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Comparative effectiveness of common treatments for new-onset atrial fibrillation within the ICU: accounting for physiological status
No full textBackground: New-onset atrial fibrillation (NOAF) is common in patients on an intensive care unit (ICU). Evidence guiding treatments is limited, though recent reports suggest beta blocker (BB) therapy is associated with reduced mortality.
Methods: We conducted a multicentre cohort study of adult patients admitted to 3 ICUs in the UK and 5 ICUs in the USA. We analysed the haemodynamic changes associated with NOAF. We analysed rate control, rhythm control, and hospital mortality associated with common NOAF treatments. We balanced admission and post-NOAF, pre-treatment covariates across treatment groups.
Results: NOAF was followed by a systolic blood pressure reduction of 5mmHg (p<0.001). After adjustment, digoxin therapy was associated with inferior rate control versus amiodarone (adjusted hazard ratio (aHR) 0.56, [95% CI 0.34 – 0.92]). Calcium channel blocker (CCB) therapy was associated with inferior rhythm control versus amiodarone (aHR 0.59 (0.37 – 0.92). No difference was detected between BBs and amiodarone in rate control (aHR 1.15 [0.91 – 1.46]), rhythm control (aHR 0.85, [0.69 – 1.05]), or hospital mortality (aHR 1.03 [0.53 – 2.03]).
Conclusions: NOAF in ICU patients is followed by decreases in blood pressure. BBs and amiodarone are associated with similar cardiovascular control and appear superior to digoxin and CCBs. Accounting for key confounders removes previously reported mortality benefits associated with BB treatment
Elastic and efficient LiDAR reconstruction for large-scale exploration tasks
No full textWe present an efficient, elastic 3D LiDAR reconstruction framework which can reconstruct up to maximum Li-DAR ranges (60 m) at multiple frames per second, thus enabling robot exploration in large-scale environments. Our approach only requires a CPU. We focus on three main challenges of large-scale reconstruction: integration of long-range LiDAR scans at high frequency, the capacity to deform the reconstruction after loop closures are detected, and scalability for long-duration exploration. Our system extends upon a state-of-the-art efficient RGB-D volumetric reconstruction technique, called supereight, to support LiDAR scans and a newly developed submapping technique to allow for dynamic correction of the 3D reconstruction. We then introduce a novel pose graph clustering and submap fusion feature to make the proposed system more scalable for large environments. We evaluate the performance using two public datasets including outdoor exploration with a handheld device and a drone, and with a mobile robot exploring an underground room network. Experimental results demonstrate that our system can reconstruct at 3 Hz with 60 m sensor range and ~5 cm resolution, while state-of-the-art approaches can only reconstruct to 25 cm resolution or 20 m range at the same frequency
USP28 deletion and small molecule inhibition destabilises c-MYC and elicits regression of squamous cell lung carcinoma
No full textLung squamous cell carcinoma (LSCC) is a considerable global health burden, with an incidence of over 600,000 cases per year. Treatment options are limited, and patient 5-year survival rate is less than 5%. The ubiquitin specific protease 28 (USP28) has been implicated in tumorigenesis through its stabilization of the oncoproteins c-MYC, c-JUN and Dp63. Here, we show that genetic inactivation of Usp28 induced regression of established murine LSCC lung tumours. We developed a small molecule that inhibits USP28 activity in the low nanomole range. While displaying cross-reactivity against the closest homologue USP25, this inhibitor showed a high degree of selectivity over other deubiquitinases. USP28 inhibitor treatment resulted in a dramatic decrease in c-MYC, c-JUN and Dp63 proteins levels and consequently induced substantial regression of autochthonous murine LSCC tumors and human LSCC xenografts, thereby phenocopying the effect observed by genetic deletion. Thus, USP28 may represent a promising therapeutic target for the treatment of squamous cell lung carcinoma
Bundled payments for chronic diseases increased health care expenditure in the Netherlands, especially for multimorbid patients
No full textBundled payments aim to stimulate the integration of healthcare services and ultimately reduce healthcare expenditure growth through improved quality of care. The Netherlands introduced bundled payments for chronic diseases in 2010 by reimbursing providers annually for a bundle of primary care services related to COPD, Diabetes, or Vascular Risk Management. We aimed to assess the long-term effects of these bundled payments on healthcare expenditure. We used health insurance claims data from 2008 to 2015 to compare the healthcare expenditure between everyone who was included in bundled payments and a control group. We performed a difference-in-difference analysis in combination with propensity score matching and found that bundled payments consistently increased health care expenditure over seven years. The average half-year increase was €233 (95%CI: 204-262) for DM2, €609 (95%CI: 533-686) for COPD, and €231 (95%CI: 208-254) for VRM, representing 13%, 52%, and 20% of 2008 half-year cost. The increase was higher for those with multimorbidity compared to those without multimorbidity. This suggests that the expectations of the bundled payments are yet to be fulfilled
The influence of finite depth on the evolution of extreme wave statistics in numerical wave tanks
No full textModel tests with unidirectional random wave fields are common for coastal engineering purposes. In this paper, we investigate the finite water depth effect on both the probability of extreme events and the averaged shape of them in such experimental conditions. We simulate some typical model test conditions with a numerical tool, which solves the fully non-linear wave equations. We find the analytical solution based on Nonlinear Schrodinger equation (NLS) to be accurate for low steepness and relatively deep water cases. However, the analytical solution underestimates the kurtosis at the steady state for high steepness cases in shallow water, and also gives zero value of kurtosis at critical water depth, whereas a small but non-zero value of kurtosis is observed in the numerical tank. We also investigate the averaged shape of the extreme events, which are modified by nonlinear physics over the distance. The horizontal asymmetry is significant initially but is greatly reduced to a steady state, and the contraction of the wave groups grows monotonically until the steady state is reached along the wave tank. Finite water depth has limited effects on the averaged shape of large events, especially for the extremely steep waves
The impact of social and physical distancing measures on COVID-19 activity in England: findings from a multi-tiered surveillance system
No full textBackground
A multi-tiered surveillance system based on influenza surveillance was adopted in the United Kingdom in the early stages of the coronavirus disease (COVID-19) epidemic to monitor different stages of the disease. Mandatory social and physical distancing measures (SPDM) were introduced on 23 March 2020 to attempt to limit transmission.
