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The RNA-editing enzyme ADAR1 is essential for the suppression of innate immune activation and pathology caused by aberrant recognition of self-RNA, a role it carries out by disrupting the duplex structure of endogenous double-stranded RNA species1,2. A point mutation in the sequence encoding the Z-DNA-binding domain (ZBD) of ADAR1 is associated with severe autoinflammatory disease3-5. ZBP1 is the only other ZBD-containing mammalian protein6, and its activation can trigger both cell death and transcriptional responses through the kinases RIPK1 and RIPK3, and the protease caspase 8 (refs. 7-9). Here we show that the pathology caused by alteration of the ZBD of ADAR1 is driven by activation of ZBP1. We found that ablation of ZBP1 fully rescued the overt pathology caused by ADAR1 alteration, without fully reversing the underlying inflammatory program caused by this alteration. Whereas loss of RIPK3 partially phenocopied the protective effects of ZBP1 ablation, combined deletion of caspase 8 and RIPK3, or of caspase 8 and MLKL, unexpectedly exacerbated the pathogenic effects of ADAR1 alteration. These findings indicate that ADAR1 is a negative regulator of sterile ZBP1 activation, and that ZBP1-dependent signalling underlies the autoinflammatory pathology caused by alteration of ADAR1.
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Adenosina Desaminase , Doenças do Sistema Imunitário , Inflamação , Mutação , Proteínas de Ligação a RNA , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Animais , Caspase 8/genética , Caspase 8/metabolismo , Morte Celular , Deleção de Genes , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/metabolismo , Doenças do Sistema Imunitário/patologia , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Mamíferos/genética , Proteínas Quinases/deficiência , Proteínas Quinases/genética , RNA de Cadeia Dupla/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/deficiência , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Transdução de SinaisRESUMO
Rotaviruses (RVs) preferentially replicate in the small intestine and frequently cause severe diarrheal disease, and the following enteric infection generally induces variable levels of protective systemic and mucosal immune responses in humans and other animals. Rhesus rotavirus (RRV) is a simian RV that was previously used as a human RV vaccine and has been extensively studied in mice. Although RRV replicates poorly in the suckling mouse intestine, infection induces a robust and protective antibody response. The recent availability of plasmid only-based RV reverse genetics systems has enabled the generation of recombinant RVs expressing foreign proteins. However, recombinant RVs have not yet been experimentally tested as potential vaccine vectors to immunize against other gastrointestinal pathogens in vivo. This is a newly available opportunity because several live-attenuated RV vaccines are already widely administered to infants and young children worldwide. To explore the feasibility of using RV as a dual vaccine vector, we rescued replication-competent recombinant RRVs harboring bicistronic gene segment 7 that encodes the native RV nonstructural protein 3 (NSP3) protein and a human norovirus (HuNoV) VP1 protein or P domain from the predominant genotype GII.4. The rescued viruses expressed HuNoV VP1 or P protein in infected cells in vitro and elicited systemic and local antibody responses to HuNoV and RRV following oral infection of suckling mice. Serum IgG and fecal IgA from infected suckling mice bound to and neutralized both RRV and HuNoV. These findings have encouraging practical implications for the design of RV-based next-generation multivalent enteric vaccines to target HuNoV and other human enteric pathogens.
