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The hepatitis E virus (HEV) is one of the main causes of acute hepatitis and the de facto global burden is underestimated. HEV-related clinical complications are often undetected and are not considered in the differential diagnosis. Convincing findings from studies suggest that HEV is clinically relevant not only in developing countries but also in industrialized countries. Eight HEV genotypes (HEV-1 to HEV-8) with different human and animal hosts and other HEV-related viruses are in circulation. Transmission routes vary by genotype and location, with large waterborne outbreaks in developing countries and zoonotic food-borne infections in developed countries. An acute infection can be aggravated in pregnant women, organ transplant recipients, patients with pre-existing liver disease and immunosuppressed patients. HEV during pregnancy affects the fetus and newborn with an increased risk of vertical transmission, preterm and stillbirth, neonatal jaundice and miscarriage. Hepatitis E is associated with extrahepatic manifestations that include neurological disorders such as neuralgic amyotrophy, Guillain-Barré syndrome and encephalitis, renal injury and haematological disorders. The risk of transfusion-transmitted HEV is increasingly recognized in Western countries where the risk may be because of a zoonosis. RNA testing of blood components is essential to determine the risk of transfusion-transmitted HEV. There are currently no approved drugs or vaccines for HEV infections. This review focuses on updating the latest developments in zoonoses, screening and diagnostics, drugs in use and under development, and vaccines.

Background Coinfections of HIV-positive individuals with Hepatitis B and D virus (HBV and HDV) are common and can be associated with rapid liver damage. Several antiretroviral drugs for HIV exhibit anti-HBV effect; however, the selection of HBV drug resistance mutations (DRMs) in individuals under HIV antiretroviral therapy (ART) has been reported but rarely in Nigeria. In this study the HBV/HDV prevalence and HBV DRMs in HIV-positive individuals in Southwestern Nigeria were assessed. Methods Plasma samples collected from 310 HIV-positive individuals including 295 ART-experienced and 15 ART-naïve persons attending the HIV clinic in three south-western states of Nigeria between June 2017 and August 2017 were analysed by ELISA for HBsAg and anti-HDV. The presence of HDV RNA and HBV DNA was analysed by (RT)-PCR followed by sequencing and phylogenetic analyses for genotyping. The HBV reverse transcription (RT) region was amplified and sequenced for the analysis of drug resistance mutations. Results Overall, 16.1% (n = 50/310) of the HIV-positive individuals were positive for HBsAg, most of which were ART-experienced (94.0%; n = 47/50). From the 50 HBsAg-positive samples, 72.0% (n = 36/50) were positive for HBV DNA and 16.0% (n = 8/50) had detectable HDV RNA while 5.6% (n = 2/36) of the HBV-DNA positive samples had anti-HDV total antibodies. Sequences were available for 31/36 of the HBV DNA-positive and 3/8 HDV RNA-positive samples. HBV DNA-positive samples were characterised as HBV genotype E infections exclusively, while HDV genotype 1 was detected in the HDV RNA-positive samples. HBV DRMs V173L, L180M, S202I and M204V/I, which are associated with lamivudine resistance, were detected in 32.2% (n = 10/31) of the HBV DNA-positive samples. Most of these mutations (90.0%; n = 9/10) were present in the ART-experienced cohort. Conclusions This study indicates that HBV/HDV coinfections are common in HIV-positive individuals under ART in Nigeria. Furthermore, a high proportion of HBV DRMs which potentially compromise future treatment options were detected, underscoring the need for HBV screening prior to starting ART. Further studies should be performed to monitor a possible increase in the spread of HDV among populations at risk of HIV and HBV infections.

The hepatitis E virus (HEV) is one of the most common causes of hepatitis worldwide. HEV is also widespread in many developed countries, where the number of infections is steadily increasing. In those countries, the virus is transmitted mainly through consumption of undercooked or raw food or through contact with animals. Especially, pigs serve as a main reservoir of HEV. Here, we investigated the prevalence of HEV RNA in pork livers and pork meat products to assess the actual risk of HEV infection through food consumption in Germany. A total of 131 pork products were collected from grocery stores and butcher shops between October 2019 and February 2020 and screened for HEV RNA using nested PCR and subsequent sequencing. Overall, 10% of the samples were positive for HEV, including pork livers (5%), spreadable liver sausages (13%) and liver pâté samples (15%). Sequence analyses indicated that the large majority of HEV strains belonged to subtype HEV-3c, representing the most frequent subtype in Germany. One sample belonged to subtype HEV-3f. Further sequence analysis revealed large sequence variation between the samples; however, most of the mutations identified were synonymous. Although infectivity of the virus was not tested, the results suggest a considerable risk of HEV infection through food consumption. Therefore, preventive measures should be taken according to a One Health approach.

SummaryDuring brain homeostasis, stem cell fate determination is crucial to guarantee function, adaptation and regeneration while preventing neurodegeneration and cognitive impairment. How neural stem cells (NSCs) are instructed to generate neurons or glia is not well understood. Here we addressed how fate is resolved in multipotent adult hippocampal NSCs, and identify Scaffold Attachment Factor B1 (Safb1) as a determinant of neuron production by blocking glial commitment. Safb1 is sufficient to block oligodendrocytic differentiation of NSCs by preventing expression of the transcription factor NFIB at the post-transcriptional level. Detailed interrogation of the Drosha interactome and functional validation revealed that Safb1 enhances NFIB mRNA cleavage in a Drosha-dependent fashion. Thus, our study provides a cellular mechanism for selective NSC fate regulation by post-transcriptional destabilization of mRNAs. Given the importance of NSC maintenance and fate determination in the adult brain, our findings have major implications for cell-specific gene expression, brain disease and aging.

Infections with HEV in low- and middle-income countries (LMICs) are associated with increased rates of preterm birth, miscarriage, and stillbirth. The aim of the present study was to investigate HEV infections in pregnant women and the possibility of mother-to-child transmission, and associated outcomes. A total of 183 pregnant women in their third trimester were recruited and followed until delivery. Anti-HEV IgG and IgM were determined via enzyme-linked immunosorbent assay (ELISA), and HEV nucleic acids were detected in stool and cord blood samples. HEV genotypes were identified by Sanger sequencing, and phylogenetic analyses were performed. Mother-to-child transmission and associated adverse outcomes were not observed. Only 2% of patients (n = 4/183) tested positive for anti-HEV IgM, and 8% (n = 14/183) tested positive for anti-HEV IgG antibodies. Cord blood (n = 150) analysis showed that there was no IgM detected, while 4% (n = 6/150) tested positive for anti-HEV IgG, which was consistent with mothers testing positive for anti-HEV IgG. Nucleic acid tests for HEV RNA yielded 2% (n = 4/183) from the serum and stool of pregnant women, and none from cord blood. The HEV isolates belonged to the genotype HEV-3a, with 99% homology with humans and 96% with pigs. No association was found between the risk of HEV infection and pregnancy outcomes or HEV transmission from mother to child. HEV-3 infections of zoonotic origin in pregnancy might have eventually resolved without complications.

The diagnosis of acute and chronic myocarditis remains a challenge for clinicians. Characterization of this disease has been hampered by its diverse etiologies and heterogeneous clinical presentations. Most cases of myocarditis are caused by infectious agents. Despite successful research in the last few years, the pathophysiology of viral myocarditis and its sequelae leading to severe heart failure with a poor prognosis is not fully understood and represents a significant public health issue globally. Most likely, at a certain point, besides viral persistence, several etiological types merge into a common pathogenic autoimmune process leading to chronic inflammation and tissue remodeling, ultimately resulting in the clinical phenotype of dilated cardiomyopathy. Understanding the underlying molecular mechanisms is necessary to assess the prognosis of patients and is fundamental to appropriate specific and personalized therapeutic strategies. To reach this clinical prerequisite, there is the need for advanced diagnostic tools, including an endomyocardial biopsy and guidelines to optimize the management of this disease. The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has currently led to the worst pandemic in a century and has awakened a special sensitivity throughout the world to viral infections. This work aims to summarize the pathophysiology of viral myocarditis, advanced diagnostic methods and the current state of treatment options.

