The underreporting of hepatocellular carcinoma to the cancer register and a log-linear model to estimate a more correct incidence.

The Cancer Register (CR) in Sweden has reported that the incidence of primary liver cancer (PLC) has slowly declined over the last decades. Even though all cancers, irrespective of diagnostic method, should be reported to the CR, the PLC incidence may not reflect the true rate. Improved diagnostic tools have enabled diagnosis of hepatocellular carcinoma based on noninvasive methods without histological verification, possibly associated with missed cancer reports or misclassification in the CR. Our objective was to study the completeness and assess the underreporting of PLC to the CR and to produce a more accurate estimate based on three registers. The CR, the Cause of Death Register, and the Patient Register were investigated. Differences and overlap were examined, the incidence was estimated by merging data from the registers, and the number reported to none of the registers was estimated using a log-linear capture-recapture model. The results show that 98% of the PLCs reported to the CR were histologically verified; 80% were hepatocellular carcinoma and 20% were intrahepatic cholangiocarcinoma. Unspecified liver cancer decreased over time and constituted <10% of all reported liver cancers. The CR may underestimate the liver cancer incidence by 37%-45%, primarily due to missed cancer reports. The estimated annual number of liver cancers increased over time, but the standardized incidence was stable around 11 per 100,000. Hepatitis C-associated liver cancer increased and constituted 20% in 2010. CONCLUSION: There was an underreporting of PLC diagnosed by noninvasive methods; the incidence was considerably higher than estimated by the CR, with a stable incidence over time; reporting needs to improve and combining registers is recommended when studying incidence. (Hepatology 2017;65:885-892).

Rationale and design of the Cyclosporine to ImpRove Clinical oUtcome in ST-elevation myocardial infarction patients (the CIRCUS trial).

BACKGROUND: Both acute myocardial ischemia and reperfusion contribute to cardiomyocyte death in ST-elevation myocardial infarction (STEMI). The final infarct size is the principal determinant of subsequent clinical outcome in STEMI patients. In a proof-of-concept phase II trial, the administration of cyclosporine prior to primary percutaneous coronary intervention (PPCI) has been associated with a reduction of infarct size in STEMI patients. METHODS: CIRCUS is an international, prospective, multicenter, randomized, double-blinded, placebo-controlled trial. The study is designed to compare the efficacy and safety of cyclosporine versus placebo, in addition to revascularization by PPCI, in patients presenting with acute anterior myocardial infarction within 12 hours of symptoms onset and initial TIMI flow ≤1 in the culprit left anterior descending coronary artery. Patients are randomized in a 1:1 fashion to 2.5 mg/kg intravenous infusion of cyclosporine or matching placebo performed in the minutes preceding PCI. The primary efficacy end point of CIRCUS is a composite of 1-year all-cause mortality, rehospitalization for heart failure or heart failure worsening during initial hospitalization, and left ventricular adverse remodeling as determined by sequential transthoracic echochardiography. Secondary outcomes will be tested using a hierarchical sequence of left ventricular (LV) ejection fraction and absolute measurements of LV volumes. The composite of death and rehospitalization for heart failure or heart failure worsening during initial hospitalization will be further assessed at three years after the initial infarction. RESULTS: Recruitment lasted from April 2011 to February 2014. The CIRCUS trial has recruited 975 patients with acute anterior myocardial infarction. The 12-months results are expected to be available in 2015. CONCLUSIONS: The CIRCUS trial is testing the hypothesis that cyclosporine in addition to early revascularization with PPCI compared to placebo in patients with acute anterior myocardial infarction reduces the incidence of death, heart failure and adverse LV remodeling at one-year follow-up.

The visible subtitler: Blockchain technology towards right management and minting.

