Clinical trials evaluating desensitising agents. Some design and analysis issues.

INTRODUCTION: The purpose of this short communication is to draw attention to an efficient design for trials to evaluate desensitising agents, and an appropriate statistical analysis. METHODS: Two recent sensitivity trials conducted by the Bristol Dental School Clinical Trials Group are reviewed. RESULTS: The methodology used was effective to establish efficacy of the products evaluated. CONCLUSIONS: This methodology is recommended for wider use. CLINICAL SIGNIFICANCE: Effective clinical trial methodology enables establishment of efficacy of desensitising products leading to patient benefit.

The SARS-CoV2 envelope differs from host cells, exposes procoagulant lipids, and is disrupted in vivo by oral rinses.

The lipid envelope of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an essential component of the virus; however, its molecular composition is undetermined. Addressing this knowledge gap could support the design of antiviral agents as well as further our understanding of viral-host protein interactions, infectivity, pathogenicity, and innate immune system clearance. Lipidomics revealed that the virus envelope comprised mainly phospholipids (PLs), with some cholesterol and sphingolipids, and with cholesterol/phospholipid ratio similar to lysosomes. Unlike cellular membranes, procoagulant amino-PLs were present on the external side of the viral envelope at levels exceeding those on activated platelets. Accordingly, virions directly promoted blood coagulation. To investigate whether these differences could enable selective targeting of the viral envelope in vivo, we tested whether oral rinses containing lipid-disrupting chemicals could reduce infectivity. Products containing PL-disrupting surfactants (such as cetylpyridinium chloride) met European virucidal standards in vitro; however, components that altered the critical micelle concentration reduced efficacy, and products containing essential oils, povidone-iodine, or chlorhexidine were ineffective. This result was recapitulated in vivo, where a 30-s oral rinse with cetylpyridinium chloride mouthwash eliminated live virus in the oral cavity of patients with coronavirus disease 19 for at least 1 h, whereas povidone-iodine and saline mouthwashes were ineffective. We conclude that the SARS-CoV-2 lipid envelope i) is distinct from the host plasma membrane, which may enable design of selective antiviral approaches; ii) contains exposed phosphatidylethanolamine and phosphatidylserine, which may influence thrombosis, pathogenicity, and inflammation; and iii) can be selectively targeted in vivo by specific oral rinses.

Healthy eating and lifestyle in pregnancy (HELP): a cluster randomised trial to evaluate the effectiveness of a weight management intervention for pregnant women with obesity on weight at 12 months postpartum.

OBJECTIVE: To assess whether a weight management intervention for pregnant women with obesity was effective in reducing body mass index (BMI) 12 months after giving birth. METHODS: Pragmatic, cluster randomised controlled trial (RCT) with embedded cost-effectiveness analysis. 598 women with a BMI of ≥30 kg/m2 (between 12 and 20 weeks gestation) were recruited from 20 secondary care maternity units in England and Wales. BMI at 12 months postpartum was the primary outcome. A range of clinical and behavioural secondary outcomes were examined. INTERVENTIONS: Women attending maternity units randomised to intervention were invited to a weekly weight management group, which combined expertise from a commercial weight loss programme with clinical advice from midwives. Both intervention and control participants received usual care and leaflets on diet and physical activity in pregnancy. RESULTS: Mean (SD) BMI at 12 months postpartum was 36.0 kg/m2 (5.2) in the control group, and 37.5 kg/m2 (6.7) in the intervention group. After adjustment for baseline BMI, the intervention effect was -0.02 (95% CI -0.04 to 0.01). The intervention group had an improved healthy eating score (3.08, 95% CI 0.16 to 6.00, p < 0.04), improved fibre score (3.22, 1.07 to 5.37, p < 0.01) and lower levels of risky drinking at 12 months postpartum compared to the control group (OR 0.45, 0.27 to 0.74, p < 0.002). The net incremental monetary benefit was not statistically significantly different between arms, although the probability of the intervention being cost-effective was above 60%, at policy-relevant thresholds. CONCLUSIONS: There was no significant difference between groups on the primary outcome of BMI at 12 months. Analyses of secondary outcomes indicated improved healthy eating and lower levels of risky drinking. TRIAL REGISTRATION: Current Controlled Trials ISRCTN25260464.

