Liver Transplantation for Primary Sclerosing Cholangitis (PSC) With or Without Inflammatory Bowel Disease (IBD)-A European Society of Organ Transplantation (ESOT) Consensus Statement.

Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of inflammatory bowel disease (IBD) and a lead indication for liver transplantation (LT) in the western world. In this article, we present a Consensus Statement on LT practice, developed by a dedicated Guidelines' Taskforce of the European Society of Organ Transplantation (ESOT). The overarching goal is to provide practical guidance on commonly debated topics, including indications and timing of LT, management of bile duct stenosis in patients on the transplant waiting list, technical aspects of transplantation, immunosuppressive strategies post-transplant, timing and extension of intestinal resection and futility criteria for re-transplantation.

Quality control in cochlear implant therapy: clinical practice guidelines and registries in European countries.

PURPOSE: The treatment with a cochlear implant (CI) is the gold standard in therapy of patients with profound hearing loss or deafness. Successful hearing rehabilitation with a CI is a complex, multi-stage process. In medicine, "Clinical Practice Guidelines" (CPG) are widely accepted for the standardization of such processes. These are supplemented by medical registries in which data regarding the treatment can be collected and evaluated. The aim of this paper is to identify currently existing CI-related CPGs and registries in Europe. METHODS: Between 01/2021 and 06/2021, 42 countries on the European continent, including the United Kingdom, Russia and Turkey, were screened using an internet search (search engine: Google) and a key word search in the Pubmed database. Search terms were the respective country name combined with the following terms: "Cochlear Implant", "CI", "Cochlear implant clinical practice guideline", "CI Guideline", "Cochlear Implant Registry", "CI Registry", "Ear nose throat society". The internet search was conducted in English as well as in the corresponding national language. The objective was to identify a CI-related CPG or registry. RESULTS: A CPG was found in 16 of 42 (38%) countries. In terms of population, this accounts for 645 million out of 838 million people (77%). A registry existed in 4 of the 42 (10%) countries assessed. This corresponds to 102 million out of 838 million (12%) people. In total, 4 out of 42 countries (10%) had both a CPG and a registry. CONCLUSION: Our work shows numerous efforts in Europe to standardize CI care at the national level. While most people in Europe already live in countries with a CPG, this is not the case for CI registries. European-wide consensus on CPGs or registries does not yet exist. The present study thus provides a first assessment of the distribution of CI-related CPGs and registries.

[Guidelines for the Management of Community Acquired Pneumonia in Children and Adolescents (Pediatric Community Acquired Pneumonia, pCAP) - Issued under the Responsibility of the German Society for Pediatric Infectious Diseases (DGPI) and the German Society for Pediatric Pulmonology (GPP)]. / S2k-Leitlinie Management der ambulant erworbenen Pneumonie bei Kindern und Jugendlichen (pädiatrische ambulant erworbene Pneumonie, pCAP).

The present guideline aims to improve the evidence-based management of children and adolescents with pediatric community-acquired pneumonia (pCAP). Despite a prevalence of approx. 300 cases per 100 000 children per year in Central Europe, mortality is very low. Prevention includes infection control measures and comprehensive immunization. The diagnosis can and should be established clinically by history, physical examination and pulse oximetry, with fever and tachypnea as cardinal features. Additional signs or symptoms such as severely compromised general condition, poor feeding, dehydration, altered consciousness or seizures discriminate subjects with severe pCAP from those with non-severe pCAP. Within an age-dependent spectrum of infectious agents, bacterial etiology cannot be reliably differentiated from viral or mixed infections by currently available biomarkers. Most children and adolescents with non-severe pCAP and oxygen saturation > 92 % can be managed as outpatients without laboratory/microbiology workup or imaging. Anti-infective agents are not generally indicated and can be safely withheld especially in children of young age, with wheeze or other indices suggesting a viral origin. For calculated antibiotic therapy, aminopenicillins are the preferred drug class with comparable efficacy of oral (amoxicillin) and intravenous administration (ampicillin). Follow-up evaluation after 48 - 72 hours is mandatory for the assessment of clinical course, treatment success and potential complications such as parapneumonic pleural effusion or empyema, which may necessitate alternative or add-on therapy.

