Breast-Conserving Surgery with or without Irradiation in Early Breast Cancer.

BACKGROUND: Limited level 1 evidence is available on the omission of radiotherapy after breast-conserving surgery in older women with hormone receptor-positive early breast cancer receiving adjuvant endocrine therapy. METHODS: We performed a phase 3 randomized trial of the omission of irradiation; the trial population included women 65 years of age or older who had hormone receptor-positive, node-negative, T1 or T2 primary breast cancer (with tumors ≤3 cm in the largest dimension) treated with breast-conserving surgery with clear excision margins and adjuvant endocrine therapy. Patients were randomly assigned to receive whole-breast irradiation (40 to 50 Gy) or no irradiation. The primary end point was local breast cancer recurrence. Regional recurrence, breast cancer-specific survival, distant recurrence as the first event, and overall survival were also assessed. RESULTS: A total of 1326 women were enrolled; 658 were randomly assigned to receive whole-breast irradiation and 668 to receive no irradiation. The median follow-up was 9.1 years. The cumulative incidence of local breast cancer recurrence within 10 years was 9.5% (95% confidence interval [CI], 6.8 to 12.3) in the no-radiotherapy group and 0.9% (95% CI, 0.1 to 1.7) in the radiotherapy group (hazard ratio, 10.4; 95% CI, 4.1 to 26.1; P<0.001). Although local recurrence was more common in the group that did not receive radiotherapy, the 10-year incidence of distant recurrence as the first event was not higher in the no-radiotherapy group than in the radiotherapy group, at 1.6% (95% CI, 0.4 to 2.8) and 3.0% (95% CI, 1.4 to 4.5), respectively. Overall survival at 10 years was almost identical in the two groups, at 80.8% (95% CI, 77.2 to 84.3) with no radiotherapy and 80.7% (95% CI, 76.9 to 84.3) with radiotherapy. The incidence of regional recurrence and breast cancer-specific survival also did not differ substantially between the two groups. CONCLUSIONS: Omission of radiotherapy was associated with an increased incidence of local recurrence but had no detrimental effect on distant recurrence as the first event or overall survival among women 65 years of age or older with low-risk, hormone receptor-positive early breast cancer. (Funded by the Chief Scientist Office of the Scottish Government and the Breast Cancer Institute, Western General Hospital, Edinburgh; ISRCTN number, ISRCTN95889329.).

Evaluation of the association of area-level socioeconomic deprivation and breast cancer recurrence by oestrogen receptor subtypes in Scotland.

BACKGROUND: Women from socioeconomically deprived areas have lower breast cancer (BC) incidence rates for screen-detected oestrogen receptor (ER) + tumours and higher mortality for select tumour subtypes. We aimed to determine if ipsilateral breast cancer recurrence (IBR) differs by Scottish Index of Multiple Deprivation (SIMD) quintile and tumour subtype in Scotland. METHODS: Patient data for primary invasive BC diagnosed in 2007-2008 in Scotland was analysed. Manual case-note review for 3495 patients from 10 years post-diagnosis was used. To determine the probability of IBR while accounting for the competing risk of death from any cause, cumulative incidence functions stratified by ER subtype and surgery were plotted. Multivariable Cox Proportional Hazards models were used to estimate the association of SIMD accounting for other predictors of IBR. RESULTS: Among 2819 ER + tumours, 423 patients had a recurrence and 438 died. SIMD was related to death (p = 0.018) with the most deprived more likely to have died in the 10-year period (17.7% vs. 12.9%). We found no significant differences by SIMD in prognostic tumour characteristics (grade, TNM stage, treatment, screen-detection) or risk of IBR. Among 676 patients diagnosed with ER- tumours, 105 died and 185 had a recurrence. We found no significant differences in prognostic tumour characteristics by SIMD except screen detection with the most deprived more likely than the least to have their tumours detected from screening (46.9% vs. 28%, p = 0.03). Among patients with ER- tumours, 50% had mastectomy and the most deprived had increased 5-year IBR risk compared to the least deprived (HR 3.03 [1.41-6.53]). CONCLUSIONS: IBR is not a major contributor to mortality differences by SIMD for the majority of BC patients in our study. The lack of inequities in IBR are likely due to standardised treatment protocols and access to healthcare. The association with socioeconomic deprivation and recurrence for ER- tumours requires further study.

The Value of In Vivo Reflectance Confocal Microscopy as an Assessment Tool in Chemotherapy-Induced Peripheral Neuropathy: A Pilot Study.

