Predictors of severe and recurrent adult anaphylaxis, and gaps in the cascade of care: a retrospective, single-centre study 2009-2018.

BACKGROUND: Anaphylaxis is a severe, potentially fatal, systemic allergic reaction. Understanding predictors of recurrent and severe anaphylaxis in adults, and identifying gaps in ongoing anaphylaxis care, is needed to minimise its impact. AIMS: To evaluate the risk factors in adults with severe and recurrent anaphylaxis presentations and to evaluate the management of patients in regard to the recommended cascade of care. METHODS: We completed a retrospective audit of adults with confirmed anaphylaxis who presented to an inner-city emergency department from 1 January 2009 through 31 December 2018. Data recorded included demographics, background history, medication use, severity, co-factors, triggers, management, discharge disposition and referral for follow-up. Data were managed in REDCap and analysed using Stata. Associations were assessed through odds ratios (ORs) and t tests. RESULTS: Six hundred sixteen individuals had 689 episodes of anaphylaxis over the audit period. Age over 65 (OR: 5.4 (95% confidence interval, CI: 2.3-13.2), P < 0.0001) and history of asthma (OR: 1.6 (95% CI: 1.03-2.5), P = 0.03) were independent risk factors for severe anaphylaxis. History of food allergy (P < 0.001) and food as the trigger were associated with recurrent presentations (OR: 2.1, 95% CI: 1.1-3.9, P = 0.01). Only 19% of patients met the recommended cascade of care, with post-adrenaline monitoring and recommending follow-up with an allergy specialist demonstrating the largest gaps. There were increased presentations with time but no difference in triggers or severity. CONCLUSIONS: Increased age and asthma were identified as risk factors for severe presentations. History of food allergy was a risk factor for recurrent presentations. Further research is needed on the gaps in care for adults with anaphylaxis to identify the reasons why, so we can better care for these patients.

Delabeling, safety, and impact of ß-lactam allergy testing: A systematic review.

Background: To improve ß-lactam delabeling outcomes, we need to understand current practice and the evidence base regarding its outcomes, safety, and impact. Objectives: We sought to assess the existing published evidence reporting on the effectiveness of penicillin allergy testing and delabeling. Methods: We conducted a systematic review of studies reporting ß-lactam delabeling practices and outcomes after testing, including ß-lactam use and patient understanding of the delabeling result. Searches of the PubMed, Scopus, and Embase databases; clinical trial registries; and websites of professional organizations were conducted. Data were extracted from the included studies in duplicate, with a third extraction if discrepancies remained. Results: We included 284 publications (covering 98,316 participants); 173 were prospective studies, with no randomized controlled trials. The overall study quality was low. In all, 95.6% of individuals who underwent provocation testing were delabeled. Factors associated with successful delabeling could not be determined because of significant heterogeneity between studies. Anaphylaxis due to testing occurred in 0.3% of participants (95 of 31,667). Subjects who did not undergo skin testing (6,980 patients in 31 studies) before challenge had higher rates of provocation test positivity (8.8% vs 4.1% [P < .0001]) and anaphylaxis (15.9% vs 2.7% [P < .0001]) than those subjects who underwent skin testing (51,607 patients in 177 studies). Six studies (2.1%) followed patients after testing to assess their adherence to prescribing recommendations. In all, 136 participants (20.6%) were actively avoiding ß-lactams despite delabeling. Conclusions: The available data suggest that penicillin allergy testing is safe and effective in delabeling most individuals, but the evidence base is incomplete and more work is required to assess the role of skin testing and the impact that delabeling is having on prescribing habits.

Specific human leucocyte antigen-DQ risk epitope mismatches are associated with chronic lung allograft dysfunction after lung transplantation.

