Menopause-Biology, consequences, supportive care, and therapeutic options.

Menopause is the cessation of ovarian function, with loss of reproductive hormone production and irreversible loss of fertility. It is a natural part of reproductive aging. The physiology of the menopause is complex and incompletely understood. Globally, menopause occurs around the age of 49 years, with geographic and ethnic variation. The hormonal changes of the menopause transition may result in both symptoms and long-term systemic effects, predominantly adverse effects on cardiometabolic and musculoskeletal health. The most effective treatment for bothersome menopausal symptoms is evidence-based, menopausal hormone therapy (MHT), which reduces bone loss and may have cardiometabolic benefits. Evidence-based non-hormonal interventions are also available for symptom relief. Treatment should be individualized with shared decision-making. Most MHT regimens are not regulator approved for perimenopausal women. Studies that include perimenopausal women are needed to determine the efficacy and safety of treatment options. Further research is crucial to improve menopause care, along with research to guide policy and clinical practice.

Nephrotoxicity of Vancomycin in Combination With Beta-Lactam Agents: Ceftolozane-Tazobactam vs Piperacillin-Tazobactam.

BACKGROUND: Vancomycin (VAN)-associated acute kidney injury (AKI) is increased when VAN is combined with certain beta-lactams (BLs) such as piperacillin-tazobactam (TZP) but has not been evaluated with ceftolozane-tazobactam (C/T). Our aim was to investigate the AKI incidence of VAN in combination with C/T (VAN/C/T) compared with VAN in combination to TZP (VAN-TZP). METHODS: We conducted a multicenter, observational, comparative study across the United States. The primary analysis was a composite outcome of AKI and risk, injury, failure, loss, end stage renal disease; Acute Kidney Injury Network; or VAN-induced nephrotoxicity according to the consensus guidelines. Multivariable logistic regression analysis was conducted to adjust for confounding variables and stratified Kaplan-Meir analysis to assess the time to nephrotoxicity between the 2 groups. RESULTS: We included VAN/C/T (n = 90) and VAN-TZP (n = 284) at an enrollment ratio of 3:1. The primary outcome occurred in 12.2% vs 25.0% in the VAN-C/T and VAN-TZP groups, respectively (P = .011). After adjusting for confounding variables, VAN-TZP was associated with increased odds of AKI compared with VAN-C/T; with an adjusted odds ratio of 3.308 (95% confidence interval, 1.560-6.993). Results of the stratified Kaplan-Meir analysis with log-rank time-to-nephrotoxicity analysis indicate that time to AKI was significantly shorter among patients who received VAN-TZP (P = .004). Cox proportional hazards analysis demonstrated that TZP was consistent with the primary analysis (P = .001). CONCLUSIONS: Collectively, our results suggest that the AKI is not likely to be related to tazobactam but rather to piperacillin, which is a component in VAN-TZP but not in VAN-C/T.

Q-122 as a novel, non-hormonal, oral treatment for vasomotor symptoms in women taking tamoxifen or an aromatase inhibitor after breast cancer: a phase 2, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Vasomotor symptoms (hot flushes and night sweats) are experienced by more than two-thirds of women with breast cancer taking oral adjuvant endocrine therapy. Safe and effective treatments are lacking. Q-122 is a novel, non-hormonal compound that has shown promise for reducing vasomotor symptoms by modulation of oestrogen-responsive neurons in the hypothalamus. We aimed to assess the efficacy and safety of Q-122 in women with breast cancer taking oral adjuvant endocrine therapy and experiencing vasomotor symptoms. METHODS: We conducted a multicentre, randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial at 18 sites in Australia, New Zealand, and the USA. Eligible participants were women, aged 18-70 years, taking a stable dose of tamoxifen or an aromatase inhibitor following breast cancer and experiencing at least 50 self-reported moderate to severe vasomotor symptoms per week. Participants were randomly assigned (1:1) using an interactive web response system to oral Q-122 100 mg or identical placebo, twice daily for 28 days. Randomisation was stratified by BMI (≤30 kg/m2 or >30 kg/m2) and use of any of a selective serotonin reuptake inhibitor, selective norepinephrine reuptake inhibitor, gabapentin, or pregabalin. Q-122 and placebo capsules were identical in appearance and containers identically labelled. During the double-blind treatment and analysis phases, the participants, investigators, clinical research organisation staff, and sponsor were masked to treatment allocation. The primary outcome was the difference in the mean percentage change from baseline in the Vasomotor Symptom Severity Score of moderate and severe hot flushes and night sweats (msVMS-SS) between Q-122 and placebo after 28 days of treatment. Primary analysis was by modified intention-to-treat and safety was assessed in all participants receiving at least one dose of study drug. This study is registered at ClinicalTrials.gov, NCT03518138. FINDINGS: Between Oct 24, 2018, and Sept 9, 2020, 243 patients were screened, 131 of whom were randomly assigned and received treatment (Q-122 n=65 and placebo n=66). Q-122 resulted in a significantly greater mean percentage change in msVMS-SS from baseline over 28 days of treatment compared with placebo (least squares mean: Q-122 -39% [95% CI -46 to -31] vs placebo -26% [-33 to -18]; p=0·018). Treatment-emergent adverse events were generally mild to moderate and similar between the two groups (treatment-related treatment-emergent adverse events in 11 [17%] of 65 patients in the Q-122 group vs nine [14%] of 66 in the placebo group); zero patients in the Q-122 group and two (3%) patients in the placebo group had serious adverse events. INTERPRETATION: Q-122 is an effective and well tolerated non-hormonal oral treatment for vasomotor symptoms in women taking oral adjuvant endocrine therapy after breast cancer. Our results support the conduct of larger and longer studies of Q-122, with potential use extending to postmenopausal women who require an alternative to menopausal hormone therapy. FUNDING: QUE Oncology.

