125 research outputs found
Respiratory support in patients with severe COVID-19 in the International Severe Acute Respiratory and Emerging Infection (ISARIC) COVID-19 study : a prospective, multinational, observational study
No full textPublisher Copyright: © 2022, The Author(s).Background: Up to 30% of hospitalised patients with COVID-19 require advanced respiratory support, including high-flow nasal cannulas (HFNC), non-invasive mechanical ventilation (NIV), or invasive mechanical ventilation (IMV). We aimed to describe the clinical characteristics, outcomes and risk factors for failing non-invasive respiratory support in patients treated with severe COVID-19 during the first two years of the pandemic in high-income countries (HICs) and low middle-income countries (LMICs). Methods: This is a multinational, multicentre, prospective cohort study embedded in the ISARIC-WHO COVID-19 Clinical Characterisation Protocol. Patients with laboratory-confirmed SARS-CoV-2 infection who required hospital admission were recruited prospectively. Patients treated with HFNC, NIV, or IMV within the first 24 h of hospital admission were included in this study. Descriptive statistics, random forest, and logistic regression analyses were used to describe clinical characteristics and compare clinical outcomes among patients treated with the different types of advanced respiratory support. Results: A total of 66,565 patients were included in this study. Overall, 82.6% of patients were treated in HIC, and 40.6% were admitted to the hospital during the first pandemic wave. During the first 24 h after hospital admission, patients in HICs were more frequently treated with HFNC (48.0%), followed by NIV (38.6%) and IMV (13.4%). In contrast, patients admitted in lower- and middle-income countries (LMICs) were less frequently treated with HFNC (16.1%) and the majority received IMV (59.1%). The failure rate of non-invasive respiratory support (i.e. HFNC or NIV) was 15.5%, of which 71.2% were from HIC and 28.8% from LMIC. The variables most strongly associated with non-invasive ventilation failure, defined as progression to IMV, were high leukocyte counts at hospital admission (OR [95%CI]; 5.86 [4.83–7.10]), treatment in an LMIC (OR [95%CI]; 2.04 [1.97–2.11]), and tachypnoea at hospital admission (OR [95%CI]; 1.16 [1.14–1.18]). Patients who failed HFNC/NIV had a higher 28-day fatality ratio (OR [95%CI]; 1.27 [1.25–1.30]). Conclusions: In the present international cohort, the most frequently used advanced respiratory support was the HFNC. However, IMV was used more often in LMIC. Higher leucocyte count, tachypnoea, and treatment in LMIC were risk factors for HFNC/NIV failure. HFNC/NIV failure was related to worse clinical outcomes, such as 28-day mortality. Trial registration This is a prospective observational study; therefore, no health care interventions were applied to participants, and trial registration is not applicable.Peer reviewe
Use of an extended KDIGO definition to diagnose acute kidney injury in patients with COVID-19: A multinational study using the ISARIC–WHO clinical characterisation protocol
No full textBackground
Acute kidney injury (AKI) is one of the most common and significant problems in patients with Coronavirus Disease 2019 (COVID-19). However, little is known about the incidence and impact of AKI occurring in the community or early in the hospital admission. The traditional Kidney Disease Improving Global Outcomes (KDIGO) definition can fail to identify patients for whom hospitalisation coincides with recovery of AKI as manifested by a decrease in serum creatinine (sCr). We hypothesised that an extended KDIGO (eKDIGO) definition, adapted from the International Society of Nephrology (ISN) 0by25 studies, would identify more cases of AKI in patients with COVID-19 and that these may correspond to community-acquired AKI (CA-AKI) with similarly poor outcomes as previously reported in this population.