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Norovirus , Infecções por Rotavirus , Rotavirus , Criança , Lactente , Humanos , Animais , Camundongos , Pré-Escolar , Rotavirus/genética , Anticorpos Neutralizantes , Mucosa , Anticorpos AntiviraisRESUMO
Depression in older adults with cognitive impairment increases progression to dementia. Microbiota is associated with current mood and cognition, but the extent to which it predicts future symptoms is unknown. In this work, we identified microbial features that reflect current and predict future cognitive and depressive symptoms. Clinical assessments and stool samples were collected from 268 participants with varying cognitive and depressive symptoms. Seventy participants underwent 2-year follow-up. Microbial community diversity, structure, and composition were assessed using high-resolution 16 S rRNA marker gene sequencing. We implemented linear regression to characterize the relationship between microbiome composition, current cognitive impairment, and depressive symptoms. We leveraged elastic net regression to discover features that reflect current or future cognitive function and depressive symptoms. Greater microbial community diversity associated with lower current cognition in the whole sample, and greater depression in participants not on antidepressants. Poor current cognitive function associated with lower relative abundance of Bifidobacterium, while greater GABA degradation associated with greater current depression severity. Future cognitive decline associated with lower cognitive function, lower relative abundance of Intestinibacter, lower glutamate degradation, and higher baseline histamine synthesis. Future increase in depressive symptoms associated with higher baseline depression and anxiety, lower cognitive function, diabetes, lower relative abundance of Bacteroidota, and lower glutamate degradation. Our results suggest cognitive dysfunction and depression are unique states with an overall biological effect detectable through gut microbiota. The microbiome may present a noninvasive readout and prognostic tool for cognitive and psychiatric states.
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BACKGROUND: Chronic norovirus infection (CNI) causes significant morbidity in immunocompromised patients. No effective prevention or treatment currently exists. METHODS: Two patients with inborn errors of immunity, X- linked severe combined immunodeficiency (X-SCID) and DOCK8 deficiency, were followed longitudinally for clinical course, immune reconstitution, norovirus-specific T cell (NST) response, B cell reconstitution, and norovirus-specific antibody production. Samples were obtained in the peri-hematopoietic stem cell transplant setting (HSCT) before and after CNI clearance. The norovirus strain causing CNI was followed longitudinally for norovirus stool viral loads and sequencing. RESULTS: The noroviruses were identified as GII.4 Sydney[P4 New Orleans] in one patient and GII.17[P17] in the other. An exacerbation of diarrhea post-HSCT in the patient with X-SCID was consistent with norovirus infection but not with graft-vs-host-disease on pathologic samples. Both patients recovered polyfunctional NSTs in the CD4 and CD8 T cell compartments which recognized multiple norovirus structural and non-structural viral antigens. T cell responses were minimal during active CNI but detectable after resolution. Mapping of norovirus-specific T cell responses between the patient with DOCK8 and his matched sibling donor were nearly identical. B cell reconstitution or new endogenous antibody production for IgA or IgG were not observed. CONCLUSION: This report is the first to demonstrate reconstitution of norovirus-specific T cell immunity after HSCT closely temporally aligned with clearance of CNI suggesting that cellular immunity is sufficient for norovirus clearance.
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BACKGROUND & AIMS: Dysbiosis of gut microbiota is linked to the development of colorectal cancer (CRC). However, microbiota-based stratification of CRC tissue and how this relates to clinicomolecular characteristics and prognosis remains to be clarified. METHODS: Tumor and normal mucosa from 423 patients with stage I to IV CRC were profiled by bacterial 16S rRNA gene sequencing. Tumors were characterized for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), APC, BRAF, KRAS, PIK3CA, FBXW7, SMAD4, and TP53 mutations, subsets for chromosome instability (CIN), mutation signatures, and consensus molecular subtypes (CMS). Microbial clusters were validated in an independent cohort of 293 stage II/III tumors. RESULTS: Tumors reproducibly stratified into 3 oncomicrobial community subtypes (OCSs) with distinguishing features: OCS1 (Fusobacterium/oral pathogens, proteolytic, 21%), right-sided, high-grade, MSI-high, CIMP-positive, CMS1, BRAF V600E, and FBXW7 mutated; OCS2 (Firmicutes/Bacteroidetes, saccharolytic, 44%), and OCS3 (Escherichia/Pseudescherichia/Shigella, fatty acid ß-oxidation, 35%) both left-sided and exhibiting CIN. OCS1 was associated with MSI-related mutation signatures (SBS15, SBS20, ID2, and ID7) and OCS2 and OCS3 with SBS18 related to damage by reactive oxygen species. Among stage II/III patients, OCS1 and OCS3 both had poorer overall survival compared with OCS2 for microsatellite stable tumors (multivariate hazard ratio [HR], 1.85; 95% confidence interval [CI], 1.15-2.99; P = .012; and HR, 1.52; 95% CI 1.01-2.29; P = .044, respectively) and left-sided tumors (multivariate HR, 2.66; 95% CI, 1.45-4.86; P = .002; and HR, 1.76; 95% CI, 1.03-3.02; P = .039, respectively). CONCLUSIONS: OCS classification stratified CRCs into 3 distinct subgroups with different clinicomolecular features and outcomes. Our findings provide a framework for a microbiota-based stratification of CRC to refine prognostication and to inform the development of microbiota-targeted interventions.
