Extracellular vesicles from pluripotent stem cell-derived mesenchymal stem cells acquire a stromal modulatory proteomic pattern during differentiation

Mesenchymal stem/stromal cells (MSCs) obtained from pluripotent stem cells (PSCs) constitute an interesting alternative to classical MSCs in regenerative medicine. Among their many mechanisms of action, MSC extracellular vesicles (EVs) are a potential suitable substitute for MSCs in future cell-free-based therapeutic approaches. Unlike cells, EVs do not elicit acute immune rejection, and they can be produced in large quantities and stored until ready to use. Although the therapeutic potential of MSC EVs has already been proven, a thorough characterization of MSC EVs is lacking. In this work, we used a label-free liquid chromatography tandem mass spectrometry proteomic approach to identify the most abundant proteins in EVs that are secreted from MSCs derived from PSCs (PD-MSCs) and from their parental induced PSCs (iPSCs). Next, we compared both datasets and found that while iPSC EVs enclose proteins that modulate RNA and microRNA stability and protein sorting, PD-MSC EVs are rich in proteins that organize extracellular matrix, regulate locomotion, and influence cell–substrate adhesion. Moreover, compared to their respective cells, iPSCs and iPSC EVs share a greater proportion of proteins, while the PD-MSC proteome appears to be more specific. Correlation and principal component analysis consistently aggregate iPSCs and iPSC EVs but segregate PD-MSC and their EVs. Altogether, these findings suggest that during differentiation, compared with their parental iPSC EVs, PD-MSC EVs acquire a more specific set of proteins; arguably, this difference might confer their therapeutic properties.Fil: la Greca, Alejandro Damián. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Solari, Claudia María. Ministerio de Ciencia. Tecnología e Innovación Productiva. Agencia Nacional de Promoción Científica y Tecnológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Furmento, Verónica Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lombardi, Antonella. Universidad de Buenos Aires; ArgentinaFil: Biani, María Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Aban, Cyntia Estefania. Ministerio de Ciencia. Tecnología e Innovación Productiva. Agencia Nacional de Promoción Científica y Tecnológica; ArgentinaFil: Moro, Lucía Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: García, Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Guberman, Alejandra Sonia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Sevlever, Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Miriuka, Santiago Gabriel. Universidad Nacional de La Plata; ArgentinaFil: Luzzani, Carlos Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Global, regional, and national burden of meningitis, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

Zunt JR, Kassebaum NJ, Blake N, et al. Global, regional, and national burden of meningitis, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurology. 2018;17(12):1061-1082.Background Acute meningitis has a high case-fatality rate and survivors can have severe lifelong disability. We aimed to provide a comprehensive assessment of the levels and trends of global meningitis burden that could help to guide introduction, continuation, and ongoing development of vaccines and treatment programmes. Methods The Global Burden of Diseases, Injuries, and Risk Factors (GBD) 2016 study estimated meningitis burden due to one of four types of cause: pneumococcal, meningococcal, Haemophilus influenzae type b, and a residual category of other causes. Cause-specific mortality estimates were generated via cause of death ensemble modelling of vital registration and verbal autopsy data that were subject to standardised data processing algorithms. Deaths were multiplied by the GBD standard life expectancy at age of death to estimate years of life lost, the mortality component of disability-adjusted life-years (DALYs). A systematic analysis of relevant publications and hospital and daims data was used to estimate meningitis incidence via a Bayesian meta-regression tool. Meningitis deaths and cases were split between causes with meta-regressions of aetiological proportions of mortality and incidence, respectively. Probabilities of long-term impairment by cause of meningitis were applied to survivors and used to estimate years of life lived with disability (YLDs). We assessed the relationship between burden metrics and Socio-demographic Index (SDI), a composite measure of development based on fertility, income, and education. Findings Global meningitis deaths decreased by 21.0% from 1990 to 2016, from 403 012 (95% uncertainty interval [UI] 319426-458 514) to 318 400 (265 218-408 705). Incident cases globally increased from 2.50 million (95% UI 2.19-2.91) in 1990 to 2.82 million (2.46-3.31) in 2016. Meningitis mortality and incidence were dosely related to SDI. The highest mortality rates and incidence rates were found in the peri-Sahelian countries that comprise the African meningitis belt, with six of the ten countries with the largest number of cases and deaths being located within this region. Haemophilus influenzae type b was the most common cause of incident meningitis in 1990, at 780 070 cases (95% UI 613 585-978 219) globally, but decreased the most (-494%) to become the least common cause in 2016, with 397 297 cases (291076-533 662). Meningococcus was the leading cause of meningitis mortality in 1990 (192833 deaths [95% UI 153 358-221 503] globally), whereas other meningitis was the leading cause for both deaths (136 423 [112 682-178 022]) and incident cases (1.25 million [1.06-1.49]) in 2016. Pneumococcus caused the largest number of YLDs (634458 [444 787-839 749]) in 2016, owing to its more severe long-term effects on survivors. Globally in 2016, 1.48 million (1.04-1.96) YLDs were due to meningitis compared with 21.87 million (18.20-28.28) DALYs, indicating that the contribution of mortality to meningitis burden is far greater than the contribution of disabling outcomes. Interpretation Meningitis burden remains high and progress lags substantially behind that of other vaccine-preventable diseases. Particular attention should be given to developing vaccines with broader coverage against the causes of meningitis, making these vaccines affordable in the most affected countries, improving vaccine uptake, improving access to low-cost diagnostics and therapeutics, and improving support for disabled survivors. Substantial uncertainty remains around pathogenic causes and risk factors for meningitis. Ongoing, active cause-specific surveillance of meningitis is crucial to continue and to improve monitoring of meningitis burdens and trends throughout the world. Copyright (C) The Author(s). Published by Elsevier Ltd

