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.

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.

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.

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.

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.

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.

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.

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.

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}.

Temporal and external validation of a prediction model for adverse outcomes among inpatients with diabetes.

AIM: To temporally and externally validate our previously developed prediction model, which used data from University Hospitals Birmingham to identify inpatients with diabetes at high risk of adverse outcome (mortality or excessive length of stay), in order to demonstrate its applicability to other hospital populations within the UK. METHODS: Temporal validation was performed using data from University Hospitals Birmingham and external validation was performed using data from both the Heart of England NHS Foundation Trust and Ipswich Hospital. All adult inpatients with diabetes were included. Variables included in the model were age, gender, ethnicity, admission type, intensive therapy unit admission, insulin therapy, albumin, sodium, potassium, haemoglobin, C-reactive protein, estimated GFR and neutrophil count. Adverse outcome was defined as excessive length of stay or death. RESULTS: Model discrimination in the temporal and external validation datasets was good. In temporal validation using data from University Hospitals Birmingham, the area under the curve was 0.797 (95% CI 0.785-0.810), sensitivity was 70% (95% CI 67-72) and specificity was 75% (95% CI 74-76). In external validation using data from Heart of England NHS Foundation Trust, the area under the curve was 0.758 (95% CI 0.747-0.768), sensitivity was 73% (95% CI 71-74) and specificity was 66% (95% CI 65-67). In external validation using data from Ipswich, the area under the curve was 0.736 (95% CI 0.711-0.761), sensitivity was 63% (95% CI 59-68) and specificity was 69% (95% CI 67-72). These results were similar to those for the internally validated model derived from University Hospitals Birmingham. CONCLUSIONS: The prediction model to identify patients with diabetes at high risk of developing an adverse event while in hospital performed well in temporal and external validation. The externally validated prediction model is a novel tool that can be used to improve care pathways for inpatients with diabetes. Further research to assess clinical utility is needed.

Content of First Prenatal Visits.

Objective The purpose of this study was to examine the content of the first prenatal visit within an academic medical center clinic and to compare the topics discussed to 2014 American College of Obstetrics and Gynecologists guidelines for the initial prenatal visit. Methods Clinical interactions were audio recorded and transcribed (n = 30). A content analysis was used to identify topics discussed during the initial prenatal visit. Topics discussed were then compared to the 2014 ACOG guidelines for adherence. Coded data was queried though the qualitative software and reviewed for accuracy and content. Results First prenatal visits included a physician, nurse practitioner, nurse midwife, medical assistant, medical students, or a combination of these providers. In general, topics that were covered in most visits and closely adhered to ACOG guidelines included vitamin supplementation, laboratory testing, flu vaccinations, and cervical cancer screening. Topics discussed less often included many components of the physical examination, education about pregnancy, and screening for an identification of psychosocial risk. Least number of topics covered included prenatal screening. Conclusions for Practice While the ACOG guidelines may include many components that are traditional in addition to those based on evidence, the guidelines were not closely followed in this study. Identifying new ways to disseminate information during the time constrained initial prenatal visit are needed to ensure improved patient outcomes.

Combined Analysis of Neutrino and Antineutrino Oscillations at T2K.

T2K reports its first results in the search for CP violation in neutrino oscillations using appearance and disappearance channels for neutrino- and antineutrino-mode beams. The data include all runs from January 2010 to May 2016 and comprise 7.482×10^{20} protons on target in neutrino mode, which yielded in the far detector 32 e-like and 135 µ-like events, and 7.471×10^{20} protons on target in antineutrino mode, which yielded 4 e-like and 66 µ-like events. Reactor measurements of sin^{2}2θ_{13} have been used as an additional constraint. The one-dimensional confidence interval at 90% for the phase δ_{CP} spans the range (-3.13, -0.39) for normal mass ordering. The CP conservation hypothesis (δ_{CP}=0, π) is excluded at 90% C.L.

Cobalt hydroxide nanoflakes and their application as supercapacitors and oxygen evolution catalysts.

