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Retinoic acid, produced by intestinal dendritic cells (DCs), promotes T cell trafficking to the intestinal mucosa by upregulating α4ß7 integrin and inhibiting the generation of cutaneous leukocyte Ag (CLA) required for skin entry. In the present study, we report that activation of human naive CD4 T cells in an APC-free system generates cells expressing α4ß7 alone; in contrast, activation by intestinal DCs that produce retinoic acid and induce high levels of α4ß7 also results in CLA expression, generating CLA+α4ß7+ "dual tropic" cells, with both gut and skin trafficking potential, that also express high levels of α4ß1 integrin. DC generation of CLA+α4ß7+ T cells is associated with upregulation of FUT7, a fucosyltransferase involved in CLA generation; requires cell contact; and is enhanced by IL-12/IL-23. The blood CD4+ T cell population contains CLA+α4ß7+ cells, which are significantly enriched for cells capable of IFN-γ, IL-17, and TNF-α production compared with conventional CLA-α4ß7+ cells. Dual tropic lymphocytes are increased in intestinal tissue from patients with Crohn's disease, and single-cell RNA-sequencing analysis identifies a transcriptionally distinct cluster of FUT7-expressing cells present only in inflamed tissue; expression of genes associated with cell proliferation suggests that these cells are undergoing local activation. The expression of multiple trafficking molecules by CLA+α4ß7+ T cells can enable their recruitment by alternative pathways to both skin and gut; they may contribute to both intestinal and cutaneous manifestations of inflammatory bowel disease.
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Linfocitos T CD4-Positivos , Tretinoina , Humanos , Tretinoina/farmacología , Piel , Integrina alfa4beta1 , Células DendríticasRESUMEN
Single cell RNA sequencing of human full thickness Crohn's disease (CD) small bowel resection specimens was used to identify potential therapeutic targets for stricturing (S) CD. Using an unbiased approach, 16 cell lineages were assigned within 14,539 sequenced cells from patient-matched SCD and non-stricturing (NSCD) preparations. SCD and NSCD contained identical cell types. Amongst immune cells, B cells and plasma cells were selectively increased in SCD samples. B cell subsets suggested formation of tertiary lymphoid tissue in SCD and compared with NSCD there was an increase in IgG, and a decrease in IgA plasma cells, consistent with their potential role in CD fibrosis. Two Lumican-positive fibroblast subtypes were identified and subclassified based on expression of selectively enriched genes as fibroblast clusters (C) 12 and C9. Cells within these clusters expressed the profibrotic genes Decorin (C12) and JUN (C9). C9 cells expressed ACTA2; ECM genes COL4A1, COL4A2, COL15A1, COL6A3, COL18A1 and ADAMDEC1; LAMB1 and GREM1. GO and KEGG Biological terms showed extracellular matrix and stricture organization associated with C12 and C9, and regulation of WNT pathway genes with C9. Trajectory and differential gene analysis of C12 and C9 identified four sub-clusters. Intra sub-cluster gene analysis detected 13 co-regulated gene modules that aligned along predicted pseudotime trajectories. CXCL14 and ADAMDEC1 were key markers in module 1. Our findings support further investigation of fibroblast heterogeneity and interactions with local and circulating immune cells at earlier time points in fibrosis progression. Breaking these interactions by targeting one or other population may improve therapeutic management for SCD.
