The Development of Cannabinoids as Therapeutic Agents in the United States.

Cannabis is one of the oldest and widely used substances in the world. Cannabinoids within the cannabis plant, known as phytocannabinoids, mediate cannabis' effects through interactions with the body's endogenous cannabinoid system. This endogenous system, the endocannabinoid system, has important roles in physical and mental health. These roles point to the potential to develop cannabinoids as therapeutic agents while underscoring the risks related to interfering with the endogenous system during nonmedical use. This scoping narrative review synthesizes the current evidence for both the therapeutic and adverse effects of the major (i.e., Δ9-tetrahydrocannabinol and cannabidiol) and lesser studied minor phytocannabinoids, from nonclinical to clinical research. We pay particular attention to the areas where evidence is well established, including analgesic effects after acute exposures and neurocognitive risks after acute and chronic use. In addition, drug development considerations for cannabinoids as therapeutic agents within the United States are reviewed. The proposed clinical study design considerations encourage methodological standards for greater scientific rigor and reproducibility to ultimately extend our knowledge of the risks and benefits of cannabinoids for patients and providers. SIGNIFICANCE STATEMENT: This work provides a review of prior research related to phytocannabinoids, including therapeutic potential and known risks in the context of drug development within the United States. We also provide study design considerations for future cannabinoid drug development.

The effect of learning to drum on behavior and brain function in autistic adolescents.

This current study aimed to investigate the impact of drum training on behavior and brain function in autistic adolescents with no prior drumming experience. Thirty-six autistic adolescents were recruited and randomly assigned to one of two groups. The drum group received individual drum tuition (two lessons per week over an 8-wk period), while the control group did not. All participants attended a testing session before and after the 8-wk period. Each session included a drumming assessment, an MRI scan, and a parent completing questionnaires relating to the participants' behavioral difficulties. Results showed that improvements in drumming performance were associated with a significant reduction in hyperactivity and inattention difficulties in drummers compared to controls. The fMRI results demonstrated increased functional connectivity in brain areas responsible for inhibitory control, action outcomes monitoring, and self-regulation. In particular, seed-to-voxel analyses revealed an increased functional connectivity in the right inferior frontal gyrus and the right dorsolateral prefrontal cortex. A multivariate pattern analysis demonstrated significant changes in the medial frontal cortex, the left and right paracingulate cortex, the subcallosal cortex, the left frontal pole, the caudate, and the left nucleus accumbens. In conclusion, this study investigates the impact of a drum-based intervention on neural and behavioral outcomes in autistic adolescents. We hope that these findings will inform further research and trials into the potential use of drum-based interventions in benefitting clinical populations with inhibition-related disorders and emotional and behavioral difficulties.

Development and acceptability of a decision-aid for food allergy Oral immunotherapy in children.

BACKGROUND: Limited decision-support tools are available to help shared decision-making (SDM) regarding food oral immunotherapy (OIT) initiation. No current tool covers all foods, forms, and pediatric ages for which OIT is offered. METHODS: In compliance with International Patient Decision Aid Standards criteria, this pediatric decision-aid comparing OIT versus avoidance was developed in three stages. Nested qualitative data assessing OIT decisional needs were supplemented with evidence-synthesis from the OIT literature to create the prototype decision-aid content. This underwent iterative development with food allergy experts and patient advocacy stakeholders until unanimous consensus was reached regarding content, bias, readability, and utility in making a choice. Lastly, the tool underwent validated assessment of decisional acceptability, decisional conflict, and decisional self-efficacy. RESULTS: The decision-aid underwent 5 iterations, resulting in a 4-page written aid (Flesch-Kincaid reading level 6.1) explaining therapy choices, risks and benefits, providing self-rating for attribute importance for the options and self-assessment regarding how adequate the information was in decision-making. A total of n = 135 caregivers of food-allergic children assessed the decision-aid, noting good acceptability, high decisional self-efficacy (mean score 85.9/100) and low decisional conflict (mean score 20.9/100). Information content was rated adequate and sufficient, the therapy choices wording balanced, and presented without bias for a "best choice." Lower decisional conflict was associated with caregiver-reported anaphylaxis. CONCLUSIONS: This first pediatric OIT decision-aid, agnostic to product, allergen, and age has good acceptability, limited bias, and is associated with low decisional conflict and high decisional self-efficacy. It supports SDM in navigating the decision to start OIT or continue allergen avoidance.