A randomised controlled trial to compare the efficacy of an aluminium lactate/potassium nitrate/hydroxylapatite toothpaste with a control toothpaste for the prevention of dentine hypersensitivity.

OBJECTIVES: To determine the efficacy of a cosmetic aluminium lactate/potassium nitrate/hydroxylapatite toothpaste for the reduction of dentine hypersensitivity (DH) pain as compared to a control toothpaste containing potassium nitrate. METHODS: The study was a randomised, examiner-blind, two treatment arm, parallel controlled trial in healthy adults with at least 2 sensitive teeth (Schiff >2). At baseline, immediately after treatment and at 7 and 14 days of twice-daily brushing of the test or control toothpaste the sensitivity of 2 test teeth was measured following iced-water (Schiff and VAS) and tactile (Yeaple probe) stimuli, and a whole mouth plaque score was obtained. Participants also completed a whole-mouth VAS and DHEQ15 quality of life questionnaire at baseline, 7 and 14 days. RESULTS: Both toothpastes reduced DH in test teeth, but pain reduction in the test group was significantly better at all timepoints and by all measures (p = 0.005, tooth-level VAS immediately after brushing; p < 0.001 all other comparisons). There was a relative risk reduction of Schiff sensitivity of 55 % immediately after brushing which rose to 81 % after 7 and 88.6 % after 14 days (all p < 0.001). There were no differences in plaque, whole mouth VAS or DHEQ15 scores at any time point. CONCLUSION: This study demonstrated the efficacy of an aluminium lactate/potassium nitrate/hydroxylapatite toothpaste compared to a potassium nitrate control toothpaste for the prevention of dentine hypersensitivity both immediately and over a 2 week period. This agent appears to have potential for pain alleviation from the common oral pain condition of DH and further research is warranted. CLINICAL SIGNIFICANCE: DH pain, whilst transient in nature, is arresting in magnitude, affecting quality of life. Daily application of efficacious toothpastes can relieve DH pain however, as yet, there is no gold standard treatment. The results of this study support further investigation of an aluminium lactate/potassium nitrate/hydroxylapatite toothpaste for DH management.

Randomised controlled trial of a microneedle patch with a topical anaesthetic for relieving the pain of dental injections.

OBJECTIVES: To determine whether a microneedle patch combined with 5% topical lidocaine reduces dental injection pain more than a patch without microneedles combined with 5% topical lidocaine. METHODS: This proof of principle randomised, two-treatment, double-blind, crossover split-unit design study in 16 healthy participants investigated levels of perceived pain from 3 increasing pain provoking challenges, when topical 5% lidocaine dental gel was applied to the oral mucosa with a microneedle patch and a patch with no microneedles, prior to infiltration with local anaesthesia on 2 visits. Pain was assessed by visual analogue scale (VAS) and 4-point verbal rating scale (VRS). RESULTS: 15 participants completed the study. Mean pain scores, lower at buccal sites, increased in both groups across challenges 1-3: Test palatal 5.1, 11.9, 26.8; buccal 0.7, 2.8, 18.3; Control palatal 12.3, 18.7, 39.5; buccal 4.0, 6.9, 30.6. The microneedle patch plus lidocaine significantly lowered VAS pain scores at both sites for all challenges, the biggest mean difference seen palatally after challenge 3 (12.7, p < 0.001). VRS pain scores were also significantly reduced for test compared to control for all 3 challenges (p = 0.014). Buccal scores favoured the microneedle patch, significantly for pain challenge 3 (p = 0.025). No adverse events occurred. CONCLUSIONS: Prior oral application of a microneedle patch combined with 5% topical lidocaine gel reduced the pain experienced from dental infiltration. Microneedle patch use in the dental setting offers the prospect of improving degree and depth of anaesthesia from topically applied anaesthetic gel, without itself causing any pain. CLINICAL SIGNIFICANCE: Dental injections are associated with fear and anxiety. Application of a microneedle patch, combined with topical anaesthetic, to the oral mucosa prior to delivery of the injection reduces the pain from this dental procedure. This novel technique may allay patients' apprehension of local anaesthesia and improve quality of life outcomes.

