Blood pressure lowering and prevention of dementia: an individual patient data meta-analysis.

AIMS: Observational studies indicate U-shaped associations of blood pressure (BP) and incident dementia in older age, but randomized controlled trials of BP-lowering treatment show mixed results on this outcome in hypertensive patients. A pooled individual participant data analysis of five seminal randomized double-blind placebo-controlled trials was undertaken to better define the effects of BP-lowering treatment for the prevention of dementia. METHODS AND RESULTS: Multilevel logistic regression was used to evaluate the treatment effect on incident dementia. Effect modification was assessed for key population characteristics including age, baseline systolic BP, sex, and presence of prior stroke. Mediation analysis was used to quantify the contribution of trial medication and changes in systolic and diastolic BP on risk of dementia. The total sample included 28 008 individuals recruited from 20 countries. After a median follow-up of 4.3 years, there were 861 cases of incident dementia. Multilevel logistic regression reported an adjusted odds ratio 0.87 (95% confidence interval: 0.75, 0.99) in favour of antihypertensive treatment reducing risk of incident dementia with a mean BP lowering of 10/4 mmHg. Further multinomial regression taking account of death as a competing risk found similar results. There was no effect modification by age or sex. Mediation analysis confirmed the greater fall in BP in the actively treated group was associated with a greater reduction in dementia risk. CONCLUSION: The first single-stage individual patient data meta-analysis from randomized double-blind placebo-controlled clinical trials provides evidence to support benefits of antihypertensive treatment in late-mid and later life to lower the risk of dementia. Questions remain as to the potential for additional BP lowering in those with already well-controlled hypertension and of antihypertensive treatment commenced earlier in the life-course to reduce the long-term risk of dementia. CLASSIFICATION OF EVIDENCE: Class I evidence in favour of antihypertensive treatment reducing risk of incident dementia compared with placebo.

A Randomized Trial of Early Endovenous Ablation in Venous Ulceration.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 .).

Effect of Platelet-Rich Plasma Injection vs Sham Injection on Tendon Dysfunction in Patients With Chronic Midportion Achilles Tendinopathy: A Randomized Clinical Trial.

Importance: Platelet-rich plasma injections are used as a treatment for chronic midportion Achilles tendinopathy, but evidence for this treatment is limited. Objective: In adults with midportion Achilles tendinopathy, to assess the effects of a single platelet-rich plasma injection, compared with sham injection, on the outcome of the Victorian Institute of Sport Assessment-Achilles (VISA-A) score (a single composite measure of Achilles tendinopathy severity). Design, Setting, and Participants: A participant-blinded, multicenter randomized clinical trial that included 240 people from 24 sites assigned to either a platelet-rich plasma injection or a sham injection between April 2016 and February 2020. Final follow-up was July 2020. Participants were older than 18 years with midportion Achilles tendon pain for more than 3 months as confirmed by ultrasound, magnetic resonance imaging, or both. Interventions: A single intratendinous platelet-rich plasma injection (n = 121) or a single sham injection (insertion of a subcutaneous dry needle not entering the tendon) (n = 119). Main Outcomes and Measures: The primary outcome was the VISA-A score, measured 6 months after treatment allocation. The VISA-A score contains 8 questions that cover 3 domains of pain, function, and activity, analyzed as a composite score (range, 0 [worst symptoms] to 100 [no symptoms]; minimal clinically important difference in score, 12 points). The primary analysis was adjusted for laterality, age, sex, and baseline VISA-A score. Results: Among 240 patients assigned to a platelet-rich plasma or sham injection (mean age, 52 years; 138 [58%] women), 221 (92%) completed the trial. At 6-month follow-up, mean VISA-A score values in the plasma-rich plasma group vs the sham injection group were 54.4 vs 53.4 (adjusted mean difference, -2.7 [95% CI, -8.8 to 3.3]). The most common adverse events compared between patients in the platelet-rich plasma group vs the sham group were injection site discomfort (97 vs 73 patients), swelling (56 vs 52 patients) and bruising (48 vs 49 patients). Conclusions and Relevance: Among patients with chronic midportion Achilles tendinopathy, treatment with a single injection of intratendinous platelet-rich plasma, compared with insertion of a subcutaneous dry needle, did not reduce Achilles tendon dysfunction at 6 months. These findings do not support the use of this treatment for chronic midportion Achilles tendinopathy. Trial Registration: isrctn.org Identifier: ISRCTN13254422.

Tourniquet use for knee replacement surgery.

