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There is some evidence that the river migration success of Atlantic salmon smolts, on their first migration to sea, varies both spatially and temporally. However, we have only a poor understanding of what may be driving this variation. In this study, we used acoustic telemetry to quantify the spatial and temporal variations in river migration success in Atlantic salmon smolts on their first migration to sea. In total 4120 Atlantic salmon smolts migrating through 22 rivers in Scotland, England, Ireland, and Northern Ireland over multiple years were included in the study. Individuals were defined as successful migrants if detected leaving the river to enter marine waters. The results show significant temporal (up to 4 years) and spatial (river) variations in migration success, with overall between-river migration success varying from 3.4% to 97.0% and between years from 3.4% and 61.0%. Temporal variation in migration success was river specific, with some rivers being more temporally stable (exhibiting little variation between years) than others. Across all rivers and years, individual migration success was predicted positively by body condition and negatively by tag burden. The rate of migration success for a population (migration success standardized to a common river distance [proportion km-1]) was predicted by a number of environmental factors. The proportion of river catchment that comprised wetland and woodland positively predicted migration success, whereas the proportion of grassland and peatland in a catchment negatively predicted the rate of migration success. Although the mechanisms through which these effects may be operating were not directly examined in this study, we discuss some potential routes through which they may occur.
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Discussing serious news is a fundamental communication skill, and many clinicians have been taught to ask their patients how much detail they want to hear before sharing difficult information. Over the past decade, we have taught hundreds of medical students how to discuss serious news and reviewed hundreds of their recorded conversations. We've found that asking how much detail a patient wants to hear often results in confusion and is not an effective way to understand their communication preferences. Instead of asking how much detail your patient wants to hear, we propose an alternative way to tailor information to their needs when discussing serious news. By asking permission to share, presenting the news in a succinct, jargon-free headline, and providing emotional support and expert guidance at the right times, you can give the correct amount of detail while avoiding unnecessary confusion resulting in high-quality, patient centered communication every time you discuss serious news.
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Sipuleucel-T is an autologous cellular immunotherapy that targets prostatic acid phosphatase (PAP) and is available for treatment of men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). In this single-arm, two-cohort, multicenter clinical study, potential racial differences in immune responses to sipuleucel-T in men with mCRPC were explored. Patients' blood samples were obtained to assess serum cytokines, humoral responses, and cellular immunity markers before and after treatment. Baseline cumulative product parameters (total nucleated and CD54+ cell counts and CD54 upregulation) were evaluated. IgM titers against the immunogen PA2024, the target antigen PAP, prostate-specific membrane antigen (PSMA) and prostate-specific antigen (PSA) were quantified by ELISA. Cytotoxic T-lymphocyte activity was determined by ELISpots, and cytokine and chemokine concentrations were determined by Luminex.Twenty-nine African American (AA) men and 28 non-African American (non-AA) men with mCRPC received sipuleucel-T. Baseline total nucleated cell count, CD54+ cell count, CD54 expression, and cumulative product parameters were higher in non-AA men. Although PSA baseline levels were higher in AA men, there were no racial differences in IgM antibody and IFNγ ELISpots responses against PA2024, PAP, PSA, and PSMA before and after treatment. Expression of co-stimulatory receptor ICOS on CD4+ and CD8+ T cells, and the levels of Th1 cytokine granulocyte-macrophage colony-stimulating factor and chemokines CCL4 and CCL5, were significantly higher in AA men before and/or after treatment. Despite no difference in the overall survival, PSA changes from baseline were significantly different between the two races. The data suggest that immune correlates in blood differ in AA and non-AA men with mCRPC pre- and post-sipuleucel-T. SIGNIFICANCE: Our novel findings of higher expression of co-stimulatory receptor ICOS on CD4+ and CD8+ T cells in African American patients with metastatic castrate-resistant prostate cancer (mCRPC) prior and post-sipuleucel-T suggest activation of CD4+ and CD8+ T cells. The data indicate that racial differences observed in these and other immune correlates before and after sipuleucel-T warrant additional investigation to further our understanding of the immune system in African American men and other men with mCRPC.
