Increased cancer rates in patients with chronic hepatitis C.

AIMS: As previous reports show an association of chronic hepatitis C (HCV) with hepatocellular carcinoma (HCC) and non-liver cancers, we examine the association of HCV with liver cancer and non-liver cancers. METHODS: Retrospective cross-sectional study at Kaiser Permanente Southern California (KPSC) evaluating HCV and non-HCV patients from 1 January 2008 to 12 December 2012. Cancer diagnoses were obtained from the KPSC-SEER-affiliated registry. Logistic regression analyses were used for rate ratios and time-to-event analyses were performed using Cox proportional hazards models, adjusted for age, gender, race, smoking and cirrhosis. Cancer rate ratios were stratified by tobacco, alcohol abuse, diabetes and body mass index (BMI). RESULTS: The initial population and final population of multivariable analysis were N = 5 332 903 and N = 2 080 335 respectively. Cancer burden (all sites) was significantly higher in HCV than in non-HCV patients and HCV patients had a high rate of liver cancer. When liver cancer was excluded, cancer rates remained significantly increased in HCV. Unadjusted cancer rates were significantly higher in HCV compared to non-HCV for oesophageal, stomach, colorectal, pancreas, myeloma, non-Hodgkin's lymphoma, head/neck, lung, renal and prostate cancer. After stratification for alcohol abuse, tobacco, diabetes and BMI, increased cancer rates remained significant for all cancer sites, liver cancer and non-Hodgkin's lymphoma. Multivariable analyses demonstrated a strong correlation between cirrhosis and cancer. Tobacco use and diabetes were also associated with cancer. In the absence of cirrhosis, HCV, tobacco use and diabetes significantly increased the cancer risk. Mediation analyses showed that cirrhosis was responsible for a large proportion on the effect of HCV on cancer risk. CONCLUSION: This study supports the concept of HCV as a systemic illness and treating HCV regardless of disease severity and prior to progression to cirrhosis.

Epidemiology of fungaemia in Sweden: A nationwide retrospective observational survey.

OBJECTIVES: To identify the epidemiology and antifungal susceptibilities of Candida spp. among blood culture isolates to identify the epidemiology and antifungal susceptibilities of Candida spp. among blood culture isolates in Sweden. METHODS: The study was a retrospective, observational nationwide laboratory-based surveillance for fungaemia and fungal meningitis and was conducted from September 2015 to August 2016. RESULTS: In total, 488 Candida blood culture isolates were obtained from 471 patients (58% males). Compared to our previous study, the incidence of candidaemia has increased from 4.2/100 000 (2005-2006) to 4.7/100 000 population/year (2015-2016). The three most common Candida spp. isolated from blood cultures were Candida albicans (54.7%), Candida glabrata (19.7%) and species in the Candida parapsilosis complex (9.4%). Candida resistance to fluconazole was 2% in C. albicans and between 0% and 100%, in non-albicans species other than C. glabrata and C. krusei. Resistance to voriconazole was rare, except for C. glabrata, C. krusei and C. tropicalis. Resistance to anidulafungin was 3.8% while no Candida isolate was resistant to amphotericin B. CONCLUSIONS: We report an overall increase in candidaemia but a minor decrease of C. albicans while C. glabrata and C. parapsilosis remain constant over this 10-year period.

ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV.

