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Purpose: This review aims to discuss the psychological aspects of Graves’ ophthalmopathy (GO), estimate the prevalence of depression and anxiety disorders in GO, examine whether these psychiatric disorders are more prevalent in GO than in Graves’ disease (GD) without eye disease, and evaluate the main contributors for depression and anxiety in GO. Methods: A review of the literature. Results: Both depression and anxiety are associated with GO. The prevalence of depression and anxiety disorders specifically in GO patients was estimated at 18–33% and 26–41%, respectively. The reported prevalence in GD patients ranged from 9% to 70% for depression and from 18% to 88% for anxiety disorders. Significantly higher levels of depression and anxiety were found in GD patients compared with patients with non-autoimmune hyperthyroidism. Conflicting results have been reported regarding the association of antithyroid autoantibodies with depression and anxiety disorders. Serum thyroid hormone levels do not correlate with the severity of depression and anxiety. An improvement of psychiatric symptoms is observed in hyperthyroid patients after treatment of thyrotoxicosis. Moreover, depression and anxiety are significantly related to impaired quality of life (QoL) in GO. Exophthalmos and diplopia were not associated with depression nor anxiety, but orbital decompression and strabismus surgery do seem to improve QoL in GO patients. Conclusions: The results of this review suggest that altered thyroid hormone levels and autoimmunity are prognostic factors for depression and anxiety in GO. With regard to the visual and disfiguring aspects of GO as contributing factors for depression and anxiety, no decisive conclusions can be made.

Abstract Melanism, the process of heavier melanin deposition, can interact with climate variation at both micro and macro scales, ultimately influencing color evolution in organisms. While the ecological processes regulating melanin production in relation to climate have been extensively studied, intraspecific variations of melanism are seldom considered. Such scientific gap hampers our understanding of how species adapt to rapidly changing climates. For example, dark coloration may lead to higher heat absorption and be advantageous in cool climates, but also in hot environments as a UV or antimicrobial protection mechanism. To disentangle such opposing predictions, here we examined the effect of climate on shaping melanism variation in 150 barred grass snakes (Natrix helvetica) and 383 green whip snakes (Hierophis viridiflavus) across Italy. By utilizing melanistic morphs (charcoal and picturata in N. helvetica, charcoal and abundistic in H. viridiflavus) and compiling observations from 2002 to 2021, we predicted that charcoal morphs in H. viridiflavus would optimize heat absorption in cold environments, while offering protection from excessive UV radiation in N. helvetica within warm habitats; whereas picturata and abundistic morphs would thrive in humid environments, which naturally have a denser vegetation and wetter substrates producing darker ambient light, thus providing concealment advantages. While picturata and abundistic morphs did not align with our initial humidity expectations, the charcoal morph in N. helvetica is associated with UV environments, suggesting protection mechanisms against damaging solar radiation. H. viridiflavus is associated with high precipitations, which might offer antimicrobial protection. Overall, our results provide insights into the correlations between melanin‐based color morphs and climate variables in snake populations. While suggestive of potential adaptive responses, future research should delve deeper into the underlying mechanisms regulating this relationship.

ABSTRACT Introduction Sellar masses are common intracranial neoplasms. Their clinical manifestations vary widely and include headache. We aimed to determine whether the prevalence and characteristics of headache in patients with sellar tumours differ from the general population and to investigate the effect of tumour resection on this complaint. Methods We performed a prospective, controlled study in a single tertiary centre and included 57 patients that underwent transsphenoidal resection for a sellar mass (53% females, mean age 53.5 ± 16.4) and 29 of their partners (controls; 45% females, mean age 54.8 ± 14.9). Outcome measures were prevalence, characteristics and impact of headache 1 month preoperatively and at neurosurgical follow‐up 3 months postoperatively. Results Preoperatively, the prevalence of regular headache (≥1 time per month) was higher in patients than in controls (54% vs. 17%, p

