Delayed allergic reaction from bupropion in a 27-year-old male with MDD: A case report and literature review.

Introduction: Bupropion is an antidepressant approved for the treatment of major depressive disorder (MDD), seasonal affective disorder, and smoking cessation. Nausea, headache, tremor, and insomnia are well-known adverse effects of this medication. Less well-recognized adverse effects include delayed allergic reactions, which, in some cases, can appear 2 or more weeks after bupropion initiation. Case Report: A 27-year-old male with recurrent MDD was referred for medication treatment at an outpatient mental health clinic and prescribed bupropion XL. On day 28 of treatment, he reported significant improvement in depressive symptoms and the development of itchiness and urticaria on his extremities and back. Bupropion was tapered over the course of 7 days, and he was given cetirizine 10 mg daily. He was transitioned to venlafaxine treatment and experienced complete resolution of hives and pruritus. Discussion: Despite published reports on bupropion causing delayed hypersensitivity reactions, there remains limited clinical recognition of this side effect, and the risk of underrecognition may be greater when the onset of the reaction is more than 2 weeks after bupropion initiation. Conclusion: Bupropion can cause delayed hypersensitivity reactions, including delayed pruritis and urticaria. The risk may be highest in males aged 17 to 40 years and those with a history of allergic reactions.

Immunogenicity of monoclonal antibody: Causes, consequences, and control strategies.

Antibody-based treatment was first used in 1891 for the treatment of diphtheria. Since then, monoclonal antibodies (mAbs) have been developed to treat many diseases such as cancer and act as vaccines. However, murine-derived therapeutic mAbs were found to be highly immunogenic, and caused anti-drug antibodies (ADAs) reaction, reducing their efficacy and causing severe infusion reactions. Fully human, humanised, and chimeric antibodies were then introduced for better therapeutic efficacy. With the introduction of immune response associated with mAbs immunogenicity. This review explores the immunogenicity of mAbs, its mechanism, contributing factors, and its impact on therapeutic efficacy. It also discusses immunogenicity assessment for preclinical studies and strategies for minimising immunogenicity for effective therapeutic treatment in various diseases. Finally, predicting immunogenicity in drug development is essential for selecting top drug candidates. A lot of methods can be implemented by the researchers and developers to reduce the development of ADAs while simultaneously minimising the immunogenicity reaction of mAbs.

Comparative histopathology of virulent and avirulent Meloidogyne javanica populations on susceptible and resistant tomato plants.

The Mi-1.2 gene confers resistance to a wide range of Meloidogyne species, being the most important resistance factor employed in tomato breeding so far. However, many aspects related to the interaction of Mi-1.2-carrying tomato cultivars and virulent/avirulent Meloidogyne populations have not yet been clarified. Herein, comparative histopathological analyses were carried after inoculation of the homozygous (Mi-1.2/Mi-1.2) tomato rootstock 'Guardião' and the susceptible cultivar 'Santa Clara' (mi-1.2/mi-1.2) with virulent and avirulent populations of M. javanica. In the susceptible control, it was possible to visualize second stage juveniles (J2) of avirulent population and feeding sites from 2 to 30 days after infection (DAI) with females reaching maturity at 24-34 DAI. In the resistant rootstock, the Mi-1.2 gene-mediated resistance was related mainly to early defense responses (pre-infection and hypersensitive reaction), which led to an immunity-like phenotype that completely prevented the reproduction of the avirulent Meloidogyne population. On the other hand, J2s of the virulent M. javanica population were able to penetrate roots much more than the avirulent population, migrated and developed normally, showing intense and similar pattern of penetration from 4 to 34 DAI in the root tissues of both resistant and susceptible tomato genotypes. The total numbers of J2, J3, J4, and females counted in 'Santa Clara' for the virulent population of M. javanica were higher than in 'Guardião'.

Allergic reactions to enzyme replacement therapy in children with lysosomal storage diseases and their management.

