Coupling between waveguides and microresonators: the local approach.

Coupling between optical microresonators and waveguides is a critical characteristic of resonant photonic devices that has complex behavior that is not well understood. When the characteristic variation length of the microresonator modes is much larger than the waveguide width, local coupling parameters emerge that are independent of the resonator mode distributions and offer a simplified description of coupling behavior. We develop a robust numerical-fitting-based methodology for experimental determination of the local coupling parameters in all coupling regimes and demonstrate their characterization along a microfiber waveguide coupled to an elongated bottle microresonator.

Pruritus secondary to primary biliary cholangitis: a review of the pathophysiology and management with phototherapy.

BACKGROUND: Primary biliary cholangitis (PBC) is an autoimmune hepatobiliary disorder characterized by destruction of liver bile ducts leading to intrahepatic cholestasis. It causes intractable pruritus for which ultraviolet (UV)B phototherapy is an experimental treatment when alternative therapies fail. The pathophysiology of cholestatic itch and the mechanism of action of narrowband UVB in this condition remains poorly understood. OBJECTIVES: To summarize the current literature and propose testable hypotheses for the mechanism of action of phototherapy in attenuating itch. METHODS: A focused PubMed search for articles relating to the pathogenesis of itch in cholestatic disease was performed. A total of 3855 articles were screened and 50 were found suitable for literature review. Evidence from this literature review was combined with author expertise in the area. RESULTS: Formulated hypotheses focus on the role of bile salts, autotaxin and specific receptors including G-protein-coupled bile acid receptor, Gpbar1 (also known as TGR5) and the nuclear transcription factor farnesoid X receptor. CONCLUSIONS: Several testable mechanisms through which phototherapy may exert its effects are discussed in this review. The next steps are to carry out an objective assessment of the efficacy of phototherapy in cholestatic pruritus, gain further knowledge on the underlying pathways, and subsequently trial its use against current licensed therapies. Such studies could lead to increased mechanistic understanding, identification of novel therapeutic targets and the potential to refine phototherapy protocols, leading to improved control of itch and quality of life in patients with PBC. What's already known about this topic? Primary biliary cholangitis (PBC) is frequently associated with intractable pruritus for which current treatment options are often unsuccessful. Phototherapy is used as an experimental treatment for PBC-associated pruritus when alternative better-studied treatments fail. What does this study add? This study reviews the current literature on the pathophysiology and management of cholestatic pruritus, an area which remains poorly understood. We propose testable hypotheses of the mechanisms behind the attenuation of cholestatic pruritus with phototherapy.

Molecular mechanisms for anthelmintic resistance in strongyle nematode parasites of veterinary importance.

Veterinarians rely on a relatively limited spectrum of anthelmintic agents to control nematode parasites in domestic animals. Unfortunately, anthelmintic resistance has been an emerging problem in veterinary medicine. In particular, resistance has emerged among the strongyles, a group of gastrointestinal nematodes that infect a variety of hosts that range from large herbivores to small companion animals. Over the last several decades, a great deal of research effort has been directed toward developing an understanding of the mechanisms conferring resistance against the three major groups of anthelmintics: macrocyclic lactones, benzimidazoles, and nicotinic agonists. Our understanding of anthelmintic resistance has been largely formed by determining the mechanism of action for each drug class and then evaluating drug-resistant nematode isolates for mutations or differences in expression of target genes. More recently, drug efflux pumps have been recognized for their potential contribution to anthelmintic resistance. In this mini-review, we summarize the evidence for mechanisms of resistance in strongyle nematodes.

Nanofiber-segment ring resonator.

We describe a fiber ring resonator comprised of a relatively long loop of standard single-mode fiber with a short nanofiber segment. The evanescent mode of the nanofiber segment allows the cavity-enhanced field to interact with atoms in close proximity to the nanofiber surface. We report on an experiment using a warm atomic vapor and low-finesse cavity, and briefly discuss the potential for reaching the strong coupling regime of cavity QED by using trapped atoms and a high-finesse cavity of this kind.

Public health decisions: actions and consequences.

