Progression of stroke risk in patients aged <65 years diagnosed with atrial fibrillation: a cohort study in general practice.

BACKGROUND: As a result of new technologies, atrial fibrillation (AF) is more likely to be diagnosed in people aged <65 years. AIM: To investigate the risk of someone diagnosed with AF aged <65 years developing an indication for anticoagulation before they reach 65 years. DESIGN AND SETTING: Population-based cohort study of patients from English practices using the Clinical Practice Research Datalink, a primary care database of electronic medical records. METHOD: The study included patients aged <65 years newly diagnosed with AF. The CHA2DS2-VASc score was derived at time of diagnosis based on patients' medical records. Patients not eligible for anticoagulation were followed up until they became eligible or turned 65 years old. The primary outcome of interest was development of a risk factor for stroke in AF. RESULTS: Among 18 178 patients aged <65 years diagnosed with AF, 9188 (50.5%) were eligible for anticoagulation at the time of diagnosis. Among the 8990 patients not eligible for anticoagulation, 1688 (18.8%) developed a risk factor during follow-up before reaching 65 years of age or leaving the cohort for other reasons, at a rate of 6.1 per 100 patient-years. Hypertension and heart failure were the most common risk factors to occur, with rates of 2.65 (95% CI = 2.47 to 2.84) and 1.58 (95% CI = 1.45 to 1.72) per 100 patient-years, respectively. The rate of new diabetes was 0.95 (95% CI = 0.85 to 1.06) per 100 patient-years. CONCLUSION: People aged <65 years with AF are at higher risk of developing hypertension, heart failure, and diabetes than the general population, so may warrant regular review to identify new occurrence of such risk factors.

Temporal trends in incidence of atrial fibrillation in primary care records: a population-based cohort study.

OBJECTIVES: Atrial fibrillation (AF) is a heart condition associated with a fivefold increased risk of stroke. The condition can be detected in primary care and treatment can greatly reduce the risk of stroke. In recent years, a number of policy initiatives have tried to improve diagnosis and treatment of AF, including local National Health Service schemes and the Quality and Outcomes Framework. We aimed to examine trends in the incidence of recorded AF in primary care records from English practices between 2004 and 2018. DESIGN: Longitudinal cohort study. SETTING: English primary care electronic health records linked to Index of Multiple Deprivation data. PARTICIPANTS: Cohort of 3.5 million patients over 40 years old registered in general practices in England, contributing 22 million person-years of observation between 2004 and 2018. PRIMARY AND SECONDARY OUTCOME MEASURES: Incident AF was identified through newly recorded AF codes in the patients' records. Yearly incidence rates were stratified by gender, age group and a measure of deprivation. RESULTS: Incidence rates were stable before 2010 and then rose and peaked in 2015 at 5.07 (95% CI 4.94 to 5.20) cases per 1000 person-years. Incidence was higher in males (4.95 (95% CI 4.91 to 4.99) cases per 1000 person-years vs 4.12 (95% CI 4.08 to 4.16) in females) and rises markedly with age (0.58 (95% CI 0.56 to 0.59) cases per 1000 person-years in 40-54 years old vs 21.7 (95% CI 21.4 to 22.0) cases in over 85s). The increase in incidence over time was observed mainly in people over the age of 75, particularly men. There was no evidence that temporal trends in incidence were associated with deprivation. CONCLUSIONS: Changes in clinical practice and policy initiatives since 2004 have been associated with increased rates of diagnosis of AF up until 2015, but rates declined from 2015 to 2018.

Development and validation of the Cambridge Multimorbidity Score.

BACKGROUND: Health services have failed to respond to the pressures of multimorbidity. Improved measures of multimorbidity are needed for conducting research, planning services and allocating resources. METHODS: We modelled the association between 37 morbidities and 3 key outcomes (primary care consultations, unplanned hospital admission, death) at 1 and 5 years. We extracted development (n = 300 000) and validation (n = 150 000) samples from the UK Clinical Practice Research Datalink. We constructed a general-outcome multimorbidity score by averaging the standardized weights of the separate outcome scores. We compared performance with the Charlson Comorbidity Index. RESULTS: Models that included all 37 conditions were acceptable predictors of general practitioner consultations (C-index 0.732, 95% confidence interval [CI] 0.731-0.734), unplanned hospital admission (C-index 0.742, 95% CI 0.737-0.747) and death at 1 year (C-index 0.912, 95% CI 0.905-0.918). Models reduced to the 20 conditions with the greatest combined prevalence/weight showed similar predictive ability (C-indices 0.727, 95% CI 0.725-0.728; 0.738, 95% CI 0.732-0.743; and 0.910, 95% CI 0.904-0.917, respectively). They also predicted 5-year outcomes similarly for consultations and death (C-indices 0.735, 95% CI 0.734-0.736, and 0.889, 95% CI 0.885-0.892, respectively) but performed less well for admissions (C-index 0.708, 95% CI 0.705-0.712). The performance of the general-outcome score was similar to that of the outcome-specific models. These models performed significantly better than those based on the Charlson Comorbidity Index for consultations (C-index 0.691, 95% CI 0.690-0.693) and admissions (C-index 0.703, 95% CI 0.697-0.709) and similarly for mortality (C-index 0.907, 95% CI 0.900-0.914). INTERPRETATION: The Cambridge Multimorbidity Score is robust and can be either tailored or not tailored to specific health outcomes. It will be valuable to those planning clinical services, policymakers allocating resources and researchers seeking to account for the effect of multimorbidity.