Background: Subtitles are produced through different workflows and technologies: from fully automatic to human in open source web editors or in-house platforms, and increasingly through hybrid human-machine interaction. There is little agreement regarding subtitle copyright beyond the understanding that it is a derivative work. While same language verbatim subtitles may have little room for creativity, interlingual subtitling is heavily dependent on the subtitler skills to translate, prioritise, and condense information. These days creative subtitles are increasingly being used as one more aesthetic element in audiovisual narrative. Though they may be in the same language, the visual attributes that contribute to the narrative development make creative subtitles one more element that should be acknowledged and copyright protected. Methods: The paper will present a short introduction to subtitling copyright. It will then describe centralised and decentralised copyright management - where blockchain technology can be applied to aid subtitler identification. A focus group with expert professional subtitlers was organised, and feedback is reported. Conclusions: Subtitle copyright is country dependent, still subtitling working practices and media asset distribution have no geographical borders. Blockchain technology -as a concept- could aid subtitle traceability. This can be useful beyond financial and moral right management and work towards media sustainability, allowing for reuse and repurpose of existing media assets.

A method to visualize and adjust for selection bias in prevalent cohort studies.

Selection bias and confounding are concerns in cohort studies where the reason for inclusion of subjects in the cohort may be related to the outcome of interest. Selection bias in prevalent cohorts is often corrected by excluding observation time and events during the first time period after inclusion in the cohort. This time period must be chosen carefully-long enough to minimize selection bias but not too long so as to unnecessarily discard observation time and events. A novel method visualizing and estimating selection bias is described and exemplified by using 2 real cohort study examples: a study of hepatitis C virus infection and a study of monoclonal gammopathy of undetermined significance. The method is based on modeling the hazard for the outcome of interest as a function of time since inclusion in the cohort. The events studied were "hospitalizations for kidney-related disease" in the hepatitis C virus cohort and "death" in the monoclonal gammopathy of undetermined significance cohort. Both cohorts show signs of considerable selection bias as evidenced by increased hazard in the time period after inclusion in the cohort. The method was very useful in visualizing selection bias and in determining the initial time period to be excluded from the analyses.

A proposed method to adjust for selection bias in cohort studies.

Selection bias is a concern in cohort studies in which selection into the cohort is related to the studied outcome. An example is chronic infection with hepatitis C virus, where the initial infection may be asymptomatic for decades. This problem leads to selection of more severely ill individuals into registers of such infections. Cohort studies often adjust for this bias by introducing a time window between entry into the cohort and entry into the study. This paper describes and assesses a novel method to improve adjustment for this type of selection bias. The size of the time window is decided by calculating a standardized incidence ratio as a continuous function of the size of the time window. The resulting graph is used to decide on an appropriate window size. The method is evaluated by using the Swedish register of hepatitis C virus infections for 1990-2006. The complications studied were non-Hodgkin lymphoma and liver cancer. Selection bias differed for the studied outcomes, and a time window of a minimum of 2 months and 12 months, respectively, was judged to be appropriate. The novel method may have advantages compared with an interval-based method, especially in cohort studies with small numbers of events.

Hepatocellular carcinoma in individuals with HBV infection or HBV-HCV co-infection in a low endemic country.

OBJECTIVE: The aim of this nationwide cohort study was to assess the risk for hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection or HBV and hepatitis C virus (HCV) co-infection in Sweden, a low endemic country. MATERIAL AND METHODS: A total of 12,080 patients with HBV and 3238 patients with HBV-HCV co-infection were notified to the Swedish institute for Infectious Disease Control between 1990 and 2004. After excluding 1850 patients with acute HBV and 584 patients infected in adult life, we analyzed the cohort of 9646 subjects with chronic HBV infection. In the co-infection cohort, 1697 patients were analyzed after excluding 1541 cases with acute HBV. The Swedish national cancer registry was used for follow-up. The HCC incidence rate in the cohorts was compared with the HCC incidence rate in the general population and the standardized incidence ratio (SIR) was calculated for different strata according to estimated infection period. RESULTS: HCC was found in 45 patients in the HBV cohort. In the stratum of 40-49 years of infection we found a SIR of 47 and in stratum 50-59 years the SIR was 54. In the co-infected cohort 10 HCCs were found. The SIR in the stratum 20-29 years of infection was 34 and the SIR in the stratum 30 years and over was 91. CONCLUSIONS: This national cohort study of HBV infected and HBV-HCV co-infected subjects in a low endemic country confirms a highly increased risk of liver cancer compared to the general population.

