Single-centre, single-blinded, randomised, parallel group, feasibility study protocol investigating if mandibular advancement device treatment for obstructive sleep apnoea can reduce nocturnal gastro-oesophageal reflux (MAD-Reflux trial).

INTRODUCTION: Just under half of patients with obstructive sleep apnoea (OSA) also have gastro-oesophageal reflux disease (GORD). These conditions appear to be inter-related and continual positive airway pressure (CPAP) therapy, the gold standard treatment for OSA to prevent airway collapse, has been shown to reduce GORD. As the impact of mandibular advancement devices, a second-line therapy for OSA, on GORD has yet to be investigated, a feasibility study is needed prior to a definitive trial. METHODS: This will be a single-centre, single-blinded, tertiary-care based, interdisciplinary, parallel randomised controlled study. Potential OSA participants presenting to the sleep department will be pre-screened for GORD using validated questionnaires, consented and invited to receive simultaneous home sleep and oesophageal pH monitoring. Those with confirmed OSA and GORD (n=44) will be randomly allocated to receive either CPAP (n=22) or MAD therapy (n=22). Following successful titration and 3 weeks customisation period, participants will repeat the simultaneous sleep and oesophageal pH monitoring while wearing the device. The number of patients screened for recruitment, drop-out rates, patient feedback of the study protocol, costs of interventions and clinical information to inform a definitive study design will be investigated. ETHICS AND DISSEMINATION: Health Research Authority approval has been obtained from the Nottingham 2 Research Ethics Committee, ref:22/EM/0157 and the trial has been registered on ISRCTN (https://doi.org/10.1186/ISRCTN16013232). Definitive findings about the feasibility of doing 24 hour pH oesophageal monitoring while doing a home sleep study will be disseminated via clinical and research networks facilitating valuable insights into the simultaneous management of both conditions. TRIAL REGISTRATION NUMBER: ISRCTN Reg No: 16013232.

Study protocol for the management of impacted maxillary central incisors: a multicentre randomised clinical trial: the iMAC Trial.

BACKGROUND: Failure of eruption of the maxillary permanent incisor teeth usually presents in the mixed dentition between the ages of 7 and 9 years. Missing and unerupted maxillary incisors can be regarded as unattractive and have a potentially negative impact on facial and dental aesthetics. The presence of a supernumerary tooth (or odontoma) is commonly responsible for failed eruption or impaction of the permanent maxillary incisors. The primary objective of this trial is to investigate the success of eruption associated with maxillary incisor teeth that have failed to erupt because of a supernumerary tooth in the anterior maxilla. METHODS: This protocol describes an interventional multicentre two-arm randomised clinical trial. Participants meeting the eligibility criteria will be randomised (unrestricted equal participant allocation [1:1]) to either space creation with an orthodontic appliance, removal of the supernumerary tooth and application of direct orthodontic traction or space creation with an orthodontic appliance, removal of the supernumerary tooth and monitoring. The primary outcome of this trial is to determine the prevalence of successfully erupted maxillary central permanent incisors at 6 months following removal of the supernumerary tooth. Secondary outcome measures include (1) the effect of initial tooth position (assessed radiographically) on time taken for the tooth to erupt, (2) time taken to align the unerupted tooth to the correct occlusal position, (3) gingival aesthetics and (4) changes in the self-reported Oral Health Related-Quality of Life (OHRQoL) (pre-and post-treatment). DISCUSSION: There is a lack of high-quality robust prospective studies comparing the effectiveness of interventions to manage this condition. Furthermore, the UK national clinical guidelines have highlighted a lack of definitive treatment protocols for the management of children who present with an unerupted maxillary incisor due to the presence of a supernumerary tooth. The results of this trial will inform future treatment guidelines for the management of this condition in young children. TRIAL REGISTRATION: ISRCTN Registry ISRCTN12709966 . Registered on 16 June 2022.

Pulpotomy for the Management of Irreversible Pulpitis in Mature Teeth (PIP): a feasibility study.

