Early Fatality Research Articles

IL-27 Gene Therapy Ameliorates IPEX Syndrome Caused by Germline Mutation of Foxp3 Gene: A Major Role for Induction of IL-10.

Inactivating mutations of Foxp3, the master regulator of regulatory T cell development and function, lead to immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome in mice and humans. IPEX is a fatal autoimmune disease, with allogeneic stem cell transplant being the only available therapy. In this study, we report that a single dose of adeno-associated virus (AAV)-IL-27 to young mice with naturally occurring Foxp3 mutation (Scurfy mice) substantially ameliorates clinical symptoms, including growth retardation and early fatality. Correspondingly, AAV-IL-27 gene therapy significantly prevented naive T cell activation, as manifested by downregulation of CD62L and upregulation of CD44, and immunopathology typical of IPEX. Because IL-27 is known to induce IL-10, a key effector molecule of regulatory T cells, we evaluated the contribution of IL-10 induction by crossing IL-10-null allele to Scurfy mice. Although IL-10 deficiency does not affect the survival of Scurfy mice, it largely abrogated the therapeutic effect of AAV-IL-27. Our study revealed a major role for IL-10 in AAV-IL-27 gene therapy and demonstrated that IPEX is amenable to gene therapy.

Leucyl-tRNA Synthetase Contributes to Muscle Weakness through Mammalian Target of Rapamycin Complex 1 Activation and Autophagy Suppression in a Mouse Model of Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD), caused by loss-of-function mutations in the dystrophin gene, results in progressive muscle weakness and early fatality. Impaired autophagy is one of the cellular hallmarks of DMD, contributing to the disease progression. Molecular mechanisms underlying the inhibition of autophagy in DMD are not well understood. In the current study, the DMD mouse model mdx was used for the investigation of signaling pathways leading to suppression of autophagy. Mammalian target of rapamycin complex 1 (mTORC1) was hyperactive in the DMD muscles, accompanying muscle weakness and autophagy impairment. Surprisingly, Akt, a well-known upstream regulator of mTORC1, was not responsible for mTORC1 activation or the dystrophic muscle phenotypes. Instead, leucyl-tRNA synthetase (LeuRS) was overexpressed in mdx muscles compared with the wild type. LeuRS activates mTORC1 in a noncanonical mechanism that involves interaction with RagD, an activator of mTORC1. Disrupting LeuRS interaction with RagD by the small-molecule inhibitor BC-LI-0186 reduced mTORC1 activity, restored autophagy, and ameliorated myofiber damage in the mdx muscles. Furthermore, inhibition of LeuRS by BC-LI-0186 improved dystrophic muscle strength in an autophagy-dependent manner. Taken together, our findings uncovered a noncanonical function of the housekeeping protein LeuRS as a potential therapeutic target in the treatment of DMD.

Optimization method for offsite consequence analysis by efficient plume segmentation

The speed of offsite consequence analysis is highly important due to the extensive calculations required to handle all the scenarios for a single-unit or multi-unit Level 3 PSA (probabilistic safety assessment). To perform an offsite consequence analysis as part of Level 3 PSA, various input parameters are considered, amongst which certain parameters, such as plume segments, spatial grids, and particle size distributions, have flexible input formats. This study describes the development of an effective optimization method to reduce the analysis time as much as possible while maintaining the accuracy of the offsite consequence analysis results. The effect of plume segmentation on offsite consequence analysis was investigated by observing deviations in analysis results and changes in the required analysis times following changes in plume release. Then a plume segmentation optimization method based on the cumulative release fraction slope was developed to intensively analyze the sections with rapid release and to simplify the analysis for the sections with nonsignificant release. As a result of applying this method, the analysis time was reduced by about 54.5 % compared to the base case, while the resulting health effects showed very small deviations of 0.03 % and 1.77 % for early fatality risk and cancer fatality risk, respectively.

