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The work of the serial killers William Burke and William Hare, immigrant Ulstermen who came to Scotland in 1818, is well known. When they were finally caught, having murdered 16 people and sold their bodies for dissection, Hare turned King's evidence and after a dramatic trial Burke was hanged in January 1829. The notoriety of the case resulted in a crowd for Burke's public execution that is generally regarded as the largest that ever assembled in Edinburgh for a hanging, being estimated at between 25,000 and 35,000 people. A contemporary journal kept by a medical student named Thomas Hume was recently acquired by The Royal College of Surgeons of Edinburgh. It contains new information regarding a contingent of immigrant Irishmen who were present at the hanging. In the lead-up to the execution, they took up a position in front of the gallows and tried to prevent any non-Irish from approaching the area immediately in front of the gallows, a futile aim given the huge, rapidly accumulating mob. On being questioned by Hume on their motives, they said it was bad enough for Burke, 'the poor devil', to be hanged, but they feared he would be mocked and denigrated by the crowd and so they were there to keep the crowd away from him as much as they could. The Irish in Scotland at that time were a marginalised and ghettoised group who saw Burke as one of their own. Therefore, they most likely saw it as their duty to at least try and protect him during, in their view, his final and most harsh mistreatment by a society that had habitually mistreated him and them.
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BACKGROUND/PURPOSE: To determine and compare the efficacy of a surgical internal limiting membrane (ILM) flap technique with the traditional ILM peel on long-term visual and anatomical outcomes for large (>400 µm) full-thickness macular holes. METHODS: From October 2016 to July 2022, patients undergoing initial full-thickness macular hole repair with the ILM flap or ILM peel technique were reviewed. Final outcomes were recorded and based on size in microns: 401 to 800, 801 to 1,200, and >1,200. RESULTS: Patients treated with ILM flap (n = 52, 94.2% closure rate) or ILM peel (n = 407, 93.6% closure rate) were followed with a mean follow-up time of 15.0 ± 10.2 and 20.0 ± 13.4 months, respectively. Success rates for ILM flaps and ILM peels were compared for full-thickness macular holes of 401 to 800 (100%, 95.8%, P = 0.39), 801 to 1,200 (95%, 93%, P = 0.74), and >1,200 (86.7%, 86.7%, P = 1.0) µm. Mean best-recorded logarithm of the minimal angle of resolution visual acuity for ILM flaps and ILM peels, respectively, was 1.02 ± 0.46 and 0.87 ± 0.47 preoperatively, with follow-up acuity of 0.48 ± 0.32 (P < 0.03) and 0.39 ± 0.42 (P < 0.01) at Year 3. CONCLUSION: Both techniques provide a similar anatomical closure rate and functional improvement in vision. Comparisons should be cautiously made based on difference in preoperative hole size.
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Membrana Basal , Perfurações Retinianas , Retalhos Cirúrgicos , Tomografia de Coerência Óptica , Acuidade Visual , Vitrectomia , Humanos , Perfurações Retinianas/cirurgia , Perfurações Retinianas/fisiopatologia , Feminino , Membrana Basal/cirurgia , Masculino , Acuidade Visual/fisiologia , Vitrectomia/métodos , Estudos Retrospectivos , Idoso , Seguimentos , Pessoa de Meia-Idade , Resultado do Tratamento , Tamponamento Interno/métodos , Fatores de Tempo , Membrana Epirretiniana/cirurgiaRESUMO
Dr Robert Knox was publicly scorned and disgraced for his unwitting involvement in the Burke and Hare serial murders in 1828. Far less appreciated is his brilliance as an anatomist and he espoused the European movement in Transcendental Anatomy, which aimed to uncover the laws governing what we now know as evolution and the origin of species. Knox fully embraced Transcendental Anatomy during a sojourn in Paris and taught it on his return to Edinburgh, where there was a critical mass of like-minded Transcendental Anatomists. Charles Darwin spent 1825-1827 as a medical student in Edinburgh when Transcendental Anatomy was at its peak amongst the city's anatomists, and evolution - then known as transmutation - was a source of great interest and controversy. Knox intended to research Transcendental Anatomy, but this was thwarted by conflicting demands on his time in the second half of the 1820s decade and the Burke and Hare tragedy. He did, however, go on to champion Transcendental Anatomy and write extensively on it.