Infection of the heart muscle with cardiotropic viruses is one of the major aetiologies of myocarditis and acute and chronic inflammatory cardiomyopathy (DCMi). However, viral myocarditis and subsequent dilated cardiomyopathy is still a challenging disease to diagnose and to treat and is therefore a significant public health issue globally. Advances in clinical examination and thorough molecular genetic analysis of intramyocardial viruses and their activation status have incrementally improved our understanding of molecular pathogenesis and pathophysiology of viral infections of the heart muscle. To date, several cardiotropic viruses have been implicated as causes of myocarditis and DCMi. These include, among others, classical cardiotropic enteroviruses (Coxsackieviruses B), the most commonly detected parvovirus B19, and human herpes virus 6. A newcomer is the respiratory virus that has triggered the worst pandemic in a century, SARS-CoV-2, whose involvement and impact in viral cardiovascular disease is under scrutiny. Despite extensive research into the pathomechanisms of viral infections of the cardiovascular system, our knowledge regarding their treatment and management is still incomplete. Accordingly, in this review, we aim to explore and summarize the current knowledge and available evidence on viral infections of the heart. We focus on diagnostics, clinical relevance and cardiovascular consequences, pathophysiology, and current and novel treatment strategies.

As the global effort to eradicate hepatitis B continues, immune escape mutations (IEMs) and drug resistance mutations (DRMs) affecting its diagnosis, treatment, and prevention are compromising this goal. However, knowledge about the prevalence and circulation of these mutations in Nigeria is scarce. Serum samples (n = 199) from apparently healthy prospective blood donors, pregnant women, and individuals presenting with fever in southwestern Nigeria were analyzed for the presence of IEMs and DRMs by means of nested PCR in the HBV S (HBs) and HBV polymerase (Pol) genes, followed by phylogenetic and mutational analyses. In total, 25.1% (n = 50/199) of samples were positive for HBV, as measured by PCR. In 41 samples (20.6%), both fragments could be amplified, whereas the HBs gene and the Pol gene fragment alone were detected in 0.5% (n = 1/199) and 4% (n = 8/199) of samples, respectively. Sequences were successfully obtained for all 42 HBs gene fragments but for only 31/49 Pol gene fragments (totaling 73 sequences from 44 individuals). All sequences were identified as HBV genotype E. IEMs were present in 18.2% (n = 8/44) of the sequences of HBV-positive individuals with available sequences. IEM Q129H was detected in eight out of the 44 (18.2%) HBV isolates sequenced in this study, however, no DRMs were observed. This study confirms the circulation of HBV IEMs and reports the presence of Q129H IEM for the first time in Nigeria. Intensified research on the dynamics of IEM is necessary in order to enhance the elimination of HBV.

Human parvovirus B19 (B19V) is the predominant cardiotropic virus associated with dilated inflammatory cardiomyopathy (DCMi). Transcriptionally active cardiotropic B19V infection is clinically relevant and triggers adverse long-term mortality. During the study, we evaluated whether antiviral treatment with the nucleoside analogue telbivudine (LTD) is effective in suppressing transcriptional active B19V in endomyocardial biopsies (EMBs) of B19V positive patients and improving clinical outcomes. Seventeen B19V-positive patients (13 male, mean age 45.7 ± 13.9 years, mean left ventricular ejection fraction (LVEF) 37.7 ± 13.5%) with positive B19V DNA and transcriptional activity (B19V mRNA) in EMBs were treated with 600 mg/d LTD over a period of six months. Patients underwent EMBs before and after termination of the LTD treatment. B19V RNA copy numbers remained unchanged in 3/17 patients (non-responder) and declined or disappeared completely in the remaining 14/17 patients (responder) (p ≤ 0.0001). Notably, LVEF improvement was more significant in patients who reduced or lost B19V RNA (responder, p = 0.02) in contrast to non-responders (p = 0.7). In parallel, responder patients displayed statistically significant improvement in quality of life (QoL) questionnaires (p = 0.03) and dyspnea on exertion (p = 0.0006), reflecting an improvement in New York Heart Association (NYHA) Classification (p = 0.001). Our findings demonstrated for the first time that suppression of B19V transcriptional activity by LTD treatment improved hemodynamic and clinical outcome significantly. Thus, the present study substantiates the clinical relevance of detecting B19V transcriptional activity of the myocardium.

Erythroparvovirus (B19V) genomes have been detected in various organs of infected individuals including endothelial cells of the heart muscle. However, the role of B19V as a causative pathogen of myocardial damage is still unknown. The majority of reports focus on the presence of viral DNA ignoring proof of viral RNAs as important markers for viral activity. During this study, we established (RT-) qPCR to characterize expression of B19V RNAs (NS1 and VP1/2) in endomyocardial biopsies (EMBs) of 576 patients with unexplained heart failure. 403/576 (70%) EMBs were positive for B19V DNA. B19V mRNAs NS1 and/or VP1/2, indicating viral activity, could be detected in 38.5% of B19V DNA positive samples using the newly established B19V RT-PCRs. 22.1% of samples were characterized by only NS1 mRNA detection while 6.0% revealed only VP1/2 mRNA expression. Detection of both intermediates was successful in 10.4% of samples. Applying the molecular testing, our study revealed that a high proportion (38.5%) of B19V DNA positive EMBs was characterized by viral transcriptional activity. Further prospective studies will evaluate relevance of viral transcription intermediates as a diagnostic marker to differentiate between latent B19V infection and clinically relevant transcriptionally active B19V-infection of the heart muscle.

Hepatitis E virus (HEV) infection is a major public health concern in low-income countries, yet incidence and prevalence estimates are often lacking. Serum (n = 653) and faecal (n = 150) samples were collected from apparently healthy individuals using convenience sampling technique in six communities (Ore, Oke-Osun, Osogbo, Ede, Esa-Odo, and Iperindo) from Osun State, Nigeria. Serum samples were analysed for total anti-HEV IgG/IgM and anti-HEV IgM using commercially available HEV ELISA kits. Total anti-HEV positive serum and all stool samples were analysed for HEV RNA by RT-PCR. Overall, 15.0% (n = 98/653) and 3.8% (n = 25/653) of the serum samples were positive for anti-HEV total and IgM antibodies, respectively. Total anti-HEV and IgM in Ore, Oke-Osun, Osogbo, Ede, Esa-Odo, and Iperindo was 21.0% (n = 13/62) and 3.2% (n = 2/62), 19.4% (n = 20/103) and 6.8% (n = 7/103), 11.4% (n = 12/105) and 2.9% (n = 3/105), 8.0% (n = 16/199) and 1.5% (n = 3/199), 22.0% (n = 22/100) and 10.0% (n = 10/100), and 17.9% (n = 15/84) and 0.0% (n = 0/84), respectively. All samples (stool and serum) were HEV RNA negative. Anti-HEV seroprevalence was associated with rural location, increasing age, alcohol consumption, and rearing of animals. This study demonstrated a high anti-HEV seroprevalence in Osun State, indicating the need to implement surveillance and asses the hepatitis E burden in Nigeria.

Aims Since December 2019, the novel coronavirus SARS‐CoV‐2 has spread rapidly throughout China and keeps the world in suspense. Cardiovascular complications with myocarditis and embolism due to COVID‐19 have been reported. SARS‐CoV‐2 genome detection in the heart muscle has not been demonstrated so far, and the underlying pathophysiological mechanisms remain to be investigated. Methods and results Endomyocardial biopsies (EMBs) of 104 patients (mean age: 57.90 ± 16.37 years; left ventricular ejection fraction: 33.7 ± 14.6%, sex: n = 79 male/25 female) with suspected myocarditis or unexplained heart failure were analysed. EMB analysis included histology, immunohistochemistry, and detection of SARS‐CoV‐2 genomes by real‐time reverse transcription polymerase chain reaction in the IKDT Berlin, Germany. Among 104 EMBs investigated, five were confirmed with SARS‐CoV‐2 infected by reverse real‐time transcriptase polymerase chain reaction. We describe patients of different history of symptoms and time duration. Additionally, we investigated histopathological changes in myocardial tissue showing that the inflammatory process in EMBs seemed to permeate vascular wall leading to small arterial obliteration and damage. Conclusions This is the first report that established the evidence of SARS‐CoV‐2 genomes detection in EMBs. In these patients, myocardial injury ischaemia may play a role, which could explain the ubiquitous troponin increases. EMB‐based identification of the cause of myocardial injury may contribute to explain the different evolution of complicated SARS‐CoV‐2‐infection and to design future specific and personalized treatment strategies.

Are mental disorders on the rise, or rather the willingness to disclose them and ask for help? Is humanity becoming increasingly ill or is illness becoming more and more human? Which perspective on mental disorders, especially psychosis, helps the patient to integrate their own experience, and others to avoid social distance? Can psychiatry learn and eventually teach to view these distinct human characteristics not only as pathologic foreignness and abnormality, but also from an anthropological perspective, as a profoundly human expression that exists on a continuum? What value can categories such as purpose and happiness have in this context? The paper introduces the example of Hamburg as city of contradictions with high levels of sickness absence, but simultaneously top scores in the happiness index. Then follows an attempt to outline which perspective on mental illness and which therapeutic stance might be helpful, so that illness and happiness are no longer seen as mutually exclusive. The final case history asks the provocative question if there can be a "successful psychosis".