A high-risk epitope mismatch (REM) (found in DQA1∗05 + DQB1∗02/DQB1∗03:01) is associated with de novo donor specific antibodies after lung transplantation (LTx). Chronic lung allograft dysfunction (CLAD) remains a barrier to LTx survival. This study aimed to measure the association between DQ REM and the risk of CLAD and death after LTx. A retrospective analysis of LTx recipients at a single center was conducted between January 2014 and April 2019. Molecular typing at human leucocyte antigen-DQA/DQB identified DQ REM. Multivariable competing risk and Cox regression models were used to measure the association between DQ REM, time-to-CLAD, and time-to-death. DQ REM was detected in 96/268 (35.8%), and DQ REM de novo donor specific antibodies were detected in 34/96 (35.4%). CLAD occurred in 78 (29.1%), and 98 (36.6%) recipients died during follow-up. When analyzed as a baseline predictor, DQ REM status was associated with CLAD (subdistribution hazard ratio (SHR), 2.19; 95% confidence interval [CI], 1.40-3.43; P = .001). After adjustment for time-dependent variables, DQ REM dn-DSA (SHR, 2.43; 95% CI, 1.10-5.38; P = .029) and A-grade rejection score (SHR, 1.22; 95% CI, 1.11-1.35; P = <.001), DQ REM status was not independently associated with CLAD. DQ REM was not associated with death (hazard ratio, 1.18; 95% CI, 0.72-1.93; P = .51). Classification of DQ REM may identify patients at risk of poor outcomes and should be incorporated into clinical decision-making.

Study protocol: Australasian Registry of Severe Cutaneous Adverse Reactions (AUS-SCAR).

INTRODUCTION: Severe cutaneous adverse reactions (SCAR) are a group of T cell-mediated hypersensitivities associated with significant morbidity, mortality and hospital costs. Clinical phenotypes include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP). In this Australasian, multicentre, prospective registry, we plan to examine the clinical presentation, drug causality, genomic predictors, potential diagnostic approaches, treatments and long-term outcomes of SCAR in Australia and New Zealand. METHODS AND ANALYSIS: Adult and adolescent patients with SCAR including SJS, TEN, DRESS, AGEP and another T cell-mediated hypersensitivity, generalised bullous fixed drug eruption, will be prospectively recruited. A waiver of consent has been granted for some sites to retrospectively include cases which result in early mortality. DNA will be collected for all prospective cases. Blood, blister fluid and skin biopsy sampling is optional and subject to patient consent and site capacity. To develop culprit drug identification and prevention, genomic testing will be performed to confirm human leukocyte antigen (HLA) type and ex vivo testing will be performed via interferon-γ release enzyme linked immunospot assay using collected peripheral blood mononuclear cells. The long-term outcomes of SCAR will be investigated with a 12-month quality of life survey and examination of prescribing and mortality data. ETHICS AND DISSEMINATION: This study was reviewed and approved by the Austin Health Human Research Ethics Committee (HREC/50791/Austin-19). Results will be published in peer-reviewed journals and presented at relevant conferences. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12619000241134).

Standardized testing and written communication improve patient understanding of beta-lactam allergy testing outcomes: A multicenter, prospective study.

Background: Historical penicillin allergy is commonly reported, but the lack of standardized allergy clinic practices may diminish the ability to delabel beta-lactam allergy appropriately. Objective: We sought to improve beta-lactam allergy testing and patient understanding of their antibiotic allergy status by standardizing testing and communication practices between 7 adult and pediatric hospital centers. Methods: Phase 1 prospectively described the beta-lactam allergy testing practices at each center. Following this, practice was standardized to achieve a defined panel of skin testing reagents, pro forma result letters for patients and referring doctors, and provision of medical alert jewelry to those with confirmed allergy. Testing outcomes and patient perception regarding allergy status 8 weeks postassessment were compared before (phase 1) and after standardization (phase 2). Primary outcomes were the percentage of participants delabeled after testing, and concordance rates between participant perception of their allergy status and their status as determined by the treating physician at 8-week follow-up. Results: Of 195 adult and pediatric participants (median age, 50 years; 21.5% <18 years; 36.9% males), 75% were delabeled of their beta-lactam allergy. No patient experienced anaphylaxis related to any beta-lactam delabeling testing. In phase 1, 75% of participants received written results, 52% were informed verbally, and 48% received results in more than 1 form. All phase 2 participants received written results (P < .01), 61% received verbal results from a physician as well (P > .05). At 8-week follow-up, 54% of phase 1 participants had concordant perceptions of their allergy status as the testing team versus 91.6% in phase2 (P < .001). Of the 17 participants who were delabeled and treated with a beta-lactam antibiotic during the 8-week follow-up period, there were no reported allergic reactions, although 1 participant experienced anaphylaxis following exposure to amoxicillin-clavulanic acid 1 year after delabeling. Conclusions: Standardization of testing and written patient information improved short-term patient perception of beta-lactam allergy status.

