This is the first report of the health economic benefits derived from preventing infections through Immunoglobulin Replacement Therapy (IgRT) in patients with secondary immunodeficiency due to ...hematological malignancies. We conducted a retrospective population-based cohort study using patient medical history and pharmacy data from the Hospital Clínico San Carlos for 21 patients between 2011 and 2020. The pharmacoeconomic impact of using prophylactic IgRT was assessed by comparing characteristics of the SID patients 1 year before and after initiating IgRT measured by direct medical and tangible indirect costs. Results indicate a marked reduction in hospitalization days following IgRT initiation, decreasing from an average of 13.9 to 6.1 days per patient, with the elimination of ICU admissions. While emergency department visits decreased significantly, the number of routine consultations remained unchanged. Notably, absenteeism from work dropped substantially. The financial analysis revealed significant reductions in medication use and fewer ancillary tests, resulting in considerable cost savings. Specifically, total expenditure dropped from €405,088.18 pre-IgRT to €295,804.42 post-IgRT—including the cost of IgRT itself at €156,309.60. Overall, the annual savings amounted to €109,283.84, validating the cost-effectiveness of IgRT in managing SID in patients with hematological cancers.
Background. Depending on the cytokine microenvironment, macrophages (M ) can adopt a proinflammatory (M1) or a profibrotic (M2) phenotype characterized by the expression of cell surface proteins such ...as CD206 and CD163 and soluble factors such as CC chemokine ligand 18 (CCL18). A key role for M in fibrosis has been observed in diverse organ settings. We studied the M population in a human model of peritoneal dialysis in which continuous stress due to dialysis fluids and recurrent peritonitis represent a risk for peritoneal membrane dysfunction reflected as ultrafiltration failure (UFF) and peritoneal fibrosis.
Methods. We used flow cytometry and quantitative reverse transcription-polymerase chain reaction to analyse the phenotype of peritoneal effluent M and tested their ability to stimulate the proliferation of human fibroblasts. M from non-infected patients were compared with those from patients with active peritonitis. Cytokine production was evaluated by enzyme-linked immunosorbent assay (ELISA) in spent dialysates and cell culture supernatants.
Results. CD206+ and CD163+ M2 were found within peritoneal effluents by flow cytometry analysis, with increased frequencies of CD163+ cells during peritonitis (P = 0.003). TGFB1, MMP9 and CCL18 messenger RNA (mRNA) levels in peritoneal macrophages (pM ) were similar to those found in M2 cells differentiated in vitro. The ability of pM to stimulate fibroblast proliferation correlated with CCL18 mRNA levels (r = 0.924, P = 0.016). CCL18 production by pM was confirmed by immunostaining of cytospin samples and ELISA. Moreover, CCL18 effluent concentrations correlated with decreased peritoneal function, which was evaluated as dialysate to plasma ratio of creatinine (r = 0.724, P < 0.0001), and were significantly higher in patients with UFF (P = 0.0025) and in those who later developed sclerosing peritonitis (P = 0.024).
Conclusions. M2 may participate in human peritoneal fibrosis through the stimulation of fibroblast cell growth and CCL18 production as high concentrations of CCL18 are associated with functional deficiency and fibrosis of the peritoneal membrane.
Peritoneal membrane failure (PMF) and, ultimately, encapsulating peritoneal sclerosis (EPS) are the most serious peritoneal dialysis (PD) complications. Combining clinical and peritoneal transport ...data with the measurement of molecular biomarkers, such as the chemokine CCL18, would improve the complex diagnosis and management of PMF. We measured CCL18 levels in 43 patients' effluent and serum at baseline and after 1, 2, and 3 years of PD treatment by retrospective longitudinal study, and evaluated their association with PMF/EPS development and peritoneal risk factors. To confirm the trends observed in the longitudinal study, a cross-sectional study was performed on 61 isolated samples from long-term (more than 3 years) patients treated with PD. We observed that the patients with no membrane dysfunction showed sustained low CCL18 levels in peritoneal effluent over time. An increase in CCL18 levels at any time was predictive of PMF development (final CCL18 increase over baseline, p = .014; and maximum CCL18 increase, p = .039). At year 3 of PD, CCL18 values in effluent under 3.15 ng/ml showed an 89.5% negative predictive value, and higher levels were associated with later PMF (odds ratio 4.3; 95% CI 0.90-20.89; p = .067). Moreover, CCL18 levels in effluent at year 3 of PD were independently associated with a risk of PMF development, adjusted for the classical (water and creatinine) peritoneal transport parameters. These trends were confirmed in a cross-sectional study of 61 long-term patients treated with PD. In conclusion, our study shows the diagnostic capacity of chemokine CCL18 levels in peritoneal effluent to predict PMF and suggests CCL18 as a new marker and mediator of this serious condition as well as a new potential therapeutic target.