Mass Spectral Library for DNA Adductomics.

Endogenous electrophiles, ionizing and non-ionizing radiation, and hazardous chemicals present in the environment and diet can damage DNA by forming covalent adducts. DNA adducts can form in critical cancer driver genes and, if not repaired, may induce mutations during cell division, potentially leading to the onset of cancer. The detection and quantification of specific DNA adducts are some of the first steps in studying their role in carcinogenesis, the physiological conditions that lead to their production, and the risk assessment of exposure to specific genotoxic chemicals. Hundreds of different DNA adducts have been reported in the literature, and there is a critical need to establish a DNA adduct mass spectral database to facilitate the detection of previously observed DNA adducts and characterize newly discovered DNA adducts. We have collected synthetic DNA adduct standards from the research community, acquired MSn (n = 2, 3) fragmentation spectra using Orbitrap and Quadrupole-Time-of-Flight (Q-TOF) MS instrumentation, processed the spectral data and incorporated it into the MassBank of North America (MoNA) database, and created a DNA adduct portal Web site (https://sites.google.com/umn.edu/dnaadductportal) to serve as a central location for the DNA adduct mass spectra and metadata, including the spectral database downloadable in different formats. This spectral library should prove to be a valuable resource for the DNA adductomics community, accelerating research and improving our understanding of the role of DNA adducts in disease.

Multi-adductomics: Advancing mass spectrometry techniques for comprehensive exposome characterization.

Adductomics, an emerging field within the 'omics sciences, focuses on the formation and prevalence of DNA, RNA, and protein adducts induced by endogenous and exogenous agents in biological systems. These modifications often result from exposure to environmental pollutants, dietary components, and xenobiotics, impacting cellular functions and potentially leading to diseases such as cancer. This review highlights advances in mass spectrometry (MS) that enhance the detection of these critical modifications and discusses current and emerging trends in adductomics, including developments in MS instrument use, screening techniques, and the study of various biomolecular modifications from mono-adducts to complex hybrid crosslinks between different types of biomolecules. The review also considers challenges, including the need for specialized MS spectra databases and multi-omics integration, while emphasizing techniques to distinguish between exogenous and endogenous modifications. The future of adductomics possesses significant potential for enhancing our understanding of health in relation to environmental exposures and precision medicine.

Clinical updates in inborn errors of immunity: a focus on the noninfectious clinical manifestations.

PURPOSE OF REVIEW: In the last 5 years, several new inborn errors of immunity (IEI) have been described, especially in the areas of immune dysregulation and autoinflammation. As a result, the clinical presentation of IEIs has broadened. We review the heterogeneous presentation of IEIs and detail several of the recently described IEIs with a focus on the noninfectious manifestations commonly seen. RECENT FINDINGS: IEIs may present with early onset and/or multiple autoimmune manifestations, increased risk for malignancy, lymphoproliferation, severe atopy, autoinflammation and/or hyperinflammation. Because of this, patients can present to a wide array of providers ranging from primary care to various pediatric subspecialists. The International Union of Immunological Societies (IUIS) expert committee has created a phenotypic classification of IEIs in order to help clinicians narrow their evaluation based on the laboratory and clinical findings. SUMMARY: Both primary care pediatricians and pediatric subspecialists need to be aware of the common clinical features associated with IEI and recognize when to refer to allergy-immunology for further evaluation. Early diagnosis can lead to earlier treatment initiation and improve clinical outcomes for our patients.

Pearls for practice from the 2023 allergy immunology joint task force on practice parameters GRADE and institute of medicine based atopic dermatitis guidelines.

