The value of follicle-stimulating hormone concentration and clinical findings as markers of the late menopausal transition

CONTEXT: The Stages of Reproductive Aging Workshop proposed bleeding and hormonal criteria for the menopausal transition, but operational definitions of hormone parameters were not specified. OBJECTIVE: This paper investigates the longitudinal relationship of annual serum FSH levels with four proposed bleeding criteria for the late menopausal transition in two cohort studies. The goal is to provide empirically based guidance regarding application of hormonal criteria that may be optimal for widespread application in clinical and research settings for assessing menopausal stage. DESIGN/SETTING: Prospective menstrual calendar and annual serum FSH data were collected from two population-based cohort studies: the Melbourne Women\u27s Midlife Health Project and the Study of Women\u27s Health Across the Nation. PARTICIPANTS: Participants in the study were 193 Melbourne Women\u27s Midlife Health Project and 2223 Study of Women\u27s Health Across the Nation women aged 42-57 yr at baseline who contributed 10 or more menstrual cycles and at least one annual serum FSH value. MAIN OUTCOME MEASURE(S): Association between bleeding criteria for the late menopausal transition and FSH was a main outcome measure. Associations of bleeding criteria, FSH, and hot flashes with the final menstrual period were also measured. RESULTS: A single FSH measure is an independent marker of the late menopausal transition, but FSH concentrations are less predictive of menopausal stage than any of four proposed bleeding criteria. Criterion FSH values for the late transition are similar across both studies. Experience of hot flashes adds no information in the presence of hormonal and bleeding criteria. CONCLUSIONS: An annual serum FSH concentration of 40 IU/liter could be incorporated, in conjunction with bleeding markers, into the Stages of Reproductive Aging Workshop paradigm for markers of the late menopausal transition

Increased sediment oxygen flux in lakes and reservoirs:The impact of hypolimnetic oxygenation

Hypolimnetic oxygenation is an increasingly common lake management strategy for mitigating hypoxia/anoxia and associated deleterious effects on water quality. A common effect of oxygenation is increased oxygen consumption in the hypolimnion and predicting the magnitude of this increase is the crux of effective oxygenation system design. Simultaneous measurements of sediment oxygen flux (JO2) and turbulence in the bottom boundary layer of two oxygenated lakes were used to investigate the impact of oxygenation on JO2. Oxygenation increased JO2 in both lakes by increasing the bulk oxygen concentration, which in turn steepens the diffusive gradient across the diffusive boundary layer. At high flow rates, the diffusive boundary layer thickness decreased as well. A transect along one of the lakes showed JO2 to be spatially quite variable, with near-field and far-field JO2 differing by a factor of 4. Using these in situ measurements, physical models of interfacial flux were compared to microprofile-derived JO2 to determine which models adequately predict JO2 in oxygenated lakes. Models based on friction velocity, turbulence dissipation rate, and the integral scale of turbulence agreed with microprofile-derived JO2 in both lakes. These models could potentially be used to predict oxygenation-induced oxygen flux and improve oxygenation system design methods for a broad range of reservoir systems

Use of temperature to improve West Nile virus forecasts

Ecological and laboratory studies have demonstrated that temperature modulates West Nile virus (WNV) transmission dynamics and spillover infection to humans. Here we explore whether inclusion of temperature forcing in a model depicting WNV transmission improves WNV forecast accuracy relative to a baseline model depicting WNV transmission without temperature forcing. Both models are optimized using a data assimilation method and two observed data streams: mosquito infection rates and reported human WNV cases. Each coupled model-inference framework is then used to generate retrospective ensemble forecasts of WNV for 110 outbreak years from among 12 geographically diverse United States counties. The temperature-forced model improves forecast accuracy for much of the outbreak season. From the end of July until the beginning of October, a timespan during which 70% of human cases are reported, the temperature-forced model generated forecasts of the total number of human cases over the next 3 weeks, total number of human cases over the season, the week with the highest percentage of infectious mosquitoes, and the peak percentage of infectious mosquitoes that on average increased absolute forecast accuracy 5%, 10%, 12%, and 6%, respectively, over the non-temperature forced baseline model. These results indicate that use of temperature forcing improves WNV forecast accuracy and provide further evidence that temperature influences rates of WNV transmission. The findings provide a foundation for implementation of a statistically rigorous system for real-time forecast of seasonal WNV outbreaks and their use as a quantitative decision support tool for public health officials and mosquito control programs

Network 'small-world-ness': a quantitative method for determining canonical network equivalence

Background: Many technological, biological, social, and information networks fall into the broad class of 'small-world' networks: they have tightly interconnected clusters of nodes, and a shortest mean path length that is similar to a matched random graph (same number of nodes and edges). This semi-quantitative definition leads to a categorical distinction ('small/not-small') rather than a quantitative, continuous grading of networks, and can lead to uncertainty about a network's small-world status. Moreover, systems described by small-world networks are often studied using an equivalent canonical network model-the Watts-Strogatz (WS) model. However, the process of establishing an equivalent WS model is imprecise and there is a pressing need to discover ways in which this equivalence may be quantified. Methodology/Principal Findings: We defined a precise measure of 'small-world-ness' S based on the trade off between high local clustering and short path length. A network is now deemed a 'small-world' if S. 1-an assertion which may be tested statistically. We then examined the behavior of S on a large data-set of real-world systems. We found that all these systems were linked by a linear relationship between their S values and the network size n. Moreover, we show a method for assigning a unique Watts-Strogatz (WS) model to any real-world network, and show analytically that the WS models associated with our sample of networks also show linearity between S and n. Linearity between S and n is not, however, inevitable, and neither is S maximal for an arbitrary network of given size. Linearity may, however, be explained by a common limiting growth process. Conclusions/Significance: We have shown how the notion of a small-world network may be quantified. Several key properties of the metric are described and the use of WS canonical models is placed on a more secure footing

