Insights from multi-omic modeling of neurodegeneration in xeroderma pigmentosum using an induced pluripotent stem cell system.

Xeroderma pigmentosum (XP) is caused by defective nucleotide excision repair of DNA damage. This results in hypersensitivity to ultraviolet light and increased skin cancer risk, as sunlight-induced photoproducts remain unrepaired. However, many XP patients also display early-onset neurodegeneration, which leads to premature death. The mechanism of neurodegeneration is unknown. Here, we investigate XP neurodegeneration using pluripotent stem cells derived from XP patients and healthy relatives, performing functional multi-omics on samples during neuronal differentiation. We show substantially increased levels of 5',8-cyclopurine and 8-oxopurine in XP neuronal DNA secondary to marked oxidative stress. Furthermore, we find that the endoplasmic reticulum stress response is upregulated and reversal of the mutant genotype is associated with phenotypic rescue. Critically, XP neurons exhibit inappropriate downregulation of the protein clearance ubiquitin-proteasome system (UPS). Chemical enhancement of UPS activity in XP neuronal models improves phenotypes, albeit inadequately. Although more work is required, this study presents insights with intervention potential.

Long COVID Clinical Severity Types Based on Symptoms and Functional Disability: A Longitudinal Evaluation.

Background: Long COVID (LC) is a multisystem clinical syndrome with functional disability and compromised overall health. Information on LC clinical severity types is emerging in cross-sectional studies. This study explored the pattern and consistency of long COVID (LC) clinical severity types over time in a prospective sample. Methods: Participants with LC completed the condition-specific outcome measure C19-YRSm (Yorkshire Rehabilitation Scale modified version) at two assessment time points. A cluster analysis for clinical severity types was undertaken at both time points using the k-means partition method. Results: The study included cross-sectional data for 759 patients with a mean age of 46.8 years (SD = 12.7), 69.4% females, and a duration of symptoms of 360 days (IQR 217 to 703 days). The cluster analysis at first assessment revealed three distinct clinical severity type clusters: mild (n = 96), moderate (n = 422), and severe (n = 241). Longitudinal data on 356 patients revealed that the pattern of three clinical severity types remained consistent over time between the two assessments, with 51% of patients switching clinical severity types between the assessments. Conclusions: This study is the first of its kind to demonstrate that the pattern of three clinical severity types is consistent over time, with patients also switching between severity types, indicating the fluctuating nature of LC.

Prevalence of orthostatic intolerance in long covid clinic patients and healthy volunteers: A multicenter study.

Orthostatic intolerance (OI), including postural orthostatic tachycardia syndrome (PoTS) and orthostatic hypotension (OH), are often reported in long covid, but published studies are small with inconsistent results. We sought to estimate the prevalence of objective OI in patients attending long covid clinics and healthy volunteers and associations with OI symptoms and comorbidities. Participants with a diagnosis of long covid were recruited from eight UK long covid clinics, and healthy volunteers from general population. All undertook standardized National Aeronautics and Space Administration Lean Test (NLT). Participants' history of typical OI symptoms (e.g., dizziness, palpitations) before and during the NLT were recorded. Two hundred seventy-seven long covid patients and 50 frequency-matched healthy volunteers were tested. Healthy volunteers had no history of OI symptoms or symptoms during NLT or PoTS, 10% had asymptomatic OH. One hundred thirty (47%) long covid patients had previous history of OI symptoms and 144 (52%) developed symptoms during the NLT. Forty-one (15%) had an abnormal NLT, 20 (7%) met criteria for PoTS, and 21 (8%) had OH. Of patients with an abnormal NLT, 45% had no prior symptoms of OI. Relaxing the diagnostic thresholds for PoTS from two consecutive abnormal readings to one abnormal reading during the NLT, resulted in 11% of long covid participants (an additional 4%) meeting criteria for PoTS, but not in healthy volunteers. More than half of long covid patients experienced OI symptoms during NLT and more than one in 10 patients met the criteria for either PoTS or OH, half of whom did not report previous typical OI symptoms. We therefore recommend all patients attending long covid clinics are offered an NLT and appropriate management commenced.

Complement dysregulation is a prevalent and therapeutically amenable feature of long COVID.

