Community antibiotic prescribing in patients with COVID-19 across three pandemic waves: a population-based study in Scotland, UK.

OBJECTIVES: This study aims to examine community antibiotic prescribing across a complete geographical area for people with a positive COVID-19 test across three pandemic waves, and to examine health and demographic factors associated with antibiotic prescribing. DESIGN: A population-based study using administrative data. SETTING: A complete geographical region within Scotland, UK. PARTICIPANTS: Residents of two National Health Service Scotland health boards with SARS-CoV-2 virus test results from 1 February 2020 to 31 March 2022 (n=184 954). Individuals with a positive test result (n=16 025) had data linked to prescription and hospital admission data ±28 days of the test, general practice data for high-risk comorbidities and demographic data. OUTCOME MEASURES: The associations between patient factors and the odds of antibiotic prescription in COVID-19 episodes across three pandemic waves from multivariate binary logistic regression. RESULTS: Data included 768 206 tests for 184 954 individuals, identifying 16 240 COVID-19 episodes involving 16 025 individuals. There were 3263 antibiotic prescriptions ±28 days for 2395 episodes. 35.6% of episodes had a prescription only before the test date, 52.3% of episodes after and 12.1% before and after. Antibiotic prescribing reduced over time: 20.4% of episodes in wave 1, 17.7% in wave 2 and 12.0% in wave 3. In multivariate logistic regression, being female (OR 1.31, 95% CI 1.19 to 1.45), older (OR 3.02, 95% CI 2.50 to 3.68 75+ vs <25 years), having a high-risk comorbidity (OR 1.45, 95% CI 1.31 to 1.61), a hospital admission ±28 days of an episode (OR 1.58, 95% CI 1.42 to 1.77) and health board region (OR 1.14, 95% CI 1.03 to 1.25, board B vs A) increased the odds of receiving an antibiotic. CONCLUSION: Community antibiotic prescriptions in COVID-19 episodes were uncommon in this population and likelihood was associated with patient factors. The reduction over pandemic waves may represent increased knowledge regarding COVID-19 treatment and/or evolving symptomatology.

Activin type I receptor polymorphisms and body composition in older individuals with sarcopenia-Analyses from the LACE randomised controlled trial.

BACKGROUND: Ageing is associated with changes in body composition including an overall reduction in muscle mass and a proportionate increase in fat mass. Sarcopenia is characterised by losses in both muscle mass and strength. Body composition and muscle strength are at least in part genetically determined, consequently polymorphisms in pathways important in muscle biology (e.g., the activin/myostatin signalling pathway) are hypothesised to contribute to the development of sarcopenia. METHODS: We compared regional body composition measured by DXA with genotypes for two polymorphisms (rs10783486, minor allele frequency (MAF) = 0.26 and rs2854464, MAF = 0.26) in the activin 1B receptor (ACVR1B) determined by PCR in a cross-sectional analysis of DNA from 110 older individuals with sarcopenia from the LACE trial. RESULTS: Neither muscle mass nor strength showed any significant associations with either genotype in this cohort. Initial analysis of rs10783486 showed that males with the AA/AG genotype were taller than GG males (174±7cm vs 170±5cm, p = 0.023) and had higher arm fat mass, (median higher by 15%, p = 0.008), and leg fat mass (median higher by 14%, p = 0.042). After correcting for height, arm fat mass remained significantly higher (median higher by 4% padj = 0.024). No associations (adjusted or unadjusted) were seen in females. Similar analysis of the rs2854464 allele showed a similar pattern with the presence of the minor allele (GG/AG) being associated with greater height (GG/AG = 174±7 cm vs AA = 170 ±5cm, p = 0.017) and greater arm fat mass (median higher by 16%, p = 0.023). Again, the difference in arm fat remained after correction for height. No similar associations were seen in females analysed alone. CONCLUSION: These data suggest that polymorphic variation in the ACVR1B locus could be associated with body composition in older males. The activin/myostatin pathway might offer a novel potential target to prevent fat accumulation in older individuals.

ACE I/D genotype associates with strength in sarcopenic men but not with response to ACE inhibitor therapy in older adults with sarcopenia: Results from the LACE trial.

BACKGROUND: Angiotensin II (AII), has been suggested to promote muscle loss. Reducing AII synthesis, by inhibiting angiotensin converting enzyme (ACE) activity has been proposed as a method to inhibit muscle loss. The LACE clinical trial was designed to determine whether ACE inhibition would reduce further muscle loss in individuals with sarcopenia but suffered from low recruitment and returned a negative result. Polymorphic variation in the ACE promoter (I/D alleles) has been associated with differences in ACE activity and muscle physiology in a range of clinical conditions. This aim of this analysis was to determine whether I/D polymorphic variation is associated with muscle mass, strength, in sarcopenia or contributed to the lack of response to treatment in the LACE study. METHODS: Sarcopenic individuals were recruited into a 2x2 factorial multicentre double-blind study of the effects of perindopril and/or leucine versus placebo on physical performance and muscle mass. DNA extracted from blood samples (n = 130 72 women and 58 men) was genotyped by PCR for the ACE I/D polymorphism. Genotypes were then compared with body composition measured by DXA, hand grip and quadriceps strength before and after 12 months' treatment with leucine and/or perindopril in a cross-sectional analysis of the influence of genotype on these variables. RESULTS: Allele frequencies for the normal UK population were extracted from 13 previous studies (I = 0.473, D = 0.527). In the LACE cohort the D allele was over-represented (I = 0.412, D = 0.588, p = 0.046). This over-representation was present in men (I = 0.353, D = 0.647, p = 0.010) but not women (I = 0.458, D = 0.532, p = 0.708). In men but not women, individuals with the I allele had greater leg strength (II/ID = 18.00 kg (14.50, 21.60) vs DD = 13.20 kg (10.50, 15.90), p = 0.028). Over the 12 months individuals with the DD genotype increased in quadriceps strength but those with the II or ID genotype did not. Perindopril did not increase muscle strength or mass in any polymorphism group relative to placebo. CONCLUSION: Our results suggest that although ACE genotype was not associated with response to ACE inhibitor therapy in the LACE trial population, sarcopenic men with the ACE DD genotype may be weaker than those with the ACE I/D or II genotype.

