Long-term clinical course of adult-onset refractory epilepsy in cardiofaciocutaneous syndrome with a pathogenic MAP2K1 variant: a case report.

Cardiofaciocutaneous syndrome (CFC) is a rare genetic disorder that presents with cardiac, craniofacial, and cutaneous symptoms, and is often accompanied by neurological abnormalities, including neurodevelopmental disorders and epilepsy. Regarding epilepsy in CFC, the onset of seizures commonly occurs in childhood. Since research data has mainly been collected from young patients with relatively short observation period, there is insufficient information regarding adult-onset epilepsy in CFC. Here, we report the long-term clinical course of epilepsy and other complications in a 45-year-old female with genetically confirmed CFC carrying a pathogenic de novo heterozygous variant of MAP2K1, c.389 A>G (p.Tyr130Cys). The patient presented psychomotor delay from infancy and had severe intellectual disability with autistic features. At the age of 30, she first developed combined generalized and focal epilepsy that was resistant to anti-seizure medication. Her refractory epilepsy was fairly controlled with a combination of three anti-seizure medications, especially lacosamide, which effectively suppressed both generalized and focal seizures. The present case provides detailed information regarding the clinical course and treatment of adult-onset epilepsy, which may be useful for optimal treatment and prognostic prediction of CFC.

The Immediate and Delayed Maximal Non-Irritating Skin Testing Concentrations of ß-lactam Antibiotics.

BACKGROUND: Maximal skin testing (ST) nonirritant concentrations (NICs) are consistent for penicillin and aminopenicillin amongst guidelines. However, there is variability amongst guidelines for maximal ST NICs of cephalosporins. OBJECTIVE: To determine maximal immediate and delayed ST NICs of 15 ß-lactams in ß-lactam-tolerant and ß-lactam-naïve participants. METHODS: We performed a single-center, nonrandomized prospective study between September 2019 and January 2022 in adult participants. Participants received skin prick testing (SPT) and intradermal test (IDT) injections at six increasing concentrations of 1 or more ß-lactams. A concentration was considered irritant when more than 5% of participants had a positive test. A positive test was defined as a wheal ≥3 mm than negative control accompanied by a ≥5 mm flare for SPT/IDT and induration ≥5 mm with associated erythema at 48 hours for delayed readings (dIDT). Sensitivity analyses using 3 alternative IDT positive criteria were conducted. RESULTS: A total of 747 participants with a median age of 64 (IQR 54-72), 52% males, 85% White, and 92% Non-Hispanic underwent 20,858 skin tests. All undiluted SPT concentrations were nonirritant. We found the following maximal IDT/dIDT NICs (mg/ml): ampicillin (41.6/125), ampicillin-sulbactam (93.8/187.5), aztreonam (6.3/25), cefazolin (55/165), cefepime (35/140), cefoxitin (45/90), ceftaroline (7.5/15), ceftriaxone (58.3/175), cefuroxime (55/110), ertapenem (16.6/50), imipenem-cilastin (6.3/25), meropenem (8.3/25), nafcillin (31.3/62.5), oxacillin (20.9/83.5), and piperacillin-tazobactam (112.5/225). dIDTs were almost all completely non-irritant close or at undiluted concentrations. There were no differences when we applied 3 IDT positivity criteria to our raw data. CONCLUSION: Our results suggest that SPTs with undiluted stock ß-lactam antibiotic concentrations are nonirritant. Compared to previously published nonirritant concentrations, we propose a 2 to 50-fold increase to the maximal IDT and dIDT NICs of 15 ß-lactam antibiotics. When performing dIDTs, a higher concentration should be used rather than the same IDT concentration.

Navigating Aspirin Hypersensitivity in Patients Undergoing Percutaneous Coronary Intervention.

