Menopause depression: Under recognised and poorly treated.

Menopause is a biological process experienced by all people assigned female at birth. A significant number of women experience mental ill health related to the major brain gonadal hormone shifts that occur in their midlife. There is poor understanding and management of the complex mental ill health issues, with the biological brain hormone changes receiving little formal attention. The current treatment advice is to manage this special type of mental ill health in the same way that all mental ill health is managed. This leads to poor outcomes for women and their families. Many women leave the workforce earlier than expected due to menopause-related depression and anxiety, with subsequent loss of salary and superannuation. Others describe being unable to adequately parent or maintain meaningful relationships - all ending in a poor quality of life. We are a large and diverse group of national and international clinicians, lived experience and social community advocates, all working together to innovate the current approaches available for women with menopausal mental ill health. Above all, true innovation is only possible when the woman with lived experience of menopause is front and centre of this debate.

A 10-year update to the principles for clinical trial data sharing by pharmaceutical companies: perspectives based on a decade of literature and policies.

Data sharing is essential for promoting scientific discoveries and informed decision-making in clinical practice. In 2013, PhRMA/EFPIA recognised the importance of data sharing and supported initiatives to enhance clinical trial data transparency and promote scientific advancements. However, despite these commitments, recent investigations indicate significant scope for improvements in data sharing by the pharmaceutical industry. Drawing on a decade of literature and policy developments, this article presents perspectives from a multidisciplinary team of researchers, clinicians, and consumers. The focus is on policy and process updates to the PhRMA/EFPIA 2013 data sharing commitments, aiming to enhance the sharing and accessibility of participant-level data, clinical study reports, protocols, statistical analysis plans, lay summaries, and result publications from pharmaceutical industry-sponsored trials. The proposed updates provide clear recommendations regarding which data should be shared, when it should be shared, and under what conditions. The suggested improvements aim to develop a data sharing ecosystem that supports science and patient-centred care. Good data sharing principles require resources, time, and commitment. Notwithstanding these challenges, enhancing data sharing is necessary for efficient resource utilization, increased scientific collaboration, and better decision-making for patients and healthcare professionals.

Rationale and design for the myocardial ischemia and transfusion (MINT) randomized clinical trial.

BACKGROUND: Accumulating evidence from clinical trials suggests that a lower (restrictive) hemoglobin threshold (<8 g/dL) for red blood cell (RBC) transfusion, compared with a higher (liberal) threshold (≥10 g/dL) is safe. However, in anemic patients with acute myocardial infarction (MI), maintaining a higher hemoglobin level may increase oxygen delivery to vulnerable myocardium resulting in improved clinical outcomes. Conversely, RBC transfusion may result in increased blood viscosity, vascular inflammation, and reduction in available nitric oxide resulting in worse clinical outcomes. We hypothesize that a liberal transfusion strategy would improve clinical outcomes as compared to a more restrictive strategy. METHODS: We will enroll 3500 patients with acute MI (type 1, 2, 4b or 4c) as defined by the Third Universal Definition of MI and a hemoglobin <10 g/dL at 144 centers in the United States, Canada, France, Brazil, New Zealand, and Australia. We randomly assign trial participants to a liberal or restrictive transfusion strategy. Participants assigned to the liberal strategy receive transfusion of RBCs sufficient to raise their hemoglobin to at least 10 g/dL. Participants assigned to the restrictive strategy are permitted to receive transfusion of RBCs if the hemoglobin falls below 8 g/dL or for persistent angina despite medical therapy. We will contact each participant at 30 days to assess clinical outcomes and at 180 days to ascertain vital status. The primary end point is a composite of all-cause death or recurrent MI through 30 days following randomization. Secondary end points include all-cause mortality at 30 days, recurrent adjudicated MI, and the composite outcome of all-cause mortality, nonfatal recurrent MI, ischemia driven unscheduled coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting), or readmission to the hospital for ischemic cardiac diagnosis within 30 days. The trial will assess multiple tertiary end points. CONCLUSIONS: The MINT trial will inform RBC transfusion practice in patients with acute MI.

