Obesity-Associated GNAS Mutations and the Melanocortin Pathway.

BACKGROUND: GNAS encodes the Gαs (stimulatory G-protein alpha subunit) protein, which mediates G protein-coupled receptor (GPCR) signaling. GNAS mutations cause developmental delay, short stature, and skeletal abnormalities in a syndrome called Albright's hereditary osteodystrophy. Because of imprinting, mutations on the maternal allele also cause obesity and hormone resistance (pseudohypoparathyroidism). METHODS: We performed exome sequencing and targeted resequencing in 2548 children who presented with severe obesity, and we unexpectedly identified 22 GNAS mutation carriers. We investigated whether the effect of GNAS mutations on melanocortin 4 receptor (MC4R) signaling explains the obesity and whether the variable clinical spectrum in patients might be explained by the results of molecular assays. RESULTS: Almost all GNAS mutations impaired MC4R signaling. A total of 6 of 11 patients who were 12 to 18 years of age had reduced growth. In these patients, mutations disrupted growth hormone-releasing hormone receptor signaling, but growth was unaffected in carriers of mutations that did not affect this signaling pathway (mean standard-deviation score for height, -0.90 vs. 0.75, respectively; P = 0.02). Only 1 of 10 patients who reached final height before or during the study had short stature. GNAS mutations that impaired thyrotropin receptor signaling were associated with developmental delay and with higher thyrotropin levels (mean [±SD], 8.4±4.7 mIU per liter) than those in 340 severely obese children who did not have GNAS mutations (3.9±2.6 mIU per liter; P = 0.004). CONCLUSIONS: Because pathogenic mutations may manifest with obesity alone, screening of children with severe obesity for GNAS deficiency may allow early diagnosis, improving clinical outcomes, and melanocortin agonists may aid in weight loss. GNAS mutations that are identified by means of unbiased genetic testing differentially affect GPCR signaling pathways that contribute to clinical heterogeneity. Monogenic diseases are clinically more variable than their classic descriptions suggest. (Funded by Wellcome and others.).

Reassessing the association: Evaluation of a polyalanine deletion variant of RUNX2 in non-syndromic sagittal and metopic craniosynostosis.

The RUNT-related transcription factor RUNX2 plays a critical role in osteoblast differentiation, and alterations to gene dosage cause distinct craniofacial anomalies. Uniquely amongst the RUNT-related family, vertebrate RUNX2 encodes a polyglutamine/polyalanine repeat (Gln23-Glu-Ala17 in humans), with the length of the polyalanine component completely conserved in great apes. Surprisingly, a frequent 6-amino acid deletion polymorphism, p.(Ala84_Ala89)del, occurs in humans (termed 11A allele), and a previous association study (Cuellar et al. Bone 137:115395;2020) reported that the 11A variant was significantly more frequent in non-syndromic sagittal craniosynostosis (nsSag; allele frequency [AF] = 0.156; 95% confidence interval [CI] 0.126-0.189) compared to non-syndromic metopic craniosynostosis (nsMet; AF = 0.068; 95% CI 0.045-0.098). However, the gnomAD v.2.1.1 control population used by Cuellar et al. did not display Hardy-Weinberg equilibrium, hampering interpretation. To re-examine this association, we genotyped the RUNX2 11A polymorphism in 225 individuals with sporadic nsSag as parent-child trios and 164 singletons with sporadic nsMet, restricting our analysis to individuals of European ancestry. We compared observed allele frequencies to the non-transmitted alleles in the parent-child trios, and to the genome sequencing data from gnomAD v.4, which display Hardy-Weinberg equilibrium. Observed AFs (and 95% CI) were 0.076 (0.053-0.104) in nsSag and 0.082 (0.055-0.118) in nsMet, compared with 0.062 (0.042-0.089) in non-transmitted parental alleles and 0.065 (0.063-0.067) in gnomAD v.4.0.0 non-Finnish European control genomes. In summary, we observed a non-significant excess, compared to gnomAD data, of 11A alleles in both nsSag (relative risk 1.18, 95% CI 0.83-1.67) and nsMet (relative risk 1.29, 95% CI 0.87-1.92), but we did not replicate the much higher excess of RUNX2 11A alleles in nsSag previously reported (p = 0.0001).

