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Objective: To investigate the cadence of recurrence in patients with low grade intermediate-risk non-muscle invasive bladder cancer (LG IR-NMIBC) based on clinical determinants. We aim to describe patterns in rates of recurrence to better inform surveillance regimens for this chronic, burdensome, and costly disease., Methods: Using baseline and follow-up data from participants in the West Midlands' (United Kingdom, UK) Bladder Cancer Prognosis Programme (BCPP), we assessed overall recurrence rate and recurrence-free intervals throughout the follow-up period for IR-NMIBC participants. Recurrence-free intervals were calculated using the Kaplan-Meier method., Results: We identified 379 patients with G1/G2 pTa tumors classified as intermediate risk. Median age was 70 and 284/379 (75%) were male. The median follow-up time was 4.2 years (95% CI: 3.9-4.8). After 5 years of follow-up, 53% of patients had at least one recurrence. One-year recurrence-free survival (RFS) was 75% and 4-year RFS was 50%. The median time to or between 1st, 2nd, 3rd, 4th, and 5th sequential recurrences was 49, 19, 12, 14, and 10 months, respectively., Conclusion: Over half of patients with IR-NMIBC are destined to recur. Our data suggest that a subset of patients experience acceleration of recurrence over time and that this acceleration may serve as a potential kinetic biomarker for these individuals that could inform surveillance intervals and future treatment strategies., Competing Interests: Declaration of Competing Interest Dr. Alexander Sankin is a paid consultant to Ambu Inc; Nicholas D. James has contributed to advisory boards for Merck USA and Pierre Fabre; Richard Bryan is a paid consultant to Cystotech ApS (Denmark), an unpaid charity trustee for Action Bladder Cancer UK, and has research funded by grants from Cancer Research UK and Janssen. The remaining authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Physical activity (PA) improves dyspnoea, psychological wellbeing and quality of life (QoL) for people with COPD reducing their risk of exacerbation. However, engagement in PA is low especially amongst those with anxiety and depression, and PA programmes are limited in countries with limited resources such as Brazil. We explored perceptions of 21 people with COPD about the impact of their disease on taking part in community-based PA programmes in Sao Paulo, Brazil through semi-structured telephone interviews from October 2020 to April 2021. Discussions were audio-recorded, transcribed, and analysed using the Framework method. Five themes were identified: Knowledge about COPD and its management; Self-perception of life with COPD; Knowledge and experiences of depression and anxiety; Opinions on PA and repercussions of COVID-19. PA was considered to be important in bringing physical and mental health benefits but there were barriers in accessibility of formal PR programmes and therefore local community PA programmes were considered to be important. People with mental health conditions tended to view PA more negatively. COVID-19 had reduced PA opportunities, access to COPD treatment and social interaction, and was associated with more exacerbations and emotional suffering. In general, this study showed an urgent need to improve knowledge about COPD and its risk factors and management among both patients, the public and primary healthcare professionals. We provide important content for the formulation of public policies for the implementation of specific activity programmes for people with COPD in community spaces using local resources and intersectoral partnerships., (© 2024. The Author(s).)

Background: Postpartum depression (PPD) is an important public health problem worldwide. China is planning to launch PPD screening in community settings, but there are questions on the community prevalence of PPD and validated screening tools., Methods: We sought to recruit all eligible new mothers during postnatal home visits in two districts of Changsha, China, and after informed consent, screened them for PPD using three self-administered questionnaires-the Edinburgh Postpartum Depression Scale (EPDS), the Patient Health Questionnaire (PHQ-9), and Whooley Questions for Depression Screening. Video structured diagnostic interviews were performed online according to Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) by qualified specialists who were blinded to screening results. Optimal screening was determined based on the acceptability of scales and diagnostic accuracy metrics including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV)., Results: Out of 3004 eligible women, 2730 (90.9 %) completed the screening questionnaires. Among those screened, the video structured diagnostic interview was administered to 1862 (68.2 %) and 62 (3.3 %) were diagnosed with a current depressive condition. The optimal screening approach involved combining Whooley Questions (at least one "yes") with EPDS (cutoff >10) in series, with sensitivity of 0.76 (95 % CI 0.63 to 0.85), specificity of 0.93 (0.92 to 0.94), PPV of 0.28 (0.21 to 0.36) and NPV of 0.99 (0.98 to 1.00)., Limitations: Due to the regional sample and exclusion of mothers with telephone contact rather than home visits, our findings may not be fully generalizable to the entire population., Conclusions: The prevalence of PPD among women in this sample was substantially lower than those reported in previous studies in China, the majority of which used screen positivity in measuring prevalence. Combining Whooley Questions with EPDS in series is the most optimal screening approach in this population, though this would still result in a high number of false positives at current prevalence., Competing Interests: Declaration of competing interest The authors declares that there is no conflict of interest regarding the publication of this article., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Effective stakeholder engagement in health research is increasingly being recognised and promoted as an important pathway to closing the gap between knowledge production and its use in health systems. However, little is known about its process and impacts, particularly in low-and middle-income countries. This opinion piece draws on the stakeholder engagement experiences from a global health research programme on Chronic Obstructive Pulmonary Disease (COPD) led by clinician researchers in Brazil, China, Georgia and North Macedonia, and presents the process, outcomes and lessons learned., Main Body: Each country team was supported with an overarching engagement protocol and mentored to develop a tailored plan. Patient involvement in research was previously limited in all countries, requiring intensive efforts through personal communication, meetings, advisory groups and social media. Accredited training programmes were effective incentives for participation from healthcare providers; and aligning research findings with competing policy priorities enabled interest and dialogue with decision-makers. The COVID-19 pandemic severely limited possibilities for planned engagement, although remote methods were used where possible. Planned and persistent engagement contributed to shared knowledge and commitment to change, including raised patient and public awareness about COPD, improved skills and practice of healthcare providers, increased interest and support from clinical leaders, and dialogue for integrating COPD services into national policy and practice., Conclusion: Stakeholder engagement enabled relevant local actors to produce and utilise knowledge for small wins such as improving day-to-day practice and for long-term goals of equitable access to COPD care. For it to be successful and sustained, stakeholder engagement needs to be valued and integrated throughout the research and knowledge generation process, complete with dedicated resources, contextualised and flexible planning, and commitment., (© 2024. The Author(s).)

Importance: Selenium and vitamin E have been identified as promising agents for the chemoprevention of recurrence and progression of non-muscle-invasive bladder cancer., Objective: To determine whether selenium and/or vitamin E may prevent disease recurrence in patients with newly diagnosed NMIBC., Design, Setting, and Participants: This multicenter, prospective, double-blinded, placebo-controlled, 2 × 2 factorial randomized clinical trial included patients with newly diagnosed NMIBC recruited from 10 secondary or tertiary care hospitals in the UK. A total of 755 patients were screened for inclusion; 484 did not meet the inclusion criteria, and 1 declined to participate. A total of 270 patients were randomly assigned to 4 groups (selenium plus placebo, vitamin E plus placebo, selenium plus vitamin E, and placebo plus placebo) in a double-blind fashion between July 17, 2007, and October 10, 2011. Eligibility included initial diagnosis of NMIBC (stages Ta, T1, or Tis); randomization within 12 months of first transurethral resection was required., Interventions: Oral selenium (200 μg/d of high-selenium yeast) and matched vitamin E placebo, vitamin E (200 IU/d of d-alfa-tocopherol) and matched selenium placebo, selenium and vitamin E, or placebo and placebo., Main Outcome and Measures: Recurrence-free interval (RFI) on an intention-to-treat basis (analyses completed on November 28, 2022)., Results: The study randomized 270 patients (mean [SD] age, 68.9 [10.4] years; median [IQR] age, 69 [63-77] years; 202 male [75%]), with 65 receiving selenium and vitamin E placebo, 71 receiving vitamin E and selenium placebo, 69 receiving selenium and vitamin E, and 65 receiving both placebos. Median overall follow-up was 5.5 years (IQR, 5.1-6.1 years); 228 patients (84%) were followed up for more than 5 years. Median treatment duration was 1.5 years (IQR, 0.9-2.5 years). The study was halted because of slow accrual. For selenium (n = 134) vs no selenium (n = 136), there was no difference in RFI (hazard ratio, 0.92; 95% CI, 0.65-1.31; P = .65). For vitamin E (n = 140) vs no vitamin E (n = 130), there was a statistically significant detriment to RFI (hazard ratio, 1.46; 95% CI, 1.02-2.09; P = .04). No significant differences were observed for progression-free interval or overall survival time with either supplement. Results were unchanged after Cox proportional hazards regression modeling to adjust for known prognostic factors. In total, 1957 adverse events were reported; 85 were serious adverse events, and all were considered unrelated to trial treatment., Conclusions and Relevance: In this randomized clinical trial of selenium and vitamin E, selenium supplementation did not reduce the risk of recurrence in patients with NMIBC, but vitamin E supplementation was associated with an increased risk of recurrence. Neither selenium nor vitamin E influenced progression or overall survival. Vitamin E supplementation may be harmful to patients with NMIBC, and elucidation of the underlying biology is required., Trial Registration: isrctn.org Identifier: ISRCTN13889738.