Endogenous testosterone concentrations and muscle mass, strength and performance in women, a systematic review of observational studies.

OBJECTIVE: To explore the associations between endogenous testosterone blood concentrations and muscle mass, strength and performance in community dwelling women. DESIGN, PATIENTS AND MEASUREMENTS: Online databases, including Ovid MEDLINE, EMBASE and Web of Science, were searched for observational studies, with at least 100 female participants, reporting associations between endogenous testosterone blood concentrations and muscle mass, strength and performance. The findings were synthesized in a narrative review. Heterogeneity in study design and analysis precluded a meta-analysis. RESULTS: Of the 36 articles retrieved for full-text review, 10 met the inclusion criteria. Eight studies were cross-sectional, 1 longitudinal and 1 provided both cross-sectional and longitudinal data. Testosterone was measured by liquid chromatography-tandem mass spectrometry in two studies and by immunoassay in 8. An association between total testosterone and muscle mass, strength or performance in women was not found. The studies of calculated free or bioavailable testosterone and lean muscle mass reported a positive association, but no association was reported for muscle strength or performance. Each included study was limited by a high risk of bias in at least one assessed domain. CONCLUSIONS: This review does not support an association between testosterone and muscle mass, strength or performance in women. This, together with the reported associations between free or bioavailable testosterone and muscle mass should be interpreted cautiously due to the predominant use of immunoassay and the inaccuracy of calculated variables. Additionally, biological significance of nonprotein bound testosterone has not been established. Further studies examining the relationship between precisely measured testosterone and muscle mass and function in women are required.

The association between sex hormones and the change in brain-predicted age difference in older women.

OBJECTIVE: The role of circulating sex hormones on structural brain ageing is yet to be established. This study explored whether concentrations of circulating sex hormones in older women are associated with the baseline and longitudinal changes in structural brain ageing, defined by the brain-predicted age difference (brain-PAD). DESIGN: Prospective cohort study using data from NEURO and Sex Hormones in Older Women; substudies of the ASPirin in Reducing Events in the Elderly clinical trial. PATIENTS: Community-dwelling older women (aged 70+ years). MEASUREMENTS: Oestrone, testosterone, dehydroepiandrosterone (DHEA), and sex-hormone binding globulin (SHBG) were quantified from plasma samples collected at baseline. T1-weighted magnetic resonance imaging was performed at baseline, 1 and 3 years. Brain age was derived from whole brain volume using a validated algorithm. RESULTS: The sample comprised of 207 women not taking medications known to influence sex hormone concentrations. A statistically higher baseline brain-PAD (older brain age relative to chronological age) was seen for women in the highest DHEA tertile compared with the lowest in the unadjusted analysis (p = .04). This was not significant when adjusted for chronological age, and potential confounding health and behavioural factors. Oestrone, testosterone and SHBG were not associated with brain-PAD cross-sectionally, nor were any of the examined sex hormones or SHBG associated with brain-PAD longitudinally. CONCLUSION: No strong evidence of an association between circulating sex hormones and brain-PAD. Given there is prior evidence to suggests sex hormones may be important for brain ageing, further studies of circulating sex hormones and brain health in postmenopausal women are warranted.

Implementation of indication-based antibiotic order sentences improves antibiotic use in emergency departments.