BACKGROUND: Long COVID encompasses a heterogeneous set of ongoing symptoms that affect many individuals after recovery from infection with SARS-CoV-2. The underlying biological mechanisms nonetheless remain obscure, precluding accurate diagnosis and effective intervention. Complement dysregulation is a hallmark of acute COVID-19 but has not been investigated as a potential determinant of long COVID. METHODS: We quantified a series of complement proteins, including markers of activation and regulation, in plasma samples from healthy convalescent individuals with a confirmed history of infection with SARS-CoV-2 and age/ethnicity/sex/infection/vaccine-matched patients with long COVID. FINDINGS: Markers of classical (C1s-C1INH complex), alternative (Ba, iC3b), and terminal pathway (C5a, TCC) activation were significantly elevated in patients with long COVID. These markers in combination had a receiver operating characteristic predictive power of 0.794. Other complement proteins and regulators were also quantitatively different between healthy convalescent individuals and patients with long COVID. Generalized linear modeling further revealed that a clinically tractable combination of just four of these markers, namely the activation fragments iC3b, TCC, Ba, and C5a, had a predictive power of 0.785. CONCLUSIONS: These findings suggest that complement biomarkers could facilitate the diagnosis of long COVID and further suggest that currently available inhibitors of complement activation could be used to treat long COVID. FUNDING: This work was funded by the National Institute for Health Research (COV-LT2-0041), the PolyBio Research Foundation, and the UK Dementia Research Institute.

SARS-CoV-2 reservoir in post-acute sequelae of COVID-19 (PASC).

Millions of people are suffering from Long COVID or post-acute sequelae of COVID-19 (PASC). Several biological factors have emerged as potential drivers of PASC pathology. Some individuals with PASC may not fully clear the coronavirus SARS-CoV-2 after acute infection. Instead, replicating virus and/or viral RNA-potentially capable of being translated to produce viral proteins-persist in tissue as a 'reservoir'. This reservoir could modulate host immune responses or release viral proteins into the circulation. Here we review studies that have identified SARS-CoV-2 RNA/protein or immune responses indicative of a SARS-CoV-2 reservoir in PASC samples. Mechanisms by which a SARS-CoV-2 reservoir may contribute to PASC pathology, including coagulation, microbiome and neuroimmune abnormalities, are delineated. We identify research priorities to guide the further study of a SARS-CoV-2 reservoir in PASC, with the goal that clinical trials of antivirals or other therapeutics with potential to clear a SARS-CoV-2 reservoir are accelerated.

A measurement and modelling investigation of the indoor air chemistry following cooking activities.

Domestic cooking is a source of indoor air pollutants, including volatile organic compounds (VOCs), which can impact on indoor air quality. However, the real-time VOC emissions from cooking are not well characterised, and similarly, the resulting secondary chemistry is poorly understood. Here, selected-ion flow-tube mass spectrometry (SIFT-MS) was used to monitor the real-time VOC emissions during the cooking of a scripted chicken and vegetable stir-fry meal, in a room scale, semi-realistic environment. The VOC emissions were dominated by alcohols (70% of total emission), but also contained a range of aldehydes (14%) and terpenes (5%), largely attributable to the heating of oil and the preparation and heating of spices, respectively. The direct cooking-related VOC emissions were then simulated using the Indoor Chemical Model in Python (INCHEM-Py), to investigate the resulting secondary chemistry. Modelling revealed that VOC concentrations were dominated by direct emissions, with only a small contribution from secondary products, though the secondary species were longer lived than the directly emitted species. Following cooking, hydroxyl radical concentrations reduced by 86%, while organic peroxy radical levels increased by over 700%, later forming secondary organic nitrates, peroxyacylnitrates (PANs) and formaldehyde. Monoterpene emissions were shown to drive the formation of secondary formaldehyde, albeit to produce relatively modest concentrations (average of 60 ppt). Sensitivity analysis of the simulation conditions revealed that increasing the outdoor concentrations of ozone and NOx species (2.9× and 9×, respectively) resulted in the greatest increase in secondary product formation indoors (≈400%, 200% and 600% increase in organic nitrates, PANs and formaldehyde production, respectively). Given the fact that climate change is likely to result in increased ozone concentrations in the future, and that increased window-opening in response to rising temperatures is also likely, higher concentrations of indoor oxidants are likely in homes in the future. This work, therefore, suggests that cooking could be a more important source of secondary pollutants indoors in the future.

