Clinicians' perspectives on diagnosing polycystic ovary syndrome in Australia: a qualitative study

STUDY QUESTION: What are clinicians' views about the diagnosis of polycystic ovary syndrome (PCOS), and how do they handle any complexities and uncertainties in practice?SUMMARY ANSWER: Clinicians have to navigate many areas of complexity and uncertainty regarding the diagnosis of PCOS, related to the diagnostic criteria, limitations in current evidence and misconceptions surrounding diagnosis, and expressed concern about the risk and consequences of both under- and overdiagnosis.WHAT IS KNOWN ALREADY: PCOS is a complex, heterogeneous condition with many areas of uncertainty, raising concerns about both underdiagnosis and overdiagnosis. Quantitative studies with clinicians have found considerable variation in diagnostic criteria used and care provided, as well as a lack of awareness around the breadth of PCOS features and poor uptake of recommended screening for metabolic complications. Clinicians' views about the uncertainties and complexities of diagnosing PCOS have not been explored.STUDY DESIGN, SIZE, DURATION: Semi-structured telephone interviews were conducted with clinicians from September 2017 to July 2018 to explore their perceptions about the diagnosis of PCOS, including how they handle any complexities and uncertainties in practice.PARTICIPANTS/MATERIALS, SETTING, METHODS: A group of 36 clinicians (15 general practitioners, 10 gynaecologists and 11 endocrinologists) currently practicing in Australia, were recruited through advertising via professional organisations, contacting a random sample of endocrine and gynaecology teams across Australia and snowballing. Transcribed audio-recordings were analysed thematically using Framework analysis.MAIN RESULTS AND THE ROLE OF CHANCE: Clinicians expressed a range of uncertainties and complexities regarding the diagnosis of PCOS, which were organised into three areas: (i) establishing diagnosis (e.g. lack of standardisation regarding diagnostic cut-offs, risk of misdiagnosis), (ii) factors influencing the diagnostic process (e.g. awareness of limitations in evidence and consideration of the benefits and harms) and (iii) strategies for handling challenges and uncertainties (e.g. using caution and communication of uncertainties). Clinicians also varied in their concerns regarding under- and overdiagnosis. Overall, most felt the diagnosis was beneficial for women provided that it was the correct diagnosis and time was taken to assess patient expectations and dispel misconceptions, particularly concerning fertility.LIMITATIONS, REASONS FOR CAUTION: There is possible selection bias, as clinicians who are more knowledgeable about PCOS may have been more likely to participate. Clinicians' views may also differ in other countries.WIDER IMPLICATIONS OF THE FINDINGS: These findings underscore the vital need to first consider PCOS a diagnosis of exclusion and use caution before giving a diagnosis in order to reduce misdiagnosis, as suggested by clinicians in our study. Until there is greater standardisation of diagnostic criteria, more transparent conversations with women may help them understand the uncertainties surrounding the criteria and limitations in the evidence. Additionally, clinicians emphasised the importance of education and reassurance to minimise the potential harmful impact of the diagnosis and improve patient-centred outcomes

The benefits and harms of receiving a polycystic ovary syndrome diagnosis: a qualitative study of women's experiences

