Time trade-off study to establish utility decrements in individuals with a spinal cord injury who perform intermittent catheterization.

AIMS: To generate utility decrements for three attributes associated with catheterization for individuals with a spinal cord injury (SCI): the process of catheterization, the physical impact of urinary tract infections (UTIs) and worry associated with hospitalization. MATERIALS AND METHODS: Health state vignettes comprising various levels of the three attributes were developed. Two cohorts of respondents, corresponding to people with SCIs and a sample broadly representative of the UK population, were presented with nine vignettes (three vignettes for the mild, moderate and severe health states in addition to a random set of six vignettes). It was assumed no or a nominal decrement was associated with the mild health state. Utility decrements were derived from analysing the data obtained from the online time trade-off (TTO). A proportion of the SCI cohort (n = 57) also completed the EQ-5D-5L questionnaire. RESULTS: Utility decrements were generated using statistical models for the general population (n = 358), the SCI population (n = 48) and the two populations combined (merged model, n = 406). Results from the two cohorts showed minimal differences. For the merged model, SCI status was not statistically significant. All interaction terms, excluding SCI and the severe level of the physical attribute, were not statistically significant. Compared to the mild level, the greatest utility decrement calculated was the severe level of the emotional (worry) attribute (0.09, p < .001) for the SCI population. A significant decrement of 0.02 (p < .001) was calculated for the moderate level of the emotional attribute for all models. The mean utility score for those with SCI having completed the EQ-5D-5L was 0.371. LIMITATIONS: Modest sample size of respondents from the SCI population (n = 48). CONCLUSIONS: Worry associated with hospitalization had the greatest impact on patients' health-related quality of life (HRQoL). The catheterization process, such as the lubrication and repositioning of the catheter, also impacted on patients' HRQoL.

Treatment outcomes of patients with Atopic Dermatitis (AD) treated with dupilumab through the Early Access to Medicines Scheme (EAMS) in the UK.

BACKGROUND: Dupilumab, a monoclonal antibody against interleukin (IL)-4 receptor alpha that inhibits IL-4/IL-13 signalling is indicated in dermatology for the treatment of moderate-to-severe atopic dermatitis (AD) in adult and adolescent patients 12 years and older and severe AD in children 6-11 years, who are candidates for systemic therapy. Dupilumab received Early Access to Medicines Scheme (EAMS) approval for adults in March 2017. OBJECTIVES: The purpose of this study was to assess the efficacy outcomes of treatment with dupilumab in EAMS. METHODS: A retrospective analysis of adult patients enrolled in the dupilumab EAMS in the UK. Scores were assessed at baseline and follow up, including the Eczema Area and Severity Index (EASI), Investigator's Global Assessment Score (IGA) and Dermatology Life Quality Index (DLQI). RESULTS: Data were available for 57 adult patients treated with dupilumab for at least 12 weeks; 73.6% of patients had received prior treatment with 3 or 4 immunosuppressants. Baseline scores for the EASI and DLQI were 27.93 (standard deviation, SD 13.09) and 18.26 (SD 6.18) respectively. AD severity scores showed statistically significant improvement at week 16±4 weeks (p <0.001 for all). The mean change in EASI was 14.13 points with 66.7% and 36.7% achieving a 50% (EASI-50) and 75% (EASI-75) improvement in EASI, respectively at 16+/- 4 weeks. IGA scores improved by at least two categories for 75% patients. DLQI scores decreased by a mean of 9.0 points, with 80% patients demonstrating a MCID 4-point improvement. For 85% patients, clinicians rated the treatment response as being either 'better' (19%) or 'much better' (65%). CONCLUSIONS: Dupilumab is associated with a significant and clinically relevant improvements in AD as measured by patient- and physician-reported outcome measures. Importantly, the clinical efficacy, despite the refractory disease of this EAMS cohort, is comparable to that previously reported in clinical trials.

Psychological intervention (ConquerFear) for treating fear of cancer recurrence: mediators and moderators of treatment efficacy.