Aspirin hypersensitivity continues to be a major clinical challenge in patients with coronary artery disease (CAD), particularly in those requiring percutaneous coronary intervention (PCI) in the absence of a validated alternative antiplatelet regimen. Although true aspirin allergies are uncommon, they can manifest with severe reactions such as angioedema or anaphylaxis, highlighting the critical role of diagnostic challenge tests and tolerance induction strategies. Here, a 61-year-old female with end-stage renal disease (ESRD) on hemodialysis presented with new-onset heart failure and elevated troponins in the setting of a hypertensive emergency. A subsequent left heart catheterization revealed severe multivessel disease, but PCI was deferred due to her history suggestive of aspirin-induced angioedema and the absence of a known optimal approach in this scenario. Given the feasibility of completing a desensitization protocol, aspirin desensitization was pursued, facilitating the successful placement of a drug-eluting stent. This case highlights the need for validated protocols to manage aspirin hypersensitivity, as the current treatment paradigm necessitates a highly individualized approach by the treating clinician.

Health care resource use and costs in patients with food allergies: a United States insurance claims database analysis.

Aims: Food allergies impose a large clinical and financial burden on patients and the health care system. However, little is known about the factors associated with health care resource use and costs. The aim of this study was to investigate health care resource use and costs in individuals with food allergies utilizing health care in the United States.Methods: We conducted a retrospective analysis of insurance claims data from the Merative™ MarketScan® Research Databases (indexed from January 1, 2015, to June 30, 2022). All-cause and food allergy-related health care resource use, direct medical, and out-of-pocket costs for medical services were estimated for 12 months post-index using International Classification of Diseases [ICD] codes.Results: Of 355,520 individuals with food allergies continuously enrolled in a health insurance plan for ≥12 months pre- and post-index, 17% had a food allergy-related emergency department visit and 0.9% were hospitalized. The top patient characteristics associated with all-cause and food allergy-related hospitalizations, all-cause costs, and food allergy-related outpatient visit costs was a Charlson Comorbidity Index score of ≥2. Food allergy-related direct medical and out-of-pocket costs were high among patients with a food allergy-related visit. Out-of-pocket cost per patient per year for outpatient visits, emergency department visits, and hospitalizations had an estimated mean of $1,631 for patients with food allergy-related visits, which is approximately 11% of the total costs for these services ($14,395 per patient per year).Limitations: Study limitations are primarily related to the nature of claims databases, including generalizability and reliance on ICD codes. Nevertheless, MarketScan databases provide robust patient-level insights into health care resource use and costs from a large, commercially insured patient population.Conclusion: The health care resource use of patients with food allergies imposes a burden on both the health care system and on patients and their families, especially if patients had comorbidities.

Trajectories of egg sensitization in childhood: Two birth cohorts in Asia and Europe.

BACKGROUND: Hen's egg exposure through impaired skin barrier is considered a major mechanism of sensitization to eggs. However, the impact of filaggrin (FLG) gene loss-of-function mutations on the natural history of egg sensitization lacks consensus among studies. OBJECTIVE: To evaluate the association between the natural course of egg sensitization and FLG mutations. METHODS: We used Japanese and the UK birth cohorts (CHIBA and MAAS) to identify the longitudinal patterns of egg sensitization until mid-school age and examined the relationship between the identified patterns and FLG mutations. Sensitization was assessed using egg white-specific IgE levels or skin prick tests (SPTs). Egg allergy was confirmed by parental reports and sensitization. Latent class growth analysis identified longitudinal patterns. RESULTS: Three similar patterns of egg sensitization (persistent, early-onset remitting, and no/low grade classes) were identified in both cohorts, with differing prevalence estimates. The proportion of children with egg allergy in the persistent class at 7 or 8 years of age was 23% (CHIBA) and 20% (MAAS). Consistently in both cohorts, FLG mutations were significantly associated only with the persistent class. Children with FLG mutations had an approximately four-fold increased risk of being in the persistent sensitization class (RRRs: 4.3, 95%C.I. (1.2-16.0), p = .03 in CHIBA; 4.3 (1.3-14.7), p = .02 in MAAS). CONCLUSION: FLG loss-of-function mutations are associated with persistent egg sensitization in both Japanese and European ethnicities, and the mutations might be a potential biomarker for identifying the risk of persistent egg sensitization/allergy in early infancy. Future studies should incorporate oral food challenges to confirm this relationship.

Intravenous injection of nattokinase-heparin electrostatic complex improves the therapeutic effect of advanced tumors by dissolving cancer-related thrombosis.

