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3,700 |
Recommendations by a UK expert panel on an aflibercept treat-and-extend pathway for the treatment of neovascular age-related macular degeneration
|
OBJECTIVES: This report aims to provide clear recommendations and practical guidance from a panel of UK retinal experts on an aflibercept treat-and-extend (T&E) pathway that can be implemented in clinical practice. These recommendations may help service providers across the NHS intending to implement a T&E approach, with the aim of effectively addressing the capacity and resource issues putting strain on UK neovascular age-related macular degeneration (nAMD) services while promoting patients’ best interests throughout. METHODS: Two structured roundtable meetings of retinal specialists were held in London, UK on 7 December 2018 and 1 March 2019. These meetings were organised and funded by Bayer. RESULTS: The panel provided recommendations for an aflibercept T&E pathway and developed specific criteria based on visual acuity, retinal morphology and optical coherence tomography imaging to guide reduction, maintenance and extension of injection intervals. They also discussed the extension of treatment intervals by 2- or 4-week adjustments to a maximum treatment interval of 16 weeks, the management of retinal fluid and the stopping of treatment. CONCLUSIONS: The long-term benefits of implementing a T&E pathway may include superior visual outcomes compared with a pro re nata (PRN; as needed) protocol, and a lower treatment burden compared with a fixed protocol, which is likely to improve service capacity. Furthermore, the predictable nature of a T&E approach compared with a PRN service may aid capacity planning for the future nAMD treatment demand.
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3,701 |
Accuracy of IOL power calculations in the very elderly
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BACKGROUND/OBJECTIVES: To analyze the refractive predictability and outcomes of cataract surgery in the very elderly (≥85 years old). SUBJECTS/METHODS: A retrospective case-series performed at the Shiley Eye Institute, University of California San Diego, USA. Electronically pulled data of 2444 surgeries revealed 147 surgeries on 133 very elderly patients. Chart review was conducted for all very elderly and corresponding control patients (75–84 years old). The first operated eyes of patients with final best-corrected visual acuity ≥20/40, axial length (AL) 22–26 mm, and implanted SN60WF IOL were included. Patients with ocular comorbidities and/or intra- or post-operative complications were excluded. Prediction errors of refractive outcome and percentage of eyes within ±0.50D and ±1.00D were compared between the groups for the Holladay 1 and Barrett Universal II (Barrett) formulas. Logistic regression analysis for achievement of ±1.00D was conducted. RESULTS: Final analysis included 90 eyes (n = 44, very elderly, n = 46, control patients). Median absolute refractive error (MedAE) with Holladay 1, but not Barrett formula, was significantly higher in the older group (p = 0.02 and p = 0.07, respectively). The MedAE in the older group was lower using the Barrett compared to Holladay 1 (p = 0.02). Fewer older patients than younger patients achieved refraction within ±0.50D and ±1.00D from goal, using the Holladay 1 (p = 0.049 and p = 0.002 respectively). Logistic regression analysis supported the relationship between Holladay 1 predictive refractive error of >1.00D and patient’s age (p = 0.046). CONCLUSIONS: Very elderly patients undergoing cataract surgery may be prone to reduced refractive precision, particularly with utilization of the Holladay 1 formula.
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3,702 |
sFRP1 protects H9c2 cardiac myoblasts from doxorubicin-induced apoptosis by inhibiting the Wnt/PCP-JNK pathway
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Doxorubicin (Dox) is an effective chemotherapy drug against a wide range of cancers, including both hematological and solid tumors. However, the serious cardiotoxic effect restricted its clinical application. We previously have illuminated the protective role of canonical Wnt/β-catenin signaling in Dox-induced cardiotoxicity. Secreted frizzled-related protein 1 (sFRP1) is one of the endogenous inhibitors of both canonical and noncanonical Wnt signaling. In this study, we investigated the relationship between sFRP1 and noncanonical Wnt/PCP-JNK (Wnt/planar cell polarity-c-Jun N-terminal kinase) pathway in Dox-induced cardiotoxicity in vitro and in vivo. We showed that treatment of H9c2 cardiac myoblasts with Dox (1 μM) time-dependently suppressed cell viability accompanied by significantly decreased sFRP1 protein level and increased Wnt/PCP-JNK signaling. Pretreatment with SP600125, the Wnt/PCP-JNK signaling inhibitor, attenuated Dox-induced apoptosis of H9c2 cells. Overexpression of sFRP1 protected H9c2 cells from Dox-induced apoptosis by inhibiting the Wnt/PCP-JNK pathway. After intraperitoneal injection of a cumulative dose of 15 mg/kg Dox, rats displayed significant cardiac dysfunction; their heart showed inhibited Wnt/β-catenin signaling and activated Wnt/PCP-JNK signaling. These results suggest that sFRP1 may be a novel target for Dox-induced cardiotoxicity.
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3,703 |
Erratum zu: Ocrelizumab zur Behandlung der Multiplen Sklerose
| null |
3,704 |
Macular ganglion cell complex thinning in children with visual field defects due to central nervous system pathology
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PURPOSE: To study the relationship between macular ganglion cell complex (GCC) thickness and visual field defects (VFD) caused by central nervous system (CNS) lesions in children and evaluate the possibility of predicting VFD according to GCC maps. METHODS: The GCC maps of a group of children with VFD due to CNS lesions with respect of the vertical meridian in at least one eye (study group), as well as of children with other neuro-ophthalmological problems and healthy children were presented to two masked evaluators, who were asked to predict the patients’ VFD on the basis of GCC damage: the evaluators classified VFD as normal, hemianopia (homonymous or heteronymous) or diffuse. RESULTS: Seventeen patients were included in the study group, with a median age of 12 years. Fifteen had brain tumours and two epilepsy. The mean MD of the affected hemifields was −26.00 dB (SD 7.89 dB) versus −5.51 dB (SD 3.52 dB) for the nonaffected hemifields, p < 0.001. The mean GCC thickness was of 56.04 μm (SD 11.95 μm) in the affected hemiretinas versus 74.31 μm (SD 10.64 μm) for the non-affected, p < 0.001. Kappa coefficients between VFD and those estimated by the evaluators were 0.705 and 0.658 (p < 0.001) for evaluators 1 and 2. CONCLUSIONS: GCC thickness can reflect damage to the visual pathway and GCC maps may be useful to identify chiasmal and retrochiasmal lesions, since GCC atrophy in most of these cases respects the vertical meridian. GCC maps might be used as a surrogate marker for visual damage in patients unable to perform perimetry.
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3,705 |
Correction: Allogeneic hematopoietic stem cell transplantation should be in preference to conventional chemotherapy as post-remission treatment for adults with lymphoblastic lymphoma
| null |
3,706 |
RNA and the PIEZO force sensor
| null |
3,707 |
Erratum: Therapeutically relevant structural and functional mechanisms triggered by physical and cognitive exercise
| null |
3,708 |
Correction: Measurement of blood pressure in people with atrial fibrillation
| null |
3,709 |
Lack of efficacy of eplerenone for treatment of active central serous chorioretinopathy
| null |
3,710 |
Management of recurrent sebaceous gland carcinoma
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OBJECTIVE: To evaluate the incidence and management of recurrent periocular sebaceous gland carcinoma at a tertiary ocular oncology service in the United Kingdom. METHODS: This was a retrospective cohort study of 62 patients with sebaceous gland carcinoma treated between 2004 and 2017. A total of 10 eyes were treated for local recurrence. The following variables were recorded: age and sex of patient; tumour location, histological subtype; recurrence type; treatment and outcome. RESULTS: Of the 62 cases with eyelid SGC, 10 (16%) had recurrences during the study period and satisfied inclusion criteria. There were six (60%) females and four males in the recurrent group. The mean time interval between initial excision and tumour recurrence was 37 months (median 23 months; range 4 to 84 months). Four patients received cryotherapy to the lids and conjunctiva to control recurrent disease and two patients were treated with topical or intralesional chemotherapy. Four patients (40%) underwent orbital exenteration during the study period. Metastasis occurred in 20% over a mean follow-up of 113 months (median 106; range 47–184 months). CONCLUSIONS: The risk factors for local recurrence of SGC after wide excision with paraffin section control were reported, and an approach to these recurrent lesions was proposed. The results of this study will help guide surgeons dealing with the medical and surgical conundrum of recurrent disease. The risk of recurrence is highest in the first 2 years after initial excision.