BACKGROUND: Progression of dental caries can result in irreversible pulpal damage. Partial irreversible pulpitis is the initial stage of this damage, confined to the coronal pulp whilst the radicular pulp shows little or no sign of infection. Preserving the pulp with sustained vitality and developing minimally invasive biologically based therapies are key themes within contemporary clinical practice. However, root canal treatment involving complete removal of the pulp is often the only option (other than extraction) given to patients with irreversible pulpitis, with substantial NHS and patient incurred costs. The European Society of Endodontology's (ESE 2019) recent consensus statement recommends full pulpotomy, where the inflamed coronal pulp is removed with the goal of keeping the radicular pulp vital, as a more minimally invasive technique, potentially avoiding complex root canal treatment. Although this technique may be provided in secondary care, it has not been routinely implemented or evaluated in UK General Dental Practice. METHOD: This feasibility study aims to identify and assess in a primary care setting the training needs of general dental practitioners and clinical fidelity of the full pulpotomy intervention, estimate likely eligible patient pool and develop recruitment materials ahead of the main randomised controlled trial comparing the clinical and cost-effectiveness of full pulpotomy compared to root canal treatment in pre/molar teeth of adults 16 years and older showing signs indicative of irreversible pulpitis. The feasibility study will recruit and train 10 primary care dentists in the full pulpotomy technique. Dentists will recruit and provide full pulpotomy to 40 participants (four per practice) with indications of partial irreversible pulpitis. DISCUSSION: The Pulpotomy for the Management of Irreversible Pulpitis in Mature Teeth (PIP) study will address the lack of high-quality evidence in the treatment of irreversible pulpitis, to aid dental practitioners, patients and policymakers in their decision-making. The PIP feasibility study will inform the main study on the practicality of providing both training and provision of the full pulpotomy technique in general dental practice. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN17973604 . Registered on 28 January 2021. Protocol version Protocol version: 1; date: 03.02.2021.

Effect of Vitamin D Supplementation on Outcomes in People With Early Psychosis: The DFEND Randomized Clinical Trial.

Importance: People with psychotic disorders have an increased risk of vitamin D deficiency, which is evident during first-episode psychosis (FEP) and associated with unfavorable mental and physical health outcomes. Objective: To examine whether vitamin D supplementation contributes to improved clinical outcomes in FEP. Design, Setting, and Participants: This multisite, double-blind, placebo-controlled, parallel-group randomized clinical trial from the UK examined adults 18 to 65 years of age within 3 years of a first presentation with a functional psychotic disorder who had no contraindication to vitamin D supplementation. A total of 2136 patients were assessed for eligibility, 835 were approached, 686 declined participation or were excluded, 149 were randomized, and 104 were followed up at 6 months. The study recruited participants from January 19, 2016, to June 14, 2019, with the final follow-up (after the last dose) completed on December 20, 2019. Interventions: Monthly augmentation with 120 000 IU of cholecalciferol or placebo. Main Outcomes and Measures: The primary outcome measure was total Positive and Negative Syndrome Scale (PANSS) score at 6 months. Secondary outcomes included total PANSS score at 3 months; PANSS positive, negative, and general psychopathology subscale scores at 3 and 6 months; Global Assessment of Function scores (for symptoms and disability); Calgary Depression Scale score, waist circumference, body mass index, and glycated hemoglobin, total cholesterol, C-reactive protein, and vitamin D concentrations at 6 months; and a planned sensitivity analysis in those with insufficient vitamin D levels at baseline. Results: A total of 149 participants (mean [SD] age, 28.1 (8.5) years; 89 [59.7%] male; 65 [43.6%] Black or of other minoritized racial and ethnic group; 84 [56.4%] White [British, Irish, or of other White ethnicity]) were randomized. No differences were observed in the intention-to-treat analysis in the primary outcome, total PANSS score at 6 months (mean difference, 3.57; 95% CI, -1.11 to 8.25; P = .13), or the secondary outcomes at 3 and 6 months (PANSS positive subscore: mean difference, -0.98; 95% CI, -2.23 to 0.27 at 3 months; mean difference, 0.68; 95% CI, -0.69 to 1.99 at 6 months; PANSS negative subscore: mean difference, 0.68; 95% CI, -1.39 to 2.76 at 3 months; mean difference, 1.56; 95% CI, -0.31 to 3.44 at 6 months; and general psychopathology subscore: mean difference, -2.09; 95% CI, -4.36 to 0.18 at 3 months; mean difference, 1.31; 95% CI, -1.42 to 4.05 at 6 months). There also were no significant differences in the Global Assessment of Function symptom score (mean difference, 0.02; 95% CI, -4.60 to 4.94); Global Assessment of Function disability score (mean difference, -0.01; 95% CI, -5.25 to 5.23), or Calgary Depression Scale score (mean difference, -0.39; 95% CI, -2.05 to 1.26) at 6 months. Vitamin D levels were very low in the study group, especially in Black participants and those who identified as another minoritized racial and ethnic group, 57 of 61 (93.4%) of whom had insufficient vitamin D. The treatment was safe and led to a significant increase in 25-hydroxyvitamin D concentrations. Conclusions and Relevance: In this randomized clinical trial, no association was found between vitamin D supplementation and mental health or metabolic outcomes at 6 months. Because so few patients with FEP were vitamin D replete, the results of this study suggest that this group would benefit from active consideration in future population health strategies. Trial Registration: isrctn.org Identifier: ISRCTN12424842.

