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The role of Z-disc proteins in myopathy and cardiomyopathy
No full textThe Z-disc acts as a protein-rich structure to tether thin filament in the contractile units, the sarcomeres, of striated muscle cells. Proteins found in the Z-disc are integral for maintaining the architecture of the sarcomere. They also enable it to function as a (bio-mechanical) signalling hub. Numerous proteins interact in the Z-disc to facilitate force transduction and intracellular signalling in both cardiac and skeletal muscle. This review will focus on six key Z-disc proteins: α-actinin 2, filamin C, myopalladin, myotilin, telethonin and Z-disc alternatively spliced PDZ-motif (ZASP), which have all been linked to myopathies and cardiomyopathies. We will summarise pathogenic variants identified in the six genes coding for these proteins and look at their involvement in myopathy and cardiomyopathy. Listing the Minor Allele Frequency (MAF) of these variants in the Genome Aggregation Database (GnomAD) version 3.1 will help to critically re-evaluate pathogenicity based on variant frequency in normal population cohorts
Trans-cutaneous electrical nerve stimulation to treat dry mouth (xerostomia) following radiotherapy for head and neck cancer. A systematic review
No full textBackground
A dry mouth or xerostomia is one of the most common long-term complications following radiotherapy for head and neck cancer and has a negative impact on quality of life in cancer survivors. Transcutaneous electrical nerve stimulation (TENS) is a novel approach to improving saliva flow in these patients.
Objective
To perform a systematic review of studies evaluating TENS in the treatment of radiotherapy induced xerostomia in head and neck cancer patients.
Data collection and analysis
A comprehensive electronic search was performed in PubMed/MEDLINE, the Cochrane Library, and Google Scholar databases for appropriate published studies. The last search was conducted in January 2020. Two review authors assessed all studies identified by the search strategy and carried out data extraction.
Results
Five studies were included in the systematic review which analysed a total of 280 patients with head and neck cancer. Methodological quality and outcomes were evaluated in every study included. The outcome measure was either subjectively assessed or objectively measured. Three studies used conventional TENS therapy to stimulate parotid glands which produced a significant increase in saliva production following therapy. Two studies used acupunctured TENS type to electrically stimulate acupuncture points scattered in the body and they reported improvement in saliva production at the same level as medical treatment. No reported adverse effect of TENS was identified.
Conclusions
This systematic review confirms the safety and feasibility of TENS in the treatment of xerostomia. It is established that commencing daily TENS therapy simultaneously with radiotherapy has the most efficacy. Given the nonspecific parameters used in the included studies, further evidence is needed in order to establish optimal settings and parameters of TENS for treatment of xerostomia
The impact of age on genetic risk for common diseases
No full textInherited genetic variation contributes to individual risk for many complex diseases and is increasingly being used for predictive patient stratification. Previous work has shown that genetic factors are not equally relevant to human traits across age and other contexts, though the reasons for such variation are not clear. Here, we introduce methods to infer the form of the longitudinal relationship between genetic relative risk for disease and age and to test whether all genetic risk factors behave similarly. We use a proportional hazards model within an interval-based censoring methodology to estimate age-varying individual variant contributions to genetic relative risk for 24 common diseases within the British ancestry subset of UK Biobank, applying a Bayesian clustering approach to group variants by their relative risk profile over age and permutation tests for age dependency and multiplicity of profiles. We find evidence for age-varying relative risk profiles in nine diseases, including hypertension, skin cancer, atherosclerotic heart disease, hypothyroidism and calculus of gallbladder, several of which show evidence, albeit weak, for multiple distinct profiles of genetic relative risk. The predominant pattern shows genetic risk factors having the greatest relative impact on risk of early disease, with a monotonic decrease over time, at least for the majority of variants, although the magnitude and form of the decrease varies among diseases. As a consequence, for diseases where genetic relative risk decreases over age, genetic risk factors have stronger explanatory power among younger populations, compared to older ones. We show that these patterns cannot be explained by a simple model involving the presence of unobserved covariates such as environmental factors. We discuss possible models that can explain our observations and the implications for genetic risk prediction
Control effectiveness: a capture-the-flag study
No full textAs cybersecurity breaches continue to increase in number and cost,
and the demand for cyber-insurance rises, the ability to reason
accurately about an organisation’s residual risk is of paramount importance. Security controls are integral to risk practice and decisionmaking: organisations deploy controls in order to reduce their risk
exposure, and cyber-insurance companies provide coverage to these
organisations based on their cybersecurity posture. Therefore, in
order to reason about an organisation’s residual risk, it is critical
to possess an accurate understanding of the controls organisations
have in place and of the influence that these controls have on the
likelihood that organisations will be harmed by a cyber-incident.
