| 1. |
- Ruilope, LM, et al.
(author)
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Design and Baseline Characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial
- 2019
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In: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 50:5, s. 345-356
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Journal article (peer-reviewed)abstract
- <b><i>Background:</i></b> Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. <b><i>Patients and</i></b> <b><i>Methods:</i></b> The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m<sup>2</sup> and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. <b><i>Conclusions:</i></b> FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.
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| 2. |
- Underwood, J, et al.
(author)
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Validation of a Novel Multivariate Method of Defining HIV-Associated Cognitive Impairment
- 2019
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In: Open forum infectious diseases. - : Oxford University Press (OUP). - 2328-8957. ; 6:6, s. ofz198-
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Journal article (peer-reviewed)abstract
- BackgroundThe optimum method of defining cognitive impairment in virally suppressed people living with HIV is unknown. We evaluated the relationships between cognitive impairment, including using a novel multivariate method (NMM), patient– reported outcome measures (PROMs), and neuroimaging markers of brain structure across 3 cohorts.MethodsDifferences in the prevalence of cognitive impairment, PROMs, and neuroimaging data from the COBRA, CHARTER, and POPPY cohorts (total n = 908) were determined between HIV-positive participants with and without cognitive impairment defined using the HIV-associated neurocognitive disorders (HAND), global deficit score (GDS), and NMM criteria.ResultsThe prevalence of cognitive impairment varied by up to 27% between methods used to define impairment (eg, 48% for HAND vs 21% for NMM in the CHARTER study). Associations between objective cognitive impairment and subjective cognitive complaints generally were weak. Physical and mental health summary scores (SF-36) were lowest for NMM-defined impairment (P < .05).There were no differences in brain volumes or cortical thickness between participants with and without cognitive impairment defined using the HAND and GDS measures. In contrast, those identified with cognitive impairment by the NMM had reduced mean cortical thickness in both hemispheres (P < .05), as well as smaller brain volumes (P < .01). The associations with measures of white matter microstructure and brain-predicted age generally were weaker.ConclusionDifferent methods of defining cognitive impairment identify different people with varying symptomatology and measures of brain injury. Overall, NMM-defined impairment was associated with most neuroimaging abnormalities and poorer self-reported health status. This may be due to the statistical advantage of using a multivariate approach.
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| 3. |
- Palmer, Nicholette D, et al.
(author)
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A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
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In: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
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Journal article (peer-reviewed)abstract
- African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
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| 4. |
- Nightingale, S., et al.
(author)
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Cognitive impairment in people living with HIV: consensus recommendations for a new approach
- 2023
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In: Nature Reviews Neurology. - 1759-4758. ; 19:7, s. 424-433
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Journal article (peer-reviewed)abstract
- Current approaches to classifying cognitive impairment in people living with HIV can overestimate disease burden and lead to ambiguity around disease mechanisms. In this Consensus Statement, the International HIV-Cognition Working Group have outlined six recommendations towards a new approach, intended to better represent changes in the spectrum of HIV disease in the modern era of antiretroviral therapy. Current approaches to classifying cognitive impairment in people living with HIV can overestimate disease burden and lead to ambiguity around disease mechanisms. The 2007 criteria for HIV-associated neurocognitive disorders (HAND), sometimes called the Frascati criteria, can falsely classify over 20% of cognitively healthy individuals as having cognitive impairment. Minimum criteria for HAND are met on the basis of performance on cognitive tests alone, which might not be appropriate for populations with diverse educational and socioeconomic backgrounds. Imprecise phenotyping of cognitive impairment can limit mechanistic research, biomarker discovery and treatment trials. Importantly, overestimation of cognitive impairment carries the risk of creating fear among people living with HIV and worsening stigma and discrimination towards these individuals. To address this issue, we established the International HIV-Cognition Working Group, which is globally representative and involves the community of people living with HIV. We reached consensus on six recommendations towards a new approach for diagnosis and classification of cognitive impairment in people living with HIV, intended to focus discussion and debate going forward. We propose the conceptual separation of HIV-associated brain injury - including active or pretreatment legacy damage - from other causes of brain injury occurring in people living with HIV. We suggest moving away from a quantitative neuropsychological approach towards an emphasis on clinical context. Our recommendations are intended to better represent the changing profile of cognitive impairment in people living with HIV in diverse global settings and to provide a clearer framework of classification for clinical management and research studies.
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| 5. |
- Winston, A, et al.
