Progestogen hypersensitivity: successful use of progesterone desensitisation and omalizumab to facilitate in vitro fertilisation.

Hypersensitivity to exogenous or endogenous progesterone presents with a variety of clinical, usually cutaneous, manifestations. The condition can occur at any age during the reproductive years, causes debilitating symptoms and can impact the use of exogenous hormones. Management strategies include symptom control or hormonal manipulation via desensitisation. Strategic testing confirms the diagnosis, while targeted intervention can significantly and positively impact quality of life and further childbearing.

Omalizumab for management of hypersensitivity reactions to anticancer drugs.

Hypersensitivity reactions to anticancer drugs include treatment-limiting toxicity. Standard drug desensitisation offers temporary tolerance and hence requires repetition. We used omalizumab, an anti-immunoglobulin E antibody, to overcome immediate and delayed hypersensitivity reactions to various anticancer drugs. Seven of the eight patients in the current study successfully resumed the desired anticancer drug regimen without standard desensitisation. No safety issues from omalizumab were observed.

Eye movement desensitisation and reprocessing as add-on treatment to enhanced cognitive behaviour therapy for patients with anorexia nervosa reporting childhood maltreatment: A quasi-experimental multicenter study.

OBJECTIVE: This quasi-experimental study aimed to compare the outcome of patients with Anorexia Nervosa (AN) reporting moderate/severe childhood maltreatment (CM) treated exclusively with Enhanced Cognitive Behaviour Therapy (CBT-E) or with CBT-E plus Eye Movement Desensitisation and Reprocessing (EMDR). METHOD: A total of 75 patients with AN reporting moderate/severe CM were initially assessed regarding body mass index (BMI), general and eating disorder (ED)-specific psychopathology, and dissociative symptoms, and re-evaluated after 40 CBT-E sessions (T1). Then, 18 patients received EMDR, whereas the others were placed on a waiting list and continued CBT-E. T2 assessment was performed after 20-25 sessions of EMDR or CBT-E. A control group of 67 patients without CM was also enroled and treated with CBT-E. RESULTS: Contrary to patients without CM, neither of the traumatised groups improved in BMI, general and ED psychopathology, or dissociation at T1. However, at T2, both traumatised groups improved in BMI and ED-specific psychopathology, with the CBT + EMDR group demonstrating greater improvements. Moreover, only the CBT + EMDR group improved in general psychopathology and dissociative symptoms. The reduction of ED symptoms in traumatised patients was mediated by the amelioration of dissociation. DISCUSSION: The addition of EMDR to CBT-E may benefit patients with AN reporting moderate/severe CM.

Postpartum cryptococcosis in an HIV-negative patient.

PURPOSE AND METHODS: We present an unusual case of an HIV-negative patient with postpartum pulmonary cryptococcosis and cryptococcemia. RESULTS: The diagnostic methods and treatment of cryptococcosis in a postpartum patient are presented in this case report. Due to anaphylaxis to liposomal amphotericin B, desensitisation to the drug was performed. CONCLUSION: We would like to raise awareness about rare infections such as cryptococcosis in pregnancy and the postpartum period. In addition, we were able to document a successful desensitisation to liposomal amphotericin B.

Therapy and Prevention of Noise Fears in Dogs-A Review of the Current Evidence for Practitioners.

Noise fears represent the most common behavioural problem in dogs. This manuscript provides an overview of diverse approaches for alleviating fear of noises in dogs and the supporting evidence. In the treatment of noise fears, both short-term solutions to prevent trauma or the deterioration of fear during unavoidable noise events and longer-term training need to be considered. Environmental management, the provision of incentives (food/play) during noise exposure, and, when indicated, anxiolytic medication, can safeguard dogs' welfare during noise events. Most "alternative" products (such as nutraceuticals, herbal remedies, pheromones, homeopathy, Bach flowers, and essential oils) are unlikely to be sufficient as monotherapy for noise fears, whereas there is good evidence for the efficacy of several anxiolytic medications. In the longer term, counterconditioning to real-life noises, relaxation training, and desensitisation/counterconditioning using noise recordings have been shown to improve fear of noises in dogs. Preventative training appears to be highly effective in preventing the development of noise fears in puppies and adult dogs.

