Local inhomogeneities resolved by scanning probe techniques and their impact on local 2DEG formation in oxide heterostructures.

Lateral inhomogeneities in the formation of two-dimensional electron gases (2DEG) directly influence their electronic properties. Understanding their origin is an important factor for fundamental interpretations, as well as high quality devices. Here, we studied the local formation of the buried 2DEG at LaAlO3/SrTiO3 (LAO/STO) interfaces grown on STO (100) single crystals with partial TiO2 termination, utilizing in situ conductive atomic force microscopy (c-AFM) and scattering-type scanning near-field optical microscopy (s-SNOM). Using substrates with different degrees of chemical surface termination, we can link the resulting interface chemistry to an inhomogeneous 2DEG formation. In conductivity maps recorded by c-AFM, a significant lack of conductivity is observed at topographic features, indicative of a local SrO/AlO2 interface stacking order, while significant local conductivity can be probed in regions showing TiO2/LaO interface stacking order. These results could be corroborated by s-SNOM, showing a similar contrast distribution in the optical signal which can be linked to the local electronic properties of the material. The results are further complemented by low-temperature conductivity measurements, which show an increasing residual resistance at 5 K with increasing portion of insulating SrO-terminated areas. Therefore, we can correlate the macroscopic electrical behavior of our samples to their nanoscopic structure. Using proper parameters, 2DEG mapping can be carried out without any visible alteration of sample properties, proving c-AFM and s-SNOM to be viable and destruction-free techniques for the identification of local 2DEG formation. Furthermore, applying c-AFM and s-SNOM in this manner opens the exciting prospect to link macroscopic low-temperature transport to its nanoscopic origin.

[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.

Increase in Streptococcus pneumoniae serotype 3 associated parapneumonic pleural effusion/empyema after the introduction of PCV13 in Germany.

INTRODUCTION: Pediatric pneumococcal pneumonia complicated by parapneumonic pleural effusion/empyema (PPE/PE) remains a major concern despite general immunization with pneumococcal conjugate vaccines (PCVs). METHODS: In a nationwide pediatric hospital surveillance study in Germany we identified 584 children <18 years of age with bacteriologically confirmed PPE/PE from October 2010 to June 2018. Streptococcus pneumoniae was identified by culture and/or PCR of blood samples and/or pleural fluid and serotyped. RESULTS: S. pneumoniae was identified in 256 of 584 (43.8%) children by culture (n = 122) and/or PCR (n = 207). The following pneumococcal serotypes were detected in 114 children: serotype 3 (42.1%), 1 (25.4%), 7F (12.3%), 19A (7.9%), other PCV13 serotypes (4.4%) and non-PCV13 serotypes (7.9%). Between October 2010 and June 2014 serotype 1 (38.1%) and serotype 3 (25.4%) were most prevalent, whereas between July 2014 and June 2018 serotype 3 (62.7%) and non-PCV13 serotypes (15.7%) were dominant. Compared to children with other pneumococcal serotypes, children with serotype 3 associated PPE/PE were younger (median 3.2 years [IQR 2.1-4.3 years] vs. median 5.6 years [IQR 3.8-8.2 years]; p < 0.001) and more frequently admitted to intensive care (43 [89.6%] vs. 48 [73.8%]; p = 0.04). Seventy-six of 114 (66.7%) children with pneumococcal PPE/PE had been vaccinated with pneumococcal vaccines. Thirty-nine of 76 (51.3%) had received a vaccine covering the serotype detected. Thirty of these 39 breakthrough cases were age-appropriately vaccinated with PCV13 and considered vaccine failures, including 26 children with serotype 3, three children with serotype 19A and one child with serotype 1. CONCLUSION: Following the introduction of PCV13 in general childhood vaccination we observed a strong emergence of serotype 3 associated PPE/PE in the German pediatric population, including a considerable number of younger children with serotype 3 vaccine breakthrough cases and failures. Future PCVs should not only cover newly emerging serotypes, but also include a more effective component against serotype 3.

Consensus clinical scoring for suspected perioperative immediate hypersensitivity reactions.