(author)
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Host and disease factors are associated with cognitive function in European HIV-infected adults prior to initiation of antiretroviral therapy
- 2016
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In: HIV Medicine. - : Wiley. - 1468-1293 .- 1464-2662. ; 17:6, s. 471-478
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Journal article (peer-reviewed)abstract
- OBJECTIVES: Deficits in cognitive function remain prevalent in HIV-infected individuals. The aim of this European multicentre study was to assess factors associated with cognitive function in antiretroviral therapy (ART)-naïve HIV-infected subjects at the time of enrolment in the NEAT 001/Agence Nationale de Recherche sur le SIDA (ANRS) 143 study.METHODS: Prior to starting ART, seven cognitive tests exploring domains including episodic memory, verbal fluency, executive function and psychomotor speed were administered with scores standardized to z-score using the study population sample mean and standard deviation. The primary measure was overall z-score average (NPZ). We assessed associations between baseline factors and test results using multivariable regression models.RESULTS: Of 283 subjects with baseline cognitive assessments, 90% were male and 12% of black ethnicity. Median (interquartile range) age, years of education, years of known HIV infection, baseline CD4 count and baseline HIV RNA were 39 (31, 47) years, 13 (11, 17) years, 1 (0, 4) years, 344 (279, 410) cells/μL and 4.74 (4.28, 5.14) log10 HIV-1 RNA copies/mL, respectively. Forty per cent were current smokers. Factors significantly associated with poorer overall cognitive performance in multivariable models included older age, shorter duration of education, black ethnicity, lower height, and lower plasma HIV RNA.CONCLUSIONS: In this large, European-wide, ART-naïve population with relatively preserved immunity and early HIV infection, cognitive function scores at the time of ART initiation were associated with demographic and HIV-disease factors.
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| 6. |
- Voight, Benjamin F., et al.
(author)
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Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:7, s. 579-589
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Journal article (peer-reviewed)abstract
- By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P < 5 x 10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.
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| 7. |
- Alagaratnam, J., et al.
(author)
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No evidence of neuronal damage as measured by neurofilament light chain in a HIV cure study utilising a kick-and-kill approach
- 2021
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In: Journal of Virus Eradication. - : Elsevier BV. - 2055-6640. ; 7:3
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Journal article (peer-reviewed)abstract
- Objective: HIV-remission strategies including kick-and-kill could induce viral transcription and immune activation in the central nervous system, potentially causing neuronal injury. We investigated the impact of kick-and-kill on plasma neurofilament light (NfL), a marker of neuro-axonal injury, in RIVER trial participants commencing antiretroviral treatment (ART) during primary infection and randomly allocated to ART-alone or kick-and-kill (ART + vaccination + vorinostat (ART + V + V)). Design: Sub-study measuring serial plasma NfL concentrations. Methods: Plasma NfL (using Simoa digital immunoassay), plasma HIV-1 RNA (using single-copy assay) and total HIV-1 DNA (using quantitative polymerase chain reaction in peripheral CD4(+) T-cells) were measured at randomisation (following >= 22 weeks ART), week 12 (on final intervention day in ART + V + V) and week 18 post randomisation. HIV-specific T-cells were quantified by intracellular cytokine staining at randomisation and week 12. Differences in plasma NfL longitudinally and by study arm were analysed using mixed models and Student's t-test. Associations with plasma NfL were assessed using linear regression and rank statistics. Results: At randomisation, 58 male participants had median age 32 years and CD4(+) count 696 cells/mu L. No significant difference in plasma NfL was seen longitudinally and by study arm, with median plasma NfL (pg/mL) in ART-only vs ART + V + V: 7.4 vs 6.4, p = 0.16 (randomisation), 8.0 vs 6.9, p = 0.22 (week 12) and 7.1 vs 6.8, p = 0.74 (week 18). Plasma NfL did not significantly correlate with plasma HIV-1 RNA and total HIV-1 DNA concentration in peripheral CD4(+) T-cells at any timepoint. While higher HIV-specific T-cell responses were seen at week 12 in ART + V + V, there were no significant correlations with plasma NfL. In multivariate analysis, higher plasma NfL was associated with older age, higher CD8(+) count and lower body mass index. Conclusions: Despite evidence of vaccine-induced HIV-specific T-cell responses, we observed no evidence of increased neuro-axonal injury using plasma NfL as a biomarker up to 18 weeks following kick-and-kill, compared with ART-only.
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| 8. |
- Booiman, T., et al.
