Risk of radiation-induced second malignant neoplasms from photon and proton radiotherapy in paediatric abdominal neuroblastoma.

BACKGROUND AND PURPOSE: State-of-the-art radiotherapy modalities have the potential of reducing late effects of treatment in childhood cancer survivors. Our aim was to investigate the carcinogenic risk associated with 3D conformal (photon) radiation (3D-CRT), intensity modulated arc therapy (IMAT) and pencil beam scanning proton therapy (PBS-PT) in the treatment of paediatric abdominal neuroblastoma. MATERIALS AND METHODS: The risk of radiation-induced second malignant neoplasm (SMN) was estimated using the concept of organ equivalent dose (OED) for eleven organs (lungs, rectum, colon, stomach, small intestine, liver, bladder, skin, central nervous system (CNS), bone, and soft tissues). The risk ratio (RR) between radiotherapy modalities and lifetime absolute risks (LAR) were reported for twenty abdominal neuroblastoma patients (median, 4y; range, 1-9y) historically treated with 3D-CRT that were also retrospectively replanned for IMAT and PBS-PT. RESULTS: The risk of SMN due to primary radiation was reduced in PBS-PT against 3D-CRT and IMAT for most patients and organs. The RR across all organs ranged from 0.38 ± 0.22 (bladder) to 0.98 ± 0.04 (CNS) between PBS-PT and IMAT, and 0.12 ± 0.06 (rectum and bladder) to 1.06 ± 0.43 (bone) between PBS-PT and 3D-CRT. The LAR for most organs was within 0.01-1% (except the colon) with a cumulative risk of 21 ± 13%, 35 ± 14% and 35 ± 16% for PBS-PT, IMAT and 3D-CRT, respectively. CONCLUSIONS: PBS-PT was associated with the lowest risk of radiation-induced SMN compared to IMAT and 3D-CRT in abdominal neuroblastoma treatment. Other clinical endpoints and plan robustness should also be considered for optimal plan selection.

Comorbid Conditions, Mental Health and Cognitive Functions in Adults with Fibromyalgia.

This study examined age group differences across adulthood in comorbid conditions, mental health, and cognitive function in people with fibromyalgia. Participants completed an online survey about how fibromyalgia affects their everyday life. Chi square analyses were conducted to examine associations between age groups and (a) comorbid conditions and (b) severity of anxiety and depression. ANOVA analyses examined age group differences on aspects of self-report cognitive function. The greatest prevalence of comorbid conditions was found in middle adulthood. Early adulthood was associated with more cases of severe anxiety with the lowest number of cases being in the oldest age group. Middle adulthood was associated with worse self-report pain compared to the youngest age group. Older adults showed better self-report cognitive function compared to younger adults. Distinct age profiles based on comorbid conditions, mental health, and symptom severity across adulthood in fibromyalgia have been demonstrated.

Efficacy and safety of once-daily nitisinone for patients with alkaptonuria (SONIA 2): an international, multicentre, open-label, randomised controlled trial.

BACKGROUND: Alkaptonuria is a rare, genetic, multisystem disease characterised by the accumulation of homogentisic acid (HGA). No HGA-lowering therapy has been approved to date. The aim of SONIA 2 was to investigate the efficacy and safety of once-daily nitisinone for reducing HGA excretion in patients with alkaptonuria and to evaluate whether nitisinone has a clinical benefit. METHODS: SONIA 2 was a 4-year, open-label, evaluator-blind, randomised, no treatment controlled, parallel-group study done at three sites in the UK, France, and Slovakia. Patients aged 25 years or older with confirmed alkaptonuria and any clinical disease manifestations were randomly assigned (1:1) to receive either oral nitisinone 10 mg daily or no treatment. Patients could not be masked to treatment due to colour changes in the urine, but the study was evaluator-blinded as far as possible. The primary endpoint was daily urinary HGA excretion (u-HGA24) after 12 months. Clinical evaluation Alkaptonuria Severity Score Index (cAKUSSI) score was assessed at 12, 24, 36, and 48 months. Efficacy variables were analysed in all randomly assigned patients with a valid u-HGA24 measurement at baseline. Safety variables were analysed in all randomly assigned patients. The study was registered at ClinicalTrials.gov (NCT01916382). FINDINGS: Between May 7, 2014, and Feb 16, 2015, 139 patients were screened, of whom 138 were included in the study, with 69 patients randomly assigned to each group. 55 patients in the nitisinone group and 53 in the control group completed the study. u-HGA24 at 12 months was significantly decreased by 99·7% in the nitisinone group compared with the control group (adjusted geometric mean ratio of nitisinone/control 0·003 [95% CI 0·003 to 0·004], p<0·0001). At 48 months, the increase in cAKUSSI score from baseline was significantly lower in the nitisinone group compared with the control group (adjusted mean difference -8·6 points [-16·0 to -1·2], p=0·023). 400 adverse events occurred in 59 (86%) patients in the nitisinone group and 284 events occurred in 57 (83%) patients in the control group. No treatment-related deaths occurred. INTERPRETATION: Nitisinone 10 mg daily was well tolerated and effective in reducing urinary excretion of HGA. Nitisinone decreased ochronosis and improved clinical signs, indicating a slower disease progression. FUNDING: European Commission Seventh Framework Programme.

