Burden of Disease and Treatment Patterns Amongst Patients With Vitiligo: Findings From a National, Longitudinal Retrospective Study in the United Kingdom.

This retrospective study, using UK Clinical Practice Research Datalink and Hospital Episode Statistics databases, analysed 17,239 incident patients with vitiligo. Mean incidence of vitiligo was 0.16 (2010-2021) per 1000 person-years (range: 0.10 [2010-COVID] to 0.19 [2013/2018]); prevalence increased from 0.21% (2010) to 0.38% (2021). The most common comorbidities recorded after vitiligo diagnosis were diabetes (19.4%), eczema (8.9%), thyroid disease (7.5%), and rheumatoid arthritis (6.9%). Mental health diagnoses recorded at any time were most commonly depression and/or anxiety (24.6%), depression (18.5%), anxiety (16.0%), and sleep disturbance (12.7%); recorded after vitiligo diagnosis in 6.4%, 4.4%, 5.5%, and 3.9%, respectively. Mental health comorbidities were more common among White patients (eg, depression and/or anxiety, 29.0%) than Black (18.8%), Asian (16.1%), and other ethnicities (21.4%). In adolescents, depression and/or anxiety was most commonly diagnosed after vitiligo diagnosis (7.4% vs before, 1.8%). Healthcare resources were used most frequently in the first year after vitiligo diagnosis (incident cohort), typically dermatology-related outpatient appointments (101.9/100 person-years) and general practitioner consultations (97.9/100 person-years). In the year after diagnosis, 60.8% of incident patients did not receive vitiligo-related treatments (ie, topical corticosteroids, topical calcineurin inhibitors, oral corticosteroids, phototherapy), increasing to 82.0% the next year; median (95% CI) time from diagnosis to first treatment was 34.0 (31.6-36.4) months. Antidepressants and/or anxiolytics were recorded for 16.7% of incident patients in the year after diagnosis. In 2019, 85.0% of prevalent patients did not receive vitiligo-related treatments; 16.6% had a record of antidepressant and/or anxiolytic treatments. Most patients were not on vitiligo-related treatments within a year of diagnosis, with time to first treatment >2 years, suggesting that vitiligo may be dismissed as unimportant and not treated early, in part due to limited effectiveness of available treatments. New effective treatments, early initiation, and psychological intervention and support are needed to reduce vitiligo burden on patients.

Subacromial balloon spacer for irreparable rotator cuff tears of the shoulder (START:REACTS): a group-sequential, double-blind, multicentre randomised controlled trial.

BACKGROUND: New surgical procedures can expose patients to harm and should be carefully evaluated before widespread use. The InSpace balloon (Stryker, USA) is an innovative surgical device used to treat people with rotator cuff tears that cannot be repaired. We aimed to determine the effectiveness of the InSpace balloon for people with irreparable rotator cuff tears. METHODS: We conducted a double-blind, group-sequential, adaptive randomised controlled trial in 24 hospitals in the UK, comparing arthroscopic debridement of the subacromial space with biceps tenotomy (debridement only group) with the same procedure but including insertion of the InSpace balloon (debridement with device group). Participants had an irreparable rotator cuff tear, which had not resolved with conservative treatment, and they had symptoms warranting surgery. Eligibility was confirmed intraoperatively before randomly assigning (1:1) participants to a treatment group using a remote computer system. Participants and assessors were masked to group assignment. Masking was achieved by using identical incisions for both procedures, blinding the operation note, and a consistent rehabilitation programme was offered regardless of group allocation. The primary outcome was the Oxford Shoulder Score at 12 months. Pre-trial simulations using data from early and late timepoints informed stopping boundaries for two interim analyses. The primary analysis was on a modified intention-to-treat basis, adjusted for the planned interim analysis. The trial was registered with ISRCTN, ISRCTN17825590. FINDINGS: Between June 1, 2018, and July 30, 2020, we assessed 385 people for eligibility, of which 317 were eligible. 249 (79%) people consented for inclusion in the study. 117 participants were randomly allocated to a treatment group, 61 participants to the debridement only group and 56 to the debridement with device group. A predefined stopping boundary was met at the first interim analysis and recruitment stopped with 117 participants randomised. 43% of participants were female, 57% were male. We obtained primary outcome data for 114 (97%) participants. The mean Oxford Shoulder Score at 12 months was 34·3 (SD 11·1) in the debridement only group and 30·3 (10·9) in the debridement with device group (mean difference adjusted for adaptive design -4·2 [95% CI -8·2 to -0·26];p=0·037) favouring control. There was no difference in adverse events between the two groups. INTERPRETATION: In an efficient, adaptive trial design, our results favoured the debridement only group. We do not recommend the InSpace balloon for the treatment of irreparable rotator cuff tears. FUNDING: Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health and Care Research partnership.

