Epstein-Barr virus-associated gastric cancer reveals intratumoral heterogeneity of PIK3CA mutations.

Background: Recent whole-genome sequencing identified four molecular subtypes of gastric cancer (GC), of which the subgroup of Epstein-Barr virus-associated GC (EBVaGC) showed a significant enrichment of PIK3CA mutations. We here aimed to validate independently the enrichment of PIK3CA mutations in EBVaGC of a Central European GC cohort, to correlate EBV status with clinico-pathological patient characteristics and to test for a major issue of GC, intratumoral heterogeneity. Patients and methods: In a first step, 484 GCs were screened for EBV and PIK3CA hot spot mutations of exon 9/20 using EBER in situ hybridization and pyrosequencing, respectively. Secondly, an extended sequencing of PIK3CA also utilizing next generation sequencing was carried out in all EBVaGCs and 96 corresponding lymph node metastases. Results: Twenty-two GCs were EBER-positive, all being of latency type I. Intratumoral heterogeneity of EBER-positivity was found in 18% of EBVaGCs. Twenty-three GCs held PIK3CA mutations in hot spot regions of exon 9 or 20, being significantly more common in EBVaGCs (P < 0.001). Subsequent extended sequencing of PIK3CA of EBVaGCs showed that 14% harvested three to five different PIK3CA genotypes (including wildtype) in the same primary tumor, albeit in histologically and spatially distinct tumor areas, and that intratumoral heterogeneity of PIK3CA was also present in the corresponding lymph node metastases. Conclusions: Our findings unravel issues of tumor heterogeneity and illustrate that the assessment of the EBV status in tissue biopsies might carry the risk of sampling errors, which may significantly hamper adequate molecular tumor classification in a more clinical setting. Moreover, this is the first report of intratumoral heterogeneity of PIK3CA mutations in GC, and our findings lead to the conclusion that PIK3CA mutant and -wildtype tumor subclones are skilled to metastasize independently to different regional lymph nodes.

Food allergy: a practice parameter update-2014.

This parameter was developed by the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma & Immunology (JCAAI). The AAAAI and the ACAAI have jointly accepted responsibility for establishing "Food Allergy: A practice parameter update-2014." This is a complete and comprehensive document at the current time. The medical environment is a changing one, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, ACAAI, and JCAAI. These parameters are not designed for use by pharmaceutical companies in drug promotion.

Oral food challenges in children with a diagnosis of food allergy.

OBJECTIVE: To assess the outcome of oral food challenges in patients placed on elimination diets based primarily on positive serum immunoglobulin E (IgE) immunoassay results. STUDY DESIGN: This is a retrospective chart review of 125 children aged 1-19 years (median age, 4 years) evaluated between January 2007 and August 2008 for IgE-mediated food allergy at National Jewish Health and who underwent an oral food challenge. Clinical history, prick skin test results, and serum allergen-specific IgE test results were obtained. RESULTS: The data were summarized for food avoidance and oral food challenge results. Depending on the reason for avoidance, 84%-93% of the foods being avoided were returned to the diet after an oral food challenge, indicating that the vast majority of foods that had been restricted could be tolerated at discharge. CONCLUSIONS: In the absence of anaphylaxis, the primary reliance on serum food-specific IgE testing to determine the need for a food elimination diet is not sufficient, especially in children with atopic dermatitis. In those circumstances, oral food challenges may be indicated to confirm food allergy status.

National prevalence and risk factors for food allergy and relationship to asthma: results from the National Health and Nutrition Examination Survey 2005-2006.