BACKGROUND: Many surgeons prefer to perform total knee replacement surgery with the aid of a tourniquet. A tourniquet is an occlusive device that restricts distal blood flow to help create a bloodless field during the procedure. A tourniquet may be associated with increased risk of pain and complications. OBJECTIVES: To determine the benefits and harms of tourniquet use in knee replacement surgery. SEARCH METHODS: We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) up to 26 March 2020. We searched clinicaltrials.gov, the World Health Organization trials portal, and several international registries and joint registries up to March 2020. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing knee replacement with use of a tourniquet versus without use of a tourniquet and non-randomised studies with more than 1000 participants. Major outcomes included pain, function, global assessment of success, health-related quality of life, serious adverse events (including venous thromboembolism, infection, re-operation, and mortality), cognitive function, and survival of the implant. Minor outcomes included blood loss, economic outcomes, implant stability, and adverse events. DATA COLLECTION AND ANALYSIS: Two review authors screened abstracts and full texts, extracted data, performed risk of bias assessments, and assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included 41 RCTs with 2819 participants. Trials included from 20 to 199 participants. Mean age ranged between 58 and 84 years. More than half of the RCTs had unclear risk of selection bias and unclear risk of performance and detection bias due to absence of blinding of participants and surgeons. Major outcomes Pain: at postoperative day 1, pain (on a scale from zero to 10, with higher scores indicating worse pain) was ranked at 4.56 points after surgery without a tourniquet and at 1.25 points (MD) higher (95% CI 0.32 higher to 2.19 higher) with a tourniquet (8 studies; 577 participants), for an absolute difference of 12.5% higher pain scores (95% CI 3.2% higher to 21.9% higher) and a relative difference of 19% higher pain scores (95% CI 3.4% higher to 49% higher) with a tourniquet. Evidence for these findings was of moderate certainty, downgraded due to risk of bias. Knee replacement with a tourniquet probably led to higher postoperative pain scores at day 1, although this difference may or may not be noticeable to patients (based on a minimal clinically important difference (MCID) of 1.0). Function: at 12 months, tourniquet use probably makes little or no difference to function, based on an MCID of 5.3 for Knee Society Score (KSS) and 5.0 for Oxford Knee Score (OKS). Mean function (on a scale from 0 to 100, with higher scores indicating better outcomes) was 90.03 points after surgery without a tourniquet and was 0.29 points worse (95% CI 1.06 worse to 0.48 better) on a 0 to 100 scale, absolute difference was 0.29% worse (1.06% worse to 0.48% better), with a tourniquet (5 studies; 611 participants). This evidence was downgraded to moderate certainty due to risk of bias. Global assessment of success: low-certainty evidence (downgraded due to bias and imprecision) indicates that tourniquet use may have little or no effect on success. At six months, 47 of 50 (or 940 per 1000) reported overall successful treatment after surgery without a tourniquet and 47 of 50 (or 940 per 1000) with a tourniquet (risk ratio (RR) 1.0, 95% CI 0.91 to 1.10) based on one study with 100 participants. Health-related quality of life: at six months, tourniquet may have little or no effect on quality of life. The 12-Item Short Form Survey (SF-12) score (mental component from zero to 100 (100 is best)) was 54.64 after surgery without a tourniquet and 1.53 (MD) better (95% CI 0.85 worse to 3.91 better) with a tourniquet (1 study; 199 participants); absolute difference was 1.53% better (0.85% worse to 3.91% better). Evidence was of low certainty, downgraded due to risk of bias and small number of participants. Serious adverse events: the risk of serious adverse events was probably higher with tourniquet; 26 of 898 (29 per 1000) reported events following surgery without a tourniquet compared to 53 of 901 (59 per 1000) with a tourniquet (RR 1.73, 95% CI 1.10 to 2.73) in 21 studies (1799 participants). Twenty-nine more per 1000 patients (95% CI 3 to 50 more per 1000 patients) had a serious adverse event with a tourniquet. Forty-eight (95% CI 20 to 345) participants would need to have surgery without a tourniquet to avoid one serious adverse event. This evidence was downgraded to moderate certainty due to risk of bias. Cognitive function: one study reported cognitive function as an outcome; however the data were incompletely reported and could not be extracted for analysis. Survival of implant: it is uncertain if tourniquet has an effect on implant survival due to very low certainty evidence (downgraded for bias, and twice due to very low event rates); 2 of 107 (19 per 1000) required revision surgery in the surgery with a tourniquet group compared to 1 of 107 (9 per 1000) without a tourniquet group at up to two years' follow-up (RR 1.44, 95% CI 0.23 to 8.92). This equates to a 0.4% (0.7% lower to 7% more) increased absolute risk in surgery with a tourniquet. AUTHORS' CONCLUSIONS: Moderate certainty evidence shows that knee replacement surgery with a tourniquet is probably associated with an increased risk of serious adverse events. Surgery with a tourniquet is also probably associated with higher postoperative pain, although this difference may or may not be noticeable to patients. Surgery with a tourniquet does not appear to confer any clinically meaningful benefit on function, treatment success or quality of life. Further research is required to explore the effects of tourniquet use on cognitive function and implant survival, to identify any additional harms or benefits. If a tourniquet continues to be used in knee replacement surgery, patients should be informed about the potential increased risk of serious adverse events and postoperative pain.

