Atlas of Mexican Triatominae (Reduviidae: Hemiptera) and vector transmission of Chagas disease.

Chagas disease is one of the most important yet neglected parasitic diseases in Mexico and is transmitted by Triatominae. Nineteen of the 31 Mexican triatomine species have been consistently found to invade human houses and all have been found to be naturally infected with Trypanosoma cruzi. The present paper aims to produce a state-of-knowledge atlas of Mexican triatomines and analyse their geographic associations with T. cruzi, human demographics and landscape modification. Ecological niche models (ENMs) were constructed for the 19 species with more than 10 records in North America, as well as for T. cruzi. The 2010 Mexican national census and the 2007 National Forestry Inventory were used to analyse overlap patterns with ENMs. Niche breadth was greatest in species from the semiarid Nearctic Region, whereas species richness was associated with topographic heterogeneity in the Neotropical Region, particularly along the Pacific Coast. Three species, Triatoma longipennis, Triatoma mexicana and Triatoma barberi, overlapped with the greatest numbers of human communities, but these communities had the lowest rural/urban population ratios. Triatomine vectors have urbanised in most regions, demonstrating a high tolerance to human-modified habitats and broadened historical ranges, exposing more than 88% of the Mexican population and leaving few areas in Mexico without the potential for T. cruzi transmission.

Atlas of Mexican Triatominae (Reduviidae: Hemiptera) and vector transmission of Chagas disease

Chagas disease is one of the most important yet neglected parasitic diseases in Mexico and is transmitted by Triatominae. Nineteen of the 31 Mexican triatomine species have been consistently found to invade human houses and all have been found to be naturally infected with Trypanosoma cruzi. The present paper aims to produce a state-of-knowledge atlas of Mexican triatomines and analyse their geographic associations with T. cruzi, human demographics and landscape modification. Ecological niche models (ENMs) were constructed for the 19 species with more than 10 records in North America, as well as for T. cruzi. The 2010 Mexican national census and the 2007 National Forestry Inventory were used to analyse overlap patterns with ENMs. Niche breadth was greatest in species from the semiarid Nearctic Region, whereas species richness was associated with topographic heterogeneity in the Neotropical Region, particularly along the Pacific Coast. Three species, Triatoma longipennis, Triatoma mexicana and Triatoma barberi, overlapped with the greatest numbers of human communities, but these communities had the lowest rural/urban population ratios. Triatomine vectors have urbanised in most regions, demonstrating a high tolerance to human-modified habitats and broadened historical ranges, exposing more than 88% of the Mexican population and leaving few areas in Mexico without the potential for T. cruzi transmission.

Disparities in uptake of BRCA1/2 genetic testing in a randomized trial of telephone counseling.

PURPOSE: As genetic counseling and testing become more fully integrated into clinical care, alternative delivery models are increasingly prominent. This study examines predictors of genetic testing for hereditary breast/ovarian cancer among high-risk women in a randomized trial of in-person versus telephone-based genetic counseling. METHODS: Methods include multivariable logistic regression and interaction analyses. RESULTS: Of the 669 participants, 600 completed counseling and 523 received test results. As previously reported, participants randomized to telephone counseling were significantly less likely to be tested. In intention-to-treat analyses, completion of counseling and testing was associated with: race/ethnicity (odds ratio (OR) = 1.96, 95% confidence interval (CI): 1.20-3.20), perceived stress (OR = 0.89, 95% CI: 0.81-0.98), knowledge (OR = 1.12, 95% CI: 1.02-1.23), and randomization group (OR = 1.48, 95% CI: 1.01-2.16). Further, race/ethnicity moderated the association between randomization group and testing; minority women receiving telephone counseling were least likely to complete testing. CONCLUSION: Evidence for logistical and communication-based explanations for this interaction is presented. The overall increased access made possible with telephone genetic counseling should be considered in light of the possibility that this may also lead to lower rates of testing among high-risk minority women. Additional care should be taken to assess and address potential barriers when services are delivered by telephone.Genet Med 17 6, 467-475.

Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations.

Germline loss-of-function mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) cause immunodeficiency, whereas somatic gain-of-function mutations in STAT3 are associated with large granular lymphocytic leukemic, myelodysplastic syndrome, and aplastic anemia. Recently, germline mutations in STAT3 have also been associated with autoimmune disease. Here, we report on 13 individuals from 10 families with lymphoproliferation and early-onset solid-organ autoimmunity associated with 9 different germline heterozygous mutations in STAT3. Patients exhibited a variety of clinical features, with most having lymphadenopathy, autoimmune cytopenias, multiorgan autoimmunity (lung, gastrointestinal, hepatic, and/or endocrine dysfunction), infections, and short stature. Functional analyses demonstrate that these mutations confer a gain-of-function in STAT3 leading to secondary defects in STAT5 and STAT1 phosphorylation and the regulatory T-cell compartment. Treatment targeting a cytokine pathway that signals through STAT3 led to clinical improvement in 1 patient, suggesting a potential therapeutic option for such patients. These results suggest that there is a broad range of autoimmunity caused by germline STAT3 gain-of-function mutations, and that hematologic autoimmunity is a major component of this newly described disorder. Some patients for this study were enrolled in a trial registered at www.clinicaltrials.gov as #NCT00001350.

Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K.