Using the Gibbs Function as a Measure of Human Brain Development Trends from Fetal Stage to Advanced Age.

We propose to use a Gibbs free energy function as a measure of the human brain development. We adopt this approach to the development of the human brain over the human lifespan: from a prenatal stage to advanced age. We used proteomic expression data with the Gibbs free energy to quantify human brain's protein-protein interaction networks. The data, obtained from BioGRID, comprised tissue samples from the 16 main brain areas, at different ages, of 57 post-mortem human brains. We found a consistent functional dependence of the Gibbs free energies on age for most of the areas and both sexes. A significant upward trend in the Gibbs function was found during the fetal stages, which is followed by a sharp drop at birth with a subsequent period of relative stability and a final upward trend toward advanced age. We interpret these data in terms of structure formation followed by its stabilization and eventual deterioration. Furthermore, gender data analysis has uncovered the existence of functional differences, showing male Gibbs function values lower than female at prenatal and neonatal ages, which become higher at ages 8 to 40 and finally converging at late adulthood with the corresponding female Gibbs functions.

Physics of animal health: on the mechano-biology of hoof growth and form.

Global inequalities in economic access and agriculture productivity imply that a large number of developing countries rely on working equids for transport/agriculture/mining. Therefore, the understanding of hoof conditions/shape variations affecting equids' ability to work is still a persistent concern. To bridge this gap, using a multi-scale interdisciplinary approach, we provide a bio-physical model predicting the shape of equids' hooves as a function of physical and biological parameters. In particular, we show (i) where the hoof growth stress originates from, (ii) why the hoof growth rate is one order of magnitude higher than the proliferation rate of epithelial cells and (iii) how the soft-to-hard transformation of the epithelium is possible allowing the hoof to fulfil its function as a weight-bearing element. Finally (iv), we demonstrate that the reason for hoof misshaping is linked to the asymmetrical design of equids' feet (shorter quarters/long toe) together with the inability of the biological growth stress to compensate for such an asymmetry. Consequently, the hoof can adopt a dorsal curvature and become 'dished' overtime, which is a function of the animal's mass and the hoof growth rate. This approach allows us to discuss the potential occurrence of this multifaceted pathology in equids.

Patients' perspective of the effectiveness and acceptability of pharmacological and non-pharmacological treatments of fibromyalgia.

Background and aims Fibromyalgia is a complex condition characterised by widespread pain, sleep disturbance, fatigue and cognitive impairment, with a global mean prevalence estimated at 2.7%. There are inconsistencies in guidelines on the treatment of fibromyalgia leading to dissatisfaction from patients and healthcare professionals. This study investigated patient-reported outcomes of pharmacological and non-pharmacological treatment usage and effectiveness with an assessment of acceptability. Methods Nine hundred and forty-one participants completed a self-administered anonymous questionnaire giving quantitative data of demographics, treatment usage and treatment outcomes. Participant-reported effectiveness and side effects were compared in the following treatment classes: analgesics, antidepressants, gabapentinoids, gastrointestinal treatments, activity interventions, dietary-based treatments, and psychological, physical and alternative therapies. Participants also reported whether they knew about or had tried different treatments. Results The results from the online survey indicated that the range of mean effectiveness ratings were similar for pharmacological and non-pharmacological treatments, whereas non-pharmacological treatments had lower side effects ratings and higher acceptability relative to pharmacological treatments. Participants were not aware of some treatment options. Conclusions The results show lower side effects ratings and higher acceptability for non-pharmacological treatments compared to pharmacological treatments despite similar effectiveness ratings. Implications This article presents results from a large online survey on fibromyalgia patient perspectives of pharmacological and non-pharmacological treatments. Results will inform healthcare professionals and patients about optimal treatments based on ratings of effectiveness, side effects and acceptability that are tailored to patient symptom profiles. Some participants were unaware of treatment options highlighting the importance of patient education allowing collaboration between patients and healthcare professionals to find optimal treatments.