Finding alternative routes to access and store energy has become a major issue recently. Transition metal oxides have shown promising behaviour as catalysts and supercapacitors. Recently, liquid exfoliation of bulk metal oxides appears to be an effective route which provides access to two-dimensional (2D) nano-flakes, the size of which can be easily selected. These 2D materials exhibit excellent electrochemical charge storage and catalytic activity for the oxygen evolution reaction. In this study, various sized selected cobalt hydroxide nano-flake materials are fabricated by this time efficient and highly reproducible process. Subsquently, the electrochemical properties of the standard size Co(OH)2 nanoflakes were investigated. The oxide modified electrodes were prepared by spraying the metal oxide flake suspension onto a porous conductive support electrode foam, either glassy carbon or nickel. The cobalt hydroxide/nickel foam system was found to have an overpotential value at 10 mA cm-2 in 1 M NaOH as low as 280 mV and an associated redox capacitance exhibiting numerical values up to 1500 F g-1, thereby making it a viable dual use electrode.

Light scattering and random lasing in aqueous suspensions of hexagonal boron nitride nanoflakes.

Liquid phase exfoliation allows large scale production of 2D materials in solution. The particles are highly anisotropic and strongly scatter light. While spherical particles can be accurately and precisely described by a single parameter-the radius, 2D nanoflakes, however, cannot be so easily described. We investigate light scattering in aqueous solutions of 2D hexagonal boron nitride nanoflakes in the single and multiple scattering regimes. In the single scattering regime, the anisotropic 2D materials show a much stronger depolarization of light when compared to spherical particles of similar size. In the multiple scattering regime, the scattering as a function of optical path for hexagonal boron nitride nanoflakes of a given lateral length was found to be qualitatively equivalent to scattering from spheres with the same diameter. We also report the presence of random lasing in high concentration suspensions of aqueous h-BN mixed with Rhodamine B dye. The h-BN works as a scattering agent and Rhodamine B as a gain medium for the process. We observed random lasing at 587 nm with a threshold energy of 0.8 mJ.

Measurement of Coherent π

We report the first measurement of the flux-averaged cross section for charged current coherent π^{+} production on carbon for neutrino energies less than 1.5 GeV, and with a restriction on the final state phase space volume in the T2K near detector, ND280. Comparisons are made with predictions from the Rein-Sehgal coherent production model and the model by Alvarez-Ruso et al., the latter representing the first implementation of an instance of the new class of microscopic coherent models in a neutrino interaction Monte Carlo event generator. We observe a clear event excess above background, disagreeing with the null results reported by K2K and SciBooNE in a similar neutrino energy region. The measured flux-averaged cross sections are below those predicted by both the Rein-Sehgal and Alvarez-Ruso et al.

Measurement of Muon Antineutrino Oscillations with an Accelerator-Produced Off-Axis Beam.

T2K reports its first measurements of the parameters governing the disappearance of ν[over ¯]_{µ} in an off-axis beam due to flavor change induced by neutrino oscillations. The quasimonochromatic ν[over ¯]_{µ} beam, produced with a peak energy of 0.6 GeV at J-PARC, is observed at the far detector Super-Kamiokande, 295 km away, where the ν[over ¯]_{µ} survival probability is expected to be minimal. Using a data set corresponding to 4.01×10^{20} protons on target, 34 fully contained µ-like events were observed. The best-fit oscillation parameters are sin^{2}(θ[over ¯]_{23})=0.45 and |Δm[over ¯]_{32}^{2}|=2.51×10^{-3} eV^{2} with 68% confidence intervals of 0.38-0.64 and 2.26-2.80×10^{-3} eV^{2}, respectively. These results are in agreement with existing antineutrino parameter measurements and also with the ν_{µ} disappearance parameters measured by T2K.

Standardization of definitions in focal therapy of prostate cancer: report from a Delphi consensus project.

