Omalizumab for the Treatment of Multiple Food Allergies.

BACKGROUND: Food allergies are common and are associated with substantial morbidity; the only approved treatment is oral immunotherapy for peanut allergy. METHODS: In this trial, we assessed whether omalizumab, a monoclonal anti-IgE antibody, would be effective and safe as monotherapy in patients with multiple food allergies. Persons 1 to 55 years of age who were allergic to peanuts and at least two other trial-specified foods (cashew, milk, egg, walnut, wheat, and hazelnut) were screened. Inclusion required a reaction to a food challenge of 100 mg or less of peanut protein and 300 mg or less of the two other foods. Participants were randomly assigned, in a 2:1 ratio, to receive omalizumab or placebo administered subcutaneously (with the dose based on weight and IgE levels) every 2 to 4 weeks for 16 to 20 weeks, after which the challenges were repeated. The primary end point was ingestion of peanut protein in a single dose of 600 mg or more without dose-limiting symptoms. The three key secondary end points were the consumption of cashew, of milk, and of egg in single doses of at least 1000 mg each without dose-limiting symptoms. The first 60 participants (59 of whom were children or adolescents) who completed this first stage were enrolled in a 24-week open-label extension. RESULTS: Of the 462 persons who were screened, 180 underwent randomization. The analysis population consisted of the 177 children and adolescents (1 to 17 years of age). A total of 79 of the 118 participants (67%) receiving omalizumab met the primary end-point criteria, as compared with 4 of the 59 participants (7%) receiving placebo (P<0.001). Results for the key secondary end points were consistent with those of the primary end point (cashew, 41% vs. 3%; milk, 66% vs. 10%; egg, 67% vs. 0%; P<0.001 for all comparisons). Safety end points did not differ between the groups, aside from more injection-site reactions in the omalizumab group. CONCLUSIONS: In persons as young as 1 year of age with multiple food allergies, omalizumab treatment for 16 weeks was superior to placebo in increasing the reaction threshold for peanut and other common food allergens. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT03881696.).

Desensitization and remission after peanut sublingual immunotherapy in 1- to 4-year-old peanut-allergic children: A randomized, placebo-controlled trial.

BACKGROUND: Prior studies of peanut sublingual immunotherapy (SLIT) have suggested a potential advantage with younger age at treatment initiation. OBJECTIVE: We studied the safety and efficacy of SLIT for peanut allergy in 1- to 4-year-old children. METHODS: Peanut-allergic 1- to 4-year-old children were randomized to receive 4 mg peanut SLIT versus placebo. Desensitization was assessed by double-blind, placebo-controlled food challenge (DBPCFC) after 36 months of treatment. Participants desensitized to at least 443 mg peanut protein discontinued therapy for 3 months and then underwent DBPCFC to assess for remission. Biomarkers were measured at baseline and longitudinally during treatment. RESULTS: Fifty participants (25 peanut SLIT, 25 placebo) with a median age of 2.4 years were enrolled across 2 sites. The primary end point of desensitization was met with actively treated versus placebo participants having a significantly greater median cumulative tolerated dose (4443 mg vs 143 mg), higher likelihood of passing the month 36 DBPCFC (60% vs 0), and higher likelihood of demonstrating remission (48% vs 0). The highest rate of desensitization and remission was seen in 1- to 2-year-olds, followed by 2- to 3-year-olds and 3- to 4-year-olds. Longitudinal changes in peanut skin prick testing, peanut-specific IgG4, and peanut-specific IgG4/IgE ratio were seen in peanut SLIT but not placebo participants. Oropharyngeal itching was more commonly reported by peanut SLIT than placebo participants. Skin, gastrointestinal, upper respiratory, lower respiratory, and multisystem adverse events were similar between treatment groups. CONCLUSION: Peanut SLIT safely induces desensitization and remission in 1- to 4-year-old children, with improved outcomes seen with younger age at initiation.

Awareness and Application of United States Food Allergy Prevention Guidelines Among Pediatricians and Other Clinicians.