The Efficacy of Passive Valve Antimicrobial Swab Caps Against Existing Clabsi Prevention Bundle in an Adult Hematology Inpatient Population: A Quality Improvement Initiative

Background: Central line associated blood stream infections (CLABSI) have been the costliest of all healthcare associated infections. The average CLABSI cost is approximately 46,000 (Haddadin & Regunath, 2019). Most cases may be preventable with utilization of aseptic techniques, surveillance, and management through local protocols. The majority of CLABSI occur more than five days after central vascular access (CVA); therefore, there has been a growing focus on central line handling and maintenance techniques. CLABSI prevention data has been largely focused on the intensive care unit (ICU) patient population where an average of about half of patients have CVA. There have been few studies exploring the rates of CLABSI in the adult hematology population, a population with unique risk factors due to their immunosuppressing treatments and prolonged immunocompromised states. There has been emerging data that suggests the use of new technology in addition to existing central line maintenance recommendations by the Center for Disease Control may further reduce the rate of CLABSI occurrences in high-risk patient populations. Aim: To determine the efficacy of passive valve antimicrobial swab caps on the reduction of CLABSI in an inpatient hematology patient population when compared to current existing local practices. Outcomes of reported incidents of CLABSI have been evaluated against pre-interventional data for this setting. Methods: Retrospective analysis of medical records from January 2016 - September 2019 identified the existing rate of CLABSI occurrence among inpatient hematology patients at a single institution. We utilized the intervention of antimicrobial swab caps for 10 months and tracked the rate of CLABSI during this time. The nursing staff were educated on the quality improvement project, the use of the new equipment, and expectations that existing standard practices per local policy for CLABSI prevention bundles would be adhered to prior to the start of the intervention. To evaluate the impact of the antimicrobial swab caps on the rate of CLABSI we compared the number of infections pre- and post-intervention. Randomized audits, including chart reviews for compliance with existing standard CLABSI bundle practices were performed during the initial 3 months of the intervention. Results: Prior to the introduction of the passive valve antimicrobial swab cap to the existing CLABSI prevention protocol, CLABSI rates on the hematology unit exceeded the standardized infection ratio 75th percentile on 9 of the previous 15 calendar quarters. The intervention was observed for 6,674 central line days. The CLABSI rate during the intervention was 0.4495 per 1,000 central line days. The CLABSIs identified were due to nosocomial opportunistic infection in setting of immunosuppressed status (66%) and gastrointestinal translocation (33%). The common diagnosis in setting of CLABSI was refractory/relapse diffuse large B-cell lymphoma (66%) and active acute myeloid leukemia (33%). The two patients who were diagnosed with CLABSI were neutropenic with an absolute neutrophil count of 0 at time of CLABSI diagnosis. The organisms identified at time of CLABSI diagnosis were Clostridium ramosom, Enterococcus faecium, Staphylococcus epidermisis, and Candida parapsilosis. When considering the cost of a CLABSI to be about 46,000 per event and the annual cost for the inpatient hematology unit\u27s use of the caps of approximately $19,710, the implementation of the antimicrobial swab cap reduced the cost associated with CLASBI in the hematology unit by approximately$26,290 annually. Conclusions: The introduction of the passive valve antimicrobial swab caps appears to demonstrate potential for reduced costs due to CLABSI when implemented into current CLABSI prevention bundles. This resulted in a 25% reduction in rates of CLABSI in the adult hematology patient population when compared to the previous year. The prevention of CLABSI in hematology patients with central vascular access remains challenging, however, standardized protocols for CLABSI prevention and use of antimicrobial swab caps may help further reduce the rate of CLABSI in hematology patients