Reducing sickness absence and stigma due to mental health difficulties: a randomised control treatment trial (RCT) of a low intensity psychological intervention and stigma reduction programme for common mental disorder (Prevail).

BACKGROUND: Common mental disorders are the leading cause of workplace absences. The Prevail intervention programme aims to reduce stigma and to educate staff and managers about evidence-based low intensity psychological interventions for common mental disorders (depression, anxiety, stress, and distress). Prevail is innovative in taking a public health approach. It is designed to be given to all employees irrespective of their past or current mental health. Prevail was evaluated in three studies examining: (1) the acceptability of the intervention and perceived usefulness; (2) whether the intervention altered stigmatic attitudes and motivation to seek help; and (3) whether the intervention reduced sickness absence, both overall and due to mental health problems. METHODS: A two-armed cluster randomised control trial (RCT) evaluated the effectiveness of Prevail. Employees (N = 1051) at a large UK government institution were randomised to an active intervention or control arm in teams identified by their managers (n = 67). Employees in the active arm received the Prevail Staff Intervention. The managers in the active arm also received the Prevail Managers Intervention. Participants' satisfaction and analysis of the Prevail Intervention were gathered by a bespoke questionnaire. Questionnaire measures of attitudes to mental health and mental health stigma were taken 1-2 weeks prior to the intervention and approximately 4 weeks post-intervention. Data relating to sickness absence were gathered via the official records in the time period 3-month post-intervention and for the same period 12 months earlier. RESULTS: Prevail was evaluated highly favourably by both the staff and their managers. Prevail produced significant reductions in self-stigma and anticipated stigma due to mental health difficulties. Crucially, sickness absence was significantly reduced by the Prevail Intervention. DISCUSSION: Prevail achieved its goals of producing a palatable and engaging intervention that altered staff's attitudes and stigmatic beliefs related to mental health and, crucially, produced a strong reduction in work-pace absenteeism. As the Prevail programme is aimed at common mental health problems and was not specialised to this particular workforce, the study provides the evidence-base for a mental health intervention programme that could be used by many organisations across the world. TRIAL REGISTRATION: ISRCTN12040087. Registered 04/05/2020. https://doi.org/10.1186/ISRCTN12040087 . A full protocol for the randomised control trial was published: Gray NS, Davies H, Snowden RJ: Reducing stigma and increasing workplace productivity due to mental health difficulties in a large government organization in the UK: a protocol for a randomised control treatment trial (RCT) of a low intensity psychological intervention and stigma reduction programme for common mental disorder (Prevail). BMC Public Health 2020, 20(1):1-9.

Non-BRCA1/BRCA2 high-risk familial breast cancers are not associated with a high prevalence of BRCAness.

BACKGROUND: Familial breast cancer is in most cases unexplained due to the lack of identifiable pathogenic variants in the BRCA1 and BRCA2 genes. The somatic mutational landscape and in particular the extent of BRCA-like tumour features (BRCAness) in these familial breast cancers where germline BRCA1 or BRCA2 mutations have not been identified is to a large extent unknown. METHODS: We performed whole-genome sequencing on matched tumour and normal samples from high-risk non-BRCA1/BRCA2 breast cancer families to understand the germline and somatic mutational landscape and mutational signatures. We measured BRCAness using HRDetect. As a comparator, we also analysed samples from BRCA1 and BRCA2 germline mutation carriers. RESULTS: We noted for non-BRCA1/BRCA2 tumours, only a small proportion displayed high HRDetect scores and were characterized by concomitant promoter hypermethylation or in one case a RAD51D splice variant previously reported as having unknown significance to potentially explain their BRCAness. Another small proportion showed no features of BRCAness but had mutationally active tumours. The remaining tumours lacked features of BRCAness and were mutationally quiescent. CONCLUSIONS: A limited fraction of high-risk familial non-BRCA1/BRCA2 breast cancer patients is expected to benefit from treatment strategies against homologue repair deficient cancer cells.

Passive Dynamics of the Head, Neck and Forelimb in Equine Foetuses-An Observational Study.

