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Article ; Online: Burkholderia pseudomallei and melioidosis.

Meumann, Ella M / Limmathurotsakul, Direk / Dunachie, Susanna J / Wiersinga, Willem J / Currie, Bart J

2023 Volume 22, Issue 3, Page(s) 155–169

Abstract: Burkholderia pseudomallei, the causative agent of melioidosis, is found in soil and water of tropical and subtropical regions globally. Modelled estimates of the global burden predict that melioidosis remains vastly under-reported, and a call has been ... ...

Abstract	Burkholderia pseudomallei, the causative agent of melioidosis, is found in soil and water of tropical and subtropical regions globally. Modelled estimates of the global burden predict that melioidosis remains vastly under-reported, and a call has been made for it to be recognized as a neglected tropical disease by the World Health Organization. Severe weather events and environmental disturbance are associated with increased case numbers, and it is anticipated that, in some regions, cases will increase in association with climate change. Genomic epidemiological investigations have confirmed B. pseudomallei endemicity in newly recognized regions, including the southern United States. Melioidosis follows environmental exposure to B. pseudomallei and is associated with comorbidities that affect the immune response, such as diabetes, and with socioeconomic disadvantage. Several vaccine candidates are ready for phase I clinical trials. In this Review, we explore the global burden, epidemiology and pathophysiology of B. pseudomallei as well as current diagnostics, treatment recommendations and preventive measures, highlighting research needs and priorities.
MeSH term(s)	Humans ; Burkholderia pseudomallei/genetics ; Melioidosis/diagnosis ; Melioidosis/epidemiology ; Melioidosis/prevention & control ; Environmental Exposure ; World Health Organization ; Genomics
Language	English
Publishing date	2023-10-04
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2139054-X
ISSN	1740-1534 ; 1740-1526
ISSN (online)	1740-1534
ISSN	1740-1526
DOI	10.1038/s41579-023-00972-5
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Article ; Online: The challenges of estimating the human global burden of disease of antimicrobial resistant bacteria.

Dunachie, Susanna J / Day, Nicholas Pj / Dolecek, Christiane

Current opinion in microbiology

2020 Volume 57, Page(s) 95–101

Abstract: Estimating the contribution of antimicrobial resistance (AMR) to global mortality and healthcare costs enables evaluation of interventions, informs policy decisions on resource allocation, and drives research priorities. However assembling the high ... ...

Abstract	Estimating the contribution of antimicrobial resistance (AMR) to global mortality and healthcare costs enables evaluation of interventions, informs policy decisions on resource allocation, and drives research priorities. However assembling the high quality, patient-level data required for global estimates is challenging. Capacity for accurate microbiology culture and antimicrobial susceptibility testing is woefully neglected in low and middle-income countries, and further surveillance and research on community antimicrobial usage, bias in blood culture sampling, and the contribution of co-morbidities such as diabetes is essential. International collaboration between governments, policy makers, academics, microbiologists, front-line clinicians, veterinarians, the food and agriculture industry and the public is critical to understand and tackle AMR.
MeSH term(s)	Animals ; Anti-Bacterial Agents/pharmacology ; Bacteria/drug effects ; Bacteria/genetics ; Bacteria/metabolism ; Bacterial Infections/drug therapy ; Bacterial Infections/microbiology ; Drug Resistance, Bacterial ; Global Burden of Disease ; Humans
Chemical Substances	Anti-Bacterial Agents
Language	English
Publishing date	2020-11-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1418474-6
ISSN	1879-0364 ; 1369-5274
ISSN (online)	1879-0364
ISSN	1369-5274
DOI	10.1016/j.mib.2020.09.013
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Article: The challenges of estimating the human global burden of disease of antimicrobial resistant bacteria