Estimating health related quality of life effects in vitiligo. Mapping EQ-5D-5 L utilities from vitiligo specific scales: VNS, VitiQoL and re-pigmentation measures using data from the HI-Light trial.

BACKGROUND: Vitiligo is reported to affect 2% of the world's population and has a significant impact on health related quality of life (HRQoL). The relationship between HRQoL and clinical outcomes used in vitiligo require further examination. Mapping condition specific measures of HRQoL: vitiligo specific quality of life instrument (VitiQoL), vitiligo noticeability scale (VNS) and vitiligo re-pigmentation scores (RPS) to the EQ-5D have not yet been reported. METHODS: Data collected from a randomised clinical trial (HI-Light) in vitiligo was used to develop mapping algorithms for the EQ-5D-5 L and the relationship between HRQoL, clinical outcomes and EQ-5D were investigated. Two EQ-5D-5 L value sets (Van Hout and Alava) using linear and non-linear models were considered. Logistic regression models were used to model the probability of vitiligo noticeability (VNS) in terms of RPS, EQ-5D and VitiQoL scores. RESULTS: Mapping from RPS appeared to perform better followed by VNS for the Alava crosswalks using polynomial models: Mean observed vs. predicted utilities of 0.9008 (0.005) vs. 0.8984 (0.0004) were observed for RPS. For VNS, mean observed vs. predicted utilities of 0.9008 (0.005) vs. 0.8939 (0.0003) were observed. For VitiQoL, mean observed vs. predicted utilities of 0.9008 (0.005) vs. 0.8912 (0.0002) were observed. For patients with the least re-pigmentation (RPS < 25%), a Total VitiQoL score of about 20 points gives around an 18% chance of vitiligo being no longer or a lot less noticeable. CONCLUSION: The algorithm based on RPS followed by VNS performed best. The relationship between effects from vitiligo specific HRQoL instruments and clinical RPS was established allowing for plausible clinically relevant differences to be identified, although further work is required in this area.

Group sequential designs in pragmatic trials: feasibility and assessment of utility using data from a number of recent surgical RCTs.

BACKGROUND: Assessing the long term effects of many surgical interventions tested in pragmatic RCTs may require extended periods of participant follow-up to assess effectiveness and use patient-reported outcomes that require large sample sizes. Consequently the RCTs are often perceived as being expensive and time-consuming, particularly if the results show the test intervention is not effective. Adaptive, and particularly group sequential, designs have great potential to improve the efficiency and cost of testing new and existing surgical interventions. As a means to assess the potential utility of group sequential designs, we re-analyse data from a number of recent high-profile RCTs and assess whether using such a design would have caused the trial to stop early. METHODS: Many pragmatic RCTs monitor participants at a number of occasions (e.g. at 6, 12 and 24 months after surgery) during follow-up as a means to assess recovery and also to keep participants engaged with the trial process. Conventionally one of the outcomes is selected as the primary (final) outcome, for clinical reasons, with others designated as either early or late outcomes. In such settings, novel group sequential designs that use data from not only the final outcome but also from early outcomes at interim analyses can be used to inform stopping decisions. We describe data from seven recent surgical RCTs (WAT, DRAFFT, WOLLF, FASHION, CSAW, FIXDT, TOPKAT), and outline possible group sequential designs that could plausibly have been proposed at the design stage. We then simulate how these group sequential designs could have proceeded, by using the observed data and dates to replicate how information could have accumulated and decisions been made for each RCT. RESULTS: The results of the simulated group sequential designs showed that for two of the RCTs it was highly likely that they would have stopped for futility at interim analyses, potentially saving considerable time (15 and 23 months) and costs and avoiding patients being exposed to interventions that were either ineffective or no better than standard care. We discuss the characteristics of RCTs that are important in order to use the methodology we describe, particularly the value of early outcomes and the window of opportunity when early stopping decisions can be made and how it is related to the length of recruitment period and follow-up. CONCLUSIONS: The results for five of the RCTs tested showed that group sequential designs using early outcome data would have been feasible and likely to provide designs that were at least as efficient, and possibly more efficient, than the original fixed sample size designs. In general, the amount of information provided by the early outcomes was surprisingly large, due to the strength of correlations with the primary outcome. This suggests that the methods described here are likely to provide benefits more generally across the range of surgical trials and more widely in other application areas where trial designs, outcomes and follow-up patterns are structured and behave similarly.