Somatic reversion of pathogenic DOCK8 variants alters lymphocyte differentiation and function to effectively cure DOCK8 deficiency.

Inborn errors of immunity cause monogenic immune dysregulatory conditions such as severe and recurrent pathogen infection, inflammation, allergy, and malignancy. Somatic reversion refers to the spontaneous repair of a pathogenic germline genetic variant and has been reported to occur in a number of inborn errors of immunity, with a range of impacts on clinical outcomes of these conditions. DOCK8 deficiency due to biallelic inactivating mutations in DOCK8 causes a combined immunodeficiency characterized by severe bacterial, viral, and fungal infections, as well as allergic disease and some cancers. Here, we describe the clinical, genetic, and cellular features of 3 patients with biallelic DOCK8 variants who, following somatic reversion in multiple lymphocyte subsets, exhibited improved clinical features, including complete resolution of infection and allergic disease, and cure over time. Acquisition of DOCK8 expression restored defective lymphocyte signalling, survival and proliferation, as well as CD8+ T cell cytotoxicity, CD4+ T cell cytokine production, and memory B cell generation compared with typical DOCK8-deficient patients. Our temporal analysis of DOCK8-revertant and DOCK8-deficient cells within the same individual established mechanisms of clinical improvement in these patients following somatic reversion and revealed further nonredundant functions of DOCK8 in human lymphocyte biology. Last, our findings have significant implications for future therapeutic options for the treatment of DOCK8 deficiency.

A Comparison of Gender-Affirming Chest Surgery in Nonbinary Versus Transmasculine Patients.

BACKGROUND: Increasingly more nonbinary patients are obtaining better access for gender-affirming chest surgery (top surgery), representing an important subset of patients who undergo such surgery. OBJECTIVE: We review our experience at gender-affirming chest surgery in nonbinary versus transmasculine patients in an integrated health care setting. METHODS: We performed a retrospective study of nonbinary and transmasculine patients who underwent gender-affirming chest surgery from May 1, 2012, to December 27, 2017. RESULTS: There were 111 nonbinary patients and 665 transmasculine patients included in the final analyses. Nonbinary patients were more likely to seek more than 1 surgical consultations than transmasculine patients (24.3% vs 1.7%, respectively, P < 0.0001). More nonbinary patients (17.3%) indicated nipple sensation to be important relative to their transmasculine counterparts (0.4%, P < 0.0001). Fewer nonbinary patients were on testosterone before surgery (33.64%) in comparison to transmasculine patients (86.14%, P < 0.0001). When only prior reduction mammaplasty or top surgery were considered, nonbinary patients (8.1%) were more likely than transmasculine patients (3.5%) to have had a prior chest surgery. When evaluating patients who did not have prior chest surgery before undergoing top surgery at our institution (n = 721), rates of major complications, minor complications, as well as revisions, were comparable between nonbinary and transmasculine patients. CONCLUSIONS: This study demonstrated that more nonbinary patients requested nonflat chests relative to their transmasculine counterparts. Both groups in our sample displayed comparable rates of complications after top surgery.

Switch from tenofovir disoproxil fumarate to raltegravir is not associated with weight gain over 96 weeks.

: Integrase strand transfer inhibitor-based antiretroviral therapy can cause weight gain. It is unknown if this is a class effect, with limited data regarding raltegravir. In 37 virologically suppressed adults (36 men, mean age 49 years) who switched from tenofovir disoproxil fumarate to raltegravir 400 mg twice daily, mean weight changes from baseline at weeks 24, 48 and 96 were not significant (maximum 0.8 kg at week 24; all P ≥ 0.16). Weight gain may not occur with all integrase strand transfer inhibitors.

Successful cholecalciferol desensitisation in a case of delayed hypersensitivity.

