Simulations of Electron Acceleration at Collisionless Shocks: The Effects of Surface Fluctuations

Energetic electrons are a common feature of interplanetary shocks and planetary bow shocks, and they are invoked as a key component of models of nonthermal radio emission, such as solar radio bursts. A simulation study is carried out of electron acceleration for high Mach number, quasi-perpendicular shocks, typical of the shocks in the solar wind. Two dimensional self-consistent hybrid shock simulations provide the electric and magnetic fields in which test particle electrons are followed. A range of different shock types, shock normal angles, and injection energies are studied. When the Mach number is low, or the simulation configuration suppresses fluctuations along the magnetic field direction, the results agree with theory assuming magnetic moment conserving reflection (or Fast Fermi acceleration), with electron energy gains of a factor only 2 - 3. For high Mach number, with a realistic simulation configuration, the shock front has a dynamic rippled character. The corresponding electron energization is radically different: Energy spectra display: (1) considerably higher maximum energies than Fast Fermi acceleration; (2) a plateau, or shallow sloped region, at intermediate energies 2 - 5 times the injection energy; (3) power law fall off with increasing energy, for both upstream and downstream particles, with a slope decreasing as the shock normal angle approaches perpendicular; (4) sustained flux levels over a broader region of shock normal angle than for adiabatic reflection. All these features are in good qualitative agreement with observations, and show that dynamic structure in the shock surface at ion scales produces effective scattering and can be responsible for making high Mach number shocks effective sites for electron acceleration.Comment: 26 pages, 12 figure

Advances in the genetic classification of amyotrophic lateral sclerosis

Purpose of review Amyotrophic lateral sclerosis (ALS) is an archetypal complex disease wherein disease risk and severity are, for the majority of patients, the product of interaction between multiple genetic and environmental factors. We are in a period of unprecedented discovery with new large-scale genome-wide association study (GWAS) and accelerating discovery of risk genes. However, much of the observed heritability of ALS is undiscovered and we are not yet approaching elucidation of the total genetic architecture, which will be necessary for comprehensive disease subclassification. Recent findings We summarize recent developments and discuss the future. New machine learning models will help to address nonlinear genetic interactions. Statistical power for genetic discovery may be boosted by reducing the search-space using cell-specific epigenetic profiles and expanding our scope to include genetically correlated phenotypes. Structural variation, somatic heterogeneity and consideration of environmental modifiers represent significant challenges which will require integration of multiple technologies and a multidisciplinary approach, including clinicians, geneticists and pathologists. Summary The move away from fully penetrant Mendelian risk genes necessitates new experimental designs and new standards for validation. The challenges are significant, but the potential reward for successful disease subclassification is large-scale and effective personalized medicine

Global Assessment Report on Disaster Risk Reduction 2019

The Global Assessment Report on Disaster Risk Reduction (GAR) is the flagship report of the United Nations on worldwide efforts to reduce disaster risk

Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy

GGGGCC repeat expansions of C9ORF72 represent the most common genetic variant of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We and others have proposed that RNA transcribed from the repeat sequence is toxic via sequestration of RNA-binding factors. Both GGGGCC-repeat (sense) and CCCCGG-repeat (antisense) molecules are detectable by fluorescence in situ hybridisation as RNA foci, but their relative expression pattern within the CNS and contribution to disease has not been determined. Blinded examination of CNS biosamples from ALS patients with a repeat expansion of C9ORF72 showed that antisense foci are present at a significantly higher frequency in cerebellar Purkinje neurons and motor neurons, whereas sense foci are present at a significantly higher frequency in cerebellar granule neurons. Consistent with this, inclusions containing sense or antisense derived dipeptide repeat proteins were present at significantly higher frequency in cerebellar granule neurons or motor neurons, respectively. Immunohistochemistry and UV-crosslinking studies showed that sense and antisense RNA molecules share similar interactions with SRSF2, hnRNP K, hnRNP A1, ALYREF, and hnRNP H/F. Together these data suggest that, although sense and antisense RNA molecules might be expected to be equally toxic via their shared protein binding partners, distinct patterns of expression in various CNS neuronal populations could lead to relative differences in their contribution to the pathogenesis of neuronal injury. Moreover in motor neurons, which are the primary target of pathology in ALS, the presence of antisense foci (χ2, p 2, p = 0.75) correlated with mislocalisation of TDP-43, which is the hallmark of ALS neurodegeneration. This has implications for translational approaches to C9ORF72 disease, and furthermore interacting RNA-processing factors and transcriptional activators responsible for antisense versus sense transcription might represent novel therapeutic targets

Report 12: The global impact of COVID-19 and strategies for mitigation and suppression

The world faces a severe and acute public health emergency due to the ongoing COVID-19 global pandemic. How individual countries respond in the coming weeks will be critical in influencing the trajectory of national epidemics. Here we combine data on age-specific contact patterns and COVID-19 severity to project the health impact of the pandemic in 202 countries. We compare predicted mortality impacts in the absence of interventions or spontaneous social distancing with what might be achieved with policies aimed at mitigating or suppressing transmission. Our estimates of mortality and healthcare demand are based on data from China and high-income countries; differences in underlying health conditions and healthcare system capacity will likely result in different patterns in low income settings. We estimate that in the absence of interventions, COVID-19 would have resulted in 7.0 billion infections and 40 million deaths globally this year. Mitigation strategies focussing on shielding the elderly (60% reduction in social contacts) and slowing but not interrupting transmission (40% reduction in social contacts for wider population) could reduce this burden by half, saving 20 million lives, but we predict that even in this scenario, health systems in all countries will be quickly overwhelmed. This effect is likely to be most severe in lower income settings where capacity is lowest: our mitigated scenarios lead to peak demand for critical care beds in a typical low-income setting outstripping supply by a factor of 25, in contrast to a typical high-income setting where this factor is 7. As a result, we anticipate that the true burden in low income settings pursuing mitigation strategies could be substantially higher than reflected in these estimates. Our analysis therefore suggests that healthcare demand can only be kept within manageable levels through the rapid adoption of public health measures (including testing and isolation of cases and wider social distancing measures) to suppress transmission, similar to those being adopted in many countries at the current time. If a suppression strategy is implemented early (at 0.2 deaths per 100,000 population per week) and sustained, then 38.7 million lives could be saved whilst if it is initiated when death numbers are higher (1.6 deaths per 100,000 population per week) then 30.7 million lives could be saved. Delays in implementing strategies to suppress transmission will lead to worse outcomes and fewer lives saved. We do not consider the wider social and economic costs of suppression, which will be high and may be disproportionately so in lower income settings. Moreover, suppression strategies will need to be maintained in some manner until vaccines or effective treatments become available to avoid the risk of later epidemics. Our analysis highlights the challenging decisions faced by all governments in the coming weeks and months, but demonstrates the extent to which rapid, decisive and collective action now could save millions of lives

Response to COVID-19 in South Korea and implications for lifting stringent interventions

Background After experiencing a sharp growth in COVID-19 cases early in the pandemic, South Korea rapidly controlled transmission while implementing less stringent national social distancing measures than countries in Europe and the US. This has led to substantial interest in their “test, trace, isolate” strategy. However, it is important to understand the epidemiological peculiarities of South Korea’s outbreak and characterise their response before attempting to emulate these measures elsewhere. Methods We systematically extracted numbers of suspected cases tested, PCR-confirmed cases, deaths, isolated confirmed cases, and numbers of confirmed cases with an identified epidemiological link from publicly available data. We estimated the time-varying reproduction number, Rt, using an established Bayesian framework, and reviewed the package of interventions implemented by South Korea using our extracted data, plus published literature and government sources. Results We estimated that after the initial rapid growth in cases, Rt dropped below one in early April before increasing to a maximum of 1.94 (95%CrI; 1.64-2.27) in May following outbreaks in Seoul Metropolitan Region. By mid-June Rt was back below one where it remained until the end of our study (July 13th). Despite less stringent “lockdown” measures, strong social distancing measures were implemented in high incidence areas and studies measured a considerable national decrease in movement in late-February. Testing capacity was swiftly increased, and protocols were in place to isolate suspected and confirmed cases quickly however we could not estimate the delay to isolation using our data. Accounting for just 10% of cases, individual case-based contact-tracing picked up a relatively minor proportion of total cases, with cluster investigations accounting for 66%. Conclusions Whilst early adoption of testing and contact-tracing are likely to be important for South Korea’s successful outbreak control, other factors including regional implementation of strong social distancing measures likely also contributed. The high volume of testing and low number of deaths suggests that South Korea experienced a small epidemic relative to other countries. Caution is needed in attempting to replicate the South Korean response in populations with larger more geographically widespread epidemics where finding, testing and isolating cases that are linked to clusters may be more difficult

