Limited neutralisation of the SARS-CoV-2 Omicron subvariants BA.1 and BA.2 by convalescent and vaccine serum and monoclonal antibodies.

BACKGROUND: In recent months, Omicron variants of SARS-CoV-2 have become dominant in many regions of the world, and case numbers with Omicron subvariants BA.1 and BA.2 continue to increase. Due to numerous mutations in the spike protein, the efficacy of currently available vaccines, which are based on Wuhan-Hu 1 isolate of SARS-CoV-2, is reduced, leading to breakthrough infections. Efficacy of monoclonal antibody therapy is also likely impaired. METHODS: In our in vitro study using A549-AT cells constitutively expressing ACE2 and TMPRSS2, we determined and compared the neutralizing capacity of vaccine-elicited sera, convalescent sera and monoclonal antibodies against authentic SARS-CoV-2 Omicron BA.1 and BA.2 compared with Delta. FINDINGS: Almost no neutralisation of Omicron BA.1 and BA.2 was observed using sera from individuals vaccinated with two doses 6 months earlier, regardless of the type of vaccine taken. Shortly after the booster dose, most sera from triple BNT162b2-vaccinated individuals were able to neutralise both Omicron variants. In line with waning antibody levels three months after the booster, only weak residual neutralisation was observed for BA.1 (26%, n = 34, 0 median NT50) and BA.2 (44%, n = 34, 0 median NT50). In addition, BA.1 but not BA.2 was resistant to the neutralising monoclonal antibodies casirivimab/imdevimab, while BA.2 exhibited almost a complete evasion from the neutralisation induced by sotrovimab. INTERPRETATION: Both SARS-CoV-2 Omicron subvariants BA.1 and BA.2 escape antibody-mediated neutralisation elicited by vaccination, previous infection with SARS-CoV-2, and monoclonal antibodies. Waning immunity renders the majority of tested sera obtained three months after booster vaccination negative in BA.1 and BA.2 neutralisation. Omicron subvariant specific resistance to the monoclonal antibodies casirivimab/imdevimab and sotrovimab emphasizes the importance of genotype-surveillance and guided application. FUNDING: This study was supported in part by the Goethe-Corona-Fund of the Goethe University Frankfurt (M.W.) and the Federal Ministry of Education and Research (COVIDready; grant 02WRS1621C (M.W.).

Characterization of the Antibody and Interferon-Gamma Release Response after a Second COVID-19 Booster Vaccination.

The emergence of SARS-CoV-2 Omicron subvariants prompted countries to call for accelerated booster vaccinations to limit disease and transmission. Here, we characterized correlates of protection over time after the second booster or after Omicron BA.1 infection comparing variants of concern (VOCs). Sera from subjects before and two and seven weeks after the second booster or after Omicron infection were examined for the level of Spike receptor-binding-domain (RBD)-specific antibodies. Furthermore, neutralizing antibodies (nABs) were characterized in in vitro neutralization assays comparing the variants of concern Alpha, Beta, Delta, and Omicron BA.1 and BA.2 against the ancestral strain B.1. Here, the second booster resulted in an increase in anti-RBD-IgG-antibodies, remaining nearly constant over time, accompanied by an increase in nABs against B.1 and the VOCs Alpha, Beta, Delta, and Omicron BA.1 and BA.2. However, compared to B.1, the neutralizing capacity against the Omicron subvariants remained low and was limited after the second booster vaccination. This indicates that antibody-mediated protection against infection with this VOC is unlikely, as evidenced by the fact that three individuals of our study cohort became infected with Omicron BA.1 after the second booster. T cell activation was measured by interferon-gamma release assays in a subgroup of subjects and was increased in all subjects tested after the second booster vaccination, correlating with the amount of Spike-specific antibodies. In subjects with Omicron BA.1 breakthrough infection, a significant increase in nABs to all VOCs studied was observed independently of booster vaccinations. Taken together, our data indicate that a second booster or Omicron BA.1 infection mediate a substantial increase in anti-Spike IgG antibodies; however, infection with Omicron BA.1 induced a stronger increase in neutralizing antibodies against the different VOCs.