Comparison between transthoracic echocardiography and transoesophageal echocardiography in the diagnosis of acute aortic dissection from an emergency perspective. A systematic review and meta-analysis.

Acute aortic dissection (AAD) is a life-threatening medical condition with high early fatality. Therefore, a prompt and precise diagnosis, which can be achieved through invasive and non-invasive techniques is vital. Echocardiography, unlike MRI and CT, is accessible in emergency units and bedside-compatible. The recommended echocardiographic techniques for AAD are transthoracic and transoesophageal echocardiography (TTE and TOE). Therefore, our review compares their diagnostic roles in AAD. Studies relevant to our topic were attained through a database search and manual scrutiny of references lists of articles obtained from the electronic databases. The Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2) has been used for quality assessment. All quantitative analyses were performed using either STATA 16 or Comprehensive Meta-Analyst software. The search strategy yielded 1,798 articles, of which only 11 were eligible for inclusion. Our subgroup analysis showed that conventional TTE had a sensitivity and specificity of 85.35% and 84.51% for the diagnosis of Stanford type A AAD and was 45.89% sensitive and 87.05% specific for the diagnosis of type B AAD. However, the subgroup analysis shows that contrast-enhancement of TTE results in a sensitivity and specificity of 93.30% and 97.60% for diagnosis of type A AAD, and 83.60% and 94.50% for diagnosis of type B AAD, respectively. On the other hand, conventional TOE was 93.64% sensitive and 95.50% specific for the diagnosis of type A AAD, 99.80% sensitive and 99.87% specific for the diagnosis of type B AAD. Moreover, our analyses show that TTE has pooled false negative and positive rates of 28.6% and 18.6%, while TOE has shown false negative and positive rates of 2.4% and 4.3%, respectively. TOE is the more favorable diagnostic tool for AAD diagnosis than TTE. However, it cannot be used as a stand-alone diagnostic tool since misdiagnosis cases are being reported. Contrast-enhanced TTE can also diagnose AAD since it provides similar results to conventional TOE.

Patient-level and system-level determinants of stroke fatality across 16 large hospitals in Ghana and Nigeria: a prospective cohort study

Every minute, six indigenous Africans develop new strokes. Patient-level and system-level contributors to early stroke fatality in this region are yet to be delineated. We aimed to identify and quantify the contributions of patient-level and system-level determinants of inpatient stroke fatality across 16 hospitals in Ghana and Nigeria. The Stroke Investigative Research and Educational Network (SIREN) is a multicentre study involving 16 sites in Ghana and Nigeria. Cases include adults (aged ≥18 years) with clinical and radiological evidence of an acute stroke. Data on stroke services and resources available at each study site were collected and analysed as system-level factors. A host of demographic and clinical variables of cases were analysed as patient-level factors. A mixed effect log-binomial model including both patient-level and system-level covariates was fitted. Results are presented as adjusted risk ratios (aRRs) with respective 95% CIs. Overall, 814 (21·8%) of the 3739 patients admitted with stroke died as inpatients: 476 (18·1%) of 2635 with ischaemic stroke and 338 (30·6%) of 1104 with intracerebral haemorrhage. The variability in the odds of stroke fatality that could be attributed to the system-level factors across study sites assessed using model intracluster correlation coefficient was substantial at 7·3% (above a 5% threshold). Stroke units were available at only five of 16 centres. The aRRs of six patient-level factors associated with stroke fatality were: low vegetable consumption, 1·19 (95% CI 1·07-1·33); systolic blood pressure, 1·02 (1·01-1·04) for each 10 mm Hg rise; stroke lesion volume more than 30 cm3, 1·48 (1·22-1·79); National Institutes of Health Stroke Scale (NIHSS) score, 1·20 (1·13-1·26) for each 5-unit rise; elevated intracranial pressure, 1·75 (1·31-2·33); and aspiration pneumonia, 1·79 (1·16-2·77). Studies are needed to assess the efficacy of interventions targeting patient-level factors such as aspiration pneumonia in reducing acute stroke fatality in this region. Policy directives to improve stroke unit access are warranted. US National Institutes of Health. For the Twi, Yoruba and Hausa translations of the abstract see Supplementary Materials section.

