The evolution of conspicuousness in frogs: When to signal toxicity?

Many organisms use conspicuous colour patterns to advertise their toxicity or unpalatability, a strategy known as aposematism. Despite the recognized benefits of this anti-predator tactic, not all chemically defended species exhibit warning coloration. Here, we use a comparative approach to investigate which factors predict the evolution of conspicuousness in frogs, a group in which conspicuous coloration and toxicity have evolved multiple times. We extracted colour information from dorsal and ventral photos of 594 frog species for which chemical defence information was available. Our results show that chemically defended and diurnal species have higher internal chromatic contrast, both ventrally and dorsally, than chemically undefended and/or nocturnal species. Among species that are chemically defended, conspicuous coloration is more likely to occur if species are diurnal. Our results also suggest that the evolution of conspicuous colour is more likely to occur in chemically defended prey with smaller body size. We discuss potential explanations for this association and suggest that prey profitability (related to body size) could be an important force driving the macroevolution of warning signals.

Better long-term speech outcomes in stroke survivors who received early clinical speech and language therapy: What's driving recovery?

Establishing whether speech and language therapy after stroke has beneficial effects on speaking ability is challenging because of the need to control for multiple non-therapy factors known to influence recovery. We investigated how speaking ability at three time points post-stroke differed in patients who received varying amounts of clinical therapy in the first month post-stroke. In contrast to prior studies, we factored out variance from: initial severity of speaking impairment, amount of later therapy, and left and right hemisphere lesion size and site. We found that speaking ability at one month post-stroke was significantly better in patients who received early therapy (n = 79), versus those who did not (n = 64), and the number of hours of early therapy was positively related to recovery at one year post-stroke. We offer two non-mutually exclusive interpretations of these data: (1) patients may benefit from the early provision of self-management strategies; (2) therapy is more likely to be provided to patients who have a better chance of recovery (e.g., poor physical and/or mental health may impact suitability for therapy and chance of recovery). Both interpretations have implications for future studies aiming to predict individual patients' speech outcomes after stroke, and their response to therapy.

Necessity is the mother of invention: how the COVID-19 pandemic could change medical student placements for the better.

COVID-19 led to the widespread withdrawal of face-to-face hospital-based clinical placements, with many medical schools switching to online learning. This precipitated concern about potential negative impact on clinical and interprofessional skill acquisition. To overcome this problem, we piloted a 12-week COVID-19 safe face-to-face clinical placement for 16 medical students at the Hospital for Tropical Diseases, London, during the first wave of the COVID-19 pandemic. COVID-19 infection control measures necessitated that students remained in 'social bubbles' for placement duration. This facilitated an apprenticeship-style teaching approach, integrating students into the clinical team for placement duration. Team-based learning was adopted to develop and deliver content. Teaching comprised weekly seminars, experiential ward-based attachments and participation in quality improvement and research projects. The taught content was evaluated through qualitative feedback, reflective practice, and pre-apprenticeship and post-apprenticeship confidence questionnaires across 17 domains. Students' confidence improved in 14 of 17 domains (p<0.05). Reflective practice indicated that students valued the apprenticeship model, preferring the longer clinical attachment to existent shorter, fragmented clinical placements. Students described improved critical thinking, group cohesion, teamwork, self-confidence, self-worth and communication skills. This article describes a framework for the safe and effective delivery of a longer face-to-face apprenticeship-based clinical placement during an infectious disease pandemic. Longer apprenticeship-style attachments have hidden benefits to general professional training, which should be explored by medical schools both during the COVID-19 pandemic and, possibly, for any future clinical placements.

Current and Emerging 3D Models to Study Breast Cancer.

For decades 2D culture has been used to study breast cancer. In recent years, however, the importance of 3D culture to recapitulate the complexity of human disease has received attention. A breakthrough for 3D culture came as a result of a Nature editorial 'Goodbye Flat Biology' (Anonymous, Nature 424:861-861, 2003). Since then scientists have developed and implemented a range of different and more clinically relevant models, which are used to study breast cancer. In this chapter multiple different 3D models will be discussed including spheroids, microfluidic and bio-printed models and in silico models.

The Association between Blood Test Trends and Undiagnosed Cancer: A Systematic Review and Critical Appraisal.

