Rare variants and HLA haplotypes associated in patients with neuromyelitis optica spectrum disorders

Neuromyelitis optica spectrum disorders (NMOSD) are rare, debilitating autoimmune diseases of the central nervous system. Many NMOSD patients have antibodies to Aquaporin-4 (AQP4). Prior studies show associations of NMOSD with individual Human Leukocyte Antigen (HLA) alleles and with mutations in the complement pathway and potassium channels. HLA allele associations with NMOSD are inconsistent between populations, suggesting complex relationships between the identified alleles and risk of disease. We used a retrospective case-control approach to identify contributing genetic variants in patients who met the diagnostic criteria for NMOSD and their unaffected family members. Potentially deleterious variants identified in NMOSD patients were compared to members of their families who do not have the disease and to existing databases of human genetic variation. HLA sequences from patients from Belgrade, Serbia, were compared to the frequency of HLA haplotypes in the general population in Belgrade. We analyzed exome sequencing on 40 NMOSD patients and identified rare inherited variants in the complement pathway and potassium channel genes. Haplotype analysis further detected two haplotypes, HLA-A*01, B*08, DRB1*03 and HLA-A*01, B*08, C*07, DRB1*03, DQB1*02, which were more prevalent in NMOSD patients than in unaffected individuals. In silico modeling indicates that HLA molecules within these haplotypes are predicted to bind AQP4 at several sites, potentially contributing to the development of autoimmunity. Our results point to possible autoimmune and neurodegenerative mechanisms that cause NMOSD, and can be used to investigate potential NMOSD drug targets.Published versio

Health System, Community-Based, or Usual Dementia Care for Persons With Dementia and Caregivers

ImportanceThe effectiveness of different approaches to dementia care is unknown.ObjectiveTo determine the effectiveness of health system-based, community-based dementia care, and usual care for persons with dementia and for caregiver outcomes.Design, setting, and participantsRandomized clinical trial of community-dwelling persons living with dementia and their caregivers conducted at 4 sites in the US (enrollment June 2019-January 2023; final follow-up, August 2023).InterventionsParticipants were randomized 7:7:1 to health system-based care provided by an advanced practice dementia care specialist (n = 1016); community-based care provided by a social worker, nurse, or licensed therapist care consultant (n = 1016); or usual care (n = 144).Main outcomes and measuresPrimary outcomes were caregiver-reported Neuropsychiatric Inventory Questionnaire (NPI-Q) severity score for persons living with dementia (range, 0-36; higher scores, greater behavioral symptoms severity; minimal clinically important difference [MCID], 2.8-3.2) and Modified Caregiver Strain Index for caregivers (range, 0-26; higher scores, greater strain; MCID, 1.5-2.3). Three secondary outcomes included caregiver self-efficacy (range, 4-20; higher scores, more self-efficacy).ResultsAmong 2176 dyads (individuals with dementia, mean age, 80.6 years; 58.4%, female; and 20.6%, Black or Hispanic; caregivers, mean age, 65.2 years; 75.8%, female; and 20.8% Black or Hispanic), primary outcomes were assessed for more than 99% of participants, and 1343 participants (62% of those enrolled and 91% still alive and had not withdrawn) completed the study through 18 months. No significant differences existed between the 2 treatments or between treatments vs usual care for the primary outcomes. Overall, the least squares means (LSMs) for NPI-Q scores were 9.8 for health system, 9.5 for community-based, and 10.1 for usual care. The difference between health system vs community-based care was 0.30 (97.5% CI, -0.18 to 0.78); health system vs usual care, -0.33 (97.5% CI, -1.32 to 0.67); and community-based vs usual care, -0.62 (97.5% CI, -1.61 to 0.37). The LSMs for the Modified Caregiver Strain Index were 10.7 for health system, 10.5 for community-based, and 10.6 for usual care. The difference between health system vs community-based care was 0.25 (97.5% CI, -0.16 to 0.66); health system vs usual care, 0.14 (97.5% CI, -0.70 to 0.99); and community-based vs usual care, -0.10 (97.5% CI, -0.94 to 0.74). Only the secondary outcome of caregiver self-efficacy was significantly higher for both treatments vs usual care but not between treatments: LSMs were 15.1 for health system, 15.2 for community-based, and 14.4 for usual care. The difference between health system vs community-based care was -0.16 (95% CI, -0.37 to 0.06); health system vs usual care, 0.70 (95% CI, 0.26-1.14); and community-based vs usual care, 0.85 (95% CI, 0.42 to 1.29).Conclusions and relevanceIn this randomized trial of dementia care programs, no significant differences existed between health system-based and community-based care interventions nor between either active intervention or usual care regarding patient behavioral symptoms and caregiver strain.Trial registrationClinicalTrials.gov Identifier: NCT03786471