PURPOSE: ConquerFear is an efficacious intervention for fear of cancer recurrence (FCR) that demonstrated greater improvements than an attention control (relaxation training) in a randomized controlled trial. This study aimed to determine mediators and moderators of the relative treatment efficacy of ConquerFear versus relaxation. METHODS: One hundred and fifty-two cancer survivors completed 5 therapy sessions and outcome measures before and after intervention and at 6 months' follow-up. We examined theoretically relevant variables as potential mediators and moderators of treatment outcome. We hypothesized that metacognitions and intrusions would moderate and mediate the relationship between treatment group and FCR level at follow-up. RESULTS: Only total FCR score at baseline moderated treatment outcome. Participants with higher levels of FCR benefited more from ConquerFear relative to relaxation on the primary outcome. Changes in metacognitions and intrusive thoughts about cancer during treatment partially mediated the relationship between treatment group and FCR. CONCLUSIONS: These results show that ConquerFear is relatively more effective than relaxation for those with overall higher levels of FCR. The mediation analyses confirmed that the most likely mechanism of treatment efficacy was the reduction in unhelpful metacognitions and intrusive thoughts during treatment, consistent with the theoretical framework underpinning ConquerFear. IMPLICATIONS FOR CANCER SURVIVORS: ConquerFear is a brief, effective treatment for FCR in cancer survivors with early-stage disease. The treatment works by reducing intrusive thoughts about cancer and changing beliefs about worry and is particularly helpful for people with moderate to severe FCR.

Mitchell-Hoole-Kanatas (MHK) questionnaire: the first to measure patient-reported outcomes relating to problems with intimacy after diagnosis and treatment of head and neck cancer.

Patient-reported outcomes are increasingly used by clinical teams as indicators of quality when assessing treatment after a diagnosis of head and neck cancer. About a third of patients report reduced sexual interest or enjoyment after such treatment but, despite that, there is no questionnaire about intimacy that has been developed specifically for them. The aim of this study was to develop such a questionnaire, to gain an indication of the relative incidence of individual items, and to compare characteristics such as age, stage, treatment, time since treatment for an established head and neck cancer, and a health-related quality of life (QoL) measure (European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-C30 with the Head and Neck 35 module). The development of the new instrument was based on an exploratory observational study that included quantitative and qualitative methods. The qualitative element was achieved by the generation of items - from published studies, the comments of patients and carers, and a cross-sectional survey of patients with head and neck cancer who were alive and free of disease. The quantitative element comprised analysis of exploratory and confirmatory factors, internal reliability assessment (Cronbach's alpha), and a correlation analysis. Forty-two patients were included in the focus groups, and 101 patients participated in the cross-sectional survey (both male and female, in a relationship and single, age range 30-70 years for the focus group, and 62-117 in the cross-sectional survey). All treatments were included. We found that the ability to enjoy a sex life had been adversely affected in about half the sample and that this had significantly changed from before their cancer in a third. The qualitative part of the study resulted in 22 items that covered a range of domains from dry mouth and thick saliva to loss of sensation (lips, fingertips), restricted head/neck movement, fatigue, and pain. The exploratory analysis covered four domains (physical, sensation, movement, and communication) from 12 of 22 items. Cronbach's alphas ranged from 0.62 to 0.84, and the correlation analysis indicated "good fit" statistics for these domains. In terms of the EORTC QoL Questionnnaire - Head and Neck 35, the four MHK domains showed good levels of association with anticipated domains. Head and neck cancer and its associated treatments significantly adversely affect intimacy and sexuality in half the population sampled. The MHK tool may be used to identify specific issues related to intimacy in patients with a history of diagnosis and treatment of head and neck cancer. Further work is essential to identify its precise role and to help develop specific interventions.

Margins and survival in oral cancer.

In the surgical management of oral squamous cell carcinoma (SCC) we aim to resect the tumour with clear margins in all planes. The aim of this study was to identify and compare overall survival in a group of 591 patients who had resections, and to relate this to the clearance of margins at the tumour bed. We used life tables to calculate survival at one, two, three, five, and 10 years after diagnosis by margin (clear=5mm or more; close=2-5mm; and involved=less than 2mm). Kaplan-Meier curves were produced for the margins alone, which were defined as clear in 480 patients (81%), close in 63 (11%), and involved in 48 (8%). Five-year survival was 81%, 75%, and 54% for clear, close, and involved margins, respectively, which highlights the importance of clear margins for survival. There is a significant prognostic implication associated with close, and particularly with involved, margins.

Survival after surgery for oral cancer: a 30-year experience.