BACKGROUND: Grading schemes for severity of suspected allergic reactions have been applied to the perioperative setting, but there is no scoring system that estimates the likelihood that the reaction is an immediate hypersensitivity reaction. Such a score would be useful in evaluating current and proposed tests for the diagnosis of suspected perioperative immediate hypersensitivity reactions and culprit agents. METHODS: We conducted a Delphi consensus process involving a panel of 25 international multidisciplinary experts in suspected perioperative allergy. Items were ranked according to appropriateness (on a scale of 1-9) and consensus, which informed development of a clinical scoring system. The scoring system was assessed by comparing scores generated for a series of clinical scenarios against ratings of panel members. Supplementary scores for mast cell tryptase were generated. RESULTS: Two rounds of the Delphi process achieved stopping criteria for all statements. From an initial 60 statements, 43 were rated appropriate (median score 7 or more) and met agreement criteria (disagreement index <0.5); these were used in the clinical scoring system. The rating of clinical scenarios supported the validity of the scoring system. Although there was variability in the interpretation of changes in mast cell tryptase by the panel, we were able to include supplementary scores for mast cell tryptase. CONCLUSION: We used a robust consensus development process to devise a clinical scoring system for suspected perioperative immediate hypersensitivity reactions. This will enable objectivity and uniformity in the assessment of the sensitivity of diagnostic tests.

Management of a surgical patient with a label of penicillin allergy: narrative review and consensus recommendations.

Unsubstantiated penicillin-allergy labels are common in surgical patients, and can lead to significant harm through avoidance of best first-line prophylaxis of surgical site infections and increased infection with resistant bacterial strains. Up to 98% of penicillin-allergy labels are incorrect when tested. Because of the scarcity of trained allergists in all healthcare systems, only a minority of surgical patients have the opportunity to undergo testing and de-labelling before surgery. Testing pathways can be modified and shortened in selected patients. A variety of healthcare professionals can, with appropriate training and in collaboration with allergists, provide testing for selected patients. We review how patients might be assessed, the appropriate testing strategies that can be used, and the minimum standards of safe testing.

Changes in the incidence and bacterial aetiology of paediatric parapneumonic pleural effusions/empyema in Germany, 2010-2017: a nationwide surveillance study.

OBJECTIVES: Parapneumonic pleural effusions/empyema (PPE/PE) are severe complications of community-acquired pneumonia. We investigated the bacterial aetiology and incidence of paediatric PPE/PE in Germany after the introduction of universal pneumococcal conjugate vaccine (PCV) immunization for infants. METHODS: Children <18 years of age hospitalized with pneumonia-associated PPE/PE necessitating pleural drainage or persisting >7 days were reported to the German Surveillance Unit for Rare Diseases in Childhood between October 2010 and June 2017. All bacteria detected in blood or pleural fluid (by culture/PCR) were included, with serotyping for Streptococcus pneumoniae. RESULTS: The median age of all 1447 PPE/PE patients was 5 years (interquartile range 3-10). In 488 of the 1447 children with PPE/PE (34%), 541 bacteria (>40 species) were detected. Aerobic gram-positive cocci accounted for 469 of 541 bacteria detected (87%); these were most frequently Streptococcus pneumoniae (41%), Streptococcus pyogenes (19%) and Staphylococcus aureus (6%). Serotype 3 accounted for 45% of 78 serotyped S. pneumoniae strains. Annual PPE/PE incidence varied between 14 (95%CI 12-16) and 18 (95%CI 16-21) PPE/PE per million children. Incidence of S. pneumoniae PPE/PE decreased from 3.5 (95%CI 2.5-4.6) per million children in 2010/11 to 1.5 (95%CI 0.9-2.4) in 2013/14 (p 0.002), followed by a re-increase to 2.2 (95%CI 1.5-3.2) by 2016/17 (p 0.205). CONCLUSIONS: In the era of widespread PCV immunization, cases of paediatric PPE/PE were still caused mainly by S. pneumoniae and, increasingly, by S. pyogenes. The re-increase in the incidence of PPE/PE overall and in S. pneumoniae-associated PPE/PE indicates ongoing changes in the bacterial aetiology and requires further surveillance.

Halogenated Meroditerpenoids from a South Pacific Collection of the Red Alga Callophycus serratus.

A detailed examination of the red alga Callophycus serratus collected in Tonga led to the isolation of six new halogenated meroditerpenoids: callophycol C (1), callophycoic acid I (2), iodocallophycols E (3) and F (4), iodocallophycoic acid B (5), and callophycoic acid J (6). Of these, compounds 3-5 are new iodinated additions to the growing family of Callophycus meroditerpenoids. The relative configurations of compounds 1-6 were deduced by analyses of 1D NOE data and 1H-1H scalar coupling constants, and 3-6 are proposed to differ from the closely related compounds reported in the literature, iodocallophycoic acid A and iodocallophycols A-D. Iodocallophycol E (3) exhibited moderate cytotoxicity against the promyelocytic leukemia cell line HL-60 with an IC50 value of 6.0 µM.