ANTECEDENTES: Muchos cirujanos prefieren realizar una cirugía de reemplazo total de rodilla con la ayuda de un torniquete. Un torniquete es un dispositivo oclusivo que restringe el flujo sanguíneo distal para ayudar a crear un campo sin sangre durante el procedimiento. El torniquete se puede asociar con un mayor riesgo de dolor y complicaciones. OBJETIVOS: Determinar los efectos beneficiosos y perjudiciales del uso de torniquetes en la cirugía de reemplazo de rodilla. MÉTODOS DE BÚSQUEDA: Se hicieron búsquedas en MEDLINE, Embase y en el Registro Cochrane central de ensayos controlados (CENTRAL) hasta el 26 de marzo de 2020. Se realizaron búsquedas en clinicaltrials.gov, el portal de ensayos de la Organización Mundial de la Salud, y en varios registros internacionales y registros conjuntos hasta marzo de 2020. CRITERIOS DE SELECCIÓN: Se incluyeron los ensayos controlados aleatorizados (ECA) que compararon el reemplazo de rodilla con el uso de un torniquete versus sin el uso de un torniquete y los estudios no aleatorizados con más de 1000 participantes. Los desenlaces principales fueron el dolor, la funcionalidad, la evaluación general del éxito, la calidad de vida relacionada con la salud, los eventos adversos graves (incluido el tromboembolismo venoso, la infección, la reintervención y la mortalidad), la función cognitiva y la supervivencia del implante. Los desenlaces secundarios incluyeron la pérdida de sangre, los desenlaces económicos, la estabilidad del implante y los eventos adversos. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión examinaron los resúmenes y los textos completos, extrajeron los datos, realizaron las evaluaciones del riesgo de sesgo y evaluaron la certeza de la evidencia utilizando el enfoque GRADE. RESULTADOS PRINCIPALES: Se incluyeron 41 ECA con 2819 participantes. Los ensayos incluyeron de 20 a 199 participantes. La media de edad varió entre 58 y 84 años. Más de la mitad de los ECA tenían riesgo incierto de sesgo de selección y riesgo incierto de sesgo de realización y detección debido a la falta de cegamiento de los participantes y los cirujanos. Desenlaces principales Dolor: en el primer día después de la cirugía, el dolor (en una escala de 0 a 10, con puntuaciones mayores que indican un peor dolor) se clasificó en 4,56 puntos después de la cirugía sin torniquete y en 1,25 puntos (DM) mayor (IC del 95%: 0,32 mayor a 2,19 mayor) con un torniquete (ocho estudios; 577 participantes), para una diferencia absoluta de 12,5% de puntuaciones mayores de dolor (IC del 95%: 3,2% mayor a 21,9% mayor) y una diferencia relativa de 19% de puntuaciones mayores de dolor (IC del 95%: 3,4% mayor a 49% mayor) con un torniquete. La evidencia de estos hallazgos fue de certeza moderada, disminuida debido al riesgo de sesgo. El reemplazo de rodilla con un torniquete probablemente dio lugar a mayores puntuaciones de dolor en el primer día después de la cirugía, aunque esta diferencia puede o no ser perceptible para los pacientes (sobre la base de una diferencia mínima clínicamente importante [DMCI] de 1,0). Funcionalidad: a los 12 meses el uso de torniquetes probablemente da lugar a poca o ninguna diferencia en la funcionalidad, según una DMCI de 5,3 en la Knee Society Score (KSS) y de 5,0 en la Oxford Knee Score (OKS). La funcionalidad media (en una escala de 0 a 100, con puntuaciones más altas que indican mejores desenlaces) fue de 90,03 puntos después de la cirugía sin torniquete y fue 0,29 puntos peor (IC del 95%: 1,06 peor a 0,48 mejor) en una escala de 0 a 100, la diferencia absoluta