A novel cervical tooth wear and recession index, the cervical localisation code, and its application in the prevention and management of dentine hypersensitivity.

OBJECTIVES: To design and validate a new index to assess tooth wear (TW) in the cervical region and its association with gingival recession (GR), for use both in research studies and as resource in General Dental Practice, with focused prevention and management strategiesparticularly related to aetiology of dentine hypersensitivity provided for each Code score. METHODS: Codes to reflect clinical presentations of the cervical region in health and disease recording both TW and GR were defined. Validation of the Code was undertaken by 3 trained examiners who scored buccal and lingual surfaces of eligible teeth in 42 adult healthy volunteers. Each volunteer underwent 4 identical clinical examinations, being assessed twice by the examiner who performed the first and last exam. RESULTS: Cervical Localisation Code definitions were A: no GR, no coronal TW, B: no GR, distinct coronal TW, C: GR but no coronal TW, D: GR with distinct coronal and root TW. For validation 2073 eligible tooth surfaces were scored. There were only 57 within and 201 between examiner disagreements, the most common being between scores C and D. CONCLUSIONS: The Cervical Localisation Code was used reproducibly by three independent examiners. It will provide focussed data on the cervical region in research studies allowing the association of patient reported dietary and lifestyle factors with specific lesion types, and a tool to aid the management of clinical scenarios, specifically those that lead to dentine hypersensitivity in general dental practice. CLINICAL SIGNIFICANCE: Exposure of dentine at the cervical margin by TW and/or GR often results in dentine hypersensitivity, however current TW indices do not record TW location or GR presence. The Cervical Localisation Code captures both parameters and suggests likely aetiology for dentine hypersensitivity and guide clinical management of the cervical region.

A randomised controlled trial investigating efficacy of a novel toothpaste containing calcium silicate and sodium phosphate in dentine hypersensitivity pain reduction compared to a fluoride control toothpaste.

OBJECTIVES: To compare a calcium silicate and sodium phosphate toothpaste (CSSP) with a fluoride negative control toothpaste for dentine hypersensitivity (DH) pain reduction after 14, 28 and 29 days. METHODS: This was a double blind, parallel study in 247 healthy adults with DH (Schiff score >2, tactile 10-20 g) in 2 teeth in different quadrants of the mouth. After acclimatisation, participants were randomised to CSSP or control toothpaste. After measuring baseline sensitivity products were applied twice-daily by toothbrushing, and once daily massaging into the sensitive teeth. Sensitivity was assessed following airblast (Schiff and VAS) and tactile (Yeaple probe) stimuli at baseline, 14 and 28 days, and at 29 days, 12 h after last product application. Participants completed a quality of life questionnaire at each study visit up to day 28. RESULTS: After 14, 28 and 29 days the CSSP group had significantly lower Schiff, lower VAS and higher Yeaple probe scores compared to control (VAS at 14 days, p < 0.04; all other comparisons, p < 0.001). Quality of life scores improved in both groups, but no significant differences between groups were observed. CONCLUSIONS: The CSSP toothpaste was more effective than the fluoride control toothpaste at reducing DH pain with benefit persisting 12 h following application. CLINICAL SIGNIFICANCE: This novel calcium silicate and sodium phosphate toothpaste (CSSP) toothpaste is an effective twice-daily treatment when brushed on the teeth for dentine hypersensitivity sufferers compared to brushing with a conventional fluoride paste. Twice-daily brushing provides a sustained effect for long-lasting pain relief from dentine hypersensitivity.

A randomised controlled trial to determine patient experience of a magnetostrictive stack scaler as compared to a piezoelectric scaler, in supportive periodontal therapy.

