Premature ovarian insufficiency: the need for evidence on the effectiveness of hormonal therapy

Premature ovarian insufficiency (POI) – the loss of ovarian function before the age of 40 years, a decade before natural menopause – is a life-changing diagnosis for women. POI causes significant short-term and long-term morbidity related to estrogen deficiency. The condition is managed by providing exogenous estrogen replacement, usually as the oral contraceptive pill or hormone therapy. These preparations have different estrogen formulations and may have differing benefits and risks. At present, there are no robust data to inform clinical recommendations and women’s decision-making about treatment that they may be taking for many years. The POISE study (Premature Ovarian Insufficiency Study of Effectiveness of hormonal therapy) has been designed to determine whether hormone therapy is superior to combined oral contraceptives on important clinical outcomes and patient-reported symptoms, based on the hypothesis that hormone therapy provides more physiological continuous hormone supplementation with natural estrogens. The study is an open and pragmatic, parallel, randomized controlled trial. The primary outcome is absolute bone mineral density assessed by dual-energy X-ray absorptiometry of the lumbar spine after 2 years of treatment. The study will also investigate cardiovascular markers, symptom relief and acceptability of treatment, and will continue to collect long-term data on fractures and cardiovascular events. Results will inform future guidance on management of POI

Characterization traffic induced compaction in controlled traffic farming (CTF) and random traffic farming (RTF) - A multivariate approach

A field scale experiment was carried out in Pukekohe in 2020 under an annual grass crop season to characterize the subsoil compaction in controlled traffic farming (CTF) and random traffic farming systems (RTF). Soil penetration resistance (PR) measurements were taken in each field using a cone penetrometer fitted with a 100 mm2 60° top angle cone. Multivariate analysis was performed to identify penetration resistance by depth through cluster analysis and principal component analysis (PCA). Repeated measures ANOVA was performed on the penetration data using the mixed model procedure to determine the treatment effects. In RTF, the penetrometer values increased more rapidly with depth resulting in higher values being recorded from 20cm compared to CTF. In contrast, it was greater in CTF than in RTF at the subsurface (55-60cm). The differences in PR declined beyond 55cm depth at both sites. All depths showed that differences in soil PR were most apparent in the 5-40cm depth, with significant differences between CTF and RTF (P0.05) showing that the soil layers were homogeneous in both systems beyond 40cm depth. The propagation of subsurface compaction was identified at the deeper layer (40-60cm) in CTF systems whereas it was identified from shallower depths (25-55cm) in RTF system

Sarcopenia during COVID-19 lockdown restrictions: long-term health effects of short-term muscle loss.

The COVID-19 pandemic is an extraordinary global emergency that has led to the implementation of unprecedented measures in order to stem the spread of the infection. Internationally, governments are enforcing measures such as travel bans, quarantine, isolation, and social distancing leading to an extended period of time at home. This has resulted in reductions in physical activity and changes in dietary intakes that have the potential to accelerate sarcopenia, a deterioration of muscle mass and function (more likely in older populations), as well as increases in body fat. These changes in body composition are associated with a number of chronic, lifestyle diseases including cardiovascular disease (CVD), diabetes, osteoporosis, frailty, cognitive decline, and depression. Furthermore, CVD, diabetes, and elevated body fat are associated with greater risk of COVID-19 infection and more severe symptomology, underscoring the importance of avoiding the development of such morbidities. Here we review mechanisms of sarcopenia and their relation to the current data on the effects of COVID-19 confinement on physical activity, dietary habits, sleep, and stress as well as extended bed rest due to COVID-19 hospitalization. The potential of these factors to lead to an increased likelihood of muscle loss and chronic disease will be discussed. By offering a number of home-based strategies including resistance exercise, higher protein intakes and supplementation, we can potentially guide public health authorities to avoid a lifestyle disease and rehabilitation crisis post-COVID-19. Such strategies may also serve as useful preventative measures for reducing the likelihood of sarcopenia in general and in the event of future periods of isolation

Determinants of Perinatal Outcomes in Dialyzed and Transplanted Women in Australia.

