Venous disease is the most common cause of leg ulceration. Although compression therapy improves venous ulcer healing, it does not treat the underlying causes of venous hypertension. Treatment of ...superficial venous reflux has been shown to reduce the rate of ulcer recurrence, but the effect of early endovenous ablation of superficial venous reflux on ulcer healing remains unclear.
In a trial conducted at 20 centers in the United Kingdom, we randomly assigned 450 patients with venous leg ulcers to receive compression therapy and undergo early endovenous ablation of superficial venous reflux within 2 weeks after randomization (early-intervention group) or to receive compression therapy alone, with consideration of endovenous ablation deferred until after the ulcer was healed or until 6 months after randomization if the ulcer was unhealed (deferred-intervention group). The primary outcome was the time to ulcer healing. Secondary outcomes were the rate of ulcer healing at 24 weeks, the rate of ulcer recurrence, the length of time free from ulcers (ulcer-free time) during the first year after randomization, and patient-reported health-related quality of life.
Patient and clinical characteristics at baseline were similar in the two treatment groups. The time to ulcer healing was shorter in the early-intervention group than in the deferred-intervention group; more patients had healed ulcers with early intervention (hazard ratio for ulcer healing, 1.38; 95% confidence interval CI, 1.13 to 1.68; P=0.001). The median time to ulcer healing was 56 days (95% CI, 49 to 66) in the early-intervention group and 82 days (95% CI, 69 to 92) in the deferred-intervention group. The rate of ulcer healing at 24 weeks was 85.6% in the early-intervention group and 76.3% in the deferred-intervention group. The median ulcer-free time during the first year after trial enrollment was 306 days (interquartile range, 240 to 328) in the early-intervention group and 278 days (interquartile range, 175 to 324) in the deferred-intervention group (P=0.002). The most common procedural complications of endovenous ablation were pain and deep-vein thrombosis.
Early endovenous ablation of superficial venous reflux resulted in faster healing of venous leg ulcers and more time free from ulcers than deferred endovenous ablation. (Funded by the National Institute for Health Research Health Technology Assessment Program; EVRA Current Controlled Trials number, ISRCTN02335796 .).
Abstract
Aims
Systematically reviewing the literature found orthostatic hypotension (OH) to be associated with an increased risk of incident dementia but limited data were available in those at ...highest risk, the hypertensive oldest-old. Our aim was to analyse the relationship between OH and incident cognitive decline or dementia in this group and to synthesize the evidence base overall.
Method and results
Participants aged ≥80 years, with hypertension, were from the Hypertension in the Very Elderly Trial (HYVET) cohort. Orthostatic hypotension was defined as a fall of ≥15 mmHg in systolic and or ≥7 mmHg in diastolic pressure after 2 min standing from a sitting position. Subclinical orthostatic hypotension with symptoms (SOH) was defined as a fall <OH but with unsteadiness, light-headedness, or faintness in the week before blood pressure measurement. Proportional hazard regression was used to examine the relationship between baseline OH, SOH, and cognitive outcomes. There were 3121 in the analytical sample, 538 with OH. Orthostatic hypotension was associated with increased risk of cognitive decline (906 events), hazard ratio (HR) 1.36 (95% confidence interval 1.14–1.59). For incident dementia (241 events), HR 1.34 (0.98–1.84). When competing risk of cardiovascular events were taken into account results were HR 1.39 (1.19–1.62) and HR 1.34 (1.05–1.73), respectively. Subclinical orthostatic hypotension was associated with an increased risk of cognitive decline HR 1.56 (1.12–2.17) and dementia HR 1.79 (1.00–3.20). Combining the results from the HYVET cohort in a meta-analysis with the existing published literature in this area found a 21% (9–35%) increased risk of dementia with OH.
Conclusion
Orthostatic hypotension indicates an increased risk of dementia and cognitive decline. SOH may also be considered a risk factor, at least in older hypertensive adults. Questions remain regarding the mechanisms and whether interventions to reduce impact of OH could protect cognition.