Background Intracranial aneurysms (IAs) are more common in women than in men; however, there is still limited knowledge on sex‐dependent differences regarding aneurysm location, multiplicity, rupture risk, risk factors, and histopathology. Methods This cross‐sectional, consecutive cohort study examined whether IAs differ in multiplicity, location, geometry, rupture risk, risk factors, and histology between sexes. Results We included 982 patients (714 women, 268 men) totaling 1484 IAs (1056 unruptured, 397 ruptured). A total of 363 patients (36.97%) had multiple IAs, the proportion of which was significantly higher in women. In women, the internal carotid artery (40.79%) was the most frequent location for IAs, whereas in men most were found along the anterior carotid artery territory (32.86%). Men were significantly more often diagnosed with ruptured aneurysms. Aneurysm geometry did not differ between sexes; however, ruptured aneurysms in men presented with a significantly larger neck diameter than unruptured ones. Regarding risk factors for aneurysm rupture, blood pressure control was more effective in women, whereas the effect of smoking status did not show clear sex‐dependent differences. Histologically, wall‐type classification analysis showed significantly more severe aneurysm wall types in men. Conclusion IA prevalence in women is significantly higher than in men. Women more often present with multiple IAs, whereas men were more often diagnosed with ruptured IAs. Sex‐specific differences in IA location were identified, whereas geometry of IAs did not differ between sexes. IAs in men showed a more severe histological wall type. Further research is needed to unravel the molecular mechanisms underlying these important sex‐dependent manifestations in IAs.

Understanding the demographic history of populations is a key goal in population genetics, and with improving methods and data, ever more complex models are being proposed and tested. Demographic models of current interest typically consist of a set of discrete populations, their sizes and growth rates, and continuous and pulse migrations between those populations over a number of epochs, which can require dozens of parameters to fully describe. There is currently no standard format to define such models, significantly hampering progress in the field. In particular, the important task of translating the model descriptions in published work into input suitable for population genetic simulators is labor intensive and error prone. We propose the Demes data model and file format, built on widely used technologies, to alleviate these issues. Demes provide a well-defined and unambiguous model of populations and their properties that is straightforward to implement in software, and a text file format that is designed for simplicity and clarity. We provide thoroughly tested implementations of Demes parsers in multiple languages including Python and C, and showcase initial support in several simulators and inference methods. An introduction to the file format and a detailed specification are available at https://popsim-consortium.github.io/demes-spec-docs/.

BackgroundBlockchain has been proposed as a critical technology to facilitate more patient-centric research and health information sharing. For instance, it can be applied to coordinate and document dynamic informed consent, a procedure that allows individuals to continuously review and renew their consent to the collection, use, or sharing of their private health information. Such has been suggested to facilitate ethical, compliant longitudinal research, and patient engagement. However, blockchain-based dynamic consent is a relatively new concept, and it is not yet clear how well the suggested implementations will work in practice. Efforts to critically evaluate implementations in health research contexts are limited. ObjectiveThe objective of this protocol is to guide the identification and critical appraisal of implementations of blockchain-based dynamic consent in health research contexts, thereby facilitating the development of best practices for future research, innovation, and implementation. MethodsThe protocol describes methods for an integrative review to allow evaluation of a broad range of quantitative and qualitative research designs. The PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols) framework guided the review’s structure and nature of reporting findings. We developed search strategies and syntax with the help of an academic librarian. Multiple databases were selected to identify pertinent academic literature (CINAHL, Embase, Ovid MEDLINE, PubMed, Scopus, and Web of Science) and gray literature (Electronic Theses Online Service, ProQuest Dissertations and Theses, Open Access Theses and Dissertations, and Google Scholar) for a comprehensive picture of the field’s progress. Eligibility criteria were defined based on PROSPERO (International Prospective Register of Systematic Reviews) requirements and a criteria framework for technology readiness. A total of 2 reviewers will independently review and extract data, while a third reviewer will adjudicate discrepancies. Quality appraisal of articles and discussed implementations will proceed based on the validated Mixed Method Appraisal Tool, and themes will be identified through thematic data synthesis. ResultsLiterature searches were conducted, and after duplicates were removed, 492 articles were eligible for screening. Title and abstract screening allowed the removal of 312 articles, leaving 180 eligible articles for full-text review against inclusion criteria and confirming a sufficient body of literature for project feasibility. Results will synthesize the quality of evidence on blockchain-based dynamic consent for patient-centric research and health information sharing, covering effectiveness, efficiency, satisfaction, regulatory compliance, and methods of managing identity. ConclusionsThe review will provide a comprehensive picture of the progress of emerging blockchain-based dynamic consent technologies and the rigor with which implementations are approached. Resulting insights are expected to inform best practices for future research, innovation, and implementation to benefit patient-centric research and health information sharing. Trial RegistrationPROSPERO CRD42023396983; http://tinyurl.com/cn8a5x7t International Registered Report Identifier (IRRID)DERR1-10.2196/50339