Cross-cutting view of current challenges in paediatric solid organ and haematopoietic stem cell transplantation in Europe: the European Reference Network TransplantChild.

The low prevalence of European paediatric transplanted patients and scarcity of resources and expertise led to the need for a multidisciplinary network able to improve the quality of life of paediatric patients and families requiring a solid organ or haematopoietic stem cell transplantation. The European Reference Network (ERN) TransplantChild is one of the 24 ERNs established in a European legal framework to improve the care of patients with rare diseases. ERN TransplantChild is the only ERN focused on both solid organ and haematopoietic stem cell paediatric transplantation, based on the understanding of paediatric transplantation as a complex and highly specialised process where specific complications appear regardless the organ involved, thus linking the skills and knowledge of different organ disciplines. Gathering European centres of expertise in paediatric transplantation will give access to a correct and timely diagnosis, share expertise and knowledge and collect a critical mass of patients and data that increases the speed and value of clinical research outcomes. Therefore, the ERN TransplantChild aims for a paediatric Pan-European, Pan-transplant approach.

[Biliary atresia and congenital cholestatic syndromes : Characteristics before, after and during transition]. / Gallengangatresie und angeborene Cholestasesyndrome : Besonderheiten vor, nach und während der Transition.

BACKGROUND: A growing number of patients with biliary atresia and congenital cholestatic syndromes are reaching adulthood. These patients often have a number of typical medical features, including specific characteristics of liver transplantation medicine. OBJECTIVE: What are the special features in the care of adults suffering from liver diseases with manifestation in childhood and adolescence, both before and after liver transplantation (LTX). How does the progression of individual diseases differ depending on age at manifestation? What are specific aspects following pediatric LTX? PATIENTS AND METHODS: Evaluation and discussion of existing guidelines and recommendations of the individual disciplines and professional societies as well as the current literature. Joint discussion of the recommendations between disciplines (gastroenterology, pediatric gastroenterology, surgery). Inclusion of center-specific experiences with transition from existing transition outpatient departments and training. RESULTS: The recommendations are presented specifically for each disease. Special features in individual diseases after LTX are also discussed. Diagnosis-independent general treatment concepts for cholestasis and chronic liver disease are presented. CONCLUSION: Patients with biliary atresia and congenital cholestatic syndromes have a life-long chronic liver disease with and without LTX and require specific medical care. The patients benefit from the pooling of expertise in the individual disciplines.

Diagnosis of monogenic liver diseases in childhood by next-generation sequencing.

Next-generation sequencing (NGS) has opened up novel diagnostic opportunities for children with unidentified, but suspected inherited diseases. We describe our single-center experience with NGS diagnostics in standard clinical scenarios in pediatric hepatology. We investigated 135 children with suspected inherited hepatopathies, where initially no causative pathogenic variant had been identified, with an amplicon-based NGS panel of 21 genes associated with acute and chronic hepatopathies. In 23 of these patients, we detected pathogenic or likely pathogenic variants in 10 different genes. We present 6 novel variants. A total of 14 of these patients presented with the characteristic phenotype of the related hepatopathy. Nine patients showed only few or atypical clinical symptoms or presented with additional signs. In another 13 out of 135 cases, we detected variants of unknown significance (VUS) in 9 different genes. Only 2 of these patients showed characteristic phenotypes conclusive with the detected variants, whereas 11 patients showed unspecific or atypical phenotypes. Our multi-gene panel is a fast and comprehensive tool to diagnose inherited pediatric hepatopathies. We also illustrate the challenge of dealing with genetic variants and highlight arising clinical questions, especially in patients with atypical phenotypes.