High mammographic density is associated with both risk of cancers being missed at mammography, and increased risk of developing breast cancer. Stratification of breast cancer prevention and screening ...requires mammographic density measures predictive of cancer. This study compares five mammographic density measures to determine the association with subsequent diagnosis of breast cancer and the presence of breast cancer at screening.
Women participating in the "Predicting Risk Of Cancer At Screening" (PROCAS) study, a study of cancer risk, completed questionnaires to provide personal information to enable computation of the Tyrer-Cuzick risk score. Mammographic density was assessed by visual analogue scale (VAS), thresholding (Cumulus) and fully-automated methods (Densitas, Quantra, Volpara) in contralateral breasts of 366 women with unilateral breast cancer (cases) detected at screening on entry to the study (Cumulus 311/366) and in 338 women with cancer detected subsequently. Three controls per case were matched using age, body mass index category, hormone replacement therapy use and menopausal status. Odds ratios (OR) between the highest and lowest quintile, based on the density distribution in controls, for each density measure were estimated by conditional logistic regression, adjusting for classic risk factors.
The strongest predictor of screen-detected cancer at study entry was VAS, OR 4.37 (95% CI 2.72-7.03) in the highest vs lowest quintile of percent density after adjustment for classical risk factors. Volpara, Densitas and Cumulus gave ORs for the highest vs lowest quintile of 2.42 (95% CI 1.56-3.78), 2.17 (95% CI 1.41-3.33) and 2.12 (95% CI 1.30-3.45), respectively. Quantra was not significantly associated with breast cancer (OR 1.02, 95% CI 0.67-1.54). Similar results were found for subsequent cancers, with ORs of 4.48 (95% CI 2.79-7.18), 2.87 (95% CI 1.77-4.64) and 2.34 (95% CI 1.50-3.68) in highest vs lowest quintiles of VAS, Volpara and Densitas, respectively. Quantra gave an OR in the highest vs lowest quintile of 1.32 (95% CI 0.85-2.05).
Visual density assessment demonstrated a strong relationship with cancer, despite known inter-observer variability; however, it is impractical for population-based screening. Percentage density measured by Volpara and Densitas also had a strong association with breast cancer risk, amongst the automated measures evaluated, providing practical automated methods for risk stratification.
IntroductionMulti-cancer early detection (MCED) blood tests look for cancer signals in cell-free deoxyribonucleic acid. These tests have the potential to detect cancers at an earlier (asymptomatic) ...stage, improving cancer outcomes. Any screening method needs careful consideration of the psychological harms prior to implementation. The aim of this research is to explore the psychological impact of having a cancer signal detected following an MCED blood test.Methods and analysisThe project is embedded in the NHS-Galleri trial (ISRCTN91431511; NCT05611632), a large clinical trial in eight Cancer Alliances in England. In the trial, over 140 000 members of the general population aged 50–77 have been randomised 1:1 to either the intervention (blood tested with MCED test) or control (blood stored) arm. The proposed project focuses on participants in the intervention arm, who have a cancer signal detected. All participants who have a cancer signal detected (expected to be around 700 assuming a 1% test positive rate) will be sent a questionnaire at three timepoints: soon after receiving their result, 6 months and approximately 12 months later. The primary outcome is anxiety, assessed using the short-form 6-item Spielberger State Trait Anxiety Inventory. We will also assess the psychological consequences of screening (using the Psychological Consequences of Screening Questionnaire), reassurance/concern about the test result, understanding of results and help/health-seeking behaviour. A subsample of 40 participants (20 with a cancer diagnosis and 20 for whom no cancer was found) will be invited to take part in a one-to-one semistructured interview.Ethics and disseminationEthical approval for this work has been granted by the Wales Research Ethics Committee as part of the NHS-Galleri trial (Ref 21/WA/0141). Consent to be sent questionnaires is collected as part of the main trial. A separate consent form will be required for interview. Results will be disseminated via peer-reviewed publication and conference presentations.
Mammographic density is well-established as a risk factor for breast cancer, however, adjustment for age and body mass index (BMI) is vital to its clinical interpretation when assessing individual ...risk. In this paper we develop a model to adjust mammographic density for age and BMI and show how this adjusted mammographic density measure might be used with existing risk prediction models to identify high-risk women more precisely.