Infectivity and stability of hepatitis C virus in different perfusion solutions.

BACKGROUND: Owing to organ shortage, transplantation of organs from HCV (hepatitis C virus) viremic donors into HCV negative individuals is getting more and more accepted. However, transmission of HCV to the host is nearly universal. Until now it is unknown if preservation solutions (PS) might alter infectivity and stability of HCV in the transplant setting. Therefore, seven different preservation solutions (PS) with variable composition were tested in vitro for their direct anti- and proviral effects on HCV. METHODS: In vitro grown HCV based on the JFH-1 isolate was used to characterize the effect of seven different PS on the HCV replication cycle including HCV attachment, entry, replication, and assembly. In addition, HCV stability in PS was tested. RESULTS: Overall, 6/7 PS enhanced HCV infectivity: IGL-1 increased HCV attachment and entry, UW Belzer and Perfadex boosted HCV entry. Production of novel viral particles was enhanced in HTK, UW Belzer, and IGL-1. In contrast, viral replication was significantly reduced in HTK solution while all other PS had no effect on HCV RNA replication. HCV was significantly more stable in HTK solution. Euro Collins was the only PS that did not support HCV infectivity in cell culture. None of the used PS showed cytotoxic effects. CONCLUSION: Our data indicate that HCV infectivity and stability is maintained by several PS.

Impact of RAS mutation subtype on clinical outcome-a cross-entity comparison of patients with advanced non-small cell lung cancer and colorectal cancer.

Mutated RAS onco-proteins are key drivers across many cancers. The distribution of somatic RAS mutations varies between cancer entities. Retrospective analyses have associated some RAS mutations with distinct clinical outcomes. However, the clinical impact of the full spectrum of RAS mutations in their disease contextuality remains to be defined. To improve upon this situation, we studied genomically and clinically annotated, prospectively recruited cohorts of patients with RAS-mutated metastatic lung cancer and colorectal cancer. Mutational spectra were compared with predictions derived from analyzing the mutagenic impact at the genome level for each entity. Interestingly, we found concordance of predicted signatures with those actually observed in our patients. Thus, composition of the functionally active RAS mutational subtypes is primarily determined by the mutagenic context. Most RAS mutations seemed dominant oncogenic drivers with entity-dependent clinical outcomes. RAS comutations were enriched in tumors harboring class 2/3 BRAF mutations, highlighting the functional dependency of some mutated BRAF isoforms on RAS. With our dataset, we established a probabilistic model for cross-entity comparison of the prognostic impact of specific RAS mutational subtypes. The resulting prognostic clusters showed largely consistent clinical categorizations in both entities. This suggests mutant subtype-specific functional properties leading to similar clinical effects. A notable exception is KRAS G12C, which imparted an adverse prognosis only in colorectal cancer. Our findings provide a framework for risk stratification of specific RAS mutations across several cancer entities, which is required to guide the analysis of clinical findings in patients treated with direct RAS inhibitors or agents targeting downstream pathways.

Methylene Blue Treatment of Grafts During Cold Ischemia Time Reduces the Risk of Hepatitis C Virus Transmission.