Multicenter Randomized Trial Assessing MRI and Image-guided Biopsy for Suspected Prostate Cancer: The MULTIPROS Study.

Background The optimal diagnostic pathway for prostate cancer (PCa) is evolving, requiring further evaluation in a randomized controlled trial. Purpose To assess the diagnostic accuracy of prebiopsy multiparametric MRI in the identification of clinically significant PCa (csPCa) using radical prostatectomy (RP) specimens as the reference standard, and to test the diagnostic accuracy of combined US and MRI fusion-targeted biopsy with systematic biopsies. Materials and Methods In a prospective randomized controlled trial including university hospitals, men with suspected PCa were recruited between January 2015 and August 2020 to assess the diagnostic accuracy of multiparametric MRI before biopsy in detection of csPCa at biopsy and RP histopathologic structure (primary outcome). Men with lesions suspicious for cancer (Prostate Imaging and Reporting Data System [PI-RADS] ≥3) at multiparametric MRI were first randomized to either systematic random prostate biopsies alone (control group) or US and MRI fusion-targeted biopsies with systematic random prostate biopsies (intervention group) at a one-to-one ratio to compare the diagnostic accuracy of systematic random versus combined fusion with systematic random biopsies (secondary outcome). A subset of recruited participants (n = 89) underwent RP and histologic sectioning. Results There were 582 participants who were eligible to undergo multiparametric MRI (mean age, 65 years ± 6 [SD]). In total, 413 had a PI-RADS score of at least 3 and were randomized into either the intervention group (207 of 413; 50.1%) or control group (206 of 413; 49.9%). The csPCa detection rate in the intervention group was higher, with an adjusted odds ratio of 1.79 (95% CI: 1.14, 2.79; P = .01). A subgroup of 89 men underwent RP (21.5%; 89 of 413). Multiparametric MRI helped correctly identify 131 of 182 csPCa foci in 89 men (sensitivity, 72%; 95% CI: 65, 78). The specificity, positive predictive value, and negative predictive value were 71% (91 of 128), 78% (131 of 168), and 64% (91 of 142), respectively. Conclusion Prebiopsy multiparametric MRI was accurate in the depiction of clinically significant PCa. Combining US and MRI fusion-targeted biopsies with systematic biopsies helped detect more clinically significant lesions than did systematic biopsies alone. Clinical trial registration no. NCT02745496 © RSNA, 2023 Supplemental material is available for this article.

External validation of the QLifetime cardiovascular risk prediction tool: population cohort study.

BACKGROUND: Prediction of lifetime cardiovascular disease (CVD) risk is recommended in many clinical guidelines, but lifetime risk models are rarely externally validated. The aim of this study was to externally validate the QRiskLifetime incident CVD risk prediction tool. METHODS: Independent external validation of QRiskLifetime using Clinical Practice Research Datalink data, examining discrimination and calibration in the whole population and stratified by age, and reclassification compared to QRISK3. Since lifetime CVD risk is unobservable, performance was evaluated at 10-years' follow-up, and lifetime performance inferred in terms of performance for in the different age-groups from which lifetime predictions are derived. RESULTS: One million, two hundreds sixty thousand and three hundreds twenty nine women and 1,223,265 men were included in the analysis. Discrimination was excellent in the whole population (Harrell's-C = 0.844 in women, 0.808 in men), but moderate to poor stratified by age-group (Harrell's C in people aged 30-44 0.714 for both men and women, in people aged 75-84 0.578 in women and 0.556 in men). Ten-year CVD risk was under-predicted in the whole population, and in all age-groups except women aged 45-64, with worse under-prediction in older age-groups. Compared to those at highest QRISK3 estimated 10-year risk, those with highest lifetime risk were younger (mean age: women 50.5 vs. 71.3 years; men 46.3 vs. 63.8 years) and had lower systolic blood pressure and prevalence of treated hypertension, but had more family history of premature CVD, and were more commonly minority ethnic. Over 10-years, the estimated number needed to treat (NNT) with a statin to prevent one CVD event in people with QRISK3 ≥ 10% was 34 in women and 37 in men, compared to 99 and 100 for those at highest lifetime risk. CONCLUSIONS: QRiskLifetime underpredicts 10-year CVD risk in nearly all age-groups, so is likely to also underpredict lifetime risk. Treatment based on lifetime risk has considerably lower medium-term benefit than treatment based on 10-year risk.

Derivation and validation of the CFracture competing risk fracture prediction tool compared with QFracture in older people and people with comorbidity: a population cohort study.