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Linfocitos B , Enfermedad de Crohn , Fibroblastos , Análisis de la Célula Individual , Humanos , Enfermedad de Crohn/genética , Enfermedad de Crohn/patología , Enfermedad de Crohn/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patología , Análisis de la Célula Individual/métodos , Linfocitos B/metabolismo , Linfocitos B/inmunología , Linfocitos B/patología , Masculino , Femenino , Adulto , Perfilación de la Expresión GénicaRESUMEN
OBJECTIVE: This study aimed to examine the impact of maternal metformin use during pregnancy on offspring neurodevelopmental outcomes. DATA SOURCES: MEDLINE, Embase, and Web of Science (Core Collection) were searched from inception until July 1, 2023. STUDY ELIGIBILITY CRITERIA: Studies of women who received treatment with metformin at any stage of pregnancy for any indication with neurodevelopmental data available for their offspring were included. Studies without a control group were excluded. Randomized controlled trials, case-control, cohort, and cross-sectional studies were included in the review. METHODS: Studies were screened for inclusion and data were extracted independently by 2 reviewers. Risk of bias was assessed using a modified version of the Newcastle-Ottawa Scale for nonrandomized studies, and the Risk of Bias 2 tool for randomized trials. RESULTS: A total of 7 studies met the inclusion criteria, including a combined cohort of 14,042 children with 7641 children who were exposed and followed for up to 14 years of age. Metformin use during pregnancy was not associated with neurodevelopmental delay in infancy (relative risk, 1.09; 95% confidence interval, 0.54-2.17; 3 studies; 9668 children) or at ages 3 to 5 years (relative risk, 0.90; 95% confidence interval, 0.56-1.45; 2 studies; 6118 children). When compared with unexposed peers, metformin use during pregnancy was not associated with altered motor scores (mean difference, 0.30; 95% confidence interval, -1.15 to 1.74; 3 studies; 714 children) or cognitive scores (mean difference, -0.45; 95% confidence interval, -1.45 to 0.55; 4 studies; 734 children). Studies that were included were of high quality and deemed to be at low risk of bias. CONCLUSION: In utero exposure to metformin does not seem to be associated with adverse neurodevelopmental outcomes in children up to the age of 14 years. These findings provide reassurance to clinicians and pregnant women considering metformin use during pregnancy.
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AIMS: Postpartum length of stay (LOS) in Australian hospitals has reduced over the past three decades. Although a reduction in LOS likely reduces hospital costs in the immediate postpartum period, there is concern that this is increasing the burden on emergency services, domiciliary staff and primary care providers. The aims were to determine whether the recent reduction in LOS at an Australian tertiary obstetric hospital resulted in a change in emergency department (ED) presentations by women in the first six weeks postpartum, and newborns within the first 28 days of life. METHODS: We conducted a cross-sectional cohort study of all newborns ≤28 days of age and women ≤6 weeks postpartum who presented to the ED during four comparable time periods (2019-2022) at an Australian tertiary obstetric hospital. Logistic regression was used to determine the relationship between neonatal and maternal postpartum ED presentations and year of birth. RESULTS: Reduced postpartum LOS was associated with a significant increase in maternal and neonatal presentations to the ED (odds ratio (OR): 1.15 (95% confidence interval (CI): 1.08-1.23), and OR: 1.11 (95% CI: 1.03-1.19), respectively). For every 100 births, an extra six women and three neonates presented to the ED for postpartum care in 2022 compared with 2019. There was no difference in maternal or neonatal admissions throughout the study periods. CONCLUSION: The increase in maternal and neonatal ED presentations associated with reduced LOS should prompt reassessment of postnatal practice and encourage further research into allocation of in-hospital resources and postpartum education.
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Community health workers are responsible for finding, processing, and transferring health information to communities with limited access to health-related resources, including farmworkers. This paper is the culmination of an undergraduate student research project to explore the learning processes and preferences of farmworker-serving community health workers in the USA. The project was designed for students from farmworker or agricultural backgrounds at two North Carolina universities and was supported by a North Carolina Department of Health and Human Services workforce development grant. Semi-structured interviews were conducted, in person and virtually, with a convenience sample of 17 current and former community health workers. The interview data were analysed thematically and identified a preference for a combination of learning styles, with visual and hands-on learning being the most preferred. Community health workers also identified the importance of learning preferences in relation to their responsibilities as health educators. This study provides librarians, along with public health and medical professionals, with useful information about learning preferences to inform the creation of new and varied learning materials for community health workers.