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Neoplasias de la Próstata Resistentes a la Castración , Extractos de Tejidos , Anciano , Humanos , Masculino , Persona de Mediana Edad , Negro o Afroamericano , Vacunas contra el Cáncer/uso terapéutico , Citocinas/sangre , Metástasis de la Neoplasia , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata Resistentes a la Castración/inmunología , Neoplasias de la Próstata Resistentes a la Castración/patología , Extractos de Tejidos/uso terapéutico , Extractos de Tejidos/farmacologíaRESUMEN
It has been presumed that rheumatoid arthritis (RA) joint pain is related to inflammation in the synovium; however, recent studies reveal that pain scores in patients do not correlate with synovial inflammation. We developed a machine-learning approach (graph-based gene expression module identification or GbGMI) to identify an 815-gene expression module associated with pain in synovial biopsy samples from patients with established RA who had limited synovial inflammation at arthroplasty. We then validated this finding in an independent cohort of synovial biopsy samples from patients who had early untreated RA with little inflammation. Single-cell RNA sequencing analyses indicated that most of these 815 genes were most robustly expressed by lining layer synovial fibroblasts. Receptor-ligand interaction analysis predicted cross-talk between human lining layer fibroblasts and human dorsal root ganglion neurons expressing calcitonin gene-related peptide (CGRP+). Both RA synovial fibroblast culture supernatant and netrin-4, which is abundantly expressed by lining fibroblasts and was within the GbGMI-identified pain-associated gene module, increased the branching of pain-sensitive murine CGRP+ dorsal root ganglion neurons in vitro. Imaging of solvent-cleared synovial tissue with little inflammation from humans with RA revealed CGRP+ pain-sensing neurons encasing blood vessels growing into synovial hypertrophic papilla. Together, these findings support a model whereby synovial lining fibroblasts express genes associated with pain that enhance the growth of pain-sensing neurons into regions of synovial hypertrophy in RA.
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Artritis Reumatoide , Péptido Relacionado con Gen de Calcitonina , Humanos , Ratones , Animales , Péptido Relacionado con Gen de Calcitonina/genética , Péptido Relacionado con Gen de Calcitonina/metabolismo , Artritis Reumatoide/complicaciones , Artritis Reumatoide/genética , Artritis Reumatoide/metabolismo , Membrana Sinovial/patología , Inflamación/patología , Fibroblastos/patología , Dolor/metabolismo , Expresión Génica , Células CultivadasRESUMEN
5q-associated spinal muscular atrophy (SMA) is the most common autosomal recessive neurological disease. Depletion in functional SMN protein leads to dysfunction and irreversible degeneration of the motor neurons. Over 95 % of individuals with SMA have homozygous exon 7 deletions in the SMN1 gene. Most of the remaining 4-5 % are compound heterozygous for deletion and a disease-associated sequence variant in the non-deleted allele. Individuals with SMA due to bi-allelic SMN1 sequence variants have rarely been reported. Data regarding their clinical phenotype, disease progression, outcome and treatment response are sparse. This study describes six individuals from three families, all with homozygous sequence variants in SMN1, and four of whom received treatment with disease-modifying therapies. We also describe the challenges faced during the diagnostic process and intrafamilial phenotypic variability observed between siblings.