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3,711 |
A second cohort of CHD3 patients expands the molecular mechanisms known to cause Snijders Blok-Campeau syndrome
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There has been one previous report of a cohort of patients with variants in Chromodomain Helicase DNA-binding 3 (CHD3), now recognized as Snijders Blok-Campeau syndrome. However, with only three previously-reported patients with variants outside the ATPase/helicase domain, it was unclear if variants outside of this domain caused a clinically similar phenotype. We have analyzed 24 new patients with CHD3 variants, including nine outside the ATPase/helicase domain. All patients were detected with unbiased molecular genetic methods. There is not a significant difference in the clinical or facial features of patients with variants in or outside this domain. These additional patients further expand the clinical and molecular data associated with CHD3 variants. Importantly we conclude that there is not a significant difference in the phenotypic features of patients with various molecular disruptions, including whole gene deletions and duplications, and missense variants outside the ATPase/helicase domain. This data will aid both clinical geneticists and molecular geneticists in the diagnosis of this emerging syndrome.
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3,712 |
Whole-genome sequencing of 508 patients identifies key molecular features associated with poor prognosis in esophageal squamous cell carcinoma
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Esophageal squamous cell carcinoma (ESCC) is a poor-prognosis cancer type with limited understanding of its molecular etiology. Using 508 ESCC genomes, we identified five novel significantly mutated genes and uncovered mutational signature clusters associated with metastasis and patients’ outcomes. Several functional assays implicated that NFE2L2 may act as a tumor suppressor in ESCC and that mutations in NFE2L2 probably impaired its tumor-suppressive function, or even conferred oncogenic activities. Additionally, we found that the NFE2L2 mutations were significantly associated with worse prognosis of ESCC. We also identified potential noncoding driver mutations including hotspot mutations in the promoter region of SLC35E2 that were correlated with worse survival. Approximately 5.9% and 15.2% of patients had high tumor mutation burden or actionable mutations, respectively, and may benefit from immunotherapy or targeted therapies. We found clinically relevant coding and noncoding genomic alterations and revealed three major subtypes that robustly predicted patients’ outcomes. Collectively, we report the largest dataset of genomic profiling of ESCC useful for developing ESCC-specific biomarkers for diagnosis and treatment.
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3,713 |
Cochrane corner: Atropine: an ancient remedy for a twenty-first century problem?
| null |
3,714 |
Global distribution of a chlorophyll f cyanobacterial marker
|
Some cyanobacteria use light outside the visible spectrum for oxygenic photosynthesis. The far-red light (FRL) region is made accessible through a complex acclimation process that involves the formation of new phycobilisomes and photosystems containing chlorophyll f. Diverse cyanobacteria ranging from unicellular to branched-filamentous forms show this response. These organisms have been isolated from shaded environments such as microbial mats, soil, rock, and stromatolites. However, the full spread of chlorophyll f-containing species in nature is still unknown. Currently, discovering new chlorophyll f cyanobacteria involves lengthy incubation times under selective far-red light. We have used a marker gene to detect chlorophyll f organisms in environmental samples and metagenomic data. This marker, apcE2, encodes a phycobilisome linker associated with FRL-photosynthesis. By focusing on a far-red motif within the sequence, degenerate PCR and BLAST searches can effectively discriminate against the normal chlorophyll a-associated apcE. Even short recovered sequences carry enough information for phylogenetic placement. Markers of chlorophyll f photosynthesis were found in metagenomic datasets from diverse environments around the globe, including cyanobacterial symbionts, hypersaline lakes, corals, and the Arctic/Antarctic regions. This additional information enabled higher phylogenetic resolution supporting the hypothesis that vertical descent, as opposed to horizontal gene transfer, is largely responsible for this phenotype’s distribution.
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3,715 |
MiRNA-210 induces microglial activation and regulates microglia-mediated neuroinflammation in neonatal hypoxic-ischemic encephalopathy
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Neuroinflammation is a major contributor to secondary neuronal injury that accounts for a significant proportion of final brain cell loss in neonatal hypoxic-ischemic encephalopathy (HIE). However, the immunological mechanisms that underlie HIE remain unclear. MicroRNA-210 (miR-210) is the master “hypoxamir” and plays a key role in hypoxic-ischemic tissue damage. Herein, we report in an animal model of neonatal rats that HIE significantly upregulated miR-210 expression in microglia in the neonatal brain and strongly induced activated microglia. Intracerebroventricular administration of miR-210 antagomir effectively suppressed microglia-mediated neuroinflammation and significantly reduced brain injury caused by HIE. We demonstrated that miR-210 induced microglial M1 activation partly by targeting SIRT1, thereby reducing the deacetylation of the NF-κB subunit p65 and increasing NF-κB signaling activity. Thus, our study identified miR-210 as a novel regulator of microglial activation in neonatal HIE, highlighting a potential therapeutic target in the treatment of infants with hypoxic-ischemic brain injury.
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3,716 |
Watch this space: a systematic review of the use of video-based media as a patient education tool in ophthalmology
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Effective clinician-patient communication is particularly important in ophthalmology where long-term adherence to treatment is often required. However, in the context of increasingly pressurised clinics, there is a tendency to resort to written information leaflets not suited to patients with visual impairment, non-English speakers or those with low levels of literacy. Video-based media could be harnessed to enhance clinician-patient communication. This systematic review aimed to assess the efficacy of using video-based media for patient education in ophthalmology. A pre-defined search strategy was used by two independent researchers to systematically review the PubMed, MEDLINE, EMBASE and PsycINFO databases. Eligible articles included peer-reviewed studies involving ophthalmology patients, who received a solely video-based educational intervention to assess for improvement in patient knowledge, behaviour and overall health-related outcomes. The search yielded 481 studies of which 31 passed initial screening. Following full-text analysis, 12 studies met the inclusion criteria, of which seven studies (58.3%) were randomised controlled trials. The majority of studies (58.3%) reported outcomes on patient comprehension with 5/7 (71%) showing statistically significant improvement after video intervention. Four studies (33.3%) reported on patient performance in a task (e.g. drop application method) or overall health-related outcome with 2/4 (50%) showing statistically significant improvement after intervention. Though more evidence is needed, the use of video-based media appears to be effective in improving patient understanding and in certain cases may ameliorate overall outcome. There is a paucity of well-designed studies and future research is required to fully examine the role of video-based media in patient education.
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3,717 |
Functional interaction between sensory neurons and mast cells in the early stage of house dust mite-induced type 2 inflammation and itch: a novel therapeutic target of allergic disease
| null |
3,718 |
Author Correction: Climate change: an enduring challenge for vector-borne disease prevention and control
| null |
3,719 |
Correction: Airway epithelial cells prime plasmacytoid dendritic cells to respond to pathogens via secretion of growth factors
| null |
3,720 |
Correction: Despite mutation acquisition in hematopoietic stem cells, JMML-propagating cells are not always restricted to this compartment
| null |
3,721 |
Interruption of continuous opioid exposure exacerbates drug-evoked adaptations in the mesolimbic dopamine system
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Drug-evoked adaptations in the mesolimbic dopamine system are postulated to drive opioid abuse and addiction. These adaptations vary in magnitude and direction following different patterns of opioid exposure, but few studies have systematically manipulated the pattern of opioid administration while measuring neurobiological and behavioral impact. We exposed male and female mice to morphine for one week, with administration patterns that were either intermittent (daily injections) or continuous (osmotic minipump infusion). We then interrupted continuous morphine exposure with either naloxone-precipitated or spontaneous withdrawal. Continuous morphine exposure caused tolerance to the psychomotor-activating effects of morphine, whereas both intermittent and interrupted morphine exposure caused long-lasting psychomotor sensitization. Given links between locomotor sensitization and mesolimbic dopamine signaling, we used fiber photometry and a genetically encoded dopamine sensor to conduct longitudinal measurements of dopamine dynamics in the nucleus accumbens. Locomotor sensitization caused by interrupted morphine exposure was accompanied by enhanced dopamine signaling in the nucleus accumbens. To further assess downstream consequences on striatal gene expression, we used next-generation RNA sequencing to perform genome-wide transcriptional profiling in the nucleus accumbens and dorsal striatum. The interruption of continuous morphine exposure exacerbated drug-evoked transcriptional changes in both nucleus accumbens and dorsal striatum, dramatically increasing differential gene expression and engaging unique signaling pathways. Our study indicates that opioid-evoked adaptations in brain function and behavior are critically dependent on the pattern of drug administration, and exacerbated by interruption of continuous exposure. Maintaining continuity of chronic opioid administration may, therefore, represent a strategy to minimize iatrogenic effects on brain reward circuits.