OBJECTIVE: To characterize the awareness of, adherence to, and barriers to the 2017 National Institute of Allergy and Infectious Diseases (NIAID) peanut allergy prevention guidelines among the pediatrics health care workforce. STUDY DESIGN: Pediatricians, family physicians, advanced practice providers (APPs), and dermatologists who provide care for infants were solicited for a population-based online survey, administered from June 6, 2022, through July 3, 2022. The survey collected information about NIAID guideline awareness, implementation, and barriers as well as concerns related to the guidelines. RESULTS: A total of 250 pediatricians, 250 family physicians, 504 APPs, and 253 dermatologists met inclusion criteria. Self-reported guideline awareness was significantly higher for pediatricians (76%) compared with dermatologists (58%), family physicians (52%), and APPs (45%) (P < .05). Among participants who were aware of the guidelines, most reported using part or all of the guidelines in their clinical practices. Reported practice patterns for peanut introduction in 6-month-old infants were variable and did not always align with guidelines, particularly for infants with mild-to-moderate atopic dermatitis. CONCLUSIONS: Although pediatricians have the highest self-reported level of NIAID guideline awareness, awareness was suboptimal irrespective of provider type. Education for all pediatric clinicians is urgently needed to promote evidence-based peanut allergy prevention practices.

The oral health of adults with learning disabilities: A secondary analysis of the Adult Dental Health Survey 2009.

OBJECTIVES: Adults who have learning disabilities are a vulnerable group, little is known about their oral health and how this affects their quality of life. The aims of this secondary analysis of data from the 2009 Adult Dental Health Survey (ADHS) were to describe the oral health status of adults with learning disabilities, determine if severity of learning disability is associated with oral health and identify some of the methodological complexities of working with this population. The survey yields the most recent representative data on the oral health of adults with learning disabilities in England and importantly, contains information about oral health related quality of life (OHRQoL). BASIC RESEARCH DESIGN: Secondary analysis of data from a supplemental survey of adults with learning disabilities collected alongside the 2009 ADHS. PARTICIPANTS: 607 participants with a diagnosed learning disability aged 18 years and over. RESULTS: Adults with learning disabilities had similar levels of active dental caries, fewer natural teeth, and fewer fillings than comparable participants from the general population. Self-reported oral and general health were worse for adults with learning disabilities than the general population. Possible associations between the severity of learning disability and the numbers of decayed, missing or filled teeth were identified. However, large amounts of missing data limited the analysis. CONCLUSIONS: There are important questions relating to the accessibility of existing self-reported oral health questionnaires and the reliability of proxy-reported questions about OHRQoL that should be addressed to give a fuller picture of the oral health of adults with learning disabilities.

Untargeted serum metabolomic analysis reveals a role for purinergic signaling in FPIES.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy with a typical onset in infancy. Its symptoms are distinct from those of IgE-mediated food allergies and include severe repetitive vomiting, lethargy, and pallor. FPIES reactions are associated with TH17 cytokines and a systemic innate immune activation; however, the link between immune activation and symptoms is poorly understood. OBJECTIVE: Our aim was to use an untargeted metabolomics approach to identify novel pathways associated with FPIES reactions. METHODS: Serum samples were obtained before, during, and after oral food challenge (OFC) (10 subjects with FPIES and 10 asymptomatic subjects), and they were analyzed by untargeted metabolomics. Two-way ANOVA with false discovery rate adjustment was used for analysis of metabolites. Stomach and duodenal biopsy specimens from non-FPIES donors were stimulated with adenosine in vitro and serotonin measured by immunoassay. RESULTS: The levels of a total of 34 metabolites, including inosine and urate of the purine signaling pathway, were increased during OFCs performed on the patients with symptomatic FPIES compared with the levels found for asymptomatic subjects. Expression of the purine receptors P2RX7 and P2RY10 and the ectonucleotidase CD73 in peripheral blood was significantly reduced after OFC of the patients with FPIES. The level of the serotonin metabolite 5-hydroxyindoleacetate was significantly elevated after reaction. Adenosine stimulation of gastric and duodenal biopsy specimens from FPIES-free donors induced a significant release of serotonin, suggesting a link between purinergic pathway activation and serotonin release. CONCLUSIONS: Activation of the purinergic pathway during FPIES reactions provides a possible mechanism connecting inflammation and vomiting by triggering serotonin release from gastric and duodenal mucosa.

