Upper gastrointestinal bleeding in Scotland 2000-2010: Improved outcomes but a significant weekend effect

Aim: To assess numbers and case fatality of patients with upper gastrointestinal bleeding (UGIB), effects of deprivation and whether weekend presentation affected outcomes. Methods: Data was obtained from Information Services Division (ISD) Scotland and National Records of Scotland (NRS) death records for a ten year period between 2000-2001 and 2009-2010. We obtained data from the ISD Scottish Morbidity Records (SMR01) database which holds data on inpatient and day-case hospital discharges from non-obstetric and non-psychiatric hospitals in Scotland. The mortality data was obtained from NRS and linked with the ISD SMR01 database to obtain 30-d case fatality. We used 23 ICD-10 (International Classification of diseases) codes which identify UGIB to interrogate database. We analysed these data for trends in number of hospital admissions with UGIB, 30-d mortality over time and assessed effects of social deprivation. We compared weekend and weekday admissions for differences in 30-d mortality and length of hospital stay. We determined comorbidities for each admission to establish if comorbidities contributed to patient outcome. Results: A total of 60643 Scottish residents were admitted with UGIH during January, 2000 and October, 2009. There was no significant change in annual number of admissions over time, but there was a statistically significant reduction in 30-d case fatality from 10.3% to 8.8% (P < 0.001) over these 10 years. Number of admissions with UGIB was higher for the patients from most deprived category (P < 0.05), although case fatality was higher for the patients from the least deprived category (P < 0.05). There was no statistically significant change in this trend between 2000/01-2009/10. Patients admitted with UGIB at weekends had higher 30-d case fatality compared with those admitted on weekdays (P < 0.001). Thirty day mortality remained significantly higher for patients admitted with UGIB at weekends after adjusting for comorbidities. Length of hospital stay was also higher overall for patients admitted at the weekend when compared to weekdays, although only reached statistical significance for the last year of study 2009/10 (P < 0.0005). Conclusion: Despite reduction in mortality for UGIB in Scotland during 2000-2010, weekend admissions show a consistently higher mortality and greater lengths of stay compared with weekdays

Mediastinal node staging by positron emission tomography-computed tomography and selective endoscopic ultrasound with fine needle aspiration for patients with upper gastrointestinal cancer: results from a regional centre

Aim: To investigate the impact of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and positron emission tomography-computed tomography (PET-CT) in the nodal staging of upper gastrointestinal (GI) cancer in a tertiary referral centre. Methods: We performed a retrospective review of prospectively recorded data held on all patients with a diagnosis of upper GI cancer made between January 2009 and December 2015. Only those patients who had both a PET-CT and EUS with FNA sampling of a mediastinal node distant from the primary tumour were included. Using a positive EUS-FNA result as the gold standard for lymph node involvement, the sensitivity, specificity, positive and negative predictive values (PPV and NPV) and accuracy of PET-CT in the staging of mediastinal lymph nodes were calculated. The impact on therapeutic strategy of adding EUS-FNA to PET-CT was assessed. Results: One hundred and twenty one patients were included. Sixty nine patients had a diagnosis of oesophageal adenocarcinoma (Thirty one of whom were junctional), forty eight had oesophageal squamous cell carcinoma and four had gastric adenocarcinoma. The FNA results were inadequate in eleven cases and the PET-CT findings were indeterminate in two cases, therefore thirteen patients (10.7%) were excluded from further analysis. There was concordance between PET-CT and EUS-FNA findings in seventy one of the remaining one hundred and eight patients (65.7%). The sensitivity, specificity, PPV and NPV values of PET-CT were 92.5%, 50%, 52.1% and 91.9% respectively. There was discordance between PET-CT and EUS-FNA findings in thirty seven out of one hundred and eight patients (34.3%). MDT discussion led to a radical treatment pathway in twenty seven of these cases, after the final tumour stage was altered as a direct consequence of the EUS-FNA findings. Of these patients, fourteen (51.9%) experienced clinical remission of a median of nine months (range three to forty two months). Conclusion: EUS-FNA leads to altered staging of upper GI cancer, resulting in more patients receiving radical treatment that would have been the case using PET-CT staging alone

Fluid Status in Peritoneal Dialysis Patients: The European Body Composition Monitoring (EuroBCM) Study Cohort