Classification performance of clinical risk scoring in suspected acute coronary syndrome beyond a rule-out troponin profile.

AIMS: High-sensitivity cardiac troponin strategies can provide risk stratification in patients with suspected acute coronary syndrome (ACS) in the emergency department (ED). This study evaluated whether clinical risk scoring improves the classification performance of a rule-out profile in suspected ACS. METHODS AND RESULTS: Patients presenting to ED with suspected ACS as part of the RAPID-TnT trial randomized to the intervention arm were included. Results ≥5 ng/L were available for all participants in this analysis. We evaluated the Thrombolysis In Myocardial Infarction (TIMI) risk score, History ECG Age Risk factors Troponin (HEART) score, and Emergency Department Assessment of Chest pain Score (EDACS) in addition to a rule-out profile based on the 0/1-h high-sensitivity cardiac troponin T protocol (<5 ng/L or ≤12 ng/L and a change of <3 ng/L at 1-h) using test performance parameters focusing on low-risk groups to identify the primary endpoint (TIMI ≤ 1, HEART ≤ 3, EDACS < 16). Primary endpoint was a composite of type 1/2 myocardial infarction (MI) at index presentation and all-cause mortality or type 1/2 MI at 30 days. A total of 3378 participants were enrolled between August 2015 and April 2019 of which 108 were ineligible/withdrew consent (intervention arm: n = 1638). Sensitivity, specificity, negative predictive value (NPV), and area under the curve (AUC) of the rule-out profile was 94.4%, 76.8%, 99.6%, and 0.86, respectively with 72.9% identified as 'low-risk'. Adding the clinical risk scores did not improve the sensitivity, NPV, or AUC with significantly lower specificity and 'low-risk' classified participants. CONCLUSIONS: Addition of clinical risk scores to rule-out profile did not demonstrate improved classification performance for identifying the composite of type 1/2 MI at index presentation and all-cause mortality or type 1/2 MI at 30 days. CLINICAL TRIALS REGISTRATION: URL: https://www.anzctr.org.au. Reg. No. ACTRN12615001379505.

Late Outcomes of the RAPID-TnT Randomized Controlled Trial: 0/1-Hour High-Sensitivity Troponin T Protocol in Suspected ACS.

BACKGROUND: High-sensitivity troponin assays are increasingly being adopted to expedite evaluation of patients with suspected acute coronary syndromes. Few direct comparisons have examined whether the enhanced performance of these assays at low concentrations leads to changes in care that improves longer-term outcomes. This study evaluated late outcomes of participants managed under an unmasked 0/1-hour high-sensitivity cardiac troponin T (hs-cTnT) protocol compared with a 0/3-hour masked hs-cTnT protocol. METHODS: We conducted a multicenter prospective patient-level randomized comparison of care informed by unmasked 0/1-hour hs-cTnT protocol (reported to <5 ng/L) versus standard practice masked hs-cTnT testing (reported to ≤29 ng/L) assessed at 0/3 hours and followed participants for 12 months. Participants included were those presenting to metropolitan emergency departments with suspected acute coronary syndromes, without ECG evidence of coronary ischemia. The primary end point was time to all-cause death or myocardial infarction using Cox proportional hazards models adjusted for clustering within hospitals. RESULTS: Between August 2015 and April 2019, we randomized 3378 participants, of whom 108 withdrew, resulting in 12-month follow-up for 3270 participants (masked: 1632; unmasked: 1638). Among these, 2993 (91.5%) had an initial troponin concentration of ≤29 ng/L. Deployment of the 0/1-hour hs-cTnT protocol was associated with reductions in functional testing. Over 12-month follow-up, there was no difference in invasive coronary angiography (0/1-hour unmasked: 232/1638 [14.2%]; 0/3-hour masked: 202/1632 [12.4%]; P=0.13), although an increase was seen among patients with hs-cTnT levels within the masked range (0/1-hour unmasked arm: 168/1507 [11.2%]; 0/3-hour masked arm: 124/1486 [8.3%]; P=0.010). By 12 months, all-cause death and myocardial infarction did not differ between study arms overall (0/1-hour: 82/1638 [5.0%] versus 0/3-hour: 62/1632 [3.8%]; hazard ratio, 1.32 [95% CI, 0.95-1.83]; P=0.10). Among participants with initial troponin T concentrations ≤29 ng/L, unmasked hs-cTnT reporting was associated with an increase in death or myocardial infarction (0/1-hour: 55/1507 [3.7%] versus 0/3-hour: 34/1486 [2.3%]; hazard ratio, 1.60 [95% CI, 1.05-2.46]; P=0.030). CONCLUSIONS: Unmasked hs-cTnT reporting deployed within a 0/1-hour protocol did not reduce ischemic events over 12-month follow-up. Changes in practice associated with the implementation of this protocol may be associated with an increase in death and myocardial infarction among those with newly identified troponin elevations. Registration: URL: https://www.anzctr.org.au; Unique identifier: ACTRN12615001379505.