BACKGROUND: There is a lack of standardized objective and reliable assessment tools for chemotherapy-induced peripheral neuropathy (CIPN). In vivo reflectance confocal microscopy (RCM) imaging offers a non-invasive method to identify peripheral neuropathy markers, namely Meissner's corpuscles (MC). This study investigated the feasibility and value of RCM in CIPN. PATIENTS AND METHODS: Reflectance confocal microscopy was performed on the fingertip to evaluate MC density in 45 healthy controls and 9 patients with cancer (prior, during, and post-chemotherapy). Quantification was completed by 2 reviewers (one blinded), with maximum MC count/3 × 3 mm image reported. Quantitative Sensory Testing (QST; thermal and mechanical detection thresholds), Grooved pegboard test, and patient-reported outcomes measures (PROMS) were conducted for comparison. RESULTS: In controls (25 females, 20 males; 24-81 years), females exhibited greater mean MC density compared with males (49.9 ± 7.1 vs 30.9 ± 4.2 MC/3 × 3 mm; P = .03). Differences existed across age by decade (P < .0001). Meissner's corpuscle density was correlated with mechanical detection (ρ = -0.51), warm detection (ρ = -0.47), cold pain (ρ = 0.49) thresholds (P < .01); and completion time on the Grooved pegboard test in both hands (P ≤ .02). At baseline, patients had reduced MC density vs age and gender-matched controls (P = .03). Longitudinal assessment of MC density revealed significant relationships with QST and PROMS. Inter-rater reliability of MC count showed an intraclass correlation of 0.96 (P < .0001). CONCLUSIONS: The findings support the clinical utility of RCM in CIPN as it provides meaningful markers of sensory nerve dysfunction. Novel, prospective assessment demonstrated the ability to detect subclinical deficits in patients at risk of CIPN and potential to monitor neuropathy progression.

Breast cancer incidence and survival in Scotland by socio-economic deprivation and tumour subtype.

BACKGROUND: Women from socio-economically deprived areas are less likely to develop and then to survive breast cancer (BC). Whether associations between deprivation and BC incidence and survival differ by tumour molecular subtypes and mode of detection in Scotland are unknown. METHODS: Data consisted of 62,378 women diagnosed with invasive BC between 2000 and 2016 in Scotland. Incidence rates and time trends were calculated for oestrogen receptor positive (ER+) and negative (ER-) tumours and stratified by the Scottish Index of Multiple Deprivation (SIMD) quintiles and screening status. SIMD is an area-based measure derived across seven domains: income, employment, education, health, access to services, crime and housing. We calculated adjusted hazard ratios (aHR [95% confidence intervals]) for BC death by immunohistochemical surrogates of molecular subtypes for the most versus the least deprived quintile. We adjusted for mode of detection and other confounders. RESULTS: In Scotland, screen-detected ER+tumour incidence increased over time, particularly in the least deprived quintile [Average Annual Percentage Change (AAPC) = 2.9% with 95% CI from 1.2 to 4.7]. No marked differences were observed for non-screen-detected ER+tumours or ER- tumours by deprivation. BC mortality was higher in the most compared to the least deprived quintile irrespective of ER status (aHR = 1.29 [1.18, 1.41] for ER+ and 1.27 [1.09, 1.47] for ER- tumours). However, deprivation was associated with significantly higher mortality for luminal A and HER2-enriched tumours (aHR = 1.46 [1.13, 1.88] and 2.10 [1.23, 3.59] respectively) but weaker associations for luminal B and TNBC tumours that were not statistically significant. CONCLUSIONS: Deprivation is associated with differential BC incidence trends for screen-detected ER+tumours and with higher mortality for select tumour subtypes. Future efforts should evaluate factors that might be associated with reduced survival in deprived populations and monitor progress stratified by tumour subtypes and mode of detection.

Interventions for perceptual disorders following stroke.

BACKGROUND: Perception is the ability to understand information from our senses. It allows us to experience and meaningfully interact with our environment. A stroke may impair perception in up to 70% of stroke survivors, leading to distress, increased dependence on others, and poorer quality of life. Interventions to address perceptual disorders may include assessment and screening, rehabilitation, non-invasive brain stimulation, pharmacological and surgical approaches. OBJECTIVES: To assess the effectiveness of interventions aimed at perceptual disorders after stroke compared to no intervention or control (placebo, standard care, attention control), on measures of performance in activities of daily living.  SEARCH METHODS: We searched the trials registers of the Cochrane Stroke Group, CENTRAL, MEDLINE, Embase, and three other databases to August 2021. We also searched trials and research registers, reference lists of studies, handsearched journals, and contacted authors. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of adult stroke survivors with perceptual disorders. We defined perception as the specific mental functions of recognising and interpreting sensory stimuli and included hearing, taste, touch, smell, somatosensation, and vision. Our definition of perception excluded visual field deficits, neglect/inattention, and pain. DATA COLLECTION AND ANALYSIS: One review author assessed titles, with two review authors independently screening abstracts and full-text articles for eligibility. One review author extracted, appraised, and entered data, which were checked by a second author. We assessed risk of bias (ROB) using the ROB-1 tool, and quality of evidence using GRADE.  A stakeholder group, comprising stroke survivors, carers, and healthcare professionals, was involved in this review update. MAIN RESULTS: We identified 18 eligible RCTs involving 541 participants. The trials addressed touch (three trials, 70 participants), somatosensory (seven trials, 196 participants) and visual perception disorders (seven trials, 225 participants), with one (50 participants) exploring mixed touch-somatosensory disorders. None addressed stroke-related hearing, taste, or smell perception disorders. All but one examined the effectiveness of rehabilitation interventions; the exception evaluated non-invasive brain stimulation. For our main comparison of active intervention versus no treatment or control, one trial reported our primary outcome of performance in activities of daily living (ADL):  Somatosensory disorders: one trial (24 participants) compared an intervention with a control intervention and reported an ADL measure.  Touch perception disorder: no trials measuring ADL compared an intervention with no treatment or with a control intervention.  Visual perception disorders: no trials measuring ADL compared an intervention with no treatment or control.  In addition, six trials reported ADL outcomes in a comparison of active intervention versus active intervention, relating to somatosensation (three trials), touch (one trial) and vision (two trials).   AUTHORS' CONCLUSIONS: Following a detailed, systematic search, we identified limited RCT evidence of the effectiveness of interventions for perceptual disorders following stroke. There is insufficient evidence to support or refute the suggestion that perceptual interventions are effective. More high-quality trials of interventions for perceptual disorders in stroke are needed. They should recruit sufficient participant numbers, include a 'usual care' comparison, and measure longer-term functional outcomes, at time points beyond the initial intervention period. People with impaired perception following a stroke should continue to receive neurorehabilitation according to clinical guidelines.