Support Needs Approach for Patients (SNAP) tool: a validation study.

OBJECTIVES: Patient-identified need is key to delivering holistic, supportive, person-centred care, but we lack tools enabling patients to express what they need to manage life with a long-term condition. The Support Needs Approach for Patients (SNAP) tool was developed to enable patients with advanced chronic obstructive pulmonary disease (COPD) identify and express their unmet support needs to healthcare professionals (HCPs), but its validity is unknown. This study aimed to establish face, content and criterion validity of the SNAP tool. DESIGN: Two-stage mixed-methods study involving patients with advanced COPD and their carers. Stage 1: Face and content validity assessed though focus groups involving patients and carers considering appropriateness, relevance and completeness of the SNAP tool. Data were analysed using conventional content analysis. Stage 2: Content and criterion validity assessed in a postal survey through patient self-completion of the SNAP tool and disease impact measures (Chronic Respiratory Questionnaire, COPD Assessment Test, and Hospital Anxiety and Depression Scale). Content validity assessed using summary statistics; criterion validity via correlations between tool items and impact measures. SETTINGS AND PARTICIPANTS: Two hundred and forty patients and carers participated. Stage 1 patient and informal carer participants were recruited from two primary care practices and Stage 2 patients from 28 practices. Participating practices located in the East of England were recruited via the NIHR Clinical Research Network: Eastern. RESULTS: Patients and carers found the tool patient-friendly and comprehensive, with potential clinical utility. No tool items were redundant. Clear correlations were found between tool items and the majority of items in the impact measures. CONCLUSIONS: The SNAP tool has good face, content and criterion validity. It has potential to support the delivery of holistic, supportive, person-centred care by enabling patients to identify and express their unmet support needs to HCPs.

Impact of the Southwark and Lambeth Integrated Care Older People's Programme on hospital utilisation and costs: controlled time series and cost-consequence analysis.

OBJECTIVES: To estimate the impact on hospital utilisation and costs of a multi-faceted primary care intervention for older people identified as being at risk of avoidable hospitalisation. DESIGN: Observational study: controlled time series analysis and estimation of costs and cost consequences of the Programme. General practitioner (GP)'s practice level data were analysed from 2009 to 2016 (intervention operated from 2012 to 2016). Mixed-effect Poisson regression models of hospital utilisation included comparisons with control practices and background trends in addition to within-practice comparisons. Cost estimation used standard tariff values. SETTING: 94 practices in Southwark and Lambeth and 263 control practices from other parts of England. MAIN OUTCOME MEASURES: Hospital utilisation: emergency department attendance, emergency admissions, emergency admissions for ambulatory sensitive conditions, outpatient attendance, elective admission and length of stay. RESULTS: By the fourth year of the Programme, there were reductions in accident and emergency (A&E) attendance (rate ratio 0.944, 95% CI 0.913 to 0.976), outpatient attendances (rate ratio 0.938, 95% CI 0.902 to 0.975) and elective admissions (rate ratio 0.921, 95% CI 0.908 to 0.935) but there was no evidence of reduced emergency admissions. The costs of the Programme were £149 per resident aged 65 and above but savings in hospital costs were only £86 per resident aged 65 and above, equivalent to a net increase in health service expenditure of £64 per resident though the Programme was nearly cost neutral if set-up costs were excluded. Holistic assessments carried out by GPs and consequent Integrated Care Management (ICM) plans were associated with increases in elective activity and costs; £126 increase in outpatient attendance and £936 in elective admission costs per holistic assessment carried out, and £576 increase in outpatient and £5858 in elective admission costs per patient receiving ICM. CONCLUSIONS: The Older People's Programme was not cost saving. Some aspects of the Programme were associated with increased costs of elective care, possibly through the identification of unmet need.

Associations between general practice characteristics with use of urgent referrals for suspected cancer and endoscopies: a cross-sectional ecological study.

