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  • 1
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    Online Resource
    MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in amyotrophic lateral sclerosis-frontotemporal dementia
    Oxford University Press (OUP) ; 2021
    In:  Brain Communications Vol. 3, No. 2 ( 2021-04-05)
    Details
    In: Brain Communications, Oxford University Press (OUP), Vol. 3, No. 2 ( 2021-04-05)
    Abstract: Amyotrophic lateral sclerosis and frontotemporal dementia are overlapping diseases in which MRI reveals brain structural changes in advance of symptom onset. Recapitulating these changes in preclinical models would help to improve our understanding of the molecular causes underlying regionally selective brain atrophy in early disease. We therefore investigated the translational potential of the TDP-43Q331K knock-in mouse model of amyotrophic lateral sclerosis-frontotemporal dementia using MRI. We performed in vivo MRI of TDP-43Q331K knock-in mice. Regions of significant volume change were chosen for post-mortem brain tissue analyses. Ex vivo computed tomography was performed to investigate skull shape. Parvalbumin neuron density was quantified in post-mortem amyotrophic lateral sclerosis frontal cortex. Adult mutants demonstrated parenchymal volume reductions affecting the frontal lobe and entorhinal cortex in a manner reminiscent of amyotrophic lateral sclerosis-frontotemporal dementia. Subcortical, cerebellar and brain stem regions were also affected in line with observations in pre-symptomatic carriers of mutations in C9orf72, the commonest genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Volume loss was also observed in the dentate gyrus of the hippocampus, along with ventricular enlargement. Immunohistochemistry revealed reduced parvalbumin interneurons as a potential cellular correlate of MRI changes in mutant mice. By contrast, microglia was in a disease activated state even in the absence of brain volume loss. A reduction in immature neurons was found in the dentate gyrus, indicative of impaired adult neurogenesis, while a paucity of parvalbumin interneurons in P14 mutant mice suggests that TDP-43Q331K disrupts neurodevelopment. Computerized tomography imaging showed altered skull morphology in mutants, further suggesting a role for TDP-43Q331K in development. Finally, analysis of human post-mortem brains confirmed a paucity of parvalbumin interneurons in the prefrontal cortex in sporadic amyotrophic lateral sclerosis and amyotrophic lateral sclerosis linked to C9orf72 mutations. Regional brain MRI changes seen in human amyotrophic lateral sclerosis-frontotemporal dementia are recapitulated in TDP-43Q331K knock-in mice. By marrying in vivo imaging with targeted histology, we can unravel cellular and molecular processes underlying selective brain vulnerability in human disease. As well as helping to understand the earliest causes of disease, our MRI and histological markers will be valuable in assessing the efficacy of putative therapeutics in TDP-43Q331K knock-in mice.
    Type of Medium: Online Resource
    ISSN: 2632-1297
    URL: Article
    DOI: 10.1093/braincomms/fcab114
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 3020013-1
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  • 2
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    2272. High Interest in Doxycycline for Sexually Transmitted Infection Post-Exposure Prophylaxis (Doxy-PEP) in a Multi-city Survey of Men Having Sex With Men (MSM) Using a Social-Networking App
    Oxford University Press (OUP) ; 2018
    In:  Open Forum Infectious Diseases Vol. 5, No. suppl_1 ( 2018-11-26), p. S672-S673
    Details
    In: Open Forum Infectious Diseases, Oxford University Press (OUP), Vol. 5, No. suppl_1 ( 2018-11-26), p. S672-S673
    Type of Medium: Online Resource
    ISSN: 2328-8957
    URL: Article
    DOI: 10.1093/ofid/ofy210.1925
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2018
    detail.hit.zdb_id: 2757767-3
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  • 3
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    Characteristics of amnestic patients with hypometabolism patterns suggestive of Lewy body pathology
    Oxford University Press (OUP) ; 2023
    In:  Brain ( 2023-06-07)
    Details
    In: Brain, Oxford University Press (OUP), ( 2023-06-07)
