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Ethnopharmacological Relevance: Uncaria rhynchophylla (UR) is recognized for its therapeutic applications in treating hypertension and inflammation. However, the specific molecular mechanisms how UR and its bioactive constituents modulate inflammatory pathways remain unknown. This study investigates the effects of UR extract and its constituent, hirsuteine (HST), on TRPV1 channel modulation which is related to hypertension and inflammation., Materials and Methods: Electrophysiological recordings and calcium imaging experiments were conducted to assess TRPV1 activation by UR extract and HST in HEK293T cells and sensory neurons., Results: UR extract and HST activated TRPV1 in HEK293T cells, with repeated applications causing channel desensitization. HST application on TRPV1-positive sensory neurons significantly reduced electrical activity compared to capsaicin., Conclusion: This study demonstrated UR extract and HST are a novel TRPV1 agonists inducing channel desensitization and a potent agent for treatment of TRPV1 dependent pain relief., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 KIST. Published by Elsevier B.V. All rights reserved.)

Background: Oral Mucosal Immunotherapy (OMIT) uses a specifically formulated toothpaste to deliver allergenic proteins to immunologically active areas of the oral cavity. This represents a new delivery mechanism with several features designed to improve food allergy desensitization. OMIT presents advantages over other approaches to allergy immunotherapy due to its targeted delivery and simplified administration., Objective: To determine the safety, tolerability, and adherence of OMIT with INT301 in peanut allergic adults., Methods: This Oral Mucosal Escalation Goal Assessment (OMEGA) study enrolled 32 adults, age 18-55, with peanut allergy in a 3:1 ratio to receive either an escalating dose of INT301 or placebo. Entry criteria included a positive SPT with a wheal diameter ≥ 3mm greater than control and/or psIgE ≥ 0.35 kU/L. Subjects were required to fail an oral food challenge ≤ 100 mg dose of peanut protein. Safety and tolerability were monitored during this 48-week trial., Results: 100% of active subjects tolerated the pre-specified protocol highest dose. No moderate nor severe systemic reactions occurred in active participants. Non-systemic adverse reactions were mostly local (oral and nasal cavity), mild and transient. Active subjects adhered to treatment 97% of days on study, with no withdrawals due to study medication., Conclusion: In the OMEGA trial, INT301 met all primary and secondary endpoints of safety, tolerability, and adherence. OMIT appears to be a safe and convenient option for individuals with food allergies. These results support its further evaluation in the pediatric population., Competing Interests: Declaration of competing interest William E. Berger MD. MBA, is a Medical Advisor to Intrommune Therapeutics, Inc., Nicole Faris, MSc. is a Scientific Advisor to Intrommune Therapeutics, Inc., Mark Weinstein, MD. - none, Gregory E. Wilding, PhD – none, Erick Berglund, PhD, is employed by Intrommune Therapeutics, Inc. and holds equity in the company., (Copyright © 2025. Published by Elsevier Inc.)

Background: Data on oral immunotherapy (OIT) for hazelnut allergy is limited and its potential to cross-desensitize for other nuts is unknown., Objective: To study the efficacy and safety of hazelnut OIT in desensitizing hazelnut and additional tree nuts., Methods: A prospective observational study of 30 hazelnut allergic patients aged ≥4 years who underwent hazelnut OIT. Full desensitization (4000 mg protein) rates were compared to 14 observational controls, and immunological changes during OIT were measured. Cross-desensitization was determined in cases of walnut and cashew co-allergy (n=12). Inhibition of IgE binding to walnut by hazelnut was evaluated in a separate set of walnut-hazelnut dual allergic patients, by ELISA., Results: The rate of full hazelnut desensitization following OIT was 96.7% (29/30) compared to 14.3% (2/14) in controls (OR=25.7, 95% CI 3.7-178.7, p<0.001). Five patients (16.7%) were treated with injectable epinephrine for home reactions. Hazelnut SPT and sIgE to hazelnut and its main components, Cor a 9, 14 and 16, decreased while sIgG4 increased during OIT. A maintenance dose of 1200 mg hazelnut protein was sufficient to maintain full desensitization. No cross-desensitization was noted in dual hazelnut-cashew allergic patients (n=6). In dual hazelnut-walnut allergic patients, an increase in the walnut eliciting dose was observed in 2/6 (33.2%) patients (to 1200 and 4200 mg, respectively). Similarly, by cross-inhibition ELISA, hazelnut competed for IgE-binding to walnut in 5/25 (20%) hazelnut-walnut co-allergic patients., Conclusions: Hazelnut OIT is highly effective, with a similar safety profile as OIT to other nuts. Cross-desensitization to walnut and cashew is unlikely., (Copyright © 2025. Published by Elsevier Inc.)

Background: Mesalamine is the first-line drug for treating mild-to-moderate ulcerative colitis (UC); however, some patients develop symptoms of intolerance. Although several desensitization methods have been reported, these desensitization regimens were rather complicated for physicians to prescribe in daily clinical practice; therefore, it has not yet become a major therapeutic option for intolerance patients. Thus, we developed an alternative desensitization protocol., Methods: We performed a single-center, retrospective study of patients with UC, who were intolerant to mesalamine and had undergone desensitization therapy. Desensitization starts with 50mg of granule mesalamine, with an increase in the dose by 50mg every week up to 200mg, followed by incremental doses of 100mg every week. After patients received dosages of more than 1000mg, the dose was increased by 200mg every week up to the target dose. Concomitant medications such as oral prednisolone or budesonide rectal foam were allowed during the protocol but were withdrawn before the end of desensitization. We evaluated the success rate of our mesalamine desensitization method and performed safety assessments during the protocol., Results: Of 115 patients, 17 were intolerant to mesalamine. We excluded six patients who had severe disease or organ disorders. Overall, 11 patients received desensitization therapy without hospitalization. All 11 patients successfully underwent desensitization therapy and received the target dose of mesalamine (3000-4000mg/day) at the end of the protocol. No serious adverse events were observed during this protocol., Conclusions: This retrospective study reports a successful and safe desensitization method for UC patients with mesalamine intolerance., (Copyright © 2025 The Authors. Publicado por Elsevier España, S.L.U. All rights reserved.)

Retinal ganglion cells (RGCs) typically respond to light stimulation over their spatially restricted receptive field. Using large-scale recordings in the mouse retina, we show that a subset of non- direction-selective (DS) RGCs exhibit asymmetric activity, selective to motion direction, in response to a stimulus crossing an area far beyond the classic receptive field. The extraclassical response arises via inputs from an asymmetric distal zone and is enhanced by desensitization mechanisms and an inherent DS component, creating a network of neurons responding to motion toward the optic disc. Pharmacological manipulations revealed the necessity of glycinergic amacrine cells for this response. Using in vivo recordings, we identified similar extraclassical responses in lateral geniculate nucleus neurons, suggesting such non conventional DS information is transferred to downstream structures. Our results suggest a complex integration of motion direction processing across the visual field, which arises beyond the classical receptive field boundaries., Competing Interests: Competing interests statement:The authors declare no competing interest.