Dunachie, Susanna J / Day, Nicholas PJ / Dolecek, Christiane

Current opinion in microbiology. 2020 Oct., v. 57

2020

Abstract	Estimating the contribution of antimicrobial resistance (AMR) to global mortality and healthcare costs enables evaluation of interventions, informs policy decisions on resource allocation, and drives research priorities. However assembling the high quality, patient-level data required for global estimates is challenging. Capacity for accurate microbiology culture and antimicrobial susceptibility testing is woefully neglected in low and middle-income countries, and further surveillance and research on community antimicrobial usage, bias in blood culture sampling, and the contribution of co-morbidities such as diabetes is essential. International collaboration between governments, policy makers, academics, microbiologists, front-line clinicians, veterinarians, the food and agriculture industry and the public is critical to understand and tackle AMR.
Keywords	agricultural industry ; antibiotic resistance ; blood ; burden of disease ; diabetes ; humans ; issues and policy ; monitoring ; mortality ; resource allocation
Language	English
Dates of publication	2020-10
Size	p. 95-101.
Publishing place	Elsevier Ltd
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	1418474-6
ISSN	1879-0364 ; 1369-5274
ISSN (online)	1879-0364
ISSN	1369-5274
DOI	10.1016/j.mib.2020.09.013
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: T cell immune memory after covid-19 and vaccination.

Wang, Lulu / Nicols, Alex / Turtle, Lance / Richter, Alex / Duncan, Christopher Ja / Dunachie, Susanna J / Klenerman, Paul / Payne, Rebecca P

BMJ medicine

2023 Volume 2, Issue 1, Page(s) e000468

Abstract: The T cell memory response is a crucial component of adaptive immunity responsible for limiting or preventing viral reinfection. T cell memory after infection with the SARS-CoV-2 virus or vaccination is broad, and spans multiple viral proteins and ... ...

Abstract	The T cell memory response is a crucial component of adaptive immunity responsible for limiting or preventing viral reinfection. T cell memory after infection with the SARS-CoV-2 virus or vaccination is broad, and spans multiple viral proteins and epitopes, about 20 in each individual. So far the T cell memory response is long lasting and provides a high level of cross reactivity and hence resistance to viral escape by variants of the SARS-CoV-2 virus, such as the omicron variant. All current vaccine regimens tested produce robust T cell memory responses, and heterologous regimens will probably enhance protective responses through increased breadth. T cell memory could have a major role in protecting against severe covid-19 disease through rapid viral clearance and early presentation of epitopes, and the presence of cross reactive T cells might enhance this protection. T cell memory is likely to provide ongoing protection against admission to hospital and death, and the development of a pan-coronovirus vaccine might future proof against new pandemic strains.
Language	English
Publishing date	2023-11-22
Publishing country	England
Document type	Journal Article ; Review
ISSN	2754-0413
ISSN (online)	2754-0413
DOI	10.1136/bmjmed-2022-000468
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Article ; Online: Incident dementia risk among patients with type 2 diabetes receiving metformin versus alternative oral glucose-lowering therapy: an observational cohort study using UK primary healthcare records.

Doran, William / Tunnicliffe, Louis / Muzambi, Rutendo / Rentsch, Christopher T / Bhaskaran, Krishnan / Smeeth, Liam / Brayne, Carol / Williams, Dylan M / Chaturvedi, Nish / Eastwood, Sophie V / Dunachie, Susanna J / Mathur, Rohini / Warren-Gash, Charlotte

BMJ open diabetes research & care

2024 Volume 12, Issue 1

Abstract: Introduction: 4.2 million individuals in the UK have type 2 diabetes, a known risk factor for dementia and mild cognitive impairment (MCI). Diabetes treatment may modify this association, but existing evidence is conflicting. We therefore aimed to ... ...