[Simulation of speech perception with cochlear implants : Influence of frequency and level of fundamental frequency components with electronic acoustic stimulation]. / Simulation von Sprachverstehen mit Cochleaimplantat : Einfluss von Frequenz und Pegel der Grundfrequenzkomponente bei elektrisch-akustischer Stimulation.

BACKGROUND: After implantation of cochlear implants with hearing preservation for combined electronic acoustic stimulation (EAS), the residual acoustic hearing ability relays fundamental speech frequency information in the low frequency range. With the help of acoustic simulation of EAS hearing perception the impact of frequency and level fine structure of speech signals can be systematically examined. OBJECTIVE: The aim of this study was to measure the speech reception threshold (SRT) under various noise conditions with acoustic EAS simulation by variation of the frequency and level information of the fundamental frequency f0 of speech. The study was carried out to determine to what extent the SRT is impaired by modification of the f0 fine structure. MATERIAL AND METHODS: Using partial tone time pattern analysis an acoustic EAS simulation of the speech material from the Oldenburg sentence test (OLSA) was generated. In addition, determination of the f0 curve of the speech material was conducted. Subsequently, either the parameter frequency or level of f0 was fixed in order to remove one of the two fine contour information of the speech signal. The processed OLSA sentences were used to determine the SRT in background noise under various test conditions. The conditions "f0 fixed frequency" and "f0 fixed level" were tested under two different situations, under "amplitude modulated background noise" and "continuous background noise" conditions. A total of 24 subjects with normal hearing participated in the study. RESULTS: The SRT in background noise for the condition "f0 fixed frequency" was more favorable in continuous noise with 2.7 dB and in modulated noise with 0.8 dB compared to the condition "f0 fixed level" with 3.7 dB and 2.9 dB, respectively. DISCUSSION: In the simulation of speech perception with cochlear implants and acoustic components, the level information of the fundamental frequency had a stronger impact on speech intelligibility than the frequency information. The method of simulation of transmission of cochlear implants allows investigation of how various parameters influence speech intelligibility in subjects with normal hearing.

[Inpatient rehabilitation of adult CI users: Results in dependency of duration of deafness, CI experience and age]. / Stationäre Rehabilitationsmaßnahmen bei erwachsenen CI-Trägern: Ergebnisse in Abhängigkeit von der Dauer der Taubheit, Nutzungsdauer und Alter.

BACKGROUND: Cochlear implants (CI) have proven to be a highly effective treatment for severe hearing loss or deafness. Inpatient rehabilitation therapy is frequently discussed as a means to increase the speech perception abilities achieved by CI. However, thus far there exists no quantitative evaluation of the effect of these therapies. METHODS: A retrospective analysis of audiometric data obtained from 1355 CI users compared standardized and qualitative speech intelligibility tests conducted at two time points (admission to and discharge from inpatient hearing therapy, duration 3-5 weeks). The test battery comprised examination of vowel/consonant identification, the Freiburg numbers and monosyllabic test (65 and 80 dB sound pressure level, SPL, free-field sound level), the Hochmair-Schulz-Moser (HSM) sentence test in quiet and in noise (65 dB SPL speech level; 15 dB signal-to-noise ratio, SNR), and a speech tracking test with and without lip-reading. RESULTS: An average increase of 20 percentage points was scored at discharge compared to the admission tests. Patients of all ages and duration of deafness demonstrated the same amount of benefit from the rehabilitation treatment. After completion of inpatient rehabilitation treatment, patients with short duration of CI experience (below 4 months) achieved test scores comparable to experienced long-term users. The demonstrated benefit of the treatment was independent of age and duration of deafness or CI experience. CONCLUSION: The rehabilitative training program significantly improved hearing abilities and speech perception in CI users, thus promoting their professional and social inclusion. The present results support the efficacy of inpatient rehabilitation for CI recipients. Integration of this or similar therapeutic concepts in the German catalog of follow-up treatment measures appears justified.

Modifications in integrin expression and extracellular matrix composition in children with biliary atresia.