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Neoplasias Colorretais , Proteínas Proto-Oncogênicas B-raf , Humanos , Prognóstico , Proteína 7 com Repetições F-Box-WD/genética , Proteínas Proto-Oncogênicas B-raf/genética , RNA Ribossômico 16S , Metilação de DNA , Mutação , Instabilidade de Microssatélites , Instabilidade Cromossômica , Fenótipo , Neoplasias Colorretais/patologia , Ilhas de CpGRESUMO
BACKGROUND: Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups. PATIENTS AND METHODS: This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR). RESULTS: Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]. CONCLUSIONS: Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.
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We introduce a fully-integrated two-color sub-nanosecond fiber laser system that incorporates a backward-pumped polarization-maintaining (PM) Raman phosphosilicate fiber amplifier (RFA) followed by two fully-integrated fiber-coupled second harmonic generator (SHG) modules. The RFA is pumped by a continuous-wave (CW) Yb laser operating at 1116â nm. The pulsed signals are generated by gain-switched distributed feedback (DFB) laser diodes at 1178â nm and 1310â nm, respectively. The output pulsed DFB signals are independently or simultaneously amplified in the RFA. This amplification is achieved using both the broad SiO2 (â¼13.2 THz) and relatively narrow P2O5 (39.9 THz) Stokes shifts. The laser system produces sub-nanosecond pulses at 589 and 655â nm, featuring repetition rates ranging from 40 to 100â MHz and an average power of up to 3 W (limited by the SHG crystal damage threshold) at each wavelength. The diffraction-limited output beams maintain an M2 value of < 1.05 across the entire range of output powers and repetition rates for both wavelengths.
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The known I^{π}=8_{1}^{+}, E_{x}=2129-keV isomer in the semimagic nucleus ^{130}Cd_{82} was populated in the projectile fission of a ^{238}U beam at the Radioactive Isotope Beam Factory at RIKEN. The high counting statistics of the accumulated data allowed us to determine the excitation energy, E_{x}=2001.2(7) keV, and half-life, T_{1/2}=57(3) ns, of the I^{π}=6_{1}^{+} state based on γγ coincidence information. Furthermore, the half-life of the 8_{1}^{+} state, T_{1/2}=224(4) ns, was remeasured with high precision. The new experimental information, combined with available data for ^{134}Sn and large-scale shell model calculations, allowed us to extract proton and neutron effective charges for ^{132}Sn, a doubly magic nucleus far-off stability. A comparison to analogous information for ^{100}Sn provides first reliable information regarding the isospin dependence of the isoscalar and isovector effective charges in heavy nuclei.
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BACKGROUND: Despite its recognized importance, there is currently no reliable tool for surgical quality assurance (SQA) of gastrectomy in surgical oncology. The aim of this study was to develop an SQA tool for gastrectomy and to apply this tool within the ADDICT Trial in order to assess the extent and completeness of lymphadenectomy. METHODS: The operative steps for D1+ and D2 gastrectomy have been previously described in the literature and ADDICT trial manual. Two researchers also performed fieldwork in the UK and Japan to document key operative steps through photographs and semi-structured interviews with expert surgeons. This provided the steps that were used as the framework for the SQA tool. Sixty-two photographic cases from the ADDICT Trial were rated by three independent surgeons. Generalizability (G) theory determined inter-rater reliability. D-studies examined the effect of varying the number of assessors and photographic series they rated. Chi-square assessed intra-rater reliability, comparing how the individual assessor's responses corresponded to their global rating for extent of lymphadenectomy. RESULTS: The tool comprised 20 items, including 19 anatomical landmarks and a global rating score. Overall reliability had G-coefficient of 0.557. Internal consistency was measured with a Cronbach's alpha score of 0.869 and Chi-square confirmed intra-rater reliability for each assessor as < 0.05. CONCLUSIONS: A photographic surgical quality assurance tool is presented for gastrectomy. Using this tool, the assessor can reliably determine not only the quality but also the extent of the lymphadenectomy performed based on remaining anatomy rather than the excised specimen.
