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The GWAS candidate far upstream element binding protein 3 (FUBP3), is required for normal skeletal growth, and adult bone mass and strength in mice
No full textBone mineral density (BMD) and height are highly heritable traits for which hundreds of genetic loci have been linked through genome wide association studies (GWAS). FUBP3 is a DNA and RNA binding protein best characterised as a transcriptional regulator of c-Myc, but little is known about its role in vivo. Single nucleotide polymorphisms in FUBP3 at the 9q34.11 locus have been associated with BMD, fracture and height in multiple GWAS, but FUBP3 has no previously established role in the skeleton. We analysed Fubp3-deficient mice to determine the consequence of FUBP3 deficiency in vivo. Mice lacking Fubp3 had reduced survival to adulthood and impaired skeletal growth. Bone mass was decreased, most strikingly in the vertebrae, with altered trabecular micro-architecture. Fubp3 deficient bones were also weak. These data provide the first functional demonstration that Fubp3 is required for normal skeletal growth and development and maintenance of adult bone structure and strength, indicating that FUBP3 contributes to the GWAS association of 9q34.11 with variation in height, BMD and fracture
Reassessing the association between age at menarche and cardiovascular disease: observational and Mendelian randomization analyses
No full textAims
Observational studies have shown a U-shaped association between age at menarche (AAM) and cardiovascular disease (CVD). We assessed non-linearity of the observational association and the potential causal relationship between AAM and CVD using data from the European Prospective Investigation into Cancer and Nutrition—Cardiovascular Disease (EPIC-CVD) study and the UK Biobank.
Methods and results
We included women without pre-existing myocardial infarction (MI) or stroke at baseline. We estimated hazard ratios for incident MI, ischaemic and haemorrhagic stroke later in life using Cox regression in observational analyses and conducted non-linear Mendelian randomization (MR) based on fractional polynomials and linear MR based on inverse-variance weighted regression. We analysed 283 210 women with a median AAM of 13 (IQR 12–14) years in both EPIC-CVD and the UK Biobank, of which 8468 experienced a MI, 5501 an ischaemic and 1887 a haemorrhagic stroke. The association between AAM and MI and ischaemic stroke was U-shaped with higher risks in women aged ≤12 and ≥16 compared with those aged 13 years at menarche. Our MR analyses found no evidence for non-linearity between genetically proxied AAM and any CVD endpoint later in life, but each year higher genetically proxied AAM was related to a lower risk of MI (hazard ratio 0.92 [95% CI 0.86–0.99]), but not to ischaemic and haemorrhagic stroke.
Conclusion
This study supported non-linear observational associations between AAM and MI and ischaemic stroke. MR analyses suggested a causal relationship between higher AAM and risk of MI without an indication for non-linearity. There was no support for a potential causal link with ischaemic and haemorrhagic stroke
Global, regional, and national burden of suicide, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021
No full textBackground
Deaths from suicide are a tragic yet preventable cause of mortality. Quantifying the burden of suicide to understand its geographical distribution, temporal trends, and variation by age and sex is an essential step in suicide prevention. We aimed to present a comprehensive set of global, regional, and national estimates of suicide burden.
Methods
We produced estimates of the number of deaths and age-standardised mortality rates of suicide globally, regionally, and for 204 countries and territories from 1990 to 2021, and disaggregated these results by age and sex. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 estimates of deaths attributable to suicide were broken down into two comprehensive categories: those by firearms and those by other specified means. For this analysis, we also produced estimates of mean age at the time of death from suicide, incidence of suicide attempts compared with deaths, and age-standardised rates of suicide by firearm. We acquired data from vital registration, verbal autopsy, and mortality surveillance that included 23 782 study-location-years of data from GBD 2021. Point estimates were calculated from the average of 1000 randomly selected possible values of deaths from suicide by age, sex, and geographical location. 95% uncertainty intervals (UIs) were derived from the 2·5th and 97·5th percentiles from a 1000-draw distribution.
