The effect of incidental ethanol exposures on the formation of blood phosphatidylethanol.

Blood phosphatidylethanol (PEth), a metabolite of ethanol, is emerging as a direct biomarker of choice for characterizing ethanol consumption in clinical, research, and forensic contexts. An accumulating body of evidence, and a recent international consensus conference, supports a cutoff of 20 µg/L of PEth (16:0/18:1) to distinguish abstinence from beverage ethanol consumption. There is a dearth of research, however, on whether exposures to nonbeverage ethanol sources are sufficient to produce PEth concentrations that exceed this cutoff. To explore this possibility, we recruited 30 participants, who indicated past-90-day abstinence from beverage alcohol, to characterize their past-30-day nonbeverage ethanol exposures (including source, frequency, and intensity of exposures) and to undergo PEth testing. Two of the 30 participants (6.7%) produced PEth concentrations ≥20 µg/L. One of these participants (PEth = 26 µg/L) reported multiple ethanol exposure sources, including near-daily intensive exposures to ethanol vapor. The other participant (PEth = 49 µg/L) reported only once-daily use of an ethanol-containing mouthwash; the veracity of his abstinence claim is refuted. The results of this study support a rebuttable presumption that PEth ≥20 µg/L is indicative of beverage ethanol consumption. They suggest, however, that intensive, incidental alcohol exposures have the potential, under unusual circumstances, to result in PEth concentrations that modestly exceed this threshold.

Urine and hair drug test results associated with daily consumption of codeine-predominant poppy seed food products.

This study examined the urine and hair opiate profiles associated with the daily consumption of presumptive codeine-predominant poppy seed food products. Ten participants consumed one of five food products at breakfast for 10 consecutive days. Baseline urine and hair samples were collected on Day 1. The urine samples were collected 4, 8 and 12 h following poppy seed consumption on Days 1 and 10, and the first morning void urine samples were collected on Days 2-10. A second hair specimen was collected on Day 20 ± 2. Urine drug test results: Three of the food products were associated with opiate-negative urine drug test results at all time points at a 300 ng/mL cut-off. Two of the food products were associated with opiate-positive drug test results at all non-baseline time points at a 300 ng/mL cut-off. Of these, all samples (n = 60) were codeine-positive, and 27 (45%) were morphine-positive. Codeine concentrations exceeded morphine concentrations in every sample and always by multiples. Thirty-nine of the 60 samples (65%) were codeine-positive at a 2,000 ng/mL cut-off, while none of these samples were morphine-positive at this cut-off. None of the 60 samples reached an opiate threshold of 15,000 ng/mL, although one participant produced a maximum codeine concentration of 13,161 ng/mL (13,854 ng/mg creatinine). There was no clear trend toward increasing urinary opiate concentrations over the course of the study. Hair drug test results: The hair samples of two participants produced quantifiable codeine (41 pg/mg and 51 pg/mg), but no sample reached a common reporting threshold of 200 pg/mg for codeine or morphine.

Feasibility, Effectiveness and Safety of Elastomeric Pumps for Delivery of Antibiotics to Adult Hospital Inpatients-A Systematic Review.

Elastomeric infusion pumps (EMPs) have been implemented in many fields, including analgesia, chemotherapy and cardiology. Their application in antimicrobials is mainly limited to the outpatient setting, but with a need to optimise inpatient antimicrobial treatment, the use of EMPs presents a potential option. This review aimed to identify if the use of EMPs within an inpatient setting is feasible, effective and safe for antimicrobial use. Criteria for inclusion were human studies that involved the treatment of an infection with intravenous antimicrobial agents via an EMP. A search strategy was developed covering both the indexed and grey literature, with all study designs included. The review found 1 eligible study enrolling 6 patients. There was strong patient preference for EMPs (6/6), and daily tasks were easily completed whilst attached to the EMP. Nurses (5/5) also preffered the pumps, and the majority reported them as easy to use. The review has identified the need for further research in the area. Evidence for the use of EMPs to administer antibiotics in the inpatient setting is scarce, and more work is needed to understand the advantages to patients, to healthcare workers and from an antimicrobial stewardship perspective. Potential disadvantages that may put patients at risk also need investigating.

Identification of antibiotic consumption targets for the management of Clostridioides difficile infection in hospitals- a threshold logistic modelling approach.

