AbstractObjectiveTo develop and validate a pragmatic risk score to predict mortality in patients admitted to hospital with coronavirus disease 2019 (covid-19).DesignProspective observational cohort ...study.SettingInternational Severe Acute Respiratory and emerging Infections Consortium (ISARIC) World Health Organization (WHO) Clinical Characterisation Protocol UK (CCP-UK) study (performed by the ISARIC Coronavirus Clinical Characterisation Consortium—ISARIC-4C) in 260 hospitals across England, Scotland, and Wales. Model training was performed on a cohort of patients recruited between 6 February and 20 May 2020, with validation conducted on a second cohort of patients recruited after model development between 21 May and 29 June 2020.ParticipantsAdults (age ≥18 years) admitted to hospital with covid-19 at least four weeks before final data extraction.Main outcome measureIn-hospital mortality.Results35 463 patients were included in the derivation dataset (mortality rate 32.2%) and 22 361 in the validation dataset (mortality rate 30.1%). The final 4C Mortality Score included eight variables readily available at initial hospital assessment: age, sex, number of comorbidities, respiratory rate, peripheral oxygen saturation, level of consciousness, urea level, and C reactive protein (score range 0-21 points). The 4C Score showed high discrimination for mortality (derivation cohort: area under the receiver operating characteristic curve 0.79, 95% confidence interval 0.78 to 0.79; validation cohort: 0.77, 0.76 to 0.77) with excellent calibration (validation: calibration-in-the-large=0, slope=1.0). Patients with a score of at least 15 (n=4158, 19%) had a 62% mortality (positive predictive value 62%) compared with 1% mortality for those with a score of 3 or less (n=1650, 7%; negative predictive value 99%). Discriminatory performance was higher than 15 pre-existing risk stratification scores (area under the receiver operating characteristic curve range 0.61-0.76), with scores developed in other covid-19 cohorts often performing poorly (range 0.63-0.73).ConclusionsAn easy-to-use risk stratification score has been developed and validated based on commonly available parameters at hospital presentation. The 4C Mortality Score outperformed existing scores, showed utility to directly inform clinical decision making, and can be used to stratify patients admitted to hospital with covid-19 into different management groups. The score should be further validated to determine its applicability in other populations.Study registrationISRCTN66726260
Persistent androgen receptor (AR) signaling drives castration-resistant prostate cancer (CRPC) and confers resistance to AR-targeting therapies. Novel therapeutic strategies to overcome this are ...urgently required. We evaluated how bromodomain and extra-terminal (BET) protein inhibitors (BETi) abrogate aberrant AR signaling in CRPC.
We determined associations between BET expression, AR-driven transcription, and patient outcome; and the effect and mechanism by which chemical BETi (JQ1 and GSK1210151A; I-BET151) and BET family protein knockdown regulates AR-V7 expression and AR signaling in prostate cancer models.
Nuclear BRD4 protein expression increases significantly (
≤ 0.01) with castration resistance in same patient treatment-naïve (median
-score; interquartile range: 100; 100-170) and CRPC (150; 110-200) biopsies, with higher expression at diagnosis associating with worse outcome (HR, 3.25; 95% CI, 1.50-7.01;
≤ 0.001). BRD2, BRD3, and BRD4 RNA expression in CRPC biopsies correlates with AR-driven transcription (all
≤ 0.001). Chemical BETi, and combined BET family protein knockdown, reduce AR-V7 expression and AR signaling. This was not recapitulated by C-MYC knockdown. In addition, we show that BETi regulates RNA processing thereby reducing alternative splicing and AR-V7 expression. Furthermore, BETi reduce growth of prostate cancer cells and patient-derived organoids with known AR mutations, AR amplification and AR-V7 expression. Finally, BETi, unlike enzalutamide, decreases persistent AR signaling and growth (
≤ 0.001) of a patient-derived xenograft model of CRPC with AR amplification and AR-V7 expression.
BETi merit clinical evaluation as inhibitors of AR splicing and function, with trials demonstrating their blockade in proof-of-mechanism pharmacodynamic studies.
