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.

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.

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.

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.

Human Papillomavirus-associated oropharyngeal cancer: an observational study of diagnosis, prevalence and prognosis in a UK population.

BACKGROUND: The incidence of Human Papillomavirus (HPV) associated oropharyngeal cancer (OPC) is increasing. HPV-associated OPC appear to have better prognosis than HPV-negative OPC. The aim of this study was to robustly determine the prevalence of HPV-positive OPC in an unselected UK population and correlate HPV positivity with clinical outcome. METHODS: HPV testing by GP5+/6+ PCR, In Situ Hybridisation (ISH) and p16 immunohistochemistry (IHC) was performed on 138 OPCs diagnosed in South Wales (UK) between 2001-06. Kaplan-Meier analysis was used to correlate HPV status with clinical outcome. RESULTS: Using a composite definition of HPV positivity (HPV DNA and p16 overexpression), HPV was detected in 46/83 (55%) samples where DNA quality was assured. Five year overall survival was 75.4% (95% CI: 65.2 to 85.5) in HPV-positives vs 25.3% (95% CI: 14.2 to 36.4) in HPV negatives, corresponding to a 78% reduction in death rate (HR 0.22, p < 0.001). HPV-positives had less locoregional recurrence but second HPV-positive Head and Neck primaries occurred. Poor quality DNA in fixed pathological specimens reduced both HPV prevalence estimates and the prognostic utility of DNA-based HPV testing methods. As a single marker, p16 was least affected by sample quality and correlated well with prognosis, although was not sufficient on its own for accurate HPV prevalence reporting. CONCLUSIONS: This study highlights the significant burden of OPC associated with HPV infection. HPV positive cases are clinically distinct from other OPC, and are associated with significantly better clinical outcomes. A composite definition of HPV positivity should be used for accurate prevalence reporting and up-front DNA quality assessment is recommended for any DNA-based HPV detection strategy.

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.

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.

A randomised controlled trial evaluating the impact of oral health advice on gingival health using intra oral images combined with a gingivitis specific toothpaste.

OBJECTIVES: Does a complex intervention of oral hygiene advice (OHA) delivered with intra-oral scanner images, anti-gingivitis toothpaste and motivational reminders, improve oral health more than a standard of care control arm of fluoride toothpaste, with OHA without scanner images? METHODS: Adult participants with pre-existing gingivitis were randomised to intervention or control. Following enrolment, baseline and each subsequent visit (V) (3-weeks, V2; 3-months, V3; 6-months, V4) followed the same schedule. Bleeding on Probing (BOP) was assessed and Intra Oral Scan IOS(1) recorded. Plaque was disclosed, scored and re-scanned (IOS(2)). The intervention group received OHA with IOS images, control group receiving OHA without IOS images. Participants brushed with their allocated toothpaste (fluoride, control; anti-gingivitis, intervention), IOS(3) was recorded. Between visits participants brushed with their allocated toothpaste, intervention group received motivational reminders. RESULTS: BOP scores from baseline were significantly improved in the intervention group compared to control at all visits for all surfaces (p<0.001); differences at V4 were 0.292 (all), 0.211 (buccal/labial) and 0.375 (lingual/palatal). Plaque scores from baseline pre-brushing to each visit pre- and post-brushing also favoured the intervention group, the difference always significant on lingual/palatal surfaces (p<0.05), significant for all but pre-brushing-V4 (p<0.05) on all surfaces, but only significant for pre-brushing-V3 (p<0.05) buccally/labially. Differences from baseline to post-brushing at V4 were: 0.200 (all), 0.098 (buccal/labial) and 0.291 (lingual/palatal). CONCLUSION: A complex intervention comprising OHA delivered with IOS-images, anti-gingivitis toothpaste and motivational reminders improved gingival health more than existing standard of care-OHA together with a standard fluoride toothpaste over a 6-month period. CLINICAL SIGNIFICANCE STATEMENT: Intra-oral scans (IOS) are now frequently used in general dental practice for a variety of purposes. IOS use, in combination with motivational texts and an anti-gingivitis toothpaste, could be further deployed to promote oral hygiene behaviour change in patients and improve gingival health, in a cost-effective manner.