Objective Risk Assessment vs Standard Care for Acute Coronary Syndromes: A Randomized Clinical Trial.

Importance: Although international guidelines recommend use of the Global Registries of Acute Coronary Events (GRACE) risk score (GRS) to guide acute coronary syndrome (ACS) treatment decisions, the prospective utility of the GRS in improving care and outcomes is unproven. Objective: To assess the effect of routine GRS implementation on guideline-indicated treatments and clinical outcomes of hospitalized patients with ACS. Design, Setting, and Participants: Prospective cluster (hospital-level) randomized open-label blinded end point (PROBE) clinical trial using a multicenter ACS registry of acute care cardiology services. Fixed sampling of the first 10 patients within calendar month, with either ST-segment elevation or non-ST-segment elevation ACS. The study enrolled patients from June 2014 to March 2018, and data were analyzed between February 2020 and April 2020. Interventions: Implementation of routine risk stratification using the GRS and guideline recommendations. Main Outcomes and Measures: The primary outcome was a performance score based on receipt of early invasive treatment, discharge prescription of 4 of 5 guideline-recommended pharmacotherapies, and cardiac rehabilitation referral. Clinical outcomes included a composite of all-cause death and/or myocardial infarction (MI) within 1 year. Results: This study enrolled 2318 patients from 24 hospitals and was stopped prematurely owing to futility. Of the patients enrolled, median age was 65 years (interquartile range, 56-74 years), 29.5% were women (n = 684), and 62.9% were considered high risk (n = 1433). Provision of all 3 measures among high-risk patients did not differ between the randomized arms (GRS: 424 of 717 [59.9%] vs control: 376 of 681 [55.2%]; odds ratio [OR], 1.04; 95% CI, 0.63-1.71; P = .88). The provision of early invasive treatment was increased compared with the control arm (GRS: 1042 of 1135 [91.8%] vs control: 989 of 1183 [83.6%]; OR, 2.26; 95% CI, 1.30-3.96; P = .004). Prescription of 4 of 5 guideline-recommended pharmacotherapies (GRS: 864 of 1135 [76.7%] vs control: 893 of 1183 [77.5%]; OR, 0.97; 95% CI, 0.68-1.38) and cardiac rehabilitation (GRS: 855 of 1135 [75.1%] vs control: 861 of 1183 [72.8%]; OR, 0.68; 95% CI, 0.32-1.44) were not different. By 12 months, GRS intervention was not associated with a significant reduction in death or MI compared with the control group (GRS: 96 of 1044 [9.2%] vs control: 146 of 1087 [13.4%]; OR, 0.66; 95% CI, 0.38-1.14). Conclusions and Relevance: Routine GRS implementation in cardiology services with high levels of clinical care was associated with an increase in early invasive treatment but not other aspects of care. Low event rates and premature study discontinuation indicates the need for further, larger scale randomized studies. Trial Registration: anzctr.org.au Identifier: ACTRN12614000550606.