Passive dynamics is an aspect of locomotion which is entirely dependent on the mechanical configuration and linkages of adjacent body segments. Tension distribution along mechanical linkages enables the execution of movement patterns with reduced need for complex neurological pathways and may play a role in reestablishing postural stability following external disturbances. Here we demonstrate a uni-directional mechanical relationship between the equine forelimb, head and neck, which may have implications for balance and forelimb loading in the horse. These observations suggest that forelimb, head and neck movement coordination (observed in the horse during unrestrained locomotion) is significantly influenced by the mechanical linkages between body segments, rather than being entirely dependent on neurological input as previously thought. This highlights the potential significance of research directed at investigating passively induced movements in understanding common locomotory patterns. Additionally, it suggests a mode of postural control which may provide instantaneous adjustments to postural disturbances, thus promoting rapid and efficient locomotion.

Variation in palmaromedial articulations of carpometacarpal joints in Thoroughbred and Standardbred racehorses.

Background: Carpal conformation is an important factor in relation to joint soundness. The equine carpometacarpal joint (CMCJ) was reported to have variations in its three palmaromedial articulations. Lacking one or more of these articulations has not been radiographically evaluated in Thoroughbred (TB) and Standardbred (SB) racehorses. Aim: The study aimed to identify the prevalence of the variation in the palmaromedial articulation of the carpometacarpal joint (PM-CMCJ) in TB and SB horses. Additionally, to detect the probability of having each of the three articulations within and between the breeds. Finally, to establish an anatomical description for the different patterns of the articulations in these horses. Methods: 313 dorsopalmar radiographs from 174 horses (117 TB and 57 SB) were used. Three articulations at PM-CMCJ were evaluated based on their presence or absence: the articulations between the second and third carpal bones (C2-C3), the second carpal-second metacarpal (C2-Mc2), and the second and third metacarpal (Mc2-Mc3) bones. The probability of each articulation was determined in the breeds. Depending on the presence/absence of one or more of these articulations in each horse, each group of horses that had the same patterns of articulation was gathered into one category. Results: Prevalence of variation in articulations of PM-CMCJ was identified in about 28% of the horses. SB showed a higher variation than TB throughout the comparisons. C2-C3 articulation was significantly the most common articulation, especially in TB (98%). The most common pattern of articulations (73%) was found in category I, which had three articulations whereas three horses grouped in category VI had no palmaromedial articulations. Conclusion: The variations in the articulations of PM-CMCJ in TB and SB racehorse might show a breed association. C2-C3 articulation was considerably the most frequent feature and category I was the common pattern of articulations in PM-CMCJ. The potential clinical effects of the varied patterns of the articulations require investigation.

Diagnosis of Ovarian Carcinoma Homologous Recombination DNA Repair Deficiency From Targeted Gene Capture Oncology Assays.

PURPOSE: Homologous recombination DNA repair deficiency (HRD) is a therapeutic biomarker for sensitivity to platinum and poly(ADP-ribose) polymerase inhibitor therapies in breast and ovarian cancers. Several molecular phenotypes and diagnostic strategies have been developed to assess HRD; however, their clinical implementation remains both technically challenging and methodologically unstandardized. METHODS: We developed and validated an efficient and cost-effective strategy for HRD determination on the basis of calculation of a genome-wide loss of heterozygosity (LOH) score through targeted, hybridization capture and next-generation DNA sequencing augmented with 3,000 common, polymorphic single-nucleotide polymorphism (SNP) sites distributed genome-wide. This approach requires minimal sequence reads and can be readily integrated into targeted gene capture workflows already in use for molecular oncology. We interrogated 99 ovarian neoplasm-normal pairs using this method and compared results with patient mutational genotypes and orthologous predictors of HRD derived from whole-genome mutational signatures. RESULTS: LOH scores of ≥11% had >86% sensitivity for identifying tumors with HRD-causing mutations in an independent validation set (90.6% sensitivity for all specimens). We found strong agreement of our analytic approach with genome-wide mutational signature assays for determining HRD, yielding an estimated 96.7% sensitivity and 50% specificity. We observed poor concordance with mutational signatures inferred using only mutations detected by the targeted gene capture panel, suggesting inadequacy of the latter approach. LOH score did not significantly correlate with treatment outcomes. CONCLUSION: Targeted sequencing of genome-wide polymorphic SNP sites can be used to infer LOH events and subsequently diagnose HRD in ovarian tumors. The methods presented here are readily generalizable to other targeted gene oncology assays and could be adapted for HRD diagnosis in other tumor types.