Assessment of CMV-specific T cell immunity might be a useful tool in predicting CMV infection after solid organ transplantation. We have investigated CD4 and CD8 T-cell responses to CMV pp65 and IE-1 ...antigens in a prospective study of 28 CMV-seropositive kidney transplant recipients who were administered lymphocyte-depleting antibodies (Thymoglobulin®) as induction treatment and with universal prophylaxis for CMV infection. The response was analyzed by intracellular flow cytometry analysis of IFN-γ production in pretransplant samples and at 1, 6, 12 and 24 months post-transplant. Overall, only pretransplant CD4 T-cell responses to pp65 were significantly lower (p = .004) in patients with CMV replication post-transplant. ROC curve analysis showed that pre-transplant frequencies of pp65-specific CD4 + T cells below 0.10% could predict CMV infection with 75% sensitivity and 83.33% specificity (AUC: 0.847; 95% CI: 0.693–1.001; p = .0054) and seem to be mandatory for efficient control of CMV viral replication by the host immune system. In conclusion, the functional assessment of CMV-specific CD4 T-cell immunity pretransplant in seropositive patients may allow the identification of Thymoglobulin®-treated kidney transplant recipients at risk of developing CMV infection post-transplantation.
Several cases of patients with anaphylactic or systemic hypersensitivity reactions to polysulfone (PS) hemodialysis (HD) membranes and tolerance to cellulose triacetate (CTA) membranes have recently ...been reported. To investigate the mechanisms involved in PS hypersensitivity, basophil, T cell, and complement activation were analyzed in acute‐phase samples from two patients with systemic reactions to PS‐based membranes. Basophil and T cell activation, as well as higher serum tryptase levels were detected in acute‐phase samples compared with basal levels. Complement levels (C3 and C4) were decreased in acute‐phase samples from PS‐allergic patients to a higher extent than in samples from control donors taken at the same time points, indicating complement activation during the acute reactions. An experimental external circuit was established on pediatric membranes after rinsing with low or high priming volumes of saline solution, to analyze basophils, T cells, and complement activation in blood samples from 10 PS‐allergic and 8 nonallergic HD patients upon contact with PS‐based or CTA membranes. Predialysis and postdialysis samples were collected. Basophils from PS‐allergic patients exhibited increased degranulation, and T cells showed significantly increased activation after contact with PS‐based membranes primed with low volumes of saline. No activation was detected in leukocytes from nonallergic patients under the same experimental conditions. Membrane priming with high volumes of saline abrogated activation of basophils and T cells. However, basophils from allergic donors showed significantly higher responses to Fcεc stimulation after contact with PS membranes. Basophil degranulation and elevated serum tryptase levels in allergic patients during acute reactions support the systemic activation of mast cells and basophils during hypersensitivity reactions to PS‐based membranes. A leachable component of the membranes might be responsible for cell activation in some patients.
Condensed polycyclic heteroaromatic cations bearing a bridgehead nitrogen with pyridazino1′,6′:1,2pyrido3,4-bindolinium and pyridazino1,6-abenzimidazolium structures were assayed as inhibitors of ...LPS-induced TNF-α production by THP-1 cells. The hit compound 1e, which had the best IC50 value (4.49 μM) and low toxicity, was further assayed on human PMBCs (IC50 3.91 μM) and monocytes (IC50 1.82 μM). This compound also inhibited TNF-α production following poly I:C stimulation of human monocytes and monocyte-derived dendritic cells; in the latter case, inhibition of IL-12 production was also observed. Compound 1e was also able to inhibit TNF-α expression at the transcriptional level and proved to be effective in vivo. Compound 1e is an interesting potential therapeutic agent in IMIDs.