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Pantothenate kinase-associated neurodegeneration (PKAN) is characterized by a motor disorder with combinations of dystonia, parkinsonism, and spasticity, leading to premature death. PKAN is caused by mutations in the PANK2 gene that result in loss or reduction of PANK2 protein function. PANK2 is one of three kinases that initiate and regulate coenzyme A biosynthesis from vitamin B5, and the ability of BBP-671, an allosteric activator of pantothenate kinases, to enter the brain and elevate coenzyme A was investigated. The metabolic stability, protein binding, and membrane permeability of BBP-671 all suggest that it has the physical properties required to cross the blood-brain barrier. BBP-671 was detected in plasma, liver, cerebrospinal fluid, and brain following oral administration in rodents, demonstrating the ability of BBP-671 to penetrate the brain. The pharmacokinetic and pharmacodynamic properties of orally administered BBP-671 evaluated in cannulated rats showed that coenzyme A (CoA) concentrations were elevated in blood, liver, and brain. BBP-671 elevation of whole-blood acetyl-CoA served as a peripheral pharmacodynamic marker and provided a suitable method to assess target engagement. BBP-671 treatment elevated brain coenzyme A concentrations and improved movement and body weight in a PKAN mouse model. Thus, BBP-671 crosses the blood-brain barrier to correct the brain CoA deficiency in a PKAN mouse model, resulting in improved locomotion and survival and providing a preclinical foundation for the development of BBP-671 as a potential treatment of PKAN. SIGNIFICANCE STATEMENT: The blood-brain barrier represents a major hurdle for drugs targeting brain metabolism. This work describes the pharmacokinetic/pharmacodynamic properties of BBP-671, a pantothenate kinase activator. BBP-671 crosses the blood-brain barrier to correct the neuron-specific coenzyme A (CoA) deficiency and improve motor function in a mouse model of pantothenate kinase-associated neurodegeneration. The central role of CoA and acetyl-CoA in intermediary metabolism suggests that pantothenate kinase activators may be useful in modifying neurological metabolic disorders.
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Neurodegeneração Associada a Pantotenato-Quinase , Camundongos , Animais , Ratos , Neurodegeneração Associada a Pantotenato-Quinase/tratamento farmacológico , Neurodegeneração Associada a Pantotenato-Quinase/genética , Acetilcoenzima A/metabolismo , Acetilcoenzima A/uso terapêutico , Coenzima A/metabolismo , Modelos Animais de Doenças , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Encéfalo/metabolismoRESUMO
Education in endoscopy encompasses a wide breadth of topics and skills. Despite a shared interest in improving training in endoscopy, there is wide variation among programs, largely because of broad requirements put forth by the Accreditation Council on Graduate Medical Education. Historically, efforts to improve education in endoscopy were focused on numerics as a surrogate for competence. However, there is a role for "milestone" development goals to ensure trainees are on the right track to developing procedural competence. These milestones should encompass aspects of preprocedural assessment, intraprocedural technique, and postprocedural management and interpretation. Two important aspects of intraprocedural technique that are not universally emphasized among training programs but would be immensely beneficial to fellow education are (i) mucosal examination and (ii) device education. In this article, we will discuss the importance of developing the aforementioned skills and how we can approach a competency-based assessment of endoscopic skills during fellowship.
