An atlas of cells in the human tonsil.

Palatine tonsils are secondary lymphoid organs (SLOs) representing the first line of immunological defense against inhaled or ingested pathogens. We generated an atlas of the human tonsil composed of >556,000 cells profiled across five different data modalities, including single-cell transcriptome, epigenome, proteome, and immune repertoire sequencing, as well as spatial transcriptomics. This census identified 121 cell types and states, defined developmental trajectories, and enabled an understanding of the functional units of the tonsil. Exemplarily, we stratified myeloid slan-like subtypes, established a BCL6 enhancer as locally active in follicle-associated T and B cells, and identified SIX5 as putative transcriptional regulator of plasma cell maturation. Analyses of a validation cohort confirmed the presence, annotation, and markers of tonsillar cell types and provided evidence of age-related compositional shifts. We demonstrate the value of this resource by annotating cells from B cell-derived mantle cell lymphomas, linking transcriptional heterogeneity to normal B cell differentiation states of the human tonsil.

Neighborhood ethnic density and disparities in proximal blood donation opportunities.

BACKGROUND: Despite being the largest racial/ethnic minority group in the United States, Hispanic/Latinos (H/L) are significantly underrepresented among blood donors. A lack of proximal blood donation opportunities may be one factor contributing to these disparities. However, few studies have investigated this possibility. STUDY DESIGN AND METHODS: Proprietary data on mobile blood collections in Maricopa County, Arizona, were gathered for the period of January 01, 2022 to April 30, 2022 and paired with census tract information using ArcGIS. Maricopa County encompasses the city of Phoenix with a total population of approximately 4.5 million people, including 1.5 million H/L residents. Blood drive count was regressed on H/L ethnic density and total population, and model estimates were exponentiated to obtain odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: During the specified period, approximately 27,000 red blood cell units were collected through mobile drives. Consistent with expectations, when controlling for total neighborhood population, each 10% increase in H/L ethnic density lowered the odds of having a blood drive in the corresponding neighborhood by 12% (OR = 0.88, 95% CI (0.83, 0.92), p < .001). DISCUSSION: These findings provide initial evidence of fewer proximal donation opportunities in areas with greater H/L population density which may contribute to H/L underrepresentation in blood donation and the need for more inclusive collection efforts. Improved access to blood collection is modifiable and could help to increase the overall blood supply, enhance the ability to successfully match specific blood antigen needs of an increasingly diverse population, and bring about a more resilient blood system.

Experiences of using the MINDSET Self-Management mobile health app among Hispanic Patients:Results of a qualitative study.

BACKGROUND: Interventions focusing on epilepsy self-management (ESM) are vital for promoting the health of people living with epilepsy. E-technology and mobile health (mHealth) tools are becoming increasingly integrated into practice to promote self-management strategies for chronic diseases, enhance care delivery, and reduce health disparities. Management Information and Decision Support Epilepsy Tool (MINDSET), a bilingual decision support tool (available in English and Spanish), was found to be both feasible and effective in facilitating goal-based ESM in the clinic. PURPOSE: To assess the experience of using MINDSET as an ESM intervention among Hispanic patients with epilepsy to inform future interventional studies. METHODS: This study used a Qualitative Descriptive (QD) framework to provide a rich and straightforward description of patients' subjective experiences using MINDSET. Participants were enrolled in the intervention group of a larger parent study (RCT) to assess the efficacy of MINDSET among Hispanic People with Epilepsy (PWE). The purposive, convenient, criterion-based sample for this qualitative analysis comprised of 42 patients who agreed to participate in a semi-structured interview at the end of the larger RCT. This RCT was conducted between August 2017 and January 2019. Spanish and English-speaking Hispanic adult patients (n = 94) with epilepsy in Arizona (n = 53) and Texas (n = 41) were randomly assigned within 6 neurology clinics to treatment (MINDSET plus Usual Care, hereafter referred to as MINDSET; n = 46) and comparison (Usual Care Only; n = 48) conditions. RESULTS: Patient demographics, epilepsy conditions, and ESM behavioral characteristics were representative of the intervention group. Study participants were Hispanic, mainly of Mexican descent (94 %), with a mean age of 39 years, mostly female (53 %), and most of the participants reported having had one or more seizures per month (54 %). The MINDSET intervention revealed five ESM themes: (1) Awareness and Realization of Epilepsy Self-Management, (2) Communication and Partnership with Health Care Providers HCP, (3) Epilepsy Self-Management and Quality of Life, (4) Seizure Control, and (5) Optimism and Agency. CONCLUSION: The participants who used MINDSET as a self-management intervention reported an overall positive experience. Qualitative data in this study show that MINDSET is a valuable ESM tool for Hispanic patients with epilepsy. Findings from this qualitative study were consistent with results from a larger parent study that recognized MINDSET as an effective platform for improving epilepsy self-management adherence.