Aim
To describe the impact of SPDM on COVID-19 activity as detected through the different surveillance systems.
Methods
Data from national population surveys, web-based indicators, syndromic surveillance, sentinel swabbing, respiratory outbreaks, secondary care admissions and mortality indicators from the start of the epidemic to week 18 2020 were used to identify the timing of peaks in surveillance indicators relative to the introduction of SPDM. This timing was compared with median time from symptom onset to different stages of illness and levels of care or interactions with healthcare services.
Results
The impact of SPDM was detected within 1 week through population surveys, web search indicators and sentinel swabbing reported by onset date. There were detectable impacts on syndromic surveillance indicators for difficulty breathing, influenza-like illness and COVID-19 coding at 2, 7 and 12 days respectively, hospitalisations and critical care admissions (both 12 days), laboratory positivity (14 days), deaths (17 days) and nursing home outbreaks (4 weeks).
Conclusion
The impact of SPDM on COVID-19 activity was detectable within 1 week through community surveillance indicators, highlighting their importance in early detection of changes in activity. Community swabbing surveillance may be increasingly important as a specific indicator, should circulation of seasonal respiratory viruses increase
Assessing antigen structural integrity through glycosylation analysis of the SARS-CoV-2 viral spike
No full textSevere acute respiratory syndrome coronavirus 2 is the causative pathogen of the COVID-19 pandemic which as of March 29, 2021, has claimed 2 776 175 lives worldwide. Vaccine development efforts focus on the viral trimeric spike glycoprotein as the main target of the humoral immune response. Viral spikes carry glycans that facilitate immune evasion by shielding specific protein epitopes from antibody neutralization, and antigen efficacy is influenced by spike glycoprotein production in vivo. Therefore, immunogen integrity is important for glycoprotein-based vaccine candidates. Here, we show how site-specific glycosylation differs between virus-derived spikes, spike proteins derived from a construct similar to a SARS-CoV-2 vaccine candidate, and commonly used recombinant, engineered spike glycoproteins. Furthermore, we show that their distinctive cellular secretion pathways result in different protein glycosylation and secretion patterns, including shedding of spike monomeric subunits for the vaccine candidate tested, which may have implications for the resulting immune response and vaccine design
Design bioethics: a theoretical framework and argument for innovation in bioethics research
No full textEmpirical research in bioethics has developed rapidly over the past decade, but has largely eschewed the use of technology-driven methodologies. We propose “design bioethics” as an area of conjoined theoretical and methodological innovation in the field, working across bioethics, health sciences and human-centred technological design. We demonstrate the potential of digital tools, particularly purpose-built digital games, to align with theoretical frameworks in bioethics for empirical research, integrating context, narrative and embodiment in moral decision-making. Purpose-built digital tools can engender situated engagement with bioethical questions; can achieve such engagement at scale; and can access groups traditionally under-represented in bioethics research and theory. If developed and used with appropriate rigor, tools motivated by “design bioethics” could offer unique insights into new and familiar normative and empirical issues in the field
Early language screening and intervention can be delivered successfully at scale: evidence from a cluster randomized controlled trial
No full textBackground
It is well established that oral language skills provide a critical foundation for formal education. This study evaluated the effectiveness of the Nuffield Early Language Intervention (NELI) programme in ameliorating language difficulties in the first year of school when delivered at scale.
Methods
We conducted a cluster randomized controlled trial (RCT) in 193 primary schools (containing 238 Reception classrooms). Schools were randomly allocated to either a 20‐week oral language intervention or a business‐as‐usual control group. All classes (N = 5,879 children) in participating schools were screened by school staff using an automated App to assess children’s oral language skills. Screening identified 1,173 children as eligible for language intervention: schools containing 571 of these children were allocated to the control group and 569 to the intervention group.
Results
Children receiving the NELI programme made significantly larger gains than the business‐as‐usual control group on a latent variable reflecting standardized measures of language ability (d = .26) and on the school‐administered automated assessment of receptive and expressive language skills (d = .32). The effects of intervention did not vary as a function of home language background or gender.
Conclusions
This study provides strong evidence for the effectiveness of a school‐based language intervention programme (NELI) delivered at scale. These findings demonstrate that language difficulties can be identified by school‐based testing and ameliorated by a TA delivered intervention; this has important implications for educational and social policy
SARS-CoV-2 vaccination in IBD: past lessons, current evidence and future challenges
No full textSince the beginning of the pandemic, patients with inflammatory bowel diseases [IBD] have been considered at high risk for infection and complications of COVID-19. IBD patients and patients taking immunosuppressive therapy were excluded from clinical phase III vaccine trials, complicating the assessment of effectiveness of these new vaccines. From past experience we know that adapted vaccination strategies may be appropriate in some IBD patients to optimise immunogenicity. We review current evidence on SARS-CoV-2 vaccination relevant to IBD patients, including immune responses from humoral to cellular, emerging data on new variants, and off-label vaccination schemes. We also identify clinical and scientific knowledge gaps that can be translated into both large-scale population-based studies and targeted vaccine studies to describe the precise immune responses induced by SARS-CoV-2 vaccines in IBD patients. We strongly endorse the recommendation of vaccinating IBD patients to ensure maximal protection from COVID-19 both for the individual and the community