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3,722 |
Erratum: A genome-wide analysis of putative functional and exonic variation associated with extremely high intelligence
| null |
3,723 |
Running interference on miR-33: a new amplification loop for type I interferon in the host antiviral response
| null |
3,724 |
Harmful vimentin manifests itself as multiorgan failure
| null |
3,725 |
Gastrodin protects H9c2 cardiomyocytes against oxidative injury by ameliorating imbalanced mitochondrial dynamics and mitochondrial dysfunction
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Gastrodin (GAS) is the main bioactive component of Tianma, a traditional Chinese medicine widely used to treat neurological disorders as well as cardio- and cerebrovascular diseases. In the present study, the protective effects of GAS on H9c2 cells against ischemia–reperfusion (IR)-like injury were found to be related to decreasing of oxidative stress. Furthermore, GAS could protect H9c2 cells against oxidative injury induced by H(2)O(2). Pretreatment of GAS at 20, 50, and 100 μM for 4 h significantly ameliorated the decrease in cell viability and increase in apoptosis of H9c2 cells treated with 400 μM H(2)O(2) for 3 h. Furthermore, we showed that H(2)O(2) treatment induced fragmentation of mitochondria and significant reduction in networks, footprint, and tubular length of mitochondria; H(2)O(2) treatment strongly inhibited mitochondrial respiration; H(2)O(2) treatment induced a decrease in the expression of mitochondrial fusion factors Mfn2 and Opa1, and increase in the expression of mitochondrial fission factor Fis1. All these alterations in H(2)O(2)-treated H9c2 cells could be ameliorated by GAS pretreatment. Moreover, we revealed that GAS pretreatment enhanced the nuclear translocation of Nrf2 under H(2)O(2) treatment. Knockdown of Nrf2 expression abolished the protective effects of GAS on H(2)O(2)-treated H9c2 cells. Our results suggest that GAS may protect H9c2 cardiomycytes against oxidative injury via increasing the nuclear translocation of Nrf2, regulating mitochondrial dynamics, and maintaining the structure and functions of mitochondria.
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3,726 |
A 20-year audit of retinoblastoma treatment outcomes
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OBJECTIVES: To evaluate the long-term treatment outcomes in intraocular retinoblastoma (RB) including the associated factors for eventual treatment with external beam radiotherapy (EBRT) and enucleation as well as to analyse the risk factors for metastasis and death in extraocular RB. METHODS: Retrospective analysis of 390 eyes from 256 (89.8%) intraocular RB and 29 (10.2%) extraocular RB cases diagnosed and treated between October 1998 and May 2018 at one of the largest tertiary care centers in Turkey. RESULTS: Of 351 intraocular RB eyes, 53.3% had group D/E disease at presentation. 75 (21.4%) of 351 eyes underwent primary enucleation. Of the remaining 276 eyes undergoing eye-conserving treatments, 201 (72.8%) were salvaged. Most of these eyes were treated using intravenous chemotherapy and/or focal treatments [transpupillary thermotherapy (TTT) and cryotherapy] initially. EBRT was eventually required in 48 (17.4%) eyes and secondary enucleation in 75 (27.2%) eyes. At mean follow-ups of 76.7 and 39.7 months for intraocular and extraocular RB cohorts, respectively, 180 (46.2%) eyes underwent primary/secondary enucleation and exenteration. Overall, 13 cases developed metastasis and 9 died. Two patients with trilateral RB also expired. Multivariable risk factors for enucleation were the presence of vitreous seeds (p < 0.001), absence of EBRT administration (p = 0.033), 5–9 TTT applications compared with no TTT (p = 0.031), and each 1 mm increase in tumour base diameter (p < 0.001). Univariate factors predictive of metastasis were the presence of extraocular RB detected by imaging methods (p < 0.001) and extrascleral/optic nerve cut end involvement at histopathological examination (p < 0.001). CONCLUSIONS: In our series, 72.8% of the intraocular RB eyes undergoing eye-conserving treatments were saved. The globe salvage rate for all intraocular and extraocular RB eyes was 53.8% and the overall survival rate was 96.1%.
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3,727 |
Correction: Validation of the use of p-aminobenzoic acid to determine completeness of 24 h urine collections in surveys of diet and nutrition
| null |
3,728 |
Correction: Control of PD-L1 expression by miR-140/142/340/383 and oncogenic activation of the OCT4–miR-18a pathway in cervical cancer
| null |
3,729 |
Brolucizumab—another anti-VEGF or beyond
| null |
3,730 |
Galactose supramolecular docking orchestrates macrophage phenotype
| null |
3,731 |
Correction: The phenotypic spectrum of WWOX-related disorders: 20 additional cases of WOREE syndrome and review of the literature
| null |
3,732 |
Alflutinib (AST2818), primarily metabolized by CYP3A4, is a potent CYP3A4 inducer
|
Alflutinib (AST2818) is a third-generation epidermal growth factor receptor (EGFR) inhibitor that inhibits both EGFR-sensitive mutations and T790M mutations. Previous study has shown that after multiple dosages, alflutinib exhibits nonlinear pharmacokinetics and displays a time- and dose-dependent increase in the apparent clearance, probably due to its self-induction of cytochrome P450 (CYP) enzyme. In this study, we investigated the CYP isozymes involved in the metabolism of alflutinib and evaluated the enzyme inhibition and induction potential of alflutinib and its metabolites. The data showed that alflutinib in human liver microsomes (HLMs) was metabolized mainly by CYP3A4, which could catalyze the formation of AST5902. Alflutinib did not inhibit CYP isozymes in HLMs but could induce CYP3A4 in human hepatocytes. Rifampin is a known strong CYP3A4 inducer and is recommended by the FDA as a positive control in the CYP3A4 induction assay. We found that the induction potential of alflutinib was comparable to that of rifampin. The E(max) of CYP3A4 induction by alflutinib in three lots of human hepatocytes were 9.24-, 11.2-, and 10.4-fold, while the fold-induction of rifampin (10 μM) were 7.22-, 19.4- and 9.46-fold, respectively. The EC(50) of alflutinib-induced CYP3A4 mRNA expression was 0.25 μM, which was similar to that of rifampin. In addition, AST5902 exhibited much weak CYP3A4 induction potential compared to alflutinib. Given the plasma exposure of alflutinib and AST5902, both are likely to affect the pharmacokinetics of CYP3A4 substrates. Considering that alflutinib is a CYP3A4 substrate and a potent CYP3A4 inducer, drug–drug interactions are expected during alflutinib treatment.
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3,733 |
Author Correction: NICE’s rejection of pembrolizumab for platinum-refractory urothelial carcinoma: is there a greater good?
| null |
3,734 |
Erratum to: Abstracts: XXXI International Congress of the IAP and 28th Congress of the ESP
| null |
3,735 |
Activation of tyrosine phosphatase PTP1B in pyramidal neurons impairs endocannabinoid signaling by tyrosine receptor kinase trkB and causes schizophrenia-like behaviors in mice
|
Schizophrenia is a debilitating disorder affecting young adults displaying symptoms of cognitive impairment, anxiety, and early social isolation prior to episodes of auditory hallucinations. Cannabis use has been tied to schizophrenia-like symptoms, indicating that dysregulated endogenous cannabinoid signaling may be causally linked to schizophrenia. Previously, we reported that glutamatergic neuron-selective ablation of Lmo4, an endogenous inhibitor of the tyrosine phosphatase PTP1B, impairs endocannabinoid (eCB) production from the metabotropic glutamate receptor mGluR5. These Lmo4-deficient mice display anxiety-like behaviors that are alleviated by local shRNA knockdown or pharmacological inhibition of PTP1B that restores mGluR5-dependent eCB production in the amygdala. Here, we report that these Lmo4-deficient mice also display schizophrenia-like behaviors: impaired working memory assessed in the Y maze and defective sensory gating by prepulse inhibition of the acoustic startle response. Modulation of inhibitory inputs onto layer 2/3 pyramidal neurons of the prefrontal cortex relies on eCB signaling from the brain-derived neurotrophic factor receptor trkB, rather than mGluR5, and this mechanism was defective in Lmo4-deficient mice. Genetic ablation of PTP1B in the glutamatergic neurons lacking Lmo4 restored tyrosine phosphorylation of trkB, trkB-mediated eCB signaling, and ameliorated schizophrenia-like behaviors. Pharmacological inhibition of PTP1B with trodusquemine also restored trkB phosphorylation and improved schizophrenia-like behaviors by restoring eCB signaling, since the CB1 receptor antagonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide blocked this effect. Thus, activation of PTP1B in pyramidal neurons contributes to schizophrenia-like behaviors in Lmo4-deficient mice and genetic or pharmacological intervention targeting PTP1B ameliorates schizophrenia-related deficits.