Emergence and spread of Chlamydia trachomatis variant, Sweden.

A variant of Chlamydia trachomatis that had escaped detection by commonly used systems was discovered in Sweden in 2006. In a nationwide study, we found that it is now prevalent across Sweden, irrespective of the detection system used. Genetic analysis by multilocus sequence typing identified a predominant variant, suggesting recent emergence.

Hepatocellular carcinoma and other primary liver cancers in hepatitis C patients in Sweden - a low endemic country.

The aim of this study was to assess the risk of hepatocellular carcinoma (HCC) and other primary liver cancers (PLC) in the nationwide cohort of hepatitis C virus (HCV) infected patients in Sweden. The basis was the total HCV-cohort notified in 1990-2004, after excluding 3238 people also reported with hepatitis B, the study cohort consisted of 36 126 people contributing an observation time of 246 105 person-years. The most common route of transmission was intravenous drug use (57%). The national Cancer Registry was used for follow-up, and 354 developed PLC (mainly HCC), of whom 234 were eligible for statistical analysis. The PLC incidence in the HCV cohort was compared with the incidence in the general population, and a standardized incidence ratio (SIR) was calculated for six different strata according to estimated duration of infection. The highest relative risk, SIR: 46 (95% CI: 36-56) was found in the stratum 25-30 years with HCV infection and SIR: 40 (95% CI: 31-51) in the stratum 30-35 years with infection. In the entire community-based HCV cohort in Sweden we found a highly increased risk of liver cancer compared to the general population. The highest relative risk was among people who had been infected for more than 25 years.

Cause of death in individuals with chronic HBV and/or HCV infection, a nationwide community-based register study.

Studies on chronic viral hepatitis and mortality have often been made on selected populations or in high-endemic countries. The aim of this study was to investigate the causes of death and the mortality rates in the nationwide cohorts of people chronically infected with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) in Sweden, a low-endemic country. All notifications on chronic HBV infection and HCV infection 1990-2003 were linked to the Cause of Death Register. A total of 9517 people with chronic HBV infection, 34 235 people with HCV infection and 1601 with chronic HBV-HCV co-infection were included, and the mean observation times were 6.4, 6.3 and 7.9 years, respectively. The mortality in the cohorts was compared with age- and gender-specific mortality in the general population and standardized mortality ratios (SMR) were calculated. All-cause mortality was significantly increased, SMR 2.3 (HBV), 5.8 (HCV) and 8.5 (HBV-HCV), with a great excess liver-related mortality in all cohorts, SMR 21.7, 35.5 and 46.2, respectively. In HCV and HBV-HCV infected there was an increased mortality due to drug-related psychiatric diagnoses (SMR: 20.7 and 27.6) and external causes (SMR: 12.4 and 11.4), predominantly at younger age. To conclude, this study demonstrated an increased all-cause mortality, with a great excess mortality from liver disease, in all cohorts. In people with HCV infection the highest excess mortality in younger ages was from drug-related and external reasons.

Mortality following Campylobacter infection: a registry-based linkage study.

