Custom-engineered hydrogels for delivery of human iPSC-derived neurons into the injured cervical spinal cord.

Cervical damage is the most prevalent type of spinal cord injury clinically, although few preclinical research studies focus on this anatomical region of injury. Here we present a combinatorial therapy composed of a custom-engineered, injectable hydrogel and human induced pluripotent stem cell (iPSC)-derived deep cortical neurons. The biomimetic hydrogel has a modular design that includes a protein-engineered component to allow customization of the cell-adhesive peptide sequence and a synthetic polymer component to allow customization of the gel mechanical properties. In vitro studies with encapsulated iPSC-neurons were used to select a bespoke hydrogel formulation that maintains cell viability and promotes neurite extension. Following injection into the injured cervical spinal cord in a rat contusion model, the hydrogel biodegraded over six weeks without causing any adverse reaction. Compared to cell delivery using saline, the hydrogel significantly improved the reproducibility of cell transplantation and integration into the host tissue. Across three metrics of animal behavior, this combinatorial therapy significantly improved sensorimotor function by six weeks post transplantation. Taken together, these findings demonstrate that design of a combinatorial therapy that includes a gel customized for a specific fate-restricted cell type can induce regeneration in the injured cervical spinal cord.

Age-related differences in vertical jump height and handgrip strength measurements.

PURPOSE: This study aimed to examine the effects of age on vertical jump height and handgrip strength measurements in women. A secondary aim was to investigate the correlations between vertical jump height and handgrip strength. METHODS: Twenty young (21.5 ± 2.8 years) and twenty older (67.0 ± 5.5 years) healthy women participated in this study. Handgrip contractions were used to assess strength measurements of peak force and rate of force development at different time intervals. Vertical jumps were performed on a jump mat. The jump mat measured vertical jump height based on flight time. RESULTS: The older women had lower vertical jump height (P < 0.001) and handgrip peak force (P = 0.028) and rate of force development values (P = 0.003-0.016) than the younger women. A larger difference was observed between the groups for vertical jump height (41%) than handgrip peak force and rate of force development (12-17%). Of all the strength measurements, handgrip rate of force development at 200 ms in the young (r = 0.502, P = 0.024) and older (r = 0.446, P = 0.049) women exhibited the strongest correlation with vertical jump height. CONCLUSIONS: This investigation showed significantly lower vertical jump height and handgrip peak force and rate of force development values in older compared to younger women. Interestingly, the difference between age groups was larger for jump height than handgrip peak force and rate of force development. This suggests that vertical jump performance may be more severely affected by age than handgrip strength characteristics.

Vapor Pressure versus Temperature Relations of Common Elements.

The vapor pressure values of common elements are available in the literature over a limited temperature range and the accuracy and reliability of the reported data are not generally available. We evaluate the reliability and uncertainty of the available vapor pressure versus temperature data of fifty common pure elements and recommend vapor pressure versus temperature relations. By synthesizing the vapor pressure values from measurements reported in the literature with the values computed using the Clausius Clapeyron relation beyond the boiling point, we extend the vapor pressure range from 10-8 atm to 10 atm. We use a genetic algorithm to optimize the fitting of the vapor pressure data as a function of temperature over the extended vapor pressure range for each element. The recommended vapor pressure values are compared with the corresponding literature values to examine the reliability of the recommended values.

Number Formats, Error Mitigation, and Scope for 16-Bit Arithmetics in Weather and Climate Modeling Analyzed With a Shallow Water Model.

The need for high-precision calculations with 64-bit or 32-bit floating-point arithmetic for weather and climate models is questioned. Lower-precision numbers can accelerate simulations and are increasingly supported by modern computing hardware. This paper investigates the potential of 16-bit arithmetic when applied within a shallow water model that serves as a medium complexity weather or climate application. There are several 16-bit number formats that can potentially be used (IEEE half precision, BFloat16, posits, integer, and fixed-point). It is evident that a simple change to 16-bit arithmetic will not be possible for complex weather and climate applications as it will degrade model results by intolerable rounding errors that cause a stalling of model dynamics or model instabilities. However, if the posit number format is used as an alternative to the standard floating-point numbers, the model degradation can be significantly reduced. Furthermore, mitigation methods, such as rescaling, reordering, and mixed precision, are available to make model simulations resilient against a precision reduction. If mitigation methods are applied, 16-bit floating-point arithmetic can be used successfully within the shallow water model. The results show the potential of 16-bit formats for at least parts of complex weather and climate models where rounding errors would be entirely masked by initial condition, model, or discretization error.