Selective degradation of tRNASer(AGY) is the primary driver for mitochondrial seryl-tRNA synthetase-related disease.

Mitochondrial translation is of high significance for cellular energy homeostasis. Aminoacyl-tRNA synthetases (aaRSs) are crucial translational components. Mitochondrial aaRS variants cause various human diseases. However, the pathogenesis of the vast majority of these diseases remains unknown. Here, we identified two novel SARS2 (encoding mitochondrial seryl-tRNA synthetase) variants that cause a multisystem disorder. c.654-14T>A mutation induced mRNA mis-splicing, generating a peptide insertion in the active site; c.1519dupC swapped a critical tRNA-binding motif in the C-terminus due to stop codon readthrough. Both mutants exhibited severely diminished tRNA binding and aminoacylation capacities. A marked reduction in mitochondrial tRNASer(AGY) was observed due to RNA degradation in patient-derived induced pluripotent stem cells (iPSCs), causing impaired translation and comprehensive mitochondrial function deficiencies. These impairments were efficiently rescued by wild-type SARS2 overexpression. Either mutation caused early embryonic fatality in mice. Heterozygous mice displayed reduced muscle tissue-specific levels of tRNASers. Our findings elucidated the biochemical and cellular consequences of impaired translation mediated by SARS2, suggesting that reduced abundance of tRNASer(AGY) is a key determinant for development of SARS2-related diseases.

128 TO BLEED OR NOT TO BLEED: THE INTRACEREBRAL HAEMORRHAGE MANAGEMENT QUESTION

Abstract Background Intracerebral Haemorhage (ICH) accounts for 9-27 per cent of all strokes. There are high rates of early case fatality and poor functional outcome. Clear guidelines and pathways exist around the management of ischaemic stroke. Pathways for the haemorrhagic stroke patient are lacking. Good evidence exists for early Blood Pressure (BP) management, reversal of Oral Anti-Coagulation (OAC) and admission to a Hyper-Acute Stroke Unit (HASU) in terms of improving outcomes. Methods A retrospective cohort analysis was performed, looking at all the presentations with ICH over one calendar year. The factors measured included time to CT Brain, BP at presentation, documented target systolic BP of under 140mmHg, time to treatment of hypertension, number on OAC, OAC reversal, time to OAC reversal, admission to HASU. The findings were compared to standards outlined in the European Stroke Organisation and American Heart Association’s ICH management guidance. Results 76 patients were include (40 female). Mean age was 73, age range 34-93. median age 77. 44 were hypertensive on admission (20 info unavailable [u/a]). Of the 44, 34 had a documented target BP under 140mmHg (12 = n/a, 20 u/a). Time to treatment of hypertension was within 60 minutes for 3 patients. Of those that were hypertensive, 57 per cent were 75 or younger. 16 were on an OAC, of which 11 were appropriately reversed (3 u/a). Of the 11, 2 were reversed within 90 mins (7 u/a). Of those on an OAC, 75 per cent were over 75. 32 were admitted to HASU within 72h (all of these made it within 24h), (10 did not reach HASU, 3 reached HASU bed after 72h, 31 u/a). Conclusion Management of ICH is variable and suboptimal. Our goal is to produce a written pathway which will be incorporated into our hyperacute stroke document, with a plan to re-audit.

Endocytosis of the thrombopoietin receptor Mpl regulates megakaryocyte and erythroid maturation in mice.

