Synthesis of fatty acid ethyl esters in mammalian tissues after ethanol exposure: a systematic review of the literature.

The ability to undergo non-oxidative metabolism from ethanol to fatty acid ethyl esters (FAEEs) varies greatly among tissues and organs. To gain a greater understanding of non-oxidative ethanol metabolism to FAEE, we aimed to collect all published data on FAEE synthesis in mammalian organs and tissues to identify all tissues, organs, and enzymes that are known to, or likely possess FAEE-synthetic activity. A systematic search for relevant papers was performed and two independent reviewers examined potentially relevant abstracts (articles on FAEEs that pertain to ethanol exposure) to determine whether they met the inclusion criteria. Information on FAEE synthesis was retrieved from papers meeting the inclusion/exclusion criteria and summarized by organ/tissue/matrix examined. The systematic search through four databases yielded 78 articles that investigated FAEE synthesis by tissues, tissue fractions and cell lines, and 29 articles that attempted to purify and/or characterize the enzymes involved in FAEE synthesis. Two enzyme activities have been studied: FAEE synthase (FAEES, which conjugates ethanol and free fatty acid) and acyl-CoA: ethanol O-acyltransferase (AEAT, which conjugates ethanol and fatty acyl-CoA). Both activities are expressed by a variety of different enzymes. FAEES activity is the most widely studied and has been purified from several tissues and shown to be associated with several well-known enzymes, while the identity of enzymes possessing AEAT activity remains unknown. The organs and tissues that have been shown to synthesize FAEEs are discussed, with special emphasis on the studies that attempted to elucidate the enzymology of FAEE synthesis in those tissues.

Tdap vaccination during pregnancy to reduce pertussis infection in young infants.

QUESTION: What is the basis for the new recommendations to vaccinate pregnant women against pertussis after the first trimester? ANSWER: There have been outbreaks of epidemic proportions of pertussis, mostly among young infants who have not received sufficient passive immunity from their mothers. This strategy of vaccination during pregnancy aims at stopping these life-threatening epidemics.

Is carbamazepine safe to take during pregnancy?

QUESTION: Some of my pregnant patients are afraid to take their antiepileptic drugs during pregnancy because of the known risk of malformations and the neurodevelopmental problems associated with valproic acid. Are there similar concerns with carbamazepine? ANSWER: Similar to valproic acid, carbamazepine increases the risk of neural tube defects; however, it does not increase the risk of other malformations. Carbamazepine is also not associated with an increased risk of developmental delay.

Sex-Specific Differences in End-of-Life Burdensome Interventions and Antibiotic Therapy in Nursing Home Residents With Advanced Dementia.

Importance: Nursing home residents with advanced dementia have limited life expectancies yet are commonly subjected to burdensome interventions at the very end of life. Whether sex-specific differences in the receipt of these interventions exist and what levels of physical restraints and antibiotics are used in this terminal setting are unknown. Objective: To evaluate the population-based frequency, factors, and sex differences in burdensome interventions and antibiotic therapy among nursing home residents with advanced dementia. Design, Setting, and Participants: This population-based cohort study from Ontario, Canada, used linked administrative databases held at ICES, including the Continuing Care Resident Reporting System Long-Term Care database, which contains data from the Resident Assessment Instrument Minimum Data Set, version 2.0. Nursing home residents (n = 27 243) with advanced dementia who died between June 1, 2010, and March 31, 2015, at 66 years or older were included in the analysis. Initial statistical analysis was completed in May 2017, and analytical revisions were conducted from November 2018 to January 2019. Exposure: Sex of the nursing home resident. Main Outcomes and Measures: Burdensome interventions (transitions of care, invasive procedures, and physical restraints) and antibiotic therapy in the last 30 days of life. Results: The final cohort included 27 243 nursing home residents with advanced dementia (19 363 [71.1%] women) who died between June 1, 2010, and March 31, 2015, at the median (interquartile range) age of 88 (83-92) years. In the last 30 days of life, burdensome interventions were common, especially among men: 5940 (21.8%) residents were hospitalized (3661 women [18.9%] vs 2279 men [28.9%]; P < .001), 2433 (8.9%) had an emergency department visit (1579 women [8.2%] vs 854 men [10.8%]; P < .001), and 3701 (13.6%) died in an acute care facility (2276 women [11.8%] vs 1425 men [18.1%]; P < .001). Invasive procedures were also common; 2673 residents (9.8%) were attended for life-threatening critical care (1672 women [8.6%] vs 1001 men [12.7%]; P < .001), and 210 (0.8%) received mechanical ventilation (113 women [0.6%] vs 97 men [1.2%]; P < .001). Among the 9844 residents (36.1%) who had a Resident Assessment Instrument Minimum Data Set, version 2.0, completed in the last 30 days of life, 2842 (28.9%) were physically restrained (2002 women [28.3%] vs 840 men [30.4%]; P = .005). More than one-third (9873 [36.2%]) of all residents received an antibiotic (6599 women [34.1%] vs 3264 men [41.4%]; P < .001). In multivariable models, men were more likely to have a transition of care (adjusted odds ratio, 1.41; 95% CI, 1.33-1.49; P < .001) and receive antibiotics (adjusted odds ratio, 1.33; 95% CI, 1.26-1.41; P < .001). Only 3309 residents (12.1%; 2382 women [12.3%] vs 927 men [11.8%]) saw a palliative care physician in the year before death, but those who did experienced greater than 50% lower odds of an end-of-life transition of care (adjusted odds ratio, 0.48; 95% CI, 0.43-0.54); P < .001) and greater than 25% lower odds of receiving antibiotics (adjusted odds ratio, 0.74; 95% CI, 0.68-0.81; P < .001). Conclusions and Relevance: In this study, many nursing home residents with advanced dementia, especially men, received burdensome interventions and antibiotics in their final days of life. These findings appear to emphasize the need for sex-specific analysis in dementia research as well as the expansion of palliative care and end-of-life antimicrobial stewardship in nursing homes.

