A further case of chondrodysplasia with growth failure occurring after hematopoietic stem cell transplantation (HSCT).

There is an emerging body of evidence showing that young patients, post haematopoietic stem cell transplantation (HSCT), can develop skeletal changes that mimic an osteochondrodysplasia process. The key discriminator is that these children have had otherwise normal growth and skeletal development before the therapeutic intervention (HSCT), typically for a haematological malignancy. Herein we present that case of a boy who underwent HSCT for Haemophagocytic Lymphohistiocytosis (HLH) aged 2 years. Following Intervention with HSCT this boy's growth has severely decelerated (stature less than 1st centile matched for age) and he has developed a spondyloepiphyseal dysplasia.

Measurements of neutrino oscillation parameters from the T2K experiment using 3.6×1021 protons on target.

The T2K experiment presents new measurements of neutrino oscillation parameters using 19.7(16.3)×1020 protons on target (POT) in (anti-)neutrino mode at the far detector (FD). Compared to the previous analysis, an additional 4.7×1020 POT neutrino data was collected at the FD. Significant improvements were made to the analysis methodology, with the near-detector analysis introducing new selections and using more than double the data. Additionally, this is the first T2K oscillation analysis to use NA61/SHINE data on a replica of the T2K target to tune the neutrino flux model, and the neutrino interaction model was improved to include new nuclear effects and calculations. Frequentist and Bayesian analyses are presented, including results on sin2θ13 and the impact of priors on the δCP measurement. Both analyses prefer the normal mass ordering and upper octant of sin2θ23 with a nearly maximally CP-violating phase. Assuming the normal ordering and using the constraint on sin2θ13 from reactors, sin2θ23=0.561-0.032+0.021 using Feldman-Cousins corrected intervals, and Δm322=2.494-0.058+0.041×10-3eV2 using constant Δχ2 intervals. The CP-violating phase is constrained to δCP=-1.97-0.70+0.97 using Feldman-Cousins corrected intervals, and δCP=0,π is excluded at more than 90% confidence level. A Jarlskog invariant of zero is excluded at more than 2σ credible level using a flat prior in δCP, and just below 2σ using a flat prior in sinδCP. When the external constraint on sin2θ13 is removed, sin2θ13=28.0-6.5+2.8×10-3, in agreement with measurements from reactor experiments. These results are consistent with previous T2K analyses.

The utility of multiple genomic technologies for interpretation of modern next generation sequencing: A novel case of three FANCA gene variants resulting in autosomal recessive Fanconi anaemia.

Fanconi anaemia (FA) is a rare autosomal recessive condition resulting in changes in the FANC gene family. This report describes a case of Fanconi anaemia in a family with complex biallelic variants. The patient is a 32-year-old female diagnosed with FA on cascade testing during childhood with chromosome breakage studies. On examination she had a fixed deformity of the right thumb and the proximal interphalangeal joint was immobile. Her brother shared this radial abnormality and had FA, requiring a bone marrow transplant. She presented in adulthood seeking further BRCA advice and had next generation sequencing that showed three variants in the FANCA gene. One allele a known pathogenic change, the other had two sequence variants in tandem that have been reported as variants of uncertain significance. There is one other unrelated case of these two variants occurring together in cis, resulting in Fanconi anaemia. This case is an interesting example of three variants in the FANCA gene, one allele with a pathogenic deletion and the other with a single complex allele made up of two missense variants of uncertain significance, likely manifesting with FA. It highlights the utility of different genetic technologies in the interpretation of next generation sequencing.

Antimicrobial stewardship using electronic prescribing systems in hospital settings: a scoping review of interventions and outcome measures.

Objectives: To identify interventions implemented in hospital electronic prescribing systems and the outcome measures used to monitor their impact. Methods: We systematically searched CINAHL, EMBASE, Google Scholar and Medline using keywords in three strands: (i) population: hospital inpatient or emergency department; (ii) intervention: electronic prescribing functionality; and (iii) outcome: antimicrobial stewardship. The interventions were grouped into six themes: alerts, order sets, restriction of access, mandated documentation, embedded guidelines and automatic prescription stop. The outcome measures were organized into those that measure the quality or quantity of prescribing or clinical decision support (CDS) activity. The impact of each intervention reported was grouped into a positive, negative or no change. Results: A total of 28 studies were eligible for inclusion. There were 28 different interventions grouped into the six themes. Alerts visible to the practitioner in the electronic health record (EHR) were most frequently implemented (n = 11/28). Twenty different outcome measures were identified, divided into quality (n = 13/20) and quantity outcomes (n = 4/20) and CDS activity (n = 3/20). One-third of outcomes reported across the 28 studies showed positive change (34.4%, n = 42/122) and 61.4% (n = 75/122) showed no change. Conclusions: The most frequently implemented interventions were alerts, the majority of which were to influence behaviour or decision-making of the practitioner within the EHR. Quality outcomes were most frequently selected by researchers. The review supports previous research that larger well-designed randomized studies are needed to investigate the impact of interventions on AMS and outcome measures to be standardized.

