Interleukin-6 and total antioxidant capacity levels following N-acetylcysteine and a combination nutraceutical intervention in a randomised controlled trial for bipolar disorder.

OBJECTIVE: The aims of this study were to evaluate changes in inflammatory and oxidative stress levels following treatment with N-acetylcysteine (NAC) or mitochondrial-enhancing agents (CT), and to assess the how these changes may predict and/or moderate clinical outcomes primarily the Montgomery-Åsberg Depression Rating Scale (MADRS). METHODS: This study involved secondary analysis of a placebo-controlled randomised trial (n = 163). Serum samples were collected at baseline and week 16 of the clinical trial to determine changes in Interleukin-6 (IL-6) and total antioxidant capacity (TAC) following adjunctive CT and/or NAC treatment, and to explore the predictability of the outcome or moderator effects of these markers. RESULTS: In the NAC-treated group, no difference was observed in serum IL-6 and TAC levels after 16 weeks of treatment with NAC or CT. However, results from a moderator analysis showed that in the CT group, lower IL-6 levels at baseline was a significant moderator of MADRS χ2 (df) = 4.90, p = 0.027) and Clinical Global Impression-Improvement (CGI-I, χ2 (df) = 6.28 p = 0.012). In addition, IL-6 was a non-specific but significant predictor of functioning (based on the Social and Occupational Functioning Assessment Scale (SOFAS)), indicating that individuals with higher IL-6 levels at baseline had a greater improvement on SOFAS regardless of their treatment (p = 0.023). CONCLUSION: Participants with lower IL-6 levels at baseline had a better response to the adjunctive treatment with the mitochondrial-enhancing agents in terms of improvements in MADRS and CGI-I outcomes.

ENACT: a protocol for a randomised placebo-controlled trial investigating the efficacy and mechanisms of action of adjunctive N-acetylcysteine for first-episode psychosis.

BACKGROUND: First-episode psychosis (FEP) may lead to a progressive, potentially disabling and lifelong chronic illness; however, evidence suggests that the illness course can be improved if appropriate treatments are given at the early stages. Nonetheless, the efficacy of antipsychotic medications is suboptimal, particularly for negative and cognitive symptoms, and more efficacious and benign treatments are needed. Previous studies have shown that the antioxidant amino acid N-acetylcysteine (NAC) reduces negative symptoms and improves functioning in chronic schizophrenia and bipolar disorder. Research is scarce as to whether NAC is beneficial earlier in the course of illness. The primary aim of this study is to determine the efficacy of treatment with adjunctive NAC (2 g/day for 26 weeks) compared with placebo to improve psychiatric symptoms in young people experiencing FEP. Secondary aims are to explore the neurobiological mechanisms underpinning NAC and how they relate to various clinical and functional outcomes at 26- and 52-week follow-ups. METHODS/DESIGN: ENACT is a 26-week, randomised controlled trial of adjunctive NAC versus placebo, with a 26-week non-treatment follow-up period, for FEP. We will be recruiting 162 young people aged 15-25 years who have recently presented to, and are being treated at, the Early Psychosis Prevention and Intervention Centre, Melbourne, Australia. The primary outcome is the Total Score on the Positive and Negative Syndrome Scale which will be administered at baseline, and weeks 4, 8, 12, 26 (primary endpoint), and 52 (end of study). Secondary outcomes include: symptomatology, functioning, quality of life, neurocognition, blood-derived measures of: inflammation, oxidative and nitrosative stress, and magnetic resonance spectroscopy measures of glutathione concentration. DISCUSSION: Targeted drug development for FEP to date has generally not involved the exploration of neuroprotective agents. This study has the potential to offer a new, safe, and efficacious treatment for people with FEP, leading to better treatment outcomes. Additionally, the neuroprotective dimension of this study may lead to a better long-term prognosis for people with FEP. It has the potential to uncover a novel treatment that targets the neurobiological mechanisms of FEP and, if successful, will be a major advance for psychiatry. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ID: ACTRN12618000413224. Registered on 21 March 2018.

Reduction in colposcopy workload and associated clinical activity following human papillomavirus (HPV) catch-up vaccination programme in Scotland: an ecological study.