What causes fibromyalgia? An online survey of patient perspectives.

Fibromyalgia is a severe chronic pain condition that affects every aspect of life. Causes of the condition remain unclear, and quantitative research cannot account for patients' personal illness narratives and perceptions. This online survey gathered qualitative accounts of the perceived causes of their condition from 596 people with fibromyalgia, which were analyzed thematically. Themes were "Bodily assault, ill-health, and change"; "Emotional trauma and distress"; "Stress and vulnerability"; and "Explaining and authenticating fibromyalgia." Discussion focuses on the complexity of causation, the importance of understanding and having symptoms validated, and the potential for benefiting from patient expertise in building better practitioner-client relationships.

Enrichment activities in the medical school psychiatry programme - could this be a key to engaging medical students in psychiatry? A study from a high secure forensic psychiatric UK hospital.

BACKGROUND: The majority of research studies on medical student attitudes toward psychiatry focus on influencing factors and the medical school experience. This study evaluates the effectiveness of a one-day visit to a high secure forensic psychiatric unit on medical students' attitudes towards psychiatry and also assesses career intentions and the factors influencing these. METHOD: Change in attitudes and career intention were measured by administering a questionnaire, which included the 30-item Attitudes Toward Psychiatry (ATP-30) survey, at the start (time 1) and end (time 2) of the one-day visit. Qualitative data on factors influencing career choice was also gathered. RESULTS: Evaluation of 284 responses revealed a significant increase in positive attitude towards psychiatry from time 1 to time 2 in the sample as a whole. The most influential factor on consideration of psychiatry as a career across all groups was the medical school clinical placement. For those that tended away from choosing psychiatry as a career, patient prognosis was important. CONCLUSIONS: Poor recruitment in psychiatry in the UK is already established which will doubtless be compounded by controversies surrounding the proposed new junior doctors' contract. Now more than ever, the need to inspire and motivate those at medical school encountering psychiatry is crucial. Our findings add to the body of evidence that the medical school clinical attachment is fundamental in shaping attitudes. However, these results also show that a well-planned visit to a specialised psychiatric unit outside of traditional placements can have a significant impact on students' attitudes toward psychiatry and mental illness in general. There is limited literature in the UK on enrichment activities within the psychiatry medical school curriculum. We propose that developing opportunities for enrichment activities within psychiatry could increase the scope of how we engage students in this fascinating field of medicine.

A qualitative exploration of the experiences of living with and being treated for fibromyalgia.

This study explores the life and treatment experience of people in the United Kingdom with fibromyalgia in order to inform the development of treatments which are both effective and acceptable to users. Qualitative interviews were conducted with 14 participants with interpretative phenomenological analysis used as the theoretical framework and analytical method. The themes identified were as follows: Inauthenticity of fibromyalgia, An Unconventional healthcare experience, Re-creating support networks, Challenging the working identity, Threatening the family dynamic and Fighting, accepting or accommodating? The biopsychosocial impacts of fibromyalgia disrupted the identity, lifestyle, roles and relationships of our participants with such challenges further exacerbated by the contested nature of the illness.

The longitudinal development of social and executive functions in late adolescence and early adulthood.

Our earlier work suggests that, executive functions and social cognition show protracted development into late adolescence and early adulthood (Taylor et al., 2013). However, it remains unknown whether these functions develop linearly or non-linearly corresponding to dynamic changes to white matter density at these age ranges. Executive functions are particularly in demand during the transition to independence and autonomy associated with this age range (Ahmed and Miller, 2011). Previous research examining executive function (Romine and Reynolds, 2005) and social cognition (Dumontheil et al., 2010a) in late adolescence has utilized a cross sectional design. The current study employed a longitudinal design with 58 participants aged 17, 18, and 19 years completing social cognition and executive function tasks, Wechsler Abbreviated Scale of Intelligence (Wechsler, 1999), Positive and Negative Affect Schedule (Watson et al., 1988), and Hospital Anxiety and Depression Scale (Zigmond and Snaith, 1983) at Time 1 with follow up testing 12-16 months later. Inhibition, rule detection, strategy generation and planning executive functions and emotion recognition with dynamic stimuli showed longitudinal development between time points. Self-report empathy and emotion recognition functions using visual static and auditory stimuli were stable by age 17 whereas concept formation declined between time points. The protracted development of some functions may reflect continued brain maturation into late adolescence and early adulthood including synaptic pruning (Sowell et al., 2001) and changes to functional connectivity (Stevens et al., 2007) and/or environmental change. Clinical implications, such as assessing the effectiveness of rehabilitation following Head Injury, are discussed.