BACKGROUND: Large variation in measures of diagnostic activity has been described previously between English general practices, but related predictors remain understudied. OBJECTIVE: To examine associations between general practice population and characteristics, with the use of urgent referrals for suspected cancer, and use of endoscopy. METHODS: Cross-sectional observational study of English general practices. We examined practice-level use (/1000 patients/year) of urgent referrals for suspected cancer, gastroscopy, flexible sigmoidoscopy and colonoscopy. We used mixed-effects Poisson regression to examine associations with the sociodemographic profile of practice populations and other practice attributes, including the average age, sex and country of qualification of practice doctors. RESULTS: The sociodemographic characteristics of registered patients explained much of the between-practice variance in use of urgent referrals (32%) and endoscopic investigations (18-25%), all being higher in practices with older and more socioeconomically deprived patients. Practice-level attributes explained a substantial amount of between-practice variance in urgent referral (19%) but little of the variance in endoscopy (3%-4%). Adjusted urgent referral rates were higher in training practices and those with younger GPs. Practices with mean doctor ages of 41 and 57 years (at the 10th/90th centiles of the national distribution) would have urgent referral rates of 24.1 and 19.1/1000 registered patients, P < 0.001. CONCLUSION: Most between-practice variation in use of urgent referrals and endoscopies seems to reflect health need. Some practice characteristics, such as the mean age of GPs, are associated with appreciable variation in use of urgent referrals, though these associations do not seem strong enough to justify targeted interventions.

Associations between diagnostic pathways and care experience in colorectal cancer: evidence from patient-reported data.

OBJECTIVE: To examine how different pathways to diagnosis of colorectal cancer may be associated with the experience of subsequent care. DESIGN: Patient survey linked to information on diagnostic route.English patients with colorectal cancer (analysis sample n=6837) who responded to a patient survey soon after their hospital treatment. MAIN OUTCOME MEASURES: Odds Ratios and adjusted proportions of negative evaluation of key aspects of care for colorectal cancer, including the experience of shared decision-making about treatment, specialist nursing and care coordination, by diagnostic route (ie, screening detection, emergency presentation, urgent and elective general practitioner referral). RESULTS: For 14 of 18 questions, there was evidence (p≤0.02) for variation in patient experience by diagnostic route, with 6-31 percentage point differences between routes in adjusted proportions of negative experience. Emergency presenters were more likely to report a negative experience for most questions, including those about adequacy of information about their diagnosis and sufficient explanation before operations. Screen-detected patients were least likely to report negative experiences except for support from primary care. Patients diagnosed through elective primary care referrals were most likely to report worse experience for questions for which overall variation by route was generally small. CONCLUSIONS: Screening-detected patients tend to report the best and emergency presenters the worst experience of subsequent care. Improvement efforts can target care integration for screening-detected patients and provision of information about the diagnosis and treatment of emergency presenters.

Variation and statistical reliability of publicly reported primary care diagnostic activity indicators for cancer: a cross-sectional ecological study of routine data.

OBJECTIVES: Recent public reporting initiatives in England highlight general practice variation in indicators of diagnostic activity related to cancer. We aimed to quantify the size and sources of variation and the reliability of practice-level estimates of such indicators, to better inform how this information is interpreted and used for quality improvement purposes. DESIGN: Ecological cross-sectional study. SETTING: English primary care. PARTICIPANTS: All general practices in England with at least 1000 patients. MAIN OUTCOME MEASURES: Sixteen diagnostic activity indicators from the Cancer Services Public Health Profiles. RESULTS: Mixed-effects logistic and Poisson regression showed that substantial proportions of the observed variance in practice scores reflected chance, variably so for different indicators (between 7% and 85%). However, after accounting for the role of chance, there remained substantial variation between practices (typically up to twofold variation between the 75th and 25th centiles of practice scores, and up to fourfold variation between the 90th and 10th centiles). The age and sex profile of practice populations explained some of this variation, by different amounts across indicators. Generally, the reliability of diagnostic process indicators relating to broader populations of patients most of whom do not have cancer (eg, rate of endoscopic investigations, or urgent referrals for suspected cancer (also known as 'two week wait referrals')) was high (≥0.80) or very high (≥0.90). In contrast, the reliability of diagnostic outcome indicators relating to incident cancer cases (eg, per cent of all cancer cases detected after an emergency presentation) ranged from 0.24 to 0.54, which is well below recommended thresholds (≥0.70). CONCLUSIONS: Use of indicators of diagnostic activity in individual general practices should principally focus on process indicators which have adequate or high reliability and not outcome indicators which are unreliable at practice level.

Associations between diagnostic activity and measures of patient experience in primary care: a cross-sectional ecological study of English general practices.

BACKGROUND: Lower use of endoscopies and urgent referrals for suspected cancer has been linked to poorer outcomes for patients with cancer; it is important to examine potential predictors of variable use. AIM: To examine the associations between general practice measures of patient experience and practice use of endoscopies or urgent referrals for suspected cancer. DESIGN AND SETTING: Cross-sectional ecological analysis in English general practices. METHOD: Data were taken from the GP Patient Survey and the Cancer Services Public Health Profiles. After adjustment for practice population characteristics, practice-level associations were examined between the use of endoscopy and urgent referrals for suspected cancer, and the ability to book an appointment (used as proxy for ease of access), the ability to see a preferred doctor (used as proxy for relational continuity), and doctor/nurse communication skills. RESULTS: Taking into account practice scores for the ability to book an appointment, practices rated higher for the proxy measure of relational continuity used urgent referrals and endoscopies less often (for example, 30% lower urgent referral and 15% lower gastroscopy rates between practices in the 90th/10th centiles, respectively). In contrast, practices rated higher for doctor communication skills used urgent referrals and endoscopies more often (for example, 26% higher urgent referral and 17% higher gastroscopy rates between practices in the 90th/10th centiles, respectively). Patients with cancer in practices that were rated higher for doctor communication skills were less likely to be diagnosed as emergencies (1.7% lower between practices in the 90th than in the 10th centile). CONCLUSION: Practices where patients rated doctor communication highly were more likely to investigate and refer patients urgently but, in contrast, practices where patients could see their preferred doctor more readily were less likely to do so. This article discusses the possible implications of these findings for clinical practice.