Stochastic simulation is a key tool in population genetics, since the models involved are often analytically intractable and simulation is usually the only way of obtaining ground-truth data to evaluate inferences. Because of this, a large number of specialized simulation programs have been developed, each filling a particular niche, but with largely overlapping functionality and a substantial duplication of effort. Here, we introduce msprime version 1.0, which efficiently implements ancestry and mutation simulations based on the succinct tree sequence data structure and the tskit library. We summarize msprime's many features, and show that its performance is excellent, often many times faster and more memory efficient than specialized alternatives. These high-performance features have been thoroughly tested and validated, and built using a collaborative, open source development model, which reduces duplication of effort and promotes software quality via community engagement.

Introduction: In our hospital, physicians noticed high free thyroxine (fT4) concentrations without complete suppression of thyroid-stimulating hormone (TSH) in blood samplesof patients at the outpatient clinic, which appeared to occur more often following the introduction of a new fT4 immunoassay. This discordance may be explained by incorrect reference intervals, analytical issues, or patient-related factors. We aimed to establish the contribution of the possible factors involved. Methods: Reference intervals of both fT4 immunoassays were re-evaluated using blood samples of healthy volunteers and the new immunoassay’s performance was assessed using internal quality controls and external quality rounds. The frequency of discordant fT4 and TSH pairings obtained from laboratory requests were retrospectively analysed using a Delfia (n = 3174) and Cobas cohort (n = 3408). Last, a literature search assessed whether the time of blood draw and the time of levothyroxine (L-T4) ingestion may contribute to higher fT4 concentrations in L-T4 users. Results: The original reference intervals of both fT4 immunoassays were confirmed and no evidence for analytical problems was found. The Delfia (n = 176, 5.5%) and Cobas cohorts (n = 295, 8.7%) showed comparable frequencies of discordance. Interestingly, 72–81% of the discordant results belonged to L-T4 users. Literature indicated the time of blood withdrawal of L-T4 users and, therefore, the time of L-T4 intake as possible explanations. Conclusions: High fT4 without suppressed TSH concentrations can mainly be explained by L-T4 intake. Physicians and laboratory specialists should be aware of this phenomenon to avoid questioning the assay’s performance or unnecessarily adapting the L-T4 dose in patients.

Can intangible cultural heritage (ICH) help to reduce biodiversity loss and and water shortages related to climate change? Can it contribute to managing water shortages and surpluses on a local level? This article argues that some useful forms of intangible, “living” heritage offer valuable knowledge and practices that can serve as adaptive strategies in a changing environment. Binding practitioners to a specific place and to each other and connecting past and future generations, ICH can bring local knowledge and experience into the work field. The examples introduced here include grassland irrigation, water milling and hedge-laying: all used in the past, replaced by new inventions (e.g. fertilizers, new techniques for grinding grains and barbed wire taking the place of hedges respectively), and reintroduced because of their potential role in water management and ability to help create a climate-robust landscape. The valuable insights and practices of “citizen scientists” using these traditional techniques are too often overlooked by policy makers and academics.

As an activity “of intervention on the activity of others” (Barbier, 2011, p. 62), when conceived as the experience that emerges from the dynamic coupling between an actor and his/her environment in a situation of facilitating a work group, the manager’s activity remains largely hidden to an outside observer. To understand it, one therefore requires methods that reveal the way in which the managers construct a point of view on the activity of those they are supervising. With a view to achieving such understanding, this research proposes to document the variables of the situation relating to the activity of the supervisees, to their states and to their evolution according to the situational transformations that the manager takes into account in order to know, do and control what is to be done (Tourmen, 2014). To this end, our research examines the experience of army cadets during a training course. The results show how, in order to deploy their activity, the managers combine two simultaneous perspectives on the situation: their own; the one they attribute to others and which they infer from combinations of information gathered about the group and its members, the environment, the performance of the task and their own activity (what they think, do and feel). This research sheds additional light on what the activity-based approach can contribute to the understanding of a complex activity such as that of the managers, in particular by documenting it not only from the description of what they do (Mintzberg, 1984) but also from what they live and experience within themselves and with others. It leads to a range of proposals for the training of future managers.