Key epidemiological drivers and impact of interventions in the 2020 SARS-CoV-2 epidemic in England

We fitted a model of SARS-CoV-2 transmission in care homes and the community to regional surveillance data for England. Compared with other approaches, our model provides a synthesis of multiple surveillance data streams into a single coherent modelling framework allowing transmission and severity to be disentangled from features of the surveillance system. Of the control measures implemented, only national lockdown brought the reproduction number (Rteff ) below 1 consistently; if introduced one week earlier it could have reduced deaths in the first wave from an estimated 48,600 to 25,600 (95% credible interval [95%CrI]: 15,900-38,400). The infection fatality ratio decreased from 1.00% (95%CrI: 0.85%-1.21%) to 0.79% (95%CrI: 0.63%-0.99%), suggesting improved clinical care. The infection fatality ratio was higher in the elderly residing in care homes (23.3%, 95%CrI: 14.7%-35.2%) than those residing in the community (7.9%, 95%CrI: 5.9%-10.3%). On 2nd December 2020 England was still far from herd immunity, with regional cumulative infection incidence between 7.6% (95%CrI: 5.4%-10.2%) and 22.3% (95%CrI: 19.4%-25.4%) of the population. Therefore, any vaccination campaign will need to achieve high coverage and a high degree of protection in vaccinated individuals to allow non-pharmaceutical interventions to be lifted without a resurgence of transmission

Key epidemiological drivers and impact of interventions in the 2020 SARS-CoV-2 epidemic in England

We fitted a model of SARS-CoV-2 transmission in care homes and the community to regional surveillance data for England. Compared with other approaches, our model provides a synthesis of multiple surveillance data streams into a single coherent modelling framework allowing transmission and severity to be disentangled from features of the surveillance system. Of the control measures implemented, only national lockdown brought the reproduction number (Rteff ) below 1 consistently; if introduced one week earlier it could have reduced deaths in the first wave from an estimated 48,600 to 25,600 (95% credible interval [95%CrI]: 15,900-38,400). The infection fatality ratio decreased from 1.00% (95%CrI: 0.85%-1.21%) to 0.79% (95%CrI: 0.63%-0.99%), suggesting improved clinical care. The infection fatality ratio was higher in the elderly residing in care homes (23.3%, 95%CrI: 14.7%-35.2%) than those residing in the community (7.9%, 95%CrI: 5.9%-10.3%). On 2nd December 2020 England was still far from herd immunity, with regional cumulative infection incidence between 7.6% (95%CrI: 5.4%-10.2%) and 22.3% (95%CrI: 19.4%-25.4%) of the population. Therefore, any vaccination campaign will need to achieve high coverage and a high degree of protection in vaccinated individuals to allow non-pharmaceutical interventions to be lifted without a resurgence of transmission

Report 11: Evidence of initial success for China exiting COVID-19 social distancing policy after achieving containment

The COVID-19 epidemic was declared a Global Pandemic by WHO on 11 March 2020. As of 20 March 2020, over 254,000 cases and 10,000 deaths had been reported worldwide. The outbreak began in the Chinese city of Wuhan in December 2019. In response to the fast-growing epidemic, China imposed strict social distancing in Wuhan on 23 January 2020 followed closely by similar measures in other provinces. At the peak of the outbreak in China (early February), there were between 2,000 and 4,000 new confirmed cases per day. For the first time since the outbreak began there have been no new confirmed cases caused by local transmission in China reported for five consecutive days up to 23 March 2020. This is an indication that the social distancing measures enacted in China have led to control of COVID-19 in China. These interventions have also impacted economic productivity in China, and the ability of the Chinese economy to resume without restarting the epidemic is not yet clear. Here, we estimate transmissibility from reported cases and compare those estimates with daily data on within-city movement, as a proxy for economic activity. Initially, within-city movement and transmission were very strongly correlated in the 5 provinces most affected by the epidemic and Beijing. However, that correlation is no longer apparent even though within-city movement has started to increase. A similar analysis for Hong Kong shows that intermediate levels of local activity can be maintained while avoiding a large outbreak. These results do not preclude future epidemics in China, nor do they allow us to estimate the maximum proportion of previous within-city activity that will be recovered in the medium term. However, they do suggest that after very intense social distancing which resulted in containment, China has successfully exited their stringent social distancing policy to some degree. Globally, China is at a more advanced stage of the pandemic. Policies implemented to reduce the spread of COVID-19 in China and the exiting strategies that followed can inform decision making processes for countries once containment is achieved