BACKGROUND: UK guidelines recommend the QFracture tool to predict the risk of major osteoporotic fracture and hip fracture, but QFracture calibration is poor, partly because it does not account for competing mortality risk. The aim of this study was to derive and validate a competing risk model to predict major osteoporotic fracture and hip fracture (CFracture) and compare its performance with that of QFracture in UK primary care. METHODS: We used UK linked primary care data from the Clinical Practice Research Datalink GOLD database to identify people aged 30-99 years, split into derivation and validation cohorts. In the derivation cohort, we derived models (CFracture) using the same covariates as QFracture with Fine-Gray competing risk modelling, and included the Charlson Comorbidity Index score as an additional predictor of non-fracture death. In a separate validation cohort, we examined discrimination (using Harrell's C-statistic) and calibration of CFracture compared with QFracture. Reclassification analysis examined differences in the characteristics of patients reclassified as higher risk by CFracture but not by QFracture. FINDINGS: The derivation cohort included 1 831 606 women and 1 789 820 men, and the validation cohort included 915 803 women and 894 910 men. Overall discrimination of CFracture was excellent (C-statistic=0·813 [95% CI 0·810-0·816] for major osteoporotic fracture and 0·914 [0·908-0·919] for hip fracture in women; 0·734 [0·729-0·740] for major osteoporotic fracture and 0·886 [0·877-0·895] for hip fracture in men) and was similar to QFracture. CFracture calibration overall and in people younger than 75 years was generally excellent. CFracture overpredicted major osteoporotic fracture and hip fracture in older people and people with comorbidity, but was better calibrated than QFracture. Patients classified as high-risk by CFracture but not by QFracture had a higher prevalence of current smoking and previous fracture, but lower prevalence of dementia, cancer, cardiovascular disease, renal disease, and diabetes. INTERPRETATION: CFracture has similar discrimination to QFracture but is better calibrated overall and in younger people. Both models performed poorly in adults aged 85 years and older. Competing risk models should be recommended for fracture risk prediction to guide treatment recommendations. FUNDING: National Institute for Health and Care Research, Wellcome Trust, Health Data Research UK.

Free-text analysis of general practice out-of-hours (GPOOH) use by people with advanced cancer: an analysis of coded and uncoded free-text data.

BACKGROUND: People with advanced cancer frequently use the GP out-of-hours (GPOOH) service. Considerable amounts of routine GPOOH data are uncoded. Therefore, these data are omitted from existing healthcare datasets. AIM: To conduct a free-text analysis of a GPOOH dataset, to identify reasons for attendance and care delivered through GPOOH to people with advanced cancer. DESIGN AND SETTING: An analysis of a GPOOH healthcare dataset was undertaken. It contained all coded and free- text information for 5749 attendances from a cohort of 2443 people who died from cancer in Tayside, Scotland, from 2013-2015. METHOD: Random sampling methods selected 575 consultations for free-text analysis. Each consultation was analysed by two independent reviewers to determine the following: assigned presenting complaints; key and additional palliative care symptoms recorded in free text; evidence of anticipatory care planning; and free-text recording of dispensed medications. Inter-rater reliability concordance was established through Kappa testing. RESULTS: More than half of all coded reasons for attendance (n = 293; 51.0%) were 'other' or 'missing'. Free-text analysis demonstrated that nearly half (n = 284; 49.4%) of GPOOH attendances by people with advanced cancer were for pain or palliative care. More than half of GPOOH attendances (n = 325; 56.5%) recorded at least one key or additional palliative care symptom in free text, with the commonest being breathlessness, vomiting, cough, and nausea. Anticipatory care planning was poorly recorded in both coded and uncoded records. Uncoded medications were dispensed in more than one- quarter of GPOOH consultations. CONCLUSION: GPOOH delivers a substantial amount of pain management and palliative care, much of which is uncoded. Therefore, it is unrecognised and under-reported in existing large healthcare data analyses.

Community prescribing trends and prevalence in the last year of life, for people who die from cancer.

BACKGROUND: People who die from cancer ('cancer decedents') may latterly experience unpleasant and distressing symptoms. Prescribing medication for pain and symptom control is essential for good-quality palliative care; however, such provision is variable, difficult to quantify and poorly characterised in current literature. This study aims to characterise trends in prescribing analgesia, non-analgesic palliative care medication and non-palliative medications, to cancer decedents, in their last year of life, and to assess any associations with demographic or clinical factors. METHODS: This descriptive study, analysed all 181,247 prescriptions issued to a study population of 2443 cancer decedents in Tayside, Scotland (2013-2015), in the last year of life, linking prescribing data to demographic, and cancer registry datasets using the unique patient-identifying Community Health Index (CHI) number. Anonymised linked data were analysed in Safe Haven using chi-squared test for trend, binary logistic regression and Poisson regression in SPSSv25. RESULTS: In their last year of life, three in four cancer decedents were prescribed strong opioids. Two-thirds of those prescribed opioids were also prescribed laxatives and/or anti-emetics. Only four in ten cancer decedents were prescribed all medications in the 'Just in Case' medication categories and only one in ten was prescribed breakthrough analgesia in the last year of life. The number of prescriptions for analgesia and palliative care drugs increased in the last 12 weeks of life. The number of prescriptions for non-palliative care medications, including anti-hypertensives, statins and bone protection, decreased over the last year, but was still substantial. Cancer decedents who were female, younger, or had lung cancer were more likely to be prescribed strong opioids; however, male cancer decedents had higher odds of being prescribed breakthrough analgesia. Cancer decedents who had late diagnoses had lower odds of being prescribed strong opioids. CONCLUSIONS: A substantial proportion of cancer decedents were not prescribed strong opioids, breakthrough medication, or medication to alleviate common palliative care symptoms (including 'Just in Case' medication). Many patients continued to be prescribed non-palliative care medications in their last days and weeks of life. Age, gender, cancer type and timing of diagnosis affected patients' odds of being prescribed analgesic and non-analgesic palliative care medication.

Patient outcomes following AKI and AKD: a population-based cohort study.