Prenatal diagnosis of tracheo-oesophageal fistula/oesophageal atresia: is MRI helpful?

BACKGROUND: Oesophageal atresia (OA) with or without tracheo-oesophageal fistula (TOF) affects 2.75 per 10,000 births within the UK. It is most frequently suspected on antenatal imaging when the stomach is absent or appears small. Studies have shown fetal magnetic resonance imaging (MRI) has greater diagnostic accuracy than ultrasound; however, there remains uncertainty over what size constitutes a small stomach and how frequently this correlates with a diagnosis of TOF/OA. METHODS: A retrospective study of patients referred for fetal MRI due to suspicions of TOF/OA on antenatal ultrasound from 2011 to 2022. We also included patients with a fetal MRI suspecting TOF/OA who had been referred for other reasons. The indication, MRI findings and postnatal outcome were compared to assess diagnostic accuracy. For each case, the size of the stomach bubble was measured on MRI, and stomach volumes in a control group were measured for comparison. RESULTS: The positive predictive value for USS was 45.5% and 51.7% for fetal MRI. Fetal MRI had a negative predictive value and sensitivity of 100% (p = 0.027). The control group showed a strong positive correlation between stomach size and increasing gestational age (R2 = 0.69, p < 0.001), but this correlation was less positive in the TOF/OA group (R2 = 0.26, p = 0.03), and the stomach volumes in TOF/OA were consistently lower than the control group. The receiver operating characteristic curve illustrates that an absent stomach or unmeasurably small stomach is more diagnostic of TOF/OA as volumes ≤0.06 ml had 90% sensitivity. CONCLUSION: Fetal MRI can accurately exclude TOF/OA but only has marginally improved positive predictive value over ultrasound. Research with larger numbers is required to further aid the development of a cut-off value for what can be considered a pathologically small stomach. IMPACT: There are several features on imaging that raise the suspicion of TOF/OA. Fetal MRI has some improved diagnostic accuracy compared with antenatal ultrasound alone; however, it is only marginally better. Absence of stomach bubble and presence of oesophageal dilatation combined on fetal MRI are more diagnostic of TOF/OA.

The value of fetal magnetic resonance imaging in diagnosis of congenital anomalies of the fetal body: a systematic review and meta-analysis.

OBJECTIVES: To undertake a systematic review to assess the accuracy of fetal MRI in diagnosis of non-CNS congenital anomalies of the fetal body in comparison with antenatal ultrasound when correlated to postnatal diagnosis. METHODS: Searches were conducted from electronic databases, key journals and reference lists for eligible papers. Inclusion criteria was original research studies comparing the diagnostic results of antenatal ultrasound, fetal MRI and final postnatal diagnosis via imaging, surgery or post-mortem testing. Studies of CNS anomalies were excluded. Studies were assessed for risk of bias by two reviewers working independently and data was then extracted by a single reviewer. RESULTS: 12 studies were included with a total of 361 eligible patients who underwent USS and MRI and had a postnatal diagnosis. USS alone had a diagnostic accuracy of 60.6% whereas MRI had an improved diagnostic accuracy of 86.4%. The overall odds ratio was 0.86 (CI 0.202-1.519 and p-value < 0.01). CONCLUSION: Fetal MRI makes a significant contribution to accurate diagnosis of congenital abnormalities of the fetal body; especially in genito-urinary anomalies. More research is needed to improve the evidence base for the role of fetal MRI in diagnosis of congenital anomalies in other body systems.

Pathogenic variants in the paired-related homeobox 1 gene (PRRX1) cause craniosynostosis with incomplete penetrance.