Introduction: Central venous catheter (CVC) placement is commonly performed in children. We aim to develop simple formulas to predict CVC intravascular length to minimise radiation exposure associated with the procedure., Methods: 124 paediatric patients who received tunnelled neck CVCs and subsequent CT thorax at Hong Kong Children's Hospital from January 2020 to July 2022 were reviewed retrospectively. Formula development cohorts were subdivided by insertion sites-9 right external jugular vein (REJV), 41 right internal jugular vein (RIJV), 14 left external jugular vein (LEJV), 10 left internal jugular vein (LIJV). Using measurements from CT by two radiologists, formulas predicting the CVC intravascular length based on height and insertion sites were developed using a linear regression model. These formulas were tested with validation cohorts (10 randomly selected cases in REJV and RIJV groups respectively). Validation cohorts were not available for LEJV and LIJV groups due to small sample sizes., Result: The goodness-of-fit (R^2) of all formulas are above 0.8. In the validation cohorts, the REJV formula was predictive of intravascular CVC length within 1 cm in 70% of CVC with mean absolute difference of 0.63 cm (SD 0.48 cm), and the RIJV formula was predictive of intravascular CVC length within 1 cm in 80% of CVC with mean absolute difference of 0.67 cm (SD 0.53 cm)., Conclusion: Intravascular CVC length can be estimated using simple formulas based on height and insertion sites. Further prospective validation of the LEJV and LIJV formulas is needed., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Timely screening and referral can improve the outcomes of perinatal depression (PND). However, uptake rates of referral after PND screening are low in China and the reasons are unclear. The aim of this article is to explore the barriers and facilitators for referring women with positive results of PND screening in the Chinese primary maternal health care system., Methods: Qualitative data were collected from four primary health centers located in four different provinces of China. Each of the four investigators conducted 30 days of participant observations in the primary health centers from May to August 2020. Data were collected via participant observations and semi-structured in-depth interviews with new mothers who had positive results of PND screening, their family members, and primary health providers. Two investigators analyzed qualitative data independently. A thematic analysis was conducted, and data were framed using the social ecological model., Results: A total of 870 hours of observation and 46 interviews were carried out. Five themes were identified: individual (new mothers' knowledge of PND, perceived need to seek help), interpersonal (new mothers' attitudes towards providers, family support), institutional (providers' perception of PND, lack of training, time constraints), community (accessibility to mental health services, practical factors), and public policy (policy requirements, stigma)., Conclusions: The likelihood of new mothers accepting PND referral is related to factors in five areas. Intervention strategies can be developed around these themes and may include educating new mothers and their families about PND, training primary health providers to improve their awareness of condition and indication for referral, building mental health support in routine postpartum home visits, and providing support through mobile technology., (© 2023. The Author(s).)

Background: There is an unmet need for an accurate, validated, noninvasive test for diagnosing and monitoring bladder cancer (BC). Detection of BC-associated mutations in urinary DNA via targeted deep sequencing could meet this need., Objective: To test the ability of mutational analysis of urinary DNA to noninvasively detect BC within the context of haematuria investigations and non-muscle-invasive BC (NMIBC) surveillance., Design, Setting, and Participants: Capture-based ultra-deep sequencing was performed for 443 somatic mutations in 23 genes in 591 urine cell-pellet DNAs from haematuria clinic patients and 293 from NMIBC surveillance patients. Variant calling was optimised to minimise false positives using urine samples from 162 haematuria clinic patients without BC., Outcome Measurements and Statistical Analysis: The sensitivity and specificity for BC diagnosis were determined., Results and Limitations: Mutational analysis of urinary DNA detected 144 of the 165 haematuria patients diagnosed with incident BC from two independent cohorts, yielding overall sensitivity of 87.3% (95% confidence interval [CI] 81.2-92.0%) at specificity of 84.8% (95% CI 79.9-89.0%). The sensitivity was 97.4% for grade 3, 86.5% for grade 2, and 70.8% for grade 1 BC. Among NMIBC surveillance patients, 25 out of 29 recurrent BCs were detected, yielding sensitivity of 86.2% (95% CI 70.8-97.7%) at specificity of 62.5% (95% CI 56.1-68.0%); a positive urine mutation test in the absence of clinically detectable disease was associated with a 2.6-fold increase in the risk of future recurrence. The low number of recurrences in the NMIBC surveillance cohort and the lower sensitivity for detecting grade 1 pTa BC are limitations., Conclusions: Detection of mutations in a small panel of BC-associated genes could facilitate noninvasive BC testing and expedite haematuria investigations. Following further validation, the test could also play a role in NMIBC surveillance., Patient Summary: Identification of alterations in genes that are frequently mutated in bladder cancer appears to be a promising strategy for detecting disease from urine samples and reducing reliance on examination of the bladder via a telescopic camera inserted through the urethra., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Mutations at specific hotspots in non-coding regions of ADGRG6, PLEKHS1, WDR74, TBC1D12 and LEPROTL1 frequently occur in bladder cancer (BC). These mutations could function as biomarkers for the non-invasive detection of BC but this remains largely unexplored. Massively-parallel sequencing of non-coding hotspots was applied to 884 urine cell pellet DNAs: 591 from haematuria clinic patients (165 BCs, 426 non-BCs) and 293 from non-muscle invasive BC surveillance patients (29 with recurrence). Urine samples from 142 non-BC haematuria clinic patients were used to optimise variant calling. Non-coding mutations are readily detectable in the urine of BC patients and undetectable, or present at much lower frequencies, in the absence of BC. The mutations can be used to detect incident BC with 66% sensitivity (95% CI 58-75) at 92% specificity (95% CI 88-95) and recurrent disease with 55% sensitivity (95% CI 36-74) at 85% specificity (95% CI 80-89%) using a 2% variant allele frequency threshold. In the NMIBC surveillance setting, the detection of non-coding mutations in urine in the absence of clinically detectable disease was associated with an increased relative risk of future recurrence (RR = 4.62 (95% CI 3.75-5.48)). As urinary biomarkers, non-coding hotspot mutations behave similarly to driver mutations in BC-associated genes and could be included in biomarker panels for BC detection., (© 2023. The Author(s).)

In Brazil, prevalence of diagnosed COPD among adults aged 40 years and over is 16% although over 70% of cases remain undiagnosed. Hypertension is common and well-recorded in primary care, and frequently co-exists with COPD because of common causes such as tobacco smoking, therefore we conducted a cross-sectional screening test accuracy study in nine Basic Health Units in Brazil, among hypertensive patients aged ≥40 years to identify the optimum screening test/combinations to detect undiagnosed COPD. We compared six index tests (four screening questionnaires, microspirometer and peak flow) against the reference test defined as those below the lower limit of normal (LLN-GLI) on quality diagnostic spirometry, with confirmed COPD at clinical review. Of 1162 participants, 6.8% (n = 79) had clinically confirmed COPD. Peak flow had a higher specificity but lower sensitivity than microspirometry (sensitivity 44.3% [95% CI 33.1, 55.9], specificity 95.5% [95% CI 94.1, 96.6]). SBQ performed well compared to the other questionnaires (sensitivity 75.9% [95% CI 65.0, 84.9], specificity 59.2% [95% CI 56.2, 62.1]). A strategy requiring both SBQ and peak flow to be positive yielded sensitivity of 39.2% (95% CI 28.4, 50.9) and specificity of 97.0% (95% CI 95.7, 97.9). The use of simple screening tests was feasible within the Brazilian primary care setting. The combination of SBQ and peak flow appeared most efficient, when considering performance of the test, cost and ease of use (costing £1690 (5554 R$) with 26.7 cases detected per 1,000 patients). However, the choice of screening tests depends on the clinical setting and availability of resources.ISRCTN registration number: 11377960., (© 2022. The Author(s).)