Peanut cross-contamination in randomly selected baked goods.

BACKGROUND: The current standard of care for managing peanut allergy includes avoidance of peanut and use of injectable epinephrine; however, strict avoidance is difficult and accidental ingestion is common with potentially serious consequences. Despite vigilance and efforts to minimize the risk of accidental exposure, peanut protein cross-contamination continues to occur in a variety of foods, including baked goods. OBJECTIVE: To assess and quantify the presence of peanut protein contamination in certain baked goods. METHODS: Randomly selected baked goods were collected from bakeries in the New York and Miami metropolitan areas that sold a variety of ethnic cuisines. A second set of samples from the same bakeries was collected at least 1 week after to evaluate between-batch variability. Samples were sent to the Food Allergy Research and Resource Program to analyze peanut contamination by enzyme-linked immunosorbent assay. Consumption estimates were based on 2003 to 2010 National Health and Nutrition Examination Survey survey data. RESULTS: Of 154 samples from 18 bakeries, 4 (2.6%) had detectable peanut contamination with peanut protein levels ranging from 0.1 mg/100 g to 650 mg/100 g. Consumption estimates for single occasion ingestion of a contaminated item ranged from 0.07 mg to 832 mg of peanut protein. CONCLUSION: In this study, unintended peanut protein was present in a small, but not insignificant, proportion of baked goods, with the potential to trigger a reaction in individuals with peanut allergy. Some products contained high levels of unintended peanut protein. The current data support the potential for accidental exposure to peanut protein with its associated risk.

Acute FPIES reactions are associated with an IL-17 inflammatory signature.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy characterized by profuse vomiting within hours of ingestion of the causative food. We have previously reported that FPIES is associated with systemic innate immune activation in the absence of a detectable antigen-specific antibody or T-cell response. The mechanism of specific food recognition by the immune system remains unclear. OBJECTIVE: Our aim was to identify immune mechanisms underlying FPIES reactions by proteomic and flow cytometric analysis of peripheral blood. METHODS: Children with a history of FPIES underwent supervised oral food challenge. Blood samples were taken at baseline, at symptom onset, and 4 hours after symptom onset. We analyzed samples from 23 children (11 reactors and 12 outgrown). A total of 184 protein markers were analyzed by proximity ligation assay and verified by multiplex immunoassay. Analysis of cell subset activation was performed by mass cytometry and spectral cytometry. RESULTS: Symptomatic FPIES challenge results were associated with significant elevation of levels of cytokines and chemokines, including IL-17 family markers (IL-17A, IL-22, IL-17C, and CCL20) and T-cell activation (IL-2), and innate inflammatory markers (IL-8, oncostatin M, leukemia inhibitory factor, TNF-α, IL-10, and IL-6). The level of the mucosal damage marker regenerating family member 1 alpha (REG1A) was also significantly increased. These biomarkers were not increased in asymptomatic challenges or IgE-mediated allergy. The level of phospho-STAT3 was significantly elevated in myeloid and T cells after challenge in individuals with symptoms. Mass cytometry indicated preferential activation of nonconventional T-cell populations, including γδ T cells and CD3+CD4-CD8-CD161+ cells; however, the potential sources of IL-17 in PBMCs were primarily CD4+ TH17 cells. CONCLUSIONS: These results demonstrate a unique IL-17 signature and activation of innate lymphocytes in FPIES.

Remote Mesoscopic Signatures of Induced Magnetic Texture in Graphene.

Mesoscopic conductance fluctuations are a ubiquitous signature of phase-coherent transport in small conductors, exhibiting universal character independent of system details. In this Letter, however, we demonstrate a pronounced breakdown of this universality, due to the interplay of local and remote phenomena in transport. Our experiments are performed in a graphene-based interaction-detection geometry, in which an artificial magnetic texture is induced in the graphene layer by covering a portion of it with a micromagnet. When probing conduction at some distance from this region, the strong influence of remote factors is manifested through the appearance of giant conductance fluctuations, with amplitude much larger than e^{2}/h. This violation of one of the fundamental tenets of mesoscopic physics dramatically demonstrates how local considerations can be overwhelmed by remote signatures in phase-coherent conductors.