BACKGROUND: Acute kidney injury (AKI) is common and associated with adverse outcomes as well as important healthcare costs. However, evidence examining the epidemiology of acute kidney disease (AKD)-recently defined as AKI persisting between 7 and 90 days-remains limited. The aims of this study were to establish the rates of early AKI recovery, progression to AKD and non-recovery; examine risk factors associated with non-recovery and investigate the association between recovery timing and adverse outcomes, in a population-based cohort. METHODS: All adult residents of Tayside & Fife, Scotland, UK, with at least one episode of community or hospital-managed AKI using KDIGO creatinine-based definition during the period 1 January 2010 to 31 December 2018 were identified. Logistic regression was used to examine factors associated with non-recovery, and Cox modelling was used to establish associations between AKI recovery timing and risks of mortality and development of de novo CKD. RESULTS: Over 9 years, 56,906 patients with at least one AKI episode were identified with 18,773 (33%) of these progressing to AKD. Of those progressing to AKD, 5059 (27%) had still not recovered at day 90 post AKI diagnosis. Risk factors for AKD included: increasing AKI severity, pre-existing cancer or chronic heart failure and recent use of loop diuretics. Compared with early AKI recovery, progression to AKD was associated with increased hazard of 1-year mortality and de novo CKD (HR = 1.20, 95% CI 1.13 to 1.26 and HR = 2.21, 95% CI 1.91 to 2.57 respectively). CONCLUSIONS: These findings highlight the importance of early AKI recognition and management to avoid progression to AKD and long-term adverse outcomes.

Predictive performance of a competing risk cardiovascular prediction tool CRISK compared to QRISK3 in older people and those with comorbidity: population cohort study.

BACKGROUND: Recommended cardiovascular disease (CVD) prediction tools do not account for competing mortality risk and over-predict incident CVD in older and multimorbid people. The aim of this study was to derive and validate a competing risk model (CRISK) to predict incident CVD and compare its performance to that of QRISK3 in UK primary care. METHODS: We used UK linked primary care data from the Clinical Practice Research Datalink (CPRD) GOLD to identify people aged 25-84 years with no previous CVD or statin treatment split into derivation and validation cohorts. In the derivation cohort, we derived models using the same covariates as QRISK3 with Fine-Gray competing risk modelling alone (CRISK) and with Charlson Comorbidity score (CRISK-CCI) as an additional predictor of non-CVD death. In a separate validation cohort, we examined discrimination and calibration compared to QRISK3. Reclassification analysis examined the number of patients recommended for treatment and the estimated number needed to treat (NNT) to prevent a new CVD event. RESULTS: The derivation and validation cohorts included 989,732 and 494,865 women and 946,784 and 473,392 men respectively. Overall discrimination of CRISK and CRISK-CCI were excellent and similar to QRISK3 (for women, C-statistic = 0.863/0.864/0.863 respectively; for men 0.833/0.819/0.832 respectively). CRISK and CRISK-CCI calibration overall and in younger people was excellent. CRISK over-predicted in older and multimorbid people although performed better than QRISK3, whilst CRISK-CCI performed the best. The proportion of people reclassified by CRISK-CCI varied by QRISK3 risk score category, with 0.7-9.7% of women and 2.8-25.2% of men reclassified as higher risk and 21.0-69.1% of women and 27.1-57.4% of men reclassified as lower risk. Overall, CRISK-CCI recommended fewer people for treatment and had a lower estimated NNT at 10% risk threshold. Patients reclassified as higher risk were younger, had lower SBP and higher BMI, and were more likely to smoke. CONCLUSIONS: CRISK and CRISK-CCI performed better than QRISK3. CRISK-CCI recommends fewer people for treatment and has a lower NNT to prevent a new CVD event compared to QRISK3. Competing risk models should be recommended for CVD primary prevention treatment recommendations.

Death from cancer: frequent unscheduled care.

OBJECTIVE: To examine the demographic, clinical, and temporal factors associated with cancer decedents being a frequent or very frequent unscheduled care (GP-general practice Out-Of-Hours (GPOOH) and Accident & Emergency (A&E)) attender, in their last year of life. METHODS: Retrospective cohort study, of all 2443 cancer decedents in Tayside, Scotland, over 30- months period up to 06/2015, comparing frequent attenders (5-9 attendances/year) and very frequent attenders (≥10 attendances/year) to infrequent attenders (1-4 attendances/year) and non-attenders. Clinical and demographic datasets were linked to routinely-collected clinical data using the Community Health Index number. Anonymised linked data were analysed in SafeHaven, using binary/multinomial logistic regression, and Generalised Estimating Equations analysis. RESULTS: Frequent attenders were more likely to be older, and have upper gastrointestinal (GI), haematological, breast and ovarian malignancies, and less likely to live in accessible areas or have a late cancer diagnosis. They were more likely to use GPOOH than A&E, less likely to have face-to-face unscheduled care attendances, and less likely to be admitted to hospital following unscheduled care attendance. CONCLUSIONS: Age, cancer type, accessibility and timing of diagnosis relative to death were associated with increased likelihood of being a frequent or very frequent attender at unscheduled care.

Effect of perindopril or leucine on physical performance in older people with sarcopenia: the LACE randomized controlled trial.