We explored the association between age, BMI, visually assessed percent dense area and breast cancer risk in a nested case-control study of women from the placebo arm of the International Breast Cancer Intervention Study I (72 cases, 486 controls). Linear regression was used to adjust mammographic density for age and BMI. This adjusted measure was evaluated in a multivariable logistic regression model that included the Tyrer-Cuzick (TC) risk score, which is based on classical breast cancer risk factors.
Percent dense area adjusted for age and BMI (the density residual) was a stronger measure of breast cancer risk than unadjusted percent dense area (odds ratio per standard deviation 1.55 versus 1.38; area under the curve (AUC) 0.62 versus 0.59). Furthermore, in this population at increased risk of breast cancer, the density residual added information beyond that obtained from the TC model alone, with the AUC for the model containing both TC risk and density residual being 0.62 compared to 0.51 for the model containing TC risk alone (P =0.002).
In women at high risk of breast cancer, adjusting percent mammographic density for age and BMI provides additional predictive information to the TC risk score, which already incorporates BMI, age, family history and other classic breast cancer risk factors. Furthermore, simple selection criteria can be developed using mammographic density, age and BMI to identify women at increased risk in a clinical setting.
http://www.controlled-trials.com/ISRCTN91879928 (Registered: 1 June 2006).
Behaviour problems emerge early in childhood and place children at risk for later psychopathology.
To evaluate the clinical effectiveness and cost-effectiveness of a parenting intervention to prevent ...enduring behaviour problems in young children.
A pragmatic, assessor-blinded, multisite, two-arm, parallel-group randomised controlled trial.
Health visiting services in six NHS trusts in England.
A total of 300 at-risk children aged 12-36 months and their parents/caregivers.
Families were allocated in a 1 : 1 ratio to six sessions of Video-feedback Intervention to promote Positive Parenting and Sensitive Discipline (VIPP-SD) plus usual care or usual care alone.
The primary outcome was the Preschool Parental Account of Children's Symptoms, which is a structured interview of behaviour symptoms. Secondary outcomes included caregiver-reported total problems on the Child Behaviour Checklist and the Strengths and Difficulties Questionnaire. The intervention effect was estimated using linear regression. Health and social care service use was recorded using the Child and Adolescent Service Use Schedule and cost-effectiveness was explored using the Preschool Parental Account of Children's Symptoms.
In total, 300 families were randomised: 151 to VIPP-SD plus usual care and 149 to usual care alone. Follow-up data were available for 286 (VIPP-SD,
= 140; usual care,
= 146) participants and 282 (VIPP-SD,
= 140; usual care,
= 142) participants at 5 and 24 months, respectively. At the post-treatment (primary outcome) follow-up, a group difference of 2.03 on Preschool Parental Account of Children's Symptoms (95% confidence interval 0.06 to 4.01;
= 0.04) indicated a positive treatment effect on behaviour problems (Cohen's
= 0.20, 95% confidence interval 0.01 to 0.40). The effect was strongest for children's conduct 1.61, 95% confidence interval 0.44 to 2.78;
= 0.007 (
= 0.30, 95% confidence interval 0.08 to 0.51) versus attention deficit hyperactivity disorder symptoms 0.29, 95% confidence interval -1.06 to 1.65;
= 0.67 (
= 0.05, 95% confidence interval -0.17 to 0.27). The Child Behaviour Checklist 3.24, 95% confidence interval -0.06 to 6.54;
= 0.05 (
= 0.15, 95% confidence interval 0.00 to 0.31) and the Strengths and Difficulties Questionnaire 0.93, 95% confidence interval -0.03 to 1.9;
= 0.06 (
= 0.18, 95% confidence interval -0.01 to 0.36) demonstrated similar positive treatment effects to those found for the Preschool Parental Account of Children's Symptoms. At 24 months, the group difference on the Preschool Parental Account of Children's Symptoms was 1.73 95% confidence interval -0.24 to 3.71;
= 0.08 (
= 0.17, 95% confidence interval -0.02 to 0.37); the effect remained strongest for conduct 1.07, 95% confidence interval -0.06 to 2.20;
= 0.06 (
= 0.20, 95% confidence interval -0.01 to 0.42) versus attention deficit hyperactivity disorder symptoms 0.62, 95% confidence interval -0.60 to 1.84;
= 0.32 (
= 0.10, 95% confidence interval -0.10 to 0.30), with little evidence of an effect on the Child Behaviour Checklist and the Strengths and Difficulties Questionnaire. The primary economic analysis showed better outcomes in the VIPP-SD group at 24 months, but also higher costs than the usual-care group (adjusted mean difference £1450, 95% confidence interval £619 to £2281). No treatment- or trial-related adverse events were reported. The probability of VIPP-SD being cost-effective compared with usual care at the 24-month follow-up increased as willingness to pay for improvements on the Preschool Parental Account of Children's Symptoms increased, with VIPP-SD having the higher probability of being cost-effective at willingness-to-pay values above £800 per 1-point improvement on the Preschool Parental Account of Children's Symptoms.