BACKGROUND: The national prevalence and patterns of food allergy (FA) in the United States are not well understood. OBJECTIVE: We developed nationally representative estimates of the prevalence of and demographic risk factors for FA and investigated associations of FA with asthma, hay fever, and eczema. METHODS: A total of 8203 participants in the National Health and Nutrition Examination Survey 2005-2006 had food-specific serum IgE measured to peanut, cow's milk, egg white, and shrimp. Food-specific IgE and age-based criteria were used to define likely FA (LFA), possible FA, and unlikely FA and to develop estimates of clinical FA. Self-reported data were used to evaluate demographic risk factors and associations with asthma and related conditions. RESULTS: In the United States, the estimated prevalence of clinical FA was 2.5% (peanut, 1.3%; milk, 0.4%; egg, 0.2%; shrimp, 1.0%; not mutually exclusive). Risk of possible FA/LFA was increased in non-Hispanic blacks (odds ratio, 3.06; 95% CI, 2.14-4.36), males (1.87; 1.32-2.66), and children (2.04; 1.42-2.93). Study participants with doctor-diagnosed asthma (vs no asthma) exhibited increased risk of all measures of food sensitization. Moreover, in those with LFA, the adjusted odds ratio for current asthma (3.8; 1.5-10.7) and an emergency department visit for asthma in the past year (6.9; 2.4-19.7) were both notably increased. CONCLUSION: Population-based serologic data on 4 foods indicate an estimated 2.5% of the US population has FA, and increased risk was found for black subjects, male subjects, and children. In addition, FA could be an under-recognized risk factor for problematic asthma.

Clinical Importance of Binaural Information: Extending Auditory Assessment in Clinical Populations Using a Portable Testing Platform.

Purpose The purpose of this study is to use variability on tests of basic auditory processing to allow identification of those tests that could be used clinically to describe functional hearing ability beyond the pure-tone audiogram and clinical speech-in-noise tests. Method Psychoacoustic tests implemented using the Portable Automated Rapid Testing system on a calibrated iPad were evaluated for nine young normal-hearing participants (M age = 21.3, SD = 2.5) and seven hearing-impaired participants (M age = 64.9, SD = 13.5). Participants completed 10 psychoacoustic subtests in a quiet room. Correlational analyses were used to compare performance on the psychoacoustic test battery with performance on a clinical speech-in-noise test and with the 4-frequency pure-tone average (4FreqPTA). Results Spectral processing ability was highly correlated with 4FreqPTA, and temporal processing ability showed minimal variability across the hearing-impaired group. Tests involving binaural processing captured variability across hearing-impaired listeners not associated with 4FreqPTA or speech-in-noise performance. Conclusions Tests that capture the ability to use binaural cues may add information to what current clinical protocols reveal about patients with auditory complaints. Further testing with a larger sample size is needed to confirm the need for binaural measurements and to develop normative data for clinical settings.

Proton beam quality enhancement by spectral phase control of a PW-class laser system.

We report on experimental investigations of proton acceleration from solid foils irradiated with PW-class laser-pulses, where highest proton cut-off energies were achieved for temporal pulse parameters that varied significantly from those of an ideally Fourier transform limited (FTL) pulse. Controlled spectral phase modulation of the driver laser by means of an acousto-optic programmable dispersive filter enabled us to manipulate the temporal shape of the last picoseconds around the main pulse and to study the effect on proton acceleration from thin foil targets. The results show that applying positive third order dispersion values to short pulses is favourable for proton acceleration and can lead to maximum energies of 70 MeV in target normal direction at 18 J laser energy for thin plastic foils, significantly enhancing the maximum energy compared to ideally compressed FTL pulses. The paper further proves the robustness and applicability of this enhancement effect for the use of different target materials and thicknesses as well as laser energy and temporal intensity contrast settings. We demonstrate that application relevant proton beam quality was reliably achieved over many months of operation with appropriate control of spectral phase and temporal contrast conditions using a state-of-the-art high-repetition rate PW laser system.

First experiences with pudendal nerve stimulation in fecal incontinence: a technical report.