Identifying regions of the genome that act as barriers to gene flow between recently diverged taxa has remained challenging given the many evolutionary forces that generate variation in genetic diversity and divergence along the genome, and the stochastic nature of this variation. Progress has been impeded by a conceptual and methodological divide between analyses that infer the demographic history of speciation and genome scans aimed at identifying locally maladaptive alleles i.e. genomic barriers to gene flow. Here we implement genomewide IM blockwise likelihood estimation (gIMble), a composite likelihood approach for the quantification of barriers, that bridges this divide. This analytic framework captures background selection and selection against barriers in a model of isolation with migration (IM) as heterogeneity in effective population size (Ne) and effective migration rate (me), respectively. Variation in both effective demographic parameters is estimated in sliding windows via pre-computed likelihood grids. gIMble includes modules for pre-processing/filtering of genomic data and performing parametric bootstraps using coalescent simulations. To demonstrate the new approach, we analyse data from a well-studied pair of sister species of tropical butterflies with a known history of post-divergence gene flow: Heliconius melpomene and H. cydno. Our analyses uncover both large-effect barrier loci (including well-known wing-pattern genes) and a genome-wide signal of a polygenic barrier architecture.

Abstract Evolution has traditionally been a historical and descriptive science, and predicting future evolutionary processes has long been considered impossible. However, evolutionary predictions are increasingly being developed and used in medicine, agriculture, biotechnology and conservation biology. Evolutionary predictions may be used for different purposes, such as to prepare for the future, to try and change the course of evolution or to determine how well we understand evolutionary processes. Similarly, the exact aspect of the evolved population that we want to predict may also differ. For example, we could try to predict which genotype will dominate, the fitness of the population or the extinction probability of a population. In addition, there are many uses of evolutionary predictions that may not always be recognized as such. The main goal of this review is to increase awareness of methods and data in different research fields by showing the breadth of situations in which evolutionary predictions are made. We describe how diverse evolutionary predictions share a common structure described by the predictive scope, time scale and precision. Then, by using examples ranging from SARS‐CoV2 and influenza to CRISPR‐based gene drives and sustainable product formation in biotechnology, we discuss the methods for predicting evolution, the factors that affect predictability and how predictions can be used to prevent evolution in undesirable directions or to promote beneficial evolution (i.e. evolutionary control). We hope that this review will stimulate collaboration between fields by establishing a common language for evolutionary predictions.

Summary: Background: Generic and disease-specific patient-reported outcome measures (PROMs) may lack relevance and sensitivity on a patient-level in chronic diseases with differential disease expression and high individual variability, such as Cystic Fibrosis (CF). This study aimed to develop and validate a novel personalized electronic PROM (ePROM) that captures relevant aspects of quality of life in individuals with CF. Methods: The Q-Life app was developed as a short personalized ePROM to assess individual quality of life. Psychometric properties were assessed in a single-center cross-sectional study between September 2019 and September 2021 and in a prospective cohort study between September 2021 and September 2022. Findings: Combined studies included 223 participants (median age: 24 years, IQR: 19.0–32.5 years, range: 12.0–58.0 years). Internal consistency (Cronbach's alpha: 0.83–0.90) and test-retest reliability (intraclass correlation coefficient: 0.90; 95% CI: 0.65–0.92; p