Indwelling Pleural Catheter: Management of Complications.

Multiple randomized clinical trials have established the advantages of indwelling pleural catheter (IPC) in the management of malignant pleural effusions, resulting in its widespread adoption in clinical practice. Complications can occur with IPC use and must be recognized and managed effectively. This review provides a comprehensive overview of IPC complications and their best care. Pain postinsertion or during drainage of IPC is easily manageable and must be distinguished from tumor-related chest wall pain. IPC-related infections require systemic antibiotics and often intrapleural fibrinolytic/deoxyribonuclease therapy. The removal of IPC for infection is usually unnecessary. Symptomatic loculation usually responds to fibrinolytics but may recur. Catheter tract metastases are common in mesothelioma patients and usually respond to radiotherapy without inducing damages to the IPC. Less common complications include dislodgement, irreversible blockage, and fractures (upon removal) of the catheter. Recommendations on the management of IPC complications by recent consensus statement/guideline are discussed. Expert opinions on management approaches are included in areas where evidence is lacking to guide care.

A living biobank of patient-derived ductal carcinoma in situ mouse-intraductal xenografts identifies risk factors for invasive progression.

Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer (IBC). Due to a lack of biomarkers able to distinguish high- from low-risk cases, DCIS is treated similar to early IBC even though the minority of untreated cases eventually become invasive. Here, we characterized 115 patient-derived mouse-intraductal (MIND) DCIS models reflecting the full spectrum of DCIS observed in patients. Utilizing the possibility to follow the natural progression of DCIS combined with omics and imaging data, we reveal multiple prognostic factors for high-risk DCIS including high grade, HER2 amplification, expansive 3D growth, and high burden of copy number aberrations. In addition, sequential transplantation of xenografts showed minimal phenotypic and genotypic changes over time, indicating that invasive behavior is an intrinsic phenotype of DCIS and supporting a multiclonal evolution model. Moreover, this study provides a collection of 19 distributable DCIS-MIND models spanning all molecular subtypes.

Malignant neoplasm of lacrimal gland with pulmonary metastasis.

Adenoid cystic carcinomas (ACC) make up 3%-5% of head and neck malignancies. They have a high propensity to metastasise, in particular to the lungs. A 65-year-old male diagnosed with a right lacrimal gland ACC T2N0M0 (surgically resected 12 years prior) presented with an incidentally noted 1.2 cm right lower lobe lung nodule seen on MRI liver. Subsequent imaging confirmed a non-FDG avid 1.6 cm solitary ovoid subpleural lesion, percutaneous biopsy confirmed adenocarcinoma. A surgical metastasectomy was performed and recovery was complete. Prognosis in ACC is improved with radical management of metastatic disease. Rather than a simple chest radiograph, more detailed imaging, such as MRI or CT scanning may increase the probability of early detection of pulmonary metastasis and, thereby facilitate radical treatment and improve survival.

Vibrational kinetics in repetitively pulsed atmospheric pressure nitrogen discharges: average-power-dependent switching behaviour.