OBJECTIVE: To measure patterns of clinical activity at colposcopy before and after vaccinated women entered the Scottish Cervical Screening Programme (SCSP). DESIGN: Population-based observational study using nationally collected data. SETTING: Scottish colposcopy clinics. SAMPLE: All women with a date of birth on or after 1 January 1985 who attended colposcopy in Scotland between 2008 and 2014. METHODS: Routinely collected data from the Scottish National Colposcopy Clinical Information Audit System (NCCIAS) were extracted, including: referral criteria, referral cervical cytology, colposcopic findings, clinical procedures, and histology results. Analysis was restricted to those referred to colposcopy at age 20 or 21 years. MAIN OUTCOME MEASURES: Referral criteria, positive predictive value of colposcopy, default rates, and rates of cervical biopsies and treatments. RESULTS: A total of 7372 women referred for colposcopy at age 20 or 21 years were identified. There was a downward trend in the proportion of those referred with abnormal cytology (2008/9, 91.0%; 2013/14, 90.3%; linear trend P = 0.03). Women were less likely to have diagnostic or therapeutic interventions. The proportion with no biopsy (2008/9, 19.5%; 2013/14, 26.9%; linear trend P < 0.0001) and no treatment (2008/9, 74.9%; 2013/14, 91.8%; linear trend P < 0.0001) increased over the period of observation. CONCLUSIONS: A reduction in clinical activity related to abnormal screening referrals is likely to be associated with the human papillomavirus (HPV) catch-up immunisation programme. Referral criteria and the service provision of colposcopy needs to be planned carefully, taking account of the increasing number of women who have been immunised against HPV that will be entering cervical screening programmes worldwide. TWEETABLE ABSTRACT: Colposcopy referral criteria and service planning need attention following HPV immunisation programme.

The impact of human papillomavirus type on colposcopy performance in women offered HPV immunisation in a catch-up vaccine programme: a two-centre observational study.

OBJECTIVE: To determine whether human papillomavirus (HPV) immunisation has affected the prevalence of HPV genotypes and colposcopic features of cervical intraepithelial neoplasia (CIN) in young women referred for colposcopy. DESIGN: A two-centre observational study including vaccinated and unvaccinated women. SETTING: Colposcopy clinics serving two health regions in Scotland, UK. POPULATION: A total of 361 women aged 20-25 years attending colposcopy following an abnormal cervical cytology result at routine cervical screening. METHODS: Cervical samples were obtained from women for HPV DNA genotyping and mRNA E6/E7 expression of HPV 16, 18, 31, 33, and 45. Demographic data, cytology, and histology results and colposcopic features were recorded. Chi-square analysis was conducted to identify associations between vaccine status, HPV genotypes, and colposcopic features. MAIN OUTCOME MEASURES: Colposcopic features, HPV genotypes, mRNA expression, and cervical histology. RESULTS: The prevalence of HPV 16 was significantly lower in the vaccinated group (8.6%) compared with the unvaccinated group (46.7%) (P = 0.001). The number of cases of CIN2+ was significantly lower in women who had been vaccinated (P = 0.006). The HPV vaccine did not have a statistically significant effect on commonly recognised colposcopic features, but there was a slight reduction in the positive predictive value (PPV) of colposcopy for CIN2+, from 74% (unvaccinated) to 66.7% (vaccinated). CONCLUSIONS: In this group of young women with abnormal cytology referred to colposcopy, HPV vaccination via a catch-up programme reduced the prevalence of CIN2+ and HPV 16 infection. The reduced PPV of colposcopy for the detection of CIN2+ in women who have been vaccinated is at the lower acceptable level of the UK national cervical screening programme guidelines. TWEETABLE ABSTRACT: Reduction of hrHPV positivity and CIN in immunised women consistent with lower PPV of colposcopy for CIN2+.

Psychosocial morbidity in women with abnormal cervical cytology managed by cytological surveillance or initial colposcopy: longitudinal analysis from the TOMBOLA randomised trial.