Food protein-induced enterocolitis syndrome oral food challenge: Time for a change?

OBJECTIVE: Food protein-induced enterocolitis syndrome (FPIES) is typically diagnosed based on a characteristic clinical history; however, an oral food challenge (OFC) may be necessary to confirm the diagnosis or evaluate for the development of tolerance. FPIES OFC methods vary globally, and there is no universally agreed upon protocol. The objective of this review is to summarize reported FPIES OFC approaches and consider unmet needs in diagnosing and managing FPIES. DATA SOURCES: PubMed database was searched using the keywords food protein-induced enterocolitis syndrome, oral food challenge, cow milk allergy, food allergy, non-immunoglobulin E-mediated food allergy and FPIES. STUDY SELECTIONS: Primary and review articles were selected based on relevance to the diagnosis of FPIES and the FPIES OFC. RESULTS: We reviewed the history of FPIES and the evolution and variations in the FPIES OFC. A summary of current literature suggests that most patients with FPIES will react with 25% to 33% of a standard serving of the challenged food, there is little benefit to offering a divided dose challenge unless there is suspicion of specific immunoglobulin E to the food being challenged, reactions typically appear within 1 to 4 hours of ingestion, and reactions during OFC rarely result in emergency department or intensive care unit admission. CONCLUSION: International standardization in the FPIES OFC approach is necessary with particular attention to specific dose administration across challenged foods, timing between the patient's reaction and offered OFC to verify tolerance, patient safety considerations before the OFC, and identification of characteristics that would indicate home reintroduction is appropriate.

Long-term, open-label extension study of the efficacy and safety of epicutaneous immunotherapy for peanut allergy in children: PEOPLE 3-year results.

BACKGROUND: The PEPITES (Peanut EPIT Efficacy and Safety) trial, a 12-month randomized controlled study of children with peanut allergy and 4 to 11 years old, previously reported the safety and efficacy of epicutaneous immunotherapy (EPIT) for peanut allergy (250 µg, daily epicutaneous peanut protein; DBV712 250 µg). OBJECTIVE: We sought to assess interim safety and efficacy of an additional 2 years of EPIT from the ongoing (5-year treatment) PEOPLE (PEPITES Open-Label Extension) study. METHODS: Subjects who completed PEPITES were offered enrollment in PEOPLE. Following an additional 2 years of daily DBV712 250 µg, subjects who had received DBV712 250 µg in PEPITES underwent month-36 double-blind, placebo-controlled food challenge with an optional month-38 sustained unresponsiveness assessment. RESULTS: Of 213 eligible subjects who had received DBV712 250 µg in PEPITES, 198 (93%) entered PEOPLE, of whom 141 (71%) had assessable double-blind, placebo-controlled food challenge at month 36. At month 36, 51.8% of subjects (73 of 141) reached an eliciting dose of ≥1000 mg, compared with 40.4% (57 of 141) at month 12; 75.9% (107 of 141) demonstrated increased eliciting dose compared with baseline; and 13.5% (19 of 141) tolerated the full double-blind, placebo-controlled food challenge of 5444 mg. Median cumulative reactive dose increased from 144 to 944 mg. Eighteen subjects underwent an optional sustained unresponsiveness assessment; 14 of those (77.8%) maintained an eliciting dose of ≥1000 mg at month 38. Local patch-site skin reactions were common but decreased over time. There was no treatment-related epinephrine use in years 2 or 3. Compliance was high (96.9%), and withdrawals due to treatment-related adverse events were low (1%). CONCLUSIONS: These results demonstrate that daily EPIT treatment for peanut allergy beyond 1 year leads to continued response from a well-tolerated, simple-to-use regimen.

Giant Zero Bias Anomaly due to Coherent Scattering from Frozen Phonon Disorder in Quantum Point Contacts.

We demonstrate an unusual manifestation of coherent scattering for electron waves in mesoscopic quantum point contacts, in which fast electron dynamics allows the phonon system to serve as a quasistatic source of disorder. The low-temperature conductance of these devices exhibits a giant (≫2e^{2}/h) zero bias anomaly (ZBA), the features of which are reproduced in a nonequilibrium model for coherent scattering from the "frozen" phonon disorder. According to this model, the ZBA is understood to result from the in situ electrical manipulation of the phonon disorder, a mechanism that could open up a pathway to the on-demand control of coherent scattering in the solid state.