Scalable live-attenuated SARS-CoV-2 vaccine candidate demonstrates preclinical safety and efficacy.

Successfully combating the COVID-19 pandemic depends on mass vaccination with suitable vaccines to achieve herd immunity. Here, we describe COVI-VAC, the only live attenuated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine currently in clinical development. COVI-VAC was developed by recoding a segment of the viral spike protein with synonymous suboptimal codon pairs (codon-pair deoptimization), thereby introducing 283 silent (point) mutations. In addition, the furin cleavage site within the spike protein was deleted from the viral genome for added safety of the vaccine strain. Except for the furin cleavage site deletion, the COVI-VAC and parental SARS-CoV-2 amino acid sequences are identical, ensuring that all viral proteins can engage with the host immune system of vaccine recipients. COVI-VAC was temperature sensitive in vitro yet grew robustly (>107 plaque forming units/mL) at the permissive temperature. Tissue viral loads were consistently lower, lung pathology milder, and weight loss reduced in Syrian golden hamsters (Mesocricetus auratus) vaccinated intranasally with COVI-VAC compared to those inoculated with wild-type (WT) virus. COVI-VAC inoculation generated spike IgG antibody levels and plaque reduction neutralization titers similar to those in hamsters inoculated with WT virus. Upon challenge with WT virus, COVI-VAC vaccination reduced lung challenge viral titers, resulted in undetectable virus in the brain, and protected hamsters from almost all SARS-CoV-2-associated weight loss. Highly attenuated COVI-VAC is protective at a single intranasal dose in a relevant in vivo model. This, coupled with its large-scale manufacturing potential, supports its potential use in mass vaccination programs.

Phenomenological Constraints on the Transport Properties of QCD Matter with Data-Driven Model Averaging.

Using combined data from the Relativistic Heavy Ion and Large Hadron Colliders, we constrain the shear and bulk viscosities of quark-gluon plasma (QGP) at temperatures of ∼150-350 MeV. We use Bayesian inference to translate experimental and theoretical uncertainties into probabilistic constraints for the viscosities. With Bayesian model averaging we propagate an estimate of the model uncertainty generated by the transition from hydrodynamics to hadron transport in the plasma's final evolution stage, providing the most reliable phenomenological constraints to date on the QGP viscosities.

Frailty is a better predictor than age for outcomes in geriatric patients with rectal cancer undergoing proctectomy.

BACKGROUND: Both frailty and older age are risk factors for adverse surgical outcomes. We hypothesized that frailty, regardless of patient age, is a predictor of poor postoperative outcome among patients with rectal cancer undergoing proctectomy. METHODS: Patients with primary rectal cancer undergoing proctectomy between 2012 to 2015 were identified in the database of the National Quality Improvement Program. The simplified, 5-item frailty index was grouped into 0, 1, 2, and ≥3. Outcomes were morbidity and 30-day mortality. RESULTS: This study involved 9,252 patients from the National Quality Improvement Program database. Increasingly frail patients had greater morbidity and mortality (P < .001). Logistic regression revealed that frailty was a predictor of morbidity (odds ratio = 6.7, P < .0001); in contrast, older age was not associated with morbidity when adjusting for frailty (odds ratio = 1.2, P = .14). Both older age and frailty were associated with greater mortality, with frailty (odds ratio = 20.8, P < .0001) more so than older age (odds ratio = 10.3, P < .0001). CONCLUSION: Frailty was more strongly associated with morbidity and mortality than older age in patients undergoing proctectomy. Surgical options can be expanded to older patients with the use of simplified, 5-item frailty index as a decision-making tool.

Search for Electron Antineutrino Appearance in a Long-Baseline Muon Antineutrino Beam.