Hypersensitivity to cholecalciferol (vitamin D3) or its active metabolite, calcitriol, is an exceedingly rare clinical phenomenon, with only 2 previously reported cases of suspected immediate hypersensitivity. Diagnosis of delayed drug hypersensitivity reactions is inherently difficult due to the lack of any robust in vitro diagnostic assay, particularly in those patients for whom provocation testing confers an unacceptable risk. In these situations, diagnosis relies on reproducible clinical manifestations following administration of the culprit agent, resolution upon its withdrawal and exclusion of other potential differential diagnoses. Based on these criteria, we propose the first reported case of delayed hypersensitivity to cholecalciferol successfully managed with a desensitisation protocol to pure cholecalciferol.

Early Experiences With the Buttonhole Modification of the Double-Incision Technique for Gender-Affirming Mastectomies.

BACKGROUND: Little has been published about transmasculine and nonbinary gender-affirming mastectomies, particularly for patients with skin excess who desire reliable vascularity and sensation to the nipple-areolar complex. In this case series, we describe our experiences with the "buttonhole technique." METHODS: This was a retrospective case series of all consecutive patients who had a buttonhole mastectomy by a single surgeon. This technique maintains the nipple-areolar complex on a dermal pedicle rather than using a free nipple graft. RESULTS: Seventeen patients were included, with ages ranging from 21 to 49 years (median, 28 years). There were no major complications. Four patients had minor complications and/or required revision. CONCLUSIONS: The buttonhole technique should be considered for transmasculine and nonbinary patients with skin excess who are concerned about nipple vascularity and sensation.

Does Previous Breast Reduction Affect the Outcome of Gender-Affirming Subcutaneous Mastectomy?

INTRODUCTION: Despite the rising popularity of subcutaneous mastectomy (top surgery) in patients born female and identifying as male or nonbinary, there are limited studies on how prior breast surgeries affect subcutaneous mastectomy. This study evaluates if previous breast reduction affected subcutaneous mastectomy in this patient population. METHODS: The case series consists of 5 patients who, having had prior breast reductions, elected to have subcutaneous mastectomy. The data were collected retrospectively for mastectomy conducted from 2015 to 2016. Demographic data collected included age at surgery, body mass index, smoking status, medical comorbidity, and use of hormone medication. Outcome data included postoperative complications and need for operative revision. Postoperative follow-up was at 1 week and at 1, 3, 6, and 12 months. RESULTS: Patients' ages were between 29 and 46 years with body mass index from 24 to 33 kg/m. They underwent breast reduction approximately 9 to 26 months prior to subcutaneous mastectomy. All 5 patients successfully underwent subcutaneous mastectomy via double incision and free nipple grafts. Blood loss was estimated to be approximately 42 mL. All patients were discharged on the same day of surgery. The last follow-up averaged at 13 months after surgery and no major complication was reported. However, 1 patient required revision of the nipple graft and chest scars. CONCLUSIONS: This small case series suggests that subcutaneous mastectomy could be safely performed in transmasculine or nonbinary patients who had previous breast reduction.

The associations between psychological stress and psoriasis: a systematic review.

Psoriasis is estimated to affect around 2-3% of the general population. More than one-third of Australians report having a significant level of distress in their daily lives. Psychological stress has long been shown to play an important role in the natural history of psoriasis, but the details of this relationship remain to be clearly defined. We performed a systematic review of the literature with the aim of determining whether there is a temporal association between psychological stress as the predictor and onset and/or exacerbation of psoriasis as the outcome measure. Our secondary aim was to establish whether there is a relationship between the degree of psychological stress and clinical severity of psoriasis. Our systematic review demonstrates a probable temporal association between different measures of psychological stress and onset, recurrence, and severity of psoriasis. In the light of this, we suggest clinicians include "stress" as a trigger factor in their psoriasis assessment and consider psychological interventions as adjuncts, particularly in those who identify as "stress-responders".

Engineering Multifunctional RNAi Nanomedicine To Concurrently Target Cancer Hallmarks for Combinatorial Therapy.

