Exploring the Association Between Help-Seeking Intentions and Suicidal Ideation in Australian Adult Men.

Background: Men account for three-quarters of suicide deaths in Australia. Self-reliant masculine norms may act as barriers to men's help-seeking and contribute to suicidal ideation. Men who seek help may be less likely to experience suicidal ideation. Aim: We evaluated the association between help-seeking intentions and suicidal ideation in Australian adult men using data from Wave 2 of the Australian Longitudinal Study on Male Health (Ten to Men). Method: Using scores on the General Help-Seeking Questionnaire, we explored the association between informal help-seeking intentions (e.g., friend, family), formal help-seeking intentions (e.g., psychologist), overall help-seeking intentions (all sources), and new-onset suicidal ideation. We conducted logistic regression analyses using a sample of 7,828 men aged 18-60 years. Results: Increased overall help-seeking intentions and informal help-seeking intentions were significantly associated with lower odds of new-onset suicidal ideation, whereas formal help-seeking intentions were not significantly associated. Limitations: The cross-sectional design limits inferences about causality. Conclusion: Men who have greater informal help-seeking intentions may be less likely to experience a new onset of suicidal ideation; however, more longitudinal research is needed.

Advanced midwifery practice: A scoping review.

PROBLEM: There is no international standard for advanced midwifery scope of practice. BACKGROUND: Globally, there is variance in how scope of midwifery practice is determined and regulated, with no consensus on extended or advanced scope. This can lead to under-utilised staff potential, un-met consumer need, and loss of professional skill. AIMS: The aim of this scoping review was to synthesise and map what is reported in the international literature on the advanced scope of midwifery practice. METHODS: A systematic scoping review methodology was adopted utilising Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). A full search was conducted of databases including MEDLINE, CINAHL, Scopus, Google. Publications from 2019 to August 2022 that met criteria were included. Reported skills were mapped to the International Confederation of Midwives (ICM) competencies of pre-conception, antenatal, labour and birth, postnatal plus globally identified areas for midwifery investment. FINDINGS: 28 articles met inclusion criteria. Reported skills included abortion care (n = 6), prescribing (n = 7), ultrasound (n = 2), advanced practice skills (n = 7), midwifery-led skills, primary health, post-graduate education, HIV/AIDS testing, advocacy, and acupressure (all n = 1). DISCUSSION: This review presents a synopsis of publications describing what has been defined as advanced midwifery scope of practice in international contexts. CONCLUSION: Establishing evidence of midwives working to the peak of professional scope is important to continue to develop professional capacity and support contemporary practice, regulation, governance, and policy while improving consumer access to equitable care. Findings aid service development, provision, and professional planning.

Population pharmacokinetic analysis of acetaminophen overdose with immediate release, extended release and modified release formulations.

OBJECTIVES: The introduction of delayed release formulations of acetaminophen (APAP) has created concern about the role of formulation in overdose. We examined the APAP overdose pharmacokinetic (PK) profiles to assess the role of dose, coingestants and formulation: immediate release (IR), extended release (ER), and modified release (MR) on APAP pharmacokinetic measures. METHODS: We collected by-subject APAP PK data: subject description, timed blood APAP concentrations, dose, and coingestants. We sought both overdose and randomized controlled trials (RCTs) for supratherapeutic doses involving ER or MR formulations. Data analysis and simulation used the non-linear mixed-effects modeling program NONMEM-version 7.4. RESULTS: The final dataset comprised 3,033 [APAP] from 356 subjects and 15 sources including 3 RCTs (179 subjects receiving IR, 122 ER, 65 MR). The final population PK (PopPK) model was a linear 2-compartment model with first-order (oral) absorption. Covariate relationships included: APAP absorption rate and bioavailability decreased with increased oral dose (p < 0.00005) for all 3 formulations (MR > ER > IR). Post hoc analyses showed opioid coingestant increased exposure (area under the curve, AUC) by factor of 1.6. Simulations of 100 g vs 10 g doses for IR, ER and MR showed overdose of the ER formulation exhibits slower absorption and lower Cmax, overall exposure (AUC) is less than 80% of an equivalent dose of IR acetaminophen. The overall exposure for the MR formulation is less than 70% of an equivalent dose of IR. CONCLUSIONS: Acetaminophen ER and MR formulations have slower absorption and decreased bioavailability leading to a lower Cmax and later Tmax than the IR formulation. These results have potential clinical implications because delayed absorption could confound use of the Rumack-Matthew nomogram by underestimating the severity of ingestion early in the course of treatment.