Morphine and pholcodine-specific IgE have limited utility in the diagnosis of anaphylaxis to benzylisoquinolines.

BACKGROUND: Investigation of immediate hypersensitivity reactions in the perioperative setting involves skin testing and measurement of specific IgE (sIgE) as standard practice. In the case of the neuromuscular blocking agents (NMBAs), the main allergenic epitopes have been shown to be substituted ammonium groups. Commercial assays are available for detection of sIgE to these epitopes using morphine and pholcodine substrates but questions have been raised about the effectiveness of these assays in the diagnosis of benzylisoquinoline anaphylaxis. This study was therefore undertaken to assess the effectiveness of these assays in the diagnosis of hypersensitivity reactions to this group of NMBAs. METHODS: Analysis was carried out on all available results for patients assessed at the Royal North Shore Hospital Anaesthetic Allergy Clinic during the period June 2009 to June 2016. Standardised intradermal skin tests were performed with a panel of NMBAs. Measurement of sIgE to morphine and pholcodine was performed via the Phadia ImmunoCAP® system. RESULTS: For all patients with positive skin test results to NMBAs which included a benzylisoquinoline NMBA (n = 24), 75% exhibited negative sIgE to both morphine and pholcodine. Where patients were reactive to benzylisoquinoline NMBAs alone (n = 12), 100% exhibited negative sIgE results, indicating 0% sensitivity of the assays relative to skin testing, in this subgroup. CONCLUSION: Use of sIgE testing to morphine and pholcodine in the assessment of NMBA immediate hypersensitivity is a valuable tool particularly in the case of reactions to the aminosteroid NMBAs. However, these assays are unreliable in detecting sensitisation to benzylisoquinoline NMBAs.

[Chronic cough and protracted bacterial bronchitis in children and adolescents]. / Feuchter Husten und protrahierte bakterielle Bronchitis bei Kindern und Jugendlichen.

Persistent cough is one of the most common reasons patients present to outpatient practices. Especially in children, chronic cough (>4 weeks) is a significant burden on the child and family. While in the past, the lower airways were considered sterile, the concept of a physiologic microbiome of the lower respiratory tract has increasingly emerged. Of the differential diagnoses of chronic cough, protracted bacterial bronchitis (PBB) is more common in otherwise (pulmonary) healthy children under 6 years of age. Tracheomalacia may primarily exist or be the result of mechanically straining coughing, whereas apart from a reduced alveolar phagocytosis, there is usually no systemic or local immune weakness. Instead, an activated innate immunity with increased gene expression of the interleukin-1ß signaling pathway can be immunologically detected. Here too, it is difficult to differentiate between cause and effect of chronic inflammatory events. Today, PBB and non-CF bronchiectasis, i.e., bronchiectasis not caused by cystic fibrosis (CF), are two sides of a disease spectrum of suppurative lung diseases, thus, making consequent therapy and long-term pediatric pneumological support of children with chronic productive cough necessary.

Australian and New Zealand Anaesthetic Allergy Group Perioperative Anaphylaxis Investigation Guidelines.

These guidelines are a consensus document developed by a working party of the Australian and New Zealand Anaesthetic Allergy Group (ANZAAG) to provide an approach to the investigation of perioperative anaphylaxis. They focus primarily on the use of skin testing as it is the investigation with the greatest clinical utility for the identification of the likely causative agent and potentially safer alternatives. The practicalities and process of skin testing, its limitations, and the place of other tests are discussed. These guidelines also address the roles of graded challenge and in vitro testing. The implications of anaphylaxis associated with neuromuscular blocking agents, beta-lactam antibiotics, local anaesthetic agents and chlorhexidine are discussed. Evidence for the recommendations is derived from literature searches using the words skin test, allergy, anaphylaxis, anaesthesia, and each of the individual agents listed in these guidelines. The individual articles were then reviewed for suitability for inclusion in these guidelines. Where evidence was not strong, as is the situation for many perioperative agents, expert consensus from the ANZAAG working party was used. These guidelines are intended for use by specialists involved in the investigation of perioperative allergy. They have been approved following peer review by members of ANZAAG and are available on the ANZAAG website: http://www.anzaag.com/anaphylaxis-management/testing-guidelines.pdf.

Radiation-induced carcinosarcoma of the submandibular gland: case report and review of literature.