Study Question: What are the benefits and harms of receiving a polycystic ovary syndrome (PCOS) diagnosis in a community sample of women, including impact on psychosocial wellbeing, lifestyle choices and behaviour? Summary Answer: Although some women benefit considerably from the diagnosis, such as through increased awareness and reassurance, women with minimal symptoms may experience more harm than benefit, including long-lasting anxiety and altered life plans. What Is Known Already: Disease labels can validate symptoms and play a vital role in understanding and coping with illness; however, they can also cause harm by evoking illness schemas about severity and permanence. Regarding PCOS, the diagnostic criteria have expanded over time to include women with milder phenotypes (such as those without signs of androgen excess). This has occurred despite limited investigation of the benefits and harms of the diagnosis and has increased the number of women diagnosed. Study Design, Size, Duration: Semi-structured interviews were conducted face-to-face or by telephone with 26 participants from April-July 2018 to explore women's experiences with the diagnosis, including the benefits and harms of receiving the diagnosis and the impact on their life. Participants/Materials, Setting, Methods: In total, 26 women in the community self-reporting a diagnosis of PCOS (reporting mild to severe symptoms) made by a medical doctor, aged 18-45 years and living in Australia were recruited through social media. Data were analysed thematically using Framework analysis. Main Results and the Role of Chance: The study identified a range of both positive and negative effects of a PCOS diagnosis in the immediate, short and long-term, which were influenced by symptom severity, expectations and experience. For women with previously unexplained and bothersome symptoms, it was a relief to receive a diagnosis, and this resulted in an increased understanding about the importance of a healthy lifestyle. By contrast, women with milder symptoms often reported feeling shocked and overwhelmed by the diagnosis, consequently experiencing anxiety about the associated long-term risks. The majority of women, regardless of symptom severity, experienced prolonged worry and anxiety about infertility, resulting for some in risk taking with contraception, unintended pregnancies, pressure to conceive early or altered life plans. With time, many women developed positive coping strategies and perceived the diagnosis to be valuable, including those who felt they had experienced minimal benefit or even harm. Limitations, Reasons for Caution: PCOS diagnosis was self-reported and the sample was highly educated. Wider Implications of the Findings: Fear of infertility was salient for many women, underscoring the need for accurate information, counselling and reassurance of fertility potential. Given the risk of significant consequences, health professionals should use a tailored approach to PCOS diagnosis to increase the benefits of appropriate and timely diagnosis for women affected by significant symptoms, while reducing the harms of unnecessarily labelling healthy women for whom the benefits of a diagnosis are small.T. Copp, J. Hersch, D.M. Muscat, K.J. McCaffery, J. Doust, A. Dokras, B.W. Mol, and J. Janse

On the Quantization of the Chern-Simons Fields Theory on Curved Space-Times: the Coulomb Gauge Approach

We consider here the Chern-Simons field theory with gauge group SU(N) in the presence of a gravitational background that describes a two-dimensional expanding ``universe". Two special cases are treated here in detail: the spatially flat {\it Robertson-Walker} space-time and the conformally static space-times having a general closed and orientable Riemann surface as spatial section. The propagator and the vertices are explicitely computed at the lowest order in perturbation theory imposing the Coulomb gauge fixing.Comment: 15 pp., Preprint LMU-TPW 93-5, (Plain TeX + Harvmac

Haploinsufficiency of SF3B2 causes craniofacial microsomia

Craniofacial microsomia (CFM) is the second most common congenital facial anomaly, yet its genetic etiology remains unknown. We perform whole-exome or genome sequencing of 146 kindreds with sporadic (n = 138) or familial (n = 8) CFM, identifying a highly significant burden of loss of function variants in SF3B2 (P = 3.8 × 10−10), a component of the U2 small nuclear ribonucleoprotein complex, in probands. We describe twenty individuals from seven kindreds harboring de novo or transmitted haploinsufficient variants in SF3B2. Probands display mandibular hypoplasia, microtia, facial and preauricular tags, epibulbar dermoids, lateral oral clefts in addition to skeletal and cardiac abnormalities. Targeted morpholino knockdown of SF3B2 in Xenopus results in disruption of cranial neural crest precursor formation and subsequent craniofacial cartilage defects, supporting a link between spliceosome mutations and impaired neural crest development in congenital craniofacial disease. The results establish haploinsufficient variants in SF3B2 as the most prevalent genetic cause of CFM, explaining ~3% of sporadic and ~25% of familial cases

Correction:A two-arm parallel double-blind randomised controlled pilot trial of the efficacy of Omega-3 polyunsaturated fatty acids for the treatment of women with endometriosis-associated pain (PurFECT1)

[This corrects the article DOI: 10.1371/journal.pone.0227695.]

Connecting the multiple dimensions of global soil fungal diversity

How the multiple facets of soil fungal diversity vary worldwide remains virtually unknown, hindering the management of this essential species-rich group. By sequencing high-resolution DNA markers in over 4000 topsoil samples from natural and human-altered ecosystems across all continents, we illustrate the distributions and drivers of different levels of taxonomic and phylogenetic diversity of fungi and their ecological groups. We show the impact of precipitation and temperature interactions on local fungal species richness (alpha diversity) across different climates. Our findings reveal how temperature drives fungal compositional turnover (beta diversity) and phylogenetic diversity, linking them with regional species richness (gamma diversity). We integrate fungi into the principles of global biodiversity distribution and present detailed maps for biodiversity conservation and modeling of global ecological processes

Combination of gefitinib and methotrexate to treat tubal ectopic pregnancy (GEM3): a multicentre, randomised, double-blind, placebo-controlled trial