Highly sensitized (HS) patients in need of kidney transplantation (KTx) typically spend a longer time waiting for compatible kidneys, are unlikely to receive an organ offer, and are at increased risk of antibody-mediated rejection (AMR). Desensitization using imlifidase, which is more rapid and removes total body immunoglobulin G (IgG) to a greater extent than other methods, enables transplantation to occur between HLA-incompatible (HLAi) donor-recipient pairs and allows patients to have greater access to KTx. However, when the project was launched there was limited data and clinical experience with desensitization in general and with imlifidase specifically. Hence, this Delphi methodology was used to reach a consensus from a multi-disciplinary team (MDT) of experts from 15 countries on the management of HS patients undergoing imlifidase HLAi from a deceased donor (DD) KTx. This Delphi consensus provides clinical practice guidance on the use of imlifidase in the end-to-end management of HS patients undergoing an HLAi DD KTx and supports centers in the development of guidelines for the utilization and integration of imlifidase into clinical practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Furian, Heemann, Bengtsson, Bestard, Binet, Böhmig, Boletis, Briggs, Claas, Couzi, Cozzi, Crespo, De Vries, Diekmann, Durlik, Glotz, Helantera, Jackson, Jordan, Kuypers, Lefaucheur, Legendre, Lorant, Maggiore, Mamode, Marinaki, Massart, Müller, Oberbauer, Renders, Roelen, Taupin, Viklický, Vittoraki, de Weerd and Naesens.)

Cannabidiol (CBD), a phytocannabinoid, has emerged as a promising candidate for addressing a wide array of symptoms. It has the ability to bind to multiple proteins and receptors, including 5-HT1AR, transient receptor potential vanilloid 1 (TRPV1), and cannabinoid receptors. However, CBD's pharmacodynamic interaction with 5-HT1AR and its medicinal outcomes are still debated. This review explores recent literature to elucidate these questions, highlighting the neurotherapeutic outcomes of this pharmacodynamic interaction and proposing a signaling pathway underlying the mechanism by which CBD desensitizes 5-HT1AR signaling. A comprehensive survey of the literature underscores CBD's multifaceted neurotherapeutic effects, which include antidepressant, anxiolytic, neuroprotective, antipsychotic, antiemetic, anti-allodynic, anti-epileptic, anti-degenerative, and addiction-treating properties, attributable in part to its interactions with 5-HT1AR. Furthermore, evidence suggests that the pharmacodynamic interaction between CBD and 5-HT1AR is contingent upon dosage. Moreover, we propose that CBD can induce desensitization of 5-HT1AR via both homologous and heterologous mechanisms. Homologous desensitization involves the recruitment of G protein-coupled receptor kinase 2 (GRK2) and β-arrestin, leading to receptor endocytosis. In contrast, heterologous desensitization is mediated by an elevated intracellular calcium level or activation of protein kinases, such as c-Jun N-terminal kinase (JNK), through the activity of other receptors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Background: Mucopolysaccharidosis (MPS) type 1 S and type 2 are rare lysosomal storage disorders characterized by impaired enzyme production, resulting in glycosaminoglycans accumulation within lysosomes. Enzyme Replacement Therapy (ERT) with laronidase and idursulfase are first line treatments, respectively. However, infusion-related hypersensitivity reactions (HR) may lead to ERT discontinuation. Thus, desensitization can be performed to restore ERT., Methods: We report on a two-year follow-up after a combined desensitization approach in two MPS patients experiencing HR to ERT. This approach consists of intravenous rapid desensitization combined with the subcutaneous allergen immunotherapy-like desensitization with the culprit recombinant enzyme., Results: The first patient, suffering from MPS type I, underwent to the combined desensitization approach, and subsequently tolerated weekly standard laronidase infusions for 13 months when HR occurred again. Then, a monthly omalizumab (anti-IgE monoclonal antibody) administration was implemented allowing the patient to restore ERT. The second patient, diagnosed with MPS type 2, was subjected to a similar combined desensitization strategy with idursulfase, and achieved a total desensitization after one year, confirmed by negative skin tests. Thus, he continued standard ERT infusions without HR occurrence., Conclusion: The combined desensitization approach proved effective in conferring immunotolerance for at least one year in both MPS patients, also demonstrated by the negative skin tests in one patient. However, when immunotolerance to ERT is lost, omalizumab administration can be a valid option in restoring ERT., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Written informed consent was sought after and obtained from the patients, for publication. The work was carried out in compliance with the Declaration of Helsinki. Competing interests: The authors declare that there is no conflict of interest. Signature: Federico Spataro, Department of Precision and Regenerative Medicine and Jonic Area, Internal Medicine and Allergology Unit, University of Bari Aldo Moro, Italy, (© 2024. The Author(s).)

Objectives: Traditional methods of treating allergies primarily revolve around avoiding allergens and promptly using rescue medications when allergic symptoms occur. However, this approach is known for its inefficiency and limited success in achieving long-term relief. Our aim was to conduct a comprehensive analysis of previously published randomized controlled trials (RCTs) that explore the effectiveness and safety of epicutaneous immunotherapy (EPIT) as a means to manage food allergies in children., Methods: We conducted a comprehensive search across multiple databases, including PubMed, Web of Science, Embase, and Cochrane Library, to identify RCTs comparing EPIT versus placebo for the management of allergen-triggered allergic reactions in children. Only RCTs published in English that evaluated the efficacy and safety of EPIT in pediatric patients with allergic diseases were considered eligible for inclusion. The quality assessment of the included studies was performed using the Cochrane risk-of-bias tool. The analysis comprised of seven RCTs involving a total of 1141 participants. The meta-analysis demonstrated that EPIT significantly facilitated desensitization in patients with food allergy (RR: 2.12, 95% CI: 1.74-2.59, P = 0.296, I² = 17.5%), particularly in individuals with peanut allergy (RR: 2.29, 95% CI: 1.83-2.86, P = 0.463, I² = 0%). However, it is important to note that EPIT was associated with an increased occurrence of treatment-related adverse events (TRAEs; RR: 1.24, 95% CI: 1.14-1.34, P < 0.01, I² = 99.2%). Notably, there were no notable disparities in the frequency of serious adverse events or utilization of rescue medications between the EPIT and placebo groups. EPIT may potentially induce desensitization of peanut allergy in children, but also carries an elevated risk of TRAEs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Gao, Li, Zou, Wu and Tang.)