Radiation-induced carcinosarcoma of the submandibular gland: case report and review of literature. Radiation-induced carcinosarcoma (RICS) of the head and neck is a very rare and extremely aggressive entity. We present the case of a 60-year-old man diagnosed with a T2N2cM0 squamous cell carcinoma at the right base of the tongue (BOT). The patient was treated with neoadjuvant chemotherapy and 3D-conformal radiotherapy (3D-CRT) to the BOT and bilateral neck. He developed left submandibular firmness five years after treatment, initially diagnosed as radiation-induced fibrosis. The increasing size of the left submandibular mass two years later prompted further imaging, which showed a 2.2x1.8 cm mass in the left submandibular region in the previously irradiated field. This was diagnosed as a radiation-induced submandibular gland malignancy. This is the first reported case of a RICS in the submandibular gland and demonstrates the importance of early workup and evaluation of submandibular gland pathology in a patient with a history of radiation for a head and neck malignancy.

The burden of invasive pneumococcal disease in children with underlying risk factors in North America and Europe.

BACKGROUND: Characterisation of risk groups who may benefit from pneumococcal vaccination is essential for the generation of recommendations and policy. METHODS: We reviewed the literature to provide information on the incidence and risk of invasive pneumococcal disease (IPD) in at-risk children in Europe and North America. The PubMed database was searched using predefined search terms and inclusion/exclusion criteria for papers reporting European or North American data on the incidence or risk of IPD in children with underlying medical conditions. RESULTS: Eighteen references were identified, 11 from North America and 7 from Europe, with heterogeneous study methods, periods and populations. The highest incidence was seen in US children positive for human immunodeficiency virus infection, peaking at 4167 per 100,000 patient-years in 2000. Studies investigating changes in incidence over time reported decreases in the incidence of IPD between the late 1990s and early 2000s. The highest risk of IPD was observed in children with haematological cancers or immunosuppression. Overall, data on IPD in at-risk children were limited, lacking incidence data for a wide range of predisposing conditions. There was, however, a clear decrease in the incidence of IPD in at-risk children after the introduction of 7-valent pneumococcal conjugate vaccine into immunisation programmes, as previously demonstrated in the general population. CONCLUSION: Despite the heterogeneity of the studies identified, the available data show a substantial incidence of IPD in at-risk children, particularly those who are immunocompromised. Further research is needed to determine the true risk of IPD in at-risk children, particularly in the post-PCV period, and to understand the benefits of vaccination and optimal vaccination schedules.

[Upper airway infections]. / Infektionen der oberen Atemwege.

BACKGROUND: Upper airway infections contribute significantly to paediatric morbidity and hospitalization especially of young children, are often treated polypragmatically, and are one of the main reasons for antibiotic prescriptions. The severity varies between mild, self-limiting and potentially life-threatening airway obstructions. DIAGNOSIS: The physician involved can normally make the right diagnosis based on the patient's history and physical findings; additional diagnostic procedures (blood tests, imaging) should be restricted to unclear cases. THERAPY: Antibiotic stewardship should be applied. Imminent airway obstruction will require early and competent paediatric intensive care interventions. Since viral and bacterial upper airway infections can present with similar features, it is useful to approach them under topographical aspects. PREVENTION: Following immunization recommendations can prevent an enormous amount of severe potentially life threatening airway infections.

Reference ranges and cutoff levels of pneumococcal antibody global serum assays (IgG and IgG2) and specific antibodies in healthy children and adults.

Pneumococcal antibodies represent the acquisition of natural immunity. Determination of pneumococcal antibodies is an important screening tool for immunodeficiencies. Our study generated reference ranges and cutoff levels for pneumococcal antibody global serum assays correlated to a specific pneumococcal antibody ELISA. Specific pneumococcal antibody levels were measured from 457 children undergoing elective surgery and 46 healthy adult volunteers (88 with previous pneumococcal immunization from both groups), 22 severe immunodeficient subjects with ataxia telangiectasia (A-T, negative controls), and age-matched 36 healthy allergic asthmatics. We determined a representative panel of serotype-specific pneumococcal antibodies (serotype 4, 5, 6B, 7F, 14, 18C, 19F, 23F) by ELISA and global pneumococcal IgG and IgG2 antibodies by EIA. In vaccine-naïve healthy subjects, initial pneumococcal IgG geometric mean concentrations of 13.1 µg/ml were low in the first year of life and increased over the time, reaching adult levels (70.5 µg/ml) at age 8-12 years. In parallel, IgG2 antibodies increased from 20.7 % (0.5-1 year old) to adult proportions (>30 %) in preschoolers. Correlation between the pneumococcal IgG screening assay and specific pneumococcal antibody levels was acceptable (Pearson's coefficient r = 0.4455; p = 0.001). Cutoff levels showed high sensitivity, whereas specificity was high to moderate calculated from correlations with the specific ELISA. We provide reference ranges and cutoff levels for the interpretation of specific antibody determinations in the clinical setting. The global pneumococcal IgG/IgG2 assay is a suitable screening tool and correlates with the ELISA serotype-specific pneumococcal antibodies. However, results below our cutoff values should be re-evaluated by serotype-specific ELISA testing.