Five-year oncological outcomes after selective neoadjuvant radiotherapy for resectable rectal cancer.

Introduction: There is considerable variation in selection of patients for and type of neoadjuvant radiotherapy administered in the treatment of resectable rectal cancer. The aim of this study was to report outcomes for patients with resected rectal cancer from a unit with step-wise selection for surgery alone, short course radiotherapy (SCRT) or downstaging long course chemoradiotherapy (LCCRT). Material and methods: Cohort analysis of patients with rectal adenocarcinoma resected with curative intent between 2008 and 2012 at a specialist regional colorectal surgery center. The primary endpoints were local recurrence, metastatic recurrence, disease-free survival and overall survival. Exploratory uni- and multi-variable regression analyses were performed to identify predictive factors. Results: About 240 patients were treated by surgery alone, 90 patients received SCRT and 91 patients received LCCRT. Five-year local recurrence was 10.8% in the surgery alone group, 3.3% with SCRT and 18.7% with LCCRT. Metachronous distant metastasis was highest in the SCRT group (13.8% surgery alone, 25.6% SCRT, 15.4% LCCRT). Uni- and multi-variable regression analysis found that local and distant recurrence was attributable predominantly to adverse tumor biology. Conclusions: Patients selected for SCRT had a lower rate of local recurrence than patients selected for surgery alone, but were more likely to develop distant metastasis. There was no difference in overall survival. With low local recurrence rates, distant metastasis is the predominant risk for patients with resectable rectal cancer.

Use of Infliximab Biosimilar Versus Originator in a Pediatric United Kingdom Inflammatory Bowel Disease Induction Cohort.

OBJECTIVES: The aim of the study was to summarize short-term effectiveness, safety, and cost of using infliximab biosimilar (IFX-B) drugs, (Inflectra [Hospira] and Remsima [NAAP]) compared to originator infliximab (IFX-O) (Remicade [MSD]) in biologic naive pediatric inflammatory bowel disease in the United Kingdom. METHODS: Prospective audit of patients starting anti-tumour necrosis factor (TNF) therapy. Disease severity, response to treatment, and remission rate was measured by Pediatric Crohn's Disease Activity Index (PCDAI) and/or Physician Global Assessment. RESULTS: Between March 2015 and February 2016, 278 patients (175 IFX-O, 82 IFX-B, and 21 Adalimumab) were started on anti-TNF therapy. This was compared with collected data on 398 patients started on IFX-O from 2011 to 2015. At initiation, median PCDAI was 36 (20,48) (n = 42) in the IFX-O group and 28 (20,40) (n = 29) in the IFX-B group, (P = 0.08). Immunosuppression rates were similar: 150/175 (86%) for IFX-O and 65/82 (79%) for IFX-B (P > 0.05). Post induction, median PCDAI score was 5 (0,11) (n = 19) and 0 (0,8) (n = 15) in the IFX-O and IFX-B groups, respectively (P = 0.35). There was no difference in response to treatment using Physician Global Assessment 85% (n = 28) in IFX-O group and 86% (n = 19) in IFX-B group (P > 0.05). Adverse events at initiation and post induction were not different between both groups (P > 0.05). Using conservative calculations, £875,000 would have been saved for a 1-year period with universal adoption of biosimilars in patients who were instead treated with IFX-O. CONCLUSIONS: IFX-B is likely as effective as IFX-O in treating IBD in comparable pediatric populations. Sites should adopt infliximab biosimilar for new starts due to cost reduction with no difference in other parameters.

Real-life Anti-tumor Necrosis Factor Experience in More Than 500 Patients: High Co-immunosuppression Rates But Low Rates of Quantifying Treatment Response.