N-methyl-d-aspartate receptors (NMDARs), the ligand ion glutamate receptor channels, mediate major excitatory neurotransmission in central nervous system (CNS). They highly express in CNS and involve in multiple physiological processes. Many studies implicated that NMDAR plays a crucial role in number of neurological disorders, including ischemia, dementia, and pain, indicating its potential as a therapeutic target for treatments. Chelerythrine (CHE) is a benzo-phenanthridine alkaloid extracted from Chelidonium majus with many biological activities including anti-inflammatory, anticancer effect, and antidiabetic effect. But the mechanism of CHE is not well understood. The aim of this study was to investigate the effect of CHE on the NMDAR. The results demonstrated that CHE effectively suppressed NMDA-induced currents in primary cultured cortical neurons. To elucidate the underlying mechanism, we expressed NMDARs in HEK293T cells and found that CHE and some of its structural analogues inhibited NMDAR currents and facilitated the desensitization of GluN2B NMDARs. Notably, these effects were independent of protein kinase C activity, suggesting that the effect of CHE on GluN2B-containing NMDAR may occur through a mechanism of directly interaction with NMDAR. Moreover, the inhibitory effect of CHE on GluN2B NMDARs is pH-dependent. Molecular docking prediction in conjunction with mutagenesis analysis revealed that the M3 α-helical segment of the NMDAR in close proximity to the GluN2B Thr647 amino acid plays an important role in CHE inhibition of GluN2B. This study revealed a novel function of CHE and its structural analogues in inhibiting the NMDARs and promoting GluN2B-mediated desensitization by obstructing the receptor at the channel pore region., Competing Interests: Declaration of competing interest The authors declare that there are no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Egg oral immunotherapy (OIT) can induce desensitization or remission of egg allergy in children., Objective: To determine the cost-effectiveness of OIT for raw egg allergy in school-age children compared with egg avoidance, and the most cost-effective age at which to commence treatment., Methods: A decision-analytic Markov model estimated the health and cost outcomes of 1,000 children aged 4 years with egg allergy, comparing different ages of OIT commencement (ages 4-12, inclusive) versus ongoing egg avoidance. Years lived with egg allergy, egg tolerance or remission (natural and OIT-induced), and desensitization to egg were captured, with rates of allergic reactions and utility values assigned to each health state. Treatment effects were derived from published randomized clinical trials and meta-analyses. The main outcome was the incremental cost-effectiveness ratio (ICER) from the Australian health care payer perspective (costs in Australian dollars per quality-adjusted life-year [QALY] gained), with a 20-year time horizon, 5% annual discounting, and an AU $50,000/QALY willingness-to-pay (WTP) threshold., Results: Without OIT, 858 children attained natural resolution before age 24. Under conservative assumptions, with OIT-induced remission set at zero and 84% achieving desensitization, ICERs were below the WTP threshold for treatment commencement at age 8 or older, with the smallest ICER observed at age 12 (AU $43,233/QALY; 95% CI, 32,025-73,350). However, the cost-effectiveness of OIT was achieved at all ages (ICER less than the WTP threshold) when OIT-induced remission increased to ∼40% of treated children., Conclusions: Based on current published evidence, the cost-effectiveness of egg OIT improves with increased age of treatment commencement. Cost-effectiveness increases when the proportion of children achieving OIT-induced remission increases., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Piperacillin-tazobactam is used in patients with cystic fibrosis to treat recurrent respiratory infections. Exposure is associated with a high frequency of nonimmediate hypersensitivity., Objective: To assess the applicability of the lymphocyte transformation test (LTT) for the diagnosis of piperacillin hypersensitivity and the influence of desensitization on piperacillin-specific T-cell responses., Methods: Study arm 1 was an analysis of LTT responses from 58 naive/baseline tolerant patients with samples collected over a 3-year interventional phase. In study arm 2, 17 hypersensitive patients were recruited and LTTs were conducted before and after desensitization. Clinical hypersensitivity reactions in both arms were monitored over an 8-year observational period., Results: In study arm 1, 58 patients received 611 piperacillin-tazobactam courses (range, 2-40; mean ± SD, 10.5 ± 8.1) during the interventional phase; 11 patients developed hypersensitivity. The patients who remained tolerant received 236 piperacillin-tazobactam courses in the observational period, 9 of whom developed hypersensitivity. Ten of 11 interventional phase hypersensitive patients had a positive LTT whereas one remained negative. We recorded 136 negative LTTs with 39 tolerant patients, whereas eight patients had a positive LTT and four developed hypersensitivity during the observational period. Ten LTT-positive patients in study arm 2 underwent piperacillin-tazobactam desensitization, with seven tolerating the drug. The strength of the LTT decreased during desensitization, and negative results were recorded for a minimum of 14 days. During follow-up, eight patients tolerated 62 piperacillin-tazobactam courses through desensitization., Conclusions: The LTT is a sensitive marker of drug sensitization that could be used to inform future patient management. Desensitization is associated with attenuation of the piperacillin-specific T-cell response., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: ABO-incompatible kidney transplantation (ABOi-KTx) represents a possible solution to address the shortage of kidney donors. However, these transplants present immunological challenges, particularly when isoagglutinin titers are elevated pretransplant., Methods: Single-center retrospective study describing clinical and biological outcomes of 8 patients who underwent ABOi-KTx with initial isoagglutinin titers ≥ 1/512. All patients followed a desensitization protocol combining immunosuppression (rituximab, tacrolimus, mycophenolate mofetil, steroids), and specific or semi-specific apheresis sessions. Clinical and biological data were extracted from electronic medical records., Results: There were 5 males; median age of 62 years [34-82 years]; all achieved an isoagglutinin titer of ≤1/8 before transplantation after a median of 13 (range: 9-15) apheresis sessions. Three patients (37%) experienced acute humoral rejection, which required additional plasmapheresis sessions. Two patients developed chronic active rejection, successfully treated. On the infectious side, three patients developed BK-virus reactivation. Two patients developed cytomegalovirus viremia, and two others presented with bacterial infections. Surgically, two patients developed a lymphocele, and one had a perirenal hematoma. All patients survived the transplant with stable renal function: mean serum creatinine was 138 ± 15 µmol/L after four years of follow-up., Conclusion: ABO-incompatible kidney transplantation, even in patients with high isoagglutinin titers, is feasible and can achieve favorable long-term graft and patient survival outcomes. However, these procedures require substantial clinical expertise and close follow-up to monitor and manage the elevated risks of infection and rejection in this population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Naciri Bennani, Bobo Barry, Noble, Malvezzi, Jouve and Rostaing.)

Haploidentical hematopoietic cell transplants (haplo-HCT) with donor-specific anti-HLA antibodies (DSAs) are associated with high rates of primary graft failure and poor overall survival (OS). Limited data exists regarding the effect of desensitization. Our institution began routine desensitization for patients with DSAs in 2014. Adult patients undergoing haplo-HCT at Washington University from 2009-2021 were identified and divided into three cohorts: no DSA, untreated DSA (2009-2014) or treated DSA (2014-2021). Desensitization therapy using plasmapheresis and IVIg was performed. Retrospectively, 304 patients were identified. 14 of 30 patients with DSAs underwent desensitization. By day +2, 57% of patients cleared all DSAs. After multivariable analysis, OS was similar between treated DSA and no DSA (HR: 0.69, p  = 0.37). Untreated DSA had significantly lower OS compared to no DSA group (HR 1.80, p  = 0.046). Desensitization with a backbone of plasmapheresis and IVIg before haplo-HCT may produce similar outcomes to patients without DSAs.

Background: Allogeneic hematopoietic stem cell transplantation is a definitive cure for eligible patients with thalassemia major, and calcineurin inhibitors are essential for preventing graft-versus-host disease. Although invaluable, there are few reports of life-threatening hypersensitivity reactions associated with calcineurin inhibitors. These reactions are generally rare but seem to be more prevalent among patients with thalassemia., Case Presentation: Herein, we retrospectively report four cases of patients with thalassemia major who developed hypersensitivity reactions to parenteral cyclosporine. The cases include one 19-year-old Caucasian female and three Caucasian males, aged 17, 10, and 20 years, respectively. The patients exhibited symptoms of varying severity, necessitating different management strategies. The reactions occurred either immediately or within a few minutes after the onset of cyclosporine infusion and were often worsened by rechallenge. In all cases, cyclosporine was eventually replaced with tacrolimus or sirolimus. A comprehensive literature review was conducted to investigate the basis of severe immunoglobulin E-mediated hypersensitivity reactions to calcineurin inhibitors in patients with thalassemia major undergoing hematopoietic stem cell transplantation., Conclusions: Several immunogenic factors may potentially increase the susceptibility of these patients to hypersensitivity reactions to Cremophor-containing medications. While severe reactions to calcineurin inhibitors remain rare, clinicians should be aware of the potential for serious adverse events in patients with thalassemia., Competing Interests: Declarations Ethics approval and consent to participate An ethics statement is not applicable because this study is based exclusively on retrospective data collection and does not include any interventions. Consent for publication Written informed consent was obtained from all four patients for publication of these case reports and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Competing interests The authors declare that there is no competing interests., (© 2024. The Author(s).)