(author)
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High Cellular Monocyte Activation in People Living With Human Immunodeficiency Virus on Combination Antiretroviral Therapy and Lifestyle-Matched Controls Is Associated With Greater Inflammation in Cerebrospinal Fluid
- 2017
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In: Open Forum Infectious Diseases. - : Oxford University Press (OUP). - 2328-8957. ; 4:3
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Journal article (peer-reviewed)abstract
- Background. Increased monocyte activation and intestinal damage have been shown to be predictive for the increased morbidity and mortality observed in treated people living with human immunodeficiency virus (PLHIV). Methods. A cross-sectional analysis of cellular and soluble markers of monocyte activation, coagulation, intestinal damage, and inflammation in plasma and cerebrospinal fluid (CSF) of PLHIV with suppressed plasma viremia on combination antiretroviral therapy and age and demographically comparable HIV-negative individuals participating in the Comorbidity in Relation to AIDS (COBRA) cohort and, where appropriate, age-matched blood bank donors (BBD). Results. People living with HIV, HIV-negative individuals, and BBD had comparable percentages of classical, intermediate, and nonclassical monocytes. Expression of CD163, CD32, CD64, HLA-DR, CD38, CD40, CD86, CD91, CD11c, and CX3CR1 on monocytes did not differ between PLHIV and HIV-negative individuals, but it differed significantly from BBD. Principal component analysis revealed that 57.5% of PLHIV and 62.5% of HIV-negative individuals had a high monocyte activation profile compared with 2.9% of BBD. Cellular monocyte activation in the COBRA cohort was strongly associated with soluble markers of monocyte activation and inflammation in the CSF. Conclusions. People living with HIV and HIV-negative COBRA participants had high levels of cellular monocyte activation compared with age-matched BBD. High monocyte activation was predictive for inflammation in the CSF.
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| 9. |
- Caby, F, et al.
(author)
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CD4/CD8 Ratio and the Risk of Kaposi Sarcoma or Non-Hodgkin Lymphoma in the Context of Efficiently Treated Human Immunodeficiency Virus (HIV) Infection: A Collaborative Analysis of 20 European Cohort Studies
- 2021
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In: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. - : Oxford University Press (OUP). - 1537-6591. ; 73:1, s. 50-59
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Journal article (peer-reviewed)abstract
- BackgroundA persistently low CD4/CD8 ratio has been reported to inversely correlate with the risk of non-AIDS defining cancer in people living with human immunodeficiency virus (HIV; PLWH) efficiently treated by combination antiretroviral therapy (cART). We evaluated the impact of the CD4/CD8 ratio on the risk of Kaposi sarcoma (KS) or non-Hodgkin lymphoma (NHL), still among the most frequent cancers in treated PLWH.MethodsPLWH from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) were included if they achieved virological control (viral load ≤ 500 copies/mL) within 9 months following cART and without previous KS/LNH diagnosis. Cox models were used to identify factors associated with KS or NHL risk, in all participants and those with CD4 ≥ 500/mm3 at virological control. We analyzed the CD4/CD8 ratio, CD4 count and CD8 count as time-dependent variables, using spline transformations.ResultsWe included 56 708 PLWH, enrolled between 2000 and 2014. At virological control, the median (interquartile range [IQR]) CD4 count, CD8 count, and CD4/CD8 ratio were 414 (296–552)/mm3, 936 (670–1304)/mm3, and 0.43 (0.28–0.65), respectively. Overall, 221 KS and 187 NHL were diagnosed 9 (2–37) and 18 (7–42) months after virological control. Low CD4/CD8 ratios were associated with KS risk (hazard ratio [HR] = 2.02 [95% confidence interval {CI } = 1.23–3.31]) when comparing CD4/CD8 = 0.3 to CD4/CD8 = 1) but not with NHL risk. High CD8 counts were associated with higher NHL risk (HR = 3.14 [95% CI = 1.58–6.22]) when comparing CD8 = 3000/mm3 to CD8 = 1000/mm3). Similar results with increased associations were found in PLWH with CD4 ≥ 500/mm3 at virological control (HR = 3.27 [95% CI = 1.60–6.56] for KS; HR = 5.28 [95% CI = 2.17–12.83] for NHL).ConclusionsLow CD4/CD8 ratios and high CD8 counts despite effective cART were associated with increased KS/NHL risks respectively, especially when CD4 ≥ 500/mm3.
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| 10. |
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| 11. |
- Rakshasa-Loots, A. M., et al.