INTRODUCTION: Prior data have suggested that suboptimal antibiotic prescribing in the emergency department (ED) is common for uncomplicated lower respiratory tract infections (LRTI), urinary tract infections (UTI), and acute bacterial skin and skin structure infections (ABSSSI). The objective of this study was to measure the effect of indication-based antibiotic order sentences (AOS) on optimal antibiotic prescribing in the ED. METHODS: This was an IRB-approved quasi-experiment of adults prescribed antibiotics in EDs for uncomplicated LRTI, UTI, or ABSSSI from January to June 2019 (pre-implementation) and September to December 2021 (post-implementation). AOS implementation occurred in July 2021. AOS are lean process, electronic discharge prescriptions retrievable by name or indication within the discharge order field. The primary outcome was optimal prescribing, defined as correct antibiotic selection, dose, and duration per local and national guidelines. Descriptive and bivariate statistics were performed; multivariable logistic regression was used to determine variables associated with optimal prescribing. RESULTS: A total of 294 patients were included: 147 pre-group and 147 post-group. Overall optimal prescribing improved from 12 (8%) to 34 (23%) (P < 0.001). Individual components of optimal prescribing were optimal selection at 90 (61%) vs 117 (80%) (P < 0.001), optimal dose at 99 (67%) vs 115 (78%) (P = 0.036), and optimal duration at 38 (26%) vs 50 (34%) (P = 0.13) for pre- and post-group, respectively. AOS was independently associated with optimal prescribing after multivariable logistic regression analysis (adjOR, 3.6; 95%CI,1.7-7.2). A post-hoc analysis showed low uptake of AOS by ED prescribers. CONCLUSIONS: AOS are an efficient and promising strategy to enhance antimicrobial stewardship in the ED.

The impact of endometriosis on work ability in young Australian women.

BACKGROUND: Whereas symptomatic endometriosis may affect work performance, the impact of endometriosis in the general community is not known. AIMS: The associations between endometriosis and each of sick leave and work ability, were investigated in a large sample of non-healthcare seeking women. MATERIALS AND METHODS: This community-based, cross-sectional study recruited 6986 women, aged 18-39 years, from three eastern states of Australia between 11 November 2016 and 21 July 2017. Women were identified as having endometriosis if they had undergone a pelvic ultrasound and reported a diagnosis of endometriosis. Working women completed the Work Ability Index. RESULTS: Participants were predominantly of European ancestry (73.1%) and 46.8% were overweight or had obesity. The prevalence of endometriosis was 5.4% (95%CI 4.9-6.0%) with the highest prevalence of 7.7% (95%CI 6.5 to 9.1%) for women aged 35-39 years. Among the 4618 working women, those with endometriosis had significantly more sick days from work (33.6% reported ≥10 days vs 13.5%, overall χ2 P < 0.001). Endometriosis was associated with a greater likelihood of poor to moderate work ability, after adjusting for age, body mass index, ethnicity, relationship status, student status, insecure housing, being a carer for another person, parity, ever use of assisted reproductive technologies, and depressed mood (odds ratio 1.90, 95%CI 1.40-2.58, P < 0.001). CONCLUSIONS: This study provides new evidence that the negative impact of endometriosis on work attendance and work ability is not limited to women with prevalent symptoms and severe disease, but appears to encompass women across a broader spectrum of this condition in the community.

Impact of a Standardized, Pharmacist-Initiated "Test-Claim" Workflow for Anticipating Barriers to Accessing Discharge Antimicrobials.

Background: Inability to access and afford discharge oral antimicrobials may delay discharges or result in therapeutic failure. "Test-claims" have the potential to identify such barriers. Objective: This study evaluated discharge antimicrobial access and patient outcomes after implementation of a standardized, inpatient pharmacist-initiated antimicrobial discharge medication cost inquiry (aDMCI) process. Methods: This was an Institutional Review Board (IRB)-approved, pilot retrospective cohort study that included adults admitted for ≥72 hours from November 1, 2018, to February 28, 2019, and discharged on oral antimicrobials. Patients with a cost inquiry (aDMCI group) were compared with those without (standard-of-care, SOC, group). Primary endpoint was discharge delay. Secondary endpoints included percentage of patients discharged on suboptimal antimicrobials and medication errors from aDMCI. Results: 84 patients were included: 43 in SOC and 41 in aDMCI. Seventy-five antimicrobial cost inquiries were evaluated among 41 patients. There were no discharge delays or medication errors associated with the standardized "test-claim" (aDMCI) workflow. Patients in the SOC group had a greater Charlson Comorbidity Index (4 [2-6] vs 2 [1-4], P =0.004), were more likely to be immunosuppressed (24, 56% vs 12, 29%; P =0.014), and had longer hospitalization (8 [5-15] vs 6 [5-9] days, P =0.026). Primary access barriers were prior-authorization (8, 11%) and associated with linezolid and moxifloxacin cost inquiries. Most aDMCIs results were available in <24 hours (66, 88%). Conclusions: The aDMCI process is safe and offers an actionable transition of care tool that can identify barriers to accessing discharge medications while insulating patients from surprise out-of-pocket cost.

Developing Treatment Guidelines During a Pandemic Health Crisis: Lessons Learned From COVID-19.