    Abstract: A clinical diagnosis of Alzheimer’s disease dementia (ADD) encompasses considerable pathological and clinical heterogeneity. While Alzheimer’s disease patients typically show a characteristic temporo-parietal pattern of glucose hypometabolism on 18F-fluorodeoxyglucose (FDG)-PET imaging, previous studies have identified a subset of patients showing a distinct posterior-occipital hypometabolism pattern associated with Lewy body pathology. Here, we aimed to improve the understanding of the clinical relevance of these posterior-occipital FDG-PET patterns in patients with Alzheimer’s disease-like amnestic presentations. Our study included 1214 patients with clinical diagnoses of ADD (n = 305) or amnestic mild cognitive impairment (aMCI, n = 909) from the Alzheimer’s Disease Neuroimaging Initiative, who had FDG-PET scans available. Individual FDG-PET scans were classified as being suggestive of Alzheimer’s (AD-like) or Lewy body (LB-like) pathology by using a logistic regression classifier trained on a separate set of patients with autopsy-confirmed Alzheimer’s disease or Lewy body pathology. AD- and LB-like subgroups were compared on amyloid-β and tau-PET, domain-specific cognitive profiles (memory versus executive function performance), as well as the presence of hallucinations and their evolution over follow-up (≈6 years for aMCI, ≈3 years for ADD). Around 12% of the aMCI and ADD patients were classified as LB-like. For both aMCI and ADD patients, the LB-like group showed significantly lower regional tau-PET burden than the AD-like subgroup, but amyloid-β load was only significantly lower in the aMCI LB-like subgroup. LB- and AD-like subgroups did not significantly differ in global cognition (aMCI: d = 0.15, P = 0.16; ADD: d = 0.02, P = 0.90), but LB-like patients exhibited a more dysexecutive cognitive profile relative to the memory deficit (aMCI: d = 0.35, P = 0.01; ADD: d = 0.85 P & lt; 0.001), and had a significantly higher risk of developing hallucinations over follow-up [aMCI: hazard ratio = 1.8, 95% confidence interval = (1.29, 3.04), P = 0.02; ADD: hazard ratio = 2.2, 95% confidence interval = (1.53, 4.06) P = 0.01]. In summary, a sizeable group of clinically diagnosed ADD and aMCI patients exhibit posterior-occipital FDG-PET patterns typically associated with Lewy body pathology, and these also show less abnormal Alzheimer’s disease biomarkers as well as specific clinical features typically associated with dementia with Lewy bodies.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awad194
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 4
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    Determinants of cognitive and brain resilience to tau pathology: a longitudinal analysis
    Oxford University Press (OUP) ; 2023
    In:  Brain Vol. 146, No. 9 ( 2023-09-01), p. 3719-3734
    Details
    In: Brain, Oxford University Press (OUP), Vol. 146, No. 9 ( 2023-09-01), p. 3719-3734
    Abstract: Mechanisms of resilience against tau pathology in individuals across the Alzheimer’s disease spectrum are insufficiently understood. Longitudinal data are necessary to reveal which factors relate to preserved cognition (i.e. cognitive resilience) and brain structure (i.e. brain resilience) despite abundant tau pathology, and to clarify whether these associations are cross-sectional or longitudinal. We used a longitudinal study design to investigate the role of several demographic, biological and brain structural factors in yielding cognitive and brain resilience to tau pathology as measured with PET. In this multicentre study, we included 366 amyloid-β-positive individuals with mild cognitive impairment or Alzheimer’s disease dementia with baseline 18F-flortaucipir-PET and longitudinal cognitive assessments. A subset (n = 200) additionally underwent longitudinal structural MRI. We used linear mixed-effects models with global cognition and cortical thickness as dependent variables to investigate determinants of cognitive resilience and brain resilience, respectively. Models assessed whether age, sex, years of education, APOE-ε4 status, intracranial volume (and cortical thickness for cognitive resilience models) modified the association of tau pathology with cognitive decline or cortical thinning. We found that the association between higher baseline tau-PET levels (quantified in a temporal meta-region of interest) and rate of cognitive decline (measured with repeated Mini-Mental State Examination) was adversely modified by older age (Stβinteraction = −0.062, P = 0.032), higher education level (Stβinteraction = −0.072, P = 0.011) and higher intracranial volume (Stβinteraction = −0.07, P = 0.016). Younger age, higher education and greater cortical thickness were associated with better cognitive performance at baseline. Greater cortical thickness was furthermore associated with slower cognitive decline independent of tau burden. Higher education also modified the negative impact of tau-PET on cortical thinning, while older age was associated with higher baseline cortical thickness and slower rate of cortical thinning independent of tau. Our analyses revealed no (cross-sectional or longitudinal) associations for sex and APOE-ε4 status on cognition and cortical thickness. In this longitudinal study of clinically impaired individuals with underlying Alzheimer’s disease neuropathological changes, we identified education as the most robust determinant of both cognitive and brain resilience against tau pathology. The observed interaction with tau burden on cognitive decline suggests that education may be protective against cognitive decline and brain atrophy at lower levels of tau pathology, with a potential depletion of resilience resources with advancing pathology. Finally, we did not find major contributions of sex to brain nor cognitive resilience, suggesting that previous links between sex and resilience might be mainly driven by cross-sectional differences.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awad100