Background People who inject drugs (PWID) are at high risk of hepatitis B virus (HBV) infection by sharing needles and drug use paraphernalia. In Germany, no routine surveillance of HBV prevalence and vaccination coverage among PWID exists. Methods Socio-demographic and behavioural data were collected between 2011 and 2014 through face-to-face interviews, during a bio-behavioural survey of PWID recruited in eight German cities. Dried blood spots (DBS) prepared with capillary blood were tested for HBV markers. Factors associated with past/current HBV infection and vaccination status were analysed by univariable and multivariable analysis using logistic regression. The validity of self-reported HBV infection and vaccination status was analysed by comparison to the laboratory results. Results Among 2077 participants, the prevalence of current HBV infection was 1.1%, of past HBV infection was 24%, and of vaccine-induced HBV antibodies was 32%. No detectable HBV antibodies were found in 43%. HBV infection status was significantly associated with study city, age, years of injecting, use of stimulants, migration status, and homelessness; HBV vaccination status was significantly associated with study city, age, and level of education. Correct infection status was reported by 71% and correct vaccination status by 45%. Conclusions HBV seroprevalence among PWID was about five times higher than in the general population in Germany, confirming PWID as an important risk group. Targeted information campaigns on HBV and HBV prevention for PWID and professionals in contact with PWID need to be intensified. Routinely offered HBV vaccination during imprisonment and opioid substitution therapy would likely improve vaccination rates among PWID.

Hepatitis E virus (HEV) infection is an emerging infection that is of major public health concern, especially in some vulnerable groups like immunosuppressed individuals, pregnant women and HBV-coinfected individuals. HEV is transmitted faecal/oral or zoonotically depending on the HEV-genotype. This study aimed at investigating HEV infections among different at-risk populations in Osun State, Southwestern Nigeria. A total of 720 serum samples were collected from animal handlers, pregnant women, people living with HIV/AIDS, and Hepatitis B virus (HBV) infected individuals. Commercially available Enzyme-Linked Immunosorbent Assays (ELISA) were used for the detection of anti-HEV total and IgM antibodies. Polymerase chain reaction (PCR) was carried out in the HEV seropositive samples and all the samples from individuals infected with HBV. Descriptive analysis and chi-square test of association were performed. The anti-HEV total antibody seroprevalence in HIV-positive individuals, animal handlers and pregnant women was 11.4% (n = 47/411), 7.9% (n = 7/89), and 6.3% (n = 10/160), respectively. Markers of acute HEV infection (anti-HEV IgM) were detected in 2.2% of HIV-positive individuals (n = 9/411) and 1.8% of animal handlers (n = 2/89), respectively, and in 0.6% of pregnant women (n = 1/160). However, all samples were HEV RNA negative. This study analysed the presence of markers of HEV infection among different at-risk populations without clinical symptoms of HEV infection. Our results showed that HEV is an underestimated threat to public health in Nigeria and underlines the need of an HEV surveillance system to understand the distribution and transmission of HEV infection in animals and/to humans., Highlights • The risk of HEV-infection in at-risk populations like animal handlers, pregnant, or HIV infected individuals were assessed. • Anti-HEV seroprevalence in animal handlers, HIV-positive individuals, and pregnant was 11.4%, 7.9%, and 6.3%, respectively. • Anti-HEV IgM antibodies were detected in 2.2% of HIV-positive individuals, 1.8% of animal handlers, and in 0.6% of pregnant. • The finding has One Health implication underscoring the need of HEV surveillance to understand animal-to-human transmission.

Schizophrenia is a complex psychiatric disorder with unknown and presumably heterogeneous etiology. While the disorder can have various outcomes, research is predominantly “deficit-oriented” emphasizing the hardship that the disorder inflicts on sufferers as well as their families and society. Beyond symptom reduction, imparting patients with hope and meaning in life is increasingly considered an important treatment target, which may raise self-esteem, and reduce self-stigma and suicidal ideation. The present study compared a psychotherapeutic treatment aimed at improving cognitive insight, individualized metacognitive intervention (MCT+), with an active control in order to elucidate if personal meaning-making and hope can be improved in patients with psychosis across time. A total of 92 patients were randomized to either individualized metacognitive therapy (MCT+) or CogPack (neuropsychological training) and followed up for up to 6 months. The “Subjective Sense in Psychosis Questionnaire” (SUSE) was administered which covers different salutogenetic vs pathogenetic views of the disorder, valence of symptom experiences and the consequences of psychosis. Patients in the MCT+ group showed a significant positive shift in attitudes towards the consequences of their illness over time relative to patients in the active control condition. There was some evidence that MCT+ also enhanced meaning-making. The perceived negative consequences of psychosis were highly correlated with depression and low self-esteem, as well as suicidality. The study shows that a cognitive insight training can improve meaning-making in patients and help them come to terms with their diagnosis.

Objective The objective of the study was to investigate whether a combined intervention composed of early detection plus integrated care (EDIC) enhances outcomes in patients with early psychosis compared to standard care (SC). Methods ACCESS III is a prospective non-randomized historical control design 1-year study examining the efficacy of EDIC (n = 120) vs. SC (n = 105) in patients aged 12–29 years. Primary outcome was the rate of ≥6 months combined symptomatic and functional remission. Additional outcomes comprised the reduction of DUP and course of psychopathology, functioning, quality of life, and satisfaction with care. Results In observed cases, 48.9% in the EDIC and 15.2% in the SC group reached the primary endpoint. Remission was predicted by EDIC (OR = 6.8, CI: 3.15–14.53, P

Hepatitis E virus (HEV) is an emerging zoonotic pathogen that has received an increasing amount of attention from virologists, clinicians, veterinarians, and epidemiologists over the past decade. The host range and animal reservoirs of HEV are rapidly expanding and a plethora of emerging HEV variants have been recently identified, some of which have the potential for interspecies infection. In this review, the detection of genetically diverse HEV variants, classified into and presumably associated with the species Orthohepevirus C, currently comprising HEV genotypes C1 and C2, by either serological or molecular approach is summarized. The distribution, genomic variability, and evolution of Orthohepevirus C are analyzed. Moreover, the potential risk of cross-species infection and zoonotic transmission of Orthohepevirus C are discussed.

Hepatitis E virus (HEV) can lead to chronic infection in solid-organ transplant patients. Ribavirin is efficient for treatment of chronically infected patients. Recently, the1634R mutation in the HEV polymerase has been associated with treatment failure. However, it is unclear if this mutation can be used as a prognostic marker of treatment outcome. We studied the prevalence of the 1634R mutation in the HEV polymerase of patients starting ribavirin therapy, the influence of the 1634R variants on the viral response, the frequency of the 1634R mutation in patients whose treatment failed, and its impact on ribavirin retreatment. We analyzed pretreatment samples from 63 solid-organ transplant patients with chronic hepatitis E using deep sequencing; 42 patients had a sustained virologic response (SVR), and 21 were non-SVR patients. We detected the 1634R variant by deep sequencing in 36.5% (23/63) of the patients (proportions, 1.3 to 100%). The 1634R variant was detected in 31.0% (13/42) of baseline plasma samples from patients with SVR and in 47.6% (10/21) in the other patients (P = 0.2). The presence of this mutation did not influence the initial decrease in viral RNA. Lastly, a second prolonged ribavirin treatment led to SVR in 70% of the patients who initially did not have SVR, despite the presence of the 1634R variant. We conclude that the presence of the 1634R variant at ribavirin initiation does not lead to absolute ribavirin resistance. Although its proportion increased in patients whose treatment failed, the presence of the 1634R variant did not compromise the response to a second ribavirin treatment.