Introduction: Drivers of adverse perinatal outcomes in pregnancies of women receiving chronic kidney replacement therapy (KRT) remain poorly understood. Methods: Births ≥ 20 weeks of gestation in Australian women receiving KRT were analyzed for perinatal outcomes stratified by maternal KRT exposure (dialysis or transplant, analyzed separately), by linking the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) and perinatal data sets (1991-2013). Results: Of 2,948,084 babies (1,628,181 mothers), 248 were born to mothers receiving KRT (transplant, n = 211; dialysis, n = 37), with live birth rates ≥ 94%. The perinatal death rate was 162, 62, and 9 per 1000 births in the dialysis, transplant, and non-KRT cohorts, respectively. Babies exposed to KRT had increased odds of prematurity, small-for-gestational age (SGA), poor birth condition, resuscitation, intensive care admission, and longer hospitalization, with the dialysis cohort having worse outcomes. Preterm babies of dialyzed and transplanted mothers (compared with preterm babies with no KRT exposure) experienced 1.6- to 2.7-fold higher odds for all adverse outcomes, except birthweight 10-fold higher odds of preterm birth and low birthweight and 1.8- to 4.6-fold increased odds of other adverse outcomes. In transplanted women, mediation analysis revealed that pregnancy-induced hypertension contributed only a modest proportional effect (2.5%-11.2%) on adverse outcomes. Conclusion: Maternal dialysis and transplantation conferred excess perinatal morbidity, particularly for preterm babies, and even in women with good preconception allograft function. Pregnancy-induced hypertension is not the predominant determinant of perinatal morbidity. Preconception counseling of women with kidney disease should encompass discussion of perinatal complications

Parenthood and pregnancy in Australians receiving treatment for end-stage kidney disease: protocol of a national study of perinatal and parental outcomes through population record linkage.

INTRODUCTION:Achieving parenthood is challenging in individuals receiving renal replacement therapy (RRT; dialysis or kidney transplantation) for end-stage kidney disease. Decision-making regarding parenthood in RRT recipients should be underpinned by robust data, yet there is limited data on parental factors that drive adverse health outcomes. Therefore, we aim to investigate the perinatal risks and outcomes in parents receiving RRT. METHODS AND ANALYSIS:This is a multijurisdictional probabilistic data linkage study of perinatal, hospital, birth, death and renal registers from 1991 to 2013 from New South Wales, Western Australia, South Australia and the Australian Capital Territory. This study includes all babies born ≥20 weeks' gestation or 400 g birth weight captured through mandated data collection in the perinatal data sets. Through linkage with the Australian and New Zealand Dialysis and Transplant (ANZDATA) registry, babies exposed to RRT (and their parents) will be compared with babies who have not been exposed to RRT (and their parents) to determine obstetric and fetal outcomes, birth rates and fertility rates. One of the novel aspects of this study is the method that will be used to link fathers receiving RRT to the mothers and their babies within the perinatal data sets, using the birth register, enabling the identification of family units. The linked data set will be used to validate the parenthood events directly reported to ANZDATA. ETHICS AND DISSEMINATION:Ethics approval was obtained from Human Research Ethics Committees (HREC) and Aboriginal HREC in each jurisdiction. Findings of this study will be disseminated at scientific conferences and in peer-reviewed journals in tabular and aggregated forms. De-identified data will be presented and individual patients will not be identified. We will aim to present findings to relevant stakeholders (eg, patients, clinicians and policymakers) to maximise translational impact of research findings

Analyzing the mechanisms that facilitate the subtype-specific assembly of γ-aminobutyric acid type A receptors

Impaired inhibitory signaling underlies the pathophysiology of many neuropsychiatric and neurodevelopmental disorders including autism spectrum disorders and epilepsy. Neuronal inhibition is regulated by synaptic and extrasynaptic γ-aminobutyric acid type A receptors (GABAARs), which mediate phasic and tonic inhibition, respectively. These two GABAAR subtypes differ in their function, ligand sensitivity, and physiological properties. Importantly, they contain different α subunit isoforms: synaptic GABAARs contain the α1–3 subunits whereas extrasynaptic GABAARs contain the α4–6 subunits. While the subunit composition is critical for the distinct roles of synaptic and extrasynaptic GABAAR subtypes in inhibition, the molecular mechanism of the subtype-specific assembly has not been elucidated. To address this issue, we purified endogenous α1- and α4-containing GABAARs from adult murine forebrains and examined their subunit composition and interacting proteins using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and quantitative analysis. We found that the α1 and α4 subunits form separate populations of GABAARs and interact with distinct sets of binding proteins. We also discovered that the β3 subunit, which co-purifies with both the α1 and α4 subunits, has different levels of phosphorylation on serines 408 and 409 (S408/9) between the two receptor subtypes. To understand the role S408/9 plays in the assembly of α1- and α4-containing GABAARs, we examined the effects of S408/9A (alanine) knock-in mutation on the subunit composition of the two receptor subtypes using LC-MS/MS and quantitative analysis. We discovered that the S408/9A mutation results in the formation of novel α1α4-containing GABAARs. Moreover, in S408/9A mutants, the plasma membrane expression of the α4 subunit is increased whereas its retention in the endoplasmic reticulum is reduced. These findings suggest that S408/9 play a critical role in determining the subtype-specific assembly of GABAARs, and thus the efficacy of neuronal inhibition

