Prescribing issues experienced by people living with Phenylketonuria in the UK

Background: Foods for Special Medical purposes (Phe-free protein substitutes [PS] and low protein foods [LPFs]) are central to successful dietary management of patients with phenylketonuria (PKU). In the UK, PS and LPFs are prescribed by primary care general practitioners (GPs) and dispensed by high street pharmacists or via home delivery companies. As patients and carers commonly reported access issues with PS and LPFs through the National Society for PKU (NSPKU) helpline, the NSPKU collected more information about the extent of prescriptions issues via a questionnaire. Methods: A cross sectional online survey was carried out (consisting of 7 multiple choice and 3 open questions). The questionnaire was available via the NSPKU website over a nine-month period (15th May 2018 to 31st January 2019). Carers or patients with PKU were invited to participate if they had any problems accessing PS and LPF over a 9-month period. Results: There were 252 responses. 65% for children and 35% for adults, aged ≥18y with PKU. 59% (n=146/246) of responses described difficulties accessing basic LPF (bread, pasta) and 33% (n=81/248) PS. 36% (n=88/248) said problems had re-occurred during >1y, and 40% (n=99/248) for < 3 months. 59% (n= 146/246) had supply issues with LPF and 33% (n= 81/246) with PS. 18% (n=42/234) reported that the local NHS authority had refused, restricted or had a policy to block treatment access; 27% (n=63/234) cited GPs declining requests or restricting prescription amounts. 21% (n=49/234) could not access all their products via a pharmacy, 40% (n=93/234) said their home delivery system failed, and 15% (n=34/234) of the dispensed prescribed products were out of date, incorrect, damaged or poor quality. For patients and carers these issues caused: stress (87%, n=210/241); they considered PKU was not taken seriously by professionals (66%, n=160/241); they reduced patient access to LPF and PS (53%, n=128/241); and affected the patients’ health (53%, n=128/241)

Living with Phenylketonuria: lessons from the PKU community

Introduction: We report the practical, social and psychological issues of living with phenylketonuria (PKU) from one of the largest surveys that has been completed by both adults with PKU and parents/caregivers of children. Methods: In the UK, parents/caregivers of children and adults with PKU were invited to complete an online survey between November 2017 to January 2018 by the NSPKU (National Society for Phenylketonuria). Results: 631 participants (adults, n=338; parents/caregivers of children, n=293) with PKU completed the questionnaire. Problems experienced by children with PKU were: difficulty with maintaining focus (48%,n=114/236), educational difficulties (28%, n=67/236), anxiety or depression (29%, n=68/236), and gastrointestinal symptoms (34%, n=97/282). Fifty one per cent (n=120/236) described social exclusion; 17% (n=41/236) had relationship issues with friends or family. Problems experienced by adults were: depression or anxiety (52%, n=148/286), difficulty maintaining focus (54%, n=154/286), and low mood (54%, n=180/334). Difficulties were experienced with relationships (34%, n=96/286); social exclusion (44%, n=126/286); and gastrointestinal issues (n=34%, n=112/334). Common medications used included antidepressants (40%, n=131/331) and anxiolytics (18%, n=60/334). Discussions: Adults with PKU or caregivers/parents of children identified significant neurocognitive, mental health and general health issues. Limits on socialisation, perception of social isolation and dietary stigma are major obstacles which are difficult to overcome with conventional dietary management

Reproductive experience of women living with phenylketonuria

Introduction: Many women with PKU are well-informed about the risks of maternal PKU but there are several barriers to achieving satisfactory metabolic control before and during pregnancy. Many studies have documented the outcome of maternal PKU infants, but very little has been reported about the experiences of women of reproductive age with PKU, particularly about their psychosexual development, pre-conception, pregnancy and postnatal experience. Methods: In the UK, in a subsection of an online questionnaire conducted by the National Society for PKU (NSPKU) about living with PKU, women aged 18 years and over completed 9 closed questions about their pre-conception, pregnancy and post-natal experiences and an open-ended question on their reproductive health. Results: 300 women aged 18 years and over with PKU completed this questionnaire with 37% (n= 111/300) of women already having children. 56% (n= 71/128) of pregnancies were planned and a further 18% (n= 23/128) of women had both planned and unplanned pregnancies. Most women (73%, n=200/273) expressed concerns, fears and distress about pregnancy and two thirds of women who had at least one pregnancy stated that having PKU made pregnancy more stressful and difficult. 60% (n= 164/273) were concerned that they may cause harm to a baby, 58% (n= 159/273) worried about their ability to manage a strict diet during pregnancy, 54% (n= 147/273) had anxiety about their ability to maintain blood Phe within target range, and 48% (n= 132/273) feared having an unplanned pregnancy. Postnatally, 48% (n= 45/93) had low mood or sadness, 42% (n= 38/93) were depressed, 34% (n= 32/93) felt unable to cope, 33% (n= 31/93) said they could not manage their PKU and care for their baby, 14% (n= 13/93) struggled with child care needs and 4% (n= 4/94) worried they might hurt themselves or their baby through being unable to manage their diet. Conclusions: Many women with PKU have unmet sexual and reproductive health needs Pregnancy fears are prominent from adolescence onwards and for some women overarching concerns about their ability to cope with pregnancy led to a decision not to have children. Interventions are needed to reduce the psychological impact of the risk of maternal PKU syndrome and assist with safe pregnancies. Post-natal experiences of women with PKU give rise to concern