BACKGROUND: The aetiology of biliary atresia (BA) is still unresolved. The study's aim was to investigate the distribution of extracellular matrix proteins and cellular adhesion molecules in children with BA compared to other cholestatic liver disease (CLD) and normal liver architecture (NLA). PATIENTS: Liver biopsies were obtained from children with BA (n=13), CLD (n=6) and NLA (n=8). METHOD: We systematically analysed ultra thin frozen sections from the liver hilum stained with 25 monoclonal antibodies for cellular characterisation, extracellular matrix proteins and adhesion molecules. RESULTS: 2 changes were specifically found in BA: laminin beta1 was reduced in children with BA vs. NLA and CLD. Conversely, integrin alpha 3 was increased in BA vs. NLA and CLD (p<0.05). Furthermore, we detected changes in a similar pattern for both BA and CLD vs. NLA: in BA and CLD perlecan was increased. On the contrary, integrin beta1 and entactin were decreased vs. NLA (p<0.05). DISCUSSION: Extracellular matrix proteins and adhesion molecules mediate cellular polarity and integrity, development of tubular structures, and proliferation. Therefore, our findings can be important for the understanding of the genesis of BA. CONCLUSION: The composition of extracellular matrix proteins and adhesion molecules in children with BA differs from NLA and other CLD in distribution of laminin beta1 and integrin alpha 3, which may have implications for genetic, immunologic and environmental associations in BA.

"Current state and prospects in managing liver transplanted children".

Pediatric liver transplantation (LTx) has revolutionized life chances and perspectives of children with liver disease. Following rapid establishment of the therapeutic concept in the early years of pediatric transplant medicine, more aspects beyond plain survival become increasingly important. In addition to improving the short to medium-term survival rates, researchers are focusing on themes such as rehabilitation, adherence and quality of life, long-term graft fibrosis and dysfunction, as well as the consequences of long-term immunosuppression. Also, more protocol biopsy data are available to evaluate increasing graft fibrosis. To manage their conditions, patients will need access to highly experienced pediatric liver transplant centers where clinical research will examine modulators of renal disease, endocrine and cardiovascular comorbidity and the development of graft fibrosis and malignancies. Assessment and evaluation of health-related quality of life and factors which influence clinical tolerance, adherence and transition from child to adult care will also be investigated. The analysis of multi-national registry data and more than 40years of experience with large patient cohorts will provide important clues to treatment and will thus get increasing attention. In the future, longitudinal assessment of the outcome for pediatric LTx patients should include more functional aspects than plain survival rates or laboratory parameters.

[Hearing preservation: Better hearing with advanced technology]. / Hörerhaltende Cochlea-Implantation: Besser Hören mit neuer Technik.

Preservation of residual hearing after cochlear implantation allows patients the synergetic use of electric and acoustic stimulation (EAS). The application of specific surgical and therapeutic techniques enables the reduction of inner ear trauma, which leads otherwise to complete hearing loss. Due to simultaneous electric and acoustic stimulation, speech understanding is improved especially in noise. EAS is a well-accepted therapeutic treatment for subjects with profound hearing loss in the higher frequencies and no or mild hearing loss in the low frequencies. Several Manufacturers offer individual soft electrodes specially designed for hearing preservation as well as combined electric-acoustic audio processors.

Prognostic marker for liver disease due to alpha1-antitrypsin deficiency.

BACKGROUND: Only some Alpha1-antitrypsin deficiency (A1ATD) PiZZ patients develop liver cirrhosis and portal hypertension. Aim of the study was to investigate the course of liver disease associated with PiZZ A1ATD and to determine prognostic factors. PATIENTS: We retrospectively reviewed the clinical and laboratory data of all PiZZ children up to 18 years of age admitted to our centre since 1978. 53 patients (age at first visit 2 days to 12 years) met our criteria. METHODS: The children were divided into 2 groups: group 1 'bad prognosis', meaning the patients which were on the waiting list for liver transplantation (LTx), had a liver transplantation or had died, and group 2 'good prognosis', containing the patients they were living with their own liver. We analysed family history including smoking, gestational age, maternal age at delivery, date of birth, sex, neonatal history, breast-feeding, symptoms at presentation, clinical and laboratory data and date of LTx and/or death. RESULTS: Various anamnesis parameters such as manifestation of neonatal cholestasis showed no prognostic significance. In contrast the laboratory parameters thrombocytes (p=0.008), bilirubin (p<0.001), prothrombin time (p<0.001), choline-sterase (p<0.001), gamma-GT (p=0.001) and GOT (p=0.002) showed a correlation with a liver transplantation and/or death. CONCLUSION: Prognosis is difficult to determine at an early stage of this disease, but various laboratory parameters can help to predict an outcome. Therefore a regular follow-up is necessary for the children.

