On March 11, 2020, the World Health Organization (WHO) declared a new coronavirus infection caused by the SARS-CoV-2 virus as a pandemic, making it the 11th pandemic of the 20th and 21st centuries. This study investigated the clinical and laboratory results (D-dimer, conventional coagulation, and HbA1c biomarker concentrations) of 150 patients (75 male and 75 female) with confirmed COVID-19 pneumonia and 50 controls (25 male and 25 female). For disease diagnosis, all COVID-19 patients were given a Real-Time Reverse Transcription Polymerase Chain Reaction Assay (RT-PCR). The findings revealed that D-dimer and HbA1c levels in COVID-19 patients were significantly higher (P 0.001) at the time of admission; In COVID-19 patients, there was also a strong correlation between D-dimer levels and HbA1c levels (P 0.001). In conclusion, COVID-19 patients are more likely to have a poor prognosis if their D-dimer and HbA1c levels remain uncontrolled over a lengthy period. To lower the likelihood of a bad prognosis in COVID-19, patients with higher levels of D-dimer and HbA1c should be continuously monitored.
This paper investigates a computation resource optimization problem of mobile edge computing (MEC)-aided Internet-of-Things (IoT) devices with a reinforcement learning (RL) solution. Specifically, we leverage the stochastic optimization method and formulate the Lyapunov optimization technique to maximize the long-term energy efficiency, taking into account the transmission power, network stability, and transmission latency. Based on the Markov decision process and model-free deep RL (DRL) approach, we propose a double DRL-based online computation offloading method to implement a deep neural network that learns from interactions to solve the computation offloading and transmission latency problem in the dynamic MEC-aided IoT environments. Furthermore, we design an adaptive method for continuous action-state spaces to minimize the completion time and total energy consumption of the IoT devices for stochastic computation offloading tasks. The proposed real-time Lyapunov optimization and DRL algorithms achieve low computational complexity and optimal processing time. Simulation results demonstrate that the proposed algorithm can achieve near-optimal control performance with enhanced energy efficiency performance compared to the baseline policy control algorithms.
Recent studies have reported increased levels of urea in the aging brain and various neurological disorders. Additionally, these diseased tissues also have increased expression of the UT-B transporter that regulates urea transport in the brain. However, little is known regarding the actual UT-B protein distribution across the brain in either normal or diseased states. This current study investigated UT-B protein abundance across three regions of the rat brain – anterior, posterior and cerebellum. Endpoint RT-PCR experiments showed that there were no regional differences in UT-B RNA expression (NS, N = 3, ANOVA), whilst Western blotting confirmed no difference in the abundance of a 35 kDa UT-B protein (NS, N = 3–4, ANOVA). In contrast, there was a significant variation in a non-UT-B 100 kDa protein (P < 0.001, N = 3–4, ANOVA), which was also detected by anti-UT-B antibodies. Using the C6 rat astrocyte cell line, Western blot analysis showed that 48-h incubation in either 5 mM or 10 mM significantly increased a 30–45 kDa UT-B protein signal (P < 0.05, N = 3, ANOVA). Furthermore, investigation of compartmentalized C6 protein samples showed the 30–45 kDa signal in the membrane fraction, whilst the 100 kDa non-UT-B signal was predominantly in the cytosolic fraction. Finally, immunolocalization studies gave surprisingly weak detection of rat UT-B, except for strong staining of red blood cells in the cerebellum. In conclusion, this study confirmed that RNA expression and protein abundance of UT-B were equal across all regions of the rat brain, suggesting that urea levels were also similar. However, it also highlighted some of the technical challenges of studying urea transporters at the protein level.