Can the Wii Fit Balance Board be Used as a Fall Risk Assessment Tool among Poststroke Patients?

BACKGROUND: The prevalence of falls can be as high as 73% in the stroke population. Falls occur as a result of multiple factors. Factors such as balance impairments can be improved through physical therapy intervention. However, insurance payers limit the number of visits per patient. It is crucial to find other ways to assess balance after discharge from rehabilitation. PURPOSE: The purpose of this study is to determine if the Nintendo Wii Fit can be used as a fall risk assessment tool among the poststroke population. METHODOLOGY: A sample of 11 stroke survivors were recruited (mean age 63.36 years). Each participant completed a balance and fall risk assessment using the Berg Balance Scale, Timed Up & Go, Four Square Step Test, Five Times Sit-to-Stand and 8-Foot Walk Test. Bivariate correlation will examine the validity of the Nintendo Wii Fit as a fall risk assessment tool in this population. RESULTS: The Nintendo Wii Fit Balance Test was found to be correlated with gait speed measured by the 8-Foot Walk Test. There is no correlation between the Wii Fit Balance Tests and most common standardized fall risk measures. Standardized fall risk outcome measures also significantly correlate with each other. CONCLUSIONS: The study suggests that while there is a potential utility of the game system to be used at home by patient and caregivers, the Wii Fit Balance Test may not be an appropriate substitute to the standardized fall risk assessment tool for stroke patients in the clinical setting.

A Randomized Trial of a 1-Hour Troponin T Protocol in Suspected Acute Coronary Syndromes: The Rapid Assessment of Possible Acute Coronary Syndrome in the Emergency Department With High-Sensitivity Troponin T Study (RAPID-TnT).

BACKGROUND: High-sensitivity troponin assays promise earlier discrimination of myocardial infarction. Yet, the benefits and harms of this improved discriminatory performance when incorporated within rapid testing protocols, with respect to subsequent testing and clinical events, has not been evaluated in an in-practice patient-level randomized study. This multicenter study evaluated the noninferiority of a 0/1-hour high-sensitivity cardiac troponin T (hs-cTnT) protocol in comparison with a 0/3-hour masked hs-cTnT protocol in patients with suspected acute coronary syndrome presenting to the emergency department (ED). METHODS: Patients were randomly assigned to either a 0/1-hour hs-cTnT protocol (reported to the limit of detection [<5 ng/L]) or masked hs-cTnT reported to ≤29 ng/L evaluated at 0/3-hours (standard arm). The 30-day primary end point was all-cause death and myocardial infarction. Noninferiority was defined as an absolute margin of 0.5% determined by Poisson regression. RESULTS: In total, 3378 participants with an emergency presentation were randomly assigned between August 2015 and April 2019. Ninety participants were deemed ineligible or withdrew consent. The remaining participants received care guided either by the 0/1-hour hs-cTnT protocol (n=1646) or the 0/3-hour standard masked hs-cTnT protocol (n=1642) and were followed for 30 days. Median age was 59 (49-70) years, and 47% were female. Participants in the 0/1-hour arm were more likely to be discharged from the ED (0/1-hour arm: 45.1% versus standard arm: 32.3%, P<0.001) and median ED length of stay was shorter (0/1-hour arm: 4.6 [interquartile range, 3.4-6.4] hours versus standard arm: 5.6 (interquartile range, 4.0-7.1) hours, P<0.001). Those randomly assigned to the 0/1-hour protocol were less likely to undergo functional cardiac testing (0/1-hour arm: 7.5% versus standard arm: 11.0%, P<0.001). The 0/1-hour hs-cTnT protocol was not inferior to standard care (0/1-hour arm: 17/1646 [1.0%] versus 16/1642 [1.0%]; incidence rate ratio, 1.06 [ 0.53-2.11], noninferiority P value=0.006, superiority P value=0.867), although an increase in myocardial injury was observed. Among patients discharged from ED, the 0/1-hour protocol had a negative predictive value of 99.6% (95% CI, 99.0-99.9%) for 30-day death or myocardial infarction. CONCLUSIONS: This in-practice evaluation of a 0/1-hour hs-cTnT protocol embedded in ED care enabled more rapid discharge of patients with suspected acute coronary syndrome. Improving short-term outcomes among patients with newly recognized troponin T elevation will require an evolution in management strategies for these patients. CLINICAL TRIAL REGISTRATION: URL: https://www.anzctr.org.au. Unique identifier: ACTRN12615001379505.

