A randomised trial of real-time video counselling for smoking cessation among rural and remote residents.

INTRODUCTION: Despite its reach, very limited evidence exists on the effectiveness of real-time video counselling for smoking cessation (e.g. via Skype). This study compared the effectiveness of real-time video counselling for smoking cessation to (a) telephone counselling; and (b) a control among rural and remote residents. METHODS: Between 25 May 2017 and 3 March 2020, a three-arm, parallel group, randomised trial, randomised 1244 rural and remote residents from New South Wales, Australia who smoked tobacco to: video counselling (4-6 video sessions); telephone counselling (4-6 telephone calls); or a control (printed materials). The primary outcome was 7-day point prevalence abstinence at 13 months post-baseline. Secondary outcomes were point prevalence abstinence at 4 months and 7-months post-baseline, prolonged abstinence, quit attempts, anxiety and depression. RESULTS: For the primary outcome of 7-day point prevalence abstinence at 13 months post-baseline, there was no significant difference between video counselling and telephone counselling (14.6% vs 13.3%; (OR = 1.11, 95% CI (0.75-1.64), P = 0.61) or video counselling and control (14.6% vs 13.9%; (OR = 1.06, 95% CI (0.71-1.57), P = 0.77). For secondary outcomes at 4 months post-baseline, the video counselling group had significantly higher odds than the control of 7-day point prevalence abstinence (14.3% vs 8.2%; OR = 1.88, 95% CI (1.20-2.95), P = 0.006) and 3-month prolonged abstinence (4.9% vs 2.2%; OR = 2.28, 95% CI (1.03-5.07), P = 0.04). There were no significant differences for other secondary outcomes. DISCUSSION: Video counselling increased smoking cessation in the short-term compared to a control although strategies to improve its long-term effectiveness are needed. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, https://www.anzctr.org.au ACTRN12617000514303.

Use of an emulated trial to investigate the association between use of nitrogen-based bisphosphonates and risk of epithelial ovarian cancer.

BACKGROUND: Epithelial ovarian cancer (EOC) is the eighth most common cancer in women, with poor survival outcomes. Observational evidence suggests that nitrogen-based bisphosphonate (NBB) use may be associated with reduced risk of EOC, particularly the endometrioid and serous histotypes; however, confounding by indication is a concern. An alternative approach to investigate the chemo-preventive potential of NBBs is to emulate a target trial by identifying all women who initiate use of NBBs and investigate the risk of EOC for continued users compared with discontinued users. METHODS: Using population-based linked data, we identified all Australian women aged over 50 years who first used NBBs over 2004-12. We used the year after first use to define treatment for each woman as either continued or discontinued use. We emulated randomization using stabilized inverse probability weights to balance the treatment groups using covariates including age, comorbidities and socioeconomic status. We followed women from treatment assignment until EOC diagnosis, death or 31 December 2013. We assessed the risk of EOC (overall and by histotype) using flexible parametric time-to-event models allowing for time-varying effects, and produced time-varying coefficients. RESULTS: Of the 313 383 women in the study, 472 were diagnosed with EOC during follow-up (261 serous EOC), with an average age at diagnosis of 72 years. Continued use of NBBs was associated with reduced risk of EOC overall (HR = 0.87, 95% CI: 0.69, 1.10), and serous EOC (HR = 0.71, 95% CI: 0.53, 0.96), compared with discontinued treatment, with estimates remaining constant over the 9-year follow-up. CONCLUSIONS: Results from our emulated trial suggest that in women who initiated NBB treatment, those who continued use had 13% and 29% lower hazards of being diagnosed with EOC overall and serous EOC, respectively, compared with women who discontinued use.

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.

A Comparison of Structural Variant Calling from Short-Read and Nanopore-Based Whole-Genome Sequencing Using Optical Genome Mapping as a Benchmark.

The identification of structural variants (SVs) in genomic data represents an ongoing challenge because of difficulties in reliable SV calling leading to reduced sensitivity and specificity. We prepared high-quality DNA from 9 parent-child trios, who had previously undergone short-read whole-genome sequencing (Illumina platform) as part of the Genomics England 100,000 Genomes Project. We reanalysed the genomes using both Bionano optical genome mapping (OGM; 8 probands and one trio) and Nanopore long-read sequencing (Oxford Nanopore Technologies [ONT] platform; all samples). To establish a "truth" dataset, we asked whether rare proband SV calls (n = 234) made by the Bionano Access (version 1.6.1)/Solve software (version 3.6.1_11162020) could be verified by individual visualisation using the Integrative Genomics Viewer with either or both of the Illumina and ONT raw sequence. Of these, 222 calls were verified, indicating that Bionano OGM calls have high precision (positive predictive value 95%). We then asked what proportion of the 222 true Bionano SVs had been identified by SV callers in the other two datasets. In the Illumina dataset, sensitivity varied according to variant type, being high for deletions (115/134; 86%) but poor for insertions (13/58; 22%). In the ONT dataset, sensitivity was generally poor using the original Sniffles variant caller (48% overall) but improved substantially with use of Sniffles2 (36/40; 90% and 17/23; 74% for deletions and insertions, respectively). In summary, we show that the precision of OGM is very high. In addition, when applying the Sniffles2 caller, the sensitivity of SV calling using ONT long-read sequence data outperforms Illumina sequencing for most SV types.