Clinical guidelines include monitoring blood test abnormalities to identify patients at increased risk of undiagnosed cancer. Noting blood test changes over time may improve cancer risk stratification by considering a patient's individual baseline and important changes within the normal range. We aimed to review the published literature to understand the association between blood test trends and undiagnosed cancer. MEDLINE and EMBASE were searched until 15 May 2023 for studies assessing the association between blood test trends and undiagnosed cancer. We used descriptive summaries and narratively synthesised studies. We included 29 articles. Common blood tests were haemoglobin (24%, n = 7), C-reactive protein (17%, n = 5), and fasting blood glucose (17%, n = 5), and common cancers were pancreatic (29%, n = 8) and colorectal (17%, n = 5). Of the 30 blood tests studied, an increasing trend in eight (27%) was associated with eight cancer types, and a decreasing trend in 17 (57%) with 10 cancer types. No association was reported between trends in 11 (37%) tests and breast, bile duct, glioma, haematological combined, liver, prostate, or thyroid cancers. Our review highlights trends in blood tests that could facilitate the identification of individuals at increased risk of undiagnosed cancer. For most possible combinations of tests and cancers, there was limited or no evidence.

Validation of a 3D perfused cell culture platform as a tool for humanised preclinical drug testing in breast cancer using established cell lines and patient-derived tissues.

3D cell culture models of cancer are currently being developed to recapitulate in vivo physiological conditions and to assess therapeutic responses. However, most models failed to incorporate the biochemical and biophysical stimuli from fluid flow. In this study, a three-dimensional scaffold, SeedEZ was applied within the PerfusionPal perfused culture system to investigate how perfusion, and blood-like oxygen delivery influenced breast cancer cell growth and their responses to a commonly used breast cancer drug tamoxifen. Our results showed that breast cancer cells could be maintained over 3 weeks in PerfusionPal with increased cell viability compared to static 3D culture in fully humanised conditions. This platform also supported examining the effect of tamoxifen on breast cancer cell lines and in primary patient-derived breast cancer samples. Future work is warranted to further the adaption for fully humanised assessment of drug effectiveness in a patient personalized approach with the aim to reduce the burden of animal use in cancer research and increase the degree of human pre-clinical data translation to clinic.

Automated Orientation and Registration of Cone-Beam Computed Tomography Scans.

Automated clinical decision support systems rely on accurate analysis of three-dimensional (3D) medical and dental images to assist clinicians in diagnosis, treatment planning, intervention, and assessment of growth and treatment effects. However, analyzing longitudinal 3D images requires standardized orientation and registration, which can be laborious and error-prone tasks dependent on structures of reference for registration. This paper proposes two novel tools to automatically perform the orientation and registration of 3D Cone-Beam Computed Tomography (CBCT) scans with high accuracy (<3° and <2mm of angular and linear errors when compared to expert clinicians). These tools have undergone rigorous testing, and are currently being evaluated by clinicians who utilize the 3D Slicer open-source platform. Our work aims to reduce the sources of error in the 3D medical image analysis workflow by automating these operations. These methods combine conventional image processing approaches and Artificial Intelligence (AI) based models trained and tested on de-identified CBCT volumetric images. Our results showed robust performance for standardized and reproducible image orientation and registration that provide a more complete understanding of individual patient facial growth and response to orthopedic treatment in less than 5 min.

PAX-D: study protocol for a randomised placebo-controlled trial evaluating the efficacy and mechanism of pramipexole as add-on treatment for people with treatment resistant depression.

INTRODUCTION: Clinical depression is usually treated in primary care with psychological therapies and antidepressant medication. However, when patients do not respond to at least two or more antidepressants within a depressive episode, they are considered to have treatment resistant depression (TRD). Previous small randomised controlled trials suggested that pramipexole, a dopamine D2/3 receptor agonist, may be effective for treating patients with unipolar and bipolar depression as it is known to influence motivational drive and reward processing. PAX-D will compare the effects of pramipexole vs placebo when added to current antidepressant medication for people with TRD. Additionally, PAX-D will investigate the mechanistic effect of pramipexole on reward sensitivity using a probabilistic decision-making task. METHODS AND ANALYSIS: PAX-D will assess effectiveness in the short- term (during the first 12 weeks) and in the longer-term (48 weeks) in patients with TRD from the UK. The primary outcome will be change in self-reported depressive symptoms from baseline to week 12 post-randomisation measured using the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16). Performance on the decision-making task will be measured at week 0, week 2 and week 12. Secondary outcomes include anhedonia, anxiety and health economic measures including quality of life, capability, well-being and costs. PAX-D will also assess the adverse effects of pramipexole including impulse control difficulties. DISCUSSION: Pramipexole is a promising augmentation agent for TRD and may be a useful addition to existing treatment regimes. PAX-D will assess its effectiveness and test for a potential mechanism of action in patients with TRD. TRIAL REGISTRATION NUMBER: ISRCTN84666271.

The Effect of Focal Damage to the Right Medial Posterior Cerebellum on Word and Sentence Comprehension and Production.