PURPOSE: Studies have previously implicated PRRX1 in craniofacial development, including demonstration of murine Prrx1 expression in the preosteogenic cells of the cranial sutures. We investigated the role of heterozygous missense and loss-of-function (LoF) variants in PRRX1 associated with craniosynostosis. METHODS: Trio-based genome, exome, or targeted sequencing were used to screen PRRX1 in patients with craniosynostosis; immunofluorescence analyses were used to assess nuclear localization of wild-type and mutant proteins. RESULTS: Genome sequencing identified 2 of 9 sporadically affected individuals with syndromic/multisuture craniosynostosis, who were heterozygous for rare/undescribed variants in PRRX1. Exome or targeted sequencing of PRRX1 revealed a further 9 of 1449 patients with craniosynostosis harboring deletions or rare heterozygous variants within the homeodomain. By collaboration, 7 additional individuals (4 families) were identified with putatively pathogenic PRRX1 variants. Immunofluorescence analyses showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localization. Of patients with variants considered likely pathogenic, bicoronal or other multisuture synostosis was present in 11 of 17 cases (65%). Pathogenic variants were inherited from unaffected relatives in many instances, yielding a 12.5% penetrance estimate for craniosynostosis. CONCLUSION: This work supports a key role for PRRX1 in cranial suture development and shows that haploinsufficiency of PRRX1 is a relatively frequent cause of craniosynostosis.

Symptom patterns and health service use of women in early adulthood: a latent class analysis from the Australian Longitudinal Study on Women's Health.

BACKGROUND: Symptoms can be strong drivers for initiating interaction with the health system, especially when they are frequent, severe or impact on daily activities. Research on symptoms often use counts of symptoms as a proxy for symptom burden, however simple counts don't provide information on whether groups of symptoms are likely to occur together or whether such groups are associated with different types and levels of healthcare use. Women have a higher symptom burden than men; however studies of symptom patterns in young women are lacking. We aimed to characterise subgroups of women in early adulthood who experienced different symptom patterns and to compare women's use of different types of health care across the different symptom subgroups. METHODS: Survey and linked administrative data from 7 797 women aged 22-27 years in 2017 from the 1989-95 cohort of the Australian Longitudinal Study on Women's Health were analysed. A latent class analysis was conducted to identify subgroups of women based on the frequency of 16 symptom variables. To estimate the associations between the latent classes and health service use, we used the "Bolck, Croon and Hagenaars" (BCH) approach that takes account of classification error in the assignment of women to latent classes. RESULTS: Four latent classes were identified, characterised by 1) low prevalence of most symptoms (36.6%), 2) high prevalence of menstrual symptoms but low prevalence of mood symptoms (21.9%), 3) high prevalence of mood symptoms but low prevalence of menstrual symptoms, (26.2%), and high prevalence of many symptoms (15.3%). Compared to the other three classes, women in the high prevalence of many symptoms class were more likely to visit general practitioners and specialists, use more medications, and more likely to have had a hospital admission. CONCLUSIONS: Women in young adulthood experience substantially different symptom burdens. A sizeable proportion of women experience many co-occurring symptoms across both physical and psychological domains and this high symptom burden is associated with a high level of health service use. Further follow-up of the women in our study as they enter their late 20 s and early 30 s will allow us to examine the stability of the classes of symptoms and their associations with general health and health service use. Similar studies in other populations are needed to assess the generalisability of the findings.

Diabetes in School Health (DiSH): Telementoring Collaboration Between Pediatric Diabetes Specialists and School Nurses to Improve Care of Children With Diabetes.

Rates of diabetes in youth are rising and more than 1 million children have diabetes. School nurses are central to a school-aged child's diabetes care and they must make important moment-to-moment decisions requiring understanding of and comfort with diabetes care and technology. The rapid changes in diabetes care and technology make ongoing education essential, yet access to up-to-date and practical education is limited for many school nurses. Integrating needs data and stakeholders' input, this group developed Diabetes in School Health (DiSH) to address this gap. We adapted a well-established, innovative, and easily-accessible telementoring educational model, Project ECHO, to create a collaborative learning community. In the first year, 9 diabetes experts and >150 school nurses joined live DiSH sessions. DiSH has been well-received by the school community and next steps include expansion of DiSH to other states and study of impact of DiSH on health disparities.

Menopause, hysterectomy, menopausal hormone therapy and cause-specific mortality: cohort study of UK Biobank participants.

