Aims
To evaluate unique clinical characteristics of paediatric uveitis in our locality and treatment outcomes especially the efficacy of biologics.
Methods
This was a retrospective cohort.
Results
37 ...paediatric uveitis cases involving 67 eyes were included. Male-to-female ratio was 1:1.3. Mean age of uveitis onset was 11 ± 3.7 (4–18). 81.1% cases suffered from bilateral uveitis. 75.7% cases were chronic uveitis. Nearly half of the cases (40.5%) presented with anterior uveitis. The predominant diagnosis of uveitis in our cohort was idiopathic. Unlike studies from other populations, the associated systemic conditions in this mostly Chinese cohort were Behçet’s disease (8.1%), tubulointerstitial nephritis and uveitis (8.1%) and HLA-B27 associated uveitis (8.1%). Steroid response was a common phenomenon, observed in 40.5% of cases. The most common complication was posterior synechiae (45.9%), followed by cataract (37.8%), glaucoma (27.0%), band keratopathy (18.9%) and macular oedema (13.5%). 3/37 patients encountered either first attack of uveitis or flare after receiving COVID-19 vaccine. 54.1% of patients required systemic steroid for disease control. The majority required steroid sparing immunotherapy, including Methotrexate (43.2%), Mycophenolate Mofetil (24.3%), Cyclosporine A (8.1%), Azathioprine (5.4%) and Tacrolimus (2.7%). Resistant cases required biologics including tumour necrosis factor alpha inhibitors (Adalimumab 32.4%, Infliximab 2.7%) and interleukin-6 inhibitors (Tocilizumab 2.7%).
Conclusions
Clinical presentation of the local paediatric uveitis differs from previously described features in Caucasian and other populations. According to our experience as a tertiary eye centre, Behçet’s disease, tubulointerstitial nephritis and uveitis and HLA-B27 associated uveitis were more often encountered than Juvenile Idiopathic Arthritis associated uveitis. Our report evaluated the efficacy of immunomodulatory therapy and biologics in controlling uveitis and reducing ocular complications.
Laribacter hongkongensis has been recovered from several patients with gastroenteritis. However, the causative role of this organism in human gastroenteritis is still unproven, and sources of the ...bacterium are unknown. We undertook a multicentre case-control study to investigate the association of
L hongkongensis with gastroenteritis.
Faecal samples from patients with community-acquired gastroenteritis and controls were cultured for
L hongkongensis. Targeted food surveillance was done to identify potential sources of this bacterium. All isolates of this organism from patients and food items were characterised by pulsed-field gel electrophoresis and ribotyping.
During a 4-month period,
L hongkongensis was recovered from 17 of 3788 patients with community-acquired gastroenteritis, but was absent in 1894 controls (p=0.001). Those who were culture-positive for this bacterium had a recent history of travel (ten 59% patients vs two 6% of 34 matched controls, p<0.0001), of fish consumption (16 94% vs 19 56%, p=0.009), and of eating minced freshwater fish meat (five 29% vs one 3%, p=0.012). We recovered 25
L hongkongensis isolates from intestinal samples of freshwater fish and two from minced freshwater fish meat. Bacteria with the same pulsed-field gel electrophoretic pattern and ribotype were recovered from one patient and a sample of minced freshwater fish meat, which was from the same retail market recently visited by the patient. We did not see this particular combination of electrophoretic pattern and ribotype in any other isolates.
L hongkongensis is associated with community-acquired gastroenteritis and traveller's diarrhoea. However, its causative role has not been shown. Freshwater fish is one source of this bacterium.
1 College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA 2 Bacterial Diseases of Livestock Research Unit, National Animal Disease Center, Agricultural Research Service, US ...Department of Agriculture, Ames, IA 50010, USA 3 Department of Chemistry, University of Oklahoma, Norman, OK, USA
Correspondence Yung-Fu Chang yc42{at}cornell.edu
Received December 15, 2003
Accepted May 20, 2004
The search for novel antigens suitable for improved vaccines and diagnostic reagents against leptospirosis led to the identification of LigA and LigB. LigA and LigB expression were not detectable at the translation level but were detectable at the transcription level in leptospires grown in vitro . Lig genes were present in pathogenic serovars of Leptospira , but not in non-pathogenic Leptospira biflexa . The conserved and variable regions of LigA and LigB (Con, VarA and VarB) were cloned, expressed and purified as GST-fusion proteins. Purified recombinant LigA and LigB were evaluated for their diagnostic potential in a kinetic ELISA (KELA) using sera from vaccinated and microscopic agglutination test (MAT)-positive dogs. Sera from vaccinated dogs showed reactivity to whole-cell antigens of leptospires but did not show reactivity in the KELA assay with recombinant antigens, suggesting a lack of antibodies to Lig proteins in the vaccinated animals. The diagnostic potential of recombinant Lig antigens in the KELA assay was evaluated by using 67 serum samples with MAT 1600, which showed reactivity of 76, 41 and 35 % to rConA, rVarA and rVarB, respectively. These findings suggest that recombinant antigen to the conserved region of LigA and LigB can differentiate between vaccinated and naturally infected animals.
Abbreviations: KELA, kinetic ELISA; MAT, microscopic agglutination test.
The GenBank/EMBL/DDBJ accession numbers for the nucleotide sequences of ligB and C are AF534640 and AY327260 , respectively.