Are within-person Numerical Rating Scale (NRS) ratings of breathlessness 'on average' valid in advanced disease for patients and for patients' informal carers?

INTRODUCTION: The Numerical Rating Scale (NRS) is frequently used to assess patient-reported breathlessness in both a research and clinical context. A subgroup of patients report average breathlessness as worse than their worst breathlessness in the last 24 hours (paradoxical average). The Peak/End rule describes how the most extreme and current breathlessness influence reported average. This study seeks to highlight the existence of a subpopulation who give 'paradoxical averages using the NRS, to characterise this group and to investigate the explanatory relevance of the 'Peak/End' rule. METHODS: Data were collected within mixed method face-to-face interviews for three studies: the Living with Breathlessness Study and the two subprotocols of the Breathlessness Intervention Service phase III randomised controlled trial. Key variables from the three datasets were pooled (n=561), and cases where participants reported a paradoxical average (n=45) were identified. These were compared with non-cases and interview transcripts interrogated. NRS ratings of average breathlessness were assessed for fit to Peak/End rule. RESULTS: Patients in the paradoxical average group had higher Chronic Respiratory Questionnaire physical domain scores on average p=0.042). Peak/End rule analysis showed high positive correlation (Spearman's rho=0.756, p<0.001). CONCLUSIONS: The NRS requires further standardisation with reporting of question order and construction of scale used to enable informed interpretation. The application of the Peak/End rule demonstrates fallibility of NRS-Average as a construct as it is affected by current breathlessness. Measurement of breathlessness is important for both clinical management and research, but standardisation and transparency are required for meaningful results.

Emergency diagnosis of cancer and previous general practice consultations: insights from linked patient survey data.

BACKGROUND: Emergency diagnosis of cancer is common and aetiologically complex. The proportion of emergency presenters who have consulted previously with relevant symptoms is uncertain. AIM: To examine how many patients with cancer, who were diagnosed as emergencies, have had previous primary care consultations with relevant symptoms; and among those, to examine how many had multiple consultations. DESIGN AND SETTING: Secondary analysis of patient survey data from the 2010 English Cancer Patient Experience Survey (CPES), previously linked to population-based data on diagnostic route. METHOD: For emergency presenters with 18 different cancers, associations were examined for two outcomes (prior GP consultation status; and 'three or more consultations' among prior consultees) using logistic regression. RESULTS: Among 4647 emergency presenters, 1349 (29%) reported no prior consultations, being more common in males (32% versus 25% in females, P<0.001), older (44% in ≥85 versus 30% in 65-74-year-olds, P<0.001), and the most deprived (35% versus 25% least deprived, P = 0.001) patients; and highest/lowest for patients with brain cancer (46%) and mesothelioma (13%), respectively (P<0.001 for overall variation by cancer site). Among 3298 emergency presenters with prior consultations, 1356 (41%) had three or more consultations, which were more likely in females (P<0.001), younger (P<0.001), and non-white patients (P = 0.017) and those with multiple myeloma, and least likely for patients with leukaemia (P<0.001). CONCLUSION: Contrary to suggestions that emergency presentations represent missed diagnoses, about one-third of emergency presenters (particularly those in older and more deprived groups) have no prior GP consultations. Furthermore, only about one-third report multiple (three or more) consultations, which are more likely in 'harder-to-suspect' groups.

Symptoms and patient factors associated with longer time to diagnosis for colorectal cancer: results from a prospective cohort study.

BACKGROUND: The objective of this study is to investigate symptoms, clinical factors and socio-demographic factors associated with colorectal cancer (CRC) diagnosis and time to diagnosis. METHODS: Prospective cohort study of participants referred for suspicion of CRC in two English regions. Data were collected using a patient questionnaire, primary care and hospital records. Descriptive and regression analyses examined associations between symptoms and patient factors with total diagnostic interval (TDI), patient interval (PI), health system interval (HSI) and stage. RESULTS: A total of 2677 (22%) participants responded; after exclusions, 2507 remained. Participants were diagnosed with CRC (6.1%, 56% late stage), other cancers (2.0%) or no cancer (91.9%). Half the cohort had a solitary first symptom (1332, 53.1%); multiple first symptoms were common. In this referred population, rectal bleeding was the only initial symptom more frequent among cancer than non-cancer cases (34.2% vs 23.9%, P=0.004). There was no evidence of differences in TDI, PI or HSI for those with cancer vs non-cancer diagnoses (median TDI CRC 124 vs non-cancer 138 days, P=0.142). First symptoms associated with shorter TDIs were rectal bleeding, change in bowel habit, 'feeling different' and fatigue/tiredness. Anxiety, depression and gastro-intestinal co-morbidities were associated with longer HSIs and TDIs. Symptom duration-dependent effects were found for rectal bleeding and change in bowel habit. CONCLUSIONS: Doctors and patients respond less promptly to some symptoms of CRC than others. Healthcare professionals should be vigilant to the possibility of CRC in patients with relevant symptoms and mental health or gastro-intestinal comorbidities.