Epilepsy and mortality: a retrospective cohort analysis with a nested case-control study identifying causes and risk factors from primary care and linkage-derived data.

OBJECTIVES: People with epilepsy (PWE) have a higher mortality rate than the general population. Epilepsy-related deaths have increased despite all-cause mortality decreasing in the general population pre-COVID-19. We hypothesised that clinical and lifestyle factors may identify people more at risk. DESIGN: We used a retrospective cohort study to explore cause of death and a nested case-control study to identify risk factors. SETTING: We explored factors associated with mortality using primary care population data from 1 April 2004 to 31 March 2014. Data were obtained from the Clinical Practice Research Datalink which compiles anonymised patient data from primary care in the UK. Cause of death data was supplemented from the Office of National Statistics when available. PARTICIPANTS: The analysis included 70 431 PWE, with 11 241 registered deaths. RESULTS: The number of deaths within the database increased by 69% between the first and last year of the study. Epilepsy was considered as a contributing cause in approximately 45% of deaths of PWE under 35. Factors associated with increased risk of death included attendance at emergency departments and/or emergency admissions (OR 3.48, 95% CI 3.19 to 3.80), antiepileptic drug (AED) polytherapy (2 AEDs: OR 1.60, 95% CI 1.51 to 1.71; 3 AEDs: OR 2.06, 95% CI 1.86 to 2.29; 4+AEDs: OR 2.62, 95% CI 2.23 to 3.08), status epilepticus (OR 2.78, 95% CI 1.64 to 4.71), depression (OR 1.67, 95% CI 1.57 to 1.76) and injuries (OR 1.54, 95% CI 1.43 to 1.67). No seizures in the prior year (OR 0.52, 95% CI 0.41 to 0.65). CONCLUSION: Our results add to existing evidence that deaths in epilepsy are increasing. Future studies could focus on identifying PWE at high risk and addressing them with clinical interventions or better self-management. Identifying specific risk factors for younger people should be a priority as epilepsy may be a factor in close to half of deaths of PWE under 35 years of age.

Best care for older people with epilepsy: A scoping review.

There are two peaks of diagnosis of epilepsy: in childhood and in people over 65. Older people may have complex needs like co-morbidity, polypharmacy, frailty, and social isolation. This scoping review focusses on the care of older people with epilepsy beyond diagnosis and medical treatment. We sought to identify areas within the UK health service needing development either in clinical practice or through further research. The search returned 4864 papers with 33 papers included in the review. The papers were grouped into psychosocial, self-management and services themes. Only one randomised controlled trial was found. Research was mainly based on cohort and case-control studies. Older people require more information to self-manage epilepsy and more psychological support to help with symptoms of anxiety and depression. People reported experiencing stigma and a reluctance to disclose their condition. This may increase the risk of isolation and difficulties in managing epilepsy. Studies reported that older people are referred less to neurologists, suggesting there may be a gap in care provision compared to younger people. Generalist health professionals may be better placed to provide holistic care, but they may need additional training to alleviate uncertainties in managing epilepsy. Care plans could help provide information, particularly for co-morbidity, but few had one. Our findings highlight psychological and self-management needs for managing epilepsy in older people. Health service staff may require upskilling to shift epilepsy management from neurologists to generalists. More research is needed regarding psychological and self-management interventions, particularly in the form of randomised controlled trials.

Vitamin D supplementation compared to placebo in people with First Episode psychosis - Neuroprotection Design (DFEND): a protocol for a randomised, double-blind, placebo-controlled, parallel-group trial.

