Bone health in women with premature ovarian insufficiency/early menopause: a 23-year longitudinal analysis.

STUDY QUESTION: What is the frequency of, and predictors for, osteoporosis, fractures, and osteoporosis management (investigation, treatment) in women with premature ovarian insufficiency (POI; menopause <40 years) and early menopause (EM; menopause 40-44years)? SUMMARY ANSWER: Over the 23-year follow-up duration, at a mean age of 68 years, women with POI/EM had higher osteoporosis/fracture risk and prevalence, higher osteoporosis screening and anti-osteoporosis medication use compared to women with usual age menopause; increasing age was predictive of increased risk of osteoporosis/fracture and menopause hormone therapy (MHT) prior to or at study entry (aged 45-50 years) was protective. WHAT IS KNOWN ALREADY: Women with POI/EM have increased risk of osteoporosis and fractures with limited data regarding risk factors for reduced bone density and fractures. Clinical guidelines recommend screening with dual X-ray absorptiometry (DXA) and treatment with MHT for most women with POI/EM to reduce osteoporosis and fracture risk; however, studies indicate gaps in osteoporosis knowledge, guideline uptake, and management adherence by clinicians and women. STUDY DESIGN, SIZE, DURATION: The Australian Longitudinal Study on Women's Health is a prospective longitudinal study of Australian women. This study uses the cohort of women born between 1946 and 1951, surveyed nine times between 1996 and 2019. Data from the Australian administrative health records, including hospital admissions data (fractures, osteoporosis), Medicare Benefits Schedule (DXA), and the Pharmaceutical Benefits Scheme (PBS; MHT, anti-osteoporosis medication, available only from 2002) were linked to survey data. PARTICIPANTS/MATERIALS, SETTING, METHODS: Survey respondents with self-reported age of menopause were included. POI/EM was defined as menopause <45 years. T-test or chi-square were used for comparisons at baseline (P < 0.05 indicates significance). Generalized estimating equations for panel data explored predictors for the longitudinal outcomes of osteoporosis, fractures, DXA rates, MHT use, and anti-osteoporosis medication (in women with osteoporosis/fracture, from Survey 4 onwards only). Univariable regression was performed, and variables retained where P < 0.2, to form the multivariable model, and bootstrapping with 100 repetitions at 95% sampling of the original dataset to ensure robustness of results. MAIN RESULTS AND THE ROLE OF CHANCE: Eight thousand six hundred and three women were included: 610 (7.1%) with POI/EM. Mean (SD) baseline age was 47.6 (1.45) years in the entire cohort and mean (SD) age of menopause was 38.2 (7.95) and 51.3 (3.04) years in women with POI/EM and usual age menopause, respectively (P < 0.001). Over the 23 years, of women with POI/EM, 303 (49.7%) had osteoporosis/fractures, 421 (69.0%) had DXA screening, 474 ever used MHT (77.7%), and 116 (39.1%) of those with osteoporosis/fractures used anti-osteoporosis medication. Of women with usual age menopause, 2929 (36.6%) had osteoporosis/fractures, 4920 (61.6%) had DXA screening, 4014 (50.2%) used MHT, and 964 (33.0%) of those with osteoporosis/fractures used anti-osteoporosis medication. Compared to women with menopause at age ≥45 years and after adjusting for other risk factors, women with POI/EM had increased risk of osteoporosis (odds ratio [OR] 1.37; 95% CI 1.07-1.77), fractures (OR 1.45; 1.15-1.81), DXA testing (OR 1.64; 1.42-1.90), MHT use (OR 6.87; 5.68-8.30), and anti-osteoporosis medication use (OR 1.50; 1.14-1.98). In women with POI/EM women, increasing age was associated with greater risk of osteoporosis/fracture (OR 1.09; 1.08-1.11), and MHT prior to or at study entry (aged 45-50 years), was protective (OR 0.65, 0.45-0.96). In women with POI/EM, age (OR 1.11; 1.10-1.12), fractures (OR 1.80, 1.38-2.34), current smoking (OR 0.60; 0.43-0.86), and inner (OR 0.68; 0.53-0.88) or outer regional (OR 0.63; 0.46-0.87) residential location were associated with DXA screening. In women with POI/EM, increasing age (OR 1.02; 1.01-1.02), and currently consuming alcohol (OR 1.17; 1.06-1.28), was associated with having ever used MHT. In the 299 women with POI/EM and osteoporosis/fractures, only 39.1% ever received treatment with an anti-osteoporosis medication. Increasing age (OR 1.07; 1.04-1.09) and lower BMI (OR 0.95; 0.92-0.98) were associated with greater likelihood of treatment with anti-osteoporosis medication. LIMITATIONS, REASONS FOR CAUTION: Survey data including age of menopause were self-reported by participants; fracture questions were not included in the 2001 survey, and location or level of trauma of self-reported fractures was not asked. Additional risk/protective factors such as vitamin D status, calcium intake, and exercise were not able to be included. Due to sample size, POI and EM were combined for all analyses, and we were unable to differentiate between causes of POI/EM. PBS data were only available from 2004, and hospital admissions data were state-based, with all of Australia were only available from 2007. WIDER IMPLICATIONS OF THE FINDINGS: This study supports previous literature indicating increased risk of osteoporosis and fractures in women with POI, and adds evidence for women with POI/EM, where there was a relative paucity of data. This is the first study to analyse a variety of clinical and demographic risk factors for osteoporosis and fractures in women with POI/EM, as well as analysing investigation and treatment rates. In these women, using MHT prior to or at study entry, aged 45-50 years, was protective for osteoporosis/fractures; however, having ever used MHT was not, highlighting the importance of early treatment with MHT in these women to preserve bone strength. Although women with POI/EM and osteoporosis or fractures were more likely to use anti-osteoporosis medications than those with usual age menopause, overall treatment rates are low at <40%, demonstrating a significant treatment gap that should be addressed to reduce future fracture risk. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by The Australian NHMRC Centre of Research Excellence Women's Health in Reproductive Life (CRE-WHIRL, project number APP1171592). A.R.J. is the recipient of a National Health and Medical Research Council post-graduate research scholarship (grant number 1169192). P.R.E. is supported by a National Health and Medical Research Council grant 1197958. P.R.E. reports grants paid to their institution from Amgen, Sanofi, and Alexion, honoraria from Amgen paid to their institution, and honoraria from Alexion and Kyowa-Kirin. TRIAL REGISTRATION NUMBER: N/A.