Competing Interests: We declare no competing interests. We thank Zhen Zeng (Central South University, Changsha) for her assistance.

Objectives: To assess the feasibility of delivering a culturally tailored pulmonary rehabilitation (PR) programme and conducting a definitive randomised controlled trial (RCT)., Design: A two-arm, randomised feasibility trial with a mixed-methods process evaluation., Setting: Secondary care setting in Georgia, Europe., Participants: People with symptomatic spirometry-confirmed chronic obstructive pulmonary disease recruited from primary and secondary care., Interventions: Participants were randomised in a 1:1 ratio to a control group or intervention comprising 16 twice-weekly group PR sessions tailored to the Georgian setting., Primary and Secondary Outcome Measures: Feasibility of the intervention and RCT were assessed according to: study recruitment, consent and follow-up, intervention fidelity, adherence and acceptability, using questionnaires and measurements at baseline, programme end and 6 months, and through qualitative interviews., Results: The study recruited 60 participants (as planned): 54 (90%) were male, 10 (17%) had a forced expiratory volume in 1 second of ≤50% predicted. The mean MRC Dyspnoea Score was 3.3 (SD 0.5), and mean St George's Respiratory Questionnaire (SGRQ) 50.9 (SD 17.6). The rehabilitation specialists delivered the PR with fidelity. Thirteen (43.0%) participants attended at least 75% of the 16 planned sessions. Participants and rehabilitation specialists in the qualitative interviews reported that the programme was acceptable, but dropout rates were high in participants who lived outside Tbilisi and had to travel large distances. Outcome data were collected on 63.3% participants at 8 weeks and 88.0% participants at 6 months. Mean change in SGRQ total was -24.9 (95% CI -40.3 to -9.6) at programme end and -4.4 (95% CI -12.3 to 3.4) at 6 months follow-up for the intervention group and -0.5 (95% CI -8.1 to 7.0) and -8.1 (95% CI -16.5 to 0.3) for the usual care group at programme end and 6 months, respectively., Conclusions: It was feasible to deliver the tailored PR intervention. Approaches to improve uptake and adherence warrant further research., Trial Registration Number: ISRCTN16184185., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Mutations in STAG2 cause complete loss of STAG2 protein in approximately one-third of non-muscle-invasive bladder cancers (NMIBCs). STAG2 protein expression is easily determined via immunohistochemistry (IHC) and published data suggest that loss of STAG2 expression is a good prognostic indicator in NMIBC., Objective: To confirm the relationship between STAG2 protein expression and clinical outcomes and tumour characteristics in NMIBC., Design Setting and Participants: IHC was used to determine STAG2 expression in 748 incident urothelial bladder cancers (UBCs) and recurrence-free, progression-free, and disease-specific survival were compared for patients with and without STAG2 loss. Exome and RNA sequencing were used to explore links between STAG2 loss and tumour molecular characteristics., Results and Limitations: STAG2 loss was observed in 19% of UBC patients and was 1.6-fold more common among female patients. Loss was frequent among grade 1 pTa tumours (40%), decreasing with stage and grade to only 5% among grade 3 pT2+ tumours. Loss was associated with fewer copy-number changes and less aggressive expression subtypes. In UBC, STAG2 loss was a highly significant prognostic indicator of better disease-free survival but was not independent of stage and grade. STAG2 loss was not a statistically significant predictor of NMIBC recurrence. STAG2 loss was significantly associated with better progression-free survival in NMIBC and appeared to be more prognostic for males than for females., Conclusions: A simple IHC-based STAG2 test shows promise for identifying NMIBC patients at lower risk of progression to MIBC for whom more conservative treatments may be suitable., Patient Summary: A protein called STAG2 is frequently lost in early bladder cancers, most often in less aggressive tumours. STAG2 loss is easily measured and could be used as a biomarker to help guide treatment decisions., (© 2022 The Authors.)

Aims: The short-term effects of different organic manure nitrogen (N) input on soil ammonia-oxidizing archaea (AOA) and bacterial (AOB) activity and community structure at maturity stages of early rice and late rice were investigated in the present paper, in a double-cropping rice system in southern China., Methods and Results: A field experiment was done by applying five different organic and inorganic N input treatments: (i) 100% N of chemical fertilizer (M0), (ii) 30% N of organic manure and 70% N of chemical fertilizer (M30), (iii) 50% N of organic manure and 50% N of chemical fertilizer (M50), (iv) 100% N of organic manure (M100) and (v) without N fertilizer input as control (CK). Microbial community changes were assessed using fatty acid methyl esters, and ammonia oxidizer (AO) changes were followed using quantitative PCR. The results showed that AOA were higher than that of AOB based upon amoA gene copy at maturity stages of early rice and late rice. Also, the abundance of AOB and AOA with M30, M50 and M100 treatments was significantly higher than that of CK treatment. Manure N input treatments had significant effect on AOB and AOA abundance, and a higher correlation between AOB and manure N input was observed. AOB correlated moderately with soil organic carbon content, and AOA correlated moderately with water-filled pore space., Conclusions: This study found that abundance of AOB and AOA was increased under the given organic N conditions, and the soil AOB and AOA community and diversity were changed by different short-term organic manure N input treatments., Significance and Impact of the Study: Soil microbial community and specific N-utilizing microbial groups were affected by organic manure N input practices., (© 2020 The Society for Applied Microbiology.)

The use of immune checkpoint blockade, in particular PD-1 and PD-L1 inhibitors, is now commonplace in many clinical settings including the treatment of muscle-invasive bladder cancer (MIBC). Notwithstanding, little information exists regarding the expression of the alternative PD-1 ligand, PD-L2 in urothelial bladder cancer (UBC). We therefore set out to characterise the expression of PD-L2 in comparison to PD-L1. Firstly, we assessed PD-L2 expression by immunohistochemistry and found widespread expression of PD-L2 in UBC, albeit with reduced expression in MIBC. We further investigated these findings using RNA-seq data from a cohort of 575 patients demonstrating that PDCD1LG2 (PD-L2) is widely expressed in UBC and correlated with CD274 (PD-L1). However, in contrast to our immunohistochemistry findings, expression was significantly increased in advanced disease. We have also provided detailed evidence of constitutive PD-L2 expression in normal urothelium and propose a mechanism by which PD-L2 is cleaved from the cell surface in MIBC. These data provide a comprehensive assessment of PD-L2 in UBC, showing PD-L2 is abundant in UBC and, importantly, constitutively present in normal urothelium. These data have implications for future development of immune checkpoint blockade, and also the understanding of the function of the immune system in the normal urinary bladder., Competing Interests: RB has contributed to advisory boards for Olympus Medical Systems and Janssen, and undertakes research funded by UroGen Pharma, QED Therapeutics and Janssen. NJ has contributed to advisory boards for Merck USA and Pierre Fabre. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dowell, Munford, Goel, Gordon, James, Cheng, Zeegers, Ward and Bryan.)

Purpose: Despite advances in personalizing the efficacy of cancer therapy, our ability to identify patients at risk of severe treatment side effects and provide individualized supportive care is limited. This is particularly the case for mucositis (oral and gastrointestinal), with no comprehensive risk evaluation strategies to identify high-risk patients. We, the Multinational Association for Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO) Mucositis Study Group, therefore aimed to systematically review current evidence on that factors that influence mucositis risk to provide a foundation upon which future risk prediction studies can be based., Methods: We identified 11,018 papers from PubMed and Web of Science, with 197 records extracted for full review and 113 meeting final eligibility criteria. Data were then synthesized into tables to highlight the level of evidence for each risk predictor., Results: The strongest level of evidence supported dosimetric parameters as key predictors of mucositis risk. Genetic variants in drug-metabolizing pathways, immune signaling, and cell injury/repair mechanisms were also identified to impact mucositis risk. Factors relating to the individual were variably linked to mucositis outcomes, although female sex and smoking status showed some association with mucositis risk., Conclusion: Mucositis risk reflects the complex interplay between the host, tumor microenvironment, and treatment specifications, yet the large majority of studies rely on hypothesis-driven, single-candidate approaches. For significant advances in the provision of personalized supportive care, coordinated research efforts with robust multiplexed approaches are strongly advised.