BACKGROUND: People experiencing their first episode of psychosis are often deficient in vitamin D. Observational studies have reported an association between low vitamin D concentrations and poorer subsequent health outcomes in psychosis. A vitamin D deficiency in neonates and children has been linked to a later increased risk of schizophrenia and psychotic-like experiences. This trial aims to examine the effect of high-dose vitamin D supplementation on outcomes in early psychosis. We hypothesise that vitamin D supplementation will be associated with better mental health outcomes. METHODS/DESIGN: The DFEND study is a multicentre double-blind placebo-controlled parallel-group trial of vitamin D supplementation in people with early psychosis. Patients with an ICD-10 diagnosis of functional psychosis will be randomised in a 1:1 ratio to receive either 120,000 IU/month of vitamin D (cholecalciferol) or a matched placebo for 6 months. The primary outcome is the total Positive and Negative Syndrome Scale (PANSS) score at the 6-month follow-up for all patients. Secondary outcomes include assessment of mood (Calgary Depression Scale), general function (Global Assessment of Functioning), cardiovascular risk (body mass index, waist circumference, C-reactive protein, cholesterol and HbA1c) and vitamin D levels at the 6-month follow-up. Additionally, 3- and 6-month total PANSS scores will be analysed for those with inadequate vitamin D levels at the baseline. DISCUSSION: The DFEND study is the first trial to examine whether vitamin D supplementation in early psychosis is associated with better mental health outcomes. The findings of this study may help to resolve the clinical equipoise regarding the benefits and cost-effectiveness of routine vitamin D supplementation in people with psychosis. TRIAL REGISTRATION: ISRCTN, ISRCTN12424842. Registered on 25 February 2015.

Should GPs have direct access to imaging for headache? A qualitative study of patients' views in the UK.

OBJECTIVE: We aimed to describe patients' views of a new referral pathway of general practitioner (GP) direct access to MRI, versus imaging after referral to a specialist. DESIGN: This qualitative study involved 20 semistructured interviews. Twenty patients (10 from each pathway) were purposively recruited and interviewed to describe their attitudes. SETTING: A neurology headache clinic and neuroradiology services from the boroughs of Southwark and Lambeth in South London, UK. PARTICIPANTS: Twenty patients were involved in this study. RESULTS: Over half of the participants felt relieved once they received their scan results, while some remained uncertain about the underlying cause of their symptoms. Some participants described a long wait to see a specialist. Others described a long wait time to receive scan results, especially from their GP. Spontaneous reduction in headache symptoms occurred for some participants and for others, normal imaging results allowed them to focus more on symptom management. CONCLUSION: Relief was reported especially when scan results had been explained clearly and without too much delay. Those with continuing pain focused on how to get relief from symptoms. Patient experience might be improved with clearer information from GPs about how patients can access results, standard reporting procedures and closer liaison between neuroradiology and GPs.

Self-Management education for adults with poorly controlled epILEpsy [SMILE (UK)]: a randomised controlled trial.

BACKGROUND: Epilepsy is a common neurological condition resulting in recurrent seizures. Research evidence in long-term conditions suggests that patients benefit from self-management education and that this may improve quality of life (QoL). Epilepsy self-management education has yet to be tested in a UK setting. OBJECTIVES: To determine the effectiveness and cost-effectiveness of Self-Management education for people with poorly controlled epILEpsy [SMILE (UK)]. DESIGN: A parallel pragmatic randomised controlled trial. SETTING: Participants were recruited from eight hospitals in London and south-east England. PARTICIPANTS: Adults aged ≥ 16 years with epilepsy and two or more epileptic seizures in the past year, who were currently being prescribed antiepileptic drugs. INTERVENTION: A 2-day group self-management course alongside treatment as usual (TAU). The control group received TAU. MAIN OUTCOME MEASURES: The primary outcome is QoL in people with epilepsy at 12-month follow-up using the Quality Of Life In Epilepsy 31-P (QOLIE-31-P) scale. Other outcomes were seizure control, impact of epilepsy, medication adverse effects, psychological distress, perceived stigma, self-mastery and medication adherence. Cost-effectiveness analyses and a process evaluation were undertaken. RANDOMISATION: A 1 : 1 ratio between trial arms using fixed block sizes of two. BLINDING: Participants were not blinded to their group allocation because of the nature of the study. Researchers involved in data collection and analysis remained blinded throughout. RESULTS: The trial completed successfully. A total of 404 participants were enrolled in the study [SMILE (UK), n = 205; TAU, n = 199] with 331 completing the final follow-up at 12 months [SMILE (UK), n = 163; TAU, n = 168]. In the intervention group, 61.5% completed all sessions of the course. No adverse events were found to be related to the intervention. At baseline, participants had a mean age of 41.7 years [standard deviation (SD) 14.1 years], and had epilepsy for a median of 18 years. The mean QOLIE-31-P score for the whole group at baseline was 66.0 out of 100.0 (SD 14.2). Clinically relevant levels of anxiety symptoms were reported in 53.6% of the group and depression symptoms in 28.0%. The results following an intention-to-treat analysis showed no change in any measures at the 12-month follow-up [QOLIE-31-P: SMILE (UK) mean: 67.4, SD 13.5; TAU mean: 69.5, SD 14.8]. The cost-effectiveness study showed that SMILE (UK) was possibly cost-effective but was also associated with lower QoL. The process evaluation with 20 participants revealed that a group course increased confidence by sharing with others and improved self-management behaviours. CONCLUSIONS: For people with epilepsy and persistent seizures, a 2-day self-management education course is cost-saving, but does not improve QoL after 12-months or reduce anxiety or depression symptoms. A psychological intervention may help with anxiety and depression. Interviewed participants reported attending a group course increased their confidence and helped them improve their self-management. FUTURE WORK: More research is needed on self-management courses, with psychological components and integration with routine monitoring. TRIAL REGISTRATION: Current Controlled Trials ISRCTN57937389. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 21. See the NIHR Journals Library website for further project information.