STUDY QUESTION: What is the association between menopausal hormone therapy (MHT) and cause-specific mortality? SUMMARY ANSWER: Self-reported MHT use following early natural menopause, surgical menopause or premenopausal hysterectomy is associated with a lower risk of breast cancer mortality and is not consistently associated with the risk of mortality from cardiovascular disease or other causes. WHAT IS KNOWN ALREADY: Evidence from the Women's Health Initiative randomized controlled trials showed that the use of estrogen alone is not associated with the risk of cardiovascular mortality and is associated with a lower risk of breast cancer mortality, but evidence from the Million Women Study showed that use of estrogen alone is associated with a higher risk of breast cancer mortality. STUDY DESIGN, SIZE, DURATION: Cohort study (the UK Biobank), 178 379 women, recruited in 2006-2010. PARTICIPANTS/MATERIALS, SETTING, METHODS: Postmenopausal women who had reported age at menopause (natural or surgical) or hysterectomy, and information on MHT and cause-specific mortality. Age at natural menopause, age at surgical menopause, age at hysterectomy and MHT were exposures of interest. Natural menopause was defined as spontaneous cessation of menstruation for 12 months with no previous hysterectomy or oophorectomy. Surgical menopause was defined as the removal of both ovaries prior to natural menopause. Hysterectomy was defined as removal of the uterus before natural menopause without bilateral oophorectomy. The study outcome was cause-specific mortality. MAIN RESULTS AND THE ROLE OF CHANCE: Among the 178 379 women included, 136 790 had natural menopause, 17 569 had surgical menopause and 24 020 had hysterectomy alone. Compared with women with natural menopause at the age of 50-52 years, women with natural menopause before 40 years (hazard ratio (HR): 2.38, 95% CI: 1.64, 3.45) or hysterectomy before 40 years (HR: 1.60, 95% CI: 1.23, 2.07) had a higher risk of cardiovascular mortality but not cancer mortality. MHT use was associated with a lower risk of breast cancer mortality following surgical menopause before 45 years (HR: 0.17, 95% CI: 0.08, 0.36), at 45-49 years (HR: 0.15, 95% CI: 0.07, 0.35) or at ≥50 years (HR: 0.28, 95% CI: 0.13, 0.63), and the association between MHT use and the risk of breast cancer mortality did not differ by MHT use duration (<6 or 6-20 years). MHT use was also associated with a lower risk of breast cancer mortality following natural menopause before 45 years (HR: 0.59, 95% CI: 0.36, 0.95) or hysterectomy before 45 years (HR: 0.49, 95% CI: 0.32, 0.74). LIMITATIONS, REASONS FOR CAUTION: Self-reported data on age at natural menopause, age at surgical menopause, age at hysterectomy and MHT. WIDER IMPLICATIONS OF THE FINDINGS: The current international guidelines recommend women with early menopause to use MHT until the average age at menopause. Our findings support this recommendation. STUDY FUNDING/COMPETING INTEREST(S): This project is funded by the Australian National Health and Medical Research Council (NHMRC) (grant numbers APP1027196 and APP1153420). G.D.M. is supported by NHMRC Principal Research Fellowship (APP1121844), and M.H. is supported by an NHMRC Investigator Grant (APP1193838). There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Socioeconomic, behavioural and health factors associated with chlamydia testing in sexually active young women: an Australian observational cohort study.

BACKGROUND: Chlamydia trachomatis is the most frequently notified sexually transmitted infection in Australia. Untreated infections in women can cause health problems. Professional guidelines encourage opportunistic testing of young people. To increase understanding of who is being tested, we investigated factors associated with testing in a population of young women. METHODS: In total, 14002 sexually active women, aged 18-23 years at baseline (2013), from the Australian Longitudinal Study on Women's Health, were included. We used random intercepts, mixed-effects binary logistic regression with robust standard errors to assess associations between socioeconomic, health and behavioural factors and chlamydia testing. RESULTS: Associations between chlamydia testing and partner status varied by a woman's body mass index (BMI). Compared to women with a stable partner/BMI <25kg/m2 , women with a stable partner/BMI ≥25kg/m2 were less likely to be tested (adjusted odds ratios [AOR]=0.79, 95% CI: 0.71-0.88). In contrast, although women without a partner were more likely to be tested irrespective of BMI, the odds were higher for those with a BMI <25kg/m2 (AOR=2.68, 95% CI: 2.44-2.94) than a BMI ≥25kg/m2 (AOR=1.65, 95% CI: 1.48-1.84). Women who reported a prior chlamydia infection were also more likely to be tested (AOR=2.01, 95% CI: 1.83-2.20), as were women engaging in any combination of cannabis use and/or heavy episodic drinking compared to doing neither of these activities. CONCLUSIONS: Women without a partner, women with a prior chlamydia infection and those engaging in risk-taking behaviours are more likely to have chlamydia testing. Additional research is needed to understand whether there are deficits in testing among overweight/obese women.

