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3,900 |
Cognitive and affective outcomes of genetic counselling in the Netherlands at group and individual level: a personalized approach seems necessary
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We performed a large outcome study at group and individual level in which the goals of genetic counselling were operationalized into cognitive and affective outcomes: empowerment, perceived personal control and anxiety. We then examined which socio-demographic and clinical variables were associated with changes in these outcomes. Data came from 1479 counselees who completed questionnaires (GCOS-18, PPC and STAI) at three time points: before the start of genetic counselling, after the first consultation and after the results of genetic counselling were disclosed. Results showed that at group level empowerment, perceived personal control and anxiety improved significantly after the whole genetic counselling process. Effect-sizes were medium for empowerment and small for the other outcomes. At individual level, 48% of counselees improved in empowerment, 21% in perceived personal control and 17% in anxiety. Around 10% of counselees worsened on all outcomes. Only ‘reason for referral’ and ‘genetic test result’ were significantly associated with changes in outcomes. This study demonstrated improvements among counselees in cognitive and affective outcomes after genetic counselling at group level. However, our results also suggest that there are opportunities for improvement at individual level, as many counselees remained stable and some even worsened on all outcomes. Routine outcome monitoring could help to explore the needs of counselees and could help to identify counselees who worsen.
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3,901 |
Correction: NG2 antigen is involved in leukemia invasiveness and central nervous system infiltration in MLL-rearranged infant B-ALL
| null |
3,902 |
Author Correction: Metagenomic sequencing with spiked primer enrichment for viral diagnostics and genomic surveillance
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3,903 |
Revaluating the relationship between keratoplasty and intraocular lenses
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3,904 |
Correction to: Acute respiratory failure and the kinetics of neutrophil recovery in pediatric hematopoietic cell transplantation: a multicenter study
| null |
3,905 |
Correction: (18)F-FIBT may expand PET for β-amyloid imaging in neurodegenerative diseases
| null |
3,906 |
Correction: Genomic mosaicism in the pathogenesis and inheritance of a Rett syndrome cohort
| null |
3,907 |
Predictive genetic testing in Huntington’s disease: should a neurologist be involved?
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International guidelines on Huntington’s Disease recommend neurological examination in the predictive testing trajectory. Experiences and personal wishes of persons at risk of Huntington’s Disease regarding this topic have never been evaluated. The objective was to provide an overview of the experiences of Dutch at-risk persons, opting for predictive testing, in consulting a neurologist before and after DNA analysis. Persons who were counseled in four Dutch clinics between 2017 and 2019 were retrospectively or prospectively approached for a questionnaire which listed topics as experiences with consultation and personal wishes. From 71 participants, 44 participants visited a neurologist. 41 participants indicated their visit to a neurologist as positive (93.2%). The majority of participants (n = 59) desired consulting a neurologist. Thirty-two participants indicated consultation shortly after (Desired After Group) and twenty-seven before DNA analysis (Desired Before Group) as personal wish. The Desired Before Group consisted of a significantly higher number of participants who actually consulted a neurologist before predictive testing (n = 26) compared with the number of participants who actually consulted a neurologist after DNA analysis in the Desired After Group (n = 11) (p < 0.001). The Desired After Group (n = 19) had a significantly higher number of Huntington’s disease gene expansion carriers compared with the Desired Before Group (n = 5) (p 0.003). Participants are content with consultation. However, persons without the gene expansion still feel the need to get in touch with a neurologist. Therefore, offering a consultation with a neurologist before DNA analysis might be beneficial for all.
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3,908 |
Wdfy1 deficiency impairs Tlr3-mediated immune responses in vivo
| null |
3,909 |
Correction: The induction of core pluripotency master regulators in cancers defines poor clinical outcomes and treatment resistance
| null |
3,910 |
Erratum to: A murine colitis model developed using a combination of dextran sulfate sodium and Citrobacter rodentium
| null |
3,911 |
Correction: PDGFB-expressing mesenchymal stem cells improve human hematopoietic stem cell engraftment in immunodeficient mice
| null |
3,912 |
Acute onset binocular diplopia: a retrospective observational study of 100 consecutive cases managed at a tertiary eye centre in Saudi Arabia
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OBJECTIVE: To evaluate the demography, aetiology and clinical course of acute onset binocular diplopia (AOBD) in patients presented as emergency and managed at the neuroophthalmology clinic of a tertiary eye care centre in Saudi Arabia. PATIENTS AND METHODS: A retrospective review of the medical records of 100 consecutive patients who attended the emergency department of Dhahran Eye Specialist Hospital with isolated, AOBD. The exclusion criteria were: (a) monocular diplopia, (b) binocular diplopia accompanied with neurological deficits other than ocular muscles dysfunction and (c) thyroid eye disease. All patients were followed until resolution of the diplopia or onward referral to another specialty for further management. RESULTS: Male:female ratio was 2:1. Median age of the cohort was 56 years (range 18–90 years). Associated nerve palsy included: abducens nerve (n = 57 patients), oculomotor (n = 32 patients) and trochlear nerve (n = 3 patients). Microvascular ischaemia and ocular myasthenia gravis were two most common pathogenic mechanisms. AOBD resolved spontaneously in 98% of patients. CONCLUSION: AOBD, though an alarming and distressing condition, carries reassuringly good prognosis in majority of patients. High risk factors for vascular disease in Middle-Eastern population are reflected in microvascular aetiology as the major cause.
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3,913 |
Correction: Neurotensin and its receptors mediate neuroendocrine transdifferentiation in prostate cancer
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3,914 |
Modulating microglia activation prevents maternal immune activation induced schizophrenia-relevant behavior phenotypes via arginase 1 in the dentate gyrus
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Prenatal infection during pregnancy increases the risk for developing neuropsychiatric disorders such as schizophrenia. This is linked to an inflammatory microglial phenotype in the offspring induced by maternal immune activation (MIA). Microglia are crucial for brain development and maintenance of neuronal niches, however, whether and how their activation is involved in the regulation of neurodevelopment remains unclear. Here, we used a MIA rodent model in which polyinosinic: polycytidylic acid (poly (I:C)) was injected into pregnant mice. We found fewer parvalbumin positive (PV+) cells and impaired GABAergic transmission in the dentate gyrus (DG), accompanied by schizophrenia-like behavior in the adult offspring. Minocycline, a potent inhibitor of microglia activation, successfully prevented the above-mentioned deficits in the offspring. Furthermore, by using microglia-specific arginase 1 (Arg1) ablation as well as overexpression in DG, we identified a critical role of Arg1 in microglia activation to protect against poly (I:C) imparted neuropathology and altered behavior in offspring. Taken together, our results highlight that Arg1-mediated alternative activation of microglia are potential therapeutic targets for psychiatric disorders induced by MIA.