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We describe the first cohort-based analysis of the impact of genetic disorders in craniosynostosis. We aimed to refine the understanding of prognoses and pathogenesis and to provide rational criteria ...for clinical genetic testing.
We undertook targeted molecular genetic and cytogenetic testing for 326 children who required surgery because of craniosynostosis, were born in 1993-2002, presented to a single craniofacial unit, and were monitored until the end of 2007.
Eighty-four children (and 64 relatives) had pathologic genetic alterations (86% single-gene mutations and 14% chromosomal abnormalities). The FGFR3 P250R mutation was the single largest contributor (24%) to the genetic group. Genetic diagnoses accounted for 21% of all craniosynostosis cases and were associated with increased rates of many complications. Children with an initial clinical diagnosis of nonsyndromic craniosynostosis were more likely to have a causative mutation if the synostoses were unicoronal or bicoronal (10 of 48 cases) than if they were sagittal or metopic (0 of 55 cases; P = .0003). Repeat craniofacial surgery was required for 58% of children with single-gene mutations but only 17% of those with chromosomal abnormalities (P = .01).
Clinical genetic assessment is critical for the treatment of children with craniosynostosis. Genetic testing of nonsyndromic cases (at least for FGFR3 P250R and FGFR2 exons IIIa/c) should be targeted to patients with coronal or multisuture synostoses. Single-gene disorders that disrupt physiologic signaling in the cranial sutures often require reoperation, whereas chromosomal abnormalities follow a more-indolent course, which suggests a different, secondary origin of the associated craniosynostosis.
For many blood-based diagnostic tests, including prophylactic drug analysis and malaria assays, red blood cells must be lysed effectively prior to their use in an analytical workflow. We report on a ...finger-actuated blood lysate preparation device, which utilises a previously reported acoustofluidic micromixer module. The integrated device includes a range of innovations from a sample interface, to the integration of blisters on a laser engraved surface and a large volume (130 μL) one-stroke manual pump which could be useful in other low-cost microfluidic-based point-of-care devices. The adaptability of the acoustic mixer is demonstrated on highly viscous fluids, including whole blood, with up to 65% percent volume fraction of red blood cells. Used in conjunction with a lysis buffer, the micromixer unit is also shown to lyse a finger-prick (approximately 20 μL) blood sample in 30 seconds and benchmarked across ten donor samples. Finally, we demonstrate the ease of use of the fully integrated device. Cheap, modular, but reliable, finger-actuated microfluidic functions could open up opportunities for the development of diagnostics with minimal resources.
An integrated finger-actuated device utilising an acoustofluidic mixer, allows for the preparation of a filtered blood lysate from in under 3 minutes and without any pipetting.
COVID-19 is a multisystem disease and patients who survive might have in-hospital complications. These complications are likely to have important short-term and long-term consequences for patients, ...health-care utilisation, health-care system preparedness, and society amidst the ongoing COVID-19 pandemic. Our aim was to characterise the extent and effect of COVID-19 complications, particularly in those who survive, using the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK.
We did a prospective, multicentre cohort study in 302 UK health-care facilities. Adult patients aged 19 years or older, with confirmed or highly suspected SARS-CoV-2 infection leading to COVID-19 were included in the study. The primary outcome of this study was the incidence of in-hospital complications, defined as organ-specific diagnoses occurring alone or in addition to any hallmarks of COVID-19 illness. We used multilevel logistic regression and survival models to explore associations between these outcomes and in-hospital complications, age, and pre-existing comorbidities.
Between Jan 17 and Aug 4, 2020, 80 388 patients were included in the study. Of the patients admitted to hospital for management of COVID-19, 49·7% (36 367 of 73 197) had at least one complication. The mean age of our cohort was 71·1 years (SD 18·7), with 56·0% (41 025 of 73 197) being male and 81·0% (59 289 of 73 197) having at least one comorbidity. Males and those aged older than 60 years were most likely to have a complication (aged ≥60 years: 54·5% 16 579 of 30 416 in males and 48·2% 11 707 of 24 288 in females; aged <60 years: 48·8% 5179 of 10 609 in males and 36·6% 2814 of 7689 in females). Renal (24·3%, 17 752 of 73 197), complex respiratory (18·4%, 13 486 of 73 197), and systemic (16·3%, 11 895 of 73 197) complications were the most frequent. Cardiovascular (12·3%, 8973 of 73 197), neurological (4·3%, 3115 of 73 197), and gastrointestinal or liver (10·8%, 7901 of 73 197) complications were also reported.