Background People with obesity are at increased risk of severe COVID-19, with host inflammation a key contributor. Interferon (IFN) lambda 4 (IFNλ4) is a type III IFN expressed in individuals with the rs368234815-ΔG single nucleotide polymorphism (SNP) which is implicated in host immune responses to viral infections. We explored associations of this SNP to host inflammation, body mass index (BMI) and COVID-19 disease severity. Methods Individuals with SARS-CoV-2, enrolled in the All-Ireland Infectious Diseases Cohort were genotyped for the rs368234815 SNP by allelic discrimination assay, and plasma circulating type I, II and III IFNs by immunoassay that were measured in a sub-cohort collected within ten days of symptom onset. We compared the prevalence of COVID-19 mild cases according to WHO criteria between IFNλ4 non-expressing (TT) and expressing (ΔG) genotypes using a Kruskal Wallis test. IFNλ4 polymorphisms affecting type I, II and III IFNs were assessed in the sub-cohort using a stepwise binary logistic regression adjusted for age, sex at birth, ethnicity, and comorbidities, including obesity (BMI ≥ 30 kg/m2). Results 853 participants were enrolled, of whom 471 (55%) harboured IFNλ4-TT/TT (Table 1). Expression of IFNλ4-ΔG was not significantly different between disease severity groups (P = 0.357). Within the early sampling sub-cohort (n = 321), we observed higher circulating IFNλ1 and IFNλ2 in those with more severe COVID-19 compared to mild disease (P < 0.01) (Fig 1). Only IFNλ2 remained significantly associated with mild COVID-19 in adjusted analyses (B COEFF 0.232 (0.067, 0.808), P = 0.021). We found no consistent associations between IFNλ4 genotypes and circulating interferons. Furthermore, we observed significantly higher IFNλ2 in people with obesity. However, the relationship between elevated plasma IFNλ2 and disease severity was only observed in people without obesity (P < 0.01) but not in those with obesity (Fig 2). Table 1 Clinicodemographic Details of Enrolled Patients in the AIID COVID-19 Cohort Figure 1 Plasma Circulating Levels (pg/mL) of Type I (IFN-α2a, and IFN-β), Type II (IFN-γ), and Type III (IFN-λ 1, IFN-λ 2 IL28A, IFN-λ 3 IL28B) Interferons. (A) World Health Organisation (WHO) COVID-19 disease severity criteria association with plasma circulating levels of type I, II, and III interferons. (B) Assessment of IFN-λ 4 expressing (ΔG) and non-expressing (TT) genotypes effects on circulating levels of type I, II, and III interferons. Ln - natural log; ns P > 0.05, * P ≤ 0.05, ** P ≤ 0.01, *** P ≤ 0.001. Figure 2 World Health Organisation (WHO) COVID-19 Disease Severity Association with Circulating Plasma Levels of Type III (IFN-λ 2 IL28A) Interferon and Obesity Status. Obesity defined as BMI ≥ 30 Kg/m2. Ln - natural log; ns P > 0.05, * P ≤ 0.05, ** P ≤ 0.01. Conclusion IFNλ4 genotypes were not associated with COVID-19 disease severity or levels of circulating interferons. However, IFNλ2 was higher in individuals with obesity, though associations between IFNλ2 and disease severity was lost, suggesting that obesity may contribute to increased risk of severe COVID-19 through increased expression of IFNλ2. Disclosures All Authors: No reported disclosures
Background Although SARS-CoV-2 neutralising antibodies protect against severe COVID-19, whether circulating IgG titres reflect underlying host capacity to neutralise wild type (WT) and variants of concern (VOC) and what IgG threshold reflects sufficient neutralising capacity remains unclear. Methods In plasma from individuals in the All Ireland Infectious Diseases Cohort, we measured anti receptor binding domain (RBD) IgG and neutralising capacity by a micro-neutralisation assay, which determined the maximum plasma dilution to maintain 50% inhibition of replication (NT50) of live SARS-CoV-2, using WT and VOC (Beta and Omicron). We examined 3 groups