The goal of public health is to promote the best possible health for the whole population. Public health issues are numerous and can be unbelievably complex in form, scope, and possible consequence. Most public health decisions involve assessing several different options, weighing the respective benefits and risks of those options, and making difficult decisions that hopefully provide the greatest benefit to the affected populations. Many risk management decisions involve a variety of societal factors which modify risk assessment choices. The purpose of this paper is to point out difficulties in making decisions that impact public health. The intent of such decisions is to improve public health, but as illustrated in the paper, there can be unintended adverse consequences. Such unplanned issues require continued attention and efforts for responsible officials in the protection of environmental public health. This article presents examples of such events, when in the past, it was necessary to assess and regulate a number of potentially hazardous chemicals commonly used as insecticides, gasoline additives, and wood preservatives.

Biliary epithelial senescence and plasticity in acute cellular rejection.

Biliary epithelial cells (BEC) are important targets in some liver diseases, including acute allograft rejection. Although some injured BEC die, many can survive in function compromised states of senescence or phenotypic de-differentiation. This study was performed to examine changes in the phenotype of BEC during acute liver allograft rejection and the mechanism driving these changes. Liver allograft sections showed a positive correlation (p < 0.0013) between increasing T cell mediated acute rejection and the number of BEC expressing the senescence marker p21(WAF1/Cip) or the mesenchymal marker S100A4. This was modeled in vitro by examination of primary or immortalized BEC after acute oxidative stress. During the first 48 h, the expression of p21(WAF1/Cip) was increased transiently before returning to baseline. After this time BEC showed increased expression of mesenchymal proteins with a decrease in epithelial markers. Analysis of TGF-ß expression at mRNA and protein levels also showed a rapid increase in TGF-ß2 (p < 0.006) following oxidative stress. The epithelial de-differentiation observed in vitro was abrogated by pharmacological blockade of the ALK-5 component of the TGF-ß receptor. These data suggest that stress induced production of TGF-ß2 by BEC can modify liver allograft function by enhancing the de-differentiation of local epithelial cells.

Fatigue severity remains stable over time and independently associated with orthostatic symptoms in chronic fatigue syndrome: a longitudinal study.

OBJECTIVES: to examine fatigue variability over time in chronic fatigue syndrome (CFS) and the effect of other symptoms on its predictability. DESIGN: longitudinal cohort study of patients with CFS (Fukuda criteria). SETTING: specialist CFS clinical service. SUBJECTS: phase 1: 100 patients who participated in a study of CFS symptoms in 2005 were revisited in 2009. Phase 2: 25 patients completed fatigue diaries to address intra- and inter-day variability in perceived fatigue. MAIN OUTCOME MEASURES: phase 1: subjects completed fatigue impact scale (FIS), Epworth sleepiness scale (ESS), orthostatic grading scale (OGS) and hospital anxiety and depression scale (HADS). Changes in variables represented the differences between 2005 and 2009. Phase 2: subjects rated fatigue on a scale of 0 (no fatigue) to 10 (severe fatigue) four times a day for 5 weeks. RESULTS: symptom assessment tools were available in both 2005 and 2009 for 74% of patients. FIS and HADS depression (HAD-D) and anxiety (HAD-A) scores significantly improved during follow-up whereas ESS and OGS remained stable. FIS improved in 29/74 (39%) subjects, and by ≥ 10 points in 19 (26%). FIS worsened by ≥ 10 points in 33/74 (45%) subjects. On multivariate analysis, independent predictors of current fatigue (FIS in 2009) were FIS in 2005, HAD-D in 2009, OGS in 2009 and change in HAD-A. Reported fatigue was stable from week to week and from day to day. Patients reported higher fatigue in the morning (mean ± SD; 6.4 ± 2), becoming significantly lower at lunchtime (6.2 ± 2; P < 0.05) and increasing again to 7 ± 2 at bedtime. CONCLUSIONS: current fatigue is independently associated with current autonomic symptom burden, current depression and change in anxiety during follow-up. These findings have implications for targeted symptom management in CFS.

Abnormalities in pH handling by peripheral muscle and potential regulation by the autonomic nervous system in chronic fatigue syndrome.

