Enacted stigma experiences and protective factors are strongly associated with mental health outcomes of transgender people in Aotearoa/New Zealand.

INTRODUCTION: International evidence has found large mental health inequities among transgender people and demonstrates that mental health outcomes are associated with enacted stigma experiences and protective factors. This study aimed to examine the extent of associations of enacted stigma experiences specific to transgender people alongside protective factors with mental health of transgender people in Aotearoa/New Zealand. METHODS: The 2018 Counting Ourselves survey was a nationwide community-based study of transgender people (N = 1178, Mage = 29.5) living in Aotearoa/New Zealand. The survey assessed a wide range of gender minority stress experiences and protective factors that comprised primary (support from friends and family) and secondary social ties (neighborhood and transgender community belongingness). We calculated the predicted probabilities that transgender people exhibit very high psychological distress level, non-suicidal self-injury, and suicidal risks with different combinations and exposure profiles of enacted stigma and protective factors. RESULTS: Our findings demonstrated that enacted stigma was associated with negative mental health, and support of friends and family was linked to better outcomes across all mental health measures. Beyond primary social ties, sense of belongingness to neighborhood and transgender communities were linked to reduced odds of psychological distress and suicidal ideation. For those scoring high on enacted stigma and low on protective factors, our model revealed a 25% probability of attempting suicide in the last year compared to 3% for those scoring low on enacted stigma and high on protective factors. CONCLUSIONS: Echoing previous findings, this study demonstrates that transgender people across Aotearoa/New Zealand are less likely to manifest life-threatening mental health outcomes if they experience low levels of enacted stigma and high levels of access to protective factors. Our findings suggest a need to address the enacted stigma that transgender people face across interpersonal and structural settings, and also to enhance social supports that are gender affirmative for this population.

Mental Health Inequities among Transgender People in Aotearoa New Zealand: Findings from the Counting Ourselves Survey.

There has been little international research looking at differences in mental health across different age groups. This study examines mental health inequities between transgender people and the Aotearoa/New Zealand general population from youth to older adulthood. The 2018 Counting Ourselves survey (N = 1178) assessed participants' mental health using the Kessler Psychological Distress Scale (K10) and diagnoses of depression and anxiety disorders, questions that were the same as those used in the New Zealand Health Survey. Our results showed significant mean score differences for transgender people on K10, and these differences were almost two standard deviations higher than the general population (Cohen's d = 1.87). The effect size differences, however, decreased from youth to older adults. Regression analyses indicated trans women were less likely to report psychological distress than trans men and non-binary participants. There was an interaction effect for age and gender, with lower psychological distress scores found for younger trans women but higher scores for older trans women. The stark mental health inequities faced by transgender people, especially youth, demonstrate an urgent need to improve the mental health and wellbeing of this population by implementing inclusive institutional practices to protect them from gender minority stress.

Gender Minority Stress: A Critical Review.

Past studies that compare cisgender to transgender (or trans) and gender diverse people have found a higher prevalence of mental health problems among the latter groups. This article uses Testa's gender minority stress framework, which is an expansion of minority stress theory, to assess minority stressors that are specific to the experiences of trans and gender diverse people. The concept of cisnormativity, an ideology that positions cisgender identities as a norm, is used in relation to the gender minority stress framework to describe the marginalizing nature of social environments for trans and gender diverse people. This article provides a critical review that integrates and expands on past theoretical perspectives on gender minority stressors and protective factors. Specifically, this article demonstrates the relevance of cultural and ethnic backgrounds to complement the application of intersectionality in research on health disparities experienced by trans and gender diverse people.

Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment.

No efficient treatment exists for nephrotic syndrome (NS), a frequent cause of chronic kidney disease. Here we show mutations in six different genes (MAGI2, TNS2, DLC1, CDK20, ITSN1, ITSN2) as causing NS in 17 families with partially treatment-sensitive NS (pTSNS). These proteins interact and we delineate their roles in Rho-like small GTPase (RLSG) activity, and demonstrate deficiency for mutants of pTSNS patients. We find that CDK20 regulates DLC1. Knockdown of MAGI2, DLC1, or CDK20 in cultured podocytes reduces migration rate. Treatment with dexamethasone abolishes RhoA activation by knockdown of DLC1 or CDK20 indicating that steroid treatment in patients with pTSNS and mutations in these genes is mediated by this RLSG module. Furthermore, we discover ITSN1 and ITSN2 as podocytic guanine nucleotide exchange factors for Cdc42. We generate Itsn2-L knockout mice that recapitulate the mild NS phenotype. We, thus, define a functional network of RhoA regulation, thereby revealing potential therapeutic targets.

ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development.

Previously genome-wide association methods in patients with classic bladder exstrophy (CBE) found association with ISL1, a master control gene expressed in pericloacal mesenchyme. This study sought to further explore the genetics in a larger set of patients following-up on the most promising genomic regions previously reported. Genotypes of 12 markers obtained from 268 CBE patients of Australian, British, German Italian, Spanish and Swedish origin and 1,354 ethnically matched controls and from 92 CBE case-parent trios from North America were analysed. Only marker rs6874700 at the ISL1 locus showed association (p = 2.22 × 10-08). A meta-analysis of rs6874700 of our previous and present study showed a p value of 9.2 × 10-19. Developmental biology models were used to clarify the location of ISL1 activity in the forming urinary tract. Genetic lineage analysis of Isl1-expressing cells by the lineage tracer mouse model showed Isl1-expressing cells in the urinary tract of mouse embryos at E10.5 and distributed in the bladder at E15.5. Expression of isl1 in zebrafish larvae staged 48 hpf was detected in a small region of the developing pronephros. Our study supports ISL1 as a major susceptibility gene for CBE and as a regulator of urinary tract development.