Real-Life Use of Component-Specific IgE in IgE-Mediated Cow's Milk Protein Allergy in a Spanish Paediatric Allergy Centre.

BACKGROUND: In Spain, IgE-mediated cow's milk protein allergy (CMPA) affects approximately 0.69% of infants. Molecular diagnosis may be useful for monitoring natural spontaneous tolerance development in CMPA. The aim of this study was to retrospectively analyse a cohort of paediatric patients with IgE-mediated CMPA who were avoiding milk products awaiting natural tolerance and determine the relationship between disease persistence and major cow's milk allergens. METHODS: A retrospective chart review of 200 patients diagnosed with IgE-mediated CMPA between 2011 and 2020 was conducted. Patients strictly avoided milk products until an oral food challenge was performed. The main outcome was the introduction of liquid milk following a negative oral food challenge and its correlation with IgE and SPT measurements of milk components at diagnosis. Secondary outcomes included the rate of allergic reactions and anaphylaxis during the treatment period and its correlation with IgE and SPT measurements. RESULTS: Of the 200 charts analysed, 122 patients had a negative oral food challenge to milk (61.0%) (95% confidence interval (CI): 54.1-67.5) following a period of strict avoidance of milk. Higher levels of component-specific IgE, especially casein, were associated with failure in the oral food challenge (p = 0.02). Allergic reactions were experienced by 106 children (53%), of which 34 (17%; 95% CI: 12.4-22.8) had anaphylactic reactions. The risk of anaphylaxis was not predicted by raised IgE levels. CONCLUSIONS: While a large proportion of children acquired natural tolerance to cow's milk following a period of strict avoidance, IgE-mediated CMPA persisted in many children. Casein IgE levels at diagnosis were raised in those who failed to achieve natural tolerance. Allergic reactions to milk, including anaphylaxis, occurred commonly, but this was not predicted by raised IgE levels or SPT measurements.

Post-traumatic stress disorder in doctors: Origins, approach and Eye Movement Desensitisation and Reprocessing therapy.

OBJECTIVES: Navigating a high-stakes clinical environment, medical doctors tend to consider trauma and adverse workplace events as 'part of their job'. This often leads to delays in help-seeking in doctors who develop acute traumatic stress symptoms (ATSS), post-traumatic stress disorder (PTSD) and their comorbidities. This article outlines the prevalence of acute traumatic stress and PTSD in this population and summarises the emerging evidence base for Eye Movement Desensitisation and Reprocessing (EMDR) early-intervention protocols of this population. CONCLUSION: Doctors have higher prevalence rates of ATSS and PTSD than the general public. Eye Movement Desensitisation and Reprocessing therapy's early-intervention protocols for recent, prolonged and ongoing traumatic stress have the potential to be a widely acceptable, timely and cost-effective intervention for doctors and other healthcare workers (HCWs), as highlighted in the emerging evidence base, which has grown considerably in response to the impact of the COVID pandemic on HCWs' mental health. These evidence-based interventions could potentially be routinely offered to doctors and other HCWs within 1 month of an adverse workplace experience to reduce ATSS, PTSD and other comorbidities.

Successful ABO and HLA incompatible kidney transplantation in children in the UK.

BACKGROUND: There is increasing evidence of good short-term and medium-term outcomes of ABO incompatible (ABOi) and HLA incompatible (HLAi) kidney transplantation with pre-transplant positive crossmatches in paediatric practice. However, there remain concerns regarding the higher risks of infective complications and antibody-mediated rejections. The aim of our study is to show longer-term follow-up on all ABOi and HLAi paediatric kidney transplant recipients (pKTR) in the UK. METHODS: Questionnaires specifying kidney transplant type, desensitisation requirement and kidney allograft function were sent to 13 paediatric nephrology centres that performed kidney transplantation in children and young people under 18 years of age who received an ABOi and/or HLAi transplant between 1 January 2006 and 31 December 2016. Patient and kidney allograft survival were compared between ABOi, HLAi and ABO/HLA compatible (ABOc/HLAc) groups. RESULTS: Among 711 living donor kidney transplants performed in the UK, 23 were ABOi and 6 were HLAi. Patient survival was 87%, 100% and 96% in ABOi, HLAi and ABOc/HLAc groups, respectively, at median follow-up of 6.8 (3.6-14.0) years post-transplant. Death-censored kidney allograft survival was 100% in all 3 groups at last follow-up. There were no cases of primary non-function in ABOi or HLAi groups, but 2% in the ABOc/HLAc group. There was one reported case of Epstein-Barr viral-induced post-transplant lymphoproliferative disorder. CONCLUSION: Longer term follow-up has shown that ABOi and HLAi kidney transplantation are feasible for pKTR where no compatible donors are available, and that minimising desensitisation should be achieved where possible. A higher resolution version of the Graphical abstract is available as Supplementary information.