In the developing cochlea, just before the onset of hearing on postnatal day 12, the medial olivocochlear efferent axons in synaptic contact with the inner hair cells (IHCs) start withdrawing and new efferent synaptic connections are formed on the outer hair cells (OHCs), thereby progressing towards the adult pattern of medial olivocochlear efferent innervation. The synapses are inhibitory, calcium influx through the α9α10 nicotinic acetylcholine receptors (nAChRs) driving opening of calcium-dependent potassium channels. The nAChRs appear to function similarly in IHCs and OHCs, although with probable kinetic differences. Our aim was to assess their functional similarity in the neonatal mouse cochlea by making whole-cell recordings from both hair cell types between postnatal day 7 and 10 when nAChRs are expressed. ACh was applied to voltage-clamped hair cells by pressure-ejection from a pipette. The cells were dialysed with a Cs + -based solution designed to eliminate calcium-dependent potassium currents. There were differences in amplitude, voltage-sensitivity and reversal potential of the nAChR currents between IHCs and OHCs. There was also some indication that IHC nAChRs have slower activation and desensitization kinetics, although the relatively slow ACh application limited interpretation of this result. These differences, particularly concerning the reversal potential, might indicate the presence of different auxiliary protein subunits of the α9α10 receptor in neonatal IHCs and OHCs., Competing Interests: Declarations of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The classic approach of nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NSAID-ERD) includes pharmaceutical and surgical treatments, as well as avoidance of cyclooxygenase 1-inhibitor NSAIDs. The introduction of biologics in the treatment of severe asthma and chronic rhinosinusitis with nasal polyps represents an alternative therapeutic approach to the classical aspirin therapy after desensitization (ATAD) in some regions, and with convincing results. However, their use is limited due to approval and/or high-cost restrictions. NSAID-ERD is a mainly type 2 and highly eosinophilic disease, and mAbs targeting IgE or IL-5, IL-4, and IL-13 have been shown to be effective for both severe asthma and severe chronic rhinosinusitis with nasal polyps. So far, dupilumab demonstrated greater efficacy in patients with NSAID-ERD than in aspirin-tolerant patients with regard to several clinical outcomes. Patients with NSAID-ERD respond very rapidly to omalizumab also, with reduction in the release of prostaglandin D 2 and cysteinyl leukotrienes. Patients favored biologic treatment over ATAD in multiple retrospective analyses, which must be acknowledged when choosing one or the other option. Although this review will summarize ATAD in general, it will more prominently focus on when ATAD should be considered, even when type 2 biologics are available. In addition, there are conflicting studies as to whether patients on a type 2 biologic become desensitized to NSAIDs, because omalizumab proved to restore tolerance to aspirin in only two-third of patients. This goal of NSAID tolerance should be considered as part of disease control future approaches, representing one of many aspects in a patient-centered care approach., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Immunoglobulin E (IgE)-mediated food allergies are the most common type of food allergy, often causing rapid symptoms after exposure to allergens posing a serious health risk and a high impact on patient's and caregiver's quality of life. Omalizumab, a humanized anti-IgE monoclonal antibody, reduces allergic reactions by binding to circulating IgE. Omalizumab has been successfully used in allergic asthma, chronic rhinosinusitis with nasal polyps, and chronic urticaria, and was recently approved for treating IgE-mediated food allergies by the US Food and Drug Administration (FDA). This GA 2 LEN ANACARE Consensus Statement presents our position on the use of omalizumab for treating IgE-mediated food allergies, based on a systematic review and meta-analysis, experience with use for other conditions, and expert consensus achieved via an eDelphi process. Following publication of the recent OUtMATCH study (stage 1) results and subsequent FDA approval, we propose that there is now sufficient evidence to recommend omalizumab as the only drug currently available that can mechanistically reduce IgE-mediated food allergic reactions. We acknowledge that the evidence does not reach the highest level of evidence which would be needed for a guideline recommendation., (© 2024 The Author(s). Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Background: The immunometabolic mechanisms underlying variable responses to oral immunotherapy (OIT) in patients with IgE-mediated food allergy are unknown., Objective: To identify novel pathways associated with tolerance in food allergy, we used metabolomic profiling to find pathways important for food allergy in multiethnic cohorts and responses to OIT., Methods: Untargeted plasma metabolomics data were generated from the VDAART healthy infant cohort (N = 384), a Costa Rican cohort of children with asthma (N = 1040), and a peanut OIT trial (N = 20) evaluating sustained unresponsiveness (SU, protection that lasts after therapy) versus transient desensitization (TD, protection that ends immediately afterward). Generalized linear regression modeling and pathway enrichment analysis identified metabolites associated with food allergy and OIT outcomes., Results: Compared with unaffected children, those with food allergy were more likely to have metabolomic profiles with altered histidines and increased bile acids. Eicosanoids (e.g., arachidonic acid derivatives) (q = 2.4 × 10 -20 ) and linoleic acid derivatives (q = 3.8 × 10 -5 ) pathways decreased over time on OIT. Comparing SU versus TD revealed differing concentrations of bile acids (q = 4.1 × 10 -8 ), eicosanoids (q = 7.9 × 10 -7 ), and histidine pathways (q = .015). In particular, the bile acid lithocholate (4.97 [1.93, 16.14], p = .0027), the eicosanoid leukotriene B4 (3.21 [1.38, 8.38], p = .01), and the histidine metabolite urocanic acid (22.13 [3.98, 194.67], p = .0015) were higher in SU., Conclusions: We observed distinct profiles of bile acids, histidines, and eicosanoids that vary among patients with food allergy, over time on OIT and between SU and TD. Participants with SU had higher levels of metabolites such as lithocholate and urocanic acid, which have immunomodulatory roles in key T-cell subsets, suggesting potential mechanisms of tolerance in immunotherapy., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Purpose: This study investigated the pharmacological effects of topical trans-anethole, a natural compound found in anise, star anise, and fennel essential oils, and its relationship with the transient receptor potential of ankyrin 1 (TRPA1)., Methods: The effects of topical anethole were assessed by eye wiping, nociceptive behaviour, and ear oedema in mice. Histological evaluations were performed on the ears of the animals topically treated with anethole., Results: Anethole caused less eye irritation than capsaicin (a TRPV1 agonist) and allyl isothiocyanate (a TRPA1 agonist). Anethole (250 and 500 nmol/20 µL/paw) promoted neurogenic nociception in the paw (20.89 ± 3.53 s and 47.56 ± 8.46 s, respectively) compared with the vehicle (0.88 ± 0.38 s). HC030031 (56.1 nmol/20 µL/paw), a TRPA1 antagonist, abolished this nociceptive response. Anethole (4, 10, and 20 µmol/20 µL/ear) induced ear oedema (30.25 ± 4.78 μm, 78.00 ± 3.74 μm, and 127.50 ± 27.19 μm, respectively) compared with the vehicle (5.00 ± 0.5 μm). HC030031 (56.1 nmol/20 µL/ear) inhibited the oedema induced by anethole (10 µmol/20 µL/ear). Ears pre-treated with anethole or allyl isothiocyanate on the first day and re-exposed to these compounds on the third day showed a reduction in oedema (68.16 ± 6.04% and 38.81 ± 8.98.9%, respectively). Cross-desensitisation between anethole and allyl isothiocyanate was observed. Histological analysis confirmed the beneficial effects of anethol., Conclusion: As repeated topical applications of anethole induce the desensitisation of TRPA1, we suggest its clinical application as a topical formulation for treating skin diseases or managing pain associated with this receptor. Anethole may also have advantages over capsaicin and allyl isothiocyanate because of its low pungency and pleasant aroma., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This study assesses whether the frequency of violent video game play is associated with attentional desensitization or sensitization to images depicting violence or nonviolent interpersonal conflict. Two hundred and thirty-two participants reported their three most frequently played video games and the amount of time each game was played in a typical week. Next, they completed an assessment of emotion-induced blindness, which refers to a reduction in the correct identification of a neutral target image when it follows an emotionally charged distractor image. The primary findings showed that weekly violent video game play was negatively associated with target identification following nonviolent interpersonal conflict images, but not violent images. Findings are discussed in terms of the saliency of threatening images and attentional processing., (© 2024 Wiley Periodicals LLC.)