BACKGROUND: This study aims to demonstrate the utility of a threshold logistic approach to identifying thresholds for specific antibiotic use associated with Clostridioides difficile infection (CDI) in an English teaching hospital. METHODS: A combined approach of nonlinear modeling and logistic regression, named threshold logistic, was used to identify thresholds and risk scores in hospital-level antibiotic use associated with hospital-onset, healthcare-associated (HOHA) CDI cases. RESULTS: Using a threshold logistic regression approach, an incidence greater than 0.2645 cases/1000 occupied bed-days (OBD; 85th percentile) was determined as the cutoff rate to define a critical (high) incidence rate of HOHA CDI. Fluoroquinolones and piperacillin-tazobactam were found to have thresholds at 84.8 and 54 defined daily doses (DDD)/1000 OBD, respectively. Analysis of data allowed calculating risk scores for HOHA CDI incidence rates exceeding the 85th percentile, i.e. entering critical incidence level. The threshold-logistic model also facilitated performing 'what-if scenarios' on future values of fluoroquinolones and piperacillin-tazobactam use to understand how HOHA CDI incidence rates may be affected. CONCLUSION: Using threshold logistic analysis, critical incidence levels and antibiotic use targets to control HOHA CDI were determined. Threshold logistic models can be used to inform and enhance the effective design and implementation of antimicrobial stewardship programs.

Improving Communication of Peer-Review Conference Outcomes: A Practical Experience.

Purpose: The aim of this work was to describe the design and implementation of a more robust workflow for communicating outcomes from a peer-review chart rounds conference. We also provide information regarding cycle times, plan revisions, and other key metrics that we have observed since initial implementation. Methods and Materials: A multidisciplinary team of stakeholders including physicians, physicists, and dosimetrists developed a revised peer-review workflow that addressed key needs to improve the prior process. Consensus terminology was developed to reduce ambiguity regarding the priority of peer-review outcomes and to clarify expectations of the treating physician in response to peer-review outcomes. A custom workflow software tool was developed to facilitate both upstream and downstream processes from the chart rounds conference. The peer-review outcomes of the chart rounds conference and resulting plan changes for the first 18 months of implementation were summarized. Results: In the first 18 months after implementation of the revised processes, 2294 plans were reviewed, and feedback priority levels assigned. Across all cases with feedback, the median time for the treating attending physician to acknowledge conference comments was 1 day and was within 7 calendar days for 89.1% of cases. Conference feedback was acknowledged within 1 day for 74 of 115 (64.3%) cases with level 2 comments and for 18 of 21 (85.7%) cases with level 3 comments (P = .054). Contours were modified in 13 of 116 (11%) cases receiving level 2 feedback and 10 of 21 (48%) cases receiving level 3 feedback (P < .001). The treatment plan was revised in 18 of 116 (16%) cases receiving level 2 feedback and 13 of 21 (61%) cases receiving level 3 feedback (P < .001). Conclusions: We successfully implemented a workflow to improve upstream and downstream processes for a chart rounds conference. Standardizing how peer-review outcomes were communicated and recording physician responses allow for improved ability to monitor conference activities.

Regulation of sleep by cholinergic neurons located outside the central brain in Drosophila.

Sleep is a complex and plastic behavior regulated by multiple brain regions and influenced by numerous internal and external stimuli. Thus, to fully uncover the function(s) of sleep, cellular resolution of sleep-regulating neurons needs to be achieved. Doing so will help to unequivocally assign a role or function to a given neuron or group of neurons in sleep behavior. In the Drosophila brain, neurons projecting to the dorsal fan-shaped body (dFB) have emerged as a key sleep-regulating area. To dissect the contribution of individual dFB neurons to sleep, we undertook an intersectional Split-GAL4 genetic screen focusing on cells contained within the 23E10-GAL4 driver, the most widely used tool to manipulate dFB neurons. In this study, we demonstrate that 23E10-GAL4 expresses in neurons outside the dFB and in the fly equivalent of the spinal cord, the ventral nerve cord (VNC). Furthermore, we show that 2 VNC cholinergic neurons strongly contribute to the sleep-promoting capacity of the 23E10-GAL4 driver under baseline conditions. However, in contrast to other 23E10-GAL4 neurons, silencing these VNC cells does not block sleep homeostasis. Thus, our data demonstrate that the 23E10-GAL4 driver contains at least 2 different types of sleep-regulating neurons controlling distinct aspects of sleep behavior.

Blood Phosphatidylethanol (PEth) Concentrations following Intensive Use of an Alcohol-based Hand Sanitizer.