OBJECTIVE: The aim of this study was to measure the effectiveness, safety, and use of anti-tumor necrosis Factor (TNF) therapy in pediatric inflammatory bowel disease in the United Kingdom (UK). METHODS: Prospective UK audit of patients newly starting anti-TNF therapy. Disease severity was assessed using Physician Global Assessment +/or the Paediatric Crohn Disease Activity Index. RESULTS: A total of 37 centers participated (23/25 specialist pediatric inflammatory bowel disease sites). A total of 524 patients were included: 429 with Crohn disease (CD), 76 with ulcerative colitis (UC), and 19 with IBD unclassified (IBDU). Eighty-seven percent (488/562) of anti-TNF was infliximab; commonest indication was active luminal CD 77% (330/429) or chronic refractory UC/IBDU 56% (53/95); 79% (445/562) had concomitant co-immunosuppression. In CD (267/429 male), median time from diagnosis to treatment was 1.42 years (interquartile range 0.63-2.97). Disease (at initiation) was moderate or severe in 91% (156/171) by Physician Global Assessment compared to 41% (88/217) by Paediatric Crohn Disease Activity Index (Kappa (κ) 0.28 = only "fair agreement"; P < 0.001.Where documented, 77% (53/69) of patients with CD responded to induction; and 65% (46/71) entered remission. A total of 2287 infusions and 301.96 years of patient' follow-up (n = 385) are represented; adverse events affected 3% (49/1587) infliximab and 2% (2/98) adalimumab infusions (no deaths or malignancies). Peri-anal abscess drainage was less common after anti-TNF initiation (CD), that is 26% (27/102) before, 7% (3/42) after (P = 0.01); however, pre and post anti-TNF data collection was not over equal time periods. CONCLUSIONS: Anti-TNFs are effective treatments, usually given with thiopurine co-immunosuppression. This study highlights deficiencies in formal documentation of effect and disparity between disease severity scoring tools, which need to be addressed to improve ongoing patient care.

Retrospective cohort study of breast cancer incidence, health service use and outcomes in Europe: a study of feasibility.

Background: Comparisons of outcomes of health care in different systems can be used to inform health policy. The EuroHOPE (European Healthcare Outcomes, Performance and Efficiency) project investigated the feasibility of comparing routine data on selected conditions including breast cancer across participating European countries. Methods: Routine data on incidence, treatment and mortality by age and clinical characteristics for breast cancer in women over 24 years of age were obtained (for a calendar year) from linked hospital discharge records, cancer and death registers from Finland, the Turin metropolitan area, Scotland and Sweden (all 2005), Hungary (2006) and Norway (2009). Age-adjusted breast cancer incidence and 1-year survival were estimated for each country/region. Results: In total, 24 576 invasive breast cancer cases were identified from cancer registries from over 13 million women. Age-adjusted incidence ranged from 151.1 (95%CI 147.2-155.0) in Hungary to 234.7 (95%CI 227.4-242.0)/100 000 in Scotland. One-year survival ranged from 94.1% (95%CI 93.5-94.7%) in Scotland to 97.1% (95%CI 96.2-98.1%) in Italy. Scotland had the highest proportions of poor prognostic factors in terms of tumour size, nodal status and metastases. Significant variations in data completeness for prognostic factors prevented adjustment for case mix. Conclusion: Incidence of and survival from breast cancer showed large differences between countries. Substantial improvements in the use of internationally recognised common terminology, standardised data coding and data completeness for prognostic indicators are required before international comparisons of routine data can be used to inform health policy.

Outcomes of patients with inflammatory breast cancer treated by breast-conserving surgery.

PURPOSE: Inflammatory breast cancer (IBC) is rare and associated with a poor prognosis. Following neoadjuvant chemotherapy or endocrine therapy, the multidisciplinary team selected a small number of patients for breast-conservation therapy (BCT). The aim of this study was to determine the outcome of IBC patients treated with BCT in Edinburgh. METHODS: Between January 1999 and December 2013, thirty-five women with IBC were treated by BCT. The median follow-up was 80 months. RESULTS: The 5-year actuarial survival for the 35 patients was 70.3 %. Median survival for 20 neoadjuvant chemotherapy patients was 12.9 years (95 % CI 7.6, 18.1), and for 14 patient neoadjuvant endocrine therapy patients, it was 11.8 years (95 % CI 1.1, 22.6) (p = 0.34). Five patients developed locoregional recurrence (LRR) between 11 and 72 months after BCT (median 37 months). Three had breast only recurrence, one patient had both breast and axillary recurrence, and one developed axillary recurrence. The 5-year LR-free survival was 87.5 % (95 % CI 76.0, 99.0). In 4 of the 5 patients with LRR, systemic metastases were diagnosed within 6 months and survival post-LRR in these 4 patients was short. CONCLUSION: IBC is not an absolute contraindication to BCT. LRR in patients after BCT appears part of widespread recurrent disease rather than inadequate local treatment. Multicentre data should be collected to confirm that women with IBC who have a good response to systemic therapy may be offered BCT in the knowledge that in a larger series our observations are confirmed.

Pneumonia hospitalisations in Scotland following the introduction of pneumococcal conjugate vaccination in young children.