OBJECTIVES: To examine muscle acid handling following exercise in chronic fatigue syndrome (CFS/ME) and the relationship with autonomic dysfunction. DESIGN: Observational study. SETTING: Regional fatigue service. SUBJECTS & INTERVENTIONS: Chronic fatigue syndrome (n = 16) and age and sex matched normal controls (n = 8) underwent phosphorus magnetic resonance spectroscopy (MRS) to evaluate pH handling during exercise. Subjects performed plantar flexion at fixed 35% load maximum voluntary contraction. Heart rate variability was performed during 10 min supine rest using digital photophlethysmography as a measure of autonomic function. RESULTS: Compared to normal controls, the CFS/ME group had significant suppression of proton efflux both immediately postexercise (CFS: 1.1 +/- 0.5 mmol L(-1) min(-1) vs. normal: 3.6 +/- 1.5 mmol L(-1) min(-1), P < 0.001) and maximally (CFS: 2.7 +/- 3.4 mmol L(-1) min(-1) vs. control: 3.8 +/- 1.6 mmol L(-1) min(-1), P < 0.05). Furthermore, the time taken to reach maximum proton efflux was significantly prolonged in patients (CFS: 25.6 +/- 36.1 s vs. normal: 3.8 +/- 5.2 s, P < 0.05). In controls the rate of maximum proton efflux showed a strong inverse correlation with nadir muscle pH following exercise (r(2) = 0.6; P < 0.01). In CFS patients, in contrast, this significant normal relationship was lost (r(2) = 0.003; P = ns). In normal individuals, the maximum proton efflux following exercise were closely correlated with total heart rate variability (r(2) = 0.7; P = 0.007) this relationship was lost in CFS/ME patients (r(2) < 0.001; P = ns). CONCLUSION: Patients with CFS/ME have abnormalities in recovery of intramuscular pH following standardised exercise degree of which is related to autonomic dysfunction. This study identifies a novel biological abnormality in patients with CFS/ME which is potentially open to modification.

Mariner V: Plasma and Magnetic Fields Observed near Venus.

Abrupt changes in the amplitude of the magnetic fluctuations, in the field strength, and in the plasma properties, were observed with Mariner V near Venus. They provide clear evidence for the presence of a bow shock around the planet, similar to, but much smaller than, that observed at Earth. The observations appear consistent with an interaction of the solar wind with the ionosphere of Venus. No planetary field could be detected, but a steady radial field and very low plasma density were found 10,000 to 20,000 kilometers behind Venus and 8,000 to 12,000 kilometers from the Sun-Venus line. These observations may be interpreted as relating to an expansion wave tending to fill the cavity produced by Venus in the solar wind. The upper limit to the magnetic dipole moment of Venus is estimated to be within a factor of 2 of 10(-3) items that of Earth.

Saturn's Magnetic Field and Magnetosphere.

The Pioneer Saturn vector helium magnetometer has detected a bow shock and magnetopause at Saturn and has provided an accurate characterization of the planetary field. The equatorial surface field is 0.20 gauss, a factor of 3 to 5 times smaller than anticipated on the basis of attempted scalings from Earth and Jupiter. The tilt angle between the magnetic dipole axis and Saturn's rotation axis is < 1 degrees , a surprisingly small value. Spherical harmonic analysis of the measurements shows that the ratio of quadrupole to dipole moments is < 10 percent, indicating that the field is more uniform than those of the Earth or Jupiter and consistent with Saturn having a relatively small core. The field in the outer magnetosphere shows systematic departures from the dipole field, principally a compression of the field near noon and an equatorial orientation associated with a current sheet near dawn. A hydromagnetic wake resulting from the interaction of Titan with the rotating magnetosphere appears to have been observed.

Jupiter's Magnetic Field. Magnetosphere, and Interaction with the Solar Wind: Pioneer 11.

The Pioneer 11 vector helium magnetometer provided precise, contititious measurements of the magnetic fields in interplanetary space, inside Jupiter's magnetosphere, and in the near vicinity of Jupiter. As with the Pioneer 10 data, evidence was seen of the dynanmic interaction of Jupiter with the solar wind which leads to a variety of phenomena (bow shock, upstream waves, nonlinear magnetosheath impulses) and to changes in the dimension of the dayside magnetosphere by as much as a factor of 2. The magnetosphere clearly appears to be blunt, not disk-shaped, with a well-defined outer boundary. In the outer magnetosphere, the magnetic field is irregular but exhibits a persistent southward component indicative of a closed magnetosphere. The data contain the first clear evidence in the dayside magnetosphere of the current sheet, apparently associated with centrifugal forces, that was a donminatnt feature of the outbound Pionieer 10 data. A modest westward spiraling of the field was again evident inbound but not outbound at higher latitudes and nearer the Sun-Jupiter direction. Measurements near periapsis, which were nearer the planet and provide better latitude and longitude coverage than Pioneer 10, have revealed a 5 percent discrepancy with the Pioneer 10 offset dipole mnodel (D(2)). A revised offset dipole (6-parameter fit) is presented as well as the results of a spherical harmonic analysis (23 parameters) consisting of an interior dipole, quadrupole, and octopole and an external dipole and quadrupole. The dipole moment and the composite field appear moderately larger than inferred from Pioneer 10. Maximum surface fields of 14 and 11 gauss in the northern and southern hemispheres are inferred. Jupiter's planetary field is found to be slightly more irregular than that of Earth.