Alcohol use disorders are prevalent in the USA and throughout the world. Monitoring for alcohol abstinence is useful in several clinical and forensic contexts. The direct alcohol biomarkers have the requisite sensitivity and specificity for abstinence monitoring. The relatively new direct biomarker phosphatidylethanol (PEth), measured in blood, is gaining increasing acceptance in monitoring abstinence from beverage alcohol consumption, but there remains little research addressing the potential for PEth formation consequent to incidental alcohol exposures. In the midst of the coronavirus disease 2019 pandemic, high-alcohol content hand sanitizer is a particularly important source of nonbeverage alcohol exposure. To assess the extent of alcohol absorption and subsequent formation of blood PEth related to intensive use of high alcohol content hand sanitizer, we recruited 15 participants to use a 70% ethyl alcohol-based hand sanitizer 24-100 times daily, for 12-13 consecutive days. Blood was analyzed for PEth 16:0/18:1 by liquid chromatography--tandem mass spectrometry. Our hypothesis that blood PEth concentrations would fail to reach a 20 ng/mL threshold was confirmed. This work adds to the nascent literature on the effects of incidental alcohol exposures on blood PEth formation.

Poppy Seed Consumption May Be Associated with Codeine-Only Urine Drug Test Results.

Consumption of poppy seed-containing food products can result in opiate-positive urine drug test results and may pose challenges in distinguishing poppy seed consumption from opiate administration. In this context, guidance has suggested that codeine concentrations exceeding 300 ng/mL coupled with morphine-to-codeine ratios <2 are indicative of codeine consumption and, therefore, exclude poppy seed consumption as a legitimate explanation for the test result. In recent years, we performed independent medical examinations of three individuals who produced codeine-positive/morphine-negative (300 ng/mL) forensic urine drug test results but denied codeine administration, attributing their test results to the consumption of specific poppy seed-containing food products. In the present study, 11 participants consumed one of the 10 unique poppy seed-containing food products, including the three implicated food products. Six of 33 non-baseline urine samples (18%)-representing three food products-were positive for codeine and negative for morphine at 300 ng/mL cut-offs (and therefore featured morphine-to-codeine ratios <2). This study adds to a small literature indicating that consumption of poppy seed-containing food products cannot reliably be distinguished from codeine administration based on previously published urinary opiate concentrations and ratios. An important caveat is that in none of these cases did maximum urinary codeine concentrations exceed 1,300 µg/g creatinine.

Sleep-promoting neurons remodel their response properties to calibrate sleep drive with environmental demands.

Falling asleep at the wrong time can place an individual at risk of immediate physical harm. However, not sleeping degrades cognition and adaptive behavior. To understand how animals match sleep need with environmental demands, we used live-brain imaging to examine the physiological response properties of the dorsal fan-shaped body (dFB) following interventions that modify sleep (sleep deprivation, starvation, time-restricted feeding, memory consolidation) in Drosophila. We report that dFB neurons change their physiological response-properties to dopamine (DA) and allatostatin-A (AstA) in response to different types of waking. That is, dFB neurons are not simply passive components of a hard-wired circuit. Rather, the dFB neurons intrinsically regulate their response to the activity from upstream circuits. Finally, we show that the dFB appears to contain a memory trace of prior exposure to metabolic challenges induced by starvation or time-restricted feeding. Together, these data highlight that the sleep homeostat is plastic and suggests an underlying mechanism.

Toxicology as a diagnostic tool to identify the misuse of drugs in the perinatal period.

The use, misuse, and abuse of substances are a continued public health concern in this country and around the world. Perinatal exposure to substances of abuse is associated with several long-term negative consequences for the neonate. Limited resources exist to assist perinatal health professionals on this very complex subject. The purpose of this document is to provide additional information about selecting monitoring protocols, the specifics of appropriate testing methodologies, and the interpretation of toxicological findings. Understanding these concepts better allows perinatal healthcare professionals to be a voice for the voiceless in order to protect and enrich lives during this unprecedented opioid epidemic.

Blood Phosphatidylethanol Concentrations Following Regular Exposure to an Alcohol-Based Mouthwash.

Direct biomarkers of ethanol are used to monitor individuals who are required to abstain from ethanol consumption. In recent years, blood phosphatidylethanol (PEth) has gained acceptance in clinical and forensic contexts as an abstinence marker. Its elimination half-life of several days provides a window of detection of days to weeks. However, there is no research addressing the extent of PEth formation related to extraneous ethanol exposures. To assess the degree of ethanol absorption and subsequent formation of blood PEth related a common extraneous exposure, regular use of an ethanol-containing mouthwash, we recruited 16 participants to gargle with an alcohol-based mouthwash (21.6% ethanol) 4 times daily, for 12 consecutive days. Blood was analyzed for PEth 16:0/18:1 by liquid chromatography-tandem mass spectrometry. Our hypothesis that blood PEth concentrations would not equal or exceed 20 ng/mL was confirmed. Although the data suggest that regular use of mouthwash is unlikely to result in suprathreshold PEth concentrations, this work highlights the importance of considering extraneous ethanol exposures in clinical decision-making and in future research.