OBJECTIVES: Human recombinant enzyme replacement therapy, given to compensate for genetic enzyme deficiency in lysosomal storage diseases, delays the progression of the disease and improves the quality of life. However, enzyme replacement therapy may cause hypersensitivity reactions. Within the scope of this research, we aimed to elucidate the frequency and clinical features of hypersensitivity reactions against enzyme replacement therapy in children with lysosomal storage diseases and clarify the management of these reactions. METHODS: Medical records of pediatric patients with lysosomal storage disease and receiving enzyme replacement therapy were retrospectively reviewed, and patients who experienced allergic reactions were included in the study. The demographic characteristics of the patients, their diagnosis, the responsible enzyme, the time at which the reaction started and at what dose, the signs and symptoms associated with the reaction, diagnostic tests, the management of the reaction, and the protocol applied for the maintenance of enzyme replacement therapy after the reaction were recorded. RESULTS: Hypersensitivity reactions developed in 18 of 71 patients (25.3 %) who received enzyme replacement therapy. The most common cutaneous findings were observed. Anaphylaxis developed in 6 of 18 patients. Patients who experienced recurrent hypersensitivity reactions with premedication or a slower infusion rate, those with positive skin test results, and patients who developed anaphylaxis were given enzyme replacement therapy with desensitization. CONCLUSIONS: HSR may develop during enzyme replacement therapy, which are vital in lysosomal storage diseases, and discontinuation of enzyme replacement therapy is a significant loss for patients with metabolic disorders. These reactions can be treated with premedication and long-term infusions, but some patients may require desensitization protocols for continued treatment.

Permanent Makeup Removal Severe Complication-Case Report and Proposal of the Protocol for Its Management.

Background: The purpose of this paper is to report the case of a patient who developed a local allergic reaction to the pigment used for permanent eyebrow makeup. In addition, the authors' protocol for the treatment of such a complication is proposed. Methods: A patient visited the clinic to remove permanent eyebrow makeup. In the patient's opinion, the eyebrows were too dark and incorrectly shaped. Upon physical examination of the brows, they were found to be over-pigmented and drawn outside the area of hair growth of the natural brow. Results: The patient underwent 24 treatment procedures to remove the pigmentation including four sessions of laser therapy and subsequent treatments using a chemical substance (remover). No adverse effects occurred during the initial phase of makeup removal (black pigment removal), but an allergic reaction appeared with the removal of the red-orange colored pigment (after the fourth laser therapy session). The following symptoms appeared: redness, swelling, and the appearance of papules filled with both serous fluid and pigment used for the permanent makeup. After each remover treatment, the allergic reaction decreased, and local symptoms gradually subsided. Additionally, topical corticosteroid treatment was implemented peri-procedurally. The patient's case suggests a secondary allergic reaction to the red-orange pigment used for permanent makeup. Conclusions: The literature on this topic is scarce; therefore, we present a regimen for the management of such complications. In addition, we draw attention to the fact that allergic reactions to pigment may not always occur immediately following skin pigmentation but may become apparent long after the procedure, such as when the allergen is "exposed" during an attempt to remove or correct the makeup.

Bilateral purtscher-like retinopathy associated with DRESS syndrome: a case report.

BACKGROUND: To report a case of Bilateral Purtscher-like retinopathy associated with DRESS syndrome managed with ocular and systemic treatments. CASE PRESENTATION: A 29-year-old healthy female developed multi-organ (cutaneous, hematologic, renal and hepatic) disfunction and profound vision loss 1 month after Human papillomavirus vaccine injection. At the first presentation, her visual acuity was counting fingers in both eyes. Fundus exam showed remarkable cotton-wool spots, retinal hemorrhages and macular edema. She was diagnosed DRESS syndrome and Purtscher-like retinopathy and treated with intravitreal injection of ranibizumab, systemic steroids anticoagulants, and plasma exchange. The patient finally recovered from this life-threatening condition but left with permanent visual damage. CONCLUSION: Purtscher-like retinopathy could be complicated by DRESS syndrome which is usually considered a type IV hypersensitivity reaction.