Abstract This clinical study explored the associations between the intestinal microbiota, chemotherapy toxicity, and treatment response in postmenopausal oestrogen receptor positive breast cancer patients.Oestrogen receptor positive postmenopausal breast cancer patients were prospectively enroled in a multicentre cohort study and treated with 4 cycles of (neo)adjuvant adriamycin, cyclophosphamide (AC) followed by 4 cycles of docetaxel (D). Patients collected a faecal sample and completed a questionnaire before treatment, during AC, during D, and after completing AC-D. Chemotherapy toxicity and tumour response were determined. Intestinal microbiota was analysed by amplicon sequencing of the 16 S rRNA V4 gene-region. In total, 44 patients, including 18 neoadjuvant patients, were included, and 153 faecal samples were collected before AC-D (n = 44), during AC (n = 43), during D (n = 29), and after AC-D treatment (n = 37), 28 participants provided all four samples. In the whole group, observed species richness reduced during treatment (p = 0.042). The abundance of Proteobacteria, unclassified Enterobacterales, Lactobacillus, Ruminococcaceae NK4A214 group, Marvinbryantia, Christensenellaceae R7 group, and Ruminococcaceae UCG-005 changed significantly over time. Patients with any grade diarrhoea during docetaxel treatment had a significantly lower observed species richness compared to patients without diarrhoea. In the small group neoadjuvant treated patients, pathologic response was unrelated to baseline intestinal microbiota richness, diversity and composition. While the baseline microbiota was not predictive for pathologic response in a rather small group of neoadjuvant treated patients in our study, subsequent shifts in microbial richness, as well as the abundance of specific bacterial taxa, were observed during AC-D treatment in the whole group and the neoadjuvant group.

This review focuses on providing physicians with insights into the complex relationship between bone marrow adipose tissue (BMAT) and bone health, in the context of weight loss through caloric restriction or metabolic and bariatric surgery (MBS), in people living with obesity (PwO). We summarize the complex relationship between BMAT and bone health, provide an overview of noninvasive imaging techniques to quantify human BMAT, and discuss clinical studies measuring BMAT in PwO before and after weight loss. The relationship between BMAT and bone is subject to variations based on factors such as age, sex, menopausal status, skeletal sites, nutritional status, and metabolic conditions. The Bone Marrow Adiposity Society (BMAS) recommends standardizing imaging protocols to increase comparability across studies and sites, they have identified both water–fat imaging (WFI) and spectroscopy (1H-MRS) as accepted standards for in vivo quantification of BMAT. Clinical studies measuring BMAT in PwO are limited and have shown contradictory results. However, BMAT tends to be higher in patients with the highest visceral adiposity, and inverse associations between BMAT and bone mineral density (BMD) have been consistently found in PwO. Furthermore, BMAT levels tend to decrease after caloric restriction-induced weight loss. Although weight loss was associated with overall fat loss, a reduction in BMAT did not always follow the changes in fat volume in other tissues. The effects of MBS on BMAT are not consistent among the studies, which is at least partly related to the differences in the study population, skeletal site, and duration of the follow-up. Overall, gastric bypass appears to decrease BMAT, particularly in patients with diabetes and postmenopausal women, whereas sleeve gastrectomy appears to increase BMAT. More research is necessary to evaluate changes in BMAT and its connection to bone metabolism, either in PwO or in cases of weight loss through caloric restriction or MBS, to better understand the role of BMAT in this context and determine the local or systemic factors involved.

IntroductionThe notion of autonomy in Self-Determination Theory is at the core of intrinsically motivated learning, and fulfilment of the need for autonomy is essential for thriving at school. Therefore teacher-provided autonomy support has grown into a key concern in educational research. In the present study into primary school music education, the notion of creative autonomy support is introduced. Research into autonomy support is typically focused on verbal interaction. However, from an enactive perspective, teachers’ gesturing, bodily movement, facial expression, and musical action form an integral part of the socially situated interaction in music lessons, inherently involving autonomy support. In the present study, a distinction is made between creative verbal autonomy support and creative musical and non-verbal autonomy support.MethodsApplying a process-based time-serial methodology, rooted in a Complex Dynamic Systems and Enactive perspective, the effects of an intervention with Video Feedback Coaching for teachers were investigated. Video data of 105 music lessons of 18 teachers (intervention and control condition) from six primary schools was gathered, to examine teachers’ creative autonomy support at both the individual and group level.ResultsThe findings show that teachers in the intervention condition, compared to the control group, achieved a meaningful increase in their ability to offer creative autonomy support verbally. Teachers also showed development for the non-verbal and musical aspects of offering creative autonomy support. However, particularly for offering higher-level creative autonomy support in the non-verbal and musical mode, significant results were found for less than half of the intervention teachers.DiscussionThese results underline the importance of embracing and studying the bodily dimension as an integral part of teacher autonomy support, aimed at emergence of students’ musical creativity, in primary school music education and in teacher training. We explain how these results might be relevant for autonomy enhancing musical activities in vulnerable groups.