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 5
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    Molecular genetic overlap between posttraumatic stress disorder and sleep phenotypes
    Oxford University Press (OUP) ; 2020
    In:  Sleep Vol. 43, No. 4 ( 2020-04-15)
    Details
    In: Sleep, Oxford University Press (OUP), Vol. 43, No. 4 ( 2020-04-15)
    Abstract: Sleep problems are common, serving as both a predictor and symptom of posttraumatic stress disorder (PTSD), with these bidirectional relationships well established in the literature. While both sleep phenotypes and PTSD are moderately heritable, there has been a paucity of investigation into potential genetic overlap between sleep and PTSD. Here, we estimate genetic correlations between multiple sleep phenotypes (including insomnia symptoms, sleep duration, daytime sleepiness, and chronotype) and PTSD, using results from the largest genome-wide association study (GWAS) to date of PTSD, as well as publicly available GWAS results for sleep phenotypes within UK Biobank data (23 variations, encompassing four main phenotypes). Methods Genetic correlations were estimated utilizing linkage disequilibrium score regression (LDSC), an approach that uses GWAS summary statistics to compute genetic correlations across traits, and Mendelian randomization (MR) analyses were conducted to follow up on significant correlations. Results Significant, moderate genetic correlations were found between insomnia symptoms (rg range 0.36–0.49), oversleeping (rg range 0.32–0.44), undersleeping (rg range 0.48–0.49), and PTSD. In contrast, there were mixed results for continuous sleep duration and daytime sleepiness phenotypes, and chronotype was not correlated with PTSD. MR analyses did not provide evidence for casual effects of sleep phenotypes on PTSD. Conclusion Sleep phenotypes, particularly insomnia symptoms and extremes of sleep duration, have shared genetic etiology with PTSD, but causal relationships were not identified. This highlights the importance of further investigation into the overlapping influences on these phenotypes as sample sizes increase and new methods to investigate directionality and causality become available.
    Type of Medium: Online Resource
    ISSN: 0161-8105 , 1550-9109
    URL: Article
    DOI: 10.1093/sleep/zsz257
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 2056761-3
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  • 6
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    Global overview of the management of acute cholecystitis during the COVID-19 pandemic (CHOLECOVID study)
    Oxford University Press (OUP) ; 2022
    In:  BJS Open Vol. 6, No. 3 ( 2022-05-02)
    Details
    In: BJS Open, Oxford University Press (OUP), Vol. 6, No. 3 ( 2022-05-02)
    Abstract: This study provides a global overview of the management of patients with acute cholecystitis during the initial phase of the COVID-19 pandemic. Methods CHOLECOVID is an international, multicentre, observational comparative study of patients admitted to hospital with acute cholecystitis during the COVID-19 pandemic. Data on management were collected for a 2-month study interval coincident with the WHO declaration of the SARS-CoV-2 pandemic and compared with an equivalent pre-pandemic time interval. Mediation analysis examined the influence of SARS-COV-2 infection on 30-day mortality. Results This study collected data on 9783 patients with acute cholecystitis admitted to 247 hospitals across the world. The pandemic was associated with reduced availability of surgical workforce and operating facilities globally, a significant shift to worse severity of disease, and increased use of conservative management. There was a reduction (both absolute and proportionate) in the number of patients undergoing cholecystectomy from 3095 patients (56.2 per cent) pre-pandemic to 1998 patients (46.2 per cent) during the pandemic but there was no difference in 30-day all-cause mortality after cholecystectomy comparing the pre-pandemic interval with the pandemic (13 patients (0.4 per cent) pre-pandemic to 13 patients (0.6 per cent) pandemic; P = 0.355). In mediation analysis, an admission with acute cholecystitis during the pandemic was associated with a non-significant increased risk of death (OR 1.29, 95 per cent c.i. 0.93 to 1.79, P = 0.121). Conclusion CHOLECOVID provides a unique overview of the treatment of patients with cholecystitis across the globe during the first months of the SARS-CoV-2 pandemic. The study highlights the need for system resilience in retention of elective surgical activity. Cholecystectomy was associated with a low risk of mortality and deferral of treatment results in an increase in avoidable morbidity that represents the non-COVID cost of this pandemic.