Learning health systems and evidence ecosystems: a perspective on the future of evidence-based medicine and evidence-based guideline development.

Despite forming the cornerstone of modern clinical practice for decades, implementation of evidence-based medicine at scale remains a crucial challenge for health systems. As a result, there has been a growing need for conceptual models to better contextualise and pragmatize the use of evidence-based medicine, particularly in tandem with patient-centred care. In this commentary, we highlight the emergence of the learning health system as one such model and analyse its potential role in pragmatizing both evidence-based medicine and patient-centred care. We apply the learning health system lens to contextualise the key activity of evidence-based guideline development and implementation, and highlight how current inefficiencies and bottlenecks in the evidence synthesis phase of evidence-based guideline development threaten downstream adherence. Lastly, we introduce the evidence ecosystem as a complementary model to learning health systems, and propose how innovative developments from the evidence ecosystem may be integrated with learning health systems to better enable health impact at speed and scale.

Externally validated prediction models for pre-eclampsia: systematic review and meta-analysis.

OBJECTIVE: This systematic review and meta-analysis aimed to evaluate the performance of existing externally validated prediction models for pre-eclampsia (specifically for any- early- late-onset and preterm pre-eclampsia). METHODS: A systematic search was conducted in five databases (MEDLINE, Embase, Emcare, CINAHL, and Maternity and Infant Care Database) to identify studies based on Population, Index model, Comparator, Outcome, Timing, and Setting (PICOTS) approach until May 20, 2023. We extracted data using the CHARMS checklist and appraised risk of bias using PROBAST tool. Discrimination and calibration performance were meta-analysed when appropriate. RESULTS: Twenty-three publications reported 52 externally validated prediction models on pre-eclampsia (twenty any-onset, seventeen early-onset, fourteen late-onset, and one preterm pre-eclampsia). No model had the same set of predictors. Fifteen, two, and three any-onset pre-eclampsia models were externally validated once, twice, and thrice, respectively, and the Fetal Medicine Foundation (FMF) preterm model was widely validated in sixteen different settings. The most common predictors were maternal characteristics (pre-pregnancy BMI, prior pre-eclampsia, family history of pre-eclampsia, chronic medical conditions, and ethnicity) and biomarkers (uterine artery pulsatility index and pregnancy-associated plasma protein-A). The model for preterm pre-eclampsia (triple test FMF) had the best performances with a pooled area under the receiver operating characteristics curve (AUROC) of 0.90 (95% prediction interval (PI) 0.76 - 0.96) and was well-calibrated. The other models generally had poor to fair discrimination performance (AUROC median 0.66, range 0.53 to 0.77) and were overfitted in calibration after external validation. Apart from the FMF model, only the two most validated models in any-onset pre-eclampsia using isolated maternal characteristics, produced reasonable pooled AUROCs of 0.71 (95% PI 0.66 - 0.76) and 0.73 (0.55 - 0.86). CONCLUSION: Existing externally validated prediction models for any-, early-, and late-onset pre-eclampsia have limited discrimination and calibration performance with inconsistent input variables. The triple test FMF model had excellent discrimination performance in predicting preterm pre-eclampsia in numerous settings, but the inclusion of specialised biomarkers may limit feasibility and implementation outside of high-resource settings. This article is protected by copyright. All rights reserved.

Increased mortality and non-cancer morbidity risk may be associated with early menopause and varies with aetiology: An exploratory population-based study using data-linkage.

