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We lead multidisciplinary applied research and training to rethink the way health care is delivered in general practice and across the community.
J/psi production in sqrt s_NN=200 GeV Cu+Cu collisions.
Yields for J/psi production in Cu+Cu collisions at sqrt s_NN=200 GeV have been measured over the rapidity range |y|<2.2 and compared with results in p+p and Au+Au collisions at the same energy. The Cu+Cu data offer greatly improved precision over existing Au+Au data for J/psi production in collisions with small to intermediate numbers of participants, in the range where the quark-gluon plasma transition threshold is predicted to lie. Cold nuclear matter estimates based on ad hoc fits to d+Au data describe the Cu+Cu data up to N_part approximately 50, corresponding to a Bjorken energy density of at least 1.5 GeV/fm(3).
Medium modification of jet fragmentation in Au+Au collisions at √[s(NN)]=200 GeV measured in direct photon-hadron correlations.
The jet fragmentation function is measured with direct photon-hadron correlations in p+p and Au+Au collisions at √[s(NN)]=200 GeV. The p(T) of the photon is an excellent approximation to the initial p(T) of the jet and the ratio z(T)=p(T)(h)/p(T)(γ) is used as a proxy for the jet fragmentation function. A statistical subtraction is used to extract the direct photon-hadron yields in Au+Au collisions while a photon isolation cut is applied in p+p. I(AA), the ratio of hadron yield opposite the photon in Au+Au to that in p+p, indicates modification of the jet fragmentation function. Suppression, most likely due to energy loss in the medium, is seen at high z(T). The associated hadron yield at low z(T) is enhanced at large angles. Such a trend is expected from redistribution of the lost energy into increased production of low-momentum particles.
ASTRO's Framework for Radiopharmaceutical Therapy Curriculum Development for Trainees.
In 2017, the American Society for Radiation Oncology (ASTRO) board of directors prioritized radiopharmaceutical therapy (RPT) as a leading area for new therapeutic development, and the ASTRO RPT workgroup was created. Herein, the workgroup has developed a framework for RPT curriculum development upon which education leaders can build to integrate this modality into radiation oncology resident education. Through this effort, the workgroup aims to provide a guide to ensure robust training in an emerging therapeutic area within the context of existing radiation oncology training in radiation biology, medical physics, and clinical radiation oncology. The framework first determines the core RPT knowledge required to select patients, prescribe, safely administer, and manage related adverse events. Then, it defines the most important topics for preparing residents for clinical RPT planning and delivery. This framework is designed as a tool to supplement the current training that exists for radiation oncology residents. The final document was approved by the ASTRO board of directors in the fall of 2021.
Source breakup dynamics in Au + Au collisions at sqrt[s(NN)]=200 GeV via three-dimensional two-pion source imaging.
A three-dimensional correlation function obtained from midrapidity, low p(T), pion pairs in central Au+Au collisions at sqrt[s(NN)]=200 GeV is studied. The extracted model-independent source function indicates a long range tail in the directions of the pion pair transverse momentum (out) and the beam (long). A proper breakup time tau(0) ~ 9 fm/c and a mean proper emission duration Delta tau ~ 2 fm/c, leading to sizable emission time differences ({|Delta t(LCM)|} approximately 12 fm/c), are required to allow models to be successfully matched to these tails. The model comparisons also suggest an outside-in "burning" of the emission source reminiscent of many hydrodynamical models.
Measurement of direct photons in Au+Au collisions at √(s(NN))=200 GeV.
We report the measurement of direct photons at midrapidity in Au+Au collisions at √(s(NN))=200 GeV. The direct photon signal was extracted for the transverse momentum range of 4 GeV/c
Beam Energy and Centrality Dependence of Direct-Photon Emission from Ultrarelativistic Heavy-Ion Collisions.
The PHENIX collaboration presents first measurements of low-momentum (0.41 GeV/c) direct-photon yield dN_{γ}^{dir}/dη is a smooth function of dN_{ch}/dη and can be well described as proportional to (dN_{ch}/dη)^{α} with α≈1.25. This scaling behavior holds for a wide range of beam energies at the Relativistic Heavy Ion Collider and the Large Hadron Collider, for centrality selected samples, as well as for different A+A collision systems. At a given beam energy, the scaling also holds for high p_{T} (>5 GeV/c), but when results from different collision energies are compared, an additional sqrt[s_{NN}]-dependent multiplicative factor is needed to describe the integrated-direct-photon yield.