OBJECTIVE: To compare psychosocial outcomes (follow-up related worries and satisfaction with follow-up related information and support) over 30 months of two alternative management policies for women with low-grade abnormal cervical cytology. METHODS: Women aged 20-59 years with low-grade cytological abnormalities detected in the National Health Service Cervical Screening Programme were randomised to cytological surveillance or initial colposcopy. A total of 3399 women who completed psychosocial questionnaires at recruitment were invited to complete questionnaires at 12, 18, 24 and 30 months. Linear mixed models were used to investigate differences between arms in the two psychosocial outcomes. Each outcome had a maximum score of 100, and higher scores represented higher psychosocial morbidity. RESULTS: On average, over 30 months, women randomised to colposcopy scored 2.5 points (95%CI -3.6 to -1.3) lower for follow-up related worries than women randomised to cytological surveillance. Women in the colposcopy arm also scored significantly lower for follow-up related satisfaction with information and support (-2.4; -3.3 to -1.4) over 30 months. For both outcomes, the average difference between arms was greatest at 12th- and 18th-month time points. These differences remained when the analysis was stratified by post-school education. CONCLUSIONS: Women with low-grade cytology, irrespective of their management, have substantial initial psychosocial morbidity that reduces over time. Implementation of newer screening strategies, which include surveillance, such as primary HPV screening, need to consider the information and support provided to women. © 2016 The Authors. Psycho-Oncology published by John Wiley & Sons Ltd.

HPV immunisation and cervical screening--confirmation of changed performance of cytology as a screening test in immunised women: a retrospective population-based cohort study.

BACKGROUND: To document the effect of bivalent HPV immunisation on cervical cytology as a screening test and assess the implications of any change, using a retrospective analysis of routinely collected data from the Scottish Cervical Screening Programme (SCSP). METHODS: Data were extracted from the Scottish Cervical Call Recall System (SCCRS), the Scottish Population Register and the Scottish Index of Multiple Deprivation. A total of 95 876 cytology records with 2226 linked histology records from women born between 1 January 1988 and 30 September 1993 were assessed. Women born in or after 1990 were eligible for the national catch-up programme of HPV immunisation. The performance of cervical cytology as a screening test was evaluated using the key performance indicators used routinely in the English and Scottish Cervical Screening Programmes (NHSCSP and SCSP), and related to vaccination status. RESULTS: Significant reductions in positive predictive value (16%) and abnormal predictive value (63%) for CIN2+ and the mean colposcopy score (18%) were observed. A significant increase (38%) in the number of women who had to be referred to colposcopy to detect one case of CIN2+ was shown. The negative predictive value of negative- or low-grade cytology for CIN2+ increased significantly (12%). Sensitivity and specificity, as used by the UK cervical screening programmes, were maintained. CONCLUSIONS: The lower incidence of disease in vaccinated women alters the key performance indicators of cervical cytology used to monitor the quality of the screening programme. These findings have implications for screening, colposcopy referral criteria, colposcopy practice and histology reporting.

Behavioural recovery after treatment for varicose veins.

BACKGROUND: The aim of this study was to assess behavioural recovery from the patient's perspective as a prespecified secondary outcome in a multicentre parallel-group randomized clinical trial comparing ultrasound-guided foam sclerotherapy (UGFS), endovenous laser ablation (EVLA) and surgery for the treatment of primary varicose veins. METHODS: Participants were recruited from 11 UK sites as part of the CLASS trial, a randomized trial of UGFS, EVLA or surgery for varicose veins. Patients were followed up 6 weeks after treatment and asked to complete the Behavioural Recovery After treatment for Varicose Veins (BRAVVO) questionnaire. This is a 15-item instrument that covers eight activity behaviours (tasks or actions an individual is capable of doing in an idealized situation) and seven participation behaviours (what the individual does in an everyday, real-world situation) that were identified to be important from the patient's perspective. RESULTS: A total of 798 participants were recruited. Both UGFS and EVLA resulted in a significantly quicker recovery compared with surgery for 13 of the 15 behaviours assessed. UGFS was superior to EVLA in terms of return to full-time work (hazard ratio 1·43, 95 per cent c.i. 1·11 to 1·85), looking after children (1·45, 1·04 to 2·02) and walks of short (1·48, 1·19 to 1·84) and longer (1·32, 1·05 to 1·66) duration. CONCLUSION: Both UGFS and EVLA resulted in more rapid recovery than surgery, and UGFS was superior to EVLA for one-quarter of the behaviours assessed. The BRAVVO questionnaire has the potential to provide important meaningful information to patients about their early recovery and what they may expect to be able to achieve after treatment.

Is increased time to diagnosis and treatment in symptomatic cancer associated with poorer outcomes? Systematic review.