Evaluating the efficacy of thoracoscopy and talc poudrage versus pleurodesis using talc slurry (TAPPS trial): protocol of an open-label randomised controlled trial

INTRODUCTION: The management of recurrent malignant pleural effusions (MPE) can be challenging. Various options are available, with the most efficacious and widely used being talc pleurodesis. Talc can either be applied via a chest drain in the form of slurry, or at medical thoracoscopy using poudrage. Current evidence regarding which method is most effective is conflicting and often methodologically flawed. The TAPPS trial is a suitably powered, multicentre, open-label, randomised controlled trial designed to compare the pleurodesis success rate of medical thoracoscopy and talc poudrage with chest drain insertion and talc slurry. METHODS AND ANALYSIS: 330 patients with a confirmed MPE requiring intervention will be recruited from UK hospitals. Patients will be randomised (1:1) to undergo either small bore (<14 Fr) Seldinger chest drain insertion followed by instillation of sterile talc (4 g), or to undergo medical thoracoscopy and simultaneous poudrage (4 g). The allocated procedure will be performed as an inpatient within 3 days of randomisation taking place. Following discharge, patients will be followed up at regular intervals for 6 months. The primary outcome measure is pleurodesis failure rates at 3 months. Pleurodesis failure is defined as the need for further pleural intervention for fluid management on the side of the trial intervention. ETHICS AND DISSEMINATION: The trial has received ethical approval from the National Research Ethics Service Committee North West-Preston (12/NW/0467). There is a trial steering committee which includes independent members and a patient and public representative. The trial results will be published in a peer-reviewed journal and presented at international conferences, as well as being disseminated via local and national charities and patient groups. All participants who wish to know the study results will also be contacted directly on their publication. TRIAL REGISTRATION NUMBER: ISRCTN47845793

Disturbing Times: Medieval Pasts, Reimagined Futures

From Kehinde Wiley to W.E.B. Du Bois, from Nubia to Cuba, Willie Doherty’s terror in ancient landscapes to the violence of institutional Neo-Gothic, Reagan’s AIDS policies to Beowulf fanfiction, this richly diverse volume brings together art historians and literature scholars to articulate a more inclusive, intersectional medieval studies. It will be of interest to students working on the diaspora and migration, white settler colonialism and pogroms, Indigenous studies and decolonial methodology, slavery, genocide, and culturecide. The authors confront the often disturbing legacies of medieval studies and its current failures to own up to those, and also analyze fascist, nationalist, colonialist, anti-Semitic, and other ideologies to which the medieval has been and is yoked, collectively formulating concrete ethical choices and aims for future research and teaching. In the face of rising global fascism and related ideological mobilizations, contemporary and past, and of cultural heritage and history as weapons of symbolic and physical oppression, this volume’s chapters on Byzantium, Medieval Nubia, Old English, Hebrew, Old French, Occitan, and American and European medievalisms examine how educational institutions, museums, universities, and individuals are shaped by ethics and various ideologies in research, collecting, and teaching