Discretization of the Bloch sphere, fractal invariant sets and Bell's theorem.

An arbitrarily dense discretization of the Bloch sphere of complex Hilbert states is constructed, where points correspond to bit strings of fixed finite length. Number-theoretic properties of trigonometric functions (not part of the quantum-theoretic canon) are used to show that this constructive discretized representation incorporates many of the defining characteristics of quantum systems: completementarity, uncertainty relationships and (with a simple Cartesian product of discretized spheres) entanglement. Unlike Meyer's earlier discretization of the Bloch Sphere, there are no orthonormal triples, hence the Kocken-Specker theorem is not nullified. A physical interpretation of points on the discretized Bloch sphere is given in terms of ensembles of trajectories on a dynamically invariant fractal set in state space, where states of physical reality correspond to points on the invariant set. This deterministic construction provides a new way to understand the violation of the Bell inequality without violating statistical independence or factorization, where these conditions are defined solely from states on the invariant set. In this finite representation, there is an upper limit to the number of qubits that can be entangled, a property with potential experimental consequences.

The physics of numerical analysis: a climate modelling case study.

The case is made for a much closer synergy between climate science, numerical analysis and computer science. This article is part of a discussion meeting issue 'Numerical algorithms for high-performance computational science'.

Nosocomial outbreak of measles amongst a highly vaccinated population in an English hospital setting.

In May 2017 a patient attended the emergency department at a hospital in England, with a presumed allergic reaction. He was subsequently diagnosed with measles. There were seven further confirmed cases, five of whom had received two doses of MMR vaccine. This outbreak highlights the importance of not relying on vaccination status to rule out the diagnosis of measles. Epidemiological investigations of this outbreak were particularly challenging due to the highly infectious nature of the measles virus, and prevented full elucidation of either the source of this outbreak or the transmission pathways.

The Impact of a Stochastic Parameterization Scheme on Climate Sensitivity in EC-Earth.

Stochastic schemes, designed to represent unresolved subgrid-scale variability, are frequently used in short and medium-range weather forecasts, where they are found to improve several aspects of the model. In recent years, the impact of stochastic physics has also been found to be beneficial for the model's long-term climate. In this paper, we demonstrate for the first time that the inclusion of a stochastic physics scheme can notably affect a model's projection of global warming, as well as its historical climatological global temperature. Specifically, we find that when including the "stochastically perturbed parametrization tendencies" (SPPT) scheme in the fully coupled climate model EC-Earth v3.1, the predicted level of global warming between 1850 and 2100 is reduced by 10% under an RCP8.5 forcing scenario. We link this reduction in climate sensitivity to a change in the cloud feedbacks with SPPT. In particular, the scheme appears to reduce the positive low cloud cover feedback and increase the negative cloud optical feedback. A key role is played by a robust, rapid increase in cloud liquid water with SPPT, which we speculate is due to the scheme's nonlinear interaction with condensation.

UK families with children with rare chromosome disorders: Changing experiences of diagnosis and counselling (2003-2013).

The latest United Kingdom (UK) strategy for rare diseases emphasises the need to empower affected populations to improve diagnosis, intervention, and coordination of care. Families who have a child with a rare chromosome disorder (RCD) are a challenging group to include. We report the findings of 2 large-scale surveys, undertaken by the UK RCD Support Group Unique, of these families' experiences over a 10-year period. Seven stages of the patient journey were examined. From pre-testing, through diagnosis, genetics consultation, clinical follow-up and peer support. Overall, 1158 families replied; 36.4% response rate (2003) and 53.6% (2013). Analysis of responses identifies significant differences (P < .001) over time with a decrease in results reported face to face (76%-62%), doubling by telephone (12%-22%), improved explanation of chromosome disorder (57%-75%), and increased signposting to peer support group (34%-62%). However, conduct of the consultation raises a number of important questions. Overall, 28 aspects of the patient journey are recognised as requiring improvement; only 12/28 are currently incorporated in UK service specifications. Involvement of RCD families has identified key service improvements. This approach can empower those affected by such extremely rare disorders, and also enable professionals to design improved services in partnership with "expert families." Further surveys are planned.

Experimental Non-Violation of the Bell Inequality.