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•Synthesis of new pyridazino1′,6′:1,2pyrido3,4-bindolinium salts.•Synthesis of new pyridazino1,6-abenzimidazolium salts.•Evaluation of cell viability and inhibition of TNF-α production for the series.•IC50 of 4.49, 3.91 and 1.82 μM in THP-1, PMBCs and monocytes for 1e.•1e inhibits IL-12 production in dendritic cells and TNF-production in vivo.
The Mobilia project is facing the new challenges appearing in the forthcoming wireless communication scenarios in which one of the distinctive factors is their intrinsic and remarkable heterogeneity. ...The evolution of the technologies has brought about the possibility of having terminals equipped with different interfaces, and thus the end-user device should be able to select the most suitable from a broad range of access alternatives. This paper presents an illustrative use case, based on a businessperson who presents different communication needs while traveling through heterogeneous networking scenarios. Starting from this point, we derive a set of requirements which should be addressed by Mobilia, following the concept of always best connected. Finally, the paper presents a platform developed so as to evaluate the entities performing the mobility management, handover decision algorithms and architectural protocol extensions, as proposed in the project.
Summary
This phase I/II trial evaluated the combination of the kinesin spindle protein inhibitor filanesib with pomalidomide and dexamethasone in relapsed or refractory multiple myeloma (RRMM) ...patients. Forty‐seven RRMM patients with a median of three prior lines (2–8) and 94% refractory to lenalidomide were included: 14 in phase I and 33 in phase II. The recommended dose was 1·25 mg/m2 of filanesib on days 1, 2, 15, 16, with pomalidomide 4 mg on days 1–21 and dexamethasone 40 mg weekly. The defined threshold for success was achieved, with 18 out of 31 patients obtaining at least minor response (MR) in the phase II. In the global population, 51% of patients achieved at least partial response (PR) and 60% ≥MR, resulting in a median progression‐free survival (mPFS) of seven months and overall survival (OS) of 19 months. The main toxicity was haematological. Importantly, patients with low serum levels of alpha 1‐acid glycoprotein (AAG) at baseline (<800 mg/l) had a superior response (overall response rate of 62% vs. 17%; P = 0·04), which also translated into a longer mPFS (9 vs. 2 months; P = 0·014). In summary, filanesib with pomalidomide and dexamethasone is active in RRMM although with significant haematological toxicity. Most importantly, high levels of AAG can identify patients unlikely to respond to this strategy.
Trial registration: clinicaltrials.gov identifier: NCT02384083.
To determine the predictive factors of pulmonary thromboembolic (PTE) in patients with SARS-CoV-2 infection (COVID-19) assessed in the emergency department at a tertiary hospital during the first ...pandemic wave.
Observational single-center study conducted in a retrospective cohort of patients with confirmed SARS-CoV-2 infection (or high clinical-radiological suspicion) who underwent PTE screening by computed tomography pulmonary angiography (CTPA). Predictive factors of PTE were explored using logistic regression, creating two predictive models (without or with D-dimer values).
Out of a total of 274 CTPA performed, 70 procedures presented diagnostic findings of PTE, representing a cumulative incidence of 25.54% (95% confidence interval CI: 20.49-31.14). In the non-D-dimer based model, respiratory rate>22bpm (odds ratio OR: 3.162; 95% CI: 1.627-6.148; p=0.001) and the absence of findings suggestive of COVID-19 in plain chest X-ray (OR: 3.869; 95% CI: 0.869-17.225; p=0.076) were predictors of PTE. In the D-dimer-based model, tachypnea remained as a predictive factor (OR: 4.967; 95% CI: 2.053-12.018; p<0.001), as well as D-dimers>3,000ng/ml (OR: 7.494; 95% CI: 3.038-18.485; p<0.001).
The presence of tachypnea (>22bpm) and the absence of radiological findings suggestive of SARS-CoV-2 infection in the chest X-ray, in addition to D-dimer values>3,000 ng/mL, were identified as predictive factors of PTE in patients with COVID-19.
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