The effectiveness of a group self-management education course for adults with poorly controlled epilepsy, SMILE (UK): A randomized controlled trial.

OBJECTIVE: Epilepsy is one of the most common neurological conditions affecting about 1% of adults. Up to 40% of people with epilepsy (PWE) report recurring seizures while on medication. And optimal functioning requires good self-management. Our objective was to evaluate a group self-management education courses for people with epilepsy and drug-resistant seizures by means of a multicenter, pragmatic, parallel group, randomized controlled trial. METHODS: We recruited adults with epilepsy, having ≥2 seizures in the prior 12 months, from specialist clinics. Consenting participants were randomized 1:1 to a group course or treatment as usual. The primary outcome measure was quality of life 12 months after randomization using Quality of Life 31-P (QOLIE-31-P). Secondary outcome measures were seizure frequency and recency, psychological distress, impact and stigma of epilepsy, self-mastery, medication adherence, and adverse effects. Analysis of outcomes followed the intention-to-treat principle using mixed-effects regression models. RESULTS: We enrolled 404 participants (intervention: n = 205, control: n = 199) with 331 (82%) completing 12-month follow-up (intervention: n = 163, control: n = 168). Mean age was 41.7 years, ranging from 16 to 85, 54% were female and 75% were white. From the intervention arm, 73.7% attended all or some of the course. At 12-month follow-up, there were no statistically significant differences between trial arms in QOLIE-31-P (intervention mean: 67.4, standard deviation [SD]: 13.5; control mean: 69.5, SD 14.8) or in secondary outcome measures. SIGNIFICANCE: This is the first pragmatic trial of group education for people with poorly controlled epilepsy. Recruitment, course attendance, and follow-up rates were higher than expected. The results show that the primary outcome and quality of life did not differ between the trial arms after 12 months. We found a high prevalence of felt-stigma and psychological distress in this group of people with drug-resistant seizures. To address this, social and psychological interventions require evaluation, and may be necessary before or alongside self-management-education courses.

Fenretinide differentially modulates the levels of long- and very long-chain ceramides by downregulating Cers5 enzyme: evidence from bench to bedside.

Cystic fibrosis is the most common genetic disease, in which symptoms may be alleviated but not fully eliminated. Ceramides have long been implicated in the inflammatory etiology of cystic fibrosis, with contradicting reports with regards to their role. Recently, significant biological and biophysical differences have been observed between long- and very long-chain ceramides. This work reveals that long-chain ceramides are upregulated whereas very long-chain ceramides are downregulated in cell lines, mouse animal model, and patients with cystic fibrosis, compared with their controls. Treatment with fenretinide decreases the levels of long-chain ceramides and increases the levels of very long-chain ceramides. Our results show that restoration of cystic fibrosis conductance regulator (CFTR) expression is associated with normalization of aberrant levels of specific ceramides. This demonstrates for the first time a correlation between CFTR protein expression and regulation of specific ceramide levels. Furthermore, using cystic fibrosis lung epithelial cell lines, we demonstrate that this effect can be attributed to the transcriptional downregulation of ceramide synthase 5 (Cers5) enzyme. We also discovered a partial synergism between fenretinide and zinc (Zn2+), which deficiency has been reported in patients with cystic fibrosis. Overall, in addition to having direct translational application, we believe that our findings contribute to the understanding of ceramide metabolism in cystic fibrosis, as well as other inflammatory diseases where imbalances of ceramides have also been observed. KEY MESSAGES: Long- and very long-chain ceramides (LCCs and VLCCs) are biochemically distinct. LCCs are upregulated whereas VLCCs are downregulated in cystic fibrosis. Fenretinide downregulates the levels of LCCs and upregulates the levels of VLCCs. Fenretinide changes the balance of LCCs and VLCCs by downregulating Cers5 enzyme. Fenretinide and zinc ions cooperate in the modulation of ceramide levels.