(author)
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Biomarkers of central and peripheral inflammation mediate the association between HIV and depressive symptoms
- 2023
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In: Translational Psychiatry. - 2158-3188. ; 13:1
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Journal article (peer-reviewed)abstract
- People living with HIV are at increased risk for depression, though the underlying mechanisms for this are unclear. In the general population, depression is associated with peripheral and central inflammation. Given this, and since HIV infection elicits inflammation, we hypothesised that peripheral and central inflammatory biomarkers would at least partly mediate the association between HIV and depressive symptoms. People living with HIV (n = 125) and without HIV (n = 79) from the COmorBidity in Relation to AIDS (COBRA) cohort were included in this study. Participants living with and without HIV had similar baseline characteristics. All participants living with HIV were on antiretroviral therapy and were virally suppressed. Plasma, CSF, and brain MR spectroscopy (MRS) biomarkers were measured. Using logistic regression models adjusted for sociodemographic factors, we found that participants with HIV were more likely to have Any Depressive Symptoms (Patient Health Questionnaire [PHQ-9] score >4) (odds ratio [95% confidence interval] 3.27 [1.46, 8.09]). We then sequentially adjusted the models for each biomarker separately to determine the mediating role of each biomarker, with a >10% reduction in OR considered as evidence of potential mediation. Of the biomarkers analysed, MIG (-15.0%) and TNF-alpha (-11.4%) in plasma and MIP1-alpha (-21.0%) and IL-6 (-18.0%) in CSF mediated the association between HIV and depressive symptoms in this sample. None of the other soluble or neuroimaging biomarkers substantially mediated this association. Our findings suggest that certain biomarkers of central and peripheral inflammation may at least partly mediate the relationship between HIV and depressive symptoms.
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| 12. |
- Van Zoest, Rosan A, et al.
(author)
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Structural brain abnormalities in successfully treated HIV infection: associations with disease and cerebrospinal fluid biomarkers.
- 2018
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In: The Journal of infectious diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 217:1, s. 69-81
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Journal article (peer-reviewed)abstract
- Brain structural abnormalities have been reported in persons with HIV (PWH) on suppressive combination antiretroviral therapy (cART), but their pathophysiology remains unclear.We investigated factors associated with brain tissue volumes and white matter microstructure (fractional anisotropy) in 134 PWH on suppressive cART and 79 comparable HIV-negative controls, aged ≥45 years from the Co-morBidity in Relation to AIDS (COBRA) cohort, using multimodal neuroimaging and cerebrospinal fluid (CSF) biomarkers.Compared to controls, PWH had lower grey matter volumes (-13.7 mL [95%-confidence interval -25.1, -2.2 mL]) and fractional anisotropy (-0.0073 [-0.012, -0.0024]), with the largest differences observed in those with prior clinical AIDS. Hypertension and CSF soluble CD14 concentration were associated with lower fractional anisotropy. These associations were independent of HIV serostatus (Pinteraction=0.32 and Pinteraction=0.59, respectively) and did not explain the greater abnormalities in brain structure in relation to HIV.The presence of lower grey matter volumes and more white matter microstructural abnormalities in well-treated PWH partly reflect a combination of historical effects of AIDS, as well as the more general influence of systemic factors such as hypertension and ongoing neuroinflammation. Additional mechanisms explaining the accentuation of brain structure abnormalities in treated HIV infection remain to be identified.
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| 13. |
- Babbin, Brian A., et al.
(author)
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Annexin A1 regulates intestinal mucosal injury, inflammation, and repair
- 2008
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In: Journal of Immunology. - Bethesda, United States : American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 181:7, s. 5035-5044
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Journal article (peer-reviewed)abstract
- During mucosal inflammation, a complex array of proinflammatory and protective mechanisms regulates inflammation and severity of injury. Secretion of anti-inflammatory mediators is a mechanism that is critical in controlling inflammatory responses and promoting epithelial restitution and barrier recovery. AnxA1 is a potent anti-inflammatory protein that has been implicated to play a critical immune regulatory role in models of inflammation. Although AnxA1 has been shown to be secreted in intestinal mucosal tissues during inflammation, its potential role in modulating the injury/inflammatory response is not understood. In this study, we demonstrate that AnxA1-deficient animals exhibit increased susceptibility to dextran sulfate sodium (DSS)-induced colitis with greater clinical morbidity and histopathologic mucosal injury. Furthermore, impaired recovery following withdrawal of DSS administration was observed in AnxA1 (-/-) animals compared with wild-type (WT) control mice that was independent of inflammatory cell infiltration. Since AnxA1 exerts its anti-inflammatory properties through stimulation of ALX/FPRL-1, we explored the role of this receptor-ligand interaction in regulating DSS-induced colitis. Interestingly, treatment with an ALX/FPRL-1 agonist, 15-epi-lipoxin A4 reversed the enhanced sensitivity of AnxA1 (-/-) mice to DSS colitis. In contrast, 15-epi-lipoxin A4 did not significantly improve the severity of disease in WT animals. Additionally, differential expression of ALX/FPLR-1 in control and DSS-treated WT and AnxA1-deficient animals suggested a potential role for AnxA1 in regulating ALX/FPRL-1 expression under pathophysiological conditions. Together, these results support a role of endogenous AnxA1 in the protective and reparative properties of the intestinal mucosal epithelium.