Genetic variants associated with ALT elevation from therapeutic acetaminophen.

BACKGROUND: Several studies have suggested genetic variants associated with acetaminophen induced liver injury (DILI) following overdose. Genetic variation associated with acetaminophen-induced alanine aminotransferase elevation during therapeutic dosing has not been examined. METHODS: We performed genetic analyses on patients that ingested therapeutic doses of 4 grams of acetaminophen for up to 16 days. We examined 20 genes previously implicated in the metabolism of acetaminophen or the development of immune-mediated DILI using the Illumina Multi-Ethnic Global Array 2. Autosomes were aligned and imputed using TOPMed. A candidate gene region analysis was performed by testing each gene individually using linkage disequilibrium (LD) pruned variants with the adaptive sum of powered scores (aSPU) test from the aSPU R package. The highest measured ALT during therapy, the maximum ALT, was used as the outcome. RESULTS: 192 subjects taking therapeutic APAP were included in the genetic analysis. 136 (70.8%) were female, 133 (69.2%) were Caucasian race, and the median age was 34 years (IQR: 26, 46). Age > 50 years was the only clinical factor associated with maximum ALT increase. Variants in SULT1E1, the gene responsible for Sulfotransferase Family 1E Member 1 enzyme production, were associated with maximum ALT. No single variant drove this association, but rather the association was due to the additive effects of numerous variants within the gene. No other genes were associated with maximum ALT increase in this cohort. CONCLUSION: Acetaminophen induced ALT elevation at therapeutic doses was not associated with variation in most genes associated with acetaminophen metabolism or immune-induced DILI in this cohort. The role of SULT1E1 polymorphism in acetaminophen-induced elevated ALT needs further examination.

Maternity research priorities in country Western Australia: a Delphi study.

Objective Health research priorities are commonly identified and resourced by strategic leaders. The importance of recognising the expertise of clinician-researchers is being prioritised by a national funding shift towards applied research. There is a dearth of evidence regarding research priorities for maternity care in rural and remote health in Australia. This study aimed to develop an evidence-based consensus of maternity research priorities in regional, rural, and remote areas of Australia's largest rural health service (by land area) in Western Australia. Methods A three-phased Delphi method was selected to achieve an interdisciplinary, evidence-based consensus on maternity research priorities within Western Australian Country Health Service. Results Across three study phases, 432 participants responded. Representation was from seven regions and all stakeholder roles within the regions. Phase 1 included 173 responses yielding 53 concepts categorised under five domains. Phase 2 involved 161 participants who prioritised concepts under domains of (i) workforce and education; (ii) health equity; (iii) Aboriginal health; (iv) logistics and health systems; and (v) clinical. Phase 3 included 96 participants revealing 15 maternity research priorities with the top four ranked concepts: 'recruitment and retention of staff'; 'care for women and families with vulnerabilities', 'models of care offering continuity' and 'systems efficiencies'. Conclusions The novel evidence provided in this study, in conjunction with a strong consensus on research priorities and an interdisciplinary approach, strengthens the findings of this study and amplifies the mandate of action without delay.

Metabolomic Evaluation of N-Acetyl-p-Benzoquinone Imine Protein Adduct Formation with Therapeutic Acetaminophen Administration: Sex-based Physiologic Differences.