Objective: To develop and validate a prediction model for airflow obstruction (AO) in older Chinese., Design: Multivariable logistic regression analysis in large population cohort of Chinese aged ≥50 years., Participants: Model development: 8762 Chinese aged ≥50 years were selected from the early phase recruits to the Guangzhou Biobank Cohort Study (GBCS) (recruited from September 2003 to May 2006). Internal validation: 100 bootstrap samples drawn with replacement from the development sample. External validation: 8395 Chinese aged ≥50 years from later phase GBCS (recruited from September 2006 to January 2008)., Outcomes: AO was defined by a forced expiratory volume in 1 s/forced vital capacity ratio < lower limits of normal., Results: 839 (9.6%) and 764 (9.1%) individuals had AO in the development and temporal validation samples respectively. The predictors in the prediction model included sex, age, body mass index groups, smoking status, presence of respiratory symptoms, and history of asthma. Model development and validation was stratified by sex. Model performance including calibration (calibration-in-the-large -0.017 vs. -0.157; and calibration slope 0.88 vs. 1.02), discrimination (C-statistic 0.72 vs. 0.63 with 95% confidence interval 0.69-0.75 vs. 0.62-0.73) and clinical usefulness (decision curve analysis) in the external temporal validation sample were more satisfactory in men than that in women. Prediction models with risk thresholds (13% in men and 7% in women) and easy-to-use nomograms were developed to assess the probability of AO., Conclusion: The diagnostic models based on readily available epidemiologic and clinical information with satisfactory performance can assist physicians to identify older individuals at high risk of AO and may improve the efficiency of spirometry for active case finding. Further validation beyond the Chinese population is warranted., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aims: Perinatal depression threatens the health of maternal women and their offspring. Although screening programs for perinatal depression exist, non-uptake of referral to further mental health care after screening reduces the utility of these programs. Uptake rates among women with positive screening varied widely across studies and little is known about how to improve the uptake rate. This study aimed to systematically review the available evidence on uptake rates, estimate the pooled rate, identify interventions to improve uptake of referral and explore the effectiveness of those interventions., Methods: This systematic review has been registered in PROSPERO (registration number: CRD42019138095). We searched Pubmed, Web of Science, Cochrane Library, Ovid, Embase, CNKI, Wanfang Database and VIP Databases from database inception to January 13, 2019 and scanned reference lists of relevant researches for studies published in English or Chinese. Studies providing information on uptake rate and/or effectiveness of interventions on uptake of referral were eligible for inclusion. Studies were excluded if they did not report the details of the referral process or did not provide exact uptake rate. Data provided by observational studies and quasi-experimental studies were used to estimate the pooled uptake rate through meta-analysis. We also performed meta-regression and subgroup analyses to explore the potential source of heterogeneity. To evaluate the effectiveness of interventions, we conducted descriptive analyses instead of meta-analyses since there was only one randomised controlled trial (RCT)., Results: Of 2302 records identified, 41 studies were eligible for inclusion, including 39 observational studies (n = 9337), one quasi-experimental study (n = 43) and one RCT (n = 555). All but two studies were conducted in high-income countries. The uptake rates reported by included studies varied widely and the pooled uptake rate of referral was 43% (95% confidence intervals [CI] 35-50%) by a random-effect model. Meta-regression and subgroup analyses both showed that referral to on-site assessment or treatment (60%, 95% CI 51-69%) had a significantly higher uptake rate than referral to mental health service (32%, 95% CI 23-41%) (odds ratio 1.31, 95% CI 1.13-1.52). The included RCT showed that the referral intervention significantly improved the uptake rate (p ＜ 0.01)., Conclusions: Almost three-fifths of women with positive screening results do not take up the referral offers after perinatal depression screening. Referral to on-site assessment and treatment may improve uptake of referral, but the quality of evidence on interventions to increase uptake was weak. More robust studies are needed, especially in low-and middle-income countries.

Circularized transcript isoforms due to back-splicing are increasingly being reported in different tissues types and pathological states including cancer. Since these circular RNAs (circRNAs) are more stable than linear messenger RNA their identification and profiling in tumor tissue could aid in stratifying patients and may serve as biomarkers. In this study, we have investigated the relationship between circRNA expression and tumor grade in a cohort of 58, mostly non-muscle-invasive bladder cancer patients. From 4571 circRNAs detected, we identified 157 that were significantly differentially expressed between tumor grades relative to the linear transcript. We demonstrated that such grade-related differences can be identified in an independent cohort, and that a large fraction of circRNAs can be, in principle, detected in urine. The differentially expressed circRNAs cluster into subgroups according to their co-expression, subgroups which are enriched for DNA repair, cell cycle and intracellular signaling genes. Since one proposed function of circRNAs is to interfere with gene-regulation by acting as microRNA "sponges," candidates which were differentially expressed between tumor grades were investigated for potential miRNA target sites. By investigating the circRNAs from bladder cancer related pathways we demonstrated that the expression of these pathways, the circRNAs, and their parental genes are often decoupled and do not correlate, yet that some circRNAs do not follow this tendency. The present study provides the next step for the comprehensive evaluation of this novel class of RNAs in the context of non-muscle-invasive bladder cancer. Intriguingly, despite their possible function as microRNA sponges, they potentially affect host mRNA levels at the transcriptional stage, as compared to post-transcriptional control by miRNAs. Our analysis indicates differences of their activity between bladder cancer tumor stages, and their relative expression levels may provide an additional layer of information for patient stratification., (Copyright © 2020 Goel, Ward, Gordon, Abbotts, Zeegers, Cheng, James, Bryan and Arnold.)

Objective: Between 10 and 20% of bladder cancer patients who are diagnosed with nonmuscle-invasive bladder cancer will progress to muscle-invasive disease. Risk of progression depends on several factors at diagnosis including age, tumour stage, grade, size and number, and the presence or absence of carcinoma in situ. Fluid intake may be related to these factors., Methods: Data of 1123 participants from the West Midlands Bladder Cancer Prognosis Programme were used. Data collection was via a semistructured questionnaire, and case report forms were used to collect clinicopathological data. Fluid intake was measured for six main categories: alcoholic fluids, hot fluids, fruit fluids, milk, fizzy drinks, and water, and converted into quintile variables. Multilevel mixed-effects linear regression was performed for every beverage category per clinicopathological variable and corrected for age, gender, and smoking status., Results: Age at diagnosis was distributed differently amongst those in different total fluid intake quintiles (predicted means 71.5, 70.9, 71.5, 69.9, and 67.4, respectively) and showed a significant inverse linear trend in alcohol (P < 0.01), hot fluids (P < 0.01), and total fluids intake (P < 0.01), in nonmuscle-invasive bladder cancer patients., Conclusion: Our results suggest an inverse association for alcohol intake and total fluid intake with age at diagnosis. These results should be confirmed by future studies, alongside a possible (biological) mechanism that could influence tumour growth, and the effect of micturition frequency.

Background: Due to the high risk of recurrence of non-muscle invasive bladder cancer, all patients undergo regular cystoscopic surveillance for early detection. As cystoscopy is invasive, costly and increases the burden of the disease considerably, there is significant ongoing research and development into non-invasive urinary biomarker substitutes. This study aims to assess the level of sensitivity required before patients accept a new urinary biomarker., Methods: We studied the preferences for a hypothetical diagnostic urinary biomarker and compared this to usual care (cystoscopy) at different levels of sensitivity among 437 patients with bladder cancer (354 men and 83 women) from the UK Bladder Cancer Prognosis Programme. A standard gamble approach was used to estimate the minimally acceptable sensitivity (MAS) of the new biomarker. Additionally, non-parametric statistical analyses were performed to investigate the association between surveillance preference and various patient characteristics., Results: Almost half of patients (183, 43%) would not replace cystoscopy with a urinary biomarker unless it was 100% sensitive. The median MAS was 99.9999%, and nearly 85% of patients demanded a sensitivity of at least 99% before preferring a urinary biomarker test over cystoscopy. These results were consistent across all patient characteristics and demographic categories., Conclusions: Our results indicate that patients demand urinary biomarkers as sensitive as cystoscopy before they would be willing to forego cystoscopy for bladder cancer surveillance.