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MOTIVATION: The importance and rate of development of genome-scale metabolic models have been growing for the last few years, increasing the demand for software solutions that automate several steps of this process. However, since TRIAGE's release, software development for the automatic integration of transport reactions into models has stalled. RESULTS: Here, we present the Transport Systems Tracker (TranSyT). Unlike other transport systems annotation software, TranSyT does not rely on manual curation to expand its internal database, which is derived from highly curated records retrieved from the Transporters Classification Database and complemented with information from other data sources. TranSyT compiles information regarding transporter families and proteins, and derives reactions into its internal database, making it available for rapid annotation of complete genomes. All transport reactions have GPR associations and can be exported with identifiers from four different metabolite databases. TranSyT is currently available as a plugin for merlin v4.0 and an app for KBase. AVAILABILITY AND IMPLEMENTATION: TranSyT web service: https://transyt.bio.di.uminho.pt/; GitHub for the tool: https://github.com/BioSystemsUM/transyt; GitHub with examples and instructions to run TranSyT: https://github.com/ecunha1996/transyt_paper.
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Software , Bases de Dados FactuaisRESUMO
Introduction: Machine learning tasks often require a significant amount of training data for the resultant network to perform suitably for a given problem in any domain. In agriculture, dataset sizes are further limited by phenotypical differences between two plants of the same genotype, often as a result of different growing conditions. Synthetically-augmented datasets have shown promise in improving existing models when real data is not available. Methods: In this paper, we employ a contrastive unpaired translation (CUT) generative adversarial network (GAN) and simple image processing techniques to translate indoor plant images to appear as field images. While we train our network to translate an image containing only a single plant, we show that our method is easily extendable to produce multiple-plant field images. Results: Furthermore, we use our synthetic multi-plant images to train several YoloV5 nano object detection models to perform the task of plant detection and measure the accuracy of the model on real field data images. Discussion: The inclusion of training data generated by the CUT-GAN leads to better plant detection performance compared to a network trained solely on real data.
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Predicting elemental cycles and maintaining water quality under increasing anthropogenic influence requires understanding the spatial drivers of river microbiomes. However, the unifying microbial processes governing river biogeochemistry are hindered by a lack of genome-resolved functional insights and sampling across multiple rivers. Here we employed a community science effort to accelerate the sampling, sequencing, and genome-resolved analyses of river microbiomes to create the Genome Resolved Open Watersheds database (GROWdb). This resource profiled the identity, distribution, function, and expression of thousands of microbial genomes across rivers covering 90% of United States watersheds. Specifically, GROWdb encompasses 1,469 microbial species from 27 phyla, including novel lineages from 10 families and 128 genera, and defines the core river microbiome for the first time at genome level. GROWdb analyses coupled to extensive geospatial information revealed local and regional drivers of microbial community structuring, while also presenting a myriad of foundational hypotheses about ecosystem function. Building upon the previously conceived River Continuum Concept 1 , we layer on microbial functional trait expression, which suggests the structure and function of river microbiomes is predictable. We make GROWdb available through various collaborative cyberinfrastructures 2, 3 so that it can be widely accessed across disciplines for watershed predictive modeling and microbiome-based management practices.
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In this news and views, we discuss our recent publication where we described how ER-PM membrane contact sites (MCS) are modulated during store operated calcium entry (SOCE). We also examine why enforcing ER-PM MCS by tethering proteins does not not enhance, but rather inhibits SOCE.
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Drug safety monitoring is essential for developing efficient and safe treatments. It starts with preclinical toxicology studies and continues with the observation and analysis of potentially harmful effects in humans throughout the whole drug life cycle. Safety surveillance during the clinical phase is of paramount importance for protecting the health of clinical trial (CT) participants at a period when relatively little is known about the drug safety profile, and for reassuring that detected risks are minimized when the product obtains marketing approval. This review aimed to investigate current safety surveillance methods during drug development worldwide, in order to identify potential gaps and opportunities for amelioration. To this end, international guidelines, standards, and local legislations about CTs were reviewed and compared. Our review revealed common strategies, mainly in alignment with international guidelines, especially concerning the systematic collection, assessment, and expedition of adverse events by investigators and sponsors and the preparation of periodic aggregate safety reports by sponsors, as a means to inform health authorities (HAs) about the evolving benefit-risk balance of the investigational product. Inconsistencies in safety surveillance mainly concerned local expedited reporting requirements. Significant gaps were identified in the methodologies for aggregate analyses and the responsibilities of HAs. Addressing the regulatory discrepancies and harmonizing the safety surveillance processes at a global level would increase the usability of safety data accumulated by clinical studies worldwide, thus enabling and hopefully accelerating the development of safe and efficient drug therapies.