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3,736 |
Author Correction: Cryptic inoviruses revealed as pervasive in bacteria and archaea across Earth’s biomes
| null |
3,737 |
Fisetin alleviates sepsis-induced multiple organ dysfunction in mice via inhibiting p38 MAPK/MK2 signaling
|
Sepsis-induced multiple organ dysfunction and inflammatory response are life-threatening symptoms without effective treatment. Fisetin, a dietary flavonoid extracted from berries and family Fabaceae, has displayed neuroprotective and anti-oxidant activities. In this study we investigated whether fisetin exerted a protective effect against sepsis-induced multiple organ dysfunction in mouse cecum ligation and puncture (CLP) model. The mice were injected with fisetin (10 mg/kg, ip) 0.5 h prior to CLP, and sacrificed 18 h after CLP. We found that fisetin administration significantly alleviated CLP-induced lung, liver and kidney injury, as well as the expression levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α and IL-1β in bronchoalveolar lavage fluid (BALF). In lipopolysaccharide (LPS)-treated mouse bone marrow-derived macrophages (BMDMs), application of fisetin (3–10 μM) dose-dependently inhibited the expression levels of IL-6, TNF-α, IL-1β, and inducible nitric oxide synthase (iNOS). Furthermore, fisetin dose-dependently inhibited the phosphorylation of p38 MAPK, MK2, and transforming growth factor-β-activated kinase (TAK) 1 via attenuating the interaction between TAK1 and TAK-binding proteins (TAB) 1. These results demonstrate that fisetin is a promising agent for protecting against sepsis-induced inflammatory response and organ injury via inhibiting macrophage activation.
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3,738 |
Wnt signaling and Loxl2 promote aggressive osteosarcoma
|
Osteosarcoma (OS) is the most frequent primary malignant bone tumor in urgent need of better therapies. Using genetically modified mouse models (GEMMs), we demonstrate that Wnt signaling promotes c-Fos-induced OS formation via the actions of the collagen-modifying enzyme Loxl2. c-Fos/AP-1 directly regulates the expression of the Wnt ligands Wnt7b and Wnt9a in OS cells through promoter binding, and Wnt7b and Wnt9a in turn promote Loxl2 expression in murine and human OS cells through the transcription factors Zeb1 and Zeb2. Concordantly, inhibition of Wnt ligand secretion by inactivating the Wnt-less (Wls) gene in osteoblasts in c-Fos GEMMs either early or in a therapeutic setting reduces Loxl2 expression and progression of OS. Wls-deficient osteosarcomas proliferate less, are less mineralized and are enriched in fibroblastic cells surrounded by collagen fibers. Importantly, Loxl2 inhibition using either the pan-Lox inhibitor BAPN or a specific inducible shRNA reduces OS cell proliferation in vitro and decreases tumor growth and lung colonization in murine and human orthotopic OS transplantation models. Finally, OS development is delayed in c-Fos GEMMs treated with BAPN or with specific Loxl2 blocking antibodies. Congruently, a strong correlation between c-FOS, LOXL2 and WNT7B/WNT9A expression is observed in human OS samples, and c-FOS/LOXL2 co-expression correlates with OS aggressiveness and decreased patient survival. Therefore, therapeutic targeting of Wnt and/or Loxl2 should be considered to potentiate the inadequate current treatments for pediatric, recurrent, and metastatic OS.
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3,739 |
What is the optimal glaucoma treatment: reducing aqueous humour production or facilitating its outflow?
| null |
3,740 |
Author Correction: Chemosynthetic symbionts of marine invertebrate animals are capable of nitrogen fixation
| null |
3,741 |
Erratum: Clinical impact of bone marrow morphology for the diagnosis of essential thrombocythemia: comparison between the BCSH and the WHO criteria
| null |
3,742 |
Depth-dependent mycoplankton glycoside hydrolase gene activity in the open ocean—evidence from the Tara Oceans eukaryote metatranscriptomes
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Mycoplankton are widespread components of marine ecosystems, yet the full extent of their functional role remains poorly known. Marine mycoplankton are likely functionally analogous to their terrestrial counterparts, including performing saprotrophy and degrading high-molecular weight organic substrates using carbohydrate-active enzymes (CAZymes). We investigated the prevalence of transcribed oceanic fungal CAZyme genes using the Marine Atlas of Tara Ocean Unigenes database. We revealed an abundance of unique transcribed fungal glycoside hydrolases in the open ocean, including a particularly high number that act upon cellulose in surface waters and the deep chlorophyll maximum (DCM). A variety of other glycoside hydrolases acting on a range of biogeochemically important polysaccharides including β-glucans and chitin were also found. This analysis demonstrates that mycoplankton are active saprotrophs in the open ocean and paves the way for future research into the depth-dependent roles of marine fungi in oceanic carbon cycling, including the biological carbon pump.
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3,743 |
Correction: Cancer from the perspective of stem cells and misappropriated tissue regeneration mechanisms
| null |
3,744 |
Author Correction: Regulation of sister chromatid cohesion by nuclear PD-L1
| null |
3,745 |
mGlu5 receptor availability in youth at risk for addictions: effects of vulnerability traits and cannabis use
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The excitatory neurotransmitter glutamate has been implicated in experience-dependent neuroplasticity and drug-seeking behaviors. Type 5 metabotropic glutamate (mGlu5) receptors might be particularly important. They are critically involved in synaptic plasticity and their availability has been reported to be lower in people with alcohol, tobacco, and cocaine use disorders. Since these reductions could reflect effects of drug use or pre-existing traits, we used positron emission tomography to measure mGlu5 receptor availability in young adults at elevated risk for addictions. Fifty-nine participants (age 18.5 ± 0.6) were recruited from a longitudinal study that has followed them since birth. Based on externalizing traits that predict future substance use problems, half were at low risk, half were at high risk. Cannabis use histories varied markedly and participants were divided into three subgroups: zero, low, and high use. Compared to low risk volunteers, those at elevated risk had lower [(11)C]ABP688 binding potential (BP(ND)) values in the striatum, amygdala, insula, and orbitofrontal cortex (OFC). Cannabis use by risk group interactions were observed in the striatum and OFC. In these regions, low [(11)C]ABP688 BP(ND) values were only seen in the high risk group that used high quantities of cannabis. When these high risk, high cannabis use individuals were compared to all other participants, [(11)C]ABP688 BP(ND) values were lower in the striatum, OFC, and insula. Together, these results provide evidence that mGlu5 receptor availability is low in youth at elevated risk for addictions, particularly those who frequently use cannabis.
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3,746 |
Setting a new standard in cystic fibrosis newborn screening illustrates controversial issues as new data emerge
| null |
3,747 |
Biallelic PDE2A variants: a new cause of syndromic paroxysmal dyskinesia
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Cause of complex dyskinesia remains elusive in some patients. A homozygous missense variant leading to drastic decrease of PDE2A enzymatic activity was reported in one patient with childhood-onset choreodystonia preceded by paroxysmal dyskinesia and associated with cognitive impairment and interictal EEG abnormalities. Here, we report three new cases with biallelic PDE2A variants identified by trio whole-exome sequencing. Mitochondria network was analyzed after Mitotracker™ Red staining in control and mutated primary fibroblasts. Analysis of retrospective video of patients’ movement disorder and refinement of phenotype was carried out. We identified a homozygous gain of stop codon variant c.1180C>T; p.(Gln394*) in PDE2A in siblings and compound heterozygous variants in young adult: a missense c.446C>T; p.(Pro149Leu) and splice-site variant c.1922+5G>A predicted and shown to produce an out of frame transcript lacking exon 22. All three patients had cognitive impairment or developmental delay. The phenotype of the two oldest patients, aged 9 and 26, was characterized by childhood-onset refractory paroxysmal dyskinesia initially misdiagnosed as epilepsy due to interictal EEG abnormalities. The youngest patient showed a proven epilepsy at the age of 4 months and no paroxysmal dyskinesia at 15 months. Interestingly, analysis of the fibroblasts with the biallelic variants in PDE2A variants revealed mitochondria network morphology changes. Together with previously reported case, our three patients confirm that biallelic PDE2A variants are a cause of childhood-onset refractory paroxysmal dyskinesia with cognitive impairment, sometimes associated with choreodystonia and interictal baseline EEG abnormalities or epilepsy.