Failure to investigate anaesthetic anaphylaxis resulting in a preventable second anaphylactic reaction.

We present a case of anaphylaxis to suxamethonium and/or vecuronium in a patient who had previously suffered an anaphylactic reaction, presumably to rocuronium. The patient had not been referred for formal allergy testing after the first anaphylactic reaction. Subsequent formal allergy testing revealed sensitivities to suxamethonium, rocuronium and vecuronium. Her next anaesthetic, using cisatracurium, was uneventful. It is recommended that all patients with suspected perioperative anaphylaxis are referred for testing. This is the responsibility of the anaesthetist. Particular caution should be used with suspected neuromuscular blocking drug allergy as cross-reactivity is common and not predictable by drug structure.

[Quality of life for adolescents with vocal cord dysfunction]. / Lebensqualität bei jugendlichen mit vocal cord dysfunction.

BACKGROUND: Vocal cord dysfunction (VCD) is a functional breathing disorder. A psychosomatic aetiology has been discussed and associations with depression, anxiety disorders, and social stress have been reported. We have undertaken a screening of behavioural and emotional problems in adolescent patients using standardised questionnaires. METHODS: Thirty-one patients (8 - 16 years) with the clinical suspicion of VCD were investigated using the Youth-Self-Report (YSR/11 - 18) and for the assessment of the parents we used the analoguous Child-Behaviour-Checklist (CBCL/6 - 18). YSR and CBCL contain two sub-areas: (a) competence scales that measure the child's participation in activities, social skills and school achievements and (b) items that contain subscales for emotional problems such as depressive and anxiety symptoms, conduct problems such as oppositional defiant problems and aggressive behaviour, social problems and physical complaints. RESULTS: On average, the features of VCD patients were not significantly different from those of the reference population. But we did observe tendencies of psychological problems (YSR 16.7 %, CBCL 20 %) compared with the standard (2 %) in the syndrome scales of both questionnaires Adolescents reported particularly more internalising disorders such as social retreat, physical complaint and anxiety and depressive symptoms. The parents reported more often "physical complaints" (13.3 %) and "aggressive behaviour" (10 %). CONCLUSIONS: We found tendencies of psychological strain, mainly social retreat, physical complaints and anxiety and depressive symptoms. Further investigations should focus on those emotional problems as well as on psychosomatically caused physical problems. Personality and psychological stress of the parents should be included in the investigation in order to evaluate the reports of the parents on higher aggressive behaviour and enhanced physical problems of their children in relation to their own psychological strain. We suggest family therapies, family counselling, or parental coaching as a therapeutic approach.

Lipid-Laden Alveolar Macrophages and pH Monitoring in Gastroesophageal Reflux-Related Respiratory Symptoms.

Lipid-laden alveolar macrophages and pH monitoring have been used in the diagnosis of chronic aspiration in children with gastroesophageal reflux (GER). This study was conducted to prove a correlation between the detection of alimentary pulmonary fat phagocytosis and an increasing amount of proximal gastroesophageal reflux. It was assumed that proximal gastroesophageal reflux better correlates with aspiration than distal GER. Patients from 6 months to 16 years with unexplained recurrent wheezy bronchitis and bronchial hyperreactivity, or recurrent pneumonia with chronic cough underwent 24-hour double-channel pH monitoring and bronchoscopy with bronchoalveolar lavage (BAL). Aspiration of gastric content was determined by counting lipid laden alveolar macrophages from BAL specimens. There were no correlations between any pH-monitoring parameters and counts of lipid-laden macrophages in the whole study population, even when restricting analysis to those with abnormal reflux index expressing clinically significant GER. Quantifying lipid-laden alveolar macrophages from BAL in children with gastroesophageal-related respiratory disorders does not have an acceptable specificity to prove chronic aspiration as an underlying etiology. Therefore, research for other markers of pulmonary aspiration is needed.