Acalabrutinib Plus RICE Followed By Autologous Hematopoietic Cell Transplantation and/or Acalabrutinib Maintenance Therapy for Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Background: Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) often have a poor prognosis despite therapies using second-line chemoimmunotherapy. Achievement of CR with second-line therapy is associated with improved long-term outcomes. Unfortunately, only 25-35% of patients achieve complete response (CR) with RICE chemotherapy alone. The addition of novel targeted agents such as Bruton Tyrosine Kinase inhibitors (BTKi) to second-line therapy may offer improved treatment responses given the importance of B-cell receptor (BCR) signaling in DLBCL. BTK has been shown to be essential for BCR-mediated activation of the NF- κB/Rel family of transcription factors and BCR signaling has been recognized as a key pathway in the pathogenesis of DLBCL. Moreover, NF-κB activity relies upon chronic active BCR signaling in activated B-cell-like DLBCL, which can be potentially blocked by kinase inhibitors targeting BTK. The goal of this study is to examine the feasibility and efficacy of adding the BTKi, acalabrutinib, to standard second-line therapy as a means to improve disease response. Establishing the feasibility of combining acalabrutinib with RICE chemotherapy in autologous hematopoietic cell transplantation (HCT) eligible and HCT ineligible patients with R/R DLBCL may provide the foundation for a larger study of efficacy and long-term outcomes of the combination therapy for patients with R/R DLBCL. Study Design and Methods: The primary objective of this phase 2 trial is to evaluate the tolerability, feasibility, and efficacy of combining acalabrutinib with RICE as second line therapy in R/R DLBCL patients. There are two study cohorts. Cohort A is open to R/R DLBCL patients who are eligible for autologous HCT. Cohort B is open to R/R DLBCL patients who are considered medically ineligible for autologous HCT. The primary endpoint for cohort A is to estimate the confirmed CR rate (RECIL 2017 criteria) prior to HCT in patients undergoing second-line therapy. The primary endpoint for cohort B is defined as the estimate of one-year progression-free survival in patients undergoing second-line induction and maintenance acalabrutinib therapy. Secondary endpoints include assessment of the proportion of patients completing 3 cycles of acalabrutinib with RICE and proceeding with HCT or 2 additional cycles of maintenance acalabrutinib for HCT ineligible patients, overall response rate, incidence of Grade 3/4 adverse events, and incidence of SAEs. Patients in cohort A receive 2 cycles of standard RICE salvage chemoimmunotherapy in combination with acalabrutinib, 100mg BID day 1-21 of a 21 day cycle. After 2 cycles of therapy, patients in cohort A undergo autologous stem cell mobilization and collection. Patients then receive a 3rd cycle of RICE in combination with acalabrutinib. PET-CT (PET3) is performed 14-21 days after day 1 of cycle 3 to assess response. Those patients with CR or partial response (PR) after PET3 proceed to autologous HCT with BEAM conditioning within 28-42 days of PET3. After adequate hematopoietic recovery, patients restart acalabrutinib 100mg BID as maintenance therapy for a period of 12 additional months. Patients in cohort B receive 3 cycles of RICE salvage chemoimmunotherapy in combination with acalabrutinib 100mg BID day 1-21 of a 21-day cycle followed by PET-CT (PET3) 14-21 days after start of Cycle 3. Patients without progressive disease at PET3 continue with acalabrutinib maintenance up to 12 additional cycles until disease progression or unacceptable toxicity. Patients demonstrating progressive disease are withdrawn from study treatment but their outcomes continue to be recorded and will be included in the final data analysis. Historical outcomes from completed, published prospective clinical trials using RICE chemoimmunotherapy serve as a reference for statistical calculations. This trial is currently ongoing and additional information can be found on clinicaltrials.gov NCT listing NCT0373661