Methods and findings
All individuals recruited using the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC)–World Health Organization (WHO) Clinical Characterisation Protocol (CCP) and admitted to 1,609 hospitals in 54 countries with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection from February 15, 2020 to February 1, 2021 were included in the study. Data were collected and analysed for the duration of a patient’s admission. Incidence, staging, and timing of AKI were evaluated using a traditional and eKDIGO definition, which incorporated a commensurate decrease in sCr. Patients within eKDIGO diagnosed with AKI by a decrease in sCr were labelled as deKDIGO. Clinical characteristics and outcomes—intensive care unit (ICU) admission, invasive mechanical ventilation, and in-hospital death—were compared for all 3 groups of patients. The relationship between eKDIGO AKI and in-hospital death was assessed using survival curves and logistic regression, adjusting for disease severity and AKI susceptibility. A total of 75,670 patients were included in the final analysis cohort. Median length of admission was 12 days (interquartile range [IQR] 7, 20). There were twice as many patients with AKI identified by eKDIGO than KDIGO (31.7% versus 16.8%). Those in the eKDIGO group had a greater proportion of stage 1 AKI (58% versus 36% in KDIGO patients). Peak AKI occurred early in the admission more frequently among eKDIGO than KDIGO patients. Compared to those without AKI, patients in the eKDIGO group had worse renal function on admission, more in-hospital complications, higher rates of ICU admission (54% versus 23%) invasive ventilation (45% versus 15%), and increased mortality (38% versus 19%). Patients in the eKDIGO group had a higher risk of in-hospital death than those without AKI (adjusted odds ratio: 1.78, 95% confidence interval: 1.71 to 1.80, p-value < 0.001). Mortality and rate of ICU admission were lower among deKDIGO than KDIGO patients (25% versus 50% death and 35% versus 70% ICU admission) but significantly higher when compared to patients with no AKI (25% versus 19% death and 35% versus 23% ICU admission) (all p-values <5 × 10−5). Limitations include ad hoc sCr sampling, exclusion of patients with less than two sCr measurements, and limited availability of sCr measurements prior to initiation of acute dialysis.
Conclusions
An extended KDIGO definition of AKI resulted in a significantly higher detection rate in this population. These additional cases of AKI occurred early in the hospital admission and were associated with worse outcomes compared to patients without AKI
Neurocognitive disorders in young adults commencing highly active anti-retroviral treatment in the Western Cape
No full textIncludes abstract.Includes bibliographical references.HIV-associated neurocognitive disorders (HAND) remain prevalent in the era of highly active anti-retroviral therapy (HAART). The aim of the study was to investigate whether HAND are as prevalent in South Africa as in other regions, and whether individuals with HAND in South Africa will respond to HAART. The literature was reviewed to elucidate potential mechanisms of the development of HIV-associated dementia (HAD), the most severe form of HAND, and to establish the effect that HAART has exerted on HAND across diverse studies. A prospective clinical cohort study was initiated in Cape Town, comprising 170 participants. The reviewed literature suggests that HAD is likely mediated by a range of HIV-related factors (including possible difference in HIV sub-type) and host-related factors
Whole-genome analysis of diverse Chlamydia trachomatis strains identifies phylogenetic relationships masked by current clinical typing
No full textChlamydia trachomatis is responsible for both trachoma and sexually transmitted infections, causing substantial morbidity and economic cost globally. Despite this, our knowledge of its population and evolutionary genetics is limited. Here we present a detailed phylogeny based on whole-genome sequencing of representative strains of C. trachomatis from both trachoma and lymphogranuloma venereum (LGV) biovars from temporally and geographically diverse sources. Our analysis shows that predicting phylogenetic structure using ompA, which is traditionally used to classify Chlamydia, is misleading because extensive recombination in this region masks any true relationships present. We show that in many instances, ompA is a chimera that can be exchanged in part or as a whole both within and between biovars. We also provide evidence for exchange of, and recombination within, the cryptic plasmid, which is another key diagnostic target. We used our phylogenetic framework to show how genetic exchange has manifested itself in ocular, urogenital and LGV C. trachomatis strains, including the epidemic LGV serotype L2b
Microstate connectivity alterations in patients with early Alzheimer's disease
