Plasma-photonic spatiotemporal synchronization of relativistic electron and laser beams

Modern particle accelerators and their applications increasingly rely on precisely coordinated interactions of intense charged particle and laser beams. Femtosecond-scale synchronization alongside micrometre-scale spatial precision are essential e.g. for pump-probe experiments, seeding and diagnostics of advanced light sources and for plasma-based accelerators. State-of-the-art temporal or spatial diagnostics typically operate with low-intensity beams to avoid material damage at high intensity. As such, we present a plasma-based approach, which allows measurement of both temporal and spatial overlap of high-intensity beams directly at their interaction point. It exploits amplification of plasma afterglow arising from the passage of an electron beam through a laser-generated plasma filament. The corresponding photon yield carries the spatiotemporal signature of the femtosecond-scale dynamics, yet can be observed as a visible light signal on microsecond-millimetre scales

Addition of four doses of rituximab to standard induction chemotherapy in adult patients with precursor B-cell acute lymphoblastic leukaemia (UKALL14): a phase 3, multicentre, randomised controlled trial

BACKGROUND: Treatment for adults with acute lymphoblastic leukaemia requires improvement. UKALL14 was a UK National Cancer Research Institute Adult ALL group study that aimed to determine the benefit of adding the anti-CD20 monoclonal antibody, rituximab, to the therapy of adults with de novo B-precursor acute lymphoblastic leukaemia. METHODS: This was an investigator-initiated, phase 3, randomised controlled trial done in all UK National Health Service Centres treating patients with acute lymphoblastic leukaemia (65 centres). Patients were aged 25-65 years with de-novo BCR-ABL1-negative acute lymphoblastic leukaemia. Patients with de-novo BCR-ABL1-positive acute lymphoblastic leukaemia were eligible if they were aged 19-65 years. Participants were randomly assigned (1:1) to standard-of-care induction therapy or standard-of-care induction therapy plus four doses of intravenous rituximab (375 mg/m2 on days 3, 10, 17, and 24). Randomisation used minimisation and was stratified by sex, age, and white blood cell count. No masking was used for patients, clinicians, or staff (including the trial statistician), although the central laboratory analysing minimal residual disease and CD20 was masked to treatment allocation. The primary endpoint was event-free survival in the intention-to-treat population. Safety was assessed in all participants who started trial treatment. This study is registered with ClincialTrials.gov, NCT01085617. FINDINGS: Between April 19, 2012, and July 10, 2017, 586 patients were randomly assigned to standard of care (n=292) or standard of care plus rituximab (n=294). Nine patients were excluded from the final analysis due to misdiagnosis (standard of care n=4, standard of care plus rituximab n=5). In the standard-of-care group, median age was 45 years (IQR 22-65), 159 (55%) of 292 participants were male, 128 (44%) were female, one (<1%) was intersex, and 143 (59%) of 244 participants had high-risk cytogenetics. In the standard-of-care plus rituximab group, median age was 46 years (IQR 23-65), 159 (55%) of 294 participants were male, 130 (45%) were female, and 140 (60%) of 235 participants had high-risk cytogenetics. After a median follow-up of 53·7 months (IQR 40·3-70·4), 3-year event-free survival was 43·7% (95% CI 37·8-49·5) for standard of care versus 51·4% (45·4-57·1) for standard of care plus rituximab (hazard ratio [HR] 0·85 [95% CI 0·69-1·06]; p=0·14). The most common adverse events were infections and cytopenias, with no difference between the groups in the rates of adverse events. There were 11 (4%) fatal (grade 5) events in induction phases 1 and 2 in the standard-of-care group and 13 (5%) events in the standard-of-care plus rituximab group). 3-year non-relapse mortality was 23·7% (95% CI 19·0-29·4) in the standard-of-care group versus 20·6% (16·2-25·9) in the standard-of-care plus rituximab group (HR 0·88 [95% CI 0·62-1·26]; p=0·49). INTERPRETATION: Standard of care plus four doses of rituximab did not significantly improve event-free survival over standard of care. Rituximab is beneficial in acute lymphoblastic leukaemia but four doses during induction is likely to be insufficient. FUNDING: Cancer Research UK and Blood Cancer UK