Cancer hallmarks allow the complexity and heterogeneity of tumor biology to be better understood, leading to the discovery of various promising targets for cancer therapy. An amorphous iron oxide nanoparticle (NP)-based RNAi strategy is developed to co-target two cancer hallmarks. The NP technology can modulate the glycolysis pathway by silencing MCT4 to induce tumor cell acidosis, and concurrently exacerbate oxidative stress in tumor cells via the Fenton-like reaction. This strategy has the following features for systemic siRNA delivery: 1) siRNA encapsulation within NPs for improving systemic stability; 2) effective endosomal escape through osmotic pressure and/or endosomal membrane oxidation; 3) small size for enhancing tumor tissue penetration; and 4) triple functions (RNAi, Fenton-like reaction, and MRI) for combinatorial therapy and in vivo tracking.

Association of IMMP2L deletions with autism spectrum disorder: A trio family study and meta-analysis.

IMMP2L, the gene encoding the inner mitochondrial membrane peptidase subunit 2-like protein, has been reported as a candidate gene for Tourette syndrome, autism spectrum disorder (ASD) and additional neurodevelopmental disorders. Here we genotyped 100 trio families with an index proband with autism spectrum disorder in Han Chinese population and found three cases with rare exonic IMMP2L deletions. We have conducted a comprehensive meta-analysis to quantify the association of IMMP2L deletions with ASD using 5,568 cases and 10,279 controls. While the IMMP2L deletions carried non-recurrent breakpoints, in contrast to previous reports, our meta-analysis found no evidence of association (P > 0.05) between IMMP2L deletions and ASD. We also observed common exonic deletions impacting IMMP2L in a separate control (5,971 samples) cohort where subjects were screened for psychiatric conditions. This is the first systematic review and meta-analysis regarding the effect of IMMP2L deletions on ASD, but further investigations in different populations, especially Chinese population may be still needed to confirm our results.

Atlantic salmon endothelial cells from the heart were more susceptible than fibroblasts from the bulbus arteriosus to four RNA viruses but protected from two viruses by dsRNA pretreatment.

Heart diseases caused by viruses are major causes of Atlantic salmon aquaculture loss. Two Atlantic salmon cardiovascular cell lines, an endothelial cell line (ASHe) from the heart and a fibroblast cell line (BAASf) from the bulbus arteriosus, were evaluated for their response to four fish viruses, CSV, IPNV, VHSV IVa and VHSV IVb, and the innate immune agonist, double-stranded RNA mimic poly IC. All four viruses caused cytopathic effects in ASHe and BAASf. However, ASHe was more susceptible to all four viruses than BAASf. When comparing between the viruses, ASHe cells were found to be moderately susceptible to CSV and VHSV IVb, but highly susceptible to IPNV and VHSV IVa induced cell death. All four viruses were capable of propagating in the ASHe cell line, leading to increases in virus titre over time. In BAASf, CSV and IPNV produced more than one log increase in titre from initial infection, but VHSV IVb and IVa did not. When looking at the antiviral response of both cell lines, Mx proteins were induced in ASHe and BAASf by poly IC. All four viruses induced Mx proteins in BAASf, while only CSV and VHSV IVb induced Mx proteins in ASHe. IPNV and VHSV IVa suppressed Mx proteins expression in ASHe. Pretreatment of ASHe with poly IC to allow for Mx proteins accumulation protected the culture from subsequent infections with IPNV and VHSV IVa, resulting in delayed cell death, reduced virus titres and reduced viral proteins expression. These data suggest that endothelial cells potentially can serve as points of infections for viruses in the heart and that two of the four viruses, IPNV and VHSV IVa, have mechanisms to avoid or downregulate antiviral responses in ASHe cells. Furthermore, the high susceptibility of the ASHe cell line to IPNV and VHSV IVa can make it a useful tool for studying antiviral compounds against these viruses and for general detection of fish viruses.

Tantalum Sulfide Nanosheets as a Theranostic Nanoplatform for Computed Tomography Imaging-Guided Combinatorial Chemo-Photothermal Therapy.