Ideas para el Desarrollo en las Américas (IDEA): Volumen 28: Mayo - Agosto, 2012: Financiamiento de la familia

Esta edición de IDEA se enfoca sobre el impacto que las remesas ejercen sobre la calidad de vida de sus receptores y en general sobre la economía de países centroamericanos teniendo en cuenta factores como la recesión económica estadounidense. La presente edición se basa en el próximo libro del BID titulado "Financiamiento de la familia: remesas a Centroamérica en tiempos de crisis" .

Ideas for Development in the Americas (IDEA): Volume 27: January-April, 2012: The Skills Gap: Teens in the Workforce

This edition of IDEA focuses on secondary education in Latin America and examines the serious mismatch between what employers are seeking in terms of knowledge and skills, and what young people are actually learning in the region`s schools. It draws on the findings of a new IDB book, Disconnected: Skills, Education and Employment in Latin America, and what they imply for public policy in education throughout the region.

Abstract 5632: Immunoprotected, microencapsulated bacterial cytosine deaminase mediated conversion of 5-fluorocytosine to 5-fluorouracil

Abstract Introduction Enzymes of non-human origin possess tremendous potential as anticancer agents, especially in enzyme-prodrug therapy. Unfortunately, these enzymes are recognized as foreign agents by the human immune system and are targeted by an immune response. This immune reaction limits enzymes’ efficacy, particularly in treatments requiring repeated dosing. Current strategies for deimmunizing these therapeutic enzymes are labor/time intensive and yield limited success. Encapsulating enzymes in a hydrogel, such as sodium alginate, can confer immunoprotection and enhance in vivo stability. Alginate serves as a barrier between enzyme and host and its porosity can be controlled to prevent antibody infiltration while allowing the diffusion of the prodrug and the drug. The bacterial enzyme cytosine deaminase (bCD) mediates the conversion of 5-fluorocytosine (5-FC) to the anticancer drug 5-fluorouracil (5-FU). We encapsulated the bCD in sodium alginate microbeads and tested enzyme efficacy post encapsulation as determined by conversion of 5-FC to 5-FU, with concomitant cell kill assays. Methods bCD was encapsulated in sodium alginate microbeads, ∼200 microns, using a NISCO microencapsulation system (www.nisco.ch). The beads were incubated with 5-FC (25, 50, 100 and 200 microM), and conversion to 5-FU was monitored over time using spectrophotometry. Unencapsulated bCD was used as controls. Then, microbeads were incubated with 9L rat glioma cells in the presence of 5-FC. Cytotoxicity of the enzyme-prodrug system to 9L cells was evaluated using an MTT assay. 5-FC alone in the absence of bCD and 5-FU were used as controls. Experiments were repeated using beads stored for 72 h at 4°C and 37°C and temperature effects on the stability of encapsulated bCD were noted. Results summary We observed the complete conversion of 5-FC to 5-FU for all concentrations of encapsulated enzyme, albeit at a slower rate than unencapsulated controls. Cytotoxicity of the encapsulated enzyme-prodrug system toward 9L cells was similar to that of 5-FU alone, and of unencapsulated controls, indicating that encapsulation had no deleterious effect on enzyme efficacy. Though the enzyme kinetics were slower for the stored beads (at 4°C and 37°C), these beads resulted in similar cell kill. Our results suggest that sodium alginate microencapsulation of bCD maintained the enzyme's functionality and may therefore be a suitable platform for immunoisolative enzyme-prodrug therapy. We are extending our work to other cancer cell lines and to in vivo study of the anti-tumor effects of these encapsulated enzymes. This system has the advantage of localized 5-FC to 5-FU conversion, thereby potentially reducing systemic toxicity and increasing the locally available dose of the toxic drug. The strategy can be extended to the encapsulation of enzyme-producing cells that serve as de novo drug factories. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5632. doi:1538-7445.AM2012-5632</jats:p