Pre-referral GP consultations in patients subsequently diagnosed with rarer cancers: a study of patient-reported data.

BACKGROUND: Some patients with cancer experience multiple pre-diagnostic consultations in primary care, leading to longer time intervals to specialist investigations and diagnosis. Patients with rarer cancers are thought to be at higher risk of such events, but concrete evidence of this is lacking. AIM: To examine the frequency and predictors of repeat consultations with GPs in patients with rarer cancers. DESIGN AND SETTING: Patient-reported data on pre-referral consultations from three English national surveys of patients with cancer (2010, 2013, and 2014), pooled to maximise the sample size of rarer cancers. METHOD: The authors examined the frequency and crude and adjusted odds ratios for ≥3 (versus 1-2) pre-referral consultations by age, sex, ethnicity, level of deprivation, and cancer diagnosis (38 diagnosis groups, including 12 rarer cancers without prior relevant evidence). RESULTS: Among 7838 patients with 12 rarer cancers, crude proportions of patients with ≥3 pre-referral consultations ranged from >30.0% to 60.0% for patients with small intestine, bone sarcoma, liver, gallbladder, cancer of unknown primary, soft-tissue sarcoma, and ureteric cancer. The range was 15.0-30.0% for patients with oropharyngeal, anal, parotid, penile, and oral cancer. The overall proportion of responders with any cancer who had ≥3 consultations was 23.4%. Multivariable logistic regression indicated concordant patterns, with strong evidence for variation between rarer cancers (P <0.001). CONCLUSION: Patients with rarer cancers experience pre-referral consultations at frequencies suggestive of middle-to-high diagnostic difficulty. The findings can guide the development of new diagnostic interventions and 'safety-netting' approaches for symptomatic presentations encountered in patients with rarer cancers.

Effectiveness and long-term retention of anti-tumour necrosis factor treatment in juvenile and adult patients with juvenile idiopathic arthritis: data from Reuma.pt.

OBJECTIVES: Assess the effectiveness and safety of biologic therapy as well as predictors of response at 1 year of therapy, retention rate in biologic treatment and predictors of drug discontinuation in JIA patients in the Portuguese register of rheumatic diseases. METHODS: We prospectively collected patient and disease characteristics from patients with JIA who started biological therapy. Adverse events were collected during the follow-up period. Predictors of response at 1 year and drug retention rates were assessed at 4 years of treatment for the first biologic agent. RESULTS: A total of 812 JIA patients [65% females, mean age at JIA onset 6.9 years (s.d. 4.7)], 227 received biologic therapy; 205 patients (90.3%) were treated with an anti-TNF as the first biologic. All the parameters used to evaluate disease activity, namely number of active joints, ESR and Childhood HAQ/HAQ, decreased significantly at 6 months and 1 year of treatment. The mean reduction in Juvenile Disease Activity Score 10 (JADAS10) after 1 year of treatment was 10.4 (s.d. 7.4). According to the definition of improvement using the JADAS10 score, 83.3% respond to biologic therapy after 1 year. Fourteen patients discontinued biologic therapies due to adverse events. Retention rates were 92.9% at 1 year, 85.5% at 2 years, 78.4% at 3 years and 68.1% at 4 years of treatment. Among all JIA subtypes, only concomitant therapy with corticosteroids was found to be univariately associated with withdrawal of biologic treatment (P = 0.016). CONCLUSION: Biologic therapies seem effective and safe in patients with JIA. In addition, the retention rates for the first biologic agent are high throughout 4 years.

Symptoms and patient factors associated with diagnostic intervals for pancreatic cancer (SYMPTOM pancreatic study): a prospective cohort study.