BACKGROUND: Scotland introduced PCV7 and PCV13 immunisation in young children in 2006 and 2010 respectively. One recent study from the United States reported a decrease in hospitalisation rates for all-cause pneumonia most notably in adults older than 75 years of age following PCV7 introduction in the US child population. We aimed to examine the effect of PCV7 and PCV13 on hospitalisation rates for all-cause pneumonia across all age groups in Scotland. METHODS: We linked hospital records and death certification datasets for the entire Scottish population for the period 2000 to 2012. We included all cases where the primary / secondary diagnosis was pneumonia. Differences in hospital admission rates for pneumonia by age group were calculated using the difference in average annual rates for each period. RESULTS: We estimated that all-cause pneumonia hospitalisation rates in children <2 years decreased by about 30 % in the post-PCV-13 period compared with the pre-PCV period. However, in adults aged 75-84 years and ≥85 years, all-cause pneumonia hospitalisation rates increased by 63 and 46 % respectively in the post-PCV 13 period compared to the pre-PCV period. This resulted in an additional 7000 hospitalisations across all age groups in Scotland in 2012 about half of which were in adults >75 years. At the same time, the median length of hospital stay decreased by a third in children <2 years and by about 20 % in adults >75 years in the post-PCV13 period compared to the pre-PCV period. Additionally, there was an 11 % reduction in deaths due to all-cause pneumonia, and 30 % reduction in pneumococcal hospitalisations across all age groups in the post-PCV13 period compared with pre-PCV period. DISCUSSION: The modest and sustained decline in the rates of hospitalisation for all-cause pneumonia in children and the reduction in proportion of pneumonia hospitalisations in children coded as pneumococcal disease in the post-PCV period should alleviate concerns that pneumococcal serotype replacement may have resulted in an increased pneumonia burden in this age group. The indirect impact of child PCV immunisation in those not vaccinated (in terms of reduction in all-cause pneumonia hospitalisations in the elderly) has not been seen in Scotland. Our results are likely to be confounded by changes in clinical coding and healthcare practices over the same period. CONCLUSIONS: Our results illustrate that health care planners cannot, with confidence, predict indirect PCV vaccine impacts on hospitalisations. IPD surveillance across all age groups is needed to assess the indirect effects of PCV in the community.

Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial.

BACKGROUND: For most older women with early breast cancer, standard treatment after breast-conserving surgery is adjuvant whole-breast radiotherapy and adjuvant endocrine treatment. We aimed to assess the effect omission of whole-breast radiotherapy would have on local control in older women at low risk of local recurrence at 5 years. METHODS: Between April 16, 2003, and Dec 22, 2009, 1326 women aged 65 years or older with early breast cancer judged low-risk (ie, hormone receptor-positive, axillary node-negative, T1-T2 up to 3 cm at the longest dimension, and clear margins; grade 3 tumour histology or lymphovascular invasion, but not both, were permitted), who had had breast-conserving surgery and were receiving adjuvant endocrine treatment, were recruited into a phase 3 randomised controlled trial at 76 centres in four countries. Eligible patients were randomly assigned to either whole-breast radiotherapy (40-50 Gy in 15-25 fractions) or no radiotherapy by computer-generated permuted block randomisation, stratified by centre, with a block size of four. The primary endpoint was ipsilateral breast tumour recurrence. Follow-up continues and will end at the 10-year anniversary of the last randomised patient. Analyses were done by intention to treat. The trial is registered on ISRCTN.com, number ISRCTN95889329. FINDINGS: 658 women who had undergone breast-conserving surgery and who were receiving adjuvant endocrine treatment were randomly assigned to receive whole-breast irradiation and 668 were allocated to no further treatment. After median follow-up of 5 years (IQR 3·84-6·05), ipsilateral breast tumour recurrence was 1·3% (95% CI 0·2-2·3; n=5) in women assigned to whole-breast radiotherapy and 4·1% (2·4-5·7; n=26) in those assigned no radiotherapy (p=0·0002). Compared with women allocated to whole-breast radiotherapy, the univariate hazard ratio for ipsilateral breast tumour recurrence in women assigned to no radiotherapy was 5·19 (95% CI 1·99-13·52; p=0·0007). No differences in regional recurrence, distant metastases, contralateral breast cancers, or new breast cancers were noted between groups. 5-year overall survival was 93·9% (95% CI 91·8-96·0) in both groups (p=0·34). 89 women died; eight of 49 patients allocated to no radiotherapy and four of 40 assigned to radiotherapy died from breast cancer. INTERPRETATION: Postoperative whole-breast radiotherapy after breast-conserving surgery and adjuvant endocrine treatment resulted in a significant but modest reduction in local recurrence for women aged 65 years or older with early breast cancer 5 years after randomisation. However, the 5-year rate of ipsilateral breast tumour recurrence is probably low enough for omission of radiotherapy to be considered for some patients. FUNDING: Chief Scientist Office (Scottish Government), Breast Cancer Institute (Western General Hospital, Edinburgh).