Microenvironment acidity as a major determinant of tumor chemoresistance: Proton pump inhibitors (PPIs) as a novel therapeutic approach.

Despite the major progresses in biomedical research and the development of novel therapeutics and treatment strategies, cancer is still among the dominant causes of death worldwide. One of the crucial challenges in the clinical management of cancer is primary (intrinsic) and secondary (acquired) resistance to both conventional and targeted chemotherapeutics. Multiple mechanisms have been identifiedthat underlie intrinsic and acquired chemoresistance: these include impaired drug uptake, increased drug efflux, deletion of receptors, altered drug metabolism, quantitative and qualitative alterations in drug targets, increased DNA damage repair and various mechanisms of anti-apoptosis. The fast efflux of anticancer drugs mediated by multidrug efflux pumps and the partial or complete reversibility of chemoresistance combined with the absence of genetic mutations suggests a multifactorial process. However, a growing body of recent evidence suggests that chemoresistance is often triggered by the highly acidic microenvironment of tumors. The vast majority of drugs, including conventional chemotherapeutics and more recent biological agents, are weak bases that are quickly protonated and neutralized in acidic environments, such as the extracellular microenvironment and the acidic organelles of tumor cells. It is therefore essential to develop new strategies to overcome the entrapment and neutralization of weak base drugs. One such strategy is the use of proton pump inhibitors which can enhance tumor chemosensitivity by increasing the pH of the tumor microenvironment. Recent clinical trials in animals with spontaneous tumors have indicated that patient alkalization is capable of reversing acquired chemoresistance in a large percentage of tumors that are refractory to chemotherapy. Of particular interest was the benefit of alkalization for patients undergoing metronomic regimens which are becoming more widely used in veterinary medicine. Overall, these results provide substantial new evidence that altering the acidic tumor microenvironment is an effective, well tolerated and low cost strategy for the overcoming of anticancer drug resistance.

Resistance to cancer chemotherapy: failure in drug response from ADME to P-gp.

Cancer chemotherapy resistance (MDR) is the innate and/or acquired ability of cancer cells to evade the effects of chemotherapeutics and is one of the most pressing major dilemmas in cancer therapy. Chemotherapy resistance can arise due to several host or tumor-related factors. However, most current research is focused on tumor-specific factors and specifically genes that handle expression of pumps that efflux accumulated drugs inside malignantly transformed types of cells. In this work, we suggest a wider and alternative perspective that sets the stage for a future platform in modifying drug resistance with respect to the treatment of cancer.

The typical developmental trajectory of social and executive functions in late adolescence and early adulthood.

Executive functions and social cognition develop through childhood into adolescence and early adulthood and are important for adaptive goal-oriented behavior (Apperly, Samson, & Humphreys, 2009; Blakemore & Choudhury, 2006). These functions are attributed to frontal networks known to undergo protracted maturation into early adulthood (Barker, Andrade, Morton, Romanowski, & Bowles, 2010; Lebel, Walker, Leemans, Phillips, & Beaulieu, 2008), although social cognition functions are also associated with widely distributed networks. Previously, nonlinear development has been reported around puberty on an emotion match-to-sample task (McGivern, Andersen, Byrd, Mutter, & Reilly, 2002) and for IQ in midadolescence (Ramsden et al., 2011). However, there are currently little data on the typical development of social and executive functions in late adolescence and early adulthood. In a cross-sectional design, 98 participants completed tests of social cognition and executive function, Wechsler Abbreviated Scale of Intelligence (Wechsler, 1999), Positive and Negative Affect Schedule (Watson, Clark, & Tellegen, 1988), Hospital Anxiety and Depression Scale (Zigmond & Snaith, 1983), and measures of pubertal development and demographics at ages 17, 18, and 19. Nonlinear age differences for letter fluency and concept formation executive functions were found, with a trough in functional ability in 18-year-olds compared with other groups. There were no age group differences on social cognition measures. Gender accounted for differences on 1 scale of concept formation, 1 dynamic social interaction scale, and 2 empathy scales. The clinical, developmental, and educational implications of these findings are discussed.