The German national registry for primary immunodeficiencies (PID).

In 2009, a federally funded clinical and research consortium (PID-NET, http://www.pid-net.org) established the first national registry for primary immunodeficiencies (PID) in Germany. The registry contains clinical and genetic information on PID patients and is set up within the framework of the existing European Database for Primary Immunodeficiencies, run by the European Society for Primary Immunodeficiencies. Following the example of other national registries, a central data entry clerk has been employed to support data entry at the participating centres. Regulations for ethics approvals have presented a major challenge for participation of individual centres and have led to a delay in data entry in some cases. Data on 630 patients, entered into the European registry between 2004 and 2009, were incorporated into the national registry. From April 2009 to March 2012, the number of contributing centres increased from seven to 21 and 738 additional patients were reported, leading to a total number of 1368 patients, of whom 1232 were alive. The age distribution of living patients differs significantly by gender, with twice as many males than females among children, but 15% more women than men in the age group 30 years and older. The diagnostic delay between onset of symptoms and diagnosis has decreased for some PID over the past 20 years, but remains particularly high at a median of 4 years in common variable immunodeficiency (CVID), the most prevalent PID.

Outcomes of splenectomy in patients with common variable immunodeficiency (CVID): a survey of 45 patients.

Splenectomy has been used in patients with common variable immunodeficiency disorders (CVID), mainly in the context of refractory autoimmune cytopenia and suspected lymphoma, but there are understandable concerns about the potential of compounding an existing immunodeficiency. With increasing use of rituximab as an alternative treatment for refractory autoimmune cytopenia, the role of splenectomy in CVID needs to be re-examined. This retrospective study provides the largest cohesive data set to date describing the outcome of splenectomy in 45 CVID patients in the past 40 years. Splenectomy proved to be an effective long-term treatment in 75% of CVID patients with autoimmune cytopenia, even in some cases when rituximab had failed. Splenectomy does not worsen mortality in CVID and adequate immunoglobulin replacement therapy appears to play a protective role in overwhelming post-splenectomy infections. Future trials comparing the effectiveness and safety of rituximab and splenectomy are needed to provide clearer guidance on the second-line management of autoimmune cytopenia in CVID.

[Interdisciplinary AWMF guideline for the treatment of primary antibody deficiencies]. / Interdisziplinäre AWMF-Leitlinie zur Therapie primärer Antikörpermangelerkrankungen.

BACKGROUND: Currently, management of antibody deficient patients differs significantly among caregivers. Evidence and consensus based (S3) guidelines for the treatment of primary antibody deficiencies were developed to improve the management of these patients. METHODS: Based on a thorough analysis of current evidence (systematic literature search in PubMed; deadline November 2011) 14 recommendations were finalized during a consensus meeting in Frankfurt in November 2011 using structured consensus methods (nominal group technique). Experts were nominated by their scientific societies/patient initiatives (Tab. 1). RESULTS: The guidelines focus on indication, practical issues and monitoring of immunoglobulin replacement therapy as well as on different routes of administration. Furthermore recommendations regarding supportive measures such as antiinfective therapy, vaccinations and physiotherapy are given. Combining literature evidence and experience of caregivers within this evidence and consensus based guidelines offers the chance to improve the quality of care for anti-body deficient patients.