No full textElectroencephalography (EEG) microstates and brain network are altered in patients with Alzheimer's disease (AD) and discussed as potential biomarkers for AD. Microstates correspond to defined states of brain activity, and their connectivity patterns may change accordingly. Little is known about alteration of connectivity in microstates, especially in patients with amnestic mild cognitive impairment with stable or improving cognition within 30 months (aMCI).; Thirty-five outpatients with aMCI or mild dementia (mean age 77 ± 7 years, 47 % male, Mini Mental State Examination score ≥24) had comprehensive neuropsychological and clinical examinations. Subjects with cognitive decline over 30 months were allocated to the AD group, subjects with stable or improving cognition to the MCI-stable group. Results of neuropsychological testing at baseline were summarized in six domain scores. Resting state EEG was recorded with 256 electrodes and analyzed using TAPEEG. Five microstates were defined and individual data fitted. After phase transformation, the phase lag index (PLI) was calculated for the five microstates in every subject. Networks were reduced to 22 nodes for statistical analysis.; The domain score for verbal learning and memory and the microstate segmented PLI between the left centro-lateral and parieto-occipital regions in the theta band at baseline differentiated significantly between the groups. In the present sample, they separated in a logistic regression model with a 100 % positive predictive value, 60 % negative predictive value, 100 % specificity and 77 % sensitivity between AD and MCI-stable.; Combining neuropsychological and quantitative EEG test results allows differentiation between subjects with aMCI remaining stable and subjects with aMCI deteriorating over 30 months
Respiratory support in patients with severe COVID-19 in the International Severe Acute Respiratory and Emerging Infection (ISARIC) COVID-19 study: a prospective, multinational, observational study
No full textBACKGROUND: Up to 30% of hospitalised patients with COVID-19 require advanced respiratory support, including high-flow nasal cannulas (HFNC), non-invasive mechanical ventilation (NIV), or invasive mechanical ventilation (IMV). We aimed to describe the clinical characteristics, outcomes and risk factors for failing non-invasive respiratory support in patients treated with severe COVID-19 during the first two years of the pandemic in high-income countries (HICs) and low middle-income countries (LMICs). METHODS: This is a multinational, multicentre, prospective cohort study embedded in the ISARIC-WHO COVID-19 Clinical Characterisation Protocol. Patients with laboratory-confirmed SARS-CoV-2 infection who required hospital admission were recruited prospectively. Patients treated with HFNC, NIV, or IMV within the first 24 h of hospital admission were included in this study. Descriptive statistics, random forest, and logistic regression analyses were used to describe clinical characteristics and compare clinical outcomes among patients treated with the different types of advanced respiratory support. RESULTS: A total of 66,565 patients were included in this study. Overall, 82.6% of patients were treated in HIC, and 40.6% were admitted to the hospital during the first pandemic wave. During the first 24 h after hospital admission, patients in HICs were more frequently treated with HFNC (48.0%), followed by NIV (38.6%) and IMV (13.4%). In contrast, patients admitted in lower- and middle-income countries (LMICs) were less frequently treated with HFNC (16.1%) and the majority received IMV (59.1%). The failure rate of non-invasive respiratory support (i.e. HFNC or NIV) was 15.5%, of which 71.2% were from HIC and 28.8% from LMIC. The variables most strongly associated with non-invasive ventilation failure, defined as progression to IMV, were high leukocyte counts at hospital admission (OR [95%CI]; 5.86 [4.83-7.10]), treatment in an LMIC (OR [95%CI]; 2.04 [1.97-2.11]), and tachypnoea at hospital admission (OR [95%CI]; 1.16 [1.14-1.18]). Patients who failed HFNC/NIV had a higher 28-day fatality ratio (OR [95%CI]; 1.27 [1.25-1.30]). CONCLUSIONS: In the present international cohort, the most frequently used advanced respiratory support was the HFNC. However, IMV was used more often in LMIC. Higher leucocyte count, tachypnoea, and treatment in LMIC were risk factors for HFNC/NIV failure. HFNC/NIV failure was related to worse clinical outcomes, such as 28-day mortality. Trial registration This is a prospective observational study; therefore, no health care interventions were applied to participants, and trial registration is not applicable.SCOPUS: ar.jinfo:eu-repo/semantics/publishe
A systematic review of evidence on malignant spinal metastases : natural history and technologies for identifying patients at high risk of vertebral fracture and spinal cord compression
No full textBackground: Spinal metastases can lead to significant morbidity and reduction in quality of life due to spinal cord compression (SCC). Between 5% and 20% of patients with spinal metastases develop metastatic spinal cord compression during the course of their disease. An early study estimated average survival for patients with SCC to be between 3 and 7 months, with a 36% probability of survival to 12 months. An understanding of the natural history and early diagnosis of spinal metastases and prediction of collapse of the metastatic vertebrae are important.
Objective: To undertake a systematic review to examine the natural history of metastatic spinal lesions and to identify patients at high risk of vertebral fracture and SCC.
