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Loss of microbial diversity and pathogen domination of the gut microbiota in critically ill patients.
No full textAmong long-stay critically ill patients in the adult intensive care unit (ICU), there are often marked changes in the complexity of the gut microbiota. However, it remains unclear whether such patients might benefit from enhanced surveillance or from interventions targeting the gut microbiota or the pathogens therein. We therefore undertook a prospective observational study of 24 ICU patients, in which serial faecal samples were subjected to shotgun metagenomic sequencing, phylogenetic profiling and microbial genome analyses. Two-thirds of the patients experienced a marked drop in gut microbial diversity (to an inverse Simpson's index of <4) at some stage during their stay in the ICU, often accompanied by the absence or loss of potentially beneficial bacteria. Intravenous administration of the broad-spectrum antimicrobial agent meropenem was significantly associated with loss of gut microbial diversity, but the administration of other antibiotics, including piperacillin/tazobactam, failed to trigger statistically detectable changes in microbial diversity. In three-quarters of ICU patients, we documented episodes of gut domination by pathogenic strains, with evidence of cryptic nosocomial transmission of . In some patients, we also saw an increase in the relative abundance of apparent commensal organisms in the gut microbiome, including the archaeal species . In conclusion, we have documented a dramatic absence of microbial diversity and pathogen domination of the gut microbiota in a high proportion of critically ill patients using shotgun metagenomics
Interventions for the management and prevention of sarcopenia in the critically ill: A systematic review.
No full textPURPOSE
In the critically ill, sarcopenia is associated with a variety of adverse outcomes however there is no consensus regarding its management. This study aimed to systematically review the evidence for interventions for the management and prevention of sarcopenia in critically ill patients.
MATERIALS AND METHODS
Bibliographic databases were searched according to pre-specified criteria (PROSPERO-CRD42018086271). Randomised controlled trials (RCTs) investigating interventions to preserve muscle mass and/or function in critically ill patients were included. Two independent authors selected the articles and assessed bias using the Cochrane Risk of Bias Tool.
RESULTS
Twenty-two eligible RCTs were identified comprising 2792 patients. Three main groups of interventions were implemented in these trials: neuromuscular electrical stimulation (NMES), exercise-based and nutritional. Both the interventions and outcomes measured varied significantly between studies. NMES was most frequently studied as an intervention to preserve muscle mass whilst exercise-based treatments were evaluated as interventions to preserve muscle function. There was significant variation in the efficacy of the interventions on sarcopenia markers and secondary outcomes.
CONCLUSIONS
NMES and exercise-based interventions may preserve muscle mass and function in patients with critical illness. There is a lack of consistency seen in the effects of these interventions. Further, large, high quality RCTs are required
Outcomes of DCD liver transplantation using organs treated by hypothermic oxygenated perfusion before implantation.
No full textBACKGROUND & AIMS
Donation after circulatory death (DCD) liver transplantation is known for potentially worse outcomes because of higher rates of graft non-function or irreversible cholangiopathy. The impact of machine liver perfusion techniques on these complications remains elusive. We aimed to provide data on 5-year outcomes in patients receiving DCD liver transplants, after donor organs had been treated by hypothermic oxygenated perfusion (HOPE).
METHODS
Fifty HOPE-treated DCD liver transplants performed in Zurich between 2012 and 3/2017 were matched with 50 primary donation after brain death (DBD) liver transplants, and with 50 untreated DCD liver transplants in Birmingham. Match factors focussed on short cold ischaemia, comparable recipient age and low recipient laboratory model for end-stage liver disease scores. Primary endpoints were post-transplant complications, and non-tumour-related patient death or graft loss.
RESULTS
Despite extended donor warm ischaemia, HOPE-treated DCD liver transplants achieved similar overall graft survival, compared to standard DBD liver transplants. Particularly, graft loss due to any non-tumour-related causes occurred in 8% (4/50) of cases. In contrast, untreated DCD livers resulted in non-tumour-related graft failure in one-third (16/50) of cases (p = 0.005), despite significantly (p <0.001) shorter functional donor warm ischaemia. Five-year graft survival, censored for tumour death, was 94% for HOPE-treated DCD liver transplants vs. 78% in untreated DCD liver transplants (p = 0.024).
CONCLUSIONS
The 5-year outcomes of HOPE-treated DCD liver transplants were similar to those of DBD primary transplants and superior to those of untreated DCD liver transplants, despite much higher risk. These results suggest that a simple end-ischaemic perfusion approach is very effective and may open the field for safe utilisation of extended DCD liver grafts.