Findings
Globally, 746 000 deaths (95% UI 692 000–800 000) from suicide occurred in 2021, including 519 000 deaths (485 000–556 000) among males and 227 000 (200 000–255 000) among females. The age-standardised mortality rate has declined over time, from 14·9 deaths (12·8–15·7) per 100 000 population in 1990 to 9·0 (8·3–9·6) per 100 000 in 2021. Regionally, mortality rates due to suicide were highest in eastern Europe (19·2 [17·5–20·8] per 100 000), southern sub-Saharan Africa (16·1 [14·0–18·3] per 100 000), and central sub-Saharan Africa (14·4 [11·0–19·1] per 100 000). The mean age at which individuals died from suicide progressively increased during the study period. For males, the mean age at death by suicide in 1990 was 43·0 years (38·0–45·8), increasing to 47·0 years (43·5–50·6) in 2021. For females, it was 41·9 years (30·9–46·7) in 1990 and 46·9 years (41·2–52·8) in 2021. The incidence of suicide attempts requiring medical care was consistently higher at the regional level for females than for males. The number of deaths by suicide using firearms was higher for males than for females, and substantially varied by country and region. The countries with the highest age-standardised rate of suicides attributable to firearms in 2021 were the USA, Uruguay, and Venezuela.
Interpretation
Deaths from suicide remain variable by age and sex and across geographical locations, although population mortality rates have continued to improve globally since the 1990s. This study presents, for the first time in GBD, a quantification of the mean age at the time of suicide death, alongside comprehensive estimates of the burden of suicide throughout the world. These analyses will help guide future approaches to reduce suicide mortality that consider a public health framework for prevention
HTLV screening of blood donations in England between 2002 and 2021—comparison of screening strategies
No full textBackground
Human T-lymphotropic virus (HTLV) is associated with adult T-cell leukemia/lymphoma and myelopathy. Here we present virological and epidemiological data on HTLV screening of blood donations in England between 2002 and 2021, implemented to prevent its transmission via blood transfusion.
Methods
Data on HTLV testing of blood donations was reviewed; it was initially conducted in pools (2002–2012) and subsequently using individual samples (all donors, 2013–2016; first-time donors and non-leucodepleted component donors, 2017–2021). Data included annual number of donations screened, initial and repeat reactives as well as confirmed positives. Further information, such as likely source of infection, was obtained for HTLV-positives.
Results
Over the 20-year study period, a total of 30 679 741 blood donations were screened for HTLV in England. Under pooled screening strategy, the annual rate of repeat reactive donations remained <5:100 000. However, this rate increased to 51:100 000 with individual screening and further to 123:100 000 with selective screening. A total of 5032 samples were repeat reactive, of which 278 were confirmed HTLV-positives. Although the specificity under each scenario exceeded 99.9%, the rate of repeat reactives was around 50-fold higher in individual compared to pooled screening. Most HTLV infected were UK-born, most likely acquired their infection unknowingly through breast feeding or heterosexual intercourse with an individual associated with an HTLV-endemic country.
Conclusions
These data highlight that pooled testing can be advantageous in low-prevalence settings due to its high specificity and reduced non-specific reactivity. Whether pooling is an applicable strategy to tackle the burden of HTLV infection in resource-poor, HTLV-endemic countries requires further investigations
Institutional theories of innovation
No full textWhile institutional theory is sometimes drawn on by innovation scholars, the authors believe it has much more potential than has thus far been recognized. This chapter focuses on the usefulness of institutional theory as a theoretical lens through which innovation scholars can examine the effects of context on innovation. Institutional theory highlights the importance of social structure in shaping innovation and refocuses attention beyond the innovation process itself to the institutional context in which innovation occurs. More specifically, four topics are discussed. First, how institutions enable and constrain innovation. Second, the important role of institutions in the acceptance, diffusion, and hold-up of innovation. Third, how new organizational forms and hybrid organizations enable innovation. Finally, the insights that can be drawn from another closely related form of institutional theory that has been developed in economics, commonly referred to as ‘institutional economics.