fue 0,29% peor (1,06% peor a 0,48% mejor), con un torniquete (cinco estudios; 611 participantes). Esta evidencia se disminuyó a certeza moderada debido al riesgo de sesgo. Evaluación general del éxito: evidencia de certeza baja (disminuida debido al sesgo y la imprecisión) indica que el uso de torniquetes puede tener poco o ningún efecto en el éxito. A los seis meses, 47 de 50 (o 940 por 1000) informaron de un tratamiento general exitoso después de la cirugía sin torniquete y 47 de 50 (o 940 por 1000) con torniquete (razón de riesgos [RR] 1,0; IC del 95%: 0,91 a 1,10), según un estudio con 100 participantes. Calidad de vida relacionada con la salud: a los seis meses, el torniquete puede tener poco o ningún efecto en la calidad de vida. La puntuación de la 12­Item Short Form Survey (SF­12) (componente mental de 0 a 100 [100 es mejor]) fue de 54,64 después de la cirugía sin torniquete y 1,53 (DM) mejor (IC del 95%: 0,85 peor a 3,91 mejor) con torniquete (un estudio; 199 participantes); la diferencia absoluta fue 1,53% mejor (0,85% peor a 3,91% mejor). La evidencia fue de certeza baja, y se disminuyó debido al riesgo de sesgo y al escaso número de participantes. Eventos adversos graves: el riesgo de eventos adversos graves probablemente fue mayor con el uso de un torniquete; 26 de 898 (29 por 1000) notificaron eventos después de la cirugía sin torniquete en comparación con 53 de 901 (59 por 1000) con un torniquete (RR 1,73; IC del 95%: 1,10 a 2,73) en 21 estudios (1799 participantes). Veintinueve más por cada 1000 pacientes (95% CI 3 a 50 más por 1000 pacientes) presentaron un evento adverso grave con un torniquete. Cuarenta y ocho (IC del 95%: 20 a 345) participantes tendrían que ser operados sin torniquete para evitar un evento adverso grave. Esta evidencia se disminuyó a certeza moderada debido al riesgo de sesgo. Función cognitiva: un estudio informó de la función cognitiva como un desenlace; sin embargo, los datos se informaron de manera incompleta y no se pudieron extraer para el análisis. Supervivencia del implante: no está claro si el torniquete tiene un efecto sobre la supervivencia del implante debido a evidencia de certeza muy baja (disminuida por el sesgo, y dos veces debido a las tasas de eventos muy bajas); dos de 107 (19 por 1000) requirieron cirugía de revisión en el grupo de cirugía con torniquete en comparación con uno de 107 (nueve por 1000) en el grupo sin torniquete hasta los dos años de seguimiento (RR 1,44; IC del 95%: 0,23 a 8,92). Esto equivale a un 0,4% (0,7% menos a 7% más) de aumento del riesgo absoluto en la cirugía con torniquete. CONCLUSIONES DE LOS AUTORES: Evidencia de certeza moderada muestra que la cirugía de reemplazo de rodilla con torniquete probablemente se asocia con un mayor riesgo de eventos adversos graves. La cirugía con torniquete también se asocia probablemente con un mayor dolor posoperatorio, aunque esta diferencia puede o no ser perceptible para los pacientes. La cirugía con torniquete no parece conferir efectos beneficiosos clínicamente significativos en la funcionalidad, el éxito del tratamiento o la calidad de vida. Se necesitan estudios de investigación adicionales para explorar los efectos del uso de torniquetes en la función cognitiva y la supervivencia del implante, para identificar cualquier efecto perjudicial o beneficioso adicional. Si se sigue utilizando un torniquete en la cirugía de reemplazo de rodilla, se debe informar a los pacientes sobre el posible aumento del riesgo de que se produzcan efectos adversos graves y dolor posoperatorio.