LAY SUMMARY
Machine perfusion techniques are currently being introduced into the clinic, with the aim of optimising injured grafts prior to implantation. While short-term effects of machine liver perfusion have been frequently reported in terms of hepatocellular enzyme release and early graft function, the long-term benefit on irreversible graft loss has been unclear. Herein, we report on 5-year graft survival in donation after cardiac death livers, treated either by conventional cold storage, or by 1-2 h of hypothermic oxygenated perfusion (HOPE) after cold storage. Graft loss was significantly less in HOPE-treated livers, despite longer donor warm ischaemia times. Therefore, HOPE after cold storage appears to be a simple and effective method to treat high-risk livers before implantation
Whole-Genome Sequencing for Predicting Clarithromycin Resistance in .
No full textis emerging as an important pathogen in chronic lung diseases, with concern regarding patient-to-patient transmission. The recent introduction of routine whole-genome sequencing (WGS) as a replacement for existing reference techniques in England provides an opportunity to characterize the genetic determinants of resistance. We conducted a systematic review to catalogue all known resistance-determining mutations. This knowledge was used to construct a predictive algorithm based on mutations in the (41) and genes which was tested on a collection of 203 sequentially acquired clinical isolates for which there were paired genotype/phenotype data. A search for novel resistance-determining mutations was conducted using a heuristic algorithm. The sensitivity of existing knowledge for predicting resistance in clarithromycin was 95% (95% confidence interval [CI], 89 to 98%), and the specificity was 66% (95% CI, 54 to 76%). The subspecies alone was a poor predictor of resistance to clarithromycin. Eight potential new resistance-conferring single nucleotide polymorphisms (SNPs) were identified. WGS demonstrated probable resistance-determining SNPs in regions that the NTM-DR line probe cannot detect. These mutations are potentially clinically important, as they all occurred in samples that were predicted to be inducibly resistant and for which a macrolide would therefore currently be indicated. We were unable to explain all resistance, raising the possibility of the involvement of other as yet unidentified genes
Distinct fibroblast subsets drive inflammation and damage in arthritis.
No full textThe identification of lymphocyte subsets with non-overlapping effector functions has been pivotal to the development of targeted therapies in immune-mediated inflammatory diseases (IMIDs). However, it remains unclear whether fibroblast subclasses with non-overlapping functions also exist and are responsible for the wide variety of tissue-driven processes observed in IMIDs, such as inflammation and damage. Here we identify and describe the biology of distinct subsets of fibroblasts responsible for mediating either inflammation or tissue damage in arthritis. We show that deletion of fibroblast activation protein-α (FAPα) fibroblasts suppressed both inflammation and bone erosions in mouse models of resolving and persistent arthritis. Single-cell transcriptional analysis identified two distinct fibroblast subsets within the FAPα population: FAPαTHY1 immune effector fibroblasts located in the synovial sub-lining, and FAPαTHY1 destructive fibroblasts restricted to the synovial lining layer. When adoptively transferred into the joint, FAPαTHY1 fibroblasts selectively mediate bone and cartilage damage with little effect on inflammation, whereas transfer of FAPα THY1 fibroblasts resulted in a more severe and persistent inflammatory arthritis, with minimal effect on bone and cartilage. Our findings describing anatomically discrete, functionally distinct fibroblast subsets with non-overlapping functions have important implications for cell-based therapies aimed at modulating inflammation and tissue damage
A comprehensive evaluation of the long-term economic impact of major bile duct injury.
No full textBACKGROUND
Complications and litigation after bile duct injury (BDI) result in clinical and economic burden. The aim of this study was to comprehensively evaluate the long-term clinical and economic impact of major BDI.
METHOD
Patients with long-term follow-up after Strasberg E BDI were identified. Costs of treatment and litigation were the primary outcome. Relationships between these outcomes and repair factors, like timing of repair and surgeon expertise, were secondary outcomes.
RESULTS
Among 139 patients with a median follow up of 10.7 years, 40% of patients developed biliary complications. Repairs by non-specialist surgeons had significantly higher follow up and treatment costs than those by specialists (£25,814 vs. £14,269, p < 0.001). Estimated litigation costs were higher in delayed than immediate repairs (£23,295 vs. £12,864). As such, the lowest average costs per BDI are after immediate specialist repair and the highest after delayed non-specialist repair (£27,133 vs. £49,109, ×1.81 more costly, p < 0.001). Repair by a non-specialist surgeon (HR: 4.00, p < 0.001) and vascular injury (HR: 2.35, p = 0.013) were significant independent predictors of increased complication rates.
CONCLUSION
Costs of major BDI are considerable. They can be reduced by immediate on-table repair by specialist surgeons. This must therefore be considered the standard of care wherever possible
Chronic Obstructive Pulmonary Disease Biomarkers and Their Interpretation.