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3,915 |
Erratum to: Abstracts of the 53rd Annual Meeting of the EASD, Lisbon 2017. Abstract 788: ‘Pharmacokinetics and tolerability of oral semaglutide in subjects with renal impairment’
| null |
3,916 |
Correction: Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia
| null |
3,917 |
Correction: Management of nystagmus in children: a review of the literature and current practice in UK specialist services
| null |
3,918 |
Correction: Association of ACE2 genetic polymorphisms with hypertension-related target organ damages in south Xinjiang
| null |
3,919 |
Trainee experience with capsular tension rings in Scotland—the need for structured simulation exposure to surgical adjuncts
| null |
3,920 |
A pan-cancer blueprint of the heterogeneous tumor microenvironment revealed by single-cell profiling
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The stromal compartment of the tumor microenvironment consists of a heterogeneous set of tissue-resident and tumor-infiltrating cells, which are profoundly moulded by cancer cells. An outstanding question is to what extent this heterogeneity is similar between cancers affecting different organs. Here, we profile 233,591 single cells from patients with lung, colorectal, ovary and breast cancer (n = 36) and construct a pan-cancer blueprint of stromal cell heterogeneity using different single-cell RNA and protein-based technologies. We identify 68 stromal cell populations, of which 46 are shared between cancer types and 22 are unique. We also characterise each population phenotypically by highlighting its marker genes, transcription factors, metabolic activities and tissue-specific expression differences. Resident cell types are characterised by substantial tissue specificity, while tumor-infiltrating cell types are largely shared across cancer types. Finally, by applying the blueprint to melanoma tumors treated with checkpoint immunotherapy and identifying a naïve CD4(+) T-cell phenotype predictive of response to checkpoint immunotherapy, we illustrate how it can serve as a guide to interpret scRNA-seq data. In conclusion, by providing a comprehensive blueprint through an interactive web server, we generate the first panoramic view on the shared complexity of stromal cells in different cancers.
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3,921 |
Correction: Effectiveness of plasma lyso-Gb3 as a biomarker for selecting high-risk patients with Fabry disease from multispecialty clinics for genetic analysis
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3,922 |
Parallel reductive genome evolution in Desulfovibrio ectosymbionts independently acquired by Trichonympha protists in the termite gut
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Several Trichonympha protist species in the termite gut have independently acquired Desulfovibrio ectosymbionts in apparently different stages of symbiosis. Here, we obtained the near-complete genome sequence of Desulfovibrio phylotype ZnDsv-02, which attaches to the surface of Trichonympha collaris cells, and compared it with a previously obtained genome sequence of ‘Candidatus Desulfovibrio trichonymphae’ phylotype Rs-N31, which is almost completely embedded in the cytoplasm of Trichonympha agilis. Single-nucleotide polymorphism analysis indicated that although Rs-N31 is almost clonal, the ZnDsv-02 population on a single host cell is heterogeneous. Despite these differences, the genome of ZnDsv-02 has been reduced to 1.6 Mb, which is comparable to that of Rs-N31 (1.4 Mb), but unlike other known ectosymbionts of protists with a genome similar in size to their free-living relatives. Except for the presence of a lactate utilization pathway, cell-adhesion components and anti-phage defense systems in ZnDsv-02, the overall gene-loss pattern between the two genomes is very similar, including the loss of genes responsive to environmental changes. Our study suggests that genome reduction can occur in ectosymbionts, even when they can be transmitted horizontally and obtain genes via lateral transfer, and that the symbiont genome size depends heavily on their role in the symbiotic system.
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3,923 |
The role of dopamine dysregulation and evidence for the transdiagnostic nature of elevated dopamine synthesis in psychosis: a positron emission tomography (PET) study comparing schizophrenia, delusional disorder, and other psychotic disorders
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There have been few studies performed to examine the pathophysiological differences between different types of psychosis, such as between delusional disorder (DD) and schizophrenia (SZ). Notably, despite the different clinical characteristics of DD and schizophrenia (SZ), antipsychotics are deemed equally effective pharmaceutical treatments for both conditions. In this context, dopamine dysregulation may be transdiagnostic of the pathophysiology of psychotic disorders such as DD and SZ. In this study, an examination is made of the dopamine synthesis capacity (DSC) of patients with SZ, DD, other psychotic disorders, and the DSC of healthy subjects. Fifty-four subjects were recruited to the study, comprising 35 subjects with first-episode psychosis (11 DD, 12 SZ, 12 other psychotic disorders) and 19 healthy controls. All received an (18)F-DOPA positron emission tomography (PET)/magnetic resonance (MR) scan to measure DSC (K(occ;30–60) value) within 1 month of starting antipsychotic treatment. Clinical assessments were also made, which included Positive and Negative Syndrome Scale (PANSS) measurements. The mean K(occ;30–60) was significantly greater in the caudate region of subjects in the DD group (ES = 0.83, corrected p = 0.048), the SZ group (ES = 1.40, corrected p = 0.003) and the other psychotic disorder group (ES = 1.34, corrected p = 0.0045), compared to that of the control group. These data indicate that DD, SZ, and other psychotic disorders have similar dysregulated mechanisms of dopamine synthesis, which supports the utility of abnormal dopamine synthesis in transdiagnoses of these psychotic conditions.
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3,924 |
s-HBEGF/SIRT1 circuit-dictated crosstalk between vascular endothelial cells and keratinocytes mediates sorafenib-induced hand–foot skin reaction that can be reversed by nicotinamide
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Hand–foot skin reaction (HFSR), among the most significant adverse effects of sorafenib, has been limiting the clinical benefits of this frontline drug in treating various malignant tumors. The mechanism underlying such toxicity remains poorly understood, hence the absence of effective intervention strategies. In the present study, we show that vascular endothelial cells are the primary cellular target of sorafenib-induced HFSR wherein soluble heparin-binding epidermal growth factor (s-HBEGF) mediates the crosstalk between vascular endothelial cells and keratinocytes. Mechanistically, s-HBEGF released from vascular endothelial cells activates the epidermal growth factor receptor (EGFR) on keratinocytes and promotes the phosphorylation of c-Jun N-terminal kinase 2 (JNK2), which stabilizes sirtuin 1 (SIRT1), an essential keratinization inducer, and ultimately gives rise to HFSR. The administration of s-HBEGF in vivo could sufficiently induce hyper-keratinization without sorafenib treatment. Furthermore, we report that HBEGF neutralization antibody, Sirt1 knockdown, and a classic SIRT1 inhibitor nicotinamide could all significantly reduce the sorafenib-induced HFSR in the mouse model. It is noteworthy that nicotinic acid, a prodrug of nicotinamide, could substantially reverse the sorafenib-induced HFSR in ten patients in a preliminary clinical study. Collectively, our findings reveal the mechanism of vascular endothelial cell-promoted keratinization in keratinocytes and provide a potentially promising therapeutic strategy for the treatment of sorafenib-induced HFSR.
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3,925 |
Comment on: ‘You’ve got dry macular degeneration, end of story: a qualitative study into the experience of living with non-neovascular age-related macular degeneration’
| null |
3,926 |
Author Correction: USP29 maintains the stability of cGAS and promotes cellular antiviral responses and autoimmunity
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3,927 |
Erratum: Host and viral traits predict zoonotic spillover from mammals
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3,928 |
Unconventional secretion: cargo channeling by TMED10
| null |
3,929 |
Erratum to: Abstracts: XXXI International Congress of the IAP and 28th Congress of the ESP
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3,930 |
Correction: Corrigendum: Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing
| null |
3,931 |
Erratum: Functional proteomics identifies miRNAs to target a p27/Myc/phospho-Rb signature in breast and ovarian cancer
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3,932 |
Genetic aspects of congenital nephrotic syndrome: a consensus statement from the ERKNet–ESPN inherited glomerulopathy working group
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Congenital nephrotic syndrome (CNS) is a heterogeneous group of disorders presenting with massive proteinuria within the first 3 months of life almost inevitably leading to end-stage kidney disease. The Work Group for the European Reference Network for Kidney Diseases (ERKNet) and the European Society for Pediatric Nephrology (ESPN) has developed consensus statement on genetic aspects of CNS diagnosis and management. The presented expert opinion recommends genetic diagnostics as the key diagnostic test to be ordered already during the initial evaluation of the patient, discusses which phenotyping workup should be performed and presents known genotype–phenotype correlations.