Oral squamous cell carcinoma is the most common intraoral malignancy, for which we advocate radical primary resection with adjuvant treatment where indicated. The main aims of this paper are to identify the overall survival of a consecutive series of patients and to relate survival to clinical and pathological factors. Kaplan-Meier curves were produced for site, sex, TNM status, and use of postoperative radiotherapy. The data were analysed using IBM SPSS Statistics for Windows and probabilities of less than 0.05 were accepted as significant. A total of 921 patients were recorded in the database with a diagnosis of oral squamous cell carcinoma out of a total of 1958 with salivary gland conditions or other cancers of the head and neck (43.1%). The earliest date of diagnosis was 1973, and the data were censored at 31 March 2016. The database comprised 340 women (36.9%) and 581 men (63.1%). A total of 339 patients died (34.5%): 117 women (33.7%) and 222 men (65.5%). The mean (range) age at death was 73.4 (31.4-97.5) years for women and 68.7 (33.3-95.5) years for men (t (337)=3.28, p=0.001). Our overall survival was somewhat better than the 56% five-year survival reported for oral cancer in England in 2010, which may be a reflection of the treatment. This work supports the view that aggressive management may improve overall survival.

e-TC: Development and pilot testing of a web-based intervention to reduce anxiety and depression in survivors of testicular cancer.

e-TC is an online intervention designed to address common psychosocial concerns of testicular cancer survivors. It aims to reduce anxiety, depression and fear of cancer recurrence by providing evidence-based information and psychological intervention. This paper details the development and pilot testing of e-TC. During pilot testing, 25 men (with varying psychological profiles) who had completed treatment for testicular cancer, 6 months to 5 years ago (which had not recurred), used e-TC over a 10-week period and provided quantitative and qualitative feedback on the feasibility and acceptability of the programme. Six men also completed a qualitative interview to provide detailed feedback on their experiences using e-TC. Fourteen men (56%) completed at least 80% of the programme. Participants reported a high level of satisfaction with the programme. Men's limited time was a barrier to programme use and completion, and participants suggested that men with a more recent diagnosis and a higher level of distress may be more likely to engage with the programme. e-TC appears to be a feasible and acceptable online intervention for survivors of testicular cancer. Findings from this study are currently being used to refine e-TC and guide the design of a larger efficacy study.

Validated questionnaires on intimacy in patients who have had cancer.

Problems with intimacy in patients with cancer of the head and neck may not be recognised. Our aim was to review published papers on patient-reported outcomes that record concerns about intimacy, sex, and function, to help develop a tool for use in head and neck cancer. We specifically looked for instruments with evidence of validation in patients with cancer, which could be used to identify problems with intimacy and sexuality. After evaluating 2563 papers, we identified 20 that satisfied our inclusion criteria, and these have been presented in a tabulated form. This review has shown the need to develop a questionnaire on intimacy that is specific to patients with cancer of the head and neck. It is an important issue that must be addressed by clinical and research teams, and will be done most effectively if it is linked to specific interventions.

Disorder-specific grey matter deficits in attention deficit hyperactivity disorder relative to autism spectrum disorder.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are two common childhood disorders that exhibit genetic and behavioural overlap and have abnormalities in similar brain systems, in particular in frontal and cerebellar regions. This study compared the two neurodevelopmental disorders to investigate shared and disorder-specific structural brain abnormalities. METHOD: Forty-four predominantly medication-naïve male adolescents with ADHD, 19 medication-naïve male adolescents with ASD and 33 age-matched healthy male controls were scanned using high-resolution T1-weighted volumetric imaging in a 3-T magnetic resonance imaging (MRI) scanner. Voxel-based morphometry (VBM) was used to test for group-level differences in structural grey matter (GM) and white matter (WM) volumes. RESULTS: There was a significant group difference in the GM of the right posterior cerebellum and left middle/superior temporal gyrus (MTG/STG). Post-hoc analyses revealed that this was due to ADHD boys having a significantly smaller right posterior cerebellar GM volume compared to healthy controls and ASD boys, who did not differ from each other. ASD boys had a larger left MTG/STG GM volume relative to healthy controls and at a more lenient threshold relative to ADHD boys. CONCLUSIONS: The study shows for the first time that the GM reduction in the cerebellum in ADHD is disorder specific relative to ASD whereas GM enlargement in the MTG/STG in ASD may be disorder specific relative to ADHD. This study is a first step towards elucidating disorder-specific structural biomarkers for these two related childhood disorders.