BACKGROUND: The interferon-free regimen of ABT-450 with ritonavir (ABT-450/r), ombitasvir, and dasabuvir with or without ribavirin has shown efficacy in inducing a sustained virologic response in a phase 2 study involving patients with hepatitis C virus (HCV) genotype 1 infection. We conducted two phase 3 trials to examine the efficacy and safety of this regimen in previously untreated patients with HCV genotype 1 infection and no cirrhosis. METHODS: We randomly assigned 419 patients with HCV genotype 1b infection (PEARL-III study) and 305 patients with genotype 1a infection (PEARL-IV study) to 12 weeks of ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), dasabuvir (250 mg twice daily), and ribavirin administered according to body weight or to matching placebo for ribavirin. The primary efficacy end point was a sustained virologic response (an HCV RNA level of <25 IU per milliliter) 12 weeks after the end of treatment. RESULTS: The study regimen resulted in high rates of sustained virologic response among patients with HCV genotype 1b infection (99.5% with ribavirin and 99.0% without ribavirin) and among those with genotype 1a infection (97.0% and 90.2%, respectively). Of patients with genotype 1b infection, 1 had virologic failure, and 2 did not have data available at post-treatment week 12. Among patients with genotype 1a infection, the rate of virologic failure was higher in the ribavirin-free group than in the ribavirin group (7.8% vs. 2.0%). In both studies, decreases in the hemoglobin level were significantly more common in patients receiving ribavirin. Two patients (0.3%) discontinued the study drugs owing to adverse events. The most common adverse events were fatigue, headache, and nausea. CONCLUSIONS: Twelve weeks of treatment with ABT-450/r-ombitasvir and dasabuvir without ribavirin was associated with high rates of sustained virologic response among previously untreated patients with HCV genotype 1 infection. Rates of virologic failure were higher without ribavirin than with ribavirin among patients with genotype 1a infection but not among those with genotype 1b infection. (Funded by AbbVie; PEARL-III and PEARL-IV ClinicalTrials.gov numbers, NCT01767116 and NCT01833533.).

Safety and Efficacy of Simeprevir/Sofosbuvir in Hepatitis C-Infected Patients With Compensated and Decompensated Cirrhosis.

UNLABELLED: Risks and benefits of simeprevir plus sofosbuvir (SIM+SOF) in patients with advanced cirrhosis are unknown. We assessed the safety and sustained virological responses (SVR) of SIM+SOF with and without ribavirin (RBV) in patients with Child-Pugh (CP)-B/C versus CP-A cirrhosis and compared to matched untreated controls. This study was of a multicenter cohort of adults with hepatitis C virus genotype 1 and cirrhosis treated with SIM+SOF with/without RBV for 12 weeks. Controls were matched on treatment center, age, CP class, and Model for End-Stage Liver Disease (MELD) score. Of 160 patients treated with SIM+SOF with/without RBV, 35% had CP-B/C and 64% had CP-A, with median baseline MELD 9 (interquartile range, 8-11). Sustained virological response at week 12 (SVR12) was achieved by 73% of CP-B/C versus 91% of CP-A (P < 0.01). CP-B/C versus CP-A had more early treatment discontinuations (11% vs. 1%), adverse events (AEs) requiring hospitalization (22% vs. 2%), infections requiring antibiotics (20% vs. 1%), and hepatic decompensating events (20% vs. 3%; all P < 0.01). There were 2 deaths: 1 CP-B/C (liver related) and 1 CP-A (not liver related). In multivariate analysis, CP-B/C independently predicted lack of SVR12 (odds ratio, 0.27; 95% confidence interval: 0.08-0.92). In comparing SIM+SOF-treated patients versus matched untreated controls, AEs requiring hospitalization (9% vs. 13%; P = 0.55), infections (8% vs. 6%; P = 0.47), and events of decompensation (9% vs. 10%; P = 0.78) occurred at similar frequency. CONCLUSIONS: SIM+SOF with/without RBV has lower efficacy and higher rates of AEs in patients with CP-B/C cirrhosis, compared to CP-A. Frequency of adverse safety outcomes were similar to matched untreated controls, suggesting that safety events reflect the natural history of cirrhosis and are not related to treatment.

Real-world value of direct-acting antivirals for hepatitis C at Kaiser Permanente Southern California.