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3,933 |
Correction: gr/gr deletion predisposes to testicular germ cell tumour independently from altered spermatogenesis: results from the largest European study
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3,934 |
Correction to: Hybridization capture-based next-generation sequencing reliably detects FLT3 mutations and classifies FLT3-internal tandem duplication allelic ratio in acute myeloid leukemia: a comparative study to standard fragment analysis
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3,935 |
Publisher Correction: Past and future spread of the arbovirus vectors Aedes aegypti and Aedes albopictus
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3,936 |
Household cleaning product-related ocular exposures reported to the United States poison control centres
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BACKGROUND/OBJECTIVES: To investigate ocular exposures associated with household cleaning products in the United States. SUBJECTS/METHODS: A retrospective analysis of ocular exposures associated with household cleaning products was conducted using data from the National Poison Data System from 2000 through 2016. RESULTS: From January 2000 through December 2016, poison control centres in the United States received 319,508 calls for household cleaning product-related ocular exposures, averaging 18,795 exposures annually. The annual frequency of exposures decreased significantly by 28.8% during the study period. The rate of exposures per 100,000 US residents was 28.4 among young children (<6 years), 4.8 among older children (6–12 years), 4.2 among teenagers (13–19 years), and 4.2 among adults (≥20 years); children 2 years old had the highest rate of exposure (62.8). Bleaches (25.9%), wall/floor/tile cleaners (13.4%), disinfectants (10.8%), laundry detergents (6.1%), and glass cleaners (5.3%) were the non-miscellaneous product subcategories most commonly associated with ocular exposures. The product subcategories associated with the greatest proportion of major medical outcomes were drain cleaners (1.4%), oven cleaners (1.1%), and automatic dishwasher detergents (0.4%). CONCLUSIONS: On average, the United States poison control centres received approximately two reports of household cleaning product-related ocular exposures every hour during the 17-year study period. Although the annual number and rate of exposures declined during this time, the number of these exposures remains high, especially among young children, underscoring the need for additional prevention efforts. Contrary to the overall trend, ocular exposures to laundry detergent packets have increased significantly and merit special preventive action.
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3,937 |
Author Correction: Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia
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3,938 |
Correction: Recent development of AAV-based gene therapies for inner ear disorders
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3,939 |
Erratum: Extended survival and reduced risk of AML progression in erythroid-responsive lenalidomide-treated patients with lower-risk del(5q) MDS
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3,940 |
USP29 maintains the stability of cGAS and promotes cellular antiviral responses and autoimmunity
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Cyclic GMP-AMP synthase (cGAS) is an essential sensor of cytosolic DNA and critically mediates innate immune responses and autoimmunity. Modulating the activity and stability of cGAS provides potential strategies for treating viral or autoimmune diseases. Here, we report that ubiquitin-specific protease 29 (USP29) deubiquitinates and stabilizes cGAS and promotes cellular antiviral responses and autoimmunity. Knockdown or knockout of USP29 severely impairs Herpes simplex virus 1 (HSV-1)- or cytosolic DNA-induced expression of type I interferons (IFNs) and proinflammatory cytokines. Consistently, Usp29(m/m) mice produce decreased type I IFNs and proinflammatory cytokines after HSV-1 infection and are hypersensitive to HSV-1 infection compared to the wild-type littermates. In addition, genetic ablation of USP29 in Trex1(−/−) mice eliminated the detectable pathological and molecular autoimmune phenotypes. Mechanistically, USP29 constitutively interacts with cGAS, deconjugates K48-linked polyubiquitin chains from cGAS and stabilizes cGAS in uninfected cells or after HSV-1 infection. Reconstitution of cGAS into Usp29(−/−) cells fully rescues type I IFN induction and cellular antiviral responses after HSV-1 infection. Our findings thus reveal a critical role of USP29 in the innate antiviral responses against DNA viruses and autoimmune diseases and provide insight into the regulation of cGAS.
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3,941 |
Correction: Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa
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3,942 |
Three-dimensional bioprinted glioblastoma microenvironments model cellular dependencies and immune interactions
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Brain tumors are dynamic complex ecosystems with multiple cell types. To model the brain tumor microenvironment in a reproducible and scalable system, we developed a rapid three-dimensional (3D) bioprinting method to construct clinically relevant biomimetic tissue models. In recurrent glioblastoma, macrophages/microglia prominently contribute to the tumor mass. To parse the function of macrophages in 3D, we compared the growth of glioblastoma stem cells (GSCs) alone or with astrocytes and neural precursor cells in a hyaluronic acid-rich hydrogel, with or without macrophage. Bioprinted constructs integrating macrophage recapitulate patient-derived transcriptional profiles predictive of patient survival, maintenance of stemness, invasion, and drug resistance. Whole-genome CRISPR screening with bioprinted complex systems identified unique molecular dependencies in GSCs, relative to sphere culture. Multicellular bioprinted models serve as a scalable and physiologic platform to interrogate drug sensitivity, cellular crosstalk, invasion, context-specific functional dependencies, as well as immunologic interactions in a species-matched neural environment.
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3,943 |
Erratum to: JAK–STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects
| null |
3,944 |
Erratum zu: Impfen bei Immundefizienz: Anwendungshinweise zu den von der Ständigen Impfkommission empfohlenen Impfungen. (III) Impfen bei hämatologischen und onkologischen Erkrankungen (antineoplastische Therapie, Stammzelltransplantation), Organtransplantation und Asplenie
| null |
3,945 |
Correction: Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia
| null |
3,946 |
Longitudinal follow-up of dome-shaped macula
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BACKGROUND/OBJECTIVES: To determine if the presence of sub-retinal fluid (SRF) was associated with reduced vision in dome-shaped macula (DSM), and to assess its effect and response to treatment during follow-up. METHODS: Patients were identified retrospectively. Baseline and follow-up data were recorded. The diagnosis of DSM, and presence or absence of SRF and intra-retinal fluid (IRF) was confirmed using Spectral Domain-Optical Coherence Tomography (SD-OCT). Decisions to treat oedema were based on clinician preference. RESULTS: 193 eyes of 106 patients (71 female) were confirmed to have DSM. Overall mean duration of follow-up for this cohort was 3.5 years. Mean BRVA for all eyes at baseline was 0.38 (range: −0.20 to ‘light perception’). A significant difference was noted in mean baseline BRVA between those eyes with SRF compared with those without SRF at baseline (0.48 vs. 0.31, p < 0.001). Intra-retinal fluid moderately correlated with poorer baseline BRVA (r = 0.31, p < 0.003). No significant change in BRVA was noted during follow-up. No significant effect of treatment on BRVA was observed. CONCLUSIONS: The presence of SRF at baseline was associated with poorer vision. Vision appears to remain stable irrespective of the presence or absence of SRF at baseline. The treatments administered in this cohort did not affect final vision or SRF.
