AAV-DJ, a leading candidate vector for liver gene therapy, was created through random homologous recombination followed by directed evolution, selecting for in vivo liver tropism and resistance to ...in vitro immune neutralization. Here, the 4.5 Å resolution cryo-EM structure is determined for the engineered AAV vector, revealing structural features that illuminate its phenotype. The heparan sulfate receptor-binding site is little changed from AAV-2, and heparin-binding affinity is similar. A loop that is antigenic in other serotypes has a unique conformation in AAV-DJ that would conflict with the binding of an AAV-2 neutralizing monoclonal antibody. This is consistent with increased resistance to neutralization by human polyclonal sera, raising the possibility that changed tropism may be a secondary effect of altered immune interactions. The reconstruction exemplifies analysis of fine structural changes and the potential of cryo-EM, in favorable cases, to characterize mutant or ligand-bound complexes.
Display omitted
► The 4.5 Åcryo-EM structure of AAV-DJ fully resolves the polypeptide backbone ► Liver tropism selected for in AAV-DJ has not changed the heparin binding site ► Changed conformation in an antigenic loop blocks binding of a neutralizing mAb ► Changed in vivo tropism may result from changed immune interactions
AAV-DJ is an engineered adeno-associated virus (AAV) vector and a leading candidate for liver gene therapy. Here, Lerch et al. report a 4.5Å resolution cryo-EM structure of AAV-DJ, revealing structural features that underscore its unique phenotype. The reconstruction exemplifies potential of cryo-EM to analyze fine structural changes.
Stressor events can be highly emotional and disruptive to our functioning, yet they also present opportunities for learning and growth via self‐reflections. Self‐distanced reflections in which one ...reasons about target events in ways that maximise their removal of the current self from the experiential reality are said to facilitate this reflective process. We tested the expectation that self‐distanced reflections offer an advantage over self‐immersed vistas via a pre‐registered systematic review of seven electronic databases (Scopus, Medline, Web of Science, PsycInfo, CINAHL Plus, Embase, and ProQuest Dissertations and Theses Global) to identify experimental tests with adults aged 18–65 years where the focus of the reflection was a stressor or adverse event that participants had already experienced. A three‐level, random effects meta‐analysis of 25 experiments (N = 2,397, 68 effects) revealed a small‐to‐moderate advantage of self‐distanced reflections (g = 0.19, SE = 0.07, 95% CI 0.05, 0.33) and were most effective when they targeted a stressor experience that emphasised one's emotional state or lifetime. Nevertheless, our assessment of the overall quality of evidence including risk of bias suggested uncertainty regarding the benefit of this pragmatic self‐regulatory tactic and therefore the need for future high‐powered, high‐quality experiments.
This study extends recent coach stress research by evaluating how coaches perceive their stress experiences to affect athletes, and the broader coach-athlete relationship. A total of 12 coaches ...working across a range of team sports at the elite level took part in semi-structured interviews to investigate the 3 study aims: how they perceive athletes to detect signals of coach stress; how they perceive their stress experiences to affect athletes; and, how effective they perceive themselves to be when experiencing stress. Following content analysis, data suggested that coaches perceived athletes able to detect when they were experiencing stress typically via communication, behavioural, and stylistic cues. Although coaches perceived their stress to have some positive effects on athletes, the overwhelming effects were negative and affected "performance and development", "psychological and emotional", and "behavioural and interaction" factors. Coaches also perceived themselves to be less effective when stressed, and this was reflected in their perceptions of competence, self-awareness, and coaching quality. An impactful finding is that coaches are aware of how a range of stress responses are expressed by themselves, and to how they affect athletes, and their coaching quality. Altogether, findings support the emerging view that coach stress affects their own, and athlete performance.
ABSTRACT
We measure the small-scale clustering of the Data Release 16 extended Baryon Oscillation Spectroscopic Survey Luminous Red Galaxy sample, corrected for fibre-collisions using Pairwise ...Inverse Probability weights, which give unbiased clustering measurements on all scales. We fit to the monopole and quadrupole moments and to the projected correlation function over the separation range $7-60\, h^{-1}{\rm Mpc}$ with a model based on the aemulus cosmological emulator to measure the growth rate of cosmic structure, parametrized by fσ8. We obtain a measurement of fσ8(z = 0.737) = 0.408 ± 0.038, which is 1.4σ lower than the value expected from 2018 Planck data for a flat ΛCDM model, and is more consistent with recent weak-lensing measurements. The level of precision achieved is 1.7 times better than more standard measurements made using only the large-scale modes of the same sample. We also fit to the data using the full range of scales $0.1\text{--}60\, h^{-1}{\rm Mpc}$ modelled by the aemulus cosmological emulator and find a 4.5σ tension in the amplitude of the halo velocity field with the Planck + ΛCDM model, driven by a mismatch on the non-linear scales. This may not be cosmological in origin, and could be due to a breakdown in the Halo Occupation Distribution model used in the emulator. Finally, we perform a robust analysis of possible sources of systematics, including the effects of redshift uncertainty and incompleteness due to target selection that were not included in previous analyses fitting to clustering measurements on small scales.