BACKGROUND: It is unclear whether more timely cancer diagnosis brings favourable outcomes, with much of the previous evidence, in some cancers, being equivocal. We set out to determine whether there is an association between time to diagnosis, treatment and clinical outcomes, across all cancers for symptomatic presentations. METHODS: Systematic review of the literature and narrative synthesis. RESULTS: We included 177 articles reporting 209 studies. These studies varied in study design, the time intervals assessed and the outcomes reported. Study quality was variable, with a small number of higher-quality studies. Heterogeneity precluded definitive findings. The cancers with more reports of an association between shorter times to diagnosis and more favourable outcomes were breast, colorectal, head and neck, testicular and melanoma. CONCLUSIONS: This is the first review encompassing many cancer types, and we have demonstrated those cancers in which more evidence of an association between shorter times to diagnosis and more favourable outcomes exists, and where it is lacking. We believe that it is reasonable to assume that efforts to expedite the diagnosis of symptomatic cancer are likely to have benefits for patients in terms of improved survival, earlier-stage diagnosis and improved quality of life, although these benefits vary between cancers.

Management of women with low grade cytology: how reassuring is a normal colposcopy examination?

OBJECTIVES: To determine the rate of cervical intraepithelial neoplasia grade 2 (CIN2+) in women with low grade cervical cytology and a normal colposcopy examination over 3 years of follow-up. DESIGN: Cohort study within a randomised controlled trial. SETTING: NHS Cervical Screening Programmes in Grampian, Tayside and Nottingham. POPULATION: Eight hundred and eighty-four women aged 20-59 years with borderline nuclear abnormalities (BNA) or mild dyskaryosis with a normal and adequate colposcopy examination. METHODS: Samples at baseline were tested for 14 high-risk (Hr) types using GP5+6+ methodology and for HPV 16 and 18 using type-specific primers. Women were followed up post-colposcopy by cervical cytology at 6-month intervals in primary care. After 3 years, women were invited for an exit colposcopy examination and underwent LLETZ if any colposcopic abnormality was identified. MAIN OUTCOME MEASURES: Absolute and relative risks of CIN2+ during follow-up and/or at exit colposcopy. RESULTS: The median age was 36 years. The absolute risk of developing CIN2+ within 3 years was 1.86 per 100 woman years and for CIN3+, 0.64 per 100 woman years. One microinvasive cancer was identified. The relative risk (RR) was highest for women with initial mild dyskaryosis who were HrHPV-positive (RR 5.86, 95% confidence interval 2.53-13.56) compared with women with BNA who were HrHPV-negative. CONCLUSION: For women with low grade cervical cytology, the risk of a high grade CIN within 3 years of a normal colposcopy examination is low. Women can be reassured that, even with a positive HPV test, the risk of developing CIN2 or worse is sufficiently low to return to the routine 3-year recall.

A normal colposcopy examination fails to provide psychological reassurance for women who have had low-grade abnormal cervical cytology.

OBJECTIVE: Worldwide, each year, large numbers of women are referred for colposcopy following low-grade abnormal cervical cytology. Many have no visible abnormality on examination. The risk of cervical intra-epithelial neoplasia grade 2/3 (CIN2/3) in these women is low. It is unknown whether, for women, a normal colposcopy resolves the anxiety which often follows the receipt of an abnormal cytology result. We investigated the prevalence of adverse psychological outcomes over 30 months following a normal colposcopy. METHODS: This cohort study was nested within the UK TOMBOLA randomized controlled trial. Women aged 20-59 years, with recent low-grade cytology, who had a satisfactory colposcopy examination and normal transformation zone, completed the Hospital Anxiety and Depression Scale (HADS) and Process Outcome Specific Measure (POSM) at recruitment and during follow-up (12, 18, 24 and 30 months post-recruitment). Outcomes included percentages reporting significant anxiety (HADS anxiety subscale score ≥11), significant depression (HADS depression subscale score ≥8) or worries about the result of the next cytology test, cervical cancer, having sex, future fertility and general health at each time point (point prevalence) and during follow-up (cumulative prevalence). RESULTS: The study included 727 women. All psychological measures (except depression) had high prevalence at recruitment, falling substantially by 12 months. During follow-up, the cumulative prevalence of significant anxiety was 27% and significant depression was 21%. The most frequently reported worry was that the next cytology test would be abnormal (cumulative prevalence of 71%; point prevalence of ≥50% at 12 and 18 months). The cumulative prevalence values of worries about cervical cancer, having sex and future fertility were 33%, 20% and 16%, respectively. CONCLUSIONS: For some women who have low-grade cytology, a normal colposcopy does not appear to provide psychological reassurance.