A novel G protein-biased agonist at the µ opioid receptor induces substantial receptor desensitisation through G protein-coupled receptor kinase.

BACKGROUND AND PURPOSE: G protein-biased µ opioid receptor agonists have the potential to induce less receptor desensitisation and tolerance than balanced opioids. Here, we investigated if the cyclic endomorphin analogue Tyr-c[D-Lys-Phe-Tyr-Gly] (Compound 1) is a G protein-biased µ agonist and characterised its ability to induce rapid receptor desensitisation in mammalian neurones. EXPERIMENTAL APPROACH: The signalling and trafficking properties of opioids were characterised using bioluminescence resonance energy transfer assays, enzyme-linked immunosorbent assay and phosphosite-specific immunoblotting in human embryonic kidney 293 cells. Desensitisation of opioid-induced currents were studied in rat locus coeruleus neurones using whole-cell patch-clamp electrophysiology. The mechanism of Compound 1-induced µ receptor desensitisation was probed using kinase inhibitors. KEY RESULTS: Compound 1 has similar intrinsic activity for G protein signalling as morphine. As predicted for a G protein-biased µ agonist, Compound 1 induced minimal agonist-induced internalisation and phosphorylation at intracellular µ receptor serine/threonine residues known to be involved in G protein-coupled receptor kinase (GRK)-mediated desensitisation. However, Compound 1 induced robust rapid µ receptor desensitisation in locus coeruleus neurons, to a greater degree than morphine. The extent of Compound 1-induced desensitisation was unaffected by activation or inhibition of protein kinase C (PKC) but was significantly reduced by inhibition of GRK. CONCLUSION AND IMPLICATIONS: Compound 1 is a novel G protein-biased µ agonist that induces substantial rapid receptor desensitisation in mammalian neurons. Surprisingly, Compound 1-induced desensitisation was demonstrated to be GRK dependent despite its G protein bias. Our findings refute the assumption that G protein-biased agonists will evade receptor desensitisation and tolerance. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.

Heparin desensitisation prior to cardiopulmonary bypass in a patient with alpha-gal allergy.

This case report describes the implementation of a heparin desensitisation strategy for a patient with confirmed galactose-alpha-1,3-galactose (alpha-gal) allergy, prior to cardiac surgery. We describe the pre-, intra- and postoperative management. We believe this report can enhance the limited data currently in existence on alternative strategies for heparin utilisation in cardiopulmonary bypass in a previously intolerant patient population.

Using eye movement desensitisation and reprocessing (EMDR) with autistic individuals: A qualitative interview study with EMDR therapists.

OBJECTIVES: Eye Movement Desensitisation and Reprocessing (EMDR) is an evidence-based psychological therapy that targets distress associated with trauma and affective disturbance. Few studies have examined EMDR for autistic individuals who have co-occurring mental health conditions, but there is preliminary evidence of effectiveness. The current study explored EMDR therapists' experiences of working with autistic individuals, and adaptations incorporated into clinical practice to make this more accessible and effective. DESIGN: A qualitative interview design was used. Data were thematically analysed. METHOD: Twenty-three UK-based EMDR therapists attended one-off semi-structured qualitative interviews. RESULTS: Four main themes emerged: (1) the experience of being autistic; (2) factors around accessing EMDR; (3) adapting EMDR; and (4) supervision and support for EMDR therapists. Participants described offering a nuanced and tailored approach; one that retained the integral components of the eight phases of EMDR, while also being flexible and responsive to each client. CONCLUSIONS: Findings reinforce the importance of offering formulation-based psychological therapy that flexes in an evidence-informed way, according to the preferences and needs of autistic individuals. Further research should establish factors influencing accessibility and effectiveness of EMDR for autistic individuals, and the impact of autism-relevant training on the knowledge, skills and confidence of EMDR therapists and clinical supervisors working with this client group.

