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"Webb, Steve"
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A sailor went to sea, sea, sea : favourite rhymes from an Irish childhood
An illustrated collection of Irish nursery rhymes, songs, and poems.
Book
Exome sequencing highlights the role of wild-relative introgression in shaping the adaptive landscape of the wheat genome
Introgression is a potential source of beneficial genetic diversity. The contribution of introgression to adaptive evolution and improvement of wheat as it was disseminated worldwide remains unknown. We used targeted re-sequencing of 890 diverse accessions of hexaploid and tetraploid wheat to identify wild-relative introgression. Introgression, and selection for improvement and environmental adaptation, each reduced deleterious allele burden. Introgression increased diversity genome wide and in regions harboring major agronomic genes, and contributed alleles explaining a substantial proportion of phenotypic variation. These results suggest that historic gene flow from wild relatives made a substantial contribution to the adaptive diversity of modern bread wheat.
Targeted re-sequencing of 890 diverse accessions of hexaploid and tetraploid wheat identifies regions showing the signals of wild emmer introgression, thus suggesting that historic wild-relative gene flow shaped modern bread wheat's adaptive diversity.
Journal Article
City Kitty Cat
\"City Kitty Cat has always loved living and driving his cab in the city. But when some new friends convince him to visit their jungle home, will Kitty be able to adjust?\"-- Provided by publisher.
Book
Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19
The interleukin-6 receptor blockers tocilizumab and sarilumab were tested against standard care in a randomized trial involving patients newly admitted to the intensive care unit and requiring respiratory or blood-pressure support. The median number of organ support–free days was 10 with tocilizumab, 11 with sarilumab, and 0 with standard care.
Journal Article
Early Intensive Care Sedation Predicts Long-Term Mortality in Ventilated Critically Ill Patients
Choice and intensity of early (first 48 h) sedation may affect short- and long-term outcome.
To investigate the relationships between early sedation and time to extubation, delirium, and hospital and 180-day mortality among ventilated critically ill patients in the intensive care unit (ICU).
Multicenter (25 Australia and New Zealand hospitals) prospective longitudinal (ICU admission to 28 d) cohort study of medical/surgical patients ventilated and sedated 24 hours or more. We assessed administration of sedative agents, ventilation time, sedation depth using Richmond Agitation Sedation Scale (RASS, four hourly), delirium (daily), and hospital and 180-day mortality. We used multivariable Cox regression to quantify relationships between early deep sedation (RASS, -3 to -5) and patients' outcomes.
We studied 251 patients (mean age, 61.7 ± 15.9 yr; mean Acute Physiology and Chronic Health Evaluation [APACHE] II score, 20.8 ± 7.8), with 21.1% (53) hospital and 25.8% (64) 180-day mortality. Over 2,678 study days, we completed 14,736 RASS assessments. Deep sedation occurred in 191 (76.1%) patients within 4 hours of commencing ventilation and in 171 (68%) patients at 48 hours. Delirium occurred in 111 (50.7%) patients with median (interquartile range) duration of 2 (1-4) days. After adjusting for diagnosis, age, sex, APACHE II, operative, elective, hospital type, early use of vasopressors, and dialysis, early deep sedation was an independent predictor of time to extubation (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.87-0.94; P < 0.001), hospital death (HR, 1.11; 95% CI, 1.02-1.20; P = 0.01), and 180-day mortality (HR, 1.08; 95% CI, 1.01-1.16; P = 0.026) but not delirium occurring after 48 hours (P = 0.19).
Early sedation depth independently predicts delayed extubation and increased mortality, making it a potential target for interventional studies.