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).

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.

A systems approach to assist policy action to prevent falls among community-dwelling older people in Australia.

OBJECTIVES: While systems thinking has gained recognition as an important approach in health policy and prevention research, its application in the context of fall prevention among community-dwelling older adults has been underutilised. Here, we build on the guiding principles of the systemic lens component of the Prevention System Change Framework to assess and identify potential changes that are required to facilitate policy action in the field of falls prevention. METHODS: We conducted a desktop search to identify policy documents encompassing falls prevention among community-dwelling older adults in Australia. Documents were considered eligible if they were published in the last 10 years and were authored or endorsed by federal or state government bodies. We collaboratively examined eligible documents to gain insights into the current policy landscape in falls prevention and to illustrate opportunities for action and the potential for strengthening partnerships. RESULTS: There is no current national policy on preventing falls in older adults in Australia. While we identified eight policy documents, none focused exclusively on falls prevention, indicating that falls are currently not perceived as a public health issue that warrants a dedicated policy framework. We identified a need for a comprehensive national policy that draws upon insights from various disciplines, suggests intersectoral collaboration, addresses health inequities and involves meaningful engagement with key stakeholders. Future falls prevention policies may benefit from clear governance structures and specific targets, along with mechanisms for monitoring and evaluating outcomes. CONCLUSION: Falls prevention is a pressing public health concern that requires dedicated policy resources. Adopting a systems-oriented approach can help reduce falls and their associated burdens on individuals and the healthcare system. Acknowledging the urgency and complexity of this challenge is a first, essential step toward crafting a comprehensive national falls prevention policy.

Risk of Fracture After Bilateral Oophorectomy.

Fragility fractures, resulting from low-energy trauma, occur in approximately 1 in 10 Danish women aged 50 years or older. Bilateral oophorectomy (surgical removal of both ovaries) may increase the risk of fragility fractures due to loss of ovarian sex steroids, particularly estrogen. We investigated the association between bilateral oophorectomy and risk of fragility fracture and whether this was conditional on age at time of bilateral oophorectomy, hormone therapy (HT) use, hysterectomy, physical activity level, body mass index (BMI), or smoking. We performed a cohort study of 25,853 female nurses (≥45 years) participating in the Danish Nurse Cohort. Nurses were followed from age 50 years or entry into the cohort, whichever came last, until date of first fragility fracture, death, emigration, or end of follow-up on December 31, 2018, whichever came first. Cox regression models with age as the underlying time scale were used to estimate the association between time-varying bilateral oophorectomy (all ages, <51/≥51 years) and incident fragility fracture (any and site-specific [forearm, hip, spine, and other]). Exposure and outcome were ascertained from nationwide patient registries. During 491,626 person-years of follow-up, 6600 nurses (25.5%) with incident fragility fractures were identified, and 1938 (7.5%) nurses had a bilateral oophorectomy. The frequency of fragility fractures was 24.1% in nurses who were <51 years at time of bilateral oophorectomy and 18.1% in nurses who were ≥51 years. No statistically significant associations were observed between bilateral oophorectomy at any age and fragility fractures at any site. Neither HT use, hysterectomy, physical activity level, BMI, nor smoking altered the results. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Peripheral intravenous catheter material and design to reduce device failure: A systematic review and meta-analysis.

BACKGROUND: Patients require vascular access for medical treatments, diagnostic procedures and symptom management. Current failure rates of peripheral intravascular catheters (PIVCs) are unacceptably high (40-50%). This systematic review aimed to determine the effect of different PIVC materials and designs on the incidence of PIVC failure. METHODS: A systematic search was conducted in November 2022 using CINAHL, PubMed, EMBASE and Cochrane Central Register of Controlled Trials databases. Randomised controlled trials that compared PIVC novel PIVC material/design and standard material/design were included. The primary outcome was all causes of PIVC failure, any reason for device removal due to cessation of device function; and secondary outcomes included individual PIVC complications and infection (local or systemic), and dwell times. Quality appraisal was conducted using the Cochrane risk of bias tool. A meta-analysis was performed using random effects model. RESULTS: Seven randomised controlled trials were eligible for inclusion. In meta-analysis, the impact of material and design on PIVC failure in the studies favoured the intervention arms (RR 0.71, 95% CI 0.57-0.89), however there was substantial heterogeneity (I2 = 81%, 95% CI 61-91%). Through subgroup analyses, a significant difference on PIVC failure favoured the closed system over the open system (RR 0.85, 95% CI 0.73 to 0.99; I2 = 23%, 95% CI 0-90%). CONCLUSION: Catheter material and design can impact PIVC outcome. Conclusive recommendations are limited due to the small number of studies and inconsistent reporting of clinical outcomes. Further rigorous research of PIVC types is necessary to improve clinical practice and device selection pathways should reflect the resulting evidence.