Data sources: The search strategy covered the concepts of metastasis, the spine and adults. Searches were undertaken from inception to June 2011 in 13 electronic databases [MEDLINE; MEDLINE In-Process & Other Non-Indexed Citations; EMBASE; Cochrane Database of Systematic Reviews; Cochrane Central Register of Controlled Trials (CENTRAL); Database of Abstracts of Reviews of Effects (DARE), NHS Economic Evaluation Database (NHS EED), HTA databases (NHS Centre for Reviews and Dissemination); Science Citation Index and Conference Proceedings (Web of Science); UK Clinical Research Network (UKCRN) Portfolio Database; Current Controlled Trials; ClinicalTrials.gov].
Review methods: Titles and abstracts of retrieved studies were assessed by two reviewers independently. Disagreement was resolved by consensus agreement. Full data were extracted independently by one reviewer. All included studies were reviewed by a second researcher with disagreements resolved by discussion. A quality assessment instrument was used to assess bias in six domains: study population, attrition, prognostic factor measurement, outcome measurement, confounding measurement and account, and analysis. Data were tabulated and discussed in a narrative review. Each tumour type was looked at separately.
Results: In all, 2425 potentially relevant articles were identified, of which 31 met the inclusion criteria. No study examined natural history alone. Seventeen studies reported retrospective data, 10 were prospective studies, and three were other study designs. There was one systematic review. There were no randomised controlled trials (RCTs). Approximately 5782 participants were included. Sample sizes ranged from 41 to 859. The age of participants ranged between 7 and 92 years. Types of cancers reported on were lung alone (n= 3), prostate alone (n= 6), breast alone (n= 7), mixed cancers (n= 13) and unclear (n= 1). A total of 93 prognostic factors were identified as potentially significant in predicting risk of SCC or collapse. Overall findings indicated that the more spinal metastases present and the longer a patient was at risk, the greater the reported likelihood of development of SCC and collapse. There was an increased risk of developing SCC if a cancer had already spread to the bones. In the prostate cancer studies, tumour grade, metastatic load and time on hormone therapy were associated with increased risk of SCC. In one study, risk of SCC before death was 24%, and 2.37 times greater with a Gleason score 7 than with a score of < 7 (p= 0.003). Other research found that patients with six or more bone lesions were at greater risk of SCC than those with fewer than six lesions [odds ratio (OR) 2.9, 95% confidence interval (CI) 1.012 to 8.35, p= 0.047]. For breast cancer patients who received a computerised tomography (CT) scan for suspected SCC, multiple logistic regression in one study identified four independent variables predictive of a positive test: bone metastases 2 years (OR 3.0 95% CI 1.2 to 7.6; p= 0.02); metastatic disease at initial diagnosis (OR 3.4, 95% CI 1.0 to 11.4; p= 0.05); objective weakness (OR 3.8, 95% CI 1.5 to 9.5; p= 0.005); and vertebral compression fracture on spine radiograph (OR 2.6, 95% CI 1.0 to 6.5; p= 0.05). A further study on mixed cancers, among patients who received surgery for SCC, reported that vertebral body compression fractures were associated with presurgery chemotherapy (OR 2.283, 95% CI 1.064 to 4.898; p= 0.03), cancer type [primary breast cancer (OR 4.179, 95% CI 1.457 to 11.983; p= 0.008)], thoracic involvement (OR 3.505, 95% CI 1.343 to 9.143; p= 0.01) and anterior cord compression (OR 3.213, 95% CI 1.416 to 7.293; p= 0.005).
Limitations: Many of the included studies provided limited information about patient populations and selection criteria and they varied in methodological quality, rigour and transparency. Several studies identified type of cancer (e.g. breast, lung or prostate cancer) as a significant factor in predicting SCC, but it remains difficult to determine the risk differential partly because of residual bias. Consideration of quantitative results from the studies does not easily allow generation of a coherent numerical summary, studies were heterogeneous especially with regard to population, results were not consistent between studies, and study results almost universally lacked corroboration from other independent studies.