Objective: The ACCESS treatment model offers assertive community treatment (ACT) embedded in an integrated care program to patients with severe psychotic disorders. Compared to standard care, it proved to be more effective in terms of service disengagement and other outcomes in patients with psychotic disorders over 12, 24, and 48 months. Many patients with severe mental disorders experience involuntary admissions which can be potentially traumatic. In this study, we assessed the effect of ACT on reducing involuntary admissions over an observation period of 4 years.Method: One hundred seventy-one patients treated in ACCESS were included in this study. The primary outcome was rate of involuntary admissions during 48 months. Secondary outcomes were differences between those with and without involuntary admissions in the 2 years prior to ACCESS regarding change of psychopathology, severity of illness, psychosocial functioning, quality of life, satisfaction with care, medication non-adherence, and service-disengagement.Results: Of 171 patients, 58 patients (33.9%) were involuntarily admitted to hospital in the past 2 years before entry. During the 4 years of treatment, 16 patients (9.4%) were involuntarily admitted to hospital which was a significantly lower rate compared to the 2 years before inclusion in ACCESS (p < .001). Comparing the two groups, larger improvements in severity of illness (p = .004) and functional status (p = .043) were detected in the group with no history of involuntary admissions. At 4-year follow-up, of the remaining patients, 69.2% (n = 81) were full adherent (p < .001), compared to 18.9% (n = 31) at baseline with no differences between the two groups over the study period (p = .25). Over 4 years, only 13 patients (13.2%) were service-disengaged due to non-practical reasons.Conclusions: In this long-term study, we were able to demonstrate a reduction in involuntary admissions in four treatment years compared to the 2 years prior to admission to the ACCESS model in patients with severe and mostly multiphase schizophrenia spectrum disorders and affective disorders with psychotic features. This may help prevent patients from suffering from a potentially traumatic experience during treatment in the psychiatric system.Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT01888627.

Background HBV and HIV infections are highly endemic in sub-Saharan Africa and Nigeria while HBV–HIV coinfection is not uncommon. Antiretroviral (ART)-treatment for HIV can affect HBV whereby antiviral resistance mutations in the HBV genome can be selected. Here, we determined the prevalence of resistance mutations among ART-experienced and ART-naive HIV–HBV-coinfected patients in southwestern Nigeria. Methods A total of 81 serum samples from HBV–HIV-coinfected patients who were either ART-naive or received lamivudine (3TC)-containing ART-therapy and HBV-monoinfected patients were analysed. Hepatitis B surface antigen (HBsAg) was detected using ELISA. HBV-positive samples were confirmed by PCR amplification of the surface and polymerase regions. Mutations conferring drug resistance to HBV were analysed by direct sequencing. Phylogenetic analysis was performed to identify the HBV genotype. Results Of the 81 HBsAg-positive samples, 27 had detectable HBV DNA by real-time PCR with mean viral loads of 6.77 log IU/ml. Phylogenetic analyses showed a predominance of HBV genotype E. A high prevalence (22.2%; 6/27) of HBV resistance mutations among ART-experienced HBV–HIV-coinfected patients was detected. However, a relatively high selection rate of resistance mutations in drug-naive HIV–HBV-coinfected (3.7%; 1/27) and in HBV-monoinfected patients, potential drug resistance mutations (7.4%; 2/27) were also observed. HBV polymerase amino acid substitutions found included rtV173L, rtL180M, rtM204V, rtK212R, rtS213T, rtV214A, rtL229V and rtP237A/S. Conclusions Drug resistant mutations were detected frequently in ART-experienced HIV–HBV patients. Well-coordinated antiviral therapy for HIV patients coinfected with HBV should include proper HBV diagnosis and resistance testing to minimize the emergence and spread of antiviral drug resistance.

Aim The Integrated Care in Early Psychosis (ACCESS III) Study examined the efficacy and cost-effectiveness of a combined intervention consisting of strategies to improve early detection and quality of care (integrated care including therapeutic assertive community treatment) in adolescents and young adults in the early phase of a severe psychotic disorder from 2011 to 2014. Methods This is a prospective, single-centre, 1-year cohort study comparing an intervention condition (early detection plus integrated care, n = 120) to the historical control condition (standard care, SC, n = 105) for adolescents and young adults aged 12–29 years suffering from a severe, early-phase psychotic disorder (i.e. within 2 years of treatment). Results Primary outcome is the rate of combined symptomatic (i.e. Positive and Negative Syndrome Scale (PANSS) criteria) and functional (i.e. Global Assessment of Functioning scale (GAF) ≥ 60 points criterion) remission over at least 6 months at study endpoint. Secondary outcome comprises the comparison of the reduction in the duration of untreated psychosis within the 4-year study duration between integrated care and SC, course of psychopathology, functioning, quality of life, satisfaction with care, cost and quality-adjusted life years (QALYs) in comparison to a historical control group. Conclusion To the authors’ knowledge, this is the first study assessing the efficacy and cost-effectiveness of a combined intervention consisting of early detection strategies and strategies to improve quality of care in both adolescents and young adults with early-phase psychosis. The results will be published in 2016.

// Nghiem Xuan Hoan 1,2,3,* , Hoang Van Tong 1,3,* , Dao Phuong Giang 1,2,3,* , Nguyen Linh Toan 3,4 , Christian G. Meyer 1,3 , C.-Thomas Bock 5 , Peter G. Kremsner 1,3 , Le Huu Song 2,3,** and Thirumalaisamy P. Velavan 1,3,4,** 1 Institute of Tropical Medicine, University of Tubingen, Tubingen, Germany 2 108 Military Central Hospital, Hanoi, Vietnam 3 Vietnamese-German Center for Medical Research, Hanoi, Vietnam 4 Department of Pathophysiology, Vietnam Military Medical University, Hanoi, Vietnam 5 Department of Infectious Diseases, Robert Koch Institute, Berlin, Germany * These authors have contributed equally to this work ** Shared senior authors Correspondence to: Thirumalaisamy P. Velavan, email: // Keywords : HBV infection, liver diseases, ISG15, ISG15 polymorphism, ISGlation, Pathology Section Received : June 11, 2016 Accepted : September 05, 2016 Published : September 10, 2016 Abstract This study investigates the association of Interferon-stimulated gene 15 ( ISG15 ) polymorphisms, ISG15 serum levels and expression with HBV-related liver diseases. The ISG15 promoter and the two exons of the gene were screened for polymorphisms in 766 HBV-infected patients and in 223 controls. Soluble ISG15 levels were measured by ELISA. ISG15 mRNA expression was quantified by qRT-PCR in 36 tumor and adjacent non-tumor tissues. The exon 2 allele rs1921A was found associated with decreased progression of HBV-related liver diseases (LC vs. CHB: OR = 0.6, 95%CI = 0.4-0.8, adjusted P = 0.003; HCC vs. CHB: OR = 0.6, 95%CI = 0.4-0.9, adjusted P = 0.005). The rs1921AA genotype was associated with low levels of AST, ALT and total bilirubin, but with high prothrombin levels ( P < 0.05). ISG15 serum levels were higher among HBV patients compared to controls ( P < 0.0001) and positively associated with HBV-related liver diseases, with highest levels among LC patients. ISG15 levels were correlated with HBV-DNA loads ( P = 0.001). In non-tumor tissues from HCC patients, ISG15 mRNA expression was increased in HBV compared to non-HBV infection ( P = 0.016). The ISG15 rs1921 variant and ISG15 expression are associated with HBV-related liver diseases. Taken together, ISG15 appears to be a proviral factor involved in HBV replication and triggering progression of HBV-related liver diseases.

Infection with hepatitis E virus (HEV) represents the most common source of viral hepatitis globally. Although infecting over 20 million people annually in endemic regions, with major outbreaks described since the 1950s, hepatitis E remains an underestimated disease. This review gives a current view of the global circulation and epidemiology of this emerging virus. The history of HEV, from the first reported enteric non-A non-B hepatitis outbreaks, to the discovery of the viral agent and the molecular characterization of the different human pathogenic genotypes, is discussed. Furthermore, the current state of research regarding the virology of HEV is critically assessed, and the challenges towards prevention and diagnosis, as well as clinical risks of the disease described. Together, these points aim to underline the significant impact of hepatitis E on global health and the need for further in-depth research to better understand the pathophysiology and its role in the complex disease manifestations of HEV infection.