Parameter Heterogeneity In Breast Cancer Cost Regressions - Evidence From Five European Countries.

We investigate parameter heterogeneity in breast cancer 1-year cumulative hospital costs across five European countries as part of the EuroHOPE project. The paper aims to explore whether conditional mean effects provide a suitable representation of the national variation in hospital costs. A cohort of patients with a primary diagnosis of invasive breast cancer (ICD-9 codes 174 and ICD-10 C50 codes) is derived using routinely collected individual breast cancer data from Finland, the metropolitan area of Turin (Italy), Norway, Scotland and Sweden. Conditional mean effects are estimated by ordinary least squares for each country, and quantile regressions are used to explore heterogeneity across the conditional quantile distribution. Point estimates based on conditional mean effects provide a good approximation of treatment response for some key demographic and diagnostic specific variables (e.g. age and ICD-10 diagnosis) across the conditional quantile distribution. For many policy variables of interest, however, there is considerable evidence of parameter heterogeneity that is concealed if decisions are based solely on conditional mean results. The use of quantile regression methods reinforce the need to consider beyond an average effect given the greater recognition that breast cancer is a complex disease reflecting patient heterogeneity.

Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis.

BACKGROUND: Lower extremity peripheral artery disease is the third leading cause of atherosclerotic cardiovascular morbidity, following coronary artery disease and stroke. This study provides the first comparison of the prevalence of peripheral artery disease between high-income countries (HIC) and low-income or middle-income countries (LMIC), establishes the primary risk factors for peripheral artery disease in these settings, and estimates the number of people living with peripheral artery disease regionally and globally. METHODS: We did a systematic review of the literature on the prevalence of peripheral artery disease in which we searched for community-based studies since 1997 that defined peripheral artery disease as an ankle brachial index (ABI) lower than or equal to 0·90. We used epidemiological modelling to define age-specific and sex-specific prevalence rates in HIC and in LMIC and combined them with UN population numbers for 2000 and 2010 to estimate the global prevalence of peripheral artery disease. Within a subset of studies, we did meta-analyses of odds ratios (ORs) associated with 15 putative risk factors for peripheral artery disease to estimate their effect size in HIC and LMIC. We then used the risk factors to predict peripheral artery disease numbers in eight WHO regions (three HIC and five LMIC). FINDINGS: 34 studies satisfied the inclusion criteria, 22 from HIC and 12 from LMIC, including 112,027 participants, of which 9347 had peripheral artery disease. Sex-specific prevalence rates increased with age and were broadly similar in HIC and LMIC and in men and women. The prevalence in HIC at age 45-49 years was 5·28% (95% CI 3·38-8·17%) in women and 5·41% (3·41-8·49%) in men, and at age 85-89 years, it was 18·38% (11·16-28·76%) in women and 18·83% (12·03-28·25%) in men. Prevalence in men was lower in LMIC than in HIC (2·89% [2·04-4·07%] at 45-49 years and 14·94% [9·58-22·56%] at 85-89 years). In LMIC, rates were higher in women than in men, especially at younger ages (6·31% [4·86-8·15%] of women aged 45-49 years). Smoking was an important risk factor in both HIC and LMIC, with meta-OR for current smoking of 2·72 (95% CI 2·39-3·09) in HIC and 1·42 (1·25-1·62) in LMIC, followed by diabetes (1·88 [1·66-2·14] vs 1·47 [1·29-1·68]), hypertension (1·55 [1·42-1·71] vs 1·36 [1·24-1·50]), and hypercholesterolaemia (1·19 [1·07-1·33] vs 1·14 [1·03-1·25]). Globally, 202 million people were living with peripheral artery disease in 2010, 69·7% of them in LMIC, including 54·8 million in southeast Asia and 45·9 million in the western Pacific Region. During the preceding decade the number of individuals with peripheral artery disease increased by 28·7% in LMIC and 13·1% in HIC. INTERPRETATION: In the 21st century, peripheral artery disease has become a global problem. Governments, non-governmental organisations, and the private sector in LMIC need to address the social and economic consequences, and assess the best strategies for optimum treatment and prevention of this disease. FUNDING: Peripheral Arterial Disease Research Coalition (Europe).

Precision rehabilitation for aphasia by patient age, sex, aphasia severity, and time since stroke? A prespecified, systematic review-based, individual participant data, network, subgroup meta-analysis.