Changes in the investigation and management of suspected myocardial infarction and injury during COVID-19: a multi-centre study using routinely collected healthcare data

Objective: The COVID-19 pandemic was associated with a reduction in the incidence of myocardial infarction (MI) diagnosis, in part because patients were less likely to present to hospital. Whether changes in clinical decision making with respect to the investigation and management of patients with suspected MI also contributed to this phenomenon is unknown. Methods: Multicentre retrospective cohort study in three UK centres contributing data to the National Institute for Health Research Health Informatics Collaborative. Patients presenting to the Emergency Department (ED) of these centres between 1st January 2020 and 1st September 2020 were included. Three time epochs within this period were defined based on the course of the first wave of the COVID-19 pandemic: pre-pandemic (epoch 1), lockdown (epoch 2), post-lockdown (epoch 3). Results: During the study period, 10,670 unique patients attended the ED with chest pain or dyspnoea, of whom 6,928 were admitted. Despite fewer total ED attendances in epoch 2, patient presentations with dyspnoea were increased (p < 0.001), with greater likelihood of troponin testing in both chest pain (p = 0.001) and dyspnoea (p < 0.001). There was a dramatic reduction in elective and emergency cardiac procedures (both p < 0.001), and greater overall mortality of patients (p < 0.001), compared to the pre-pandemic period. Positive COVID-19 and/or troponin test results were associated with increased mortality (p < 0.001), though the temporal risk profile differed. Conclusions: The first wave of the COVID-19 pandemic was associated with significant changes not just in presentation, but also the investigation, management, and outcomes of patients presenting with suspected myocardial injury or MI

Efficacious Intermittent Dosing of a Novel JAK2 Inhibitor in Mouse Models of Polycythemia Vera

A high percentage of patients with the myeloproliferative disorder polycythemia vera (PV) harbor a Val617→Phe activating mutation in the Janus kinase 2 (JAK2) gene, and both cell culture and mouse models have established a functional role for this mutation in the development of this disease. We describe the properties of MRLB-11055, a highly potent inhibitor of both the WT and V617F forms of JAK2, that has therapeutic efficacy in erythropoietin (EPO)-driven and JAK2V617F-driven mouse models of PV. In cultured cells, MRLB-11055 blocked proliferation and induced apoptosis in a manner consistent with JAK2 pathway inhibition. MRLB-11055 effectively prevented EPO-induced STAT5 activation in the peripheral blood of acutely dosed mice, and could prevent EPO-induced splenomegaly and erythrocytosis in chronically dosed mice. In a bone marrow reconstituted JAK2V617F-luciferase murine PV model, MRLB-11055 rapidly reduced the burden of JAK2V617F-expressing cells from both the spleen and the bone marrow. Using real-time in vivo imaging, we examined the kinetics of disease regression and resurgence, enabling the development of an intermittent dosing schedule that achieved significant reductions in both erythroid and myeloid populations with minimal impact on lymphoid cells. Our studies provide a rationale for the use of non-continuous treatment to provide optimal therapy for PV patients

Prophylactic Melatonin for Delirium in Intensive Care (Pro-MEDIC): Study protocol for a randomised controlled trial

Background: Delirium is an acute state of brain dysfunction characterised by fluctuating inattention and cognitive disturbances, usually due to illness. It occurs commonly in the intensive care unit (ICU), and it is associated with greater morbidity and mortality. It is likely that disturbances of sleep and of the day-night cycle play a significant role. Melatonin is a naturally occurring, safe and cheap hormone that can be administered to improve sleep. The main aim of this trial will be to determine whether prophylactic melatonin administered to critically ill adults, when compared with placebo, decreases the rate of delirium. Methods: This trial will be a multi-centre, randomised, placebo-controlled study conducted in closed ICUs in Australia. Our aim is to enrol 850 adult patients with an expected ICU length of stay (LOS) of 72h or more. Eligible patients for whom there is consent will be randomised to receive melatonin 4mg enterally or placebo in a 1:1 ratio according to a computer-generated randomisation list, stratified by site. The study drug will be indistinguishable from placebo. Patients, doctors, nurses, investigators and statisticians will be blinded. Melatonin or placebo will be administered once per day at 21:00 until ICU discharge or 14days after enrolment, whichever occurs first. Trained staff will assess patients twice daily to determine the presence or absence of delirium using the Confusion Assessment Method for the ICU score. Data will also be collected on demographics, the overall prevalence of delirium, duration and severity of delirium, sleep quality, participation in physiotherapy sessions, ICU and hospital LOS, morbidity and mortality, and healthcare costs. A subgroup of 100 patients will undergo polysomnographic testing to further evaluate the quality of sleep. Discussion: Delirium is a significant issue in ICU because of its frequency and associated poorer outcomes. This trial will be the largest evaluation of melatonin as a prophylactic agent to prevent delirium in the critically ill population. This study will also provide one of the largest series of polysomnographic testing done in ICU. Trial registration: Australian New Zealand Clinical Trial Registry (ANZCTR) number: ACTRN12616000436471. Registered on 20 December 2015