Near-infrared (NIR)-absorbing metal-based nanomaterials have shown tremendous potential for cancer therapy, given their facile and controllable synthesis, efficient photothermal conversion, capability of spatiotemporal-controlled drug delivery, and intrinsic imaging function. Tantalum (Ta) is among the most biocompatible metals and arouses negligible adverse biological responses in either oxidized or reduced forms, and thus Ta-derived nanomaterials represent promising candidates for biomedical applications. However, Ta-based nanomaterials by themselves have not been explored for NIR-mediated photothermal ablation therapy. In this work, we report an innovative Ta-based multifunctional nanoplatform composed of biocompatible tantalum sulfide (TaS2) nanosheets (NSs) for simultaneous NIR hyperthermia, drug delivery, and computed tomography (CT) imaging. The TaS2 NSs exhibit multiple unique features including (i) efficient NIR light-to-heat conversion with a high photothermal conversion efficiency of 39%. (ii) high drug loading (177% by weight), (iii) controlled drug release triggered by NIR light and moderate acidic pH, (iv) high tumor accumulation via heat-enhanced tumor vascular permeability, (v) complete tumor ablation and negligible side effects, and (vi) comparable CT imaging contrast efficiency to the widely clinically used agent iobitridol. We expect that this multifunctional NS platform can serve as a promising candidate for imaging-guided cancer therapy and selection of cancer patients with high tumor accumulation.

Microgeographic factors and patterns of aeroallergen sensitisation.

OBJECTIVE: To examine patterns of airborne allergen (aeroallergen) sensitisation in the Greater Sydney area (Sydney), and their relationships with climate, coastal proximity and environment (urban v regional). DESIGN, SETTING, PARTICIPANTS: Retrospective cross-sectional study of patients who underwent aeroallergen skin prick testing at three Sydney allergy clinics, January 2001 - October 2014. MAIN OUTCOME MEASUREMENTS: Proportions of patients sensitised to specific aeroallergen types; relationships between sensitisation patterns and climate and geography. RESULTS: Of 1421 patients who met the selection criteria (mean age, 28.3 years [SD, 21.3]; 53.3% were female), 1092 (76.8%) were sensitised to at least one aeroallergen. Those living less than 15 km from the coast were less commonly sensitised to cockroach (< 15 km, 15.1%; 15-30 km, 40.0%; > 30 km, 39.7%; P < 0.001) and grass aeroallergens (< 15 km, 36.5%; 15-30 km, 52.2%; > 30 km, 58.1%; P < 0.001) than patients further inland; the same applied to mould, weed and tree aeroallergens. Subtropical grass sensitisation was more common in temperate/warm summer climates (about 50%) than in temperate/hot summer (27.1%) or subtropical climates (15%) (P < 0.001), and less common in urban (36.7%) than in regional areas (54%; P = 0.014). 72.4% of grass-sensitised patients were co-sensitised to both temperate and subtropical grasses. A selected ten-aeroallergen skin prick test panel identified 98.5% of atopic patients in this Sydney sample. CONCLUSIONS: Environmental and geographic factors are associated with different patterns of allergic sensitisation in Sydney. Extensive co-sensitisation to subtropical and temperate grasses has implications for immunotherapy in Australia, where most currently available therapies are based on formulations directed at temperate grasses only.

Ability to detect high-grade squamous anal intraepithelial lesions at high resolution anoscopy improves over time.

UNLABELLED: Background Anal cancer is increasing in incidence, has very high rates in specific populations and shares many similarities with cervical cancer. High-grade squamous intraepithelial lesions (HSIL) are regarded as precursors to anal cancer. High resolution anoscopy (HRA), which is derived from colposcopy, is the only currently available tool that can identify areas of the anal canal for targeted biopsy and identification of HSIL. METHODS: This study investigated the ability over a period of time of a single anoscopist to identify and adequately biopsy HSIL, correlating with contemporary anal cytological findings. RESULTS: Four hundred paired cytology and histology samples collected from 283 patients over a 7-year period from 2004 to 2010 were compared. There was a significant increase in HSIL detection rates when anal squamous cells of undetermined significance (ASC-US; 38.6-66.0%) or low-grade squamous intra-epithelial lesion (38.8-68.3%) were taken as cut-off points (P<0.001 for both). Detection rates did not change significantly when atypical squamous cells-cannot exclude HSIL (ASC-H) or a higher grade lesion (70-76.6%) was taken as the cut-off point. CONCLUSIONS: The increase in ability to detect histological HSIL over time and with increasing experience has the potential to impact on delivery of clinical services and the interpretation of clinical trial data. Further studies are required to determine the extent of this effect on other clinicians practising HRA.