SARS-CoV-2 evolution during treatment of chronic infection
The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.
Improved dose-volume histogram estimates for radiopharmaceutical therapy by optimizing quantitative SPECT reconstruction parameters.
In radiopharmaceutical therapy, an understanding of the dose distribution in normal and target tissues is important for optimizing treatment. Three-dimensional (3D) dosimetry takes into account patient anatomy and the nonuniform uptake of radiopharmaceuticals in tissues. Dose-volume histograms (DVHs) provide a useful summary representation of the 3D dose distribution and have been widely used for external beam treatment planning. Reliable 3D dosimetry requires an accurate 3D radioactivity distribution as the input. However, activity distribution estimates from SPECT are corrupted by noise and partial volume effects (PVEs). In this work, we systematically investigated OS-EM based quantitative SPECT (QSPECT) image reconstruction in terms of its effect on DVHs estimates. A modified 3D NURBS-based Cardiac-Torso (NCAT) phantom that incorporated a non-uniform kidney model and clinically realistic organ activities and biokinetics was used. Projections were generated using a Monte Carlo (MC) simulation; noise effects were studied using 50 noise realizations with clinical count levels. Activity images were reconstructed using QSPECT with compensation for attenuation, scatter and collimator-detector response (CDR). Dose rate distributions were estimated by convolution of the activity image with a voxel S kernel. Cumulative DVHs were calculated from the phantom and QSPECT images and compared both qualitatively and quantitatively. We found that noise, PVEs, and ringing artifacts due to CDR compensation all degraded histogram estimates. Low-pass filtering and early termination of the iterative process were needed to reduce the effects of noise and ringing artifacts on DVHs, but resulted in increased degradations due to PVEs. Large objects with few features, such as the liver, had more accurate histogram estimates and required fewer iterations and more smoothing for optimal results. Smaller objects with fine details, such as the kidneys, required more iterations and less smoothing at early time points post-radiopharmaceutical administration but more smoothing and fewer iterations at later time points when the total organ activity was lower. The results of this study demonstrate the importance of using optimal reconstruction and regularization parameters. Optimal results were obtained with different parameters at each time point, but using a single set of parameters for all time points produced near-optimal dose-volume histograms.
Measurements of Elliptic and Triangular Flow in High-Multiplicity 3He+Au Collisions at √(s(NN))=200 GeV.
We present the first measurement of elliptic (v(2)) and triangular (v(3)) flow in high-multiplicity (3)He+Au collisions at √(s(NN))=200 GeV. Two-particle correlations, where the particles have a large separation in pseudorapidity, are compared in (3)He+Au and in p+p collisions and indicate that collective effects dominate the second and third Fourier components for the correlations observed in the (3)He+Au system. The collective behavior is quantified in terms of elliptic v(2) and triangular v(3) anisotropy coefficients measured with respect to their corresponding event planes. The v(2) values are comparable to those previously measured in d+Au collisions at the same nucleon-nucleon center-of-mass energy. Comparisons with various theoretical predictions are made, including to models where the hot spots created by the impact of the three (3)He nucleons on the Au nucleus expand hydrodynamically to generate the triangular flow. The agreement of these models with data may indicate the formation of low-viscosity quark-gluon plasma even in these small collision systems.
Enhanced production of direct photons in Au + Au collisions at square root(S(NN)) = 200 GeV and implications for the initial temperature.
The production of e+ e- pairs for m(e+ e-)<0.3 GeV/c2 and 1
Efficacy and Safety of COVID-19 Convalescent Plasma in Hospitalized Patients: A Randomized Clinical Trial.