No full textThe pathology and impact of chronic obstructive pulmonary disease (COPD) results from an abnormal inflammatory process resulting in tissue damage with ineffective repair in response to toxic inhalants (especially cigarette smoke). Identification of mechanisms provides the opportunity to develop new therapies and a personalized approach to management. The collection of multiple genetic and detailed biochemical data from small and large patient cohorts has led to an explosion of studies investigating biomarkers to achieve these aims. Despite widespread enthusiasm and many statistically significant associations, the interpretation of COPD biomarker results requires thought and leaves many questions unanswered. The present review assesses the importance of these associations, whether they represent cause or effect, reflect disease severity or activity, the complexity of the pathway to the final pathogenic and hence interventional step, and problems with interpreting cross-sectional studies without knowing individual disease trajectories. The complexity of biomarker specificity without sufficient clinical phenotype and endotype information contributes to problems of interpretation. A strategic change is needed to develop useful COPD biomarkers; this includes focusing on endotype biomarkers within specific clinical phenotypes, biomarkers in early COPD, exacerbation subtype biomarkers, and biomarkers to predict or measure drug effects
Association between time of hospitalization with acute myocardial infarction and in-hospital mortality.
No full textAIMS
To study the association between time of hospitalization and in-hospital mortality for acute myocardial infarction (AMI).
METHODS AND RESULTS
Patients admitted with ST-elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) across 243 hospitals in England and Wales between 1 January 2004 and 31 March 2013 were included. The outcome measure was in-hospital mortality. Adjusted odds ratios (ORs) for in-hospital mortality were estimated across six 4-hourly time periods over the 24-h clock using multilevel logistic regression, inverse-probability weighting propensity score, and instrumental variable analysis. Among 615 035 patients [median age 70.0 years, interquartile range 59.0-80.0 years; 406 519 (66.0%) men], there were 52 777 (8.8%) in-hospital deaths. At night, patients with NSTEMI were more frequently comorbid, and for STEMI had longer symptom-onset-to-reperfusion times. For STEMI, unadjusted in-hospital mortality was highest between 20:00 and 23:59 [4-h period range 8.4-9.9%; OR compared with 00:00-03:59 reference 1.13, 95% confidence interval (CI) 1.07-1.20], and for NSTEMI highest between 12:00 and 15:59 (8.0-8.8%; OR compared with 00:00-03:59 reference 1.07, 95% CI 1.03-1.12). However, these differences were only apparent in the earlier years of the study, and were attenuated by adjustment for demographics, comorbidities, and clinical presentation. Differences were not statistically significant after adjustment for acute clinical treatment provided.
CONCLUSION
There is little evidence to support an association between time of hospitalization and in-hospital mortality for AMI; variation in in-hospital mortality may be explained by case mix and the use of treatments
Speech, language and swallowing impairments in functional neurological disorder: a scoping review.
No full textBACKGROUND
Functional neurological disorder (FND) is common across healthcare settings. The Diagnostic and Statistical Manual of Mental Disorders states that speech and swallowing symptoms can be present in FND. Despite this, there is a dearth of guidelines for speech and language therapists (SLTs) for this client group.
AIMS
To address the following question in order to identify gaps for further research: What is known about speech, language and swallowing symptoms in patients with FND?
METHODS & PROCEDURES
A scoping review was conducted. Six healthcare databases were searched for relevant literature: CINAHL PLUS, MEDLINE, ProQuest Nursing and Allied Health Professionals, Science Citation Index, Scopus, and PsychINFO. The following symptoms were excluded from the review: dysphonia, globus pharyngeus, dysfluency, foreign accent syndrome and oesophageal dysphagia.
MAIN CONTRIBUTION
A total of 63 papers were included in the final review; they ranged in date from 1953 to 2018. Case studies were the most frequent research method (n = 23, 37%). 'Psychogenic' was the term used most frequently (n = 24, 38%), followed by 'functional' (n = 21, 33%). Speech symptoms were reported most frequently (n = 41, 65%), followed by language impairments (n = 35, 56%) and dysphagia (n = 13, 21%). Only 11 publications comment on the involvement of SLTs. Eight papers report direct speech and language therapy input; however, none studied the effectiveness of speech and language therapy.
CONCLUSIONS & IMPLICATIONS
Speech, language and swallowing symptoms do occur in patients with FND, yet it is a highly under-researched area. Further research is required to create a set of positive diagnostic criteria, gather accurate data on numbers of patients with FND and speech, language or swallowing symptoms, and to evaluate the effectiveness of direct speech and language therapy involvement