sampled at 3 time periods: unvaccinated, prior infected (group 1, WT dominated), primary (2 dose) vaccinated (group 2) and group 3 with hybrid immunity (booster vaccine and Omicron infection). Although an NT50 ≥100 IU is considered sufficient protection in vaccine trials, as some VOC induce up to 6-fold reduction in NT50, we used NT50 ≥ 1000 IU as a cut off for WT neutralisation that would retain neutralisation against VOC. We used ROC curves to explore sensitivity and specificity and Youden Index to determine the RBD threshold associated with WT NT50 < 1000 IU. We validated the accuracy of this RBD threshold to predict NT50 < 100 IU against Beta and Omicron in groups 2 and 3 respectively. Results We included 255 participants across the 3 groups (table 1). In all groups, RBD highly correlated with WT NT50 (rho 0.81, 0.76 and 0.77 in groups 1, 2 and 3, all p< 0.001). In group 1 Youden’s Index determined RBD < 456 BAU/ml to best predict WT NT50 < 1000 IU (sensitivity 77% (95% CI 69, 84%), specificity 100% (95% CI 82, 100%)). All 99 samples with RBD < 456 BAU/ml had WT NT50 < 1000 IU; positive predictive value (PPV) 100%, (95% CI 95, 100%), and overall accuracy 80% (95% CI 73, 86%). When validated in groups 2 and 3, RBD < 456 BAU/ml retained good accuracy at predicting underlying neutralisation against VOC (group 2, accuracy 80% (95% CI 67, 90%) in predicting NT50 < 100 IU against Beta, and in group 3, overall accuracy of 87% (95% CI 77, 94%) to determine an NT50 of < 100 IU against Omicron.Table 1Participant Characteristics Conclusion Host RBD titres closely correlate with NT50. An RBD threshold of < 456 BAU/ml accurately predicts a clinically relevant neutralising capacity against both WT and common VOC. Disclosures Oliver A. Cornely, MD PhD, DZIF: Advisor/Consultant|DZIF: Board Member|DZIF: Grant/Research Support|DZIF: Honoraria|DZIF: Stocks/Bonds
Background Vaccination remains crucial for protection against severe SARS-CoV-2 infection, especially in aged population. Methods We evaluated, with a randomised controlled, adaptive, multicentre phase II study, the safety and immunogenicity of a 3rd vaccination dose (1st booster) in individuals ≥75 years (ClinicalTrials.gov Identifier: NCT05160766, EudraCT Number: 2021-004526-29). Participants were randomized to either a full-dose (100µg) of mRNA-1273 (Spikevax®) or 30 µg of BNT162b2 (Comirnaty®). The primary endpoint was the rate of 2-fold antibody titre increase 14 days post-vaccination measured by quantitative enzyme-linked immunosorbent assay (Anti-RBD-ELISA). Secondary endpoints included changes in neutralising capacity (ACE2 Virus Neutralisation Assay) against wild-type and 25 variants at 14 days and up to 12 months. Results Fifty-three volunteers were randomised between 8 November 2021 and 4 January 2022, with 52 receiving a COVID-19 vaccine as 1st booster. Fifty subjects (BNT162b2 n=25/mRNA-1273 n=25) were included in the analyses for immunogenicity after day 14. The primary endpoint of a 2-fold anti-RBD IgG titre increase 14 days post-vaccination was reached in all subjects. A 3rd full-dose mRNA-1273 vaccination provided higher anti-RBD IgG titres (GMT D14 7090 [95% CI 5688 – 8837] BNT162b2 vs. 10711 [95% CI 8003 – 14336] mRNA-1273). A pattern showing higher neutralising capacity of full-dose mRNA-1273 against Wuhan wild-type so as for 23/25 tested variants was observed. Conclusion Third doses of either BNT162b2 or mRNA-1273 provide substantial antibody increase 14 days post-vaccination, with full-dose mRNA providing higher antibody levels and an overall similar safety profile for ≥75 subjects. Additional booster doses should be prioritised, particularly in aged people and others at high-risk. In-depth data on waning of immune response is needed to assess duration of protection, and evaluation of vaccine-dosage for individuals at risk may be reconsidered. With the data on full-dose (100µg) mRNA-1273evaluation of vaccine-dosage for individuals at risk may be reconsidered, despite the small sample size. Disclosures Jannik Stemler, -, Ministry of Education and Research (BMBF): Grant/Research Support Oliver A. Cornely, MD PhD, DZIF: Advisor/Consultant|DZIF: Board Member|DZIF: Grant/Research Support|DZIF: Honoraria|DZIF: Stocks/Bonds