OBJECTIVES: To compare the pain/discomfort experienced by patients in supportive periodontal therapy, following treatment with a piezoelectric ultrasonic scaler, designed for use with warmed water irrigation, and a magnetostrictive ultrasonic scaler. METHODS: This was a single-centre, randomised, split mouth study with regard to side, and crossover with regard to treatment order. Patients attending general dental practice for supportive periodontal therapy were randomised to receive treatment from one scaler on the left and the other scaler on the right-hand side of the mouth, the left side of the mouth always being treated first. The piezo scaler (Tigon+®) was used with room temperature irrigation for half of the participants (approx 20 °C) and warmed water irrigation (approx 36 °C) for the other half. The magnetostrictive scaler (Cavitron Select SPS 30K®) was used with room temperature irrigation (approx 20 °C) only. Participants rated their pain/discomfort, noise and vibration by VAS scale. RESULTS: 140 participants completed the study. Mean VAS scores for all measures were significantly better for the piezo scaler used with warm irrigation as compared to the magnetostrictive scaler p < 0.001. When both scalers were used with room temperature irrigant, there were no significant differences in the VAS scores between scalers (pain/discomfort, p = 0.68; noise p = 0.2; vibration p = 0.85). CONCLUSIONS: Participants indicated to statistical significance, less pain/discomfort, noise and vibration when the piezo scaler (Tigon+®) device was used with warmed irrigant, compared to the magnetostrictive scaler (Cavitron Select SPS 30K®). There were no significant differences between the instruments when room temperature irrigant was used. CLINICAL SIGNIFICANCE: Regular scaling in supportive periodontal therapy, is essential for maintenance of susceptible patients, however it can be painful due to dentine hypersensitivity deterring patients from attending. Using a piezo scaler with warm water improves patient quality of life and subsequent oral health. This may have positive effects on patient attendance. ISRCTN REGISTERED: ISRCTN15573995.

Patients' perception of their oral and periodontal health and its impact: a cross-sectional study in the NHS.

Aims To determine patient awareness of periodontal health, dentine hypersensitivity and tooth wear, and their impact on oral health quality of life in patients attending NHS practices in South West England.Method In this cross-sectional, multi-centre epidemiological study 814 adult NHS patients completed an oral health questionnaire and then underwent a clinical examination. Pocket probing depths (mm), gingival recession (mm), gingival bleeding (yes/no), dentine hypersensitivity (Schiff score, and yes/no) and tooth wear (basic erosive wear examination score) were measured.Results Participants were regular dental attenders, with good oral hygiene practices and a low prevalence of periodontal disease (probing depth of 4 mm or more) (25%). For all conditions assessed, self-reported data and clinical indices were significantly positively associated, with the strongest associations being seen for dentine hypersensitivity and the weakest for tooth wear. Periodontal disease and dentine hypersensitivity were significantly associated with all four patient-reported measures of oral health quality of life studied.Conclusion This NHS patient population is well cared for and educated with respect to their oral health. The findings confirm the negative impact of periodontal disease and dentine hypersensitivity, and identifies the need to increase awareness of the signs and symptoms of tooth wear.

Supporting shared decision making using an Option Grid for osteoarthritis of the knee in an interface musculoskeletal clinic: A stepped wedge trial.

OBJECTIVE: To evaluate whether introducing tools, specifically designed for use in clinical encounters, namely Option Grids, into a clinical practice setting leads to higher levels of shared decision making. METHODS: A stepped wedge trial design where 6 physiotherapists at an interface clinic in Oldham, UK, were sequentially instructed in how to use an Option Grid for osteoarthritis of the knee. Patients with suspected or confirmed osteoarthritis of the knee were recruited, six per clinician prior to instruction, and six per clinician afterwards. We measured shared decision making, patient knowledge, and readiness to decide. RESULTS: A total of 72 patients were recruited; 36 were allocated to the intervention group. There was an 8.4 point (95% CI 4.4 to 12.2) increase in the Observer OPTION score (range 0-100) in the intervention group. The mean gain in knowledge was 0.9 points (score range 0-5, 95% CI, 0.3 to 1.5). There was no increase in encounter duration. CONCLUSION: Shared decision making increased when clinicians used the knee osteoarthritis Option Grid. PRACTICE IMPLICATIONS: Tools designed to support collaboration and deliberation about treatment options lead to increased levels of shared decision making.