BACKGROUND: Tubal ectopic pregnancies can cause substantial morbidity or even death. Current treatment is with methotrexate or surgery. Methotrexate treatment fails in approximately 30% of women who subsequently require rescue surgery. Gefitinib, an epidermal growth factor receptor inhibitor, might improve the effects of methotrexate. We assessed the efficacy of oral gefitinib with methotrexate, versus methotrexate alone, to treat tubal ectopic pregnancy. METHODS: We performed a multicentre, randomised, double-blind, placebo-controlled trial across 50 UK hospitals. Participants diagnosed with tubal ectopic pregnancy were administered a single dose of intramuscular methotrexate (50 mg/m2) and randomised (1:1 ratio) to 7 days of additional oral gefitinib (250 mg daily) or placebo. The primary outcome, analysed by intention to treat, was surgical intervention to resolve the ectopic pregnancy. Secondary outcomes included time to resolution of ectopic pregnancy and serious adverse events. This trial is registered at the ISRCTN registry, ISCRTN 67795930. FINDINGS: Between Nov 2, 2016, and Oct 6, 2021, 328 participants were allocated to methotrexate and gefitinib (n=165) or methotrexate and placebo (n=163). Three participants in the placebo group withdrew. Surgical intervention occurred in 50 (30%) of 165 participants in the gefitinib group and in 47 (29%) of 160 participants in the placebo group (adjusted risk ratio 1·15, 95% CI 0·85 to 1·58; adjusted risk difference -0·01, 95% CI -0·10 to 0·09; p=0·37). Without surgical intervention, median time to resolution was 28·0 days in the gefitinib group and 28·0 days in the placebo group (subdistribution hazard ratio 1·03, 95% CI 0·75 to 1·40). Serious adverse events occurred in five (3%) of 165 participants in the gefitinib group and in six (4%) of 162 participants in the placebo group. Diarrhoea and rash were more common in the gefitinib group. INTERPRETATION: In women with a tubal ectopic pregnancy, adding oral gefitinib to parenteral methotrexate does not offer clinical benefit over methotrexate and increases minor adverse reactions. FUNDING: National Institute of Health Research

Domestication as innovation : the entanglement of techniques, technology and chance in the domestication of cereal crops

The origins of agriculture involved pathways of domestication in which human behaviours and plant genetic adaptations were entangled. These changes resulted in consequences that were unintended at the start of the process. This paper highlights some of the key innovations in human behaviours, such as soil preparation, harvesting and threshing, and how these were coupled with genetic ‘innovations’ within plant populations. We identify a number of ‘traps’ for early cultivators, including the needs for extra labour expenditure on crop-processing and soil fertility maintenance, but also linked gains in terms of potential crop yields. Compilations of quantitative data across a few different crops for the traits of nonshattering and seed size are discussed in terms of the apparently slow process of domestication, and parallels and differences between different regional pathways are identified. We highlight the need to bridge the gap between a Neolithic archaeobotanical focus on domestication and a focus of later periods on crop-processing activities and labour organization. In addition, archaeobotanical data provide a basis for rethinking previous assumptions about how plant genetic data should be related to the origins of agriculture and we contrast two alternative hypotheses: gradual evolution with low selection pressure versus metastable equilibrium that prolonged the persistence of ‘semi-domesticated’ populations. Our revised understanding of the innovations involved in plant domestication highlight the need for new approaches to collecting, modelling and integrating genetic data and archaeobotanical evidence

Positive definite metric spaces

Magnitude is a numerical invariant of finite metric spaces, recently introduced by T. Leinster, which is analogous in precise senses to the cardinality of finite sets or the Euler characteristic of topological spaces. It has been extended to infinite metric spaces in several a priori distinct ways. This paper develops the theory of a class of metric spaces, positive definite metric spaces, for which magnitude is more tractable than in general. Positive definiteness is a generalization of the classical property of negative type for a metric space, which is known to hold for many interesting classes of spaces. It is proved that all the proposed definitions of magnitude coincide for compact positive definite metric spaces and further results are proved about the behavior of magnitude as a function of such spaces. Finally, some facts about the magnitude of compact subsets of l_p^n for p \le 2 are proved, generalizing results of Leinster for p=1,2, using properties of these spaces which are somewhat stronger than positive definiteness.Comment: v5: Corrected some misstatements in the last few paragraphs. Updated reference