Evaluating the performance of a clinical genome sequencing program for diagnosis of rare genetic disease, seen through the lens of craniosynostosis.

PURPOSE: Genome sequencing (GS) for diagnosis of rare genetic disease is being introduced into the clinic, but the complexity of the data poses challenges for developing pipelines with high diagnostic sensitivity. We evaluated the performance of the Genomics England 100,000 Genomes Project (100kGP) panel-based pipelines, using craniosynostosis as a test disease. METHODS: GS data from 114 probands with craniosynostosis and their relatives (314 samples), negative on routine genetic testing, were scrutinized by a specialized research team, and diagnoses compared with those made by 100kGP. RESULTS: Sixteen likely pathogenic/pathogenic variants were identified by 100kGP. Eighteen additional likely pathogenic/pathogenic variants were identified by the research team, indicating that for craniosynostosis, 100kGP panels had a diagnostic sensitivity of only 47%. Measures that could have augmented diagnoses were improved calling of existing panel genes (+18% sensitivity), review of updated panels (+12%), comprehensive analysis of de novo small variants (+29%), and copy-number/structural variants (+9%). Recent NHS England recommendations that partially incorporate these measures should achieve 85% overall sensitivity (+38%). CONCLUSION: GS identified likely pathogenic/pathogenic variants in 29.8% of previously undiagnosed patients with craniosynostosis. This demonstrates the value of research analysis and the importance of continually improving algorithms to maximize the potential of clinical GS.

A Gulf in lockdown: How an enforced ban on recreational vessels increased dolphin and fish communication ranges.

From midnight of 26 March 2020, New Zealand became one of the first countries to enter a strict lockdown to combat the spread of COVID-19. The lockdown banned all non-essential services and travel both on land and sea. Overnight, the country's busiest coastal waterway, the Hauraki Gulf Marine Park, became devoid of almost all recreational and non-essential commercial vessels. An almost instant change in the marine soundscape ensued, with ambient sound levels in busy channels dropping nearly threefold the first 12 h. This sudden drop led fish and dolphins to experience an immediate increase in their communication ranges by up to an estimated 65%. Very low vessel activity during the lockdown (indicated by the presence of vessel noise over the day) revealed new insights into cumulative noise effects from vessels on auditory masking. For example, at sites nearer Auckland City, communication ranges increased approximately 18 m (22%) or 50 m (11%) for every 10% decrease in vessel activity for fish and dolphins, respectively. However, further from the city and in deeper water, these communication ranges were increased by approximately 13 m (31%) or 510 m (20%). These new data demonstrate how noise from small vessels can impact underwater soundscapes and how marine animals will have to adapt to ever-growing noise pollution.

Hospitalisations for falls and hip fractures attributable to vitamin D deficiency in older Australians.

Vitamin D deficiency is associated with an increased risk of falls and fractures. Assuming this association is causal, we aimed to identify the number and proportion of hospitalisations for falls and hip fractures attributable to vitamin D deficiency (25 hydroxy D (25(OH)D) <50 nmol/l) in Australians aged ≥65 years. We used 25(OH)D data from the 2011/12 Australian Health Survey and relative risks from published meta-analyses to calculate population-attributable fractions for falls and hip fracture. We applied these to data published by the Australian Institute of Health and Welfare to calculate the number of events each year attributable to vitamin D deficiency. In men and women combined, 8·3 % of hospitalisations for falls (7991 events) and almost 8 % of hospitalisations for hip fractures (1315 events) were attributable to vitamin D deficiency. These findings suggest that, even in a sunny country such as Australia, vitamin D deficiency contributes to a considerable number of hospitalisations as a consequence of falls and for treatment of hip fracture in older Australians; in countries where the prevalence of vitamin D deficiency is higher, the impact will be even greater. It is important to mitigate vitamin D deficiency, but whether this should occur through supplementation or increased sun exposure needs consideration of the benefits, harms, practicalities and costs of both approaches.