Objectives: To quantify the health-related quality of life (HRQoL) of patients with bladder cancer around the time of diagnosis and to test the hypotheses of a two-factor model for the HRQoL questionnaire QLQ-C30., Methods: From participants in the Bladder Cancer Prognoses Programme, a multicentre cohort study, sociodemographic data were collected using semi-structured face-to-face interviews. Answers to the QLQ-C30 were transformed into a scale from 0 to 100. HRQoL data were analysed in multivariate analyses. The hypothesized two-factor (Physical and Mental Health) domain structure of the QLQ-C30 was also tested with confirmatory factor analyses (CFA)., Results: A total of 1160 participants (78%) completed the questionnaire after initial visual diagnosis and before pathological confirmation. Despite non-muscle-invasive bladder cancer (NMIBC) being associated with a higher HRQoL than carcinoma invading bladder muscle, only the domain Role Functioning was clinically significantly better in patients with NMIBC. Age, gender, bladder cancer stage and comorbidity all had a significant influence on QLQ-C30 scores. The CFA showed an overall good fit of the hypothesized two-factor model., Conclusion: This study identified a baseline reference value for HRQoL for patients with bladder cancer, which allows better evaluation of any changes in HRQoL as disease progresses or after treatment. In addition, a two-factor (Physical and Mental Health) model was developed for the QLQ-C30., (© 2019 The Authors BJU International Published by John Wiley & Sons Ltd on behalf of BJU International.)

Objectives: To develop a focused panel of somatic mutations (SMs) present in the majority of urothelial bladder cancers (UBCs), to investigate the diagnostic and prognostic utility of this panel, and to compare the identification of SMs in urinary cell-pellet (cp)DNA and cell-free (cf)DNA as part of the development of a non-invasive clinical assay., Patients and Methods: A panel of SMs was validated by targeted deep-sequencing of tumour DNA from 956 patients with UBC. In addition, amplicon and capture-based targeted sequencing measured mutant allele frequencies (MAFs) of SMs in 314 urine cpDNAs and 153 urine cfDNAs. The association of SMs with grade, stage, and clinical outcomes was investigated by univariate and multivariate Cox models. Concordance between SMs detected in tumour tissue and cpDNA and cfDNA was assessed., Results: The panel comprised SMs in 23 genes: TERT (promoter), FGFR3, PIK3CA, TP53, ERCC2, RHOB, ERBB2, HRAS, RXRA, ELF3, CDKN1A, KRAS, KDM6A, AKT1, FBXW7, ERBB3, SF3B1, CTNNB1, BRAF, C3orf70, CREBBP, CDKN2A, and NRAS; 93.5-98.3% of UBCs of all grades and stages harboured ≥1 SM (mean: 2.5 SMs/tumour). RAS mutations were associated with better overall survival (P = 0.04). Mutations in RXRA, RHOB and TERT (promoter) were associated with shorter time to recurrence (P < 0.05). MAFs in urinary cfDNA and cpDNA were highly correlated; using a capture-based approach, >94% of tumour SMs were detected in both cpDNA and cfDNA., Conclusions: SMs are reliably detected in urinary cpDNA and cfDNA. The technical capability to identify very low MAFs is essential to reliably detect UBC, regardless of the use of cpDNA or cfDNA. This 23-gene panel shows promise for the non-invasive diagnosis and risk stratification of UBC., (© 2019 The Authors BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Background: DNA double strand breaks are the cytotoxic lesions produced by ionising radiation. Critical for the repair of these lesions is the DNA damage response protein MRE11 which, in a complex with RAD50 and NBS1, mediates DNA damage signalling and double-strand break repair. We previously found the presence of an MRE11 germline single nucleotide polymorphism (SNP), rs1805363 ( G  > A), to be associated with poor outcome following radiotherapy (RT) and increased expression of MRE11 isoform 2 in a limited panel of bladder cancer cell lines and tumours., Objectives: To look for further evidence in support of the SNP/isoform association in a larger panel of germline and tumour samples donated by patients diagnosed with invasive bladder cancer, and to test the hypothesis that bladder cancer cells expressing MRE11 isoform 2 would be more radio resistant than cells expressing MRE11 isoform 1., Methods: Germline DNA from 189 patients with invasive bladder cancer (141 T2, 48 T1) was genotyped for the rs1805363 G  > A SNP. Loss of heterozygosity was determined by genotyping tumour DNA in 17GA germline patients. The Cancer Genome Atlas was mined to correlate presence of the GA germline genotype with MRE11 isoform expression. We used colony formation assays and γ H2AX foci kinetics after ionising radiation in RT112 MRE11 knockdown cells expressing ectopic MRE11 isoform 1 or 2., Results: Of the 189 germline DNA samples, 22 contained both the A minor allele and G major allele with the remaining wild type containing only the G major allele. LOH was identified in seven of 17 available tumour samples. Tumour MRE11 isoform 2 expression was found to be significantly higher ( p  = 0.007) in patients's samples containing the A minor allele compared to those with only the G major allele ( n  = 23). In the TCGA database we found 16% (66 out of 406) of bladder tumours heterozygous for the SNP and only two homozygous, and a significant relative increase of isoform 2 usage ( p  = 0.017). We identified no significant difference in radio sensitivity between bladder cancer cells expressing either MRE11 isoform., Conclusions: In this study the MRE11 isoform 2 was not found to be associated with increased cellular sensitivity to radiation. We conclude that the previously reported association between the germline rs1805363 SNP and poor survival in MIBC patients following RT is unlikely to be related to the DNA damage response function of MRE11 isoform 2., Competing Interests: The authors have no conflict of interest to report., (© 2019 – IOS Press and the authors. All rights reserved.)

Introduction: 'One-off' systematic case-finding for COPD using a respiratory screening questionnaire is more effective and cost-effective than routine care at identifying new cases. However, it is not known whether early diagnosis and treatment is beneficial in the longer term. We estimated the long-term cost-effectiveness of a regular case-finding programme in primary care., Methods: A Markov decision analytic model was developed to compare the cost-effectiveness of a 3-yearly systematic case-finding programme targeted to ever smokers aged ≥50 years with the current routine diagnostic process in UK primary care. Patient-level data on case-finding pathways was obtained from a large randomised controlled trial. Information on the natural history of COPD and treatment effects was obtained from a linked COPD cohort, UK primary care database and published literature. The discounted lifetime cost per quality-adjusted life-year (QALY) gained was calculated from a health service perspective., Results: The incremental cost-effectiveness ratio of systematic case-finding versus current care was £16 596 per additional QALY gained, with a 78% probability of cost-effectiveness at a £20 000 per QALY willingness-to-pay threshold. The base case result was robust to multiple one-way sensitivity analyses. The main drivers were response rate to the initial screening questionnaire and attendance rate for the confirmatory spirometry test., Discussion: Regular systematic case-finding for COPD using a screening questionnaire in primary care is likely to be cost-effective in the long-term despite uncertainties in treatment effectiveness. Further knowledge of the natural history of case-found patients and the effectiveness of their management will improve confidence to implement such an approach., Competing Interests: Competing interests: KKC reports grants from Pfizer China, outside of the submitted work. RS reports personal fees from Boehringer Ingelheim, personal fees from GSK, personal fees from Chiesi, personal fees from Takeda, personal fees from Novartis, personal fees from Polyphor, grants from CSL Behring, grants from Talecris, and personal fees from Dyax, outside of the submitted work. AMT reports grants from Linde REAL fund, grants from Alpha 1 Foundation, non-financial support from GSK, non-financial support from Boehringer Ingelheim, personal fees and non-financial support from Chiesi and personal fees and non-financial support from AZ, outside of the submitted work. SJ, PA, REJ, KKC, MM KJ, RR, DF, SS, AD, BGC, RS, JGA and SG report grants from NIHR, during the conduct of the study. Other authors declare no competing interests., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Background: Low and high birthweight is known to increase the risk of acute and longer-term adverse outcomes, such as stillbirth, infant mortality, obesity, type 2 diabetes and cardiovascular diseases. Gestational dyslipidaemia is associated with a numbers of adverse birth outcomes, but evidence regarding birthweight is still inconsistent to reliably inform clinical practice and treatment recommendations., Objective: The aim of this study was to explore the relationship between maternal gestational dyslipidaemia and neonatal health outcomes, namely, birthweight, metabolic factors and inflammatory parameters., Methods: We searched systematically Embase, MEDLINE, PubMed, CINAHL Plus and Cochrane Library up to 1 August 2016 (with an updated search in MEDLINE at the end of July 2017) for longitudinal studies that assessed the association of maternal lipid levels during pregnancy with neonatal birthweight, or metabolic and inflammatory parameters up to 3 years old., Results: Data from 46 publications including 31,402 pregnancies suggest that maternal high triglycerides and low high-density-lipoprotein cholesterol levels throughout pregnancy are associated with increased birthweight, higher risk of large for gestational age and macrosomia and lower risk of small-for-gestational age. The findings were consistent across the studied populations, but stronger associations were observed in women who were overweight or obese prior to pregnancy., Conclusions: This meta-analysis suggested that the potential under-recognized adverse effects of intrauterine exposure to maternal dyslipidaemia may warrant further investigation into the relationship between maternal dyslipidaemia and birthweight in large prospective cohorts or in randomized trials., (© 2018 World Obesity Federation.)