In February 2024, omalizumab was approved by the U.S. Food and Drug Administration for the treatment of food allergy, based on data from the landmark phase 3 clinical trial, Omalizumab as Monotherapy and as Adjunct Therapy in Children and Adults (OUtMATCH). In this Rostrum, OUtMATCH investigators share their perspectives on the trial results, the implications for translation into daily practice, and on remaining gaps in the field. The study met its primary and key secondary end points, demonstrating a large effect size in multiallergen desensitization compared with placebo; yet there were some participants who did not respond, and the percentage of responders tolerating all 3 food allergens was lower than that for single foods. Clinicians are likely to have many questions about appropriate patient selection, monitoring for treatment responsiveness, and how to manage off-label considerations such as dietary incorporation or cotreatment with oral immunotherapy. Additional research is needed to answer these remaining questions and ensure that the translation of omalizumab in real-world practice leads to high-quality outcomes., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Donor specific antibodies against human leukocyte antigen (HLA) can cause engraftment failure in hemopoietic stem cell transplantation, or antibody mediated rejection in solid organ transplantation. To increase the chance of successful transplants, donor specific antibodies have to be reduced or depleted in patients with high levels of HLA antibodies. However, no current therapies have been proven to remove or reduce HLA antibodies effectively in the majority of patients. Blinatumomab, a bi-specific antibody, is used as a treatment for B-cell acute lymphoblastic leukemia (ALL) by targeting B cells. To determine if blinatumomab can reduce HLA antibodies, we tested HLA antibodies pre- and post-blinatumomab treatment in 7 B-ALL patients who had HLA antibodies. We found that 6 of 7 patients showed a substantial reduction in HLA antibodies after blinatumomab infusion. Calculated Panel Reactive Antibody (cPRA), a measurement of the possibility of getting immunologically compatible donors, was also lowered after blinatumomab infusion. Our observation suggests that blinatumomab can be a potential drug for desensitization therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Low-dose aspirin remains the most commonly used antiplatelet agent among patients with atherosclerotic cardiovascular disease. Aspirin hypersensitivity occurs in 1% to 5% of patients and is among the most frequent causes for prohibiting the use of aspirin, posing a significant dilemma on how to manage these patients in clinical practice. Aspirin hypersensitivity is often misinterpreted and confused with aspirin intolerance, with treatment approaches being often unclear and lacking specific recommendations. Aspirin desensitization and low-dose aspirin challenge have emerged as pragmatic, effective, and safe approaches in patients with suspected or confirmed aspirin hypersensitivity who require aspirin therapy, but they are underused systematically in clinical practice. Furthermore, there is confusion over alternative antiplatelet agents to be used in these patients. The pathophysiological mechanisms and classification of aspirin hypersensitivity, as well as alternative strategies and practical algorithms to overcome the need for aspirin use in patients with atherosclerotic cardiovascular disease with suspected aspirin hypersensitivity, are discussed., Competing Interests: Funding Support and Author Disclosures Dr Angiolillo has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, CSL Behring, Daiichi-Sankyo, Eli Lilly, Faraday, Haemonetics, Janssen, Merck, Novartis, Novo Nordisk, PhaseBio, PLx Pharma, Pfizer, and Sanofi; and his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Faraday, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, and the Scott R. MacKenzie Foundation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: ABO-incompatible (ABOi) kidney transplantation (KT) has become an important option to overcome organ shortage. Plasmapheresis/rituximab-based desensitization therapy has successfully reduced anti-ABO antibody levels and suppressed antibody-mediated rejection (AMR) in ABOi KT. However, high titers of anti-ABO antibodies in some patients are refractory to standard desensitization, leading to loss of KT opportunities or AMR., Methods: Eculizumab treatment was used an adjunctive therapy to rescue high-titer ABOi KT patients refractory to plasmapheresis/rituximab-based desensitization. Molecular phenotypes of allograft biopsies and cellular phenotypes of peripheral blood mononuclear cells of eculizumab group were compared with those of control groups using the Banff Human Organ Transplant gene panel and flow-cytometric analysis, respectively., Results: The initial titers of anti-ABO antibodies in the two patients were 1:512 and >1:1024; the final pre-transplant titers after desensitization were 1:128 and 1:64. Both patients received eculizumab from KT day to two or four weeks post-KT and maintained stable renal function up to one-year post-transplantation without overt infection, despite early episodes of probable AMR or borderline T cell-mediated rejection. Molecular phenotype analysis revealed that gene expression patterns in the ABOi KT with eculizumab group overlapped with those in the ABOi KT with AMR group more than in the ABOi KT without AMR group, except for complement pathway-related gene expression. Anti-ABO antibody titers decreased to low levels 1-3 months post-transplant in the eculizumab group in parallel with decreasing anti-B-specific B cells., Conclusions: Short-term eculizumab therapy is promising for rescuing ABOi KT recipients with high anti-ABO antibody titers refractory to plasmapheresis-based desensitization therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Heo, Jung, Piao, Kim, Kim, Lee, Huh, Kim and Yang.)

Transactivation of epidermal growth factor receptors (EGFR) provides intricate control over multiple regulatory cellular processes that merge the diversity of G protein-coupled receptors (GPCRs) with the robust signaling capacities of receptor tyrosine kinases. Contrary to the typical assertions, our findings demonstrate that EGFR transactivation contributes to the desensitization of GPCRs. Repeated agonist stimulation of certain GPCRs enhanced EGFR transactivation, triggering a series of cellular events associated with GPCR desensitization. This effect was observed in receptors undergoing desensitization (D 3 R, K149C-D 2 R, β 2 AR) but not in those resistant to desensitization (D 2 R, C147K-D 3 R, D 4 R, β 2 AR mutants lacking GRK2 or GRK6 phosphorylation sites). The EGFR inhibitor AG1478 prevented both desensitization and the associated cellular events. Similarly, these cellular events were also observed when cells were treated with EGF, but only in GPCRs that undergo desensitization. These findings suggest that EGFR transactivation diversifies pathways involved in ERK activation through the EGFR signaling system and also mediates GPCR desensitization. Alongside the widely accepted steric hindrance model, these findings offer new insights into understanding the mechanisms of GPCR desensitization, which occurs through complex cellular processes., (© 2024. The Author(s).)