Complications and worse functional outcomes in patients admitted to hospital with COVID-19 are high, even in young, previously healthy individuals. Acute complications are associated with reduced ability to self-care at discharge, with neurological complications being associated with the worst functional outcomes. COVID-19 complications are likely to cause a substantial strain on health and social care in the coming years. These data will help in the design and provision of services aimed at the post-hospitalisation care of patients with COVID-19.
National Institute for Health Research and the UK Medical Research Council.
Precision medicine based upon molecular testing is heralded as a revolution in how cancer is prevented, diagnosed, and treated. Large efforts across the world aim to conduct comprehensive molecular ...profiling of disease to inform preclinical models, translational research studies and clinical trials. However, most studies have only been performed in patients from high-income countries. As the burden on non-communicable diseases increases, cancer will become a pressing burden across the world, disproportionately affecting low-middle income settings. There is emerging evidence that the molecular landscape of disease differs geographically and by genetic ancestry, which cannot be explained by environmental factors alone. There is a lack of good quality evidence that characterises the molecular landscape of cancers found in low-middle income countries. As cancer medicine becomes increasingly driven by molecular alterations in high-income settings, low-income settings may become left behind. Further efforts on an international scale must be made by researchers, funders, and policymakers to ensure cancer research addresses disease across the world, so models are not limited to subtypes of disease found in high-income countries. In this review, we discuss differences found in the molecular profiles of tumours worldwide and the implication this has for the future of global cancer care. Finally, we identify several barriers currently limiting progress in this field and innovative solutions, which may address these shortcomings.
Prognostic models to predict the risk of clinical deterioration in acute COVID-19 cases are urgently required to inform clinical management decisions.
We developed and validated a multivariable ...logistic regression model for in-hospital clinical deterioration (defined as any requirement of ventilatory support or critical care, or death) among consecutively hospitalised adults with highly suspected or confirmed COVID-19 who were prospectively recruited to the International Severe Acute Respiratory and Emerging Infections Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) study across 260 hospitals in England, Scotland, and Wales. Candidate predictors that were specified a priori were considered for inclusion in the model on the basis of previous prognostic scores and emerging literature describing routinely measured biomarkers associated with COVID-19 prognosis. We used internal–external cross-validation to evaluate discrimination, calibration, and clinical utility across eight National Health Service (NHS) regions in the development cohort. We further validated the final model in held-out data from an additional NHS region (London).
74 944 participants (recruited between Feb 6 and Aug 26, 2020) were included, of whom 31 924 (43·2%) of 73 948 with available outcomes met the composite clinical deterioration outcome. In internal–external cross-validation in the development cohort of 66 705 participants, the selected model (comprising 11 predictors routinely measured at the point of hospital admission) showed consistent discrimination, calibration, and clinical utility across all eight NHS regions. In held-out data from London (n=8239), the model showed a similarly consistent performance (C-statistic 0·77 95% CI 0·76 to 0·78; calibration-in-the-large 0·00 –0·05 to 0·05); calibration slope 0·96 0·91 to 1·01), and greater net benefit than any other reproducible prognostic model.
The 4C Deterioration model has strong potential for clinical utility and generalisability to predict clinical deterioration and inform decision making among adults hospitalised with COVID-19.
National Institute for Health Research (NIHR), UK Medical Research Council, Wellcome Trust, Department for International Development, Bill & Melinda Gates Foundation, EU Platform for European Preparedness Against (Re-)emerging Epidemics, NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, NIHR HPRU in Respiratory Infections at Imperial College London.