Objectives: To investigate the role of fluid intake from beverages before and after a diagnosis of bladder cancer in relation to the risk of developing bladder cancer recurrence., Study Design: Prospective cohort study., Methods: 716 patients with non-muscle invasive bladder cancer (NMIBC), who received transurethral resection of a primary bladder tumour (TURBT) and completed self-administrated questionnaires on usual fluid intake from beverages at time of diagnosis (over the year before diagnosis) and during follow-up (over the year after diagnosis), were included. Multivariable Cox regression was used to calculate hazard ratios and 95% confidence intervals of developing recurrent bladder cancer in relation to the intake of total fluid, total alcohol, and individual beverages., Results: During 2,025 person-years of follow-up, 238 (33%) of the included 716 NMIBC patients developed one or more recurrences of bladder cancer. Total fluid intake before diagnosis was not associated with a first recurrence of bladder cancer when comparing the highest and lowest intake group (HR = 0.98, 95% C.I. 0.70-1.38, p = 0.91). Comparable results were obtained for total fluid intake pre-diagnosis and the risk of developing multiple recurrences of bladder cancer (HR = 1.01, 95% C.I. 0.87-1.19, p = 0.85). A total of 379 of the 716 patients reported on usual fluid intake within 1 year of diagnosis. No significant associations between total fluid intake 1 year after diagnosis and a first recurrence of bladder cancer were found when comparing the highest and lowest intake group (HR = 0.91; 95% C.I. 0.60-1.37, p = 0.65) or with multiple recurrences of bladder cancer (HR = 1.06; 95% C.I. 0.89-1.26, p = 0.54). In addition, total alcohol intake and individual beverages were not associated with bladder cancer recurrence., Conclusions: The results indicate that an individual's fluid intake from beverages is unlikely to have an important role in bladder cancer recurrence.

Given the contradictory nature of the literature regarding the role of human papillomaviruses and polyomaviruses in the pathogenesis of urothelial bladder cancer (UBC), we sought to investigate the frequency of their involvement in a large cohort of primary UBCs. DNA was extracted from 689 fresh-frozen UBC tissues and screened for the presence of high-risk human papillomavirus (HPV) types 16 and 18 and BKV/JCV genomic DNA by qPCR. In positive cases, viral identity was confirmed by Sanger sequencing and viral gene expression was analysed by RT-PCR or immunohistochemistry. All 689 UBCs were negative for HPV18. One UBC from a female patient with areas of squamous differentiation was positive for HPV16. The qPCR data indicated variable levels of polyomavirus in 49 UBCs. In the UBCs with low C t s we were able to confirm that 23 were BKV and 6 were JCV by Sanger sequencing. Polyomavirus large T antigen expression was low but detectable in 70% of the sequencing-confirmed polyomavirus positive samples. Thus, in United Kingdom patients, the presence of HPV DNA sequences is extremely rare in UBC (<1% of cases). Polyomavirus DNA (predominantly BKV) is more common in UBC, but still only detectable in 7% of cases and in many of these cases at low copy number. We have performed the largest virus screening to date in UBC, finding that HPV16, HPV18 and HPyV are unlikely to be common causative agents in UBC.

Background: Smoking is a major risk factor for bladder cancer, but the relationship between smoking cessation after initial treatment and bladder cancer recurrence has been investigated less frequently and not prospectively yet., Methods: 722 non-muscle-invasive bladder cancer (NMIBC) patients (pTa, pT1, and CIS) from the prospective Bladder Cancer Prognosis Programme (BCPP) cohort, selected in the UK between 2005 and 2011, provided complete data on smoking behavior before and up to 5 years after diagnosis. The impact of smoking behavior on NMIBC recurrence was explored by multivariable Cox regression models investigating time-to-first NMIBC recurrence., Results: Over a median follow-up period of 4.21 years, 403 pathologically confirmed NMIBC recurrences occurred in 210 patients. Only 25 current smokers at diagnosis quit smoking (14%) during follow-up and smoking cessation after diagnosis did not decrease risk of recurrence compared to continuing smokers (p = 0.352)., Conclusions: Although quitting smoking after diagnosis might reduce the risk of recurrence based on retrospective evidence, this is not confirmed in this prospective study because the number of NMIBC patients quitting smoking before their first recurrence was too low. Nevertheless, this indicates an important role for urologists and other health care professionals in promoting smoking cessation in NMIBC.

Introduction: There is some evidence that greater consumption of fruit and vegetables decreases the risk of bladder cancer. The role of fruit and vegetables in bladder cancer recurrence is still unknown., Objective: The role of total fruit and vegetable intake in relation to the risk of developing bladder cancer recurrence in a prospective cohort study., Methods: 728 patients with non-muscle invasive bladder cancer (NMIBC), who completed self-administrated questionnaires on fruit and vegetable intake at time of diagnosis (over the year before diagnosis) and 1 year after diagnosis, were included. Hazard ratios and 95% confidence intervals were calculated by multivariable Cox regression for developing recurrent bladder cancer in relation to fruit and vegetable intake., Results: During 2,051 person-years of follow-up [mean (SD) follow-up 3.7 (1.5) years], 241 (33.1%) of the included 728 NMIBC patients developed a recurrence of bladder cancer. The sum of total fruit and vegetables before diagnosis was not related to a first bladder cancer recurrence (HR 1.07; 95% CI 0.78-1.47, p = 0.66). No association was found between greater consumption of fruit and vegetables over the year before diagnosis and the risk of developing multiple recurrences of bladder cancer (HR 1.02; 95% CI 0.90-1.15, p = 0.78). Among the remaining 389 NMIBC patients who reported on fruit and vegetable intake 1 year after diagnosis, no association was found between greater consumption of fruit and vegetables and a first recurrence of bladder cancer (HR 0.65; 95% CI 0.42-1.01, p = 0.06) nor with multiple recurrences of bladder cancer (HR 1.00, 95% CI 0.85-1.18, p = 1.00). Similar results were obtained when investigating the association between total intakes of fruit and vegetables separately and bladder cancer recurrence., Conclusion: Results from this study did not indicate a protective role for total fruit and vegetables in the development of a recurrence of NMIBC.

Objectives: To investigate whether elevated urinary HAI-1, EpCAM and EGFR are independent prognostic biomarkers within non-muscle-invasive bladder cancer (NMIBC) patients, and have utility for risk stratification to facilitate treatment decisions., Results: After accounting for EAU risk group in NMIBC patients, the risk of BC-specific death was 2.14 times higher (95% CI: 1.08 to 4.24) if HAI-1 was elevated and 2.04 times higher (95% CI: 1.02 to 4.07) if EpCAM was elevated. The majority of events occurred in the high-risk NMIBC group and this is where the biggest difference is seen in the survival curves when plotted for EAU risk groups separately. In MIBC patients, being elevated for any of the three biomarkers was significantly associated with BC-specific mortality after accounting for other risk factors, HR = 4.30 (95% CI: 1.85 to 10.03)., Patients and Methods: Urinary levels of HAI-1, EpCAM and EGFR were measured by ELISA in 683 and 175 patients with newly-diagnosed NMIBC and MIBC, respectively, recruited to the Bladder Cancer Prognosis Programme. Associations between biomarkers and progression, BC-specific mortality and all-cause mortality were evaluated using univariable and multivariable Cox regression models, adjusted for European Association of Urology (EAU) NMIBC risk groups. The upper 25% of values for each biomarker within NMIBC patients were considered as elevated. Exploratory analyses in urine from MIBC patients were also undertaken., Conclusion: Urinary HAI-1 and EpCAM are prognostic biomarkers for NMIBC patients. These biomarkers have potential to guide treatment decisions for high-risk NMIBC patients. Further analyses are required to define the roles of HAI-1, EpCAM and EGFR in MIBC patients., Competing Interests: CONFLICTS OF INTEREST RT Bryan has contributed to advisory boards for Olympus Medical Systems with regard to narrow band imaging cystoscopy. ND James has contributed to advisory boards for Merck USA and Pierre Fabre.