The appropriateness of coronary investigation in myocardial injury and type 2 myocardial infarction (ACT-2): A randomized trial design.

BACKGROUND: Elevated troponin level findings among patients presenting with suspected acute coronary syndrome (ACS) or another intercurrent illness undeniably identifies patients at increased risk of mortality. Whilst enhancing our capacity to discriminate risk, the use of high-sensitivity troponin assays frequently identifies patients with myocardial injury (i.e. troponin rise without acute signs of myocardial ischemia) or type 2 myocardial infarction (T2MI; oxygen supply-demand imbalance). This leads to the clinically challenging task of distinguishing type 1 myocardial infarction (T1MI; coronary plaque rupture) from myocardial injury and T2MI in the context of concurrent acute illness. Diagnostic discernment in this context is crucial because MI classification has implications for further investigation and care. Early invasive management is of well-established benefit among patients with T1MI. However, the appropriateness of this investigation in the heterogeneous context of T2MI, where there is high competing mortality risk, remains unknown. Although coronary angiography in T2MI is advocated by some, there is insufficient evidence in existing literature to support this opinion as highlighted by current national guidelines. OBJECTIVE: The objective is to evaluate the clinical and economic impact of early invasive management with coronary angiography in T2MI in terms of all-cause mortality and cost effectiveness. DESIGN: This prospective, pragmatic, multicenter, randomized trial among patients with suspected supply demand ischemia leading to troponin elevation (n=1,800; T2MI [1,500], chronic myocardial injury [300]) compares the impact of invasive angiography (or computed tomography angiography as per local preference) within 5 days of randomization versus conservative management (with or without functional testing at clinician discretion) on all-cause mortality by 2 years. Randomized treatment allocation will be stratified by baseline estimated risk of mortality using the Acute Physiology, Age, and Chronic Health Evaluation (APACHE) III risk score. Cost-effectiveness will be evaluated by follow-up on clinical events, quality of life, and resource utilization over 24 months. SUMMARY: Ascertaining the most appropriate first-line investigative strategy for these commonly encountered high-risk T2MI patients in a randomized comparative study will be pivotal in informing evidence-based guidelines that lead to better patient and health care outcomes.

A randomized trial of a 1-hour troponin T protocol in suspected acute coronary syndromes: Design of the Rapid Assessment of Possible ACS In the emergency Department with high sensitivity Troponin T (RAPID-TnT) study.

BACKGROUND: Protocols incorporating high-sensitivity troponin to guide decision making in the disposition of patients with suspected acute coronary syndromes (ACS) in the emergency department have received a lot of attention. Traditionally, patients with chest pain have required long periods of observation in emergency department before being deemed safe for discharge. In an era of limited health service resources, a protocol that could discharge patients safely within an hour of presentation is extremely attractive. Unfortunately, despite incorporation into some guidelines, these protocols have not been subjected to randomized comparisons evaluating safety, effectiveness, and cost-effectiveness. OBJECTIVE: This study is designed to provide the evidence required to allow key decision makers to implement these protocols: specifically, to provide evidence that a decision rule based on 0- and 1-hour high-sensitivity troponin T (hs-TnT) is safe, provides noninferior outcomes in all patients with suspected ACS, and that implementation of a rapid troponin protocol leads to efficient care. DESIGN: This prospective pragmatic trial (n=5,400, 5 hospitals) randomly allocates patients with suspected ACS to either a 0/1-hour hs-TnT protocol as advocated in clinical guidelines, versus usual care of standard troponin reporting evaluated at 3 and 6hours. The primary effectiveness composite end points of this study are all-cause death and new/recurrent ACS within 30days. To evaluate cost-effectiveness, follow-up will determine clinical events, quality of life, and resource utilization within 12 months. SUMMARY: Demonstrating that a 0/1-hour hs-TnT protocol improves the effectiveness and efficiency of care within a robust comparative study will fill an evidence gap that currently limits the translation of more precise hs-TnT testing into better patient and health service outcomes.