Background: Although organ shortage is a rising problem, organs from hepatitis C virus (HCV) ribonucleic acid (RNA)-positive donors are not routinely transplanted in HCV-negative individuals. Because HCV only infects hepatocytes, other organs such as kidneys are merely contaminated with HCV via the blood. In this study, we established a protocol to reduce HCV virions during the cold ischemic time. Methods: Standard virological assays were used to investigate the effect of antivirals, including methylene blue (MB), in different preservation solutions. Kidneys from mini pigs were contaminated with Jc1 or HCV RNA-positive human serum. Afterwards, organs were flushed with MB. Hypothermic machine perfusion was used to optimize reduction of HCV. Results: Three different antivirals were investigated for their ability to inactivate HCV in vitro. Only MB completely inactivated HCV in the presence of all perfusion solutions. Hepatitis C virus-contaminated kidneys from mini pigs were treated with MB and hypothermic machine perfusion without any negative effect on the graft. Human liver-uPA-SCID mice did not establish HCV infection after inoculation with flow through from these kidneys. Conclusions: This proof-of-concept study is a first step to reduce transmission of infectious HCV particles in the transplant setting and might serve as a model for other relevant pathogens.

Environmental Stability and Infectivity of Hepatitis C Virus (HCV) in Different Human Body Fluids.

Background: Hepatitis C virus (HCV) is a hepatotropic, blood-borne virus, but in up to one-third of infections of the transmission route remained unidentified. Viral genome copies of HCV have been identified in several body fluids, however, non-parental transmission upon exposure to contaminated body fluids seems to be rare. Several body fluids, e.g., tears and saliva, are renowned for their antimicrobial and antiviral properties, nevertheless, HCV stability has never been systematically analyzed in those fluids. Methods: We used state of the art infectious HCV cell culture techniques to investigate the stability of HCV in different body fluids to estimate the potential risk of transmission via patient body fluid material. In addition, we mimicked a potential contamination of HCV in tear fluid and analyzed which impact commercially available contact lens solutions might have in such a scenario. Results: We could demonstrate that HCV remains infectious over several days in body fluids like tears, saliva, semen, and cerebrospinal fluid. Only hydrogen-peroxide contact lens solutions were able to efficiently inactivate HCV in a suspension test. Conclusion: These results indicate that HCV, once it is present in various body fluids of infected patients, remains infective and could potentially contribute to transmission upon direct contact.

Clinical course and core variability in HBV infected patients without detectable anti-HBc antibodies.

BACKGROUND: The presence of anti-HBc antibodies indicates direct encounter of the immune system with hepatitis B virus (HBV). OBJECTIVES: Aim of our study was to seek for anti-HBc negative but HBV replicating patients and analyze their clinical course and preconditions. STUDY DESIGN: From 1568 HBV-DNA positive patients, 29 patients (1.85%) tested negative for anti-HBc. The absence of anti-HBc could be confirmed in 19 patients using an alternative assay. In 16 of 19 cases, a partial or full HBV genome analysis was performed with NGS sequencing to evaluate if specific mutations were associated with anti-HBc absence. As a control group samples from 32 matched HBV infected patients with detectable anti-HBc were sequenced. RESULTS: Patients with detectable HBV-DNA and sequenced HBV core region in the confirmed absence of anti-HBc were diagnosed with acute HBV infection (n=3), HBV reactivation (n=9) and chronic hepatitis B (n=4). Most patients (12/16) were immunosuppressed: 3/16 patients had an HIV coinfection, 7/16 patients suffered from a malignant disease and 4/16 patients underwent solid organ transplantation (from which 2/4 had a malignant disease). Compared to the control cohort, HBV variants from anti-HBc negative patients showed less variability in the core region. CONCLUSIONS: In the absence of anti-HBc, HBV-DNA was most often found in immunocompromised hosts. Distinct mutations or deletions in the core region did not explain anti-HBc negativity. It would be advisable not to rely only on a single result of anti-HBc negativity to exclude HBV infection in immunocompromised hosts, but to measure anti-HBc repeatedly or with different methods.

Modulation of HCV reinfection after orthotopic liver transplantation by fibroblast growth factor-2 and other non-interferon mediators.