The Long-Term Effectiveness of Internet-Based Interventions on Multiple Health Risk Behaviors: Systematic Review and Robust Variance Estimation Meta-analysis.

BACKGROUND: Smoking tobacco, poor nutrition, risky alcohol use, and physical inactivity (SNAP) behaviors tend to cluster together. Health benefits may be maximized if interventions targeted multiple health risk behaviors together rather than addressing single behaviors. The internet has wide reach and is a sustainable mode for delivery of interventions for multiple health behaviors. However, no systematic reviews have examined the long-term effectiveness of internet-based interventions on any combination of or all SNAP behaviors in adults aged 18 years or older. OBJECTIVE: This systematic review examined, among adults (aged ≥18 years), the effectiveness of internet-based interventions on SNAP behaviors collectively in the long term compared with a control condition. METHODS: The electronic databases Medline, PsycINFO, Embase, CINAHL, and Scopus were searched to retrieve studies describing the effectiveness of internet-based interventions on ≥2 SNAP behaviors published by November 18, 2019. The reference lists of retrieved articles were also checked to identify eligible publications. The inclusion criteria were randomized controlled trials or cluster randomized controlled trials with adults examining an internet-based intervention measuring the effect on ≥2 SNAP behaviors at least 6 months postrecruitment and published in English in a peer-reviewed journal. Two reviewers independently extracted data from included studies and assessed methodological quality using the Quality Assessment Tool for Quantitative Studies. A robust variance estimation meta-analysis was performed to examine the long-term effectiveness of internet-based interventions on all 4 SNAP risk behavior outcomes. All SNAP outcomes were coded so they were in the same direction, with higher scores equating to worse health risk behaviors. RESULTS: The inclusion criteria were met by 11 studies: 7 studies measured the effect of an internet-based intervention on nutrition and physical activity; 1 study measured the effect on smoking, nutrition, and physical activity; and 3 studies measured the effect on all SNAP behaviors. Compared with the control group, internet-based interventions achieved an overall significant improvement across all SNAP behaviors in the long term (standardized mean difference -0.12 [improvement as higher scores = worse health risk outcomes], 95% CI -0.19 to -0.05; I2=1.5%, P=.01). The global methodological quality rating was "moderate" for 1 study, while the remaining 10 studies were rated as "weak." CONCLUSIONS: Internet-based interventions were found to produce an overall significant improvement across all SNAP behaviors collectively in the long term. Internet-based interventions targeting multiple SNAP behaviors have the potential to maximize long-term improvements to preventive health outcomes.

A genome-wide association study implicates the BMP7 locus as a risk factor for nonsyndromic metopic craniosynostosis.

Our previous genome-wide association study (GWAS) for sagittal nonsyndromic craniosynostosis (sNCS) provided important insights into the genetics of midline CS. In this study, we performed a GWAS for a second midline NCS, metopic NCS (mNCS), using 215 non-Hispanic white case-parent triads. We identified six variants with genome-wide significance (P ≤ 5 × 10-8): rs781716 (P = 4.71 × 10-9; odds ratio [OR] = 2.44) intronic to SPRY3; rs6127972 (P = 4.41 × 10-8; OR = 2.17) intronic to BMP7; rs62590971 (P = 6.22 × 10-9; OR = 0.34), located ~ 155 kb upstream from TGIF2LX; and rs2522623, rs2573826, and rs2754857, all intronic to PCDH11X (P = 1.76 × 10-8, OR = 0.45; P = 3.31 × 10-8, OR = 0.45; P = 1.09 × 10-8, OR = 0.44, respectively). We performed a replication study of these variants using an independent non-Hispanic white sample of 194 unrelated mNCS cases and 333 unaffected controls; only the association for rs6127972 (P = 0.004, OR = 1.45; meta-analysis P = 1.27 × 10-8, OR = 1.74) was replicated. Our meta-analysis examining single nucleotide polymorphisms common to both our mNCS and sNCS studies showed the strongest association for rs6127972 (P = 1.16 × 10-6). Our imputation analysis identified a linkage disequilibrium block encompassing rs6127972, which contained an enhancer overlapping a CTCF transcription factor binding site (chr20:55,798,821-55,798,917) that was significantly hypomethylated in mesenchymal stem cells derived from fused metopic compared to open sutures from the same probands. This study provides additional insights into genetic factors in midline CS.