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

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

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

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

Vancomycin Anaphylaxis and Kounis Syndrome Case Report.

Preoperative antibiotic administration has become a standard practice to mitigate the risk of surgical site infections; however, it is not devoid of potential complications. This report delves into the case of a 67-year-old male who underwent a routine preoperative vancomycin infusion prior to an elective total knee arthroplasty and subsequently experienced an unexpected adverse reaction including diaphoresis, cutaneous flushing, hypotension, and eventually unresponsiveness involving cardiovascular collapse and non-ST-segment elevation myocardial infarction (NSTEMI), despite minimal underlying coronary artery disease. The report focuses on the management of the emergent condition at our facility, highlighting the immediate response and following management of additional complications. The successful management led to a full recovery with the electrocardiogram (EKG) returning to the preoperative baseline of sinus rhythm with first-degree atrioventricular (AV) block within two hours of the event. This study contributes valuable insights into the complexities associated with preoperative antibiotic use, underscores the importance of understanding individual patient profiles, and raises awareness of potential risks and strategies to be used for antibiotic administration from a healthcare professional perspective.

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

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

Low-Salicylate Diet in Patients with Non-Steroidal Anti-Inflammatory Drug-Exacerbated Respiratory Disease: Personalization of Indications to Dietary Treatment.

INTRODUCTION: A particularly aggressive course of chronic sinusitis with nasal polyps is seen in patients with bronchial asthma and hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs). These patients often report exacerbation associated with consumption of foods reach in salicylates. Therefore, the authors analyzed the effect of a low-salicylate diet (LSD) on the course of chronic sinusitis with polyps in patients with NSAID-exacerbated respiratory disease (N-ERD) to answer the question: which patients would obtain the best therapeutic benefit? METHODS: Adult patients with N-ERD were selected for dietary intervention with LSD. Patients were seen on two occasions: at an initial visit and a follow-up after 12 weeks of diet. At both visits, an evaluation was performed with total nasal symptom score (TNSS) and modified Lund-Kennedy (L-K) endoscopy score. RESULTS: Forty patients (21 female, 52.5%, median and IQR of age 52; 43.5-61) used LSD for 12 weeks. Initial analysis of dietary intervention in the whole group revealed a significant decrease in TNSS and each symptom assessed separately, and the L-K score. The group was further divided into two subgroups based on the distance between NSAID intake and the beginning of symptoms: patients with immediate (n = 9; 22.5%) or non-immediate (n = 31; 77.5%) symptoms. The absolute change in nasal obstruction, itching, TNSS, and L-K scores were significantly higher in patients with immediate than with non-immediate symptoms. CONCLUSION: Results of the study indicate that patients with N-ERD and immediate symptoms may clinically benefit more from an LSD as an additional therapeutic option than patients with non-immediate symptoms.

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

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

Mirvetuximab after anaphylaxis to Paclitaxel: A case report.