We present a genome assembly from an individual female Anthocharis cardamines (the orange-tip; Arthropoda; Insecta; Lepidoptera; Pieridae). The genome sequence is 360 megabases in span. The majority (99.74%) of the assembly is scaffolded into 31 chromosomal pseudomolecules, with the W and Z sex chromosomes assembled. Gene annotation of this assembly on Ensembl has identified 12,477 protein coding genes.

BackgroundIn multiple endocrine neoplasia type 1 (MEN1), pancreatic neuroendocrine tumors (PanNETs) have a high prevalence and represent the main cause of death. This study aimed to assess the diagnostic accuracy of the currently used conventional pancreatic imaging techniques and the added value of fine needle aspirations (FNAs).MethodsPatients who had at least one imaging study were included from the population-based MEN1 database of the DutchMEN Study Group from 1990 to 2017. Magnetic resonance imaging (MRI), computed tomography (CT), endoscopic ultrasonography (EUS), FNA, and surgical resection specimens were obtained. The first MRI, CT, or EUS was considered as the index test. For a comparison of the diagnostic accuracy of MRI versus CT, patients with their index test taken between 2010 and 2017 were included. The reference standard consisted of surgical histopathology or radiological follow-up.ResultsA total of 413 patients (92.8% of the database) underwent 3,477 imaging studies. The number of imaging studies per patient increased, and a preference for MRI was observed in the last decade. Overall diagnostic accuracy was good with a positive (PPV) and negative predictive value (NPV) of 88.9% (95% confidence interval, 76.0–95.6) and 92.8% (89.4–95.1), respectively, for PanNET in the pancreatic head and 92.0% (85.3–96.0) and 85.3% (80.5–89.1), respectively, in the body/tail. For MRI, PPV and NPV for pancreatic head tumors were 100% (76.1–100) and 87.1% (76.3–93.6) and for CT, 60.0% (22.9–88.4) and 70.4% (51.3–84.3), respectively. For body/tail tumors, PPV and NPV were 91.3% (72.0–98.8) and 87.0% (75.3–93.9), respectively, for MRI and 100% (74.9–100) and 77.8% (54.3–91.5), respectively, for CT. Pathology confirmed a PanNET in 106 out of 110 (96.4%) resection specimens. FNA was performed on 34 lesions in 33 patients and was considered PanNET in 24 [all confirmed PanNET by histology (10) or follow-up (14)], normal/cyst/unrepresentative in 6 (all confirmed PanNET by follow-up), and adenocarcinoma in 4 (2 confirmed and 2 PanNET). Three patients, all older than 60 years, had a final diagnosis of pancreatic adenocarcinoma.ConclusionAs the accuracy for diagnosing MEN1-related PanNET of MRI was higher than that of CT, MRI should be the preferred (non-invasive) imaging modality for PanNET screening/surveillance. The high diagnostic accuracy of pancreatic imaging and the sporadic occurrence of pancreatic adenocarcinoma question the need for routine (EUS-guided) FNA.