PURPOSE OF REVIEW: To review the updated 2023 Allergy Immunology Joint Task Force on Practice Parameters (JTFPP) GRADE and Institute of Medicine (IOM) Based Guidelines for the management of atopic dermatitis. RECENT FINDINGS: Topical corticosteroids and/or calcineurin inhibitors are recommended in individuals with atopic dermatitis refractory to moisturizer alone and may be used to maintain remission after acute flare control is achieved. Calcineurin inhibitors are a class of immunosuppressants used to effectively manage different autoimmune disorders. Bleach baths and allergen immunotherapy may be beneficial for individuals with moderate-to-severe disease, while elimination diets, azathioprine, methotrexate, mycophenolate, and systemic corticosteroids are not recommended. Dupilumab is strongly recommended for refractory atopic dermatitis. Oral Janus kinase (JAK) inhibitors carry significant risks; however, this class of medicines may be considered in cases of severe or refractory atopic dermatitis with intolerance to dupilumab. Patient preferences regarding cost, availability, feasibility, and tolerability should be integrated into all treatment plans using a shared decision-making approach. SUMMARY: The 2023 JTFPP Atopic Dermatitis Guidelines offer up-to-date guidance for the management of atopic dermatitis of varying severity in infants, children, and adults.

Pearls for practice from the 2023 joint task force anaphylaxis practice parameter.

PURPOSE OF REVIEW: To share important highlights on the management of anaphylaxis from the latest 2023 practice parameter. RECENT FINDINGS: The 2023 Allergy Immunology Joint Task Force on Practice Parameters (JTFPP) anaphylaxis practice parameter provides updated anaphylaxis guidance. Criteria for the diagnosis of anaphylaxis are reviewed. The parameter highlights that while anaphylaxis is not more severe in younger children, age-specific symptoms can vary. Activation of emergency medical services may not be required in patients who experience prompt resolution of symptoms following epinephrine use and caregivers are comfortable with observation. For children weighing <15 kg, the anaphylaxis parameter suggests the clinician may prescribe either the 0.1 mg or the 0.15 mg epinephrine autoinjector, with the 0.3 mg autoinjector prescribed for those weighing 25 kg or greater. In patients with heart disease, discontinuing or changing beta blockers and/or angiotensin converting enzyme inhibitors may pose a larger risk for worsened cardiovascular disease compared with risk for severe anaphylaxis with medication continuation. Furthermore, in patients with a history of perioperative anaphylaxis, shared decision-making based on diagnostic testing and clinical history is recommended prior to repeat anesthesia use. Beyond the recent parameter update, novel contemporary therapies can decrease risk of community anaphylaxis. SUMMARY: The 2023 JTFPP Anaphylaxis Guidelines offer up-to-date guidance for the diagnosis and management of anaphylaxis in infants, children, and adults.

Oral food immunotherapy in patients with atopic dermatitis.

Atopic dermatitis (AD) is one of the main risk factors for infants in the development of food allergy. Oral immunotherapy (OIT) in early childhood has been found to be highly effective and safe in preschoolers with and without AD, especially in young infants. Delays in initiation of OIT in infants and children due to uncontrolled AD risk expansion of the number of foods children develop allergy to through unnecessary avoidance of multiple foods. Parents and caregivers may attribute eczema flares to OIT doses, which physicians usually ascribe to non-food triggers such as weather changes, psychological stress, and infection. There is a lack of published literature confirming OIT as a trigger of AD flares, and the degree to which OIT may be associated with AD flares needs to be further studied. We describe 8 case scenarios with varying degrees of AD flare before and during OIT. We propose management algorithms for children with preexisting concurrent AD and food allergy who are being considered for starting OIT and children with AD flares during OIT. Optimizing AD control strategies and providing adequate AD care education before starting OIT can reduce confusion for both parents and allergists if rashes arise during OIT, thus improving adherence to OIT.

Serologic measurements for peanut allergy: Predicting clinical severity is complex.

Allergist-immunologists use serologic peanut allergy testing to maximize test sensitivity and specificity while minimizing cost and inconvenience. Recent advances toward this goal include a better understanding of specific IgE (sIgE) and component testing, epitope-sIgE assays, and basophil activation testing. Predicting reaction severity with serologic testing is challenged by a range of co-factors that influence reaction severity, such as the amount and form of any allergen consumed and comorbid disease. In 2020, the Allergy Immunology Joint Task Force on Practice Parameters recommended Ara h 2-sIgE as the most cost-effective diagnostic test for peanut allergy because of its superior performance, when compared with skin prick testing and serum IgE. Basophil activation testing, a functional test of allergic response not evaluated in the Joint Task Force on Practice Parameters guideline, is a promising option for both allergy diagnosis and prognosis. Similarly, epitope-sIgE testing may improve prediction of reaction thresholds, but further validation is needed. Despite advances in food allergy testing, many of these tools remain limited by cost, accessibility, and feasibility. In addition, there is a need for further research on how atopic dermatitis may be modifying serologic food allergy severity assessments. Given these limitations, allergy test selection requires a shared decision-making approach so that a patient's values and preferences regarding financial impact, inconvenience, and psychological effects are considered in the context of clinician expertise on the timing and use of optimized testing.