Preclinical evaluation of FLT190, a liver-directed AAV gene therapy for Fabry disease.

Fabry disease is an X-linked lysosomal storage disorder caused by loss of alpha-galactosidase A (α-Gal A) activity and is characterized by progressive accumulation of glycosphingolipids in multiple cells and tissues. FLT190, an investigational gene therapy, is currently being evaluated in a Phase 1/2 clinical trial in patients with Fabry disease (NCT04040049). FLT190 consists of a potent, synthetic capsid (AAVS3) containing an expression cassette with a codon-optimized human GLA cDNA under the control of a liver-specific promoter FRE1 (AAV2/S3-FRE1-GLAco). For mouse studies FLT190 genome was pseudotyped with AAV8 for efficient transduction. Preclinical studies in a murine model of Fabry disease (Gla-deficient mice), and non-human primates (NHPs) showed dose-dependent increases in plasma α-Gal A with steady-state observed 2 weeks following a single intravenous dose. In Fabry mice, AAV8-FLT190 treatment resulted in clearance of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) in plasma, urine, kidney, and heart; electron microscopy analyses confirmed reductions in storage inclusion bodies in kidney and heart. In NHPs, α-Gal A expression was consistent with the levels of hGLA mRNA in liver, and no FLT190-related toxicities or adverse events were observed. Taken together, these studies demonstrate preclinical proof-of-concept of liver-directed gene therapy with FLT190 for the treatment of Fabry disease.

Longitudinal assessment of kidney function in migrant farm workers.

Chronic kidney disease of unknown etiology (CKDu) is an epidemic that affects young agricultural workers in several warm regions of the world. However, there is a lack of monitoring of kidney issues in regions with extremely warm environments such as the Northwest of Mexico, a semi-arid region with a growing agricultural industry, where migrant and seasonal farm workers (MSFWs) travel to work in the fields. The objective of this study was to longitudinally assess kidney functioning of MSFWs in relation to pesticide exposure, heat stress and dehydration in a large-scale farm in Mexico. We enrolled 101 MSFWs, of whom 50 were randomly selected to work in an organic certified area and 51 were randomly selected to work in a conventional area. We also enrolled 50 office workers within the same region as a reference group. We collected urine and blood samples from all workers in addition to demographic, behavioral, and occupational characteristics. The physiological strain index (PSI) was used to estimate workers' heat strain. Sampling was conducted at pre-harvest (March) and late in the harvest (July). Linear mixed models were built with the estimated glomerular filtration rate (eGFR) as the dependent variable. We found a significant decrease in kidney function in MSFWs compared to office workers. By the late harvest, one MSFW developed kidney disease, two MSFWs suffered a kidney injury, and 14 MSFWs were at risk of a kidney injury. We found that the eGFR in MSFWs decreased significantly from pre-harvest (125 ± 13.0 mL/min/1.73 m2) to late harvest (109 ± 13.6 mL/min/1.73 m2) (p < 0.001), while no significant change was observed in office workers. The eGFR was significantly lower in MSFWs who worked in the conventional field (101.2 ± 19.4 mL/min/1.73 m2) vs the organic field (110.9 ± 13.6 mL/min/1.73 m2) (p = 0.002). In our final model, we found that dehydration was associated with the decrease of eGFR. We also found an interaction between heat strain and job category, as a significant decline in eGFR by job category (conventional/organic MSFWs and office workers) was related to an increase in heat strain. This suggests that pesticide exposure needs to be considered in combination with heat stress and dehydration. This study provides valuable information on kidney function in MSFWs, and it shows the importance of early long-term monitoring in farm workers in other regions where CKDu has not been evaluated yet.