A finite non-classical framework for qubit physics is described that challenges the conclusion that the Bell Inequality has been shown to have been violated experimentally, even approximately. This framework postulates the primacy of a fractal-like 'invariant set' geometry I U in cosmological state space, on which the universe evolves deterministically and causally, and from which space-time and the laws of physics in space-time are emergent. Consistent with the assumed primacy of I U , a non-Euclidean (and hence non-classical) metric g p is defined in cosmological state space. Here, p is a large but finite integer (whose inverse may reflect the weakness of gravity). Points that do not lie on I U are necessarily g p -distant from points that do. g p is related to the p-adic metric of number theory. Using number-theoretic properties of spherical triangles, the Clauser-Horne-Shimony-Holt (CHSH) inequality, whose violation would rule out local realism, is shown to be undefined in this framework. Moreover, the CHSH-like inequalities violated experimentally are shown to be g p -distant from the CHSH inequality. This result fails in the singular limit p = ∞ , at which g p is Euclidean and the corresponding model classical. Although Invariant Set Theory is deterministic and locally causal, it is not conspiratorial and does not compromise experimenter free will. The relationship between Invariant Set Theory, Bohmian Theory, The Cellular Automaton Interpretation of Quantum Theory and p-adic Quantum Theory is discussed.

Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder.

Maternal immune activation (MIA) via infection during pregnancy is known to increase risk for autism spectrum disorder (ASD). However, it is unclear how MIA disrupts fetal brain gene expression in ways that may explain this increased risk. Here we examine how MIA dysregulates rat fetal brain gene expression (at a time point analogous to the end of the first trimester of human gestation) in ways relevant to ASD-associated pathophysiology. MIA downregulates expression of ASD-associated genes, with the largest enrichments in genes known to harbor rare highly penetrant mutations. MIA also downregulates expression of many genes also known to be persistently downregulated in the ASD cortex later in life and which are canonically known for roles in affecting prenatally late developmental processes at the synapse. Transcriptional and translational programs that are downstream targets of highly ASD-penetrant FMR1 and CHD8 genes are also heavily affected by MIA. MIA strongly upregulates expression of a large number of genes involved in translation initiation, cell cycle, DNA damage and proteolysis processes that affect multiple key neural developmental functions. Upregulation of translation initiation is common to and preserved in gene network structure with the ASD cortical transcriptome throughout life and has downstream impact on cell cycle processes. The cap-dependent translation initiation gene, EIF4E, is one of the most MIA-dysregulated of all ASD-associated genes and targeted network analyses demonstrate prominent MIA-induced transcriptional dysregulation of mTOR and EIF4E-dependent signaling. This dysregulation of translation initiation via alteration of the Tsc2-mTor-Eif4e axis was further validated across MIA rodent models. MIA may confer increased risk for ASD by dysregulating key aspects of fetal brain gene expression that are highly relevant to pathophysiology affecting ASD.

Taller height as a risk factor for venous thromboembolism: a Mendelian randomization meta-analysis.

Essentials Observational data suggest taller people have a higher risk of venous thromboembolism (VTE). We used Mendelian randomization techniques to further explore this association in three studies. Risk of VTE increased by 30-40% for each 10 cm increment in height. Height was more strongly associated with deep vein thrombosis than with pulmonary embolism. SUMMARY: Background Taller height is associated with a greater risk of venous thromboembolism (VTE). Objectives To use instrumental variable (IV) techniques (Mendelian randomization) to further explore this relationship. Methods Participants of European ancestry were included from two cohort studies (Atherosclerosis Risk in Communities [ARIC] study and Cardiovascular Health Study [CHS]) and one case-control study (Mayo Clinic VTE Study [Mayo]). We created two weighted genetic risk scores (GRSs) for height; the full GRS included 668 single-nucleotide polymorphisms (SNPs) from a previously published meta-analysis, and the restricted GRS included a subset of 362 SNPs not associated with weight independently of height. Standard logistic regression and IV models were used to estimate odds ratios (ORs) for VTE per 10-cm increment in height. ORs were pooled across the three studies by the use of inverse variance-weighted random effects meta-analysis. Results Among 9143 ARIC and 3180 CHS participants free of VTE at baseline, there were 367 and 109 incident VTE events. There were 1143 VTE cases and 1292 controls included from Mayo. The pooled ORs from non-IV models and models using the full and restricted GRSs as IVs were 1.27 (95% confidence interval [CI] 1.11-1.46), 1.34 (95% CI 1.04-1.73) and 1.45 (95% CI 1.04-2.01) per 10-cm greater height, respectively. Conclusions Taller height is associated with an increased risk of VTE in adults of European ancestry. Possible explanations for this association, including taller people having a greater venous surface area, a higher number of venous valves, or greater hydrostatic pressure, need to be explored further.