BACKGROUND: Campylobacteriosis is one of the most commonly identified causes of bacterial diarrheal disease and a common cause of gastroenteritis in travellers from developed nations. Despite the widespread occurrence, there is little information on Campylobacter mortality. METHODS: Mortality among a cohort of Campylobacter cases were compared with the general population 0-1, 1-3, 3-12 and more than 12 month after the onset of the illness. The cases were sub-grouped according to if they had been infected domestically or abroad. RESULTS: The standardized mortality ratio for cases infected domestically was 2.9 (95% CI: 1.9-4.0) within the first month following the illness. The risk then gradually diminished and approached 1.0 after one year or more have passed since the illness. This initial excess risk was not attributable to any particular age group (such as the oldest). In contrast, for those infected abroad, a lower standardized mortality ratio 0.3 (95% CI: 0.04-0.8) was shown for the first month after diagnosis compared to what would be expected in the general population. CONCLUSION: Infection with Campylobacter is associated with an increased short-term risk of death among those who were infected domestically. On the contrary, for those infected abroad a lower than expected risk of death was evident. We suggest that the explanation behind this is a "healthy traveler effect" among imported cases, and effects of a more frail than average population among domestic cases.

A phase I clinical study of a live attenuated Bordetella pertussis vaccine--BPZE1; a single centre, double-blind, placebo-controlled, dose-escalating study of BPZE1 given intranasally to healthy adult male volunteers.

BACKGROUND: Acellular pertussis vaccines do not control pertussis. A new approach to offer protection to infants is necessary. BPZE1, a genetically modified Bordetella pertussis strain, was developed as a live attenuated nasal pertussis vaccine by genetically eliminating or detoxifying 3 toxins. METHODS: We performed a double-blind, placebo-controlled, dose-escalating study of BPZE1 given intranasally for the first time to human volunteers, the first trial of a live attenuated bacterial vaccine specifically designed for the respiratory tract. 12 subjects per dose group received 10³, 105 or 107 colony-forming units as droplets with half of the dose in each nostril. 12 controls received the diluent. Local and systemic safety and immune responses were assessed during 6 months, and nasopharyngeal colonization with BPZE1 was determined with repeated cultures during the first 4 weeks after vaccination. RESULTS: Colonization was seen in one subject in the low dose, one in the medium dose and five in the high dose group. Significant increases in immune responses against pertussis antigens were seen in all colonized subjects. There was one serious adverse event not related to the vaccine. Other adverse events were trivial and occurred with similar frequency in the placebo and vaccine groups. CONCLUSIONS: BPZE1 is safe in healthy adults and able to transiently colonize the nasopharynx. It induces immune responses in all colonized individuals. BPZE1 can thus undergo further clinical development, including dose optimization and trials in younger age groups. TRIAL REGISTRATION: ClinicalTrials.gov NCT01188512.

A nationwide cohort study of mortality risk and long-term prognosis in infective endocarditis in Sweden.

OBJECTIVES: Infective endocarditis (IE) remains a serious disease with substantial mortality. In this study we investigated the incidence of IE, as well as its associated short and long term mortality rates. METHODS: The IE cases were identified in the Swedish national inpatient register using ICD-10 codes, and then linked to the population register in order to identify deaths in the cohort. Crude mortality rates among IE patients were obtained for different time intervals. These rates were directly standardized using sex- and age-matched mortality in the general population. RESULTS: The cohort consisted of 7603 individuals and 7817 episodes of IE during 1997-2007. The 30 days all-cause crude mortality rate was 10.4% and the standardized mortality ratio (SMR) was 33.7 (95% confidence interval [CI]: 31.0-36.6). Excluding the first year of follow-up, the long term mortality (1-5 years) showed an increased SMR of 2.2 (95% CI: 2.0-2.3) compared to the general population. Significantly higher SMR was found for cases of IE younger than 65 years of age with a 1-5 year SMR of 6.3, and intravenous drug-users with a SMR of 19.1. Native valve IE cases, in which surgery was performed had lower crude mortality rates and Mantel-Haenzel odds ratios of less than one compared to those with medical therapy alone during 30-day and 5-years follow-up. CONCLUSIONS: The 30-days crude mortality rate for IE was 10.4% and long-term relative mortality risk remains increased even up to 5 years of follow-up, therefore a close monitoring of these patients would be of value.

Risk of kidney cancer and chronic kidney disease in relation to hepatitis C virus infection: a nationwide register-based cohort study in Sweden.