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| 14. |
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| 15. |
- Kaneda, Atsushi, et al.
(author)
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Enhanced sensitivity to IGF-II signalling links loss of imprinting of IGF2 to increased cell proliferation and tumour risk
- 2007
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 104:52, s. 20926-20931
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Journal article (peer-reviewed)abstract
- Loss of imprinting (LOI) of the insulin-like growth factor-II gene (IGF2), leading to abnormal activation of the normally silent maternal allele, is a common human epigenetic population variant associated with a 5-fold increased frequency of colorectal neoplasia. Here, we show first that LOI leads specifically to increased expression of proliferation-related genes in mouse intestinal crypts. Surprisingly, LOI(+) mice also have enhanced sensitivity to IGF-II signaling, not simply increased IGF-II levels, because in vivo blockade with NVP-AEW541, a specific inhibitor of the IGF-II signaling receptor, showed reduction of proliferation-related gene expression to levels half that seen in LOI(-) mice. Signal transduction assays in microfluidic chips confirmed this enhanced sensitivity with marked augmentation of Akt/PKB signaling in LOI(+) cells at low doses of IGF-II, which was reduced in the presence of the inhibitor to levels below those found in LOI(-) cells, and was associated with increased expression of the IGF1 and insulin receptor genes. We exploited this increased IGF-II sensitivity to develop an in vivo chemopreventive strategy using the azoxymethane (AOM) mutagenesis model. LOI(+) mice treated with AOM showed a 60% increase in premalignant aberrant crypt foci (ACF) formation over LOI(-) mice. In vivo IGF-II blockade with NVP-AEW541 abrogated this effect, reducing ACF to a level 30% lower even than found in exposed LOI(-) mice. Thus, LOI increases cancer risk in a counterintuitive way, by increasing the sensitivity of the IGF-II signaling pathway itself, providing a previously undescribed epigenetic chemoprevention strategy in which cells with LOI are "IGF-II addicted" and undergo reduced tumorigenesis in the colon upon IGF-II pathway blockade.
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| 16. |
- Nightingale, S., et al.
(author)
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Moving on From HAND: Why We Need New Criteria for Cognitive Impairment in Persons Living With Human Immunodeficiency Virus and a Proposed Way Forward
- 2021
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In: Clinical Infectious Diseases. - : Oxford University Press (OUP). - 1058-4838 .- 1537-6591. ; 73:6, s. 1113-1118
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Journal article (peer-reviewed)abstract
- Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) criteria are frequently used to describe cognitive impairment in persons living with HIV (PLWH) across diverse populations globally. These criteria typically find 20-60% of PLWH meet criteria for HAND, which does not tally with clinical observations in the modern era that cognitive disorders present relatively infrequently. Most with HAND have asymptomatic neurocognitive impairment; however, the significance of low cognitive test performance without symptoms is uncertain. Methods underlying HAND criteria carry a false-positive rate that can exceed 20%. Comorbidities, education, and complex socioeconomic factors can influence cognitive test performance, further increasing the potential for misclassification. We propose a new framework to characterize cognitive impairment in PLWH that requires a clinical history and acknowledges the multifactorial nature of low cognitive test performance. This framework is intended to be applicable across diverse populations globally, be more aligned with clinical observations, and more closely represent HIV brain pathology.
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| 17. |
- Vakharia, V. N., et al.