Reduction in colposcopy workload and associated clinical activity following human papillomavirus (HPV) catch-up vaccination programme in Scotland: an ecological study.

OBJECTIVE: To measure patterns of clinical activity at colposcopy before and after vaccinated women entered the Scottish Cervical Screening Programme (SCSP). DESIGN: Population-based observational study using nationally collected data. SETTING: Scottish colposcopy clinics. SAMPLE: All women with a date of birth on or after 1 January 1985 who attended colposcopy in Scotland between 2008 and 2014. METHODS: Routinely collected data from the Scottish National Colposcopy Clinical Information Audit System (NCCIAS) were extracted, including: referral criteria, referral cervical cytology, colposcopic findings, clinical procedures, and histology results. Analysis was restricted to those referred to colposcopy at age 20 or 21 years. MAIN OUTCOME MEASURES: Referral criteria, positive predictive value of colposcopy, default rates, and rates of cervical biopsies and treatments. RESULTS: A total of 7372 women referred for colposcopy at age 20 or 21 years were identified. There was a downward trend in the proportion of those referred with abnormal cytology (2008/9, 91.0%; 2013/14, 90.3%; linear trend P = 0.03). Women were less likely to have diagnostic or therapeutic interventions. The proportion with no biopsy (2008/9, 19.5%; 2013/14, 26.9%; linear trend P < 0.0001) and no treatment (2008/9, 74.9%; 2013/14, 91.8%; linear trend P < 0.0001) increased over the period of observation. CONCLUSIONS: A reduction in clinical activity related to abnormal screening referrals is likely to be associated with the human papillomavirus (HPV) catch-up immunisation programme. Referral criteria and the service provision of colposcopy needs to be planned carefully, taking account of the increasing number of women who have been immunised against HPV that will be entering cervical screening programmes worldwide. TWEETABLE ABSTRACT: Colposcopy referral criteria and service planning need attention following HPV immunisation programme.

The impact of human papillomavirus type on colposcopy performance in women offered HPV immunisation in a catch-up vaccine programme: a two-centre observational study.

OBJECTIVE: To determine whether human papillomavirus (HPV) immunisation has affected the prevalence of HPV genotypes and colposcopic features of cervical intraepithelial neoplasia (CIN) in young women referred for colposcopy. DESIGN: A two-centre observational study including vaccinated and unvaccinated women. SETTING: Colposcopy clinics serving two health regions in Scotland, UK. POPULATION: A total of 361 women aged 20-25 years attending colposcopy following an abnormal cervical cytology result at routine cervical screening. METHODS: Cervical samples were obtained from women for HPV DNA genotyping and mRNA E6/E7 expression of HPV 16, 18, 31, 33, and 45. Demographic data, cytology, and histology results and colposcopic features were recorded. Chi-square analysis was conducted to identify associations between vaccine status, HPV genotypes, and colposcopic features. MAIN OUTCOME MEASURES: Colposcopic features, HPV genotypes, mRNA expression, and cervical histology. RESULTS: The prevalence of HPV 16 was significantly lower in the vaccinated group (8.6%) compared with the unvaccinated group (46.7%) (P = 0.001). The number of cases of CIN2+ was significantly lower in women who had been vaccinated (P = 0.006). The HPV vaccine did not have a statistically significant effect on commonly recognised colposcopic features, but there was a slight reduction in the positive predictive value (PPV) of colposcopy for CIN2+, from 74% (unvaccinated) to 66.7% (vaccinated). CONCLUSIONS: In this group of young women with abnormal cytology referred to colposcopy, HPV vaccination via a catch-up programme reduced the prevalence of CIN2+ and HPV 16 infection. The reduced PPV of colposcopy for the detection of CIN2+ in women who have been vaccinated is at the lower acceptable level of the UK national cervical screening programme guidelines. TWEETABLE ABSTRACT: Reduction of hrHPV positivity and CIN in immunised women consistent with lower PPV of colposcopy for CIN2+.

A personal perspective on modelling the climate system.

Given their increasing relevance for society, I suggest that the climate science community itself does not treat the development of error-free ab initio models of the climate system with sufficient urgency. With increasing levels of difficulty, I discuss a number of proposals for speeding up such development. Firstly, I believe that climate science should make better use of the pool of post-PhD talent in mathematics and physics, for developing next-generation climate models. Secondly, I believe there is more scope for the development of modelling systems which link weather and climate prediction more seamlessly. Finally, here in Europe, I call for a new European Programme on Extreme Computing and Climate to advance our ability to simulate climate extremes, and understand the drivers of such extremes. A key goal for such a programme is the development of a 1 km global climate system model to run on the first exascale supercomputers in the early 2020s.