Estimated risk reduction to packaged food reactions by epicutaneous immunotherapy (EPIT) for peanut allergy.

BACKGROUND: Peanut allergy is a generally persistent, sometimes life-threatening food allergy. With no treatments demonstrating the ability to cure a food allergy, the focus of drugs in development has been on providing a level of protection against accidental exposure reactions. However, no study has estimated the relative risk reduction of a food-allergic population receiving a specific immunotherapeutic treatment for their allergies. OBJECTIVE: To estimate the relative risk reduction when consuming peanut-contaminated packaged food products in a double-blind, placebo-controlled Phase 3 study population of children treated with epicutaneous immunotherapy (EPIT) for 12 months with either a patch containing 250 µg peanut protein (250-µg patch) or a placebo patch. METHODS: The probability of an allergic reaction due to the unintended presence of peanut protein in packaged food products was modeled per study group and food category combination using Monte Carlo simulations. Risks per eating occasion of a contaminated packaged food product and the number of individuals per study population predicted to react on a yearly basis were investigated. RESULTS: The population treated with the 250-µg patch demonstrated a significantly increased dose-response distribution after 12 months of treatment, which resulted in a relative risk reduction of 73.2% to 78.4% when consuming peanut-contaminated packaged food products. In contrast, no statistically significant change was observed for the placebo group at the 12-month point. CONCLUSION: Our study estimates a substantial relative risk reduction for allergic reactions among peanut-allergic children after 12 months of EPIT with the 250-µg patch, supporting the potential real-world clinical relevance of this investigational immunotherapy and its possible role as a future therapy for peanut-allergic children. ClinicalTrials.gov Identifier: NCT02636699.

Effect of Epicutaneous Immunotherapy vs Placebo on Reaction to Peanut Protein Ingestion Among Children With Peanut Allergy: The PEPITES Randomized Clinical Trial.

Importance: There are currently no approved treatments for peanut allergy. Objective: To assess the efficacy and adverse events of epicutaneous immunotherapy with a peanut patch among peanut-allergic children. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled trial conducted at 31 sites in 5 countries between January 8, 2016, and August 18, 2017. Participants included peanut-allergic children (aged 4-11 years [n = 356] without a history of a severe anaphylactic reaction) developing objective symptoms during a double-blind, placebo-controlled food challenge at an eliciting dose of 300 mg or less of peanut protein. Interventions: Daily treatment with peanut patch containing either 250 µg of peanut protein (n = 238) or placebo (n = 118) for 12 months. Main Outcomes and Measures: The primary outcome was the percentage difference in responders between the peanut patch and placebo patch based on eliciting dose (highest dose at which objective signs/symptoms of an immediate hypersensitivity reaction developed) determined by food challenges at baseline and month 12. Participants with baseline eliciting dose of 10 mg or less were responders if the posttreatment eliciting dose was 300 mg or more; participants with baseline eliciting dose greater than 10 to 300 mg were responders if the posttreatment eliciting dose was 1000 mg or more. A threshold of 15% or more on the lower bound of a 95% CI around responder rate difference was prespecified to determine a positive trial result. Adverse event evaluation included collection of treatment-emergent adverse events (TEAEs). Results: Among 356 participants randomized (median age, 7 years; 61.2% male), 89.9% completed the trial; the mean treatment adherence was 98.5%. The responder rate was 35.3% with peanut-patch treatment vs 13.6% with placebo (difference, 21.7% [95% CI, 12.4%-29.8%; P < .001]). The prespecified lower bound of the CI threshold was not met. TEAEs, primarily patch application site reactions, occurred in 95.4% and 89% of active and placebo groups, respectively. The all-causes rate of discontinuation was 10.5% in the peanut-patch group vs 9.3% in the placebo group. Conclusions and Relevance: Among peanut-allergic children aged 4 to 11 years, the percentage difference in responders at 12 months with the 250-µg peanut-patch therapy vs placebo was 21.7% and was statistically significant, but did not meet the prespecified lower bound of the confidence interval criterion for a positive trial result. The clinical relevance of not meeting this lower bound of the confidence interval with respect to the treatment of peanut-allergic children with epicutaneous immunotherapy remains to be determined. Trial Registration: ClinicalTrials.gov Identifier: NCT02636699.