The development of the National Institutes of Health (NIH) COVID-19 Treatment Guidelines began in March 2020 in response to a request from the White House Coronavirus Task Force. Within 4 days of the request, the NIH COVID-19 Treatment Guidelines Panel was established and the first meeting took place (virtually-as did subsequent meetings). The Panel comprises 57 individuals representing 6 governmental agencies, 11 professional societies, and 33 medical centers, plus 2 community members, who have worked together to create and frequently update the guidelines on the basis of evidence from the most recent clinical studies available. The initial version of the guidelines was completed within 2 weeks and posted online on 21 April 2020. Initially, sparse evidence was available to guide COVID-19 treatment recommendations. However, treatment data rapidly accrued based on results from clinical studies that used various study designs and evaluated different therapeutic agents and approaches. Data have continued to evolve at a rapid pace, leading to 24 revisions and updates of the guidelines in the first year. This process has provided important lessons for responding to an unprecedented public health emergency: Providers and stakeholders are eager to access credible, current treatment guidelines; governmental agencies, professional societies, and health care leaders can work together effectively and expeditiously; panelists from various disciplines, including biostatistics, are important for quickly developing well-informed recommendations; well-powered randomized clinical trials continue to provide the most compelling evidence to guide treatment recommendations; treatment recommendations need to be developed in a confidential setting free from external pressures; development of a user-friendly, web-based format for communicating with health care providers requires substantial administrative support; and frequent updates are necessary as clinical evidence rapidly emerges.

Testosterone and androstenedione are positively associated with anti-Müllerian hormone in premenopausal women.

OBJECTIVE: To document associations between anti-Müllerian hormone (AMH) and circulating androgens in nonhealthcare-seeking premenopausal women. DESIGN: Community-based, cross-sectional study. SETTING: Eastern states of Australia. PARTICIPANTS: Women aged 18-39 years not using systemic hormones, not pregnant or breastfeeding within 3 months, and not postmenopausal. MEASUREMENTS: AMH, measured by the Beckman Access 2, 2 site immunometric assay from fresh samples, and testosterone, androstenedione, dehydroepiandrosterone (DHEA) and 11-oxygenated C19 steroids, measured by liquid chromatography-tandem mass spectrometry. RESULTS: Data were available for 794 women, median age of 33 years (range: 18-39). 76.1% were of European ancestry and 48.2% were parous. Serum AMH was positively associated with testosterone (rho = .29, p < .001) androstenedione (rho = .39, p < .001) and DHEA (rho = .10, p = .005) but not 11-ketoandrostenedione or 11-ketotestosterone. When adjusted for age, body mass index and smoking, using quantile regression, independent positive associations remained between AMH and testosterone (ß coefficient: 20.90, 95% confidence interval [CI]: 13.79-28.03; p < .001) and androstenedione (ß coefficient: 5.90, 95% CI: 3.76-8.03; p < .001). The serum concentration of testosterone was greater at the top AMH quintile than other quintiles (0.56 nmol/L [range: 0.21-1.90] vs. 0.36 nmol/L [range: 0.13-0.87]; p = .001) in women with self-reported polycystic ovary syndrome. CONCLUSIONS: The positive associations between serum testosterone and androstenedione and AMH in premenopausal women is consistent with androgens directly or indirectly influencing AMH production during follicular development. As the highest AMH concentrations are most likely to be seen in women with multifollicular ovaries, it would be expected that women with multifollicular ovaries would have higher serum testosterone. Therefore, whether hyperandrogenemia and multifollicular ovaries should be considered independent characteristics of polycystic ovary syndrome warrants review.

Differing performance of two assays for the measurement of anti-Mullerian hormone in premenopausal women: A cross-sectional study.

OBJECTIVE: To compare the performance of two anti-Mullerian (AMH) assays over a range of concentrations, in samples collected from young women. DESIGN: A cross-sectional method-comparison study of 168 non-healthcare-seeking women. PARTICIPANTS: Included women were aged 18-39 years, not recently pregnant, breast feeding or using systemic hormones. MEASUREMENTS: Serum AMH levels were analysed with the Beckman Coulter Access 2 assay from fresh samples and the Ansh picoAMH assay using samples stored at -80°C, in a parallel setting. Comparisons between the two assays were examined using Bland-Altman plots. RESULTS: Participants had a mean ± SD age of 32.6 ± 5.4 years and body mass index of 28.1 ± 7.9 kg/m2 , and 60.1% were parous. Although the assay results were highly correlated (Spearman correlation .982, P < .001), the relationship between the assays was nonlinear. Serum AMH values below 4 pmol/L were lower with the picoAMH assay compared with the Access AMH assay (mean difference in this range was -0.49 pmol/L), but for samples with a mean value above 10 pmol/L, the picoAMH assay consistently measured higher than the Access AMH assay (mean difference in this range was +8.2 pmol/L). As AMH concentrations increased the absolute discrepancy between the assays also increased. CONCLUSIONS: This study demonstrates that despite the high correlation between two commercially available AMH assays, the assays performed in a discordant manner at high and low concentrations. Hence, the results of these assays are not interchangeable, highlighting the need to establish specific reference limits for individual assays to guide clinical decision-making and the challenge of establishing future universal cut-offs for the application of AMH levels in clinical practice.