Journal Article
Talking to the people that really matter about their participation in pandemic clinical research: A qualitative study in four European countries
Background Pandemics of new and emerging infectious diseases are unpredictable, recurrent events that rapidly threaten global health and security. We aimed to identify public views regarding provision of information and consent to participate in primary and critical care clinical research during a future influenza‐like illness pandemic. Methods Descriptive‐interpretive qualitative study, using focus groups (n = 10) and semi‐structured interviews (n = 16), with 80 members of the public (>18 years) in Belgium, Spain, Poland and the UK. Local qualitative researchers followed a scenario‐based topic guide to collect data. Data were transcribed verbatim, translated into English and subject to framework analysis. Results Public understandings of pandemics were shaped by personal factors (illness during the previous H1N1 pandemic, experience of life‐threatening illness) and social factors (historical references, media, public health information). Informants appreciated safeguards provided by ethically robust research procedures, but current enrolment procedures were seen as a barrier. They proposed simplified enrolment processes for higher risk research and consent waiver for certain types of low‐risk research. Decision making about research participation was influenced by contextual, research and personal factors. Informants generally either carefully weighed up various approaches to research participation or responded instinctively. They supported the principle of using routinely collected, anonymized clinical biological samples for research without explicit consent, but regarded this as less acceptable if researchers were motivated primarily by commercial gain. Conclusions This bottom‐up approach to ascertaining public views on pandemic clinical research has identified support for more proportionate research protection procedures for publically funded, low‐risk studies.
Journal Article
Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study
Purpose
Current reports on acute kidney injury (AKI) in the intensive care unit (ICU) show wide variation in occurrence rate and are limited by study biases such as use of incomplete AKI definition, selected cohorts, or retrospective design. Our aim was to prospectively investigate the occurrence and outcomes of AKI in ICU patients.
Methods
The Acute Kidney Injury–Epidemiologic Prospective Investigation (AKI-EPI) study was an international cross-sectional study performed in 97 centers on patients during the first week of ICU admission. We measured AKI by Kidney Disease: Improving Global Outcomes (KDIGO) criteria, and outcomes at hospital discharge.
Results
A total of 1032 ICU patients out of 1802 [57.3 %; 95 % confidence interval (CI) 55.0–59.6] had AKI. Increasing AKI severity was associated with hospital mortality when adjusted for other variables; odds ratio of stage 1 = 1.679 (95 % CI 0.890–3.169;
p
= 0.109), stage 2 = 2.945 (95 % CI 1.382–6.276;
p
= 0.005), and stage 3 = 6.884 (95 % CI 3.876–12.228;
p
< 0.001). Risk-adjusted rates of AKI and mortality were similar across the world. Patients developing AKI had worse kidney function at hospital discharge with estimated glomerular filtration rate less than 60 mL/min/1.73 m
2
in 47.7 % (95 % CI 43.6–51.7) versus 14.8 % (95 % CI 11.9–18.2) in those without AKI,
p
< 0.001.
Conclusions
This is the first multinational cross-sectional study on the epidemiology of AKI in ICU patients using the complete KDIGO criteria. We found that AKI occurred in more than half of ICU patients. Increasing AKI severity was associated with increased mortality, and AKI patients had worse renal function at the time of hospital discharge. Adjusted risks for AKI and mortality were similar across different continents and regions.
Journal Article
Early mobilisation in intensive care units in Australia and Scotland: a prospective, observational cohort study examining mobilisation practises and barriers
Introduction
Mobilisation of patients in the intensive care unit (ICU) is an area of growing research. Currently, there is little data on baseline mobilisation practises and the barriers to them for patients of all admission diagnoses.
Methods
The objectives of the study were to (1) quantify and benchmark baseline levels of mobilisation in Australian and Scottish ICUs, (2) compare mobilisation practises between Australian and Scottish ICUs and (3) identify barriers to mobilisation in Australian and Scottish ICUs. We conducted a prospective, observational, cohort study with a 4-week inception period. Patients were censored for follow-up upon ICU discharge or after 28 days, whichever occurred first. Patients were included if they were >18 years of age, admitted to an ICU and received mechanical ventilation in the ICU.