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Gastrectomia , Excisão de Linfonodo , Garantia da Qualidade dos Cuidados de Saúde , Neoplasias Gástricas , Gastrectomia/normas , Gastrectomia/métodos , Humanos , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/patologia , Garantia da Qualidade dos Cuidados de Saúde/normas , Excisão de Linfonodo/normas , Excisão de Linfonodo/métodos , Reprodutibilidade dos TestesRESUMO
BACKGROUND: The EORTC QLQ-STO22 (QLQ-STO22) is a firmly established and validated measure of health-related quality of life (HRQoL) for people with gastric cancer (GC), developed over two decades ago. Since then there have been dramatic changes in treatment options for GC. Also, East Asian patients were not involved in the development of QLQ-STO22, where GC is most prevalent and the QLQ-STO22 is widely used. A review with appropriate updating of the measure was planned. This study aims to capture HRQoL issues associated with new treatments and the perspectives of patients and health care professionals (HCPs) from different cultural backgrounds, including East Asia. METHODS: A systematic literature review and open-ended interviews were preformed to identify potential new HRQoL issues relating to GC. This was followed by structured interviews where HCPs and patients reviewed the QLQ-STO22 alongside new issues regarding relevance, importance, and acceptability. RESULTS: The review of 267 publications and interviews with 104 patients and 18 HCPs (48 and 9 from East Asia, respectively) generated a list of 58 new issues. Three of these relating to eating small amounts, flatulence, and neuropathy were recommended for inclusion in an updated version of the QLQ-STO22 and covered by five additional questions. CONCLUSIONS: This study supports the content validity of the QLQ-STO22, suggesting its continued relevance to patients with GC, including those from East Asia. The updated version with additional questions and linguistic changes will enhance its specificity, but further testing is required.
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Qualidade de Vida , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/psicologia , Neoplasias Gástricas/terapia , Feminino , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Idoso , Comparação Transcultural , AdultoRESUMO
BACKGROUND: Nitrous oxide (N2O) is a common adjuvant to general anaesthesia. It is also a potent greenhouse gas and causes ozone depletion. We sought to quantify the influence of N2O as an adjuvant to general anaesthesia on postoperative patient outcomes. METHODS: We searched Medline, EMBASE, and Cochrane Central for works published from inception to July 6, 2023. RCTs comparing general anaesthesia with or without N2O were included. Risk ratios (RRs) and standardised mean differences (SMDs) were calculated, along with 95% confidence intervals (CIs), using a random-effects model. Outcomes were derived from the Standardised Endpoints for Perioperative Medicine (StEP) outcome set. Primary outcomes were mortality and organ-related morbidity, and secondary outcomes were anaesthetic and surgical morbidity. RESULTS: Of 3305 records, 179 full-text articles were assessed, and 71 RCTs, totalling 22 147 patients, were included in the meta-analysis. Addition of N2O to general anaesthesia did not influence postoperative mortality or most morbidity outcomes. N2O increased the incidence of atelectasis (RR 1.62, 95% CI 1.24 to 2.12) and postoperative nausea and vomiting (RR 1.27, 95% CI 1.15 to 1.40), and decreased intraoperative opioid consumption (SMD -0.19, 95% CI -0.35 to -0.04) and time to extubation (MD -2.17 min, 95% CI -3.32 to -1.03 min). CONCLUSIONS: N2O did not influence postoperative mortality or most morbidity outcomes. Considering the environmental effects of N2O, these findings confirm that current policy recommendations to limit its use do not affect patient safety. SYSTEMATIC REVIEW PROTOCOL: PROSPERO CRD42023443287.