Prospective comparison of noninvasive, bedside ultrasound methods for assessing central venous pressure.

PURPOSE: To prospectively evaluate the accuracy of noninvasive central venous pressure (CVP) assessment by compression ultrasound of a forearm vein (CUS), inferior vena cava (IVC-C) and internal jugular vein collapsibility (IJV-C) compared to invasive CVP measurement (invCVP) as the gold standard. MATERIALS AND METHODS: CUS, IVC-C and IJV-C were performed in a random sequence in 81 consecutive intensive care patients with simultaneous invCVP monitoring. Examiners were blinded to invCVP and previous examinations. RESULTS: Median invCVP was 12.0 mmHg (range 1 - 23). CUS, IVC-C and IJV-C could be obtained in 89 %, 95 % and 100 % of cases, respectively, within a median time of 188 sec [IQR 125; 270], 133 sec [IQR 100; 211] and 60 sec [IQR 50; 109], respectively. The Spearman correlation coefficient between invCVP and CUS, IVC-C, and IJV-C was 0.485 95 %-CI [0.25; 0.65], -0.186 [-0.42; 0.07], and -0.408 [-0.59; -0.18], respectively. The median absolute difference between CUS and invCVP was 3 mmHg [IQR 2; 6.75]. CVP was categorized as low (< 7 mmHg; collapsibility > 0.6), normal (7 - 12 mmHg; collapsibility 0.6 - 0.2) and high (> 12 mmHg; collapsibility < 0.2) as prespecified. The proportions of identical CVP classifications compared to invCVP were 61.4% 95%-CI [49.3%; 72.4%] with CUS, 48.7% [37.4%; 60%] with IVC-C and 51.3% [40.3%; 62.3%] with IJV-C (p > 0.10 for all pair-wise comparisons). CONCLUSION: The overall ability of CUS, IVC-C and IJV-C to assess invCVP was only moderate. CUS seems to be the preferable method if absolute CVP values are needed. IJV-C seems to be the fastest and most easily acquirable method, and thus may be especially valuable in emergency rooms.

[Immunoglobulins in PID, SID and neurological autoimmune disease]. / Anwendung von Immunglobulinen bei primären und sekundären Immundefekten und neurologischen Autoimmunerkrankungen.

Human immunoglobulins (IG, mostly IgG) are used as replacement therapy in patients with inherited primary immunodeficiencies, and in patients with secondary immuno-deficiencies often observed in multiple myeloma or chronic lymphocytic leukemia. Ig are also approved as immunomodulatory therapy in neurological autoimmune diseases (NAID) such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). 16 different Ig preparations for intravenous and subcutaneous use are at the moment available in Germany. The SIGNS study (Assessment of immunoglobulins in a long-term non-interventional study) investigates the clinical use of these drugs under clinical practice conditions. In this non-interventional prospective open-label cohort study, 550 patients with new or maintenance Ig therapy are observed with respect to drug utilization, effectiveness, (i. e. number of infections in PID and SID, functionality in NAID), tolerability, quality of life and costs in approximately 50 sites throughout Germany (neurologists, pediatricians, oncologists, other) for at least two years. This largest study of its kind is expected to contribute to optimization of Ig therapy in the postmarketing setting.

[Guideline for antiretroviral therapy of HIV-infected children and adolescents]. / Leitlinie der Pädiatrische Arbeitsgemeinschaft AIDS (PAAD) e.V. zur antiretroviralen Therapie bei HIV-infizierten Kindern und Jugendlichen (2011).

The HIV-infection in adults or children and adolescent differs substantially. Differences include the mode of infection, viral dynamics facing a developing immune system and the clinical course of the infection. In addition to the virological, immunological and epidemiological aspects the psychosocial situation is also very different. The above aspects and the decreased number of antiretroviral substances underline the need for specific guidelines for HIV-therapy in children and adolescents. The German Pediatric Working group AIDS (PAAD) has formulated this guideline in 2011 based on new study results, changes in international recommendations and newly available drugs.