BACKGROUND: Stroke rehabilitation interventions are routinely personalized to address individuals' needs, goals, and challenges based on evidence from aggregated randomized controlled trials (RCT) data and meta-syntheses. Individual participant data (IPD) meta-analyses may better inform the development of precision rehabilitation approaches, quantifying treatment responses while adjusting for confounders and reducing ecological bias. AIM: We explored associations between speech and language therapy (SLT) interventions frequency (days/week), intensity (h/week), and dosage (total SLT-hours) and language outcomes for different age, sex, aphasia severity, and chronicity subgroups by undertaking prespecified subgroup network meta-analyses of the RELEASE database. METHODS: MEDLINE, EMBASE, and trial registrations were systematically searched (inception-Sept2015) for RCTs, including ⩾ 10 IPD on stroke-related aphasia. We extracted demographic, stroke, aphasia, SLT, and risk of bias data. Overall-language ability, auditory comprehension, and functional communication outcomes were standardized. A one-stage, random effects, network meta-analysis approach filtered IPD into a single optimal model, examining SLT regimen and language recovery from baseline to first post-intervention follow-up, adjusting for covariates identified a-priori. Data were dichotomized by age (⩽/> 65 years), aphasia severity (mild-moderate/ moderate-severe based on language outcomes' median value), chronicity (⩽/> 3 months), and sex subgroups. We reported estimates of means and 95% confidence intervals. Where relative variance was high (> 50%), results were reported for completeness. RESULTS: 959 IPD (25 RCTs) were analyzed. For working-age participants, greatest language gains from baseline occurred alongside moderate to high-intensity SLT (functional communication 3-to-4 h/week; overall-language and comprehension > 9 h/week); older participants' greatest gains occurred alongside low-intensity SLT (⩽ 2 h/week) except for auditory comprehension (> 9 h/week). For both age-groups, SLT-frequency and dosage associated with best language gains were similar. Participants ⩽ 3 months post-onset demonstrated greatest overall-language gains for SLT at low intensity/moderate dosage (⩽ 2 SLT-h/week; 20-to-50 h); for those > 3 months, post-stroke greatest gains were associated with moderate-intensity/high-dosage SLT (3-4 SLT-h/week; ⩾ 50 hours). For moderate-severe participants, 4 SLT-days/week conferred the greatest language gains across outcomes, with auditory comprehension gains only observed for ⩾ 4 SLT-days/week; mild-moderate participants' greatest functional communication gains were associated with similar frequency (⩾ 4 SLT-days/week) and greatest overall-language gains with higher frequency SLT (⩾ 6 days/weekly). Males' greatest gains were associated with SLT of moderate (functional communication; 3-to-4 h/weekly) or high intensity (overall-language and auditory comprehension; (> 9 h/weekly) compared to females for whom the greatest gains were associated with lower-intensity SLT (< 2 SLT-h/weekly). Consistencies across subgroups were also evident; greatest overall-language gains were associated with 20-to-50 SLT-h in total; auditory comprehension gains were generally observed when SLT > 9 h over ⩾ 4 days/week. CONCLUSIONS: We observed a treatment response in most subgroups' overall-language, auditory comprehension, and functional communication language gains. For some, the maximum treatment response varied in association with different SLT-frequency, intensity, and dosage. Where differences were observed, working-aged, chronic, mild-moderate, and male subgroups experienced their greatest language gains alongside high-frequency/intensity SLT. In contrast, older, moderate-severely impaired, and female subgroups within 3 months of aphasia onset made their greatest gains for lower-intensity SLT. The acceptability, clinical, and cost effectiveness of precision aphasia rehabilitation approaches based on age, sex, aphasia severity, and chronicity should be evaluated in future clinical RCTs.

Objective and Subjective Prevalence of Obstructive Sleep Apnoea/Hypopnoea Syndrome in UK Adults with Down Syndrome: A Strong Marker for Diurnal Behavioural Disturbances.

Prior to this study, the prevalence of obstructive sleep apnoea/hypopnoea syndrome (OSAHS) in adults with Down syndrome was unknown. We hypothesized that unrecognised OSAHS could have an additional deleterious impact on mood and behavioural disturbances in this group of people. AIMS: To assess the prevalence of OSAHS in adults with Down syndrome in the United Kingdom, subjectively and objectively, and ascertain its association with diurnal behavioural disturbances. METHOD: Cross-sectional questionnaire study with home sleep apnoea testing (HSAT) during 2011-2015 across the four nations of the United Kingdom. Participants were adults aged ≥16 years with Down syndrome. Main outcome measures were: self- or caregiver-completed questionnaire data, including the Pictorial Epworth Sleepiness Scale (pESS), selected domains of the Developmental Behavioural Checklist for Adults (DBC-A), anthropometric measures, and symptoms of OSAHS. Objective prevalence was undertaken in a sample of responders using HSAT. RESULTS: Responses were received from 1321/5270 participants (25%), with 1105 valid responses (21%). Eighty-one participants (7%) reported a prior diagnosis of OSA, of whom 38 were receiving therapy. Using validated algorithms, a diagnosis of OSAHS was probable in 366 participants (35%), who were younger, with higher BMI and higher mean total pESS (p < 0.0001). A total of 23% of participants had a pESS > 10. OSAHS was a strong marker for behavioural disturbances on the DBC-A depression, disruption and anti-social subscales (p < 0.001). Of 149 individuals who underwent HSAT, 42% were diagnosed with OSAHS. CONCLUSIONS: Untreated OSAHS in Down syndrome is common and associated with behavioural and mood disturbances. Improving awareness of OSAHS amongst adults with Down syndrome, their families and healthcare professionals is essential.

External validation of the RISC, RISC-Malawi, and PERCH clinical prediction rules to identify risk of death in children hospitalized with pneumonia.