Abstract Background First-line treatment for prolactinomas is a medical treatment with dopamine agonists (DAs), which effectively control hyperprolactinaemia in most patients, although post-withdrawal remission rates are approximately 34%. Therefore, many patients require prolonged DA treatment, while side effects negatively impact health-related quality of life (HRQoL). Endoscopic transsphenoidal resection is reserved for patients with severe side effects, or with DA-resistant prolactinoma. Surgery has a good safety profile and high probability of remission and may thus deserve a more prominent place in prolactinoma treatment. The hypothesis for this study is that early or upfront surgical resection is superior to DA treatment both in terms of HRQoL and remission rate in patients with a non-invasive prolactinoma of limited size. Methods We present a combined randomised clinical trial and observational cohort study design, which comprises three unblinded randomised controlled trials (RCTs; PRolaCT-1, PRolaCT-2, PRolaCT-3), and an observational study arm (PRolaCT-O) that compare neurosurgical counselling, and potential subsequent endoscopic transsphenoidal adenoma resection, with current standard care. Patients with a non-invasive prolactinoma (< 25 mm) will be eligible for one of three RCTs based on the duration of pre-treatment with DAs: PRolaCT-1: newly diagnosed, treatment-naïve patients; PRolaCT-2: patients with limited duration of DA treatment (4–6 months); and PRolaCT-3: patients with persisting prolactinoma after DA treatment for > 2 years. PRolaCT-O will include patients who decline randomisation, due to e.g. a clear treatment preference. Primary outcomes are disease remission after 36 months and HRQoL after 12 months. Discussion Early or upfront surgical resection for patients with a limited-sized prolactinoma may be a reasonable alternative to the current standard practice of DA treatment, which we will investigate in three RCTs and an observational cohort study. Within the three RCTs, patients will be randomised between neurosurgical counselling and standard care. The observational study arm will recruit patients who refuse randomisation and have a pronounced treatment preference. PRolaCT will collect randomised and observational data, which may facilitate a more individually tailored practice of evidence-based medicine. Trial registration US National Library of Medicine registry (ClinicalTrials.gov) NCT04107480 . Registered on 27 September 2019, registered retrospectively (by 2 months).

Extracting information on the selective and demographic past of populations that is contained in samples of genome sequences requires a description of the distribution of the underlying genealogies. Using the Laplace transform, this distribution can be generated with a simple recursive procedure, regardless of model complexity. Assuming an infinite-sites mutation model, the probability of observing specific configurations of linked variants within small haplotype blocks can be recovered from the Laplace transform of the joint distribution of branch lengths. However, the repeated differentiation required to compute these probabilities has proven to be a serious computational bottleneck in earlier implementations. Here, I show that the state space diagram can be turned into a computational graph, allowing efficient evaluation of the Laplace transform by means of a graph traversal algorithm. This general algorithm can, for example, be applied to tabulate the likelihoods of mutational configurations in non-recombining blocks. This work provides a crucial speed up for existing composite likelihood approaches that rely on the joint distribution of branch lengths to fit isolation with migration models and estimate the parameters of selective sweeps. The associated software is available as an open-source Python library, agemo.

Microbiomes are involved in most vital processes, such as immune response, detoxification, and digestion and are thereby elementary to organismal functioning and ultimately the host’s fitness. In turn, the microbiome may be influenced by the host and by the host’s environment. To understand microbiome dynamics during the process of adaptation to new resources, we performed an evolutionary experiment with the two-spotted spider mite, Tetranychus urticae. We generated genetically depleted strains of the two-spotted spider mite and reared them on their ancestral host plant and two novel host plants for approximately 12 generations. The use of genetically depleted strains reduced the magnitude of genetic adaptation of the spider mite host to the new resource and, hence, allowed for better detection of signals of adaptation via the microbiome. During the course of adaptation, we tested spider mite performance (number of eggs laid and longevity) and characterized the bacterial component of its microbiome (16S rRNA gene sequencing) to determine: (1) whether the bacterial communities were shaped by mite ancestry or plant environment and (2) whether the spider mites’ performance and microbiome composition were related. We found that spider mite performance on the novel host plants was clearly correlated with microbiome composition. Because our results show that only little of the total variation in the microbiome can be explained by the properties of the host (spider mite) and the environment (plant species) we studied, we argue that the bacterial community within hosts could be valuable for understanding a species’ performance on multiple resources.