SMAD6 variants in craniosynostosis: genotype and phenotype evaluation.

PURPOSE: Enrichment of heterozygous missense and truncating SMAD6 variants was previously reported in nonsyndromic sagittal and metopic synostosis, and interaction of SMAD6 variants with a common polymorphism nearBMP2 (rs1884302) was proposed to contribute to inconsistent penetrance. We determined the occurrence of SMAD6 variants in all types of craniosynostosis, evaluated the impact of different missense variants on SMAD6 function, and tested independently whether rs1884302 genotype significantly modifies the phenotype. METHODS: We performed resequencing of SMAD6 in 795 unsolved patients with any type of craniosynostosis and genotyped rs1884302 in SMAD6-positive individuals and relatives. We examined the inhibitory activity and stability of SMAD6 missense variants. RESULTS: We found 18 (2.3%) different rare damaging SMAD6 variants, with the highest prevalence in metopic synostosis (5.8%) and an 18.3-fold enrichment of loss-of-function variants comparedwith gnomAD data (P < 10-7). Combined with eight additional variants, ≥20/26 were transmitted from an unaffected parent but rs1884302 genotype did not predict phenotype. CONCLUSION: Pathogenic SMAD6 variants substantially increase the risk of both nonsyndromic and syndromic presentations of craniosynostosis, especially metopic synostosis. Functional analysis is important to evaluate missense variants. Genotyping of rs1884302 is not clinically useful. Mechanisms to explain the remarkable diversity of phenotypes associated with SMAD6 variants remain obscure.

Correction: SMAD6 variants in craniosynostosis: genotype and phenotype evaluation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Hysterectomy with and without oophorectomy and all-cause and cause-specific mortality.

BACKGROUND: Hysterectomy is one of the most commonly performed gynecologic surgeries, with an estimated 30% of women in Australia undergoing the procedure by age of 70 years. In the United States, about 45% of women undergo hysterectomy in their lifetime. Some studies have suggested that this procedure increases the risk of premature mortality. With many women making the decision to undergo hysterectomy for a benign indication each year, additional research is needed to clarify whether there are long-term health consequences of hysterectomy. OBJECTIVE: This study aimed to examine the association between hysterectomy for benign indications, with or without removal of the ovaries, and cause-specific and all-cause mortality. STUDY DESIGN: Our cohort of 666,588 women comprised the female population of Western Australia with linked hospital and health records from 1970 to 2015. Cox regression models were used to assess the association between hysterectomy and all-cause, cardiovascular disease, cancer, and other mortality by oophorectomy type (categorized as none, unilateral, and bilateral), with no hysterectomy or oophorectomy as the reference group. We repeated these analyses using hysterectomy without oophorectomy as the reference group. We also investigated whether associations varied by age at the time of surgery, although small sample size precluded this analysis in women who underwent hysterectomy with unilateral salpingo-oophorectomy. In our main analysis, women who underwent hysterectomy or oophorectomy as part of cancer treatment were retained in the analysis and considered unexposed to that surgery. For a sensitivity analysis, we censored procedures performed for cancer. RESULTS: Compared with no surgery, hysterectomy without oophorectomy before 35 years was associated with an increase in all-cause mortality (hazard ratio, 1.29; 95% confidence interval, 1.19-1.40); for surgery after 35 years of age, there was an inverse association (35-44 years: hazard ratio, 0.93; 95% confidence interval, 0.89-0.97). Similarly, hysterectomy with bilateral salpingo-oophorectomy before 45 years of age was associated with increased all-cause mortality (35-44 years: hazard ratio, 1.15; 95% confidence interval, 1.04-1.27), but decreased mortality rates after 45 years of age. In our sensitivity analysis, censoring gynecologic surgeries for cancer resulted in many cancer-related deaths being excluded for women who did not have surgery for benign indications and thus increased the hazard ratios for the associations between both hysterectomy without oophorectomy and hysterectomy with bilateral salpingo-oophorectomy and risk of all-cause and cancer-specific mortality. The sensitivity analysis therefore potentially biased the results in favor of no surgery. CONCLUSION: Among women having surgery for benign indications, hysterectomy without oophorectomy performed before 35 years of age and hysterectomy with bilateral salpingo-oophorectomy performed before 45 years of age were associated with an increase in all-cause mortality. These procedures are not associated with poorer long-term survival when performed at older ages.