Chronic hepatitis C virus (HCV) infection is an established cause of liver cancer, and recent studies have suggested a link with kidney cancer. The aim of this study was to evaluate risk of kidney cancer in relation to HCV infection in a nationwide registry-based study of Swedish residents diagnosed with HCV between 1990 and 2006. A total of 43 000 individuals with chronic HCV infection were included, and the mean follow-up time was 9.3 years. Observed kidney cancer incidence and mortality in the cohort were compared with expected values based on the age-adjusted and sex-adjusted rates in the general population. Risk of hospitalization for other chronic kidney disease was also evaluated using Cox proportional hazards regression. No association between HCV infection and risk of kidney cancer was observed [standardized incidence ratio with 1-year lag=1.2; 95% confidence interval (CI): 0.8-1.7]. Risk of hospitalization for noncancer kidney disease was significantly elevated in the HCV cohort, with significantly stronger associations observed among women than among men [hazard ratio=5.8 (95% CI: 4.2-7.9) and 3.9 (95% CI: 3.2-4.8) for women and men, respectively]. Results of this study do not support the hypothesis that chronic HCV infection confers an increased risk of kidney cancer. However, we did find an association between HCV infection and chronic kidney disease, particularly among women. Given inconsistent findings in the literature, it is premature to consider HCV infection to be a risk factor for kidney cancer.

Short- and long-term effects of bacterial gastrointestinal infections.

During 1997-2004, microbiologically confirmed gastrointestinal infections were reported for 101,855 patients in Sweden. Among patients who had Salmonella infection (n = 34,664), we found an increased risk for aortic aneurysm (standardized incidence ratio [SIR] 6.4, 95% confidence interval [CI] 3.1-11.8) within 3 months after infection and an elevated risk for ulcerative colitis (SIR 3.2, 95% CI 2.2-4.6) within 1 year after infection. We also found this elevated risk for ulcerative colitis among Campylobacter infections (n = 57,425; SIR 2.8, 95% CI 2.0-3.8). Within 1 year, we found an increased risk for reactive arthritis among patients with Yersinia enteritis (n = 5,133; SIR 47.0, 95% CI 21.5-89.2), Salmonella infection (SIR 18.2, 95% CI 12.0-26.5), and Campylobacter infection (SIR 6.3, 95% CI 3.5-10.4). Acute gastroenteritis is sometimes associated with disease manifestations from several organ systems that may require hospitalization of patients.

Renal function in community-dwelling frail elderly. Comparison between measured and predicted glomerular filtration rate in the elderly and proposal for a new cystatin C-based prediction equation.

BACKGROUND AND AIMS: There is a great need to evaluate renal function regularly in elderly people. This study aimed at analyzing renal function in stable, community-dwelling elderly people of 75 years and over, to compare measured and predicted glomerular filtration rates (GFR) and to develop an accurate prediction equation for this age group. METHODS: Forty-five ambulatory elderly people in stable health in ordinary living were randomly selected into four age-classes, aged 75-95. Demographic data, personal activities of daily living, continuous drug prescriptions, body composition, blood pressure and blood chemistry were analysed. GFR was measured as Iohexol clearance based on three time-points 3, 4 and 7 hours after Iohexol injection. RESULTS: Mean GFR was well preserved in all four age-classes. The GFR range was 18-83 mL/min and declined with age. The Cockcroft-Gault prediction equation systematically underestimated measured GFR. A new 'GFRA' prediction equation is presented, based on the inverse of serum cystatin C and independent of gender, body surface area, body weight, lean body mass or serum creatinine. The proposed equation underestimated measured GFR with a mean of only 0.1 mL/min, had better precision compared with the Cockcroft-Gault equation, and was evaluated by the method of cross-validation. CONCLUSIONS: GFR exhibits extensive heterogeneity in frail, community-dwelling elderly people. The proposed GFRA was clearly more precise than the Cockcroft-Gault prediction equation in the study group. However, it needs to be validated in a larger population of elderly subjects, including more individuals in stable health with substantially reduced renal function in whom GFR is measured by a reference method with adequate sampling time.