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Atrofia Muscular Espinal , Niño , Humanos , Exones , Neuronas Motoras , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/diagnóstico , Proteínas del Tejido Nervioso/genética , Fenotipo , Proteína 1 para la Supervivencia de la Neurona Motora/genéticaRESUMEN
INTRODUCTION: Fellows in critical care medicine (CCM) routinely help patients and families navigate complex decisions near the end of life. These "late goals of care" (LGOC) discussions require rigorous skills training and impact patient care. Innovation is needed to ensure that fellow training in leading these discussions is centered on reproducible competency-based standards. The aims of this study were to (1) describe the development of a simulation-based mastery learning (SBML) curriculum for LGOC discussions and (2) set a defensible minimum passing standard (MPS) to ensure uniform skill acquisition among learners. INNOVATION: We developed an SBML curriculum for CCM fellows structured around REMAP, a mnemonic outlining foundational components of effective communication around serious illness. A multidisciplinary expert panel iteratively created an LGOC discussion assessment tool. Pilot testing was completed to refine the checklist, set the MPS, and assess skill acquisition. OUTCOMES: The LGOC discussion assessment tool included an 18-item checklist and 6 scaled items. The tool produced reliable data (k ≥ 0.7 and ICC of ≥ 0.7). Using the Mastery Angoff method, the panel set the MPS at 87%. Ten CCM fellows participated in the pilot study. Performance on the checklist significantly improved from a median score of 52% (IQR 44%-72%) at pretest to 96% (IQR 82%-97%) at post-test (P = 0.005). The number of learners who met the MPS similarly improved from 10% during pre-testing to 70% during post-testing (P = 0.02). COMMENT: We describe the development of a LGOC SBML curriculum for CCM fellows which includes a robust communication skills assessment and the delineation of a defensible MPS.
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Curriculum , Humanos , Cuidados Críticos , Competencia Clínica , Entrenamiento Simulado/métodos , Cuidado Terminal , Planificación de Atención al Paciente , Comunicación , Proyectos PilotoRESUMEN
A birthweight centile (BWC) below the 25th is associated with an elevated risk of adverse perinatal outcomes, particularly among males. This male vulnerability may stem from alterations in placenta-specific androgen signalling, a signalling axis that involves the androgen receptor (AR)-mediated regulation of target genes containing androgen response elements (AREs). In this study, we examined global and ARE-specific transcriptomic signatures in term male placentae (≥37 weeks of gestation) across BWC subcategories (<10th, 10th-30th, >30th) using RNA-seq and gene set enrichment analysis. ARE-containing transcripts in placentae with BWCs below the 10th percentile were upregulated compared to those in the 10th-30th and >30th percentiles, which coincided with the enrichment of gene sets related to hypoxia and the suppression of gene sets associated with mitochondrial function. In the absence of ARE-containing transcripts in silico, <10th and 10th-30th BWC subcategory placentae upregulated gene sets involved in vasculature development, immune function, and cell adhesion when compared to those in the >30th BWC subcategory. Collectively, our in silico findings suggest that changes in the expression of ARE-containing transcripts in male placentae may contribute to impaired placental vasculature and therefore result in reduced fetal growth outcomes.
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Andrógenos , Placenta , Embarazo , Masculino , Humanos , Femenino , Andrógenos/farmacología , Desarrollo Fetal , Perfilación de la Expresión Génica , Elementos de RespuestaRESUMEN