Current Status of Potential Therapies for IgE-Mediated Food Allergy.

PURPOSE OF REVIEW: The goal of this review is to provide the reader with an updated summary of published trial data regarding the use of oral immunotherapy (OIT), sublingual immunotherapy (SLIT), and epicutaneous immunotherapy (EPIT) for treatment of IgE-mediated food allergies. RECENT FINDINGS: Data from phase 2 trials for treatment of peanut allergy with OIT and EPIT reveal an increase in the threshold of reactivity for peanut-allergic children. Compared to EPIT, OIT promotes a greater increase in the threshold of reactivity; however, adverse events are more common with OIT. OIT, EPIT, and SLIT appear to modulate the immune response for some food-allergic individuals. Data regarding utility for treatment of food allergies regardless of modality is limited to few foods, as is investigation into treatment of food-allergic infants, young children, and adults. Future trials are likely to focus on young children, food allergies other than peanut, and treatment of multifood-allergic individuals.

Effect of Varying Doses of Epicutaneous Immunotherapy vs Placebo on Reaction to Peanut Protein Exposure Among Patients With Peanut Sensitivity: A Randomized Clinical Trial.

Importance: Epicutaneous immunotherapy may have potential for treating peanut allergy but has been assessed only in preclinical and early human trials. Objective: To determine the optimal dose, adverse events (AEs), and efficacy of a peanut patch for peanut allergy treatment. Design, Setting, and Participants: Phase 2b double-blind, placebo-controlled, dose-ranging trial of a peanut patch in peanut-allergic patients (6-55 years) from 22 centers, with a 2-year, open-label extension (July 31, 2012-July 31, 2014; extension completed September 29, 2016). Patients (n = 221) had peanut sensitivity and positive double-blind, placebo-controlled food challenges to an eliciting dose of 300 mg or less of peanut protein. Interventions: Randomly assigned patients (1:1:1:1) received an epicutaneous peanut patch containing 50 µg (n = 53), 100 µg (n = 56), or 250 µg (n = 56) of peanut protein or a placebo patch (n = 56). Following daily patch application for 12 months, patients underwent a double-blind, placebo-controlled food challenge to establish changes in eliciting dose. Main Outcomes and Measures: The primary efficacy end point was percentage of treatment responders (eliciting dose: ≥10-times increase and/or reaching ≥1000 mg of peanut protein) in each group vs placebo patch after 12 months. Secondary end points included percentage of responders by age strata and treatment-emergent adverse events (TEAEs). Results: Of 221 patients randomized (median age, 11 years [quartile 1, quartile 3: 8, 16]; 37.6% female), 93.7% completed the trial. A significant absolute difference in response rates was observed at month 12 between the 250-µg (n = 28; 50.0%) and placebo (n = 14; 25.0%) patches (difference, 25.0%; 95% CI, 7.7%-42.3%; P = .01). No significant difference was seen between the placebo patch vs the 100-µg patch. Because of statistical testing hierarchical rules, the 50-µg patch was not compared with placebo. Interaction by age group was only significant for the 250-µg patch (P = .04). In the 6- to 11-year stratum, the response rate difference between the 250-µg (n = 15; 53.6%) and placebo (n = 6; 19.4%) patches was 34.2% (95% CI, 11.1%-57.3%; P = .008); adolescents/adults showed no difference between the 250-µg (n = 13; 46.4%) and placebo (n = 8; 32.0%) patches: 14.4% (95% CI, -11.6% to 40.4%; P = .40). No dose-related serious AEs were observed. The percentage of patients with 1 or more TEAEs (largely local skin reactions) was similar across all groups in year 1: 50-µg patch = 100%, 100-µg patch = 98.2%, 250-µg patch = 100%, and placebo patch = 92.9%. The overall median adherence was 97.6% after 1 year; the dropout rate for treatment-related AEs was 0.9%. Conclusions and Relevance: In this dose-ranging trial of peanut-allergic patients, the 250-µg peanut patch resulted in significant treatment response vs placebo patch following 12 months of therapy. These findings warrant a phase 3 trial. Trial Registration: clinicaltrials.gov Identifier: NCT01675882.