Major skull manifestations of skeletal dysplasias - pictorial essay.

Skeletal dysplasias are a large group of rare conditions with widely heterogeneous manifestations and a reputation for being diagnostically difficult. Involvement of the brain and craniovertebral junction are features familiar to the paediatric neuroradiologist. Involvement of the skull itself represents an area of overlap between the domains of the neuroradiologist and the skeletal dysplasia radiologist. In this pictorial essay, we review the principal skull manifestations of skeletal dysplasias as they present to the neuroradiologist.

The impact of reducing alcohol consumption in Australia: An estimate of the proportion of potentially avoidable cancers 2013-2037.

The International Agency for Research on Cancer first concluded that alcohol causes cancer in humans in 1988. The World Cancer Research Fund has declared that alcohol causes cancer of the oral cavity, pharynx, larynx, oesophagus (squamous cell carcinoma), female breast, colon, rectum, stomach and liver. It recommended that alcohol be avoided altogether to prevent cancer. We aimed to quantify the impact of reducing alcohol consumption on future cancer incidence in Australia. We used PREVENT 3.01 simulation modelling software to estimate the proportion of cancers that could potentially be prevented over a 25-year period under two hypothetical intervention scenarios and two latency periods (20 and 30 years). Under a scenario where alcohol consumption abruptly ceases, we estimated up to 4% of alcohol-related cancers could be avoided over a 25-year period (~49,500 cancers, depending on assumed latency). If the maximum consumption of all Australian adults was ≤20 g/day (~two Australian standard drinks), up to 2% of alcohol-related cancers could be avoided (~29,600 cancers). The maximum proportions were higher for men (6% for no alcohol consumption; 5% for ≤20 g/day) than women (3%; 1%). The proportion avoidable was highest for oesophageal squamous cell carcinoma (17% no alcohol consumption; 9% ≤20 g/day), followed by cancers of the oral cavity (12%; 5%) and pharynx (11%; 5%). The cancer sites with the highest numbers of potentially avoidable cases were colon in men (11,500; 9,900) and breast in women (14,400; 4,100). Successful interventions to reduce alcohol intake could lead to significant reductions in cancer incidence.

The impact of changing the prevalence of overweight/obesity and physical inactivity in Australia: An estimate of the proportion of potentially avoidable cancers 2013-2037.

Globally, 39% of the world's adult population is overweight or obese and 23% is insufficiently active. These percentages are even larger in high-income countries with 58% overweight/obese and 33% insufficiently active. Fourteen cancer types have been declared by the World Cancer Research Fund to be causally associated with being overweight or obese: oesophageal adenocarcinoma, stomach cardia, colon, rectum, liver, gallbladder, pancreas, breast, endometrium, ovary, advanced/fatal prostate, kidney, thyroid and multiple myeloma. Colon, postmenopausal breast and endometrial cancers have also been judged causally associated with physical inactivity. We aimed to quantify the proportion of cancer cases that would be potentially avoidable in Australia if the prevalence of overweight/obesity and physical inactivity in the population could be reduced. We used the simulation modelling software PREVENT 3.01 to calculate the proportion of avoidable cancers over a 25-year period under different theoretical intervention scenarios that change the prevalence of overweight/obesity and physical inactivity in the population. Between 2013 and 2037, 10-13% of overweight/obesity-related cancers in men and 7-11% in women could be avoided if overweight and obesity were eliminated in the Australian population. If everyone in the population met the Australian physical activity guidelines for cancer prevention (i.e. engaged in at least 300 min of moderate-intensity physical activity per week), an estimated 2-3% of physical inactivity-related cancers could be prevented in men (colon cancer) and 1-2% in women (colon, breast and endometrial cancers). This would translate to the prevention of up to 190,500 overweight/obesity-related cancers and 19,200 inactivity-related cancers over 25 years.