BACKGROUND: Whole-genome sequencing (WGS) is the gold standard diagnostic tool to identify and genetically characterise emerging pathogen mutations (variants), but cost, capacity, and timeliness limit its use when large populations need rapidly assessing. We assessed the potential of genotyping assays to provide accurate and timely variant information at scale by retrospectively examining surveillance for SARS-CoV-2 variants in England between March and September, 2021, when genotyping assays were used widely for variant detection. METHODS: We chose a panel of four RT-PCR genotyping assays to detect circulating variants of SARS-COV-2 in England and developed a decision algorithm to assign a probable SARS-CoV-2 variant to samples using the assay results. We extracted surveillance data from the UK Health Security Agency databases for 115 934 SARS-CoV-2-positive samples (March 1-Sept 6, 2021) when variant information was available from both genotyping and WGS. By comparing the genotyping and WGS variant result, we calculated accuracy metrics (ie, sensitivity, specificity, and positive predictive value [PPV]) and the time difference between the sample collection date and the availability of variant information. We assessed the number of samples with a variant assigned from genotyping or WGS, or both, over time. FINDINGS: Genotyping and an initial decision algorithm (April 10-May 11, 2021 data) were accurate for key variant assignment: sensitivities and PPVs were 0·99 (95% CI 0·99-0·99) for the alpha, 1·00 (1·00-1·00) for the beta, and 0·91 (0·80-1·00) for the gamma variants; specificities were 0·97 (0·96-0·98), 1·00 (1·00-1·00), and 1·00 (1·00-1·00), respectively. A subsequent decision algorithm over a longer time period (May 27-Sept 6, 2021 data) remained accurate for key variant assignment: sensitivities were 0·91 (95% CI 0·74-1·00) for the beta, 0·98 (0·98-0·99) for the delta, and 0·93 (0·81-1·00) for the gamma variants; specificities were 1·00 (1·00-1·00), 0·96 (0·96-0·97), and 1·00 (1·00-1·00), respectively; and PPVs were 0·83 (0·62-1·00), 1·00 (1·00-1·00), and 0·78 (0·59-0·97), respectively. Genotyping produced variant information a median of 3 days (IQR 2-4) after the sample collection date, which was faster than with WGS (9 days [8-11]). The flexibility of genotyping enabled a nine-times increase in the quantity of samples tested for variants by this method (from 5000 to 45 000). INTERPRETATION: RT-PCR genotyping assays are suitable for high-throughput variant surveillance and could complement WGS, enabling larger scale testing for known variants and timelier results, with important implications for effective public health responses and disease control globally, especially in settings with low WGS capacity. However, the choice of panels of RT-PCR assays is highly dependent on database information on circulating variants generated by WGS, which could limit the use of genotyping assays when new variants are emerging and spreading rapidly. FUNDING: UK Health Security Agency and National Institute for Health Research Health Protection Research Unit in Emergency Preparedness and Response.
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COVID-19 , Humanos , COVID-19/diagnóstico , COVID-19/epidemiología , Genotipo , Estudios Retrospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , SARS-CoV-2/genética , Inglaterra/epidemiología , Prueba de COVID-19RESUMEN
OBJECTIVE: Minimal research has examined teletherapy for group or intensive eating disorder (ED) treatment, particularly partial hospital programme (PHP). This study compared treatment outcomes for individuals treated before and after a pandemic-driven implementation of virtual PHP. METHOD: Patients received care at ED treatment centres using the Renfrew Unified Treatment for Eating Disorders and Comorbidity. Patients treated with virtual PHP were compared to patients treated with traditional PHP. Measures of ED symptomology and behaviours, depressive symptoms, anxiety severity, anxiety sensitivity, experiential avoidance, mindfulness, and body mass index (BMI; reported for anorexia nervosa [AN] patients only) were collected at intake and discharge. Multiple regression analyses were conducted to examine the effect of treatment group on outcomes, controlling for intake score, comorbidity, discharge status, AN diagnosis, and step-down status. RESULTS: Differences in treatment type were only found for binge eating frequency, with those in virtual PHP reporting significantly lower binge eating episodes at discharge than those in traditional PHP. Body mass index showed significantly less improvement in virtual PHP than in traditional PHP. CONCLUSIONS: Preliminary results suggest virtual PHP is feasible and effective, potentially increasing access to evidence-based, intensive ED treatment. However, additional research is needed to establish efficacious support for weight gain among individuals with AN in virtual programs.