"Freeing" Graphene from Its Substrate: Observing Intrinsic Velocity Saturation with Rapid Electrical Pulsing.

Rapid (nanosecond-scale) electrical pulsing is used to study drift-velocity saturation in graphene field-effect devices. In these experiments, high-field pulses are utilized to drive graphene's carriers on time scales much faster than that on which energy loss to the underlying substrate can occur, thereby allowing the observation of the highest saturation velocities reported to date. In a dramatic departure from the behavior exhibited by conventional metals and semiconductors, as the electron or hole density is reduced toward the charge-neutrality point, the drift velocity is found to reach values comparable to the Fermi velocity itself. Corresponding current densities are as large as 10(9) A/cm(2), similar to the values reported for carbon nanotubes and for graphene-on-diamond transistors. In essence, our approach of rapid pulsing allows us to "free" graphene from the deleterious influence of its substrate, revealing a pathway to achieve the superior electrical performance promised by this material. The usefulness of this approach is not merely limited to graphene but should extend also to a broad variety of two-dimensional semiconductors.

Thermally Assisted Nonvolatile Memory in Monolayer MoS2 Transistors.

We demonstrate a novel form of thermally-assisted hysteresis in the transfer curves of monolayer MoS2 FETs, characterized by the appearance of a large gate-voltage window and distinct current levels that differ by a factor of ∼102. The hysteresis emerges for temperatures in excess of 400 K and, from studies in which the gate-voltage sweep parameters are varied, appears to be related to charge injection into the SiO2 gate dielectric. The thermally-assisted memory is strongly suppressed in equivalent measurements performed on bilayer transistors, suggesting that weak screening in the monolayer system plays a vital role in generating its strongly sensitive response to the charge-injection process. By exploiting the full features of the hysteretic transfer curves, programmable memory operation is demonstrated. The essential principles demonstrated here point the way to a new class of thermally assisted memories based on atomically thin two-dimensional semiconductors.

Controversies in the management of caustic ingestion injury: an evidence-based review.

BACKGROUND: Caustic ingestion of acid or alkaline substances can cause damage to the upper respiratory and upper digestive tract. Initial presentation following caustic ingestion can include oropharyngeal pain, dysphagia and stridor. It is due to this clinical presentation that the resident otolaryngologist is consulted to review and examine these patients to assess for airway compromise and commence initial management and care until airway concern has passed. OBJECTIVE OF REVIEW: This review aims to provide evidence-based guidance in the management of those presenting with acute ingestion injury so that informed initial medical therapy can be commenced and appropriate investigations are arranged to optimize patient outcome. TYPE OF REVIEW AND SEARCH STRATEGY: A literature review searched PubMed citing variations on the areas of controversies with 'caustic ingestion', 'corrosive ingestion', 'acid ingestion' and 'alkali ingestion' - from 1956 to present with language restrictions. EVALUATION METHOD: The bibliographies of articles were searched for relevant references. The references were then compiled and reviewed independently by two authors (JB and SK), overseen by the senior authors (CP and JR). The review process was conducted independently, with the results then collated, with the aim of identifying the highest levels of evidence in each of the areas of controversy. RESULTS: Over 100 full-text articles were retrieved. Several specific areas of controversy were identified and addressed, with the highest available evidence referenced for each area. CONCLUSIONS: In caustic ingestion injury, the urgent assessment of the airway is the first priority with a definitive airway secured in those with airway compromise. In those patients with a stable airway and no clinical or radiological sign of perforation, then medical therapy should be commenced and an urgent oesophagogastroduodenoscopy (OGD) is arranged and this should take place within the first 24 h to grade the degree of injury and establish long-term prognosis. In suspected perforation, a surgical opinion should be sought. For those adults who are asymptomatic following ingestion an OGD may not be necessary; however, asymptomatic paediatric patients should be treated with more caution and a period of observation is important. Those who are at risk of developing late complications must be followed up.