International cometary explorer encounter with giacobini-zinner: magnetic field observations.

The vector helium magnetometer on the International Cometary Explorer observed the magnetic fields induced by the interaction of comet Giacobini-Zinner with the solar wind. A magnetic tail was penetrated approximately 7800 kilometers downstream from the comet and was found to be 10(4) kilometers wide. It consisted of two lobes, containing oppositely directed fields with strengths up to 60 nanoteslas, separated by a plasma sheet approximately 10(3)kilometers thick containing a thin current sheet. The magnetotail was enclosed in an extended ionosheath characterized by intense hydromagnetic turbulene and interplanetary fields draped around the comet. A distant bow wave, which may or may not have been a bow shock, was observed at both edges of the ionosheath. Weak turbulence was observed well upstream of the bow wave.

Magnetic field of jupiter and its interaction with the solar wind.

Jupiter's magnetic field and its interaction with the magnetized solar wind were observed with the Pioneer 10 vector helium magnetometer. The magnetic dipole is directed opposite to that of the earth with a moment of 4.0 gauss R(J)(3) (R(J), Jupiter radius), and an inclination of 15 degrees lying in a system III meridian of 230 degrees . The dipole is offset about 0.1 R(J) north of the equatorial plane and about 0.2 R(J) toward longitude 170 degrees . There is severe stretching of the planetary field parallel to the equator throughout the outer magnetosphere, accompanied by a systematic departure from meridian planes. The field configuration implies substantial plasma effects inside the magnetosphere, such as thermal pressure, centrifugal forces, and differential rotation. As at the earth, the outer boundary is thin, nor diffuse, and there is a detached bow shock.

Activation of peripheral blood monocytes results in more robust production of IL-10 in neonatal foals compared to adult horses.

Foals are particularly vulnerable to infection by Rhodococcus equi during the first 2 weeks of life whereas mature horses are not. While an innate immunodeficiency likely accounts for this clinically relevant vulnerability, the factors that contribute to infection by R. equi have not been fully elucidated. In this study, we demonstrate that cells of the monocyte lineage, including monocytes, macrophages, and dendritic cells, that have been activated with LPS and IFN-gamma, respond with a statistically significant, greater amount of cytokine mRNA production of IL-10, IL-12p35, and IL-12p40 than unstimulated control cells. Interestingly, activation of neonatal cells resulted in a twofold log increase in baseline cytokine mRNA expression of IL-10 compared with adult cells. In contrast, no significant differences in mean cytokine mRNA expression of IL-12p35 and IL-12p40 were detected, suggesting that the defect in chromosomal remodeling that prevents IL-12p35 gene transcription as a cause for decreased IL-12 synthesis in human neonates is not a likely occurrence in equine neonates. Collectively, these differences indicate that in vivo activation of equine cells of the monocyte lineage may result in different autocrine and paracrine cellular responses that vary according to age, with potential impact on regulation of adaptive and innate immune responses.

Detection of polycyclic aromatic hydrocarbons in the shed skins of corn snakes (Elaphe guttata).

Previous work has shown that organochlorine compounds, including chlordane, lindane and polychlorinated biphenyls, and heavy metals, including lead, mercury and cadmium, are readily detected in the shed skins of snakes dosed with these toxicants. This suggested the shed skins may have broad utility as a non-lethal biomarker tissue for environmental contamination. In the present study, two polycyclic aromatic hydrocarbons (PAHs), benzo[a]pyrene (B[a]P) and 3-methylcholanthrene (3-MC), were similarly studied, as representatives of a third major pollutant category of environmental concern. Both compounds were again readily detected in shed snake skins. These collective results suggest considerable environmental contamination information might be obtained from the evaluation of field-collected shed skins. An advantage of such evaluation is that capture, handling or sacrifice of the live animals is not required.