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3,748 |
Ligand recognition by the γδ TCR and discrimination between homeostasis and stress conditions
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T lymphocytes comprise cells expressing either an αβ or a γδ TCR. The riddle how αβ TCRs are triggered by specific peptides presented in the context of MHC was elucidated some time ago. In contrast, the mechanisms that underlie antigen recognition by γδ TCRs are still baffling the scientific community. It is clear that activation of γδ TCRs does not necessarily depend on MHC antigen presentation. To date, diverse and largely host-cell-derived molecules have been identified as cognate antigens for the γδ TCR. However, for most γδ TCRs, the activating ligand is still unknown and many open questions with regard to physiological relevance and generalizable concepts remain. Especially the question of how γδ T cells can distinguish homeostatic from stress conditions via their TCR remains largely unresolved. Recent discoveries in the field might have paved the way towards a better understanding of antigen recognition by the γδ TCR and have made it conceivable to revise the current knowledge and contextualize the new findings.
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3,749 |
Potential application of endocannabinoid system agents in neuropsychiatric and neurodegenerative diseases—focusing on FAAH/MAGL inhibitors
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The endocannabinoid system (ECS) has received extensive attention for its neuroprotective effect on the brain. This system comprises endocannabinoids, endocannabinoid receptors, and the corresponding ligands and proteins. The molecular players involved in their regulation and metabolism are potential therapeutic targets for neuropsychiatric diseases including anxiety, depression and neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). The inhibitors of two endocannabinoid hydrolases, i.e., fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), have the capacity to increase the level of endocannabinoids indirectly, causing fewer side effects than those associated with direct supplementation of cannabinoids. Their antidepressant and anxiolytic mechanisms are considered to modulate the hypothalamic-pituitary-adrenal axis and regulate synaptic and neural plasticity. In terms of AD/PD, treatment with FAAH/MAGL inhibitors leads to reduction in amyloid β-protein deposition and inhibition of the death of dopamine neurons, which are commonly accepted to underlie the pathogenesis of AD and PD, respectively. Inflammation as the cause of depression/anxiety and PD/AD is also the target of FAAH/MAGL inhibitors. In this review, we summarize the application and involvement of FAAH/MAGL inhibitors in related neurological diseases. Focus on the latest research progress using FAAH/MAGL inhibitors is expected to facilitate the development of novel approaches with therapeutic potential.
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3,750 |
Correction: Src and SHP2 coordinately regulate the dynamics and organization of vimentin filaments during cell migration
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3,751 |
Presumed ocular tuberculosis in the United Kingdom: a British Ophthalmological Surveillance Unit (BOSU) study
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INTRODUCTION: Ocular tuberculosis (TB) is an extrapulmonary manifestation of mycobacterium infection that most commonly presents as uveitis. This is the first prospective incidence study of presumed ocular tuberculosis performed in the United Kingdom (UK). METHOD: New cases of ocular tuberculosis presenting to hospitals in the UK were prospectively ascertained between October 2016 and November 2017 with the aid of the British Ophthalmological Surveillance Unit (BOSU). Initial presentation data and 1-year follow-up data was collected using questionnaires. RESULTS: Forty-eight patients were recruited giving an overall incidence for ocular TB of 0.73 per million population per annum. The origin of birth for 71% of the patients was a non-UK country and 87.5% had their initial diagnosis of TB made by an ophthalmologist. The most common first line treatment was isoniazid, rifampicin, ethambutol and pyrazinamide which 71% of patients were treated with 60% of patients were commenced on a reducing course of oral steroids. At 1-year follow-up, 29 patients (83%) had complete resolution of active clinical signs. Mean best corrected visual acuity (BCVA) at presentation was +0.41 LogMAR(SD = 0.62), compared to +0.31 LogMAR (SD = 0.56) at 12-month follow-up. DISCUSSION: It is increasingly the responsibility of the ophthalmologist to diagnose ocular TB and although it remains a rare condition, consensus on diagnostic criteria and treatment is required. Increasing recognition and accessibility to gamma-interferon testing should enable earlier detection. Treatment with quadruple ATT treatment regimens for at least 6 months shows good clinical outcomes. However, it is still unclear whether steroid use is beneficial. Further large studies with longer follow-up would be warranted to answer these questions.
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3,752 |
Comment on: ‘Giant cell arteritis in patients of Indian subcontinental descent in the UK’
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3,753 |
Correction to: The Intensive Care Global Study on Severe Acute Respiratory Infection (IC-GLOSSARI): a multicenter, multinational, 14-day inception cohort study
| null |
3,754 |
Correction to: Accelerating evidence gathering and approval of precision medicine therapies: the FDA takes aim at rare mutations
| null |
3,755 |
Pachydrusen: the epidemiology of pachydrusen and its relevance to progression of pachychoroid disease spectrum
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3,756 |
Trends in licence approvals for ophthalmic medicines in the United Kingdom
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OBJECTIVES: The grant of marketing authorisation (MA) for new medicines requires comprehensive assessment by regulatory authorities. This study sought to identify ophthalmic medicines granted United Kingdom MA and consider trends in licence approvals. METHODS: This retrospective study reviewed published lists of products granted MA by the UK Medicines & Healthcare products Regulatory Agency between January 2001 and December 2018, inclusive. Eye drops and medicinal products intended for ophthalmic use were identified. All regulatory data sources consulted are in the public domain. Data analyses were descriptive. RESULTS: A total of 295 MAs were issued for ophthalmic products between 2001 and 2018, inclusive. Of these 229 (78%) were for single-active substances and 66 (22%) fixed-dose combination (FDC). Approvals for products with single-active substance included ocular hypotensives (115; 50%), antibiotics (48; 22%), allergy medicines (30; 13%), lubricants (18; 8%) and anti-inflammatories (11; 5%). Approvals for FDCs were predominantly ocular hypotensives (56; 85%), with timolol combined with carbonic anhydrase inhibitors (27; 48%) and prostaglandin analogues (26; 46%) accounting for the majority of glaucoma FDCs. Other FDCs were approved for antibiotic/inflammatory (5; 7.5%), pupillary mydriasis (2; 3%), allergy (2; 3%) and ocular surface lubrication (1; 1.5%) products. A median of 16 licences were approved per year (range 7 [2005] to 35 [2011]). CONCLUSIONS: The majority of MAs granted were for single-agent products, particularly ocular hypotensives and antibiotic preparations. Most products were generic versions of well-established active substances. A trend for increased approvals for FDCs is evident, particularly for the treatment of raised IOP.
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3,757 |
The Association with rhegmatogenous retinal detachment and paediatric atopic dermatitis: a 12-year Nationwide Cohort Study
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PURPOSE: Historically, atopic dermatitis (AD) is associated with an increased risk of rhegmatogenous retinal detachment (RRD). However, uncertainty remained regarding the effect of AD itself and comorbidities (e.g., allergic diseases, cataract surgery) on RRD occurrence in a large, population-based paediatric population. PATIENTS AND METHODS: We analysed the 12-year National Health Insurance Service database (2002–2013) covering the entire Korean population to estimate the association between AD and RRD in people aged under 20 years. RESULTS: We identified 3142 RRD patients, and matched 18,852 controls (six controls to each RRD patient); therefore, we included 21,994 peoples under aged 20 years in the analyses. AD was more prevalent in the RRD group (329 patients, 10.47%) than the control group (1043 patients, 5.53%; P < 0.001), and so were severe AD (153 patients [4.87%] and 223 patients [1.18%], respectively; P < 0.001). In conditional logistic regression analysis, AD was associated with RRD (OR, 1.61; 95% CI, 1.93–1.87) even after adjusting for allergic conditions, connective tissue disease, uveitis, and cataract surgery. In addition, severity of AD was associated with an increased risk of RRD (OR for non-severe AD and severe AD, 1.26 [95% CI, 1.05–1.51] and 2.88 [95% CI, 2.25–3.68]). CONCLUSION: This study suggests that AD itself is a risk factor of RRD in children by showing the association between AD and RRD occurrence and the biologic gradient even after adjustment for known confounders including allergic conditions, uveitis, and cataract surgery.
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3,758 |
Correction: Evaluation of medical and surgical decompression in patients with dysthyroid optic neuropathy
| null |
3,759 |
Nintedanib inhibits keloid fibroblast functions by blocking the phosphorylation of multiple kinases and enhancing receptor internalization
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Keloid is a benign skin tumor characterized by its cell hyperproliferative activity, invasion into normal skin, uncontrolled growth, overproduction and deposition of extracellular matrices and high recurrence rate after various therapies. Nintedanib is a receptor tyrosine kinase inhibitor targeting VEGF, PDGF, FGF, and TGF-β receptors with proved efficacy in anti-angiogenesis and in treating various types of cancers. In this study, we investigated the effects of nintedanib on keloid fibroblasts in both in vitro and ex vivo models. Keloid fibroblasts were prepared from 54 keloid scar samples in active stages collected from 49 patients. We found that nintedanib (1−4 μM) dose-dependently suppressed cell proliferation, induced G(0)/G(1) cell cycle arrest, and inhibited migration and invasion of keloid fibroblasts. The drug also significantly inhibited the gene and protein expression of collagen I (COL-1) and III (COL-3), fibronectin (FN), and connective growth factor (CTGF), as well as the gene expression of other pathological factors, such as alpha smooth muscle actin (α-SMA), plasminogen activator inhibitor-1 (PAI-1), FK506-binding protein 10 (FKBP10), and heat shock protein 47 (HSP47) in keloid fibroblasts. Furthermore, nintedanib treatment significantly suppressed the phosphorylation of p38, JNK, ERK, STAT3, and Smad, enhanced endocytosis of various growth factor receptors. Using an ex vivo tissue explant model, we showed that nintedanib significantly suppressed cell proliferation, migration, and collagen production. The drug also significantly disrupted microvessel structure ex vivo. In summary, our results demonstrate that nintedanib is likely to become a potential targeted drug for keloid systemic therapy.