BACKGROUND: Euvolemia is an important adequacy parameter in peritoneal dialysis (PD) patients. However, accurate tools to evaluate volume status in clinical practice and data on volume status in PD patients as compared to healthy population, and the associated factors, have not been available so far. METHODS: We used a bio-impedance spectroscopy device, the Body Composition Monitor (BCM) to assess volume status in a cross-sectional cohort of prevalent PD patients in different European countries. The results were compared to an age and gender matched healthy population. RESULTS: Only 40% out of 639 patients from 28 centres in 6 countries were normovolemic. Severe fluid overload was present in 25.2%. There was a wide scatter in the relation between blood pressure and volume status. In a multivariate analysis in the subgroup of patients from countries with unrestricted availability of all PD modalities and fluid types, older age, male gender, lower serum albumin, lower BMI, diabetes, higher systolic blood pressure, and use of at least one exchange per day with the highest hypertonic glucose were associated with higher relative tissue hydration. Neither urinary output nor ultrafiltration, PD fluid type or PD modality were retained in the model (total R² of the model = 0.57). CONCLUSIONS: The EuroBCM study demonstrates some interesting issues regarding volume status in PD. As in HD patients, hypervolemia is a frequent condition in PD patients and blood pressure can be a misleading clinical tool to evaluate volume status. To monitor fluid balance, not only fluid output but also dietary input should be considered. Close monitoring of volume status, a correct dialysis prescription adapted to the needs of the patient and dietary measures seem to be warranted to avoid hypervolemia

Pharmacogenomic variants and drug interactions identified through the genetic analysis of clozapine metabolism

Objective: Clozapine is the only effective medication for treatment-resistant schizophrenia, but its worldwide use is still limited because of its complex titration protocols. While the discovery of pharmacogenomic variants of clozapine metabolism may improve clinical management, no robust findings have yet been reported. This study is the first to adopt the framework of genome-wide association studies (GWASs) to discover genetic markers of clozapine plasma concentrations in a large sample of patients with treatment-resistant schizophrenia. Methods: The authors used mixed-model regression to combine data from multiple assays of clozapine metabolite plasma concentrations from a clozapine monitoring service and carried out a genome-wide analysis of clozapine, norclozapine, and their ratio on 10,353 assays from 2,989 individuals. These analyses were adjusted for demographic factors known to influence clozapine metabolism, although it was not possible to adjust for all potential mediators given the available data. GWAS results were used to pinpoint specific enzymes and metabolic pathways and compounds that might interact with clozapine pharmacokinetics. Results: The authors identified four distinct genome-wide significant loci that harbor common variants affecting the metabolism of clozapine or its metabolites. Detailed examination pointed to coding and regulatory variants at several CYP* and UGT* genes as well as corroborative evidence for interactions between the metabolism of clozapine, coffee, and tobacco. Individual effects of single single-nucleotide polymorphisms (SNPs) fine-mapped from these loci were large, such as the minor allele of rs2472297, which was associated with a reduction in clozapine concentrations roughly equivalent to a decrease of 50 mg/day in clozapine dosage. On their own, these single SNPs explained from 1.15% to 9.48% of the variance in the plasma concentration data. Conclusions: Common genetic variants with large effects on clozapine metabolism exist and can be found via genome-wide approaches. Their identification opens the way for clinical studies assessing the use of pharmacogenomics in the clinical management of patients with treatment-resistant schizophrenia

The risk of hepatocellular carcinoma in cirrhotic patients with hepatitis C and sustained viral response:role of the treatment regimen