Magnetohydrodynamic simulations of kelvin-helmholtz generated surface waves and vortices at earth’s magnetopause
No full textWhen the magnetised solar wind blows across the magnetopause, a process translates shearing momentum into rotational momentum thus driving vortices and magnetopause surface waves (MSWs) along the magnetopause. This process is called the Kelvin-Helmholtz instability (KHI) and it plays a significant role in the viscous-like mass, momentum, and energy transfer from the solar wind into the magnetosphere.
It is unclear how the plasma properties and magnetic field orientation of the solar wind influence the different evolutionary stages of the KHI. To unbiasedly analyse evolution, a formal definition of a vortex is needed. As one does not exist, a magnetohydrodynamic vortex identification technique, called , is derived which is composed of four parts: vortical momentum, density gradients, compressibility, and rotational magnetic tension. Applying this definition to a local simulation shows different drivers are more important in some stages of the KHI than others.
However, the local simulation is a simplification as a realistic magnetopause has a thickness, continuously varying plasma properties, and varying magnetic geometry. Applying to a global MHD simulation of the Sun-Earth interaction tests this and finds that the boundary thickness results in inner- and outer-modes which, as they are in different plasma, evolve differently. It is also shown the magnetic geometry limits the latitudinal extent of the vortices.
Finally, there are competing theories surrounding how the KHI influences MSW frequency. These are tested by using dynamic mode decomposition (DMD) - a machine learning technique - on the global simulation. DMD reveals that the KHI generates, amplifies, and advects MSW frequency across the magnetopause. This results in a complex superposition of frequencies at any one local time. When isolating a single frequency, it is shown that MSW wavelength is Doppler-shifted by the accelerating magnetosheath flow. These results have implications for how MSW frequencies and wavelengths are analysed.Open Acces
Hot-drawing ionic liquid-spun lignin-poly(vinyl alcohol) fibres increases strength and polymer alignment
No full textLignin is an attractive raw material for low-cost sustainable carbon fibres, however, the resulting mechanical properties require improvement before they can be implemented in composite applications. The mechanical properties of conventional polyacrylonitrile-derived carbon fibres depend critically on the molecular alignment induced in the polymer fibres by fibre drawing and on retention of the alignment during subsequent thermal treatments. In this study, alignment was induced in high lignin content fibres wet-spun from a low-cost ionic liquid water mixture by employing similar hot-drawing methods. 75/25 wt/wt% lignin–poly(vinyl alcohol) (lignin–PVA) fibres were continuously wet-spun from a 60/40 wt/wt% N,N-dimethylbutylammonium hydrogen sulfate, [DMBA][HSO4] water mixture, using deionised water used as the coagulant. Hot-drawn fibres with high draw ratios of up to 20 were generated at 180 °C. By careful selection of the initial extrusion diameter and the subsequent draw ratio, the influence of fibre diameter and draw ratio was systematically distinguished. The draw ratio was found to dominate the mechanical properties of the ductile precursor fibres, while the fibre diameter was more significant after stabilisation. The precursor fibres that experienced the highest draw ratios had tensile strengths of 235–249 MPa (up to four times higher than the undrawn lignin–PVA fibres) and tensile modulus of 7.5–8.2 GPa, while the fibre diameter was reduced from 64–106 μm to 15–23 μm. Wide-Angle X-ray Scattering (WAXS) studies showed that hot-drawing induced orientation and crystallisation of PVA at high draw ratios. The crystallisation and orientation of PVA was lost during the slow oxidative stabilisation at 250 °C, associated with a plateau at around 110 MPa tensile strength and 4 GPa tensile modulus for the stabilised lignin–PVA fibres, regardless of draw ratio. Improvements to the stabilisation aimed at retaining alignment are proposed
New insights on thaumasite precipitation based on thermodynamic modeling and 3-year exposure of cement pastes to Na₂SO₄ and MgSO₄ solutions
