Cross infection control measures and the treatment of patients at risk of Creutzfeldt Jakob disease in UK general dental practice

AIMS: To determine the suitability of key infection control measures currently employed in UK dental practice for delivery of dental care to patients at risk of prion diseases. MATERIALS AND METHODS: Subjects: Five hundred dental surgeons currently registered with the General Dental Council of the UK. Data collection: Structured postal questionnaire. Analysis: Frequencies, cross-tabulations and chi-squared analysis. RESULTS: The valid response rate to the questionnaire was 69%. 33% of practices had no policy on general disinfection and sterilisation procedures. Only 10 of the 327 responding practices (3%) possessed a vacuum autoclave. 49% of dentists reported using the BDA medical history form but less than 25% asked the specific questions recommended by the BDA to identify patients at risk of iatrogenic or familial CJD. However, 63% of practitioners would refer such patients, if identified, to a secondary care facility. Of the 107 practitioners who were prepared to provide dental treatment, 75 (70%) would do so using routine infection control procedures. CONCLUSIONS: Most of the dental practices surveyed were not actively seeking to identify patients at risk of prion diseases. In many cases, recommended procedures for providing safe dental care for such patients were not in place

The Functional Domains of PHLDA1: Modulation of Intracellular Localization Impacts Apoptotic Cell Death

Pleckstrin homology like domain family A, member 1 (PHLDA1) is a member of the PHLDA family of homologous proteins recognized for their role in apoptotic cell death. PHLDA1 was first reported as a proapoptotic factor involved in Fas-mediated T-cell apoptosis. The role of this protein with regards to apoptosis remains poorly understood, with literature demonstrating both proapoptotic and antiapoptotic functions in a cell and/or pathway specific manner. Intracellular localization may account for the apoptotic potential of this protein, with nuclear accumulation of PHLDA1 increasing its apoptotic potential. We hypothesize that the functional regions of PHLDA1 including its localization signals (pNLS/pNES), pleckstrin homology like domain (PHLD), and PQ region direct cellular localization of PHLDA1, thereby regulating its apoptotic potential. In this thesis, well-established molecular and cellular approaches were utilized to better define the functional regions within PHLDA1 and to gain further understanding of the role of its localization on apoptosis. Using an EGFP fusion construct and leptomycin B, we confirmed that PHLDA1 contains a weak, CRM1-responsive NES. Using an EGFP-β-galactosidase fusion protein we examined the putative NLS of PHLDA1 and determined that it was not sufficient to direct nuclear localization. However, the PHLD was found to direct cellular localization, mirroring the distribution and punctate patterning of full length PHLDA1. Evidence of association of the PHLD with the membrane was confirmed using fluorescence and electron microscopy, and changes in cell morphology indicative of EMT were apparent following overexpression of the PHLD. Although previous reports have suggested that the PQ region of PHLDA1 is responsible for its proapoptotic function, its cellular localization was not clearly defined. Nuclear accumulation of the PQ region was found to be highly cytotoxic, indicating that it is sufficient to induce apoptosis and that its proapoptotic activity occurs within the nucleus. The findings of this thesis provide fresh insight into the functional regions of PHLDA1 and their respective contributions to the protein’s intracellular localization and apoptotic function, demonstrating that localization dictates the apoptotic potential of PHLDA1. This data provides a solid foundation for identifying the cellular mechanisms by which PHLDA1 influences the progression of chronic human diseases including diabetes, cancer and obesity.Master of Science (MSc

Monotonicity of Fitness Landscapes and Mutation Rate Control

A common view in evolutionary biology is that mutation rates are minimised. However, studies in combinatorial optimisation and search have shown a clear advantage of using variable mutation rates as a control parameter to optimise the performance of evolutionary algorithms. Much biological theory in this area is based on Ronald Fisher's work, who used Euclidean geometry to study the relation between mutation size and expected fitness of the offspring in infinite phenotypic spaces. Here we reconsider this theory based on the alternative geometry of discrete and finite spaces of DNA sequences. First, we consider the geometric case of fitness being isomorphic to distance from an optimum, and show how problems of optimal mutation rate control can be solved exactly or approximately depending on additional constraints of the problem. Then we consider the general case of fitness communicating only partial information about the distance. We define weak monotonicity of fitness landscapes and prove that this property holds in all landscapes that are continuous and open at the optimum. This theoretical result motivates our hypothesis that optimal mutation rate functions in such landscapes will increase when fitness decreases in some neighbourhood of an optimum, resembling the control functions derived in the geometric case. We test this hypothesis experimentally by analysing approximately optimal mutation rate control functions in 115 complete landscapes of binding scores between DNA sequences and transcription factors. Our findings support the hypothesis and find that the increase of mutation rate is more rapid in landscapes that are less monotonic (more rugged). We discuss the relevance of these findings to living organisms

Polymorphisms in the WNK1 gene are asociated with blood pressure variation and urinary potassium excretion