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Agentes Comunitarios de Salud , Agricultores , Humanos , Agentes Comunitarios de Salud/psicología , North Carolina , Agricultores/psicología , Agricultores/estadística & datos numéricos , Entrevistas como Asunto/métodos , Aprendizaje , Investigación Cualitativa , Masculino , Femenino , AdultoRESUMEN
The bumblebee gut parasite, Crithidia bombi, is widespread and prevalent in the field. Its interaction with Bombus spp. is a well-established epidemiological model. It is spread faecal-orally between colonies via the shared use of flowers when foraging. Accurately measuring the level of infection in bumblebees is important for assessing its distribution in the field, and also when conducting epidemiological experiments. Studies generally use 1 of 2 methods for measuring infection. One approach measures infection in faeces whereas the other method measures infection in guts. We tested whether the method of measuring infection affected the estimation of infection. Bumblebees were inoculated with a standardized inoculum and infection was measured 1 week later using either the faecal or gut method. We found that when the gut method was used to measure infection intensity estimates were significantly different to and approximately double those from the faecal method. These results have implications for the interpretation of previous study results and for the planning of future studies. Given the importance of bumblebees as pollinators, the impact of C. bombi on bumblebee health, and its use as an epidemiological model, we call on researchers to move towards consistent quantification of infections to enable future comparisons and meta-analyses of studies.
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Parásitos , Abejas , Animales , Interacciones Huésped-Parásitos , Crithidia , HecesRESUMEN
Intestinal fibrosis and stricture formation is an aggressive complication of Crohns disease (CD), linked to increased morbidity and costs. The present study investigates the contribution of Wingless-Int-1 (Wnt) signalling to intestinal fibrogenesis, considers potential cross-talk between Wnt and transforming growth factor ß1 (TGFß) signalling pathways, and assesses the therapeutic potential of small-molecule Wnt inhibitors. ß-catenin expression was explored by immunohistochemistry (IHC) in formalin-fixed paraffin embedded (FFPE) tissue from patient-matched nonstrictured (NSCD) and strictured (SCD) intestine (n=6 pairs). Functional interactions between Wnt activation, TGFß signalling, and type I collagen (Collagen-I) expression were explored in CCD-18Co cells and primary CD myofibroblast cultures established from surgical resection specimens (n=16) using small-molecule Wnt inhibitors and molecular techniques, including siRNA-mediated gene knockdown, immunofluorescence (IF), Wnt gene expression arrays, and western blotting. Fibrotic SCD tissue was marked by an increase in ß-catenin-positive cells. In vitro, activation of Wnt-ß-catenin signalling increased Collagen-I expression in CCD-18Co cells. Conversely, ICG-001, an inhibitor of ß-catenin signalling, reduced Collagen-I expression in cell lines and primary CD myofibroblasts. TGFß increased ß-catenin protein levels but did not activate canonical Wnt signalling. Rather, TGFß up-regulated WNT5B, a noncanonical Wnt ligand, and the Wnt receptor FZD8, which contributed directly to the up-regulation of Collagen-I through a ß-catenin-independent mechanism. Treatment of CCD-18Co fibroblasts and patient-derived myofibroblasts with the FZD8 inhibitor 3235-0367 reduced extracellular matrix (ECM) expression. Our data highlight small-molecule Wnt inhibitors of both canonical and noncanonical Wnt signalling, as potential antifibrotic drugs to treat SCD intestinal fibrosis. They also highlight the importance of the cross-talk between Wnt and TGFß signalling pathways in CD intestinal fibrosis.
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Enfermedad de Crohn , beta Catenina , Colágeno Tipo I/metabolismo , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/metabolismo , Enfermedad de Crohn/patología , Fibrosis , Formaldehído/metabolismo , Humanos , Intestinos , Ligandos , Miofibroblastos/metabolismo , ARN Interferente Pequeño/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Vía de Señalización Wnt , beta Catenina/metabolismoRESUMEN
BACKGROUND AND AIMS: Twin studies have long been used to infer heritability. Within the 'omics era, twin cohorts have even greater research potential. This study describes the formation of the UK IBD Twin Registry and analysis of concordance and environmental factors. METHOD: Twin pairs with IBD were recruited by advertising via IBD charities and social media, re-tracing a dormant IBD database and clinician referral. Details of zygosity, concordance, disease history and environmental factors were assessed. Pair concordance was calculated, and environmental factors were analysed with logistic regression models adjusted for zygosity and concordance. RESULTS: Ninety-one twin pairs were included in the analysis; forty-two with CD and forty-nine with UC. More MZ twin pairs with CD were concordant compared with DZ pairs, thus inferring heritability (Chi-sq. 15.6. P < 0.001). In UC, MZ concordance was also numerically greater. Cigarette smoking was predictive of CD (OR 2.66, 95% CI 1.16 to 6.07 P = 0.02); there may be an independent association with cannabis smoking (OR 2.59 95% CI 0.89 to 7.55 P = 0.08). Breastfeeding was protective against UC (OR 0.48, 95% CI 0.25-0.93, P = 0.03), but not CD. Self-reports of less occurrences of gastroenteritis than peers were protective against future UC onset (OR 0.33 95% CI 0.15 to 0.74, P = 0.01). Method of delivery, parental attitudes towards hygiene and recall of diet did not impact future IBD concordance. CONCLUSIONS: This study supports the heritability of IBD. Twin study analysis was able to elucidate environmental factors associated with IBD.