Post-transcriptional regulatory feedback encodes JAK-STAT signal memory of interferon stimulation.

Immune cells fine tune their responses to infection and inflammatory cues. Here, using live-cell confocal microscopy and mathematical modelling, we investigate interferon-induced JAK-STAT signalling in innate immune macrophages. We demonstrate that transient exposure to IFN-γ stimulation induces a long-term desensitisation of STAT1 signalling and gene expression responses, revealing a dose- and time-dependent regulatory feedback that controls JAK-STAT responses upon re-exposure to stimulus. We show that IFN-α/ß1 elicit different level of desensitisation from IFN-γ, where cells refractory to IFN-α/ß1 are sensitive to IFN-γ, but not vice versa. We experimentally demonstrate that the underlying feedback mechanism involves regulation of STAT1 phosphorylation but is independent of new mRNA synthesis and cognate receptor expression. A new feedback model of the protein tyrosine phosphatase activity recapitulates experimental data and demonstrates JAK-STAT network's ability to decode relative changes of dose, timing, and type of temporal interferon stimulation. These findings reveal that STAT desensitisation renders cells with signalling memory of type I and II interferon stimulation, which in the future may improve administration of interferon therapy.

Peanut oral immunotherapy: current trends in clinical trials.

Immunotherapy for allergy has been practiced for over 100 years. Low-dose repeated exposure to specific allergen extracts over several months to years can successfully induce clinical tolerance in patients with allergy to insect venoms, pollen, house dust mite, and domestic animals. Different regimens and routes for immunotherapy include subcutaneous, sublingual, oral, and intralymphatic. Food allergies have been difficult to treat in this way due to high anaphylactic potential and only recently the first immunotherapy for peanut allergy has received regulatory approval. Several clinical trials have indicated high efficacy in desensitisation of peanut-allergic individuals using oral immunotherapy, which allows for safer administration of relatively high allergen concentrations. Still, the risk of adverse events including serious allergic reactions and high anxiety levels for patients remains, demonstrating the need for further optimisation of treatment protocols. Here we discuss the design and outcomes of recent clinical trials with traditional oral immunotherapy, and consider alternative protocols and formulations for safer and more effective oral treatment strategies for peanut allergy.

Tolerance to sterilised cow's milk in patients with eosinophilic oesophagitis triggered by milk.

BACKGROUND: Cow's milk protein is the main food trigger for eosinophilic oesophagitis (EoE) in children and adults and should be continuously avoided once identified as such. AIMS: To evaluate tolerance of sterilised cow's milk (boiled instead of UHT processing) with regard to maintenance of EoE remission, health-related quality of life (HRQoL), nutritional intake and allergic sensitisation in patients of all ages with milk-triggered EoE METHODS: We prospectively recruited patients in whom cow's milk was demonstrated to trigger EoE after an empirical food elimination diet-based study. They were given 200 ml of sterilised cow's milk twice daily for 8 weeks. Endoscopic assessment, peak eosinophil counts, oesophageal-related symptoms, HRQoL, blood eosinophils, eosinophil cationic protein (ECP), skin prick test and serum total and specific immunoglobulin E (IgE) to major milk proteins were monitored before and after sterilised milk intake. RESULTS: Eighteen patients (13 male) in EoE remission underwent a sterilised milk challenge. Twelve maintained EoE remission (<15 eos/hpf) while EoE recurred in the remainder. Endoscopic appearances deteriorated in non-tolerant patients. HRQoL scored well at baseline and was maintained among patients tolerant to sterilised milk, but deteriorated in reactive ones. No significant changes in blood eosinophil count, ECP, tryptase or total and milk-specific IgE serum levels were observed from baseline. However, cow's milk-specific IgE increased slightly in non-tolerant patients. Clinical and histological remission were maintained in patients who regularly consumed sterilised milk for 1 year. CONCLUSION: Sterilised milk did not trigger EoE in two-thirds of patients with documented milk-induced EoE, in either the short or long term.