Characterisation of the vibrational kinetics in nitrogen-based plasmas at atmospheric pressure is crucial for understanding the wider plasma chemistry, which is important for a variety of biomedical, agricultural and chemical processing applications. In this study, a 0-dimensional plasma chemical-kinetics model has been used to investigate vibrational kinetics in repetitively pulsed, atmospheric pressure plasmas operating in pure nitrogen, under application-relevant conditions (average plasma powers of 0.23-4.50 W, frequencies of 1-10 kHz, and peak pulse powers of 23-450 W). Simulations predict that vibrationally excited state production is dominated by electron-impact processes at lower average plasma powers. When the average plasma power increases beyond a certain limit, due to increased pulse frequency or peak pulse power, there is a switch in behaviour, and production of vibrationally excited states becomes dominated by vibrational energy transfer processes (vibration-vibration (V-V) and vibration-translation (V-T) reactions). At this point, the population of vibrational levels up to v ⩽ 40 increases significantly, as a result of V-V reactions causing vibrational up-pumping. At average plasma powers close to where the switching behaviour occurs, there is potential to control the energy efficiency of vibrational state production, as small increases in energy deposition result in large increases in vibrational state densities. Subsequent pathways analysis reveals that energy in the vibrational states can also influence the wider reaction chemistry through vibrational-electronic (V-E) linking reactions (N + N 2 ( 40 ⩽ v ⩽ 45 ) → N ( 2 D ) + N 2 ( A ) and N + N 2 ( 39 ⩽ v ⩽ 45 ) → N + N 2 ( a ' ) ), which result in increased Penning ionisation and an increased average electron density. Overall, this study investigates the potential for delineating the processes by which electronically and vibrationally excited species are produced in nitrogen plasmas. Therefore, potential routes by which nitrogen-containing plasma sources could be tailored, both in terms of chemical composition and energy efficiency, are highlighted.

The influence of equine hoof conformation on the initiation and progression of laminitis.

BACKGROUND: The health and performance of horses are significantly affected by diseases associated with the hoof. Laminitis is a critical hoof disease that causes pain and, potentially, severe hoof and bone pathology. OBJECTIVE: To generate an equine hoof finite element (FE) model to investigate the impact of normal and toe-in hoof conformations on the degeneration (decrease in elastic modulus) of the laminar junction (LJ), as occurs in chronic laminitis. STUDY DESIGN: Computer software modelling. METHODS: A hoof FE model was generated to investigate the biomechanics of hoof laminitis. A 3D model, consisting of nine components, was constructed from computed tomography scans of an equine left forelimb hoof. The model was loaded with 100 cycles of trotting. Two different centres of pressure (COP) paths representing normal and toe-in conformations were assigned to the model. LJ injury was modelled by degenerating the tissue's elastic modulus in the presence of excessive maximum principal stresses. RESULTS: FE models successfully showed findings similar to clinical observations, confirming third phalanx (P3) dorsal rotation, a symmetric distal displacement of the P3 (2 mm at the lateral and medial sides) in the normal model, and an asymmetric distal displacement of the P3 (4 mm at the lateral and 1.5 mm at the medial side) in the toe-in model. The proximal distance between P3 and the ground after LJ degeneration in the current model was significantly different from experimental measurements from healthy hooves (P < 0.01). MAIN LIMITATIONS: The inability to account for variations in population geometry and approximation of boundary conditions and system relations were the limitations of the current study. CONCLUSIONS: The distribution of LJ tissue degeneration was symmetric at the quarters in the normal hoof and in comparison, there was a lateral concentration of degeneration in the toe-in model.

HISTORIAL: La salud y el desempeño atlético de los caballos son afectados por patologías asociadas al casco. La laminitis es una enfermedad critica del casco que causa dolor y, potencialmente, patología severa del casco y ósea. OBJETIVO: Generar un modelo finito del casco equino para investigar el impacto de la conformación normal y del dedo-hacia-adentro sobre la degeneración (reducción del módulo elástico) de la unión laminar (UL), como ocurre en la laminitis crónica. DISEÑO DEL ESTUDIO: Modelado por computadora. MÉTODOS: Un modelo de elemento finito (EF) de casco fue generado para investigar la biomecánica de la laminitis en el casco. Un modelo 3D, que consistía de nueve componentes, fue construido a partir de imágenes de tomografía computarizada de un casco equino izquierdo. El modelo fue cargado con 100 ciclos de trote. Dos vías con centros de presión (VCP) distintos representando la conformación normal y dedo-hacia-adentro fueron asignadas al modelo. La lesión de la UL fue modelada degenerando el modelo elástico del tejido en la presencia de estrés principales excesivos máximos. RESULTADOS: Los modelos EF mostraron exitosamente hallazgos similares a las observaciones clínicas, confirmando que la rotación dorsal de la tercera falange (F3), con un desplazamiento distal simétrico de F3 (2 mm por medial y lateral) en el modelo normal, y un desplazamiento distal asimétrico de F3 (4 mm por lateral y 1.5 mm por medial) en el modelo dedo-hacia-adentro. La distancia proximal entre F3 y el suelo después de la degeneración de la UL en el modelo actual fue significativamente diferente de las mediciones experimentales de casco saludables (P < 0.01). LIMITACIONES DEL ESTUDIO: La inhabilidad de tomar en cuenta las variaciones en la geometría de la población y la aproximación de condiciones marginales, y relaciones de sistemas fueron las limitantes de este estudio. CONCLUSIONES: La distribución de la degeneración del tejido de la UL fue simétrico en los cuartos en el casco normal, hubo una concentración lateral de la degeneración en el modelo dedo-hacia-adentro. PALABRAS CLAVE: laminitis, conformación del casco del caballo, centro de presión, método de elemento finito, modelo hiperelástico.