TPS2078
Background: GBM AGILE (Glioblastoma Adaptive, Global, Innovative Learning Environment) is a biomarker based, multi-arm, international, seamless Phase 2/3 Response Adaptive Randomization ...platform trial designed to rapidly identify experimental therapies that improve overall survival and confirm efficacious experimental therapies and associated biomarker signatures to support new drug approvals and registration. GBM AGILE is a collaboration between academic investigators, patient organizations and industry to support new drug applications for newly diagnosed and recurrent GBM. With its adaptable structure, GBM AGILE has continued trial activation, inclusion of new investigational therapies, and enrollment globally through the challenges of a global pandemic. Methods: The primary objective of GBM AGILE is to identify therapies that effectively improve the overall survival in patients with ND or recurrent GBM. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. Operating under a Master Protocol, GBM AGILE allows multiple drugs from different pharmaceutical/biotech companies to be evaluated simultaneously and/or over time against a common control. New experimental therapies are added as new information about promising new drugs is identified while other therapies are removed as they complete their evaluation. The master protocol/ trial infrastructure includes efficiencies through an adaptive trial design, shared control arm and operational processes such as risk-based monitoring and enhanced remote activities. GBM AGILE has screened over 1000 patients and enrollment rates are 3 to 4 times greater than traditional GBM trials, with active sites averaging 0.75 to 1 patients/sites/month. While enrollment had an initial dip during the early stages of the pandemic (April-May, 2020), with flexible processes including remote based monitoring, minimizing in person visits, and remote provision of IMP, the enrollment rebounded by June, 2020. Through the use of improved and efficient processes allowed within a master protocol/adaptive platform trial infrastructure, GBM AGILE has been seamlessly operating a global trial during a global pandemic. Clinical trial information: NCT03970447.
The phosphatidylinositol 3-kinase pathway is an important regulator of a wide spectrum of tumor-related biological processes,
including cell proliferation, survival, and motility, as well as ...neovascularization. Protein kinase B/Akt is activated in
a complex manner through the phosphorylation of protein kinase B/Akt on Thr 308 and Ser 473 . Although protein-dependent kinase-1 has been shown to phosphorylate Akt at Thr 308 , it is not clear whether there is a distinct kinase that exclusively phosphorylates Akt at Ser 473 . A possible candidate is integrin-linked kinase (ILK), which has been shown to phosphorylate Akt at Ser 473 in vitro . ILK is a multidomain focal adhesion protein that is believed to be involved in signal transmission from integrin and growth
factor receptors. Further, ILK is implicated in the regulation of anchorage-dependent cell growth/survival, cell cycle progression,
invasion and migration, and tumor angiogenesis. In this study, we tested the hypothesis that ILK inhibition would inhibit
these processes in gliomas in which it is constitutively expressed. We found that a newly developed small-molecule compound
(QLT0267) effectively inhibited signaling through the ILK/Akt cascade in glioma cells by blocking the phosphorylation of Akt
and downstream targets, including mammalian target of rapamycin and glycogen synthase kinase-3β. Treatment of glioma cells
with 12.5 μmol/L QLT0267 inhibited cell growth by 50% at 48 hours. An anchorage-dependent cell growth assay confirmed the
cell growth-inhibitory effect of QLT0267. Further, the decrease in cell growth was associated with a dramatic accumulation
of cells in the G 2 -M phase of the cell cycle. Although the cell growth-inhibitory effects of the ILK inhibitor were achieved only at a high
concentration, the QLT0267 was able to reduce cellular invasion and angiogenesis at much lower concentrations as shown by
in vitro invasion assays and vascular endothelial growth factor secretion. Thus, blocking the ILK/Akt pathway is a potential strategy
for molecular targeted therapy for gliomas.
Abstract
Background
GBM AGILE (Glioblastoma Adaptive, Global, Innovative Learning Environment) is a biomarker based, multi-arm, international, seamless Phase 2/3 Response Adaptive Randomization ...platform trial designed to rapidly identify experimental therapies that improve overall survival and confirm efficacious experimental therapies and associated biomarker signatures to support new drug approvals and registration. It is a collaboration between academic investigators, patient organizations and industry, under the sponsorship of the non-profit organization, Global Coalition for Adaptive Research, to support new drug applications for newly diagnosed and recurrent GBM.
Material and Methods
The primary objective of GBM AGILE is to identify therapies that effectively improve overall survival in patients with newly diagnosed or recurrent GBM. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. Operating under a master protocol, GBM AGILE allows multiple drugs from different pharmaceutical companies to be evaluated simultaneously and/or over time against a common control arm. Based on performance, a drug may graduate and move to a Stage 2 (Phase 3) within the trial, and the totality of the data can be used for a new drug application and registration process. New experimental therapies are added as information about promising new drugs is identified while other therapies are removed as they complete their evaluation. The master protocol/ trial infrastructure includes efficiencies through an adaptive trial design, shared control arm and operational processes such as risk-based monitoring and enhanced remote activities. With its adaptable structure, GBM AGILE has continued trial activation, inclusion of new investigational therapies, and enrollment globally through the challenges of a global pandemic.GBM AGILE provides an efficient mechanism to screen and develop robust information regarding the efficacy of proposed novel therapeutics and associated biomarkers for GBM and to quickly move therapies and biomarkers into clinic. GBM AGILE received initial approval from the United States FDA in April 2019, and in Europe through the Voluntary Harmonization Procedure (VHP) in April, 2021. As of 2022, AGILE has screened over 1000 patients studying multiple investigational treatments. Enrollment rates are 3 to 4 times greater than traditional GBM trials, with active sites averaging 0.75 to 1 patients/site/month.
Currently, there are 41 sites activated in the US, 4 in Canada and 2 in Switzerland and an estimated 24 sites yet to open in Germany, France, Switzerland, Italy and Austria. In addition to the continued expansion in Europe, effort is undergoing to extend the trial to China and Australia as well. Clinical trial information: NCT03970447
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