Longitudinal relationship between expressed emotion and cannabis misuse in young people with first-episode psychosis.

Carers' expressed emotion (EE) and patients' cannabis misuse are two of the most robust predictors of psychotic relapse. We aimed to examine the temporal relationship between EE and cannabis misuse. Sixty-three key carers of young people with first-episode psychosis (FEP) were assessed at baseline and 7-month follow-up. EE was measured in carers using the Family Questionnaire (FQ) and cannabis misuse in patients using the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST). Correlational and hierarchical logistic regression analyses were conducted to examine the temporal relationship between EE components (i.e. criticism and emotional over involvement) and cannabis misuse. Carers' criticism at baseline significantly predicted cannabis misuse according to the ASSIST at 7-month follow-up. The association remained significant after controlling for baseline symptom severity and social functioning (B=0.15, P=.02). Conversely, baseline cannabis misuse was not associated with carers' criticism at 7-month follow-up. Patients in families with high criticism showed a tendency to increase cannabis misuse over time whereas the opposite trend was observed in those with carers with low criticism. A family environment characterized by high criticism may become a key risk factor for worsening cannabis misuse over time in young people with FEP. Further studies should investigate the potential mechanisms (e.g., patient's anxiety or perceived stress) through which criticism increases cannabis misuse in FEP.

Cost-effectiveness of ultrasound-guided foam sclerotherapy, endovenous laser ablation or surgery as treatment for primary varicose veins from the randomized CLASS trial.

BACKGROUND: The treatment of patients with varicose veins constitutes a considerable workload and financial burden to the National Health Service. This study aimed to assess the cost-effectiveness of ultrasound-guided foam sclerotherapy (UGFS) and endovenous laser ablation (EVLA) compared with conventional surgery as treatment for primary varicose veins. METHODS: Participant cost and utility data were collected alongside the UK CLASS multicentre randomized clinical trial, which compared EVLA, surgery and UGFS. Regression methods were used to estimate the effects of the alternative treatments on costs to the health service and quality-adjusted life-years (QALYs) at 6 months. A Markov model, incorporating available evidence on clinical recurrence rates, was developed to extrapolate the trial data over a 5-year time horizon. RESULTS: Compared with surgery at 6 months, UGFS and EVLA reduced mean costs to the health service by £655 and £160 respectively. When additional overhead costs associated with theatre use were included, these cost savings increased to £902 and £392 respectively. UGFS produced 0·005 fewer QALYs, whereas EVLA produced 0·011 additional QALYs. Extrapolating to 5 years, EVLA was associated with increased costs and QALYs compared with UGFS (costing £3640 per QALY gained), and generated a cost saving (£206-439) and QALY gain (0·078) compared with surgery. Applying a ceiling willingness-to-pay ratio of £20 000 per QALY gained, EVLA had the highest probability (78·7 per cent) of being cost-effective. CONCLUSION: The results suggest, for patients considered eligible for all three treatment options, that EVLA has the highest probability of being cost-effective at accepted thresholds of willingness to pay per QALY.

Clinical and economic evaluation of laparoscopic surgery compared with medical management for gastro-oesophageal reflux disease: 5-year follow-up of multicentre randomised trial (the REFLUX trial).