Protocol for A randomised feasibility trial comparing fluoride interventions to prevent dental decay in older people in care homes (FInCH trial).

BACKGROUND: The number and proportion of older people globally is growing faster than that of any other age group. At the same time the number of people retaining some of their own teeth is rising. There significant differences between those living in care and their community dwelling peers, with evidence showing those in care having fewer teeth and significantly higher levels of dental decay. There are numerous Cochrane reviews linking the use of fluoride to a reduction in dental decay, however, the majority of research on effectiveness has been conducted on children and consequently, children and adolescents tend to be the main recipients of fluoride interventions. There are to date no studies comparing the effectiveness of fluoride interventions in older people in care homes in the UK. However, prior to developing an appropriate protocol for full-scale trial comparing clinical effectiveness of fluoride interventions, there are a number of trial feasibility and statistical parameters that need to be clarified. METHODS: This trial is a single centre, multi-site randomised controlled assessor blind parallel group (three groups) trial, with the primary objective of establishing the feasibility, practicability and compliance of fluoride interventions to prevent dental decay in care homes. Secondary and tertiary objectives will aim to explore the acceptability of the interventions from resident, care home and dental services perspectives, and estimate the efficacy of the three different fluoride treatments. DISCUSSION: This feasibility trial will produce new knowledge and add value to a landscape that is under researched. Although the efficacy of fluoride interventions is proven, the feasibility of dental research and prevention in this vulnerable group and in the complex care home setting is novel. This work will not only add to our understanding of the interface of dental care and social care but will also contribute to our broader understanding on undertaking research in care home settings. Dental care for older people has been a longstanding issue, and the events of this past year has shone a light on the vulnerabilities of those residing in care homes and so this research is landing at a pivotal time. Trial registration EudraCT Registration 2017-002248-34. Registered 20th February 2018 https://www.clinicaltrialsregister.eu/ctr-search/search?query=2017-002248-34 .

Efficacy of alternative or additional methods to professional mechanical plaque removal during supportive periodontal therapy: A systematic review and meta-analysis.

AIMS: To systematically review the literature addressing the following focused questions: "What is the efficacy of either (#1) alternative or (#2) additional methods to professional mechanical plaque removal (PMPR) on progression of attachment loss during supportive periodontal therapy (SPT) in periodontitis patients?". METHODS: A systematic search for randomized clinical trials was performed. Change in clinical attachment level (CAL) from baseline was the primary outcome. RESULTS: Routine PMPR performed with either a combination of ultrasonic/hand instruments or Er:Yag laser showed similarly effective in preventing CAL loss. Moreover, a routine SPT regimen based on PMPR led to stability of CAL irrespective of a daily sub-antimicrobial doxycycline dose (SDD). Finally, an adjunctive photodynamic therapy (PDT) did not enhance the magnitude of CAL gain when sites with probing depth ≥4 mm were repeatedly treated. After pooling all data, the results of the meta-analysis showed no statistical differences in CAL change from baseline: mean overall CAL change was -0.233 mm (95% confidence interval: -1.065, 0.598; p = .351). CONCLUSIONS: Weak evidence indicate that in treated periodontitis patients enrolled in a 3-4 month SPT based on PMPR, Er:Yag laser (as alternative), SDD and PDT (as additional) do not produce a greater clinical effect on periodontal conditions compared to PMPR.

Tracking genomic cancer evolution for precision medicine: the lung TRACERx study.

The importance of intratumour genetic and functional heterogeneity is increasingly recognised as a driver of cancer progression and survival outcome. Understanding how tumour clonal heterogeneity impacts upon therapeutic outcome, however, is still an area of unmet clinical and scientific need. TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy [Rx]), a prospective study of patients with primary non-small cell lung cancer (NSCLC), aims to define the evolutionary trajectories of lung cancer in both space and time through multiregion and longitudinal tumour sampling and genetic analysis. By following cancers from diagnosis to relapse, tracking the evolutionary trajectories of tumours in relation to therapeutic interventions, and determining the impact of clonal heterogeneity on clinical outcomes, TRACERx may help to identify novel therapeutic targets for NSCLC and may also serve as a model applicable to other cancer types.

