Silvia C Mendonca

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.

Pre-referral general practitioner consultations and subsequent experience of cancer care: evidence from the English Cancer Patient Experience Survey.

Prolonged diagnostic intervals may negatively affect the patient experience of subsequent cancer care, but evidence about this assertion is sparse. We analysed data from 73 462 respondents to two English Cancer Patient Experience Surveys to examine whether patients with three or more (3+) pre‐referral consultations were more likely to report negative experiences of subsequent care compared with patients with one or two consultations in respect of 12 a priori selected survey questions. For each of 12 experience items, logistic regression models were used, adjusting for prior consultation category, cancer site, socio‐demographic case‐mix and response tendency (to capture potential variation in critical response tendencies between individuals). There was strong evidence (P < 0.01 for all) that patients with 3+ pre‐referral consultations reported worse care experience for 10/12 questions, with adjusted odds ratios compared with patients with 1–2 consultations ranging from 1.10 (95% confidence intervals 1.03–1.17) to 1.68 (1.60–1.77), or between +1.8% and +10.6% greater percentage reporting a negative experience. Associations were stronger for processes involving primary as opposed to hospital care; and for evaluation than report items. Considering 1, 2, 3–4 and ‘5+’ pre‐referral consultations separately a ‘dose–response’ relationship was apparent. We conclude that there is a negative association between multiple pre‐diagnostic consultations with a general practitioner and the experience of subsequent cancer care.

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.

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

Summary 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.

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.

Variation in ‘fast-track’ referrals for suspected cancer by patient characteristic and cancer diagnosis: evidence from 670 000 patients with cancers of 35 different sites

Background:In England, ‘fast-track’ (also known as ‘two-week wait’) general practitioner referrals for suspected cancer in symptomatic patients are used to shorten diagnostic intervals and are supported by clinical guidelines. However, the use of the fast-track pathway may vary for different patient groups.Methods:We examined data from 669 220 patients with 35 cancers diagnosed in 2006–2010 following either fast-track or ‘routine’ primary-to-secondary care referrals using ‘Routes to Diagnosis’ data. We estimated the proportion of fast-track referrals by sociodemographic characteristic and cancer site and used logistic regression to estimate respective crude and adjusted odds ratios. We additionally explored whether sociodemographic associations varied by cancer.Results:There were large variations in the odds of fast-track referral by cancer (P<0.001). Patients with testicular and breast cancer were most likely to have been diagnosed after a fast-track referral (adjusted odds ratios 2.73 and 2.35, respectively, using rectal cancer as reference); whereas patients with brain cancer and leukaemias least likely (adjusted odds ratios 0.05 and 0.09, respectively, for brain cancer and acute myeloid leukaemia). There were sex, age and deprivation differences in the odds of fast-track referral (P<0.013) that varied in their size and direction for patients with different cancers (P<0.001). For example, fast-track referrals were least likely in younger women with endometrial cancer and in older men with testicular cancer.Conclusions:Fast-track referrals are less likely for cancers characterised by nonspecific presenting symptoms and patients belonging to low cancer incidence demographic groups. Interventions beyond clinical guidelines for ‘alarm’ symptoms are needed to improve diagnostic timeliness.

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.

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.

P216 Associations between the psychological health of patients and their informal carers in advanced copd: what are the risk factors for anxiety and depression in patients, carers and patient-carer dyads?