BACKGROUND: Acetaminophen (APAP)-associated transaminase elevation, induced by N-acetyl-p-benzoquinone imine (NAPQI) protein adduction, remains an area of research interest. Distinct from known genetic, physiologic, and dosage associations dictating severity of hepatic injury, no known factors predict an absence of protein adduct formation at therapeutic APAP dosing. HYPOTHESIS: Sex-based physiology is predictive of APAP-induced protein adduct formation and differential metabolite expression at therapeutic doses. METHODS: This retrospective study interrogated serum samples collected for a prior study investigating fluctuations of alanine aminotransferase (ALT) over time with 4G daily APAP dosing for ≥ 16 days in subjects from Denver, Colorado. Subjects were grouped by adduct formation (n = 184) vs no adducts (n = 20). Samples were run on ultra-high-performance liquid chromatography mass spectrometry from study days 0, 7, 16, and 31. Significant metabolite expressions were identified using t-tests with false discovery rate correction (FDR), partial least squares discriminant, and ANOVA simultaneous comparison analyses. Demographic and clinical data were explored using t-tests with FDR (age, weight, BMI, ALT) and Chi-square (sex, ethnicity, race) analyses. RESULTS: In pre-treatment samples, relative quantitation caprylic acid was expressed ninefold higher and 6-carboxyhexanoate was expressed threefold lower in subjects who did not develop adducts. Lactate had greater expression in the no adducts group (p = 0.001). Using absolute quantitation, glutathione was expressed 2.6-fold greater among no adduct subjects. Odds of males developing NAPQI protein adducts at therapeutic APAP dosing were 5.91 times lower than females (95% CI = 2.3-14.9; p = 0.0001). CONCLUSION: Multiple metabolites were differentially expressed based on adduct group and sex. Metabolites were identified unique to adduct development independent of sex. At therapeutic APAP dosing, males were less likely to develop APAP protein adducts. Further research into lipid biosynthesis and metabolism may provide further insight into physiology associated with adduct production.

Adverse Events Related to Accidental Unintentional Ingestions From Cough and Cold Medications in Children.

OBJECTIVES: Previous research has demonstrated that accidental unsupervised ingestions (AUIs) were responsible for the majority of cough and cold medication (CCM) ingestions leading to significant adverse events (AEs) in children. The objective of this analysis was to characterize the role of AUIs in the morbidity associated with CCM exposure in children. METHODS: This surveillance study collected data from 5 United States data sources from 2009 to 2016, in children younger than 6 years with an AE from an AUI involving at least 1 CCM over-the-counter pharmaceutical ingredient. An expert panel reviewed each case to determine causality. RESULTS: From 4756 total cases reviewed, 3134 (65.9%) had an AE from an AUI determined to be at least potentially related to a CCM ingredient. The majority (61.3%) of cases occurred in children aged 2 to younger than 4 years. Most exposures occurred in the child's own residence (94.9%), and 43.8% were admitted to a health care facility (22.0% to a critical care unit). Dextromethorphan and diphenhydramine, when packaged alone or in combination products, contributed to 96.0% of AUIs. The most common specific products involved were single-ingredient pediatric liquid diphenhydramine (30.1%) and single-ingredient pediatric liquid dextromethorphan (21.4%). There were 3 deaths from solid diphenhydramine formulations. CONCLUSIONS: There continues to be opportunities for the implementation of interventions to prevent AUIs of CCM in children. Additional emphasis on engineering controls, such as flow restrictors for liquid formulations targeting diphenhydramine and dextromethorphan products, represent additional opportunities to further reduce AEs from AUIs of CCM.

Metabolomic markers predictive of hepatic adaptation to therapeutic dosing of acetaminophen.

BACKGROUND: Drug induced liver injury (DILI) remains a prominent global issue and acetaminophen (APAP) overdose represents a common cause of hepatic injury and DILI. Transient alanine aminotransferase (ALT) elevations have been documented while adhering to recommended daily dosing. However, no metabolites have been identified in pre-treatment samples predicting which patients will develop these transient increases. METHODS: This was a secondary analysis of samples collected from a parent study describing the course of ALT levels in subjects receiving therapeutic APAP dosing. Two hundred and four subjects recruited from Denver, Colorado received 4 g APAP/daily for at least 16 days. Subjects were grouped by ALT at any monitored time point above 60 units/L (n = 25) vs. no increase (n = 179). Serum samples from days 0, 7, 16, and 31 were run on ultra-high performance liquid chromatography mass spectrometry. We report the metabolomic results of samples analyzed prior to APAP administration and over time. Significant changes in metabolite and demographic variable expressions were explored using t-tests with false discovery rate correction, chi square, and partial least squares discriminant analyses. RESULTS: Within pre-treatment day 0 samples, allantoate and ornithine were significantly elevated in subjects of the ALT elevation group (p = .032). Baseline ALT (p = .011) and alkaline phosphatase (p = .006) were also significant. These metabolites were significant independent of race, ethnicity, gender, or BMI. CONCLUSIONS: Allantoate and ornithine are directly involved in pathways related to nitrogen release and urea production. Further investigation into alterations in the glutathione metabolism and urea cycle pathways may lead to a greater understanding of the mechanisms associated with hepatic adaptation for a variety of pharmaceuticals.