Demolition or Refurbishment of Social Housing? A review of the evidence

This report provides a review of technical models, evidence and case studies for decision making relating to the retention or demolition of social housing stock. Technical assessments of building suitability for refurbishment or demolition are often based on models of building performance. These include energy performance of the building compared to standards for new buildings, and assessment of environmental and energy impacts of the building over its lifetime from construction to demolition. Decisions can also be based on a series of performance and cost indicators. All modelling and indicator based approaches require assumptions about the building and the economic and policy context in which regeneration will take place, which need to be examined and justified in each case. Evaluation of the economic case for refurbishment is sensitive to the institutional factors such as the UK retrofit supply chain and market; tenure types and management capacity; access to finance and/or willingness to invest. Typical cost indicators are capital expenditure, operational and maintenance expenditure and capital investment appraisal. Estimating the costs and impacts of refurbishment or demolition is complex, uncertain and subjective – especially where nonmonetary costs and benefits have to be assigned a value. Finance mechanisms for refurbishment are less well established than for construction. The energy performance of a building is an increasingly important consideration in decisions to demolish or refurbish, and it has a big impact on the health of residents and the cost of their energy bills. Energy is used by residents as they live in a building throughout its lifetime. Energy is also used to manufacture building materials and construct the building in the first place and then in demolition, reusing, recycling and moving materials to dispose of them. Reducing carbon emissions associated with the built environment means reducing the emissions associated with the whole lifecycle of buildings. However, refurbishment and retrofitting of buildings, including insulation, replacing windows and boilers, heating networks, and installing renewable energy, can improve the performance of existing buildings to near-new standards. Decarbonising the UK electricity grid will also reduce the climate change impacts of energy used in buildings, and will increase the relative importance of embodied carbon and energy in the lifecycle impacts of a building. Case studies demonstrate that even older, high rise or poorly insulated structures, known as hard to treat buildings, can be retrofitted to achieve high energy efficiency standards. In these cases, the costs of retrofitting compared to demolition and new construction can also be lower, particularly when construction work has been organised so that residents have been able to stay in their homes avoiding the costs and disruption of temporarily housing people elsewhere. The carbon emissions associated with building use depend on the source of energy used. Increased low carbon sources of energy to produce electricity on the grid in the future may reduce the environmental impacts of energy used in homes. Research has shown that there are often differences between the predicted and actual performance of buildings (performance gaps) and that people sometimes adapt their behaviour in ways that increase consumption after an energy efficiency project (rebound effects). Performance gaps and rebound effects are often not taken into account when assessing benefits to residents like a reduction in bills or improvements in thermal comfort. If future savings have been over-estimated, it is residents (rather than the professionals estimating the savings) who are doubly and disproportionately penalised, firstly, because what has been promised is not delivered and, secondly, because they pay the energy bills. Relatively simple water efficiency retrofitting can achieve savings of 17.5 litres per person per day, compared with the London average of 160 litres of water used per person per day. Sustainable drainage methods can also be cost effectively retrofitted into existing buildings and estates, delivering a wide range of benefits including reduced overheating of buildings. The construction and demolition sector contributes 35% of all waste in the UK every year. Much of this is due to demolition waste. The UK construction sector currently recycles 73% of its waste, but still contributes more than 4 million tonnes of waste to landfill each year. Recycling demolition waste reduces the environmental impacts of demolition, but refurbishment avoids waste to landfill and many of the environmental impacts of new construction. Improving the quality of social housing stock is essential to reduce health inequalities in the UK. Housing has significant impacts on mental and physical health and wellbeing, and should be a key factor in regeneration decision making. Refurbishment can deliver improvements in housing quality at a faster rate than demolition and rebuilding of social housing, but health issues such as ventilation and indoor air quality can be complex issues to address in refurbishment. Refurbishment of buildings presents opportunities for the creation of jobs requiring a new set of skills that will be in demand if the UK is to meet its carbon emission reduction targets. Operation of renewable energy systems also provides opportunities for community development through refurbishment of buildings and estates. It is clear that the ability for communities to engage in refurbishment and demolition decisions would be enhanced by a consistent and transparent approach to the reporting of lifecycle costs, energy and carbon, water and waste and monitoring the wellbeing of those affected by refurbishment and demolition. The literature reviewed here is emerging from different fields – engineers, energy modellers, planners and public health specialists – and shows some useful results but is often hard to disaggregate in a way that shows how the effects of refurbishment and demolition play out for different groups of people. However, many aspects of refurbishment and demolition are complex and interact with each other: what is needed is a more balanced inter-disciplinary view of what housing interventions mean for people, and who the winners and losers are in the short and longer term

Spectrin-beta 2 facilitates the selective accumulation of GABAA receptors at somatodendritic synapses

Fast synaptic inhibition is dependent on targeting specific GABAAR subtypes to dendritic and axon initial segment (AIS) synapses. Synaptic GABAARs are typically assembled from α1-3, β and γ subunits. Here, we isolate distinct GABAARs from the brain and interrogate their composition using quantitative proteomics. We show that α2-containing receptors co-assemble with α1 subunits, whereas α1 receptors can form GABAARs with α1 as the sole α subunit. We demonstrate that α1 and α2 subunit-containing receptors co-purify with distinct spectrin isoforms; cytoskeletal proteins that link transmembrane proteins to the cytoskeleton. β2-spectrin was preferentially associated with α1-containing GABAARs at dendritic synapses, while β4-spectrin was associated with α2-containing GABAARs at AIS synapses. Ablating β2-spectrin expression reduced dendritic and AIS synapses containing α1 but increased the number of synapses containing α2, which altered phasic inhibition. Thus, we demonstrate a role for spectrins in the synapse-specific targeting of GABAARs, determining the efficacy of fast neuronal inhibition