OBJECTIVES: Direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) lead to cure in more than 95% of recipients; however, payers may limit access to these lifesaving drugs due to high initial cost. Here, the cost-effectiveness of treating HCV with DAAs vs no treatment over a lifetime horizon is evaluated from the perspective of Kaiser Permanente Southern California (KPSC). STUDY DESIGN: A hybrid decision-tree Markov model. METHODS: The model simulated the health and economic outcomes for a real cohort of patients with HCV treated with either ledipasvir-sofosbuvir or sofosbuvir-velpatasvir between November 1, 2014, and October 31, 2019, at KPSC. Patients entered the model at different stages of liver disease and received either active treatment with DAAs or no treatment. Patients who did not achieve sustained virological response experienced disease progression; those who achieved sustained virological response experienced either significantly slower or no disease progression depending on the stage of fibrosis at model start. Demographics, treatment experience, genotype, baseline fibrosis stage, treatment rates, and treatment efficacy were sourced from KPSC real-world data. Costs and utilities were sourced from published literature. RESULTS: A total of 7255 patients with a mean age of 59 years were treated during the study period. Over a lifetime horizon, DAAs resulted in significant reduction in advanced liver disease events and a total cost savings of $1 billion compared with no treatment based on a hybrid decision-tree Markov state-transition model. Cost savings were achieved after only 3 years. DAA intervention dominated no treatment on a per-patient and cohort basis. CONCLUSIONS: DAA treatment at KPSC is predicted to significantly reduce HCV-related morbidity and mortality, providing an anticipated return on investment in drug costs after 3 years of treatment.

The Natural History of NAFLD, a Community-Based Study at a Large Health Care Delivery System in the United States.

Nonalcoholic fatty liver disease (NAFLD) is a global public health problem. However, the natural history of NAFLD is incomplete. This is a retrospective cohort study of patients identified with NAFLD by diagnosis codes in a large, community-based health care delivery system. The objectives were (1) to follow patients from initial NAFLD presentation through progression to cirrhosis and/or decompensated cirrhosis to liver cancer, liver transplant, and death for up to 10 years; and (2) to conduct disease progression analysis restricted to patients with NAFLD identified as having diabetes at baseline. A total of 98,164 patients with full NAFLD and 26,488 with diabetes were divided into three baseline prevalent states: (1) no cirrhosis, (2) compensated cirrhosis, and (3) decompensated cirrhosis. In baseline patients without cirrhosis, annual rates of compensated cirrhosis, decompensated cirrhosis, and death were 0.28%, 0.31%, and 0.63% per year, respectively. With baseline compensated cirrhosis, the annual rates of decompensation and death were 2.4% and 6.7% per year. Finally, in those with decompensated cirrhosis at baseline, the death rate was 8.0% per year. In those without cirrhosis and with cirrhosis at baseline, the rates of liver cancer and death were increased approximately 2-fold in the diabetic subpopulation compared with the full NAFLD cohort. Age and comorbidities increased with increasing disease severity. Cox proportional hazards regression analysis showed that cirrhosis was strongly associated with death and liver cancer, and that diabetes was associated with a significant increase in the hazard of both liver cancer and death (2.56 [2.04-3.20] and 1.43 [1.35-1.52]), respectively. Conclusion: The findings of this community-based study further our understanding of the natural history of NAFLD and demonstrate that diabetes is a major factor in the progression of this disease.

Young drivers--reduced crash risk with passengers in the vehicle.

Studies have shown that the effect of passengers on accident propensity among young drivers is ambiguous--in some cases positive and some negative. In Sweden, various kinds of information are compiled in registers, including a national accident database and exposure data collected in a national investigation of the driving habits of license holders. Access to such data offers a good opportunity to study crash risks related to driving with and without passengers. This was done for drivers in three different age groups (18-24, 25-64 and >65 years) accompanied by one, two or three or more passengers. Differences in crash risk were estimated using incidence density ratios (IDRs) and 95% confidence intervals. The results show that passengers had an overall protective effect, that is, the crash risk was higher for those who drove alone, regardless of their age or gender. This protective effect increased with every extra passenger (up to eight), indicating that the more passengers in the vehicle, the safer the driving. The influence of passengers was weakest (albeit still positive) among the youngest drivers (ages 18-24 years), especially the males in that group. The protective impact showed the same pattern on all days of the week, but was most marked from Friday to Sunday for most of the drivers, regardless of age.

Practicing in relation to the outcome of the driving test.

In Sweden, a written and a driving test must be passed for licensure, and these two examinations are the only means of verifying that learner drivers have acquired the competencies stipulated in the national curriculum. The present study investigated 18-24-year olds regarding the effects of personal background and mode of driver education instruction on the outcome of the driving test. This was done by analysing the following for individual subjects: data on practicing obtained using a questionnaire, and test results of license tests. The results suggest that among the candidates under study, there are equal opportunities in the context of obtaining a driver's license independent of a person's background. The rate of passing was higher for those who started behind-the-wheel training at 16 and applied to take the driving test via a driving school, than for those who started the training at an older age and applied to take the test in person. It was also found that the probability of passing the test was greater if there is successful cooperation between learner and driving school instructor, and if a large proportion of the training been devoted to the task speed adaptation.