Abstract	Introduction: 4.2 million individuals in the UK have type 2 diabetes, a known risk factor for dementia and mild cognitive impairment (MCI). Diabetes treatment may modify this association, but existing evidence is conflicting. We therefore aimed to assess the association between metformin therapy and risk of incident all-cause dementia or MCI compared with other oral glucose-lowering therapies (GLTs). Research design and methods: We conducted an observational cohort study using the Clinical Practice Research Datalink among UK adults diagnosed with diabetes at ≥40 years between 1990 and 2019. We used an active comparator new user design to compare risks of dementia and MCI among individuals initially prescribed metformin versus an alternative oral GLT using Cox proportional hazards regression controlling for sociodemographic, lifestyle and clinical confounders. We assessed for interaction by age and sex. Sensitivity analyses included an as-treated analysis to mitigate potential exposure misclassification. Results: We included 211 396 individuals (median age 63 years; 42.8% female), of whom 179 333 (84.8%) initiated on metformin therapy. Over median follow-up of 5.4 years, metformin use was associated with a lower risk of dementia (adjusted HR (aHR) 0.86 (95% CI 0.79 to 0.94)) and MCI (aHR 0.92 (95% CI 0.86 to 0.99)). Metformin users aged under 80 years had a lower dementia risk (aHR 0.77 (95% CI 0.68 to 0.85)), which was not observed for those aged ≥80 years (aHR 0.95 (95% CI 0.87 to 1.05)). There was no interaction with sex. The as-treated analysis showed a reduced effect size compared with the main analysis (aHR 0.90 (95% CI 0.83 to 0.98)). Conclusions: Metformin use was associated with lower risks of incident dementia and MCI compared with alternative GLT among UK adults with diabetes. While our findings are consistent with a neuroprotective effect of metformin against dementia, further research is needed to reduce risks of confounding by indication and assess causality.
MeSH term(s)	Adult ; Humans ; Female ; Middle Aged ; Male ; Diabetes Mellitus, Type 2/complications ; Diabetes Mellitus, Type 2/drug therapy ; Diabetes Mellitus, Type 2/epidemiology ; Metformin/adverse effects ; Cohort Studies ; Hypoglycemic Agents/adverse effects ; Glucose ; Dementia/epidemiology ; Dementia/prevention & control ; Primary Health Care ; United Kingdom/epidemiology
Chemical Substances	Metformin (9100L32L2N) ; Hypoglycemic Agents ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2024-01-25
Publishing country	England
Document type	Observational Study ; Journal Article
ZDB-ID	2732918-5
ISSN	2052-4897 ; 2052-4897
ISSN (online)	2052-4897
ISSN	2052-4897
DOI	10.1136/bmjdrc-2023-003548
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Article ; Online: The SARS-CoV-2 neutralizing antibody response to SD1 and its evasion by BA.2.86.

Zhou, Daming / Supasa, Piyada / Liu, Chang / Dijokaite-Guraliuc, Aiste / Duyvesteyn, Helen M E / Selvaraj, Muneeswaran / Mentzer, Alexander J / Das, Raksha / Dejnirattisai, Wanwisa / Temperton, Nigel / Klenerman, Paul / Dunachie, Susanna J / Fry, Elizabeth E / Mongkolsapaya, Juthathip / Ren, Jingshan / Stuart, David I / Screaton, Gavin R

Nature communications

2024 Volume 15, Issue 1, Page(s) 2734

Abstract: Under pressure from neutralising antibodies induced by vaccination or infection the SARS-CoV-2 spike gene has become a hotspot for evolutionary change, leading to the failure of all mAbs developed for clinical use. Most potent antibodies bind to the ... ...