BACKGROUND: Despite promising evidence that laparoscopic fundoplication provides better short-term relief of gastro-oesophageal reflux disease (GORD) than continued medical management, uncertainty remains about whether benefits are sustained and outweigh risks. OBJECTIVE: To evaluate the long-term clinical effectiveness, cost-effectiveness and safety of laparoscopic surgery among people with GORD requiring long-term medication and suitable for both surgical and medical management. DESIGN: Five-year follow-up of a randomised trial (with parallel non-randomised preference groups) comparing a laparoscopic surgery-based policy with a continued medical management policy. Cost-effectiveness was assessed alongside the trial using a NHS perspective for costs and expressing health outcomes in terms of quality-adjusted life-years (QALYs). SETTING: Follow-up was by annual postal questionnaire and selective hospital case notes review; initial recruitment in 21 UK hospitals. PARTICIPANTS: Questionnaire responders among the 810 original participants. At entry, all had documented evidence of GORD and symptoms for > 12 months. Questionnaire response rates (years 1-5) were from 89.5% to 68.9%. INTERVENTIONS: Three hundred and fifty-seven participants were recruited to the randomised comparison (178 randomised to surgical management and 179 randomised to continued medical management) and 453 to the preference groups (261 surgical management and 192 medical management). The surgeon chose the type of fundoplication. MAIN OUTCOME MEASURES: Primary: disease-specific outcome measure (the REFLUX questionnaire); secondary: Short Form questionnaire-36 items (SF-36), European Quality of Life-5 Dimensions (EQ-5D), NHS resource use, reflux medication, complications. RESULTS: The randomised groups were well balanced. By 5 years, 63% in the randomised surgical group and 13% in the randomised medical management group had received a total or partial wrap fundoplication (85% and 3% in the preference groups), with few perioperative complications and no associated deaths. At 1 year (and 5 years) after surgery, 36% (41%) in the randomised surgical group - 15% (26%) of those who had surgery - were taking proton pump inhibitor medication compared with 87% (82%) in the randomised medical group. At each year, differences in the REFLUX score significantly favoured the randomised surgical group (a third of a SD; p< 0.01 at 5 years). SF-36 and EQ-5D scores also favoured surgery, but differences attenuated over time and were generally not statistically significant at 5 years. The worse the symptoms at trial entry, the larger the benefit observed after surgery. Those randomised to medical management who subsequently had surgery had low baseline scores that markedly improved after surgery. Following fundoplication, 3% had surgical treatment for a complication and 4% had subsequent reflux-related operations - most often revision of the wrap. Dysphagia, flatulence and inability to vomit were similar in the two randomised groups. The economic analysis indicated that surgery was the more cost-effective option for this patient group. The incremental cost-effectiveness ratio for surgery in the base case was £7028 per additional QALY; these findings were robust to changes in approaches and assumptions. The probability of surgery being cost-effective at a threshold of £20,000 per additional QALY was > 0.80 for all analyses. CONCLUSIONS: After 5 years, laparoscopic fundoplication continues to provide better relief of GORD symptoms with associated improved health-related quality of life. Complications of surgery were uncommon. Despite being initially more costly, a surgical policy is highly likely to be cost-effective. TRIAL REGISTRATION: Current Controlled Trials ISRCTN15517081. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 22. See the HTA programme website for further project information.

Minimal access surgery compared with medical management for gastro-oesophageal reflux disease: five year follow-up of a randomised controlled trial (REFLUX).

OBJECTIVES: To determine the long term clinical effectiveness of laparoscopic fundoplication as an alternative to drug treatment for chronic gastro-oesophageal reflux disease (GORD). DESIGN: Five year follow-up of multicentre, pragmatic randomised trial (with parallel non-randomised preference groups). SETTING: Initial recruitment in 21 UK hospitals. PARTICIPANTS: Responders to annual questionnaires among 810 original participants. At entry, all had had GORD for >12 months. INTERVENTION: The surgeon chose the type of fundoplication. Medical therapy was reviewed and optimised by a specialist. Subsequent management was at the discretion of the clinician responsible for care, usually in primary care. MAIN OUTCOME MEASURES: Primary outcome measure was self reported quality of life score on disease-specific REFLUX questionnaire. Other measures were health status (with SF-36 and EuroQol EQ-5D questionnaires), use of antireflux medication, and complications. RESULTS: By five years, 63% (112/178) of patients randomised to surgery and 13% (24/179) of those randomised to medical management had received a fundoplication (plus 85% (222/261) and 3% (6/192) of those who expressed a preference for surgery and for medical management). Among responders at 5 years, 44% (56/127) of those randomised to surgery were taking antireflux medication versus 82% (98/119) of those randomised to medical management. Differences in the REFLUX score significantly favoured the randomised surgery group (mean difference 8.5 (95% CI 3.9 to 13.1), P<0.001, at five years). SF-36 and EQ-5D scores also favoured surgery, but were not statistically significant at five years. After fundoplication, 3% (12/364) had surgical treatment for a complication and 4% (16) had subsequent reflux-related operations-most often revision of the wrap. Long term rates of dysphagia, flatulence, and inability to vomit were similar in the two randomised groups. CONCLUSIONS: After five years, laparoscopic fundoplication continued to provide better relief of GORD symptoms than medical management. Adverse effects of surgery were uncommon and generally observed soon after surgery. A small proportion had re-operations. There was no evidence of long term adverse symptoms caused by surgery. TRIAL REGISTRATION: Current Controlled Trials ISRCTN15517081.

The risk of a subsequent cancer diagnosis after herpes zoster infection: primary care database study.