Longitudinal changes over three years in sex steroid hormone levels in women aged 70 years and over.

OBJECTIVE: Sex steroid levels in women vary with increasing age from the age of 70 years (70+). Whether this reflects change within individuals with age or a survival advantage is not known. This study aimed to determine the stability of circulating sex steroids and SHBG over time in individual women aged 70+. DESIGN: A prospective cohort study. PARTICIPANTS: 400 women, aged 70+ not using any sex steroid, anti-androgen/oestrogen or glucocorticoid therapy. MAIN OUTCOME MEASUREMENTS: Sex steroid concentrations, measured by liquid chromatography-tandem mass spectrometry and sex hormone-binding globulin (SHBG) by immunoassay, in paired blood samples drawn 3 years apart and analysed together. RESULTS: 400 women, median (IQR) age 78.0 (8.6) years, were included in the analysis. Mean testosterone concentrations were statistically significantly higher in follow-up samples compared with baseline. The change was modest (mean change 31 pmol/L, 95% confidence interval (CI) 2.4-59.8; p = .034), and an increase was not observed in all women. There was a statistically significant decline in mean body mass index (mean change -0.4 kg/m2 , 95% CI 0.6 to -0.3; p < .001) and a significant increase in the mean serum SHBG concentration (mean change 4.0 nmol/L, 95% CI 2.7-5.4; p < .001). The change observed in testosterone was not explained by the observed change in SHBG. There was no significant change in the mean oestrone or dehydroepiandrosterone concentration. CONCLUSIONS: Testosterone concentrations in women aged 70+ were more likely to increase than decrease. Whether increasing testosterone concentrations in older women confer a survival advantage needs investigation.

Substituting serum anti-Müllerian hormone for polycystic ovary morphology increases the number of women diagnosed with polycystic ovary syndrome: a community-based cross-sectional study.

STUDY QUESTION: Can serum anti-Müllerian hormone (AMH) replace polycystic ovary morphology (PCOM) determined by ultrasound as a diagnostic component of polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Despite good correlations between serum AMH and PCOM, the use of a high serum AMH as a proxy for PCOM resulted in the reclassification of PCOS in 5% of study participants, with the main effect being more women identified, although some women previously classified as having PCOS were no longer classified as such. WHAT IS KNOWN ALREADY: AMH has been proposed as an alternative to PCOM as a diagnostic component of PCOS. Previous studies are limited by poorly defining PCOS, use of infertile women as comparators, measurement of hormones by immunoassay that lack precision in the female range, low-resolution ovarian ultrasound and inconsistent handling and storage of serum samples. STUDY DESIGN, SIZE, DURATION: This is an Australian cross-sectional study of 163 non-healthcare-seeking women. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum AMH was measured by both the Ansh picoAMH assay and the Beckman Coulter Access 2 (BA2) assay, in parallel with androgens measured by liquid chromatography-tandem mass spectrometry, in blood samples of women, not pregnant, breast feeding or using systemic steroids, who also underwent high-resolution ovarian ultrasound. PCOS was determined by the Rotterdam criteria with PCOM defined by the Androgen Excess-PCOS Taskforce recommendation of ≥25 follicles in at least one ovary. Cut-off serum concentrations that best identified women as having PCOM were identified by receiver operator characteristic (ROC) curves. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 163 women, mean (SD) age 32.5 (5.5) years, who provided a blood sample and had both ovaries visualized on ultrasound were included in the analysis. Women with isolated PCOM had higher median (range) Ansh AMH and BA2 AMH concentrations than those with no PCOS characteristics [56.9 pmol/l (34.6, 104.2) versus 18.7 (3.2, 50.9), P = 0.002 and 38.5 pmol/l (22.2, 100.2) versus 16.7 (3.5, 38.9), P = 0.002, respectively]. An AMH ≥ 44.0 pmol/l, suggested by the ROC curve, identified 80.6% of women with PCOM, falsely identified 15.2% of women without PCOM as having PCOS and had a positive predictive value of 55.6%. The negative predictive value was 94.9%. An AMH BA2 assay cut-off of ≥33.2 pmol/l provided a sensitivity of 80.6%, a specificity of 79.5% and a positive predictive value for PCOM of 48.1%. The negative predictive value was 94.6% for PCOM. When serum AMH was used in the place of PCOM as a diagnostic criterion for PCOS, the Ansh assay resulted in an additional seven women classified as having PCOS and no longer classified one woman as having PCOS. For the BA2 assay, eight additional and two fewer women were classified as having PCOS. Overall, both assays resulted in six more women being classified as having PCOS. LIMITATIONS, REASONS FOR CAUTION: Women with functional hypogonadotrophic hypogonadism were not excluded and may have been misclassified as having an oligo-amenorrhoea-PCOM phenotype. As study participants were predominantly Caucasian/White, our findings cannot be generalized to women of other ethnicities. WIDER IMPLICATIONS OF THE FINDINGS: Although serum AMH reflects the number of developing ovarian follicles, the absolute values vary between assays and specific reference ranges for individual assays are required. Irrespective of the assay used, replacing PCOM with serum AMH to diagnose PCOS in a community-based sample altered the number of women classified as having or not having PCOS. Consequently, although overall the risk of women being identified as having PCOS would be increased, some women would no longer be classified as having this condition. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the Norman Beischer Research Foundation and the Grollo-Ruzzene Foundation. S.R.D. is an NHMRC Senior Principal Research Fellow (Grant No. 1135843). S.R.D. reports unrelated support that includes grants from the NHMRC Australia, personal fees for educational activities from Besins Healthcare, Abbott Chile, BioFemme and Pfizer Australia, personal Advisory Board/consultancy fees from Theramex, Abbott Laboratories, Astellas, Mayne Pharmaceuticals, Roche Diagnostics, Lawley Pharmaceuticals and Que Oncology and has received institutional grant funding from Que Oncology and Ovoca research. The other authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Use of community-based reference ranges to estimate the prevalence of polycystic ovary syndrome by the recognised diagnostic criteria, a cross-sectional study.