Objectives: The aim of this study was to investigate the association between detention experience and hepatitis C virus (HCV) status, the role of duration and frequency of detention, and whether risk behaviours practiced in detention could explain an observed increase in risk. Methods: Current drug injectors (injecting in the last 12 months) were recruited to participate in a sero-behavioural, cross-sectional survey using respondent-driven sampling in eight German cities during the years 2011–2014. Using multivariable logistic regression, the association between HCV status and reported detention experience was investigated. Results: A total of 1998 participants were included in the analysis. Of these, 19.9% reported no detention experience, 28.6% short and rare experience (≤3.5 years in total, ≤3 times), 12.1% short but frequent experience, 7.1% long but rare experience, and 32.4% long and frequent experience. After correcting for HCV risk factors, the association between detention experience and HCV status remained statistically significant. By adjusting the model for intramural risk behaviours, the odds ratios of detention experience were reduced but remained significant. Conclusions: The proportion of people who inject drugs positive for HCV increased with both frequency and duration of their detention experience. As intramural risk behaviours could not fully explain this increase, it appears that transfers between community and custody may confer additional risks. Keywords: HCV, PWID, Prison, Incarceration, Detention, Germany

Background: In 2017 the Nigerian Ministry of Health notified the World Health Organization (WHO) of an outbreak of hepatitis E located in the north-east region of the country with 146 cases with 2 deaths. The analysis of the hepatitis E virus (HEV) genotypes responsible for the outbreak revealed the predominance of HEV genotypes 1 (HEV-1) and 2 (HEV-2). Molecular data of HEV-2 genomes are limited; therefore we characterized a HEV-2 strain of the outbreak in more detail. Finding: The full-length genome sequence of an HEV-2 strain (NG/17–0500) from the outbreak was amplified using newly designed consensus primers. Comparison with other HEV complete genome sequences, including the only HEV-2 strain (Mex-14) with available complete genome sequences and the availability of data of partial HEV-2 sequences from Sub-Saharan Africa, suggests that NG/17–0500 belongs to HEV subtype 2b (HEV-2b). Conclusions: We identified a novel HEV-2b strain from Sub-Saharan Africa, which is the second complete HEV-2 sequence to date, whose natural history and epidemiology merit further investigation.

Hepatitis E virus (HEV) infection may cause acute hepatitis and lead to hepatic failure in developing and developed countries. We studied HEV seroprevalences in patients with hepatitis B virus (HBV) infection to understand the consequences of HEV superinfection in a Vietnamese population. This cross-sectional study was conducted from 2012 to 2013 and included 1318 Vietnamese patients with HBV-related liver diseases and 340 healthy controls. The case group included patients with acute (n = 26) and chronic hepatitis B (n = 744), liver cirrhosis (n = 160), hepatocellular carcinoma (n = 166) and patients with both liver cirrhosis and hepatocellular carcinoma (n = 222). Anti-HEV IgG and IgM antibodies were assessed in patients and controls by ELISA. HEV-RNA was identified by PCR assays and sequencing. Seroprevalences of anti-HEV IgG among hepatitis B patients and controls were 45% and 31%, respectively (adjusted P = 0.034). Anti-HEV IgM seroprevalences were 11.6% and 4.7% in patients and controls, respectively (adjusted P = 0.005). Seroprevalences were higher among the elder individuals. When stratifying for patient groups, those with liver cirrhosis had the highest anti-HEV IgG (52%) and anti-HEV IgM (19%) seroprevalences. Hepatitis B patients with current HEV infection had abnormal liver function tests compared to patients with past or without HEV infection. One HEV isolate was retrieved from a patient with both liver cirrhosis and hepatocellular carcinoma and identified as HEV genotype 3. This study indicates high prevalences of HEV infection in Vietnamese HBV patients and among healthy individuals and shows that HEV superinfection may influence the outcome and progression of HBV-related liver disease.

PURPOSE: Classical Hodgkin lymphoma (cHL) is characterized by a low percentage of tumor cells in a background of diverse, reactive immune cells. cHL cells commonly derive from preapoptotic germinal-center B cells and are characterized by the loss of B cell markers and the varying expression of other hematopoietic lineage markers. This phenotypic variability and the scarcity of currently available cHL-specific cell surface markers can prevent clear distinction of cHL from related lymphomas. EXPERIMENTAL DESIGN: We applied the Cell Surface Capture (CSC) technology to directly measure the pool of cell surface exposed proteins in four cHL and four non-Hodgkin lymphoma (NHL) cell lines. RESULTS: More than 1 000 membrane proteins, including 178 CD annotated proteins, were identified and allowed the generation of lymphoma surfaceome maps. The functional properties of identified cell surface proteins enable, but also limit the information exchange of lymphoma cells with their microenvironment. CONCLUSIONS AND CLINICAL RELEVANCE: Selected candidate proteins with potential diagnostic value were evaluated on a tissue microarray (TMA). Primary lymphoma tissue of 126 different B cell derived lymphoma cases were included in the TMA analysis. The TMA analysis indicated gamma-glutamyltranspeptidase 1 as a potential additional marker that can be included in a panel of markers for differential diagnosis of cHL versus NHL. This article is protected by copyright. All rights reserved.

OBJECTIVE The ACCESS treatment model offers assertive community treatment embedded in an integrated care program to patients with psychoses. Compared to standard care and within a controlled study, it proved to be more effective in terms of service disengagement and illness outcomes in patients with schizophrenia spectrum disorders over 12 months. ACCESS was implemented into clinical routine and its effectiveness assessed over 24 months in severe schizophrenia spectrum disorders and bipolar I disorder with psychotic features (DSM-IV) in a cohort study. METHOD All 115 patients treated in ACCESS (from May 2007 to October 2009) were included in the ACCESS II study. The primary outcome was rate of service disengagement. Secondary outcomes were change of psychopathology, severity of illness, psychosocial functioning, quality of life, satisfaction with care, medication nonadherence, length of hospital stay, and rates of involuntary hospitalization. RESULTS Only 4 patients (3.4%) disengaged with the service. Another 11 (9.6%) left because they moved outside the catchment area. Patients received a mean of 1.6 outpatient contacts per week. Involuntary admissions decreased from 34.8% in the 2 previous years to 7.8% during ACCESS (P < .001). Mixed models repeated-measures analyses revealed significant improvements among all patients in psychopathology (effect size d = 0.64, P < .001), illness severity (d = 0.84, P = .03), functioning level (d = 0.65, P < .001), quality of life (d = 0.50, P < .001), and client satisfaction (d = 0.11, P < .001). At 24 months, 78.3% were fully adherent to medication, compared to 25.2% at baseline (P = .002). CONCLUSIONS ACCESS was successfully implemented in clinical routine and maintained excellent rates of service engagement and other outcomes in patients with schizophrenia spectrum disorders or bipolar I disorder with psychotic features over 24 months. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01888627.

Background High prevalence of drug use and injection-related risk behaviours have been reported among former Soviet Union (FSU)-migrants. To investigate hepatitis C (HCV) and HIV seroprevalence and related risk behaviours in this subgroup in Germany, we compared first generation FSU-migrants and native Germans using data from a sero-behavioural survey of people who inject drugs (PWID). Methods Current injectors were recruited using respondent-driven sampling in eight German cities in 2011–2014. Questionnaire-based interviews were conducted and dried blood spots collected and tested for anti-HCV, HCV-RNA, and anti-HIV1/2. Descriptive and multivariable analyses (MVA) were performed. Results A total of 208 FSU-born and 1318 native German PWID were included in the analysis. FSU-migrants were younger than Germans (median age: 33 vs. 39 years), and more often male (83.1% vs. 75.9%, p = 0.022). HCV seroprevalence was 74.5% in FSU-migrants vs. 64.6% in Germans (p = 0.006), HIV seroprevalence was 5.8% and 4.6%, respectively (p = 0.443). The proportion of FSU-migrants reporting injecting-related risk behaviours was higher than among Germans: injecting daily (39.4% vs. 30.2%, p = 0.015), with friends (39.2% vs. 31.2%, p = 0.038), cocaine (32.7% vs. 23.8%, p = 0.044), more than one drug (18.2% vs. 9.6%, p = 0.006), and sharing filters/cookers (35.5% vs. 28.0%, p = 0.045). No statistically significant differences were observed in HIV/HCV testing rates (range: 50.7%–65.6%), opioid substitution treatment (43.9% vs. 50.5%), and access to clean needles/syringes (89.8% vs. 90.3%). In MVA, risk for HCV-infection was increased in male FSU-migrants compared to German males (OR 3.32, p = 0.006), no difference was identified between female FSU-migrants and German females (OR: 0.83, p = 0.633). Conclusion Male FSU-migrants were at highest risk of being HCV infected. Therefore, targeted actions are needed to ensure access and acceptance of harm reduction measures, including HCV-testing and -treatment for this subpopulation of PWID.