Fatigue in non-alcoholic fatty liver disease (NAFLD) is significant and associates with inactivity and excessive daytime sleepiness but not with liver disease severity or insulin resistance.

OBJECTIVE: To quantify fatigue in non-alcoholic fatty liver disease (NAFLD), to determine whether perceived fatigue reflects impairment of physical function and to explore potential causes. PATIENTS AND METHODS: A cohort study was carried out on 156 consecutive patients with histologically proven NAFLD studied in two cohorts. Phase 1 determined the perceived fatigue experienced by NAFLD patients (assessed using the Fatigue Impact Scale (FIS)) in comparison with normal and liver disease controls, and the relationship to physical function (actigraphy). In phase 2, biological associations of fatigue in NAFLD were explored. RESULTS: Fatigue was markedly higher in NAFLD patients than in controls (mean (SD) FIS 51 (38) vs 8 (12), p<0.001). NAFLD patients showed significantly lower physical activity over 6 days (7089 (2909) mean steps/day vs 8676 (2894), p = 0.02). A significant inverse correlation was seen between FIS and physical activity (r = 0.1, p = 0.02). Fatigue experienced by NAFLD patients was similar to that in primary biliary cirrhosis (n = 36) (FIS 64 (9) vs 61 (2), p = NS). No association was seen between FIS and biochemical and histological markers of liver disease severity or insulin resistance (homeostasis model assessment (HOMA)) (r < 0.005). Significant association was seen between fatigue severity and daytime somnolence (Epworth Sleepiness Scale) (r = 0.2, p < 0.001). CONCLUSION: Fatigue is a significant problem in NAFLD, is similar in degree to that in primary biliary cirrhosis patients and is associated with impairment in physical function. Fatigue in NAFLD appears to be unrelated to either severity of underlying liver disease or insulin resistance, but is associated with significant daytime somnolence.

An open study of modafinil for the treatment of daytime somnolence and fatigue in primary biliary cirrhosis.

BACKGROUND: Fatigue is a debilitating symptom which frequently impairs the quality of life of patients with primary biliary cirrhosis (PBC). Although the mechanisms underpinning fatigue in PBC remain unclear, there is an emerging consensus that CNS mechanisms play a key role. It has recently been shown that there is a strong association between abnormalities in sleep regulation, in particular excessive daytime somnolence, and fatigue severity in PBC. The CNS-acting drug modafinil has an established role in the treatment of excessive daytime somnolence in non-liver disease states. AIM: To explore, in an open label study, the responses of PBC patients suffering from significant daytime somnolence and associated fatigue to modafinil therapy. METHODS: All patients in the series (n = 21) underwent daytime somnolence assessment using the Epworth Sleepiness Scale and PBC symptom assessment using the PBC-40, a multi-domain, disease specific, psychometrically robust quality of life measure. Modafinil was started at a dose of 100 mg/day and was titrated according to tolerability and response. Patients underwent repeat Epworth Sleepiness Scale and PBC-40 assessment after 2 months of treatment. RESULTS: Significant improvement was seen in Epworth Sleepiness Scale scores with modafinil therapy [15 +/- 3 vs. 8 +/- 6, P < 0.0005 (intention-to-treat analysis)]. An equally significant improvement in fatigue severity was also seen [PBC-40 fatigue domain score (46 +/- 6 vs. 34 +/- 12, P < 0.0001) (intention-to-treat analysis)]. CONCLUSIONS: Open label modafinil therapy was associated, where tolerated by patients, with improvement in excessive daytime somnolence and associated fatigue in PBC. Further study in placebo-controlled trials is warranted.

Symptoms of autonomic dysfunction in chronic fatigue syndrome.