BACKGROUND: Herpes zoster and cancer are associated with immunosuppression. Zoster occurs more often in patients with an established cancer diagnosis. Current evidence suggests some risk of cancer after zoster but is inconclusive. We aimed to assess the risk of cancer following zoster and the impact of prior zoster on cancer survival. METHODS: A primary care database retrospective cohort study was undertaken. Subjects with zoster were matched to patients without zoster. Risk of cancer following zoster was assessed by generating hazard ratios using Cox regression. Time to cancer was generated from the index date of zoster diagnosis. RESULTS: In total, 2054 cancers were identified in 74,029 patients (13,428 zoster, 60,601 matches). The hazard ratio for cancer diagnosis after zoster was 2.42 (95% confidence interval 2.21, 2.66) and the median time to cancer diagnosis was 815 days. Hazard ratios varied between cancers, and were highest in younger patients. There were more cancers in patients with zoster than those without for all age groups and both genders. Prior immunosuppression was not associated with change in risk, and diagnosis of zoster before cancer did not affect survival. CONCLUSION: This study establishes an association between zoster and future diagnosis of cancer having implications for cancer case finding after zoster diagnosis.

Which women default from follow-up cervical cytology tests? A cohort study within the TOMBOLA trial.

OBJECTIVE: To identify factors associated with default from follow-up cervical cytology tests. METHODS: A cohort study was conducted involving 2166 women, aged 20-59, with recent low-grade cervical cytology taken within the NHS Cervical Screening Programmes in Scotland and England, and managed by 6-monthly cytology in primary care. For the first (6-month) and second (12-month) surveillance cytology tests separately, women were categorized as 'on-time attendees' (attended ≤6 months of test being due), 'late attendees' (attended greater than 6 months after test was due) or 'non-attendees' (failed to attend). Multivariate odds ratios (ORs) were computed for factors associated with late and non-attendance. RESULTS: For the first surveillance test, risk of non-attendance was significantly higher in younger women, those without post-secondary education, and non-users of prescribed contraception. Factors significantly associated with late attendance for the first test were the same as for non-attendance, plus current smoking and having children. The most important predictor of non-attendance for the second surveillance test was late attendance for the first test (OR = 9.65; 95% CI, 6.60-16.62). Non-attendance for the second test was also significantly higher among women who were younger, smokers and had negative cytology on the first surveillance test. Late attendance for the second surveillance test was higher in women who were younger, smokers, had children and attended late for the first test. CONCLUSIONS: Women at highest risk of default from follow-up cytology tend to be young, smoke, lack post-secondary education, and have defaulted from a previous surveillance appointment. Tackling default will require development of targeted strategies to encourage attendance and research to better understand the reasons underpinning default.

Long-term psychosocial impact of alternative management policies in women with low-grade abnormal cervical cytology referred for colposcopy: a randomised controlled trial.

BACKGROUND: The debate continues regarding the best management for women with low-grade abnormal cervical cytology attending colposcopy. We compared psychosocial outcomes of alternative management policies in these women. METHODS: In all, 989 women, aged 20-59 years, with low-grade abnormal cytology, were randomised to immediate large loop excision (LLETZ) or two to four targeted punch biopsies taken immediately with recall for LLETZ if these showed cervical intra-epithelial neoplasia 2/3. At 6 weeks after the last procedure, women completed the hospital anxiety and depression scale (HADS) and the impact of event scale (IES). At 12, 18, 24 and 30 months post recruitment, women completed the HADS and process outcome specific measure (POSM). Prevalence of significant depression (≥ 8), significant anxiety (≥ 11) and distress (≥ 9) and median POSM scores were compared between arms. Multivariate odds ratios (ORs) for immediate LLETZ vs biopsy and recall were computed. RESULTS: Over the entire follow-up, there was no significant difference between arms in cumulative prevalence or risk of significant depression (OR=0.78, 95% CI 0.52-1.17) or significant anxiety (OR=0.83, 95% CI 0.57-1.19). At 6 weeks post procedure, distress did not differ significantly between arms. At later time points, 8-11% had significant depression and 14-16% had significant anxiety but with no differences between arms. The POSM scores did not differ between the arms. CONCLUSIONS: There is no difference in long- or short-term psychosocial outcomes of immediate LLETZ and punch biopsies with selective recall.

