Practices and Outcomes Associated With Sublingual Buprenorphine Use in a Critically Ill Population.

IMPORTANCE: Buprenorphine for opioid use disorder (OUD) is commonly used in the outpatient setting with increasing use in hospitalized patients. However, there is limited literature describing its use in critically ill populations. OBJECTIVES: The primary objective was to report the practices of buprenorphine prescribing among ICU teams. We also assessed the effect of a novel initiation strategy on opioid requirements in the ICU and the incidence of precipitated withdrawal. DESIGN SETTING PARTICIPANTS: Single-center, retrospective, descriptive study of patients receiving buprenorphine in the ICU. MAIN OUTCOMES AND MEASURES: The main outcome was to describe the use of buprenorphine in ICU patients through indication, initiation strategy, dosing information, and time from ICU admission to the first dose. We also detailed the incidence of precipitated withdrawal overall and the difference in opioid requirements before and after a low-dose induction strategy (buprenorphine initiated while receiving full agonist opioids [5-d titration from 150 µg to 4 mg four times daily]). RESULTS: A total of 153 patients were included. Most patients (86.3%) received buprenorphine for treatment of OUD. Of the 75 patients taking buprenorphine before admission, 46 (61%) had it restarted within 24 hours of ICU admission. Among 95 patients requiring buprenorphine induction, 57 (60%) underwent standard induction and 38 (40%) underwent low-dose induction, with only one instance of precipitated withdrawal. Median morphine milligram equivalents (MMEs) of concomitant full agonist opioids in patients completing low-dose induction decreased from 1057.5 mg to 262.5 mg in the 24 hours before initiation compared with the 24 hours after target buprenorphine dose was reached (p < 0.005). CONCLUSIONS AND RELEVANCE: Use of sublingual buprenorphine was most often in patients with OUD. Timely continuation of home buprenorphine in the ICU was suboptimal. Both standard and low-dose induction strategies appear to be safe with a low risk of precipitating withdrawal. When implemented appropriately, low-dose buprenorphine induction may lead to significant reduction in full agonist opioids in critically ill patients.

Determining the Risk of Elevated Digoxin Concentrations Following Loading Dose in Patients With Acute and Chronic Kidney Disease.

BACKGROUND: The optimal loading dose of digoxin in patients with reduced kidney function is unknown. Tertiary references recommend reduced loading doses; however, these recommendations are based on immunoassays that are falsely elevated by the presence of digoxin-like immunoreactive substances, a problem that is minimized in modern assays. OBJECTIVE: To determine whether chronic kidney disease (CKD) or acute kidney injury (AKI) is associated with supratherapeutic digoxin concentrations after a digoxin loading dose. METHODS: A retrospective analysis on patients who received an intravenous loading dose of digoxin with a digoxin concentration collected 6 to 24 hours after the end of the dose. Patients were stratified into 3 groups: AKI, CKD, and non-AKI/CKD (NKI) based on glomerular filtration rate and serum creatinine. The primary outcome was frequency of supratherapeutic digoxin concentrations (>2 ng/mL) and secondary outcomes included frequency of adverse events. RESULTS: A total of 146 digoxin concentrations were included (AKI = 59, CKD = 16, NKI = 71). Frequencies of supratherapeutic concentrations were similar between groups (AKI: 10.2%, CKD: 18.8%, NKI: 11.3%; P = 0.61). Pre-planned logistic regression demonstrated no significant relationship between kidney function group and the development of a supratherapeutic concentration (AKI: odds ratio [OR]: 1.3, 95% confidence interval [CI]: 0.4-4.5; CKD: OR 4.3, 95% CI: 0.7-23). CONCLUSION AND RELEVANCE: This is the first study in routine clinical practice evaluating the relationship between kidney function and digoxin peak concentrations that differentiates AKI from CKD. We did not find a relationship between kidney function and peak concentrations; however, the group with CKD was underpowered.

Low-dose Initiation of Buprenorphine in Hospitalized Patients on Full Agonist Opioid Therapy: A Retrospective Observational Study.