Dnm2fl/fl Pf4-Cre (Dnm2Plt–/– ) mice lacking the endocytic GTPase dynamin 2 (DNM2) in platelets and megakaryocytes (MKs) develop hallmarks of myelofibrosis. At the cellular level, the tyrosine kinase JAK2 is constitutively active but decreased in expression in Dnm2Plt–/– platelets. Additionally, Dnm2Plt–/– platelets cannot endocytose the thrombopoietin (TPO) receptor Mpl, leading to elevated circulating TPO levels. Here, we assessed whether the hyperproliferative phenotype of Dnm2Plt–/– mice was due to JAK2 constitutive activation or to elevated circulating TPO levels. In unstimulated Dnm2Plt–/– platelets, STAT3 and, to a lower extent, STAT5 were phosphorylated, but their phosphorylation was slowed and diminished upon TPO stimulation. We further crossed Dnm2Plt–/– mice in the Mpl–/– background to generate Mpl–/–Dnm2Plt–/– mice lacking Mpl ubiquitously and DNM2 in platelets and MKs. Mpl–/– Dnm2Plt–/– platelets had severely reduced JAK2 and STAT3 but normal STAT5 expression. Mpl–/– Dnm2Plt–/– mice had severely reduced bone marrow MK and hematopoietic stem and progenitor cell numbers. Additionally, Mpl–/– Dnm2Plt–/– mice had severe erythroblast (EB) maturation defects, decreased expression of hemoglobin and heme homeostasis genes and increased expression of ribosome biogenesis and protein translation genes in spleen EBs, and developed anemia with grossly elevated plasma erythropoietin (EPO) levels, leading to early fatality by postnatal day 25. Mpl–/– Dnm2Plt+/+ mice had impaired EB development at three weeks of age, which normalized with adulthood. Together, the data shows that DNM2-dependent Mpl-mediated endocytosis in platelets and MKs is required for steady-state hematopoiesis and provides novel insights into a developmentally controlled role for Mpl in normal erythropoiesis, regulating hemoglobin and heme production.

Incidence, early case fatality and determinants of stroke in Iran: Golestan Cohort Study

Objectives: While few studies investigated the incidence of stroke in Iran, no Iranian cohort has estimated the standardized-incidence rate and early fatality of first-ever-stroke subtypes along with associated factors. Methods: Golestan Cohort Study is a prospective study launched in northeastern Iran in 2004, including 50,045 individuals aged 40-75 at baseline. Age-standardized incidence rate of first-ever-stroke was calculated per 100,000 person-years, according to World Standard Population. The 28-day case fatality was calculated by dividing the number of fatal first-ever-stroke during the first 28 days by total events. Cox proportional hazard models were conducted to assess incidence and fatality risk factors. We used Population Attributable Fractions to estimate the incidence and early fatality proportions reduced by ideal risk factor control. Results: 1,135 first-ever-strokes were observed during 8.6 (median) years follow-up. First-ever-stroke standardized incidence rate was estimated 185.2 (95% CI: 173.2-197.2) per 100,000 person-years. The 28-day case fatality was 44.1% (95% CI: 40.4-48.2). Hypertension and pre-stroke physical activity were the strongest risk factors associated with first-ever-stroke incidence (Hazard ratio: 2.83; 2.47-3.23) and 28-day case fatality (Hazard ratio: 0.59; 0.44-0.78), respectively. Remarkably, opium consumption was strongly associated with hemorrhagic stroke incidence (Hazard ratio: 1.52; 1.04-2.23) and ischemic stroke fatality (Hazard ratio: 1.44; 1.01-2.09). Overall, modifiable risk factors contributed to 83% and 61% of first-ever-stroke incidence and early fatality, respectively. Conclusion: Efficient risk factor control can considerably reduce stroke occurrence and fatality in our study. Establishing awareness campaigns and 24-hour stroke units seem necessary for improving the stroke management in this area.