Knowledge, attitude, practice and associated factors among patients with type 2 diabetes in Cotonou, Southern Benin.

BACKGROUND: Type 2 diabetes (T2D) is becoming an epidemic with significant disability and premature death in Sub-Saharan Africa, including Benin. However, little is known about the level of knowledge, attitude, and practice (KAP) necessary for diabetic patients to enhance therapeutic outcomes and prevent diabetes complications. The study aimed to assess patients' KAP levels and identify the factors associated in Cotonou, southern Benin. METHODS: A cross-sectional study was conducted from July to August 2019 among 300 diabetic patients from four health centers. Data was collected using validated questionnaires. KAP levels were determined by calculating the scores, and multivariate logistic regression was used to explore factors influencing KAP scores. RESULTS: About 53, 52, and 47% of all patients had good knowledge, attitude, and practice towards diabetes. In logistic regression, factors such as being female, married, educated, government/non-government employee, and longer duration of diabetes were significantly associated with good knowledge. Being married, having a longer duration of diabetes, and good knowledge were significantly associated with a good attitude while being educated, having a longer duration of diabetes, and good knowledge with good practice. CONCLUSIONS: Lack of knowledge, poor attitude, and inadequate practice were found in this surveyed community, suggesting a need for structured educational programs to assist diabetic patients. However, education should be considered a priority for male, newly diagnosed, and uneducated patients.

Mental health and diabetes self-management: assessing stakeholder perspectives from health centers in Northern Mexico.

BACKGROUND: People living with diabetes have an increased risk of developing mental health issues. Mexico has observed a high prevalence of people living with diabetes suffering from mental health issues, such as anxiety and depression. Self-management programs have demonstrated promise in helping participants address and prevent not only physiological health complications but mental health issues as well. This qualitative study aimed to understand the mental health benefits of a diabetes self-management intervention for health centers in Northern Mexico and opportunities for improvement through assessing stakeholder perspectives. METHODS: Trained research staff used a semi-structured questionnaire guide to conduct all interviews and focus groups from February-May 2018. Individual interviews (n = 16) were conducted face-to-face at four health center sites among all health center directors and key staff located throughout the state of Sonora. One focus group (n = 41) was conducted at each of the four health centers among intervention participants. Directed content analysis was used to establish themes by understanding relationships, identifying similar experiences, and determining patterns across datasets. RESULTS: In total 57 health center directors, health center staff, and intervention participants were involved in the interviews and focus groups across the four health centers. Overall the analysis identified four themes throughout the data, two were categorized as benefits and two as improvements. The primary themes for participant benefits were an increase in self-efficacy and social support to manage their chronic conditions. These were evident from not only participant perspectives, but health staff observations. Conversely, increased family involvement, and increased mental health integration and services within diabetes care were identified themes for opportunities to improve the intervention to be more inclusive and holistic. CONCLUSION: All stakeholders observed the benefits for intervention participants and opportunities for more inclusivity of the family and integration as well as an increase in mental health services. The themes identified demonstrated a need to more proactively enhance and utilize diabetes self-management as a means to improve mental health outcomes among people living with diabetes in Mexico. This is an opportunity to employ a more comprehensive approach to diabetes self-management, and integrate mental health services into overall diabetes care. TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier: NCT02804698 . Registered on June 17, 2016.

Therapeutic expression of human clotting factors IX and X following adeno-associated viral vector-mediated intrauterine gene transfer in early-gestation fetal macaques.