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Anorexia Nerviosa , Trastorno por Atracón , Trastornos de Alimentación y de la Ingestión de Alimentos , Humanos , Estudios de Factibilidad , Trastornos de Alimentación y de la Ingestión de Alimentos/terapia , Anorexia Nerviosa/terapia , Trastorno por Atracón/terapia , HospitalesRESUMEN
The 2019/2020 Australian bushfires were unprecedented in terms of total area burned and impact on livestock and wildlife populations. However, there is currently limited literature available relating the consequences of bushfire or smoke exposure to livestock health, welfare, and carcase quality. A retrospective cross-sectional study was conducted using historical monitoring data from a Meat Standards Australia (MSA) accredited abattoir located on the mid-north coast of New South Wales, Australia. The spatiotemporal association between exposure to bushfire smoke (specifically the duration of the bushfires, distance from closest bushfire, annual bushfire season, proportion of the property of origin burned during the bushfires and time frame since exposure to bushfires) and effects on carcase meat quality metrics and pathology were measured, by building linear, generalised linear and cumulative link mixed models. Our findings indicate that hot carcase weight increased as the distance between the property of origin and the closest bushfire became greater and decreased with exposure to bushfires of longer duration or when greater proportions of the property of origin were burnt during bushfires. Subcutaneous rib fat of carcases also increased with an increasing distance of properties from the closest recorded bushfire and decreased with exposure to bushfires during the 2019/2020 season. Higher meat colour scores (darker meat colour) were associated with exposure to bushfires during the 2019/2020 season and exposure to bushfires of longer durations. There was only a weak association between increasing distance to the closest bushfire and higher marbling scores. Evidence of pneumonia in carcases was associated with exposure to bushfires of longer duration, specifically increasing risk of pneumonia was associated with fires of longer durations. Greater periods of time since exposure (i.e., >6 months) to bushfires were also associated with a higher risk of evidence of pneumonia at the time of processing. With increasing incidence of bushfires in Australia forecasted as a result of climate change, there is an urgent need to understand the impact of bushfires on livestock, to limit the effects on livestock health and mitigate the risk of significant socioeconomic impacts to the livestock industry. By providing a greater understanding of the impact of bushfires, the findings of this study can support producers to make informed decisions to mitigate the effects of bushfires on livestock health and carcase meat quality.
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Ganado , Neumonía , Animales , Australia/epidemiología , Estudios Transversales , Estudios Retrospectivos , Humo/análisis , Neumonía/veterinariaRESUMEN
In a 70-day study, 36 Jabbali and Sahrawi bucks, aged 11 months, were utilized to evaluate the effects of different levels of spirulina dietary supplement (SP) on carcass characteristics, fatty acid profile, and meat quality traits in Omani goat breeds. The goats were put into six groups of six bucks, each at random. The diet consisted of a conventional concentrate feed ration (CFR) without spirulina (CON), and the CFR diet supplemented with spirulina at the levels of 2 g/head daily (T1) and 4 g/head daily (T2). In general, Sahrawi bucks showed a highly significant response to SP feeding compared with Jabbali bucks. The treatment groups, especially T1, showed a significant increase in average daily gain and carcass traits (body length, leg length, and the rack weight) compared with the CON group of Sahrawi bucks. The weights of omental and kidney fat were also significantly higher in T1 compared with CON and T2 groups of Sahrawi goats, while they were significantly higher in T2 compared with CON and T1 groups of Jabbali goats. Carcass profile and meat quality, including ultimate ph and meat color lightness (L*) were increased significantly with dietary spirulina in both LD and SM muscles of Sahrawi goats. Most of the Sfa, Mufa, Pufa, Pufa n-6, Pufa n-3, and n-6/n-3 ratios of the LD showed significant differences in diets supplemented with SP compared with CON for Sahrawi bucks, while some of them were significant in Jabbali bucks. The LD muscle of Sahrawi goats fed diets supplemented with SP of the T1 group significantly decreased in the amounts of pentadecanoic and margaric acids compared with the T2 and CON groups. The study concluded that incorporating SP (2 g and 4 g/head daily) into the diet of Omani goats, especially Sahrawi goats, can increase growth performance, as well as improve fatty acid composition and meat quality.