BACKGROUND: Existing scores to identify children at risk of hospitalized pneumonia-related mortality lack broad external validation. Our objective was to externally validate three such risk scores. METHODS: We applied the Respiratory Index of Severity in Children (RISC) for HIV-negative children, the RISC-Malawi, and the Pneumonia Etiology Research for Child Health (PERCH) scores to hospitalized children in the Pneumonia REsearch Partnerships to Assess WHO REcommendations (PREPARE) data set. The PREPARE data set includes pooled data from 41 studies on pediatric pneumonia from across the world. We calculated test characteristics and the area under the curve (AUC) for each of these clinical prediction rules. RESULTS: The RISC score for HIV-negative children was applied to 3574 children 0-24 months and demonstrated poor discriminatory ability (AUC = 0.66, 95% confidence interval (CI) = 0.58-0.73) in the identification of children at risk of hospitalized pneumonia-related mortality. The RISC-Malawi score had fair discriminatory value (AUC = 0.75, 95% CI = 0.74-0.77) among 17 864 children 2-59 months. The PERCH score was applied to 732 children 1-59 months and also demonstrated poor discriminatory value (AUC = 0.55, 95% CI = 0.37-0.73). CONCLUSIONS: In a large external application of the RISC, RISC-Malawi, and PERCH scores, a substantial number of children were misclassified for their risk of hospitalized pneumonia-related mortality. Although pneumonia risk scores have performed well among the cohorts in which they were derived, their performance diminished when externally applied. A generalizable risk assessment tool with higher sensitivity and specificity to identify children at risk of hospitalized pneumonia-related mortality may be needed. Such a generalizable risk assessment tool would need context-specific validation prior to implementation in that setting.

Early Postoperative Death in Patients Undergoing Emergency High-Risk Surgery: Towards a Better Understanding of Patients for Whom Surgery May Not Be Beneficial.

The timing, causes, and quality of care for patients who die after emergency laparotomy have not been extensively reported. A large database of 13,953 patients undergoing emergency laparotomy, between July 2014 and March 2017, from 28 hospitals in England was studied. Anonymized data was extracted on day of death, patient demographics, operative details, compliance with standards of care, and 30-day and in-patient mortality. Thirty-day mortality was 8.9%, and overall inpatient mortality was 9.8%. Almost 40% of postoperative deaths occurred within three days of surgery, and 70% of these early deaths occurred on the day of surgery or the first postoperative day. Such early deaths could be considered nonbeneficial surgery. Patients who died within three days of surgery had a significantly higher preoperative lactate, American Society of Anesthesiologists Physical Status (ASA-PS) grade, and Physiological and Operative Severity Score for the enumeration of Mortality and morbidity (P-POSSUM). Compliance with perioperative standards of care based on the Emergency Laparotomy Collaborative care bundle was high overall and better for those patients who died within three days of surgery. Multidisciplinary team involvement from intensive care, care of the elderly physicians, and palliative care may help both the communication and the burden of responsibility in deciding on the risk-benefit of operative versus nonoperative approaches to care.

Mortality and morbidity in obstructive sleep apnoea-hypopnoea syndrome: results from a 30-year prospective cohort study.

BACKGROUND: Obstructive sleep apnoea-hypopnoea syndrome (OSAHS) carries substantial negative health consequences. This study examines factors affecting mortality and morbidity according to continuous positive airway pressure (CPAP) use and predictors affecting CPAP adherence in a longitudinal cohort of OSAHS patients. MATERIALS AND METHODS: This prospective, cohort study comprised 4502 patients who were diagnosed with OSAHS at a tertiary sleep disorders centre between 1982 and 2003. Of these, 1174 patients completed follow-up in 2012. Data collected included anthropometric, sleep and demographic characteristics, including comorbidities, ongoing medications and CPAP adherence. Patients were followed up for an average of 14.8±3.7 years. RESULTS: Imputation analysis showed that long-term CPAP users (>5 years) were 5.63 times more likely to be alive at study end than non-CPAP users (95% CI: 4.83-6.58, p<0.001) and 1.74-times more likely than short-term CPAP users (≤5 years) (95% CI: 1.49-2.02, p<0.001). Females had a significantly higher mortality rate during the follow-up period (26.8% versus 19.6%, p<0.001). Respiratory mortality was more common in patients with OSAHS, in particular those who did not use CPAP, compared to the general population (17.2% versus 12.2%, p=0.002 respectively), whereas deaths from cancer were less common compared to the general population (16.2% versus 25.6%, p<0.001). Compared to CPAP users, non-CPAP-users had a significantly increased incidence of type II diabetes mellitus (DMII) (27.9% versus 18.7%, p=0.003), ischaemic heart disease (IHD) (25.5% versus 12.7%, p<0.001) and myocardial infarction (MI) (14.7% versus 4.2%, p<0.001) at long-term follow-up. CONCLUSIONS: Long-term CPAP use in men and women with OSAHS reduces mortality and decreases the incidence of DMII and cardiovascular disease.