Reporting errors in plain radiographs for lower limb trauma-a systematic review and meta-analysis.

INTRODUCTION: Plain radiographs are a globally ubiquitous means of investigation for injuries to the musculoskeletal system. Despite this, initial interpretation remains a challenge and inaccuracies give rise to adverse sequelae for patients and healthcare providers alike. This study sought to address the limited, existing meta-analytic research on the initial reporting of radiographs for skeletal trauma, with specific regard to diagnostic accuracy of the most commonly injured region of the appendicular skeleton, the lower limb. METHOD: A prospectively registered, systematic review and meta-analysis was performed using published research from the major clinical-science databases. Studies identified as appropriate for inclusion underwent methodological quality and risk of bias analysis. Meta-analysis was then performed to establish summary rates for specificity and sensitivity of diagnostic accuracy, including covariates by anatomical site, using HSROC and bivariate models. RESULTS: A total of 3887 articles were screened, with 10 identified as suitable for analysis based on the eligibility criteria. Sensitivity and specificity across the studies were 93.5% and 89.7% respectively. Compared with other anatomical subdivisions, interpretation of ankle radiographs yielded the highest sensitivity and specificity, with values of 98.1% and 94.6% respectively, and a diagnostic odds ratio of 929.97. CONCLUSION: Interpretation of lower limb skeletal radiographs operates at a reasonably high degree of sensitivity and specificity. However, one in twenty true positives is missed on initial radiographic interpretation and safety netting systems need to be established to address this. Virtual fracture clinic reviews and teleradiology services in conjunction with novel technology will likely be crucial in these circumstances.

Pediatric Fatalities Associated With Over-the-Counter Cough and Cold Medications.

BACKGROUND AND OBJECTIVES: In 2008, over-the-counter cough and cold medications (CCMs) underwent labeling changes in response to safety concerns, including fatalities, reported in children exposed to CCMs. The objective of this study is to describe fatalities associated with exposures to CCMs in children <12 years old that were detected by a safety surveillance system from 2008 to 2016. METHODS: Fatalities in children <12 years old that occurred between 2008 and 2016 associated with oral exposure to one or more CCMs were identified by the Pediatric Cough and Cold Safety Surveillance System. An expert panel reviewed all cases to determine the causal relationship between the exposure and death, if the intent of exposure was therapeutic, and if the dose was supratherapeutic. Other contributing factors related to the child's death were also identified as part of a root cause analysis. RESULTS: Of the 180 eligible fatalities captured during the study period, 40 were judged by the expert panel to be either related or potentially related to the CCM. Of these, the majority (n = 24; 60.0%) occurred in children <2 years old and involved nontherapeutic intent (n = 22; 55.0%). The most frequently involved index ingredient was diphenhydramine (n = 28; 70.0%). In 6 cases (n = 6; 15.0%), the CCM was administered to murder the child. In another 7 cases (n = 7; 17.5%), death followed the intentional use of the CCM to sedate the child. CONCLUSIONS: Pediatric fatalities associated with CCMs occurred primarily in young children after deliberate medication administration with nontherapeutic intent by a caregiver.

The Genomics of Elevated ALT and Adducts in Therapeutic Acetaminophen Treatment: a Pilot Study.