Environmental and economic impact of using increased fresh gas flow to reduce carbon dioxide absorbent consumption in the absence of inhalational anaesthetics.

BACKGROUND: Increasing fresh gas flow (FGF) to a circle breathing system reduces carbon dioxide (CO2) absorbent consumption. We assessed the environmental and economic impacts of this trade-off between gas flow and absorbent consumption when no inhalational anaesthetic agent is used. METHODS: A test lung with fixed CO2 inflow was ventilated via a circle breathing system of an anaesthetic machine (Dräger Primus or GE Aisys CS2) using an FGF of 1, 2, 4, or 6 L min-1. We recorded the time to exhaustion of the CO2 absorbent canister, defined as when inspired partial pressure of CO2 exceeded 0.3 kPa. For each FGF, we calculated the economic costs and the environmental impact associated with the manufacture of the CO2 absorbent canister and the supply of medical air and oxygen. Environmental impact was measured in 100 yr global-warming potential, analysed using a life cycle assessment 'cradle to grave' approach. RESULTS: Increasing FGF from 1 to 6 L min-1 was associated with up to 93% reduction in the combined running cost with minimal net change to the 100 yr global-warming potential. Most of the reduction in cost occurred between 4 and 6 L min-1. Removing the CO2 absorbent from the circle system, and further increasing FGF to control CO2 rebreathing, afforded minimal further economic benefit, but more than doubled the global-warming potential. CONCLUSIONS: In the absence of inhalational anaesthetic agents, increasing FGF to 6 L min-1 reduces running cost compared with lower FGFs, with minimal impact to the environment.

School-based Streptococcal A Sore-throat Treatment Programs and Acute Rheumatic Fever Amongst Indigenous Maori: A Retrospective Cohort Study.

BACKGROUND: Acute rheumatic fever (ARF) predominantly affects indigenous Maori schoolchildren in Bay of Plenty region, and more so male Maori students, especially when socioeconomically deprived. We evaluated the effectiveness of strategies for reducing ARF with group A streptococcal pharyngitis treatment in 2011-18. METHODS: We retrospectively assessed outcomes of 3 open cohorts of Maori schoolchildren receiving different interventions: Eastern Bay rural Cohort 1, mean deprivation decile 9.80, received school-based sore-throat programs with nurse and general practice (GP) support; Eastern Whakatane township/surrounds Cohort 2, mean deprivation 7.25, GP management; Western Bay Cohort 3, mean deprivation 5.98, received predominantly GP care, but 3 highest-risk schools received school-based programs. Cases were identified from ICD10 ARF-coded hospital discharges, notifications to Ministry of Health, and a secondary-prevention penicillin database. Primary outcomes were first-presentation ARF cohorts' incidence preintervention (2000-10) and postintervention (2011-18) with cases over annual school rolls' Maori students-year denominators. RESULTS: Overall, ARF in Maori schoolchildren declined in the cohorts with school-based programs. Cohort 1 saw a postintervention (2011-18) decline of 60%, 148 to 59/100,000/year, rate ratio (RR) = 0.40(CI 0.22-0.73) P = 0.002. Males' incidence declined 190 to 78 × 100,000/year RR = 0.41(CI 0.19-0.85) P = 0.013 and females too, narrowing gender disparities. Cohort 3 ARF incidence decreased 48%, 50 to 26/100,000/year RR = 0.52(CI 0.27-0.99) P = 0.044. In contrast, ARF doubled in Cohort 2 students with GP-only care without school-based programs increasing 30 to 69/100,000/year RR = 2.28(CI 0.99-5.27) P = 0.047, especially for males 39/100,000/year to 107/100,000/year RR = 2.71(CI 1.00-7.33) P = 0.0405. CONCLUSIONS: School-based programs with indigenous Maori health workers' sore-throat swabbing and GP/Nurse support reduced first-presentation ARF incidence in Maori students in highest-risk settings.

Sequence isomerism in uniform polyphosphoesters programmes self-assembly and folding.

We have adapted solid phase phosphoramidite synthesis commonly used to make DNA, to produce two sequence-isomeric non-biological polymers which display sequence-programmed folding and self-assembly, going beyond structures which would be trivially anticipated. These findings open up possibilities for more sophisticated sequence/structure relationships using the same synthetic platform.

The roles of phosphatidylethanol, ethyl glucuronide, and ethyl sulfate in identifying alcohol consumption among participants in professionals health programs.