An experimental assessment of detection dog ability to locate great crested newts (Triturus cristatus) at distance and through soil.

Detection dogs are increasingly used to locate cryptic wildlife species, but their use for amphibians is still rather underexplored. In the present paper we focus on the great crested newt (Triturus cristatus), a European species which is experiencing high conservation concerns across its range, and assess the ability of a trained detection dog to locate individuals during their terrestrial phase. More specifically, we used a series of experiments to document whether a range of distances between target newts and the detection dog (odour channelled through pipes 68 mm in diameter) affects the localisation, and to assess the ability and efficiency of target newt detection in simulated subterranean refugia through 200 mm of two common soil types (clay and sandy soil, both with and without air vents to mimic mammal burrows, a common refuge used by T. cristatus). The detection dog accurately located all individual T. cristatus across the entire range of tested distances (0.25 m- 2.0 m). The substrate trials revealed that the detection dog could locate individuals also through soil. Contrary to existing studies with detection dogs in human forensic contexts, however, detection was generally slower for T. cristatus under sandy soil compared to clay soil, particularly when a vent was absent. Our study provides a general baseline for the use of detection dogs in locating T. cristatus and similar amphibian species during their terrestrial phase.

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.

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.

Impact of small boat sound on the listening space of Pempheris adspersa, Forsterygion lapillum, Alpheus richardsoni and Ovalipes catharus.

Anthropogenic stressors, such as plastics and fishing, are putting coastal habitats under immense pressure. However, sound pollution from small boats has received little attention given the importance of sound in the various life history strategies of many marine animals. By combining passive acoustic monitoring, propagation modelling, and hearing threshold data, the impact of small-boat sound on the listening spaces of four coastal species was determined. Listening space reductions (LSR) were greater for fishes compared to crustaceans, for which LSR varied by day and night, due to their greater hearing abilities. Listening space also varied by sound modality for the two fish species, highlighting the importance of considering both sound pressure and particle motion. The theoretical results demonstrate that boat sound hinders the ability of fishes to perceive acoustic cues, advocating for future field-based research on acoustic cues, and highlighting the need for effective mitigation and management of small-boat sound within coastal areas worldwide.

Review of Recurrently Mutated Genes in Craniosynostosis Supports Expansion of Diagnostic Gene Panels.

Craniosynostosis, the premature fusion of the cranial sutures, affects ~1 in 2000 children. Although many patients with a genetically determined cause harbor a variant in one of just seven genes or have a chromosomal abnormality, over 60 genes are known to be recurrently mutated, thus comprising a long tail of rarer diagnoses. Genome sequencing for the diagnosis of rare diseases is increasingly used in clinical settings, but analysis of the data is labor intensive and involves a trade-off between achieving high sensitivity or high precision. PanelApp, a crowd-sourced disease-focused set of gene panels, was designed to enable prioritization of variants in known disease genes for a given pathology, allowing enhanced identification of true-positives. For heterogeneous disorders like craniosynostosis, these panels must be regularly updated to ensure that diagnoses are not being missed. We provide a systematic review of genetic literature on craniosynostosis over the last 5 years, including additional results from resequencing a 42-gene panel in 617 affected individuals. We identify 16 genes (representing a 25% uplift) that should be added to the list of bona fide craniosynostosis disease genes and discuss the insights that these new genes provide into pathophysiological mechanisms 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.

Associations of socioeconomic and health factors with dental non-attendance: A comparison of three cohorts of women.

OBJECTIVES: Most studies on factors influencing dental attendance are cross-sectional and focus on specific age groups. The associations between private ancillary health insurance, tobacco smoking, alcohol consumption and overweight/obesity with dental attendance were examined in three cohorts of Australian women of different ages using multiple waves of data over similar time periods. METHODS: Data from 10 233, 12 378 and 7892 women born in 1973-1978, 1946-1951 and 1921-1926 participating in the Australian Longitudinal Study on Women's Health were used. Poisson regression using generalized estimating equations was used to investigate factors associated with self-report of not visiting the dentist in the 12 months before completing each wave. RESULTS: The role of dental non-attendance was higher in women without insurance (versus those with insurance) in all cohorts with adjusted rate ratios (RR) of 1.52 95% CI 1.48-1.57, RR 1.45 95% CI 1.41-1.49 and RR 1.32 95% CI 1.28-1.36 in the 1973-78, 1946-51 and 1921-26 cohorts respectively. Current smokers at any intensity (versus never smokers) had a higher risk of non-attendance and the risk was strongest for women in the 1946-51 cohort who smoked ≥20 cigarettes/day (RR 1.35 95% CI 1.30-1.41). Compared with low-risk drinkers, non-drinkers were more likely to be non-attenders, but only in the two older cohorts. Women who were overweight or obese (versus healthy weight) were more likely to be non-attenders in all cohorts, with the risk of non-attendance higher with increasing BMI. CONCLUSIONS: This study emphasizes the continued need to address socioeconomic inequities in access to dental care, along with strategies to overcome barriers for those who are obese or smoke. In this study, barriers to access existed for women of all ages, indicating that interventions need to be appropriate across age groups.

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.