OBJECTIVE: Buprenorphine can be challenging to initiate in hospitalized patients with opioid dependence because of difficulty tolerating an opioid-free period for buprenorphine induction. The objective of this study was to evaluate efficacy and safety of low-dose initiation of buprenorphine in hospitalized patients receiving full agonist opioids. METHODS: This is a retrospective observational study between January 1, 2019, and December 31, 2020, at an academic tertiary care center and affiliated community hospital. Participants included adult patients at least 18 years old receiving scheduled full agonist opioids who were given sublingual buprenorphine 0.5 mg or less with the intent of increasing to at least 4 mg daily. The primary endpoint was the proportion of patients reaching a target dose of at least 4 mg total per day. The secondary endpoints included the incidence of precipitated opioid withdrawal based on documentation of symptoms and change in morphine milligram equivalents before and after low-dose buprenorphine initiation. RESULTS: A total of 76 low-dose initiation attempts were performed in 71 predominantly male (68%) patients (some patients had multiple attempts). Most patients received low-dose initiation because of history of opioid use disorder (83%). Low-dose initiation was completed in 54 of 71 patients (76%) after 76 attempts. Precipitated withdrawal was identified in 2 patients (2.8%). Median morphine milligram equivalents excluding buprenorphine 24 hours before low-dose initiation was 1000 mg (interquartile range, 303.5-1720.5 mg) compared with 37.5 mg (interquartile range, 0-254 mg) after reaching target dose ( P < 0.001). CONCLUSIONS: Buprenorphine was safely initiated using low-dose initiation in hospitalized patients. This was associated with significant reduction in full agonist opioids.

HSA Adductomics Reveals Sex Differences in NHL Incidence and Possible Involvement of Microbial Translocation.

BACKGROUND: The higher incidence of non-Hodgkin lymphoma (NHL) in males is not well understood. Although reactive oxygen species (ROS) have been implicated as causes of NHL, they cannot be measured directly in archived blood. METHODS: We performed untargeted adductomics of stable ROS adducts in human serum albumin (HSA) from 67 incident NHL cases and 82 matched controls from the European Prospective Investigation into Cancer and Nutrition-Italy cohort. Regression and classification methods were employed to select features associated with NHL in all subjects and in males and females separately. RESULTS: Sixty seven HSA-adduct features were quantified by liquid chromatography-high-resolution mass spectrometry at Cys34 (n = 55) and Lys525 (n = 12). Three features were selected for association with NHL in all subjects, while seven were selected for males and five for females with minimal overlap. Two selected features were more abundant in cases and seven in controls, suggesting that altered homeostasis of ROS may affect NHL incidence. Heat maps revealed differential clustering of features between sexes, suggesting differences in operative pathways. CONCLUSIONS: Adduct clusters dominated by Cys34 oxidation products and disulfides further implicate ROS and redox biology in the etiology of NHL. Sex differences in dietary and alcohol consumption also help to explain the limited overlap of feature selection between sexes. Intriguingly, a disulfide of methanethiol from enteric microbial metabolism was more abundant in male cases, thereby implicating microbial translocation as a potential contributor to NHL in males. IMPACT: Only two of the ROS adducts associated with NHL overlapped between sexes and one adduct implicates microbial translocation as a risk factor.

Nonlinear low dose hematotoxicity of benzene; a pooled analyses of two studies among Chinese exposed workers.