Lack of association between Chlamydophila pneumoniae seropositivity and abdominal aortic aneurysm.

Chronic Chlamydophila pneumoniae infection has been suggested as a possible contributing factor for the development and expansion of abdominal aortic aneurysm (AAA). The relevance of C pneumoniae involved in the processes underlying aneurysmal rupture is unknown. The aim of this study was to examine the relationship between C pneumoniae seropositivity and AAA rupture. In a case-control study, 119 patients with AAA and 36 matched controls were prospectively investigated with C pneumoniae serology. Patients with ruptured AAA have similar levels of IgG antibodies against C pneumoniae as patients with an electively operated AAA, a small AAA, and controls. In conclusion, this study fails to demonstrate a connection between C pneumoniae seropositivity and AAA rupture.

Practicing for and performance on drivers license tests in relation to gender differences in crash involvement among novice drivers.

PROBLEM: Young male novice drivers are overrepresented in injury motor-vehicle crashes compared to females in the same category. This difference in crash involvement is often assumed to include factors such as overestimation, risk acceptance, and sensation seeking, but it can also be related to acquisition of knowledge, skills, insight, and driving experience. Therefore, this study explored possible gender differences among 18-24-year-olds in Sweden regarding practicing as learners, outcome of the driver's tests, and crash involvement during the first year after licensure. METHOD: Data for 2005 from different sources (e.g., questionnaires, license test, and crash statistics) were examined. It was not possible to follow individual subjects through all stages or in all analyses. Nevertheless, the study design did enable scrutinization and discussion of gender differences between younger inexperienced drivers with respect to education and training, license test results, and initial period of licensure. RESULTS: Males and females assimilated tuition in different ways. Females studied more theory, pursued training in a more structured manner, practiced more elements of driving in several different environments, and participated more extensively in driving school instruction. National statistics showed that females did better on the written test but not on the driving test. Males were involved in 1.9 more injury crashes per 1,000 drivers than females during their first year of licensed driving. The proportional distribution of crash types was the same for both sexes during the first period as novice drivers, but the circumstances surrounding the accidents varied (e.g., males were involved in more night crashes). IMPACT ON TRAFFIC SAFETY: More structured training while learning appears to be one of the reasons why females initially do better than males as novice drivers. Therefore, in the future, driver education should focus not only on matters such as the amount of time spent on training and preconditioning, but also on the importance of the organization and content of the learning process.

Safety halls--an evaluation.

PROBLEM: In most countries, drivers licensing systems usually include teaching some aspects of using safety equipment (e.g., airbags and seat belts). However, there is now evidence worldwide that such education is inadequate, as indicated by, for example, the overrepresentation of young drivers who do not use seat belts. METHOD: A randomized controlled study was conducted in Sweden to evaluate the effects of visiting a facility known as a "safety hall" in combination with the mandatory skid training. The results were assessed to determine the effects of the knowledge and attitudes of learner drivers in the following subjects: airbags, securing loads, seat belts, sitting posture, speed, and tires. An experimental group and a control group comprising 658 and 668 learners, respectively, answered identical questionnaires on three different occasions (pretest, posttest 1, and posttest 2). RESULTS: The results show that, for most of the topics considered, knowledge and attitudes in both groups were better at posttest 2 than at the pretest, and in general, the best knowledge and attitudes were found in the experimental group. The combined safety/skid training seems to have had the greatest effect on seat belts and loads. The findings also indicate that the safety halls can be further improved to achieve an even better effect. IMPACT ON TRAFFIC SAFETY: The use of safety halls has improved the knowledge and attitudes of learner drivers concerning several important areas related to traffic safety. Since knowledge and attitudes are important predictors of behavior, implementing safety halls can be expected to lead to improvements, especially regarding the use of safety belts and securing loads.

Accident involvement among learner drivers--an analysis of the consequences of supervised practice.

