Paracetamol orodispersible tablets: a risk for severe poisoning in children?

Purpose: Childhood paracetamol (acetaminophen) ingestion with subsequent risk of hepatotoxicity is a major medical problem. The aim of this study was to investigate the risk of high-dose ingestion of orodispersible, fast-disintegrating paracetamol tablets in children. Methods: A retrospective single-center case study of all accidental selfadministrations of solid or orodispersible 500-mg paracetamol tablets occurring in children ≤ 6 years, reported to the Swiss Toxicological Information Centre between June 2003 and August 2009. Results: We found 187 cases with ingestion of solid 500-mg paracetamol tablets and 16 cases with ingestion of orodispersible 500-mg tablets. The mean ingested dose in the orodispersible-tablet group was 59% higher than in the solid-tablet group (p = 0.085). Administration of activated charcoal and/or N-acetylcysteine because of ingestion of a potentially hepatotoxic paracetamol dose ( ≥ 150 mg/kg body weight) was recommended in 32 patients (17.1%) in the solid-tablet group and in five (31%) in the orodispersible-tablet group. Conclusions: Orodispersible paracetamol formulations may represent an important risk factor for severe paracetamol poisoning in children. Over-the-counter availability may contribute to increasing the use of this galenic formulation and eventually the number of poisonings in childre

Immune Checkpoint Inhibitors and Pregnancy: Analysis of the VigiBase® Spontaneous Reporting System

: In pregnancy, immune checkpoint pathways are involved in the maintenance of fetomaternal immune tolerance. Preclinical studies have shown that immune checkpoint inhibitors (ICIs) increase the risk of fetal death. Despite the fact that using ICIs in pregnant women and women of childbearing potential is not recommended, some case reports of ICI exposure in pregnancy have been published showing favorable fetal outcomes. This study aimed to gain further insight into ICI safety in pregnancy by querying VigiBase®, the World Health Organization's spontaneous reporting system. We performed raw and subgroup disproportionality analyses using the reporting odds ratio and comparing ICIs with the entire database, other antineoplastic agents, and other antineoplastic agents gathered in VigiBase® since 2011. Across 103 safety reports referring to ICI exposure during the peri-pregnancy period, 56 reported pregnancy-related outcomes, of which 46 were without concomitant drugs as potential confounding factors. No signals of disproportionate reporting were found for spontaneous abortion, fetal growth restriction, and prematurity. In light of the expanding indications of ICIs, continuous surveillance by clinicians and pharmacovigilance experts is warranted, along with pharmacoepidemiological studies on other sources of real-world evidence, such as birth records, to precisely assess ICI exposure during the peri-pregnancy period and further characterize relevant outcomes

Immune Checkpoint Inhibitors and Pregnancy: Analysis of the VigiBase® Spontaneous Reporting System

In pregnancy, immune checkpoint pathways are involved in the maintenance of fetomaternal immune tolerance. Preclinical studies have shown that immune checkpoint inhibitors (ICIs) increase the risk of fetal death. Despite the fact that using ICIs in pregnant women and women of childbearing potential is not recommended, some case reports of ICI exposure in pregnancy have been published showing favorable fetal outcomes. This study aimed to gain further insight into ICI safety in pregnancy by querying VigiBase®, the World Health Organization’s spontaneous reporting system. We performed raw and subgroup disproportionality analyses using the reporting odds ratio and comparing ICIs with the entire database, other antineoplastic agents, and other antineoplastic agents gathered in VigiBase® since 2011. Across 103 safety reports referring to ICI exposure during the peri-pregnancy period, 56 reported pregnancy-related outcomes, of which 46 were without concomitant drugs as potential confounding factors. No signals of disproportionate reporting were found for spontaneous abortion, fetal growth restriction, and prematurity. In light of the expanding indications of ICIs, continuous surveillance by clinicians and pharmacovigilance experts is warranted, along with pharmacoepidemiological studies on other sources of real-world evidence, such as birth records, to precisely assess ICI exposure during the peri-pregnancy period and further characterize relevant outcomes

Comparative evaluation of three clinical decision support systems: prospective screening for medication errors in 100 medical inpatients

Purpose: Clinical decision support systems (CDSS) are promoted as powerful screening tools to improve pharmacotherapy. The aim of our study was to evaluate the potential contribution of CDSS to patient management in clinical practice. Methods: We prospectively analyzed the pharmacotherapy of 100 medical inpatients through the parallel use of three CDSS, namely, Pharmavista, DrugReax, and TheraOpt. After expert discussion that also considered all patient-specific clinical information, we selected apparently relevant alerts, issued suitable recommendations to physicians, and recorded subsequent prescription changes. Results: For 100 patients with a median of eight concomitant drugs, Pharmavista, DrugReax, and TheraOpt generated a total of 53, 362, and 328 interaction alerts, respectively. Among those we identified and forwarded 33 clinically relevant alerts to the attending physician, resulting in 19 prescription changes. Four adverse drug events were associated with interactions. The proportion of clinically relevant alerts among all alerts (positive predictive value) was 5.7, 8.0, and 7.6%, and the sensitivity to detect all 33 relevant alerts was 9.1, 87.9, and 75.8% for Pharmavista, DrugReax and TheraOpt, respectively. TheraOpt recommended 31 dose adjustments, of which we considered 11 to be relevant; three of these were followed by dose reductions. Conclusions: CDSS are valuable screening tools for medication errors, but only a small fraction of their alerts appear relevant in individual patients. In order to avoid overalerting CDSS should use patient-specific information and management-oriented classifications. Comprehensive information should be displayed on-demand, whereas a limited number of computer-triggered alerts that have management implications in the majority of affected patients should be based on locally customized and supported algorithm