Bone marrow adipose tissue (BMAT) is a dynamic tissue which is associated with osteoporosis, bone metastasis, and primary bone tumors. The aim of this study is to determine region-specific variations and age- and gender-specific differences in BMAT and BMAT composition in healthy subjects. In this cross-sectional study, we included 40 healthy subjects (26 male: mean age 49 years, range 22–75 years; 14 female: mean age 50 years, range 29–71) and determined the bone marrow signal fat fraction and bone marrow unsaturation in the spine (C3-L5), pelvis, femora, and tibiae using chemical shift encoding-based water–fat imaging (WFI) with multiple gradient echoes (mGRE). Regions of interest covered the individual vertebral bodies, pelvis and proximal epimetaphysis, diaphysis, and distal epimetaphysis of the femur and tibia. The spinal fat fraction increased from cervical to lumbar vertebral bodies (mean fat fraction ( ± SD or (IQR): cervical spine 0.37 ± 0.1; thoracic spine 0.41 ± 0.08. lumbar spine 0.46 ± 0.01; p < 0.001). The femoral fat fraction increased from proximal to distal (proximal 0.78 ± 0.09; diaphysis 0.86 (0.15); distal 0.93 ± 0.02; p < 0.001), while within the tibia the fat fraction decreased from proximal to distal (proximal 0.92 ± 0.01; diaphysis 0.91 (0.02); distal 0.90 ± 0.01; p < 0.001). In female subjects, age was associated with fat fraction in the spine, pelvis, and proximal femur (ρ = 0.88 p < 0.001; ρ = 0.87 p < 0.001; ρ = 0.63 p = 0.02; ρ = 0.74 p = 0.002, respectively), while in male subjects age was only associated with spinal fat fraction (ρ = 0.40 p = 0.04). Fat fraction and unsaturation were negatively associated within the spine (r = -0.40 p = 0.01), while in the extremities fat fraction and unsaturation were positively associated (distal femur: r = 0.42 p = 0.01; proximal tibia: r = 0.47, p = 0.002; distal tibia: r = 0.35 p = 0.03), both independent of age and gender. In conclusion, we confirm the distinct, age- and gender-dependent, distribution of BMAT throughout the human skeleton and we show that, contradicting previous animal studies, bone marrow unsaturation in human subjects is highest within the axial skeleton compared to the appendicular skeleton. Furthermore, we show that BMAT unsaturation was negatively correlated with BMAT within the spine, while in the appendicular skeleton, BMAT and BMAT unsaturation were positively associated.

Jonathan Goldenberg et al. use photographic data and ancestral state reconstruction of 126 viper species to show that substrate type influences the evolution of ventral brightness for efficient heat transfer. Their results suggest that these patterns may have been involved in the diversification of vipers during the Miocene, and highlight the importance of ventral body regions when considering behavioral ecology and evolution.

The depletion of fossil resources and the growing demand for plastic waste reduction has put industries and academic researchers under pressure to develop increasingly sustainable packaging solutions that are both functional and circularly designed. In this review, we provide an overview of the fundamentals and recent advances in biobased packaging materials, including new materials and techniques for their modification as well as their end-of-life scenarios. We also discuss the composition and modification of biobased films and multilayer structures, with particular attention to readily available drop-in solutions, as well as coating techniques. Moreover, we discuss end-of-life factors, including sorting systems, detection methods, composting options, and recycling and upcycling possibilities. Finally, regulatory aspects are pointed out for each application scenario and end-of-life option. Moreover, we discuss the human factor in terms of consumer perception and acceptance of upcycling.

Purpose: Ulnar nerve injury is the most common neurologic complication of elbow arthroscopy. The purpose of this cadaveric study was to quantify the ability of surgeons to locate the ulnar nerve behind the posteromedial capsule during elbow arthroscopy using sole arthroscopic vision. Methods: Twenty-one surgeons were asked to pin the ulnar nerve at the medial gutter and the posteromedial compartment using arthroscopic visualization of the medial capsule only. Pinning of the ulnar nerve was performed from extra-articular. Then, the cadaveric specimens were dissected and the shortest distances between the pins and ulnar nerve measured. Results: Median pin-to-nerve distances at the medial gutter and posteromedial compartment were 0 mm (interquartile range [IQR], 0-3 mm) and 2 mm (IQR, 0-6 mm), respectively. The ulnar nerve was pinned by 11/21 surgeons (52%) at the medial gutter, and 7/21 surgeons (33%) at the posteromedial compartment. Three of 21 surgeons (14%) pinned the ulnar nerve at both the medial gutter and the posteromedial compartment. Surgeon's experience and operation volume did not affect these outcomes (P > .05). Conclusions: Surgeons' ability to locate the ulnar nerve behind the posteromedial capsule using sole arthroscopic visualization, without external palpation, is poor. We recommend to proceed carefully when performing arthroscopic procedures in the posteromedial elbow, and identify and mobilize the ulnar nerve prior to any posteromedial capsular procedures.