• Germline gain-of-function mutations in STAT3 lead to lymphoproliferation and autoimmunity with prominent cytopenias.• Mutations in STAT3 cause altered regulatory T cells and cytokine signaling.Germline loss-of-function mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) cause immunodeficiency, whereas somatic gain-offunction 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. (Blood. 2015;125(4):591-599)

Lucas et al. identify humans with a gain-of-function mutation in PIK3R1, encoding the p85α subunit of PI3K. The splice site mutation causes in-frame skipping of exon 11, resulting in altered p85α association with p110δ that stabilizes the catalytic subunit but fails to properly inhibit catalytic activity. The patients have immunodeficiency and lymphoproliferation with skewing of CD8+ T cells toward terminally differentiated and senescent effector cells that have shortened telomeres.

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.

PurposeAs 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 vs. telephone-based genetic counseling.MethodsMethods include multivariable logistic regression and interaction analyses.ResultsOf 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 (OR = 1.96, 95% 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, where minority women receiving telephone counseling were least likely to complete testing.ConclusionEvidence for logistical and communication-based explanations for this interaction are 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 phone.

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.

Genetic counseling via telephone (TC) has emerged as a potential avenue of care for women at risk of breast and ovarian cancers and open to BRCA1 and BRCA2 genetic testing. However, although TC has been shown to be on level with usual care (UC) methods in terms of knowledge, satisfaction, decisional quality, quality of life, and distress, all while yielding high cost savings to the patient and increasing patient accessibility, studies have also shown that patients randomized to TC are less like to complete the genetic testing process. In order to determine the factors leading to lower rates of genetic testing uptake after TC, the authors of this study examined sociodemographic, medical, and psychosocial predictors of genetic testing uptake and evaluated patient-related moderators (knowledge, numeracy, race/ethnicity, education level, etc) in a large cohort of women.

We conducted a translational genomics 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.

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 R2 = 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.