    Type of Medium: Online Resource
    ISSN: 2474-9842
    URL: Article
    DOI: 10.1093/bjsopen/zrac052
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2902033-5
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  • 7
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    Capacity of Pneumococci to Activate Macrophage Nuclear Factor κB: Influence on Necroptosis and Pneumonia Severity
    Oxford University Press (OUP) ; 2017
    In:  The Journal of Infectious Diseases Vol. 216, No. 4 ( 2017-08-15), p. 425-435
    Details
    In: The Journal of Infectious Diseases, Oxford University Press (OUP), Vol. 216, No. 4 ( 2017-08-15), p. 425-435
    Type of Medium: Online Resource
    ISSN: 0022-1899 , 1537-6613
    URL: Article
    DOI: 10.1093/infdis/jix159
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2017
    detail.hit.zdb_id: 1473843-0
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  • 8
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    Social determinants of health and disease in companion dogs: a cohort study from the Dog Aging Project
    Oxford University Press (OUP) ; 2023
    In:  Evolution, Medicine, and Public Health Vol. 11, No. 1 ( 2023-01-01), p. 187-201
    Details
    In: Evolution, Medicine, and Public Health, Oxford University Press (OUP), Vol. 11, No. 1 ( 2023-01-01), p. 187-201
    Abstract: Exposure to social environmental adversity is associated with health and survival across many social species, including humans. However, little is known about how these health and mortality effects vary across the lifespan and may be differentially impacted by various components of the environment. Here, we leveraged a relatively new and powerful model for human aging, the companion dog, to investigate which components of the social environment are associated with dog health and how these associations vary across the lifespan. We drew on comprehensive survey data collected on 21,410 dogs from the Dog Aging Project and identified five factors that together explained 33.7% of the variation in a dog’s social environment. Factors capturing financial and household adversity were associated with poorer health and lower physical mobility in companion dogs, while factors that captured social support, such as living with other dogs, were associated with better health when controlling for dog age and weight. Notably, the effects of each environmental component were not equal: the effect of social support was 5× stronger than financial factors. The strength of these associations depended on the age of the dog, including a stronger relationship between the owner’s age and the dog’s health in younger as compared to older dogs. Taken together, these findings suggest the importance of income, stability and owner’s age on owner-reported health outcomes in companion dogs and point to potential behavioral and/or environmental modifiers that can be used to promote healthy aging across species.
    Type of Medium: Online Resource
    ISSN: 2050-6201
    URL: Article
    DOI: 10.1093/emph/eoad011
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 2684837-5
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  • 9
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    Seven newly identified loci for autoimmune thyroid disease
    Oxford University Press (OUP) ; 2012
    In:  Human Molecular Genetics Vol. 21, No. 23 ( 2012-12-01), p. 5202-5208
    Details
    In: Human Molecular Genetics, Oxford University Press (OUP), Vol. 21, No. 23 ( 2012-12-01), p. 5202-5208
    Type of Medium: Online Resource
    ISSN: 1460-2083 , 0964-6906
    URL: Article
    DOI: 10.1093/hmg/dds357
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2012
    detail.hit.zdb_id: 1474816-2
    SSG: 12
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  • 10
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    Cyclonic entrainment? The ichthyoplankton attributes of three major water mass types generated by the separation of the East Australian Current
    Oxford University Press (OUP) ; 2014
    In:  ICES Journal of Marine Science Vol. 71, No. 7 ( 2014-10-01), p. 1696-1705
    Details
    In: ICES Journal of Marine Science, Oxford University Press (OUP), Vol. 71, No. 7 ( 2014-10-01), p. 1696-1705
    Abstract: The relationship between larval fish assemblages and coastal oceanography is the basis for much of our understanding of connectivity and productivity of fish populations. Larval fish assemblages were sampled from the upper mixed layer ( 〈 50 m depth) at three prominent circulation features [separation of the East Australian Current (EAC), anticyclonic eddy, and cyclonic eddy] off the southeast Australian coast across three bathymetric zones (shelf, slope and ocean) for each feature. The separation of the EAC from the coast at ∼32°S was characterized by warmer, less saline water compared with the cyclonic and anticyclonic eddies further to the south (∼34 and ∼35°S, respectively), which were both characterized by cooler Tasman Sea water and greater fluorescence. The anticyclonic eddy had separat ed from the EAC three months prior to sampling, which facilitated the movement of a cyclonic eddy from the Tasman Sea westwards to the shelf at ∼34°S. The larval assemblage in the EAC had high numbers of fish of the families Labridae and Stomiidae. The cyclonic eddy was characterized by larval clupeids, carangids, scombrids and bothids, indicating recent entrainment of shelf waters and proximity to major spawning regions. In contrast, the anticyclonic eddy had fewer larval fish, with little evidence for entrainment of shelf assemblages into the near-surface waters. Myctophids were found in high abundance across all oceanographic features and bathymetric zones. The evidence of selective entrainment of coastal larval fish into the near-surface waters of a cyclonic eddy compared with a similar anticyclonic eddy indicates a potential offshore nursery ground.
    Type of Medium: Online Resource
    ISSN: 1054-3139 , 1095-9289
    URL: Article
    DOI: 10.1093/icesjms/fsu062
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2014
    detail.hit.zdb_id: 2463178-4
    detail.hit.zdb_id: 1468003-8
    detail.hit.zdb_id: 29056-7
    SSG: 12
    SSG: 21,3
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