Vision in high-level football officials

YesOfficiating in football depends, at least to some extent, upon adequate visual function. However, there is no vision standard for football officiating and the nature of the relationship between officiating performance and level of vision is unknown. As a first step in characterising this relationship, we report on the clinically-measured vision and on the perceived level of vision in elite-level, Portuguese football officials. Seventy-one referees (R) and assistant referees (AR) participated in the study, representing 92% of the total population of elite level football officials in Portugal in the 2013/2014 season. Nine of the 22 Rs (40.9%) and ten of the 49 ARs (20.4%) were international-level. Information about visual history was also gathered. Perceived vision was assessed using the preference-values-assigned-to-global-visual-status (PVVS) and the Quality-of-Vision (QoV) questionnaire. Standard clinical vision measures (including visual acuity, contrast sensitivity and stereopsis) were gathered in a subset (n = 44, 62%) of the participants. Data were analysed according to the type (R/AR) and level (international/national) of official, and Bonferroni corrections were applied to reduce the risk of type I errors. Adopting criterion for statistical significance of p<0.01, PVVS scores did not differ between R and AR (p = 0.88), or between national- and international-level officials (p = 0.66). Similarly, QoV scores did not differ between R and AR in frequency (p = 0.50), severity (p = 0.71) or bothersomeness (p = 0.81) of symptoms, or between international-level vs national-level officials for frequency (p = 0.03) or bothersomeness (p = 0.07) of symptoms. However, international-level officials reported less severe symptoms than their national-level counterparts (p<0.01). Overall, 18.3% of officials had either never had an eye examination or if they had, it was more than 3 years previously. Regarding refractive correction, 4.2% had undergone refractive surgery and 23.9% wear contact lenses when officiating. Clinical vision measures in the football officials were similar to published normative values for young, adult populations and similar between R and AR. Clinically-measured vision did not differ according to officiating level. Visual acuity measured with and without a pinhole disc indicated that around one quarter of participants may be capable of better vision when officiating, as evidenced by better acuity (≥1 line of letters) using the pinhole. Amongst the clinical visual tests we used, we did not find evidence for above-average performance in elite-level football officials. Although the impact of uncorrected mild to moderate refractive error upon officiating performance is unknown, with a greater uptake of eye examinations, visual acuity may be improved in around a quarter of officials.Portuguese Foundation for Science and Technology (FCT) in the framework of the Strategic Funding UID/FIS/04650/2013

Electron bunch generation from a plasma photocathode

Plasma waves generated in the wake of intense, relativistic laser or particle beams can accelerate electron bunches to giga-electronvolt (GeV) energies in centimetre-scale distances. This allows the realization of compact accelerators having emerging applications, ranging from modern light sources such as the free-electron laser (FEL) to energy frontier lepton colliders. In a plasma wakefield accelerator, such multi-gigavolt-per-metre (GV m$^{-1}$) wakefields can accelerate witness electron bunches that are either externally injected or captured from the background plasma. Here we demonstrate optically triggered injection and acceleration of electron bunches, generated in a multi-component hydrogen and helium plasma employing a spatially aligned and synchronized laser pulse. This ''plasma photocathode'' decouples injection from wake excitation by liberating tunnel-ionized helium electrons directly inside the plasma cavity, where these cold electrons are then rapidly boosted to relativistic velocities. The injection regime can be accessed via optical density down-ramp injection, is highly tunable and paves the way to generation of electron beams with unprecedented low transverse emittance, high current and 6D-brightness. This experimental path opens numerous prospects for transformative plasma wakefield accelerator applications based on ultra-high brightness beams

Human mesenchymal stromal cells deliver systemic oncolytic measles virus to treat acute lymphoblastic leukemia in the presence of humoral immunity

Key Points Human BM-MSCs can be used to successfully deliver systemic oncolytic measles virotherapy to ALL tumor targets. This approach permits circumvention of preexisting anti-measles humoral immunity and enhanced therapeutic outcomes.</jats:p

Immune response to COVID‐19 vaccination in patients with Waldenström macroglobulinaemia who pause their BTKi therapy

Abstract Patients with Waldenström macroglobulinaemia (WM) are at increased risk of severe COVID‐19 infection and have poor immune responses to COVID‐19 vaccination. This study assessed whether a closely monitored pause in Bruton's Tyrosine Kinase inhibitor (BTKi) therapy might result in an improved humoral response to a 3rd COVID‐19 vaccine dose. Improved response was observed in WM patients who paused their BTKi, compared to a group who did not pause their BTKi. However, the response was attenuated after BTKi recommencement. This data contributes to our understanding of vaccination strategies in this patient group and may help inform consensus approaches in the future