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3,947 |
Reconstruction of cell spatial organization from single-cell RNA sequencing data based on ligand-receptor mediated self-assembly
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Single-cell RNA sequencing (scRNA-seq) has revolutionized transcriptomic studies by providing unprecedented cellular and molecular throughputs, but spatial information of individual cells is lost during tissue dissociation. While imaging-based technologies such as in situ sequencing show great promise, technical difficulties currently limit their wide usage. Here we hypothesize that cellular spatial organization is inherently encoded by cell identity and can be reconstructed, at least in part, by ligand-receptor interactions, and we present CSOmap, a computational tool to infer cellular interaction de novo from scRNA-seq. We show that CSOmap can successfully recapitulate the spatial organization of multiple organs of human and mouse including tumor microenvironments for multiple cancers in pseudo-space, and reveal molecular determinants of cellular interactions. Further, CSOmap readily simulates perturbation of genes or cell types to gain novel biological insights, especially into how immune cells interact in the tumor microenvironment. CSOmap can be a widely applicable tool to interrogate cellular organizations based on scRNA-seq data for various tissues in diverse systems.
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3,948 |
Correction to: Povidone iodine gargle and mouthwash
| null |
3,949 |
Correction to: Don’t Drive Blind: Driving Pressure to Optimize Ventilator Management in ECMO
| null |
3,950 |
Generation of human hepatocytes from extended pluripotent stem cells
| null |
3,951 |
Publisher Correction: Looking forward 25 years: the future of medicine
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3,952 |
NPP statement on racism, discrimination, and abuse of power
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3,953 |
Correlation of serum amyloid A levels, clinical manifestations, treatment, and disease activity in patients with acute anterior uveitis
|
PURPOSE: To investigate the association between serum amyloid A (SAA) protein and the clinical features of acute anterior uveitis (AAU), and to evaluate the disease activity and treatment effect in relation to SAA levels. METHODS: AAU patients and healthy individuals were recruited from October 2016 to August 2017 at the Department of Uveitis, in the Eye Hospital of Wenzhou Medical University. Related demographic, clinical characteristics, and therapeutic data were analyzed. RESULTS: One hundred and eight AAU patients and 18 healthy controls were included in this study. Serum SAA levels in AAU patients were significantly higher than those of healthy controls (p all < 0.0001). Significantly higher SAA levels were found in AS(+)AAU patients than those in AS(−)AAU patients (p < 0.05). SAA levels were also significantly higher in patients with HLA-B27(+)AAU compared with those with HLA-B27(−)AAU (p < 0.05). Furthermore, in each of the AAU subgroups, higher SAA levels were observed in the active state than those in the inactive state (p all < 0.05). In addition, SAA levels were positively correlated to anterior chamber cell counts (r = 0.492, p < 0.0001). ROC curve analysis revealed that SAA had an AUC value of 0.727 for detecting active inflammation (Youden’s index = 0.38). SAA decreased with effective treatments (p = 0.0002). CONCLUSION: Serum levels of SAA were elevated in AAU patients. The increased levels of SAA were correlated with AS and HLA-B27 status. SAA levels were also positively correlated to disease activity and decreased with effective treatments. These findings suggest that SAA is associated with AAU, with a potential role in monitoring inflammatory processes and assessing the efficacy of therapy.
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3,954 |
Who ever heard of 16p11.2 deletion syndrome? Parents’ perspectives on a susceptibility copy number variation syndrome
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Chromosomal microarray analysis is an important diagnostic tool to identify copy number variations (CNV). Some of the CNVs affect susceptibility regions, which means that deletions or duplications in these regions have partial penetrance and often give an increased risk for a spectrum of neurocognitive disorders. Not much is known about the impact of rare CNV susceptibility syndromes on the life of patients or their parents. In this study, we focus on one specific susceptibility CNV disorder, 16p11.2 deletion syndrome. This rare condition is characterised by an increased risk of mild intellectual disability, autism spectrum disorder, epilepsy, and obesity. We aimed to explore the impact of such a disorder on the family members involved in the daily care of children with this syndrome. Three focus group discussions were held with 23 Dutch (grand)parents. Thematic analysis was performed by two independent researchers. The following five themes emerged: (1) the end of a diagnostic odyssey and response to the diagnosis, (2) after the diagnosis—life with a child with 16p11.2 deletion syndrome, (3) access to medical care and support services, (4) nobody knows what 16p11.2 deletion syndrome is, and (5) future perspective—ideal care. The participants experienced a lack of knowledge among involved professionals. Together with the large variability of the syndrome, this led to fragmented care and unfulfilled needs regarding healthcare, social, and/or educational assistance. Care for children with a CNV susceptibility syndrome could be improved by a multidisciplinary approach or central healthcare professional, providing education and information for all involved professionals.
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3,955 |
The exhaustive genomic scan approach, with an application to rare-variant association analysis
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Region-based genome-wide scans are usually performed by use of a priori chosen analysis regions. Such an approach will likely miss the region comprising the strongest signal and, thus, may result in increased type II error rates and decreased power. Here, we propose a genomic exhaustive scan approach that analyzes all possible subsequences and does not rely on a prior definition of the analysis regions. As a prime instance, we present a computationally ultraefficient implementation using the rare-variant collapsing test for phenotypic association, the genomic exhaustive collapsing scan (GECS). Our implementation allows for the identification of regions comprising the strongest signals in large, genome-wide rare-variant association studies while controlling the family-wise error rate via permutation. Application of GECS to two genomic data sets revealed several novel significantly associated regions for age-related macular degeneration and for schizophrenia. Our approach also offers a high potential to improve genome-wide scans for selection, methylation, and other analyses.
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3,956 |
Drought and plant litter chemistry alter microbial gene expression and metabolite production
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Drought represents a significant stress to microorganisms and is known to reduce microbial activity and organic matter decomposition in Mediterranean ecosystems. However, we lack a detailed understanding of the drought stress response of microbial decomposers. Here we present metatranscriptomic and metabolomic data on the physiological response of in situ microbial communities on plant litter to long-term drought in Californian grass and shrub ecosystems. We hypothesised that drought causes greater microbial allocation to stress tolerance relative to growth pathways. In grass litter, communities from the decade-long ambient and reduced precipitation treatments had distinct taxonomic and functional profiles. The most discernable physiological signatures of drought were production or uptake of compatible solutes to maintain cellular osmotic balance, and synthesis of capsular and extracellular polymeric substances as a mechanism to retain water. The results show a clear functional response to drought in grass litter communities with greater allocation to survival relative to growth that could affect decomposition under drought. In contrast, communities on chemically more diverse and complex shrub litter had smaller physiological differences in response to long-term drought but higher investment in resource acquisition traits across precipitation treatments, suggesting that the functional response to drought is constrained by substrate quality. Our findings suggest, for the first time in a field setting, a trade off between microbial drought stress tolerance, resource acquisition and growth traits in plant litter microbial communities.