Comparing the mapping between EQ-5D-5L, EQ-5D-3L and the EORTC-QLQ-C30 in non-small cell lung cancer patients.

BACKGROUND: Several mapping algorithms have been published with the EORTC-QLQ-C30 for estimating EQ-5D-3L utilities. However, none are available with EQ-5D-5L. Moreover, a comparison between mapping algorithms in the same set of patients has not been performed for these two instruments simultaneously. In this prospective data set of 100 non-small cell lung cancer (NSCLC) patients, we investigate three mapping algorithms using the EQ-5D-3L and EQ-5D-5L and compare their performance. METHODS: A prospective non-interventional cohort of 100 NSCLC patients were followed up for 12 months. EQ-5D-3L, EQ-5D-5L and EORTC-QLQ-C30 were assessed monthly. EQ-5D-5L was completed at least 1 week after EQ-5D-3L. A random effects linear regression model, a beta-binomial (BB) and a Limited Variable Dependent Mixture (LVDM) model were used to determine a mapping algorithm between EQ-5D-3L, EQ-5D-5L and QLQ-C30. Simulation and cross validation and other statistical measures were used to compare the performances of the algorithms. RESULTS: Mapping from the EQ-5D-5L was better: lower AIC, RMSE, MAE and higher R(2) were reported with the EQ-5D-5L than with EQ-5D-3L regardless of the functional form of the algorithm. The BB model proved to be more useful for both instruments: for the EQ-5D-5L, AIC was -485, R(2) of 75 %, MAE of 0.075 and RMSE was 0.092. This was -385, 69 %, 0.099 and 0.113 for EQ-5D-3L respectively. The mean observed vs. predicted utilities were 0.572 vs. 0.577 and 0.515 vs. 0.523 for EQ-5D-5L and EQ-5D-3L respectively, for OLS; for BB, these were 0.572 vs. 0.575 and 0.515 vs. 0.518 respectively and for LVDMM 0.532 vs 0.515 and 0.569 vs 0.572 respectively. Less over-prediction at poorer health states was observed with EQ-5D-5L. CONCLUSIONS: The BB mapping algorithm is confirmed to offer a better fit for both EQ-5D-3L and EQ-5D-5L. The results confirm previous and more recent results on the use of BB type modelling approaches for mapping. It is recommended that in studies where EQ-5D utilities have not been collected, an EQ-5D-5L mapping algorithm is used.

Interpreting small treatment differences from quality of life data in cancer trials: an alternative measure of treatment benefit and effect size for the EORTC-QLQ-C30.

BACKGROUND: The EORTC-QLQ-C30 is a widely used health related quality of life (HRQoL) questionnaire in lung cancer patients. Small HRQoL treatment effects are often reported as mean differences (MDs) between treatments, which are rarely justified or understood by patients and clinicians. An alternative approach using odds ratios (OR) for reporting effects is proposed. This may offer advantages including facilitating alignment between patient and clinician understanding of HRQoL effects. METHODS: Data from six CRUK sponsored randomized controlled lung cancer trials (2 small cell and 4 in non-small cell, in 2909 patients) were used to HRQoL effects. Results from Beta-Binomial (BB) standard mixed effects were compared. Preferences for ORs vs MDs were determined and Time to Deterioration (TD) was also compared. RESULTS: HRQoL effects using ORs offered coherent interpretations: MDs >0 resulted in ORs >1 and vice versa; effect sizes were classified as 'Trivial' if the OR was between 1 ± 0.05 (i.e. 0.95 to 1.05); 'Small': for 1 ± 0.1; 'Medium': 1 ± 0.2 and 'Large': OR <0.8 or >1.20. Small HRQoL effects on the MD scale may translate to important treatment differences on the OR scale: for example, a worsening in symptoms (MD) by 2.6 points (p = 0.1314) would be a 17 % deterioration (p < 0.0001) with an OR. Hence important differences may be missed with MD; conversely, small ORs are unlikely to yield large MDs because methods based on OR model skewed data well. Initial evidence also suggests oncologists prefer ORs over MDs since interpretation is similar to hazard ratios. CONCLUSION: Reporting HRQoL benefits as MDs can be misleading. Estimates of HRQoL treatment effects in terms of ORs are preferred over MDs. Future analysis of QLQ-C30 and other HRQoL measures should consider reporting HRQoL treatment effects as ORs.

