49 research outputs found
Shigella sonnei genome sequencing and phylogenetic analysis indicate recent global dissemination from Europe
Shigella are human-adapted Escherichia coli that have gained the ability to invade the human gut mucosa and cause dysentery1,2, spreading efficiently via low-dose fecal-oral transmission3,4. Historically, S. sonnei has been predominantly responsible for dysentery in developed countries, but is now emerging as a problem in the developing world, apparently replacing the more diverse S. flexneri in areas undergoing economic development and improvements in water quality4-6. Classical approaches have shown S. sonnei is genetically conserved and clonal7. We report here whole-genome sequencing of 132 globally-distributed isolates. Our phylogenetic analysis shows that the current S. sonnei population descends from a common ancestor that existed less than 500 years ago and has diversified into several distinct lineages with unique characteristics. Our analysis suggests the majority of this diversification occurred in Europe, followed by more recent establishment of local pathogen populations in other continents predominantly due to the pandemic spread of a single, rapidly-evolving, multidrug resistant lineage
A Novel Cre Recombinase Imaging System for Tracking Lymphotropic Virus Infection In Vivo
BACKGROUND:Detection, isolation, and identification of individual virus infected cells during long term infection are critical to advance our understanding of mechanisms of pathogenesis for latent/persistent viruses. However, current approaches to study these viruses in vivo have been hampered by low sensitivity and effects of cell-type on expression of viral encoded reporter genes. We have designed a novel Cre recombinase (Cre)-based murine system to overcome these problems, and thereby enable tracking and isolation of individual in vivo infected cells. METHODOLOGY/PRINCIPAL FINDINGS:Murine gammaherpesvirus 68 (MHV-68) was used as a prototypic persistent model virus. A Cre expressing recombinant virus was constructed and characterised. The virus is attenuated both in lytic virus replication, producing ten-fold lower lung virus titres than wild type virus, and in the establishment of latency. However, despite this limitation, when the sEGFP7 mouse line containing a Cre-activated enhanced green fluorescent protein (EGFP) was infected with the Cre expressing virus, sites of latent and persistent virus infection could be identified within B cells and macrophages of the lymphoid system on the basis of EGFP expression. Importantly, the use of the sEGFP7 mouse line which expresses high levels of EGFP allowed individual virus positive cells to be purified by FACSorting. Virus gene expression could be detected in these cells. Low numbers of EGFP positive cells could also be detected in the bone marrow. CONCLUSIONS/SIGNIFICANCE:The use of this novel Cre-based virus/mouse system allowed identification of individual latently infected cells in vivo and may be useful for the study and long-term monitoring of other latent/persistent virus infections
Improving quality of life through the routine use of the Patient Concerns Inventory for head and neck cancer patients: a cluster preference randomized controlled trial
This trial is funded by the RfPB on behalf of the NIHR (PB-PG-0215-36047).Background: The consequences of treatment for Head and Neck cancer (HNC) patients has profound detrimental impacts such as impaired QOL, emotional distress, delayed recovery and frequent use of healthcare. The aim of this trial is to determine if the routine use of the Patients Concerns Inventory (PCI) package in review clinics during the first year following treatment can improve overall quality of life, reduce the social-emotional impact of cancer and reduce levels of distress. Furthermore, we aim to describe the economic costs and benefits of using the PCI. Methods: This will be a cluster preference randomised control trial with consultants either ‘using’ or ‘not using’ the PCI package at clinic. It will involve two centres Leeds and Liverpool. 416 eligible patients from at least 10 consultant clusters are required to show a clinically meaningful difference in the primary outcome. The primary outcome is the percentage of participants with less than good overall quality of life at the final one-year clinic as measured by the University of Washington QOL questionnaire version 4 (UWQOLv4). Secondary outcomes at one-year are the mean social-emotional subscale (UWQOLv4) score, Distress Thermometer (DT) score ≥ 4, and key health economic measures (QALY-EQ-5D-5 L; CSRI). Discussion: This trial will provide knowledge on the effectiveness of a consultation intervention package based around the PCI used at routine follow-up clinics following treatment of head and neck cancer with curative intent. If this intervention is (cost) effective for patients, the next step will be to promote wider use of this approach as standard care in clinical practice. Trial registration: 32,382. Clinical Trials Identifier, NCT03086629. Protocol: Version 3.0, 1st July 2017.Publisher PDFPeer reviewe
Climate oscillations, glacial refugia, and dispersal ability: factors influencing the genetic structure of the least salmonfly, Pteronarcella badia (Plecoptera), in Western North America
Global circulation patterns of seasonal influenza viruses vary with antigenic drift.