BACKGROUND: Pancreatic cancer is the tenth most common cancer in the UK; however, outcomes are poor, in part due to late diagnosis. We aimed to identify symptoms and other clinical and sociodemographic factors associated with pancreatic cancer diagnosis and diagnostic intervals. METHODS: We did this prospective cohort study at seven hospitals in two regions in England. We recruited participants aged 40 years or older who were referred for suspicion of pancreatic cancer. Data were collected by use of a patient questionnaire and primary care and hospital records. Descriptive and regression analyses were done to examine associations between symptoms and patient factors with the total diagnostic interval (time from onset of the first symptom to the date of diagnosis), comprising patient interval (time from first symptom to first presentation) and health system interval (time from first presentation to diagnosis). FINDINGS: We recruited 391 participants between Jan 1, 2011, and Dec 31, 2014 (24% response rate). 119 (30%) participants were diagnosed with pancreatic cancer (41 [34%] had metastatic disease), 47 (12%) with other cancers, and 225 (58%) with no cancer. 212 (54%) patients had multiple first symptoms whereas 161 (41%) patients had a solitary first symptom. In this referred population, no initial symptoms were reported more frequently by patients with cancer than by those with no cancer. Several subsequent symptoms predicted pancreatic cancer: jaundice (51 [49%] of 105 patients with pancreatic cancer vs 25 [12%] of 211 patients with no cancer; p<0·0001), fatigue (48/95 [51%] vs 40/155 [26%]; p=0·0001), change in bowel habit (36/87 [41%] vs 28/175 [16%]; p<0·0001), weight loss (55/100 [55%] vs 41/184 [22%]; p<0·0001), and decreased appetite (41/86 [48%] vs 41/156 [26%]; p=0·0011). There was no difference in any interval between patients with pancreatic cancer and those with no cancer (total diagnostic interval: median 117 days [IQR 57-234] vs 131 days [IQR 66-284]; p=0·32; patient interval 18 days [0-37] vs 15 days [1-62]; p=0·22; health system interval 76 days [28-161] vs 79 days [30-156]; p=0·68). Total diagnostic intervals were shorter when jaundice (hazard ratio [HR] 1·38, 95% CI 1·07-1·78; p=0·013) and decreased appetite (1·42, 1·11-1·82; p=0·0058) were reported as symptoms, and longer in patients presenting with indigestion (0·71, 0·56-0·89; p=0·0033), back pain (0·77, 0·59-0·99; p=0·040), diabetes (0·71, 0·52-0·97; p=0·029), and self-reported anxiety or depression, or both (0·67, 0·49-0·91; p=0·011). Health system intervals were likewise longer with indigestion (0·74, 0·58-0·95; p=0·0018), back pain (0·76, 0·58-0·99; p=0·044), diabetes (0·63, 0·45-0·89; p=0·0082), and self-reported anxiety or depression, or both (0·63, 0·46-0·88; p=0·0064), but were shorter with male sex (1·41, 1·1-1·81; p=0·0072) and decreased appetite (1·56, 1·19-2·06; p=0·0015). Weight loss was associated with longer patient intervals (HR 0·69, 95% CI 0·54-0·89; p=0·0047). INTERPRETATION: Although we identified no initial symptoms that differentiated people diagnosed with pancreatic cancer from those without pancreatic cancer, key additional symptoms might signal the disease. Health-care professionals should be vigilant to the possibility of pancreatic cancer in patients with evolving gastrointestinal and systemic symptoms, particularly in those with diabetes or mental health comorbidities. FUNDING: National Institute for Health Research and Pancreatic Cancer Action.

Genetic Predictors of Poor Prognosis in Portuguese Patients with Juvenile Idiopathic Arthritis: Data from Reuma.pt.

INTRODUCTION: This study aimed to assess the genetic determinants of poor outcome in Portuguese patients with juvenile idiopathic arthritis (JIA). METHODS: Our study was conducted in Reuma.pt, the Rheumatic Diseases Portuguese Register, which includes patients with JIA. We collected prospectively patient and disease characteristics and a blood sample for DNA analysis. Poor prognosis was defined as CHAQ/HAQ >0.75 at the last visit and/or the treatment with biological therapy. A selected panel of single nucleotide polymorphisms (SNPs) associated with susceptibility was studied to verify if there was association with poor prognosis. RESULTS: Of the 812 patients with JIA registered in Reuma.pt, 267 had a blood sample and registered information used to define "poor prognosis." In univariate analysis, we found significant associations with poor prognosis for allele A of TNFA1P3/20 rs6920220, allele G of TRAF1/C5 rs3761847, and allele G of PTPN2 rs7234029. In multivariate models, the associations with TRAF1/C5 (1.96 [1.17-3.3]) remained significant at the 5% level, while TNFA1P3/20 and PTPN2 were no longer significant. Nevertheless, none of associations found was significant after the Bonferroni correction was applied. CONCLUSION: Our study does not confirm the association between a panel of selected SNP and poor prognosis in Portuguese patients with JIA.

Complicações decorrentes do posicionamento cirúrgico de clientes idosos submetidos à cirurgia de quadril / Complications arising from surgical positioning in elderly clients submitted to hip surgery / Complicaciones derivadas de la colocación quirúrgica de clientes ancianos sometidos a cirugía de cadera

Este estudo de revisão sistemática da literatura, segundo as recomendações sugeridas pela Colaboração Cochrane, teve como objetivo buscar nas publicações das bases de dados consultadas as evidências disponíveis sobre complicações decorrentes do posicionamento cirúrgico em idosos submetidos à cirurgia de quadril. Nesta revisão, os estudos identificados e discutidos apresentaram aspectos importantes no desenvolvimento de uma prática efetiva, possibilitando maior compreensão da necessidade de elaboração de pesquisas melhores delineadas que proporcionem validade interna de estudos futuros, para que seus resultados possam ser utilizados na prática clínica.