Minimum standards for the certification of patient decision support interventions: feasibility and application.

OBJECTIVE: Patient decision support interventions are not currently subject to standardized quality control. The current study aims to assess the feasibility of applying a proposed set of minimum standards (previously developed as part of a possible certification process) to a selection of existing patient decision support interventions. METHODS: A convenience sample of interventions selected from those included in the 2009 Cochrane systematic review of patient decision aids was scored by trained raters using the International Patient Decision Aids Standards (IPDAS) instrument. Scores were then evaluated against the published proposed minimum standards. RESULTS: Twenty-five out of thirty included interventions met all qualifying criteria while only three met the proposed certification criteria. The changes required for an intervention to meet the proposed certification standards were relatively minor. There was considerable variation between raters' mean scores. CONCLUSIONS: Most interventions did not meet the certification criteria due to lack of information on modifiable items such as update policy and funding source. PRACTICE IMPLICATIONS: Specifying minimum standards for patient decision support interventions is a feasible development. However, it remains unclear whether the minimum standards can be applied to interventions designed for use within clinical encounters and to those that target screening and diagnostic tests.

Healthy eating and lifestyle in pregnancy (HELP): a protocol for a cluster randomised trial to evaluate the effectiveness of a weight management intervention in pregnancy.

BACKGROUND: Approximately 1 in 5 pregnant women in the United Kingdom are obese. In addition to being associated generally with poor health, obesity is known to be a contributing factor to pregnancy and birth complications and the retention of gestational weight can lead to long term obesity.This paper describes the protocol for a cluster randomised trial to evaluate whether a weight management intervention for obese pregnant women is effective in reducing women's Body Mass Index at 12 months following birth. METHODS/DESIGN: The study is a cluster randomised controlled trial involving 20 maternity units across England and Wales. The units will be randomised, 10 to the intervention group and 10 to the control group. 570 pregnant women aged 18 years or over, with a Body Mass Index of +/=30 (kg/m2) and between 12 and 20 weeks gestation will be recruited. Women allocated to the control group will receive usual care and two leaflets giving advice on diet and physical activity. In addition to their usual care and the leaflets, women allocated to the intervention group will be offered to attend a weekly 1.5 hour weight management group, which combines expertise from Slimming World with clinical advice and supervision from National Health Service midwives, until 6 weeks postpartum.Participants will be followed up at 36 weeks gestation and at 6 weeks, 6 months and 12 months postpartum. Body Mass Index at 12 months postpartum is the primary outcome. Secondary outcomes include pregnancy weight gain, quality of life, mental health, waist-hip ratio, child weight centile, admission to neonatal unit, diet, physical activity levels, pregnancy and birth complications, social support, self-regulation and self-efficacy. A cost effectiveness analysis and process evaluation will also be conducted. DISCUSSION: This study will evaluate the effectiveness of a theory-based intervention developed for obese pregnant women. If successful the intervention will equip women with the necessary knowledge and skills to enable them to make healthier choices for themselves and their unborn child. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN25260464 Date of registration: 16th April 2010.

Option Grids to facilitate shared decision making for patients with Osteoarthritis of the knee: protocol for a single site, efficacy trial.