BACKGROUND: Impairment of the hematopoietic system is one of the primary adverse health effects from exposure to benzene. We previously have shown that exposure to benzene at low levels (<1 ppm) affects the blood forming system and that these effects were proportionally stronger at lower versus higher levels of benzene exposure. This observation is potentially explained by saturation of enzymatic systems. METHODS: Here we extend these analyses by detailed modeling of the exposure response association of benzene and its major metabolites (i.e. catechol, muconic acid, phenol, and hydroquinone) on peripheral white blood cell (WBC) counts and its major cell-subtypes (i.e. granulocytes, lymphocytes, and monocytes) using two previously published cross-sectional studies among occupationally exposed Chinese workers. RESULTS: Supra-linear exposure response associations were observed between air benzene concentrations (range âˆ¼ 0.1 - 100 ppm) and WBC counts and its cell-subtypes, with a larger than proportional decrease in cell counts at lower than at higher levels of benzene exposure. The hematotoxicity associations were largely similar in shape when the analyses were repeated with benzene urinary metabolites suggesting that enzymatic saturation is not a full explanation of the observed non-linearity with WBC endpoints. DISCUSSION: We hypothesize that the flattening of the exposure response curve especially at higher benzene exposure levels may reflect a response by the bone marrow to maintain hematopoietic homeostasis. Toxicity to the bone marrow and an induced hyper-proliferative response could both contribute to risk of subsequently developing a hematopoietic malignancy. Additional work is needed to explore this hypothesis.

An International, Multicenter Evaluation of Comprehensive Medication Management by Pharmacists in ICU Recovery Centers.

BACKGROUND: Post-intensive care syndrome (PICS) is defined as a new or worsening impairment in physical, cognitive, or mental health following critical illness. Intensive care unit recovery centers (ICU-RC) are one means to treat patients who have PICS. The purpose of this study is to describe the role of pharmacists in ICU-RCs. RESEARCH QUESTION: What is the number and type of medication interventions made by a pharmacist at an ICU-RC at 12 different centers? STUDY DESIGN AND METHODS: This prospective, observational study was conducted in 12 intensive care units (ICUs)/ICU-RCs between September 2019 and July 2021. A full medication review was conducted by a pharmacist on patients seen at the ICU-RC. RESULTS: 507 patients were referred to the ICU-RC. Of these patients, 474 attended the ICU-RC and 472 had a full medication review performed by a pharmacist. Baseline demographic and hospital course data were obtained from the electronic health record and at the ICU-RC appointment. Pharmacy interventions were made in 397 (84%) patients. The median number of pharmacy interventions per patient was 2 (interquartile range [IQR] = 1,3). Medications were stopped and started in 124 (26%) and 91 (19%) patients, respectively. The number of patients that had a dose decreased and a dose increased was 51 (11%) and 43 (9%), respectively. There was no difference in the median total number of medications that the patient was prescribed at the start and end of the patient visit (10, IQR = 5, 15). Adverse drug event (ADE) preventive measures were implemented in 115 (24%) patients. ADE events were identified in 69 (15%) patients. Medication interactions were identified in 30 (6%) patients. INTERPRETATION: A pharmacist plays an integral role in an ICU-RC resulting in the identification, prevention, and treatment of medication-related problems. This paper should serve as a call to action on the importance of the inclusion of a pharmacist in ICU-RC clinics.

A nested case-control study of untargeted albumin adductomics and acute myeloid leukemia.

Environmental exposures often produce reactive electrophiles in vivo, leading to oxidative stress, which plays a major role in carcinogenesis. These electrophiles frequently form adducts with human albumin, which can be measured to assess in vivo oxidative stress. Here, we aimed to examine the associations between circulatory albumin adducts and acute myeloid leukemia (AML), the most common adult myeloid leukemia that showed consistent associations with environmental exposures. We conducted a nested case-control study of 52 incident AML cases and 103 controls matched on age, sex and race within two prospective cohorts: the CLUE and PLCO studies. We measured 42 untargeted albumin adducts in prediagnostic samples using liquid chromatography-high-resolution mass spectrometry. Circulatory albumin adducts were associated with AML in conditional logistic regression models. For instance, higher levels of Cys34 disulfide adduct of the S-γ-glutamylcysteine, a precursor of the essential antioxidant, glutathione were associated with a lower risk of AML (odds ratios [95% confidence intervals]) for the 1st, 2nd and 3rd tertiles were 1.0, 0.65 (0.31-1.36) and 0.31 (0.12-0.80), respectively (P-trend = .01). These associations were largely driven by effects present among cases diagnosed at or above the median follow-up time of 5.5 years. In conclusion, applying a novel approach to characterize exposures in the prediagnostic samples, we found evidence supporting the notion that oxidative stress may play a role in the pathogenesis of AML. Our findings offer insight into AML etiology and may be relevant in identifying novel therapeutic targets.