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Enfermedades Inflamatorias del Intestino , Gemelos Dicigóticos , Enfermedades en Gemelos/epidemiología , Enfermedades en Gemelos/genética , Humanos , Enfermedades Inflamatorias del Intestino/etiología , Enfermedades Inflamatorias del Intestino/genética , Sistema de Registros , Factores de Riesgo , Gemelos Monocigóticos/genética , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: Endometriosis affects one in nine Australian women of reproductive age, and is often associated with pain and infertility. However, many women may be asymptomatic, or present with alternative symptoms. AIM: To identify reasons for initial specialist referral among patients with endometriosis. MATERIAL AND METHODS: Patients were identified as having endometriosis intraoperatively based on International Classification of Diseases coding. Operation reports were reviewed and graded for severity of disease. This cohort was then retrospectively audited to identify reasons for initial referral to the general gynaecology, endosurgery, gynae-oncology, reproductive medicine outpatient departments (OPD) at the Mercy Hospital for Women in Melbourne between 1 February 2015 and 31 December 2016. RESULTS: Three hundred patients were identified as having endometriosis at laparoscopy, including 90 women with Stage IV disease. Patients were a mean (SD) age of 33.1 (7.6) years. While pain remained a common reason for referral (61.7% of referrals), 36.7% of women with Grade IV disease did not have pain included in their referral letter. Severe disease was associated with increased age (regression coefficient 0.05; 95% CI: 0.03-0.07, P < 0.01), but not with pain symptoms. Women referred with ovarian cysts or masses were more likely to be diagnosed with severe disease (regression coefficient 0.69; 95% CI: 0.37-1.01, P < 0.01). CONCLUSION: Although pelvic pain is not a good predictor for a diagnosis of endometriosis, it remains a common symptom among women with the disease. However, more than one in three patients with Grade IV endometriosis presented without mention of pain symptoms, encouraging clinicians to adopt a broader approach to the presenting symptoms of endometriosis.
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Endometriosis , Dolor Pélvico , Adulto , Australia/epidemiología , Endometriosis/complicaciones , Endometriosis/diagnóstico , Femenino , Humanos , Laparoscopía , Dolor Pélvico/etiología , Estudios RetrospectivosRESUMEN
Epithelial morphogenesis, a fundamental aspect of development, generates 3-dimensional tissue structures crucial for organ function. Underlying morphogenetic mechanisms are, in many cases, poorly understood, but mutations that perturb organ development can affect epithelial cell shape and orientation - difficult features to quantify in three dimensions. The basic structure of the eye is established via epithelial morphogenesis: in the embryonic optic cup, the retinal progenitor epithelium enwraps the lens. We previously found that loss of the extracellular matrix protein laminin-alpha1 (lama1) led to mislocalization of apical polarity markers and apparent misorientation of retinal progenitors. We sought to visualize and quantify this phenotype, and determine whether loss of the apical polarity determinant pard3 might rescue the phenotype. To this end, we developed LongAxis, a MATLAB-based program optimized for the retinal progenitor neuroepithelium. LongAxis facilitates 3-dimensional cell segmentation, visualization, and quantification of cell orientation and morphology. Using LongAxis, we find that retinal progenitors in the lama1-/- optic cup are misoriented and slightly less elongated. In the lama1;MZpard3 double mutant, cells are still misoriented, but larger. Therefore, loss of pard3 does not rescue loss of lama1, and in fact uncovers a novel cell size phenotype. LongAxis enables population-level visualization and quantification of retinal progenitor cell orientation and morphology. These results underscore the importance of visualizing and quantifying cell orientation and shape in three dimensions within the retina.