Abstract	Under pressure from neutralising antibodies induced by vaccination or infection the SARS-CoV-2 spike gene has become a hotspot for evolutionary change, leading to the failure of all mAbs developed for clinical use. Most potent antibodies bind to the receptor binding domain which has become heavily mutated. Here we study responses to a conserved epitope in sub-domain-1 (SD1) of spike which have become more prominent because of mutational escape from antibodies directed to the receptor binding domain. Some SD1 reactive mAbs show potent and broad neutralization of SARS-CoV-2 variants. We structurally map the dominant SD1 epitope and provide a mechanism of action by blocking interaction with ACE2. Mutations in SD1 have not been sustained to date, but one, E554K, leads to escape from mAbs. This mutation has now emerged in several sublineages including BA.2.86, reflecting selection pressure on the virus exerted by the increasing prominence of the anti-SD1 response.
MeSH term(s)	Humans ; Antibodies, Neutralizing ; SARS-CoV-2/genetics ; COVID-19 ; Antibodies, Monoclonal ; Epitopes ; Spike Glycoprotein, Coronavirus/genetics ; Antibodies, Viral ; Syndactyly
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Monoclonal ; Epitopes ; Spike Glycoprotein, Coronavirus ; Antibodies, Viral ; spike protein, SARS-CoV-2
Language	English
Publishing date	2024-03-28
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-46982-6
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Article ; Online: Identification and function of a novel human memory-like NK cell population expressing CD160 in melioidosis.

Preechanukul, Anucha / Kronsteiner, Barbara / Saiprom, Natnaree / Rochaikun, Kitilak / Moonmueangsan, Boonthanom / Phunpang, Rungnapa / Ottiwet, Orawan / Kongphrai, Yuphin / Wapee, Soonthon / Chotivanich, Kesinee / Morakot, Chumpol / Janon, Rachan / Dunachie, Susanna J / Chantratita, Narisara

iScience

2023 Volume 26, Issue 8, Page(s) 107234

Abstract: NK cells are endowed with immunological memory to a range of pathogens but the development of NK cell memory in bacterial infections remains elusive. Here, we establish an assay inducing memory-like NK cell response ... ...

Abstract	NK cells are endowed with immunological memory to a range of pathogens but the development of NK cell memory in bacterial infections remains elusive. Here, we establish an assay inducing memory-like NK cell response to
Language	English
Publishing date	2023-06-28
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2023.107234
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Article ; Online: A whole blood intracellular cytokine assay optimised for field site studies demonstrates polyfunctionality of CD4+ T cells in acute scrub typhus.

Inthawong, Manutsanun / Pinthong, Nattapon / Thaiprakhong, Areerat / Wangrangsimakul, Tri / Sunyakumthorn, Piyanate / Hill, Jennifer / Sonthayanon, Piengchan / Paris, Daniel H / Dunachie, Susanna J / Kronsteiner, Barbara

PLoS neglected tropical diseases

2023 Volume 17, Issue 3, Page(s) e0010905

Abstract: Background: Assessment of cellular immune responses by combining intracellular cytokine staining and immunophenotyping using flow cytometry enables the simultaneous measurement of T cell phenotype and effector function in response to pathogens and ... ...

Abstract	Background: Assessment of cellular immune responses by combining intracellular cytokine staining and immunophenotyping using flow cytometry enables the simultaneous measurement of T cell phenotype and effector function in response to pathogens and vaccines. The use of whole blood samples rather than peripheral blood mononuclear cells avoids both the need for immediate processing and loss of functional antigen presenting cells due to processing and cryopreservation. Using whole blood provides the possibility to stimulate peripheral T cells in situ, and is more suitable for studies where sample volume is limited, such as those involving children, the elderly and critically ill patients. The aim of this study was to provide a robust tool for the assessment of antigen-specific T cell responses in a field site setting with limited resources. Methodology/principle findings: We optimised a flow cytometry-based whole blood intracellular cytokine assay (WBA) with respect to duration of antigen stimulation and intracellular protein retention time. We demonstrate the ability of the WBA to capture polyfunctional T cell responses in the context of acute scrub typhus infection, by measuring IFN-γ, TNF and IL-2 in CD4+ and CD8+ T cells in response to the causative agent O. tsutsugamushi (OT). Using an optimised OT antigen preparation, we demonstrate the presence of polyfunctional antigen-specific memory CD4+ T cells in the blood of scrub typhus patients. Conclusions/significance: In conclusion, this flow cytometry-based WBA is well-suited for use at field study sites, and enables the assessment of polyfunctional T cell responses to infectious agents and vaccines through delineation of antigen-specific cytokine secretion at the single cell level.
MeSH term(s)	Humans ; Scrub Typhus ; CD4-Positive T-Lymphocytes ; Leukocytes, Mononuclear ; CD8-Positive T-Lymphocytes ; Cytokines
Chemical Substances	Cytokines
Language	English
Publishing date	2023-03-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2429704-5
ISSN	1935-2735 ; 1935-2735
ISSN (online)	1935-2735
ISSN	1935-2735
DOI	10.1371/journal.pntd.0010905
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Article ; Online: Dynamic mitochondrial transcription and translation in B cells control germinal center entry and lymphomagenesis.