WNK1 - a serine/threonine kinase involved in electrolyte homeostasis and blood pressure (BP) control - is an excellent candidate gene for essential hypertension (EH). We and others have previously reported association between WNK1 and BP variation. Using tag SNPs (tSNPs) that capture 100% of common WNK1 variation in HapMap, we aimed to replicate our findings with BP and to test for association with phenotypes relating to WNK1 function in the British Genetics of Hypertension (BRIGHT) study case-control resource (1700 hypertensive cases and 1700 normotensive controls). We found multiple variants to be associated with systolic blood pressure, SBP (7/28 tSNPs min-p = 0.0005), diastolic blood pressure, DBP (7/28 tSNPs min-p = 0.002) and 24 hour urinary potassium excretion (10/28 tSNPs min-p = 0.0004). Associations with SBP and urine potassium remained significant after correction for multiple testing (p = 0.02 and p = 0.01 respectively). The major allele (A) of rs765250, located in intron 1, demonstrated the strongest evidence for association with SBP, effect size 3.14 mmHg (95%CI:1.23–4.9), DBP 1.9 mmHg (95%CI:0.7–3.2) and hypertension, odds ratio (OR: 1.3 [95%CI: 1.0–1.7]).We genotyped this variant in six independent populations (n = 14,451) and replicated the association between rs765250 and SBP in a meta-analysis (p = 7×10−3, combined with BRIGHT data-set p = 2×10−4, n = 17,851). The associations of WNK1 with DBP and EH were not confirmed. Haplotype analysis revealed striking associations with hypertension and BP variation (global permutation p10 mmHg reduction) and risk for hypertension (OR<0.60). Our data indicates that multiple rare and common WNK1 variants contribute to BP variation and hypertension, and provide compelling evidence to initiate further genetic and functional studies to explore the role of WNK1 in BP regulation and EH

Minimum Electromyographic Burst Duration in Healthy Controls: Implications for Electrodiagnosis in Movement Disorders

\ua9 2020 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder SocietyBackground: Electromyogram (EMG) burst duration can provide additional diagnostic information when investigating hyperkinetic movement disorders, particularly when a functional movement disorder is suspected. It is generally accepted that EMG bursts &lt;50 milliseconds are pathological. Objective: To reassess minimum physiological EMG burst duration. Methods: Surface EMG was recorded from face, trunk, and limb muscles in controls (n = 60; ages 19–85). Participants were instructed to generate the briefest possible ballistic movements involving each muscle (40 repetitions) or, in muscles spanning joints, to generate rapid rhythmic alternating movements (20–30 seconds), or both. Results: We found no effect of age on EMG burst duration. However, EMG burst duration varied significantly between body regions. Rhythmic EMG bursts were shorter than ballistic bursts but only significantly so for lower limbs (P &lt; 0.001). EMG bursts of duration &lt;50 milliseconds were frequently observed, particularly in appendicular muscles. Conclusion: We present normal reference data for minimum EMG burst duration, which may assist clinical interpretation when investigating hyperkinetic movement disorders

Non-invasive assessment of peripheral arterial disease: Automated ankle brachial index measurement and pulse volume analysis compared to duplex scan

Objectives: This cross-sectional study aimed to individually and cumulatively compare sensitivity and specificity of the (1) ankle brachial index and (2) pulse volume waveform analysis recorded by the same automated device, with the presence or absence of peripheral arterial disease being verified by ultrasound duplex scan. Methods: Patients (n=205) referred for lower limb arterial assessment underwent ankle brachial index measurement and pulse volume waveform recording using volume plethysmography, followed by ultrasound duplex scan. The presence of peripheral arterial disease was recorded if ankle brachial index 50% was evident with ultrasound duplex scan. Outcome measure was agreement between the measured ankle brachial index and interpretation of pulse volume waveform for peripheral arterial disease diagnosis, using ultrasound duplex scan as the reference standard. Results: Sensitivity of ankle brachial index was 79%, specificity 91% and overall accuracy 88%. Pulse volume waveform sensitivity was 97%, specificity 81% and overall accuracy 85%. The combined sensitivity of ankle brachial index and pulse volume waveform was 100%, specificity 76% and overall accuracy 85%. Conclusion: Combining these two diagnostic modalities within one device provided a highly accurate method of ruling out peripheral arterial disease, which could be utilised in primary care to safely reduce unnecessary secondary care referrals

Do red deer stags (Cervus elaphus) use roar fundamental frequency (F0) to assess rivals?