Orthostatic hypotension and symptomatic subclinical orthostatic hypotension increase risk of cognitive impairment: an integrated evidence review and analysis of a large older adult hypertensive cohort.

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

A comparison of five methods of measuring mammographic density: a case-control study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Correction to: The interface between child/adolescent and adult mental health services: results from a European 28­country survey.

The original version of this article contained an error in Table 1. The correct table is presented below.

The interface between child/adolescent and adult mental health services: results from a European 28-country survey.

Transition-related discontinuity of care is a major socioeconomic and societal challenge for the EU. The current service configuration, with distinct Child and Adolescent Mental Health (CAMHS) and Adult Mental Health Services (AMHS), is considered a weak link where the care pathway needs to be most robust. Our aim was to delineate transitional policies and care across Europe and to highlight current gaps in care provision at the service interface. An online mapping survey was conducted across all 28 European Countries using a bespoke instrument: The Standardized Assessment Tool for Mental Health Transition (SATMEHT). The survey was directed at expert(s) in each of the 28 EU countries. The response rate was 100%. Country experts commonly (12/28) reported that between 25 and 49% of CAMHS service users will need transitioning to AMHS. Estimates of the percentage of AMHS users aged under 30 years who had has previous contact with CAMHS were most commonly in the region 20-30% (33% on average).Written policies for managing the interface were available in only four countries and half (14/28) indicated that no transition support services were available. This is the first survey of CAMHS transitional policies and care carried out at a European level. Policymaking on transitional care clearly needs special attention and further elaboration. The Milestone Study on transition should provide much needed data on transition processes and outcomes that could form the basis for improving policy and practice in transitional care.

A case-control study to assess the impact of mammographic density on breast cancer risk in women aged 40-49 at intermediate familial risk.

Mammographic density is a strong risk factor for breast cancer, but its potential application in risk management is not clear, partly due to uncertainties about its interaction with other breast cancer risk factors. We aimed to quantify the impact of mammographic density on breast cancer risk in women aged 40-49 at intermediate familial risk of breast cancer (average lifetime risk of 23%), in particular in premenopausal women, and to investigate its relationship with other breast cancer risk factors in this population. We present the results from a case-control study nested with the FH01 cohort study of 6,710 women mostly aged 40-49 at intermediate familial risk of breast cancer. One hundred and three cases of breast cancer were age-matched to one or two controls. Density was measured by semiautomated interactive thresholding. Absolute density, but not percent density, was a significant risk factor for breast cancer in this population after adjusting for area of nondense tissue (OR per 10 cm(2) = 1.07, 95% CI 1.00-1.15, p = 0.04). The effect was stronger in premenopausal women, who made up the majority of the study population. Absolute density remained a significant predictor of breast cancer risk after adjusting for age at menarche, age at first live birth, parity, past or present hormone replacement therapy, and the Tyrer-Cuzick 10-year relative risk estimate of breast cancer. Absolute density can improve breast cancer risk stratification and delineation of high-risk groups alongside the Tyrer-Cuzick 10-year relative risk estimate.

No evidence that frailty modifies the positive impact of antihypertensive treatment in very elderly people: an investigation of the impact of frailty upon treatment effect in the HYpertension in the Very Elderly Trial (HYVET) study, a double-blind, placebo-controlled study of antihypertensives in people with hypertension aged 80 and over.

BACKGROUND: Treatment for hypertension with antihypertensive medication has been shown to reduce stroke, cardiovascular events, and mortality in older adults, but there is concern that such treatment may not be appropriate in frailer older adults. To investigate whether there is an interaction between effect of treatment for hypertension and frailty in older adults, we calculated the frailty index (FI) for all available participants from the HYpertension in the Very Elderly Trial (HYVET) study, a double-blind, placebo-controlled study of antihypertensives in people with hypertension aged 80 and over, and obtained frailty adjusted estimates of the effect of treatment with antihypertensive medication on risk of stroke, cardiovascular events, and mortality. METHODS: Participants in HYVET were randomised 1:1 to active treatment with indapamide sustained release 1.5 mg ± perindopril 2 to 4 mg or to matching placebo. Data relating to blood pressure, comorbidities, cognitive function, depression, and quality of life were collected at entry into the study and at subsequent follow-up visits. The FI was calculated at entry, based on 60 potential deficits. The distribution of FI was similar to that seen in population studies of adults aged 80 years and above (median FI, 0.17; IQR, 0.11-0.24). Cox regression was used to assess the impact of FI at entry to the study on subsequent risk of stroke, total mortality, and cardiovascular events. Models were stratified by region of recruitment and adjusted for sex and age at entry. Extending these models to include a term for a possible interaction between treatment for hypertension and FI provided a formula for the treatment effect as a function of FI. For all three models, the point estimates of the hazard ratios for the treatment effect decreased as FI increased, although to varying degrees and with varying certainty. RESULTS: We found no evidence of an interaction between effect of treatment for hypertension and frailty as measured by the FI. Both the frailer and the fitter older adults with hypertension appeared to gain from treatment. CONCLUSIONS: Further work to examine whether antihypertensive treatment modifies frailty as measured by the FI should be explored. TRIAL REGISTRATION: ClinicalTrials.gov NCT00122811 (July 2005).

A Comparison of Outcomes Following Laparoscopic and Open Hysterectomy With or Without Lymphadenectomy for Presumed Early-Stage Endometrial Cancer: Results From the Medical Research Council ASTEC Trial.