Body mass index mortality paradox in chronic kidney disease patients with suspected cardiac chest pain

Background: Chronic kidney disease (CKD) is a silent clinical condition associated with adverse comorbidity and high cardiovascular disease (CVD) risk. An inverse relationship with body mass index (BMI) and mortality has been demonstrated in hemodialysis patients. However, it is unclear if this risk‐factor paradox is evident in non‐dialysis CKD patients. The aims of this study were to explore the relationship between, nutritional status, markers of inflammation, autonomic and cardiac function with BMI. Longitudinal follow‐up explored the relationship between BMI and allcause mortality. Methods: 211‐consecutive CKD patients referred for dobutamine stress echocardiography to detect or exclude myocardial ischemia were recruited. BMI, albumin, C‐reactive protein (CRP) and haemoglobin (Hb) were recorded as markers of nutritional and inflammatory status. Left ventricular ejection fraction (LVEF) and heart rate variability (HRV) as an indicator of cardiac function was recorded. All subjects were followed prospectively until November 2014 and study end‐point was all‐cause mortality. Results: BMI was inversely associated with CKD status. After covariate adjustment, this association remained. During a mean follow‐up period of 3.3±0.9 years there were 35 deaths (17%). BMI was inversely associated with all‐cause mortality (HR 0.81, 95% CI 0.71‐0.9). Other important independent predictors of mortality were heart rate variability (HR 0.98, 95% CI 0.97‐0.99), myocardial ischemia (HR 1.37, 95% CI 1.17‐1.81), and albumin (HR 0.86, 95% CI 0.81‐ 0.92). Conclusions: The presence of a BMI paradox exists in non‐dialysis CKD patients. This risk‐factor paradox was an independent predictor of all‐cause mortality and may have significant clinical implications relevant to screening, assessment and treatment and requires further study

Geometric View of Measurement Errors

The slope of the best fit line from minimizing the sum of the squared oblique errors is the root of a polynomial of degree four. This geometric view of measurement errors is used to give insight into the performance of various slope estimators for the measurement error model including an adjusted fourth moment estimator introduced by Gillard and Iles (2005) to remove the jump discontinuity in the estimator of Copas (1972). The polynomial of degree four is associated with a minimun deviation estimator. A simulation study compares these estimators showing improvement in bias and mean squared error

Strongman training – Needs analysis and integration into strength and conditioning programming: part 2.

The article aims to evaluate the integration of strongman based exercises within the practice of strength and conditioning. It should give the reader a clear understanding of the specific physiological and biomechanical traits of each of the exercises discussed in the previous article. This information will then be used to discuss its amalgamation within traditional based exercises within the planning of a periodised programme for strength and conditioning practitioners

Strongman training – a rationale for its inclusion in strength & conditioning: part 1

This article, the first in a two-part series, aims to introduce the concepts of strongman-type training relative to some of the exercises adopted. It should give the reader a detailed background into the evolution of strongman training with a strong rationale for its inclusion within the practice of strength and conditioning

Refining reproduction number estimates to account for unobserved generations of infection in emerging epidemics