Neurodegeneration in patients with Parkinson's disease is correlated with the occurrence of Lewy bodies-intracellular inclusions that contain aggregates of the intrinsically disordered protein α-synuclein; 1; . The aggregation propensity of α-synuclein in cells is modulated by specific factors that include post-translational modifications; 2,3; , Abelson-kinase-mediated phosphorylation; 4,5; and interactions with intracellular machineries such as molecular chaperones, although the underlying mechanisms are unclear; 6-8; . Here we systematically characterize the interaction of molecular chaperones with α-synuclein in vitro as well as in cells at the atomic level. We find that six highly divergent molecular chaperones commonly recognize a canonical motif in α-synuclein, consisting of the N terminus and a segment around Tyr39, and hinder the aggregation of α-synuclein. NMR experiments; 9; in cells show that the same transient interaction pattern is preserved inside living mammalian cells. Specific inhibition of the interactions between α-synuclein and the chaperone HSC70 and members of the HSP90 family, including HSP90β, results in transient membrane binding and triggers a remarkable re-localization of α-synuclein to the mitochondria and concomitant formation of aggregates. Phosphorylation of α-synuclein at Tyr39 directly impairs the interaction of α-synuclein with chaperones, thus providing a functional explanation for the role of Abelson kinase in Parkinson's disease. Our results establish a master regulatory mechanism of α-synuclein function and aggregation in mammalian cells, extending the functional repertoire of molecular chaperones and highlighting new perspectives for therapeutic interventions for Parkinson's disease.

Chronic hepatitis C virus (HCV) infection results in progressive liver fibrosis leading to cirrhosis and liver cancer. The mechanism for this remains unclear but hepatocyte apoptosis is thought to play a major role. Hepatocyte apoptosis in human liver tissue was determined by immunohistochemistry for cytokeratin 18 (M30 CytoDEATH) and cleaved poly(ADP-ribose) polymerase (PARP). In vitro studies were performed with replication-defective recombinant adenoviruses expressing HCV proteins (rAdHCV) to study the effects of HCV on cell death in Huh7 cells, primary mouse hepatocytes (PMoHs) and primary human hepatocytes (PHHs). Cell viability and apoptosis were studied using crystal violet assays and Western blots probed for cleaved caspase-3 and cleaved PARP, with and without treatment with the pan-caspase inhibitor Q-VD-OPh and necrostatin-1. Liver tissue of HCV-infected patients expressed elevated levels of apoptotic markers compared with HCV-negative patients. rAdHCV infection reduced cell viability compared with uninfected controls and cells infected with control virus (rAdGFP). Huh7, PMoHs and PHHs infected with rAdHCV showed significantly increased levels of apoptotic markers compared with uninfected controls and rAdGFP-infected cells. In rAdHCV-infected Huh7, treatment with Q-VD-OPh and necrostatin-1 both improved cell viability. Q-VD-Oph also reduced cleaved PARP in rAdHCV-infected Huh7 and PMoHs. Hepatocyte apoptosis is known to be increased in the livers of HCV-infected patients. HCV promoted cell death in primary and immortalized hepatocytes, and this was inhibited by Q-VD-OPh and necrostatin-1. These findings indicate that HCV-induced cell death occurs by both apoptosis and necroptosis, and provide new insights into the mechanisms of HCV-induced liver injury.

OBJECTIVE The ACCESS treatment model offers assertive community treatment embedded in an integrated care program to patients with psychoses. Compared to standard care and within a controlled study, it proved to be more effective in terms of service disengagement and illness outcomes in patients with schizophrenia spectrum disorders over 12 months. ACCESS was implemented into clinical routine and its effectiveness assessed over 24 months in severe schizophrenia spectrum disorders and bipolar I disorder with psychotic features (DSM-IV) in a cohort study. METHOD All 115 patients treated in ACCESS (from May 2007 to October 2009) were included in the ACCESS II study. The primary outcome was rate of service disengagement. Secondary outcomes were change of psychopathology, severity of illness, psychosocial functioning, quality of life, satisfaction with care, medication nonadherence, length of hospital stay, and rates of involuntary hospitalization. RESULTS Only 4 patients (3.4%) disengaged with the service. Another 11 (9.6%) left because they moved outside the catchment area. Patients received a mean of 1.6 outpatient contacts per week. Involuntary admissions decreased from 34.8% in the 2 previous years to 7.8% during ACCESS (P < .001). Mixed models repeated-measures analyses revealed significant improvements among all patients in psychopathology (effect size d = 0.64, P < .001), illness severity (d = 0.84, P = .03), functioning level (d = 0.65, P < .001), quality of life (d = 0.50, P < .001), and client satisfaction (d = 0.11, P < .001). At 24 months, 78.3% were fully adherent to medication, compared to 25.2% at baseline (P = .002). CONCLUSIONS ACCESS was successfully implemented in clinical routine and maintained excellent rates of service engagement and other outcomes in patients with schizophrenia spectrum disorders or bipolar I disorder with psychotic features over 24 months. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01888627.

Summary Hepatitis D virus (HDV) infection is acquired as a co- /superinfection of Hepatitis B virus (HBV) and can modulate the pathophysiology of chronic hepatitis B and related liver diseases including hepatocellular carcinoma. Among the eight distinct HDV genotypes reported, relatively few studies have attempted to investigate the prevalence of HDV mixed genotypes and RNA recombination of HDV. With a recorded prevalence of 10–20% HBV infection in Vietnam, this study investigated the HDV variability, HDV genotypes and HDV recombination among twenty-one HDV isolates in Vietnamese HBsAg-positive patients. HDV subgenomic and full-length genome sequences were obtained using newly established HDV-specific RT-PCR techniques. The nucleotide homology was observed from 74.6% to 99.4% among the investigated full-length genome of the HDV isolates. We observed HDV genotype 1 and HDV genotype 2 in the investigated Vietnamese patients. Although no HDV genotype mixtures were observed, we report here a newly identified recombinant of HDV genotypes (HDV 1 and HDV 2). The identified recombinant HDV isolate C03 revealed sequence homology to both HDV genotype 1 (nt1 to nt907) and HDV genotype 2 (nt908 to nt1675; HDAg coding region) with a breakpoint at nt908. Our findings demonstrate the prevalence of intergenotypic recombination between HDV genotypes 1 and 2 in a Vietnamese HBsAg-positive patient. Extended investigation on the distribution and prevalence of HDV, HDV mixed genotypes and recombinant HDV genotypes in a larger Vietnamese population offers vital insights into understanding of the micro-epidemiology of HDV and subsequent pathophysiology in chronic HBV- /HDV-related liver diseases.

The study is focused on two research questions: What are the public's estimates of the prevalence of depression, schizophrenia, bulimia nervosa and anorexia nervosa? What is the relationship between the estimated prevalence of the mental disorders and the public's desire for social distance? Analyses are based on a telephone survey in two large German cities (Hamburg and Munich, N =2014, response rate 51%). Vignettes with typical signs and symptoms suggestive of a depression, schizophrenia, bulimia nervosa and anorexia nervosa were presented. Respondents were asked about the lifetime prevalence of the mental disorders and their desire for social distance. Across all four disorders under study the respondents markedly overestimate the rates of lifetime prevalence. Increasing prevalence estimation is associated with a significant decrease in the desire for social distance in case of schizophrenia. As for depression, anorexia nervosa and bulimia nervosa there are no significant associations. Many campaigns aimed at reducing stigma emphasize the high prevalence of mental disorders. The assumption of these campaigns is that reduction of the perceived distinction leads to a decrease of the desire for social distance towards those afflicted. Our results indicate that this may not generally be an effective way to reduce stigma.

OBJECTIVE Since the beginning of the integrated care model for severely ill patients with psychotic disorders ("Hamburg model") in 2007 different clinical parameters have been consecutively assessed within a naturalistic, observational, prospective study. METHODS Clinical outcome of the 2-year and 4-year follow-ups of n = 158 patients. RESULTS A significant and ongoing improvement of psychopathology, severity of illness, functional outcome, quality of life and satisfaction with care in this sample of severely ill and merely chronic patients with psychosis was shown. Moreover, medication adherence improved and quality and quantity of outpatient treatment increased. CONCLUSION The ongoing psychosocial stabilisation of the patients most likely result from a combination of various factors: continuity of care, multimodal and individualized care, therapeutic specialisation and the multidisciplinary ACT team. RESULTS provide clinical and scientific evidence for future implementations of the integrated care model "Hamburg Model" for the treatment of psychosis.

Two polymorphisms in the STAT4 and HLA-DQ loci were more recently reported to associate with chronic hepatitis B (CHB) induced hepatocellular carcinoma (HCC). We utilised an independent Vietnamese cohort of clinically classified HBV patients of chronic hepatitis B carriers (n = 206), liver cirrhosis (n = 222) and hepatocellular carcinoma (n = 239) and assessed the influence of the reported variants. The STAT4 variant (rs7574865) was marginally associated with HCC susceptibility in CHB carriers in allelic and recessive genetic models (OR = 0.84, 95%CI = 0.7–0.99, P = 0.048 and OR = 0.7, 95%CI = 0.5–0.99, P = 0.047). No significant association between the studied variant with several clinical parameters such as liver enzymes (ALT, AST), total and direct bilirubin, AFP, HBV genotype and viral loads were observed. Our study highlights the reported variant to be a trivial factor and possibly other confounding factors may regulate STAT4 expression during HCC development.