Comparison between early and late mortalities due to severe sepsis in a pediatric intensive care unit: five-years-experience

BackgroundThe majority of children who die of sepsis suffer from refractory shock and/or multiple organ dysfunction syndrome, with many deaths occurring within the initial 48–72 h of treatment.MethodsA retrospective observational study of deceased patients due to severe sepsis over 5 years, from the 1st of August 2015 to the end of July 2020, that were admitted in a pediatric intensive care unit.ResultsOver 5-year duration of the study, the trend of cases with severe sepsis increased from 26.4% in 2015 to 40.7% in 2020. Meanwhile, the trend of mortality among this category of patients dropped from 66.7% in 2015 to 33.9% in 2020. From the studied 163 deceased patients, results showed predominance of Klebsiella pneumoniae of the extended resistance pattern in bronchoalveolar lavage and blood cultures, and it came second to Candida in urine cultures. Pandrug-resistant organism was recorded in 8.59% (n = 14 patients). Patients with bacteremia, acidosis, high pediatric index of mortality (PIM-2), and pediatric logistic organ dysfunction (PELOD) scores were statistically related to early fatality fate.ConclusionHigh mortality was associated with the increasing spread of resistant organisms especially Klebsiella pneumoniae. Patients with bacteremia, acidosis, and high PIM-2 and PELOD scores probably will need immediate, vigorous, and intense care in order to save their lives.

Analysis of early neonatal case fatality rate among newborns with congenital hydrocephalus, a 2000-2014 multi-country registry-based study.

Congenital hydrocephalus (CH) comprises a heterogeneous group of birth anomalies with a wide-ranging prevalence across geographic regions and registry type. The aim of the present study was to analyze the early neonatal case fatality rate (CFR) and total birth prevalence of newborns diagnosed with CH. Data were provided by 25 registries from four continents participating in the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR) on births ascertained between 2000 and 2014. Two CH rates were calculated using a Poisson distribution: early neonatal CFR (death within 7 days) per 100 liveborn CH cases (CFR) and total birth prevalence rate (BPR) per 10,000 births (including live births and stillbirths) (BPR). Heterogeneity between registries was calculated using a meta-analysis approach with random effects. Temporal trends in CFR and BPR within registries were evaluated through Poisson regression modeling. A total of 13,112 CH cases among 19,293,280 total births were analyzed. The early neonatal CFR was 5.9 per 100 liveborn cases, 95% confidence interval (CI): 5.4-6.8. The CFR among syndromic cases was 2.7 times (95% CI: 2.2-3.3) higher than among non-syndromic cases (10.4% [95% CI: 9.3-11.7] and 4.4% [95% CI: 3.7-5.2], respectively). The total BPR was 6.8 per 10,000 births (95% CI: 6.7-6.9). Stratified by elective termination of pregnancy for fetal anomalies (ETOPFA), region and system, higher CFR were observed alongside higher BPR rates. The early neonatal CFR and total BPR did not show temporal variation, with the exception of a CFR decrease in one registry. Findings of early neonatal CFR and total BPR were highly heterogeneous among registries participating in ICBDSR. Most registries with higher CFR also had higher BPR. Differences were attributable to type of registry (hospital-based vs. population-based), ETOPFA (allowed yes or no) and geographical regions. These findings contribute to the understanding of regional differences of CH occurrence and early neonatal deaths.

Uncertainty analysis of source term and off-site consequence for WH600 using MELCOR and WinMACCS

In PSA, uncertainty analysis is required to assess the reliability of the safety assessment results. Uncertainties related to severe accidents have been reported in previous studies. But existing uncertainty analysis has been focused on such severe accident phenomena, as changes in pressure and temperature of the containment building and hydrogen production. However, in order to conduct uncertainty analysis of off-site risk, it is necessary to analyse the uncertainty related to the information of radioactive material released, not just the phenomenon. In this study, the source term uncertainty is evaluated using MELCOR and off-site consequence uncertainty analysis using MACCS are performed. And WH600 has been selected as a reference plant. The variables related with these result are selected. The values are adjusted taking into consideration the characteristics and environmental conditions of an actual NPP. The LHS method is used for sampling the random variables. In off-site consequence analysis, early fatality and cancer fatality are uses as measures. As a result of MELCOR uncertainty analysis source term information has significant uncertainty that affects the off-site consequence. Also in case of off-site consequence, risk band is so wide that risk has to be determined.