BACKGROUND: This trial aimed to determine the efficacy of leucine and/or perindopril in improving physical function in older people with sarcopenia. METHODS: Placebo-controlled, parallel group, double-blind, randomized two-by-two factorial trial. We recruited adults aged ≥ 70 years with sarcopenia, defined as low gait speed (<0.8 m/s on 4 m walk) and/or low handgrip strength (women < 20 kg, men < 30 kg) plus low muscle mass (using sex and body mass index category-specific thresholds derived from normative UK BioBank data) from 14 UK centres. Eligible participants were randomized to perindopril 4 mg or placebo, and to oral leucine powder 2.5 g or placebo thrice daily. The primary outcome was the between-group difference in the short physical performance battery (SPPB) score over 12-month follow-up by repeated-measures mixed models. Results were combined with existing systematic reviews using random-effects meta-analysis to derive summary estimates of treatment efficacy. RESULTS: We screened 320 people and randomized 145 participants compared with an original target of 440 participants. For perindopril [n = 73, mean age 79 (SD 6), female sex 39 (53%), mean SPPB 7.1 (SD 2.3)] versus no perindopril [n = 72, mean age 79 (SD 6), female sex 39 (54%), mean SPPB 6.9 (SD 2.4)], median adherence to perindopril was lower (76% vs. 96%; P < 0.001). Perindopril did not improve the primary outcome [adjusted treatment effect -0.1 points (95%CI -1.2 to 1.0), P = 0.89]. No significant treatment benefit was seen for any secondary outcome including muscle mass [adjusted treatment effect -0.4 kg (95%CI -1.1 to 0.3), P = 0.27]. More adverse events occurred in the perindopril group (218 vs. 165), but falls rates were similar. For leucine [n = 72, mean age 78 (SD 6), female sex 38 (53%), mean SPPB 7.0 (SD 2.1)] versus no leucine [n = 72, mean age 79 (SD 6), female sex 40 (55%), mean SPPB 7.0 (SD 2.5)], median adherence was the same in both groups (76% vs. 76%; P = 0.99). Leucine did not improve the primary outcome [adjusted treatment effect 0.1 point (95%CI -1.0 to 1.1), P = 0.90]. No significant treatment benefit was seen for any secondary outcome including muscle mass [adjusted treatment effect -0.3 kg (95%CI -1.0 to 0.4), P = 0.47]. Meta-analysis of angiotensin converting enzyme inhibitor/angiotensin receptor blocker trials showed no clinically important treatment effect for the SPPB [between-group difference -0.1 points (95%CI -0.4 to 0.2)]. CONCLUSIONS: Neither perindopril nor leucine improved physical performance or muscle mass in this trial; meta-analysis did not find evidence of efficacy of either ACE inhibitors or leucine as treatments to improve physical performance.

Real time remote symptom monitoring during chemotherapy for cancer: European multicentre randomised controlled trial (eSMART).

OBJECTIVE: To evaluate effects of remote monitoring of adjuvant chemotherapy related side effects via the Advanced Symptom Management System (ASyMS) on symptom burden, quality of life, supportive care needs, anxiety, self-efficacy, and work limitations. DESIGN: Multicentre, repeated measures, parallel group, evaluator masked, stratified randomised controlled trial. SETTING: Twelve cancer centres in Austria, Greece, Norway, Republic of Ireland, and UK. PARTICIPANTS: 829 patients with non-metastatic breast cancer, colorectal cancer, Hodgkin's disease, or non-Hodgkin's lymphoma receiving first line adjuvant chemotherapy or chemotherapy for the first time in five years. INTERVENTION: Patients were randomised to ASyMS (intervention; n=415) or standard care (control; n=414) over six cycles of chemotherapy. MAIN OUTCOME MEASURES: The primary outcome was symptom burden (Memorial Symptom Assessment Scale; MSAS). Secondary outcomes were health related quality of life (Functional Assessment of Cancer Therapy-General; FACT-G), Supportive Care Needs Survey Short-Form (SCNS-SF34), State-Trait Anxiety Inventory-Revised (STAI-R), Communication and Attitudinal Self-Efficacy scale for cancer (CASE-Cancer), and work limitations questionnaire (WLQ). RESULTS: For the intervention group, symptom burden remained at pre-chemotherapy treatment levels, whereas controls reported an increase from cycle 1 onwards (least squares absolute mean difference -0.15, 95% confidence interval -0.19 to -0.12; P<0.001; Cohen's D effect size=0.5). Analysis of MSAS sub-domains indicated significant reductions in favour of ASyMS for global distress index (-0.21, -0.27 to -0.16; P<0.001), psychological symptoms (-0.16, -0.23 to -0.10; P<0.001), and physical symptoms (-0.21, -0.26 to -0.17; P<0.001). FACT-G scores were higher in the intervention group across all cycles (mean difference 4.06, 95% confidence interval 2.65 to 5.46; P<0.001), whereas mean scores for STAI-R trait (-1.15, -1.90 to -0.41; P=0.003) and STAI-R state anxiety (-1.13, -2.06 to -0.20; P=0.02) were lower. CASE-Cancer scores were higher in the intervention group (mean difference 0.81, 0.19 to 1.43; P=0.01), and most SCNS-SF34 domains were lower, including sexuality needs (-1.56, -3.11 to -0.01; P<0.05), patient care and support needs (-1.74, -3.31 to -0.16; P=0.03), and physical and daily living needs (-2.8, -5.0 to -0.6; P=0.01). Other SCNS-SF34 domains and WLQ were not significantly different. Safety of ASyMS was satisfactory. Neutropenic events were higher in the intervention group. CONCLUSIONS: Significant reduction in symptom burden supports the use of ASyMS for remote symptom monitoring in cancer care. A "medium" Cohen's effect size of 0.5 showed a sizable, positive clinical effect of ASyMS on patients' symptom experiences. Remote monitoring systems will be vital for future services, particularly with blended models of care delivery arising from the covid-19 pandemic. TRIAL REGISTRATION: Clinicaltrials.gov NCT02356081.

Effect of competing mortality risks on predictive performance of the QRISK3 cardiovascular risk prediction tool in older people and those with comorbidity: external validation population cohort study.