Understanding the spatiotemporal patterns of emergence and circulation of new human seasonal influenza virus variants is a key scientific and public health challenge. The global circulation patterns of influenza A/H3N2 viruses are well characterized, but the patterns of A/H1N1 and B viruses have remained largely unexplored. Here we show that the global circulation patterns of A/H1N1 (up to 2009), B/Victoria, and B/Yamagata viruses differ substantially from those of A/H3N2 viruses, on the basis of analyses of 9,604 haemagglutinin sequences of human seasonal influenza viruses from 2000 to 2012. Whereas genetic variants of A/H3N2 viruses did not persist locally between epidemics and were reseeded from East and Southeast Asia, genetic variants of A/H1N1 and B viruses persisted across several seasons and exhibited complex global dynamics with East and Southeast Asia playing a limited role in disseminating new variants. The less frequent global movement of influenza A/H1N1 and B viruses coincided with slower rates of antigenic evolution, lower ages of infection, and smaller, less frequent epidemics compared to A/H3N2 viruses. Detailed epidemic models support differences in age of infection, combined with the less frequent travel of children, as probable drivers of the differences in the patterns of global circulation, suggesting a complex interaction between virus evolution, epidemiology, and human behaviour.T.B.
was
supported
by
a
Newton
International
Fellowship
from
the
Royal
Society
and
through
NIH
U54
GM111274.
S.R.
was
supported
by
MRC
(UK,
Project
MR/J008761/1),
Wellcome
Trust
(UK,
Project
093488/Z/10/Z),
Fogarty
International
Centre
(USA,
R01
TW008246‐01),
DHS
(USA,
RAPIDD
program),
NIGMS
(USA,
MIDAS
U01
GM110721‐01)
and
NIHR
(UK,
Health
Protection
Research
Unit
funding).
The
Melbourne
WHO
Collaborating
Centre
for
Reference
and
Research
on
Influenza
was
supported
by
the
Australian
Government
Department
of
Health
and
thanks
N.
Komadina
and
Y.‐M.
Deng.
The
Atlanta
WHO
Collaborating
Center
for
Surveillance,
Epidemiology
and
Control
of
Influenza
was
supported
by
the
U.S.
Department
of
13
Health
and
Human
Services.
NIV
thanks
A.C.
Mishra,
M.
Chawla‐Sarkar,
A.M.
Abraham,
D.
Biswas,
S.
Shrikhande,
AnuKumar
B,
and
A.
Jain.
Influenza
surveillance
in
India
was
expanded,
in
part,
through
US
Cooperative
Agreements
(5U50C1024407
and
U51IP000333)
and
by
the
Indian
Council
of
Medical
Research.
M.A.S.
was
supported
through
NSF
DMS
1264153
and
NIH
R01
AI
107034.
Work
of
the
WHO
Collaborating
Centre
for
Reference
and
Research
on
Influenza
at
the
MRC
National
Institute
for
Medical
Research
was
supported
by
U117512723.
P.L.,
A.R.
&
M.A.S
were
supported
by
EU
Seventh
Framework
Programme
[FP7/2007‐2013]
under
Grant
Agreement
no.
278433-‐PREDEMICS
and
ERC
Grant
agreement
no.
260864.
C.A.R.
was
supported
by
a
University
Research
Fellowship
from
the
Royal
Society.This is the author accepted manuscript. It is currently under infinite embargo pending publication of the final version
Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A
The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods - recursive partitioning and regression - to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; Pcombined = 2.01 × 10-19 and 2.35 × 10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. ©2007 Nature Publishing Group
Genetic mechanisms of critical illness in COVID-19.
Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 × 10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice
Implementation of corticosteroids in treating COVID-19 in the ISARIC WHO Clinical Characterisation Protocol UK:prospective observational cohort study
BACKGROUND: Dexamethasone was the first intervention proven to reduce mortality in patients with COVID-19 being treated in hospital. We aimed to evaluate the adoption of corticosteroids in the treatment of COVID-19 in the UK after the RECOVERY trial publication on June 16, 2020, and to identify discrepancies in care. METHODS: We did an audit of clinical implementation of corticosteroids in a prospective, observational, cohort study in 237 UK acute care hospitals between March 16, 2020, and April 14, 2021, restricted to patients aged 18 years or older with proven or high likelihood of COVID-19, who received supplementary oxygen. The primary outcome was administration of dexamethasone, prednisolone, hydrocortisone, or methylprednisolone. This study is registered with ISRCTN, ISRCTN66726260. FINDINGS: Between June 17, 2020, and April 14, 2021, 47 795 (75·2%) of 63 525 of patients on supplementary oxygen received corticosteroids, higher among patients requiring critical care than in those who received ward care (11 185 [86·6%] of 12 909 vs 36 415 [72·4%] of 50 278). Patients 50 years or older were significantly less likely to receive corticosteroids than those younger than 50 years (adjusted odds ratio 0·79 [95% CI 0·70–0·89], p=0·0001, for 70–79 years; 0·52 [0·46–0·58], p80 years), independent of patient demographics and illness severity. 84 (54·2%) of 155 pregnant women received corticosteroids. Rates of corticosteroid administration increased from 27·5% in the week before June 16, 2020, to 75–80% in January, 2021. INTERPRETATION: Implementation of corticosteroids into clinical practice in the UK for patients with COVID-19 has been successful, but not universal. Patients older than 70 years, independent of illness severity, chronic neurological disease, and dementia, were less likely to receive corticosteroids than those who were younger, as were pregnant women. This could reflect appropriate clinical decision making, but the possibility of inequitable access to life-saving care should be considered. FUNDING: UK National Institute for Health Research and UK Medical Research Council
DNA methylation profiling to predict recurrence risk in meningioma: development and validation of a nomogram to optimize clinical management
Abstract Background Variability in standard-of-care classifications precludes accurate predictions of early tumor recurrence for individual patients with meningioma, limiting the appropriate selection of patients who would benefit from adjuvant radiotherapy to delay recurrence. We aimed to develop an individualized prediction model of early recurrence risk combining clinical and molecular factors in meningioma. Methods DNA methylation profiles of clinically annotated tumor samples across multiple institutions were used to develop a methylome model of 5-year recurrence-free survival (RFS). Subsequently, a 5-year meningioma recurrence score was generated using a nomogram that integrated the methylome model with established prognostic clinical factors. Performance of both models was evaluated and compared with standard-of-care models using multiple independent cohorts. Results The methylome-based predictor of 5-year RFS performed favorably compared with a grade-based predictor when tested using the 3 validation cohorts (ΔAUC = 0.10, 95% CI: 0.03–0.018) and was independently associated with RFS after adjusting for histopathologic grade, extent of resection, and burden of copy number alterations (hazard ratio 3.6, 95% CI: 1.8–7.2, P < 0.001). A nomogram combining the methylome predictor with clinical factors demonstrated greater discrimination than a nomogram using clinical factors alone in 2 independent validation cohorts (ΔAUC = 0.25, 95% CI: 0.22–0.27) and resulted in 2 groups with distinct recurrence patterns (hazard ratio 7.7, 95% CI: 5.3–11.1, P < 0.001) with clinical implications. Conclusions The models developed and validated in this study provide important prognostic information not captured by previously established clinical and molecular factors which could be used to individualize decisions regarding postoperative therapeutic interventions, in particular whether to treat patients with adjuvant radiotherapy versus observation alone. </jats:sec
Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses
To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely