Master\u27s Project: Tending to Joy

If we dare to hope for the thriving of humans and all of life, then joy must hold a solid place in our imagination. The purpose of this project was to breathe joy into my own life and into the world around me. Following a literature review, I carried out three mini-projects – creating crowd-sourced collages out of what brings people joy, sending daily text messages with quotes about joy, and providing cookies to groups working on social change efforts. The projects succeeded in spreading delight, raising spirits, and inspiring reflection. The journey towards cultivating joy in my own life was substantially messier and remains completely unresolved. I conclude this project not yet able but still aspiring to fully say “yes” to life

Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia.

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10-6, 1.7 × 10-9, 3.5 × 10-12 and 1.0 × 10-4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes

Pregnancy Intent Among a Sample of Recently Diagnosed HIV-Positive Women and Men Practicing Unprotected Sex in Cape Town, South Africa

Background: Sexual and reproductive health (SRH) services for HIV-positive women and men often neglect their fertility desires. We examined factors associated with pregnancy intent among recently diagnosed HIV-positive women (N = 106) and men (N = 91) who reported inconsistent condom use and were enrolled in an SRH intervention conducted in public sector HIV care clinics in Cape Town. Methods: Participants were recruited when receiving their first CD4+ results at the clinic. All reported unprotected sex in the previous 3 months. Logistic regression identified predictors of pregnancy intent for the total sample and by gender. Results: About three fifths of men and one fifth of women reported intent to conceive in the next 6 months. In the full-sample multiple regression analysis, men [adjusted odds ratio (AOR = 6.62)] and those whose main partner shared intent to conceive (AOR = 3.80) had significantly higher odds of pregnancy intent; those with more years of education (AOR = 0.81) and more biological children (AOR = 0.62) had lower odds of intending pregnancy. In gender-specific analyses, partner sharing pregnancy intent was positively associated with intent among both men (AOR = 3.53) and women (AOR = 13.24). Among men, odds were lower among those having more biological children (AOR = 0.71) and those unemployed (AOR = 0.30). Among women, relying on hormonal contraception was negatively associated with intent (AOR = 0.08), and main partner knowing her HIV status (AOR = 5.80) was positively associated with intent to conceive. Conclusions: Findings underscore the importance of providing integrated SRH services, and we discuss implications for clinical practice and care

Dietary Manipulation of Oncogenic MicroRNA Expression in Human Rectal Mucosa: A Randomized Trial

Author version made available in accordance with the publisher's policy.High red meat intake is associated with increased colorectal cancer (CRC) risk, while resistant starch is probably protective. Resistant starch fermentation produces butyrate, which can alter microRNA (miRNA) levels in CRC cells in vitro; effects of red meat and resistant starch on miRNA expression in vivo were unknown. This study examined whether a high red meat (HRM) diet altered miRNA expression in rectal mucosa tissue of healthy volunteers, and if supplementation with butyrylated resistant starch (HRM+HAMSB) modified this response. In a randomised cross-over design, twenty-three volunteers undertook four 4-week dietary interventions; an HRM diet (300 g/day lean red meat) and an HRM+HAMSB diet (HRM with 40 g/day butyrylated high amylose maize starch), preceded by an entry diet and separated by a washout. Faecal butyrate increased with the HRM+HAMSB diet. Levels of oncogenic mature miRNAs, including miR-17-92 cluster miRNAs and miR-21, increased in the rectal mucosa with the HRM diet, while the HRM+HAMSB diet restored miR-17-92 miRNAs, but not miR-21, to baseline levels. Elevated miR-17-92 and miR-21 in the HRM diet corresponded with increased cell proliferation, and a decrease in miR-17-92 target gene transcript levels, including CDKN1A. The oncogenic miR-17-92 cluster is differentially regulated by dietary factors that increase or decrease risk for CRC, and this may explain, at least in part, the respective risk profiles of high red meat and resistant starch. These findings support increased resistant starch consumption as a means of reducing risk associated with an HRM diet

High levels of adherence to a rectal microbicide gel and to oral Pre-Exposure Prophylaxis (PrEP) achieved in MTN-017 among men who have sex with men (MSM) and transgender women