Electron antineutrino appearance is measured by the T2K experiment in an accelerator-produced antineutrino beam, using additional neutrino beam operation to constrain parameters of the Pontecorvo-Maki-Nakagawa-Sakata (PMNS) mixing matrix. T2K observes 15 candidate electron antineutrino events with a background expectation of 9.3 events. Including information from the kinematic distribution of observed events, the hypothesis of no electron antineutrino appearance is disfavored with a significance of 2.40σ and no discrepancy between data and PMNS predictions is found. A complementary analysis that introduces an additional free parameter which allows non-PMNS values of electron neutrino and antineutrino appearance also finds no discrepancy between data and PMNS predictions.

Steering an intense relativistic electron beam in a linear induction accelerator.

The best electron beam transport through a linear induction accelerator (LIA) is achieved when the beam is well centered on the magnetic axis of the focusing solenoids. Since the beam may be injected offset from, or at an angle to, the centerline, dipole magnets are usually provided as a means to steer the beam and center it. Steering may be accomplished by trial and error, but this is very time consuming, especially for accelerators with a low repetition rate for beam position measurements and dipole adjustments. This article presents a steering method requiring a minimal number of measurements and adjustments to position the beam at any desired location, including positioning on the centerline.

A codon-pair deoptimized live-attenuated vaccine against respiratory syncytial virus is immunogenic and efficacious in non-human primates.

Despite a critical need for a respiratory syncytial virus (RSV) vaccine and decades of development efforts, a vaccine to protect infants, elderly, and other at-risk populations from RSV infection remains elusive. We have previously generated a new, live-attenuated vaccine candidate against RSV using rational, computer-aided gene design and chemical synthesis through a process termed viral gene "deoptimization." In this study, we assessed the attenuation, immunogenicity, and efficacy of this synthetic, live-attenuated RSV vaccine candidate, RSV-MinL4.0, in African Green Monkeys. RSV-MinL4.0 was produced under good-manufacturing-practice (GMP) in Vero cells. Vaccination with RSV-MinL4.0 resulted in minimal virus shedding after vaccination, generation of robust humoral and cellular immune responses (despite the presence of baseline RSV neutralizing antibodies in one animal) that were comparable to a wildtype infection, and protection from virus shedding post-challenge with wildtype RSV. These findings demonstrate the promise of RSV-MinL4.0 as a live-attenuated vaccine which will undergo clinical trials to test its ability to safely and effectively protect pediatric and elderly populations from infection with RSV.

Familial Influences on Neuroticism and Education in the UK Biobank.

Genome-wide studies often exclude family members, even though they are a valuable source of information. We identified parent-offspring pairs, siblings and couples in the UK Biobank and implemented a family-based DNA-derived heritability method to capture additional genetic effects and multiple sources of environmental influence on neuroticism and years of education. Compared to estimates from unrelated individuals, total heritability increased from 10 to 27% and from 17 to 56% for neuroticism and education respectively by including family-based genetic effects. We detected no family environmental influences on neuroticism. The couple similarity variance component explained 35% of the variation in years of education, probably reflecting assortative mating. Overall, our genetic and environmental estimates closely replicate previous findings from an independent sample. However, more research is required to dissect contributions to the additional heritability by rare and structural genetic effects, assortative mating, and residual environmental confounding. The latter is especially relevant for years of education, a highly socially contingent variable, for which our heritability estimate is at the upper end of twin estimates in the literature. Family-based genetic effects could be harnessed to improve polygenic prediction.

Live-attenuated H1N1 influenza vaccine candidate displays potent efficacy in mice and ferrets.

Currently, influenza vaccine manufacturers need to produce 1-5 x 107 PFU of each vaccine strain to fill one dose of the current live-attenuated-influenza-vaccine (LAIV). To make a single dose of inactivated vaccine (15 ug of each hemagglutinin), the equivalent of 1010 PFU of each vaccine strains need to be grown. This high dose requirement is a major drawback for manufacturing as well as rapidly sourcing sufficient doses during a pandemic. Using our computer-aided vaccine platform Synthetic Attenuated Virus Engineering (SAVE), we created a vaccine candidate against pandemic H1N1 A/CA/07/2009 (CodaVax-H1N1) with robust efficacy in mice and ferrets, and is protective at a much lower dose than the current LAIV. CodaVax-H1N1 is currently in Phase I/II clinical trials. The hemagglutinin (HA) and neuraminidase (NA) gene segments of A/California/07/2009 (H1N1) (CA07) were "de-optimized" and a LAIV was generated ex silico using DNA synthesis. In DBA/2 mice, vaccination at a very low dose (100 or approximately 1 PFU) with CodaVax-H1N1 prevented disease after lethal challenge with wild-type H1N1. In BALB/c mice, as little as 103 PFU was protective against lethal challenge with mouse-adapted H1N1. In ferrets, CodaVax-H1N1 was more potent compared to currently licensed LAIV and still effective at a low dose of 103 PFU at preventing replication of challenge virus.