OBJECTIVE: Iatrogenic early menopause (EM), that is, menopause before the age of 45 years due to surgery or chemotherapy or radiotherapy, is associated with negative health impacts. However, it is unclear how these vary according to the cause of EM. We investigated mortality and non-cancer morbidity in women with iatrogenic EM of different aetiologies. STUDY DESIGN: Population-based retrospective cohort study with 36-year follow-up using data-linkage with the Western Australia hospital morbidity database, cancer, birth and death registries, the midwives notification system and the mental health information system. The sample comprised women aged 20-44 years at index date with iatrogenic EM associated with breast or gynaecological cancer (n = 607), or benign bilateral oophorectomy (n = 414), and age-matched female controls (n = 16,998). Index date (breast, ovarian or uterine cancer diagnosis or oophorectomy procedure) ranged from 1982 to 1997, with follow-up until 2018. MAIN OUTCOME MEASURES: Mortality and hospitalisation for circulatory disorders, endocrine, psychological, respiratory, musculoskeletal and gastrointestinal morbidities. RESULTS: Significant differences in mortality were observed (% dead by follow-up: cancer, 53.0; oophorectomy, 10.9; and controls, 3.5; p < 0.001). Incidence rate ratios (IRRs) were increased for circulatory (1.23, 95 % CI 1.07-1.42) and endocrine disorders (1.31, 95%CI 1.08-1.56) and hip fracture (3.90, 95 % CI 1.83-7.40) in cancer survivors, compared with controls. IRRs for circulatory (0.62, 95 % CI 0.53-0.72) and endocrine disorders (0.62, 95 % CI 0.38-0.97) were reduced in the oophorectomy group, but were increased for psychological (8.53, 95 % CI 7.29-9.94) and gastrointestinal morbidities (1.43, 95%CI 1.21-1.67) compared with controls. CONCLUSION: Cancer-related or benign iatrogenic EM may be associated with increased mortality and morbidity, which vary with the cause of EM.

Recruiting for research on sensitive topics in schools: an experience with Vaxcards, a collectable vaccine card game.

Undertaking recruitment for research in schools is an effective way to recruit young people for research participation but it is not without its challenges. Gaining access and coordinating many levels of different organisations and stakeholders whose cooperation and approval are crucial all add time and sometimes logistical challenges for the research team. In addition, recruiting around sensitive research topics can elicit additional barriers to successful research. The research team aimed to conduct a pragmatic cluster randomised controlled trial involving schools in a local government region in Victoria, Australia, to assess the effect of a vaccination-based educational card game called "Vaxcards" on vaccine consent returns. Schools were contacted via phone and email to determine which staff member would best be a contact point for a face-to-face meeting to discuss the methods and purpose of the study. Email follow-ups were scheduled to follow up non-responsive schools and consent forms. The minimum required sample size was 13. Of 31 eligible schools, 13 were recruited. The research team encountered several unanticipated challenges before achieving the recruitment target. The most common reasons for non-participation were being too busy with other commitments, concerns regarding the topic of vaccination being too sensitive, and concerns that key stakeholders in the school would not approve of the research topic of vaccination. One school required a review by a private research ethics board that rejected the study. Significant hesitancy and misinformation about vaccine science was observed that affected engagement with a small number of schools. This paper highlights the challenges of recruiting schools in the context of public anxieties about vaccines and has several important learning lessons for successful recruitment about sensitive topics. This includes navigating approval processes for research in schools, the importance of local champions, dealing with misinformation and the importance of strong relationships and organisational trust. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12618001753246 . Prospectively registered on 25 October 2018 8:24:21 AM.