Sacral nerve stimulation (SNS) is an established treatment for refractory lower urinary tract and bowel dysfunction. In some urological patients, SNS does not have satisfactory results. Pudendal nerve stimulation (PNS) has recently been proposed for these patients and successfully tested. Given the sometimes unsatisfactory results after SNS in fecal incontinence (FI), we tested PNS on patients suffering from FI. We used the device and implantation technique described by Spinelli et al. By making a slight change in the device, we developed a quick and easy-to-use method for successful PNS implantation, based on electrophysiological response. We present the results of a feasibility study, in which we tested the effectiveness of PNS with our modified implantation technique on 2 patients, with very satisfactory early results in a 4-month follow-up.

Work Group report: oral food challenge testing.

Oral food challenges are procedures conducted by allergists/immunologists to make an accurate diagnosis of immediate, and occasionally delayed, adverse reactions to foods. The timing of the challenge is carefully chosen based on the individual patient history and the results of skin prick tests and food specific serum IgE values. The type of the challenge is determined by the history, the age of the patient, and the likelihood of encountering subjective reactions. The food challenge requires preparation of the patient for the procedure and preparation of the office for the organized conduct of the challenge, for a careful assessment of the symptoms and signs and the treatment of reactions. The starting dose, the escalation of the dosing, and the intervals between doses are determined based on experience and the patient's history. The interpretation of the results of the challenge and arrangements for follow-up after a challenge are important. A negative oral food challenge result allows introduction of the food into the diet, whereas a positive oral food challenge result provides a sound basis for continued avoidance of the food.

Prosthetic gait of unilateral lower-limb amputees with current and novel prostheses: A pilot study.

BACKGROUND: Novel lower-limb prostheses aim to improve the quality of locomotion of individuals with an amputation. This study evaluates the biomechanics of a novel bionic foot during walking. METHODS: Able-bodied individuals (n = 7) and individuals with a transfemoral (n = 6) or transtibial amputation (n = 6) were included. Able-bodied individuals conducted one experimental trial, whereas individuals with transtibial and transfemoral amputations conducted a familiarization (with current prosthesis) and two experimental trials using a passive and bionic prosthesis. Each trial consisted of 3 bouts of 2 min of treadmill walking at different speeds. Biomechanical data were gathered using a force platform and motion capture system and analysed using Statistical Parametric Mapping and (non)-parametric tests. FINDINGS: Conventional prosthetic feet alter gait patterns and induce locomotion difficulties. While walking at a normal speed with the passive prosthesis, transtibial amputees display reduced maximum heel forces, increased ankle and trunk angular velocities at midstance, and increased knee angle during stance and swing phases on their effected side (P ≤ 0.026). Improved lower-limb kinematics was demonstrated during slow and normal speed walking with the bionic prosthesis; however, dynamic trunk stability was negatively impacted during this condition. The bionic prosthesis did not benefit transfemoral amputees at any walking speed. INTERPRETATION: Transtibial amputees can better approximate typical movement patterns at slow and normal walking speeds using the novel bionic prosthesis; however the same benefit was not observed in transfemoral amputees.

Managing Food Allergy in Schools During the COVID-19 Pandemic.

In the wake of the COVID-19 pandemic and massive disruptions to daily life in the spring of 2020, in May 2020, the Centers for Disease Control (CDC) released guidance recommendations for schools regarding how to have students attend while adhering to principles of how to reduce the risk of contracting SARS-CoV-2. As part of physical distancing measures, the CDC is recommending that schools who traditionally have had students eat in a cafeteria or common large space instead have children eat their lunch or other meals in the classroom at already physically distanced desks. This has sparked concern for the safety of food-allergic children attending school, and some question of how the new CDC recommendations can coexist with recommendations in the 2013 CDC Voluntary Guidelines on Managing Food Allergy in Schools as well as accommodations that students may be afforded through disability law that may have previously prohibited eating in the classroom. This expert consensus explores the issues related to evidence-based management of food allergy at school, the issues of managing the health of children attending school that are acutely posed by the constraints of an infectious pandemic, and how to harmonize these needs so that all children can attend school with minimal risk from both an infectious and allergic standpoint.

Modification of the active site of alkaline phosphatase by site-directed mutagenesis.