STUDY QUESTION: Does the application of reference ranges for sex steroids and the modified Ferriman-Gallwey (mFG) scale established in the community from which the study sample was drawn, combined with the most conservative polycystic ovary morphology (PCOM) criteria to the recognised diagnostic criteria for polycystic ovary syndrome (PCOS) improve the certainty of diagnosis of PCOS in non-healthcare-seeking women? SUMMARY ANSWER: Despite application of the stringent definitions of the elements used to diagnose PCOS in a non-healthcare seeking community-based sample, the risk of diagnostic uncertainty remains. WHAT IS KNOWN ALREADY: There is heterogeneity in prevalence estimates for PCOS due, in part, to lack of standardisation of the elements comprising the recognised National Institutes of Health (NIH), Rotterdam and Androgen Excess Society (AE-PCOS) diagnostic criteria. The AE-PCOS Society proposed refinements to the definitions of biochemical androgen excess and PCOM that can now be incorporated into these sets of diagnostic criteria to estimate PCOS prevalence. STUDY DESIGN, SIZE, DURATION: An Australian cross-sectional study of 168 non-healthcare-seeking women. PARTICIPANTS/MATERIALS, SETTING, METHODS: The 168 included women were aged 18-39 years, euthyroid and normoprolactinemic, not recently pregnant, breast feeding or using systemic hormones. Each provided menstrual history and assessment of the mFG, had measurement of sex steroids by liquid chromatography, tandem mass spectrometry, and a pelvic ultrasound. The presence of PCOS was determined using modified (m) NIH, Rotterdam, and AE-PCOS criteria according to AE-PCOS Society recommendations. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, 10.1% of the included participants met the mNIH PCOS criteria, which requires the presence of menstrual dysfunction, while 18.5% met the mRotterdam and 17.5% the AE-PCOS criteria, with the latter requiring hyperandrogenism. Eight of the 27 participants with menstrual dysfunction, 10 of 31 women with PCOM, and 39 of 68 women with hyperandrogenism had no other feature of PCOS. Of the 19 participants with hyperandrogenaemia, 10 met the mNIH criteria (52.5%) and 14 met both the mRotterdam and AE-PCOS criteria (78.9%). Women who had the combination of hyperandrogenism and PCOM explained the greatest discrepancy between the mNIH and the other criteria. LIMITATIONS, REASONS FOR CAUTION: Clinical androgenisation relied on participant self-assessment, which has been shown to be valid when compared with clinician assessment. The sample size was a function of both the strict inclusion criteria and the requirements of non-healthcare-seeking women having a blood draw and pelvic ultrasound which may have introduced a selection bias. WIDER IMPLICATIONS OF THE FINDINGS: Despite applying stringent cut-offs for serum androgens, the mFG scale and the ovarian follicle count, these criteria remain arbitrary. Accordingly, healthy women may be captured by these criteria, and misidentified as having PCOS, while women with the condition may be missed. Consequently, PCOS remains a diagnosis to be made with care. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the Grollo-Ruzzene Foundation. Dr S.R.D. is an NHMRC Senior Principal Research Fellow (Grant no. 1135843). S.R.D. has been paid for developing and delivering educational presentations for Besins Healthcare, BioFemme and Pfizer Australia, has been on Advisory Boards for Theramex, Abbott Laboratories, Mayne Pharmaceuticals and Roche and a consultant to Lawley Pharmaceuticals and Que Oncology and has received has received institutional grant funding for Que Oncology research; there are no other relationships or activities that could appear to have influenced the submitted work. TRIAL REGISTRATION NUMBER: N/A.