Adeno-associated viral vectors (AAVs) achieve stable therapeutic expression without long-term toxicity in adults with hemophilia. To avert irreversible complications in congenital disorders producing early pathogenesis, safety and efficacy of AAV-intrauterine gene transfer (IUGT) requires assessment. We therefore performed IUGT of AAV5 or -8 with liver-specific promoter-1 encoding either human coagulation factors IX (hFIX) or X (hFX) into Macaca fascicularis fetuses at ∼0.4 gestation. The initial cohort received 1 × 1012 vector genomes (vgs) of AAV5-hFIX ( n = 5; 0.45 × 1013 vg/kg birth weight), resulting in ∼3.0% hFIX at birth and 0.6-6.8% over 19-51 mo. The next cohort received 0.2-1 × 1013 vg boluses. AAV5-hFX animals ( n = 3; 3.57 × 1013 vg/kg) expressed <1% at birth and 9.4-27.9% up to 42 mo. AAV8-hFIX recipients ( n = 3; 2.56 × 1013 vg/kg) established 4.2-41.3% expression perinatally and 9.8-25.3% over 46 mo. Expression with AAV8-hFX ( n = 6, 3.12 × 1013 vg/kg) increased from <1% perinatally to 9.8-13.4% >35 mo. Low expressers (<1%, n = 3) were postnatally challenged with 2 × 1011 vg/kg AAV5 resulting in 2.4-13.2% expression and demonstrating acquired tolerance. Linear amplification-mediated-PCR analysis demonstrated random integration of 57-88% of AAV sequences retrieved from hepatocytes with no events occurring in or near oncogenesis-associated genes. Thus, early-IUGT in macaques produces sustained curative expression related significantly to integrated AAV in the absence of clinical toxicity, supporting its therapeutic potential for early-onset monogenic disorders.-Chan, J. K. Y., Gil-Farina I., Johana, N., Rosales, C., Tan, Y. W., Ceiler, J., Mcintosh, J., Ogden, B., Waddington, S. N., Schmidt, M., Biswas, A., Choolani, M., Nathwani, A. C., Mattar, C. N. Z. Therapeutic expression of human clotting factors IX and X following adeno-associated viral vector-mediated intrauterine gene transfer in early-gestation fetal macaques.

Non-communicable disease prevention in Mexico: policies, programs and regulations.

Non-communicable diseases (NCD), such as diabetes and cardiovascular disease, have become a leading cause of the death in Mexico. The federal government has addressed this issue through developing NCD prevention plans, regulations and policies (PRPs) that seek to address social and environmental factors, which was led by the National Institute of Public Health and Ministry of Health in concert with various non-governmental organizations. This review aims to synthesize and summarize national NCD prevention PRPs addressing social and environmental factors passed from 2010 to 2016, and to assess the extent to which these efforts successfully addressed factors contributing to the epidemic. In total nine federal NCD prevention PRPs were identified from a scan that examined executive and legislative PRPs, which identified five documents. A scoping review was conducted for evaluation studies and reports corresponding to these PRPs. The majority of PRPs focused on nutrition, specifically the access and promotion of food. Studies and reports demonstrated that taxation on energy-dense low-nutrient foods and sugar-sweetened beverages were the most effective. Other PRPs had various issues with implementation, mostly related to adherence and resources available. Overall, there lacked evidence of evaluative work on several NCD prevention PRPs, specifically assessing implementation and effectiveness. Additionally, PRPs did not sufficiently address integration of clinical, social, environmental approaches and access to physical activity. While the Mexican federal government has taken the initial steps to address the multifactorial causes of NCD, firm political commitment and investment of significant resources are still needed.

Potential limits of AAV-based gene therapy with the use of new transgenes expressing factor IX fusion proteins.

INTRODUCTION: The variety of treatment for haemophilia B (HB) has recently improved with the emergence of both AAV-based gene therapy and bioengineered human factor IX (hFIX) molecules with prolonged half-life due to fusion to either albumin (Alb) or immunoglobulin Fc fragment (Fc). AIM: Adeno-associated viral vectors (AAV) mediating expression of hFIX-Alb and hFIX-Fc fusion proteins was investigated for gene therapy of HB to explore if their extended half-life translates to higher plasma levels of FIX. METHODS: Single-stranded cross-packaged AAV2/8 vectors expressing hFIX-Alb, hFIX-Fc and hFIX were evaluated in vitro, and in mice. RESULTS: Both hFIX-Alb and hFIX-Fc fusion proteins were synthesized and expressed as single chains of expected size following AAV-mediated gene transfer in vitro and in vivo. The procoagulant properties of these hFIX-fusion proteins were comparable to wild-type hFIX. However, their expression levels were threefold lower than wild-type hFIX in vivo most likely due to inefficient secretion. CONCLUSION: This, the first, evaluation of hFIX-fusion proteins in the context of AAV gene transfer suggests that the hFIX-fusion proteins are secreted inefficiently from the liver, thus preventing their optimal use in gene therapy approaches.