A systematic review and narrative synthesis of group self-management interventions for adults with epilepsy.

BACKGROUND: Epilepsy is a serious and costly long-term condition that negatively affects quality of life, especially if seizures persist on medication. Studies show that people with epilepsy (PWE) want to learn more about the condition and some educational self-management courses have been trialled internationally. The objectives of this review were to evaluate research and summarise results on group self-management interventions for PWE. METHODS: We searched Medline and PsycINFO for results published in English between 1995 and 2015. Only studies evaluating face-to-face, group interventions for adults with epilepsy were included. Heterogeneity in study outcomes prevented the carrying out of a meta-analysis; however, a Cochrane style review was undertaken. RESULTS: We found eleven studies, nine of which were randomised controlled trials. There were variable standards of methodological reporting with some risk of bias. Seven of the studies used quality of life as an outcome, with four finding statistically significant improvements in mean total score. Two found an improvement in outcome subscales. One study included some additional semi-qualitative data. CONCLUSIONS: We identified promising trends in the trials reviewed. In particular, there were significant improvements in quality of life scales and seizure frequency in many of the interventions. However, considerable heterogeneity of interventions and outcomes made comparison between the studies difficult. Courses that included psychological interventions and others that had a high number of sessions showed more effect than short educational courses. Furthermore, the evidence was predominantly from pilot studies with small sample sizes and short follow-up duration. Further research is needed to better evaluate the role of group self-management interventions in outpatient epilepsy management.

Characteristics associated with quality of life among people with drug-resistant epilepsy.

Quality of Life (QoL) is the preferred outcome in non-pharmacological trials, but there is little UK population evidence of QoL in epilepsy. In advance of evaluating an epilepsy self-management course we aimed to describe, among UK participants, what clinical and psycho-social characteristics are associated with QoL. We recruited 404 adults attending specialist clinics, with at least two seizures in the prior year and measured their self-reported seizure frequency, co-morbidity, psychological distress, social characteristics, including self-mastery and stigma, and epilepsy-specific QoL (QOLIE-31-P). Mean age was 42 years, 54% were female, and 75% white. Median time since diagnosis was 18 years, and 69% experienced ≥10 seizures in the prior year. Nearly half (46%) reported additional medical or psychiatric conditions, 54% reported current anxiety and 28% reported current depression symptoms at borderline or case level, with 63% reporting felt stigma. While a maximum QOLIE-31-P score is 100, participants' mean score was 66, with a wide range (25-99). In order of large to small magnitude: depression, low self-mastery, anxiety, felt stigma, a history of medical and psychiatric comorbidity, low self-reported medication adherence, and greater seizure frequency were associated with low QOLIE-31-P scores. Despite specialist care, UK people with epilepsy and persistent seizures experience low QoL. If QoL is the main outcome in epilepsy trials, developing and evaluating ways to reduce psychological and social disadvantage are likely to be of primary importance. Educational courses may not change QoL, but be one component supporting self-management for people with long-term conditions, like epilepsy.

Correction of lung inflammation in a F508del CFTR murine cystic fibrosis model by the sphingosine-1-phosphate lyase inhibitor LX2931.