(author)
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Computer-assisted planning for the insertion of stereoelectroencephalography electrodes for the investigation of drug-resistant focal epilepsy: an external validation study
- 2019
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In: Journal of Neurosurgery. - 0022-3085. ; 130:2, s. 601-610
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Journal article (peer-reviewed)abstract
- OBJECTIVE One-third of cases of focal epilepsy are drug refractory, and surgery might provide a cure. Seizure-free outcome after surgery depends on the correct identification and resection of the epileptogenic zone. In patients with no visible abnormality on MRI, or in cases in which presurgical evaluation yields discordant data, invasive stereoelectroencephalography (SEEG) recordings might be necessary. SEEG is a procedure in which multiple electrodes are placed stereotactically in key targets within the brain to record interictal and ictal electrophysiological activity. Correlating this activity with seizure semiology enables identification of the seizure-onset zone and key structures within the ictal network. The main risk related to electrode placement is hemorrhage, which occurs in 1% of patients who undergo the procedure. Planning safe electrode placement for SEEG requires meticulous adherence to the following: 1) maximize the distance from cerebral vasculature, 2) avoid crossing sulcal pial boundaries (sulci), 3) maximize gray matter sampling, 4) minimize electrode length, 5) drill at an angle orthogonal to the skull, and 6) avoid critical neurological structures. The authors provide a validation of surgical strategizing and planning with EpiNav, a multimodal platform that enables automated computer-assisted planning (CAP) for electrode placement with user-defined regions of interest. METHODS Thirteen consecutive patients who underwent implantation of a total 116 electrodes over a 15-month period were studied retrospectively. Models of the cortex, gray matter, and sulci were generated from patient-specific whole-brain parcellation, and vascular segmentation was performed on the basis of preoperative MR venography. Then, the multidisciplinary implantation strategy and precise trajectory planning were reconstructed using CAP and compared with the implemented manually determined plans. Paired results for safety metric comparisons were available for 104 electrodes. External validity of the suitability and safety of electrode entry points, trajectories, and target-point feasibility was sought from 5 independent, blinded experts from outside institutions. RESULTS CAP-generated electrode trajectories resulted in a statistically significant improvement in electrode length, drilling angle, gray matter-sampling ratio, minimum distance from segmented vasculature, and risk (p < 0.05). The blinded external raters had various opinions of trajectory feasibility that were not statistically significant, and they considered a mean of 69.4% of manually determined trajectories and 62.2% of CAP-generated trajectories feasible; 19.4% of the CAP-generated electrode-placement plans were deemed feasible when the manually determined plans were not, whereas 26.5% of the manually determined electrode-placement plans were rated feasible when CAP-determined plans were not (no significant difference). CONCLUSIONS CAP generates clinically feasible electrode-placement plans and results in statistically improved safety metrics. CAP is a useful tool for automating the placement of electrodes for SEEG; however, it requires the operating surgeon to review the results before implantation, because only 62% of electrode-placement plans were rated feasible, compared with 69% of the manually determined placement plans, mainly because of proximity of the electrodes to un-segmented vasculature. Improved vascular segmentation and sulcal modeling could lead to further improvements in the feasibility of CAP-generated trajectories.
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| 18. |
- Alagaratnam, Jasmini, et al.
(author)
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Correlation between cerebrospinal fluid and plasma neurofilament light protein in treated HIV infection: results from the COBRA study.
- 2022
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In: Journal of neurovirology. - : Springer Science and Business Media LLC. - 1538-2443 .- 1355-0284. ; 28:1, s. 54-63
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Journal article (peer-reviewed)abstract
- Cerebrospinal fluid (CSF) neurofilament light protein (NfL) is a marker of central nervous system neuro-axonal injury. A novel, ultra-sensitive assay can determine plasma NfL. In untreated people-with-HIV (PWH), CSF and plasma NfL are strongly correlated. We aimed to assess this correlation in PWH on suppressive antiretroviral treatment (ART) and lifestyle-similar HIV-negative individuals enrolled into the COmorBidity in Relation to AIDS (COBRA) study. Differences in paired CSF (sandwich ELISA, UmanDiagnostics) and plasma (Simoa digital immunoassay, Quanterix™) NfL between PWH and HIV-negative participants were tested using Wilcoxon's test; associations were assessed using Pearson's correlation. CSF and plasma NfL, standardised to Z-scores, were included as dependent variables in linear regression models to identify factors independently associated with values in PWH and HIV-negative participants. Overall, 132 PWH (all with plasma HIV RNA<50 copies/mL) and 79 HIV-negative participants were included. Neither CSF (median 570 vs 568pg/mL, p=0.37) nor plasma (median 10.7 vs 9.9pg/mL, p=0.15) NfL differed significantly between PWH and HIV-negative participants, respectively. CSF and plasma NfL correlated moderately, with no significant difference by HIV status (PWH: rho=0.52; HIV-negative participants: rho=0.47, p (interaction)=0.63). In multivariable regression analysis, higher CSF NfL Z-score was statistically significantly associated with older age and higher CSF protein, and higher plasma NfL Z-score with older age, higher serum creatinine and lower bodyweight. In conclusion, in PWH on ART, the correlation between CSF and plasma NfL is moderate and similar to that observed in lifestyle-similar HIV-negative individuals. Consideration of renal function and bodyweight may be required when utilising plasma NfL.
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| 19. |
- Andersen, Casper W., et al.