OBJECTIVE: In HCV infected individuals graft infection occurs shortly after orthotopic liver transplantation (OLT). We aimed to describe the composition of the inflammatory response at this time, how it affects the HCV replication cycle and identify novel proviral and antiviral factors. DESIGN: We used a Luminex assay to quantify 50 inflammatory mediators in sera before and shortly after OLT. In vitro grown HCV based on the JFH-1 isolate were used to characterise the effects of patient sera and individual mediators on HCV. RESULTS: Although the mediator composition is highly variable between individuals, sera drawn immediately post-OLT significantly enhance HCV infectivity compared with control sera from before OLT in about half of the cases. Among 27 non-interferon inflammatory mediators fibroblast growth factor (FGF)-2 stood out as it enhanced HCV RNA replication and release of infectious particles. The effect was concentration-dependent and detectable in dividing and non-dividing cells. Moreover, pharmacological inhibition of FGF-2 receptor signalling abrogated the enhancing effect of FGF-2 and inhibited HCV replication in the absence of serum FGF-2 suggesting that HCV replication is dependent on basal activation of the FGF-2 triggered signalling pathway. Finally, in individuals with chronic HCV infection with high viral load, serum FGF-2 was significantly higher compared with those with low viral load. CONCLUSIONS: Although no single mediator may account for this effect, serum shortly post-OLT enhances HCV infection. FGF-2 is a novel endogenous driver of HCV replication and a potential therapeutic target.

Microbiological analysis of fluids in postsurgical gastroesophageal intrathoracic leaks obtained by endoscopy: a new way to optimize antibiotic therapy.

BACKGROUND/AIMS: Postsurgical gastroesophageal intrathoracic leakage is a potentially life-threatening condition that is frequently accompanied by mediastinitis and subsequent sepsis. Aspiration of fluids from intrathoracic leaks during endoscopy for microbiological analysis is rarely performed in clinical routine. The aim was to evaluate the role of routine microbiological analysis of intrathoracic leaks via endoscopy and its impact on antibiotic therapy. METHODS: This is a prospective, observational single-center study. Seventeen consecutive patients who presented for endoscopic treatment of intrathoracic leaks were included. Concomitantly, fluids from intrathoracic leaks during endoscopic intervention and blood cultures were obtained and a microbiological analysis was performed. RESULTS: Bacteria and/or fungi were detected by culture of fluid aspirated from intrathoracic leaks in 88% cases, but in none of the blood cultures. In 15 patients, microbial colonization of the leakage was detected despite previous empiric antibiotic therapy; treatment had to be adjusted in all patients according to the observed antibiotic susceptibility profile. CONCLUSIONS: The microbiological colonization of postsurgical gastroesophageal intrathoracic leaks in patients is frequent. Only the direct microbiological analysis of fluids from intrathoracic leaks, but not of blood cultures, is effective for optimizing an antibiotic therapy in such patients.

Ligation of left renal vein for spontaneous splenorenal shunt to prevent portal hypoperfusion after orthotopic liver transplantation.

We report a case of recovered portal flow by ligation of the left renal vein on the first postoperative day after orthotopic liver transplantation of a 54-year-old female with alcoholic liver cirrhosis, chronic kidney failure, and spontaneous splenorenal shunt. After reperfusion, Doppler ultrasonography showed almost total diversion of the portal flow into the existing splenorenal shunt, but because of severe coagulopathy and diffuse bleeding, ligation of the shunt was not attempted. A programmed relaparotomy was performed on the first postoperative day, and the left renal vein was ligated just to the left of the inferior vena cava. Portal flows subsequently increased to 37 cm/sec, and the patient presented a good and stable liver function. We conclude that patients with known preoperative splenorenal shunts should be closely monitored, and if the portal flow becomes insufficient, ligation of the left renal vein should be attempted in order to optimize the portal perfusion of the liver.

Rapid early HDV RNA decline in the peripheral blood but prolonged intrahepatic hepatitis delta antigen persistence after liver transplantation.