A non-linear beta-binomial regression model for mapping EORTC QLQ- C30 to the EQ-5D-3L in lung cancer patients: a comparison with existing approaches.

BACKGROUND: The performance of the Beta Binomial (BB) model is compared with several existing models for mapping the EORTC QLQ-C30 (QLQ-C30) on to the EQ-5D-3L using data from lung cancer trials. METHODS: Data from 2 separate non small cell lung cancer clinical trials (TOPICAL and SOCCAR) are used to develop and validate the BB model. Comparisons with Linear, TOBIT, Quantile, Quadratic and CLAD models are carried out. The mean prediction error, R(2), proportion predicted outside the valid range, clinical interpretation of coefficients, model fit and estimation of Quality Adjusted Life Years (QALY) are reported and compared. Monte-Carlo simulation is also used. RESULTS: The Beta-Binomial regression model performed 'best' among all models. For TOPICAL and SOCCAR trials, respectively, residual mean square error (RMSE) was 0.09 and 0.11; R(2) was 0.75 and 0.71; observed vs. predicted means were 0.612 vs. 0.608 and 0.750 vs. 0.749. Mean difference in QALY's (observed vs. predicted) were 0.051 vs. 0.053 and 0.164 vs. 0.162 for TOPICAL and SOCCAR respectively. Models tested on independent data show simulated 95% confidence from the BB model containing the observed mean more often (77% and 59% for TOPICAL and SOCCAR respectively) compared to the other models. All algorithms over-predict at poorer health states but the BB model was relatively better, particularly for the SOCCAR data. CONCLUSION: The BB model may offer superior predictive properties amongst mapping algorithms considered and may be more useful when predicting EQ-5D-3L at poorer health states. We recommend the algorithm derived from the TOPICAL data due to better predictive properties and less uncertainty.

Meniscal Transplant surgery or Optimised Rehabilitation full randomised trial (MeTeOR2): a study protocol.

INTRODUCTION: Pain and disability after meniscectomy can be a substantial lifelong problem. There are few treatment options, especially for young people. Non-surgical management (rehabilitation) is an option but increasingly surgeons are performing meniscal allograft transplants (MATs) for these individuals. However, this is still an uncommon procedure, and availability and usage of MAT vary widely both in the UK and internationally. It is not known which treatment option is the most effective and cost-effective. METHODS AND ANALYSIS: The Meniscal Transplant surgery or Optimised Rehabilitation trial is an international, multicentre, randomised controlled trial. The aim is to compare the clinical and cost effectiveness of MAT versus an optimised package of individualised, progressive, rehabilitation that we have called personalised knee therapy (PKT).Participants will be recruited from sites across the UK, Australia, Canada and Belgium. The planned 144 participants provide at least 90% power to detect a 10-point difference in the Knee injury and Osteoarthritis Outcome Score (KOOS4) at 24-months post randomisation (primary outcome). A prospectively planned economic evaluation will be conducted from a healthcare system and personal social services perspective. Secondary outcome data including health utility, occupational status, sports participation, mental well-being, further treatment, and adverse events will be collected at 3, 6, 12, 18, and 24 months. Analysis will be on an intention-to-treat basis and reported in-line with the Consolidated Standards of Reporting Trials statement. ETHICS AND DISSEMINATION: The trial was approved by the London-Bloomsbury Research Ethics Committee on 19 August 2022 (22/LO/0327) and Northern Sydney Local Health District Human Research Ethics Committee, NSW, Australia on the 13 March 2023 (2022/ETH01890).Trial results will be disseminated via peer-reviewed publications, presentations at international conferences, in lay summaries and using social media as appropriate.This protocol adheres to the recommended Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist. TRIAL REGISTRATION NUMBER: ISRCTN87336549.

Risk-stratified adoptive cellular therapy following allogeneic hematopoietic stem cell transplantation for advanced chronic lymphocytic leukaemia.