No full textCement pastes were exposed to 0.10 mol/L Na2SO4 and MgSO4 solutions at 20 °C for over three years to investigate the precipitation mechanism of thaumasite and the associated phase evolution. Powder X-ray diffraction, thermogravimetric analysis, Fourier-transform infrared spectroscopy, and scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy show that samples exposed to MgSO4 have lower contents of portlandite, calcite, and C-S-H, compared to those exposed to Na2SO4. In addition, samples exposed to MgSO4 contained significant amounts of thaumasite and brucite. Ettringite content is comparable in both conditions, but thaumasite is not detectable in samples exposed to Na2SO4. This difference can be attributed to the higher degree of supersaturation of thaumasite in samples exposed to MgSO4 compared to Na2SO4. Thermodynamic modelling was carried out to validate this hypothesis and the predicted phase assemblages show good consistency with experiments. By introducing a critical supersaturation into the thermodynamic phase equilibrium calculations, the model successfully reproduced the selective precipitation of thaumasite in samples exposed to MgSO4
Endoscopic excision of pre-cancerous complex colon polyps: improving outcomes and developing new endoscopic instruments/techniques
No full textWith improved access to colonoscopy services and the recent advent of the National Bowel Cancer Screening Programme, the number of complex polypectomies performed in the United Kingdom has increased significantly. Almost all complex pre-cancerous colon polyps can now be resected endoscopically, preceded by a thorough patient preparation and a careful lesion assessment. This thesis investigates the endoscopic management of complex colon polyps, including modifications to improve existing polypectomy techniques and the development of new endoscopic platforms and instruments. The thesis initially examines existing practice and includes a prospective audit of the short and long-term outcomes of piecemeal Endoscopic Mucosal resection (p-EMR) technique at a tertiary endoscopic centre. Several salvage modifications to the p-EMR technique, such as the addition of a cautious application of ablative modalities, are described to manage complex fibrotic
polyps. Post-polypectomy bleeding is the most common serious p-EMR complication and factors associated with bleeding risk along with the preclinical use of a new potential haemostatic and sealing agent are investigated.
En-bloc excision of complex colon polyps to ensure complete excision remains an important goal for the therapeutic endoscopist. A main body of the work in this thesis describes the development of a new device for endoscopic submucosal dissection (ESD) incorporating novel design and electrosurgical properties. The development of combined endoscopic/surgical platform is also described to improve access and facilitate the radical treatment of complex rectal polyps. Finally, to approach the management of complex colorectal polyps in a “holistic way”, a clinical service enhancement, the polyp multi-disciplinary meeting has been initiated and evaluated.Open Acces
Predicting the hydration of ground granulated blast furnace slag and recycled glass blended cements
No full textThe use of recycled glass powder (RCGP) is investigated as a partial replacement for ground granulated blast furnace slag in blended CEM II/A-LL cements using thermodynamic modelling to simulate cement paste hydration at a water-to-cement (w/c) ratio of 0.5. This study allows a rapid means of examining the likely evolution of these materials over the first two to three years, allowing experimental work to focus on promising formulations. A comparison is made between the evolving solid phase and solution chemistries of four materials: a standard Portland-limestone (CEM II/A-LL), a ‘control’ blend, comprising equal quantities of CEM II/A-LL with GGBS and two novel blended cements containing RCGP. These represent 15% replacement (by mass) of GGBS by RCGP blended with either 40% or 60% CEM II/A-LL. The simulations were performed using the code HYDCEM, a cement hydration simulator, which calls on the thermodynamic model PHREEQC to sequentially simulate the evolution of the four cements. The results suggest that partial replacement of GGBS by 15% RCGP results in no significant change in system chemistry. The partial replacement of cementitious slag by waste container glass provides a route by which this material can be diverted from the landfill inventory, and the mass-balance and energy balance implications will be reported elsewhere