The proportion of participants with graduate-level qualifications was higher than among the general public.
VIPP-SD is effective in reducing behaviour problems in young children when delivered by health visiting teams. Most of the effect of VIPP-SD appears to be retained over 24 months. However, we can be less certain about its value for money.
Current Controlled Trials ISRCTN58327365.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in
; Vol. 25, No. 29. See the NIHR Journals Library website for further project information.
Venous ulceration is a common and costly health-care issue worldwide, with poor healing rates greatly affecting patient quality of life. Compression bandaging has been shown to improve healing rates ...and reduce recurrence, but does not address the underlying cause, which is often superficial venous reflux. Surgical correction of the reflux reduces ulcer recurrence; however, the effect of early endovenous ablation of superficial venous reflux on ulcer healing is unclear.
To determine the clinical effectiveness and cost-effectiveness of compression therapy with early endovenous ablation of superficial venous reflux compared with compression therapy with deferred endovenous ablation in patients with venous ulceration.
A pragmatic, two-arm, multicentre, parallel-group, open randomised controlled trial with a health economic evaluation.
Secondary care vascular centres in England.
Patients aged ≥ 18 years with a venous leg ulcer of between 6 weeks' and 6 months' duration and an ankle-brachial pressure index of ≥ 0.8 who could tolerate compression and were deemed suitable for endovenous ablation of superficial venous reflux.
Participants were randomised 1 : 1 to either early ablation (compression therapy and superficial endovenous ablation within 2 weeks of randomisation) or deferred ablation (compression therapy followed by endovenous ablation once the ulcer had healed).
The primary outcome measure was time from randomisation to ulcer healing, confirmed by blinded assessment. Secondary outcomes included 24-week ulcer healing rates, ulcer-free time, clinical success (in addition to quality of life), costs and quality-adjusted life-years (QALYs). All analyses were performed on an intention-to-treat basis.
A total of 450 participants were recruited (224 to early and 226 to deferred superficial endovenous ablation). Baseline characteristics were similar between the two groups. Time to ulcer healing was shorter in participants randomised to early superficial endovenous ablation than in those randomised to deferred ablation hazard ratio 1.38, 95% confidence interval (CI) 1.13 to 1.68;
= 0.001. Median time to ulcer healing was 56 (95% CI 49 to 66) days in the early ablation group and 82 (95% CI 69 to 92) days in the deferred ablation group. The ulcer healing rate at 24 weeks was 85.6% in the early ablation group, compared with 76.3% in the deferred ablation group. Median ulcer-free time was 306 interquartile range (IQR) 240-328 days in the early ablation group and 278 (IQR 175-324) days in the deferred endovenous ablation group (
= 0.002). The most common complications of superficial endovenous ablation were pain and deep-vein thrombosis. Differences in repeated measures of Aberdeen Varicose Vein Questionnaire scores (
< 0.001), EuroQol-5 Dimensions index values (
= 0.03) and Short Form questionnaire-36 items body pain (
= 0.05) over the follow-up period were observed, in favour of early ablation. The mean difference in total costs between the early ablation and deferred ablation groups was £163 standard error (SE) £318;
= 0.607; however, there was a substantial and statistically significant gain in QALY over 1 year mean difference between groups 0.041 (SE 0.017) QALYs;
= 0.017. The incremental cost-effectiveness ratio of early ablation at 1 year was £3976 per QALY, with a high probability (89%) of being more cost-effective than deferred ablation at conventional UK decision-making thresholds (currently £20,000 per QALY). Sensitivity analyses using alternative statistical models give qualitatively similar results.