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INTRODUCTION AND HYPOTHESIS: The gold standard for quantifying pelvic organ prolapse is the pelvic organ prolapse quantification (POP-Q) system; however, upright magnetic resonance imaging (MRI) is a promising new method. The objective of this study was to determine the correlation between POP-Q and MRI measurements of the bladder and cervix. METHODS: This prospective study included patients with prolapse in whom POP-Q points Aa or Ba and C were measured as standard care. MRI scans were performed in an upright position, and the distances of the lowest points of the bladder and cervix to the Pelvic Inclination Correction System (PICS) were calculated. Correlations between POP-Q and MRI-PICS measurements were determined using the Pearson correlation coefficient for normally distributed data and the Spearman's rank correlation coefficient for non-normally distributed data. RESULTS: A total of 63 patients were suitable for analysis. There was a moderate positive correlation between the POP-Q and MRI-PICS measurements for bladder (r(61) = 0.480, r < 0.001) and uterus (r(61) = 0.527, p < 0.001). Measurement differences between POP-Q and MRI-PICS of the bladder and uterus vary from -3.2 cm to 7.1 cm, and from -2.1 cm to 8.5 cm respectively. In 71.4% of patients more descent was seen on upright MRI than with POP-Q measurement for both bladder and uterus. For patients with similar POP-Q measurements, a high variation in MRI measurements of the bladder and uterus was found. CONCLUSION: Despite a moderate positive correlation, upright MRI shows a larger POP extent in 71.4% of the patients than POP-Q. A high variation in MRI measurements for patients with the same POP-Q measurement was seen.
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Imageamento por Ressonância Magnética , Prolapso de Órgão Pélvico , Bexiga Urinária , Humanos , Feminino , Prolapso de Órgão Pélvico/diagnóstico por imagem , Estudos Prospectivos , Pessoa de Meia-Idade , Idoso , Bexiga Urinária/diagnóstico por imagem , Bexiga Urinária/patologia , Colo do Útero/diagnóstico por imagem , Colo do Útero/patologia , AdultoRESUMO
PURPOSE: Asymptomatic patients with clinically non-functional pituitary neuroendocrine tumors (CNF-PitNETs) are usually followed up. However, the natural course of CNF-PitNETs according to sex and age remains unclear. Therefore, this study assessed growth patterns of CNF-PitNETs according to sex and age. METHODS: In this longitudinal study, we enrolled 431 consecutive patients with CNF-PitNETs who were treated at Seoul National University Hospital from 1997 to 2021. The patients underwent hormone function testing and visual field testing, and were subsequently followed up with imaging over a median duration of 66 months. RESULTS: The median age of the patients was 53.0 years, and 37.1% (n = 160) were men. Men were older and harbored more macroadenomas than women. The annual tumor volume change was higher in men than in women (0.21 vs. 0.04 cm3/year, P < 0.001). The estimated cutoff value of age for significant tumor growth was 51 years. In men, the annual tumor volume change was similar across all age groups. In women, those aged ≤ 50 years showed significantly lower annual tumor volume change than those aged > 50 years (0.01, 0.11, and 0.17 cm3/year, P = 0.001). When comparing sexes within the same age group, the annual tumor volume changes was significantly lower for women than for men, only in patients aged ≤ 50 years (0.01 vs. 0.15 cm3/year, P < 0.001). CONCLUSIONS: Among patients with CNF-PitNET, tumor growth was slower in women aged ≤ 50 years than in men and women aged > 50. These findings may guide the customization of surveillance strategies for CNF-PitNETs according to sex and age.