Renal Cell Carcinoma Antigen Expression in Primary Cutaneous Endocrine Mucinous Carcinomas: A Case Series of 14 Patients and Review of the Literature.

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) and primary cutaneous mucinous carcinoma (PCMC) are both uncommon low-grade cutaneous adnexal tumors with predilection for the eyelids of elderly women. Their clinical appearance is nonspecific, typically presenting as a slowly growing poorly circumscribed papule, nodule, plaque, or swelling. Histological features of EMPSGC include a lobulated dermal neoplasm with bland cytology and an invasive mucinous component in up to half of the cases. PCMC exhibits tumor nests suspended in abundant pools of mucin with focal strands or nests of tumor cells infiltrating the dermis. Because of their rarity and banal cytological features, both entities pose a risk for misdiagnosis with other benign/malignant cutaneous adnexal neoplasms. Histomorphological features can suggest a diagnosis of EMPSGC or PCMC, but immunohistochemistry is necessary for confirmation. A review of the literature showed variable results of antigens present in EMPSGC, and many of the positive markers only show sparse or focal immunoreactivity of tumor cells. As a result, diffusely positive markers play a crucial role in identification of these tumors, particularly with initial superficial biopsies. We present 9 cases of EMPSGC and 5 cases of PCMC with strong and diffuse immunoreactivity to renal cell carcinoma antigen. This novel finding can be useful in the diagnosis of EMPSGC and PCMC in combination with other known positive markers to differentiate them from other cutaneous neoplasms. In addition, it provides further evidence that EMPSGC could be a precursor lesion to PCMC with both existing on a spectrum.

In Utero Transfer of Adeno-Associated Viral Vectors Produces Long-Term Factor IX Levels in a Cynomolgus Macaque Model.

The safe correction of an inherited bleeding disorder in utero prior to the onset of organ damage is highly desirable. Here, we report long-term transgene expression over more than 6 years without toxicity following a single intrauterine gene transfer (IUGT) at 0.9G using recombinant adeno-associated vector (AAV)-human factor IX (hFIX) in the non-human primate model we have previously described. Four of six treated animals monitored for around 74 months expressed hFIX at therapeutic levels (3.9%-120.0%). Long-term expression was 6-fold higher in males and with AAV8 compared to AAV5, mediated almost completely at this stage by random genome-wide hepatic proviral integrations, with no evidence of hotspots. Post-natal AAV challenge without immunosuppression was evaluated in two animals exhibiting chronic low transgene expression. The brief neutralizing immune reaction elicited had no adverse effect and, although expression was not improved at the dose administered, no clinical toxicity was observed. This long-term surveillance thus confirms the safety of late-gestation AAV-hFIX transfer and demonstrates that postnatal re-administration can be performed without immunosuppression, although it requires dose optimization for the desired expression. Nevertheless, eventual vector genotoxicity and the possibility of germline transmission will require lifelong monitoring and further evaluation of the reproductive function of treated animals.

International migration and dietary change in Mexican women from a social practice framework.

Migration from lower- and middle-income to high-income countries is associated with dietary change, and especially with the adoption of a modern, less healthy diet. In this article we analyze the dietary changes experienced by Mexican migrants, employing as a theoretical framework the concept of social practice. According to this framework, practices integrate material elements, meanings and competences that provide their conditions of possibility. Practices are shared by members of social groups, and interact with other competing or reinforcing practices. Between 2014 and 2015, we conducted semi-structured interviews with 27 women, international return migrants living in Tijuana, Mexico. The interview guide asked about history of migration and dietary change. We found three main areas of dietary change: from subsistence farming to ready meals, abundance vs. restriction, and adoption of new food items. The first one was associated with changes in food procurement and female work: when moving from rural to urban areas, participants substituted self-produced for purchased food; and as migrant women joined the labor force, consumption of ready meals increased. The second was the result of changes in income: participants of lower socioeconomic position modified the logic of food acquisition from restriction to abundance and back, depending on the available resources. The third change was relatively minor, with occasional consumption of new dishes or food items, and was associated with exposure to different cuisines and with learning how to cook them. Public health efforts to improve the migrants' diets should take into account the constitutive elements of dietary practices, instead of isolating individuals from their social contexts.