Total and free testosterone concentrations are strongly influenced by age and central obesity in men with type 1 and type 2 diabetes but correlate weakly with symptoms of androgen deficiency and diabetes-related quality of life.

OBJECTIVE: Testosterone levels are commonly lowered in men with diabetes, but it is unclear how these relate to symptoms of hypogonadism and quality of life. We sought to investigate the relationship between testosterone levels, symptoms of androgen deficiency, erectile function and quality of life in men with type 1 and type 2 diabetes. DESIGN AND SUBJECTS: Cross-sectional study of 115 men with type 2 diabetes, 93 men with type 1 diabetes and 121 healthy controls. MEASUREMENTS: Total, bioavailable and free testosterone levels were measured or calculated by Vermuelen's formula. Quality of life and symptom scores were assessed by the Audit of Diabetes Dependent Quality of Life (ADDQoL), androgen deficiency in the aging male (ADAM) and International Index of Erectile Function (IIEF) questionnaires. RESULTS: Forty-five and sixty-one per cent of men with type 2 diabetes had low total and calculated free testosterone (CFT) levels, respectively. Total testosterone (TT) levels were not lowered in men with type 1 diabetes, but 32% had low CFT. After adjustment for age and waist circumference, only CFT in men with type 2 diabetes (-0·037 nm, 95% CI -0·075 to -0·0003, P = 0.048) remained lowered compared with controls. CFT correlated weakly with ADAM (r = -0·26, 95% CI -0.42 to -0·08, P = 0·006), IIEF (r = 0.19, 95% CI 0.01-0.37, P = 0.042) and ADDQoL (r = 0.21, 95% CI 0·03 to 0·38, P = 0·022) scores in men with type 2, but not type 1 diabetes. Age exerted the predominant effect on erectile function in both groups, in a model incorporating age, testosterone level and complications. CONCLUSIONS: Testosterone levels are strongly affected by age and central obesity in men with type 1 and type 2 diabetes but correlate weakly with symptoms of androgen deficiency and erectile function. Testosterone levels do not appear to be a major determinant of quality of life in patients with diabetes.

A randomised crossover trial to compare the potential of stannous fluoride and essential oil mouth rinses to induce tooth and tongue staining.

This study compared the staining potential of two experimental amine fluoride/stannous fluoride mouth rinses (A and B), a phenolic/essential oil rinse (C) and a negative control, water, rinse (D). The study was a single centre, randomized, single-blind, four treatment crossover study design among healthy participants. Prior to each study period, participants received a dental prophylaxis. On the Monday of each period, subjects suspended oral hygiene, and under supervision, rinsed with the allocated mouth rinse immediately followed by a warm black tea solution at hourly intervals eight times a day for 4 days. On Friday, the area and intensity of staining on the teeth, the primary outcome measure and dorsum of tongue were assessed. This regimen was repeated for all the three subsequent treatment periods. Rinse B produced less stain than rinse A, but the difference was not significant (p = 0.20). Rinse B produced significantly more stain than rinse C (p < 0.05) and D (p < 0.001). For tongue staining, rinse B produced significantly more staining than D (p < 0.01) but not A or C. Overall, all test rinses produced more staining than placebo with an overall pattern for more staining with stannous formulations. Individuals using stannous or phenolic/essential oil mouth rinse formulations should be advised of the possible staining side effect and that this can be easily removed by a professional dental cleaning.

The risk of cervical cancer associated with specific types of human papillomavirus: a case-control study in a UK population.

Mounting evidence supports incorporation of HPV testing into cervical screening; however, the optimal test format and target population have yet to be confirmed. Assessment of the potential benefits of type-specific testing requires estimation of the risk associated with infection with individual HPV types. However, the risk posed by individual HPV types may be population specific and influenced by cervical screening practice. The existing data on HPV type-specific risk is derived largely from unscreened populations. Our study addressed the lack of data on HPV type-specific risk in cytologically screened populations using a case-control study of 262 invasive cervical cancers diagnosed in Wales between 2000 and 2006, and 8,428 controls who attended for cytological screening in 2004. The analysis showed that the odds ratios (ORs) for infection with HPV 16 and 18 are considerable; 2770 (95% CI 1050-7320) and 950 (95% CI 330-2740), respectively, and that the OR for other oncogenic types are in general considerably less (ranging, where quantified, from 20.2 to 386 in the same population). The effect of age on OR associated with particular HPV types was also assessed; this indicated that infection with a high-risk HPV in women older than 40 years was associated with an approximately 30-fold increased risk of invasive cervical cancer relative to women younger than 40 years. These results indicate that there is significant prognostic information associated with knowledge of HPV type.