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Tumores Neuroendócrinos , Neoplasias Hipofisárias , Humanos , Masculino , Feminino , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/epidemiologia , Neoplasias Hipofisárias/diagnóstico , Pessoa de Meia-Idade , Estudos Longitudinais , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/epidemiologia , Tumores Neuroendócrinos/diagnóstico , Fatores Sexuais , Fatores Etários , Idoso , Adulto , Carga Tumoral , Seguimentos , PrognósticoRESUMO
OBJECTIVES: In Korea, diabetes mellitus has a high disease burden, based on disability-adjusted life years. However, the disease burden is disproportionately distributed, with people with disabilities (PWD) experiencing higher rates of health disparities. Our study investigated long-term trends in diabetes prevalence and risk according to disability status, grade, and type. STUDY DESIGN: Retrospective cohort study. METHODS: Approximately 10 million individuals aged ≥30 years were included yearly from the National Health Information Database (NHID) and national disability registration data in Korea between 2008 and 2017, corresponding to 40 % of those aged ≥30 years in Korea. In 2017, 12, 975, 757 individuals were included; 5.5 % had disabilities. We estimated annual diabetes age-standardized prevalence and used multiple logistic regression analyses to estimate the odds of having diabetes in 2017, according to disability status, severity, and type. RESULTS: Diabetes age-standardized prevalence consistently increased over 2008-2017 in PWD and people without disabilities. However, the prevalence increased more rapidly and was higher in all years among PWD, with widening disparities based on disability status. Additionally, diabetes prevalence was high in all years for specific subgroups, including women, individuals with intellectual or mental disabilities or autism, and individuals with severe disabilities, suggesting further disparities among PWD. CONCLUSIONS: Our findings reveal health disparities between those with and without disabilities and among PWD subgroups. In addition to timely prevention, diabetes screening and management among PWD is vital. Public investment in improving disparities in the root causes of diabetes is essential, including health behaviours, healthcare utilization, and self-care.
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Diabetes Mellitus , Pessoas com Deficiência , Humanos , Feminino , Prevalência , Estudos Retrospectivos , Diabetes Mellitus/epidemiologia , República da Coreia/epidemiologiaRESUMO
BACKGROUND: Orbital apex syndrome (OAS) is a condition characterised by lesions within the orbital apex, leading to various ophthalmologic symptoms. This study aimed to analyse the clinical characteristics and treatment strategies of OAS with respect to aetiology. METHODS: This retrospective analysis utilised data from 5 medical institutions between 2013 and 2022. Patients who were diagnosed with OAS were initially enrolled, but patients who failed to follow up at least 1 month were excluded. The prevalence of initial ophthalmologic symptoms and visual improvement after treatment was compared according to aetiology. Factors related to visual improvement were analysed. RESULTS: Among 73 enrolled patients, the leading aetiology was tumours, followed by fungal infections and inflammation. Visual impairment and proptosis were prevalent in tumour-related OAS cases. Inflammation-related OAS exhibited a higher likelihood of painful eye movements and ophthalmoplegia. Ptosis was most frequently observed in fungal infection-related OAS. Notably, fungal infections emerged as the sole significant factor negatively impacting vision progression. In inflammation-related OAS, the time interval between symptom onset and the administration of steroids was longer in patients without visual improvement, even though there was no statistically significant difference. CONCLUSIONS: Tumours were the predominant cause of OAS. Visual impairment was a common manifestation in tumour-related OAS, while fungal infections were strongly associated with a poor visual prognosis. The timely administration of steroids might be helpful for improving vision in patients with inflammation-related OAS. However, further studies are needed to enhance understanding and management of OAS.
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In Bragg coherent diffractive imaging, the precise location of the measured crystals in the interior of the sample is usually missing. Obtaining this information would help the study of the spatially dependent behavior of particles in the bulk of inhomogeneous samples, such as extra-thick battery cathodes. This work presents an approach to determine the 3D position of particles by precisely aligning them at the instrument axis of rotation. In the test experiment reported here, with a 60â µm-thick LiNi0.5Mn1.5O4 battery cathode, the particles were located with a precision of 20â µm in the out-of-plane direction, and the in-plane coordinates were determined with a precision of 1â µm.