Introduction Anxiety and depression (AD) are highly prevalent in patients with advanced COPD and their informal carers, and are associated with lower quality of life and increased healthcare use. Previous studies have postulated risk factors for patient AD in COPD (including dyspnoea, poor functional status and poor self-management) and carer AD (including female gender, insufficient support and high subjective symptom burden). However, little is known about the association between patient and carer AD. We aimed to determine this and factors associated with patient, carer and dyad AD. Methods Prospective mixed-method interviews with a population-based cohort of 109 pairs of well-characterised advanced COPD patients and their carers. Clinical anxiety and depression (defined as Hospital Anxiety and Depression Scale [HADS] anxiety or depression score >11) were identified and a dichotomous ‘psychological morbidity’ (PM) variable created (HADS score >11 for either anxiety or depression) due to small sample size. Mann-Whitney U tests and multivariate logistic regression identified factors associated with patient (n = 39) or carer (n = 30) PM. Results Prevalence of anxiety and depression was 31.2% and 15.6% in patients and 26.6% and 11% in carers respectively. In univariate analysis, patient and carer PM were significantly associated with each other (p = 0.005), with odds ratio 3.388 (95% CI: 1.414–8.118), and mainly disease-related variables and carer characteristics (including poor coping and unmet support needs), respectively. No demographic factors were significantly associated with patient PM but female gender was associated with carer PM. Table 1 shows the results of multivariate analysis. Finally, dyad PM was associated with male patients/female carers, living apart, parent-child relationship, and more exacerbations. Conclusions For patients, more exacerbations may indicate disease progression resulting in anxiety, fatigue may limit activity leading to social isolation and depression, and poor self-management may increase symptom burden leading to AD. Patient PM could lead to carer PM by increasing carer burden and impairing intra-dyad communication. Our study, with the strength of a prospective approach and recruitment from primary care, highlights the need to assess AD in carers of COPD patients (particularly with AD), to prevent it with more information and support for carers, and for interventions targeting the dyad. Abstract P216 Table 1 Multivariate analysis of predictive factors significantly associated in univariate analysis with patient or carer PM Patient PM cases (n = 39) Patient PM non-cases (n = 70) Odds ratio (95% CI) Significance Carer PM cases, n (%) Y 17 (15.6) 13 (11.9) 3.667 (0.916–14.680) 0.066 N 22 (20.2) 57 (52.3) Patient gender, n (%) M 24 (22.0) 42 (38.5) 0.728 (0.194–2.740) 0.639 F 15 (13.8) 28 (25.7) No. of exacerbations at home, median (IQR) 3.5 (2–6) 2 (0–3) 1.313 (1.006–1.713) 0.045* CRQ dyspnoea score, median (IQR) 1.8 (1.6–2.6) 2.8 (1.8–4) 1.227 (0.628–2.398) 0.549 CRQ fatigue score, median (IQR) 2.5 (2–3) 3.75 (3–4.5) 0.392 (0.173–0.889) 0.025* CRQ mastery score, median (IQR) 3.25 (2.25–3.75) 4.75 (4.25–5.5) 0.264 (0.129–0.539) 0.000* No. of patient physical co-morbidities, median (IQR) 4 (3–6) 4 (2–5) 0.832 (0.577–1.201) 0.326 Carer PM cases (n = 30) Carer PM non-cases (n = 79) Odds ratio (95% CI) Significance Patient PM cases, n (%) Y 17 (15.6) 22 (20.2) 3.869 (1.070–13.990) 0.039* N 13 (11.9) 57 (52.3) Carer gender, n (%) M 2 (1.8) 29 (26.6) 6.180 (1.167–32.712) 0.032* F 28 (25.7) 50 (45.9) Lives with patient, n (%) Y 24 (22.4) 71 (66.4) 1.883 (0.438–8.100) 0.395 N 6 (5.6) 6 (5.6) Duration of caring in years, median (IQR) 3.5 (2–12) 7 (4–13) 0.964 (0.903–1.030) 0.278 Hours of caring, median (IQR)a 3 (2–3.5) 3 (2–4) 0.859 (0.420–1.755) 0.676 No. of exacerbations at home, median (IQR) 3 (1.5–5.5) 2 (0–3.75) 1.048 (0.880–1.247) 0.599 No. of carer physical co-morbidities, median (IQR) 1 (1–2) 1 (0–2) 1.184 (0.769–1.825) 0.443 (a) 1 = <1 h/week, 2 = 1–19h/week, 3 = 20–49h/week, 4 = >50 h/week.

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.