Following reduced intensity-conditioned allogeneic stem cell transplantation (RIC allo-SCT) for chronic lymphocytic leukaemia (CLL), there is an inverse relationship between relapse and extensive chronic graft-versus-host disease (GVHD). We evaluated outcomes in 50 consecutive patients with CLL using the approach of alemtuzumab-based RIC allo-SCT and pre-emptive donor lymphocyte infusions (DLI) for mixed chimerism or minimal residual disease (MRD), with the intention of reducing the risk of GVHD. Forty two patients had high-risk disease, including 30% with 17p deletion (17p-). Of patients who were not in complete remission (CR) entering transplant, 83% subsequently achieved MRD-negative CR. Both MRD detection and uncorrected mixed chimerism were associated with greater risks of treatment failure. Nine of sixteen patients receiving DLI for persistent or relapsed disease subsequently attained MRD-negative CR. With a median follow-up of 4.3 years, 4-year current progression-free survival was 65% and overall survival was 75% (60% and 61% in respectively, patients with 17p-). DLI was associated with a 29% cumulative incidence of severe GVHD and mortality of 6.4%. At last follow-up, 83% of patients in CR were off all immunosuppressive treatment. In conclusion, the directed delivery of allogeneic cellular therapy has the potential to induce durable remissions in high-risk CLL without incurring excessive GVHD.

Weekly intravenous bortezomib is effective and well tolerated in relapsed/refractory myeloma.

OBJECTIVES: Bortezomib is an effective antimyeloma therapy, but clinical benefits can be limited by neurotoxicity. In newly diagnosed, older patients, modification of the biweekly dosing schedule to weekly regimens improves tolerability whilst maintaining efficacy. There is less information on the efficacy and tolerability of weekly bortezomib regimens in the relapsed/refractory setting. Here, we report our experience of weekly intravenous bortezomib in clinical practice in relapsed/refractory patients. METHODS: We analysed fifty-two patients who received weekly bortezomib for relapsed/refractory MM. RESULTS: Thirty-one per cent of patients received bortezomib beyond first relapse. Almost all (94%) also received steroids and 48% also received an alkylator. The median cumulative dose was 22.6 mg/m(2) , and median length of treatment was 164 d. Three patients reported grade 2 sensory neuropathy, and one reported grade 3 motor neuropathy. There were no grade 4 neurotoxicities. Eighty-three per cent achieved a PR or greater, and the median PFS for the whole group was 13 months. One-year PFS and OS were 53% (95% CI 39-66.6%) and 78% (95% CI 66.7-89.6%), respectively. CONCLUSIONS: Weekly intravenous bortezomib when used in combination with steroids ± alkylator is effective in relapsed/refractory MM, producing outcomes comparable with biweekly regimens and with lower rates of peripheral neuropathy.

First-line erlotinib in patients with advanced non-small-cell lung cancer unsuitable for chemotherapy (TOPICAL): a double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Many patients with advanced non-small-cell lung cancer (NSCLC) receive only active supportive care because of poor performance status or presence of several comorbidities. We investigated whether erlotinib improves clinical outcome in these patients. METHODS: TOPICAL was a double-blind, randomised, placebo-controlled, phase 3 trial, done at 78 centres in the UK. Eligibility criteria were newly diagnosed, pathologically confirmed NSCLC; stage IIIb or IV; chemotherapy naive; no symptomatic brain metastases; deemed unsuitable for chemotherapy because of poor (≥2) Eastern Cooperative Oncology Group performance status or presence of several comorbidities, or both; and estimated life expectancy of at least 8 weeks. Patients were randomly assigned (by phone call, in a 1:1 ratio, stratified by disease stage, performance status, smoking history, and centre, block size 10) to receive oral placebo or erlotinib (150 mg per day) until disease progression or unacceptable toxicity. Investigators, clinicians, and patients were masked to assignment. The primary endpoint was overall survival. Analyses were by intention to treat, and prespecified subgroup analyses included development of a rash due to erlotinib within 28 days of starting treatment. This study is registered, number ISRCTN 77383050. FINDINGS: Between April 14, 2005, and April 1, 2009, we randomly assigned 350 patients to receive erlotinib and 320 to receive placebo. We followed up patients until March 31, 2011. 657 patients died; median overall survival did not differ between groups (erlotinib, 3·7 months, 95% CI 3·2-4·2, vs placebo, 3·6 months, 3·2-3·9; unadjusted hazard ratio [HR] 0·94, 95% CI 0·81-1·10, p=0·46). 59% (178 of 302) of patients assigned erlotinib and who were assessable at 1 month developed first-cycle rash, which was the only independent factor associated with overall survival. Patients with first-cycle rash had better overall survival (HR 0·76, 95% CI 0·63-0·92, p=0·0058), compared with placebo. Compared with placebo, overall survival seemed to be worse in the group that did not develop first-cycle rash (1·30, 1·05-1·61, p=0·017). Grade 3 or 4 diarrhoea was more common with erlotinib than placebo (8% [28 of 334] vs 1% [four of 313], p=0·0001), as was high-grade rash (23% [79 of 334] vs 2% [five of 313], p<0·0001); other adverse events were much the same between groups. INTERPRETATION: Patients with NSCLC who are deemed unsuitable for chemotherapy could be given erlotinib. Patients who develop a first-cycle rash should continue to receive erlotinib, whereas those who do not have a rash after 28 days should discontinue erlotinib, because of the possibility of decreased survival. FUNDING: Cancer Research UK, Roche.