It is well established that in humans, male voices are disproportionately lower pitched than female voices, and recent studies suggest that this dimorphism in fundamental frequency (F0) results from both intrasexual (male competition) and intersexual (female mate choice) selection for lower pitched voices in men. However, comparative investigations indicate that sexual dimorphism in F0 is not universal in terrestrial mammals. In the highly polygynous and sexually dimorphic Scottish red deer Cervus elaphus scoticus, more successful males give sexually-selected calls (roars) with higher minimum F0s, suggesting that high, rather than low F0s advertise quality in this subspecies. While playback experiments demonstrated that oestrous females prefer higher pitched roars, the potential role of roar F0 in male competition remains untested. Here we examined the response of rutting red deer stags to playbacks of re-synthesized male roars with different median F0s. Our results show that stags’ responses (latencies and durations of attention, vocal and approach responses) were not affected by the F0 of the roar. This suggests that intrasexual selection is unlikely to strongly influence the evolution of roar F0 in Scottish red deer stags, and illustrates how the F0 of terrestrial mammal vocal sexual signals may be subject to different selection pressures across species. Further investigations on species characterized by different F0 profiles are needed to provide a comparative background for evolutionary interpretations of sex differences in mammalian vocalizations

Update on Adverse Effects of HIV Integrase Inhibitors

PURPOSE OF REVIEW: The goal of this paper is to provide an up-to-date review of adverse events related to the class of integrase strand transfer inhibitors (INSTIs), which became the class of choice in few years. We sought answers specifically to issues pertaining to neuropsychiatric adverse events, as well as weight gain, which were the two most important categories of adverse events raised in recent studies based on real-life experience. The primary focus of this paper is on adults with a brief summary on pregnant women and children/adolescents. RECENT FINDINGS: Dolutegravir (DTG) bears the heaviest burden of neuropsychiatric side effects. Weight gain was reported with all INSTIs, although there are methodological caveats in the analyses and the findings need to be interpreted with caution. Moreover, due to recent findings on neural tube defects in infants exposed to dolutegravir during their peri-conception period, its use is not recommended for women of childbearing age without proper birth control method, while raltegravir remains the only drug which may be prescribed without caution. Given the importance of cognitive and metabolic co-morbidities in people living with HIV in regard to their quality of life, future research needs to focus on long-term effects of INSTIs in relation to these adverse events. Pharmacogenetics seems to be a promising tool. Safety during pregnancy is also another important issue to further clarify. SUMMARY: INSTIs are a generally well-tolerated class of antiretrovirals (ARV), and has a higher antiviral potency compared to other classes of ARV. Clinicians and patients need however to be aware of some red flags when starting with and monitoring patients on INSTIs. All INSTIs can lead to mild increases in creatinine levels, usually without clinical significance, but caution is needed in patients with low eGFR (<30ml/min), when using other nephrotoxic drugs, such as as tenofovir disoproxil. Neuro-psychiatric (NP) effects are to be monitored with INSTIs, especially with DTG (though reports are at times contradictory); clinicians might want to avoid DTG for patients with history of severe NP symptoms, until clarity is provided. Weight gain was reported with all INSTIs, especially with DTG, with possible differential effects according to sex and ethnicity (female and non-white patients being at increased risk). This is worrying since patients from African descent are at higher risk of cardio-vascular events and increased body mass index (BMI) can cause further increase metabolic risk. There is possibly an additional effect of tenofovir alafenamide (TAF) on weight increase. Discrepancies between clinical trials – with low rates of adverse events – and reports from real-life settings might be due partly to under-representation of some groups of patients in clinical trials, and/or the short duration of follow-up, since some adverse effects may only occur after prolonged exposure. Preliminary data on safety of bictegravir (BIC), from clinical trials and non-trial settings, are very reassuring and seem to show lower rates of adverse events compared to DTG. Elvitegravir/cobicistat (EVG/cobi) need to be used with caution in patients with other co-morbidities given potential for polypharmacy, as it is the case for aging patients, because of the high potential of drug-drug interactions due to effects of the cobicistat booster. We are awaiting the release of cabotegravir (CAB), which could represent a good option for patients struggling with adherence, despite injection site reactions. Pharmacogenetics is a promising way to explore adverse effects occurrence in the INSTI class

Modelling the nucleon wave function from soft and hard processes

Current light-cone wave functions for the nucleon are unsatisfactory since they are in conflict with the data of the nucleon's Dirac form factor at large momentum transfer. Therefore, we attempt a determination of a new wave function respecting theoretical ideas on its parameterization and satisfying the following constraints: It should provide a soft Feynman contribution to the proton's form factor in agreement with data; it should be consistent with current parameterizations of the valence quark distribution functions and lastly it should provide an acceptable value for the \jp \to N \bar N decay width. The latter process is calculated within the modified perturbative approach to hard exclusive reactions. A simultaneous fit to the three sets of data leads to a wave function whose $x$-dependent part, the distribution amplitude, shows the same type of asymmetry as those distribution amplitudes constrained by QCD sum rules. The asymmetry is however much more moderate as in those amplitudes. Our distribution amplitude resembles the asymptotic one in shape but the position of the maximum is somewhat shifted.Comment: 32 pages RevTex + PS-file with 5 figures in uu-encoded, compressed fil