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It has been presumed that rheumatoid arthritis (RA) joint pain is related to inflammation in the synovium; however, recent studies reveal that pain scores in patients do not correlate with synovial inflammation. We identified a module of 815 genes associated with pain, using a novel machine learning approach, Graph-based Gene expression Module Identification (GbGMI), in samples from patients with longstanding RA, but limited synovial inflammation at arthroplasty, and validated this finding in an independent cohort of synovial biopsy samples from early, untreated RA patients. Single-cell RNA-seq analyses indicated these genes were most robustly expressed by lining layer fibroblasts and receptor-ligand interaction analysis predicted robust lining layer fibroblast crosstalk with pain sensitive CGRP+ dorsal root ganglion sensory neurons. Netrin-4, which is abundantly expressed by lining fibroblasts and associated with pain, significantly increased the branching of pain-sensitive CGRP+ neurons in vitro . We conclude GbGMI is a useful method for identifying a module of genes that associate with a clinical feature of interest. Using this approach, we find that Netrin-4 is produced by synovial fibroblasts in the absence of inflammation and can enhance the outgrowth of CGRP+ pain sensitive nerve fibers. One Sentence Summary: Machine Learning reveals synovial fibroblast genes related to pain affect sensory nerve growth in Rheumatoid Arthritis addresses unmet clinical need.
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High yield and integrity of placental RNA are crucial for placental transcriptomics studies. We assessed the effects of time to placental collection post-delivery; tissue storage, amount and method used for extraction; mode of delivery; and tissue type on total RNA yield. The optimal protocol for RNA extraction from placental tissue includes cryofreezing of the sample upon collection and RNA extraction from 50 mg of tissue using TRIzol reagent. Decidua yielded highest RNA quantity/mg of tissue, followed by villous tissue and the chorion. Comparisons with murine kidney and HEK293T show lower placental RNA yield, likely due to highly dense and heterogeneous tissue make-up and potential high placental nuclease activity.
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Placenta , ARN , Humanos , Embarazo , Femenino , Animales , Ratones , Decidua , Células HEK293 , CorionRESUMEN
OBJECTIVE: We sought to develop computer vision methods to quantify aggregates of cells in synovial tissue and compare these with clinical and gene expression parameters. METHODS: We assembled a computer vision pipeline to quantify five features encompassing synovial cell density and aggregates and compared these with pathologist scores, disease classification, autoantibody status, and RNA expression in a cohort of 156 patients with rheumatoid arthritis (RA) and 149 patients with osteoarthritis (OA). RESULTS: All five features were associated with pathologist scores of synovial lymphocytic inflammation (P < 0.0001). Three features that related to the cells per unit of tissue were significantly increased in patients with both seronegative and seropositive RA compared with those with OA; on the other hand, aggregate features (number and diameter) were significantly increased in seropositive, but not seronegative, RA compared with OA. Aggregate diameter was associated with the gene expression of immunoglobulin heavy-chain genes in the synovial tissue. Compared with blood, synovial immunoglobulin isotypes were skewed from IGHM and IGHD to IGHG3 and IGHG1. Further, patients with RA with high levels of lymphocytic infiltrates in the synovium demonstrated parallel skewing in their blood with a relative decrease in IGHGM (P < 0.002) and IGHD (P < 0.03) and an increase in class-switched immunoglobulin genes IGHG3 (P < 0.03) and IGHG1 (P < 0.002). CONCLUSION: High-resolution automated identification and quantification of synovial immune cell aggregates uncovered skewing in the synovium from naïve IGHD and IGHM to memory IGHG3 and IGHG1 and revealed that this process is reflected in the blood of patients with high inflammatory synovium.
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Artritis Reumatoide , Osteoartritis , Humanos , Artritis Reumatoide/genética , Membrana Sinovial/metabolismo , Osteoartritis/genética , Autoanticuerpos/metabolismo , Inflamación/metabolismoRESUMEN
In 2022, the US Food and Drug Administration approved dupilumab for treatment of eosinophilic esophagitis (EoE). The aims of this study were to report physician and patient perspectives on initiating dupilumab. A 2-pronged approach was used: (1) data on physician prescribing practices was gathered via retrospective chart review of EoE patients prescribed dupilumab and (2) pediatric patients on dupilumab were approached to complete a questionnaire regarding reasons for initiation. During this time, 42 patients were prescribed dupilumab. From the physician's perspective, the primary reasons for dupilumab included nonresponse to topical corticosteroids (TCS) (52%), nonadherence (28%), adverse effects (10%), or to treat multiple atopic diseases (5%). The median dupilumab initiation time, from day prescribed to first injection, was 37 days [interquartile range (IQR) 37]. Almost all required prior authorization (PA) (98%), while 17% required letter of appeal and 2% required peer-to-peer. Fifteen patients (36%) completed the questionnaire portion of the study. From the patient's perspective, the primary reasons for dupilumab initiation included nonresponse to TCS (27%), nonadherence to TCS (27%), concern about adverse effects of TCS (7%), and treatment of multiple atopic diseases (33%). In conclusion, physicians are prescribing dupilumab primarily for nonresponse to TCS and almost all required PA with a long delay to starting dupilumab.