Background The immunological memory to SARS-CoV-2 (SCV-2) vaccination has multiple components, with robust antibody (Ab) and B cell responses demonstrated post vaccination. The extent and persistence of T cell responses to vaccination remains unclear. We explored SCV-2 specific Ab, B cell and T cell responses to 3rd dose vaccine and their relationship to incident COVID-19. Methods In plasma from adults enrolled in a multicentre prospective cohort, sampled before, 14 days and 10 months post 3rd dose vaccine (BNT162b2) we measured anti-SCV-2 receptor binding domain (RBD) Ab by electrochemiluminescence assays. Subjects reported incident COVID-19 that occurred post vaccination. In a subanalysis, we assessed SCV-2-specific plasma cell, memory B cell and T cell responses in peripheral blood mononuclear cells after stimulation with wild type (WT) RBD, WT full Spike antigen, Omicron RBD and Omicron S1 antigens by ELISpot (Mabtech ELISpot, Sweden, Fig 1). We compared between-group differences in immunological outcomes by incident infection by Wilcoxon signed rank or Mann–Whitney U tests. Data are median (IQR) unless specified. Results Of 132 subjects (age 43 [32-50], 81% female (Table 1), 47 (36%) reported incident SCV-2 infection at 18 (16-21) weeks post 3rd vaccine. 76 subjects contributed to the cellular immunity subanalysis [23 of whom provided additional samples 10 months post vaccine (Table 1)]. RBD titres and B cell responses increased significantly 2 weeks post 3rd vaccine (Fig 2, p< 0.001), with RBD titres and WT-specific memory B cell responses remaining significantly higher than pre-booster vaccine levels at 10 months (Fig 2, p< 0.001). In contrast, there was no significant difference in T cell responses at two weeks or 10 months post 3rd dose vaccine (Fig 2). There was no difference in 2-week post vaccine RBD or T cell responses in those with and without incident SCV-2 infection. However, those with incident infection had significantly lower WT RBD-specific plasma and memory B cell levels (Table 2, all p< 0.05). Conclusion 3rd dose vaccination induced robust antibody and B cell responses which persist at 10 months, but not T cell responses. Higher memory B cell responses post vaccination, rather than circulating antibody titres or T cells, are associated with protection from subsequent infection. Disclosures Oliver A. Cornely, MD PhD, DZIF: Advisor/Consultant|DZIF: Board Member|DZIF: Grant/Research Support|DZIF: Honoraria|DZIF: Stocks/Bonds
This review aims to explore the potential of biomimetic hydrogels as an alternative to bone cement in vertebral body stenting (VBS), a minimally invasive treatment for vertebral compression fractures. The use of bone cement in VBS procedures can lead to complications such as incomplete fracture reduction and cement leakage. Biomimetic hydrogels have gained significant attention as potential biomaterial alternatives for VBS due to their unique properties, including tuneable therapeutic and mechanical properties. Over the past decade, there has been significant advancements in the development of biomimetic hydrogels for bone regeneration, employing a wide range of approaches to enhance the structural and functional properties of hydrogels. Biomimetic hydrogels hold significant promise as safer and reparative alternatives to bone cement for VBS procedures. However, further research and development in this field are necessary to explore the full potential of hydrogel-based systems for vertebral bone repair.
