Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10−14, odds ratio = 0.86, 95% confidence interval = 0.82–0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression

Initiating the dialogue between infant mental health and family therapy: a qualitative inquiry and recommendations

This qualitative study explores infant-family mental health experts' perspectives and experiences regarding the inclusion of infants in the family therapy setting. Infant socioemotional development is relational in nature and evolves in the context of both dyadic attachment relationships and broader multi-person co-parenting systems. Given this, we sought to understand why family therapy interventions involving families with infants rarely include the infant in a triangular or family systemic approach. Interviews were completed by clinical and/or research experts whose work integrates tenets of both infant mental health (IMH) and family theory and therapy. All interviewees brought at least 5 years of expertise and were actively engaged in the field. Interviewees expressed consistent beliefs that infants have a rightful and helpful place in family therapy approaches. They maintained that infants' innate social drive and communicative capacities position them to make meaningful and clinically significant contributions within family and systemic psychotherapy contexts. Noting that infants have remained on the periphery of these practices, experts advocated expansion and greater integration between IMH and family therapy, while preserving each field's distinctive identity. Experts reported that the interplay between IMH and family therapy fields has been uni-directional as family systems concepts are embedded within IMH approaches, but few IMH premises are incorporated in mainstream family therapy practices. The disconnect was attributed to multiple factors, including graduate and professional training and theoretical, clinical, research, and sociocultural barriers, which were mutually reinforcing. Experts also identified clinical gains for both infants and family members when infants were meaningfully included in family interventions. Common ground was identified between the disciplines, with a belief that relationally distressed young children and parents are best served by clinical engagement with their network of relationships. Results call for greater collaboration between disciplines to challenge existing traditions and to more fully include infants in mainstream family therapy. Recommendations for integration of family therapy and IMH in clinical, theoretical, research, training, and sociocultural domains are offered

Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression

Candidate locus analysis of the TERT-CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk.

Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT-CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 × 10(-6) to P = 7.7 × 10(-5)). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERT P = 1.5 × 10(-18), CLPTM1L P = 1.5 × 10(-19)). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility.This work was supported by the NHMRC Project Grant (ID#1031333). This work was also supported by Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692)This is the published version. It first appeared at http://link.springer.com/article/10.1007%2Fs00439-014-1515-4

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Walk-in Together: A pilot study of a walk-in online family therapy intervention

Many Australians are requiring mental health care, including families, leading to long wait times in order to access support. Walk-in therapy reduces barriers to mental health support services by providing support at the time that families seek help. This paper presents a proof-of-concept study investigating the acceptability and short-term effectiveness of an online walk-in family therapy service, Walk-in Together (WIT). Part 1 of the paper describes the experiences of 44 family members from 22 families who presented to a public family therapy clinic for a virtual walk-in family therapy session. The session was conducted by a team of three experienced family therapists. Family members' experiences were sought pre-session, post-session, and at 6 weeks follow-up via survey and interview. Part 2 of the paper explores therapist perceptions (n = 7) of the WIT approach, through thematic analysis of semi-structured interview data. Post-session feedback showed 85% of family members found WIT to be helpful and 50% were optimistic about their future as a family after their WIT session. Six weeks post-session it was revealed that WIT supported planning for families in equipping them to move forward with 88% of family members reporting that they knew what to do after the session. All therapists uniformly experienced the model as offering a timely and beneficial service, suitable for diverse presentations and constellations of families. These preliminary results suggest the significant utility of this WIT intervention as a well-received and helpful service for families, who valued the easy access and rapid therapeutic response afforded by the online, walk-in delivery model. This proof-of-concept paper suggests the potential for further development and growth of WIT, as well as other mental health support services using a walk-in, telehealth model to meet the rising demand for therapeutic support for families in distress

Initiating the dialogue between infant mental health and family therapy: a qualitative inquiry and recommendations

Publication status: PublishedAbstractThis qualitative study explores infant‐family mental health experts' perspectives and experiences regarding the inclusion of infants in the family therapy setting. Infant socioemotional development is relational in nature and evolves in the context of both dyadic attachment relationships and broader multi‐person co‐parenting systems. Given this, we sought to understand why family therapy interventions involving families with infants rarely include the infant in a triangular or family systemic approach. Interviews were completed by clinical and/or research experts whose work integrates tenets of both infant mental health (IMH) and family theory and therapy. All interviewees brought at least 5 years of expertise and were actively engaged in the field. Interviewees expressed consistent beliefs that infants have a rightful and helpful place in family therapy approaches. They maintained that infants' innate social drive and communicative capacities position them to make meaningful and clinically significant contributions within family and systemic psychotherapy contexts. Noting that infants have remained on the periphery of these practices, experts advocated expansion and greater integration between IMH and family therapy, while preserving each field's distinctive identity. Experts reported that the interplay between IMH and family therapy fields has been uni‐directional as family systems concepts are embedded within IMH approaches, but few IMH premises are incorporated in mainstream family therapy practices. The disconnect was attributed to multiple factors, including graduate and professional training and theoretical, clinical, research, and sociocultural barriers, which were mutually reinforcing. Experts also identified clinical gains for both infants and family members when infants were meaningfully included in family interventions. Common ground was identified between the disciplines, with a belief that relationally distressed young children and parents are best served by clinical engagement with their network of relationships. Results call for greater collaboration between disciplines to challenge existing traditions and to more fully include infants in mainstream family therapy. Recommendations for integration of family therapy and IMH in clinical, theoretical, research, training, and sociocultural domains are offered.</jats:p