Background: TERT promotor mutations are present in >75% of bladder tumours; these mutations are also detectable in urine. Previous studies have used urinary pellet DNA, and semi-quantitative methods unsuitable for detecting very low mutant allele frequencies., Objective: In this proof-of-principle study we use ddPCR to count the DNA molecules with wt and mutant TERT sequences in urinary cfDNA from patients whose bladder cancers harbour TERT mutations., Methods: Urinary cfDNA prepared from the urine from 104 bladder cancer patients was analysed. We determined the mutant allele frequency across stages and grades of disease, analysed concordance between cfDNA and tumour DNA, compared cfDNA with pellet DNA, and analysed the quantity and size distribution of cfDNA., Results: In 71 of 77 patients with a 228 G>A/T mutant tumour, the mutation was also detected in urinary cfDNA by ddPCR; all 6 "false negatives" were low grade pTa tumours. Overall concordance between tissue and cfDNA mutation status was 92%, and 100% was achieved for high grade disease. Median mutant allele frequencies in urinary cfDNA were 3.4, 13.4 and 32.1% in grade 1, 2 and 3 disease. The 228 G>A/T mutation was not detected in urinary cfDNA in 26 out of 27 mutation-negative patients (96% specificity)., Conclusions: Concordance between tumour DNA and urinary cfDNA is high, and TERT 228 G>A/T ddPCR may prove useful for monitoring patients that harbour this mutation. Mutant allele frequencies in cfDNA are often high, but assays capable of detecting very low mutant allele frequencies will be required to achieve high sensitivity in low grade disease.

Background: High-risk non-muscle invasive bladder cancer (HR-NMIBC) is a clinically unpredictable disease. Despite clinical risk estimation tools, many patients are undertreated with intra-vesical therapies alone, whereas others may be over-treated with early radical surgery. Molecular biomarkers, particularly DNA methylation, have been reported as predictive of tumour/patient outcomes in numerous solid organ and haematologic malignancies; however, there are few reports in HR-NMIBC and none using genome-wide array assessment. We therefore sought to identify novel DNA methylation markers of HR-NMIBC clinical outcomes that might predict tumour behaviour at initial diagnosis and help guide patient management., Patients and Methods: A total of 21 primary initial diagnosis HR-NMIBC tumours were analysed by Illumina HumanMethylation450 BeadChip arrays and subsequently bisulphite Pyrosequencing. In all, 7 had not recurred at 1 year after resection and 14 had recurred and/or progressed despite intra-vesical BCG. A further independent cohort of 32 HR-NMIBC tumours (17 no recurrence and 15 recurrence and/or progression despite BCG) were also assessed by bisulphite Pyrosequencing., Results: Array analyses identified 206 CpG loci that segregated non-recurrent HR-NMIBC tumours from clinically more aggressive recurrence/progression tumours. Hypermethylation of CpG cg11850659 and hypomethylation of CpG cg01149192 in combination predicted HR-NMIBC recurrence and/or progression within 1 year of diagnosis with 83% sensitivity, 79% specificity, and 83% positive and 79% negative predictive values., Conclusions: This is the first genome-wide DNA methylation analysis of a unique HR-NMIBC tumour cohort encompassing known 1-year clinical outcomes. Our analyses identified potential novel epigenetic markers that could help guide individual patient management in this clinically unpredictable disease., Competing Interests: Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Needs assessment is the essence of quality cancer survivorship care. The aim of this study was to explore the supportive care needs of breast cancer survivors (BCS) in the first 5 years post treatment., Methods: A mixed-methods approach was employed. A quantitative study included a Supportive Care Needs Survey, which was completed by 250 BCS to identify the level of their needs for help. The quantitative data informed semistructured qualitative interviews undertaken with 60 BCS to explore in detail their posttreatment needs and experiences., Results: 32.4% and 16.8% reported 1 to 5 and greater than or equal to 6 needs for help, respectively. The regression analyses revealed that women within 2 years posttreatment and with higher educational level had higher levels of Psychological and Health Care System/Information needs. The qualitative data revealed "continuity of care" and "lifestyle advice and self-management" as prominent survivorship concerns. It was shown that determination to continue normal life, social support, and feeling overwhelmed by information were all experienced as important influences on survivors' need for help., Conclusions: Posttreatment needs vary with BCS characteristics and to the domains concerned. The approach to posttreatment care needs to be personalized and viable., (Copyright © 2017 John Wiley & Sons, Ltd.)

China has made remarkable progress in strengthening its primary health-care system. Nevertheless, the system still faces challenges in structural characteristics, incentives and policies, and quality of care, all of which diminish its preparedness to care for a fifth of the world's population, which is ageing and which has a growing prevalence of chronic non-communicable disease. These challenges include inadequate education and qualifications of its workforce, ageing and turnover of village doctors, fragmented health information technology systems, a paucity of digital data on everyday clinical practice, financial subsidies and incentives that do not encourage cost savings and good performance, insurance policies that hamper the efficiency of care delivery, an insufficient quality measurement and improvement system, and poor performance in the control of risk factors (such as hypertension and diabetes). As China deepens its health-care reform, it has the opportunity to build an integrated, cooperative primary health-care system, generating knowledge from practice that can support improvements, and bolstered by evidence-based performance indicators and incentives., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Cardiorespiratory fitness (CRF) and adiposity contribute to high blood pressure (HBP) in adults and children. However, their relative importance as risk factors is unknown. We examined the relationships between weight status, CRF and HBP among Chinese primary school children. A cross-sectional study was conducted with 4926 school children aged 5-12 years. CRF was estimated from a modified Cooper test, body mass index z-scores and weight categories were calculated from objective height and weight measurements and BP was measured using an electronic sphygmomanometer. HBP was defined as >95th percentile based on reference cutoffs for Chinese boys and girls. Generalised Linear Mixed models, adjusting for age, pubertal status and height, were developed for boys and girls to explore the independent and combined associations between fitness, weight status and HBP. Seven hundred and fifty-two (15.3%) children had HBP, with a higher prevalence in obese (40.5% and 45.9% in boys and girls, respectively) and overweight (27.6% and 30.2% in boys and girls, respectively) compared with non-overweight (9.0% and 13.8% in boys and girls, respectively) children. HBP prevalence was lower in boys with higher CRF (odds ratio (OR) for the highest vs lowest CRF quartile in boys 0.64; 95% confidence interval (CI) 0.46-0.89). This association was not seen in girls. With weight status and CRF in the same model, weight status, but not CRF, remained significantly associated with HBP (obesity in boys: OR 4.19; 95% CI 2.63-6.67; in girls: OR 2.49; 95% CI 1.19-5.19). The interaction effect for CRF and weight status was non-significant. Overweight/obesity was significantly associated with HBP among children. There was no evidence of modification of this relationship by CRF.

Aim: Whether different adiposity measures predict incident diabetes differentially in general Chinese populations is unclear. We investigated this in Chinese people aged 50+ years in the Guangzhou Biobank Cohort Study., Methods: Waist circumference and BMI were measured at baseline, and fasting glucose was measured at both baseline and follow-up examinations. Incident diabetes was defined as fasting glucose ≥ 7.0 mmol/l, glucose after 2-h oral glucose tolerance test ≥ 11.1 mmol/l, and/or self-reported physician-diagnosed diabetes during the follow-up period., Results: Of 15 752 people without diabetes at baseline from 2003 to 2008, 1779 (11.3%) developed incident diabetes during the follow-up from 2008 to 2012 (mean = 3.6 years, sd = 1.0). After mutually adjusting each other and adjusting for other potential confounders, waist circumference showed a higher predictive value than BMI. The odds ratio (OR) (95% confidence interval (CI) was 1.50 (95% CI 1.37-1.64) for a 1 sd increment in waist circumference and 1.21 (95% CI 1.11-1.33), for a 1 sd increment in BMI. Similarly, after mutual adjustment, abdominal obesity was associated with an almost twofold odds of incident diabetes (OR 1.93, 95% CI 1.71-2.17), which was higher than that for general obesity (OR 1.76, 95% CI 1.50-2.06). The area under receiver operating characteristic curve (AUC) for waist circumference was higher than that for BMI [AUC = 0.676 (95% CI 0.660-0.686) vs. 0.665 (95% CI 0.651-0.678), P = 0.02]., Conclusion: Abdominal obesity predicted incident diabetes in older people better than general obesity. Our findings may be an early warning signal for local government or public health practitioners to develop and investigate more effective intervention programmes for diabetes, and should also be disseminated to the public to pay more attention to this important public health issue., (© 2017 Diabetes UK.)