INTRODUCTION: Therapeutic acetaminophen (APAP) ingestion causes asymptomatic drug-induced liver injury in some patients. In most cases, elevations in alanine aminotransferase (ALT) are transient and return to the normal range, even with continued APAP ingestion, though ALT elevation persists in some patients unpredictably. The etiology of this liver injury or adaption is unclear. Our objective was to identify new pharmacogenomic variants associated with elevated ALT or elevated protein adduct concentrations in patients receiving therapeutic acetaminophen. METHODS: We performed genome-wide sequencing analysis on eight patients using leftover blood samples from an observational study that administered four grams of acetaminophen for up to 16 days to all patients. Two patients with ALT elevations > two times the upper limit of normal, two patients with no adduct formation, and four control patients were sequenced. The genomes were aligned with the GRCh38 reference sequence, and variants with predicted low, moderate, or high impact on the subsequent proteins were first manually curated for biologic plausibility, then organized and examined in the REACTOME pathway analysis program. RESULTS: We found 394 variants in 107 genes associated with elevated ALT. Variants associated with ALT elevation predominantly involved genes in the immune system (MHC class II complex genes), endoplasmic reticulum stress response (SEC23B and XBP1), oxidative phosphorylation (NDUFB9), and WNT/beta-catenin signaling (FZD5). Variants associated with elevated adducts were primarily in signal transduction (MUC20) and DNA repair mechanisms (P53). CONCLUSIONS: While underpowered, genetic variants in immune system genes may be associated with drug-induced liver injury at therapeutic doses of acetaminophen.

Impact of product safety changes on accidental exposures to liquid laundry packets in children.

OBJECTIVES: To evaluate the impact of the ASTM International (formerly American Society of Testing Materials) safety standard and associated product safety changes on accidental exposures to liquid laundry packets (LLPs) in children. METHODS: The National Poison Data System was queried for reports of accidental exposures to LLPs in children <6 years old received from 01 July 2012 to 31 December 2018. In 2014, ASTM International began developing a standard specifying voluntary product changes to reduce the risk of LLP exposures in young children. Product changes were made between 2013 and 2016. Exposures were grouped into baseline, transition, and post periods based on the timing of the standard's implementation. Exposure counts and sales adjusted rates were compared between the baseline and post period for all exposures and exposures involving healthcare facility (HCF) evaluation, HCF admission, and major medical outcomes. RESULTS: A total of 73,942 accidental exposures in children <6 years old were reported (baseline: 10,229, 13.8%; transition: 43,507, 58.8%; post: 20,206, 27.3%). The percentage of exposures involving HCF evaluation (41.5% to 33.8%), HCF admission (4.5% to 1.9%), and major medical outcomes (0.6% to 0.1%) decreased from the baseline to post period. Sales adjusted rates of all exposures decreased 57.4% (4.920-2.094 exposures/1 million packets sold). Decreases also occurred in HCF evaluations (65.0% decrease; 2.026-0.708 exposures/1 million packets sold), HCF admissions (81.4% decrease; 0.218-0.041 exposures/1 million packets sold), and major medical outcomes (90.9% decrease; 0.030-0.003 exposures/1 million packets sold). CONCLUSIONS: The morbidity of accidental exposures to LLPs in children decreased substantially following implementation of the ASTM International safety standard. Ongoing monitoring should be performed to determine if additional safety measures are required.

Trends in adverse events and related health-care facility utilization from cough and cold medication exposures in children.

INTRODUCTION: Initial research following regulatory changes addressing the pediatric safety of cough and cold medications (CCMs) demonstrated decreases in adverse events (AEs). Using a national multi-source surveillance system, we studied subsequent CCM-related AE case rate trends and associated health-care facility (HCF) evaluation in children. METHODS: Data were collected from 2009 to 2016. Case eligibility included: age <12 years; exposure to an over-the-counter product containing ≥1 CCM pharmaceutical ingredient; ≥1 significant AE that occurred in the United States. RESULTS: About 4756 (72.6%) cases were determined at least potentially related to an index ingredient. Accidental unsupervised ingestions (AUIs; 3134; 65.9%) were the most common case type. Nearly half of AE cases involved children 2 to <4 years old (2,159; 45.4%). The AE case rate did not change significantly over time (p = 0.22). The proportion of AE cases resulting in HCF admission increased from 32.4% (207) in 2009 to 43.4% (238) in 2016 (p < 0.01). Exposures to diphenhydramine (1,305; 67.3%) and/or dextromethorphan (591; 30.5%) were involved in the majority of HCF admissions. CONCLUSIONS: The proportion of AE cases resulting in HCF admission increased from 2009 to 2016. Efforts to prevent AUIs such as packaging innovation and engineering controls, particularly for diphenhydramine and dextromethorphan-containing products, should be pursued.