Supporting evidence, however, for the effectiveness of controls is
often lacking. With the aim of enriching internal threat data, in this
article we explore a practical exercise in the form of a capture-theflag (CTF) study. We experimented with a set of security controls
and invited four professional penetration testers to solve the challenges. The results indicate that CTFs are a viable path for enriching
threat intelligence and examining security controls, enabling us to
begin to theorise about the relative effectiveness of certain risk controls on the face of threats, and to provide some recommendations
for strengthening the cybersecurity posture
Supported online self-management versus care as usual for symptoms of fatigue, pain and urgency/incontinence in adults with inflammatory bowel disease (IBD-BOOST): study protocol for a randomised controlled trial
No full textBackground
Despite being in clinical remission, many people with inflammatory bowel disease (IBD) live with fatigue, chronic abdominal pain and bowel urgency or incontinence that limit their quality of life. We aim to test the effectiveness of an online self-management programme (BOOST), developed using cognitive behavioural principles and a theoretically informed logic model, and delivered with facilitator support.
Primary research question
In people with IBD who report symptoms of fatigue, pain or urgency and express a desire for intervention, does a facilitator-supported tailored (to patient needs) online self-management programme for fatigue, pain and faecal urgency/incontinence improve IBD-related quality of life (measured using the UK-IBDQ) and global rating of symptom relief (0–10 scale) compared with care as usual?
Methods
A pragmatic two-arm, parallel group randomised controlled trial (RCT), of a 12-session facilitator-supported online cognitive behavioural self-management programme versus care as usual to manage symptoms of fatigue, pain and faecal urgency/incontinence in IBD. Patients will be recruited through a previous large-scale survey of unselected people with inflammatory bowel disease. The UK Inflammatory Bowel Disease Questionnaire and global rating of symptom relief at 6 months are the co-primary outcomes, with multiple secondary outcomes measured also at 6 and 12 months post randomisation to assess maintenance. The RCT has an embedded pilot study, health economics evaluation and process evaluation.
We will randomise 680 patients, 340 in each group. Demographic characteristics and outcome measures will be presented for both study groups at baseline. The UK-IBDQ and global rating of symptom relief at 6 and 12 months post randomisation will be compared between the study groups.
Discussion
The BOOST online self-management programme for people with IBD-related symptoms of fatigue, pain and urgency has been designed to be easily scalable and implemented. If it is shown to improve patients’ quality of life, this trial will enable clinicians and patients to make informed management decisions. This is the first trial, to our knowledge, focused on multiple symptoms prioritised by both people with IBD and health professionals.