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Forma de la Célula , Células Epiteliales , Procesamiento de Imagen Asistido por Computador , Retina , Programas Informáticos , Pez Cebra/embriología , Animales , Animales Modificados Genéticamente , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Células Epiteliales/citología , Células Epiteliales/metabolismo , Laminina/genética , Laminina/metabolismo , Retina/citología , Retina/embriología , Pez Cebra/genética , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
Establishment of precise three-dimensional tissue structure is vital for organ function. In the visual system, optic fissure and stalk morphogenesis is a crucial yet poorly understood process, disruptions of which can lead to coloboma, a birth defect causing visual impairment. Here, we use four-dimensional imaging, cell tracking, and molecular genetics in zebrafish to define the cell movements underlying normal optic fissure and stalk formation. We determine how these events are disrupted in a coloboma model in which the Hedgehog (Hh) receptor ptch2 is lost, resulting in overactive Hh signaling. In the ptch2 mutant, cells exhibit defective motile behaviors and morphology. Cells that should contribute to the fissure do not arrive at their correct position, and instead contribute to an ectopically large optic stalk. Our results suggest that overactive Hh signaling, through overexpression of downstream transcriptional targets, impairs cell motility underlying optic fissure and stalk formation, via non-cell-autonomous and cell-autonomous mechanisms. More broadly, our cell motility and morphology analyses provide a new framework for studying other coloboma-causing mutations that disrupt optic fissure or stalk formation.
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Movimiento Celular , Ojo/citología , Ojo/crecimiento & desarrollo , Proteínas Hedgehog/metabolismo , Morfogénesis , Transducción de Señal , Pez Cebra/crecimiento & desarrollo , Pez Cebra/metabolismo , Animales , Ojo/anatomía & histología , Modelos Biológicos , Mutación/genética , Transcripción Genética , Proteínas de Pez Cebra/metabolismoRESUMEN
BACKGROUND: Patients with inflammatory bowel disease are currently managed with the assumption that trial data are applicable to all ethnic groups. Previous studies demonstrate differences in disease severity and phenotype of Asian patients with Crohn's disease (CD), including Bangladeshi Asians within the UK. No study has evaluated the impact of ethnicity on response to anti-TNFs. AIM: Our primary endpoint was a comparison of failure-free survival on first prescribed anti-TNF (anti-tumor necrosis factor) therapy in UK Bangladeshi and Caucasian patients with CD. Our secondary aims were to evaluate disease phenotype, indication for anti-TNF prescription, and duration from diagnosis until first anti-TNF prescribed between groups. METHODS: The records of consecutive outpatient appointments over a 12-month period were used to identify Caucasian and Bangladeshi patients prescribed an anti-TNF for CD. Information on patient demographics, ethnicity, disease phenotype, immunomodulator use, outcome from first biologic, duration of therapy, and reason for cessation was recorded. RESULTS: In total, 224 Caucasian and Bangladeshi patients were prescribed an anti-TNF for CD. Bangladeshi patients started an anti-TNF 4.3 years earlier after diagnosis than Caucasian patients (3.9 years vs. 8.2 years: p < 0.01). Bangladeshi patients experienced shorter failure-free survival than Caucasian patients (1.8 vs. 4.8 years p < 0.01). By 2 years, significantly more Bangladeshi patients had stopped anti-TNF due to loss of response (OR 6.35, p < 0.01). CONCLUSIONS: This is the first study to suggest that Bangladeshi patients resident in the UK with CD respond less well to treatment with TNF antagonists than Caucasian patients.