Economic and social drivers of antibiotic dispensing practices among community pharmacies in Nepal.

OBJECTIVE: To assess economic and social drivers of dispensing antibiotics without prescription by community pharmacies in Nepal. METHOD: A survey was conducted among 111 pharmacy owners and managers in five districts. Information on demographic and economic characteristics of the pharmacies (e.g. revenue and profits from antibiotics) and their inclination to sell antibiotics without a physician's prescription under various scenarios (e.g. diarrhoea in a child) was collected. Univariate analysis was conducted to assess the demographic and economic characteristics. Bivariate analysis was conducted to examine the relationship between dispensing antibiotics without prescription and economic and social factors. RESULTS: Azithromycin and amoxicillin were the most commonly dispensed antibiotics. The proportions of pharmacies reporting that they would 'most likely' or 'likely' dispense antibiotics without prescription to adult patients ranged from 36.9% (sore throat) to 67.6% (cough). The proportions for paediatric patients ranged from 62.2% (sore throat) to 80.2% (cough or diarrhoea). There was no consistent relationship between the likelihood of dispensing antibiotics and revenues, profits or the number of patients. Instead, dispensing behaviour was influenced by the pressure from the patient; the respondents were more likely to dispense antibiotics when the patient specifically asked for 'an antibiotic' rather than for 'a medicine', and 68.5% respondents ranked 'customer satisfaction' as the most important factor motivating their work. CONCLUSIONS: In Nepal, inappropriate sale of antibiotics by community pharmacists is high, particularly for paediatric patients. Additional research is needed to establish key drivers of this behaviour and to help design effective approaches to reducing AMR.

COVID-19 Isolation and Quarantine Experience for Residential Students at a Large Four-Year Public University.

Rapid identification and management of students with COVID-19 symptoms, exposure, or disease are critical to halting disease spread and protecting public health. We describe the interdisciplinary isolation and quarantine program of a large, public university, the University of Virginia, Charlottesville. The program provided students with wraparound services, including medical, mental health, academic, and other support services during their isolation or quarantine stay. The program successfully accommodated 844 cases during the fall 2020 semester, thereby decreasing exposure to the rest of the university and the local community. (Am J Public Health. 2021;111(10):1772-1775. https://doi.org/10.2105/AJPH.2021.306424).

International Society for the Study of Women's Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women.

BACKGROUND: The Global Consensus Position Statement on the Use of Testosterone Therapy for Women (Global Position Statement) recommended testosterone therapy for postmenopausal women with hypoactive sexual desire disorder (HSDD). AIM: To provide a clinical practice guideline for the use of testosterone including identification of patients, laboratory testing, dosing, post-treatment monitoring, and follow-up care in women with HSDD. METHODS: The International Society for the Study of Women's Sexual Health appointed a multidisciplinary panel of experts who performed a literature review of original research, meta-analyses, review papers, and consensus guidelines regarding testosterone use in women. Consensus was reached using a modified Delphi method. OUTCOMES: A clinically useful guideline following a biopsychosocial assessment and treatment approach for the safe and efficacious use of testosterone in women with HSDD was developed including measurement, indications, formulations, prescribing, dosing, monitoring, and follow-up. RESULTS: Although the Global Position Statement endorses testosterone therapy for only postmenopausal women, limited data also support the use in late reproductive age premenopausal women, consistent with the International Society for the Study of Women's Sexual Health Process of Care for the Management of HSDD. Systemic transdermal testosterone is recommended for women with HSDD not primarily related to modifiable factors or comorbidities such as relationship or mental health problems. Current available research supports a moderate therapeutic benefit. Safety data show no serious adverse events with physiologic testosterone use, but long-term safety has not been established. Before initiation of therapy, clinicians should provide an informed consent. Shared decision-making involves a comprehensive discussion of off-label use, as well as benefits and risks. A total testosterone level should not be used to diagnose HSDD, but as a baseline for monitoring. Government-approved transdermal male formulations can be used cautiously with dosing appropriate for women. Patients should be assessed for signs of androgen excess and total testosterone levels monitored to maintain concentrations in the physiologic premenopausal range. Compounded products cannot be recommended because of the lack of efficacy and safety data. CLINICAL IMPLICATIONS: This clinical practice guideline provides standards for safely prescribing testosterone to women with HSDD, including identification of appropriate patients, dosing, and monitoring. STRENGTHS & LIMITATIONS: This evidence-based guideline builds on a recently published comprehensive meta-analysis and the Global Position Statement endorsed by numerous societies. The limitation is that testosterone therapy is not approved for women by most regulatory agencies, thereby making prescribing and proper dosing challenging. CONCLUSION: Despite substantial evidence regarding safety, efficacy, and clinical use, access to testosterone therapy for the treatment of HSDD in women remains a significant unmet need. Parish SJ, Simon JA, Davis SR, et al. International Society for the Study of Women's Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women. J Sex Med 2021;18:849-867.