Progressive lung disease with early onset is the main cause of mortality and morbidity in cystic fibrosis patients. Here we report a reduction of sphingosine-1-phosphate (S1P) in the lung of unchallenged Cftrtm1EUR F508del CFTR mutant mice. This correlates with enhanced infiltration by inducible nitric oxide synthase (iNOS)-expressing granulocytes, B cells, and T cells. Furthermore, the ratio of macrophage-derived dendritic cells (MoDC) to conventional dendritic cells (cDC) is higher in mutant mouse lung, consistent with unprovoked inflammation. Oral application of a S1P lyase inhibitor (LX2931) increases S1P levels in mutant mouse tissues. This normalizes the lung MoDC/cDC ratio and reduces B and T cell counts. Lung granulocytes are enhanced, but iNOS expression is reduced in this population. Although lung LyC6+ monocytes are enhanced by LX2931, they apparently do not differentiate to MoDC and macrophages. After challenge with bacterial toxins (LPS-fMLP) we observe enhanced levels of proinflammatory cytokines TNF-α, KC, IFNγ, and IL-12 and the inducible mucin MUC5AC in mutant mouse lung, evidence of deficient resolution of inflammation. LX2931 does not prevent transient inflammation or goblet cell hyperplasia after challenge, but it reduces MUC5AC and proinflammatory cytokine levels toward normal values. We conclude that lung pathology in homozygous mice expressing murine F508del CFTR, which represents the most frequent mutation in CF patients, is characterized by abnormal behavior of infiltrating myeloid cells and delayed resolution of induced inflammation. This phenotype can be partially corrected by a S1P lyase inhibitor, providing a rationale for therapeutic targeting of the S1P signaling pathway in CF patients.

C-Reactive Protein in Stable Cystic Fibrosis: An Additional Indicator of Clinical Disease Activity and Risk of Future Pulmonary Exacerbations.

INTRODUCTION: In stable adult cystic fibrosis (CF) patients, we assessed the role of baseline high sensitivity C-reactive protein (hs-CRP) on CF clinical variables and frequency of intravenous (IV) treated pulmonary exacerbations (PExs) 1-year post-baseline. METHODS: We recruited 51 clinically stable CF patients from our Adult CF Center. We incorporated collected parameters into Matouk CF clinical score and CF questionnaire-revised quality of life score (QOL). We used the clinical minus complications subscores as a clinical disease activity score (CDAS). We dichotomized our patients according to the cohort median baseline hs-CRP of 5.2 mg/L. RESULTS: Patients in the high hs-CRP group (≥ 5.2 mg/L) demonstrated worse CDAS (r=0.67, p=0.0001) and QOL scores (r=0.57, p=0.0017) at a given FEV1% predicted. In both hs-CRP groups, prior-year IV-treated PExs and baseline CDASs were significant predictors of future IV-treated PExs. Interestingly, the association between baseline CDAS and future PExs frequency was more robust in the high compared to the low hs-CRP group (r=-0.88, p<0.0001, r=-0.48, p=0.017, respectively) with a steeper regression slope (p=0.001). In addition, a significant interaction was demonstrated between elevated baseline hs-CRP levels and CDASs for the prediction of increased risk of future PExs (p=0.02). This interaction provided an additional indicator of clinical disease activity and added another dimension to the prior year PExs frequency phenotype to identify patients at increased risk for future PExs. CONCLUSION: Stable CF patients with elevated baseline hs-CRP (≥ 5.2 mg/L) demonstrated worse clinical disease activity and QOL scores at a given level of disease severity (FEV1% predicted). Elevated baseline hs-CRP values combined with clinical disease activity scores are associated with increased risk for future IV-treated PExs even in those with mild clinical disease activity scores.

Cystic fibrosis-adapted Pseudomonas aeruginosa quorum sensing lasR mutants cause hyperinflammatory responses.

Cystic fibrosis lung disease is characterized by chronic airway infections with the opportunistic pathogen Pseudomonas aeruginosa and severe neutrophilic pulmonary inflammation. P. aeruginosa undergoes extensive genetic adaptation to the cystic fibrosis (CF) lung environment, and adaptive mutations in the quorum sensing regulator gene lasR commonly arise. We sought to define how mutations in lasR alter host-pathogen relationships. We demonstrate that lasR mutants induce exaggerated host inflammatory responses in respiratory epithelial cells, with increased accumulation of proinflammatory cytokines and neutrophil recruitment due to the loss of bacterial protease- dependent cytokine degradation. In subacute pulmonary infections, lasR mutant-infected mice show greater neutrophilic inflammation and immunopathology compared with wild-type infections. Finally, we observed that CF patients infected with lasR mutants have increased plasma interleukin-8 (IL-8), a marker of inflammation. These findings suggest that bacterial adaptive changes may worsen pulmonary inflammation and directly contribute to the pathogenesis and progression of chronic lung disease in CF patients.

Evolution of the Immune Response to Chronic Airway Colonization with Aspergillus fumigatus Hyphae.