Background: It is not known whether infants exposed to intermittent maternal fasting at conception are born smaller or have a higher risk of premature birth than those who are not. Doctors are therefore unsure about what advice to give women about the safety of Ramadan fasting. This cohort study aimed to investigate these questions in Muslim mother-infant pairs to inform prenatal care., Methods: Routinely collected data accessed from maternity records were the source for information. Mothers were considered exposed if they were Muslim and Ramadan overlapped with their infant conception date, estimated to be 14 days after the last menstrual period. Infants were included as exposed if their estimated conception date was in the first 21 days of Ramadan or 7 days prior to Ramadan., Results: After adjusting for gestational age, maternal age, infant gender, maternal body mass index at booking, smoking status, gestational diabetes, parity and year of birth, there was no significant difference in birth weight between infants born to Muslim mothers who were conceived during Ramadan (n=479) and those who were not (n=4677) (adjusted mean difference =24.3 g, 95% CI -16.4 to 64.9). There was no difference in rates of premature births in exposed and unexposed women (5.2% vs 4.9%; OR=1.08, 95% CI 0.71 to 1.65)., Conclusions: Healthy Muslim women considering becoming pregnant prior to, or during Ramadan, can be advised that fasting does not seem to have a detrimental effect on the size (weight) of their baby and it appears not to increase the likelihood of giving birth prematurely., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Aim: The glucagon-like peptide-1 receptor agonist (GLP1a) liraglutide has been described to benefit patients with type 2 diabetes mellitus (T2DM) at high cardiovascular risk. However, there are still uncertainties relating to these cardiovascular benefits: whether they also apply to an unselected diabetic population that includes low-risk patients, represent a class-effect, and could be observed in a real-world setting., Methods: We conducted a population-based, retrospective open cohort study using data derived from The Health Improvement Network database between Jan 2008 to Sept 2015. Patients with T2DM exposed to GLP1a (n=8345) were compared to age, gender, body mass index, duration of T2DM and smoking status-matched patients with T2DM unexposed to GLP1a (n=16,541)., Results: Patients with diabetes receiving GLP1a were significantly less likely to die from any cause compared to matched control patients with diabetes (adjusted incidence rate ratio [aIRR]: 0.64, 95% CI: 0.56-0.74, P-value<0.0001). Similar findings were observed in low-risk patients (aIRR: 0.64, 95% CI: 0.53-0.76, P -value=0.0001). No significant difference in the risk of incident CVD was detected in the low-risk patients (aIRR: 0.93, 95% CI: 0.83-1.12). Subgroup analyses suggested that effect is persistent in the elderly or across glycated haemoglobin categories., Conclusions: GLP1a treatment in a real-world setting may confer additional mortality benefit in patients with T2DM irrespective of their baseline CVD risk, age or baseline glycated haemoglobin and was sustained over the observation period., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

China's healthcare system has undergone extensive changes over recent years and the most recent reforms are designed to shift the emphasis away from hospital based services towards a more primary care based system. There is an increasing recognition that shared decision making needs to play a central role in the delivery of healthcare in China, but there are several significant barriers to overcome before this aspiration becomes a reality. Doctor-patient relationships in China are poor, consultations are often brief transactions and levels of trust are low. Implementing a shared decision making process developed in the Western World may be hampered by cultural differences, although this remains an under-researched area. There is, however, a suggestion that the academic community is starting to take an interest in encouraging shared decision making in practice and indications that the Chinese public may be willing to consider this new approach to healthcare., (Copyright © 2017. Published by Elsevier GmbH.)

Background: To investigate the association between weight status and health-related quality of life (HRQOL) among pupils in Guangzhou, China., Methods: The study comprised 5781 children aged 8-12 years from 29 schools. Height and weight were objectively measured using standardized methods, and BMI z-score derived using the age and sex specific WHO reference 2007 for 5-19 years. Weight status was classified as underweight (<-2SD), healthy weight (between -2SD and 1SD), overweight/obesity (>1SD). HRQOL was measured by the self-report version of the Pediatric Quality of Life Inventory 4.0., Results: After controlling for gender, age, school type, parental education, and family income, HRQOL scores were significantly lower in overweight/obese compared with healthy weight children only in the social functioning domain (β = -1.93, p = 0.001). Compared with healthy weight children, underweight children had significantly lower total (β = -1.47, p = 0.05) and physical summary scores (β = -2.18, p = 0.02). Subgroup analysis for gender indicated that compared to healthy weight, total (β = -1.96, p = 0.02), psychosocial (β = -2.40, p = 0.01), social functioning (β = -3.36, p = 0.001), and school functioning (β = -2.19, p = 0.03) scores were lower in overweight/obese girls, but not boys. On the other hand, being underweight was associated with lower physical functioning (β = -2.27, p = 0.047) in girls, and lower social functioning (β = -3.63, p = 0.01) in boys. The associations were mainly observed in children aged 10 and over, but were not significant in younger children. Children from private schools had generally lower HRQOL compared to those in public schools, but the associations with weight status were similar in both groups., Conclusions: The relationship between overweight/obesity and HRQOL in children in China is not as prominent as that seen in children in western or high-income countries. However, there appears to be gender and age differences, with more of an impact of overweight on HRQOL in girls and older children compared with boys and younger children. Underweight is also associated with lower HRQOL. Future intervention to prevent both obesity and undernutrition may have a positive impact on the HRQOL in children in China.

Background: Stroke is a leading cause of death and disability; worldwide it is estimated that 16.9 million people have a first stroke each year. Lipid-lowering, anticoagulant, and antihypertensive drugs can prevent strokes, but may be underused., Methods and Findings: We analysed anonymised electronic primary care records from a United Kingdom (UK) primary care database that covers approximately 6% of the UK population. Patients with first-ever stroke/transient ischaemic attack (TIA), ≥18 y, with diagnosis between 1 January 2009 and 31 December 2013, were included. Drugs were considered under-prescribed when lipid-lowering, anticoagulant, or antihypertensive drugs were clinically indicated but were not prescribed prior to the time of stroke or TIA. The proportions of strokes or TIAs with prevention drugs under-prescribed, when clinically indicated, were calculated. In all, 29,043 stroke/TIA patients met the inclusion criteria; 17,680 had ≥1 prevention drug clinically indicated: 16,028 had lipid-lowering drugs indicated, 3,194 anticoagulant drugs, and 7,008 antihypertensive drugs. At least one prevention drug was not prescribed when clinically indicated in 54% (9,579/17,680) of stroke/TIA patients: 49% (7,836/16,028) were not prescribed lipid-lowering drugs, 52% (1,647/3,194) were not prescribed anticoagulant drugs, and 25% (1,740/7,008) were not prescribed antihypertensive drugs. The limitations of our study are that our definition of under-prescribing of drugs for stroke/TIA prevention did not address patients' adherence to medication or medication targets, such as blood pressure levels., Conclusions: In our study, over half of people eligible for lipid-lowering, anticoagulant, or antihypertensive drugs were not prescribed them prior to first stroke/TIA. We estimate that approximately 12,000 first strokes could potentially be prevented annually in the UK through optimal prescribing of these drugs. Improving prescription of lipid-lowering, anticoagulant, and antihypertensive drugs is important to reduce the incidence and burden of stroke and TIA., Competing Interests: GMT reports grants from National Institute for Health Research (NIHR) School for Primary Care Research (SPCR), during the conduct of the study; TM reports funding from the NIHR through the Collaborations for Leadership in Applied Health Research and Care for West Midlands (CLAHRC-WM); MC reports funding from European Society of Cardiology & AFNET, and personal fees from Astellas Pharma, outside the submitted work. KC reports grants from Pfizer China, outside the submitted work. MGF and RR have nothing to disclose.