International Society for the Study of Women's Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women.

AIM: To provide a clinical practice guideline for the use of testosterone including identification of patients, laboratory testing, dosing, post-treatment monitoring, and follow-up care in women with hypoactive sexual desire disorder (HSDD). METHODS: The International Society for the Study of Women's Sexual Health appointed a multidisciplinary panel of experts who performed a literature review of original research, meta-analyses, review papers, and consensus guidelines regarding testosterone use in women. Consensus was reached using a modified Delphi method. OUTCOMES: A clinically useful guideline following a biopsychosocial assessment and treatment approach for the safe and efficacious use of testosterone in women with HSDD was developed including measurement, indications, formulations, prescribing, dosing, monitoring, and follow-up. RESULTS: Although the Global Position Statement endorses testosterone therapy for only postmenopausal women, limited data also support the use in late reproductive age premenopausal women, consistent with the International Society for the Study of Women's Sexual Health Process of Care for the Management of HSDD. Systemic transdermal testosterone is recommended for women with HSDD not primarily related to modifiable factors or comorbidities such as relationship or mental health problems. Current available research supports a moderate therapeutic benefit. Safety data show no serious adverse events with physiologic testosterone use, but long-term safety has not been established. Before initiation of therapy, clinicians should provide an informed consent. Shared decision-making involves a comprehensive discussion of off-label use, as well as benefits and risks. A total testosterone level should not be used to diagnose HSDD, but as a baseline for monitoring. Government-approved transdermal male formulations can be used cautiously with dosing appropriate for women. Patients should be assessed for signs of androgen excess and total testosterone levels monitored to maintain concentrations in the physiologic premenopausal range. Compounded products cannot be recommended because of the lack of efficacy and safety data. CLINICAL IMPLICATIONS: This clinical practice guideline provides standards for safely prescribing testosterone to women with HSDD, including identification of appropriate patients, dosing, and monitoring. STRENGTHS AND LIMITATIONS: This evidence-based guideline builds on a recently published comprehensive meta-analysis and the Global Position Statement endorsed by numerous societies. The limitation is that testosterone therapy is not approved for women by most regulatory agencies, thereby making prescribing and proper dosing challenging. CONCLUSION: Despite substantial evidence regarding safety, efficacy, and clinical use, access to testosterone therapy for the treatment of HSDD in women remains a significant unmet need.

Menopause workplace policy: The way forward or backward?

Workplace policies regarding women's reproductive and menopausal health are garnering global attention. The peri- and post-menopause stages may be turbulent times for many women, with some experiencing debilitating symptoms and some none at all. While the symptoms of menopause should be recognised by employers due to their various impacts, the implementation of policies that pertain to all women can alienate older female workers by creating prejudice surrounding work capability. This piece identifies other avenues for the inclusion of menopausal symptoms through pre-existing policy and highlights the issues facing menopausal women in this current age.

High-Dose Daptomycin Is Well Tolerated via 2-Minute IV Push Administration.

BACKGROUND: The purpose of this study was to evaluate the safety of administering high-dose daptomycin (HDD; > 6 mg/kg actual body weight) as a 2-minute intravenous (IV) push (IVP) compared to traditional 30-minute IV piggyback (IVPB) infusion. METHODS: Retrospective cohort study comparing patients receiving HDD as an IVP or IVPB infusion. The primary outcome was the proportion of patients with a documented infusion-related reaction (IRR) to daptomycin. RESULTS: Three hundred patients were included in the final analysis, 200 patients received IVP, and 100 patients received IVPB representing a total of 1697 administrations. Median (IQR) daptomycin dose was IVP 700 mg (550-900) and IVPB 700 mg (600-900), with mg/kg doses of 8.2 (7.9-10) and 8.3 (8-10), respectively. After adjudication, IRR occurred in 1% of subjects in each treatment group. CONCLUSIONS: This study provides data in more than 1100 administrations of HDD administered via IVP. Infusion-related reactions were documented in 1% of patients regardless of infusion method, suggesting comparable safety to traditional infusion methods. This practice may be useful during fluid shortage and in the outpatient setting.