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Sistemas de Notificação de Reações Adversas a Medicamentos , Aprovação de Drogas , Humanos , Aprovação de Drogas/métodos , Monitoramento de Medicamentos , Desenvolvimento de MedicamentosRESUMO
Microbial genome annotation is the process of identifying structural and functional elements in DNA sequences and subsequently attaching biological information to those elements. DRAM is a tool developed to annotate bacterial, archaeal, and viral genomes derived from pure cultures or metagenomes. DRAM goes beyond traditional annotation tools by distilling multiple gene annotations to genome level summaries of functional potential. Despite these benefits, a downside of DRAM is the requirement of large computational resources, which limits its accessibility. Further, it did not integrate with downstream metabolic modeling tools that require genome annotation. To alleviate these constraints, DRAM and the viral counterpart, DRAM-v, are now available and integrated with the freely accessible KBase cyberinfrastructure. With kb_DRAM users can generate DRAM annotations and functional summaries from microbial or viral genomes in a point-and-click interface, as well as generate genome-scale metabolic models from DRAM annotations. AVAILABILITY AND IMPLEMENTATION: For kb_DRAM users, the kb_DRAM apps on KBase can be found in the catalog at https://narrative.kbase.us/#catalog/modules/kb_DRAM. For kb_DRAM users, a tutorial workflow with all documentation is available at https://narrative.kbase.us/narrative/129480. For kb_DRAM developers, software is available at https://github.com/shafferm/kb_DRAM.
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Bactérias , Software , Anotação de Sequência Molecular , Bactérias/genética , Archaea/genética , MetabolômicaRESUMO
The human microbiome influences the efficacy and safety of a wide variety of commonly prescribed drugs. Designing precision medicine approaches that incorporate microbial metabolism would require strain- and molecule-resolved, scalable computational modeling. Here, we extend our previous resource of genome-scale metabolic reconstructions of human gut microorganisms with a greatly expanded version. AGORA2 (assembly of gut organisms through reconstruction and analysis, version 2) accounts for 7,302 strains, includes strain-resolved drug degradation and biotransformation capabilities for 98 drugs, and was extensively curated based on comparative genomics and literature searches. The microbial reconstructions performed very well against three independently assembled experimental datasets with an accuracy of 0.72 to 0.84, surpassing other reconstruction resources and predicted known microbial drug transformations with an accuracy of 0.81. We demonstrate that AGORA2 enables personalized, strain-resolved modeling by predicting the drug conversion potential of the gut microbiomes from 616 patients with colorectal cancer and controls, which greatly varied between individuals and correlated with age, sex, body mass index and disease stages. AGORA2 serves as a knowledge base for the human microbiome and paves the way to personalized, predictive analysis of host-microbiome metabolic interactions.
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Microbioma Gastrointestinal , Microbiota , Humanos , Medicina de Precisão , Genoma , Genômica , Microbioma Gastrointestinal/genéticaRESUMO
Richard Muir (1862-1931) began his career as a 'lab boy' in the Pathology Department of the University of Edinburgh in 1876 at the age of 13. This was a newly created category of worker that eventually became today's biomedical scientist Muir rapidly gained expertise in pathological and bacteriological techniques including staining and microscopy. Exceptionally, for someone non-medical and non-university-educated individual, he was elected a member of the Pathological Society of Great Britain and appointed Demonstrator in Pathology in the University of Edinburgh Pathology Department. He authored papers on staining techniques for bacteria and on the pathology of syphilis of the ear and became a recognised diagnostic histopathologist, despite having no medical qualifications. He especially excelled as an artist, depicting the microscopic world of pathology and microbiology and produced diagrams for hundreds of publications including his own book and also large wall hangings of the microscopic world for teaching purposes. This paper describes the unique contribution of Richard Muir to pathology in Edinburgh and beyond in the early 20th century.