Patients with treated indolent lymphomas immunized with BNT162b2 have reduced anti‐spike neutralizing IgG to SARS‐CoV‐2 variants, but preserved antigen‐specific T cell responses

Patients with indolent lymphoma undertaking recurrent or continuous B cell suppression are at risk of severe COVID-19. Patients and healthy controls (HC; N=13) received 2 doses of BNT162b2: Follicular Lymphoma (FL; N=35) who were treatment naïve (TN; N=11) or received immunochemotherapy (ICT; N=23) and Waldenström's Macroglobulinemia (WM; N=37) including TN (N=9), ICT (N=14), or treated with Bruton's Tyrosine Kinase inhibitors (BTKi; N=12). Anti-spike IgG was determined by a high-sensitivity flow-cytometric assay, in addition to live-virus neutralization. Antigen-specific T cells were identified by co-expression of CD69/CD137 and CD25/CD134 on T cells. A subgroup (N=29) were assessed for third mRNA vaccine response, including omicron neutralization. One month after second BNT162b2, median anti-spike IgG mean fluorescence intensity (MFI) in FL ICT patients (9977) was 25-fold lower than TN (245898) and HC (228255, p=0.0002 for both). Anti-spike IgG correlated with lymphocyte count (r=0.63; p=0.002), and time from treatment, (r=0.56; p=0.007) on univariate analysis, but only with lymphocyte count on multivariate analysis (p=0.03). In the WM cohort, median anti-spike IgG MFI in BTKi patients (39039) was reduced compared to TN (220645, p=0.0008) and HC (p<0.0001). Anti-spike IgG correlated with neutralization of the delta variant (r=0.62, p<0.0001). Median neutralization titer for WM BTKi (0) was lower than HC (40, p<0.0001) for early-clade and delta. All cohorts had functional T cell responses. Median anti-spike IgG decreased 4-fold from second to third dose (p=0.004). Only 5/29 poor initial responders assessed after third vaccination demonstrated seroconversion and improvement in neutralization activity, including to the omicron variant. This article is protected by copyright. All rights reserved

A modified QuickDASH-9 provides a valid outcome instrument for upper limb function

Background. The 30-item Disabilities Arm Shoulder and Hand (DASH) questionnaire was introduced to facilitate assessment of upper limb functional limitations. To improve practicality and eliminate item redundancy a modified instrument was needed. The 11-item QuickDASH was developed to fulfil these requirements and translated into several languages. However, prospective investigations of psychometric and practical characteristics are limited. No published study investigated readability or used concurrent validation with a standardized upper limb criterion measure. The validity of the QuickDASH has been questioned as the results for factor structure are conflicting, and the English-language version has not yet had factor structure reported. A shortened 9-item version, the QuickDASH-9, that addresses these issues is proposed. Methods. This two-stage observational study assessed the psychometric and practical characteristics of the QuickDASH and the extracted QuickDASH-9. The Upper Limb Functional Index (ULFI) was the criterion standard in both stages. Stage 1, calibration, reanalyzed extracted QuickDASH and QuickDASH-9 responses from a previous prospective study, by the authors, of the 30-item DASH (n = 137). Stage 2, prospective validation, investigated the QuickDASH through repeated measures in consecutive upper limb musculoskeletal participants' consulting for physical therapy in Australia (n = 67). The QuickDASH and extracted QuickDASH-9 data from both stages was analyzed and compared for psychometric properties, practical characteristics and factor structure. Results. The proposed QuickDASH-9 had a unidimensional structure, high reliability (ICC 2:1, r = 0.92), internal consistency (alpha = 0.93) and responsiveness (ES = 1.05). It correlated highly with both the DASH (r = 0.97), QuickDASH (r = 0.99) and ULFI criterion (r = 0.85). QuickDASH-9 missing responses reduced to 3.5% from 26% in the QuickDASH. Completion and scoring time was 134 ± 56 seconds and required a computational aid. The QuickDASH demonstrated a bidimensional structure making it invalid. The QuickDASH-9 summary performance was measured on the 'Measurement of Outcome Measures' at 88% and on the 'Bot' clinimetric scale at 75%. Conclusions. The proposed QuickDASH-9 had a unidimensional structure and similar psychometric precision to the full-length DASH with improved practicality and completion time. The QuickDASH was invalid as its bidimensional structure made a single summated score inappropriate. The QuickDASH-9 offers a future direction for ongoing use of the QuickDASH concept. © 2009 Gabel et al; licensee BioMed Central Ltd