Background Incorporating Public and Patient Involvement (PPI) into doctoral research is valued by PhD funders and scholars. Providing early career researchers with appropriate training to develop skills to conduct meaningful PPI involvement is important. The Health Research Board (HRB) Collaborative Doctoral Award in MultiMorbidity programme (CDA-MM) embedded formal PPI training in its structured education. The four participating PhD scholars established a PPI panel comprising people living with two or more chronic conditions, presenting an opportunity for experiential PPI training. This study aimed to evaluate the process and impact of embedding PPI training in a structured PhD programme. Methods This study was a longitudinal mixed-methods evaluation, conducted over 24 months (June 2020 to June 2022). A process evaluation provided an understanding of how PPI was embedded and explored the experiences of key stakeholders involved. An impact evaluation assessed the impact of embedding PPI training in the programme. Participants included PhD scholars, PPI contributors and PhD supervisors. The data collection and analysis was led by an independent researcher not aligned with the CDA-MM. Data collection methods included five focus groups, individual interviews (n = 6), an impact log, activity logs and group reflections. Qualitative data were analysed using thematic and content analysis and quantitative data analysed using descriptive statistics. Results Embedding formal and experiential PPI training in a structured PhD programme is feasible. Both approaches to training are fundamental to building PPI capacity. Involvement of an experienced and knowledgeable PPI lead throughout is perceived as critical. The PPI panel approach offered a good example of embedded consultation and worked well in a structured PhD programme, providing PhD scholars with ample opportunities for learning about PPI and its implementation. For PPI contributors, culture was the most important indicator of quality and was positively evaluated. Key roles for PhD supervisors were identified. Embedding formal and experiential PPI training impacted positively on many different aspects of individual PhD research projects and on PhD scholars as researchers. There were positive impacts for PPI contributors and PhD supervisors. Conclusions Embedding formal and experiential PPI training in a structured PhD programme is a novel approach. The evaluation has identified a number of lessons that can inform future doctoral programmes seeking to embed formal and experiential PPI training.
Our understanding of the complex pathophysiology of Heart failure with preserved ejection fraction (HFpEF) is limited by the lack of a robust in vivo model. Existing in-vivo models attempt to reproduce the four main phenotypes of HFpEF; ageing, obesity, diabetes mellitus and hypertension. To date, there is no in vivo model that represents all the haemodynamic characteristics of HFpEF, and only a few have proven to be reliable for the preclinical evaluation of potentially new therapeutic targets. HFpEF accounts for 50% of all the heart failure cases and its incidence is on the rise, posing a huge economic burden on the health system. Patients with HFpEF have limited therapeutic options available. The inadequate effectiveness of current pharmaceutical therapeutics for HFpEF has prompted the development of device-based treatments that target the hemodynamic changes to reduce the symptoms of HFpEF. However, despite the potential of device-based solutions to treat HFpEF, most of these therapies are still in the developmental stage and a relevant HFpEF in vivo model will surely expedite their development process. This review article outlines the major limitations of the current large in-vivo models in use while discussing how these designs have helped in the development of therapy devices for the treatment of HFpEF. Graphical abstract
Particle separation is an essential part of many processes. One mechanism to separate particles according to size, shape, or material properties is dielectrophoresis (DEP). DEP arises when a polarizable particle is immersed in an inhomogeneous electric field. DEP can attract microparticles toward the local field maxima or repulse them from these locations. In biotechnology and microfluidic devices, this is a well-described and established method to separate (bio-)particles. Increasing the throughput of DEP separators while maintaining their selectivity is a field of current research. In this study, we investigate two approaches to increase the overall throughput of an electrode-based DEP separator that uses selective trapping of particles. We studied how particle concentration affects the separation process by using two differently-sized graphite particles. We showed that concentrations up to 800 mg/L can be processed without decreasing the collection rate depending on the particle size. As a second approach to increase the throughput, parallelization in combination with two four-way valves, relays, and stepper motors was presented and successfully tested to continuously separate conducting from non-conducting particles. By demonstrating possible concentrations and enabling a semi-continuous process, this study brings the low-cost DEP setup based on printed circuit boards one step closer to real-world applications. The principle for semi-continuous processing is also applicable for other DEP devices that use trapping DEP.