Leveraging learning systems to improve quality and patient safety in allergen immunotherapy.

Adverse events occur in all fields of medicine, including allergy-immunology, in which allergen immunotherapy medical errors can cause significant harm. Although difficult to experience, such errors constitute opportunities for improvement. Identifying system vulnerabilities can allow resolution of latent errors before they become active problems. We review key aspects and frameworks of the medical error response, acknowledging the fundamental responsibility of clinical teams to learn from harm. Adverse event response comprises 4 major phases: (1) event recognition and reporting, (2) investigation (for which root cause analysis can be helpful), (3) improvement (inclusive of the plan-do-study-act cycle), and (4) communication and resolution. Throughout the process, clinician wellness must be maintained. Adverse event prevention should be prioritized, and a human factors engineering approach can be useful. Quality improvement tools and approaches complement one another and together offer a meaningful avenue for error recovery and prevention.

Anaphylaxis: A 2023 practice parameter update.

This practice parameter update focuses on 7 areas in which there are new evidence and new recommendations. Diagnostic criteria for anaphylaxis have been revised, and patterns of anaphylaxis are defined. Measurement of serum tryptase is important for diagnosis of anaphylaxis and to identify underlying mast cell disorders. In infants and toddlers, age-specific symptoms may differ from older children and adults, patient age is not correlated with reaction severity, and anaphylaxis is unlikely to be the initial reaction to an allergen on first exposure. Different community settings for anaphylaxis require specific measures for prevention and treatment of anaphylaxis. Optimal prescribing and use of epinephrine autoinjector devices require specific counseling and training of patients and caregivers, including when and how to administer the epinephrine autoinjector and whether and when to call 911. If epinephrine is used promptly, immediate activation of emergency medical services may not be required if the patient experiences a prompt, complete, and durable response. For most medical indications, the risk of stopping or changing beta-blocker or angiotensin-converting enzyme inhibitor medication may exceed the risk of more severe anaphylaxis if the medication is continued, especially in patients with insect sting anaphylaxis. Evaluation for mastocytosis, including a bone marrow biopsy, should be considered for adult patients with severe insect sting anaphylaxis or recurrent idiopathic anaphylaxis. After perioperative anaphylaxis, repeat anesthesia may proceed in the context of shared decision-making and based on the history and results of diagnostic evaluation with skin tests or in vitro tests when available, and supervised challenge when necessary.

A systematic review and expert Delphi Consensus recommendation on the use of vaccines in patients receiving dupilumab: A position paper of the American College of Allergy, Asthma and Immunology.

BACKGROUND: Dupilumab is a monoclonal antibody that targets the interleukin (IL)-4 receptor alpha subunit, thus blocking the effects of IL-4 and IL-13, and has shown efficacy in treating various conditions including asthma, atopic dermatitis, eosinophilic esophagitis, and others. Because of its immune modulatory effects, clinical trials that studied dupilumab did not allow patients to receive live vaccines during the clinical trials because of an abundance of caution, and thus package inserts recommend that patients who are being treated with dupilumab should avoid live vaccines. Because dupilumab is now approved for use in patients from 6 months of age for the treatment of atopic dermatitis, this reported contraindication is now posing a clinical dilemma for patients and clinicians. OBJECTIVE: To perform a systematic review of literature on the safety and efficacy of vaccinations in patients who are receiving dupilumab and to provide expert guidance on the use of vaccines in patients who are receiving dupilumab. METHODS: A systematic review of the literature was performed, and an expert Delphi Panel was assembled. RESULTS: The available literature on patients who received vaccinations while using dupilumab overall suggests that live vaccines are safe and that the vaccine efficacy, in general, is not affected by dupilumab. The expert Delphi panel agreed that the use of vaccines in patients receiving dupilumab was likely safe and effective. CONCLUSION: Vaccines (including live vaccines) can be administered to patients receiving dupilumab in a shared decision-making capacity.

To the ER? Can Patients Treat Their Anaphylaxis at Home?