AIMS: Cancer-related thrombosis (CAT) is a common complication in cancer patients, significantly impacting their quality of life and survival prospects. Nattokinase (NK) has potent thrombolytic properties, however, its efficacy is limited by low oral bioavailability and the risk of severe allergic reactions with intravenous use. Heparin (HP) is a widely used anticoagulant in clinical settings. This study aimed to overcome the intravenous toxicity of NK and explore its effect on CAT in advanced tumors. MAIN METHODS: In this study, NK-HP electrostatic complexes were constructed, and their safety and thrombolytic efficacy were verified through guinea pig allergy tests, mouse tail vein tests, and both in vivo and in vitro thrombolysis experiments. Additionally, an S180 advanced tumor model was developed and combined with sialic acid-modified doxorubicin liposomes (DOX-SAL) to investigate the impact of NK-HP on CAT and its antitumor effects in advanced tumors. KEY FINDINGS: We observed that NK-HP can eliminate the intravenous injection toxicity of NK, has strong thrombolytic performance, and can prevent thrombosis formation. Intravenous injection of NK-HP can enhance the antitumor effect of DOX-SAL by reducing the fibrin content in advanced tumors and increasing the levels of the cross-linked protein degradation product D-dimer. SIGNIFICANCE: This study developed a method to eliminate the intravenous injection toxicity of NK, proposing a promising therapeutic strategy for CAT treatment, particularly for CAT in advanced tumors, and improving the efficacy of nano-formulations in anti-tumor therapy.

A case report of reversible left ventricular dysfunction due to azathioprine hypersensitivity syndrome.

Background: Hypersensitivity reaction is a rare side effect during immunosuppressive treatment with azathioprine (AZA). Some cases of cardiac involvement have already been reported but causality is notoriously difficult to prove. Case summary: We present the case of a 68-year-old man with two episodes of reversible left ventricular (LV) dysfunction. One month after treatment initiation with AZA, he developed non-specific symptoms, including mild chest pain. In the context of elevated cardiac biomarkers and markers of inflammation, echocardiography showed depressed systolic LV function. Biventricular dysfunction was shown on cardiac magnetic resonance imaging (CMR), but neither myocardial oedema nor late gadolinium enhancement was documented. There was full recovery of LV function after AZA discontinuation. Very similar clinical course and echocardiography findings were observed early after restarting AZA treatment. After definitive cessation of AZA, systolic LV function recovered again and remained stable throughout long-term follow-up. Discussion: Hypersensitivity reaction with cardiac involvement due to AZA is rare. The exact mechanisms underlying AZA-related cardiac dysfunction are still not completely understood, and causality is often difficult to prove. However, because of re-exposure to the drug, which, considered retrospectively, was inappropriate, the effect was clearly apparent in our patient. Knowledge of this potentially life-threatening side effect of AZA treatment is important. AZA must be discontinued promptly if there is any evidence of hypersensitivity reaction.

Prenatal heavy metal exposure and pediatric asthma, allergic rhinitis, atopic dermatitis: a systematic review and meta-analysis.

OBJECTIVE: We review the prevalence of allergic diseases in children across prenatal exposures to heavy metals. METHODS: This systematic review and meta-analysis is registered in the PROSPERO database (CRD42023478471). A comprehensive search of PubMed, Web of Science, Medline and Cochrane library was conducted from the database inception until 31 October 2023. The Newcastle-Ottawa Quality Assessment Scale (NOS) was used to assess the quality of included studies. We used a random-effects model to summarize the effects from the studies. RESULTS: A total of 16 studies were included, 120,065 mother-child pairs enrolled. The NOS scores indicated that the quality of the literature included in the study was of a high standard. CONCLUSION: The final results indicate that prenatal exposure to Pb increased the incidence of wheeze and Eczema in infants, and exposure to Ni and CD increased the incidence of AD in infants.

[New medical technologies in cough therapy: results of a double-blind randomized placebo-controlled multicenter clinical trial].