PURPOSE: To reach standardized terminology in focal therapy (FT) for prostate cancer (PCa). METHODS: A four-stage modified Delphi consensus project was undertaken among a panel of international experts in the field of FT for PCa. Data on terminology in FT was collected from the panel by three rounds of online questionnaires. During a face-to-face meeting on June 21, 2015, attended by 38 experts, all data from the online rounds were reviewed and recommendations for definitions were formulated. RESULTS: Consensus was attained on 23 of 27 topics; Targeted FT was defined as a lesion-based treatment strategy, treating all identified significant cancer foci; FT was generically defined as an anatomy-based (zonal) treatment strategy. Treatment failure due to the ablative energy inadequately destroying treated tissue is defined as ablation failure. In targeting failure the energy is not adequately applied to the tumor spatially and selection failure occurs when a patient was wrongfully selected for FT. No definition of biochemical recurrence can be recommended based on the current data. Important definitions for outcome measures are potency (minimum IIEF-5 score of 21), incontinence (new need for pads or leakage) and deterioration in urinary function (increase in IPSS >5 points). No agreement on the best quality of life tool was established, but UCLA-EPIC and EORTC-QLQ-30 were most commonly supported by the experts. A complete overview of statements is presented in the text. CONCLUSION: Focal therapy is an emerging field of PCa therapeutics. Standardization of definitions helps to create comparable research results and facilitate clear communication in clinical practice.

Revealing the nature of excitons in liquid exfoliated monolayer tungsten disulphide.

Transition metal dichalcogenides (TMD) hold promise for applications in novel optoelectronic devices. There is therefore a need for materials that can be obtained in large quantities and with well understood optical properties. In this report, we present thorough photoluminescence (PL) investigations of monolayer tungsten disulphide obtained via liquid phase exfoliation. As shown by microscopy studies, the exfoliated nanosheets have dimensions of tens of nanometers and thickness of 2.5 monolayers on average. The monolayer content is about 20%. Our studies show that at low temperature the PL is dominated by excitons localized on nanosheet edges. As a consequence, the PL is strongly sensitive to the environment and exhibits an enhanced splitting in magnetic field. As the temperature is increased, the excitons are thermally excited out of the defect states and the dominant transition is that of the negatively charged exciton. Furthermore, upon excitation with a circularly polarized light, the PL retains a degree of polarization reaching 50% and inherited from the valley polarized photoexcited excitons. The studies of PL dynamics reveal that the PL lifetime is on the order of 10 ps, which is probably limited by non-radiative processes. Our results underline the potential of liquid exfoliated TMD monolayers in large scale optoelectronic devices.

TOOKAD® Soluble focal therapy: pooled analysis of three phase II studies assessing the minimally invasive ablation of localized prostate cancer.

PURPOSE: To evaluate the 6-month effects of the recommended drug and light dosage in focal vascular-targeted photodynamic therapy (VTP) using TOOKAD(®) Soluble in patients with localized prostate cancer (LPCa). METHODS: We performed a pooled analysis of 117 men with LPCa, PSA <10 ng/mL, and Gleason score ≤ 7 (3 + 4), from 3 studies who received a 10-min intravenous infusion of a single dose of 4 mg/kg TOOKAD(®) Soluble, activated by a 753-nm light at 200 J/cm delivered in the prostate by transperineal fibres under transrectal ultrasound guidance. Primary endpoint was 6-month negative biopsies in the treated lobe(s). PSA was measured at month 1, 3, and 6. Magnetic resonance imaging was performed at day 7, month 3, and 6. International Prostate Symptom Score (IPSS), International Index of Erectile Function (IIEF-5) and adverse events were reported at day 7, month 1, 3, and 6. RESULTS: Month 6 negative biopsy rate was 68.4 % in the overall evaluable population (N = 114) and 80.6 % for patients treated by hemiablation with light density index (LDI) ≥ 1 (N = 67). Mean prostate necroses at week-1 were 76.5 and 86.3 %, respectively. In both groups, PSA levels at month 6 decreased by 2.0 ng/mL. Small changes from baseline for IPSS and IIEF-5 indicated a slight improvement in urinary function and a slight deterioration in sexual function. CONCLUSIONS: Focal VTP treatment with TOOKAD(®) Soluble at 4 mg/kg and 200 J/cm resulted in a negative 6-month biopsy rate of 68.4 % for the whole population and 80.6 % for patients treated by hemiablation with LDI ≥ 1. The treatment was well tolerated. Two phase III studies will reach completion in early 2015.