BACKGROUND: Primary prevention of cardiovascular disease (CVD) is guided by risk-prediction tools, but these rarely account for the risk of dying from other conditions (ie, competing mortality risk). In England and Wales, the recommended risk-prediction tool is QRISK2, and a new version (QRISK3) has been derived and internally validated. We aimed to externally validate QRISK3 and to assess the effects of competing mortality risk on its predictive performance. METHODS: For this retrospective population cohort study, we used data from the Clinical Practice Research Datalink. We included patients aged 25-84 years with no previous history of CVD or statin treatment who were permanently registered with a primary care practice, had up-to-standard data for at least 1 year, and had linkage to Hospital Episode Statistics discharge and Office of National Statistics mortality data. We compared the QRISK3-predicted 10-year CVD risk with the observed 10-year risk in the whole population and in important subgroups of age and multimorbidity. QRISK3 discrimination and calibration were examined with and without accounting for competing risks. FINDINGS: Our study population included 1 484 597 women with 42 451 incident CVD events (4·9 cases per 1000 person-years of follow-up, 95% CI 4·89-4·99), and 1 420 176 men with 53 066 incident CVD events (6·7 cases per 1000 person-years, 6·66-6·78), with median follow-up of 5·0 years (IQR 1·9-9·2). Non-CVD death rose markedly with age (0·4% of women and 0·5% of men aged 25-44 years had a non-CVD death vs 20·1% of women and 19·6% of men aged 75-84 years). QRISK3 discrimination in the whole population was excellent (Harrell's C-statistic 0·865 in women and 0·834 in men) but was poor in older age groups (<0·65 in all subgroups aged 65 years or older). Ignoring competing risks, QRISK3 calibration in the whole population and in younger people was excellent, but there was significant over-prediction in older people. Accounting for competing risks, QRISK3 systematically over-predicted CVD risk, particularly in older people and in those with high multimorbidity. INTERPRETATION: QRISK3 performed well at the whole population level when ignoring competing mortality risk. The tool performed considerably less well in important subgroups, including older people and people with multimorbidity, and less well again after accounting for competing mortality risk. FUNDING: National Institute for Health Research.

Intolerance to Angiotensin Converting Enzyme Inhibitors in Asthma and the General Population: A UK Population-Based Cohort Study.

BACKGROUND: Angiotensin converting enzyme inhibitor (ACEI) intolerance commonly occurs, requiring switching to an angiotensin-II receptor blocker (ARB). Angiotensin converting enzyme inhibitor intolerance may be mediated by bradykinin, potentially affecting airway hyperresponsiveness. OBJECTIVE: To assess the risk for switching to ARBs in asthma. METHODS: We conducted a new-user cohort study of ACEI initiators identified from electronic health records from the UK Clinical Practice Research Datalink. The risk for switching to ARBs in people with asthma or chronic obstructive pulmonary disease and the general population was compared. Adjusted hazard ratios (HRs) were calculated using Cox regression, stratified by British Thoracic Society (BTS) treatment step and ACEI type. RESULTS: Of 642,336 new users of ACEI, 6.4% had active asthma. The hazard of switching to ARB was greater in people with asthma (HR = 1.16; 95% confidence interval [CI], 1.14-1.18; P ≤ .001) and highest in those at BTS step 3 or greater (HR = 1.35, 95% CI, 1.32-1.39; and HR = 1.18, 95% CI, 1.15-1.22, P ≤ .001 for patients aged ≥60 and <60 years, respectively). Hazard was highest with enalapril (HR = 1.25, 95% CI, 1.18-1.34, P ≤ .001; HR = 1.44, 95% CI, 1.32-1.58, P ≤ .001 for BTS step 3 or greater asthma). No increased hazard was observed in chronic obstructive pulmonary disease or those younger than age 60 years at BTS step 1/2. The number needed to treat varied by age, sex, and body mass index (BMI), ranging between 21 and 4, and was lowest in older women with a BMI of 25 or greater. CONCLUSIONS: People with active asthma are more likely to switch to ARBs after commencing ACEI therapy. The number needed to treat varies by age, sex, BMI, and BTS step. Angiotensin-II receptor blocker could potentially be considered first-line in people with asthma and in those with high-risk characteristics.

A novel approach to increasing community capacity for weight management a volunteer-delivered programme (ActWELL) initiated within breast screening clinics: a randomised controlled trial.

BACKGROUND: It is estimated that around 30% of breast cancers in post-menopausal women are related to lifestyle. The breast cancer-pooling project demonstrated that sustained weight loss of 2 to 4.5 kg is associated with an 18% lower risk of breast cancer, highlighting the importance of small changes in body weight. Our study aimed to assess the effectiveness a volunteer-delivered, community based, weight management programme (ActWELL) for women with a BMI > 25 kg/m2 attending NHS Scotland Breast Screening clinics. METHODS: A multicentre, 1:1 parallel group, randomised controlled trial was undertaken in 560 women aged 50 to 70 years with BMI > 25 kg/m2. On completion of baseline measures, all participants received a breast cancer prevention leaflet. Intervention group participants received the ActWELL intervention which focussed on personalised diet advice and pedometer walking plans. The programme was delivered in leisure centres by (the charity) Breast Cancer Now volunteer coaches. Primary outcomes were changes between groups at 12 months in body weight (kg) and physical activity (accelerometer measured step count). RESULTS: Two hundred seventy-nine women were allocated to the intervention group and 281 to the comparison group. Twelve-month data were available from 240 (81%) intervention and 227 (85%) comparison group participants. Coaches delivered 523 coaching sessions and 1915 support calls to 279 intervention participants. Mean weight change was - 2.5 kg (95% CI - 3.1 to - 1.9) in the intervention group and - 1.2 kg (- 1.8 to 0.6) in the comparison group. The adjusted mean difference was - 1.3 kg (95% CI - 2.2 to - 0.4, P = 0.003). The odds ratio for losing 5% weight was 2.20 (95% CI 1.4 to 3.4, p = 0.0005) in favour of the intervention. The adjusted mean difference in step counts between groups was 483 steps/day (95% CI - 635 to 1602) (NS). CONCLUSIONS: A community weight management intervention initiated at breast screening clinics and delivered by volunteer coaches doubled the likelihood of clinically significant weight loss at 12 months (compared with usual care) offering significant potential to decrease breast cancer risk. TRIAL REGISTRATION: Database of registration: ISCRTN. Registration number: 11057518 . Date trial registered:21.07.2017. Date of enrolment of first participant: 01.09.2017.