Kelp forests are characterized by high biodiversity and productivity, and the cycling of kelp-produced carbon is a vital process in this ecosystem. Although bacteria are assumed to play a major role ...in kelp forest carbon cycling, knowledge of the composition and diversity of these bacterial communities is lacking. Bacterial communities on the surface of Macrocystis pyrifera and adjacent seawater were sampled at the Hopkins Marine Station in Monterey Bay, CA, and further studied using 454-tag pyrosequencing of 16S RNA genes. Our results suggest that M. pyrifera-dominated kelp forests harbor distinct microbial communities that vary temporally. The distribution of sequence tags assigned to Gammaproteobacteria, Alphaproteobacteria and Bacteriodetes differed between the surface of the kelp and the surrounding water. Several abundant Rhodobacteraceae, uncultivated Gammaproteobacteria and Bacteriodetes-associated tags displayed considerable temporal variation, often with similar trends in the seawater and the surface of the kelp. Bacterial community structure and membership correlated with the kelp surface serving as host, and varied over time. Several kelp-specific taxa were highly similar to other bacteria known to either prevent the colonization of eukaryotic larvae or exhibit antibacterial activities. Some of these kelp-specific bacterial associations might play an important role for M. pyrifera. This study provides the first assessment of the diversity and phylogenetic profile of the bacterial communities associated with M. pyrifera.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Malnutrition is an independent predictor for postoperative complications in low- and middle-income countries (LMICs). We systematically reviewed evidence on the impact of preoperative oral nutrition ...supplementation (ONS) on patients undergoing gastrointestinal cancer surgery in LMICs. We searched EMBASE, Cochrane Library, Web of Science, Scopus, WHO Global Index Medicus, SciELO, Latin American and Caribbean Health Sciences Literature (LILACS) databases from inception to March 21, 2022 for randomised controlled trials evaluating preoperative ONS in gastrointestinal cancer within LMICs. We evaluated the impact of ONS on all postoperative outcomes using random-effects meta-analysis. Seven studies reported on 891 patients (446 ONS group, 445 control group) undergoing surgery for gastrointestinal cancer. Preoperative ONS reduced all cause postoperative surgical complications (risk ratio (RR) 0.53, 95% CI 0.46-0.60, P < 0.001, I
= 0%, n = 891), infection (0.52, 0.40-0.67, P = 0.008, I
= 0%, n = 570) and all-cause mortality (0.35, 0.26-0.47, P = 0.014, I
= 0%, n = 588). Despite heterogeneous populations and baseline rates, absolute risk ratio (ARR) was reduced for all cause (pooled effect -0.14, -0.22 to -0.06, P = 0.006; number needed to treat (NNT) 7) and infectious complications (-0.13, -0.22 to -0.06, P < 0.001; NNT 8). Preoperative nutrition in patients undergoing gastrointestinal cancer surgery in LMICs demonstrated consistently strong and robust treatment effects across measured outcomes. However additional higher quality research, with particular focus within African populations, are urgently required.
Complications following surgery are common and frequently occur the following discharge. Mobile and wearable digital health interventions (DHI) provide an opportunity to monitor and support patients ...during their postoperative recovery. Lack of high-quality evidence is often cited as a barrier to DHI implementation. This review captures and appraises the current use, evidence base and reporting quality of mobile and wearable DHI following surgery. Keyword searches were performed within Embase, Cochrane Library, Web of Science and WHO Global Index Medicus databases, together with clinical trial registries and Google scholar. Studies involving patients undergoing any surgery requiring skin incision where postoperative outcomes were measured using a DHI following hospital discharge were included, with DHI defined as mobile and wireless technologies for health to improve health system efficiency and health outcomes. Methodological reporting quality was determined using the validated mobile health evidence reporting and assessment (mERA) guidelines. Bias was assessed using the Cochrane Collaboration tool for randomised studies or MINORS depending on study type. Overall, 6969 articles were screened, with 44 articles included. The majority (n = 34) described small prospective study designs, with a high risk of bias demonstrated. Reporting standards were suboptimal across all domains, particularly in relation to data security, prior patient engagement and cost analysis. Despite the potential of DHI to improve postoperative patient care, current progress is severely restricted by limitations in methodological reporting. There is an urgent need to improve reporting for DHI following surgery to identify patient benefit, promote reproducibility and encourage sustainability.
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