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3,957 |
Correction: Toosendanin demonstrates promising antitumor efficacy in osteosarcoma by targeting STAT3
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3,958 |
Orbital mycoses in an adult subtropical population
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BACKGROUND/OBJECTIVES: To report the spectrum of fungal infections involving the orbit encountered in an Australian subtropical population with respect to presentation, host risk factors, involved pathogens, treatment and outcomes. SUBJECTS/METHODS: A retrospective chart review was performed on all adult patients with orbital mycosis treated by the senior author (TJS) from 1986 to 2017 in a tertiary setting. RESULTS: Thirty cases of fungal infection involving the orbit were included in this case series. Of these, 26 patients had invasive disease and four patients had non-invasive disease. Causative organisms included mucormycosis (16), aspergillus (8) and other fungi (7). Common risk factors included haematological disorders or malignancy, neutropenia, corticosteroid use and diabetes mellitus. Mucormycosis in three immunocompetent patients was caused by Apophysomyces elegans. Orbital apex syndrome was observed in approximately one third of patients at initial ophthalmological assessment. Amphotericin B was used in most cases of mucormycosis, while there was a more varied spectrum of anti-fungal use in other fungal infections. Seven patients with mucormycosis proceeded to orbital exenteration with a survival rate of 43%. No patients with other orbital fungal infections were exenterated. CONCLUSIONS: Orbital mycoses are not only opportunistic but true pathogenic infections. While initial symptoms may be varied, the development of orbital apex syndrome should raise suspicion for this condition, regardless of patient immune status or age. Survival and visual outcomes are often poor with invasive disease. Multidisciplinary team management with early orbital specialist involvement is essential.
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3,959 |
Publisher Correction: The UMBRELLA SIOP–RTSG 2016 Wilms tumour pathology and molecular biology protocol
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3,960 |
Clinical outcomes and aetiology of fourth cranial nerve palsy with acute vertical diplopia in adults
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BACKGROUND: We investigated the clinical outcomes of fourth cranial nerve (CN4) palsy with acute vertical diplopia in adults. METHODS: A total of 80 patients with acute CN4 palsy who underwent at least 3 months of follow-up were included in this study. We retrospectively investigated the aetiology, rate of recovery, and factors associated with recovery between March 2016 and January 2019. RESULTS: The average age of patients with CN4 palsy was about 60 years, and the duration of recovery was 1.5 months: 48 (60.0%) patients had a vascular aetiology and 17 (21.3%) patients had a trauma history. Brain lesions were found in four (5.0%) patients and decompensated cause accounted for four (5.0%) cases. Among the total of 80 patients, 13 (16.3%) failed to completely recover. Non-isolated CN4 palsy with other cranial nerve palsies were recorded in seven cases. The comparison between recovery and non-recovery groups showed that initial deviation angle, aetiology, fundus extorsion, and head tilt status were significantly different factors. CONCLUSION: The recovery rate of acute CN4 palsy was about 80% and duration of recovery was 1.5 months. However, the varying rates and duration of recovery was presented according to aetiology thus we should consider the prognosis by aetiology.
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3,961 |
Soluble cytokine receptor levels in aqueous humour of patients with specific autoimmune uveitic entities: sCD30 is a biomarker of granulomatous uveitis
|
PURPOSE: Soluble cytokine receptors are potential biomarkers for immune activation and have a promising potential as immunotherapeutic agents. We investigated the levels of soluble cytokine receptors in aqueous humour (AH) samples from patients with specific autoimmune uveitic entities. METHODS: Patients with active uveitis associated with Behçet’s disease (BD) (n = 13), sarcoidosis (n = 8), HLA-B27-related inflammation (n = 12), Vogt–Koyanagi–Harada (VKH) disease (n = 12) and control subjects (n = 9) were included. AH samples were analyzed with the use of multiplex assays for the proinflammatory cytokine tumour necrosis factor (TNF)-α and the soluble cytokine receptors sCD30, sCD163, sgp130, sIL-6 receptor-α (sIL-6R), sTNFRI and sTNFRII. RESULTS: TNF-α and soluble cytokine receptor AH levels were significantly higher in uveitis patients (n = 45) compared with controls (n = 9). When nongranulomatous uveitis (BD and HLA-B27-associated uveitis) was compared with granulomatous uveitis (sarcoidosis and VKH disease), the levels of sCD30 and sTNFRI/TNF-α and sTNFRII/TNF-α ratios were significantly enhanced in granulomatous uveitis. Finally, when comparing the profile in the specific uveitis entities, sCD30 levels were highest in patients with VKH disease. sgp130, sCD163, sIL-6R, sTNFRI and sTNFRII did not differ significantly between the four different clinical uveitic subgroups. CONCLUSIONS: Soluble cytokine receptors are significantly upregulated in autoimmune uveitis. CD30(+) T cells might contribute to the inflammatory process in granulomatous uveitis, particularly in VKH disease. Granulomatous uveitis is also characterized by significantly higher sTNFRs/TNF-α ratios than nongranulomatous uveitis.
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3,962 |
Erratum: Statin-induced expression change of INSIG1 in lymphoblastoid cell lines correlates with plasma triglyceride statin response in a sex-specific manner
| null |
3,963 |
Correction: Epalrestat, an Aldose Reductase Inhibitor, Restores Erectile Function in Streptozocin-induced Diabetic Rats
| null |
3,964 |
Correction: Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation
| null |
3,965 |
Correction: IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients
| null |
3,966 |
Judging in the genomic era: judges’ genetic knowledge, confidence and need for training
|
Genetic information is increasingly used in many contexts, including health, insurance, policing and sentencing—with numerous potential benefits and risks. Protecting from the related risks requires updates to laws and procedures by justice systems. These updates depend to a large extent on what the key stakeholders—the judiciary—know and think about the use of genetic information. This study used a battery of 25 genetic knowledge items to collect data from 73 supreme court judges from the same country (Romania) on their knowledge of genetic information. Their responses were compared with those of two other groups: lawyers (but not judges; N = 94) and non-lawyers (N = 116) from the same country. The data were collected at approximately the same time from the three groups. The judges’ results were also compared to the results obtained from a general population data collection (N = 5310). The results showed that: (1) judges had overall better knowledge of genetics than the other groups, but their knowledge was uneven across different genetic concepts; (2) judges were overall more confident in their knowledge than the other two groups, but their confidence was quite low; and (3) the correlation between knowledge and confidence was moderate for judges, weak for lawyers and not significant for non-lawyers. Finally, 100% of the judges agreed that information on gene-environment processes should be included in judges’ training. Increasing genetic expertise of the justice stakeholders is an important step towards achieving adequate legal protection against genetic data misuse.
|
3,967 |
Correction: Diabetic retinopathy and diabetic macular oedema pathways and management: UK Consensus Working Group
| null |
3,968 |
Correction: PIM2-mediated phosphorylation of hexokinase 2 is critical for tumor growth and paclitaxel resistance in breast cancer
| null |
3,969 |
Correction: Corrigendum: Distributive justice, diversity, and inclusion in precision medicine: what will success look like?
| null |
3,970 |
Medium-coverage DNA sequencing in the design of the genetic association study
|
DNA sequencing is a widely used tool in genetic association study. Sequencing cost remains a major concern in sequencing-based study, although the application of next generation sequencing has dramatically decreased the sequencing cost and increased the efficiency. The choice of sequencing depth and the sequencing sample size will largely determine the final study investment and performance. Many studies have been conducted to find a cost-effective design of sequencing depth that can achieve certain sequencing accuracy using minimal sequencing cost. The strategies previously studied can be classified into two groups: (1) single-stage to sequence all the samples using either high (>~30×) or low (<~10×) sequencing depth; and (2) two-stage to sequence an affordable number of individuals at a high-coverage followed by a large sample of low-coverage sequencing. However, limited studies examined the performance of the medium-coverage (10–30×) sequencing depth for a genetic association study, where the optimum sequencing depth may exist. In this study, using a published simulation framework, we comprehensively compared the medium-coverage sequencing (MCS) to the single- and two-stage high/low-coverage sequencing in terms of the power and type I error of the variant discovery and association testing. We found, given certain sequencing effort, MCS yielded a comparable discovery power and better type I error control compared with the best (highest power) scenarios using other high- and low-coverage single-stage or two-stage designs. However, MCS was not as competent as other designs with respect to the association power, especially for the rare variants and when the sequencing investment was limited.