Trials to assess microbicide safety require strict adherence to prescribed regimens. If adherence is suboptimal, safety cannot be adequately assessed. MTN-017 was a phase 2, randomized sequence, open-label, expanded safety and acceptability crossover study comparing 1) daily oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), 2) daily use of reduced-glycerin 1% tenofovir (RG-TFV) gel applied rectally, and 3) RG-TFV gel applied before and after receptive anal intercourse (RAI)—if participants had no RAI in a week, they were asked to use two doses of gel within 24 hours. Product use was assessed by mixed methods including unused product return count, text messaging reports, and qualitative plasma TFV pharmacokinetic (PK) results. Convergence interviews engaged participants in determining the most accurate number of doses used based on product count and text messaging reports. Client-centered adherence counseling was also used. Participants (N = 187) were men who have sex with men and transgender women enrolled in the United States (42%), Thailand (29%), Peru (19%) and South Africa (10%). Mean age was 31.4 years (range 18–64 years). Based on convergence interviews, over an 8-week period, 94% of participants had ≥80% adherence to daily tablet, 41% having perfect adherence; 83% had ≥80% adherence to daily gel, 29% having perfect adherence; and 93% had ≥80% adherence to twice-weekly use during the RAI-associated gel regimen, 75% having perfect adherence and 77% having ≥80% adherence to gel use before and after RAI. Only 4.4% of all daily product PK results were undetectable and unexpected (TFV concentrations <0.31 ng/mL) given self-reported product use near sampling date. The mixed methods adherence measurement indicated high adherence to product use in all three regimens. Adherence to RAI-associated rectal gel use was as high as adherence to daily oral PrEP. A rectal microbicide gel, if efficacious, could be an alternative for individuals uninterested in daily oral PrEP

Attitudes and Practices Among Internists Concerning Genetic Testing

Many questions remain concerning whether, when, and how physicians order genetic tests, and what factors are involved in their decisions. We surveyed 220 internists from two academic medical centers about their utilization of genetic testing. Rates of genetic utilizations varied widely by disease. Respondents were most likely to have ordered tests for Factor V Leiden (16.8 %), followed by Breast/Ovarian Cancer (15.0 %). In the past 6 months, 65 % had counseled patients on genetic issues, 44 % had ordered genetic tests, 38.5 % had referred patients to a genetic counselor or geneticist, and 27.5 % had received ads from commercial labs for genetic testing. Only 4.5 % had tried to hide or disguise genetic information, and <2 % have had patients report genetic discrimination. Only 53.4 % knew of a geneticist/genetic counselor to whom to refer patients. Most rated their knowledge as very/somewhat poor concerning genetics (73.7 %) and guidelines for genetic testing (87.1 %). Most felt needs for more training on when to order tests (79 %), and how to counsel patients (82 %), interpret results (77.3 %), and maintain privacy (80.6 %). Physicians were more likely to have ordered a genetic test if patients inquired about genetic testing (p  < .001), and if physicians had a geneticist/genetic counselor to whom to refer patients (p  < .002), had referred patients to a geneticist/genetic counselor in the past 6 months, had more comfort counseling patients about testing (p  < .019), counseled patients about genetics, larger practices (p  < .032), fewer African‐American patients (p  < .027), and patients who had reported genetic discrimination (p  < .044). In a multiple logistic regression, ordering a genetic test was associated with patients inquiring about testing, having referred patients to a geneticist/genetic counselor and knowing how to order tests. These data suggest that physicians recognize their knowledge deficits, and are interested in training. These findings have important implications for future medical practice, research, and education

Challenges and opportunities in the science of research to practice: lessons learned from a randomized controlled trial of a sexual risk-reduction intervention for psychiatric patients in a public mental health system

Objective: Human immunodeficiency virus (HIV) prevention efficacy trials with psychiatric patients have been conducted in research settings in high-resourced countries, establishing short-term efficacy for reducing sexual risk behavior. None has been implemented within systems of care. In the last decade, overcoming this research-to-practice gap has become a focus of implementation science. This paper describes the first and only HIV Prevention intervention trial for psychiatric patients conducted in real-world outpatient psychiatric settings facilitated by trained clinic-based providers. Methods: The HIV Prevention intervention, which uses the Information-Motivation-Behavioral Skills model to achieve sexual risk-reduction, was rigorously adapted to the local context and clinic services' needs. Participants from eight clinics were randomized to HIV Prevention or Health Promotion conditions. Results: HIV Prevention participants showed significant improvement in Information-Motivation-Behavioral domains; in this group, behavioral intentions were associated with significantly fewer unprotected sex occasions, but reduction of unprotected sex occasions was similar in both conditions. Conclusion: Our trial was conducted before implementation studies became widely funded. Transporting an intervention to a new culture or into real-world practice settings may require adaptations. Our results demonstrate that clear guidelines are needed regarding whether to conduct efficacy, effectiveness, and/or implementation research as the most appropriate next step. Clinical trial registration: NCT00881699

Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, Pmeta = 2.5 × 10−9, OR[T] = 0.81) and 17q21.32 (rs72823592, Pmeta = 9.3 × 10−9, OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, Pmeta = 9.1 × 10−9, OR[T] = 0.68) and at 1q43 for JME (rs12059546, Pmeta = 4.1 × 10−8, OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, Pmeta = 4.0 × 10−6) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndrome