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Studies of the crab cavities at KEKB revealed that the RF phase could shift by up to 50o within ~50 us during a quench; while the cavity voltage is still at approximately 75% of its nominal amplitude. If such a failure were to occur on the HL-LHC crab cavities, it is likely that the machine would sustain substantial damage to the beam line and surrounding infrastructure due to uncontrolled beam loss before the machine protection system could dump the beam. We have developed a low-level RF system model, including detuning mechanisms and beam loading, and use this to simulate the behaviour of a crab cavity during a quench, modeling the low-level RF system, detuning mechanisms and beam loading. We supplement this with measurement data of the actual RF response of the proof of principle Double-Quarter Wave Crab Cravity during a quench. Extrapolating these measurements to the HL-LHC, we show that Lorentz Force detuning is the dominant effect leading to phase shifts in the crab cavity during quenches; rather than pressure detuning which is expected to be dominant for the KEKB crab cavities. The total frequency shift for the HL-LHC crab cavities during quenches is expected to be about 460 Hz, leading to a phase shift of no more than 3o. The results of the quench model are read into a particle tracking simulation, SixTrack, and used to determine the effect of quenches on the HL-LHC beam. The quench model has been benchmarked against the KEKB experimental measurements. In this paper we present the results of the simulations on a crab cavity failure for HL-LHC as well as for the SPS and show that beam loss is negligible when using a realistic low-level RF response.

Energy-recovery linacs (ERLs) have been emphasised by the recent (2020) update of the European Strategy for Particle Physics as one of the most promising technologies for the accelerator base of future high-energy physics. The current paper has been written as a base document to support and specify details of the recently published European roadmap for the development of energy-recovery linacs. The paper summarises the previous achievements on ERLs and the status of the field and its basic technology items. The main possible future contributions and applications of ERLs to particle and nuclear physics as well as industrial developments are presented. The paper includes a vision for the further future, beyond 2030, as well as a comparative data base for the main existing and forthcoming ERL facilities. A series of continuous innovations, such as on intense electron sources or high-quality superconducting cavity technology, will massively contribute to the development of accelerator physics at large. Industrial applications are potentially revolutionary and may carry the development of ERLs much further, establishing another shining example of the impact of particle physics on society and its technical foundation with a special view on sustaining nature.

While Russia's submariners have managed to upset even the mild- mannered Norwegians and Canadians by planting a flag under the Arctic ice, its long range TU-95 Bear bombers have rattled America's cage by buzzing its U.S. naval base on the island of Guam in the western Pacific. The Georgians are furious after a Russian missile landed on the outskirts of a village near Tbilisi. And, a series of war games in Russia's southern Ural Mountains featuring some 6,500 troops from Russia, China, Kazakhstan, Kyrgyzstan, Tajikistan and Uzbekistan sparked Western concern over the emergence of a new Warsaw Pact. Russia also plans to spend heavily on the new TU-160 strategic bomber, which can launch cruise missiles, the SU-34 \"Fullback\" fighter-bomber capable of all-weather attacks on heavily defended targets and a new fifth-generation fighter, the Sukhoi T-50, which is expected to come into service in 2008 as Russia's main lightweight front-line fighter.

While Russia's submariners have managed to upset even the mild- mannered Norwegians and Canadians by planting a flag under the Arctic ice, its long range TU-95 Bear bombers have rattled America's cage by buzzing its US naval base on the island of Guam in the western Pacific. The Georgians are furious after a Russian missile landed on the outskirts of a village near Tbilisi and a series of war games in Russia's southern Ural Mountains featuring some 6,500 troops from Russia, China, Kazakhstan, Kyrgyzstan, Tajikistan and Uzbekistan sparked Western concern over the emergence of a new Warsaw Pact. The latest developments have exacerbated an already tense situation. Russia has responded angrily to US plans to station an anti-missile system in the Czech republic and Poland by threatening to site its own missiles in Kaliningrad to counter the threat. Earlier this summer Mr [Vladimir Putin] upped the ante by threatening to target US strategic nuclear sites in Europe. Tensions with Britain over the murder of former Russian spy Alexander Litvinenko have prompted tit-for-tat expulsions of diplomats, while on Friday the BBC's World Service was thrown off Russian FM radio. It also plans to spend heavily on the new TU-160 strategic bomber, which can launch cruise missiles, the SU-34 \"Fullback\" fighter-bomber capable of all-weather attacks on heavily defended targets and a new fifth-generation fighter, the Sukhoi T-50, which is expected to come into service in 2008 as Russia's main lightweight front-line fighter. The expanded Russian fleet will include six new nuclear powered aircraft carriers, it has just one at present, and eight ballistic missile submarines. Alex Pravda, a Russia expert at London's Chatham House foreign policy think tank, said the new aggressive approach was typical Putin.