IMPORTANCE: There is clinical equipoise for COVID-19 convalescent plasma (CCP) use in patients hospitalized with COVID-19. OBJECTIVE: To determine the safety and efficacy of CCP compared with placebo in hospitalized patients with COVID-19 receiving noninvasive supplemental oxygen. DESIGN, SETTING, AND PARTICIPANTS: CONTAIN COVID-19, a randomized, double-blind, placebo-controlled trial of CCP in hospitalized adults with COVID-19, was conducted at 21 US hospitals from April 17, 2020, to March 15, 2021. The trial enrolled 941 participants who were hospitalized for 3 or less days or presented 7 or less days after symptom onset and required noninvasive oxygen supplementation. INTERVENTIONS: A unit of approximately 250 mL of CCP or equivalent volume of placebo (normal saline). MAIN OUTCOMES AND MEASURES: The primary outcome was participant scores on the 11-point World Health Organization (WHO) Ordinal Scale for Clinical Improvement on day 14 after randomization; the secondary outcome was WHO scores determined on day 28. Subgroups were analyzed with respect to age, baseline WHO score, concomitant medications, symptom duration, CCP SARS-CoV-2 titer, baseline SARS-CoV-2 serostatus, and enrollment quarter. Outcomes were analyzed using a bayesian proportional cumulative odds model. Efficacy of CCP was defined as a cumulative adjusted odds ratio (cOR) less than 1 and a clinically meaningful effect as cOR less than 0.8. RESULTS: Of 941 participants randomized (473 to placebo and 468 to CCP), 556 were men (59.1%); median age was 63 years (IQR, 52-73); 373 (39.6%) were Hispanic and 132 (14.0%) were non-Hispanic Black. The cOR for the primary outcome adjusted for site, baseline risk, WHO score, age, sex, and symptom duration was 0.94 (95% credible interval [CrI], 0.75-1.18) with posterior probability (P[cOR<1] = 72%); the cOR for the secondary adjusted outcome was 0.92 (95% CrI, 0.74-1.16; P[cOR<1] = 76%). Exploratory subgroup analyses suggested heterogeneity of treatment effect: at day 28, cORs were 0.72 (95% CrI, 0.46-1.13; P[cOR<1] = 93%) for participants enrolled in April-June 2020 and 0.65 (95% CrI, 0.41 to 1.02; P[cOR<1] = 97%) for those not receiving remdesivir and not receiving corticosteroids at randomization. Median CCP SARS-CoV-2 neutralizing titer used in April to June 2020 was 1:175 (IQR, 76-379). Any adverse events (excluding transfusion reactions) were reported for 39 (8.2%) placebo recipients and 44 (9.4%) CCP recipients (P = .57). Transfusion reactions occurred in 2 (0.4) placebo recipients and 8 (1.7) CCP recipients (P = .06). CONCLUSIONS AND RELEVANCE: In this trial, CCP did not meet the prespecified primary and secondary outcomes for CCP efficacy. However, high-titer CCP may have benefited participants early in the pandemic when remdesivir and corticosteroids were not in use. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04364737.
Platform adaptive trial of novel antivirals for early treatment of COVID-19 in the community (PANORAMIC): Protocol for a randomised, controlled, open-label, adaptive platform trial of community novel antiviral treatment of COVID-19 in people at increased risk of more severe disease
Introduction There is an urgent need to determine the safety, effectiveness and cost-effectiveness of novel antiviral treatments for COVID-19 in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. Methods and analysis PANORAMIC is a UK-wide, open-label, prospective, adaptive, multiarm platform, randomised clinical trial that evaluates antiviral treatments for COVID-19 in the community. A master protocol governs the addition of new antiviral treatments as they become available, and the introduction and cessation of existing interventions via interim analyses. The first two interventions to be evaluated are molnupiravir (Lagevrio) and nirmatrelvir/ritonavir (Paxlovid). Eligibility criteria: community-dwelling within 5 days of onset of symptomatic COVID-19 (confirmed by PCR or lateral flow test), and either (1) aged 50 years and over, or (2) aged 18-49 years with qualifying comorbidities. Registration occurs via the trial website and by telephone. Recruitment occurs remotely through the central trial team, or in person through clinical sites. Participants are randomised to receive either usual care or a trial drug plus usual care. Outcomes are collected via a participant-completed daily electronic symptom diary for 28 days post randomisation. Participants and/or their Trial Partner are contacted by the research team after days 7, 14 and 28 if the diary is not completed, or if the participant is unable to access the diary. The primary efficacy endpoint is all-cause, non-elective hospitalisation and/or death within 28 days of randomisation. Multiple prespecified interim analyses allow interventions to be stopped for futility or superiority based on prespecified decision criteria. A prospective economic evaluation is embedded within the trial. Ethics and dissemination Ethical approval granted by South Central-Berkshire REC number: 21/SC/0393; IRAS project ID: 1004274. Results will be presented to policymakers and at conferences, and published in peer-reviewed journals. Trial registration number ISRCTN30448031; EudraCT number: 2021-005748-31.