Yazicioglu, Yavuz F / Marin, Eros / Sandhu, Ciaran / Galiani, Silvia / Raza, Iwan G A / Ali, Mohammad / Kronsteiner, Barbara / Compeer, Ewoud B / Attar, Moustafa / Dunachie, Susanna J / Dustin, Michael L / Clarke, Alexander J

Nature immunology

2023 Volume 24, Issue 6, Page(s) 991–1006

Abstract: Germinal center (GC) B cells undergo proliferation at very high rates in a hypoxic microenvironment but the cellular processes driving this are incompletely understood. Here we show that the mitochondria of GC B cells are highly dynamic, with ... ...

Abstract	Germinal center (GC) B cells undergo proliferation at very high rates in a hypoxic microenvironment but the cellular processes driving this are incompletely understood. Here we show that the mitochondria of GC B cells are highly dynamic, with significantly upregulated transcription and translation rates associated with the activity of transcription factor A, mitochondrial (TFAM). TFAM, while also necessary for normal B cell development, is required for entry of activated GC precursor B cells into the germinal center reaction; deletion of Tfam significantly impairs GC formation, function and output. Loss of TFAM in B cells compromises the actin cytoskeleton and impairs cellular motility of GC B cells in response to chemokine signaling, leading to their spatial disorganization. We show that B cell lymphoma substantially increases mitochondrial translation and that deletion of Tfam in B cells is protective against the development of lymphoma in a c-Myc transgenic mouse model. Finally, we show that pharmacological inhibition of mitochondrial transcription and translation inhibits growth of GC-derived human lymphoma cells and induces similar defects in the actin cytoskeleton.
MeSH term(s)	Mice ; Humans ; Animals ; B-Lymphocytes/pathology ; Germinal Center/pathology ; Transcription, Genetic ; Lymphoma, B-Cell/genetics ; Lymphoma, B-Cell/pathology ; Lymphoma ; Mice, Transgenic ; Tumor Microenvironment
Language	English
Publishing date	2023-04-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-023-01484-3
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Article ; Online: Deciphering the human antibody response against

Wagner, Gabriel E / Stanjek, Thomas Franz Paul / Albrecht, Dirk / Lipp, Michaela / Dunachie, Susanna J / Föderl-Höbenreich, Esther / Riedel, Katharina / Kohler, Anne / Steinmetz, Ivo / Kohler, Christian

Frontiers in immunology

2023 Volume 14, Page(s) 1294113

Abstract: Introduction: The environmental bacterium : Methods and results: In this study, : Conclusion: Our study shows that a ... ...

Abstract	Introduction: The environmental bacterium Methods and results: In this study, Conclusion: Our study shows that a comprehensive
MeSH term(s)	Humans ; Burkholderia pseudomallei ; Melioidosis ; Antibody Formation ; Antigens, Bacterial ; Immunoglobulins
Chemical Substances	Antigens, Bacterial ; Immunoglobulins
Language	English
Publishing date	2023-12-11
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1294113
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