Class IA phosphatidylinositol 3-kinases (PI3K), which generate PIP3 as a signal for cell growth and proliferation, exist as an intracellular complex of a catalytic subunit bound to a regulatory subunit. We and others have previously reported that heterozygous mutations in PIK3CD encoding the p110δ catalytic PI3K subunit cause a unique disorder termed p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI) disease. We report four patients from three families with a similar disease who harbor a recently reported heterozygous splice site mutation in PIK3R1, which encodes the p85α, p55α, and p50α regulatory PI3K subunits. These patients suffer from recurrent sinopulmonary infections and lymphoproliferation, exhibit hyperactive PI3K signaling, and have prominent expansion and skewing of peripheral blood CD8(+) T cells toward terminally differentiated senescent effector cells with short telomeres. The PIK3R1 splice site mutation causes skipping of an exon, corresponding to loss of amino acid residues 434-475 in the inter-SH2 domain. The mutant p85α protein is expressed at low levels in patient cells and activates PI3K signaling when overexpressed in T cells from healthy subjects due to qualitative and quantitative binding changes in the p85α-p110δ complex and failure of the C-terminal region to properly inhibit p110δ catalytic activity.

Discussing race-related limitations of genomic testing for colon cancer risk: implications for education and counseling.

This study examines communication about limitations of genomic results interpretation for colon cancer risk during education and counseling of minority participants. As part of a larger study conducted from 2010 to 2012, participants recruited from a large primary care clinic were offered testing for a research panel of 3 genomic markers (single nucleotide polymorphisms or SNPs) for colorectal cancer risk. Genetic counselors conducted pre- and post-test sessions which included discussion of limitations of result interpretation due to the lack of racial/ethnic diversity in research populations from which risk data are derived. Sessions were audio-recorded, transcribed and thematically analyzed. Many participants did not respond directly to this limitation. Among the participants that responded directly to this race-related limitation, many responses were negative. However, a few participants connected the limited minority information about SNPs with the importance of their current research participation. Genetic counselor discussions of this limitation were biomedically focused with limited explanations for the lacking data. The communication process themes identified included: low immediacy (infrequent use of language directly involving a participant), verbal dominance (greater speaking ratio of the counselor to the patient) and wide variation in the degree of interactivity (or the amount of turn-taking during the discussion). Placed within the larger literature on patient-provider communication, these present results provide insight into the dynamics surrounding race-related educational content for genomic testing and other emerging technologies. Clinicians may be better able to engage patients in the use of new genomic technology by increasing their awareness of specific communication processes and patterns during education or counseling sessions.

Translational Genomic Research: Protocol Development and Initial Outcomes following SNP Testing for Colon Cancer Risk.

Although single nucleotide polymorphism (SNP) testing for disease susceptibility is commercially available, translational studies are necessary to understand how to communicate genomic information and potential implications for public health. We explored attitudes about and initial responses to genomic testing for colon cancer risk. Following development of the educational materials, we offered testing for three colon cancer SNPs in a pilot study with primary care patients. Participants completed pre- and post-test sessions and interviews. We analyzed interview transcripts with qualitative software using thematic analysis. All 20 participants opted for SNP testing. Qualitative analysis identified several themes: Motivations for SNP Testing, Before/After: Meaning of Results, Emotional Responses to SNP Results and Genomic Literacy/ Information Delivery. Results demonstrate that individuals will pursue SNP testing in the context of pre and post-test education. SNP results may influence health behaviors like healthy eating and exercise yet did not appear to impact colon cancer screening intentions.

Behavioral and psychosocial responses to genomic testing for colorectal cancer risk.

We conducted a translational genomic pilot study to evaluate the impact of genomic information related to colorectal cancer (CRC) risk on psychosocial, behavioral and communication outcomes. In 47 primary care participants, 96% opted for testing of three single nucleotide polymorphisms (SNPs) related to CRC risk. Participants averaged 2.5 of 6 possible SNP risk alleles (10% lifetime risk). At 3-months, participants did not report significant increases in cancer worry/distress; over half reported physical activity and dietary changes. SNP risk scores were unrelated to behavior change at 3-months. Many participants (64%) shared their SNP results, including 28% who shared results with a physician. In this pilot, genomic risk education, including discussion of other risk factors, appeared to impact patients' health behaviors, regardless of the level of SNP risk. Future work can compare risk education with and without SNP results to evaluate if SNP information adds value to existing approaches.

Patient reactions to personalized medicine vignettes: an experimental design.

PURPOSE: Translational investigation on personalized medicine is in its infancy. Exploratory studies reveal attitudinal barriers to "race-based medicine" and cautious optimism regarding genetically personalized medicine. This study describes patient responses to hypothetical conventional, race-based, or genetically personalized medicine prescriptions. METHODS: Three hundred eighty-seven participants (mean age = 47 years; 46% white) recruited from a Baltimore outpatient center were randomized to this vignette-based experimental study. They were asked to imagine a doctor diagnosing a condition and prescribing them one of three medications. The outcomes are emotional response to vignette, belief in vignette medication efficacy, experience of respect, trust in the vignette physician, and adherence intention. RESULTS: Race-based medicine vignettes were appraised more negatively than conventional vignettes across the board (Cohen's d = -0.51-0.57-0.64, P < 0.001). Participants rated genetically personalized comparably with conventional medicine (-0.14-0.15-0.17, P = 0.47), with the exception of reduced adherence intention to genetically personalized medicine (Cohen's d = -0.38-0.41-0.44, P = 0.009). This relative reluctance to take genetically personalized medicine was pronounced for racial minorities (Cohen's d = -0.38-0.31-0.25, P = 0.02) and was related to trust in the vignette physician (change in R = 0.23, P < 0.001). CONCLUSIONS: This study demonstrates a relative reluctance to embrace personalized medicine technology, especially among racial minorities, and highlights enhancement of adherence through improved doctor- patient relationships.