Background Diagnosis of viral myocarditis is difficult by clinical criteria but facilitated by detection of inflammation and viral genomes in endomyocardial biopsies. Parvovirus B19 (B19V) targets endothelial cells where viral nucleic acid is exclusively detected in the heart. Microparticles (MPs) are released after cell damage or activation of specific cells. We aimed to investigate whether circulating endothelial MPs (EMPs) in human and experimental models of myocarditis are associated with B19V myocarditis. Methods MPs were investigated in patients with myocarditis (n = 54), divided into two groups: B19V+ (n = 23) and B19V- (n = 31) and compared with healthy controls (HCTR, n = 25). MPs were also investigated in B19V transgenic mice (B19V-NS1+) and mice infected with coxsackievirus B3 (CVB3). MPs were analyzed with fluorescent activated cell sorting (FACS). Results In human samples, EMP subpopulation patterns were significantly different in B19V+ compared to B19V- and HCTR (p < 0.001), with an increase of apoptotic but not activated EMPs. Other MPs such as platelet- (PMPs) leukocyte-(LMPs) and monocyte-derived MPs (MMPs) showed less specific patterns. Significantly different levels of EMPs were observed in transgenic B19V-NS1+ mice compared with CVB3-infected mice (p < 0.001). Conclusion EMP subpopulations are different in B19V+ myocarditis in humans and transgenic B19V mice reflecting vascular damage. EMP profiles might permit differentiation between endothelial-cell-mediated diseases like myocardial B19V infection and other causes of myocarditis.

BackgroundOne-to-one peer support is a resource-oriented approach for patients with severe mental illness. Existing trials provided inconsistent results and commonly have methodological shortcomings, such as poor training and role definition of peer supporters, small sample sizes, and lack of blinded outcome assessments.MethodsThis is a randomised controlled trial comparing one-to-one peer support with treatment as usual. Eligible were patients with severe mental illnesses: psychosis, major depression, bipolar disorder or borderline personality disorder of more than two years’ duration. A total of 216 patients were recruited through in- and out-patient services from four hospitals in Hamburg, Germany, with 114 allocated to the intervention group and 102 to the control group. The intervention was one-to-one peer support, delivered by trained peers and according to a defined role specification, in addition to treatment as usual over the course of six months, as compared to treatment as usual alone. Primary outcome was self-efficacy measured on the General Self-Efficacy Scale at six-month follow-up. Secondary outcomes included quality of life, social functioning, and hospitalisations.ResultsPatients in the intervention group had significantly higher scores of self-efficacy at the six-month follow-up. There were no statistically significant differences on secondary outcomes in the intention to treat analyses.ConclusionsThe findings suggest that one-to-one peer support delivered by trained peer supporters can improve self-efficacy of patients with severe mental disorders over a one-year period. One-to-one peer support may be regarded as an effective intervention. Future research should explore the impact of improved self-efficacy on clinical and social outcomes.

BACKGROUND/AIMS The safety and efficacy of interferons in advanced delta hepatitis have not been explored. The aim of this subanalysis of a multicenter clinical trial was to compare the efficacy and safety of 48 weeks of pegylated interferon alpha-2a (180 μg weekly) with or without adefovir (10 mg daily) in patients with chronic delta hepatitis-induced advanced liver disease and in those with non-advanced liver disease. MATERIALS AND METHODS Thirty-one patients with advanced and 27 patients with non-advanced liver disease were assessed. Patients were considered to have advanced liver disease when biopsy disclosed a fibrosis score of ≥4 according to Ishak or when imaging studies were indicative of cirrhosis. Virologic response, defined as achievement of undetectable hepatitis D virus RNA, was assessed at the end of treatment and end of 24 weeks of treatment-free follow-up. RESULTS Patients with advanced disease had lower hepatitis D virus RNA levels and platelet counts (p=0.014 and p=0.0015, respectively). End of treatment and end of follow-up virologic responses in patients with advanced vs. non-advanced liver disease were similar (29% vs. 19% and 32% vs 23%). Proportion of adverse events did not differ between groups except that thrombocytopenia was noted more often in the advanced liver disease group. Further, four cases of clinically important adverse events including two cases of hepatic decompensation and one case of tuberculosis reactivation occurred in the advanced liver disease group. CONCLUSIONS Pegylated interferon is as effective in patients with advanced liver disease due to chronic delta hepatitis as in patients with non-advanced liver disease, but patients should be monitored closely for clinically important side effects.

To compare the 1-year cost-effectiveness of therapeutic assertive community treatment (ACT) with standard care in schizophrenia. ACT was specifically developed for patients with schizophrenia, delivered by psychosis experts highly trained in respective psychotherapies, and embedded into an integrated care system.Two catchment areas in Hamburg, Germany, with similar population size and health care structures were assigned to offer 12-month ACT (n = 64) or standard care (n = 56) to 120 first- and multiple-episode patients with schizophrenia spectrum disorders (DSM-IV), the latter with a history of relapse due to medication nonadherence. Primary outcome was the incremental cost-effectiveness ratio (ICER) based on mental health care costs from a payer perspective and quality-adjusted life-years (QALYs) as a measure of health effects during the 12-month follow-up period (2006-2007).ACT was associated with significantly lower inpatient but higher outpatient costs than standard care, resulting in nonsignificantly lower total costs (P = .27). Incremental QALYs in the ACT group were 0.1 (P.001). Thus, the point estimate for the ICER showed dominance of ACT. The probability of an ICER below €50,000 per QALY gained was 99.5%.The implementation of a psychotherapeutically oriented schizophrenia-specific and -experienced ACT team led to an improved patient outcome with reduced need of inpatient care. Despite the introduction of such a rather "costly" ACT team, treatment in ACT was cost-effective with regard to improved quality of life at comparable yearly costs.ClinicalTrials.gov identifier: NCT01081418.

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 1–3days during the first 14days 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 5days (range 1–13) and 4days (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 19months 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.

Mutations in dynamin 2 (DNM2) lead to dominant intermediate Charcot-Marie-Tooth neuropathy type B, while a different set of DNM2 mutations cause autosomal dominant centronuclear myopathy. In this study, we aimed to elucidate the disease mechanisms in dominant intermediate Charcot-Marie-Tooth neuropathy type B and to find explanations for the tissue-specific defects that are associated with different DNM2 mutations in dominant intermediate Charcot-Marie-Tooth neuropathy type B versus autosomal dominant centronuclear myopathy. We used tissue derived from Dnm2-deficient mice to establish an appropriate peripheral nerve model and found that dominant intermediate Charcot-Marie-Tooth neuropathy type B-associated dynamin 2 mutants, but not autosomal dominant centronuclear myopathy mutants, impaired myelination. In contrast to autosomal dominant centronuclear myopathy mutants, Schwann cells and neurons from the peripheral nervous system expressing dominant intermediate Charcot-Marie-Tooth neuropathy mutants showed defects in clathrin-mediated endocytosis. We demonstrate that, as a consequence, protein surface levels are altered in Schwann cells. Furthermore, we discovered that myelination is strictly dependent on Dnm2 and clathrin-mediated endocytosis function. Thus, we propose that altered endocytosis is a major contributing factor to the disease mechanisms in dominant intermediate Charcot-Marie-Tooth neuropathy type B.

The increasing demand for transplantation has led to consideration of liver grafts from donors exposed to hepatitis B virus (HBV). Six transplantations of liver grafts from hepatitis B surface antigen (HBsAg) positive donors have been reported; two recipients suffered from HBV/HDV (hepatitis Delta virus) coinfection and were followed up for 10-12 months. Here, we report a 56 months follow-up of a HBV/HDV-coinfected recipient of a HBsAg positive liver graft. Posttransplant combination prophylaxis consisted of hepatitis immunoglobulin, lamivudine and adefovir dipivoxil. HBsAg remained positive during stable posttransplant follow-up and subclinical HDV reinfection with low replication rate was detected at 1 month. Pegylated interferon therapy was introduced after documentation of histological evidence of mild chronic hepatitis, but without virological response after 48 weeks. Finally, antiviral treatment was switched to tenofovir disoproxil fumarate. More than 50 months posttransplant the recipient revealed clinical symptoms of decompensated liver cirrhosis and has been relisted for liver transplantation. In conclusion HBsAg positive liver grafts in HBsAg positive recipients with HDV coinfection may result in virological recurrence and rapid development of liver cirrhosis.