BACKGROUND & AIMS: Chronic HDV infection is an inflammatory liver disease and liver transplantation (LTX) remains the only curative treatment option for most patients. The hepatitis D virus (HDV) uses HBsAg as its surface protein, however, it is controversial to what extend HDV may be detected independently of HBsAg in blood and liver after LTX. The aims of this study were to investigate kinetics of HDV RNA and HBsAg early after LTX, to apply the data to a mathematical model and to study long-term persistence of HDV after LTX. METHODS: We retrospectively analyzed 26 patients with chronic hepatitis delta who underwent LTX between 1994 and 2009. Blood samples were obtained every 1-3 days during the first 14 days after LTX. Data were applied to a mathematical model to study viral kinetics. Available liver biopsy samples were stained for HBV and HDV viral antigens and tested for HBV DNA/cccDNA. RESULTS: HBsAg and HDV RNA became negative after a median of 5 days (range 1-13) and 4 days (range 1-10), respectively. Early HDV RNA and HBsAg decline paralleled almost exactly in all patients; however the mathematical model showed a high variability of virion death. HDAg stained positive in transplanted livers in six patients in the absence of liver HBV DNA/cccDNA, serum-HBsAg, and HDV RNA for up to 19 months after LTX. CONCLUSIONS: HDV RNA and HBsAg decline follow almost identical kinetic patterns within the first days after LTX. Nevertheless, intrahepatic latency of HDAg has to be considered when exploring novel concepts to withdraw HBIG.

The novel immunosuppressive protein kinase C inhibitor sotrastaurin has no pro-viral effects on the replication cycle of hepatitis B or C virus.

The pan-protein kinase C (PKC) inhibitor sotrastaurin (AEB071) is a novel immunosuppressant currently in phase II trials for immunosuppression after solid organ transplantation. Besides T-cell activation, PKC affects numerous cellular processes that are potentially important for the replication of hepatitis B virus (HBV) and hepatitis C virus (HCV), major blood-borne pathogens prevalent in solid organ transplant recipients. This study uses state of the art virological assays to assess the direct, non-immune mediated effects of sotrastaurin on HBV and HCV. Most importantly, sotrastaurin had no pro-viral effect on either HBV or HCV. In the presence of high concentrations of sotrastaurin, well above those used clinically and close to levels where cytotoxic effects become detectable, there was a reduction of HCV and HBV replication. This reduction is very likely due to cytotoxic and/or anti-proliferative effects rather than direct anti-viral activity of the drug. Replication cycle stages other than genome replication such as viral cell entry and spread of HCV infection directly between adjacent cells was clearly unaffected by sotrastaurin. These data support the evaluation of sotrastaurin in HBV and/or HCV infected transplant recipients.

Dual function of the NK cell receptor 2B4 (CD244) in the regulation of HCV-specific CD8+ T cells.

The outcome of viral infections is dependent on the function of CD8+ T cells which are tightly regulated by costimulatory molecules. The NK cell receptor 2B4 (CD244) is a transmembrane protein belonging to the Ig superfamily which can also be expressed by CD8+ T cells. The aim of this study was to analyze the role of 2B4 as an additional costimulatory receptor regulating CD8+ T cell function and in particular to investigate its implication for exhaustion of hepatitis C virus (HCV)-specific CD8+ T cells during persistent infection. We demonstrate that (i) 2B4 is expressed on virus-specific CD8+ T cells during acute and chronic hepatitis C, (ii) that 2B4 cross-linking can lead to both inhibition and activation of HCV-specific CD8+ T cell function, depending on expression levels of 2B4 and the intracellular adaptor molecule SAP and (iii) that 2B4 stimulation may counteract enhanced proliferation of HCV-specific CD8+ T cells induced by PD1 blockade. We suggest that 2B4 is another important molecule within the network of costimulatory/inhibitory receptors regulating CD8+ T cell function in acute and chronic hepatitis C and that 2B4 expression levels could also be a marker of CD8+ T cell dysfunction. Understanding in more detail how 2B4 exerts its differential effects could have implications for the development of novel immunotherapies of HCV infection aiming to achieve immune control.