HPV immunisation and cervical screening--confirmation of changed performance of cytology as a screening test in immunised women: a retrospective population-based cohort study.

BACKGROUND: To document the effect of bivalent HPV immunisation on cervical cytology as a screening test and assess the implications of any change, using a retrospective analysis of routinely collected data from the Scottish Cervical Screening Programme (SCSP). METHODS: Data were extracted from the Scottish Cervical Call Recall System (SCCRS), the Scottish Population Register and the Scottish Index of Multiple Deprivation. A total of 95 876 cytology records with 2226 linked histology records from women born between 1 January 1988 and 30 September 1993 were assessed. Women born in or after 1990 were eligible for the national catch-up programme of HPV immunisation. The performance of cervical cytology as a screening test was evaluated using the key performance indicators used routinely in the English and Scottish Cervical Screening Programmes (NHSCSP and SCSP), and related to vaccination status. RESULTS: Significant reductions in positive predictive value (16%) and abnormal predictive value (63%) for CIN2+ and the mean colposcopy score (18%) were observed. A significant increase (38%) in the number of women who had to be referred to colposcopy to detect one case of CIN2+ was shown. The negative predictive value of negative- or low-grade cytology for CIN2+ increased significantly (12%). Sensitivity and specificity, as used by the UK cervical screening programmes, were maintained. CONCLUSIONS: The lower incidence of disease in vaccinated women alters the key performance indicators of cervical cytology used to monitor the quality of the screening programme. These findings have implications for screening, colposcopy referral criteria, colposcopy practice and histology reporting.

HPV immunisation and increased uptake of cervical screening in Scottish women; observational study of routinely collected national data.

BACKGROUND: To measure the uptake of first invitation to cervical screening by vaccine status in a population-based cohort offered HPV immunisation in a national catch-up campaign. METHODS: A retrospective observational study of routinely collected data from the Scottish Cervical Screening Programme. Data were extracted and linked from the Scottish Cervical Call Recall System, the Scottish Population Register and the Scottish Index of Multiple Deprivation. Records from 201 023 women born between 1 January 1988 and 30 September 1993 were assessed. Women born in or after 1990 were eligible for the national catch-up programme of HPV immunisation. Attendance for screening was within 12 months of the first invitation at age 20 years. RESULTS: There was a significant decline in overall attendance from the 1988 cohort to the 1993 cohort with the adjusted attendance ratio of the 1988 cohort being 1.49 times (95% CI 1.46-1.52) that of the 1993 cohort. Immunisation compensated for this decrease in uptake with unvaccinated individuals having a reduced ratio of attendance compared with those fully vaccinated (RR=0.65, 95% CI 0.64-0.65). Not taking up the opportunity for HPV immunisation was associated with an attendance for screening below the trend line for all women before the availability of HPV immunisation. CONCLUSIONS: HPV immunisation is not associated with the reduced attendance for screening that had been feared. Immunised women in the catch-up cohorts appear to be more motivated to attend than unimmunised women, but this may be a result of a greater awareness of health issues. These results, while reassuring, may not be reproduced in routinely immunised women. Continued monitoring of attendance for the first smear and subsequent routine smears is needed.

Bell's conspiracy, Schrödinger's black cat and global invariant sets.

A locally causal hidden-variable theory of quantum physics need not be constrained by the Bell inequalities if this theory also partially violates the measurement independence condition. However, such violation can appear unphysical, implying implausible conspiratorial correlations between the hidden variables of particles being measured and earlier determinants of instrumental settings. A novel physically plausible explanation for such correlations is proposed, based on the hypothesis that states of physical reality lie precisely on a non-computational measure-zero dynamically invariant set in the state space of the universe: the Cosmological Invariant Set Postulate. To illustrate the relevance of the concept of a global invariant set, a simple analogy is considered where a massive object is propelled into a black hole depending on the decay of a radioactive atom. It is claimed that a locally causal hidden-variable theory constrained by the Cosmological Invariant Set Postulate can violate the Clauser-Horne-Shimony-Holt inequality without being conspiratorial, superdeterministic, fine-tuned or retrocausal, and the theory readily accommodates the classical compatibilist notion of (experimenter) free will.