Trimethoprim-Sulfamethoxazole Associated Drug-Induced Liver Injury in Pediatrics: A Systematic Review.

BACKGROUND: Drug-induced liver injury (DILI) is a rare but known adverse event associated with trimethoprim-sulfamethoxazole (TMP-SMX) in adults. No studies to date have looked at the risk of this association in children. We systematically reviewed the evidence for a potential association between TMP-SMX and DILI in the pediatric population. METHODS: PubMed, Medline, Embase, Cochrane Database of Systematic Reviews, Scopus and Web of Science was searched using a combination of terms to identify reports of TMP-SMX exposure, liver injury and pediatrics (≤18 years old). We included any studies with hepatic adverse events occurring after exposure to TMP-SMX. Bibliographies were reviewed for additional relevant references. The Narajno scale was used to assess causality in case studies. RESULTS: A total of 22 studies were identified: 3 randomized trials, 1 prospective observational study, 8 retrospective observational studies and 10 case reports. Among the randomized trials and prospective studies, only mild, transient hepatic function abnormalities were reported. Retrospective observational studies reported 1 fatal DILI and statistically significant increased odds of DILI with TMP-SMX use compared with nonuse. Among the 10 case reports, severe liver outcomes and mild hepatic function abnormalities were both reported. Naranjo scores suggested reported hepatic adverse events were probably because of exposure in 5, possible in 4, and doubtful in 1 case report. CONCLUSIONS: Evidence regarding DILI associated with TMP-SMX exposure in pediatrics is limited. Observational population studies show mild hepatic abnormalities. Case reports suggest more severe manifestations of DILI. Additional studies may reveal the association between TMP-SMX and DILI in pediatrics.

Medication Errors From Over-the-Counter Cough and Cold Medications in Children.

OBJECTIVE: Out of hospital medication-related adverse events (AEs) from cough and cold medications (CCMs) can have significant public health impact. The objective of this study was to characterize pediatric medication error AEs involving over-the-counter (OTC) CCMs to identify preventable factors. METHODS: Multisource national data surveillance system study using an expert panel evaluating CCM AEs related to medication errors. INCLUSION CRITERIA: age <12 years, and at least 1 significant AE from at least 1 index ingredient from a CCM OTC product. RESULTS: From 2009 through 2016, 4756 cases were determined to have a significant AE related to an OTC CCM ingredient and 513 (10.8%) cases were due to a medication error. Nearly half of medication errors involved children 2 to <6 years old (n = 235; 45.8%). Many involved administration by a parent (n = 231; 45.0%) or alternative caregiver (n = 148; 28.8%). In nearly all cases (93.2%), the medication error involved the wrong dose of the medication. Health care facility evaluation occurred in 381 (74.3%) cases. Diphenhydramine and dextromethorphan were responsible for most medication errors and medication errors involving health care facility evaluation. There were no deaths from medication errors. CONCLUSION: In this multiyear surveillance study, medication errors most commonly occurred in children <6 years old who received the wrong volume of a liquid product. Diphenhydramine and dextromethorphan dosing errors were the most common cause of medication errors resulting from CCM use. Continued standardization of measuring devices, concentrations, and units of measure along with consumer education are needed to further decrease medication errors from CCMs.

Adverse events associated with diphenhydramine in children, 2008-2015.

