shared a common haplotype involving 13 SERPINC1 intragenic single nucleotide polymorphisms. CONCLUSION: Antithrombin p.Thr147Ala, responsible for antithrombin type II heparin binding site deficiency, is the first founder mutation reported in people of African ancestry. This study further emphasizes the limitations of commercial methods to diagnose this specific subtype.

Hemodialysis Does Not Induce Detectable Activation of the Contact System of Coagulation.

INTRODUCTION: Systemic anticoagulation is administered during hemodialysis to prevent clotting of the extracorporeal circuit. The role of contact system activation in thrombin generation during hemodialysis using current era dialyzer membranes is unknown. METHODS: We performed a single-center randomized crossover study. Ten patients treated with hemodialysis underwent 3 standardized hemodialysis sessions. For every patient, each session was performed with a different type of dialyzer membrane (polyphenylene [PP], polymethylmetacrylate [PMMA], polyethylenimine-coated polyacrylonitrile [AN69ST]). Blood samples were collected before and 5, 15, 30, 90, and 240 minutes after blood pump start to evaluate coagulation activation (thrombin-antithrombin complex [TAT], prothrombin fragment 1+2 [PF1+2], activated factor XII [FXIIa], kallikrein, activated factor XI [FXIa]). Plasma of healthy volunteers (n = 20) was used as a reference. RESULTS: Baseline TAT and PF1+2 levels were higher in hemodialysis patients compared to healthy controls (median [interquartile range] for TAT: 3.3 [2.9-4.2] vs. 2.4 [2.3-2.5] µg/l [P = 0.0002] and for PF1+2: 647 [478-737] vs. 138 [125-254] pmol/l [P < 0.0002]). Despite the use of systemic anticoagulation, TAT further increased during treatment, with the increase starting after 30 minutes (median TAT at t240: 9.0 µg/l (PP), 5.5 µg/l (PMMA), and 7.2 µg/l (AN69ST), all P < 0.05 vs. baseline). Contact system markers FXIIa and kallikrein did not differ significantly between dialysis patients and healthy controls, whereas baseline FXIa levels were significantly lower in dialysis patients compared to healthy controls (P = 0.001). Levels of all contact system markers remained unchanged during hemodialysis with all types of dialyzer membranes. CONCLUSION: Routine hemodialysis using systemic heparin anticoagulation induces coagulation activation without measurable contact system activation.

Performance evaluation of the prototype Abbott Alinity hq hematology analyzer.

INTRODUCTION: The analytical and clinical performance as well as the workflow efficiency of the novel, prototype Alinity hq hematology analyzer was evaluated in the clinical laboratory of Universitair Ziekenhuis Brussel, Department of Hematology, Brussels, Belgium. METHODS: Within-run and within-laboratory imprecision, linearity, and carryover were assessed using clinical blood samples and commercial blood products. Four hundred and seventeen samples were selected for method comparison with Abbott CELL-DYN Sapphire, and for flagging performance analysis in comparison with smear review and manual microscopic white blood cell (WBC) differential. RESULTS: Within-run and within-laboratory imprecision verification demonstrated low %CV for complete blood count and WBC differential results within the normal ranges (0.1%-10.4%), except for basophil granulocytes. The linearity of the analytical measuring ranges was verified for WBCs, red blood cells, hemoglobin, and platelets. Alinity hq results showed strong agreement with those of CELL-DYN Sapphire. Good correlation was demonstrated with manual WBC differential results, with negative bias for neutrophil (NEU) granulocytes, and positive bias for lymphocytes and monocytes. Blasts were detected with 75% sensitivity and 96% specificity at 1% blast threshold, and 100% sensitivity at 5% blast threshold. Immature granulocyte detection was more sensitive (81% vs 76%, P = 0.086) and specific (88% vs 78%, P = 0.0002) than with CELL-DYN Sapphire. Nucleated red blood cell detection was more sensitive (89% vs 63%, P < 0.001) and just slightly less specific (96% vs 99%, P = 0.0067) than with CELL-DYN Sapphire. Re-run and reflex testing rates were lower with Alinity hq. CONCLUSION: The Alinity hq hematology analyzer is suitable for clinical use.

Strength Endurance Training but Not Intensive Strength Training Reduces Senescence-Prone T Cells in Peripheral Blood in Community-Dwelling Elderly Women.