Does access to a portable ophthalmoscope improve skill acquisition in direct ophthalmoscopy? A method comparison study in undergraduate medical education.

BACKGROUND: Direct ophthalmoscopy (DO) is an essential skill for medical graduates but there are multiple barriers to learning this. Medical students and junior doctors typically lack confidence in DO. Most students do not own an ophthalmoscope and learn via ward devices that vary in design and usability. The Arclight ophthalmoscope (AO) is an easy to use, low-cost and portable device that could help address device access. This study aimed to assess the impact of personal ownership of an AO on DO skill acquisition and competency amongst medical students in the clinical environment. METHODS: Method comparison study with 42 medical students randomised to either traditional device ophthalmoscope (TDO) control or AO intervention group during an 18-week medical placement. Three objective assessments of DO competency were performed at the beginning and end of the placement: vertical cup to disc ratio (VCDR) measurement, fundus photo multiple-choice questions (F-MCQ) and model slide examination (MSE). DO examinations performed during the placement were recorded via an electronic logbook. RESULTS: Students in both groups recorded a median number of six examinations each during an eighteen-week placement. There was no statistically significant difference between the groups in any of the objective assessment measures (VCDR p = 0.561, MCQ p = 0.872, Model p = 0.772). Both groups demonstrated a minor improvement in VCDR measurement but a negative performance change in F-MCQ and MSE assessments. CONCLUSIONS: Students do not practice ophthalmoscopy often, even with constant access to their own portable device. The lack of significant difference between the groups suggests that device access alone is not the major factor affecting frequency of DO performance and consequent skill acquisition. Improving student engagement with ophthalmoscopy will require a more wide-ranging approach.

Shipboard Global Health Engagement Missions: Essential Lessons for Military Healthcare Personnel.

INTRODUCTION: Global health engagement missions are conducted to improve and protect the health of populations worldwide. Recognizing the strong link between health and security, the Armed Forces have increased the number of global health engagement missions over the last decade to support force health protection, medical readiness, enhance interoperability, improve host nation capacity building, combat global health threats (i.e., emerging infectious diseases), support humanitarian assistance and disaster relief efforts, as well as build trust and deepen professional medical relationships worldwide. These missions additionally support the US Global Health Security Agenda, US National Security Strategy, US National Defense Strategy and National Military Strategy.Although global health engagement missions are conducted by armed forces with numerous military units and geographical locations, military healthcare personnel assigned to US Naval hospital ships also perform a wide range of these missions. These missions comprise some of the largest global health engagement missions conducted, encompassing hundreds of subject matter expert exchanges, community health exchanges, medical symposiums, and side-by-side partnered healthcare in countries around the world. Military healthcare personnel who have completed past missions possess valuable knowledge related to ship-based global health engagement missions. Capturing and transferring this knowledge to future deployed personnel is important for future successful missions, but has remained a significant challenge. The purpose of this study was to capture and examine first-person accounts of experiential learning among active duty physicians, nurses, and hospital corpsmen who had participated in recent hospital ship-based global heath engagement missions. MATERIALS AND METHODS: We used the interpretive, ethnographic method of interviewing and data analysis described by Benner. Interviews elicited detailed, narrative examples of experiences from military health care personnel who had participated in previous global health engagement missions aboard hospital ships (N = 141). Our approach to gaining meaning from these narratives was guided by three central strategies: (1) identify paradigm cases, (2) identify themes within and across participant narratives of meaningful patterns, and (3) identify exemplars to represent common patterns of meaning and common situations. Additionally, we collected demographic information. RESULTS: Our findings provide firsthand descriptions of five essential elements to prepare military healthcare personnel for shipboard global health engagement missions. These essential elements are mission clarity, preparedness, experiential knowledge, lessons learned, and flexibility/adaptability. CONCLUSIONS: Widespread dissemination of the lessons learned from military global health engagement missions is crucial to shaping forces that operate effectively in a rapidly changing global environment. Sharing lessons learned increases efficiency, adaptability, and agility, while decreasing variance in processes and the need to relearn mission-specific lessons.