Surgical interventions for the early management of Bell's palsy.

BACKGROUND: Bell's palsy is an acute unilateral facial paralysis of unknown aetiology and should only be used as a diagnosis in the absence of any other pathology. As the proposed pathophysiology is swelling and entrapment of the nerve, some surgeons suggest surgical decompression of the nerve as a possible management option; this is ideally performed as soon as possible after onset. This is an update of a review first published in 2011, and last updated in 2013. This update includes evidence from one newly identified study. OBJECTIVES: To assess the effects of surgery in the early management of Bell's palsy. SEARCH METHODS: On 20 March 2020, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, ClinicalTrials.gov and WHO ICTRP. We handsearched selected conference abstracts for the original version of the review. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) or quasi-RCTs involving any surgical intervention for Bell's palsy. Trials compared surgical interventions to no treatment, later treatment (beyond three months), sham treatment, other surgical treatments or medical treatment. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trials for inclusion, assessed risk of bias and extracted data. We used standard methodological procedures expected by Cochrane. The primary outcome was complete recovery of facial palsy at 12 months. Secondary outcomes were complete recovery at three and six months, synkinesis and contracture at 12 months, psychosocial outcomes at 12 months, and side effects and complications of treatment. MAIN RESULTS: Two trials with 65 participants met the inclusion criteria; one was newly identified at this update. The first study randomised 25 participants into surgical or non-surgical (no treatment) groups using statistical charts. One participant declined surgery, leaving 24 evaluable participants. The second study quasi-randomised 53 participants; however, only 41 were evaluable as 12 declined the intervention they were allocated. These 41 participants were then divided into early surgery, late surgery or non-surgical (no treatment) groups using alternation. There was no mention on how alternation was decided. Neither study mentioned if there was any attempt to conceal allocation. Neither participants nor outcome assessors were blinded to the interventions in either study. There were no losses to follow-up in the first study. The second study lost three participants to follow-up, and 17 did not contribute to the assessment of secondary outcomes. Both studies were at high risk of bias. Surgeons in both studies used a retro-auricular/transmastoid approach to decompress the facial nerve. For the outcome recovery of facial palsy at 12 months, the evidence was uncertain. The first study reported no differences between the surgical and no treatment groups. The second study fully reported numerical data, but included no statistical comparisons between groups for complete recovery. There was no evidence of a difference for the early surgery versus no treatment comparison (risk ratio (RR) 0.76, 95% confidence interval (CI) 0.05 to 11.11; P = 0.84; 33 participants; very low-certainty evidence) and for the early surgery versus late surgery comparison (RR 0.47, 95% CI 0.03 to 6.60; P = 0.58; 26 participants; very low-certainty evidence). We considered the effects of surgery on facial nerve function at 12 months very uncertain (2 RCTs, 65 participants; very low-certainty evidence). Furthermore, the second study reported adverse effects with a statistically significant decrease in lacrimal control in the surgical group within two to three months of denervation. Four participants in the second study had 35 dB to 50 dB of sensorineural hearing loss at 4000 Hz, and three had tinnitus. Because of the small numbers and trial design we also considered the adverse effects evidence very uncertain (2 RCTs, 65 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: There is very low-certainty evidence from RCTs or quasi-RCTs on surgery for the early management of Bell's palsy, and this is insufficient to decide whether surgical intervention is beneficial or harmful. Further research into the role of surgical intervention is unlikely to be performed because spontaneous or medically supported recovery occurs in most cases.

Trends in gabapentinoid prescribing, co-prescribing of opioids and benzodiazepines, and associated deaths in Scotland.

BACKGROUND: Gabapentinoid drugs (gabapentin and pregabalin) are effective in neuropathic pain, which has a prevalence of ∼7%. Concerns about increased prescribing have implications for patient safety, misuse, and diversion. Drug-related deaths (DRDs) have increased and toxicology often implicates gabapentinoids. We studied national and regional prescribing rates (2006-2016) and identified associated sociodemographic factors, co-prescriptions and mortality, including DRDs. METHODS: National data from the Information Service Division, NHS Scotland were analysed for prescribing, sociodemographic, and mortality data from the Health Informatics Centre, University of Dundee. DRDs in which gabapentinoids were implicated were identified from National Records of Scotland and Tayside Drug Death Databases. RESULTS: From 2006 to 2016, the number of gabapentin prescriptions in Scotland increased 4-fold (164 630 to 694 293), and pregabalin 16-fold (27 094 to 435 490). In 2016 'recurrent users' (three or more prescriptions) had mean age 58.1 yr, were mostly females (62.5%), and were more likely to live in deprived areas. Of these, 60% were co-prescribed an opioid, benzodiazepine, or both (opioid 49.9%, benzodiazepine 26.8%, both 17.1%). The age-standardised death rate in those prescribed gabapentinoids was double that in the Scottish population (relative risk 2.16, 95% confidence interval 2.08-2.25). Increases in gabapentinoids contributing to cause of DRDs were reported regionally and nationally (gabapentin 23% vs 15%; pregabalin 21% vs 7%). In Tayside, gabapentinoids were implicated in 22 (39%) of DRDs, 17 (77%) of whom had not received a prescription. CONCLUSIONS: Gabapentinoid prescribing has increased dramatically since 2006, as have dangerous co-prescribing and death (including DRDs). Older people, women, and those living in deprived areas were particularly likely to receive prescriptions. Their contribution to DRDs may be more related to illegal use with diversion of prescribed medication.