Introduction: Patients with platinum resistant epithelial ovarian cancer have limited treatment options which are further limited by hypersensitivity reactions to first line medications such as paclitaxel. Paclitaxel is a taxane that inhibits microtubules and has a high incidence of hypersensitivity reactions. Mirvetuximab soravtansine-gynx (MIRV) is a folate receptor alpha (FRα) directed antibody and microtubule inhibitor that is approved for patients with FRα positive platinum resistant recurrent epithelial ovarian cancer. Both medications are microtubule-targeting agents with similar binding sites, therefore a theoretical risk of cross reactivity between paclitaxel and MIRV may exist. Additionally, phase II clinical trial, SORAYA, did not include data on patients with prior hypersensitivity to paclitaxel. Case: This is the case of a 33-year-old female with recurrent stage IIIC epithelial ovarian cancer with a history of severe anaphylaxis to paclitaxel. She was deemed eligible for MIRV after progression on multiple regimens, but MIRV was given with caution given her severe reaction history. With proper pre-treatment and monitoring, she was treated with MIRV without a reaction. Discussion: It is suspected that most paclitaxel reactions are due to the cremophor solvent rather than paclitaxel itself; however, cross reactivity with docetaxel which is suspended in a polysorbate solution can also occur. Therefore, there is no clear way to determine the risk of cross reactivity between paclitaxel and similar medications. MIRV is also suspended in polysorbate and has a similar mechanism to taxanes, therefore it was unknown if a patient with a prior grade 5 reaction to paclitaxel would also have a reaction to MIRV. Though this is one case, patients with a history of severe hypersensitivity to paclitaxel and meet the criteria for MIRV could be treated with MIRV with careful monitoring.

Delayed hypersensitivity reaction after hyaluronic acid filler (VCY-20).

Hyaluronic acid (HA) filler, a transient injectable used for rejuvenating facial treatments, has become increasingly popular over time since it doesn't require surgery. Although these procedures are generally safe, there are some application-related complications. These issues fall into three categories: reactions with early, delayed, or late onset. This case report features a 55-year-old female patient who developed widespread facial edema as a result of a delayed hypersensitivity reaction that happened after HA filler was applied.

Evaluating the efficacy of a premedication regimen including high-dose cetirizine in reduction of hypersensitivity reactions to paclitaxel: A retrospective cohort study.

INTRODUCTION: Hypersensitivity reactions (HSR) are a known adverse effect of paclitaxel, occurring in approximately 10% of patients, typically during the first or second infusion of the medication. Corticosteroids, histamine-1 and histamine-2 receptor antagonists are given prior to paclitaxel infusions to reduce the incidence of HSR. There are limited data that suggest administration of cetirizine given prior to a platinum infusion as secondary prophylaxis may reduce HSR rates. METHODS: The objective of this study was to assess the impact of a novel paclitaxel hypersensitivity prevention protocol including high-dose cetirizine administered 12 and 6 h prior to paclitaxel infusion on the rate of HSR compared to a historical control. The primary objective was the rate of HSR of any grade after the first cycle of paclitaxel. Secondary outcomes included grade of infusion reaction and incidence of severe HSR. RESULTS: A total of 104 patients were included for analysis in the cetirizine group and 124 in the control group. Hypersensitivity reactions occurred in 37 (16.2%) patients in the overall population, and no statistical difference was observed between groups. (13.46% vs 18.55%; p = 0.23). Numerically more grade 3-4 HSRs occurred in the control group than the treatment group (30.77% vs 69.23; p = 0.51). CONCLUSIONS: The addition of cetirizine to paclitaxel infusions resulted in numerically lower rates of HSR and a reduction in severity of grade 3-4 HSRs. Future studies with more robust compliance data and a larger patient population would be needed to appropriately assess the efficacy of our novel treatment regimen.

Temporary Delayed Hypersensitivity Reaction to Botulinum Toxin-A After COVID-19 Vaccination: A Case Series.

PURPOSE: The occurrence of a hypersensitivity reaction with the injection of botulinum toxin type A (BTX-A) in cosmetic use is a rare complication. We report the largest case series of temporary delayed hypersensitivity reaction (DHR) with BTX-A following COVID-19 vaccination and the first cases to incobotulinum toxin A (incoBTX-A). METHODS: A retrospective multicentric case series of patients who developed a DHR to BTX-A after COVID-19 vaccination. RESULTS: Twelve patients were treated with BTX-A injections for the management of facial rhytids. The age range was between 29 and 45 years. Ten (83.3%) were female. Ten (83.3%) patients received incoBTX-A, and two received onabotulinum toxin A (onaBTX-A). All patients had COVID-19 vaccination (mRNA vaccine) between 1 and 7 months before. Within an average time of 24 h after BTX-A injection, all patients developed progressive facial swelling and erythema that were more prominent at the injection points. Intradermal allergic tests to BTX-A were performed in six (50%) patients, and the results were all negative. Adequate clinical control was achieved with systemic corticosteroids and antihistamines. After 1 year with no further vaccination, a new BTX-A treatment (provocation test) was performed in all patients with no secondary effects. CONCLUSION: Previous COVID-19 vaccination and the absence of new adverse events with further BTX-A injections suggest a temporary DHR. Clinicians should be aware of the importance of immunization history and its potential post-vaccine immunogenic effects with BTX-A. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Challenging dogmas: Intravenous versus oral beta-lactam antibiotic provocation tests.