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3,760 |
A survey of current practices by the British Oculoplastic Surgery Society (BOPSS) and recommendations for delivering a sustainable multidisciplinary approach to thyroid eye disease in the United Kingdom
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BACKGROUND: The Royal College of Physicians (RCP) and Thyroid Eye Disease Amsterdam Declaration Implementation Group (TEAMeD-5) have the common goal of improving access to high quality care for thyroid eye disease (TED). The TEAMeD-5 programme recommends all patients with moderate-to-severe TED should have access to multidisciplinary clinics (MDT) with combined Ophthalmology and Endocrinology expertise. METHODS: The British Oculoplastic Surgery Society represents oculoplastic surgeons who usually lead TED care in the UK. A two-stage survey of the membership was conducted to ascertain current practice of existing resources. RESULTS: Seventy percent (45/65) of respondents in Survey 1 were aware of current RCP guidance, but only 49% (22/45) rated it as a good means of improving access to comprehensive TED service. Sixty percent (39/65) of respondents are working in a multidisciplinary TED clinic with co-location of ophthalmologists and endocrinologists. Care for TED appears not to be provided in a multidisciplinary context in up to 31% (20/65). Thirty five (54%) of the respondents rated their relationship with endocrinology colleagues as good. Best practice guidelines recommend routine quality of life assessments but only 6/28 (21%) of respondents use this modality in current practice. Six percent (4/65) of areas appear not to be using intravenous steroids. In many areas (25%, 16/65), second-line immunosuppression is provided in a different trust and in 8% (5/65), it appears not to be used at all. CONCLUSION: This survey is a ‘snapshot’ of current TED management in the UK and findings suggest scope for improvement. We recommend a framework for more robust collaboration across specialties and propose standards endorsed by multidisciplinary stakeholder societies.
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3,761 |
Short-term nicotine deprivation alters dorsal anterior cingulate glutamate concentration and concomitant cingulate-cortical functional connectivity
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Most cigarette smokers who wish to quit too often relapse within the first few days of abstinence, primarily due to the aversive aspects of the nicotine withdrawal syndrome (NWS), which remains poorly understood. Considerable research has suggested that the dorsal anterior cingulate cortex (dACC) plays a key role in nicotine dependence, with its functional connections between other brain regions altered as a function of trait addiction and state withdrawal. The flow of information between dACC and fronto-striatal regions is secured through different pathways, the vast majority of which are glutamatergic. As such, we investigated dACC activity using resting state functional connectivity (rsFC) with functional magnetic resonance imaging (fMRI) and glutamate (Glu) concentration with magnetic resonance spectroscopy (MRS). We also investigated the changes in adenosine levels in plasma during withdrawal as a surrogate for brain adenosine, which plays a role in fine-tuning synaptic glutamate transmission. Using a double-blind, placebo-controlled, randomized crossover design, nontreatment seeking smoking participants (N = 30) completed two imaging sessions, one while nicotine sated and another after 36 h nicotine abstinence. We observed reduced dACC Glu (P = 0.029) along with a significant reduction in plasma adenosine (P = 0.03) and adenosine monophosphate (AMP; P < 0.0001) concentrations during nicotine withdrawal in comparison with nicotine sated state. This withdrawal state manipulation also led to an increase in rsFC strength (P < 0.05) between dACC and several frontal cortical regions, including left superior frontal gyrus (LSFG), and right middle frontal gyrus (RMFG). Moreover, the state-trait changes in dACC Glu and rsFC strength between the dACC and both SFG and MFG were positively correlated (P = 0.012, and P = 0.007, respectively). Finally, the change in circuit strength between dACC and LSFG was negatively correlated with the change in withdrawal symptom manifestations as measured by the Wisconsin Smoking Withdrawal Scale (P = 0.04) and Tobacco Craving Questionnaire (P = 0.014). These multimodal imaging-behavioral findings reveal the complex cascade of changes induced by acute nicotine deprivation and call for further investigation into the potential utility of adenosine- and glutamate-signaling as novel therapeutic targets to treat the NWS.
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3,762 |
Correction to: 14 Years’ experience of esophageal replacement surgeries
| null |
3,763 |
Correction: A 20-year audit of retinoblastoma treatment outcomes
| null |
3,764 |
Correction: Genomic profiling reveals spatial intra-tumor heterogeneity in follicular lymphoma
| null |
3,765 |
Correction: Effectiveness of plasma lyso-Gb3 as a biomarker for selecting high-risk patients with Fabry disease from multispecialty clinics for genetic analysis
| null |
3,766 |
Correction: Whole-genome sequencing of chronic lymphocytic leukaemia reveals distinct differences in the mutational landscape between IgHV(mut) and IgHV(unmut) subgroups
| null |
3,767 |
Choroidal thickness and the retinal ganglion cell complex in chronic Leberʼs hereditary optic neuropathy: a prospective study using swept-source optical coherence tomography
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BACKGROUND/OBJECTIVES: Choroidal thinning has been suggested in Leber’s hereditary optic neuropathy (LHON). No study has been conducted of the choroid in relation to the retinal ganglion cell-inner plexiform layer (RGC-IPL). We sought to measure choroidal thickness in chronic LHON and to correlate thickness changes with the RGC-IPL. SUBJECTS/METHODS: Chronic LHON, 11778 mitochondrial DNA (mtDNA) mutation, patients (26 eyes; mean age: 35.1 ± 16.1 years) were prospectively recruited at Doheny Eye Center, University of California Los Angeles from March 2016 to July 2017. Age-matched healthy controls (27 eyes; mean age: 32.4 ± 11.1 years) were enroled for comparison. Swept-source optical coherence tomography (SS-OCT) imaging was performed in chronic LHON patients and compared with age-matched healthy controls. RESULTS: The macular choroid was significantly thinner in chronic LHON (250.5 ± 62.2 μm) compared with controls (313.9 ± 60.2 μm; p < 0.0001). The peripapillary choroid was also significantly thinner in chronic LHON (135.7 ± 51.4 μm) compared with controls (183.0 ± 61.8 μm, p < 0.001). Choroidal thickness strongly correlated with retinal nerve fibre layer (RNFL) thickness in both the macular (R(2) = 0.72; 95% CI, 0.57–0.84) and peripapillary regions (R(2) = 0.53; 95% CI, 0.31–0.70). Choroidal thickness was also significantly correlated with macular RGC-IPL thickness (R(2) = 0.51; 95% CI, 0.26–0.73). CONCLUSIONS: Choroidal thinning in chronic LHON correlated strongly with both RNFL and RGC-IPL thicknesses. These findings may suggest a pathophysiological mechanism involving vascular pathology of the choroid in relation to the retinal ganglion cell complex in LHON.
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3,768 |
The Msi1-mTOR pathway drives the pathogenesis of mammary and extramammary Paget’s disease
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Mammary and extramammary Paget’s Diseases (PD) are a malignant skin cancer characterized by the appearance of Paget cells. Although easily diagnosed, its pathogenesis remains unknown. Here, single-cell RNA-sequencing identified distinct cellular states, novel biomarkers, and signaling pathways — including mTOR, associated with extramammary PD. Interestingly, we identified MSI1 ectopic overexpression in basal epithelial cells of human PD skin, and show that Msi1 overexpression in the epidermal basal layer of mice phenocopies human PD at histopathological, single-cell and molecular levels. Using this mouse model, we identified novel biomarkers of Paget-like cells that translated to human Paget cells. Furthermore, single-cell trajectory, RNA velocity and lineage-tracing analyses revealed a putative keratinocyte-to-Paget-like cell conversion, supporting the in situ transformation theory of disease pathogenesis. Mechanistically, the Msi1-mTOR pathway drives keratinocyte-Paget-like cell conversion, and suppression of mTOR signaling with Rapamycin significantly rescued the Paget-like phenotype in Msi1-overexpressing transgenic mice. Topical Rapamycin treatment improved extramammary PD-associated symptoms in humans, suggesting mTOR inhibition as a novel therapeutic treatment in PD.