Functional imaging studies of neurologically intact adults have demonstrated that the right posterior cerebellum is activated during verb generation, semantic processing, sentence processing, and verbal fluency. Studies of patients with cerebellar damage converge to show that the cerebellum supports sentence processing and verbal fluency. However, to date there are no patient studies that investigated the specific importance of the right posterior cerebellum in language processing, because: (i) case studies presented patients with lesions affecting the anterior cerebellum (with or without damage to the posterior cerebellum), and (ii) group studies combined patients with lesions to different cerebellar regions, without specifically reporting the effects of right posterior cerebellar damage. Here we investigated whether damage to the right posterior cerebellum is critical for sentence processing and verbal fluency in four patients with focal stroke damage to different parts of the right posterior cerebellum (all involving Crus II, and lobules VII and VIII). We examined detailed lesion location by going beyond common anatomical definitions of cerebellar anatomy (i.e., according to lobules or vascular territory), and employed a recently proposed functional parcellation of the cerebellum. All four patients experienced language difficulties that persisted for at least a month after stroke but three performed in the normal range within a year. In contrast, one patient with more damage to lobule IX than the other patients had profound long-lasting impairments in the comprehension and repetition of sentences, and the production of spoken sentences during picture description. Spoken and written word comprehension and visual recognition memory were also impaired, however, verbal fluency was within the normal range, together with object naming, visual perception and verbal short-term memory. This is the first study to show that focal damage to the right posterior cerebellum leads to language difficulties after stroke; and that processing impairments persisted in the case with most damage to lobule IX. We discuss these results in relation to current theories of cerebellar contribution to language processing. Overall, our study highlights the need for longitudinal studies of language function in patients with focal damage to different cerebellar regions, with functional imaging to understand the mechanisms that support recovery.

Right cerebral motor areas that support accurate speech production following damage to cerebellar speech areas.

Specific regions of the cerebellum are activated when neurologically intact adults speak, and cerebellar damage can impair speech production early after stroke, but how the brain supports accurate speech production years after cerebellar damage remains unknown. We investigated this in patients with cerebellar lesions affecting regions that are normally recruited during speech production. Functional MRI activation in these patients, measured during various single word production tasks, was compared to that of neurologically intact controls, and patient controls with lesions that spared the cerebellar speech production regions. Our analyses revealed that, during a range of speech production tasks, patients with damage to cerebellar speech production regions had greater activation in the right dorsal premotor cortex (r-PMd) and right supplementary motor area (r-SMA) compared to neurologically intact controls. The loci of increased activation in cerebral motor speech areas motivate future studies to delineate the functional contributions of different parts of the speech production network, and test whether non-invasive stimulation to r-PMd and r-SMA facilitates speech recovery after cerebellar stroke.

Advances in the development of improved animal-free models for use in breast cancer biomedical research.

Through translational research, the outcomes for women (and men) diagnosed with breast cancer have improved significantly, with now over 80% of women surviving for at least 5 years post-diagnosis. Much of this success has been translated from the bench to the bedside using laboratory models. Here, we outline the types of laboratory models that have helped achieve this and discuss new approaches as we move towards animal-free disease modelling.

Looked After Children in Residential Homes.

BACKGROUND: Looked after children in residential children's homes constitute a particularly vulnerable group who are known to have high rates of mental health problems and limited access to services. METHOD: A survey was undertaken in Leeds to determine what proportion of these children are involved with mental health services, and to look at the different ways in which child and adolescent mental health services across the city are currently working with this group. RESULTS: Of the 177 children in residential children's homes in August 2000, 64% had had some contact with child mental health services in the previous 5 years and 27% were in current contact. Thirty-six percent had had no contact with services over the past five years. CONCLUSIONS: It was anticipated from a review of the literature that a higher proportion of children would have been currently in contact with services. The findings suggest that the pattern of services offered to this group of children is changing, with an increase in consultation with, and training of, staff in residential children's homes. The paper ends with a discussion of whether or not this is a positive change and how CAMH resources might best be utilised in the future.

Comparison of ankle and subtalar joint complex range of motion during barefoot walking and walking in Masai Barefoot Technology sandals.

BACKGROUND: Masai Barefoot Technology (MBT, Switzerland) produce footwear which they claim simulate walking barefoot on soft undulating ground. This paper reports an investigation into the effect of MBT sandals on the motion of the ankle and subtalar joint complex during walking. METHODS: Range of motion data was collected in the sagittal, frontal and transverse plane from the ankle and subtalar joint complex from 32 asymptomatic subjects using the CODA MPX30 motion analysis system during both barefoot walking and walking in the MBT sandal. Shod and un-shod data were compared using the Wilcoxon signed ranks test. RESULTS: A significantly greater range of motion in the frontal and sagittal planes was recorded when walking in the MBT sandal (p = 0.031, and p = 0.015 respectively). In the transverse plane, no significant difference was found (p = 0.470). CONCLUSIONS: MBT sandals increase the range of motion of the ankle and subtalar joint complex in the frontal and sagittal planes. MBT footwear could therefore have a role to play in the management of musculoskeletal disorders where an increase in frontal and sagittal plane range of motion is desirable.