Salmonella-associated deaths, Sweden, 1997-2003.

We examined excess deaths after infection with Salmonella in a registry-based matched cohort study of 25,060 persons infected abroad and 5,139 infected within Sweden. The domestically infected have an increased standardized mortality ratio, whereas those who acquired Salmonella infection abroad had no excess risk of death.

Risk factors for domestic sporadic campylobacteriosis among young children in Sweden.

A case-control study was conducted in Sweden to study risk factors for domestically acquired Campylobacter jejuni/coli infections among children aged less than 6 y. A total of 126 cases, reported to the national surveillance system were recruited over 1 y. Controls, selected from the population register, were matched to the cases by age, gender, place of residence and time of infection of the case. Information was gathered by posted questionnaires. Two separate conditional regression models were developed including and excluding 'protective' factors. Two of the factors significantly associated with Campylobacter infection were water-related: having a well in the household (OR=2.6) and drinking water from a lake/river (OR=7.4; 6.0). Other exposures associated with increased risk were: having a dog (OR=8.4; 3.8) and eating grilled meat (OR=5.5; 2.1). Drinking unpasteurized milk was borderline significant in 1 model (OR=3.7). Eating sausage was protective (OR=0.05). Eating chicken was not a significant risk. Exposures such as eating grilled meat and drinking water from a lake or a river were more common in the warm months, a factor that may partly explain the observed seasonality. The authors suggest that differences between risk factors across studies may reflect geographical and age-specific differences in the sources of infection.

Non-Hodgkin's lymphoma and other nonhepatic malignancies in Swedish patients with hepatitis C virus infection.

The aim of this study was to evaluate the association between hepatitis C virus (HCV) infection and non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), thyroid cancer (TC), chronic lymphatic leukemia (CLL), acute lymphatic leukemia (ALL), and Hodgkin's lymphoma (HL). A Swedish cohort of 27,150 HCV-infected persons notified during 1990-2000 was included in the study. The database was linked to other national registers to calculate the observation time, expressed as person-years, and to identify all incident malignancies in the cohort. The patients were stratified according to assumed time of previous HCV infection. The relative risk of malignancy was expressed as a standardized incidence ratio (SIR)-the observed number compared to the expected number. During 1990-2000 there were 50 NHL, 15 MM, 14 ALL, 8 TC, 6 CLL, and 4 HL diagnoses in the cohort. Altogether, 20 NHL, 7 MM, 5 TC, 4 CLL, 1 ALL, and 1 HL patient fulfilled the criteria to be included in the statistical analysis. The observation time was 122,272 person-years. The risk of NHL and MM was significantly increased in the stratum with more than 15 years of infection (SIR 1.89 [95% CI, 1.10-3.03] and 2.54 [95% CI, 1.11-5.69], respectively). The association was not significant in TC or CLL. In conclusion, we report the incidence of several malignancies in a nationwide cohort of HCV-infected persons. Although the delayed diagnosis of HCV probably has resulted in an underestimation of the risk, this study showed a significantly increased risk of NHL and MM.

Timeliness of MMR vaccination--influence on vaccination coverage.

Over the last seven years, and especially in 2001, a declining coverage for MMR vaccination in 2-year-olds has been noted in Sweden. By recording actual date of vaccination in a cohort of almost 4,000 children in a county in central Sweden, we found that parents' decision to postpone vaccination by up to 1.5 years beyond the stipulated age of 18 months accounted for about half the reported drop in 2001. Even if coverage thus improves with time, postponed vaccination adds to the pool of unprotected children in the population. The design of the current national surveillance system overestimates coverage at 2 years and fails to record delayed vaccination. To avoid future outbreaks that can appear around imported cases of measles it is crucial to attain high coverage levels by timely vaccination.