Atypical antipsychotic poisoning in young children: a multicentre analysis of poisons centres data

Although paediatric patients frequently suffer from intoxications with atypical antipsychotics, the number of studies in young children, which have assessed the effects of acute exposure to this class of drugs, is very limited. The aim of this study was to achieve a better characterization of the acute toxicity profile in young children of the atypical antipsychotics clozapine, olanzapine, quetiapine, and risperidone. We performed a multicentre retrospective analysis of cases with atypical antipsychotics intoxication in children younger than 6years, reported by physicians to German, Austrian, and Swiss Poisons Centres for the 9-year period between January 1, 2001 and December 31, 2009. One hundred and six cases (31 clozapine, 29 olanzapine, 12 quetiapine, and 34 risperidone) were available for analysis. Forty-seven of the children showed minor, 28 moderate, and 2 severe symptoms. Twenty-nine cases were asymptomatic. No fatalities were recorded. Symptoms predominantly involved the central nervous and cardiovascular systems. Minor reduction in vigilance (Glasgow Coma Scale score >9) (62%) was the most frequently reported symptom, followed by miosis (12%) and mild tachycardia (10%). Extrapyramidal motor symptoms were observed in one case (1%) after ingestion of risperidone. In most cases, surveillance and supportive care were sufficient to achieve a good outcome, and all children made full recovery. Conclusions: Paediatric antipsychotic exposure can result in significant poisoning; however, in most cases only minor or moderate symptoms occurred and were followed by complete recovery. Symptomatic patients should be monitored for central nervous system depression and an electrocardiogram should be obtained

P1245 Polymorphic Variants of HSD3B1 Gene Confer Different Outcome in Specific Subgroups of Patients Infected With SARS-CoV-2

Introduction: Severe respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the androgen receptor (AR), through ACE2 receptor and TMPRSS2, to enter nasal and upper airways epithelial cells. Genetic analyses revealed that HSD3B1 P1245C polymorphic variant increases dihydrotestosterone production and upregulation of TMPRSS2 with respect to P1245A variant, thus possibly influencing SARS-CoV-2 infection. Our aim was to characterize the HSD3B1 polymorphism status and its potential association with clinical outcomes in hospitalized patients with COVID-19 in Southern Switzerland. Materials and Methods: The cohort included 400 patients hospitalized for COVID-19 during the first wave between February and May 2020 in two different hospitals of Canton Ticino. Genomic DNA was extracted from formalin-fixed paraffin-embedded tissue blocks, and HSD3B1 gene polymorphism was evaluated by Sanger sequencing. Statistical associations were verified using different test. Results: HSD3B1 polymorphic variants were not associated with a single classical factor related to worse clinical prognosis in hospitalized patients with SARS-CoV-2. However, in specific subgroups, HSD3B1 variants played a clinical role: intensive care unit admission was more probable in patients with P1245C diabetes compared with P1245A individuals without this comorbidity and death was more associated with hypertensive P1245A>C cases than patients with P1245A diabetes without hypertension. Discussion: This is the first study showing that HSD3B1 gene status may influence the severity of SARS-CoV-2 infection. If confirmed, our results could lead to the introduction of HSD3B1 gene status analysis in patients infected with SARS-CoV-2 to predict clinical outcome. Keywords: HSD3B1 gene polymorphism; Likelihood-ratio tests; SARS-CoV-2; androgen receptor; direct sequencing

Imprinted antibody responses against SARS-CoV-2 Omicron sublineages

SARS-CoV-2 Omicron sublineages carry distinct spike mutations and represent an antigenic shift resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters result in potent plasma neutralizing activity against Omicron BA.1 and BA.2 and that breakthrough infections, but not vaccination-only, induce neutralizing activity in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1 and BA.2 receptor-binding domains whereas Omicron primary infections elicit B cells of narrow specificity. While most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant antibody, that is unaffected by any Omicron lineage spike mutations and is a strong candidate for clinical development

Neutralization, effector function and immune imprinting of Omicron variants

Currently circulating SARS-CoV-2 variants have acquired convergent mutations at hot spots in the receptor-binding domain$^{1}$ (RBD) of the spike protein. The effects of these mutations on viral infection and transmission and the efficacy of vaccines and therapies remains poorly understood. Here we demonstrate that recently emerged BQ.1.1 and XBB.1.5 variants bind host ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1, XBB.1 and BN.1 RBDs bound to the fragment antigen-binding region of the S309 antibody (the parent antibody for sotrovimab) and human ACE2 explain the preservation of antibody binding through conformational selection, altered ACE2 recognition and immune evasion. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1 and hamsters challenged with XBB.1.5. Vaccine-elicited human plasma antibodies cross-react with and trigger effector functions against current Omicron variants, despite a reduced neutralizing activity, suggesting a mechanism of protection against disease, exemplified by S309. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring the role of persistent immune imprinting

Broad betacoronavirus neutralization by a stem helix–specific human antibody

The spillovers of betacoronaviruses in humans and the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants highlight the need for broad coronavirus countermeasures. We describe five monoclonal antibodies (mAbs) cross-reacting with the stem helix of multiple betacoronavirus spike glycoproteins isolated from COVID-19 convalescent individuals. Using structural and functional studies, we show that the mAb with the greatest breadth (S2P6) neutralizes pseudotyped viruses from three different subgenera through the inhibition of membrane fusion, and we delineate the molecular basis for its cross-reactivity. S2P6 reduces viral burden in hamsters challenged with SARS-CoV-2 through viral neutralization and Fc-mediated effector functions. Stem helix antibodies are rare, oftentimes of narrow specificity, and can acquire neutralization breadth through somatic mutations. These data provide a framework for structure-guided design of pan-betacoronavirus vaccines eliciting broad protection