Introduction: Diphenhydramine (DPH) exposures in children may be the result of accidental unsupervised ingestions, caregiver error, and intentional misuse of DPH-containing cough and cold medications (CCM). We sought to understand the nature of pediatric ingestions of DPH, particularly the toxicity and outcome of a single product, single ingredient DPH (DPH-only) exposures, in order to derive ingredient-specific information about the clinical effects and course of such cases.Methods: As part of a U.S. multi-year safety surveillance program to assess the safety of over-the-counter (OTC) medications used in cough and cold preparations in children <12 years of age, an expert panel reviewed cases involving symptomatic adverse events potentially related to oral exposures to these medications. After individual review, the cases were categorized by causal relationship of the reported ingredients to the adverse event, exposure intent (therapeutic, non-therapeutic, unknown intent), and dose (therapeutic, supratherapeutic, or unknown). Following panel review, any disagreement on classification was discussed until a consensus was reached. The data were then analyzed with respect to descriptive findings.Results: The panel reviewed 6618 eligible cases and determined 2802 were at least potentially related to oral exposure to DPH. Of these, 2028 were DPH-only cases (39.1% of all cases judged at least potentially related to a cough and cold medication). The majority (79.5%) of DPH-only cases occurred in children 2 to <4 years of age and involved accidental unsupervised ingestions (74.7%). Liquid pediatric formulations were the most common (51.7%) products reported followed by solid pediatric formulations (24.0%). The most common adverse events were tachycardia (53.4%), hallucinations (46.5%), somnolence (34.7%), agitation (33.9%), and mydriasis (26.3%). Seizures occurred in only 5.5% of cases. Five (0.2%) deaths were reported; in the death cases, the DPH dose was judged supratherapeutic in one and unknown in the other four. Child abuse was reported in four of the five death cases and three of the five deaths were homicides.Conclusions: Exposures to DPH-only products were the most common type of exposure detected in our study of adverse events associated with CCM in children. The majority of the DPH-only cases were the result of accidental unsupervised ingestions. Most adverse events were relatively mild self-limited anticholinergic effects and few deaths occurred. Deaths involving DPH were often associated with child abuse or homicide. Interventions targeting the prevention of accidental unsupervised are likely to be impactful in preventing morbidity associated with DPH-only exposure.

Flow Restrictors and Reduction of Accidental Ingestions of Over-the-Counter Medications.

INTRODUCTION: Flow restrictors are child-resistant packaging innovations designed to limit the amount of liquid dispensed from a medication bottle. In 2011, flow restrictors were added to pediatric liquid single-ingredient acetaminophen formulations. The hypothesis of this study is that implementation would be associated with reduced volume and severity of pediatric acetaminophen exposures reported to the U.S. National Poison Data System. METHODS: This study describes accidental unsupervised ingestions of acetaminophen in children aged <6 years. Exposures were grouped into pre-implementation (pre-period; January 4, 2010-July 17, 2011); transition (July 18, 2011-July 15, 2012); and post-implementation (post-period; July 16, 2012-December 25, 2016) periods. Cumulative and annual rates of change per million units (i.e., bottles) sold were calculated for the pre- and post-periods for acetaminophen and pediatric liquid ibuprofen (comparator without flow restrictors). Pre- to post-period rate ratios were used to compare products and to estimate the potential effect on other over-the-counter medications. Analysis was conducted in 2017 and 2018. RESULTS: The pre- and post-period cumulative acetaminophen exposure rate was 507.2 (95% CI=481.1, 534.6) and 325.6 (95% CI=305.8, 346.7) per 1 million units sold, respectively. Declines in the pre- versus post-period rate ratios were seen for exposures with any effect (0.642, 95% CI=0.591, 0.696) and with clinically significant outcomes (0.728, 95% CI=0.581, 0.913). In the post-period, acetaminophen exposures decreased faster than ibuprofen with a rate of change ratio of 0.936 (95% CI=0.912, 0.960) for all exposures and 0.939 (95% CI=0.909, 0.970) for exposures with any effect. CONCLUSIONS: The addition of flow restrictors to pediatric liquid acetaminophen was associated with a reduction in the number and severity of exposures. Application of flow restrictors to other liquid medications should be considered.

Poison center exposures due to therapeutic misuse of nonprescription acetaminophen-containing combination products in the United States 2007-2016.