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Pueblo Asiatico , Enfermedad de Crohn/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Población Blanca , Adolescente , Adulto , Bangladesh , Biomarcadores , Enfermedad de Crohn/genética , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Masculino , Estudios Retrospectivos , Resultado del Tratamiento , Reino Unido , Adulto JovenRESUMEN
BACKGROUND: Endometrial polyps are a common cause of abnormal uterine bleeding. The MyoSureLITE intrauterine morcellation device is effective at resecting endometrial polyps; however, its use in the outpatient setting requires appraisal. AIM: To assess the feasibility, utility, acceptability and costs associated with introduction of the MyoSureLITE into an established outpatient hysteroscopy (OPH) clinic. MATERIAL AND METHODS: A prospective clinical database from a tertiary Melbourne hospital was analysed from 1 July 2015 to 30 June 2018. Three 12-month time periods were compared: pre-introduction and trial phase, early use, and established use of the MyoSureLITE. Wait times, patient acceptability, second OPH bookings and procedure costs were measured. RESULTS: Eight hundred and seventy-one women underwent OPH during the study period, with 238 (27.3%) women presenting with endometrial polyp(s). At each timepoint, 78.5, 25 and 6.3% of women required rebooking for a subsequent hysteroscopy for pathology otherwise suitable for MyoSureLITE resection. Introduction of the MyoSureLITE avoided a subsequent procedure for 4, 60 and 69 women respectively for each year of use, with potentially reduced treatment costs for the institution. Median (IQR) wait time for definitive treatment of intrauterine pathology was 56 (24-84) days at time-period 1, decreasing to 0 (0-0) days during time-period 3, (P < 0.001); 87.6% would undergo OPH again. CONCLUSIONS: Routine use of the MyoSureLITE is effective, feasible, and acceptable to women. Provision of this device in outpatient service allows a 'see-and-treat' model, saving theatre time and treatment costs, facilitating a more direct throughput from presentation to treatment.
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Enfermedades Uterinas , Femenino , Humanos , Histeroscopía , Pacientes Ambulatorios , Pólipos/cirugía , Embarazo , Estudios Prospectivos , Enfermedades Uterinas/cirugía , Hemorragia Uterina/etiología , Hemorragia Uterina/cirugíaRESUMEN
BACKGROUND: Oclacitinib is a Janus kinase inhibitor used to control pruritus and skin lesions in canine allergic skin disease; its effect on canine T cells is not well-characterized. HYPOTHESIS/OBJECTIVES: To evaluate the impact of oclacitinib on cultured T cells using peripheral blood mononuclear cells from dogs. ANIMALS: Six bluetick coonhounds. METHODS AND MATERIALS: Lymphocyte-enriched cells were incubated with or without the T-cell mitogen concanavalin A (Con A), oclacitinib (0.5, 1 or 10 µM), ciclosporin (200 ng/mL), Con A + oclacitinib 1 µM and Con A + ciclosporin. We assessed both T-cell proliferation and the secretion of cytokines. RESULTS: Ciclosporin and oclacitinib both inhibited the spontaneous proliferation of T cells; this effect was significant only after incubation with oclacitinib at 10 µM. At this concentration, oclacitinib significantly reduced the spontaneous secretion of clonal activator cytokines [interleukin (IL)-2, IL-15], pro-inflammatory cytokines (interferon-gamma (IFN-γ), IL-18) and the regulatory cytokine IL-10; tumour necrosis factor alpha (TNF-α) and IL-6 cytokine production was mildly inhibited. After Con A stimulation, only T cells co-treated with ciclosporin achieved a significant proliferation inhibition and reduction of IL-2, IL-10, IL-15, IL-18, IFN-γ and TNF-α. Surprisingly, oclacitinib at 1 µM (337 ng/mL, corresponding to the oral dosage of 0.4-0.6 mg/kg) did not significantly affect Con A-stimulated T-cell proliferation nor cytokine production (IL-2, IL-10, IL-15, IL-18, IFN-γ and TNF-α). CONCLUSIONS: Although a limited number of dogs were investigated, these preliminary results suggest that oclacitinib appears to have immunosuppressive properties, but only at dosages above those used to treat allergic pruritus in dogs.