Background & Aims: Previous studies have reported a high frequency of hepatocellular carcinoma (HCC) occurrence in patients with advanced liver disease, after receipt of interferon (IFN)-free therapy for hepatitis C virus (HCV) infection. Our objective was to verify and account for this phenomenon using data from the Scottish HCV clinical database. Methods: We identified HCC-naïve individuals with liver cirrhosis receiving a course of antiviral therapy in Scotland from 1997–2016 resulting in a sustained virologic response. Patients were followed-up from their treatment start date to the earliest of: date of death, date of HCC occurrence, or 31 January 2017. We used Cox regression to compare the risk of HCC occurrence according to treatment regimen after adjusting for relevant co-factors (including: demographic factors; baseline liver disease stage; comorbidities/health behaviours, virology, and previous treatment experience). HCC occurrence was ascertained through both the HCV clinical database and medical chart review. For our main analysis, treatment regimen was defined as IFN-free vs. IFN-containing. Results: A total of 857 patients met the study criteria, of whom 31.7% received an IFN-free regimen. Individuals receiving IFN-free therapy were more likely to be: older; of white ethnicity, Child-Turcotte-Pugh B/C vs. Child-Turcotte-Pugh A; thrombocytopenic; non-genotype 3; and treatment experienced. HCC occurrence was observed in 46 individuals during follow-up. In univariate analysis, IFN-free therapy was associated with a significantly increased risk of HCC (HR: 2.48; p = 0.021). However, after multivariate adjustment for baseline factors, no significant risk attributable to IFN-free therapy persisted (aHR: 1.15, p = 0.744). Conclusion: These findings suggest that the higher incidence of HCC following sustained virologic response with IFN-free therapy relates to baseline risk factors/patient selection, and not the use of IFN-free therapy per se. Lay summary: We examined the risk of liver cancer in 857 patients with cirrhosis in Scotland who received hepatitis C antiviral therapy and achieved a cure. We compared the risk of first-time liver cancer in patients treated with the newest interferon-free regimens, to patients treated with interferon. After accounting for the different characteristics of these two treatment groups, we found no evidence that interferon-free therapy is associated with a higher risk of liver cancer

Evidence of continued injecting drug use after attaining sustained treatment-induced clearance of the hepatitis C virus: implications for reinfection

Background: People who inject drugs (PWID) are at the greatest risk of hepatitis C virus (HCV) infection, yet are often denied immediate treatment due to fears of on-going risk behaviour. Our principal objective was to examine evidence of continued injecting drug use among PWID following successful treatment for HCV and attainment of a sustained viral response (SVR). Methods: PWID who attained SVR between 1992 and June 2012 were selected from the National Scottish Hepatitis C Clinical Database. Hospitalisation and mortality records were sourced for these patients using record linkage techniques. Our primary outcome variable was any hospitalisation or death, which was indicative of injecting drugs post-SVR. Results: The cohort comprised 1170 PWID (mean age at SVR 39.6y; 76% male). The Kaplan Meier estimate of incurring the primary outcome after three years of SVR was 10.59% (95% CI, 8.75–12.79) After adjusting for confounding, the risk of an injection related hospital episode or death post-SVR was significantly increased with advancing year of SVR: AHR:1.07 per year (95% CI, 1.01–1.14), having a pre-SVR acute alcohol intoxication-related hospital episode: AHR:1.83 (95% CI, 1.29–2.60), and having a pre-SVR opiate or injection-related hospital episode: AHR:2.59 (95% CI, 1.84–3.64). Conclusion: Despite attaining the optimal treatment outcome, these data indicate that an increasing significant minority of PWID continue to inject post-SVR at an intensity which leads to either hospitalisation or death and increased risk of reinfection

Mortality in hepatitis C patients who achieve a sustained viral response compared to the general population

Background & Aims: The number of people living with previous hepatitis C infection that have attained a sustained viral response (SVR) is expected to grow rapidly. So far, the prognosis of this group relative to the general population is unclear. Methods: Individuals attaining SVR in Scotland in 1996–2011 were identified using a national database. Through record-linkage, we obtained cause-specific mortality data complete to Dec 2013. We calculated standardised mortality ratios (SMRs) to compare the frequency of mortality in SVR patients to the general population. In a parallel analysis, we used Cox regression to identify modifiable patient characteristics associated with post-SVR mortality. Results: We identified 1824 patients, followed on average for 5.2 years after SVR. In total, 78 deaths were observed. Overall, all-cause mortality was 1.9 times more frequent for SVR patients than the general population (SMR: 1.86; 95% confidence interval (CI): 1.49–2.32). Significant cause-specific elevations were seen for death due to primary liver cancer (SMR: 23.50; 95% CI: 12.23–45.16), and death due to drug-related causes (SMR: 6.58, 95% CI: 4.15–10.45). Together these two causes accounted for 66% of the total excess death observed. All of the modifiable characteristics associated with increased mortality were markers either of heavy alcohol use or injecting drug use. Individuals without these behavioural markers (32.8% of cohort) experienced equivalent survival to the general population (SMR: 0.70; 95% CI: 0.41–1.18) Conclusions: Mortality in Scottish SVR patients is higher overall than the general population. The excess was driven by death from drug-related causes and liver cancer. Health risk behaviours emerged as important modifiable determinants of mortality in this population. Lay summary: Patients cured of hepatitis C through treatment had a higher mortality rate overall than the general population. Most of the surplus mortality was due to drug-related causes and death from liver cancer. A history of heavy alcohol and injecting drug use were associated with a higher mortality risk