Influence of the Ground Electrode on the Dynamics of Electrowetting.

The ability to manipulate a liquid meniscus using electrowetting has many applications. In any electrowetting design, at least two electrodes are required: one forms the field to change the contact angle and the other functions as a ground electrode. The contribution of the ground electrode (GE) to the dynamics of electrowetting has not yet been thoroughly investigated. In this paper, we discovered that with a bare ground electrode, the contact angle of a sessile drop increases instead of decreases when a direct current (DC) voltage varying from zero to the threshold voltage is applied. This phenomenon is opposite to what occurs when the GE is coated with a dielectric, where the contact-angle change follows the Lippmann-Young equation above the threshold voltage of electrowetting. However, this behaviour is not observed with either a dielectric-coated electrode using direct current (DC) or a bare ground electrode using alternating current (AC) voltage electrowetting. This study explains this phenomenon with finite element simulation and theory. From previous research work, the ground electrode configuration is inconsistent. In some studies, the ground electrode is exposed to water; in other studies, the ground electrode is covered with dielectric. This study identified that an exposed ground electrode is not required in electrowetting. Moreover, this research work suggests that for applications where precise control of the contact angle is paramount, a dielectric-coated ground electrode should be used since it prevents the increase in the contact angle when increasing the applied potential from zero to the threshold voltage. This study also identified that contact angle hysteresis is lower with a Cytop-coated ground electrode and DC voltage than with a bare ground electrode using AC or DC voltages.

Comparative efficacy of self-administered dentifrices for the management of dentine hypersensitivity - A systematic review and network meta-analysis.

OBJECTIVES: This systematic review with network meta-analysis synthesises available randomised controlled trials evidence concerning efficacy of self-administered dentifrices for management of dentine hypersensitivity (DH) pain. STUDY SELECTION: Following systematic review registration (CRD42019154064), three data bases (MEDLINE, Embase, CENTRAL) were searched to December 2022 for parallel randomised controlled trials conducted in adults diagnosed with DH, using at least two recognised stimuli, assessing the short-term efficacy of home-use dentifrice treatment in reducing pain. Thirty-two studies and 4,638 participants were included. A Network meta-analysis (NMA) approach was used to compare relative effectiveness between interventions. CONCLUSIONS: Twice daily application of self-applied dentifrice containing formulations of stannous, potassium +/- stannous, or arginine can be recommended for the reduction of dentine hypersensitivity pain. There is a need for standardised methodology guideline development to improve the conduct, analysis and reporting of DH clinical studies. CLINICAL RELEVANCE: This is the first comprehensive NMA to be performed, that follows guidelines for conduct of DH trials to determine the efficacy of self-applied dentifrices for the management of dentine hypersensitivity. Indirect comparisons can be made between formulations that have not been compared to one another in randomised controlled trials.

Economic Impact of Cancer Diagnosis on Employment, Wages and Intent to Return to Work.

To assess the work hours and income of patients who have been diagnosed with cancer, treatable with curative intent. The study evaluated the impact of lost wages on patients and their families in the population that is served by Bayhealth Medical Center. METHODS: This study was conducted between 2016 and 2020. The curative cancer focus included breast, lung, prostate, colorectal, testicular, uterine, cervical, bladder, esophageal, head and neck, and stomach. Patients were identified on their survivorship visit with Medical Oncology or Radiation Oncology. Two surveys were used to collect information specific to employment status, leave of absence/change in hours, and monthly income. RESULTS: Survey one had 142 participants. Survey two had 134 participants. In survey one, 99.3% of participants reported being employed at least half time at the time of diagnosis. On the Survivorship visit, 95% reported being currently employed at least half time. Only 87% were employed in the same job and title. When reporting income, 64% of participants had the same income, and 25.4% reported a reduction in income since being diagnosed and completing cancer treatment. In survey two, completed one-year post-survivorship visit, 83.6% of participants reported being employed at least half time. Of those, 76.9% were working for the same employer as they were at time of diagnosis. To that end, 26.1% of participants reported their income as lower than it was at time of diagnosis. CONCLUSION: A cancer diagnosis with treatment can and does have an impact on a person's ability to remain employed at least half time and sustain the same level of income.