BACKGROUND: Chronic fatigue syndrome (CFS) is common and its cause is unknown. AIM: To study the prevalence of autonomic dysfunction in CFS, and to develop diagnostic criteria. DESIGN: Cross-sectional study with independent derivation and validation phases. METHODS: Symptoms of autonomic dysfunction were assessed using the Composite Autonomic Symptom Scale (COMPASS). Fatigue was assessed using the Fatigue Impact Scale (FIS). Subjects were studied in two groups: phase 1 (derivation phase), 40 CFS patients and 40 age- and sex-matched controls; phase 2 (validation phase), 30 CFS patients, 37 normal controls and 60 patients with primary biliary cirrhosis. RESULTS: Symptoms of autonomic dysfunction were strongly and reproducibly associated with the presence of CFS or primary biliary cirrhosis (PBC), and correlated with severity of fatigue. Total COMPASS score >32.5 was identified in phase 1 as a diagnostic criterion for autonomic dysfunction in CFS patients, and was shown in phase 2 to have a positive predictive value of 0.96 (95%CI 0.86-0.99) and a negative predictive value of 0.84 (0.70-0.93) for the diagnosis of CFS. DISCUSSION: Autonomic dysfunction is strongly associated with fatigue in some, but not all, CFS and PBC patients. We postulate the existence of a 'cross-cutting' aetiological process of dysautonomia-associated fatigue (DAF). COMPASS >32.5 is a valid diagnostic criterion for autonomic dysfunction in CFS and PBC, and can be used to identify patients for targeted intervention studies.

Calcaneal bone mineral density in older patients who have fallen.

BACKGROUND: Annually, 35-40% of those aged >65 years fall; up to 5% of such falls result in fracture. Fracture is determined both by propensity to fall and by bone fragility. AIM: To determine osteoporosis prevalence and predictors in patients who have fallen. DESIGN: Observational cross-sectional study. METHODS: We measured calcaneal BMD in 408 consecutive patients aged >50 years attending after falling. Fall number, fracture history, weight, height, and risk factors for falls and osteoporosis were recorded. T scores (SD above or below the mean for young adults) were derived in both sexes, and Z scores (SD above or below age-related normal score) in females. RESULTS: In females (n = 300, 74%), mean (SD) T score was -1.1(1.6), and mean Z score was 0(1.4); 127 (42%) had osteoporosis (T score < - 1.6). ROC curves confirmed significant relationships between osteoporosis and age, weight and height (all p < 0.0001). Incorporating fracture history, our model (fracture aged >50 years, age >83 years, weight <57 kg, height <153 cm as dichotomous variables) predicted osteoporosis with 91% sensitivity, 34% specificity. Of 108 male fallers, 36 (33%) had osteoporosis. Age, height and weight all predicted osteoporosis (p < 0.02). The resulting model (fracture aged >50 years, age > or =80 years, weight < or =68 kg, height < or =167 cm as dichotomous variables) predicted osteoporosis with 92% sensitivity, 30% specificity. DISCUSSION: Osteoporosis prevalence is not increased in female fallers compared to age-related norms; empirical use of osteoporosis treatment solely on the basis of falls thus appears inappropriate. In both sexes, the factors predicting osteoporosis were age, height and weight. Where BMD is not practical, possible or economical, our model may be a sensitive means of predicting fallers with osteoporosis.

The inter-relationship of symptom severity and quality of life in 2055 patients with primary biliary cholangitis.

BACKGROUND: Age at presentation with primary biliary cholangitis (PBC) is associated with differential response to ursodeoxycholic acid (UDCA) therapy. Younger-presenting patients are less likely to respond to treatment and more likely to need transplant or die from the disease. PBC has a complex impact on quality of life (QoL), with systemic symptoms often having significant impact. AIM: To explain the impact of age at presentation on perceived QoL and the inter-related symptoms which impact upon it. METHODS: Using the UK-PBC cohort, symptoms were assessed using the PBC-40 and other validated tools. Data were available on 2055 patients. RESULTS: Of the 1990 patients reporting a global PBC-QoL score, 66% reported good/neutral scores and 34% reported poor scores. Each 10-year increase in age at presentation was associated with a 14% decrease in risk of poor perceived QoL (OR = 0.86, 95% CI: 0.75-0.98, P < 0.05). All symptom domains were similarly age-associated (P < 0.01). Social dysfunction was the symptom factor with the greatest impact on QoL. Median (interquartile range) PBC-40 social scores for patients with good perceived QoL were 18 (14-23) compared with 34 (29-39) for those with poor QoL. CONCLUSION: The majority of patients with primary biliary cholangitis do not feel their QoL is impaired, although impairment is reported by a sizeable minority. Age at presentation is associated with impact on perceived QoL and the symptoms impairing it, with younger patients being more affected. Social dysfunction makes the greatest contribution to QoL impairment, and it should be targeted in trials aimed at improving life quality.