Long-term safety and efficacy of factor IX gene therapy in hemophilia B.

BACKGROUND: In patients with severe hemophilia B, gene therapy that is mediated by a novel self-complementary adeno-associated virus serotype 8 (AAV8) vector has been shown to raise factor IX levels for periods of up to 16 months. We wanted to determine the durability of transgene expression, the vector dose-response relationship, and the level of persistent or late toxicity. METHODS: We evaluated the stability of transgene expression and long-term safety in 10 patients with severe hemophilia B: 6 patients who had been enrolled in an initial phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose, and 4 additional patients who received the high dose (2×10(12) vector genomes per kilogram of body weight). The patients subsequently underwent extensive clinical and laboratory monitoring. RESULTS: A single intravenous infusion of vector in all 10 patients with severe hemophilia B resulted in a dose-dependent increase in circulating factor IX to a level that was 1 to 6% of the normal value over a median period of 3.2 years, with observation ongoing. In the high-dose group, a consistent increase in the factor IX level to a mean (±SD) of 5.1±1.7% was observed in all 6 patients, which resulted in a reduction of more than 90% in both bleeding episodes and the use of prophylactic factor IX concentrate. A transient increase in the mean alanine aminotransferase level to 86 IU per liter (range, 36 to 202) occurred between week 7 and week 10 in 4 of the 6 patients in the high-dose group but resolved over a median of 5 days (range, 2 to 35) after prednisolone treatment. CONCLUSIONS: In 10 patients with severe hemophilia B, the infusion of a single dose of AAV8 vector resulted in long-term therapeutic factor IX expression associated with clinical improvement. With a follow-up period of up to 3 years, no late toxic effects from the therapy were reported. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00979238.).

Therapeutic levels of FVIII following a single peripheral vein administration of rAAV vector encoding a novel human factor VIII variant.

Recombinant adeno-associated virus (rAAV) vectors encoding human factor VIII (hFVIII) were systematically evaluated for hemophilia A (HA) gene therapy. A 5.7-kb rAAV-expression cassette (rAAV-HLP-codop-hFVIII-N6) containing a codon-optimized hFVIII cDNA in which a 226 amino acid (aa) B-domain spacer replaced the entire B domain and a hybrid liver-specific promoter (HLP) mediated 10-fold higher hFVIII levels in mice compared with non-codon-optimized variants. A further twofold improvement in potency was achieved by replacing the 226-aa N6 spacer with a novel 17-aa peptide (V3) in which 6 glycosylation triplets from the B domain were juxtaposed. The resulting 5.2-kb rAAV-HLP-codop-hFVIII-V3 cassette was more efficiently packaged within AAV virions and mediated supraphysiologic hFVIII expression (732 ± 162% of normal) in HA knock-out mice following administration of 2 × 10(12) vector genomes/kg, a vector dose shown to be safe in subjects with hemophilia B. Stable hFVIII expression at 15 ± 4% of normal was observed at this dose in a nonhuman primate. hFVIII expression above 100% was observed in 3 macaques that received a higher dose of either this vector or the N6 variant. These animals developed neutralizing anti-FVIII antibodies that were abrogated with transient immunosuppression. Therefore, rAAV-HLP-codop-hFVIII-V3 substantially improves the prospects of effective HA gene therapy.

Service learning: a vehicle for building health equity and eliminating health disparities.

Service learning (SL) is a form of community-centered experiential education that places emerging health professionals in community-generated service projects and provides structured opportunities for reflection on the broader social, economic, and political contexts of health. We describe the elements and impact of five distinct week-long intensive SL courses focused on the context of urban, rural, border, and indigenous health contexts. Students involved in these SL courses demonstrated a commitment to community-engaged scholarship and practice in both their student and professional lives. SL is directly in line with the core public health value of social justice and serves as a venue to strengthen community-campus partnerships in addressing health disparities through sustained collaboration and action in vulnerable communities.