Aging is characterized by a progressive decline in immune function known as immunosenescence. Although the causes of immunosenescence are likely to be multifactorial, an age-associated accumulation of senescent T cells and decreased naive T-cell repertoire are key contributors to the phenomenon. On the other hand, there is a growing consensus that physical exercise may improve immune response in aging. However, the optimum training modality required to obtain beneficial adaptations in older subjects is lacking. Therefore, we aimed to investigate the effects of exercise modality on T-cell phenotypes in older women. A total of 100 women (aged ≥ 65 years) were randomized to either intensive strength training (80% of one-repetition maximum ), strength endurance training (40% one-repetition maximum), or control (stretching exercise) for 2-3 times per week during 6 weeks. The T-cell percentages and absolute counts were determined using flow cytometry and a hematology analyzer. C-reactive protein was measured using immunonephelometry. We report for the first time that 6 weeks of strength endurance training significantly decreased the basal percentage and absolute counts of senescence-prone T cells, which was positively related to the number of training sessions performed. Conceivably, training protocols with many repetitions-at a sufficiently high external resistance-might assist the reduction of senescence-prone T cells in older women.

Association Between Immunosenescence Phenotypes and Pre-frailty in Older Subjects: Does Cytomegalovirus Play a Role?

Frailty is highly prevalent in old age and confers an important mortality risk. Although the causes of frailty are multiple, immunosenescence (IS)-predominantly driven by cytomegalovirus (CMV)-has been implicated in its pathophysiology. Thus far, research examining the association between IS and frailty states is sparse and equivocal. On the other hand, evidence is mounting in support of the view that frailty can be reversed, especially for those in the pre-frail stage. Therefore, we aimed to clarify the impact of CMV on IS and its relevance to pre-frailty. One hundred seventy-three persons aged 80 to 99 years were enrolled. Pre-frailty was defined according to Fried's criteria. Anti-CMV IgG and serum IL-6 were measured using Architect iSystem and Luminex, respectively. T-cell phenotypes were determined using flow cytometry. The prevalence of pre-frailty was 52.6%, increased with age (p = .001), and was greater in men than women (p = .044). No relationship was found between pre-frailty and positive CMV serology. Further, CMV-seropositivity was significantly associated with less naïve cells, more memory and senescence-prone phenotypes (all p < .001). After adjusting for potential confounders, only IL-6, age and sex were predictive of pre-frailty. We conclude that the presence of pre-frailty is independent from CMV infection in very old subjects.

Diagnostic accuracy of the Triage D-dimer test for exclusion of venous thromboembolism in outpatients.

BACKGROUND: We evaluated the diagnostic performance of the Triage D-dimer test, a new fast quantitative point-of-care whole blood D-dimer assay and compared it with the Vidas D-dimer assay. MATERIALS AND METHODS: The study population comprised 319 outpatients for whom D-dimer testing was requested in order to rule out venous thromboembolism (VTE). Routine testing consisted of a plasma ELISA D-dimer analysis (Vidas). For all included patients, an additional EDTA whole blood D-dimer test (Triage) was performed. Patients were classified by reference imaging or by follow-up of the medical record. Accuracy indices, receiver operating characteristics and the kappa coefficient for agreement were calculated using the cutoff values recommended by the manufacturer. RESULTS: Prevalence of VTE was 14%. Sensitivity and specificity for VTE were 98% (95%CI: 88-100) and 34% (95%CI: 28-40) for Vidas and 91% (95%CI: 78-97) and 42% (95%CI: 36-48) for Triage, respectively. The differences in sensitivity and specificity between both D-dimer assays were statistically significant (McNemar, p<0.0001). ROC-curve analysis yielded an area under the curve of 0.83 (95%CI: 0.76-0.89) for the Vidas and 0.81 (95%CI: 0.74-0.88) for the Triage (p=0.396). The kappa coefficient for agreement between Vidas and Triage was 0.75 (95%CI: 0.68-0.79). CONCLUSIONS: The Triage and Vidas D-dimer tests show comparable diagnostic accuracy. Vidas showed a significant higher sensitivity. Our findings strongly suggest lowering the cutoff for the Triage D-dimer test from 400 to 350 ng/mL. In this way specificity lowers from 42 to 38%, but, more importantly, sensitivity increases from 91 to 95%.