Improving decision making about clinical trial participation - a randomised controlled trial of a decision aid for women considering participation in the IBIS-II breast cancer prevention trial.

BACKGROUND: Decision aids may improve informed consent in clinical trial recruitment, but have not been evaluated in this context. This study investigated whether decision aids (DAs) can reduce decisional difficulties among women considering participation in the International Breast Cancer Intervention Study-II (IBIS-II) trial. METHODS: The IBIS-II trial investigated breast cancer prevention with anastrazole in two cohorts: women with increased risk (Prevention), and women treated for ductal carcinoma in situ (DCIS). Australia, New Zealand and United Kingdom participants were randomised to receive a DA (DA group) or standard trial consent materials (control group). Questionnaires were completed after deciding about participation in IBIS-II (post decision) and 3 months later (follow-up). RESULTS: Data from 112 Prevention and 34 DCIS participants were analysed post decision (73 DA; 73 control); 95 Prevention and 24 DCIS participants were analysed at follow-up (58 DA; 61 control). There was no effect on the primary outcome of decisional conflict. The DCIS-DA group had higher knowledge post decision, and the Prevention-DA group had lower decisional regret at follow-up. CONCLUSIONS: This was the first study to evaluate a DA in the clinical trial setting. The results suggest DAs can potentially increase knowledge and reduce decisional regret about clinical trial participation.

Anatomical restrictions in the surgical excision of scalp squamous cell carcinomas: does this affect local recurrence and regional nodal metastases?

Squamous cell carcinomas (SCCs) of the skin of the scalp have the potential for regional metastases. Microscopically, clearance may be less than the optimal dimensions. We report 101 SCCs of the scalp treated surgically under the care of a single oral and maxillofacial surgeon. Forty-two of the study patients had deep margins that were clear by less than 2mm, of whom five had margins that involved pericranium±skull. Our study demonstrated a local recurrence rate of 6% and a regional recurrence rate of 7%. All patients presented with relapse of the disease within 18 months of primary surgery. The evidence presented in this study suggests that in SCCs of the scalp, less than ideal surgical margin clearance, entirely due to anatomical restrictions, does not appear to substantially affect regional recurrence, but increases the risk of local recurrence.

Drug-specific laterality effects on frontal lobe activation of atomoxetine and methylphenidate in attention deficit hyperactivity disorder boys during working memory.

BACKGROUND: The catecholamine reuptake inhibitors methylphenidate (MPH) and atomoxetine (ATX) are the most common treatments for attention deficit hyperactivity disorder (ADHD). This study compares the neurofunctional modulation and normalization effects of acute doses of MPH and ATX within medication-naive ADHD boys during working memory (WM). METHOD: A total of 20 medication-naive ADHD boys underwent functional magnetic resonance imaging during a parametric WM n-back task three times, under a single clinical dose of either MPH, ATX or placebo in a randomized, double-blind, placebo-controlled, cross-over design. To test for normalization effects, brain activations in ADHD under each drug condition were compared with that of 20 age-matched healthy control boys. RESULTS: Relative to healthy boys, ADHD boys under placebo showed impaired performance only under high WM load together with significant underactivation in the bilateral dorsolateral prefrontal cortex (DLPFC). Both drugs normalized the performance deficits relative to controls. ATX significantly enhanced right DLPFC activation relative to MPH within patients, and significantly normalized its underactivation relative to controls. MPH, by contrast, both relative to placebo and ATX, as well as relative to controls, upregulated the left inferior frontal cortex (IFC), but only during 2-back. Both drugs enhanced fronto-temporo-striatal activation in ADHD relative to control boys and deactivated the default-mode network, which were negatively associated with the reduced DLPFC activation and performance deficits, suggesting compensation effects. CONCLUSIONS: The study shows both shared and drug-specific effects. ATX upregulated and normalized right DLPFC underactivation, while MPH upregulated left IFC activation, suggesting drug-specific laterality effects on prefrontal regions mediating WM.

Emergency centre investigation of first-onset seizures in adults in the Western Cape, South Africa.