OBJECTIVES: Laparoscopic hysterectomy (LH) is increasingly used for the management of endometrial malignancy. Its benefits may be particularly pronounced as these women are more likely to be older or obese. The aim of this study was to determine whether outcomes for LH are comparable to the open hysterectomy (OH). DESIGN: This was a prospective cohort study nested within the multicenter ASTEC (A Study in the Treatment of Endometrial Cancer) randomized controlled trial (1998-2005). POPULATION: Women with presumed early endometrial cancer were included. METHODS: Laparoscopic hysterectomy was compared with OH with or without systematic lymphadenectomy. MAIN OUTCOME MEASURES: Overall survival, time to first recurrence, complication rates, and surgical outcomes were the main outcome measures. RESULTS: Of 1408 women, 1309 (93%) received OH, and 99 (7%) had LH. LH was associated with longer operating time (median, LH 105 minutes [interquartile range (IQR), 60-150] vs OH 80 minutes [IQR, 60-95]; P < 0.001) but 50% shorter hospital stay (median, LH 4 days [IQR, 3-5] vs OH 6 days [IQR, 5-7]). The number of harvested lymph nodes was similar (median, LH 13 [IQR, 10-16] vs OH 12 [IQR, 11-13]; P = 0.67). LH had fewer intraoperative and postoperative adverse events (9% difference, LH 21% vs OH 30%; borderline significance; P = 0.07). The rate of conversion to laparotomy for the LH group was high (27%). The median follow-up was 37 months. After adjusting for significant prognostic factors, the hazard ratio for overall survival in those who underwent LH compared with those who underwent OH was 0.67 (95% confidence interval, 0.31-1.43) (P = 0.30). CONCLUSIONS: Laparoscopic hysterectomy for early endometrial cancer is safe. Although it requires longer operating time it is associated with shorter hospital stay and favorable morbidity profile. Further studies are required to assess the long-term safety.

Mammographic breast density refines Tyrer-Cuzick estimates of breast cancer risk in high-risk women: findings from the placebo arm of the International Breast Cancer Intervention Study I.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION NUMBER: http://www.controlled-trials.com/ISRCTN91879928 (Registered: 1 June 2006).

Ovarian cancer among 8,005 women from a breast cancer family history clinic: no increased risk of invasive ovarian cancer in families testing negative for BRCA1 and BRCA2.

BACKGROUND: Mutations in BRCA1/2 genes confer ovarian, alongside breast, cancer risk. We examined the risk of developing ovarian cancer in BRCA1/2-positive families and if this risk is extended to BRCA negative families. PATIENTS AND METHODS: A prospective study involving women seen at a single family history clinic in Manchester, UK. Patients were excluded if they had ovarian cancer or oophorectomy prior to clinic. Follow-up was censored at the latest date of: 31/12/2010; ovarian cancer diagnosis; oophorectomy; or death. We used person-years at risk to assess ovarian cancer rates in the study population, subdivided by genetic status (BRCA1, BRCA2, BRCA negative, BRCA untested) compared with the general population. RESULTS: We studied 8005 women from 895 families. Women from BRCA2 mutation families showed a 17-fold increased risk of invasive ovarian cancer (relative risk (RR) 16.67; 95% CI 5.41 to 38.89). This risk increased to 50-fold in women from families with BRCA1 mutations (RR 50.00; 95% CI 26.62 to 85.50). No association was found for women in families tested negative for BRCA1/2, where there was 1 observed invasive ovarian cancer in 1613 women when 2.74 were expected (RR 0.37; 95% CI 0.01 to 2.03). There was no association with ovarian cancer in families untested for BRCA1/2 (RR 0.99; 95% CI 0.45 to 1.88). DISCUSSION: This study showed no increased risk of ovarian cancer in families that tested negative for BRCA1/2 or were untested. These data help counselling women from BRCA1/2 negative families with breast cancer that their risk of invasive ovarian cancer is not higher than the general population.

Opportunistic offering of self-sampling to non-attenders within the English cervical screening programme: a pragmatic, multicentre, implementation feasibility trial with randomly allocated cluster intervention start dates (YouScreen).