A proof of concept study to confirm the suitability of an intra oral scanner to record oral images for the non-invasive assessment of gingival inflammation.

OBJECTIVES: To compare gingival inflammation scores obtained chairside using the non-invasive modified gingival index (MGI) with MGI scores from an intraoral scan (IOS) captured at the clinical visit but viewed 10 days later. METHODS: Single visit, anterior teeth, observational, proof of concept study in healthy adult participants with a spectrum of gingival inflammation. One investigator performed both clinical and intraoral scan MGI assessments, a second repeated the MGI evaluation from the IOS. RESULTS: 23 participants aged 18-72 yielded data for 552 gingival sites. There was agreement at 90 % of sites comparing clinical with IOS MGI scores. The commonest disagreements were MGI grade 0 read as 1 and 2 read as 3, the highest single probability of error occurring where a clinical score of 0 was scored 1 from the IOS: 0.118 and 0.129 for examiners 1 and 2 respectively. The second most common probability of error occurred where an IOS score of 3 was scored clinically as 2: 0.089 and 0.097 for examiners 1 and 2 respectively. MGI scores from the scans were similar for both examiners (91 % agreement), with no discrepancies of greater than 1 scale point. There was very close agreement between clinical MGI and IOS colour/texture scores. CONCLUSION: This study conclusively demonstrated that the MGI score from the scanned image was very similar to the MGI scored clinically. This study confirms that a digital IOS accurately captures gingival contour images allowing a clinician to determine health or degree of gingival inflammation from it using MGI scores. CLINICAL SIGNIFICANCE STATEMENT: This study confirms that IOS images of teeth and soft tissues are sufficiently accurate to allow the clinical evaluation of health or inflammatory gingival status using non-invasive indices. IOS has great potential for efficient and accurate data capture, for general practice and research facilitating remote evaluation and data verification.

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.

POSNOC-POsitive Sentinel NOde: adjuvant therapy alone versus adjuvant therapy plus Clearance or axillary radiotherapy: a randomised controlled trial of axillary treatment in women with early-stage breast cancer who have metastases in one or two sentinel nodes.

INTRODUCTION: ACOSOG-Z0011(Z11) trial showed that axillary node clearance (ANC) may be omitted in women with ≤2 positive nodes undergoing breast conserving surgery (BCS) and whole breast radiotherapy (RT). A confirmatory study is needed to clarify the role of axillary treatment in women with ≤2 macrometastases undergoing BCS and groups that were not included in Z11 for example, mastectomy and those with microscopic extranodal invasion. The primary objective of POsitive Sentinel NOde: adjuvant therapy alone versus adjuvant therapy plus Clearance or axillary radiotherapy (POSNOC) is to evaluate whether for women with breast cancer and 1 or 2 macrometastases, adjuvant therapy alone is non-inferior to adjuvant therapy plus axillary treatment, in terms of 5-year axillary recurrence. METHODS AND ANALYSIS: POSNOC is a pragmatic, multicentre, non-inferiority, international trial with participants randomised in a 1:1 ratio. Women are eligible if they have T1/T2, unifocal or multifocal invasive breast cancer, and 1 or 2 macrometastases at sentinel node biopsy, with or without extranodal extension. In the intervention group women receive adjuvant therapy alone, in the standard care group they receive ANC or axillary RT. In both groups women receive adjuvant therapy, according to local guidelines. This includes systemic therapy and, if indicated, RT to breast or chest wall. The UK Radiotherapy Trials Quality Assurance Group manages the in-built radiotherapy quality assurance programme. Primary endpoint is 5-year axillary recurrence. Secondary outcomes are arm morbidity assessed by Lymphoedema and Breast Cancer Questionnaire and QuickDASH questionnaires; quality of life and anxiety as assessed with FACT B+4 and State/Trait Anxiety Inventory questionnaires, respectively; other oncological outcomes; economic evaluation using EQ-5D-5L. Target sample size is 1900. Primary analysis is per protocol. Recruitment started on 1 August 2014 and as of 9 June 2021, 1866 participants have been randomised. ETHICS AND DISSEMINATION: Protocol was approved by the National Research Ethics Service Committee East Midlands-Nottingham 2 (REC reference: 13/EM/0459). Results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN54765244; NCT0240168Cite Now.