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Citocinas/metabolismo , Factores Inmunológicos/farmacología , Pirimidinas/farmacología , Sulfonamidas/farmacología , Linfocitos T/efectos de los fármacos , Animales , Ciclosporina/farmacología , Perros , Femenino , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Interleucina-15/metabolismo , Interleucina-18/metabolismo , Interleucina-2/metabolismo , Activación de Linfocitos/efectos de los fármacos , Masculino , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Leukodystrophies are a group of genetically determined disorders that affect development or maintenance of central nervous system myelin. Leukodystrophies have a reported incidence of 1 in 7500 live births, but fewer than half of patients receive a specific diagnosis. In this review, the authors discuss types of leukodystrophies: their prevalence, clinical presentation, symptoms, and diagnosis, as well as current and future treatments. Diagnosis is based on a combination of history, exam, radiological, and laboratory findings, including genetic testing. Leukodystrophies can present at any age from infancy to adulthood, with variability in disease progression and clinical presentation, ranging from developmental delay to seizures to spasticity. Although there are few cures, there are significant opportunities for care and improvements in patient well-being. Their high prevalence, combined with rapid advances in imaging, genetics, and potential treatments, makes an understanding of the leukodystrophies necessary for care providers in genetics and neurology.
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Encefalopatías/genética , Predisposición Genética a la Enfermedad , Enfermedades por Almacenamiento Lisosomal/genética , Vaina de Mielina/metabolismo , Enfermedad de Pelizaeus-Merzbacher/genética , Animales , Encefalopatías/diagnóstico , Encefalopatías/epidemiología , Humanos , Enfermedades por Almacenamiento Lisosomal/diagnóstico , Enfermedades por Almacenamiento Lisosomal/terapia , Enfermedad de Pelizaeus-Merzbacher/diagnóstico , Enfermedad de Pelizaeus-Merzbacher/terapia , PrevalenciaRESUMEN
BACKGROUND: As acceptance of artificial intelligence [AI] platforms increases, more patients will consider these tools as sources of information. The ChatGPT architecture utilizes a neural network to process natural language, thus generating responses based on the context of input text. The accuracy and completeness of ChatGPT3.5 in the context of inflammatory bowel disease [IBD] remains unclear. METHODS: In this prospective study, 38 questions worded by IBD patients were inputted into ChatGPT3.5. The following topics were covered: [1] Crohn's disease [CD], ulcerative colitis [UC], and malignancy; [2] maternal medicine; [3] infection and vaccination; and [4] complementary medicine. Responses given by ChatGPT were assessed for accuracy [1-completely incorrect to 5-completely correct] and completeness [3-point Likert scale; range 1-incomplete to 3-complete] by 14 expert gastroenterologists, in comparison with relevant ECCO guidelines. RESULTS: In terms of accuracy, most replies [84.2%] had a median score of ≥4 (interquartile range [IQR]: 2) and a mean score of 3.87 [SD: ±0.6]. For completeness, 34.2% of the replies had a median score of 3 and 55.3% had a median score of between 2 and <3. Overall, the mean rating was 2.24 [SD: ±0.4, median: 2, IQR: 1]. Though groups 3 and 4 had a higher mean for both accuracy and completeness, there was no significant scoring variation between the four question groups [Kruskal-Wallis test p > 0.05]. However, statistical analysis for the different individual questions revealed a significant difference for both accuracy [pâ <â 0.001] and completeness [pâ <â 0.001]. The questions which rated the highest for both accuracy and completeness were related to smoking, while the lowest rating was related to screening for malignancy and vaccinations especially in the context of immunosuppression and family planning. CONCLUSION: This is the first study to demonstrate the capability of an AI-based system to provide accurate and comprehensive answers to real-world patient queries in IBD. AI systems may serve as a useful adjunct for patients, in addition to standard of care in clinics and validated patient information resources. However, responses in specialist areas may deviate from evidence-based guidance and the replies need to give more firm advice.