Tobacco cessation by prescription - A 180 degree turn.

Utilisation of tobacco is one of the most serious problems affecting human health worldwide, despite the fact that the early fatality caused by tobacco use are growing, regardless of the fact that it is avoidable tobacco consumption is very common, considerable resources have been allocated to this issue. On tobacco prevention, a range of strategies have been tested but the ratio of death due to tobacco and number of tobacco consumers is increasing day by day. Various impediments to tobacco quitting have been recognized, all of which contribute to the failure of various tobacco cessation programs and methodologies. Individuals in the India have attempted or considered quitting smoking at some point in their lives but ended in failure. Existing tobacco cessation programs have not out-turned in a decrease in the figure of tobacco users or deaths, necessitating a new strategy. Tobacco cessation on prescription, developed from physical activity on prescription (PAP), can be a useful method in terms of public health. But yet no studies have ever been conducted over this. Further studies on this can explore results of tobacco quitting after prescription from general physician or other medical practitioner, evaluative beliefs about tobacco consumption and barriers in quitting even after prescription. Hence the present review was done with explore the outcomes for cessation of tobacco based upon utilization of tobacco cessation by prescription (TCP) methodology in Indian scenario. This review paper focuses on TCP as a need for newer approach pertaining to Indian perspective. Future study should look at whether raising the rate of stop attempts are improving the tobacco cessation rate in the general population after the implementation of TCP.

Novel IBA57 mutations in two chinese patients and literature review of multiple mitochondrial dysfunction syndrome.

Multiple mitochondrial dysfunction syndrome (MMDS) refers to a class of mitochondrial diseases caused by nuclear gene mutations, which usually begins in early infancy and is classically characterized by markedly impaired neurological development, generalized muscle weakness, lactic acidosis, and hyperglycinemia, cavitating leukoencephalopathy, respiratory failure, as well as early fatality resulted from dysfunction of energy metabolism in multiple systems. So far, six types of MMDS have been identified based on different genotypes, which are caused by mutations in NFU1, BOLA3, IBA57, ISCA2, ISCA1 and PMPCB, respectively. IBA57 encodes a protein involved in the mitochondrial Fe/S cluster assembly process, which plays a vital role in the activity of multiple mitochondrial enzymes. Herein, detailed clinical investigation of 2 Chinese patients from two unrelated families were described, both of them showed mildly delay in developmental milestone before disease onset, the initial symptoms were all presented with acute motor and mental retrogression, and brain MRI showed diffused leukoencephalopathy with cavities, dysplasia of corpus callosum and cerebral atrophy. Exome sequencing revealed three IBA57 variants, one shared variant (c.286T>C) has been previously reported, the remaining two (c.189delC and c.580A>G) are novel. To enhance the understanding of this rare disease, we further made a literature review about the current progress in clinical, genetic and treatment of the disorder. Due to the rapid progress of MMDS, early awareness is crucial to prompt and proper administration, as well as genetic counseling.