BACKGROUND: Patients with first-onset seizures commonly present to emergency centres (ECs). The differential diagnosis is broad, potentially life-threatening conditions need to be excluded, and these patients need to be correctly diagnosed and appropriately referred. There are currently no data on adults presenting with first-onset seizures to ECs in South Africa. OBJECTIVE: To review which investigations were performed on adults presenting with first-onset seizures to six ECs in the Western Cape Province. METHODS: A prospective, cross-sectional study was conducted from 1 July 2011 to 31 December 2011. All adults with first-onset seizures were included; children and trauma patients were excluded. Subgroup analyses were conducted regarding HIV status and inter-facility variation. RESULTS: A total of 309 patients were included. Computed tomography (CT) scans were planned in 218 (70.6%) patients, but only performed in 169; 96 (56.8%) showed abnormalities judged to be causative (infarction, intracerebral haemorrhage and atrophy being the most common). At least 80% of patients (n=247) received a full renal and electrolyte screen, blood glucose testing and a full haematological screen. Lumbar puncture (LP) was performed in 67 (21.7%) patients, with normal cerebrospinal fluid findings in 51 (76.1%). Only 27 (8%) patients had an electroencephalogram, of which 5 (18%) were abnormal. There was a statistically significant difference in the number of CT scans (p=0.002) and LPs (p<0.001) performed in the HIV-positive group (n=49). CONCLUSION: This study demonstrated inconsistency and wide local variance for all types of investigations done. It emphasises the need for a local guideline to direct doctors to appropriate investigations, ensuring better quality patient care and potential cost-saving.

Oleocanthal inhibits proliferation and MIP-1α expression in human multiple myeloma cells.

Multiple myeloma (MM) is a plasma cell malignancy that causes devastating bone destruction by activating osteoclasts in the bone marrow milieu. MM is the second of all hematological malignancies. Thus, the search for new pharmacological weapons is under intensive investigation being MM a critically important public health goal. Recently, it has been demonstrated that macrophage inflammatory protein 1- alpha (MIP-1 α) is crucially involved in the development of osteolytic bone lesions in MM. Phenolic components of extra virgin olive oil are reported to have anti tumor activity. However, the underlying mechanisms and specific targets of extra virgin olive oil remain to be elucidated. In the present study, we investigated the effects of a recently isolated novel extra virgin olive oil polyphenol, oleocanthal, on the human multiple myeloma cell line ARH-77. Here we report that this natural compound has a remarkable in vitro activity by inhibiting MIP-1 α expression and secretion in MM cells. In addition, we also demonstrated that oleocanthal inhibits MM cells proliferation by inducing the activation of apoptosis mechanisms and by down-regulating ERK1/2 and AKT signal transduction pathways. This in vitro study suggests a therapeutic potential of oleocanthal in treating multiple myeloma.

Disorder-specific functional abnormalities during sustained attention in youth with Attention Deficit Hyperactivity Disorder (ADHD) and with autism.

Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) are often comorbid and share behavioural-cognitive abnormalities in sustained attention. A key question is whether this shared cognitive phenotype is based on common or different underlying pathophysiologies. To elucidate this question, we compared 20 boys with ADHD to 20 age and IQ matched ASD and 20 healthy boys using functional magnetic resonance imaging (fMRI) during a parametrically modulated vigilance task with a progressively increasing load of sustained attention. ADHD and ASD boys had significantly reduced activation relative to controls in bilateral striato-thalamic regions, left dorsolateral prefrontal cortex (DLPFC) and superior parietal cortex. Both groups also displayed significantly increased precuneus activation relative to controls. Precuneus was negatively correlated with the DLPFC activation, and progressively more deactivated with increasing attention load in controls, but not patients, suggesting problems with deactivation of a task-related default mode network in both disorders. However, left DLPFC underactivation was significantly more pronounced in ADHD relative to ASD boys, which furthermore was associated with sustained performance measures that were only impaired in ADHD patients. ASD boys, on the other hand, had disorder-specific enhanced cerebellar activation relative to both ADHD and control boys, presumably reflecting compensation. The findings show that ADHD and ASD boys have both shared and disorder-specific abnormalities in brain function during sustained attention. Shared deficits were in fronto-striato-parietal activation and default mode suppression. Differences were a more severe DLPFC dysfunction in ADHD and a disorder-specific fronto-striato-cerebellar dysregulation in ASD.