(author)
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OPTIMADE, an API for exchanging materials data
- 2021
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In: Scientific Data. - : Nature Portfolio. - 2052-4463. ; 8:1
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Journal article (peer-reviewed)abstract
- The Open Databases Integration for Materials Design (OPTIMADE) consortium has designed a universal application programming interface (API) to make materials databases accessible and interoperable. We outline the first stable release of the specification, v1.0, which is already supported by many leading databases and several software packages. We illustrate the advantages of the OPTIMADE API through worked examples on each of the public materials databases that support the full API specification.
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| 20. |
- Chemaly, RF, et al.
(author)
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A Phase 2, Randomized, Double-blind, Placebo-Controlled Trial of Presatovir for the Treatment of Respiratory Syncytial Virus Upper Respiratory Tract Infection in Hematopoietic-Cell Transplant Recipients
- 2020
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In: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. - : Oxford University Press (OUP). - 1537-6591. ; 71:11, s. 2777-2786
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Journal article (peer-reviewed)abstract
- BackgroundHematopoietic-cell transplant (HCT) recipients are at risk for severe respiratory syncytial virus (RSV) infection. We evaluated the RSV fusion inhibitor presatovir in a randomized, double-blind, Phase II trial in HCT recipients with RSV upper respiratory tract infections.MethodsPatients were stratified by lymphopenia (<200/µL) and ribavirin use; were randomized, stratified by lymphopenia (<200/μL) and ribavirin use, to receive oral presatovir at 200 mg or a placebo on Days 1, 5, 9, 13, and 17, and were followed through Day 28. The coprimary efficacy endpoints were the time-weighted average change in the nasal RSV viral load between Days 1 and 9 and the proportion of patients developing lower respiratory tract complications (LRTCs) through Day 28.ResultsFrom 23 January 2015 to 16 June 2017, 189 patients were randomly assigned to treatment (96 to presatovir and 93 to the placebo). Presatovir treatment, compared with the placebo treatment, did not significantly affect (prespecified α = 0.01) a time-weighted average decline in the RSV viral load from Day 1 to 9 (treatment difference, −0.33 log10 copies/mL; 95% confidence interval [CI] −.64 to −.02 log10 copies/mL; P = .040) or the progression to LRTC (11.2% vs 19.5%, respectively; odds ratio, 0.50; 95% CI, .22–1.18; P = .11). In a post hoc analysis among patients with lymphopenia, presatovir decreased LRTC development by Day 28 (2/15 [13.3%] vs 9/14 [64.3%], respectively; P = .008), compared with the placebo. Adverse events were similar for patients receiving presatovir and the placebo.ConclusionsPresatovir had a favorable safety profile in adult HCT recipients with RSV but did not achieve the coprimary endpoints. Exploratory analyses suggest an antiviral effect among patients with lymphopenia.Clinical Trials RegistrationNCT02254408; EUDRA-CT#2014-002474-36.
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| 21. |
- Duggan, P, et al.
(author)
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Gamma-ray bursts and X-ray melting of material to form chondrules and planets
- 2003
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In: Astronomy & Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 409:2, s. 9-12
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Journal article (peer-reviewed)abstract
- Chondrules are millimeter sized objects of spherical to irregular shape that constitute the major component of chondritic meteorites that originate in the region between Mars and Jupiter and which fall to Earth. They appear to have solidified rapidly from molten or partially molten drops. The heat source that melted the chondrules remains uncertain. The intense radiation from a gamma-ray burst (GRB) is capable of melting material at distances up to 300 light years. These conditions were created in the laboratory for the first time when millimeter sized pellets were placed in a vacuum chamber in the white synchrotron beam at the European Synchrotron Radiation Facility (ESRF). The pellets were rapidly heated in the X-ray and gamma-ray furnace to above 1400 degreesC melted and cooled. This process heats from the inside unlike normal furnaces. The melted spherical samples were examined with a range of techniques and found to have microstructural properties similar to the chondrules that come from meteorites. This experiment demonstrates that GRBs can melt precursor material to form chondrules that may subsequently influence the formation of planets. This work extends the field of laboratory astrophysics to include high power synchrotron sources.
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| 22. |
- Evans, Matthew L., et al.
(author)
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Developments and applications of the OPTIMADE API for materials discovery, design, and data exchange
- 2024
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In: Digital Discovery. - : ROYAL SOC CHEMISTRY. - 2635-098X.
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Journal article (peer-reviewed)abstract
- The Open Databases Integration for Materials Design (OPTIMADE) application programming interface (API) empowers users with holistic access to a growing federation of databases, enhancing the accessibility and discoverability of materials and chemical data. Since the first release of the OPTIMADE specification (v1.0), the API has undergone significant development, leading to the v1.2 release, and has underpinned multiple scientific studies. In this work, we highlight the latest features of the API format, accompanying software tools, and provide an update on the implementation of OPTIMADE in contributing materials databases. We end by providing several use cases that demonstrate the utility of the OPTIMADE API in materials research that continue to drive its ongoing development. The Open Databases Integration for Materials Design (OPTIMADE) application programming interface (API) empowers users with holistic access to a federation of databases, enhancing the accessibility and discoverability of materials and chemical data.