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Norovirus is a major cause of acute gastroenteritis worldwide. Over 30 different genotypes, mostly from genogroup I (GI) and II (GII), have been shown to infect humans. Despite three decades of genome sequencing, our understanding of the role of genomic diversification across continents and time is incomplete. To close the spatiotemporal gap of genomic information of human noroviruses, we conducted a large-scale genome-wide analyses that included the nearly full-length sequencing of 281 archival viruses circulating since the 1970s in over 10 countries from four continents, with a major emphasis on norovirus genotypes that are currently underrepresented in public genome databases. We provided new genome information for 24 distinct genotypes, including the oldest genome information from 12 norovirus genotypes. Analyses of this new genomic information, together with those publicly available, showed that (i) noroviruses evolve at similar rates across genomic regions and genotypes; (ii) emerging viruses evolved from transiently-circulating intermediate viruses; (iii) diversifying selection on the VP1 protein was recorded in genotypes with multiple variants; (iv) non-structural proteins showed a similar branching on their phylogenetic trees; and (v) contrary to the current understanding, there are restrictions on the ability to recombine different genomic regions, which results in co-circulating populations of viruses evolving independently in human communities. This study provides a comprehensive genetic analysis of diverse norovirus genotypes and the role of non-structural proteins on viral diversification, shedding new light on the mechanisms of norovirus evolution and transmission.
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Genoma Viral/genética , Norovirus/genética , Evolução Biológica , Evolução Molecular , Estudo de Associação Genômica Ampla , HumanosRESUMO
The change in the power balance, temporal dynamics, emission weighted size, temperature, mass, and areal density of inertially confined fusion plasmas have been quantified for experiments that reach target gains up to 0.72. It is observed that as the target gain rises, increased rates of self-heating initially overcome expansion power losses. This leads to reacting plasmas that reach peak fusion production at later times with increased size, temperature, mass and with lower emission weighted areal densities. Analytic models are consistent with the observations and inferences for how these quantities evolve as the rate of fusion self-heating, fusion yield, and target gain increase. At peak fusion production, it is found that as temperatures and target gains rise, the expansion power loss increases to a near constant ratio of the fusion self-heating power. This is consistent with models that indicate that the expansion losses dominate the dynamics in this regime.
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We search for energetic electron recoil signals induced by boosted dark matter (BDM) from the galactic center using the COSINE-100 array of NaI(Tl) crystal detectors at the Yangyang Underground Laboratory. The signal would be an excess of events with energies above 4 MeV over the well-understood background. Because no excess of events are observed in a 97.7 kg·yr exposure, we set limits on BDM interactions under a variety of hypotheses. Notably, we explored the dark photon parameter space, leading to competitive limits compared to direct dark photon search experiments, particularly for dark photon masses below 4 MeV and considering the invisible decay mode. Furthermore, by comparing our results with a previous BDM search conducted by the Super-Kamionkande experiment, we found that the COSINE-100 detector has advantages in searching for low-mass dark matter. This analysis demonstrates the potential of the COSINE-100 detector to search for MeV electron recoil signals produced by the dark sector particle interactions.
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The excited states of unstable ^{20}O were investigated via γ-ray spectroscopy following the ^{19}O(d,p)^{20}O reaction at 8 AMeV. By exploiting the Doppler shift attenuation method, the lifetimes of the 2_{2}^{+} and 3_{1}^{+} states were firmly established. From the γ-ray branching and E2/M1 mixing ratios for transitions deexciting the 2_{2}^{+} and 3_{1}^{+} states, the B(E2) and B(M1) were determined. Various chiral effective field theory Hamiltonians, describing the nuclear properties beyond ground states, along with a standard USDB interaction, were compared with the experimentally obtained data. Such a comparison for a large set of γ-ray transition probabilities with the valence space in medium similarity renormalization group ab initio calculations was performed for the first time in a nucleus far from stability. It was shown that the ab initio approaches using chiral effective field theory forces are challenged by detailed high-precision spectroscopic properties of nuclei. The reduced transition probabilities were found to be a very constraining test of the performance of the ab initio models.