BNT162b2 mRNA and ChAdOx1 nCOV-19 adenoviral vector vaccines have been rapidly rolled out in the UK from December, 2020. We aimed to determine the factors associated with vaccine coverage for both vaccines and documented the vaccine effectiveness of the BNT162b2 mRNA vaccine in a cohort of health-care workers undergoing regular asymptomatic testing. The SIREN study is a prospective cohort study among staff (aged ≥18 years) working in publicly-funded hospitals in the UK. Participants were assigned into either the positive cohort (antibody positive or history of infection [indicated by previous positivity of antibody or PCR tests]) or the negative cohort (antibody negative with no previous positive test) at the beginning of the follow-up period. Baseline risk factors were collected at enrolment, symptom status was collected every 2 weeks, and vaccination status was collected through linkage to the National Immunisations Management System and questionnaires. Participants had fortnightly asymptomatic SARS-CoV-2 PCR testing and monthly antibody testing, and all tests (including symptomatic testing) outside SIREN were captured. Data cutoff for this analysis was Feb 5, 2021. The follow-up period was Dec 7, 2020, to Feb 5, 2021. The primary outcomes were vaccinated participants (binary ever vacinated variable; indicated by at least one vaccine dose recorded by at least one of the two vaccination data sources) for the vaccine coverage analysis and SARS-CoV-2 infection confirmed by a PCR test for the vaccine effectiveness analysis. We did a mixed-effect logistic regression analysis to identify factors associated with vaccine coverage. We used a piecewise exponential hazard mixed-effects model (shared frailty-type model) using a Poisson distribution to calculate hazard ratios to compare time-to-infection in unvaccinated and vaccinated participants and estimate the impact of the BNT162b2 vaccine on all PCR-positive infections (asymptomatic and symptomatic). This study is registered with ISRCTN, number ISRCTN11041050, and is ongoing. 23 324 participants from 104 sites (all in England) met the inclusion criteria for this analysis and were enrolled. Included participants had a median age of 46·1 years (IQR 36·0–54·1) and 19 692 (84%) were female; 8203 (35%) were assigned to the positive cohort at the start of the analysis period, and 15 121 (65%) assigned to the negative cohort. Total follow-up time was 2 calendar months and 1 106 905 person-days (396 318 vaccinated and 710 587 unvaccinated). Vaccine coverage was 89% on Feb 5, 2021, 94% of whom had BNT162b2 vaccine. Significantly lower coverage was associated with previous infection, gender, age, ethnicity, job role, and Index of Multiple Deprivation score. During follow-up, there were 977 new infections in the unvaccinated cohort, an incidence density of 14 infections per 10 000 person-days; the vaccinated cohort had 71 new infections 21 days or more after their first dose (incidence density of eight infections per 10 000 person-days) and nine infections 7 days after the second dose (incidence density four infections per 10 000 person-days). In the unvaccinated cohort, 543 (56%) participants had typical COVID-19 symptoms and 140 (14%) were asymptomatic on or 14 days before their PCR positive test date, compared with 29 (36%) with typical COVID-19 symptoms and 15 (19%) asymptomatic in the vaccinated cohort. A single dose of BNT162b2 vaccine showed vaccine effectiveness of 70% (95% CI 55–85) 21 days after first dose and 85% (74–96) 7 days after two doses in the study population. Our findings show that the BNT162b2 vaccine can prevent both symptomatic and asymptomatic infection in working-age adults. This cohort was vaccinated when the dominant variant in circulation was B1.1.7 and shows effectiveness against this variant. Public Health England, UK Department of Health and Social Care, and the National Institute for Health Research.