|
3,971 |
Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide
|
Previously we reported the identification of a homozygous COL27A1 (c.2089G>C; p.Gly697Arg) missense variant and proposed it as a founder allele in Puerto Rico segregating with Steel syndrome (STLS, MIM #615155); a rare osteochondrodysplasia characterized by short stature, congenital bilateral hip dysplasia, carpal coalitions, and scoliosis. We now report segregation of this variant in five probands from the initial clinical report defining the syndrome and an additional family of Puerto Rican descent with multiple affected adult individuals. We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape. Characterization of the in vivo murine model shows abnormal collagen deposition in the extracellular matrix and disorganization of the proliferative zone of the growth plate. We report additional COL27A1 pathogenic variant alleles identified in unrelated consanguineous Turkish kindreds suggesting Clan Genomics and identity-by-descent homozygosity contributing to disease in this population. The hypothesis that carrier states for this autosomal recessive osteochondrodysplasia may contribute to common complex traits is further explored in a large clinical population cohort. Our findings augment our understanding of COL27A1 biology and its role in skeletal development; and expand the functional allelic architecture in this gene underlying both rare and common disease phenotypes.
|
3,972 |
T-cell expression of Bruton’s tyrosine kinase promotes autoreactive T-cell activation and exacerbates aplastic anemia
|
The role of Bruton’s tyrosine kinase (BTK) in BCR signaling is well defined, and BTK is involved in B-cell development, differentiation, and malignancies. However, the expression of Btk in T cells and its role in T-cell function remain largely unknown. Here, we unexpectedly found high expression and activation of BTK in T cells. Deficiencies in BTK resulted in the impaired activation and proliferation of autoreactive T cells and ameliorated bone marrow failure (BMF) in aplastic anemia. Mechanistically, BTK is activated after TCR engagement and then phosphorylates PLCγ1, thus promoting T-cell activation. Treatment with acalabrutinib, a selective BTK inhibitor, decreased T-cell proliferation and ameliorated BMF in mice with aplastic anemia. Our results demonstrate an unexpected role of BTK in optimal T-cell activation and in the pathogenesis of autoimmune aplastic anemia, providing insights into the molecular regulation of T-cell activation and the pathogenesis of T-cell-mediated autoimmune disease.
|
3,973 |
Validation of a nicotine vapor self-administration model in rats with relevance to electronic cigarette use
|
The debate about electronic cigarettes is dividing healthcare professionals, policymakers, manufacturers, and communities. A key limitation in our understanding of the cause and consequences of vaping is the lack of animal models of nicotine vapor self-administration. Here, we developed a novel model of voluntary electronic cigarette use in rats using operant behavior. We found that rats voluntarily exposed themselves to nicotine vapor to the point of reaching blood nicotine levels that are similar to humans. The level of responding on the active (nicotine) lever was similar to the inactive (air) lever and lower than the active lever that was associated with vehicle (polypropylene glycol/glycerol) vapor, suggesting low positive reinforcing effects and low nicotine vapor discrimination. Lever pressing behavior with nicotine vapor was pharmacologically prevented by the α4β2 nicotinic acetylcholine receptor partial agonist and α7 receptor full agonist varenicline in rats that self-administered nicotine but not vehicle vapor. Moreover, 3 weeks of daily (1 h) nicotine vapor self-administration produced addiction-like behaviors, including somatic signs of withdrawal, allodynia, anxiety-like behavior, and relapse-like behavior after 3 weeks of abstinence. Finally, 3 weeks of daily (1 h) nicotine vapor self-administration produced cardiopulmonary abnormalities and changes in α4, α3, and β2 nicotinic acetylcholine receptor subunit mRNA levels in the nucleus accumbens and medial prefrontal cortex. These findings validate a novel animal model of nicotine vapor self-administration in rodents with relevance to electronic cigarette use in humans and highlight the potential addictive properties and harmful effects of chronic nicotine vapor self-administration.
|
3,974 |
The microbiome of alpine snow algae shows a specific inter-kingdom connectivity and algae-bacteria interactions with supportive capacities
|
Mutualistic interactions within microbial assemblages provide a survival strategy under extreme conditions; however, little is known about the complexity of interaction networks in multipartite, free-living communities. In the present study, the interplay within algae-dominated microbial communities exposed to harsh environmental influences in the Austrian Alps was assessed in order to reveal the interconnectivity of eukaryotic and prokaryotic inhabitants. All analyzed snowfields harbored distinct microbial communities. Network analyses revealed that mutual exclusion prevailed among microalgae in the alpine environment, while bacteria were mainly positively embedded in the interaction networks. Especially members of Proteobacteria, with a high prevalence of Oxalobacteraceae, Pseudomonadaceae, and Sphingomonadaceae showed genus-specific co-occurrences with distinct microalgae. Co-cultivation experiments with algal and bacterial isolates confirmed beneficial interactions that were predicted based on the bioinformatic analyses; they resulted in up to 2.6-fold more biomass for the industrially relevant microalga Chlorella vulgaris, and up to 4.6-fold increase in biomass for the cryophilic Chloromonas typhlos. Our findings support the initial hypothesis that microbial communities exposed to adverse environmental conditions in alpine systems harbor inter-kingdom supportive capacities. The insights into mutualistic inter-kingdom interactions and the ecology of microalgae within complex microbial communities provide explanations for the prevalence and resilience of such assemblages in alpine environments.
|
3,975 |
Correction to: Critical Care Canada Forum 2019 Abstracts
| null |
3,976 |
Correction to: Physical activity intensity, bout-duration, and cardiometabolic risk markers in children and adolescents
| null |
3,977 |
Correction to: Socioeconomic inequalities in childhood-to-adulthood BMI tracking in three British birth cohorts
| null |
3,978 |
Cancer-host battles: measures and countermeasures in radiation-induced caspase activation and tumor immunogenicity
| null |
3,979 |
Correction: Corrigendum: Structure and functions of angiotensinogen
| null |
3,980 |
Author Correction: The genome of Prasinoderma coloniale unveils the existence of a third phylum within green plants
| null |
3,981 |
Correction: Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond
| null |
3,982 |
Using prefrontal transcranial direct current stimulation (tDCS) to enhance proactive cognitive control in schizophrenia
|
The goal of this study was to use transcranial direct current stimulation (tDCS) to examine the role of the prefrontal cortex (PFC) in neural oscillatory activity associated with proactive cognitive control in schizophrenia. To do so, we tested the impact of PFC-targeted tDCS on behavioral and electrophysiological markers of proactive cognitive control engagement in individuals with schizophrenia. Using a within-participants, double-blinded, sham-controlled crossover design, we recorded EEG while participants with schizophrenia completed a proactive cognitive control task (the Dot Pattern Expectancy (DPX) Task), after receiving 20 min of active prefrontal stimulation at 2 mA or sham stimulation. We hypothesized that active stimulation would enhance proactive cognitive control, leading to changes in behavioral performance on the DPX task and in activity in the gamma frequency band during key periods of the task designed to tax proactive cognitive control. The results showed significant changes in the pattern of error rates and increases in EEG gamma power as a function of tDCS condition (active or sham), that were indicative of enhanced proactive cognitive control. These findings, considered alongside our previous work in healthy adults, provides novel support for the role gamma oscillations in proactive cognitive control and they suggest that frontal tDCS may be a promising approach to enhance proactive cognitive control in schizophrenia.