Only 7% of screened patients were recruited, treatment regimens varied significantly and technical success was assessed only in the early ablation group.
Early endovenous ablation of superficial venous reflux, in addition to compression therapy and wound dressings, reduces the time to healing of venous leg ulcers, increases ulcer-free time and is highly likely to be cost-effective.
Longer-term follow-up is ongoing and will determine if early ablation will affect recurrence rates in the medium and long term.
Current Controlled Trials ISRCTN02335796.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in
; Vol. 23, No. 24. See the NIHR Journals Library website for further project information.
IntroductionThe number of robotic-assisted hip replacement procedures has expanded globally with the intended aim of improving outcomes. Intraoperative robotic-arm systems add additional costs to ...total hip replacement (THR) surgery but may improve surgical precision and could contribute to diminished pain and improved function. Additionally, these systems may reduce the need for expensive revision surgery. Surgery with conventional instruments may be just as successful, quick and affordable. There is timely demand for a robust evaluation of this technology.Methods and analysisThe Robotic Arthroplasty Clinical and cost Effectiveness Randomised controlled trial for Hips (RACER-Hip) is a multicentre (minimum of six UK sites), participant–assessor blinded, randomised controlled trial. 378 participants with hip osteoarthritis requiring THR will be randomised (1:1) to receive robotic-assisted THR, or THR using conventional surgical instruments. The primary outcome is the Forgotten Joint Score at 12 months post-randomisation; a patient-reported outcome measure assessing participants’ awareness of their joint when undertaking daily activities. Secondary outcomes will be collected post-operatively (pain, blood loss and opioid usage) and at 3, 6, 12, 24 months, then 5 and 10 years postrandomisation (including function, pain, health-related quality of life, reoperations and satisfaction). Allocation concealment will be accomplished using a computer-based randomisation procedure on the day of surgery. Blinding methods include the use of sham incisions for marker clusters and blinded operation notes. The primary analysis will adhere to the intention-to-treat principle. Results will adhere to Consolidated Standards of Reporting Trials statements.Ethics and disseminationThe trial was approved by an ethics committee (Solihull Research Ethics Committee, 30 June 2021, IRAS: 295831). Participants will provide informed consent before agreeing to participate. Results will be disseminated using peer-reviewed journal publications, presentations at international conferences and through the use of social media. We will develop plans to disseminate to patients and public with our patient partners.Trial registration numberISRCTN13374625.
ObjectiveTourniquet use in total knee replacement (TKR) is believed to improve the bone-cement interface by reducing bleeding, potentially prolonging implant survival. This study aimed to compare the ...risk of revision for primary cemented TKR performed with or without a tourniquet.DesignWe analysed data from the National Joint Registry (NJR) for all primary cemented TKRs performed in England and Wales between April 2003 and December 2003. Kaplan-Meier plots and Cox regression were used to assess the influence of tourniquet use, age at time of surgery, sex and American Society of Anaesthesiologists (ASA) classification on risk of revision for all-causes.ResultsData were available for 16 974 cases of primary cemented TKR, of which 16 132 had surgery with a tourniquet and 842 had surgery without a tourniquet. At 10 years, 3.8% had undergone revision (95% CI 2.6% to 5.5%) in the no-tourniquet group and 3.1% in the tourniquet group (95% CI 2.8% to 3.4%). After adjusting for age at primary surgery, gender and primary ASA score, the HR for all-cause revision for cemented TKR without a tourniquet was 0.82 (95% CI 0.57 to 1.18).ConclusionsWe did not find evidence that using a tourniquet for primary cemented TKR offers a clinically important or statistically significant reduction in the risk of all-cause revision up to 13 years after surgery. Surgeons should consider this evidence when deciding whether to use a tourniquet for cemented TKR.
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