Acetylsalicylic acid (ASA) represents a cornerstone of antiplatelet therapy for the treatment of atherosclerotic coronary artery disease (CAD). ASA is in fact indicated in case of an acute coronary syndrome or after a percutaneous coronary intervention with stent implantation. Aspirin hypersensitivity is frequently reported by patients, and this challenging situation requires a careful evaluation of the true nature of the presumed sensitivity and of its mechanisms, as well as to differentiate it from a more frequent (and more easily manageable) aspirin intolerance. Two main strategies are available to allow ASA administration for patients with CAD and suspected ASA hypersensitivity: a low-dose ASA challenge, aimed at assessing the tolerability of ASA at the antiplatelet dose of 100 mg, and desensitization, a therapeutic procedure which aims to induce tolerance to ASA. For those patients who cannot undergo ASA challenge and desensitization due to previous serious adverse reactions, or for those in whom desensitization was unsuccessful, a number of further alternative strategies are available, even if these have not been validated and approved by guidelines. The aim of this state-of-the-art review is therefore to summarize the established evidence regarding pathophysiology, clinical presentation, diagnosis, and management of aspirin hypersensitivity and to provide a practical guide for cardiologists (and clinicians) who have to face the not uncommon situation of a patient with concomitant coronary artery disease and aspirin hypersensitivity.

Introduction: Cetuximab, used to treat head and neck squamous cell carcinoma and metastatic colorectal cancer, can cause severe infusion reactions., Case Presentation: We report an 87-year-old East Asian woman with stage IV ileocecal signet ring cell carcinoma who experienced severe allergic reactions to cetuximab despite pre-treatment. A dose escalation method, involving weekly incremental doses with comprehensive pre-treatment and close monitoring, was employed, successfully reducing allergic reactions and allowing safe administration., Conclusion: This approach demonstrates a viable alternative for patients with hypersensitivity to cetuximab, warranting further research for personalized treatment optimization., (© 2024. The Author(s).)

Glycine receptors (GlyRs) are members of the Cys-loop receptors that constitute a major portion of mammalian neurotransmitter receptors. Recent resolution of heteromeric GlyR structures in multiple functional states raised fundamental questions regarding the gating mechanism of GlyR, and generally the Cys-loop family receptors. Here, we characterized in detail equilibrium properties as well as the transition kinetics between functional states. We show that, while all allosteric sites bind cooperatively to glycine, occupation of 2 sites at the α-α interfaces is sufficient for activation and necessary for high-efficacy gating. Differential glycine concentration dependence of desensitization rate, extent, and its recovery suggests separate but concerted roles of ligand-binding and ionophore reorganization. Based on these observations and available structural information, we developed a quantitative gating model that accurately predicts both equilibrium and kinetical properties throughout the glycine gating cycle. This model likely applies generally to the Cys-loop receptors and informs on pharmaceutical endeavors., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was given US Food and Drug Administration approval based on its therapeutic benefits to treat patients with cystic fibrosis (CF) who had at least 1 allele of the CF transmembrane conductance regulator (CFTR) with phenylalanine deleted at position 508 (F508del). The increase in genotyping studies has increased the frequency of use of CFTR modulators; however, severe allergic reactions to CFTR modulators have also been described. It is critical to avoid the offending medication and select alternative treatments while dealing with drug allergies. Drug desensitization may be taken into consideration in situations where there is no other option. This article describes home desensitization treatment for a patient with CF who developed a maculopapular rash following CFTR modulator medication. There are currently no alternative drugs for CFTR modulators, which are crucial for patients with CF, and limited experience is available with allergic reactions to these drugs. It is important to establish desensitization protocols in order to control drug reactions to CFTR modulators, which are vital for individuals with CF., Competing Interests: Disclosure. The authors declare that there are no conflict of interests. No funding. The authors had full access to all patient information in this report and take responsibility for the integrity and accuracy of the report., (Copyright. Pediatric Pharmacy Association. All rights reserved. For permissions, email: membership@pediatricpharmacy.org.)

Food allergies are an increasing global problem and societal issue. In addition to the potential for severe allergic reactions from accidental ingestion, food allergies impose a significant burden on the quality of life, nutrition, cost of living, and social activities of both those afflicted and their caregivers. Strict avoidance of allergens and use of emergency medications to treat allergic reactions are the traditional management and treatment strategies; however, significant progress has been made in recent years toward better treatment of food allergies. Many clinical trials on food allergen immunotherapy (oral, epicutaneous, and sublingual) have revealed its efficacy in increasing reaction thresholds and desensitization. These positive results led to the first FDA approval of peanut oral immunotherapy (OIT). However, safer and more effective approaches are required, and adjunct treatments and allergen modifications are being considered. More than 100 facilities in Japan conduct OIT, and numerous studies on it have been reported. Unlike in Europe and the US, stepwise oral food challenges with dietary guidance are conducted separately from the OIT. This review describes the current perspectives on allergen immunotherapy for the treatment of food allergies, focusing on evidence from Japan., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Background: Few studies have examined long-term outcomes following oral immunotherapy (OIT); none have examined long-term risks and benefits associated with distinct clinical outcomes (desensitization, remission)., Methods: Participants completing the probiotic and peanut oral immunotherapy (PPOIT) -003 randomized trial were enrolled in a follow-on study, PPOIT-003LT. Peanut ingestion, reactions, and health-related quality of life (HRQOL) were monitored prospectively. Outcomes at 1-year and 2-years post-treatment were examined by treatment group and by post-OIT clinical outcome (remission, desensitization without remission [DWR], allergic)., Results: 86% (151/176) of eligible children enrolled. Post-treatment peanut ingestion at 2-years post-treatment were similar for PPOIT (86.7%) and OIT (78.7%) groups, both higher than placebo (10.3%). Reactions reduced over time for all treatment and clinical outcome groups (PPOIT 31.7% to 23.3%, OIT 37.7% to 19.7%, placebo 13.8% to 6.9%; remission 27.5% to 15.9%; DWR 57.9% to 36.8%; allergic 11.6% to 7%). At 2-years post-treatment, similar proportions of remission and allergic participants reported reactions (RD 0.09 (95%CI -0.03, 0.20), p = .127), whereas more DWR participants reported reactions than remission (remission vs DWR: RD -0.21 (95%CI -0.39; -0.03), p = .02) and allergic (DWR vs allergic: RD 0.30 (95%CI 0.13, 0.47), p = .001) participants. At 2-years post-treatment, 0% remission versus 5.3% DWR versus 2.3% allergic participants reported adrenaline injector usage. Remission participants had significantly greater HRQOL improvement (adjusted for baseline) compared with both DWR (MD -0.54 (95%CI -0.99, -0.10), p = .017) and allergic (MD -0.82 (95%CI -1.25, -0.38), p < .001)., Conclusion: By 2-years post-treatment, remission participants reported fewer reactions, less severe reactions and greater HRQOL improvement compared with DWR and allergic participants, indicating that remission is the patient-preferred treatment outcome over desensitization or remaining allergic., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Objective: To assess the effect of allergen immunotherapy (AIT) on patients with central compartment atopic disease (CCAD) and house dust mite (HDM) sensitization post-surgery., Methods: A retrospective cohort of surgically treated, HDM-sensitized CRSwNP patients phenotyped as CCAD was assessed. Patients were divided into two groups based on whether they had AIT commenced as part of their surgical care. All AIT patients started immunotherapy prior to their surgery. The primary endpoint was reformation of middle turbinate (MT) edema 12 months postsurgery. Secondary endpoints were corticosteroid irrigation use (<4 times/week vs. ≥4 times/week, %) and the rhinologic domain of the 22-item sino-nasal outcome test (SNOT-22). Demographic characteristics, concomitant asthma, smoking status, history of aspirin-exacerbated respiratory disease, conjunctival symptoms, polysensitization, serum eosinophils (cell × 10 9 /L), tissue eosinophilia (% > 100/HPF), and serum IgE (kU/L) were also recorded., Results: Eighty-six CCAD patients were assessed (41 ± 14 yrs, 64% female). AIT was applied in 37% (n = 32). Baseline features were similar apart from greater conjunctival symptoms (72 vs. 45%, p = 0.02) in the AIT group. At 12 months post-surgery, the AIT group has less MT edema (% ≥ diffuse 15.6 vs. 52.9, p < 0.01). Patients on AIT also had less pharmacotherapy requirements at 12 months (% ≥ 4/week, 37.5 vs. 79.6%, p < 0.01). The rhinologic symptoms were similar (21.1 ± 17.1 vs. 20.1 ± 21.6, p = 0.83)., Conclusions: Surgery and pharmacotherapy are effective in managing CCAD, but the addition of AIT improved allergic phenomenon and allowed de-escalation of topical therapy. Longer term studies are required to demonstrate further immunomodulation., (© 2024 The Author(s). International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