The role of human papillomavirus testing in the management of women with low-grade abnormalities: multicentre randomised controlled trial.

OBJECTIVE: To assess the value of a single human papillomavirus (HPV) test in making decisions on management of women with cervical cytology showing borderline nuclear abnormality (BNA) or mild dyskaryosis. In particular, to determine whether information on high-risk (hr) HPV status would be valuable in the choice between (1) cytological surveillance versus immediate referral to colposcopy, and (2) at colposcopy, between biopsy and recall versus immediate large loop excision of the transformation zone (LLETZ). DESIGN: Multicentre individually randomised controlled trial, nested within the NHS Cervical Screening Programmes, investigating the value of HPV testing by testing for interactions between HPV status and (1) cytological surveillance versus colposcopy, and (2) biopsy and recall versus immediate LLETZ. Setting Grampian, Tayside and Nottingham. Population Women (n = 4439), aged 20-59 years, with a cytology test showing borderline nuclear abnormalities or mild dyskaryosis during October 1999 to October 2002. METHODS: High-risk HPV status was determined at recruitment using the polymerase chain reaction assay with the GP5+/6+ general primer system. The results of this HPV testing were not disclosed to either the participating women or to those involved in their management. Women were randomised to either (1) 6-monthly cytological screening in primary care or (2) referral for colposcopy. Human papillomavirus status was used to stratify both randomisations. All women were followed for 3 years, concluding with an invitation to an exit appointment at which colposcopic examination was undertaken. In addition, in women who were randomised to initial colposcopy and underwent colposcopy, the association between hrHPV status and presence of cervical intraepithelial neoplasia (CIN) grade 2 or more severe disease (henceforth CIN2 or worse) was examined. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive and negative predictive values of the HPV test for predicting CIN2 or worse and the implications for the choice of management between cytological surveillance and immediate referral for colposcopy. RESULTS: There were no significant interactions between management and HPV status. Hence, in women with mild dyskaryosis or BNA who are HPV positive, there is no advantage of (1) immediate colposcopy over cytological surveillance (P = 0.76) or (2) immediate LLETZ over biopsy and recall (P = 0.27). The sensitivity of HPV testing for detection of CIN2 or worse was 75.2% (95% CI 68.8-81.0%) among women with mild dyskaryosis and 69.9% (95% CI 61.7-77.3%) among those with BNA. Specificity was higher in those with BNA (71.3%; 95% CI 68.5-74.1%) than in those with mild dyskaryosis (46.9%; 95% CI 42.2-51.6%). Sensitivity decreased with increasing age whereas specificity increased. The negative predictive value was high, particularly among women with BNA (94.5%; 95% CI 92.9-96.0%). Across all ages, 22% of women who had CIN2 or worse were HPV negative. Conversely, 40% of those who were HPV positive did not have CIN. HPV was a much more reliable predictor in women aged over 40 years. CONCLUSIONS: We conclude that in younger women with low-grade cytological abnormalities, a single HPV test would not be useful in determining who should be referred for colposcopy or the most effective management at colposcopy. In women over 40, a negative HPV test could be used to rule out further investigation.

Variation in surgical methods used for total laryngectomy in Australia.

UNLABELLED: Deglutition disorders (dysphagia) are common following total laryngectomy. As the aetiology of the disorder is poorly understood, its incidence is probably under-estimated. Dysphagia may result from many factors, including the type of laryngectomy surgery employed and the use of adjuvant treatments (e.g. radiotherapy and chemotherapy). Dysphagia may also be compounded by other co-morbid factors, such as ageing and depression. AIM: To investigate the methods of surgical closure used by Australian ENT and head and neck surgeons after undertaking total laryngectomy surgery. METHOD: In order to audit surgical variation, 56 short questionnaires were sent to all Australian ENT and head and neck surgeons who were registered members of the Australia and New Zealand Head and Neck Society. Twenty-eight questionnaires (50 per cent) were completed and returned. RESULTS: Respondents reported using a variety of different reconstructive methods after total laryngectomy surgery. Specifically, there were differences in the type and levels of pharyngeal closure employed and the suturing techniques used. CONCLUSION: Currently, there is no scientific evidence to direct surgeons to the optimal pharyngeal reconstruction technique(s) ensuring for good swallowing results post-laryngectomy. An analysis of the effect of surgical reconstruction technique on laryngectomees' post-operative swallowing ability is needed, in order to provide evidence to determine optimal surgical techniques.