PURPOSE OF REVIEW: To discuss if all patients who use self-injectable epinephrine outside the hospital setting require immediate emergency care. RECENT FINDINGS: Prior to 2023, anaphylaxis management guidance universally recommended that patients who use self-injectable epinephrine outside of the hospital or clinic setting immediately activate emergency medical services and seek further care. Additional food-induced anaphylaxis management recommendations specified that all patients always carry 2 auto-injector devices and give a second dose of epinephrine if there was not immediate response within 5 min of injection. Patients presenting for emergency care after epinephrine are often observed for up to 4-6 h afterwards, even when completely asymptomatic. These management steps have lacked evidence for improving outcomes, and universal implementation of these approaches is not cost-effective as guidance for food allergic patients. Epinephrine pharmacokinetics and pharmacodynamics suggest that peak physiologic response is more likely to occur closer to 15 min than before 5 min, that few patients require a second dose of epinephrine as most stabilize within 15 min of use, that 60 min of observation after a patient stabilizes after epinephrine use may be adequate as patients infrequently have further sequelae, and that not everyone needs to carry 2 epinephrine auto-injectors on their person at all times. The most recent anaphylaxis practice parameter promotes a contextualized approach to these management questions, outlining the option for watchful waiting to gauge response to epinephrine before seeking emergency care, which has been proven as a more cost-effective management strategy. The recent updated anaphylaxis care guidelines support the evolution of anaphylaxis care, in that universal, immediate activation of emergency services is not required for using self-injectable epinephrine outside the hospital setting.

A Novel Adductomics Workflow Incorporating FeatureHunter Software: Rapid Detection of Nucleic Acid Modifications for Studying the Exposome.

Exposure to the physicochemical agents that interact with nucleic acids (NA) may lead to modification of DNA and RNA (i.e., NA modifications), which have been associated with various diseases, including cancer. The emerging field of NA adductomics aims to identify both known and unknown NA modifications, some of which may also be associated with proteins. One of the main challenges for adductomics is the processing of massive and complex data generated by high-resolution tandem mass spectrometry (HR-MS/MS). To address this, we have developed a software called "FeatureHunter", which provides the automated extraction, annotation, and classification of different types of key NA modifications based on the MS and MS/MS spectra acquired by HR-MS/MS, using a user-defined feature list. The capability and effectiveness of FeatureHunter was demonstrated by analyzing various NA modifications induced by formaldehyde or chlorambucil in mixtures of calf thymus DNA, yeast RNA and proteins, and by analyzing the NA modifications present in the pooled urines of smokers and nonsmokers. The incorporation of FeatureHunter into the NA adductomics workflow offers a powerful tool for the identification and classification of various types of NA modifications induced by reactive chemicals in complex biological samples, providing a valuable resource for studying the exposome.

The Joint Task Force on Practice Parameters GRADE guidelines for the medical management of chronic rhinosinusitis with nasal polyposis.

These evidence-based guidelines support patients, clinicians, and other stakeholders in decisions about the use of intranasal corticosteroids (INCS), biologics, and aspirin therapy after desensitization (ATAD) for the management of chronic rhinosinusitis with nasal polyposis (CRSwNP). It is important to note that the current evidence on surgery for CRSwNP was not assessed for this guideline nor were management options other than INCS, biologics, and ATAD. The Allergy-Immunology Joint Task Force on Practice Parameters formed a multidisciplinary guideline panel balanced to include the views of multiple stakeholders and to minimize potential biases. Systematic reviews for each management option informed the guideline. The guideline panel used the Grading of Recommendations Assessment, Development and Evaluation approach to inform and develop recommendations. The guideline panel reached consensus on the following statements: (1) In people with CRSwNP, the guideline panel suggests INCS rather than no INCS (conditional recommendation, low certainty of evidence). (2) In people with CRSwNP, the guideline panel suggests biologics rather than no biologics (conditional recommendation, moderate certainty of evidence). (3) In people with aspirin (nonsteroidal anti-inflammatory drug)-exacerbated respiratory disease, the guideline panel suggests ATAD rather than no ATAD (conditional recommendation, moderate certainty of evidence). The conditions for each recommendation are discussed in the guideline.

Development of a Novel, Automated High-Throughput Device for Performing the Comet Assay.