Lanthanum masquerading as foreign body ingestion in a critically ill patient with end-stage renal disease.

PURPOSE: Medication use may affect imaging results. In this case study, we report a case of lanthanum ingestion resulting in imaging consistent with ingested metallic foreign bodies. SUMMARY: Hyperphosphatemia affects most patients with end-stage renal disease (ESRD) and is associated with morbidity and mortality. Lanthanum carbonate reduces daily phosphate absorption and is indicated as a non-calcium-based phosphate binder in patients with ESRD. A 58-year-old man with a medical history of stage 5 chronic kidney disease was admitted to the intensive care unit (ICU) for hyperkalemia and acute respiratory failure after a missed dialysis session. He required vasopressors, intubation, and continuous renal replacement therapy. Admission imaging demonstrated several ingested metallic foreign bodies within the colon. There was consideration of colorectal surgery and gastroenterology consultation. On the initial medication reconciliation, no medications that would have the radiographic appearance of ingested metallic foreign bodies were identified. On further review of prescription data available through the electronic medical record, it was noted that the patient had recently filled a prescription for lanthanum despite its apparent discontinuation on a previous admission. After interviewing the patient's wife, it was confirmed that the patient had continued taking lanthanum and that he was swallowing it whole and not chewing it. No consultations or interventions were performed, and the metallic foreign bodies were no longer present on further imaging after a period of 35 days. CONCLUSION: Escalation of care was avoided in this patient due to the performance of diligent medication reconciliation and recognition of the impact of lanthanum ingestion on imaging.

Exposure to diesel engine exhaust and alterations to the Cys34/Lys525 adductome of human serum albumin.

We investigated whether exposure to carcinogenic diesel engine exhaust (DEE) was associated with altered adduct levels in human serum albumin (HSA) residues. Nano-liquid chromatography-high resolution mass spectrometry (nLC-HRMS) was used to measure adducts of Cys34 and Lys525 residues in plasma samples from 54 diesel engine factory workers and 55 unexposed controls. An untargeted adductomics and bioinformatics pipeline was used to find signatures of Cys34/Lys525 adductome modifications. To identify adducts that were altered between DEE-exposed and unexposed participants, we used an ensemble feature selection approach that ranks and combines findings from linear regression and penalized logistic regression, then aggregates the important findings with those determined by random forest. We detected 40 Cys34 and 9 Lys525 adducts. Among these findings, we found evidence that 6 Cys34 adducts were altered between DEE-exposed and unexposed participants (i.e., 841.75, 851.76, 856.10, 860.77, 870.43, and 913.45). These adducts were biologically related to antioxidant activity.

Negative Outcome Following Systemic Alteplase Administration Prior to Extracorporeal Membrane Oxygenation in a Kidney Transplant Patient With Cardiac Arrest: A Case Report.

A case of a negative outcome following systemic alteplase administration prior to extracorporeal membrane oxygenation (ECMO) in a kidney transplant patient with cardiac arrest is reported. A patient status-post kidney transplantation was admitted to the surgical intensive care unit (ICU) and experienced cardiac arrest after developing sudden-onset chest pain and shortness of breath. During cardiopulmonary resuscitation, alteplase 50 mg was administered intravenous push for suspected pulmonary embolism (PE) before the patient was evaluated for and started on veno-arterial ECMO. Within several hours, cardiopulmonary resuscitation needed to be reinitiated. Ultimately, the decision was made to cede further resuscitation efforts due to futility. A post-mortem examination included an immediate cause of death of acute myocardial infarction with extensive retroperitoneal hemorrhage. The role of ECMO is emerging in cardiac arrest, and should be considered as a management option before the administration of systemic thrombolysis in patients with increased bleeding risk.

A Retrospective Characterization of Dexmedetomidine-Suspected Fever and Its Consequences in Adult Critically Ill Patients.