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Fármacos Dermatológicos , Esofagitis Eosinofílica , Humanos , Niño , Esofagitis Eosinofílica/tratamiento farmacológico , Estudios Retrospectivos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Glucocorticoides/uso terapéutico , Fármacos Dermatológicos/efectos adversos , Evaluación del Resultado de la Atención al Paciente , Resultado del TratamientoRESUMEN
Inflammation of non-barrier immunologically quiescent tissues is associated with a massive influx of blood-borne innate and adaptive immune cells. Cues from the latter are likely to alter and expand activated states of the resident cells. However, local communications between immigrant and resident cell types in human inflammatory disease remain poorly understood. Here, we explored drivers of fibroblast-like synoviocyte (FLS) heterogeneity in inflamed joints of patients with rheumatoid arthritis using paired single-cell RNA and ATAC sequencing, multiplexed imaging and spatial transcriptomics along with in vitro modeling of cell-extrinsic factor signaling. These analyses suggest that local exposures to myeloid and T cell-derived cytokines, TNF, IFN-γ, IL-1ß or lack thereof, drive four distinct FLS states some of which closely resemble fibroblast states in other disease-affected tissues including skin and colon. Our results highlight a role for concurrent, spatially distributed cytokine signaling within the inflamed synovium.
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Artritis Reumatoide , Humanos , Células Cultivadas , Artritis Reumatoide/genética , Membrana Sinovial , Citocinas/metabolismo , FibroblastosRESUMEN
Folic acid (FA) food fortification in Australia has resulted in a higher-than-expected intake of FA during pregnancy. High FA intake is associated with increased insulin resistance and gestational diabetes. We aimed to establish whether maternal one-carbon metabolism and hormones that regulate glucose homeostasis change in healthy pregnancies post-FA food fortification. Circulating folate, B12, homocysteine, prolactin (PRL), human placental lactogen (hPL) and placental growth hormone (GH2) were measured in early pregnancy maternal blood in women with uncomplicated pregnancies prior to (SCOPE: N = 604) and post (STOP: N = 711)-FA food fortification. FA food fortification resulted in 63% higher maternal folate. STOP women had lower hPL (33%) and GH2 (43%) after 10 weeks of gestation, but they had higher PRL (29%) and hPL (28%) after 16 weeks. FA supplementation during pregnancy increased maternal folate and reduced homocysteine but only in the SCOPE group, and it was associated with 54% higher PRL in SCOPE but 28% lower PRL in STOP. FA food fortification increased maternal folate status, but supplements no longer had an effect, thereby calling into question their utility. An altered secretion of hormones that regulate glucose homeostasis in pregnancy could place women post-fortification at an increased risk of insulin resistance and gestational diabetes, particularly for older women and those with obesity.