A living biobank of canine mammary tumor organoids as a comparative model for human breast cancer.

Mammary tumors in dogs hold great potential as naturally occurring breast cancer models in translational oncology, as they share the same environmental risk factors, key histological features, hormone receptor expression patterns, prognostic factors, and genetic characteristics as their human counterparts. We aimed to develop in vitro tools that allow functional analysis of canine mammary tumors (CMT), as we have a poor understanding of the underlying biology that drives the growth of these heterogeneous tumors. We established the long-term culture of 24 organoid lines from 16 dogs, including organoids derived from normal mammary epithelium or benign lesions. CMT organoids recapitulated key morphological and immunohistological features of the primary tissue from which they were derived, including hormone receptor status. Furthermore, genetic characteristics (driver gene mutations, DNA copy number variations, and single-nucleotide variants) were conserved within tumor-organoid pairs. We show how CMT organoids are a suitable model for in vitro drug assays and can be used to investigate whether specific mutations predict therapy outcomes. Specifically, certain CMT subtypes, such as PIK3CA mutated, estrogen receptor-positive simple carcinomas, can be valuable in setting up a preclinical model highly relevant to human breast cancer research. In addition, we could genetically modify the CMT organoids and use them to perform pooled CRISPR/Cas9 screening, where library representation was accurately maintained. In summary, we present a robust 3D in vitro preclinical model that can be used in translational research, where organoids from normal, benign as well as malignant mammary tissues can be propagated from the same animal to study tumorigenesis.

The Stigma and Self-Stigma Scales for attitudes to mental health problems: Psychometric properties and its relationship to mental health problems and absenteeism.

The Stigma and Self-Stigma scales (SASS) measure multiple aspects of stigmatic beliefs about mental health problems, including cognitive aspects of stigma towards others (Stigma to Others) and emotional stigma toward others (Social Distance), anticipated stigma by others, self-stigma, avoidant coping strategies, and help-seeking intentions, alongside an index of social desirability. The properties of the SASS were investigated by employees of a large UK government organization. With minor exceptions, each of the SASS scales had strong psychometric properties, good internal reliability, and test-retest reliability. Social Distance, Anticipated Stigma, Self-Stigma, and Avoidant Coping were all strongly associated with a lack of help-seeking for mental health problems. Similarly, Stigma to Others, Self-Stigma, and Avoidant Coping were all associated with current mental health problems. Finally, absenteeism from the workplace was found to be negatively related to Stigma to Others, and positively related to Avoidant Coping and Anticipated Stigma. In conclusion, the SASS was able to measure several different forms of stigma about mental health simultaneously in people both with and without a history of mental health problems. The SASS can be used to monitor changes in mental health attitudes outcomes following intervention programs to investigate stigmatic attitudes to mental health problems across different samples.

Substitution mutational signatures in whole-genome-sequenced cancers in the UK population.

Whole-genome sequencing (WGS) permits comprehensive cancer genome analyses, revealing mutational signatures, imprints of DNA damage and repair processes that have arisen in each patient's cancer. We performed mutational signature analyses on 12,222 WGS tumor-normal matched pairs, from patients recruited via the UK National Health Service. We contrasted our results to two independent cancer WGS datasets, the International Cancer Genome Consortium (ICGC) and Hartwig Foundation, involving 18,640 WGS cancers in total. Our analyses add 40 single and 18 double substitution signatures to the current mutational signature tally. Critically, we show for each organ, that cancers have a limited number of 'common' signatures and a long tail of 'rare' signatures. We provide a practical solution for utilizing this concept of common versus rare signatures in future analyses.