Improved response with post-ASCT consolidation by low dose thalidomide, cyclophosphamide and dexamethasone as first line treatment for multiple myeloma.

The use of consolidation or maintenance to improve disease response, and hence clinical outcome, following autologous stem cell transplantation (ASCT) remains the subject of intense clinical research. We carried out a single-arm study to assess the toxicity and efficacy of a short block of consolidation therapy with cyclophosphamide, low dose thalidomide and dexamethasone (CTD) in patients within 6 months following ASCT, as part of frontline therapy for symptomatic multiple myeloma. Forty-five patients who had not progressed were enrolled on the study, and 43 completed treatment on protocol. This regimen was well tolerated soon after ASCT, with only grade 1/2 toxicity apart from neutropenia, and no long-term sequelae. Importantly, CTD consolidation improved the depth of response in treated patients, increasing the complete/very good partial response rate from 44% at 3 months, to 72% at 12 months, which was significantly higher compared with a historical group of control patients (P = 0·002). There was a trend to longer progression-free survival that favoured the study group. Consolidation therapy did not adversely affect subsequent disease response to salvage therapies at relapse. We conclude that CTD consolidation may be a useful, non-toxic and cost-effective strategy to deepen disease response following ASCT, and deserves further study in a randomized trial.

Evaluating Characteristics in Lung Cancer Screening Program Participants and Non-Small Cell Lung Cancer (NSCLC) Patient Populations.

Objective: To assess and compare specific characteristics and identify any differences, gaps, and/or disparities among two population groups; Bayhealth Lung screening program participants and newly diagnosed non-small cell lung cancer patients. Methods: This study was conducted with 2019 data from the American College of Radiology (ACR) registry, 1st time Low Dose CT screenings (Group 1) and the Bayhealth Cancer registry, newly diagnosed non-small cell lung cancer patients (Group 2). Results: Group 1 has 615 participants and Group 2 has 140 participants. The groups are separated based upon who is a first-time participant in the Bayhealth Lung Screening program in 2019 compared to patients who were newly diagnosed with Non-small Cell Lung Cancer at Bayhealth Medical Center-Cancer Center in 2019. Groups 1 and 2 had a statistical difference in the number of packs per year of cigarettes smoked. In group 2 there is no association between smoking status and clinical stage of diagnosis. There is however an association between smoking experience and pathological stage. Conclusion: Smoking continues to be the main contributing factor in patients diagnosed with non-small cell lung cancer. In addition to prevention efforts, early detection through Lung Cancer screenings is vital to identify early stage cancer.

A pilot study to evaluate the impact of digital imaging on the delivery of oral hygiene instruction.

AIMS: To determine whether personalised Oral Hygiene Advice (OHA) using an intra-oral-camera (IOC) combined with standard OHA as provided in general dental practice reduces plaque levels after 4 weeks more than the provision of standard OHA. MATERIALS AND METHODS: 22 healthy adult participants diagnosed with gingivitis took part in this pilot parallel-designed, randomised, examiner-blind, 2x-treatment, study regarding their home-care oral hygiene habits and attitudes to oral health. An IOC-image was taken and plaque, gingival and bleeding scores were recorded. Test group participants received standard OHA with IOC-images to indicate areas for improvement, control group participants received standard OHA. Questionnaires and plaque, gingival and bleeding scores were repeated after 4 weeks. Plaque was scored from the IOC-images and scores compared to clinical plaque scores. RESULTS: Lifestyle habits, attitudes to oral health, plaque (0.63vs0.61, control vs test) and bleeding scores (1.17vs0.96, control vs test) were similar at baseline. After 4-weeks, plaque scores improved more in test as compared to control group (39.4vs20.6%, p<0.05, while gingival and bleeding scores approached significance. There was no difference in lifestyle habits between groups, but the test group reported significantly greater confidence in adhering to their bespoke oral health plan. Agreement between the clinical and IOC plaque scores was good. CONCLUSIONS: Use of IOC further personalises the prevailing standard of oral hygiene advice and generates great patient engagement with pictorial reports to facilitate a more in-depth patient explanation of their gingival health, resulting in significant plaque reduction and improved gingival health compared to the standard OHA alone.