Sodium bicarbonate to improve physical function in patients over 60 years with advanced chronic kidney disease: the BiCARB RCT.

BACKGROUND: Advanced chronic kidney disease is common in older people and is frequently accompanied by metabolic acidosis. Oral sodium bicarbonate is used to treat this acidosis, but evidence is lacking on whether or not this provides a net gain in health or quality of life for older people. OBJECTIVES: The objectives were to determine whether or not oral bicarbonate therapy improves physical function, quality of life, markers of renal function, bone turnover and vascular health compared with placebo in older people with chronic kidney disease and mild acidosis; to assess the safety of oral bicarbonate; and to establish whether or not oral bicarbonate therapy is cost-effective in this setting. DESIGN: A parallel-group, double-blind, placebo-controlled randomised trial. SETTING: The setting was nephrology and geriatric medicine outpatient departments in 27 UK hospitals. PARTICIPANTS: Participants were adults aged ≥ 60 years with advanced chronic kidney disease (glomerular filtration rate category 4 or 5, not on dialysis) with a serum bicarbonate concentration of < 22 mmol/l. INTERVENTIONS: Eligible participants were randomised 1 : 1 to oral sodium bicarbonate or matching placebo. Dosing started at 500 mg three times daily, increasing to 1 g three times daily if the serum bicarbonate concentration was < 22 mmol/l at 3 months. MAIN OUTCOME MEASURES: The primary outcome was the between-group difference in the Short Physical Performance Battery score at 12 months, adjusted for baseline. Other outcome measures included generic and disease-specific health-related quality of life, anthropometry, 6-minute walk speed, grip strength, renal function, markers of bone turnover, blood pressure and brain natriuretic peptide. All adverse events were recorded, including commencement of renal replacement therapy. For the health economic analysis, the incremental cost per quality-adjusted life-year was the main outcome. RESULTS: In total, 300 participants were randomised, 152 to bicarbonate and 148 to placebo. The mean age of participants was 74 years and 86 (29%) were female. Adherence to study medication was 73% in both groups. A total of 220 (73%) participants were assessed at the 12-month visit. No significant treatment effect was evident for the primary outcome of the between-group difference in the Short Physical Performance Battery score at 12 months (-0.4 points, 95% confidence interval -0.9 to 0.1 points; p = 0.15). No significant treatment benefit was seen for any of the secondary outcomes. Adverse events were more frequent in the bicarbonate arm (457 vs. 400). Time to commencement of renal replacement therapy was similar in both groups (hazard ratio 1.22, 95% confidence interval 0.74 to 2.02; p = 0.43). Health economic analysis showed higher costs and lower quality of life in the bicarbonate arm at 1 year, with additional costs of £564 (95% confidence interval £88 to £1154) and a quality-adjusted life-year difference of -0.05 (95% confidence interval -0.08 to -0.01); placebo dominated bicarbonate under all sensitivity analyses for incremental cost-effectiveness. LIMITATIONS: The trial population was predominantly white and male, limiting generalisability. The increment in serum bicarbonate concentrations achieved was small and a benefit from larger doses of bicarbonate cannot be excluded. CONCLUSIONS: Oral sodium bicarbonate did not improve a range of health measures in people aged ≥ 60 years with chronic kidney disease category 4 or 5 and mild acidosis, and is unlikely to be cost-effective for use in the NHS in this patient group. Once other current trials of bicarbonate therapy in chronic kidney disease are complete, an individual participant meta-analysis would be helpful to determine which subgroups, if any, are more likely to benefit and which treatment regimens are more beneficial. TRIAL REGISTRATION: Current Controlled Trials ISRCTN09486651 and EudraCT 2011-005271-16. The systematic review is registered as PROSPERO CRD42018112908. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 27. See the NIHR Journals Library website for further project information.

Patients with advanced chronic kidney disease often have excessive levels of acid in their blood (acidosis). Acidosis has been associated with a range of other problems that particularly affect patients with chronic kidney disease, including weaker muscles, weaker bones, worse blood vessel health and kidney disease that worsens more quickly. For decades, acidosis has been treated with sodium bicarbonate tablets (the ingredient found in baking soda) to neutralise the excess acid. However, sodium bicarbonate is awkward to take, may cause side effects and may increase blood pressure. To clarify whether or not sodium bicarbonate caused an overall improvement in health, we carried out a study involving 300 people aged ≥ 60 years with advanced chronic kidney disease and mild acidosis. Half received sodium bicarbonate capsules and half received dummy capsules (placebo), for up to 2 years. The treatments were chosen randomly by a computer and the participants, their doctors and the researchers were not aware of the treatment received until the end of the study. We measured physical function (walking speed, ability to stand from a chair, balance) alongside quality of life, kidney function, bone and blood vessel health, side effects and health service use over 2 years. We found that sodium bicarbonate did not improve physical function or quality of life compared with placebo. Sodium bicarbonate also did not improve kidney function, bone health or blood vessel health compared with placebo. More people in the sodium bicarbonate group than in the placebo group had side effects, although blood pressure was the same in both groups. Health-care costs were higher in the sodium bicarbonate group than in the placebo group. We conclude that oral sodium bicarbonate did not significantly improve health measures compared with placebo for older people (aged ≥ 60 years) with advanced chronic kidney disease associated with mild acidosis.