Liver transplantation: A new risk factor for intestinal intussusceptions.

BACKGROUND: Intestinal intussusception in adults is associated with chronic inflammatory bowel disease, celiac disease, abdominal tumors or previous abdominal surgery but most often of unknown origin. AIM: The aim of our study was to evaluate circumstances and identify risk factors for intussusceptions. METHODS: All 65,928 abdominal ultrasound examinations performed at our tertiary medical center between January 2001 and June 2008 were analyzed retrospectively for the diagnosis "intussusception". After identifying individuals with sonographically proven intussusception we analyzed various patients' characteristics including age, gender and underlying disease as well as sonographic findings such as localization of the intussusception, absence or presence of ascites and lymph nodes. RESULTS: We identified 32 cases of intussusceptions [mean age 45 years (range 18 to 88); 18 patients were male]. Twelve patients (38%) had a history of abdominal surgery including 8 patients who had undergone liver transplantation (2 patients with primary sclerosing cholangitis, 1 patient with cystic fibrosis, 1 patient with sarcoidosis, 1 patient with hepatocellular carcinoma and HCV infection, 1 patient with autoimmune hepatitis, 1 patient with Crigler-Najar-syndrome and one patient with echinococcus). A hepaticojejunostomy had been performed in 4 of the patients after liver transplantation. Liver transplanted patients were significantly overrepresented in the intussusceptions group compared with the overall cohort of patients undergoing abdominal ultrasound examination (25% vs. 8%, Chi-Square-test, p = 0.0023). CONCLUSION: In our retrospective study liver transplantation, in particular with hepaticojejunostomy, was identified as a new major risk factor for intestinal intussusceptions

Glucocorticosteroids increase cell entry by hepatitis C virus.

BACKGROUND & AIMS: Corticosteroids are used as immunosuppressants in patients with autoimmune disorders and transplant recipients. However, these drugs worsen hepatitis C virus (HCV) recurrence after liver transplantation, suggesting that they may directly exacerbate HCV infection. METHODS: The influence of immunosuppressive drugs on HCV replication, assembly, and entry was assessed in Huh-7.5 cells and primary human hepatocytes using cell culture- and patient-derived HCV. Replication was quantified by immunofluorescence, luciferase assays, quantitative reverse-transcriptase polymerase chain reaction, or core enzyme-linked immunosorbent assays. Expression of HCV entry factors was evaluated by cell sorting and immunoblot analyses. RESULTS: Glucocorticosteroids slightly reduced HCV RNA replication but increased efficiency of HCV entry by up to 10-fold. This was independent of HCV genotype but specific to HCV because vesicular stomatitis virus glycoprotein-dependent infection was not affected by these drugs. The increase in HCV entry was accompanied by up-regulation of messenger RNA and protein levels of occludin and the scavenger receptor class B type I-2 host cell proteins required for HCV infection; increase of entry by glucocorticosteroids was ablated by RU-486, an inhibitor of glucocorticosteroid signaling. Glucocorticosteroids increased propagation of cell culture-derived HCV approximately 5- to 10-fold in partially differentiated human hepatoma cells and increased infection of primary human hepatocytes by cell culture- and patient-derived HCV. CONCLUSIONS: Glucocorticosteroides specifically increase HCV entry by up-regulating the cell entry factors occludin and scavenger receptor class B type I. Our data suggest that the potential effects of high-dose glucocorticosteroids on HCV infection in vivo may be due to increased HCV dissemination.

Membranous Budd-Chiari syndrome in Caucasians.