Randomized clinical trials (RCTs) support the use of prehospital plasma in traumatic hemorrhagic shock, especially in long transports. The citrate added to plasma binds with calcium, yet most ...prehospital trauma protocols have no guidelines for calcium replacement. We reviewed the experience of two recent prehospital plasma RCTs regarding admission ionized-calcium (i-Ca) blood levels and its impact on survival. We hypothesized that prehospital plasma is associated with hypocalcemia, which in turn is associated with lower survival.
We studied patients enrolled in two institutions participating in prehospital plasma RCTs (control, standard of care; experimental, plasma), with i-Ca collected before calcium supplementation. Adults with traumatic hemorrhagic shock (systolic blood pressure ≤70 mm Hg or 71-90 mm Hg + heart rate ≥108 bpm) were eligible. We use generalized linear mixed models with random intercepts and Cox proportional hazards models with robust standard errors to account for clustered data by institution. Hypocalcemia was defined as i-Ca of 1.0 mmol/L or less.
Of 160 subjects (76% men), 48% received prehospital plasma (median age, 40 years interquartile range, 28-53 years) and 71% suffered blunt trauma (median Injury Severity Score ISS, 22 interquartile range, 17-34). Prehospital plasma and control patients were similar regarding age, sex, ISS, blunt mechanism, and brain injury. Prehospital plasma recipients had significantly higher rates of hypocalcemia compared with controls (53% vs. 36%; adjusted relative risk, 1.48; 95% confidence interval CI, 1.03-2.12; p = 0.03). Severe hypocalcemia was significantly associated with decreased survival (adjusted hazard ratio, 1.07; 95% CI, 1.02-1.13; p = 0.01) and massive transfusion (adjusted relative risk, 2.70; 95% CI, 1.13-6.46; p = 0.03), after adjustment for confounders (randomization group, age, ISS, and shock index).
Prehospital plasma in civilian trauma is associated with hypocalcemia, which in turn predicts lower survival and massive transfusion. These data underscore the need for explicit calcium supplementation guidelines in prehospital hemotherapy.
Therapeutic, level II.
A universal multistage cascade CSTR has been developed that is suitable for a wide range of continuous-flow processes. Coined by our group the “Freactor” (free-to-access reactor), the new reactor ...integrates the efficiency of pipe-flow processing with the advanced mixing of a CSTR, delivering a general “plug-and-play” reactor platform which is well-suited to multiphasic continuous-flow chemistry. Importantly, the reactor geometry is easily customized to accommodate reactions requiring long residence times (≥3 h tested).
STUDY QUESTION
Have ART live birth rates improved in Australia over the last 12 years?
SUMMARY ANSWER
There were striking improvements in per-cycle live birth rates observed for frozen/thaw embryo ...transfers, blastocyst transfer and single embryo transfer (SET), while live birth rates following ICSI were lower than IVF for non-male factor infertility in most years.
WHAT IS ALREADY KNOWN
ART and associated techniques have become the predominant treatment of infertility over the past 30 years in most developed countries. However, there are differences in ART laboratory and clinical practices, and success rates worldwide. Australia has one of the highest ART utilization rates and lowest multiple birth rates in the world, thus providing a unique setting to investigate the contribution of common ART strategies in an unrestricted population of patients to ART success rates.
STUDY DESIGN, SIZE, DURATION
A retrospective cohort study of 585 065 ART treatment cycles performed in Australia between 2002 and 2013 using the Australian and New Zealand Assisted Reproduction Database (ANZARD).
PARTICIPANTS MATERIALS, SETTING, METHOD
An unrestricted population of all women who underwent autologous ART treatment between 2002 and 2013. Visual descriptive analysis was used to assess the trends in ART procedures by the calendar years. Adjusted odds ratios (aORs) of a live birth for four common ART techniques were calculated after controlling for important confounders including female age, infertility diagnosis, stage of the embryo (blastocyst versus cleavage stage), type of embryo (fresh versus thawed), fertilization method (IVF versus ICSI) and number of embryos transferred (SET versus multiple embryos).