Twist1 induces distinct cell states depending on TGFBR1-activation.

Basic helix-loop-helix transcription factor Twist1 is a master regulator of Epithelial-Mesenchymal Transition (EMT), a cellular program implicated in different stages of development as well as metastatic dissemination of carcinomas. Here, we show that Twist1 requires TGF-beta type-I receptor (TGFBR1)-activation to bind an enhancer region of downstream effector ZEB1, thereby inducing ZEB1 transcription and EMT. When TGFBR1-phosphorylation is inhibited, Twist1 generates a distinct cell state characterized by collective invasion, simultaneous proliferation and expression of endothelial markers. By contrast, TGFBR1-activation directs Twist1 to induce stable mesenchymal transdifferentiation through EMT, thereby generating cells that display single-cell invasion, but lose their proliferative capacity. In conclusion, preventing Twist1-induced EMT by inhibiting TGFß-signaling does not generally block acquisition of invasion, but switches mode from single-cell/non-proliferative to collective/proliferative. Together, these data reveal that transient Twist1-activation induces distinct cell states depending on signaling context and caution against the use of TGFß-inhibitors as a therapeutic strategy to target invasiveness.

Genome-wide association study and meta-analysis identify ISL1 as genome-wide significant susceptibility gene for bladder exstrophy.

The bladder exstrophy-epispadias complex (BEEC) represents the severe end of the uro-rectal malformation spectrum, and is thought to result from aberrant embryonic morphogenesis of the cloacal membrane and the urorectal septum. The most common form of BEEC is isolated classic bladder exstrophy (CBE). To identify susceptibility loci for CBE, we performed a genome-wide association study (GWAS) of 110 CBE patients and 1,177 controls of European origin. Here, an association was found with a region of approximately 220kb on chromosome 5q11.1. This region harbors the ISL1 (ISL LIM homeobox 1) gene. Multiple markers in this region showed evidence for association with CBE, including 84 markers with genome-wide significance. We then performed a meta-analysis using data from a previous GWAS by our group of 98 CBE patients and 526 controls of European origin. This meta-analysis also implicated the 5q11.1 locus in CBE risk. A total of 138 markers at this locus reached genome-wide significance in the meta-analysis, and the most significant marker (rs9291768) achieved a P value of 2.13 × 10-12. No other locus in the meta-analysis achieved genome-wide significance. We then performed murine expression analyses to follow up this finding. Here, Isl1 expression was detected in the genital region within the critical time frame for human CBE development. Genital regions with Isl1 expression included the peri-cloacal mesenchyme and the urorectal septum. The present study identified the first genome-wide significant locus for CBE at chromosomal region 5q11.1, and provides strong evidence for the hypothesis that ISL1 is the responsible candidate gene in this region.

Stem-cell-like properties and epithelial plasticity arise as stable traits after transient Twist1 activation.

Master regulators of the epithelial-mesenchymal transition such as Twist1 and Snail1 have been implicated in invasiveness and the generation of cancer stem cells, but their persistent activity inhibits stem-cell-like properties and the outgrowth of disseminated cancer cells into macroscopic metastases. Here, we show that Twist1 activation primes a subset of mammary epithelial cells for stem-cell-like properties, which only emerge and stably persist following Twist1 deactivation. Consequently, when cells undergo a mesenchymal-epithelial transition (MET), they do not return to their original epithelial cell state, evidenced by acquisition of invasive growth behavior and a distinct gene expression profile. These data provide an explanation for how transient Twist1 activation may promote all steps of the metastatic cascade; i.e., invasion, dissemination, and metastatic outgrowth at distant sites.

Adherence to nutritional guidelines in pregnancy: evidence from the Growing Up in New Zealand birth cohort study.

OBJECTIVE: To determine adherence to nutritional guidelines by pregnant women in New Zealand and maternal characteristics associated with adherence. DESIGN: A cohort of the pregnant women enrolled into New Zealand's new birth cohort study, Growing Up in New Zealand. SETTING: Women residing within a North Island region of New Zealand, where one-third of the national population lives. SUBJECTS: Pregnant women (n 5664) were interviewed during 2009-2010. An FFQ was administered during the face-to-face interview. RESULTS: The recommended daily number of servings of vegetables and fruit (≥6) were met by 25 % of the women; of breads and cereals (≥6) by 26 %; of milk and milk products (≥3) by 58 %; and of lean meat, meat alternatives and eggs (≥2) by 21 %. One in four women did not meet the recommendations for any food group. Only 3 % met all four food group recommendations. Although adherence to recommendation for the vegetables/fruit group did not vary by ethnicity (P=0·38), it did vary for the breads/cereals, milk/milk products and meat/eggs groups (all P<0·001). Adherence to recommendations for the vegetables/fruit group was higher among older women (P=0·001); for the breads/cereals group was higher for women with previous children (P<0·001) and from lower-income households (P<0·001); and for the meat/eggs group was higher for women with previous children (P=0·003) and from lower-income households (P=0·004). CONCLUSIONS: Most pregnant women in New Zealand do not adhere to nutritional guidelines in pregnancy, with only 3 % meeting the recommendations for all four food groups. Adherence varies more so with ethnicity than with other sociodemographic characteristics.