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Livros , Humanos , História do Século XX , Reino UnidoRESUMO
INTRODUCTION: Macular edema, a common complication of uveitis, may result in vision loss. The aim of this analysis was to report integrated phase 3 trial data for triamcinolone acetonide injectable suspension for suprachoroidal use (SCS-TA) in the treatment of macular edema secondary to noninfectious uveitis using strict inclusion criteria. METHODS: This analysis included patients with central subfield thickness (CST) ≥ 300 µm and best-corrected visual acuity (BCVA) of ≥ 5 and ≤ 70 Early Treatment Diabetic Retinopathy Study (ETDRS) letters at both screening and baseline who received ≥ 1 study treatment in either PEACHTREE (randomized, double-masked SCS-TA or sham control) or AZALEA (open-label SCS-TA). Patients received SCS-TA 4.0 mg (0.1 ml of 40 mg/ml) or control at baseline and week 12. RESULTS: In the SCS-TA group (n = 95), 47.4% of patients gained ≥ 15 ETDRS letters from baseline to week 24 versus 16.7% of patients in the control group (n = 60; P < 0.001). Mean change in BCVA in the SCS-TA group was 9.6 letters at week 4 and 13.9 letters at week 24. CST also improved rapidly in the SCS-TA group (mean change: - 158.4 µm at week 4), with sustained reduction throughout the study (mean change: - 163.9 µm at week 24 versus - 19.3 µm in the control group; P < 0.001). No treatment-related serious adverse events (AEs) were reported. Incidence of AEs pertaining to elevated intraocular pressure was 12.6% and 15.0% in the SCS-TA and control groups, respectively; incidence of cataract formation/worsening AEs was 7.4% and 6.7%, respectively. CONCLUSION: In this integrated analysis utilizing strict inclusion criteria, SCS-TA was found effective in the treatment of patients with macular edema associated with noninfectious uveitis and was generally well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02595398, NCT03097315.
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PURPOSE: To study the efficacy and safety of suprachoroidal CLS-TA (proprietary suspension of triamcinolone acetonide) in uveitic macular edema (UME) with and without concurrent systemic corticosteroid or steroid-sparing therapy (ST). METHODS: Post hoc analysis of the PEACHTREE phase 3 randomized trial. RESULTS: Among UME patients receiving no ST, at week 24, mean BCVA change was +15.6 letters in 68 CLS-TA patients versus +4.9 letters in 49 sham-control patients (p < .001), while mean CST change was -169.8 µm versus -10.3 µm, respectively (p < .001). Among patients receiving ST, at week 24, mean BCVA change was +9.4 letters in 28 CLS-TA patients versus -3.2 letters in 15 sham-control patients (p = .019), while mean CST change was -108.3 µm versus -43.5 µm, respectively (p = .190). No SAEs related to treatment were reported. CONCLUSIONS: A clinically meaningful benefit of CLS-TA was noted in UME patients, regardless of concurrent ST usage.Abbreviation and AcronymsCST = central subfield thickness; BCVA = best corrected visual acuity; ME = macular edemaI; IVT = intravitreal; AE = adverse event; FA = fluocinolone acetonide; SD-OCT = spectral-domain optical coherence tomography; NIU = noninfectious uveitis; SAE = serious adverse event; TEAE = treatment emergent adverse event; ITT = intent to treat; CI = confidence interval.