Reduced total testosterone concentrations in young healthy South Asian men are partly explained by increased insulin resistance but not by altered adiposity.

OBJECTIVE: To compare ethnic differences in total, free and bioavailable testosterone amongst young healthy South Asian and Caucasian men. DESIGN AND SUBJECTS: Cross-sectional study of 134 healthy men (age 20-40 years) of South Asian (n = 67) or Caucasian (n = 67) origin, recruited from hospital staff and students working in Newport, UK. Subjects were excluded if they had a fasting plasma glucose >5.9 mmol/l, central obesity [waist circumference ≥ 94 cm (Caucasian) or ≥ 90 cm (South Asian)] or significant other disease. MEASUREMENTS: Fasting plasma glucose, total testosterone (determined by immunoassay and mass spectrometry), albumin, sex hormone-binding globulin (SHBG) and insulin were measured. Free and bioavailable testosterone were calculated using Vermeulen's formula, and insulin resistance was estimated by HOMA-IR. RESULTS: The South Asians were slightly older (P = 0.04), shorter (P < 0.001), lighter (P < 0.001), more insulin resistant (P = 0.006), and had a lower body mass index BMI (P = 0.012), waist circumference (P = 0.043) and SHBG (P = 0.001) than the Caucasians. Total testosterone was significantly lower in South Asians (mass spectrometry: geometric mean 16.3 nmol/l; 95% reference interval 9.3-28.6 nmol/l) compared with Caucasians (mass spectrometry: geometric mean 18.4 nmol/l; 95% reference interval 10.6-31.9 nmol/l; P = 0.015), but calculated free and bioavailable testosterone were not different between groups. Adjusting for HOMA-IR, but not BMI or waist circumference, partly attenuated the differences in total testosterone. CONCLUSIONS: Total, but not free, testosterone concentrations are lower in healthy South Asian men than in Caucasians. These differences are apparent at a young age and may be partly attributable to alterations in insulin sensitivity.

Supporting informed decision making online in 20 minutes: an observational web-log study of a PSA test decision aid.

BACKGROUND: Web-based decision aids are known to have an effect on knowledge, attitude, and behavior; important components of informed decision making. We know what decision aids achieve in randomized controlled trials (RCTs), but we still know very little about how they are used and how this relates to the informed decision making outcome measures. OBJECTIVE: To examine men's use of an online decision aid for prostate cancer screening using website transaction log files (web-logs), and to examine associations between usage and components of informed decision making. METHODS: We conducted an observational web-log analysis of users of an online decision aid, Prosdex. Men between 50 and 75 years of age were recruited for an associated RCT from 26 general practices across South Wales, United Kingdom. Men allocated to one arm of the RCT were included in the current study. Time and usage data were derived from website log files. Components of informed decision making were measured by an online questionnaire. RESULTS: Available for analysis were 82 web-logs. Overall, there was large variation in the use of Prosdex. The mean total time spent on the site was 20 minutes. The mean number of pages accessed was 32 (SD 21) out of a possible 60 pages. Significant associations were found between increased usage and increased knowledge (Spearman rank correlation [rho] = 0.69, P < .01), between increased usage and less favorable attitude towards PSA testing (rho = -0.52, P < .01), and between increased usage and reduced intention to undergo PSA testing (rho = -0.44, P < .01). A bimodal distribution identified two types of user: low access and high access users. CONCLUSIONS: Increased usage of Prosdex leads to more informed decision making, the key aim of the UK Prostate Cancer Risk Management Programme. However, developers realistically have roughly 20 minutes to provide useful information that will support informed decision making when the patient uses a web-based interface. Future decision aids need to be developed with this limitation in mind. We recommend that web-log analysis should be an integral part of online decision aid development and analysis. TRIAL REGISTRATION: ISRCTN48473735; http://www.controlled-trials.com/ISRCTN48473735 (Archived by WebCite at http://www.webcitation.org/5pqeF89tS).