Initial Efficacy and Safety of Acalabrutinib Plus RICE in Transplant Eligible Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Background: Patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) undergoing second-line chemoimmunotherapy (2L CIT) often have a poor prognosis with a minority achieving curative outcomes. Achievement of CR with 2L CIT is associated with favorable long-term outcomes in patients consolidated with autologous stem cell transplant (ASCT). Unfortunately, only 25-35% of patients achieve complete response (CR/CR unconfirmed) with RICE CIT (Gisselbrecht 2010). Addition of novel targeted agents such as Bruton Tyrosine Kinase inhibitors (BTKi) to 2L CIT may offer improved treatment responses given the importance of B-cell receptor (BCR) signaling in DLBCL. Here we report the feasibility and efficacy of combining acalabrutinib (acala) 100mg BID with RICE (A-RICE) chemotherapy in ASCT eligible pts with R/R DLBCL. Study Design and Methods: In a single-center, open-label, phase 2 trial (NCT03736616) we evaluate the feasibility, efficacy, and tolerability of combining acala with RICE as 2L CIT in R/R DLBCL pts. There are two study cohorts. Cohort A is open to R/R DLBCL pts who are eligible for 2L CIT followed by ASCT consolidation. Cohort B is open to R/R DLBCL pts considered medically ineligible for ASCT. The primary objective for cohort A is to estimate the confirmed CR rate (RECIL 2017 criteria) of A-RICE prior to HCT. Primary endpoint for cohort A is met if \u3e10 of maximum 24 enrolled patients achieve CR, which allows rejection of the null hypothesis that confirmed CR rate is ≤ 25% if true CR rate is 50% (one-sided α =0.05, power = 85%). The primary endpoint for cohort B is the estimate of one-year progression-free survival in patients undergoing 2L CIT followed by maintenance acala for up to 12 months. Secondary endpoints include overall response rate (ORR), incidence of Grade 3/4 adverse events (AEs), and incidence of serious AEs in both cohorts. Pts in cohort A received 2 cycles of A-RICE in a 21 day cycle. After 2 cycles A-RICE, response assessment via PET-CT (PET2) was completed with responding patients receiving a 3rd cycle of A-RICE followed by stem cell mobilization and collection. PET-CT was performed 14-21 days after day 1 of cycle 3 (PET3) to assess response to 2L CIT. Those patients with CR or partial response (PR) after PET3 proceeded to BEAM conditioned ASCT within 28-42 days of PET3. After hematopoietic recovery, patients may continue acalabrutinib 100mg BID as maintenance therapy for 12 months post ASCT. Minimal residual disease (MRD) is assessed using ctDNA (clonoseq) at time points pre-ASCT, post-ASCT, and during maintenance A. Results: Primary endpoint for Cohort A has been met and is reported here, while Cohort B has not yet met pre-specified enrollment or follow up maturity for efficacy analyses. Safety for both cohorts to date is reported. Twenty-six pts have been enrolled (19 cohort A, 7 cohort B). In Cohort A, 5 pts had refractory DLBCL, 7 pts were GCB, 10 non-GCB. Median age of Cohort A was 58, and median of Cohort B was 75 (Table 1). 19 Cohort A pts received at least 1 cycle of A-RICE, with 16 pts completing 3 cycles. One patient (4%) stopped A-RICE due to AE, 3 patients (13%) discontinued due to progressive disease (PD). All 19 pts in cohort A were considered response evaluable following initiation A-RICE: ORR was 74% (14 pts), with 53% CR (10 pts), 21% PR (4 pts). Thirteen pts (68%) underwent planned consolidative ASCT. See Figure 1 for response data. Safety data for all 26 cohort A and B patients who received at least 1 cycle A-RICE was assessed for the first three cycles of A-RICE. The most common treatment-related AEs were thrombocytopenia (All 50%, Gr 3/4 46%) and neutropenia (Gr 3/4 30%). SAEs were reported in 5 pts with 1 therapy related SAE of neutropenic fever, and 4 treatment unrelated SAEs. Of the 19 efficacy evaluable pts in cohort A, 10 pts interrupted 1 or more doses of acalabrutinib during a A-RICE cycle either due to patient error or protocol specified dose hold related to AE. Conclusions: A-RICE in ASCT eligible pts w/ R/R DLBCL demonstrated CR in 53% of response evaluable patients. Further, we observed a high ORR (74%) and high proportion of pts completing planned ASCT (68%). AEs with A-RICE were consistent with those expected for CIT. A-RICE warrants further investigation in pts w/ R/R DLBCL eligible for 2L CIT with intention to undergo ASCT. Further analyses of cohort A, including ctDNA based MRD dynamics, PFS, and OS are ongoing and will be updated at meeting

A Hundred Key Questions for the Post-2015 Development Agenda

Marcia Vera Espinoza - ORCID: 0000-0001-6238-7683 https://orcid.org/0000-0001-6238-7683Item not available in this repository.This project was financially supported by SIID, the University of Sheffield’s Research and Innovation Services (R&IS), and the Innovation, Impact and Knowledge Exchange (IIKE) programme.https://www.unrisd.org/en/library/publications/a-hundred-key-questions-for-the-post-2015-development-agendapubpu