Post-traumatic stress in adults with 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11.2DS) is associated with an elevated genetic risk of several psychiatric disorders. However, the prevalence of post-traumatic stress disorder (PTSD) in individuals with 22q11.2DS has been reported to be only 0.9%; this is lower than that of the general population (3.9%). We explored the occurrence of PTSD and traumatic events in a Dutch cohort of 112 adults with 22q11.2DS, and found PTSD in 8.0%, traumatic events in 20.5% and trauma-focused treatment in 17.9% of patients. Our novel findings suggest that PTSD may be underdiagnosed in individuals with 22q11.2DS. Clinicians and other caregivers should be alert to trauma in this population in order to enable treatment and minimise psychiatric burden.

Food allergy in children-the current status and the way forward.

Food allergy in children is a major health concern, and its prevalence is rising. It is often over-diagnosed by parents, resulting occasionally in unnecessary exclusion of some important food. It also causes stress, anxiety, and even depression in parents and affects the family's quality of life. Current diagnostic tests are useful when interpreted in the context of the clinical history, although cross-sensitivity and inability to predict the severity of the allergic reactions remain major limitations. Although the oral food challenge is the current gold standard for making the diagnosis, it is only available to a small number of patients because of its requirement in time and medical personnel. New diagnostic methods have recently emerged, such as the Component Resolved Diagnostics and the Basophil Activation Test, but their use is still limited, and the latter lacks standardisation. Currently, there is no definite treatment available to induce life-long natural tolerance and cure for food allergy. Presently available treatments only aim to decrease the occurrence of anaphylaxis by enabling the child to tolerate small amounts of the offending food, usually taken by accident. New evidence supports the early introduction of the allergenic food to infants to decrease the incidence of food allergy. If standardised and widely implemented, this may result in decreasing the prevalence of food allergy.

Efficacy and Adverse Events of Carboplatin Desensitisation Therapy for Gynaecological Cancer: A Retrospective Study.

BACKGROUND: Carboplatin, the key drug used in treating gynaecological cancer, has an approximately 12-16% risk of hypersensitivity reactions. We aimed to investigate the efficacy and adverse effects of carboplatin desensitisation therapy for gynaecological cancer. METHODS: The desensitisation protocol was standardised as a four-step, 4-h, carboplatin administration in the hospital. A retrospective medical record review was conducted on 15 patients who underwent carboplatin desensitisation for gynaecological malignancies at our hospital. Patients' data were analysed to evaluate the treatment success rate, therapeutic effect of desensitisation, adverse events, and treatment. RESULTS: Of 91 carboplatin desensitisation cycles scheduled; the completion rate was 93.4% (85/91). Adverse events occurred in 23 of these 91 (25.3%). In four (4.4%) of the 23 cycles, hypersensitivity reactions could be treated only by discontinuing the infusion and slowing the administration, while in the remaining 19 (20.9%), medication was administered intravenously after discontinuing the infusion to manage hypersensitivity reactions. No treatment-related deaths occurred. Overall, 23 series of anti-cancer agent regimens, including carboplatin desensitisation, were administered to the 15 patients. The therapeutic response rate was 82.6% and the disease control rate was 95.7%. CONCLUSIONS: Carboplatin desensitisation was beneficial in patients with a history of carboplatin-induced hypersensitivity reactions.

Longitudinal antibody responses to peanut following probiotic and peanut oral immunotherapy (PPOIT) in children with peanut allergy.