The catalytically essential amino acid in the active site of bacterial alkaline phosphatase (Ser-102) has been replaced with a cysteine by site-directed mutagenesis. The resulting thiol enzyme catalyzes the hydrolysis of a variety of phosphate monoesters. The rate-determining step of hydrolysis, however, is no longer the same for catalysis when the active protein nucleophile is changed from the hydroxyl of serine to the thiol of cysteine. Unlike the steady-state kinetics of native alkaline phosphatase, those of the mutant show sensitivity to the leaving group of the phosphate ester.

Fatal anaphylaxis to foods: epidemiology, recognition, and prevention.

The inability to accurately predict the severity of future allergic reactions to foods in a given individual coupled with the real--although usually remote--risk of a fatal anaphylactic reaction complicates care and remains a constant source of concern to food-allergic patients, their family members, and health care providers. Current epidemiologic evidence suggests that the incidence of food-induced anaphylaxis is increasing, although confidently approximating the incidence of fatal allergic reactions to foods remains difficult. This article briefly reviews the epidemiology of fatal anaphylactic reactions to foods, discusses factors that may aid in identifying individuals at higher risk, emphasizes important aspects of patient education and prevention, and touches on the psychological impact of having a family member with food allergy.

The use of serum-specific IgE measurements for the diagnosis of peanut, tree nut, and seed allergy.

BACKGROUND: The gold standard for diagnosing food allergy is the double-blind, placebo-controlled food challenge. Diagnostic food-specific IgE levels might assist in diagnosing food allergies and circumventing the need for food challenges. OBJECTIVES: The purpose of this study was to determine the utility of food-specific IgE measurements for identifying symptomatic peanut, tree nut, and seed allergies and to augment what is known about the relationships among these foods. METHODS: Patients referred for suspected peanut or tree nut allergies answered a questionnaire about their perceived food allergies. Allergen-specific diagnoses were based on questionnaire, medical history, and, when relevant, skin prick tests and serum specific IgE levels. Sera from the patients were analyzed for specific IgE antibodies to peanuts, tree nuts, and seeds by using ImmunoCAP Specific IgE (Phadia, Inc, Uppsala, Sweden). RESULTS: Three hundred twenty-four patients (61% male; median age, 6.1 years; range, 0.2-40.2 years) were evaluated. The patients were highly atopic (57% with atopic dermatitis and 58% with asthma). The majority of patients with peanut allergy were sensitized to tree nuts (86%), and 34% had documented clinical allergy. The relationship between diagnosis and allergen-specific IgE levels were estimated by using logistic regression. Diagnostic decision points are suggested for peanut and walnut. Probability curves were drawn for peanut, sesame, and several tree nuts. High correlations were found between cashew and pistachio and between pecan and walnut. CONCLUSIONS: Quantification of food-specific IgE is a valuable tool that will aid in the diagnosis of symptomatic food allergy and might decrease the need for double-blind, placebo-controlled food challenges.

Pleiotropic effects of antithrombin strand 1C substitution mutations.

Six different substitution mutations were identified in four different amino acid residues of antithrombin strand 1C and the polypeptide leading into strand 4B (F402S, F402C, F402L, A404T, N405K, and P407T), and are responsible for functional antithrombin deficiency in seven independently ascertained kindreds (Rosny, Torino, Maisons-Laffitte, Paris 3, La Rochelle, Budapest 5, and Oslo) affected by venous thromboembolic disease. In all seven families, variant antithrombins with heparin-binding abnormalities were detected by crossed immunoelectrophoresis, and in six of the kindreds there was a reduced antigen concentration of plasma antithrombin. Two of the variant antithrombins, Rosny and Torino, were purified by heparin-Sepharose and immunoaffinity chromatography, and shown to have greatly reduced heparin cofactor and progressive inhibitor activities in vitro. The defective interactions of these mutants with thrombin may result from proximity of s1C to the reactive site, while reduced circulating levels may be related to s1C proximity to highly conserved internal beta strands, which contain elements proposed to influence serpin turnover and intracellular degradation. In contrast, s1C is spatially distant to the positively charged surface which forms the heparin binding site of antithrombin; altered heparin binding properties of s1C variants may therefore reflect conformational linkage between the reactive site and heparin binding regions of the molecule. This work demonstrates that point mutations in and immediately adjacent to strand 1C have multiple, or pleiotropic, effects on this serpin, leading ultimately to failure of its regulatory function.