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3,769 |
Is HSPG2 a modifier gene for Marfan syndrome?
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Marfan syndrome (MFS) is a connective tissue disease caused by variants in the FBN1 gene. Nevertheless, other genes influence the manifestations of the disease, characterized by high clinical variability even within families. We mapped modifier loci for cardiovascular and skeletal manifestations in the mg∆(loxPneo) mouse model for MFS and the synthenic loci in the human genome. Corroborating our findings, one of those loci was identified also as a modifier locus in MFS patients. Here, we investigate the HSPG2 gene, located in this region, as a candidate modifier gene for MFS. We show a correlation between Fbn1 and Hspg2 expression in spinal column and aorta in non-isogenic mg∆(loxPneo) mice. Moreover, we show that mice with severe phenotypes present lower expression of Hspg2 than those mildly affected. Thus, we propose that HSPG2 is a strong candidate modifier gene for MFS and its role in modulating disease severity should be investigated in patients.
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3,770 |
CryoEM structure of the tegumented capsid of Epstein-Barr virus
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Epstein-Barr virus (EBV) is the primary cause of infectious mononucleosis and has been shown to be closely associated with various malignancies. Here, we present a complete atomic model of EBV, including the icosahedral capsid, the dodecameric portal and the capsid-associated tegument complex (CATC). Our in situ portal from the tegumented capsid adopts a closed conformation with its channel valve holding the terminal viral DNA and with its crown region firmly engaged by three layers of ring-like dsDNA, which, together with the penton flexibility, effectively alleviates the capsid inner pressure placed on the portal cap. In contrast, the CATCs, through binding to the flexible penton vertices in a stoichiometric manner, accurately increase the inner capsid pressure to facilitate the pressure-driven genome delivery. Together, our results provide important insights into the mechanism by which the EBV capsid, portal, packaged genome and the CATCs coordinately achieve a pressure balance to simultaneously benefit both viral genome retention and ejection.
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3,771 |
Author Correction: Increasing the bactofection capacity of a mammalian expression vector by removal of the f1 ori
| null |
3,772 |
ERCC6L2 promotes DNA orientation-specific recombination in mammalian cells
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Programmed DNA recombination in mammalian cells occurs predominantly in a directional manner. While random DNA breaks are typically repaired both by deletion and by inversion at approximately equal proportions, V(D)J and class switch recombination (CSR) of immunoglobulin heavy chain gene overwhelmingly delete intervening sequences to yield productive rearrangement. What factors channel chromatin breaks to deletional CSR in lymphocytes is unknown. Integrating CRISPR knockout and chemical perturbation screening we here identify the Snf2-family helicase-like ERCC6L2 as one such factor. We show that ERCC6L2 promotes double-strand break end-joining and facilitates optimal CSR in mice. At the cellular levels, ERCC6L2 rapidly engages in DNA repair through its C-terminal domains. Mechanistically, ERCC6L2 interacts with other end-joining factors and plays a functionally redundant role with the XLF end-joining factor in V(D)J recombination. Strikingly, ERCC6L2 controls orientation-specific joining of broken ends during CSR, which relies on its helicase activity. Thus, ERCC6L2 facilitates programmed recombination through directional repair of distant breaks.
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3,773 |
Erratum to: 38(th) EUROPEAN SOCIETY OF NEURORADIOLOGY Diagnostic and Interventional ANNUAL MEETING
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3,774 |
Adverse effects of cannabidiol: a systematic review and meta-analysis of randomized clinical trials
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Cannabidiol (CBD) is being investigated as a treatment for several medical disorders but there is uncertainty about its safety. We conducted the first systematic review and meta-analysis of the adverse effects of CBD across all medical indications. Double-blind randomized placebo-controlled clinical trials lasting ≥7 days were included. Twelve trials contributed data from 803 participants to the meta-analysis. Compared with placebo, CBD was associated with an increased likelihood of withdrawal for any reason (OR 2.61, 95% CI: 1.38–4.96) or due to adverse events (OR 2.65, 95% CI: 1.04–6.80), any serious adverse event (OR 2.30, 95% CI: 1.18–4.48), serious adverse events related to abnormal liver function tests (OR 11.19, 95% CI: 2.09–60.02) or pneumonia (OR 5.37, 95% CI: 1.17–24.65), any adverse event (OR 1.55, 95% CI: 1.03–2.33), adverse events due to decreased appetite (OR 3.56, 95% CI: 1.94–6.53), diarrhoea (OR 2.61, 95% CI: 1.46–4.67), somnolence (OR 2.23, 95% CI: 1.07–4.64) and sedation (OR 4.21, 95% CI: 1.18–15.01). Associations with abnormal liver function tests, somnolence, sedation and pneumonia were limited to childhood epilepsy studies, where CBD may have interacted with other medications such as clobazam and/or sodium valproate. After excluding studies in childhood epilepsy, the only adverse outcome associated with CBD treatment was diarrhoea (OR 5.03, 95% CI: 1.44–17.61). In summary, the available data from clinical trials suggest that CBD is well tolerated and has relatively few serious adverse effects, however interactions with other medications should be monitored carefully. Additional safety data from clinical trials outside of childhood epilepsy syndromes and from studies of over-the-counter CBD products are needed to assess whether the conclusions drawn from clinical trials can be applied more broadly.
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3,775 |
Changes in the corneal thickness and limbus after 1 year of scleral contact lens use
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PURPOSE: To assess the physiological changes in the cornea over time in patients with irregular cornea fitted with Rose K2 XL gas-permeable scleral contact lenses. METHODS: Prospective study of 16 eyes of patients who did not tolerate gas-permeable corneal contact lenses and were fitted with Rose K2 XL scleral lenses. We assessed the central vault and the corneal thickness centrally and at peripheral regions (2 to 5 mm annulus). All these measures were obtained by anterior segment optical coherence tomography. The measurements were taken immediately after fitting the lenses and 1, 6 and 12 months later. Prior to the study and at 1 year, we performed an objective test for diagnosing limbal stem cell deficiency (Limbokit). RESULTS: The mean vault was 201.7 ± 82.3 µm 20 min after fitting the contact lens; 189.4 ± 94.0 µm at 1 month; 165.1 ± 75.9 µm at 6 months and 142.1 ± 76.8 µm at 1 year, the values at 6 and 12 months being significantly different to baseline. After 1 year, the central corneal thickness had increased by 2.3% (IQR = 5.6), but the changes were only significant for the superior thickness. There is no limbal stem cell deficiency after 1 year of scleral contact lens use. CONCLUSIONS: After use of Rose K2 XL scleral contact lenses, the corneal physiology of patients with an irregular cornea remains unchanged, as assessed by corneal thickness measurements and the Limbokit test. In all cases, however, the vault decreased over time.
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3,776 |
Correction: BOADICEA: a comprehensive breast cancer risk prediction model incorporating genetic and nongenetic risk factors
| null |
3,777 |
Erratum to: Survival of Hendra Virus in the Environment: Modelling the Effect of Temperature
| null |
3,778 |
Comment on: ‘Ophthalmology Specialist Trainee Survey in the United Kingdom’. The need to increase familiarity with the management of predictable cataract surgery complications via simulation—ensuring competence to improve confidence
| null |
3,779 |
Correction: Corrigendum: Prediction of CYP2D6 phenotype from genotype across world populations
| null |
3,780 |
Improved therapeutic consistency and efficacy of mesenchymal stem cells expanded with chemically defined medium for systemic lupus erythematosus
| null |
3,781 |
Author Correction: The Apostasia genome and the evolution of orchids
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3,782 |
Unconventional CD45RA+ memory CD8 T cells to control HIV infection during antiretroviral therapy
| null |
3,783 |
Correction: Whole exome sequencing reveals mutations in FAT1 tumor suppressor gene clinically impacting on peripheral T-cell lymphoma not otherwise specified
| null |
3,784 |
Effect of chemogenetic actuator drugs on prefrontal cortex-dependent working memory in nonhuman primates
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The most common chemogenetic neuromodulatory system, designer receptors exclusively activated by designer drugs (DREADDs), uses a non-endogenous actuator ligand to activate a modified muscarinic acetylcholine receptor that is insensitive to acetylcholine. It is crucial in studies using these systems to test the potential effects of DREADD actuators prior to any DREADD transduction, so that effects of DREADDs can be attributed to the chemogenetic system rather than the actuator drug, particularly in experiments using nonhuman primates. We investigated working memory performance after injections of three DREADD actuators, clozapine, olanzapine, and deschloroclozapine, in four male rhesus monkeys tested in a spatial delayed response task before any DREADD transduction took place. Performance at 0.1 mg/kg clozapine and 0.1 mg/kg deschloroclozapine did not differ from vehicle in any of the four subjects. 0.2 mg/kg clozapine impaired working memory function in three of the four monkeys. Two monkeys were impaired after 0.1 mg/kg olanzapine and two were impaired after 0.3 mg/kg deschloroclozapine. We speculate that the unique neuropharmacology of prefrontal cortex function makes the primate prefrontal cortex especially vulnerable to off-target effects of DREADD actuator drugs with affinity for endogenous monoaminergic receptor systems. These findings underscore the importance of within-subject controls for DREADD actuator drugs in the specific tasks under study to confirm that effects following DREADD receptor transduction are not owing to the actuator drug itself. They also suggest that off-target effects of DREADD actuators may limit translational applications of chemogenetic neuromodulation.