The diabetes-fracture association in women with type 1 and type 2 diabetes is partially mediated by falls: a 15-year longitudinal study.

This study evaluated mediators of fracture risk in postmenopausal women with type 1 (T1D) and type 2 diabetes (T2D), over a 15-year follow-up period. This study provides evidence that the increased fracture risk in women with T1D or T2D is partially explained by falls. Furthermore, a shorter reproductive lifespan in women with T1D contributes modestly to fracture risk in this cohort. PURPOSE: Skeletal fragility is associated with diabetes mellitus, while limited estrogen exposure during the reproductive years also predisposes to lower bone mass and higher fracture risk. We aimed to determine osteoporosis diagnosis, fall and fracture rates in women with type 1 (T1D) and type 2 (T2D) diabetes mellitus, and explore mediators of the diabetes-fracture relationship. METHODS: Prospective observational data drawn from the Australian Longitudinal Study in Women's Health (ALSWH) from 1996 to 2010. Women were randomly selected from the national health insurance database. Standardized data collection occurred at six survey time points, with main outcome measures being self-reported osteoporosis, incident fracture, falls, and reproductive lifespan. Mediation analyses were performed to elucidate relevant intermediaries in the diabetes-fracture relationship. RESULTS: Exactly 11,313 women were included at baseline (T1D, n = 107; T2D, n = 333; controls, n = 10,873). A total of 885 new cases of osteoporosis and 1099 incident fractures were reported over 15 years. Women with T1D or T2D reported more falls and fall-related injuries; additionally, women with T1D had a shorter reproductive lifespan. While fracture risk was increased in women with diabetes (T1D: OR 2.28, 95% CI 1.53-3.40; T2D: OR 2.40, 95% CI 1.90-3.03), compared with controls, adjustment for falls attenuated the risk of fracture by 10% and 6% in T1D and T2D, respectively. In women with T1D, reproductive lifespan modestly attenuated fracture risk by 4%. CONCLUSION: Women with T1D and T2D have an increased risk of fracture, which may be partially explained by increased falls, and to a lesser extent by shorter reproductive lifespan, in T1D.

Methylprednisolone applied directly to the round window reduces dizziness after cochlear implantation: a randomized clinical trial.

This prospective, double-blind controlled, randomized clinical trial of 43 adults showed that topical methylprednisolone applied to the round window during cochlear implantation was effective in protecting inner ear function. Postoperative vestibular disturbance was significantly lower in the steroid group (5%) than the control group (29%). Electrode impedances from the middle portion of the electrode array (electrodes 10-13) were significantly reduced in steroid-treated recipients compared to controls. Hearing and vestibular function analyses were under-powered to detect any drug changes due to limited participant data.

The prognostic value of speech recognition scores at diagnosis of vestibular schwannoma.

We aimed to assess whether speech recognition scores (SRS) are predictive of outcomes in patients with small vestibular schwannoma (VS) undergoing observation. Ninety-five patients with VS whose initial management was observation with serial imaging were retrospectively analysed. Patients were divided into groups according to their average hearing level and SRS at diagnosis. About 60% of patients had good initial SRS (GIS) and 40% had poor initial SRS (PIS). Mean follow-up was 44 months, during which time data were collected regarding hearing level, tumour growth and the eventual management option (continued or failed observation). Observation was discontinued by 24% (23/95) of patients. GIS-patients were more likely to maintain stable hearing than those with PIS (p<0.05). Hearing was stable in 73% (64/87) of patients. These findings indicate that patients with PIS are more vulnerable to progressive hearing loss than those with GIS. Observation may be a suitable management option for all patients with small VS, particularly those with GIS.