BACKGROUND: Current evidence for dexmedetomidine-suspected fever (DSF) is limited. Lack of recognition may lead to costly or potentially harmful interventions for critically ill patients. OBJECTIVE: The primary objective was to characterize escalations of care related to DSF. Secondary objectives were to describe the incidence, severity, and consequences associated with DSF. METHODS: A retrospective review was conducted in critically ill adults who developed fever ≥39°C within 12 h from initiation of dexmedetomidine, with resolution of fever to <39°C within 12 h after discontinuation. The primary outcome was percentage of patients who received an escalation of care due to fever. Secondary outcomes included the percentage of patients who developed a multidrug-resistant organism or Clostridium difficile infection. RESULTS: Eighteen of 3943 patients screened in 4099 encounters met criteria for DSF (0.4%). The majority were white (83.3%), male (66.7%), and underwent cardiac surgery (61.1%). Median (interquartile range [IQR]) time to fever onset and resolution were 5.5 (3.6-7.6) and 1.3 (1.0-2.9) h. Nine patients (50%) underwent infectious workup including antimicrobial initiation (n = 1, 5.6%), broadening of antimicrobials (n = 4, 22.2%), or culture collection (n = 9, 50%). Eleven patients (61.1%) underwent attempted temperature reduction. Twelve patients (66.7%) underwent diagnostic imaging. Incidence of multidrug-resistant organism and C. difficile infection were low (11.1 and 16.7% of fever patients, respectively). CONCLUSION AND RELEVANCE: Incidence of DSF was low and more common in cardiac surgery patients. Unrecognized DSF led to an escalation of care in most patients. Dexmedetomidine exposure should be considered as a potential cause of fever in critically ill adults.

Extending the HSA-Cys34-Adductomics Pipeline to Modifications at Lys525.

We previously developed an adductomics pipeline that employed nanoflow liquid chromatography and high-resolution tandem mass spectrometry (nLC-HR-MS/MS) plus informatics to perform an untargeted detection of modifications to Cys34 in the tryptic T3 peptide of human serum albumin (HSA) (21ALVLIAFAQYLQQC34PFEDHVK41). In order to detect these peptide modifications without targeting specific masses, the pipeline interrogates MS2 ions that are signatures of the T3 peptide. The pipeline had been pilot-tested with archived plasma from healthy human subjects, and several of the 43 Cys34 adducts were highly associated with the smoking status. In the current investigation, we adapted the pipeline to include modifications to the ε-amino group of Lys525─a major glycation site in HSA─and thereby extend the coverage to products of Schiff bases that cannot be produced at Cys34. Because trypsin is generally unable to digest proteins at modified lysines, our pipeline detects miscleaved tryptic peptides with the sequence 525KQTALVELVK534. Adducts of both Lys525 and Cys34 are measured in a single nLC-HR-MS/MS run by increasing the mass range of precursor ions in MS1 scans and including both triply and doubly charged precursor ions for collision-induced dissociation fragmentation. For proof of principle, we applied the Cys34/Lys525 pipeline to archived plasma specimens from a subset of the same volunteer subjects used in the original investigation. Twelve modified Lys525 peptides were detected, including products of glycation (fructosyl-lysine plus advanced-glycated-end products), acetylation, and elimination of ammonia and water. Surprisingly, the carbamylated and glycated adducts were present at significantly lower levels in smoking subjects. By including a larger class of in vivo nucleophilic substitution reactions, the Cys34/Lys525 adductomics pipeline expands exposomic investigations of unknown human exposure to reactive electrophiles derived from both exogenous and endogenous sources.

Defining the Scope of Exposome Studies and Research Needs from a Multidisciplinary Perspective.