Rater reliability and scoring duration of the Quality Function Measure in ambulant children with hyperkinetic movement disorders.

AIM: To examine intra- and interrater reliability/agreement, and time taken to score, when the Quality Function Measure (QFM) is applied to children with hyperkinetic movement disorders (HMD; e.g. dystonia, chorea, athetosis, tremor, and myoclonus). METHOD: Fifteen ambulant children with HMD participated (eight males, seven females; mean age 13y 7mo, SD 3y 7mo). Three trained raters (two physiotherapists, one occupational therapist) independently scored the QFM using videos of each child performing Gross Motor Function Measure (GMFM) Stand and Walk/Run/Jump dimensions. Reliability was evaluated using intraclass correlation coefficient (ICC) model 2.1, Standard Error of Measurement (SEM), and Bland-Altman methods. RESULTS: Rater reliability was excellent for all five QFM attributes: intrarater ICCs ≥0.98 (95% confidence interval [CI] 0.83-1.00), and interrater ICCs ≥0.96 (95% CI 0.91-1.00). SEM varied from 2.07% to 4.72% points for intra- and interrater scores across QFM attributes. Bland-Altman tests demonstrated close agreement between ratings, with absolute mean differences varying from 0.34% to 3.23% (intrarater) to 1.67% to 3.82% (interrater). Median scoring duration time was 83 minutes (range 56-144min, SD 16.02). INTERPRETATION: Low measurement error attributable to rater effects suggests the QFM has potential as an evaluative measure in research studies involving children with HMD, though its lengthy scoring requirements are an important consideration for clinical practice. Evaluation of test-retest reliability and responsiveness is required.

Stereoselective quantification of methadone and a d(6)-labeled isotopomer using high performance liquid chromatography-atmospheric pressure chemical ionization mass-spectrometry: application to a pharmacokinetic study in a methadone maintained subject.

There is evidence that the apparent oral clearance of rac-methadone is induced during the early phase of methadone maintenance treatment. However, it is not known if this is due to changes in bioavailability or if this phenomenon is stereoselective. This knowledge can be obtained by administering a dose of stable-labeled methadone at selected times during ongoing treatment. Therefore, the authors developed a stereoselective high performance liquid chromatography-atmospheric pressure chemical ionization mass-spectrometry assay for the quantification of the enantiomers of methadone and a d(6)-labeled isotopomer. The compounds were quantified in a single assay after liquid-liquid extraction and stereoselective high performance liquid chromatograph with atmospheric pressure chemical ionization-mass spectrometry detection. The following ions were monitored: m/z 310.15 for unlabeled methadone; m/z 316.15 for methadone-d(6); and m/z 313.15 for the methadone-d(3) (internal standard). Calibration curves ranged from 0.5 to 75 ng/mL for each compound. Extraction recovery was approximately 80% for all analytes, without evidence of differences between the unlabeled and stable-labeled compounds or concentration dependency. Minor ion promotion was observed (<15%) but this was identical for all analytes including the d(3)-labeled internal standard, with peak area ratios in extracted samples identical to control injections. The isotopomers did not alter each others' ionisation, even at 10:1 concentration ratios, and 10-fold diluted samples were within 10% of the nominal concentration. Assay performance was acceptable, with interassay and intra-assay bias and precision <10% for all compounds, including the upper and lower limits of quantitation. In conclusion, the assay was successfully applied to quantify the concentration of the methadone enantiomers of both orally administered unlabeled methadone and an intravenous 5 mg dose of methadone-d(6) in a patient receiving chronic oral methadone maintenance therapy.