AIM: To study the efficacy and safety of Eladis® in comparison with placebo in patients with non-productive cough. MATERIALS AND METHODS: A phase III clinical trial enrolled 250 patients aged 18-65 years with acute respiratory viral infection with upper respiratory tract involvement or acute bronchitis. Patients were randomized into 2 groups of 125 subjects: group 1 received Eladis® (40 mg tablets), group 2 received a matching placebo. The patients received the study drugs 1 tablet BID for 7-14 days. After the treatment, patients were followed up (day 7±2) to assess the effect of therapy on the frequency of coughing attacks, the frequency and severity of daytime and nocturnal cough, the severity of cough, the duration of clinical cough cure, and the effect on the severity of the main acute respiratory viral infection symptoms. RESULTS AND CONCLUSION: The results of the study demonstrate the overall efficacy and statistically significant superiority of Eladis® over placebo: there were significant differences between the study groups in the proportion of patients who decreased the coughing attack frequency by ≥50% by day 5 (p<0.0001). In addition, the clinical cure of cough in the Eladis® group occurred 2 days earlier: the median time was 6 days, vs 8 days in placebo group. There was a decrease in the frequency of cough attacks and a decrease in its severity by more than 3.5 points by day 5 of treatment. All the effects were associated with high safety of the drug.

Translational evaluation of Gelsectan® effects on gut barrier dysfunction and visceral pain in animal models and irritable bowel syndrome with diarrhoea.

BACKGROUND: Gelsectan® is a formulation of xyloglucan (XG), pea protein, grape seed extract (PPGS) and xylo-oligosaccharides (XOS). Our aim was to examine the effect of Gelsectan® on rectal sensitivity in an animal model, abdominal pain in irritable bowel syndrome with diarrhoea (IBS-D) subjects and intestinal permeability in both conditions. METHODS: Animals: Wistar rats received gavage with XOS, XG + PPGS or XG + PPGS + XOS, as a single dose or for 7 days before a partial restraint stress (PRS). Visceromotor response to rectal distension and total gut paracellular permeability to 51Cr-EDTA were assessed. Humans: IBS-D and control patients were involved. After initial colonoscopy with biopsy sampling Gelsectan® was administered to IBS-D patients for 12 weeks. Stool count and pain scores were documented. After treatment, colonoscopy was repeated. The permeability of biopsy samples was measured in Ussing-chambers. Adherent mucus layer, Muc-2 expression as well as TNFα, Interferon IFNγ were evaluated by histology/immunohistochemistry and ELISA assays, respectively. RESULTS: Animal studies: In control rats, PRS significantly increased visceromotor response as well as gut paracellular permeability. Single dose administration of XG + PPGS + XOS failed to reverse PRS, but 7 days of oral treatment reversed PRS-induced rectal hypersensitivity and gut hyperpermeability. Human studies: Gelsectan® treatment significantly reduced and abdominal pain. Intestinal permeability in IBS-D patients was elevated compared with controls, Gelsectan® restored permeability in the ascendent colon. Periodic acid-Schiff-stained mucus layer was significantly thinner in IBS-D patients compared with controls, In both segments, mucus thickness and the proportion of Muc-2 positive cells were not affected by Gelsectan® treatment. IFNγ tissue level in the sigmoid colon shows modest mucosal inflammation in IBS-D. CONCLUSIONS: Gelsectan® prevented rectal hypersensitivity in rats, abdominal pain in human and intestinal hyperpermeability in rat and human studies respectively. These effects involve restoration of gut permeability. Based on this translational study, Gelsectan® can be considered as an effective therapy for IBS-D symptoms.

Clues of HLAs, metabolic SNPs, and epigenetic factors in T cell-mediated drug hypersensitivity reactions.

Drug hypersensitivities are common reactions due to immunologic responses. They are of utmost importance because they may generate severe and fatal outcomes. Some drugs may cause Adverse Drug Reactions (ADRs), such as drug hypersensitivity reactions (DHRs), which can occur due to the interaction of intact drugs or their metabolites with Human Leukocyte Antigens (HLAs) and T cell receptors (TCRs). This type develops over a period of 24-72 h after exposure and is classified as type IV of DHRs. Acute generalized exanthematic pustulosis (AGEP), Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) are types of Severe Cutaneous Adverse Reactions (SCARs). In this review, we aim to discuss the types of ADRs, the mechanisms involved in their development, and the role of immunogenetic factors, such as HLAs in type IV DHRs, single-nucleotide polymorphisms (SNPs), and some epigenetic modifications, e.g., DNA/histone methylation in a variety of genes and their promoters which may predispose subjects to DHRs. In conclusion, development of promising novel in vitro or in vivo diagnostic and prognostic markers is essential for identifying susceptible subjects or providing treatment protocols to work up patients with drug allergies as personalized medicine.

