After hepatitis B virus (HBV) infectionThe incubation period of a viral disease refers to the time between infection and the onset of symptoms, and has been believed to represent the phase of active viral replication before an effective host immune response. This period is generally long after infection with noncytopathic viruses such as hepatitis B virus (HBV), 1 in contrast to other viral diseases. [2][3][4] The development of symptoms, which may occur up to 6 months after HBV infection, 5 has been assumed to mark the onset of viral control by the immune system. 1 However, the observation of marked reductions in virus levels before liver injury in the chimpanzee model of HBV infection, 6 and of cytotoxic T lymphocyte (CTL)-mediated viral clearance in the absence of cytolysis, in a transgenic mouse model of HBV infection, 7 has challenged the evidence that HBV control is predominantly caused by CTL-mediated tissue injury. It is, therefore, possible that immunologic events important for the control of HBV may already be present during the long incubation phase of primary infection. However, patients are usually only diagnosed after the development of symptoms: thus, it has been difficult to study the relationship between viral dynamics and liver injury, and whether the incubation phase of HBV infection in humans represents a period of ongoing viral replication in the presence of a deficient immune response. 8 During a single-source outbreak of HBV infection, in which 30 patients were infected through a skin-piercing procedure known as autohemotherapy, 9 a number of patients were identified before the onset of clinical hepatitis. The recent development of immunologic techniques to directly quantify virusspecific lymphocytes, 10,11 enabling the dynamics of CD8 and CD4 responses during viral infections to be investigated, provided a unique opportunity to study the interaction among virus, clinical disease, and host immune responses from the incubation phase of acute HBV infection. PATIENTS AND METHODS Patients.Five patients (all women, mean age 54 years, range 37-71) were identified during the incubation phase of acute hepatitis B, and were longitudinally followed up through the course of the disease. Their infection was diagnosed on the basis of finding a positive serum hepatitis B surface antigen (HBsAg), HBV DNA by polymerase chain reaction, normal or minimally raised serum alanine transaminase (ALT) levels, a marker of hepatocyte damage, 12 and no symptoms of clinical acute hepatitis. Each patient was infected with the same variant of HBV, as assessed by viral genome sequencing and

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery datasets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5×10−8) and used pathway analysis to identify JAK-STAT/IL12/IL27 signaling and cytokine-cytokine pathways, for which relevant therapies exist.

Using patient data from a unique single source outbreak of hepatitis B virus (HBV) infection, we have characterized the kinetics of acute HBV infection by monitoring viral turnover in the serum during the late incubation and clinical phases of the disease in humans. HBV replicates rapidly with minimally estimated doubling times ranging between 2.2 and 5.8 d (mean 3.7 ± 1.5 d). After a peak viral load in serum of nearly 1010 HBV DNA copies/ml is attained, clearance of HBV DNA follows a two or three phase decay pattern with an initial rapid decline characterized by mean half-life (t 1/2) of 3.7 ± 1.2 d, similar to the t 1/2 observed in the noncytolytic clearance of covalently closed circular DNA for other hepadnaviruses. The final phase of virion clearance occurs at a variable rate (t 1/2 of 4.8 to 284 d) and may relate to the rate of loss of infected hepatocytes. Free virus has a mean t 1/2 of at most 1.2 ± 0.6 d. We estimate a peak HBV production rate of at least 1013 virions/day and a maximum production rate of an infected hepatocyte of 200–1,000 virions/day, on average. At this peak rate of virion production we estimate that every possible single and most double mutations would be created each day.

ObjectivesTo quantify post-colonoscopy colorectal cancer (PCCRC) rates in England by using recent World Endoscopy Organisation guidelines, compare incidence among colonoscopy providers, and explore associated factors that could benefit from quality improvement initiatives.DesignPopulation based cohort study.SettingNational Health Service in England between 2005 and 2013.PopulationAll people undergoing colonoscopy and subsequently diagnosed as having colorectal cancer up to three years after their investigation (PCCRC-3yr).Main outcome measuresNational trends in incidence of PCCRC (within 6-36 months of colonoscopy), univariable and multivariable analyses to explore factors associated with occurrence, and funnel plots to measure variation among providers.ResultsThe overall unadjusted PCCRC-3yr rate was 7.4% (9317/126 152), which decreased from 9.0% in 2005 to 6.5% in 2013 (P<0.01). Rates were lower for colonoscopies performed under the NHS bowel cancer screening programme (593/16 640, 3.6%), while they were higher for those conducted by non-NHS providers (187/2009, 9.3%). Rates were higher in women, in older age groups, and in people with inflammatory bowel disease or diverticular disease, in those with higher comorbidity scores, and in people with previous cancers. Substantial variation in rates among colonoscopy providers remained after adjustment for case mix.ConclusionsWide variation exists in PCCRC-3yr rates across NHS colonoscopy providers in England. The lowest incidence was seen in colonoscopies performed under the NHS bowel cancer screening programme. Quality improvement initiatives are needed to address this variation in rates and prevent colorectal cancer by enabling earlier diagnosis, removing premalignant polyps, and therefore improving outcomes.

-This paper discusses the annual incidence of liver disease and resource costs in providing a hepatology service for all new outpatient referrals to a secondary care setting. In a retrospective study, we found that 200 patients (1 in 1,000 of the West Suffolk population) with a mean age of 52 years were referred per year. One-third of patients had cirrhosis (almost half due to alcohol). Annual incidence (per 100,000 population) were as follows: non-alcoholic fatty liver disease (29: of which 23.5 non-cirrhotic and 5.5 cirrhotic), hepatitis C (25), hepatitis B (3), alcohol-related cirrhosis (12.5), primary biliary cirrhosis (3.5), autoimmune hepatitis (3), primary sclerosing cholangitis (2), haemochromatosis (2), hepatocellular carcinoma (1.5) and oesophageal variceal haemorrhage (6.5). Using national indicative tariffs, the total annual hepatology budget was £130K (£58K for resources and £72K for clinic attendances). The greatest resource expenditure was on endoscopy (almost half for oesophageal varices) and radiological imaging (one-third of the total budget). These findings will help inform commissioners in hepatology service funding. IntroductionPurchasing of NHS secondary healthcare resources was implemented at primary care level through practice-based commissioning at the end of 2006. 1,2 Important issues to be addressed, for provision of secondary care hepatology outpatient services, include identifying the local healthcare demands (based upon the local aetiology and epidemiology of liver disease) and the resources required to meet these demands with their associated cost implications. This paper addresses these issues and provides findings from a retrospective study, over a one year period, in a secondary care setting. Methods Local demographicsThe West Suffolk hepatology catchment area serves a population of about 200,000 people, is largely rural with low unemployment rates (about 2%), and 98% of the population is white. The Office for National Statistics (ONS) 3 recently reported that Moreton Hall, a council ward of Bury St Edmunds, has the longest average life expectancy from birth of all council wards in England and Wales -at 93.4 years. Parameters analysedParameters analysed in our study included:• number of annual new patient referrals and patient demographics• number of derived follow-ups • causation, incidence and stage of liver disease • resources (investigations and procedures) required from support services (including laboratory blood tests, liver imaging, liver biopsy, paracentesis of ascites, and endoscopy for screening or management of oesophageal varices)• costs of outpatient clinic attendances and resources used. Inclusion criteriaIndications for referral to the hepatology clinic included patients with decompensated liver disease, alcohol-induced liver disease, viral hepatitis, autoimmune liver disease, haemochromatosis and, more commonly, patients with persistent (more than 3-6 months) elevation of serum liver function tests (LFTs), especially alanine aminotransferase (ALT), des...