Hepatitis C reinfection following treatment induced viral clearance among people who have injected drugs

Background: Although people who inject drugs (PWID) are an important group to receive Hepatitis C Virus (HCV) antiviral therapy, initiation onto treatment remains low. Concerns over reinfection may make clinicians reluctant to treat this group. We examined the risk of HCV reinfection among a cohort of PWID (encompassing all those reporting a history of injecting drug use) from Scotland who achieved a sustained virological response (SVR). Methods: Clinical and laboratory data were used to monitor RNA testing among PWID who attained SVR following therapy between 2000 and 2009. Data were linked to morbidity and mortality records. Follow-up began one year after completion of therapy, ending on 31st December, 2012. Frequency of RNA testing during follow-up was calculated and the incidence of HCV reinfection estimated. Cox proportional hazards regression was used to examine factors associated with HCV reinfection. Results: Among 448 PWID with a SVR, 277 (61.8%) were tested during follow-up, median 4.5 years; 191 (69%) received one RNA test and 86 (31%) received at least two RNA tests. There were seven reinfections over 410 person years generating a reinfection rate of 1.7/100 py (95% CI 0.7–3.5). For PWID who have been hospitalised for an opiate or injection related cause post SVR (11%), the risk of HCV reinfection was greater [AHR = 12.9, 95% CI 2.2–76.0, p = 0.002] and the reinfection rate was 5.7/100 py (95% CI 1.8–13.3). Conclusion: PWID who have been tested, following SVR, for HCV in Scotland appear to be at a low risk of reinfection. Follow-up and monitoring of this population are warranted as treatment is offered more widely

Efficiency and safety of varying the frequency of whole blood donation (INTERVAL): a randomised trial of 45 000 donors

Background: Limits on the frequency of whole blood donation exist primarily to safeguard donor health. However, there is substantial variation across blood services in the maximum frequency of donations allowed. We compared standard practice in the UK with shorter inter-donation intervals used in other countries. Methods: In this parallel group, pragmatic, randomised trial, we recruited whole blood donors aged 18 years or older from 25 centres across England, UK. By use of a computer-based algorithm, men were randomly assigned (1:1:1) to 12-week (standard) versus 10-week versus 8-week inter-donation intervals, and women were randomly assigned (1:1:1) to 16-week (standard) versus 14-week versus 12-week intervals. Participants were not masked to their allocated intervention group. The primary outcome was the number of donations over 2 years. Secondary outcomes related to safety were quality of life, symptoms potentially related to donation, physical activity, cognitive function, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin. This trial is registered with ISRCTN, number ISRCTN24760606, and is ongoing but no longer recruiting participants. Findings: 45 263 whole blood donors (22 466 men, 22 797 women) were recruited between June 11, 2012, and June 15, 2014. Data were analysed for 45 042 (99·5%) participants. Men were randomly assigned to the 12-week (n=7452) versus 10-week (n=7449) versus 8-week (n=7456) groups; and women to the 16-week (n=7550) versus 14-week (n=7567) versus 12-week (n=7568) groups. In men, compared with the 12-week group, the mean amount of blood collected per donor over 2 years increased by 1·69 units (95% CI 1·59–1·80; approximately 795 mL) in the 8-week group and by 0·79 units (0·69–0·88; approximately 370 mL) in the 10-week group (p<0·0001 for both). In women, compared with the 16-week group, it increased by 0·84 units (95% CI 0·76–0·91; approximately 395 mL) in the 12-week group and by 0·46 units (0·39–0·53; approximately 215 mL) in the 14-week group (p<0·0001 for both). No significant differences were observed in quality of life, physical activity, or cognitive function across randomised groups. However, more frequent donation resulted in more donation-related symptoms (eg, tiredness, breathlessness, feeling faint, dizziness, and restless legs, especially among men [for all listed symptoms]), lower mean haemoglobin and ferritin concentrations, and more deferrals for low haemoglobin (p<0·0001 for each) than those observed in the standard frequency groups. Interpretation: Over 2 years, more frequent donation than is standard practice in the UK collected substantially more blood without having a major effect on donors' quality of life, physical activity, or cognitive function, but resulted in more donation-related symptoms, deferrals, and iron deficiency. Funding: NHS Blood and Transplant, National Institute for Health Research, UK Medical Research Council, and British Heart Foundation