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Enfermedades Inflamatorias del Intestino , Humanos , Estudios Prospectivos , Inteligencia Artificial , Guías de Práctica Clínica como Asunto , Vacunación/normas , Terapias Complementarias/métodos , Colitis Ulcerosa , Enfermedad de Crohn , Procesamiento de Lenguaje Natural , Femenino , Educación del Paciente como Asunto/métodos , NeoplasiasRESUMEN
This article is the second in a series of two publications on the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the management of Crohn's disease. The first article covers medical management; the present article addresses surgical management, including preoperative aspects and drug management before surgery. It also provides technical advice for a variety of common clinical situations. Both articles together represent the evidence-based recommendations of the ECCO for Crohn's disease and an update of prior ECCO guidelines.
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This study assesses NHS doctors' experiences of paternity leave and evaluates whether practices have changed since the introduction of additional paternity leave (APL) in April 2011. An anonymised online survey designed to discover experiences and uptake of APL and ordinary paternity leave (OPL) was distributed to all members of the London Deanery Synapse® network. In total, 364 fathers responded. Their seniority ranged from foundation trainees to consultants. Following the formal introduction of OPL in 2003, the number of fathers taking any paternity leave increased (from 50% to 95.6%). The majority of respondents (76.7%) felt well supported by their employer. Since the introduction of APL, 3% of respondents took additional leave. Reasons for the low uptake of APL included the impracticalities of the law, poor awareness and perceived attitudes and implications for training. Problems with OPL included the inadequate provision of cover and difficulties in timing the leave appropriately.
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Permiso Parental/estadística & datos numéricos , Médicos/estadística & datos numéricos , Adulto , Humanos , Masculino , Permiso Parental/legislación & jurisprudencia , Encuestas y Cuestionarios , Reino UnidoRESUMEN
The overproduction of cells and subsequent production of debris is a universal principle of neurodevelopment. Here we show an additional feature of the developing nervous system that causes neural debris - promoted by the sacrificial nature of embryonic microglia that irreversibly become phagocytic after clearing other neural debris. Described as long-lived, microglia colonize the embryonic brain and persist into adulthood. Using transgenic zebrafish to investigate the microglia debris during brain construction, we identified that unlike other neural cell-types that die in developmental stages after they have expanded, necroptotic-dependent microglial debris is prevalent when microglia are expanding in the zebrafish brain. Time-lapse imaging of microglia demonstrates that this debris is cannibalized by other microglia. To investigate features that promote microglia death and cannibalism, we used time-lapse imaging and fate-mapping strategies to track the lifespan of individual developmental microglia. These approaches revealed that instead of embryonic microglia being long-lived cells that completely digest their phagocytic debris, once most developmental microglia in zebrafish become phagocytic they eventually die, including ones that are cannibalistic. These results establish a paradox -- which we tested by increasing neural debris and manipulating phagocytosis -- that once most microglia in the embryo become phagocytic, they die, create debris and then are cannibalized by other microglia, resulting in more phagocytic microglia that are destined to die.
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Targeting leukocyte trafficking in the management of inflammatory bowel disease [IBD] has been a significant therapeutic advance over the past 15 years. However, as with other advanced therapies, phase III clinical trials report response to trafficking inhibitors in only a proportion of patients, with fewer achieving clinical remission or mucosal healing. Additionally, there have been significant side effects, most notably progressive multifocal leukoencephalopathy in association with the α4 inhibitor natalizumab. This article reviews the mechanisms underpinning T cell recruitment and residence, to provide a background from which the strength and limitations of agents that disrupt leukocyte trafficking can be further explored. The therapeutic impact of trafficking inhibitors is underpinned by the complexity and plasticity of the intestinal immune response. Pathways essential for gut homing in health may be bypassed in the inflamed gut, thus providing alternative routes of entry when conventional homing molecules are targeted. Furthermore, there is conservation of trafficking architecture between proinflammatory and regulatory T cells. The persistence of resident memory cells within the gut gives rise to local established pro-inflammatory populations, uninfluenced by inhibition of trafficking. Finally, trafficking inhibitors may give rise to effects beyond the intended response, such as the impact of vedolizumab on innate immunity, as well as on target side effects. With significant research efforts into predictive biomarkers already underway, it is ultimately hoped that a better understanding of trafficking and residence will help us predict which patients are most likely to respond to inhibition of leukocyte trafficking, and how best to combine therapies.