Vestibular rehabilitation in individuals with inner-ear dysfunction: a pilot study.

A randomised control prospective study was carried out examining patient outcomes after performing a 10-week vestibular home exercise programme. Thirty-two adults with vestibular dysfunction who reported vestibular symptoms negatively affecting daily life were enrolled. Test subjects were provided with an individualised vestibular rehabilitation programme designed by a physiotherapist. Control subjects received a set of strength and endurance exercises only. All subjects performed their exercises 3 times a day for 10 weeks. Subjective and objective patient measures were collected at 0, 6, 10 and 26 weeks. Results showed that both groups improved after beginning exercise, and that test subjects significantly benefited compared to the controls. These benefits were long term and measurable 6 months later. This study provides evidence that individualised vestibular exercises promote better outcomes for patients with vestibular dysfunction.

The effects of state of alertness on the vestibulo-ocular reflex in normal subjects using the vestibular rotational chair.

Twenty-four subjects with normal vestibular function underwent horizontal sinusoidal harmonic acceleration (SHA) and step-velocity rotational chair assessment twice, first in a heightened state-of-alertness, and second, in a low state-of-alertness. The effects of alertness on vestibulo-ocular reflex gain and time-constant (Tc) were then examined. Although the negative effect on SHA gain had previously been widely reported, the effect on the Tc had not been studied. It was found that SHA gain and step-velocity Tc were significantly and artificially reduced with decreased alertness. On average, SHA gain was reduced by 0.1 at each test frequency and the Tc was reduced from 15.8 seconds to 10.5 seconds. Whilst on average, step-velocity initial gain was only a little affected reducing from 0.53 to 0.49. This very small difference of 0.04 was significant, however, it suggested that this measurement is less affected by patient alertness than SHA gain and Tc.

A comparison of the monothermal and bithermal caloric tests.

This study considered whether the monothermal (MT) caloric test could predict the normality of the full conventional bithermal (BT) caloric test, and therefore be an alternative to full caloric investigation. This would have the advantages of reducing test time and patient discomfort as only two caloric tests would be needed instead of four. 744 BT caloric investigations were examined, and the unilateral weakness and directional preponderance calculated for the BT and the MT stimuli. By defining the BT results as the standard, the false-positive and false-negative results of the MT test were derived. Overall using very strict MT difference criteria of less than 5% and no spontaneous nystagmus, false-negative rates for the cool MT were very low (< 1%) and better than the warm MT (< 7.1%) suggesting that the cool MT was a reliable screen test. However, unacceptably high false-positive rates were produced reflecting more than 3/4 of normal BT results failing the MT criterion. This unacceptable false-positive rate decided against implementing the MT test at our facility. The results of this study however have guided the use of the cool air-stimulus first during BT testing and, when completion of the BT is not possible or inadvisable, satisfying the stringent MT criterion confidently indicates with a probability of > 99% the absence of an abnormal BT result.

Absence of developmental effects in CF-1 mice exposed to aspartame in utero.

Aspartame (L-aspartyl-L-phenylalanine methyl ester) is a widely used high potency dipeptide sweetener. Developmental toxicology studies have been performed in several species documenting no effects of high doses of aspartame. Recently, a study by Mahalik and Gautieri [1984) Res. Commun. Psychol. Psychiatry Behav. 9, 385-403) reported a delay in the achievement age for the visual placing response in mice pups after maternal administration of high dosages of aspartame during late gestation. In the present study developmental parameters were determined in offspring of CF-1 mice after maternal administration of aspartame at 500, 1000, 2000, and 4000 mg/kg body wt by oral gavage. Aspartame was administered on Days 15 through 18 of gestation. Maternal body weight, food consumption, gestation length, reproductive indices, and litter size were not affected by aspartame treatment. In the pups, body weights, negative geotaxis, and surface and midair righting reflexes were not altered by treatment. There was no delay in the development of the visual placing response regardless of the method employed for assessment (grid or rope) or the manner by which the data were analyzed. There were also no changes in time of eye opening, reflex pupil closure, and ophthalmoscopic examination in the offspring. Thus, neither physical nor functional development was altered in mice after in utero exposure to extremely large dosages of aspartame. More specifically, in utero exposure to aspartame did not affect the development of the visual system in mice.