Background: Self-sampling has game-changing potential to tackle the declining participation and inequities seen in many organised cervical screening programmes. Wide variation in uptake between settings and mode of kit offer highlight the importance of local piloting. Furthermore, harnessing the benefits of self-sampling in real-world settings has been surprisingly challenging. The YouScreen study estimated the impact of offering self-sampling to non-attenders within the English Programme and evaluated large-scale opportunistic offering of self-sampling in primary care. Methods: A pragmatic modified stepped-wedge implementation feasibility trial with randomly-allocated cluster intervention start dates at primary care practices in England (133 participating, 62 non-participating). Eligible women were aged 25-64 years and ≥6 months overdue for screening ("non-attenders"). Between January 13, 2021 and 30 November, 2021 self-sampling kits were distributed to non-attenders via an opportunistic offer in primary care when they consulted for any reason and direct mailout to those unscreened 15-months after routine invitation. Primary outcomes were the proportion of non-attenders screened each month; change in coverage; and uptake (90 days). YouScreen is registered with ISRCTN:12759467. Findings: 8338 women provided self-samples following recruitment between January 13, 2021 and 30 November, 2021. Self-samples were returned from 65.5% (6061/9248) who accepted an opportunistically offered kit and 12.9% (2777/17,604) directly-mailed kits. Responders were representative of the ethnically diverse and deprived underlying non-attendee population (64% ethnic minority groups, 60% from the two most deprived national quintiles). The self-sampling intervention resulted in a 22% (95% CI 18-26) increase in non-attenders screened per month (per-protocol analysis) and 12% (95% CI 9-15) (intention-to-treat analysis). Change in coverage at participating (mean intervention duration 7.5 months) vs non-participating practices was 1.6% (95% CI 0.4-2.8). Adverse effects were not formally collected. Interpretation: Opportunistically offering self-sampling to under-screened women in primary care could increase coverage in England and potentially reach underserved populations. Funding: North Central London and North East London Cancer Alliance.

Psychological Impact of the Galleri test (sIG(n)al): protocol for a longitudinal evaluation of the psychological impact of receiving a cancer signal in the NHS-Galleri trial.

INTRODUCTION: Multi-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 ANALYSIS: The 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 DISSEMINATION: Ethical 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.

UK robotic arthroplasty clinical and cost effectiveness randomised controlled trial for hips (RACER-Hip): a study protocol.

INTRODUCTION: The 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 ANALYSIS: The 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 DISSEMINATION: The 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 NUMBER: ISRCTN13374625.

Development and Evaluation of Machine Learning in Whole-Body Magnetic Resonance Imaging for Detecting Metastases in Patients With Lung or Colon Cancer: A Diagnostic Test Accuracy Study.

OBJECTIVES: Whole-body magnetic resonance imaging (WB-MRI) has been demonstrated to be efficient and cost-effective for cancer staging. The study aim was to develop a machine learning (ML) algorithm to improve radiologists' sensitivity and specificity for metastasis detection and reduce reading times. MATERIALS AND METHODS: A retrospective analysis of 438 prospectively collected WB-MRI scans from multicenter Streamline studies (February 2013-September 2016) was undertaken. Disease sites were manually labeled using Streamline reference standard. Whole-body MRI scans were randomly allocated to training and testing sets. A model for malignant lesion detection was developed based on convolutional neural networks and a 2-stage training strategy. The final algorithm generated lesion probability heat maps. Using a concurrent reader paradigm, 25 radiologists (18 experienced, 7 inexperienced in WB-/MRI) were randomly allocated WB-MRI scans with or without ML support to detect malignant lesions over 2 or 3 reading rounds. Reads were undertaken in the setting of a diagnostic radiology reading room between November 2019 and March 2020. Reading times were recorded by a scribe. Prespecified analysis included sensitivity, specificity, interobserver agreement, and reading time of radiology readers to detect metastases with or without ML support. Reader performance for detection of the primary tumor was also evaluated. RESULTS: Four hundred thirty-three evaluable WB-MRI scans were allocated to algorithm training (245) or radiology testing (50 patients with metastases, from primary 117 colon [n = 117] or lung [n = 71] cancer). Among a total 562 reads by experienced radiologists over 2 reading rounds, per-patient specificity was 86.2% (ML) and 87.7% (non-ML) (-1.5% difference; 95% confidence interval [CI], -6.4%, 3.5%; P = 0.39). Sensitivity was 66.0% (ML) and 70.0% (non-ML) (-4.0% difference; 95% CI, -13.5%, 5.5%; P = 0.344). Among 161 reads by inexperienced readers, per-patient specificity in both groups was 76.3% (0% difference; 95% CI, -15.0%, 15.0%; P = 0.613), with sensitivity of 73.3% (ML) and 60.0% (non-ML) (13.3% difference; 95% CI, -7.9%, 34.5%; P = 0.313). Per-site specificity was high (>90%) for all metastatic sites and experience levels. There was high sensitivity for the detection of primary tumors (lung cancer detection rate of 98.6% with and without ML [0.0% difference; 95% CI, -2.0%, 2.0%; P = 1.00], colon cancer detection rate of 89.0% with and 90.6% without ML [-1.7% difference; 95% CI, -5.6%, 2.2%; P = 0.65]). When combining all reads from rounds 1 and 2, reading times fell by 6.2% (95% CI, -22.8%, 10.0%) when using ML. Round 2 read-times fell by 32% (95% CI, 20.8%, 42.8%) compared with round 1. Within round 2, there was a significant decrease in read-time when using ML support, estimated as 286 seconds (or 11%) quicker ( P = 0.0281), using regression analysis to account for reader experience, read round, and tumor type. Interobserver variance suggests moderate agreement, Cohen κ = 0.64; 95% CI, 0.47, 0.81 (with ML), and Cohen κ = 0.66; 95% CI, 0.47, 0.81 (without ML). CONCLUSIONS: There was no evidence of a significant difference in per-patient sensitivity and specificity for detecting metastases or the primary tumor using concurrent ML compared with standard WB-MRI. Radiology read-times with or without ML support fell for round 2 reads compared with round 1, suggesting that readers familiarized themselves with the study reading method. During the second reading round, there was a significant reduction in reading time when using ML support.