OBJECTIVE: Budd-Chiari syndrome (BCS) is characterized by an obstruction of hepatic venous outflow. Membranous obstruction of the inferior vena cava (IVC) is a curable cause of primary BCS but is very rare in Western Europe. To date, there is only very limited information on membranous BCS in the Western world. We here report the diagnosis and management of five Caucasian patients with membranous BCS. MATERIAL AND METHODS: Out of 23 patients with BCS diagnosed between 2004 and 2007 we identified five with a membranous web of the IVC. Diagnostic evaluation of BCS included laboratory tests, ultrasound Doppler imaging, CT and MRI. RESULTS: The clinical presentation of membranous BCS was heterogeneous. The time frame from first clinical symptoms to diagnosis ranged from 3 weeks to 60 years. Liver cirrhosis was misdiagnosed in 4/5 patients. CT did not establish the correct diagnosis of membranous BCS in any of our patients. In contrast, abdominal Doppler ultrasonography showed collaterals and a web in the IVC which was confirmed by Doppler-MRI and hepatovenography. Four patients underwent interventional treatment with balloon dilatation of short-segment venous stenoses or complete occlusions. Therapy was successful: in all cases it resulted in a normalized extrahepatic blood flow and reduction of spleen size. CONCLUSIONS: Membranous BCS may be underdiagnosed in Caucasians. Doppler ultrasound should be used as the initial diagnostic procedure for membranous BCS. Although CT is considered the "gold standard" in addition to angiography, it could not detect membranous obliteration in our cases. Patients can be effectively treated by interventional endovascular therapy.

Surgery and radioablation therapy combined: introducing a 1-week-condensed procedure bonding total thyroidectomy and radioablation therapy with recombinant human TSH.

OBJECTIVE: The objective of this study was to determine whether the use of recombinant human TSH (rhTSH) to stimulate radioiodine uptake after thyroidectomy is as efficacious as a period of withholding thyroid hormones, while at the same time avoiding hypothyroidism, reducing sick leave time and shortening the hospital stay. DESIGN: Our aim was to compare the standard procedure of differentiated thyroid cancer treatment, which consists of thyroidectomy followed by 4 weeks of hypothyroidism and a conclusive ablative activity of (131)iodine, with a new shortened treatment in which l-thyroxine (T(4)) medication is initiated a day after thyroidectomy, followed by application of rhTSH stimulation and subsequent ablation a few days after surgery. We presumed our treatment to represent the most sophisticated strategy for the reduction in sick leave days overall without any reduction in safety or the efficacy of ablative therapy. METHODS: Patients (n=25) were randomized either for surgery and rhTSH stimulation or surgery and l-T(4) abstinence before the first application of radioiodine. Ablation success was determined by neck ultrasound and serum thyroglobulin during follow-up. RhTSH receivers were monitored for an average of 635 days (s.d.+/-289) and patients in l-T(4) abstinence for an average of 624 days (s.d.+/-205). Both groups were statistically compared for significant differences in treatment efficacy, safety and overall time of sick leave. RESULTS AND CONCLUSIONS: Our shortened treatment proved to be equally efficacious and safe in comparison with the conventional therapy regimen. At the same time, it showed economic advantages through the reduction in average sick leave time from approximately 29 days (l-T(4) abstinence) down to approximately 6 days (rhTSH stimulation) as well as sustaining the patient's quality of life by the complete avoidance of hypothyroidism.

Persistence of occult hepatitis B after removal of the hepatitis B virus-infected liver.

Occult hepatitis B is defined as the persistence of hepatitis B virus (HBV) DNA in persons without HBV surface antigen (HBsAg). The primary site for HBV persistence in persons with occult hepatitis B is considered to be the liver. We provide virological and immunological evidence for long-term persistence of HBV, even after removal of the infected liver, in 25 consecutive, randomly selected liver transplant recipients who tested positive for anti-HBV core antigen (anti-HBcAg) and negative for HBsAg at the time of transplantation. Furthermore, in a cohort of 101 anti-HBcAg-positive/HBsAg-negative patients, 2 showed clinical HBV reactivation after transplantation. Thus, these data indicate that a long-term extrahepatic HBV reservoir exists, which is relevant not only for liver transplantation but also for other types of transplantations, including bone marrow grafting.