Direct alcohol biomarkers, including urinary ethyl glucuronide (EtG), urinary ethyl sulfate (EtS), and blood phosphatidylethanol (PEth), are used to monitor alcohol abstinence in individuals who are mandated to abstain. In this consecutive case series study, we examined 1000 forensic reports of participants enrolled in a professionals health program who were contractually obligated to abstain from alcohol and who underwent recovery status evaluations. We identified 52 evaluations in which urinary EtG, EtS, and blood PEth were measured and which produced a positive result for at least one of these analytes. PEth, at a cutoff concentration of 20 ng/mL, revealed alcohol use more frequently than EtG or EtS at our laboratory's cutoff concentrations of 100 and 25 ng/mL, respectively. This was true, as well, at alternative EtG/EtS cutoff concentrations of 200/50, 300/75, and 400/100 ng/mL. PEth was more likely than EtG/EtS to be positive in participants previously diagnosed with alcohol use disorders (AUD), whereas EtG/EtS was more likely than PEth to be positive in participants without AUD. In this study, blood PEth was the most sensitive biomarker for evidencing alcohol use.

Persistent Urinary Ethyl Sulfate in the Absence of Urinary Ethyl Glucuronide in a Patient with Alcohol Use Disorder Who Claimed Abstinence.

A 48-year-old nurse with an alcohol use disorder history was being monitored in a professional health program. She consistently produced low-to-moderate urinary ethyl sulfate (EtS) concentrations in the absence of detectable urinary ethyl glucuronide (EtG), blood phosphatidylethanol and breath alcohol. She denied intentional ethanol consumption. After prolonged monitoring in a drug treatment program, including a period in a controlled environment, we concluded that this individual's urinary EtS likely resulted from anatomical and microbial factors related to Roux-en-Y gastric bypass surgery, with possible contributions from hidden dietary sources of ethanol. We have no definitive explanation for the lack of urinary EtG.

Anisotropic polymer nanoparticles with controlled dimensions from the morphological transformation of isotropic seeds.

Understanding and controlling self-assembly processes at multiple length scales is vital if we are to design and create advanced materials. In particular, our ability to organise matter on the nanoscale has advanced considerably, but still lags far behind our skill in manipulating individual molecules. New tools allowing controlled nanoscale assembly are sorely needed, as well as the physical understanding of how they work. Here, we report such a method for the production of highly anisotropic nanoparticles with controlled dimensions based on a morphological transformation process (MORPH, for short) driven by the formation of supramolecular bonds. We present a minimal physical model for MORPH that suggests a general mechanism which is potentially applicable to a large number of polymer/nanoparticle systems. We envision MORPH becoming a valuable tool for controlling nanoscale self-assembly, and for the production of functional nanostructures for diverse applications.

Cryo-EM of multiple cage architectures reveals a universal mode of clathrin self-assembly.

Clathrin forms diverse lattice and cage structures that change size and shape rapidly in response to the needs of eukaryotic cells during clathrin-mediated endocytosis and intracellular trafficking. We present the cryo-EM structure and molecular model of assembled porcine clathrin, providing insights into interactions that stabilize key elements of the clathrin lattice, namely, between adjacent heavy chains, at the light chain-heavy chain interface and within the trimerization domain. Furthermore, we report cryo-EM maps for five different clathrin cage architectures. Fitting structural models to three of these maps shows that their assembly requires only a limited range of triskelion leg conformations, yet inherent flexibility is required to maintain contacts. Analysis of the protein-protein interfaces shows remarkable conservation of contact sites despite architectural variation. These data reveal a universal mode of clathrin assembly that allows variable cage architecture and adaptation of coated vesicle size and shape during clathrin-mediated vesicular trafficking or endocytosis.

Longitudinal correspondence between subjective and objective memory in the oldest old: A parallel process model by gender.

Subjective memory and objective memory performance have predictive utility for clinically relevant outcomes in older adults. Previous research supports certain overlap between objective performance and subjective ratings of memory. These studies are typically cross-sectional or use baseline data only to predict subsequent change. The current study uses a parallel process model to examine concurrent changes in objective memory and subjective memory. We combined data from two population-based Swedish studies of individuals aged 80 + years, assessed every 2 years (OCTO-3 measurement occasions, OCTO-Twin-5 measurement occasions) yielding 607 participants (66% female). The results confirmed that both objective and subjective memory declined over time. The association between the slope of objective memory and subjective memory was statistically significant for women but not for men. This pattern remained after accounting for age and depressive symptoms. Our findings suggest that, in population-based samples of the oldest old, women seem to show better metacognitive abilities in detecting and reporting changes in memory. Memory changes for men may be better identified by objective performance as their self-assessment of memory changes is not associated with actual change in memory performance.