BACKGROUND: Overdoses due to therapeutic misuse result when the maximum dose of a drug is exceeded while using it for its intended purpose, due to either intentionally exceeding the label dose, misunderstanding the label or use of more than one product with the same ingredient. Nonprescription acetaminophen-containing combination products have been hypothesized to be a risk for therapeutic misuse. This study assessed the contribution of nonprescription acetaminophen-containing products to Poison Center exposures and the time trend in these exposures since public attention was brought to their potential risks. METHODS: The National Poison Data System (NPDS) was used to identify exposures involving acetaminophen-containing products in individuals 12 years or older for the period 2007-2016. Exposures due to therapeutic misuse of nonprescription acetaminophen-containing combination products were identified and demographic and clinical features of these exposures tabulated. Product sale and US population data were used to normalize the exposures. RESULTS: Therapeutic misuse exposures involving nonprescription acetaminophen-containing combination products decreased from 8753 in 2007 to 6278 in 2016. The majority of exposures occurred in individuals 12-29 years of age. The rate of therapeutic misuse exposures was highest in the 12-19 years of age cohort with an estimated 638 exposures per million population per 10 years. More than one acetaminophen-containing product was involved in 24.8% of exposures. Individuals were hospitalized in 5.4% of exposures and 51 deaths occurred in the 10-year observation period in reported exposures. CONCLUSIONS: NPDS exposures due to therapeutic misuse of nonprescription acetaminophen-containing combination products are infrequent and the number of exposures decreased from 2007 to 2016. Nonetheless, these exposures impact poison centers, healthcare facilities and patients. Additional initiatives to educate consumers on the safe use of these products and innovative labeling efforts to prevent concurrent use of multiple acetaminophen-containing products should be continued and are encouraged.

Evaluation of the quality and value of data sources for postmarket surveillance of the safety of cough and cold medications in children.

BACKGROUND: The purpose of this report is to evaluate the quality of data sources used to study cough and cold medication (CCM) safety in children via the Pediatric Cough and Cold Safety Surveillance System. METHODS: The System utilized the National Poison Data System (NPDS), FDA Adverse Event Reporting System (FAERS), English-language medical literature, manufacturer postmarket safety databases, and news/media reports to identify cases from January 2008 through September 2016. Each data source was evaluated by the proportion of detected cases determined to be eligible (met case criteria) and the proportion determined to be evaluable (able to determine causal relationship between adverse event and exposure). RESULTS: A total of 7184 unique cases were identified from 27,597 detected reports. Of these, 6447 (89.7%) were evaluable. The data source with the highest volume of detected cases was news/media; however, only 0.3% of those cases were eligible for panel review and only 0.2% (24 out of 13,450 cases) were evaluable. The data source with the highest proportion of eligible and evaluable cases was NPDS with 7691 detected cases, 6113 (79.5%) eligible cases, and 5587 (72.6%) evaluable cases. CONCLUSIONS: The data sources utilized to evaluate the safety profile of pediatric CCMs yielded variable detection and evaluation rates, but overall provided a comprehensive look at exposures that otherwise cannot be studied in clinical trials. While this study suggests that each source made a valuable contribution and that evaluable cases are generalizable, improvements are needed in case completeness and accuracy to enhance the quality of postmarket safety evaluations.

Adverse events associated with opioid-containing cough and cold medications in children.

BACKGROUND: Until recently most of the scrutiny of opioid-containing cough and cold medications (CCMs) by the US Food and Drug Administration (FDA) was focused on codeine, only recently shifting equal focus to those containing hydrocodone. We characterized adverse events (AEs) in children <12 years old associated with CCMs that include both an opioid and over-the-counter (OTC) ingredient. METHODS: US cases from multiple sources collected as part of a safety surveillance program were included if AEs followed exposure to combination CCMs containing codeine or hydrocodone between January 2008 and December 2015. An expert panel reviewed cases to identify causal relationship between exposure and AEs and identify contributing factors. Each AE term was coded using the Medical Dictionary for Regulatory Activities with preferred terms reported. RESULTS: One hundred and fourteen of the 7035 (2%) cases reviewed involved an opioid-containing product. Ninety-eight cases involved an AE at least potentially related to the opioid ingredient (38 (39%) codeine; 60 (61%) hydrocodone). All three fatality cases involved hydrocodone with an antihistamine. Among non-fatalities, somnolence, lethargy, and/or respiratory depression were more commonly reported among hydrocodone cases than codeine cases (86% vs. 61%; p = .005). DISCUSSION: These safety surveillance data support the FDA's expanded label changes limiting opioid CCMs for children.