Human societies and ecological systems face increasingly severe risks, stemming from crossing planetary boundaries, worsening inequality, rising geo-political tensions, and new technologies. In an interconnected world, these risks can exacerbate each-other, creating systemic risks, which must be thoroughly assessed and responded to. Recent years have seen the emergence of analytical frameworks designed specifically for, or applicable to, systemic risk assessment, adding to the multitude of tools and models for analysing and simulating different systems. By assessing two recent global food and energy systemic crises, we propose a methodological framework applicable to assessing systemic risks in a polycrisis context, drawing from and building on existing approaches. Our framework’s polycrisis-specific features include: exploring system architectures including their objectives and political economy; consideration of transformational responses away from risks; and cross-cutting practices including consideration of non-human life, trans-disciplinarity, and diversity, transparency and communication of uncertainty around data, evidence and methods. This paper proposes a framework to assess systemic risks that compound and cascade within and between systems. This emphasizes political economy and transformations, as well as trans-disciplinarity and diverse participation, evidence and methods.

AbstractObjectiveTo describe the incidence of, risk factors for, and impact of vaccines on primary SARS-CoV-2 infection during the second wave of the covid-19 pandemic in susceptible hospital healthcare workers in England.DesignMulticentre prospective cohort study.SettingNational Health Service secondary care health organisations (trusts) in England between 1 September 2020 and 30 April 2021.ParticipantsClinical, support, and administrative staff enrolled in the SARS-CoV-2 Immunity and Reinfection Evaluation (SIREN) study with no evidence of previous infection. Vaccination status was obtained from national covid-19 vaccination registries and self-reported.Main outcome measureSARS-CoV-2 infection confirmed by polymerase chain reaction. Mixed effects logistic regression was conducted to determine demographic and occupational risk factors for infection, and an individual based mathematical model was used to predict how large the burden could have been if vaccines had not been available from 8 December 2020 .ResultsDuring England’s second wave, 12.9% (2353/18 284) of susceptible SIREN participants became infected with SARS-CoV-2. Infections peaked in late December 2020 and decreased from January 2021, concurrent with the cohort’s rapid vaccination coverage and a national lockdown. In multivariable analysis, factors increasing the likelihood of infection in the second wave were being under 25 years old (20.3% (132/651); adjusted odds ratio 1.35, 95% confidence interval 1.07 to 1.69), living in a large household (15.8% (282/1781); 1.54, 1.23 to 1.94, for participants from households of five or more people), having frequent exposure to patients with covid-19 (19.2% (723/3762); 1.79, 1.56 to 2.06, for participants with exposure every shift), working in an emergency department or inpatient ward setting (20.8% (386/1855); 1.76, 1.45 to 2.14), and being a healthcare assistant (18.1% (267/1479); 1.43, 1.16 to 1.77). Time to first vaccination emerged as being strongly associated with infection (P<0.001), with each additional day multiplying a participant’s adjusted odds ratio by 1.02. Mathematical model simulations indicated that an additional 9.9% of all patient facing hospital healthcare workers would have been infected were it not for the rapid vaccination coverage.ConclusionsThe rapid covid-19 vaccine rollout from December 2020 averted infection in a large proportion of hospital healthcare workers in England: without vaccines, second wave infections could have been 69% higher. With booster vaccinations being needed for adequate protection from the omicron variant, and perhaps the need for further boosters for future variants, ensuring equitable delivery to healthcare workers is essential. The findings also highlight occupational risk factors that persisted in healthcare workers despite vaccine rollout; a greater understanding of the transmission dynamics responsible for these is needed to help to optimise the infection prevention and control policies that protect healthcare workers from infection and therefore to support staffing levels and maintain healthcare provision.Trial registrationISRCTN registry ISRCTN11041050.

Targeted biologic therapies can elicit an undesirable host immune response characterized by the development of antidrug antibodies (ADA), an important cause of treatment failure. The most widely used biologic across immune-mediated diseases is adalimumab, a tumor necrosis factor inhibitor. This study aimed to identify genetic variants that contribute to the development of ADA against adalimumab, thereby influencing treatment failure. In patients with psoriasis on their first course of adalimumab, in whom serum ADA had been evaluated 6-36 months after starting treatment, we observed a genome-wide association with ADA against adalimumab within the major histocompatibility complex (MHC). The association signal mapped to the presence of tryptophan at position 9 and lysine at position 71 of the HLA-DR peptide-binding groove, with both residues conferring protection against ADA. Underscoring their clinical relevance, these residues were also protective against treatment failure. Our findings highlight antigenic peptide presentation via MHC class II as a critical mechanism in the development of ADA against biologic therapies and downstream treatment response.