The concept of the exposome was introduced over 15 years ago to reflect the important role that the environment exerts on health and disease. While originally viewed as a call-to-arms to develop more comprehensive exposure assessment methods applicable at the individual level and throughout the life course, the scope of the exposome has now expanded to include the associated biological response. In order to explore these concepts, a workshop was hosted by the Gunma University Initiative for Advanced Research (GIAR, Japan) to discuss the scope of exposomics from an international and multidisciplinary perspective. This Global Perspective is a summary of the discussions with emphasis on (1) top-down, bottom-up, and functional approaches to exposomics, (2) the need for integration and standardization of LC- and GC-based high-resolution mass spectrometry methods for untargeted exposome analyses, (3) the design of an exposomics study, (4) the requirement for open science workflows including mass spectral libraries and public databases, (5) the necessity for large investments in mass spectrometry infrastructure in order to sequence the exposome, and (6) the role of the exposome in precision medicine and nutrition to create personalized environmental exposure profiles. Recommendations are made on key issues to encourage continued advancement and cooperation in exposomics.

Metabolome-wide association study of occupational exposure to benzene.

Benzene is a recognized hematotoxin and leukemogen; however, its mechanism of action in humans remain unclear. To provide insight into the processes underlying benzene hematotoxicity, we performed high-resolution metabolomic profiling of plasma collected from a cross-sectional study of 33 healthy workers exposed to benzene (median 8-h time-weighted average exposure; 20 ppma), and 25 unexposed controls in Shanghai, China. Metabolic features associated with benzene were identified using a metabolome-wide association study (MWAS) that tested for the relationship between feature intensity and benzene exposure. MWAS identified 478 mass spectral features associated with benzene exposure at false discovery rate < 20%. Comparison to a list of 13 known benzene metabolites and metabolites predicted using a multi-component biotransformation algorithm showed five metabolites were detected, which included the known metabolites phenol and benzene diolepoxide. Metabolic pathway enrichment identified 41 pathways associated with benzene exposure, with altered pathways including carnitine shuttle, fatty acid metabolism, sulfur amino acid metabolism, glycolysis, gluconeogenesis and branched chain amino acid metabolism. These results suggest disruption to fatty acid uptake, energy metabolism and increased oxidative stress, and point towards pathways related to mitochondrial dysfunction, which has previously been linked to benzene exposure in animal models and human studies. Taken together, these results suggest benzene exposure is associated with disruption of mitochondrial pathways, and provide promising, systems biology biomarkers for risk assessment of benzene-induced hematotoxicity in humans.

Utilizing a Biology-Driven Approach to Map the Exposome in Health and Disease: An Essential Investment to Drive the Next Generation of Environmental Discovery.

BACKGROUND: Recent developments in technologies have offered opportunities to measure the exposome with unprecedented accuracy and scale. However, because most investigations have targeted only a few exposures at a time, it is hypothesized that the majority of the environmental determinants of chronic diseases remain unknown. OBJECTIVES: We describe a functional exposome concept and explain how it can leverage existing bioassays and high-resolution mass spectrometry for exploratory study. We discuss how such an approach can address well-known barriers to interpret exposures and present a vision of next-generation exposomics. DISCUSSION: The exposome is vast. Instead of trying to capture all exposures, we can reduce the complexity by measuring the functional exposome-the totality of the biologically active exposures relevant to disease development-through coupling biochemical receptor-binding assays with affinity purification-mass spectrometry. We claim the idea of capturing exposures with functional biomolecules opens new opportunities to solve critical problems in exposomics, including low-dose detection, unknown annotations, and complex mixtures of exposures. Although novel, biology-based measurement can make use of the existing data processing and bioinformatics pipelines. The functional exposome concept also complements conventional targeted and untargeted approaches for understanding exposure-disease relationships. CONCLUSIONS: Although measurement technology has advanced, critical technological, analytical, and inferential barriers impede the detection of many environmental exposures relevant to chronic-disease etiology. Through biology-driven exposomics, it is possible to simultaneously scale up discovery of these causal environmental factors. https://doi.org/10.1289/EHP8327.

Cytokine Levels at Birth in Children Who Developed Acute Lymphoblastic Leukemia.