Airway colonization by the mold Aspergillus fumigatus is common in patients with underlying lung disease and is associated with chronic airway inflammation. Studies probing the inflammatory response to colonization with A. fumigatus hyphae have been hampered by the lack of a model of chronic colonization in immunocompetent mice. By infecting mice intratracheally with conidia embedded in agar beads (Af beads), we have established an in vivo model to study the natural history of airway colonization with live A. fumigatus hyphae. Histopathological examination and galactomannan assay of lung homogenates demonstrated that hyphae exited beads and persisted in the lungs of mice up to 28 days postinfection without invasive disease. Fungal lesions within the airways were surrounded by a robust neutrophilic inflammatory reaction and peribronchial infiltration of lymphocytes. Whole-lung cytokine analysis from Af bead-infected mice revealed an increase in proinflammatory cytokines and chemokines early in infection. Evidence of a Th2 type response was observed only early in the course of colonization, including increased levels of interleukin-4 (IL-4), elevated IgE levels in serum, and a mild increase in airway responsiveness. Pulmonary T cell subset analysis during infection mirrored these results with an initial transient increase in IL-4-producing CD4(+) T cells, followed by a rise in IL-17 and Foxp3(+) cells by day 14. These results provide the first report of the evolution of the immune response to A. fumigatus hyphal colonization.

Lycopene improves the distorted ratio between AA/DHA in the seminal plasma of infertile males and increases the likelihood of successful pregnancy.

AIMS: Male infertility has been associated with imbalance in the polyunsaturated fatty acids arachidonic acid/docosahexaenoic acid (AA/DHA) ratio. This study aimed to assess whether use of the potent antioxidant, lycopene, would affect this imbalance in seminal plasma and to test whether modulation of the AA/DHA ratio correlates with male fertility. METHODS: The study included 44 males from infertile couples who were treated with lycopene for three months before scheduled IVF treatment. The control group was 13 fertile males who were also treated with lycopene for three months. AA and DHA levels were measured in seminal plasma before and after treatment. The outcome of IVF treatment after lycopene use in of males from infertile couples was recorded. RESULTS: The subjects were subdivided into 21 normozoospermic males from couples with idiopathic infertility and 23 males with semen abnormalities. Prior to the treatment with lycopene, the AA/DHA ratios in both subgroups of patients were significantly higher than in fertile controls and improved following treatment with lycopene. Improvement was more marked in the normospermic males. Seven spontaneous pregnancies (16%) occurred before the scheduled IVF treatment and 15 couples (42%) achieved pregnancy after IVF. CONCLUSIONS: Three months of treatment with lycopene led to a significant improvement in the AA/DHA ratio in seminal plasma of males from infertile couples and facilitated the spontaneous as well as IVF conception.

Candidate markers associated with the probability of future pulmonary exacerbations in cystic fibrosis patients.

INTRODUCTION: Pulmonary exacerbations (PEs) cause significant morbidity and can severely impact disease progression in cystic fibrosis (CF) lung disease, especially in patients who suffer from recurrent PEs. The assessments able to predict a future PE or a recurrent PE are limited. We hypothesized that combining clinical, molecular and patient reported data could identify patients who are at risk of PE. METHODS: We prospectively followed a cohort of 53 adult CF patients for 24 months. Baseline values for spirometry, clinical status using the Matouk Disease Score, quality of life (QOL), inflammatory markers (C-reactive protein (CRP), interleukins (IL)-1ß, -6, -8, -10, macrophage inflammatory protein (MIP)-1ß, tumor necrosis factor (TNF) and vascular endothelial growth factor (VEGF)), polyunsaturated fatty acids and lipid peroxidation in blood plasma were collected for all patients during periods of stable disease, and patients were monitored for PE requiring PO/IV antibiotic treatment. Additionally, we closely followed 13 patients during PEs collecting longitudinal data on changes in markers from baseline values. We assessed whether any markers were predictors of future PE at baseline and after antibiotic treatment. RESULTS: Out of 53 patients, 37 experienced PEs during our study period. At baseline, we found that low lung function, clinical scoring and QOL values were associated with increased risk of PE events. PEs were associated with increased inflammatory markers at Day 1, and these biomarkers improved with treatment. The imbalance in arachidonic acid and docosahexaenoic acid levels improved with treatment which coincided with reductions in lipid peroxidation. High levels of inflammatory markers CRP and IL-8 were associated with an early re-exacerbation. CONCLUSION: Our results demonstrate that worse clinical and QOL assessments during stable disease are potential markers associated with a higher risk of future PEs, while higher levels of inflammatory markers at the end of antibiotic treatment may be associated with early re-exacerbation.