Conclusion: No studies were found which examined natural history. Overall burden of metastatic disease, confirmed metastatic bone involvement and immediate symptomatology suggestive of spinal column involvement are already well known as factors for metastatic SCC, vertebral collapse or progression of vertebral collapse. Although we identified a large number of additional possible prognostic factors, those which currently offer the most potential are unclear. Current clinical consensus favours magnetic resonance imaging and CT imaging modalities for the investigation of SCC and vertebral fracture. Future research should concentrate on: (1) prospective randomised designs to establish clinical and quality-of-life outcomes and cost-effectiveness of identification and treatment of patients at high risk of vertebral collapse and SCC; (2) Service Delivery and Organisation research on magnetic resonance imaging (MRI) scans and scanning (in tandem with research studies on use of MRI to monitor progression) in order to understand best methods for maximising use of MRI scanners; and (3) investigation of prognostic algorithms to calculate probability of a specified event using high-quality prospective studies, involving defined populations, randomly selected and clearly identified samples, and with blinding of investigators
Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals
No full textCopy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice.Peer reviewe
The clinical and biological consequences of different FLT3 mutations in patients with AML
No full textCharacterisation of pathogenic markers in acute myeloid leukaemia (AML) may benefit
patients through refinement of risk stratification, application of molecularly targeted
therapy and improved understanding of AML biology. Whilst the presence of an
internal tandem duplication (ITD) within the fms-like tyrosine kinase-3 (FLT3) gene is
known to predict adverse outcome in young adults with AML, the clinical significance
of activating mutations in the tyrosine kinase domain (TKD) of FLT3 is unclear.
Therefore, a highly sensitive and specific denaturing-HPLC technique was developed to
screen for FLT3/TKDs in 1339 young adult patients with AML. Mutations were
detected in 161 (12%) cases, with a high incidence in patients with inv(16) (24%;
P=.009), a group in which FLT3/ITDs are uncommon. Unlike FLT3/ITDs, FLT3/TKDs
were associated with a favourable long-term outcome with a 10-year overall survival
(OS) of 36% for FLT3 WT, 51% for FLT3/ITD-TKD+ and 24% for FLT3/ITD+TKDpatients
(P<.001). The relative FLT3/TKD mutant level was highly variable with the
favourable prognosis residing in those patients with greater than 25% mutant alleles
(10-year OS of 59%), possibly reflecting the stage at which the mutation is acquired.
The mechanism of FLT3 activation also influenced sensitivity to FLT3-inhibitor
induced cytotoxicity, with FLT3/ITD+ blast cells more sensitive than FLT3/TKD+ cells.
Following lentiviral transduction, FLT3/ITD-transduced 32Dcl3 and Ba/F3 cells
demonstrated more rapid proliferation than FLT3/TKD-transduced cells. In an NB4 cell
line model of ATRA-induced myeloid differentiation, the presence of a FLT3/ITD
inhibited differentiation unlike a FLT3/TKD mutation which increased differentiation.
Furthermore, FLT3/ITD-transduced CD34 positive haematopoietic stem cells showed
greater cytokine-free survival of colony forming cells than FLT3/TKD-transduced cells.
Signalling studies also revealed that a FLT3/ITD induced stronger STAT5 activation
than a FLT3/TKD mutation. This unexpected genotype-phenotype relationship is of
direct relevance to current clinical decision making in AML, and may also provide
insights into mechanisms of chemoresistance
Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome
No full textBackground: Detection of a retrovirus, xenotropic murine leukaemia virus-related virus (XMRV), has recently been reported in 67% of patients with chronic fatigue syndrome. We have studied a total of 170 samples from chronic fatigue syndrome patients from two UK cohorts and 395 controls for evidence of XMRV infection by looking either for the presence of viral nucleic acids using quantitative PCR (limit of detection <16 viral copies) or for the presence of serological responses using a virus neutralisation assay.
Results: We have not identified XMRV DNA in any samples by PCR (0/299). Some serum samples showed XMRV neutralising activity (26/565) but only one of these positive sera came from a CFS patient. Most of the positive sera were also able to neutralise MLV particles pseudotyped with envelope proteins from other viruses, including vesicular stomatitis virus, indicating significant cross-reactivity in serological responses. Four positive samples were specific for XMRV.
Conclusions: No association between XMRV infection and CFS was observed in the samples tested, either by PCR or serological methodologies. The non-specific neutralisation observed in multiple serum samples suggests that it is unlikely that these responses were elicited by XMRV and highlights the danger of over-estimating XMRV frequency based on serological assays. In spite of this, we believe that the detection of neutralising activity that did not inhibit VSV-G pseudotyped MLV in at least four human serum samples indicates that XMRV infection may occur in the general population, although with currently uncertain outcomes
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