BACKGROUND: Despite policy interest, an ethical imperative, and evidence of the benefits of patient decision support tools, the adoption of shared decision making (SDM) in day-to-day clinical practice remains slow and is inhibited by barriers that include culture and attitudes; resources and time pressures. Patient decision support tools often require high levels of health and computer literacy. Option Grids are one-page evidence-based summaries of the available condition-specific treatment options, listing patients' frequently asked questions. They are designed to be sufficiently brief and accessible enough to support a better dialogue between patients and clinicians during routine consultations. This paper describes a study to assess whether an Option Grid for osteoarthritis of the knee (OA of the knee) facilitates SDM, and explores the use of Option Grids by patients disadvantaged by language or poor health literacy. METHODS/DESIGN: This will be a stepped wedge exploratory trial involving 72 patients with OA of the knee referred from primary medical care to a specialist musculoskeletal service in Oldham. Six physiotherapists will sequentially join the trial and consult with six patients using usual care procedures. After a period of brief training in using the Option Grid, the same six physiotherapists will consult with six further patients using an Option Grid in the consultation. The primary outcome will be efficacy of the Option Grid in facilitating SDM as measured by observational scores using the OPTION scale. Comparisons will be made between patients who have received the Option Grid and those who received usual care. A Decision Quality Measure (DQM) will assess quality of decision making. The health literacy of patients will be measured using the REALM-R instrument. Consultations will be observed and audio-recorded. Interviews will be conducted with the physiotherapists, patients and any interpreters present to explore their views of using the Option Grid. DISCUSSION: Option Grids offer a potential solution to the barriers to implementing traditional decision aids into routine clinical practice. The study will assess whether Option Grids can facilitate SDM in day-to-day clinical practice and explore their use with patients disadvantaged by language or poor health literacy. TRIAL REGISTRATION: Current Controlled Trials ISRCTN94871417.

Human papillomavirus infection is rare in nonmalignant tonsil tissue in the UK: implications for tonsil cancer precursor lesions.

The incidence of human papillomavirus (HPV)-associated tonsil cancer is increasing but the prevalence of HPV, and of premalignant precursors, in tonsil tissue is unknown. We aimed to assess prevalence of HPV infection in nonmalignant tonsillar crypt epithelia and to histopathologically characterise positive samples. Formalin-fixed paraffin-embedded (FFPE) tonsil tissue specimens were obtained from an age- and sex-stratified random sample of patients aged 0-69 years whose paired tonsils were archived following elective tonsillectomy at hospitals throughout England and Southern Scotland from 2004 to 2008. Homogenised fresh-frozen tonsil tissue was also obtained from archive for two random subsets of males aged 25-34 and over 44. HPV status was assessed in all samples for 20 mucosal HPV types by GP5+/6+ polymerase chain reaction (PCR) enzyme immunoassay and by HPV16 type-specific PCR targeting the E6 gene. In the homogenised material, HPV status was also assessed for 44 HPV types by SPF10-PCR enzyme immunoassay. Of 4,095 randomly sampled FFPE specimens, amplifiable DNA was extracted from 3,377 (82.5%) and from 511 of 524 (97.5%) homogenised tonsils. HPV DNA was identified in 0 of 3,377 (0%, 95% CI 0-0.089%) fixed samples and 0 of 511 (0%, 95% CI 0-0.58%) homogenised samples. This suggests HPV infection may be rare in tonsil reticulated crypt epithelia. Furthermore, we found no evidence of HPV-associated premalignant neoplasia. These data suggest that if HPV-associated premalignant lesions do occur, they are likely to be rare and may have a high risk of progression to carcinoma.

UK population based study to predict impact of HPV vaccination.

BACKGROUND: In 2008 a human papillomavirus (HPV) vaccination programme for cervical cancer prevention was implemented in the UK. Surveillance of vaccine uptake, impact on prevalence of HPV infection and cervical cancer incidence were identified as key measures to evaluate the intervention. OBJECTIVE: To determine baseline HPV prevalence in unvaccinated women and predict impact of HPV vaccination on high-grade cervical disease (CIN2+). STUDY DESIGN: A pseudo-anonymous prospective cohort was sampled on entry to the routine cervical screening programme between March 2009 and November 2010. In total, 13,306 eligible females were identified and high-risk (hrHPV) type specific status determined. Potential impact of prophylactic vaccination on CIN2+ was calculated by applying HPV vaccine clinical trial data to the baseline HPV type-specific data. RESULTS: Of 13,306 samples tested, 3545 (26.6%) were confirmed positive for at least one hrHPV type and 1325 (10%) were positive for low risk HPV. HPV16 was the predominant type detected in cases positive with either single or multiple hrHPV infection(s) (5.2% and 4.7%, respectively). Based on hrHPV type-specific data, Gardasil would have prevented 33.2% HPV16/18 unrelated CIN2+ compared to 47.1% for Cervarix. This difference was not statistically significant. CONCLUSION: Prior to the introduction of the HPV vaccine, approximately one-quarter of young women were positive for hrHPV and one-tenth positive for HPV16. Post-vaccination, we anticipate a substantial absolute risk reduction in high-grade cervical disease associated with both targeted and non-targeted hrHPV types. There is no significant difference between the two commercially available vaccines in terms of clinical impact.