|
3,983 |
Diverse coral reef invertebrates exhibit patterns of phylosymbiosis
|
Microbiome assemblages of plants and animals often show a degree of correlation with host phylogeny; an eco-evolutionary pattern known as phylosymbiosis. Using 16S rRNA gene sequencing to profile the microbiome, paired with COI, 18S rRNA and ITS1 host phylogenies, phylosymbiosis was investigated in four groups of coral reef invertebrates (scleractinian corals, octocorals, sponges and ascidians). We tested three commonly used metrics to evaluate the extent of phylosymbiosis: (a) intraspecific versus interspecific microbiome variation, (b) topological comparisons between host phylogeny and hierarchical clustering (dendrogram) of host-associated microbial communities, and (c) correlation of host phylogenetic distance with microbial community dissimilarity. In all instances, intraspecific variation in microbiome composition was significantly lower than interspecific variation. Similarly, topological congruency between host phylogeny and the associated microbial dendrogram was more significant than would be expected by chance across all groups, except when using unweighted UniFrac distance (compared with weighted UniFrac and Bray–Curtis dissimilarity). Interestingly, all but the ascidians showed a significant positive correlation between host phylogenetic distance and associated microbial dissimilarity. Our findings provide new perspectives on the diverse nature of marine phylosymbioses and the complex roles of the microbiome in the evolution of marine invertebrates.
|
3,984 |
Communicating genetic information to family members: analysis of consent forms for diagnostic genomic sequencing
|
Communicating results from genomic sequencing to family members can play an essential role allowing access to surveillance, prevention, treatment or prophylactic measures. Yet, many patients struggle with communication of these results and it is unclear to what extent this is discussed during the consent process. We conducted an online systematic search and used content analysis to explore how consent forms for genomic sequencing address communication of genetic information to family members. Our search yielded 68 consent forms from 11 countries. Although 57 forms alluded to the familial nature of results, forms varied in their discussion of the potential familial implications of results. Only 11 addressed communication of genetic information with family members, with differences in who would be responsible for this process. Several forms offered patients options regarding communication, even in countries where national guidelines and legislation allow for the disclosure of results in the absence of patient consent. These findings are concerning because they show how forms may potentially mislead patients and health care professionals about whether communication is permissible in cases where the patient does not consent. We suggest that providers and health care professionals reconsider how consent forms address communicating genetic information to family members.
|
3,985 |
Opioid dose regimen shapes mesolimbic adaptations
| null |
3,986 |
IL-18: throwing off the shackles to boost anti-tumor immunity
| null |
3,987 |
Publisher Correction: Federated discovery and sharing of genomic data using Beacons
| null |
3,988 |
A systematic review of real-world evidence of the management of macular oedema secondary to branch retinal vein occlusion
|
This review assessed the real-world evidence of the management of macular oedema secondary to branch retinal vein occlusion (BRVO). A meta-analysis of 2530 eyes from 48 real-world studies of therapies for macular oedema secondary to BRVO was conducted. Baseline characteristics, visual, anatomical and safety outcomes were recorded. The weighted mean and weighted estimates from random-effects models were calculated for visual acuity (VA) and central subfield thickness (CST) changes at 6, 12 and 24 months. Primary outcome was change in VA (logMAR letters) at 12 months. Study quality was assessed using the quality appraisal checklist for case series developed by Institute of Health Economics. The mean baseline VA for the pooled data was 54.0 (51.5, 56.5) letters and the mean baseline CST was 501.3 (483.5, 519.1) µm. The random-effects estimate for mean (95% CI) change in VA was 14.6 (12.5, 16.7) letters at 12 months (n = 1727). The random-effects estimate for mean (95% CI) change in CST was −181.7 (−230.7, −132.7) µm at 12 months (n = 1325). The quality of studies varied considerably. Ocular and systemic adverse events were discussed in 79% and 42% of treatment arms respectively, with possible under-reporting. Visual and anatomical gains achieved in the real-world for anti-VEGF therapy were not as impressive as seminal RCTs, possibly due to reduced injection frequency in the real world and differences in baseline characteristics. There is an urgent need for consensus on the minimum efficacy, treatment burden and safety data to collect to strengthen the real-world evidence base.
|
3,989 |
Correction to: Behavioral Health Emergencies Encountered by Community Paramedics: Lessons from the Field and Opportunities for Skills Advancement
| null |
3,990 |
Optic disc drusen in children: morphologic features using EDI-OCT
|
AIMS: This study aimed to investigate morphologic features of optic disc drusen (ODD) and peripapillary hyperreflective ovoid mass-like structures (PHOMS) in children, using enhanced depth imaging optical coherence tomography (EDI-OCT). It also assessed if the presence of these features were associated with decreased peripapillary retinal nerve fibre layer (RNFL) thickness. METHODS: Retrospective observational study of children with ODD. All subjects underwent complete ophthalmic examination and multimodal imaging. ODD were identified on EDI-OCT as circumscribed hyporeflective spheroidal elements located in front of lamina cribrosa, fully or partially surrounded by a hyperreflective border. PHOMS were identified as hyperreflective ovoid structures located in the peripapillary circumference. Both associations between ODD and RNFL loss and PHOMS and RNFL loss were tested using chi-squared test. RESULTS: In total, 38 eyes of 20 children were analysed. PHOMS were present in 90% of patients. ODD and PHOMS were predominantly found in the nasal, superonasal and inferonasal sectors. A significant positive association was found between ODD and decreased RNFL thickness in the nasal (p = 0.02), superonasal (p = 0.05) and inferotemporal (p = 0.04) sectors. There was no significant association found with the presence of PHOMS. CONCLUSION: EDI-OCT allowed morphological analysis of ODD and PHOMS in children. Drusen were found to be distinct from PHOMS both in their appearance and impact on the RNFL. ODD are hyporeflective and appear on the ONH above the lamina cribrosa and were associated with decreased thickness of the RNFL. On the contrary, PHOMS are hyperreflective structures located around the ONH and were not associated with RNFL loss.