Background: Donor-specific antibodies (DSAs) targeting human leukocyte antigens (HLAs) substantially reduce the longevity of transplanted organs. Desensitization of DSA-positive renal transplant recipients is achieved through intravenous administration of immunoglobulin (IVIg). However, the presence and detectability of anti-HLA antibodies in IVIg preparations following administration are not fully understood. We aimed to assess whether immunoglobulin preparations contain anti-HLA antibodies that can be detected as passive antibodies when administered into the body., Methods: We evaluated 3 immunoglobulin preparations from different pharmaceutical companies, using anti-HLA class I and II antibody specificity tests and immunocomplex capture fluorescence analysis (ICFA)., Results: Direct testing for anti-HLA antibodies resulted in high background errors, particularly for Venoglobulin. Diluting Venoglobulin to physiological concentrations revealed the presence of anti-HLA class I antibodies; however, no common alleles were found between the specificity identification test and ICFA.For Glovenin and Venilon, anti-HLA class I and II antibodies were detected; however, variability was observed across different test reagent lots. Moreover, dilution of the globulin formulation revealed a prozone phenomenon., Conclusion: The administration of IVIg complicates the accurate detection of anti-HLA antibodies, underscoring the need for careful interpretation of test results post-IVIg administration., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The transient receptor potential vanilloid 1 (TRPV1) channel plays a dual role in peripheral neuropathic pain (NeuP) by acting as a "pain switch" through its sensitization and desensitization. Hyperalgesia, commonly resulting from tissue injury or inflammation, involves the sensitization of TRPV1 channels, which modulates sensory transmission from primary afferent nociceptors to spinal dorsal horn neurons. In chemotherapy-induced peripheral neuropathy (CIPN), TRPV1 is implicated in neuropathic pain mechanisms due to its interaction with ion channels, neurotransmitter signaling, and oxidative stress. Sensitization of TRPV1 in dorsal root ganglion neurons contributes to CIPN development, and inhibition of TRPV1 channels can reduce chemotherapy-induced mechanical hypersensitivity. In diabetic peripheral neuropathy (DPN), TRPV1 is involved in pain modulation through pathways including reactive oxygen species and cytokine production. TRPV1's interaction with TRPA1 channels further influences chronic pain onset and progression. Therapeutically, capsaicin, a TRPV1 agonist, can induce analgesia through receptor desensitization, while TRPV1 antagonists and siRNA targeting TRPV1 show promise in preclinical studies. Cannabinoid modulation of TRPV1 provides another potential pathway for alleviating neuropathic pain. This review summarizes recent preclinical research on TRPV1 in association with peripheral NeuP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gao, Li, Wang, Liu and Guo.)

Introduction: Etoposide phosphate is a chemotherapeutic agent used to treat various malignant neoplasms. Hypersensitivity reactions may occur with its use, and in rare cases, an anaphylactic reaction can manifest. Available options for patients experiencing hypersensitivity reactions include premedication, changing treatment, or undergoing desensitization. Various pediatric desensitization protocols have been described, ranging from six to fifteen steps, while published adult cases are rare., Case Report: We report the case of a 61-year-old woman with small-cell lung cancer and brain metastases. In November 2019, she underwent the second cycle of cisplatin and etoposide phosphate treatment. While receiving etoposide phosphate, she experienced dyspnea and suffered a cardiorespiratory arrest, leading to cardiopulmonary resuscitation and subsequent admission to the Intensive Care Unit. Her acute tryptase levels were notably elevated at 18 µg/L (compared to a baseline tryptase level of 6,6 µg/L) during the reaction., Case Management: We implemented a 16-step desensitization protocol (without premedication) under close monitoring in an intermediate care unit. The protocol was successfully executed over three cycles until tumor progression mandated a modification in systemic treatment., Discussion: To our knowledge, this is the first documented case of successful desensitization to etoposide phosphate in a patient who experienced cardiac arrest during a hypersensitivity reaction. Although protocols of varying lengths have been published, we emphasize the importance of individualizing each protocol to fit the severity of the reaction and the resources and experience of each unit., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Cow's milk and egg allergy affect approximately 1.9% and 0.9% of children, respectively. Dietary advancement therapies (DATs), including milk (ML) and egg (EL) ladders, and baked milk (BM-OIT) and baked egg (BE-OIT) oral immunotherapy, are potential therapeutic options for these patients., Objective: To perform systematic review and meta-analysis of the safety and efficacy of DATs in children with IgE-mediated milk or egg allergy., Methods: A systematic literature review was conducted, exploring 22 potential outcomes, with meta-analysis performed where ≥3 studies reported data. The GRADE approach was used to determine the certainty of evidence for each outcome, and the Johanna Briggs Institute tools were used for determining risk of bias., Results: Twenty-nine studies met inclusion criteria among 9946 titles screened. Tolerance occurred in 69% of EL, 58% of ML, 49% of BE-OIT, and 29% of BM-OIT patients. All-severity allergic reactions occurred in 21% of EL, 25% of ML, 20% of BE-OIT, and 61% of BM-OIT patients, with epinephrine use in 3% of EL, 2% of ML, and 9% of BM-OIT patients. At-home reactions occurred in 19% of BE-OIT and 10% of BM-OIT patients. Discontinuation occurred in 14% of EL, 17% of ML, 17% of BE-OIT, and 20% of BM-OIT patients. The mean time to BE egg and BE-OIT tolerance was 13.25 months (4 studies) and 19.1 months (3 studies). Certainty of evidence was very low, and risk of bias high. Study heterogeneity was high, attributable to multiple factors., Conclusions: There is very low certainty of evidence supporting DAT safety and efficacy. We cannot conclude that DAT accelerates tolerance development., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Advances in hematopoietic cell transplantation have expanded the use of alternative donors such as haploidentical family donors or mismatched unrelated donors. However, donor-specific HLA antibodies (DSA) have been recognized as a significant risk factor of primary graft failure after HLA incompatible transplantation. Therefore, screening for HLA antibodies and taking DSA into consideration in the process of donor search play an increasingly important role in donor selection. If an HLA compatible donor is not available, desensitization may enable a successful transplantation. In this review, we describe the currently most widely used methods for HLA antibody detections including their pitfalls. In addition, we summarize the results of the studies on the impact of preformed DSA on transplant outcomes and their treatment options. Many more and larger studies are needed to clarify laboratory issues as well as immunological and clinical aspects in the management of DSA., Competing Interests: Declaration of competing interest No conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Despite advancements in short-term outcomes since the inception of intestinal transplant, significant long-term graft failure persists. Early successes are attributed to the utilization of tacrolimus for maintenance therapy, coupled with T-cell modulating induction regimens, which effectively reduce the incidence of acute cellular rejection. However, the challenge of chronic allograft injury remains unresolved. There is increasing evidence indicating a correlation between donor-specific antibodies and the survival of visceral allografts. Strategies aimed at reducing the presence or load of these antibodies may potentially enhance long-term outcomes. Consequently, our focus is now turning toward B-cell induction therapies as a possible solution., Competing Interests: Disclosure The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In human leukocyte antigen (HLA)-mismatched allogeneic stem cell transplantation settings, donor-specific anti-HLA antibodies (DSAs) can independently lead to graft failure, including both primary graft rejection and primary poor graft function. Although several strategies, such as plasma exchange, intravenous immunoglobulin, rituximab, and bortezomib, have been used for DSA desensitization, the effectiveness of desensitization and transplantation outcomes in some patients remain unsatisfactory. In this review, we summarized recent research on the prevalence of anti-HLA antibodies and the underlying mechanism of DSAs in the pathogenesis of graft failure. We mainly focused on desensitization strategies for DSAs, especially novel methods that are being investigated in the preclinical stage and those with promising outcomes after preliminary clinical application., (© 2024. The Author(s).)