Determinants of prehospital coronary heart disease death

Limited data on prehospital and early in-hospital coronary heart disease (CHD) deaths is available. Aims of this study were to provide a comprehensive description on CHD cases and to analyse determinants of prehospital death. From a population-based myocardial infarction (MI) registry in Augsburg, Germany we included 12,572 CHD cases aged 25–74 years between 2003–2017 and 4754 CHD cases aged 75–84 years between 2009–2017. Multivariable logistic regression models were conducted to identify patient characteristics associated with prehospital death compared to 28-day survival. In patients aged 25–74 years, 1713 (13.6%) died prehospital, 941 (7.5%) died within the first 24 h in-hospital and 560 (4.5%) died within the 2nd and 28th day after the acute event; in patients aged 75–84 years the numbers were 1263 (26.6%), 749 (15.8%) and 329 (6.9%), respectively. In both age groups increasing age, actual smoking or nicotine abuse, previous MI, angina pectoris and previous stroke were more likely and hypertension was less likely in cases, who died prehospital compared to 28-day survivors. For example, in the 25–74 years old we revealed an adjusted odds ratio (OR) of 4.53 (95% CI 3.84–5.34) for angina pectoris and an OR of 0.69 (95% CI 0.57–0.85) for hypertension. In cases aged 25–74 years, an association of living alone (OR 1.26, 95% CI 1.06–1.49) and diabetes (OR 1.20, 95% CI 1.03–1.41) with prehospital death was found. Whereas in cases aged 75–84 years, chronic obstructive pulmonary disease (OR 2.20, 95%CI 1.69–0.2.85) was associated with prehospital death. In summary, we observed high prehospital and early in-hospital case fatality. Besides classical cardiac risk factors, the impact of living alone on prehospital death was more important in patients aged 25–74 years than in older patients.

A Bayesian estimate of the early COVID-19 infection fatality ratio in Brazil based on a random seroprevalence survey

Background:A number of estimates of the infection fatality ratio (IFR) of SARS-CoV-2 in different countries have been published. In Brazil, the fragile political situation, together with socioeconomic and ethnic diversity, could result in substantially different IFR estimates.Methods:We infer the IFR in Brazil in 2020 by combining three datasets. We compute the prevalence via the population-based seroprevalence survey, EPICOVID19-BR. For the fatalities we obtain the absolute number using the public Painel Coronavírus dataset and the age-relative number using the public SIVEP-Gripe dataset. The time delay between the development of antibodies and subsequent fatality is estimated via the SIVEP-Gripe dataset. We obtain the IFR for each survey stage and 27 federal states. We include the effect of fading IgG antibody levels by marginalizing over the test detectability time window.Results:We infer a country-wide average IFR (maximum posterior and 95% CI) of 1.03% (0.88–1.22%) and age-specific IFRs of 0.032% (0.023–0.041%) [< 30 years], 0.22% (0.18–0.27%) [30–49 years], 1.2% (1.0–1.5%) [50–69 years], and 3.0% (2.4–3.9%) [≥ 70 years]. We find that the fatality ratio in the country increased significantly at the end of June 2020, likely due to the increased strain on the health system.Conclusions: Our IFR estimate is based on data and does not rely on extrapolating models. This estimate sets a baseline value with which future medications and treatment protocols may be confronted.

A random walk Monte Carlo simulation study of COVID-19-like infection spread

Recent analysis of early COVID-19 data from China showed that the number of confirmed cases followed a subexponential power-law increase, with a growth exponent of around 2.2 (Maier and Brockmann, 2020). The power-law behavior was attributed to a combination of effective containment and mitigation measures employed as well as behavioral changes by the population. In this work, we report a random walk Monte Carlo simulation study of proximity-based infection spread. Control interventions such as lockdown measures and mobility restrictions are incorporated in the simulations through a single parameter, the size of each step in the random walk process. The step size l is taken to be a multiple of 〈r〉, which is the average separation between individuals. Three temporal growth regimes (quadratic, intermediate power-law and exponential) are shown to emerge naturally from our simulations. For l=〈r〉, we get intermediate power-law growth exponents that are in general agreement with available data from China. On the other hand, we obtain a quadratic growth for smaller step sizes l≲〈r〉∕2, while for large l the growth is found to be exponential. We further performed a comparative case study of early fatality data (under varying levels of lockdown conditions) from three other countries, India, Brazil and South Africa. We show that reasonable agreement with these data can be obtained by incorporating small-world-like connections in our simulations.