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| 23. |
- Gallenne, A., et al.
(author)
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A Geometrical 1% Distance to the Short-period Binary Cepheid V1334 Cygni
- 2018
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In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 867:2
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Journal article (peer-reviewed)abstract
- Cepheid stars play a considerable role as extragalactic distances indicators, thanks to the simple empirical relation between their pulsation period and their luminosity. They overlap with that of secondary distance indicators, such as Type Ia supernovae, whose distance scale is tied to Cepheid luminosities. However, the period-luminosity (P-L) relation still lacks a calibration to better than 5%. Using an original combination of interferometric astrometry with optical and ultraviolet spectroscopy, we measured the geometrical distance d = 720.35 +/- 7.84 pc of the 3.33 day period Cepheid V1334 Cyg with an unprecedented accuracy of +/- 1%, providing the most accurate distance for a Cepheid. Placing this star in the P-L diagram provides an independent test of existing P-L relations. We show that the secondary star has a significant impact on the integrated magnitude, particularly at visible wavelengths. Binarity in future high-precision calibrations of the P-L relations is not negligible, at least in the short-period regime. Subtracting the companion flux leaves V1334 Cyg in marginal agreement with existing photometric-based P-L relations, indicating either an overall calibration bias or a significant intrinsic dispersion at a few percent level. Our work also enabled us to determine the dynamical masses of both components, M-1 = 4.288 +/- 0.133 M-circle dot (Cepheid) and M-2 = 4.040 +/- 0.048 M-circle dot (companion), providing the most accurate masses for a Galactic binary Cepheid system.
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| 24. |
- Janko, Matthew R., et al.
(author)
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In-situ bypass is associated with superior infection-free survival compared with extra-anatomic bypass for the management of secondary aortic graft infections without enteric involvement
- 2022
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In: Journal of Vascular Surgery. - : Elsevier. - 0741-5214 .- 1097-6809. ; 76:2, s. 546-
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Journal article (peer-reviewed)abstract
- Objective: The optimal revascularization modality following complete resection of aortic graft infection (AGI) without enteric involvement remains unclear. The purpose of this investigation is to determine the revascularization approach associated with the lowest morbidity and mortality using real-world data in patients undergoing complete excision of AGI. Methods: A retrospective, multi-institutional study of AGI from 2002 to 2014 was performed using a standardized database. Baseline demographics, comorbidities, and perioperative variables were recorded. The primary outcome was infection-free survival. Descriptive statistics, Kaplan-Meier survival analysis, and univariate and multivariable analyses were performed. Results: A total of 241 patients at 34 institutions from seven countries presented with AGI during the study period (median age, 68 years; 75% male). The initial aortic procedures that resulted in AGI were 172 surgical grafts (71%), 66 endografts (27%), and three unknown (2%). Of the patients, 172 (71%) underwent complete excision of infected aortic graft material followed by in situ (in-line) bypass (ISB), including antibiotic-treated prosthetic graft (35%), autogenous femoral vein (neo-aortoiliac surgery) (24%), and cryopreserved allograft (41%). Sixty-nine patients (29%) underwent extra-anatomic bypass (EAB). Overall median Kaplan-Meier estimated survival was 5.8 years. Perioperative mortality was 16%. When stratified by ISB vs EAB, there was a significant difference in Kaplan-Meier estimated infection-free survival (2910 days; interquartile range, 391-3771 days vs 180 days; interquartile range, 27-3750 days; P <.001). There were otherwise no significant differences in presentation, comorbidities, or perioperative variables. Multivariable Cox regression showed lower infection-free survival among patients with EAB (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.6-3.6; P <.001), polymicrobial infection (HR, 2.2; 95% CI, 1.4-3.5; P = .001), methicillin-resistant Staphylococcus aureus infection (HR, 1.7; 95% CI, 1.1-2.7; P = .02), as well as the protective effect of omental/muscle flap coverage (HR, 0.59; 95% CI, 0.37-0.92; P = .02). Conclusions: After complete resection of AGI, perioperative mortality is 16% and median overall survival is 5.8 years. EAB is associated with nearly a two and one-half-fold higher reinfection/mortality compared with ISB. Omental and/or muscle flap coverage of the repair appear protective.
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