Background: Drug hypersensitivity reactions (DHRs) have a significant impact on both, patient and their treating physicians; it is considered a public health concern. The history of allergy to drugs, limits therapeutic options and will lead to the use of more expensive and potentially less effective options. Drug desensitization (DD) is considered as a procedure with a positive impact on the prognosis of the patient's disease. The objective of this study is to describe the experience with a substantial number of drugs desensitization in a fourth level center in Cali, Colombia., Methods: An observational, cross-sectional and descriptive study was conducted. Patients with DHRs who underwent a standardized institutional DD protocol, between March of 2012 and May of 2023, were included., Results: Two hundred forty-one patients were included. The median age was 47.8 years (4-88). One hundred fifty-six (64.7%) were women, including three who were pregnant. A total of 641 DDs were performed. The most frequent groups of drugs for which the desensitization was performed were monoclonal antibodies in 83 patients (34.4%), chemotherapeutic agents in 53 (21.6%), NSAIDs in 44 (18.2%), and antibiotics in 42 (17.4%). Eighty-seven patients (36.1%) experienced hypersensitivity to the culprit drug on first exposure, while 154 (63.9%) exhibited reactions during subsequent cycles. The main clinical presentation that gave rise to desensitization was anaphylaxis in 125 patients (51.8%), followed by cutaneous symptoms in 106 patients (44%). The predominant observed endophenotype was type 1 in 188 patients (78.3%), followed by mixed type in 46 patients (19.2%). Breakthrough reactions were observed in 50 patients (20.7%). Tolerance to DD was achieved in 636 of the procedures (99.2%), allowing the continuity of treatment of choice for the underlying disease., Conclusions: Most desensitized patients were women with type I reactions. Monoclonal antibodies were the most frequent culprit drugs. DD in patients with DHRs is a useful, safe and effective procedure. The administration of the implicated drug had a positive impact on the course of the disease in these patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Pardo-Manrique, Ramírez-Zuluaga, Silva-Espinosa, Hurtado-Bermudez, Gómez-Hernández, Olaya-Hernández and Serrano-Reyes.)

Introduction: Taxanes and platinum are first-line treatments in gynecological tumors with high rates of hypersensitivity reactions (HSRs), leading to discontinuation of treatment. Desensitization involves induction of temporary tolerance to previously sensitized medications. The aims of this study are to describe HSRs to paclitaxel and carboplatin and evaluate the safety and effectiveness of desensitization protocols in gynecological cancer patients., Methods: Original, retrospective, descriptive, analytical study, approved by Bioethics and Research Committee, included >18-year-old patients with gynecological tumors experiencing HSRs to first-line chemotherapy. Patients underwent 3-bag-12-step desensitization., Results: 174 desensitization (95 paclitaxel, 79 carboplatin) in 33 female patients, mean age 45.5 years (18-71y). Cancer diagnosis: breast 8 (24.2%), ovarian 14 (42.2%), endometrial 2 (6.1%) and cervix 9 (27.2%). HSR occurred in paclitaxel during cycles 1-2 and in carboplatin after 6 cycles. The most frequently seen HSR symptom was cardiovascular with paclitaxel (94.7%), and cutaneous (93.3%) with carboplatin. Three-bags 12-steps desensitization protocol (initial dilution 1:100) in 5.67hrs. All patients reached total dose desensitization: 82% with no reaction, 12% mild, 6% moderate and 0% severe reaction. Mean disease-free interval and progression-free interval in months (m): breast cancer 29 m and 14 m, ovarian 22 m and 9 m, endometrial 40 m and cervical cancer: 67.5 m and 27 m. Twenty-five patients (73.5%) are still alive., Conclusion: HSRs to paclitaxel manifest in the first 1-2 cycles and to carboplatin after 6 cycles. Symptoms include cardiovascular, atypical neuromuscular and urticaria. Changing treatment lines impacts prognosis. Our study revealed that ovarian cancer patients undergoing desensitization protocols achieved longer progression-free intervals. All patients successfully reached total dose desensitization. This study provides evidence of the effectiveness and safety of desensitization and promising perspective for continuing first-line treatment with HSRs., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: When deferasirox is used in iron chelation therapy, maculopapular rash occurs in 10% of patients, but there is no accepted and implemented protocol for the management of these drug reactions in adults., Case Report: A 23-year-old woman diagnosed with thalassemia major is presented. She had taken 1,500 mg oral deferasirox for 1 week. Five hours after the last dose, a pruritic maculopapular rash developed on the body, face, and hands. The rash spread to the whole body within 3 days. The absolute necessity for the patient to take the drug was clarified by the hematology department. The patient's history was evaluated. A delayed-type hypersensitivity reaction due to deferasirox was considered., Management: The slow desensitization protocol described in the literature and applied on a case-by-case basis in pediatric patients was modified to shorten the duration by determining appropriate doses for the current preparation. The desensitization process was started with 1/100,000 of the total dose and the therapeutic dose was reached with a 2- to 2.5-fold increase in dose. No pre-medication was applied. During the procedure, at a low dose of 0.1 mg, local flushing and erythema was observed around the auricle on the face. The reaction did not progress., Conclusion: Slow desensitization protocol for oral deferasirox was successfully applied in an adult patient., Competing Interests: The authors acknowledge that they do not have any conflict of interest regarding the study. Table 1.Deferasirox slow desensitization protocols. Bruner et al. [4] protocolOur protocolTime intervals (days)Dose (mg)Dose (mg)Dose (mL)30.050.05Solution Ba 0.5 mL40.10.1Solution B 1 mL30.20.2Solution B 2 mL40.50.5Solution B 5 mL311Solution Ab 1 mL422Solution A 2 mL345Solution A 5 mL4810Solution A 10 mL31620Solution A 20 mL43240Solution A 40 mL36480Solution A 80 mL4125150Solution A 150 mL32502501 tablet45005002 tablets77507503 tablets71,0001,5006 tablets71,500 aA suspension was made by 1 : 10 dilution of solution A to a final concentration of 0.1 mg/mL (solution B); bA suspension was prepared by dissolving 1 tablet of deferasirox (250 mg) into a volume of 250 mL of water to a final concentration of 1 mg/mL (solution A)., (© Dustri-Verlag Dr. K. Feistle.)