Misdiagnosis of severe and atypical oxaliplatin­related hypersensitivity reaction following chemotherapy combined with PD­1 inhibitor: A case report and literature review.

Although the efficacy of treatment strategies for cancer have been improving steadily over the past decade, the adverse event profile following such treatments has also become increasingly complex. The present report described the case of a 67-year-old male patient with gastric stump carcinoma with liver invasion. The patient was treated with oxaliplatin and capecitabine (CAPEOX regimen) chemotherapy, combined with the programmed cell death protein-1 (PD-1) inhibitor tislelizumab. Following treatment, the patient suffered from chills, high fever and facial flushing, followed by shock. Relevant examination results revealed severe multiple organ damage, as well as a significant elevation in IL-6 and procalcitonin (PCT) levels. Initially, the patient was diagnosed with either immune-related adverse events (irAEs) associated with cytokine release syndrome caused by tislelizumab or severe bacterial infection. However, when tislelizumab treatment was stopped and the CAPEOX chemotherapy regimen was reapplied, similar symptoms recurred. Following screening, it was finally determined that severe hypersensitivity reaction (HSR) caused by oxaliplatin was the cause underlying these symptoms. A literature review was then performed, which found that severe oxaliplatin-related HSR is rare, rendering the present case atypical. The present case exhibited no common HSR symptoms, such as cutaneous and respiratory symptoms. However, the patient suffered from serious multiple organ damage, which was misdiagnosed as irAE when oxaliplatin chemotherapy combined with the PD-1 inhibitor was administered. In addition, this apparent severe oxaliplatin-related HSR caused a significant increase in PCT levels, which was misdiagnosed as severe bacterial infection and prevented the use of glucocorticoids. This, in turn, aggravated the damage in this patient.

Manometric Abnormalities in Patients With and Without Chronic Cough.

PURPOSE: This study examines the relationship between chronic cough and vagal hypersensitivity by measuring baseline esophageal motility, with interest in the upper esophageal sphincter (UES). MATERIALS AND METHODS: Patients undergoing workup for dysphagia were assigned to a chronic cough or control group based on self-reported symptoms. Differences in demographics, medical comorbidities, and high resolution esophageal manometry findings were obtained retrospectively. RESULTS: 62.5% of our cohort had chronic cough (30/48). There were no significant differences between the two groups with respect to sex, age, and race/ethnicity. Laryngopharyngeal reflux (LPR) was the only statistically significant predictor of CC (OR 74.04, p = 0.010). Cough patients had upper esophageal sphincter relaxation duration (734 ms) significantly longer than the non-cough patients (582 ms; p = 0.03), though both groups had similar upper esophageal mean basal pressure, mean residual pressure, relaxation time-to-nadir, and recovery time. No significant difference was found in the median intrabolus pressure and UES motility mean peak pressure between groups. CONCLUSION: Subtle differences in high-resolution manometry between patients with and without cough suggest, in line with previous studies, baseline alterations of upper esophageal function may manifest in patients with chronic cough through an undetermined mechanism that may include underlying vagal hypersensitivity. These findings encourage further manometric study examining the relationship between UES dysfunction and chronic cough.

Alergia a las proteínas de la leche de vaca: proceso diagnóstico. Consenso interdisciplinario de expertos / Cow's milk allergy: diagnostic process. Expert consensus

Las proteínas de la leche de vaca pueden causar alergia alimentaria. Los distintos mecanismos de acción involucrados y la variabilidad clínica según la etapa de la vida pediátrica en la que se manifieste ocasionan dificultades en su abordaje, con riesgo de sub- o sobrediagnóstico. En este proceso, intervienen profesionales de diversas áreas y es recomendable su interacción. Es por ello que el objetivo de este consenso ha sido reflejar el conocimiento actualizado desde la interdisciplina, generando recomendaciones para su correcto diagnóstico. Hemos trabajado con el método de Delphi para sumarle a la evidencia científica, la experiencia proveniente de neonatólogos, pediatras, especialistas en alergia, nutrición y gastroenterología. Pensamos que este enfoque interdisciplinario de trabajo va a resultar de utilidad práctica y promoverá una atención más integral de estos pacientes.