Cardio-oncology is a dynamic field. Research has suggested that cancer itself can damage the heart, independent of cancer treatment-related cardiac dysfunction (CTRCD). The aim of this study was to establish the nature of cardiovascular abnormalities reported in cancer, excluding CTRCD. Scoping review search included cardiovascular abnormalities in adults with solid tumour malignancies, and excluded CTRCD and thrombotic events. Three databases (CINAHL, Embase, Medline) were searched, supplemented by a handsearch. All screening and data extraction was done by two researchers with consensus reached for any conflicts. Given the heterogeneous nature of the studies identified, data synthesis was narrative. The search identified 42 366 studies. Following deduplication and title/abstract screening, 195 studies were assessed for full-text eligibility. Forty-four studies are included in the final analysis. There are 19 prospective observational studies, 13 retrospective studies, 9 case reports and 3 cross-sectional studies. Types of abnormality identified include cardiomyopathy (16, including Takotsubo (9)), autonomic nervous system (ANS) dysfunction (10), biomarker disturbances (9), reduced myocardial strain (6) and others (3). Due to variable study design, the prevalence was not determined. Cardiovascular abnormalities were associated with morbidity (chest pain, dyspnoea, fatigue) and shortened prognosis. In conclusion: (1) There is evidence for cardiovascular dysfunction in patients with solid tumour malignancies, distinct from CTRCD. People with solid tumours have higher rates of cardiac disease, even when newly diagnosed and treatment naïve. (2) Abnormalities manifest mainly as cardiomyopathies, ANS dysfunction and raised biomarker levels and are associated with significant symptoms. (3) Treatment plans need to take account of these risks, and widen criteria for screening.
Engaging with higher education institutions from the People’s Republic of China (China or the PRC) raises difficult tensions for universities in liberal democratic contexts. Universities in China are overseen by a political party that routinely silences dissent and does not respect principles of academic freedom in the social sciences and humanities. For decades in the post–Mao era, this tension remained relatively muted outside of the PRC, but it has gained newfound significance as China’s power and assertiveness have grown globally.
Background and objectives Circulatory system disease (CSD) patterns vary over time and between countries, related to lifestyle risk factors, associated in turn with socioeconomic circumstances. Current global CSD epidemics in developing economies are similar in scale to those observed previously in the USA and Australasia. Australia exhibits an important macroeconomic phenomenon as a rapidly transitioning economy with high immigration throughout the nineteenth and twentieth centuries. We wished to examine how that historical immigration related to CSD patterns subsequently. Methods and setting We provide a novel empirical analysis employing census-derived place of birth by age bracket and sex from 1891 to 1986, in order to map patterns of immigration against CSD mortality rates from 1907 onwards. Age-specific generalised additive models for both CSD mortality in the general population, and all-cause mortality for the foreign-born (FB) only, from 1910 to 1980 were also devised for both males and females. Results The percentage of FB fell from 32% in 1891 to 9.8% in 1947. Rates of CSD rose consistently, particularly from the 1940s onwards, peaked in the 1960s, then declined sharply in the 1980s and showed a strong period effect across age groups and genders. The main effects of age and census year and their interaction were highly statistically significant for CSD mortality for males (p<0.001, each term) and for females (p<0.001, each term). The main effect of age and year were statistically significant for all-cause mortality minus net migration rates for the FB females (each p<0.001), and for FB males, age (p<0.001) was significant. Conclusions We argue our empirical calculations, supported by historical and socioepidemiological evidence, employing immigration patterns as a proxy for epidemiological transition, affirm the life course hypothesis that both early life circumstances and later life lifestyle drive CSD patterns.
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