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3,785 |
Correction: The landscape of epilepsy-related GATOR1 variants
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3,786 |
Correction: Integrative approach to sporadic Alzheimer’s disease: deficiency of TYROBP in cerebral Aβ amyloidosis mouse normalizes clinical phenotype and complement subnetwork molecular pathology without reducing Aβ burden
| null |
3,787 |
Correction: SSRIs target prefrontal to raphe circuits during development modulating synaptic connectivity and emotional behavior
| null |
3,788 |
Correction: MYC-containing amplicons in acute myeloid leukemia: genomic structures, evolution, and transcriptional consequences
| null |
3,789 |
Development and validation of a measure of comprehension of genomic screening—negative results (CoG-NR)
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To realize the promise of population genomic screening for rare medically actionable conditions, critical challenges in the return of normal/negative results must be understood and overcome. Our study objective was to assess the functioning of a new 13-item measure (CoG-NR) of understanding of and knowledge about normal/negative genomic screening results for three highly actionable conditions: Lynch Syndrome, Hereditary Breast and Ovarian Cancer, and Familial Hypercholesterolemia. Based on our prior research and expert review, we developed CoG-NR and tested how well it functioned using hypothetical scenarios in three Qualtrics surveys. We report on its psychometric properties and performance across the three different conditions. The measure performed similarly for the three conditions. Examinations of item difficulty, internal reliability, and differential item functioning indicate that the items perform well, with statistically significant positive correlations with genomic knowledge, health literacy, and objective numeracy. CoG-NR assesses understanding of normal/negative results for each of the conditions. The next step is to examine its performance among individuals who have actually undergone such tests, and subsequent use in clinical or research situations. The CoG-NR measure holds great promise as a tool to enhance benefits of population genomic screening by bringing to light the prevalence of incorrect interpretation of negative results.
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3,790 |
Comment on: ‘Recent advances in anterior chamber angle imaging’
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3,791 |
Correction: Suppression of interferon gene expression overcomes resistance to MEK inhibition in KRAS-mutant colorectal cancer
| null |
3,792 |
Anthranilic acid from Ralstonia solanacearum plays dual roles in intraspecies signalling and inter-kingdom communication
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Quorum sensing (QS) signals are widely utilized by bacteria to regulate biological functions in response to cell population density. Previous studies have demonstrated that Ralstonia solanacearum employs two different types of QS systems. We report here that anthranilic acid controls important biological functions and the production of QS signals in R. solanacearum. It was demonstrated that the biosynthesis of anthranilic acid is mainly performed by TrpEG. The accumulation of anthranilic acid and the transcription of trpEG occur in a cell density-dependent manner in R. solanacearum. Both the anthranilic acid and TrpEG homologues are conserved in various bacterial species. Moreover, we show that Sporisorium scitamineum sexual mating and hypha formation are strongly inhibited by the addition of exogenous anthranilic acid. Our results suggest that anthranilic acid is important for the physiology of bacteria in addition to its role in inter-kingdom communication.
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3,793 |
Correction: Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnosed diseases
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3,794 |
Relationship between ocular involvement and clinical manifestations, laboratory findings, and coronary artery dilatation in Kawasaki disease
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OBJECTIVES: To assess the incidence of ocular manifestations of Kawasaki disease (KD) in children and to evaluate the relationship between ocular manifestations and the other clinical manifestations, laboratory findings, and echocardiographic findings. METHODS: Complete ophthalmologic examination and echocardiography were performed in 36 patients with KD during the acute phase before starting the treatment. Clinical manifestations and laboratory data including white blood cell (WBC) count, neutrophil-to-lymphocyte ratio, platelet count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were obtained from all the patients. All the clinical and laboratory findings were compared between the group with ocular involvement and the one without ocular involvement. RESULTS: The incidence of bilateral non-exudative conjunctivitis was 63.9%. It was significantly higher in patients with skin rashes (P < 0.05). The incidence of uveitis was 36.1%, which consisted primarily of grade 1+ or 2+ acute anterior uveitis. Neutrophil count and CRP levels were significantly higher in the uveitis group than in the group without uveitis (P < 0.05). Coronary artery dilatation showed significant correlation with uveitis (P < 0.05). Uveitis did not show a significant correlation with other clinical manifestations, ESR, ALT level, AST level, and platelet count (P > 0.05). CONCLUSION: In children with Kawasaki disease, uveitis is associated with coronary artery dilatation, higher neutrophil count, and higher CRP level.
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3,795 |
Alien ectomycorrhizal plants differ in their ability to interact with co-introduced and native ectomycorrhizal fungi in novel sites
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Alien plants represent a potential threat to environment and society. Understanding the process of alien plants naturalization is therefore of primary importance. In alien plants, successful establishment can be constrained by the absence of suitable fungal partners. Here, we used 42 independent datasets of ectomycorrhizal fungal (EcMF) communities associated with alien Pinaceae and Eucalyptus spp., as the most commonly introduced tree species worldwide, to explore the strategies these plant groups utilize to establish symbioses with EcMF in the areas of introduction. We have also determined the differences in composition of EcMF communities associated with alien ectomycorrhizal plants in different regions. While alien Pinaceae introduced to new regions rely upon association with co-introduced EcMF, alien Eucalyptus often form novel interactions with EcMF species native to the region where the plant was introduced. The region of origin primarily determines species composition of EcMF communities associated with alien Pinaceae in new areas, which may largely affect invasion potential of the alien plants. Our study shows that alien ectomycorrhizal plants largely differ in their ability to interact with co-introduced and native ectomycorrhizal fungi in sites of introduction, which may potentially affect their invasive potential.
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3,796 |
Retraction Note: Interferon-mediated antiviral activities of Angelica tenuissima Nakai and its active components
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3,797 |
Correction: BRF1 accelerates prostate tumourigenesis and perturbs immune infiltration
| null |
3,798 |
Prognostic factors for TB-associated uveitis in the Asia-Pacific Region: results of a modified Delphi survey
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BACKGROUND: Prognostic factors for TB-associated uveitis (TBU) remain mostly unknown, due to the challenges in interpretation of patient data. We present consensus list of prognostic factors for resolution of inflammation in TBU, by experts across the Asia-Pacific region. METHODS: We applied a modified Delphi technique to generate consensus on prognostic factors influencing the resolution of inflammation in TB-associated: anterior uveitis (AU), retinal vasculitis (RV), and multifocal serpiginoid choroiditis (MSC). The initial questionnaire was developed through a face-to-face meeting. Sixteen uveitis experts from eleven Asia-Pacific countries were included. A single investigator circulated the questionnaire electronically and received the responses. Participants scored each item on 4-point Likert scale, in three successive rounds. After each round, a number of items were reduced based on response, and summary of responses was provided to participants. At the end of Round 3, items were considered significant if they: (1) achieved a median ≥2, and interquartile range ≤1, and (2) ≥75% of the respondents agreed on whether the item was a positive or negative prognostic factor. RESULTS: Forty-two putative questionnaire items were considered. At the end of Rounds 3, 4, 9, and 8 items in AU, RV, and MSC, respectively, met significance criteria. These included duration of disease, previous corticosteroid/immunosuppressive therapy, co-existent HIV, disease-specific imaging features, multidrug resistant TB, and duration of anti-TB therapy. CONCLUSIONS: Consensus were achieved on multiple ocular and systemic factors that influence resolution of inflammation in TBU. These will form the groundwork for validation in prospective clinical trials.
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3,799 |
Erratum: Autophagy suppresses Ras-driven epithelial tumourigenesis by limiting the accumulation of reactive oxygen species
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