Background: Estimating the transmissibility of infectious diseases is key to inform situational awareness and for response planning. Several methods tend to overestimate the basic (R0) and effective (Rt) reproduction numbers during the initial phases of an epidemic. The reasons driving the observed bias are unknown. In this work we explore the impact of incomplete observations and underreporting of the first generations of infections during the initial epidemic phase. Methods: We propose a debiasing procedure which utilises a linear exponential growth model to infer unobserved initial generations of infections and apply it to EpiEstim. We assess the performance of our adjustment using simulated data, considering different levels of transmissibility and reporting rates. We also apply the proposed correction to SARS-CoV-2 incidence data reported in Italy, Sweden, the United Kingdom and the United States of America. Results: In all simulation scenarios, our adjustment outperforms the original EpiEstim method. The proposed correction reduces the systematic bias and the quantification of uncertainty is more precise, as better coverage of the true R0 values is achieved with tighter credible intervals. When applied to real world data, the proposed adjustment produces basic reproduction number estimates which closely match the estimates obtained in other studies while making use of a minimal amount of data. Conclusions: The proposed adjustment refines the reproduction number estimates obtained with the current EpiEstim implementation by producing improved, more precise estimates earlier than with the original method. This has relevant public health implications

The Aryl Hydrocarbon Receptor as an Immune-Modulator of Atmospheric Particulate Matter-Mediated Autoimmunity

This review examines the current literature on the effects of atmospheric particulate matter (PM) on autoimmune disease and proposes a new role for the aryl hydrocarbon receptor (AHR) as a modulator of T cells in PM-mediated autoimmune disease. There is a significant body of literature regarding the strong epidemiologic correlations between PM exposures and worsened autoimmune diseases. Genetic predispositions account for 30% of all autoimmune disease leaving environmental factors as major contributors. Increases in incidence and prevalence of autoimmune disease have occurred concurrently with an increase in air pollution. Currently, atmospheric PM is considered to be the greatest environmental health risk worldwide. Atmospheric PM is a complex heterogeneous mixture composed of diverse adsorbed organic compounds such as polycyclic aromatic hydrocarbons (PAHs) and dioxins, among others. Exposure to atmospheric PM has been shown to aggravate several autoimmune diseases. Despite strong correlations between exposure to atmospheric PM and worsened autoimmune disease, the mechanisms underlying aggravated disease are largely unknown. The AHR is a ligand activated transcription factor that responds to endogenous and exogenous ligands including toxicants present in PM, such as PAHs and dioxins. A few studies have investigated the effects of atmospheric PM on AHR activation and immune function and demonstrated that atmospheric PM can activate the AHR, change cytokine expression, and alter T cell differentiation. Several studies have found that the AHR modulates the balance between regulatory and effector T cell functions and drives T cell differentiation in vitro and in vivo using murine models of autoimmune disease. However, there are very few studies on the role of AHR in PM-mediated autoimmune disease. The AHR plays a critical role in the balance of effector and regulatory T cells and in autoimmune disease. With increased incidence and prevalence of autoimmune disease occurring concurrently with increases in air pollution, potential mechanisms that drive inflammatory and exacerbated disease need to be elucidated. This review focuses on the AHR as a potential mechanistic target for modulating T cell responses associated with PM-mediated autoimmune disease providing the most up-to-date literature on the role of AHR in autoreactive T cell function and autoimmune disease

Increased complexity of Tmem16a/Anoctamin 1 transcript alternative splicing

<p>Abstract</p> <p>Background</p> <p>TMEM16A (Anoctamin 1; ANO1) is an eight transmembrane protein that functions as a calcium-activated chloride channel. <it>TMEM16A </it>in human exhibits alternatively spliced exons (6b, 13 and 15), which confer important roles in the regulation of channel function. Mouse <it>Tmem16a </it>is reported to consist of 25 exons that code for a 956 amino acid protein. In this study our aim was to provide details of mouse <it>Tmem16a </it>genomic structure and to investigate if <it>Tmem16a </it>transcript undergoes alternative splicing to generate channel diversity.</p> <p>Results</p> <p>We identified <it>Tmem16a </it>transcript variants consisting of alternative exons 6b, 10, 13, 14, 15 and 18. Our findings indicate that many of these exons are expressed in various combinations and that these splicing events are mostly conserved between mouse and human. In addition, we confirmed the expression of these exon variants in other mouse tissues. Additional splicing events were identified including a novel conserved exon 13b, tandem splice sites of exon 1 and 21 and two intron retention events.</p> <p>Conclusion</p> <p>Our results suggest that <it>Tmem16a </it>gene is significantly more complex than previously described. The complexity is especially evident in the region spanning exons 6 through 16 where a number of the alternative splicing events are thought to affect calcium sensitivity, voltage dependence and the kinetics of activation and deactivation of this calcium-activated chloride channel. The identification of multiple <it>Tmem16a </it>splice variants suggests that alternative splicing is an exquisite mechanism that operates to diversify TMEM16A channel function in both physiological and pathophysiological conditions.</p