|
3,991 |
Ten-year outcomes of antivascular endothelial growth factor therapy in neovascular age-related macular degeneration
|
PURPOSE: Single center, noninterventional cohort study to assess 10-year visual and anatomical outcomes following initiation of treatment with antivascular endothelial growth factor (anti-VEGF) agents in neovascular age-related macular degeneration (AMD) patients. Neovascular AMD patients initiated on intravitreal anti-VEGF injections in 2008–2009 and continued to be followed up for at least 10 years were included in this study. METHODS: The Moorfields OpenEyes database was searched for all patients who were initiated on anti-VEGF therapy for neovascular AMD in 2008–2009 and the visual acuity (VA) in Early Diabetic Retinopathy Study (ETDRS) letters and injection records were analyzed for those who have had at least 10-year follow-up. The spectral-domain optical coherence tomography (SD-OCT) scans, color fundus photos, and fundus fluorescein angiography (FA) were graded by two retinal physicians. The outcomes were also compared between those with good and poor VA outcomes based on pre-defined criteria. The primary end point was change in VA at 10 years; secondary outcomes included percentage with VA of 20/40 or better, 20/70 or better, VA gains and losses, anatomic outcomes and number of injections. RESULTS: After a mean of 10.04 years after initiation of anti-VEGF therapy, the mean decline in VA from baseline was −2.1 ETDRS letters (SD 19.9, p = 0.65). One hundred eyes (67.1%) achieved a VA threshold of 20/70 or better, 33.5% achieved a VA of 20/40 or better, and 76.5% eyes maintained VA defined as a loss of less than 15 letters. Fourteen percent of study eyes had VA of 20/200 or worse and 23.5% declined by 15 letters or more. 87.5% of eyes were switched from ranibizumab to aflibercept during the course of 10 years and the eyes received a mean of 52.2 (SD 18.1) injections over 10 years. From this cohort, 87 (58.3%) eyes are having on-going treatment. On OCT, 34.9% had persistent fluid at the last visit, 6.7% patients showed new onset atrophy compared to baseline, and 43.7% had increased area of macular atrophy. The mean area of atrophy at the final visit was 4.15 mm(2). Comparison between the good and worse visual outcome groups showed lower baseline VA, fovea-involving atrophy and final area of atrophy had a statistically significant negative effect on the final visual outcome (p < 0.05). CONCLUSIONS: Regular monitoring and anti-VEGF treatment over 10 years reduce the risk of visual loss of 15 letters or more in patients with neovascular AMD. The most common cause of substantial visual decline was macular atrophy.
|
3,992 |
Author Correction: Data visualisation to support obesity policy: case studies of data tools for planning and transport policy in the UK
| null |
3,993 |
High-throughput screening campaign identifies a small molecule agonist of the relaxin family peptide receptor 4
|
Relaxin/insulin-like family peptide receptor 4 (RXFP4) is a class A G protein-coupled receptor (GPCR), and insulin-like peptide 5 (INSL5) is its endogenous ligand. Although the precise physiological role of INSL5/RXFP4 remains elusive, a number of studies have suggested it to be a potential therapeutic target for obesity and other metabolic disorders. Since selective agonists of RXFP4 are scarcely available and peptidic analogs of INSL5 are hard to make, we conducted a high-throughput screening campaign against 52,000 synthetic and natural compounds targeting RXFP4. Of the 109 initial hits discovered, only 3 compounds were confirmed in secondary screening, with JK0621-D008 displaying the best agonism at human RXFP4. Its S-configuration stereoisomer (JK1) was subsequently isolated and validated by a series of bioassays, demonstrating a consistent agonistic effect in cells overexpressing RXFP4. This scaffold may provide a valuable tool to further explore the biological functions of RXFP4.
|
3,994 |
Correction: Nuclear receptor HNF4α performs a tumor suppressor function in prostate cancer via its induction of p21-driven cellular senescence
| null |
3,995 |
New insights into the evasion of host innate immunity by Mycobacterium tuberculosis
|
Mycobacterium tuberculosis (Mtb) is an extremely successful intracellular pathogen that causes tuberculosis (TB), which remains the leading infectious cause of human death. The early interactions between Mtb and the host innate immune system largely determine the establishment of TB infection and disease development. Upon infection, host cells detect Mtb through a set of innate immune receptors and launch a range of cellular innate immune events. However, these innate defense mechanisms are extensively modulated by Mtb to avoid host immune clearance. In this review, we describe the emerging role of cytosolic nucleic acid-sensing pathways at the host–Mtb interface and summarize recently revealed mechanisms by which Mtb circumvents host cellular innate immune strategies such as membrane trafficking and integrity, cell death and autophagy. In addition, we discuss the newly elucidated strategies by which Mtb manipulates the host molecular regulatory machinery of innate immunity, including the intranuclear regulatory machinery, the ubiquitin system, and cellular intrinsic immune components. A better understanding of innate immune evasion mechanisms adopted by Mtb will provide new insights into TB pathogenesis and contribute to the development of more effective TB vaccines and therapies.
|
3,996 |
Mitochondrial Ca(2+) regulation in the etiology of heart failure: physiological and pathophysiological implications
|
Heart failure (HF) represents one of the leading causes of cardiovascular diseases with high rates of hospitalization, morbidity and mortality worldwide. Ample evidence has consolidated a crucial role for mitochondrial injury in the progression of HF. It is well established that mitochondrial Ca(2+) participates in the regulation of a wide variety of biological processes, including oxidative phosphorylation, ATP synthesis, reactive oxygen species (ROS) generation, mitochondrial dynamics and mitophagy. Nonetheless, mitochondrial Ca(2+) overload stimulates mitochondrial permeability transition pore (mPTP) opening and mitochondrial swelling, resulting in mitochondrial injury, apoptosis, cardiac remodeling, and ultimately development of HF. Moreover, mitochondria possess a series of Ca(2+) transport influx and efflux channels, to buffer Ca(2+) in the cytoplasm. Interaction at mitochondria-associated endoplasmic reticulum membranes (MAMs) may also participate in the regulation of mitochondrial Ca(2+) homeostasis and plays an essential role in the progression of HF. Here, we provide an overview of regulation of mitochondrial Ca(2+) homeostasis in maintenance of cardiac function, in an effort to identify novel therapeutic strategies for the management of HF.
|
3,997 |
Deep phenotyping detects a pathological CD4(+) T-cell complosome signature in systemic sclerosis
| null |
3,998 |
The metabolic regulator Lamtor5 suppresses inflammatory signaling via regulating mTOR-mediated TLR4 degradation
|
Comprehensive immune responses are essential for eliminating pathogens but must be tightly controlled to avoid sustained immune activation and potential tissue damage. The engagement of TLR4, a canonical pattern recognition receptor, has been proposed to trigger inflammatory responses with different magnitudes and durations depending on TLR4 cellular compartmentalization. In the present study, we identify an unexpected role of Lamtor5, a newly identified component of the amino acid-sensing machinery, in modulating TLR4 signaling and controlling inflammation. Specifically, Lamtor5 associated with TLR4 via their LZ/TIR domains and facilitated their colocalization at autolysosomes, preventing lysosomal tethering and the activation of mTORC1 upon LPS stimulation and thereby derepressing TFEB to promote autophagic degradation of TLR4. The loss of Lamtor5 was unable to trigger the TFEB-driven autolysosomal pathway and delay degradation of TLR4, leading to sustained inflammation and hence increased mortality among Lamtor5 haploinsufficient mice during endotoxic shock. Intriguingly, nutrient deprivation, particularly leucine deprivation, blunted inflammatory signaling and conferred protection to endotoxic mice. This effect, however, was largely abrogated upon Lamtor5 deletion. We thus propose a homeostatic function of Lamtor5 that couples pathogenic insults and nutrient availability to optimize the inflammatory response; this function may have implications for TLR4-associated inflammatory and metabolic disorders.
|
3,999 |
Author Correction: Next-generation influenza vaccines: opportunities and challenges
| null |
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