No clear associations between subjective memory concerns and subsequent change in cognitive function: the PATH through life study.

The literature on subjective memory concerns (SMC) as a predictor for future cognitive decline is varied. Furthermore, recent research has pointed to additional complexity arising from variability in the experience of SMC themselves (i.e. whether they are remitting or sustained over time). We investigated the associations between SMC and objectively measured cognition in an Australian population-based cohort. Four waves (4-year intervals between waves) of data from 1236 participants (aged 62.4 ± 1.5 years, 53% male) were used. We categorized participants as experiencing SMC, when they indicated that their memory problems might interfere with their day-to-day life and/or they had seen a doctor about their memory. SMC was categorized as "no" reported SMC, "remitting", "new-onset" or "sustained" SMC. Cognitive assessment of immediate and delayed recall, working memory, psychomotor speed, attention and processing speed were assessed using a neuropsychological battery. Eighteen percent of participants were characterised as having SMC: 6% (77) "remitting", 6% (77) "new-onset" and 6% (69) "sustained" SMC. There was no consistent evidence for an association between SMC and subsequent decline in cognition. However, SMC was associated with poorer performance on contemporaneous tasks of attention and processing speed compared to "no" SMC. Asking about SMC may indicate a current decline in cognitive function but, in this sample at least, did not indicate an increased risk of future decline. Supplementary Information: The online version contains supplementary material available at 10.1007/s10433-022-00694-2.

Implementation of ReSPECT in acute hospitals: A retrospective observational study.

AIMS: To evaluate, in UK acute hospitals, the early implementation of the Recommended Summary Plan for Emergency Care and Treatment (ReSPECT), which embeds cardiopulmonary resuscitation (CPR) recommendations within wider emergency treatment plans. To understand for whom and how the process was being used and the quality of form completion. METHODS: A retrospective observational study evaluating emergency care and treatment planning approaches used in acute UK hospitals (2015-2019), and in six English hospital trusts the extent of ReSPECT use, patient characteristics and completion quality in a sample 3000 patient case notes. RESULTS: The use of stand-alone Do Not Attempt Cardiopulmonary Resuscitation forms fell from 133/186 hospitals in 2015 to 64/186 in 2019 (a 38% absolute reduction). ReSPECT accounted for 52% (36/69) of changes. In the six sites, ReSPECT was used for approximately 20% of patients (range 6%-41%). They tended to be older, to have had an emergency medical admission, to have cognitive impairment and a lower predicted 10 year survival. Most (653/706 (92%)) included a 'not for attempted resuscitation' recommendation 551/706 (78%) had at least one other treatment recommendation. Capacity was not recorded on 13% (95/706) of forms; 11% (79/706) did not record patient/family involvement. CONCLUSIONS: ReSPECT use accounts for 52% of the change, observed between 2015 and 2019, from using standalone DNACPR forms to approaches embedding DNACPR decisions within in wider emergency care plans in NHS hospitals in the UK. Whilst recommendations include other emergencies most still tend to focus on recommendations relating to CPR. Completion of ReSPECT forms requires improvement. STUDY REGISTRATION: https://www.isrctn.com/ISRCTN11112933.

Effect of tourniquet use on the risk of revision in total knee replacement surgery: an analysis of the National Joint Registry Data Set.

OBJECTIVE: Tourniquet 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. DESIGN: We 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. RESULTS: Data 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). CONCLUSIONS: We 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.