A preliminary site risk assessment

ABSTRACT Since the Fukushima accident, interest in the site probabilistic safety assessment (PSA) has increased worldwide. However, the standard process for the site risk assessment (SRA) has not yet been established. In addition, most of these studies have focused on the level 1 and 2 PSA. The offsite consequences of the multi-unit accidents may differ from that of the single-unit accidents, so that the full-scope site PSA is essential. In this paper, the preliminary site risk assessment has been performed. The level 1 multi-unit probabilistic safety assessment (MU-PSA) methodology considering the inter-unit dependency was established and carried out. And the mapping table method was adopted in the level 2 MU-PSA. For the level 3 MU-PSA, the grouping method was adopted to reduce the number of the source-term category combinations. Then, the early fatality risk and the latent cancer risk from the accidents in a site were estimated and the tendency of the site risk was analyzed. The process of performing a full-scope site PSA for a site with more than 2 units of varied reactor types presented through this application could contribute to developing the SRA methodology, risk metrics, and safety goals.

Off-site consequence analyses of ISLOCA & MSGTR severe accidents in CANDU-6 plants using the WinMACCS code

For interfacing system loss of coolant accident (ISLOCA) and multiple steam generator tube rupture (MSGTR) sequences, which are reactor building (RB) bypass accidents in CANDU-6 type reactors, off-site consequence analyses were performed based on an optimization method for the WinMACCS input model that reflects CANDU-6 nuclear power plant design-specific and nearby site-specific features, with related sensitivity analyses performed for important variables. As a result of assessment, it was confirmed that there is exceedingly low early fatality risk in the unmitigated case from MSGTR and ISLOCA accidents. For cancer fatality risk, it was confirmed that the averaged risk from the RB bypass accidents in CANDU-6 plants sufficiently satisfies NSSC safety goal (1.0E−6/year). Sensitivity analyses found surface roughness to be the most influential parameter in the MSGTR accident, with other parameters confirmed to be insignificant considering uncertainty in the off-site consequence analysis. Through the sensitivity analyses, long-term improvement items related to surface roughness, dry deposition velocities, initial radioactive clouds, the domestic public protection measures model, and dose conversion factors were derived for future off-site consequence analyses. The proposed long-term improvements for the best-estimate analysis of off-site consequence are applicable to all similar CANDU plants and can provide valuable insights into Level 3 PSA.

CompLement C5 Antibodies for decreasing brain injury after aneurysmal Subarachnoid Haemorrhage (CLASH): study protocol for a randomised controlled phase II clinical trial

BackgroundThe inflammatory response after aneurysmal subarachnoid haemorrhage (aSAH) has been associated with early brain injury, delayed cerebral ischaemia, poor functional outcome, and case fatality. In experimental SAH studies, complement C5 antibodies administered shortly after SAH reduced brain injury with approximately 40%. Complement component C5 may be a new therapeutic target to reduce brain injury and hereby improve the outcome after aSAH. We aim to investigate the pharmacodynamic efficacy and safety of eculizumab (complement C5 antibody) in patients with aSAH.MethodsA randomised, controlled, open-label, phase II clinical trial with blinded outcome assessment. Eculizumab (1200 mg) is administered intravenously < 12 h, on day 3 and on day 7 after ictus. Patients in the intervention group receive prophylactic antibiotics for 4 weeks, and those with a central line or an external ventricular shunt and a positive fungal or yeast culture also receive prophylactic antifungal therapy for 4 weeks. The primary outcome is C5a concentration in the cerebrospinal fluid (CSF) on day 3 after ictus. Secondary outcomes include the occurrence of adverse events, inflammatory parameters in the blood and CSF, cerebral infarction on magnetic resonance imaging, and clinical and cognitive outcomes. We aim to evaluate 26 patients with CSF assessments, 13 in the intervention group and 13 in the comparator group. To compensate for early case fatality and inability to obtain CSF, we will include 20 patients per group.DiscussionThe CLASH trial is the first trial to investigate the pharmacodynamic efficacy and safety of eculizumab in the early phase after aSAH.Trial registrationNetherlands Trial Register NTR6752. Registered on 27 October 2017European Clinical Trials Database (EudraCT) 2017-004307-51