Human parvovirus B19 (B19V) DNA is highly prevalent in endothelial cells lining up intramyocardial arterioles and postcapillary venules of patients with chronic myocarditis and cardiomyopathies. We addressed the question of a possible stimulation of B19V gene expression in endothelial cells by infection with adenoviruses. Adenovirus infection led to a strong augmentation of B19V structural and nonstructural proteins in individual endothelial cells infected with B19V or transfected with an infectious B19V genome. Transactivation was mostly mediated at the level of transcription and not due to adenovirus-mediated induction of second-strand synthesis from the single-stranded parvoviral genome. The main adenoviral functions required were E1A and E4orf6, which displayed synergistic effects. Furthermore, a limited B19V genome replication could be demonstrated in endothelial cells and adenovirus infection induced the appearance of putative dimeric replication intermediates. Thus the almost complete block in B19V gene expression seen in endothelial cells can be abrogated by infection with other viruses.

Background The aim of this study was to analyse the long-term prognosis of patients with acute myocarditis (AMC) who had been discharged from hospital while having normal left ventricular (LV) function. Methods and results 50 patients with acute myocarditis who underwent endomyocardial biopsies (EMBs) were prospectively studied. Their clinical condition was examined during a mean follow-up period of 72 (54–78) months, including tissue Doppler imaging (TDI). 4% (2/50) died, and 6% (3/50) developed dilated cardiomyopathy. 45/50 (90%) showed a normal or improvement in LV function over time. In the course of the follow-up, 49% (22/45) suffered from heart failure symptoms despite a normal ejection fraction (HFNEF). This was associated with an abnormal E/A ratio, an impaired deceleration time of early mitral flow velocity and isovolumic relaxation time, and a pathological increase in the LV filling index E/E′, in contrast to patients without heart failure symptoms (E/E′ septal 10.9 (9.3–13.8) vs 6.8 (6.4–9.1); p=0.001). Plasma N-terminal proB-type natriuretic peptide levels were increased threefold in patients with HFNEF (19.9 (10.6–24.1) vs 7.3 (4.2–11.9) pmol/l; p=0.006). Conclusions It is assumed that the evidence for AMC is associated not only with the risk of developing LV dilatation but also with an increased risk of symptomatic diastolic dysfunction after several years.

OBJECTIVE A new questionnaire to assess subjective meaning in psychosis (SuSi) will be presented. METHODS The questionnaire construction was based on an elaborate process (Delphi-method) involving patients, carers and professionals (trialogue). Statistical validation including factor analysis and assessment of internal consistency of the subscales was carried out using a sample of 90 psychosis patients. RESULTS The SuSi-questionnaire is a reliable, valid and complex instrument with six consistent factors on three time levels. 91 % of patients related their psychosis to life events, 52 % reported a positive experience of symptoms and 70 % ascribed positive consequences to their psychosis. Patients relating psychotic experiences to life events assessed their symptoms and prospects more positively. This fact highlights the great significance of subjective meaning attribution. CONCLUSIONS The SuSi-questionnaire features good psychometric qualities and offers an empirical acquisition to subjective assessment of psychosis. Results support a more biographical and in-depth psychological orientation of psychotherapy of psychosis.

Determination of hepatitis D virus (HDV) viremia represents the “gold standard” for the diagnosis of HDV infection. Hepatitis B virus (HBV)-HDV coinfection frequently leads to end-stage liver disease and hepatocellular carcinoma. No commercial assay for HDV RNA quantification that includes automated nucleic acid extraction is available, and in-house PCR tests are not well standardized. However, knowledge of HDV RNA levels may give important information for patient management and could be a useful tool for monitoring the response to antiviral therapies. One platform that is widely used for HBV DNA or HCV RNA quantification is the Cobas Ampliprep/TaqMan system. Using the utility channel of this platform, we established a novel protocol for TaqMan-based HDV RNA quantification after automatic extraction of RNA by the Ampliprep system. The assay was specific and showed linearity over a wide range from 3 × 10 2 to 10 7 copies/ml. Reproducibility was demonstrated by determination of the interrun and intrarun variabilities, which were similar to those achieved with the commercially available Cobas TaqMan assays for HCV RNA and HBV DNA. HDV RNA levels were stable in whole blood ( n = 4), plasma ( n = 3), and serum ( n = 3) samples at room temperature for up to 6 days. Importantly, HDV RNA viremia showed only minor fluctuations, with the log 10 coefficient of variation being between 1.3 and 11.2% for hepatitis delta patients studied every 2 weeks for up to 3 months ( n = 6), while a rapid viral decline was observed early during treatment with pegylated alfa-2a interferon ( n = 6). In conclusion, this novel automated HDV RNA assay is a useful tool for monitoring HDV-infected patients both before and during antiviral therapy.

Background: Circulating microRNAs (miRNA) are biomarkers for several neoplastic diseases, including hepatocellular carcinoma (HCC). We performed a literature search, followed by experimental screening and validation in order to establish a miRNA panel in combination with the assessment of alpha-fetoprotein (AFP) levels and to evaluate its performance in HCC diagnostics. Methods: Expression of miRNAs was quantified by quantitative PCR (qPCR) in 406 serum samples from 118 Vietnamese patients with hepatitis B (HBV)-related HCC, 69 patients with HBV-related liver cirrhosis (LC), 100 chronic hepatitis B (CHB) patients and 119 healthy controls (HC). Results: Three miRNAs (mir-21, mir-122, mir-192) were expressed differentially among the studied subgroups and positively correlated with AFP levels. The individual miRNAs mir-21, mir-122, mir192 or the triplex miRNA panel showed high diagnostic accuracy for HCC (HCC vs. CHB, AUC = 0.906; HCC vs. CHB+LC, AUC = 0.81; HCC vs. CHB+LC+HC, AUC = 0.854). When AFP levels were ≤20ng/ml, the triplex miRNA panel still was accurate in distinguishing HCC from the other conditions (CHB, AUC = 0.922; CHB+LC, AUC = 0.836; CHB+LC+HC, AUC = 0.862). When AFP levels were used in combination with the triplex miRNA panel, the diagnostic performance was significantly improved in discriminating HCC from the other groups (LC, AUC = 0.887; CHB, AUC = 0.948; CHB+LC, AUC = 0.887). Conclusions: The three miRNAs mir-21, mir-122, mir-192, together with AFP, are biomarkers that may be applied to improve diagnostics of HCC in HBV patients, especially in HBV-related LC patients with normal AFP levels or HCC patients with small tumor sizes.

Background & Aims The quantifiable level of HBsAg has been suggested as a predictor of treatment response in chronic hepatitis B. However, there is limited information on HBsAg levels considering the dynamic natural course of HBV-infection. This study aimed to determine HBsAg levels in the different phases of HBV-infection in European HBsAg-positive patients. Methods 226 HBV-monoinfected patients, not undergoing antiviral therapy, were analyzed in a cross-sectional study. Patients were categorized according to the phase of HBV-infection: HBeAg(+) immune tolerance phase (IT, n =30), immune clearance phase (IC, n =48), HBeAg(−) low-replicative phase (LR, n =68), HBeAg(−) hepatitis (ENH, n =68), and acute hepatitis B ( n =12). HBsAg was quantified and correlated with HBV-DNA, HBV-genotypes and clinical parameters. In addition, 30 LR-patients were followed longitudinally. Results HBsAg levels were higher in IT-patients and IC-patients compared to LR-patients and ENH-patients (4.96/4.37/3.09/3.87-log 10 IU/ml, p 0.001). HBsAg showed a strong correlation with HBV-DNA during acute hepatitis B ( R =0.79, p 0.01). Correlation of HBsAg and HBV-DNA was weak or missing when analyzing different phases of persistent HBV-infection separately. However, associations between HBsAg and HBV-DNA were observed in patients infected with HBV-genotype D but not with HBV-genotype A. LR-patients with HBV-reactivation during follow-up (increase of HBV-DNA >2000IU/ml) showed >3-fold higher baseline HBsAg levels with a NPV of 95% for an HBsAg cut-off of 3500IU/ml. Conclusions HBsAg levels show significant differences during the natural course of HBV-infection and between HBV-genotypes. These findings may have important implications for understanding the natural history of HBV-infection and for using quantitative HBsAg as a diagnostic tool, i.e. as a marker for predicting HBV-reactivation.