A comet assay is a trusted and widely used method for assessing DNA damage in individual eukaryotic cells. However, it is time-consuming and requires extensive monitoring and sample manipulation by the user. This limits the throughput of the assay, increases the risk of errors, and contributes to intra- and inter-laboratory variability. Here, we describe the development of a device which automates high throughput sample processing for a comet assay. This device is based upon our patented, high throughput, vertical comet assay electrophoresis tank, and incorporates our novel, patented combination of assay fluidics, temperature control, and a sliding electrophoresis tank to facilitate sample loading and removal. Additionally, we demonstrated that the automated device performs at least as well as our "manual" high throughput system, but with all the advantages of a fully "walkaway" device, such as a decreased need for human involvement and a decreased assay run time. Our automated device represents a valuable, high throughput approach for reliably assessing DNA damage with the minimal operator involvement, particularly if combined with the automated analysis of comets.

Optical phased array with on-chip phase calibration.

Optical phased arrays (OPAs) with phase-monitoring and phase-control capabilities are necessary for robust and accurate beamforming applications. This paper demonstrates an on-chip integrated phase calibration system where compact phase interrogator structures and readout photodiodes are implemented within the OPA architecture. This enables phase-error correction for high-fidelity beam-steering with linear complexity calibration. A 32-channel OPA with 2.5-µm pitch is fabricated in an Si-SiN photonic stack. The readout is done with silicon photon-assisted tunneling detectors (PATDs) for sub-bandgap light detection with no-process change. After the model-based calibration procedure, the beam emitted by the OPA exhibits a sidelobe suppression ratio (SLSR) of -11 dB and a beam divergence of 0.97° × 0.58° at 1.55-µm input wavelength. Wavelength-dependent calibration and tuning are also performed, allowing full 2D beam steering and arbitrary pattern generation with a low complexity algorithm.

Genome-wide mapping of genomic DNA damage: methods and implications.

Exposures from the external and internal environments lead to the modification of genomic DNA, which is implicated in the cause of numerous diseases, including cancer, cardiovascular, pulmonary and neurodegenerative diseases, together with ageing. However, the precise mechanism(s) linking the presence of damage, to impact upon cellular function and pathogenesis, is far from clear. Genomic location of specific forms of damage is likely to be highly informative in understanding this process, as the impact of downstream events (e.g. mutation, microsatellite instability, altered methylation and gene expression) on cellular function will be positional-events at key locations will have the greatest impact. However, until recently, methods for assessing DNA damage determined the totality of damage in the genomic location, with no positional information. The technique of "mapping DNA adductomics" describes the molecular approaches that map a variety of forms of DNA damage, to specific locations across the nuclear and mitochondrial genomes. We propose that integrated comparison of this information with other genome-wide data, such as mutational hotspots for specific genotoxins, tumour-specific mutation patterns and chromatin organisation and transcriptional activity in non-cancerous lesions (such as nevi), pre-cancerous conditions (such as polyps) and tumours, will improve our understanding of how environmental toxins lead to cancer. Adopting an analogous approach for non-cancer diseases, including the development of genome-wide assays for other cellular outcomes of DNA damage, will improve our understanding of the role of DNA damage in pathogenesis more generally.

Bartonella endocarditis and diffuse crescentic proliferative glomerulonephritis with a full-house pattern of immune complex deposition.

BACKGROUND: Bartonella endocarditis is often a diagnostic challenge due to its variable clinical manifestations, especially when it is first presented with involvement of organs other than skin and lymph nodes, such as the kidney. CASE PRESENTATION: This was a 13-year-old girl presenting with fever, chest and abdominal pain, acute kidney injury, nephrotic-range proteinuria and low complement levels. Her kidney biopsy showed diffuse crescentic proliferative glomerulonephritis with a full-house pattern of immune complex deposition shown by immunofluorescence, which was initially considered consistent with systemic lupus erythematous-associated glomerulonephritis (lupus nephritis). After extensive workup, Bartonella endocarditis was diagnosed. Antibiotic treatment and valvular replacement surgery were undertaken with subsequent return of kidney function to normal range. CONCLUSION: This case demonstrates the importance of considering the full clinical picture when interpreting clinical, laboratory and biopsy findings, because the treatment strategy for infective endocarditis versus lupus nephritis is drastically different.