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Diabetes Gestacional , Resistencia a la Insulina , Humanos , Embarazo , Femenino , Anciano , Lactógeno Placentario/metabolismo , Ácido Fólico , Prolactina , Alimentos Fortificados , Diabetes Gestacional/metabolismo , Estudios Prospectivos , Placenta/metabolismo , Hormona del Crecimiento/metabolismo , Glucosa/metabolismoRESUMEN
Crigler-Najjar syndrome is a rare disorder of bilirubin metabolism caused by uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) mutations characterized by hyperbilirubinemia and jaundice. No cure currently exists; treatment options are limited to phototherapy, whose effectiveness diminishes over time, and liver transplantation. Here, we evaluated the therapeutic potential of systemically administered, lipid nanoparticle-encapsulated human UGT1A1 (hUGT1A1) mRNA therapy in a Crigler-Najjar mouse model. Ugt1 knockout mice were rescued from lethal post-natal hyperbilirubinemia by phototherapy. These adult Ugt1 knockout mice were then administered a single lipid nanoparticle-encapsulated hUGT1A1 mRNA dose. Within 24 h, serum total bilirubin levels decreased from 15 mg/dL (256 µmol/L) to <0.5 mg/dL (9 µmol/L), i.e., slightly above wild-type levels. This reduction was sustained for 2 weeks before bilirubin levels rose and returned to pre-treatment levels by day 42 post-administration. Sustained reductions in total bilirubin levels were achieved by repeated administration of the mRNA product in a frequency-dependent manner. We were also able to rescue the neonatal lethality phenotype seen in Ugt1 knockout mice with a single lipid nanoparticle dose, which suggests that this may be a treatment modality appropriate for metabolic crisis situations. Therefore, lipid nanoparticle-encapsulated hUGT1A1 mRNA may represent a potential treatment for Crigler-Najjar syndrome.
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Background: Chronic pain is a leading cause of disability, often requiring multidisciplinary management. 2021 NICE guidance has questioned the quality of the evidence surrounding the efficacy of pain management programmes (PMPs), with only minor benefit demonstrated in psychological and physical outcomes. There is need for further high-quality evidence for the efficacy of PMPs for a range of chronic pain conditions and to identify barriers to successful management of chronic pain. Objective: This service evaluation utilised routinely collected outcome data of 508 PMP attendees to investigate change in pain- and patient-related outcomes across two distinct PMPs; a standard and an intensive PMP, and establish their longer-term efficacy and appropriateness for patients with differing degrees of need. Results: More people with chronic widespread pain, fibromyalgia, and osteoarthritis were referred to the intensive PMP (reflecting greater disability and distress in these conditions). Those referred to the intensive PMP demonstrated greater distress (such as more severe depression and anxiety), lower pain acceptance and poorer physical function. Improvements were observed in all outcomes across both PMPs (including physical function, pain catastrophising and pain acceptance). Depression and disability demonstrated clinically meaningful improvements in the intensive PMP, and pain severity showed clinically meaningful improvement in both PMPs. However, depression severity, disability, pain severity, and pain interference significantly deteriorated at 6-month follow-up for those on the intensive PMP, with pain severity increasing to a clinically meaningful degree (by more than 10%), though these outcomes remained better than at baseline. Conclusion: This evaluation identified that people with chronic pain most at risk of deterioration in physical and psychological wellbeing after completing a PMP require early identification to mitigate such deterioration. Established and emerging PMPs need to be tailored to the needs of this group, particularly at follow-up to reduce risks of pain severity increasing, alongside establishing/reinforcing safeguards against deterioration post-PMP.
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The search for novel microRNA (miRNA) biomarkers in plasma is hampered by haemolysis, the lysis and subsequent release of red blood cell contents, including miRNAs, into surrounding fluid. The biomarker potential of miRNAs comes in part from their multicompartment origin and the long-lived nature of miRNA transcripts in plasma, giving researchers a functional window for tissues that are otherwise difficult or disadvantageous to sample. The inclusion of red-blood-cell-derived miRNA transcripts in downstream analysis introduces a source of error that is difficult to identify posthoc and may lead to spurious results. Where access to a physical specimen is not possible, our tool will provide an in silico approach to haemolysis prediction. We present DraculR, an interactive Shiny/R application that enables a user to upload miRNA expression data from a short-read sequencing of human plasma as a raw read counts table and interactively calculate a metric that indicates the degree of haemolysis contamination. The code, DraculR web tool and its tutorial are freely available as detailed herein.