It is a well-known fact that experience is important for safe driving. Previously, this presented a problem since experience was mostly gained during the most dangerous period of driving-the first years with a licence. In many countries, this "experience paradox" has been addressed by providing increased opportunities to gain experience through supervised practice. One question, however, which still needs to be answered is what has been lost and what has been gained through supervised practice. Does this method lead to fewer accidents after licensing and/or has the number of accidents in driving practice increased? There were three aims in the study. The first was to calculate the size of the accident problem in terms of the number of accidents, health risk and accident risk during practising. The second aim was to evaluate the solution of the "experience paradox" that supervised practice suggests by calculating the costs in terms of accidents during driving practice and the benefits in terms of reduced accident involvement after obtaining a licence. The third aim was to analyse conflict types that occur during driving practice. National register data on licence holders and police-reported injury accidents and self-reported exposure were used. The results show that during the period 1994-2000, 444 driving practice injury accidents were registered, compared to 13657 accidents during the first 2 years with a licence. The health risk during the period after licensing was 33 times higher and the accident risk 10 times higher than the corresponding risk during practice. The cost-benefit analysis showed that the benefits in terms of accident reduction after licensing were 30 times higher than the costs in terms of driving practice accidents. It is recommended that measures to reduce such accidents should focus on better education of the lay instructor, but not on introducing measures to reduce the amount of lay-instructed practice.

Abdominal aortic aneurysm and infection with CagA positive strains of Helicobacter pylori.

The aim of the present study was to investigate whether virulent CagA positive Helicobacter pylori strains are those preferentially related to abdominal aortic aneurysm (AAA) rupture. Several microorganisms have been linked to aneurysm development. Chronic Chlamydophila pneumoniae infection has been suggested as a possible contributing factor for the development and expansion of AAA. Previous studies have shown increased risk of carotid atherosclerosis and coronary heart disease in subjects harbouring CagA positive strains of H. pylori. The relevance of CagA positive H. pylori involved in the processes underlying aneurysmal development, expansion, and rupture is unknown. In a case-control study, 119 patients with AAA and 36 matched controls were prospectively investigated with H. pylori serology. Patients with ruptured AAA have similar levels of IgG antibodies against H. pylori to patients with electively operated AAA, small AAA, and controls. In conclusion, this study fails to demonstrate a connection between H. pylori CagA seropositivity and abdominal aortic aneurysm rupture.

Abdominal aortic aneurysm and cytomegalovirus infection.

Cytomegalovirus (CMV) has been implicated in the pathogenesis of atherosclerosis. Abdominal aortic aneurysm is regarded traditionally as a consequence of atherosclerosis. Several microorganisms have been suggested as possible contributing factors for the development of abdominal aortic aneurysm. The relevance of CMV in the processes underlying the development, expansion, and rupture of abdominal aortic aneurysm is unknown. The aim of the present study was to investigate whether CMV infection is related to abdominal aortic aneurysm rupture. One hundred nineteen patients with abdominal aortic aneurysm and 36 matched controls without abdominal aortic aneurysm were investigated prospectively by CMV serology. Patients with ruptured abdominal aortic aneurysm have similar levels of IgG antibodies against CMV as patients with nonruptured abdominal aortic aneurysm, small abdominal aortic aneurysm, and controls without abdominal aortic aneurysm. In conclusion, this study fails to demonstrate a connection between CMV infection and abdominal aortic aneurysm rupture.

Luteococcus sanguinis sp. nov., isolated from human blood.

An unusual catalase-positive, Gram-positive, coccus-shaped bacterium that originated from a human blood specimen was subjected to a polyphasic taxonomic study. Cell-wall murein and lipid composition analyses indicated that the unknown isolate was a member of the genus Luteococcus. The results of comparative 16S rRNA gene sequence analysis were consistent with chemotaxonomic findings and showed that the unidentified bacterium represents a hitherto unknown sublineage within the genus Luteococcus that is closely related to, but distinct from, Luteococcus japonicus. On the basis of both phenotypic and phylogenetic evidence, it is proposed that the unknown bacterium from human blood should be classified as Luteococcus sanguinis sp. nov., with the type strain CCUG 33897(T) (=CIP 107216(T)).