Adenovirus-associated virus vector-mediated gene transfer in hemophilia B.

BACKGROUND: Hemophilia B, an X-linked disorder, is ideally suited for gene therapy. We investigated the use of a new gene therapy in patients with the disorder. METHODS: We infused a single dose of a serotype-8-pseudotyped, self-complementary adenovirus-associated virus (AAV) vector expressing a codon-optimized human factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco) in a peripheral vein in six patients with severe hemophilia B (FIX activity, <1% of normal values). Study participants were enrolled sequentially in one of three cohorts (given a high, intermediate, or low dose of vector), with two participants in each group. Vector was administered without immunosuppressive therapy, and participants were followed for 6 to 16 months. RESULTS: AAV-mediated expression of FIX at 2 to 11% of normal levels was observed in all participants. Four of the six discontinued FIX prophylaxis and remained free of spontaneous hemorrhage; in the other two, the interval between prophylactic injections was increased. Of the two participants who received the high dose of vector, one had a transient, asymptomatic elevation of serum aminotransferase levels, which was associated with the detection of AAV8-capsid-specific T cells in the peripheral blood; the other had a slight increase in liver-enzyme levels, the cause of which was less clear. Each of these two participants received a short course of glucocorticoid therapy, which rapidly normalized aminotransferase levels and maintained FIX levels in the range of 3 to 11% of normal values. CONCLUSIONS: Peripheral-vein infusion of scAAV2/8-LP1-hFIXco resulted in FIX transgene expression at levels sufficient to improve the bleeding phenotype, with few side effects. Although immune-mediated clearance of AAV-transduced hepatocytes remains a concern, this process may be controlled with a short course of glucocorticoids without loss of transgene expression. (Funded by the Medical Research Council and others; ClinicalTrials.gov number, NCT00979238.).

State Medicaid expansion, community interventions, and health care disparities in a United States-Mexico border community.

OBJECTIVES: We investigated whether access to and use of health care services increased among residents of a low-income, predominantly Mexican American border community affected by the expansion of Arizona's Medicaid program in 2001 and multiple community-level programs and policies. METHODS: We used data from a probability sample of 1623 adult residents of Douglas, Arizona, who participated in cross-sectional health surveys in 1998 and 2010. Response rates were 83% and 86%, respectively. RESULTS: In 2010, participants were more likely to have a usual source of care, to have visited a provider in the previous year, and to have been screened for diabetes and hypertension and less likely to have delayed needed care or to have seen a regular provider in Mexico (P < .001 for all outcomes). Improvements in access to and use of health care were most pronounced among residents with less than a high school education, which reduced or eliminated educational disparities in health care. CONCLUSIONS: Expansion of public insurance programs can effectively reduce health care disparities when paired with other community-level policies and programs that target medically underserved populations.

Evaluation of the community-based chronic disease prevention program Meta Salud in Northern Mexico, 2011-2012.

INTRODUCTION: Meta Salud is a community health worker-facilitated intervention in Hermosillo, Sonora, Mexico, and was adapted from Pasos Adelante, a similar evidence-based intervention developed for a Latino population in the United States-Mexico border region. The objective of this study was to examine outcomes for Meta Salud and compare them with outcomes for Pasos Adelante. METHODS: This pretest-posttest study took place during 13 weeks among low-income residents of an urban area. The program provided information on topics such as heart health, physical activity, nutrition, diabetes, healthy weight, community health, and emotional well-being; included individual and group activities aimed at motivating behavior change; and encouraged participants to engage in brisk physical activity. RESULTS: We found significant decreases from baseline to conclusion in body mass index, waist circumference, hip circumference, weight, triglycerides, and low-density lipoprotein (LDL) cholesterol. From baseline to 3-month follow-up, we found significant decreases in body mass index, waist circumference, weight, LDL cholesterol, and glucose, and an increase in high-density lipoprotein cholesterol. Outcomes for Meta Salud were similar to those found for Pasos Adelante. CONCLUSION: The physiological improvements found among participants in Meta Salud and comparable changes among participants in Pasos Adelante suggest a scalable and effective behavioral intervention for regions of the United States and Mexico that share a common boundary or have similar cultural and linguistic characteristics.