Cow's milk protein can cause food allergy. The different mechanisms of action involved, the clinical variability depending on the stage of pediatric life in which it manifests, leads to difficulties in its approach, with the risk of under- or over-diagnosis. Professionals from various areas intervene in this process and their interaction is recommended. That is why the objective of this consensus has been to reflect the updated knowledge in an interdisciplinary mode, generating recommendations for its correct diagnosis. We have worked with the Delphi method to add to the scientific evidence, the experience from neonatologists, pediatricians, experts in allergy, nutrition and gastroenterology. We think that this interdisciplinary approach will be of practical use and will promote more comprehensive care for these patients.

The gut microbiome in disorders of gut-brain interaction.

Functional gastrointestinal disorders (FGIDs), chronic disorders characterized by either abdominal pain, altered intestinal motility, or their combination, have a worldwide prevalence of more than 40% and impose a high socioeconomic burden with a significant decline in quality of life. Recently, FGIDs have been reclassified as disorders of gut-brain interaction (DGBI), reflecting the key role of the gut-brain bidirectional communication in these disorders and their impact on psychological comorbidities. Although, during the past decades, the field of DGBIs has advanced significantly, the molecular mechanisms underlying DGBIs pathogenesis and pathophysiology, and the role of the gut microbiome in these processes are not fully understood. This review aims to discuss the latest body of literature on the complex microbiota-gut-brain interactions and their implications in the pathogenesis of DGBIs. A better understanding of the existing communication pathways between the gut microbiome and the brain holds promise in developing effective therapeutic interventions for DGBIs.

Cutaneous hypersensitivity to chlorhexidine following facial fat grafting: a delayed intradermal response.

Chlorhexidine (CHD) is commonly included in surgical antiseptics and can be associated with adverse reactions ranging from contact dermatitis to anaphylaxis. A 32-year-old female presented to the OR for facial fat grafting. Surgical sites were prepped with CHD gluconate or topical iodine. Donor and recipient sites were infiltrated with local anesthetic injection prior to fat harvest and facial injection. Eleven days later, she presented with new painful, pruritic rash over donor sites where CHD had been applied prior to local anesthetic infiltration. Treatment with topical clobetasol and prednisone taper resulted in complete symptom resolution. This patient's response most likely represented a delayed type IV, T-cell mediated hypersensitivity. CHD is a known trigger of allergic reactions. Infiltration of local anesthetic may introduce skin prep into the subcutaneous tissue akin to intradermal testing. For those with delayed cutaneous reactions, steroids may provide symptomatic relief.

Objectifying subjective memory complaints: VR-based Verbal Word Learning Test in chronic stroke patients.

Memory impairment imposes a great burden on stroke patients and can be divided into Objective Memory Problems (OMPs) and Subjective Memory Complaints (SMCs). Studies have shown that these do not always co-occur. Possibly, the gap between SMCs and OMPs can be bridged when using a more ecologically valid memory test and considering the impact of other common stroke symptoms such as sensory hypersensitivity (SHS) and fatigue. In the present study, we applied Virtual Reality (VR) to create a sensory-rich environment with real-life stimuli. Memory performance was tested with the 15-Verbal Word Learning Test (VLT). Furthermore, we assessed SMCs (Everyday Memory Questionnaire), and the levels of SHS (Multi-Modal Evaluation of Sensory Sensitivity) and fatigue in the previous month. 31 chronic stroke patients and 32 healthy controls participated. The results showed that participants' memory performance decreased in a sensory-rich compared to a neutral environment. This decrease did not significantly differ between the groups. Interestingly, fatigue and SHS are related to the level of SMC in stroke patients but no such evidence was found in healthy controls. Last, for stroke patients, we found a significant negative correlation between SMCs and memory performance in a sensory-rich environment, but not in a neutral environment. In conclusion, our study implicates that in stroke patients, fatigue and SHS are related to SMCs and that using a sensory-rich VR environment might be a more ecologically valid way to objectify SMCs. However, interpretative caution is warranted due to the absence of sex and age-matched controls and potential selection bias.