INTRODUCTION: Probiotic and Peanut Oral Immunotherapy (PPOIT) is effective at inducing sustained unresponsiveness (SU) at end-of-treatment and this effect persists up to four years post-treatment, referred to as persistent SU. We sought to evaluate (i) how PPOIT altered peanut-specific humoral immune indices, and (ii) how such longitudinal indices relate to persistent SU. METHODS: Longitudinal serum/plasma levels of whole peanut- and peanut component- (Ara-h1, -h2, -h3, -h8, -h9) specific-IgE (sIgE) and specific-IgG4 (sIgG4) antibodies were measured by ImmunoCAP and salivary peanut-specific-IgA (sIgA) by ELISA in children (n=62) enrolled in the PPOIT-001 randomised trial from baseline (T0) to 4-years post-treatment (T5). Multivariate regression analyses of log-transformed values were used for point-in-time between group comparisons. Generalised estimating equations (GEE) were used for longitudinal comparisons between groups. RESULTS: PPOIT was associated with changes in sIgE and sIgG4 over time. sIgE levels were significantly reduced post-treatment [T5, PPOIT v.s. Placebo ratio of geometric mean (GM): Ara-h1 0.07, p=0.008; Ara-h2 0.08, p=0.007; Ara-h3 0.15, p=0.021]. sIgG4 levels were significantly increased by end-of-treatment (T1, PPOIT v.s. Placebo ratio of GM: Ara-h1 3.77, p=0.011; Ara-h2 17.97, p<0.001; Ara-h3 10.42, p<0.001) but levels in PPOIT group decreased once treatment was stopped and returned to levels comparable with Placebo group by T5. Similarly, salivary peanut sIgA increased during treatment, as early as 4 months of treatment (PPOIT v.s. Placebo, ratio of GM: 2.04, p=0.014), then reduced post-treatment. CONCLUSION: PPOIT was associated with broad reduction in peanut specific humoral responses which may mediate the clinical effects of SU that persists to 4-years post-treatment.

Preparations of exploration of immediate hypersensitivity to antineoplastic agents: An oncology pharmacy perspective.

BACKGROUND: Cancer patients are being exposed to antineoplastic drugs more frequently and for longer periods, resulting in a higher risk of hypersensitivity reactions. The aim of this study was to assess the pharmaceutical time and direct cost of drug allergy explorations following immediate hypersensitivity reactions to antineoplastic agents. METHODS: A micro-costing method was used to collect data on consumption of human and material resources for allergy exploration preparations. The monetisation was carried out on the basis of prices and hourly wage costs applied in 2018. The number and type of allergy explorations prepared by the pharmacy as well as nature of antineoplastic drugs tested, and the number of culprit drugs reintroductions were collected. RESULTS: Almost 1.5 h is required to realise allergy tests for one patient including pharmacist time for prescription analysis and pharmacy technician's time for tests preparation. The mean manufacturing cost of these tests is estimated at €62.87 (€57.82-65.49) per culprit drug for one patient. Programming patients according to culprit drugs tested allows rationalising healthcare provider time and increasing efficiency. From January 2010 to December 2018, 277 patients were tested and 490 allergy explorations were performed, corresponding to more than 5000 preparations. Mostly, the culprit drug could be reintroduced (n = 383, 78.2%) allowing patients to receive the best possible treatment. CONCLUSION: Management of hypersensitivity reactions is constantly progressing, as it contributes to improving patient care in oncology. This activity is time-consuming for the pharmacy team but allows patients with previous hypersensitivity reaction to continue effective treatment.

Treatment of post-traumatic stress disorder and substance use disorder in adults with a history of adverse childhood experiences: A systematic review of psychological interventions.

Background: Adverse childhood experiences (ACEs) have long-term effects on adult health, including unresolved trauma and substance use disorder (SUD). There are hypotheses of a mediating role of emotion regulation. This systematic literature review and narrative synthesis assessed the effectiveness of psychological interventions on emotion regulation, PTSD and SUD symptoms. Methods: Searches were conducted using the Cochrane Handbook for Systematic Reviews methodology. Eligible studies were randomised controlled trials (RCTs) and quasi-experimental psychological interventions published between 2009 and 2019. Study characteristics, results and methodological quality were systematically analysed. Results: Thirteen studies, including nine RCTs, were selected. Integrated SUD and PTSD treatments consisted of Seeking Safety, exposure-based treatment, Trauma Recovery and Empowerment Model, and integrated cognitive behavioural therapy. Two studies reported emotion regulation. Five studies found a small to medium positive effect size of psychological interventions on PTSD outcomes. Two studies had a small positive effect size on SUD outcomes and two a small negative effect size. Attrition was high across most studies. Characteristics likely to affect the applicability of the review were described. Conclusion: The review found some evidence of a small inconsistent positive effect of psychological interventions on PTSD outcomes, and no evidence of effect on SUD outcomes. The range of theoretical models was narrow. Overall quality was low with high clinical heterogeneity and missing key information, particularly on emotion regulation, an important transdiagnostic feature. Further research is required to establish interventions that can treat these multiple conditions with a focus on effectiveness, acceptability, and implementation in real life clinical practice.