Results
Ten tertiary ICUs in Australia and nine in Scotland participated in the study. The Australian cohort had a large proportion of patients admitted for cardiothoracic surgery (43.3 %), whereas the Scottish cohort had none. Therefore, comparison analysis was done after exclusion of patients admitted for cardiothoracic surgery. In total, 60.2 % of the 347 patients across 10 Australian ICUs and 40.1 % of the 167 patients across 9 Scottish ICUs mobilised during their ICU stay (
p
< 0.001). Patients in the Australian cohort were more likely to mobilise than patients in the Scottish cohort (hazard ratio 1.83, 95 % confidence interval 1.38–2.42). However, the percentage of episodes of mobilisation where patients were receiving mechanical ventilation was higher in the Scottish cohort (41.1 % vs 16.3 %,
p
< 0.001). Sedation was the most commonly reported barrier to mobilisation in both the Australian and Scottish cohorts. Physiological instability and the presence of an endotracheal tube were also frequently reported barriers.
Conclusions
This is the first study to benchmark baseline practise of early mobilisation internationally, and it demonstrates variation in early mobilisation practises between Australia and Scotland.
Journal Article
Key stakeholder perceptions about consent to participate in acute illness research: a rapid, systematic review to inform epi/pandemic research preparedness
Background
A rigorous research response is required to inform clinical and public health decision-making during an epi/pandemic. However, the ethical conduct of such research, which often involves critically ill patients, may be complicated by the diminished capacity to consent and an imperative to initiate trial therapies within short time frames. Alternative approaches to taking prospective informed consent may therefore be used. We aimed to rapidly review evidence on key stakeholder (patients, their proxy decision-makers, clinicians and regulators) views concerning the acceptability of various approaches for obtaining consent relevant to pandemic-related acute illness research.
Methods
We conducted a rapid evidence review, using the Internet, database and hand-searching for English language empirical publications from 1996 to 2014 on stakeholder opinions of consent models (prospective informed, third-party, deferred, or waived) used in acute illness research. We excluded research on consent to treatment, screening, or other such procedures, non-emergency research and secondary studies. Papers were categorised, and data summarised using narrative synthesis.
Results
We screened 689 citations, reviewed 104 full-text articles and included 52. Just one paper related specifically to pandemic research. In other emergency research contexts potential research participants, clinicians and research staff found third-party, deferred, and waived consent to be acceptable as a means to feasibly conduct such research. Acceptability to potential participants was motivated by altruism, trust in the medical community, and perceived value in medical research and decreased as the perceived risks associated with participation increased. Discrepancies were observed in the acceptability of the concept and application or experience of alternative consent models. Patients accepted clinicians acting as proxy-decision makers, with preference for two decision makers as invasiveness of interventions increased. Research regulators were more cautious when approving studies conducted with alternative consent models; however, their views were generally under-represented.
Conclusions
Third-party, deferred, and waived consent models are broadly acceptable to potential participants, clinicians and/or researchers for emergency research. Further consultation with key stakeholders, particularly with regulators, and studies focused specifically on epi/pandemic research, are required. We highlight gaps and recommendations to inform set-up and protocol development for pandemic research and institutional review board processes.
PROSPERO protocol registration number
CRD42014014000
Journal Article
Genome editing in wheat microspores and haploid embryos mediated by delivery of ZFN proteins and cell‐penetrating peptide complexes
Summary Recent advances in genome engineering technologies based on designed endonucleases (DE) allow specific and predictable alterations in plant genomes to generate value‐added traits in crops of choice. The EXZACT Precision technology, based on zinc finger nucleases (ZFN), has been successfully used in the past for introduction of precise mutations and transgenes to generate novel and desired phenotypes in several crop species. Current methods for delivering ZFNs into plant cells are based on traditional genetic transformation methods that result in stable integration of the nuclease in the genome. Here, we describe for the first time, an alternative ZFN delivery method where plant cells are transfected with ZFN protein that eliminates the need for stable nuclease genomic integration and allows generation of edited, but not transgenic cells or tissues. For this study, we designed ZFNs targeting the wheat IPK1 locus, purified active ZFN protein from bacterial cultures, complexed with cell‐penetrating peptides (CPP) and directly transfected the complex into either wheat microspores or embryos. NGS analysis of ZFN‐treated material showed targeted edits at the IPK1 locus in independent experiments. This is the first description of plant microspore genome editing by a ZFN when delivered as a protein complexed with CPP.
Journal Article