Background: Drug provocation tests (DPT) are considered the gold standard procedure to ascertain the diagnosis of beta-lactam (BL) allergy. Regarding route of administration, current recommendations prioritize oral challenges, considering them safer, and reserving the intravenous route for drugs for which this is the only formulation. Objective: To compare in terms of tolerance and safety two protocols of BL DPT, using an oral protocol (OR-DPT) and an intravenous protocol (IV-DPT). Methods: A descriptive, retrospective study was performed, including adult patients who underwent IV-DPT or OR-DPT for suspected immediate or delayed hypersensitivity to BL antibiotics, over a period of 4 years (between January 2018 and December 2021). Demographical data, index hypersensivity reactions' characteristics and tolerance to DPT were reviewed. Results: A total of 1036 patients underwent DPT, mean age of 56.8 (standard deviation, SD, 17.8) years, 655 were women (63.2%). Immediate drug hypersensitivity reactions (DHR) had occurred in 564 of patients (54.4%). OR-DPT were performed in 439 (42.4%) and IV-DPT in 597 (57.6%). The frequency of reactions during DPT, regardless of the route used, was low (3.6%): only 16 (3.6%) in OR-DPT and 21 (3.5%) in IV-DPT. From IV-DPT, 16 out 21 DHR during DPT were immediate compared with 4 out of 16 in OR-DPT. Adjusted relative risk of developing a hypersensitivity reaction during IV-DPT versus OR-DPT was 1.13 (95% confidence interval (CI)0.57-2.22). Conclusion: The results suggest that OR-DPT and IV-DPT are both safe procedures when adequately performed. However, IV-DPT protocols showed a higher rate of immediate DHR during DPT probably due to the selection of basal high-risk patients to undergo IV-DPT. In conclusion, IV-DPT may be considered as an option for challenges in drug-allergy studies, entailing a precise administration.

Perioperative Anaphylaxis in Japanese Secondary Care Institutions: Incidence, Causes, and the Imperative for Improved Diagnostic Practices.

Background This research investigates the incidence, suspected causes, and diagnostic procedures for perioperative anaphylaxis (POA), a potentially severe complication, in secondary care hospitals across Japan. Methodology We surveyed Saiseikai hospitals and gathered data on surgical procedures, POA occurrences, potential triggers, and diagnostic methods. Results Among 70,523 surgeries, seven were associated with POA, resulting in an approximate incidence rate of 0.01%. Rocuronium was the most commonly suspected trigger, followed by sugammadex, latex, and angiography contrast agents. Despite the importance of skin tests as the most basic and crucial diagnostic method, they were conducted in only three instances. No in vitro tests for drug identification were conducted, and in four cases, the cause was determined merely based on the timing of drug administration, indicating significant diagnostic limitations. Conclusions The study underscores the critical situation in Japan regarding insufficient diagnostic practices and difficulties in identifying triggering drugs rather than the consistent prevalence of POA in secondary care facilities. The findings emphasize the need for improved diagnostic proficiency and more rigorous drug identification practices to ensure prompt and accurate POA diagnosis. It is essential to conduct further research and interventions to increase patient safety during the perioperative period in secondary care settings.