Transplacental transmission of Neospora caninum in moose (Alces alces).

A 5-years-old moose (Alces alces) cow kept in a zoo in the German Federal State of Brandenburg aborted a female foetus of 44cm crown rump length (CRL). Pathohistological analysis revealed several Neospora (N.) caninum infected cells and cysts, as well as multifocal gliosis, necrosis, haemorrhages, dystrophic mineralisation and haemosiderosis in the brain, predominantly in cerebrum and brainstem. In addition, mild lymphocytic meningitis was present. Together with the fresh foetus, a mummified foetus of 16cm CRL was expelled. Neither focal necrosis, nor inflammation was detected in the brain of the mummified foetus. By two polymerase chain reactions (PCR) targeting the pNc5 gene of N. caninum (i.e. an end point PCR and a real-time PCR), by two serological methods (immunofluorescence test and immunoblot), by histological and immunohistochemical analyses, transplacental N. caninum infection was confirmed in the fresh foetus and interpreted as possible cause of abortion. Infection with other agents causing abortion including Bovine Herpesvirus 1 (BHV1), Bluetongue Virus (BTV), Bovine Virus Diarrhoea Virus (BVDV), Brucella spp., Chlamydia spp., Coxiella burnetii and Toxoplasma gondii were excluded. Our findings show that control measures may be necessary to protect captive moose against accidental N. caninum infection. Further studies are needed to explore the importance of neosporosis in wild and captive moose.

Conducting an Oral Food Challenge to Peanut in an Infant.

Results from the Learning Early About Peanut trial and its follow-up study suggest that early peanut introduction in the diets of high-risk infants may prevent the development of peanut allergy. Allergy organizations around the world released a unified statement, the Consensus Communication on Early Peanut Introduction and the Prevention of Peanut Allergy in High Risk Infants, in response to results from the Learning Early About Peanut trial, which recommends early introduction of peanut into the diet of those children at greatest risk of development of peanut allergy. As a result, it is expected that practicing allergists will experience an increased demand to perform an oral food challenge (OFC) in infants. Allergists often perform OFCs; however, conducting an OFC in an infant creates unique circumstances that have not been considered in previously published OFC guideline documents. The purpose of this workgroup report is to provide guidance to practitioners regarding the proper approach for conducting a peanut challenge in an infant.

Demonstration of a beam loaded nanocoulomb-class laser wakefield accelerator.

Laser-plasma wakefield accelerators have seen tremendous progress, now capable of producing quasi-monoenergetic electron beams in the GeV energy range with few-femtoseconds bunch duration. Scaling these accelerators to the nanocoulomb range would yield hundreds of kiloamperes peak current and stimulate the next generation of radiation sources covering high-field THz, high-brightness X-ray and γ-ray sources, compact free-electron lasers and laboratory-size beam-driven plasma accelerators. However, accelerators generating such currents operate in the beam loading regime where the accelerating field is strongly modified by the self-fields of the injected bunch, potentially deteriorating key beam parameters. Here we demonstrate that, if appropriately controlled, the beam loading effect can be employed to improve the accelerator's performance. Self-truncated ionization injection enables loading of unprecedented charges of ∼0.5 nC within a mono-energetic peak. As the energy balance is reached, we show that the accelerator operates at the theoretically predicted optimal loading condition and the final energy spread is minimized.Higher beam quality and stability are desired in laser-plasma accelerators for their applications in compact light sources. Here the authors demonstrate in laser plasma wakefield electron acceleration that the beam loading effect can be employed to improve beam quality by controlling the beam charge.