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Edema Macular , Uveíte , Humanos , Glucocorticoides/uso terapêutico , Resultado do Tratamento , Injeções Intravítreas , Triancinolona Acetonida/uso terapêutico , Uveíte/tratamento farmacológico , Corticosteroides/uso terapêutico , Edema Macular/diagnóstico , Edema Macular/tratamento farmacológico , Edema Macular/etiologia , Tomografia de Coerência Óptica/métodosRESUMO
Eight-hundred thousand to one trillion prokaryotic species may inhabit our planet. Yet, fewer than two-hundred thousand prokaryotic species have been described. This uncharted fraction of microbial diversity, and its undisclosed coding potential, is known as the "microbial dark matter" (MDM). Next-generation sequencing has allowed to collect a massive amount of genome sequence data, leading to unprecedented advances in the field of genomics. Still, harnessing new functional information from the genomes of uncultured prokaryotes is often limited by standard classification methods. These methods often rely on sequence similarity searches against reference genomes from cultured species. This hinders the discovery of unique genetic elements that are missing from the cultivated realm. It also contributes to the accumulation of prokaryotic gene products of unknown function among public sequence data repositories, highlighting the need for new approaches for sequencing data analysis and classification. Increasing evidence indicates that these proteins of unknown function might be a treasure trove of biotechnological potential. Here, we outline the challenges, opportunities, and the potential hidden within the functional dark matter (FDM) of prokaryotes. We also discuss the pitfalls surrounding molecular and computational approaches currently used to probe these uncharted waters, and discuss future opportunities for research and applications.
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Visual perception depends strongly on spatial context. A profound example is visual crowding, whereby the presence of nearby stimuli impairs the discriminability of object features. Despite extensive work on perceptual crowding and the spatial integrative properties of visual cortical neurons, the link between these two aspects of visual processing remains unclear. To understand better the neural basis of crowding, we recorded activity simultaneously from neuronal populations in V1 and V4 of fixating macaque monkeys. We assessed the information available from the measured responses about the orientation of a visual target both for targets presented in isolation and amid distractors. Both single neuron and population responses had less information about target orientation when distractors were present. Information loss was moderate in V1 and more substantial in V4. Information loss could be traced to systematic divisive and additive changes in neuronal tuning. Additive and multiplicative changes in tuning were more severe in V4; in addition, tuning exhibited other, non-affine transformations that were greater in V4, further restricting the ability of a fixed sensory readout strategy to extract accurate feature information across displays. Our results provide a direct test of crowding effects at different stages of the visual hierarchy. They reveal how crowded visual environments alter the spiking activity of cortical populations by which sensory stimuli are encoded and connect these changes to established mechanisms of neuronal spatial integration.
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Macaca , Neurônios , AnimaisRESUMO
From the identification of a specific lung disease caused by coal dust exposure in miners in 1831 until the demonstration of the association of that exposure to risk of emphysema in 1984, there was continuous argument about the harmfulness of coal dust. Ill health in miners was attributed variously to tuberculosis, quartz exposure or cigarette smoking. An acceptance that coal dust was harmful only started with investigative radiology and pathology in the 1920s, and physiology in the 1950s. Most of the early investigations were in South Wales, the centre of the most important coal field in Great Britain. Among the investigators was Professor Jethro Gough who, with his technician James Wentworth, introduced a technique for making thick sections of whole, inflated lungs on paper backing. Here, we describe this method and its central role in understanding the relationships between coal dust exposure, pneumoconiosis, emphysema and lung dysfunction in miners.
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Minas de Carvão , Enfisema , Pneumopatias , Enfisema Pulmonar , Carvão Mineral/efeitos adversos , Poeira , Enfisema/patologia , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Enfisema Pulmonar/patologia , QuartzoRESUMO
Robert Knox was publicly vilified for his suspected complicity in the 16 murders committed by Burke and Hare, although he had no involvement in them. Along with several books on anatomy Knox also wrote a book on angling in Lowland Scotland. In 'Fish and Fishing in the Lone Glens of Scotland' Knox's deep love for nature and for fishing emerges. Most interesting however is that although generally focussed on fish and fishing, the book abounds with asides on Knox's other preoccupations and passions. These provide rare insights into the character of the great anatomist, whose personality has otherwise retained its opacity over the years. In the book, Knox writes in passing and in a relatively unguarded fashion, about such topics as transcendental anatomy, Scottish Independence, empiricism, race and Edinburgh medical figures. In so-doing, we contend that he affords the reader some insight into the mind of the real Dr Robert Knox.