Trial registration
ISRCTN71618461. Registered on 9 September 2019
Domain wall competition in the Chern insulating regime of twisted bilayer graphene
No full textWe consider magic-angle twisted bilayer graphene (TBG) at filling ,
where experiments have observed a robust quantized anomalous Hall effect. This
has been attributed to the formation of a valley- and spin-polarized Chern
insulating ground state that spontaneously breaks time-reversal symmetry, and
is stabilized by a hexagonal boron nitride (hBN) substrate. We identify three
different types of domain wall, and study their properties and energetic
selection mechanisms via theoretical arguments and Hartree-Fock calculations
adapted to deal with inhomogeneous moir\'e systems. We comment on the
implications of these results for transport and scanning probe experiments
Distributed acoustic sensing (DAS) for natural microseismicity studies: A case study from Antarctica
No full textIcequakes, microseismic earthquakes at glaciers, offer insights into the dynamics of ice sheets. For the first time in the Antarctic, we explore the use of fiber optic cables as Distributed Acoustic Sensors (DAS) as a new approach for monitoring basal icequakes. We present the use of DAS for studying icequakes as a case study for the application of DAS to microseismic datasets in other geological settings. Fiber was deployed on the ice surface at Rutford Ice Stream in two different configurations. We compare the performance of DAS with a conventional geophone network for: microseismic detection and location; resolving source and noise spectra; source mechanism inversion; and measuring anisotropic shear-wave splitting parameters. Both DAS array geometries detect fewer events than the geophone array. However, DAS is superior to geophones for recording the microseism signal, suggesting the applicability of DAS for ambient noise interferometry. We also present the first full-waveform source mechanism inversions using DAS anywhere, successfully showing the horizontal stick-slip nature of the icequakes. In addition, we develop an approach to use a 2D DAS array geometry as an effective multi-component sensor capable of accurately characterizing shear-wave splitting due to the anisotropic ice fabric. Although our observations originate from a glacial environment, the methodology and implications of this work are relevant for employing DAS in other microseismic environments
Associations of skeletal muscle mass and fat mass with incident cardiovascular disease and all-cause mortality: a prospective cohort study of UK Biobank participants
No full textBackground
There is debate whether body mass index is a good predictor of health outcomes because different tissues, namely skeletal muscle mass (SMM) and fat mass (FM), may be differentially associated with risk. We investigated the association of appendicular SMM (aSMM) and FM with fatal and nonfatal cardiovascular disease (CVD) and all‐cause mortality. We compared their prognostic value to that of body mass index.
Methods and Results
We studied 356 590 UK Biobank participants aged 40 to 69 years with bioimpedance analysis data for whole‐body FM and predicted limb muscle mass (to calculate aSMM). Associations between aSMM and FM with CVD and all‐cause mortality were examined using multivariable Cox proportional hazards models. Over 3 749 501 person‐years of follow‐up, there were 27 784 CVD events and 15 844 all‐cause deaths. In men, aSMM was positively associated with CVD incidence (hazard ratio [HR] per 1 SD 1.07; 95% CI, 1.06–1.09) and there was a curvilinear association in women. There were stronger positive associations between FM and CVD with HRs per SD of 1.20 (95% CI, 1.19–1.22) and 1.25 (95% CI, 1.23–1.27) in men and women respectively. Within FM tertiles, the associations between aSMM and CVD risk largely persisted. There were J‐shaped associations between aSMM and FM with all‐cause mortality in both sexes. Body mass index was modestly better at discriminating CVD risk.
Conclusions
FM showed a strong positive association with CVD risk. The relationship of aSMM with CVD risk differed between sexes, and potential mechanisms need further investigation. Body fat and SMM bioimpedance measurements were not superior to body mass index in predicting population‐level CVD incidence or all‐cause mortality
Genome editing in livestock, complicity, and the technological fix objection
No full textGenome editing in livestock could potentially be used in ways that help resolve some of the most urgent and serious global problems pertaining to livestock, including animal suffering, pollution, antimicrobial resistance, and the spread of infectious disease. But despite this potential, some may object to pursuing it, not because genome editing is wrong in and of itself, but because it is the wrong kind of solution to the problems it addresses: it is merely a ‘technological fix’ to a complex societal problem. Yet though this objection might have wide intuitive appeal, it is often not clear what, exactly, the moral problem is supposed to be. The aim of this paper is to formulate and shed some light on the ‘technological fix objection’ to genome editing in livestock. I suggest that three concerns may underlie it, make implicit assumptions underlying the concerns explicit, and cast some doubt on several of these assumptions, at least as they apply to the use of genome editing to produce pigs resistant to the Porcine Reproductive and Respiratory Syndrome and hornless dairy cattle. I then suggest that the third, and most important, concern could be framed as a concern about complicity in factory farming. I suggest ways to evaluate this concern, and to reduce or offset any complicity in factory farming. Thinking of genome editing’s contribution to factory farming in terms of complicity, may, I suggest, tie it more explicitly and strongly to the wider obligations that come with pursuing it, including the cessation of factory farming, thereby addressing the concern that technological fixes focus only on a narrow problem