The study of this systematic literature review according to the recommendations suggested by Cochrane's Collaboration, had the aim to search in the publications listed in the databases consulted, the available evidences about complications arising from surgical positioning in elderly clients submitted to hip surgery. The studies identified and discussed in this review presented important aspects in the development of an effective practice, enabling greater understanding of the need to elaborate better delineated researches that provide internal validity for future studies, enabling the use of their results in clinical practice.

El estudio de revisión sistemática de la literatura, siguiendo las recomendaciones de la Colaboración Cochrane, tuvo como objetivo buscar en las publicaciones que figuran en las bases de datos consultadas, las evidencias disponibles para las complicaciones causadas por la colocación quirúrgica en ancianos sometidos a cirugía de cadera. Los estudios identificados y discutidos en esta revisión presentan aspectos importantes en el desarrollo de una práctica eficaz, permitiendo una mayor comprensión de la necesidad de desarrollar estudios mejores delineados que proporcionan validez interna de los futuros estudios, a fin de que sus resultados puedan ser utilizados en la práctica clínica.

Pervasive sign epistasis between conjugative plasmids and drug-resistance chromosomal mutations.

Multidrug-resistant bacteria arise mostly by the accumulation of plasmids and chromosomal mutations. Typically, these resistant determinants are costly to the bacterial cell. Yet, recently, it has been found that, in Escherichia coli bacterial cells, a mutation conferring resistance to an antibiotic can be advantageous to the bacterial cell if another antibiotic-resistance mutation is already present, a phenomenon called sign epistasis. Here we study the interaction between antibiotic-resistance chromosomal mutations and conjugative (i.e., self-transmissible) plasmids and find many cases of sign epistasis (40%)--including one of reciprocal sign epistasis where the strain carrying both resistance determinants is fitter than the two strains carrying only one of the determinants. This implies that the acquisition of an additional resistance plasmid or of a resistance mutation often increases the fitness of a bacterial strain already resistant to antibiotics. We further show that there is an overall antagonistic interaction between mutations and plasmids (52%). These results further complicate expectations of resistance reversal by interdiction of antibiotic use.

Impacto dos conectores sem agulhas na infecção da corrente sanguínea: revisão sistemática / Impacto de los conectores sin agujas en la infección de la corriente sanguínea: revisión sistemática / Impact of needleless connectors in the bloodstream infection: a systematic review

Esta revisão sistemática buscou evidenciar o impacto do uso de conectores sem agulhas para sistema fechado de infusão na ocorrência de infecção da corrente sanguínea relacionada ao cateter venoso central. A amostra constitui-se de 14 estudos, os quais investigaram somente conectores sem agulhas. A infecção da corrente sanguínea relacionada ao cateter venoso central foi o desfecho de nove estudos. Seis apresentaram diferenças a favor do conector valvulado; quatro a favor do conector puncionável com cânula; um a favor do conector puncionável com agulha; um a favor do conector valvulado com pressão positiva e dois a favor do dispositivo usado antes da troca. A heterogeneidade dos estudos não permitiu a realização de metanálise.

Esta revisión sistemática buscó evidenciar el impacto del uso de conectores sin agujas para sistemas cerrados de infusión en el caso de ocurrir una infección en la corriente sanguínea relacionada al catéter venoso central. La muestra fue constituida de 14 estudios, los cuales investigaron solamente conectores sin agujas. La infección de la corriente sanguínea relacionada al catéter venoso central fue el resultado de nueve estudios. Seis presentaron diferencias a favor del conector de válvula; cuatro a favor del conector para punción con cánula; uno a favor del conector para punción con aguja; uno a favor do conector de válvula con presión positiva y dos a favor del dispositivo usado antes del cambio. La heterogeneidad de los estudios no permitió la realización de una meta-análisis.

This systematic review was intended to evaluate the impact of using needleless connectors in closed infusion systems in the event of a bloodstream infection related to central venous catheter. The sample consisted of 14 studies, which investigated only needleless connectors. The bloodstream infection related to central venous catheter was the result of nine studies. Six produced evidence in favor of the valve connector, four in favor of the cannula connector for puncturing, one in favor of needle connector, one in favor of positive pressure valve connector, and two in favor of the device used before the change. The heterogeneity of the studies did not allow the realization of a meta-analysis.