BACKGROUND: Prenatal immune development may play an important role in the etiology of childhood acute lymphoblastic leukemia (ALL). METHODS: Seven cytokines, IL1ß, IL4, IL6, IL8, GM-CSF, TNFα, and VEGF, were analyzed in blood spots collected at birth from 1,020 ALL cases and 1,003 controls participating in the California Childhood Leukemia Study. ORs and 95% confidence intervals (95% CI) associated with an interquartile range increment in cytokine levels were calculated using logistic regression, adjusting for sociodemographic and birth characteristics. RESULTS: We found that patients with ALL were born with higher levels of a group of correlated cytokines than controls [IL1ß: OR of 1.18 (95% confidence interval [CI], 1.03-1.35); IL8: 1.19 (1.03-1.38); TNFα: 1.15 (1.01-1.30); VEGF: 1.16 (1.01-1.33)], especially among children of Latina mothers (ORs from 1.31 to 1.40) and for ALL with high hyperdiploidy (ORs as high as 1.27). We found that neonatal cytokine levels were correlated with neonatal levels of endogenous metabolites which had been previously associated with ALL risk; however, there was no evidence that the cytokines were mediating the relationship between these metabolites and ALL risk. CONCLUSIONS: We posit that children born with altered cytokine levels are set on a trajectory towards an increased risk for subsequent aberrant immune reactions that can initiate ALL. IMPACT: This is the first study to evaluate the interplay between levels of immunomodulatory cytokines at birth, prenatal exposures, and the risk of childhood ALL.

Untargeted metabolomics of newborn dried blood spots reveals sex-specific associations with pediatric acute myeloid leukemia.

The etiology of pediatric acute myeloid leukemia (AML) is largely unknown, but evidence for mutations in utero and long latency periods suggests that environmental factors play a role. Therefore, we used untargeted metabolomics of archived newborn dried blood spots (DBS) to investigate neonatal exposures as potential causal risk factors for AML. Untargeted metabolomics profiling was performed on DBS punches from 48 pediatric patients with AML and 46 healthy controls as part of the California Childhood Leukemia Study (CCLS). Because sex disparities are suggested by differences in AML incidence rates, metabolite features associated with AML were identified in analyses stratified by sex. There was no overlap between the 16 predictors of AML in females and 15 predictors in males, suggesting that neonatal metabolomic profiles of pediatric AML risk are sex-specific. In females, four predictors of AML were putatively annotated as ceramides, a class of metabolites that has been linked with cancer cell proliferation. In females, two metabolite predictors of AML were strongly correlated with breastfeeding duration, indicating a possible biological link between this putative protective risk factor and childhood leukemia. In males, a heterogeneous metabolite profile of AML predictors was observed. Replication with larger participant numbers is required to validate findings.

Predictors of Serious Opioid-Related Adverse Drug Events in Hospitalized Patients.

OBJECTIVE: Opioids are high-risk medications in the inpatient setting because of their potential for significant patient harm. The primary objective was to identify risk factors that predispose inpatients to develop opioid-related adverse drug events (ORADE) requiring the use of naloxone. METHODS: In a retrospective case-control study, patients were included according to the following criteria: 18 years or older, 1 administered opioid doses or more, and admitted for 24 hours or more. Patients were excluded if they had a prehospital drug overdose, other indications for naloxone use, or were admitted to an intensive care unit, psychiatric medical unit, or in the emergency department. Patients were classified as cases if naloxone was administered and a selection of controls were frequency matched 2:1 based on medical or surgical status. A logistic regression model was used to evaluate for risk factors for ORADE. RESULTS: A total of 275 cases and 592 control patients were included into the final analysis. Variables that were associated with greater odds of naloxone administration included age of 65 years or older, female, length of stay, pulmonary diagnoses, use of gabapentinoids, and patient-controlled analgesia use. Antihistamines, continuous infusion, and intermittent nurse administered intravenous bolus routes had a negative association with naloxone use. CONCLUSIONS: Several risk factors were found to be associated with ORADE supporting many of the previously described risk factors, and the discovery of potential new ones, such as gabapentinoid use. Health care providers should consider the risk factors for hospitalized patients receiving opioids who may warrant lower doses, additional monitoring, or alternative agents.