Implementing GRADE: calculating the risk difference from the baseline risk and the relative risk.

A key step in implementing the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system is the estimation of a risk difference based on estimates of the baseline risk and the relative risk estimated from different sources. In this paper we describe a simple and effective method to calculate confidence intervals (CIs) for the risk difference for this situation. Whenever an independent source is available to estimate the baseline risk for the population to which the effect estimates should be applied, this source should be used and CIs for the absolute risk difference should be calculated taking all sources of uncertainty into account.

Modelling the risk of visual field loss arising from long-term exposure to the antiepileptic drug vigabatrin: a cross-sectional approach.

BACKGROUND: The antiepileptic drug vigabatrin has been used widely since 1989, but has only been approved for use in the US since 2009. The risk:benefit of vigabatrin is generally predicated upon an assumed frequency of associated visual field loss (VAVFL) of approximately 31 %. This estimate is based upon relatively short-term usage (up to 4-5 years) and it is essential to determine whether the frequency of VAVFL increases with longer-term usage. OBJECTIVE: The aim of this study was to model, from cross-sectional evidence, over greater ranges of treatment duration and cumulative dose than previously evaluated, the risk (frequency) of VAVFL with increasing exposure to vigabatrin. STUDY DESIGN AND SETTING: This was a retrospective cohort study undertaken in a regional hospital epilepsy clinic. PATIENTS: The cohort comprised 147 consecutive patients treated with vigabatrin for refractory complex partial (focal) seizures, who had all undergone ophthalmological examination and who had undertaken perimetry, reliably, according to a standard and robust protocol. The visual field plots were evaluated masked to treatment duration and dose. MAIN OUTCOME MEASURE: The risk (frequency) of VAVFL with increasing exposure to vigabatrin was modelled, from the cross-sectional evidence, by standard and plateau logistic regression. RESULTS: The cohort comprised 80 females and 67 males (mean age 40.3 years, standard deviation 13.7). The median duration of vigabatrin exposure was 7.9 years (interquartile range 3.6-11.0, range 0.2-16.1 years); 46 patients (31 %) had received vigabatrin for over 10 years. Eighty-seven patients (59 %) exhibited VAVFL; the proportion with VAVFL was higher in males (66 %) than females (54 %). The plateau model for duration and for cumulative dose exhibited a better fit than the standard model (both p < 0.001). The modelled frequency of VAVFL increased with increasing exposure up to approximately 6 years duration and 5 kg cumulative dose, and plateaued at approximately 76 % (95 % CI 67-85) and 79 % (95 % CI 70-87), respectively. Severity of VAVFL, classified in terms of the visual field index Mean Deviation, was not significantly associated with either duration or cumulative dose of therapy. CONCLUSION: Clinicians and patients, in enabling informed choice, should be alert to the possible substantial increased risk:benefit for VAVFL with increasing long-term exposure to vigabatrin and the ensuing increased cost:benefit resulting from the necessary additional visual assessments.

Confidence intervals for odds ratio and relative risk based on the inverse hyperbolic sine transformation.

The inverse hyperbolic sine transformation can be used to shorten the standard delta logit interval for the odds ratio and the delta log interval for the relative risk. As it stands, this transformation does not provide sufficient coverage. A pseudo-frequency modification is suggested and evaluated. The modification achieves an improvement in coverage for both the odds ratio and the relative risk and a further improvement in interval width for the odds ratio. We also find that another closed form interval, called MOVER-R Wilson, which is based on the method of variance estimates recovery, performs well. When the more complex and software demanding intervals, such as the asymptotic score, are unavailable, the adjusted inverse sinh intervals and MOVER-R Wilson provide two simple approaches to interval estimation of the odds ratio and the relative risk.