Impacto do uso de conectores sem agulha para sistema fechado de infusão na ocorrência de infecção de corrente sanguínea relacionada ao cateter venoso central: evidências de uma revisão sistemática / Impact of needleless connectors in closed infusion systems on the occurrence of bloodstream infection related to the use of central venous catheters: evidence from a systematic revi

Os conectores sem agulhas foram introduzidos para redução de incidência de acidentes pérfuro-cortantes nos profissionais da área da saúde e a literatura apresenta evidências irrefutáveis sobre este aspecto. No entanto, não há evidências conclusivas sobre as vantagens do conector sem agulha para o paciente, no que se referem aos índices de infecção de corrente sanguínea relacionada ao cateter venoso central. Este estudo tem como objetivo evidenciar o impacto do uso de conectores sem agulhas para sistema fechado de infusão na ocorrência de infecção de corrente sanguínea relacionada ao cateter venoso central por meio de revisão sistemática, desenvolvida conforme as recomendações propostas pela Colaboração Cochrane. A estratégia de busca nas bases de dados eletrônicas utilizou os componentes do PICO: População (estudos com pacientes em uso de cateter venoso central, independente de idade, sexo, etnia e serviço de saúde vinculado); Intervenção (uso de conectores de sistema fechado sem agulhas, não-valvulados, valvulados, com pressão positiva ou não); Comparação (uso de oclusores, conectores de sistema fechado com ou sem agulhas, não-valvulados, valvulados, com pressão positiva ou não); Outcome-desfecho (infecção de corrente sanguínea, contaminação do canhão, contaminação microbiana, infecção de corrente sanguínea relacionada ao cateter). As bases eletrônicas investigadas foram: PubMEDLINE, OVID, EMBASE, LILACS, CINAHL. Também foram avaliadas as referênciasbibliográficas dos estudos incluídos. Os resultados estão apresentados em três etapas: caracterização do processo de seleção dos estudos encontrados na busca; caracterização dos estudos incluídos para a revisão sistemática (RS); avaliação de qualidade e força da evidência dos estudos incluídos segundo a Escala de Jadad e a Escala de avaliação de qualidade dos estudos na área de Controle e Prevenção de Infecção de ) Corrente Sanguínea Relacionada ao cateter Venoso Central. A amostra desta revisão sistemática constitui-se de 14 estudos, e quatro investigaram somente conectores sem agulhas. Foram encontrados 6 ensaios clínicos controlados randomizados, 4 coortes, 3 caso-controle e 1 resultado terapêutico. A infecção de corrente sanguínea relacionada ao cateter venoso central foi o desfecho de 9 estudos. Seis apresentaram diferenças a favor do conector valvulado; 04 a favor do conector puncionável com cânula; 01 a favor do conector puncionável com agulha; 01 a favor do conector valvulado com pressão positiva e 02 a favor do dispositivo usado antes da troca. A heterogeneidade dos estudos quanto aos desenhos de pesquisa, as características das populações e os fatores de riscos controlados e os resultados, não permitem a realização de meta-análise, contudo, é possível afirmar, com base nos quatro melhores estudos encontrados, que a implantação de conectores sem agulhas, quer valvulados ou com injetor pré-furado, com manutenção de sistema fechado deinfusão, apresentam impacto positivo relacionado à menor contaminação do canhão do cateter ou na ocorrência de infecção de corrente sanguínea relacionada ao cateter venoso central.

Needleless connectors were introduced to reduce the incidence of needlestick injuries in health professionals and according to the literature their effectiveness is irrefutable. However, there is no conclusive evidence on the advantages of needleless connectors for patients with regard to bloodstream infection rates from the use of central venous catheters. The objective of this study was to determine the impact of the use of needleless connectors in closed infusion systems on the occurrence of bloodstream infections related to the use of central venous catheters by conducting a Cochrane systematic review. The strategy for searching electronic databases employed the components of the PICO model: Population (studies of patients using central venous catheters, regardless of age, sex, race and associated health service); Intervention (use of closed needleless connector systems, with and without valves, with and without positive pressure); Comparison (use of plugs, closed system connectors with and without needles, with and without valves, with and without positive pressure); Outcome (bloodstream infection, cannula contamination, microbial contamination, bloodstream infection related to catheter). The electronic databases investigated were: PubMEDLINE, OVID, EMBASE, LILACS and CINAHL. Bibliographical references of the studies included were also evaluated. The results are presented in three stages: characterization of selection process for studies found inthe search; characterization of studies included in the systematic revision; evaluation of quality and strength of evidence for studies included according to the Jadad Scale and the scale of quality of studies in the control and prevention of bloodstream infections related to central venous catheters. The sample of this systematic review was made up of 14 studies of which 4 investigated only needleless connectors. We found 6 randomized control clinical trials, 4 cohort, 3 case-control and 1 therapeutic result. Bloodstream infection related to central venous catheters was the outcome for 9 studies. Six presented differences regarding the valved connector; 04 in favor of the puncturable connector with cannula; 01 in favor of the puncturable connector with needle; 01 in favor of the valved connector with positive pressure and 02 in favor of the device used before the change. The heterogeneous nature of the studies with regard to design, population characteristics and controlled risk factors and results prevented a meta-analysis. However, it is possible to state, based on the four best studies found, that the introduction of needleless connectors, whether valved or puncturable with cannula, coupled with a closed infusion system, presented a positive impact on lowering contamination of catheter cannulae and on the occurrence of bloodstream infection related to central venous catheters.