MAIN RESULTS AND THE ROLE OF CHANCE
The overall live birth rate per embryo transfer increased from 19.2% in 2002 to 23.3% in 2013 (21.9–24.3% for fresh embryo transfers and 14.6–23.3% for frozen/thaw embryo transfers). This occurred concurrently with an increase in SET from 29.7% to 78.9%, and an increase in the average age of women undergoing treatment from 35.0 to 35.9 years. Individuals who had a frozen/thaw embryo transfer cycle in 2002 had 43% (aOR: 0.57, 95% CI: 0.53–0.61) reduced odds of a live birth compared with a fresh embryo transfer cycle. This contrasted with 16% (aOR: 0.84, 95% CI: 0.80–0.98) reduced odds of a live birth from frozen/thaw embryo transfer cycles in 2013. In 2013, the odds of blastocyst transfer resulting in a live birth were more than twice as great as for cleavage stage transfer (aOR 2.01, 95% CI: 1.92–2.11). The adjusted odds of live birth per SET compared with multiple embryo transfer increased significantly over the last 12 years, from a 38% reduced odds of a live birth follow SET in 2002 (aOR: 062, 95% CI: 0.57–0.67) compared to an 8% reduced odds in 2013 (aOR: 0.92, 95% CI: 0.87–0.98). The aOR of a live birth using ICSI compared to IVF in non-male factor patients was lower in most years bringing into question its widespread use.
LIMITATION, REASONS FOR CAUTION
This is a retrospective cohort analysis and cannot confirm causality. High-level evidence on the effectiveness of particular ART techniques, particularly ICSI and blastocyst culture, requires prospective randomized controlled trials or detailed statistical analysis using large-scale data that counts for fertilization failure, embryo loss, prognostic factors and cycle characteristics.
WIDER IMPLICATION OF THE FINDINGS
The most striking improvements in ART success rates in Australia have been observed for frozen/thaw embryo transfers, blastocyst transfer and SET. Further studies of the role of ICSI in non-male factor infertility and blastocyst transfer success rates that take into account embryo loss are needed.
STUDY FUNDING/COMPETING INTEREST(S)
No funding was received to undertake this study. The authors declare that they do not have competing interests with this study.
TRIAL REGISTRATION NUMBER
NA.
Spontaneous symmetry breaking occurs in a physical system whenever the ground state does not share the symmetry of the underlying theory, e.g., the Hamiltonian. This mechanism gives rise to massless ...Nambu–Goldstone modes and massive Anderson–Higgs modes. These modes provide a fundamental understanding of matter in the Universe and appear as collective phase or amplitude excitations of an order parameter in a many-body system. The amplitude excitation plays a crucial role in determining the critical exponents governing universal nonequilibrium dynamics in the Kibble–Zurek mechanism (KZM). Here, we characterize the amplitude excitations in a spin-1 condensate and measure the energy gap for different phases of the quantum phase transition. At the quantum critical point of the transition, finite-size effects lead to a nonzero gap. Our measurements are consistent with this prediction, and furthermore, we demonstrate an adiabatic quench through the phase transition, which is forbidden at the mean field level. This work paves the way toward generating entanglement through an adiabatic phase transition.
Objective To investigate the impact of meiotic spindle normality on live birth rates in women with recurrent IVF failure. Design A retrospective comparative study. Setting A large private sector IVF ...service in Sydney, Australia. Patient(s) Five hundred five intracytoplasmic sperm injection (ICSI)/ET cycles of patients who fulfilled the criteria for recurrent IVF failure, three or more previous fresh or frozen ETs with no ongoing pregnancy. Intervention(s) Polarized light microscopy was used at the time of ICSI. Main Outcome Measure(s) Clinical pregnancy rates (PR) and live birth rates (LBR) were compared depending on the morphology of the meiotic spindle of the oocyte(s) from which the embryo(s) were transferred. Result(s) Women receiving embryos where at least one was derived from a normally spindled oocyte had significantly increased clinical PR and LBR when compared with those who had only embryos derived from abnormally spindled oocytes (clinical PR: 31% vs. 7%; odds ratio OR, 6.45; 95% confidence interval CI 3.65–11.40) and (LBR: 24% vs. 4%; OR, 7.24; 95% CI 3.62–14.49). Comparison between the abnormal spindle groups showed significantly higher clinical PR and LBR from the group of patients receiving embryos where at least one was derived from an oocyte with no visible spindle compared with the group receiving embryos from dysmorphic spindles only (clinical PR: 9% vs. 6%; OR, 0.58; 95% CI 0.22–1.57 and LBR: 8% vs. 1%; OR, 0.16; 95% CI 0.03–0.77). Conclusion(s) Normally spindled oocytes, as determined by polarized light microscopy, are associated with significantly higher clinical PRs in patients with recurrent IVF failure.
PDF