Adverse events after first and second doses of COVID-19 vaccination in England: a national vaccine surveillance platform self-controlled case series study
Objectives: To estimate the incidence of adverse events of interest (AEIs) after receiving their first and second doses of coronavirus disease 2019 (COVID-19) vaccinations, and to report the safety profile differences between the different COVID-19 vaccines. Design: We used a self-controlled case series design to estimate the relative incidence (RI) of AEIs reported to the Oxford-Royal College of General Practitioners national sentinel network. We compared the AEIs that occurred seven days before and after receiving the COVID-19 vaccinations to background levels between 1 October 2020 and 12 September 2021. Setting: England, UK. Participants: Individuals experiencing AEIs after receiving first and second doses of COVID-19 vaccines. Main outcome measures: AEIs determined based on events reported in clinical trials and in primary care during post-license surveillance. Results: A total of 7,952,861 individuals were vaccinated with COVID-19 vaccines within the study period. Among them, 781,200 individuals (9.82%) presented to general practice with 1,482,273 AEIs. Within the first seven days post-vaccination, 4.85% of all the AEIs were reported. There was a 3–7% decrease in the overall RI of AEIs in the seven days after receiving both doses of Pfizer-BioNTech BNT162b2 (RI = 0.93; 95% CI: 0.91–0.94) and 0.96; 95% CI: 0.94–0.98), respectively) and Oxford-AstraZeneca ChAdOx1 (RI = 0.97; 95% CI: 0.95–0.98) for both doses), but a 20% increase after receiving the first dose of Moderna mRNA-1273 (RI = 1.20; 95% CI: 1.00–1.44)). Conclusions: COVID-19 vaccines are associated with a small decrease in the incidence of medically attended AEIs. Sentinel networks could routinely report common AEI rates, which could contribute to reporting vaccine safety.
Participant and caregiver perspectives on health feedback from a healthy lifestyle check
Introduction: The usual output following health consultations from paediatric services is a clinical letter to the referring professional or primary care provider, with a copy sent to the patient's caregiver. There is little research on how patients and caregivers perceive the letter content. We aimed to: first understand child, young people and caregiver experiences of and preferences for receiving a health feedback letter about the child/young person's health measures within a healthy lifestyle programme; and second to provide a set of recommendations for designing letters to children, young people and their families within a healthy lifestyle programme. Methods: This qualitative study, informed by Kaupapa Māori principles, included focus groups of children aged 5–11 years and young people aged 12–18 years who were participants in a healthy lifestyle programme in Taranaki, Aotearoa New Zealand and of their respective caregivers (total n = 47). Discussions were audio-recorded, transcribed and analysed using thematic analysis. Findings: Key themes were identified: letters sometimes acted as ‘discourses of disempowerment’—some participants experienced a lack of safety, depersonalisation with medical jargon and ‘feeling like a number’. Participants described the need for acknowledgement and affirmation in written communication—health feedback should include validation, choice regarding content, respectful tone and a strengths-based approach to health messages. Interpretation: Letters to referrers, copied to families, can be perceived as disempowering, and participant and caregiver perspectives of content should be considered. This study challenges conventional practice in communicating health feedback with broader implications for written communication in healthcare. We propose separate letters aimed at the child/young person and their caregiver that offer choice in the information they receive. The administrative burden of multiple letters can be mitigated by advances in digital health. Patient Contribution: This study originated in response to feedback from service users that current health feedback was not meeting their needs or expectations. Patient perspectives, especially from children, are rarely considered in the generation of clinic letters from health professionals. Participants were child participants in the community-based clinical service and their caregivers, and care was taken to represent the demographic backgrounds of service users. Collection and interpretation of Māori data were led by researchers who were local community members to ensure prioritisation and preservation of participant voice. Where possible, results are illustrated in the text by direct quotes from participants, whose identities are protected with a pseudonym.