A qualitative study of the feasibility and acceptability of a smoking cessation program for people living with HIV and emotional dysregulation.

Despite high rates of co-occurring tobacco use and anxiety among persons living with HIV, evidence-based interventions for these individuals are limited. An existing cognitive-behavioral treatment protocol for smoking cessation and anxiety (Norton, P. J., & Barrera, T. L. (2012). Transdiagnostic versus diagnosis-specific CBT for anxiety disorders: A preliminary randomized controlled noninferiority trial. Depression and Anxiety, 29(10), 874-882. https://doi.org/10.1002/da.21974) was modified to address transdiagnostic constructs, such as anxiety sensitivity, distress tolerance, and depressive symptomatology (Labbe, A. K., Wilner, J. G., Kosiba, J. D., Gonzalez, A., Smits, J. A., Zvolensky, M. J., … O'Cleirigh, C. (2017). Demonstration of an Integrated Treatment for Smoking Cessation and Anxiety Symptoms in People with HIV: A Clinical Case Study. Cognitive and Behavioral Practice, 24(2), 200-214. https://doi.org/10.1016/j.cbpra.2016.03.009). This study examines the feasibility and acceptability of the intervention as determined from qualitative data from structured exit interviews from 10 participants who completed treatment. Results demonstrated that participants were very motivated to quit smoking and enrolled in the program for health-related reasons and to be able to quit. Participants found nearly all the treatment components to be useful for reaching their smoking cessation goal and in managing emotional dysregulation. Last, all participants stated that they would strongly recommend the treatment program. This qualitative study provides initial evidence for the feasibility and acceptability of a modified smoking cessation treatment protocol for HIV+ individuals with anxiety and emotional dysregulation. Future research will focus on evaluating the efficacy of the protocol in a full-scale randomized controlled trial, as well as working to collect qualitative data from participants who discontinue treatment to better understand reasons for treatment attrition.

Search for CP Violation in Neutrino and Antineutrino Oscillations by the T2K Experiment with 2.2×10

The T2K experiment measures muon neutrino disappearance and electron neutrino appearance in accelerator-produced neutrino and antineutrino beams. With an exposure of 14.7(7.6)×10^{20} protons on target in the neutrino (antineutrino) mode, 89 ν_{e} candidates and seven anti-ν_{e} candidates are observed, while 67.5 and 9.0 are expected for δ_{CP}=0 and normal mass ordering. The obtained 2σ confidence interval for the CP-violating phase, δ_{CP}, does not include the CP-conserving cases (δ_{CP}=0, π). The best-fit values of other parameters are sin^{2}θ_{23}=0.526_{-0.036}^{+0.032} and Δm_{32}^{2}=2.463_{-0.070}^{+0.071}×10^{-3} eV^{2}/c^{4}.

Avalanches and scaling collapse in the large-N Kuramoto model.

We study avalanches in the Kuramoto model, defined as excursions of the order parameter due to ephemeral episodes of synchronization. We present scaling collapses of the avalanche sizes, durations, heights, and temporal profiles, extracting scaling exponents, exponent relations, and scaling functions that are shown to be consistent with the scaling behavior of the power spectrum, a quantity independent of our particular definition of an avalanche. A comprehensive scaling picture of the noise in the subcritical finite-N Kuramoto model is developed, linking this undriven system to a larger class of driven avalanching systems.

Biological recognition of graphene nanoflakes.

The systematic study of nanoparticle-biological interactions requires particles to be reproducibly dispersed in relevant fluids along with further development in the identification of biologically relevant structural details at the materials-biology interface. Here, we develop a biocompatible long-term colloidally stable water dispersion of few-layered graphene nanoflakes in the biological exposure medium in which it will be studied. We also report the study of the orientation and functionality of key proteins of interest in the biolayer (corona) that are believed to mediate most of the early biological interactions. The evidence accumulated shows that graphene nanoflakes are rich in effective apolipoprotein A-I presentation, and we are able to map specific functional epitopes located in the C-terminal portion that are known to mediate the binding of high-density lipoprotein to binding sites in receptors that are abundant in the liver. This could suggest a way of connecting the materials' properties to the biological outcomes.