Use of Medications of Questionable Benefit at the End of Life in Nursing Home Residents with Advanced Dementia.

OBJECTIVES: To determine the prevalence of and resident characteristics associated with the prescription of medications of questionable benefit (MQBs) near the end of life in older adults with advanced dementia in nursing homes. DESIGN: Population-based, cross-sectional study using Resident Assessment Instrument Minimum Data Set 2.0 linked to health administrative data. SETTING: Ontario, Canada. PARTICIPANTS: All 9,298 nursing home residents with advanced dementia who died between June 1, 2010, and March 31, 2013; were aged 66 and older at time of death; and received at least one MQB in their last year of life. MEASUREMENTS: Prevalence of eight classes of MQBs (e.g., lipid-lowering agents, antidementia drugs) used in the last 120 days and last week of life. RESULTS: Of older nursing home residents with advanced dementia who received at least one MQB in the last year of life, 8,027 (86.3%) received them in the last 120 days and 4,180 (45.0%) in the last week of life. The most commonly prescribed MQB were antidementia (63.6%) and lipid-lowering agents (47.8%). Severe cognitive impairment (adjusted odds ratio (aOR) = 1.19, 95% confidence interval (CI) = 1.07-1.33, P = .002) and fewer signs and symptoms of health instability (aOR = 1.58, 95% CI = 1.44-1.74, P < .001) were associated with MQB use into the last week of life. Seeing a neurologist or psychiatrist was associated with less likelihood of MQB use in the last week of life. CONCLUSION: Many nursing home residents with advanced dementia are dispensed MQBs in the last week of life. Given that MQBs may cause more harm than benefit in this vulnerable population, it is important for physicians to actively reassess the role of all medications toward the end of life.

Acute Poisoning During Pregnancy: Observations from the Toxicology Investigators Consortium.

Acute poisonings during pregnancy pose a particular challenge to health care providers because of the potential for an immediate life threat or possible life-long implications for both the mother and fetus, including teratogenicity of the poison or its antidote. We describe recent consequential exposures among pregnant women in the USA. We identified all poisoning cases involving pregnant women that were catalogued by the medical toxicology services across the 37 sites of the Toxicology Investigators Consortium (ToxIC) Registry of the American College of Medical Toxicology between January 2010 and December 2012. Of 17,529 exposure cases reported in the ToxIC Registry, 103 (0.6 %) involved pregnant women, 80 % of whom were symptomatic and about a quarter displayed a specific toxidrome. The majority of cases (n = 53; 51.5 %) involved intentional exposures, most commonly to pharmaceutical agents, followed by unintentional pharmaceutical exposures (10 %) and withdrawal syndromes (9 %). Non-opioid analgesics were the most common class of agents encountered (31 %), followed by sedative-hypnotics/muscle relaxants (18 %), opioids (17 %), anti-convulsants (10 %), and anti-depressants (10 %). Over a third of cases involved exposure to multiple substances, and 32 % involved exposure to more than one drug class. The most commonly administered antidotes were N-acetylcysteine (23 %), sodium bicarbonate (10 %), flumazenil (4 %), and physostigmine (4 %). About half of acute poisoning cases among pregnant women presenting for emergency care involved intentional exposures, mostly with over-the-counter analgesics and psychoactive medications. Clinicians should be cognizant of the unique circumstances, maternal and fetal risks, and management principles of the acutely poisoned pregnant woman.

Transfer of dabigatran and dabigatran etexilate mesylate across the dually perfused human placenta.

OBJECTIVE: To assess the transplacental pharmacokinetics at term of the oral thrombin inhibitor, dabigatran, and its prodrug, dabigatran etexilate mesylate, to estimate fetal drug exposure. METHODS: Placentae were obtained with informed consent after cesarean delivery of healthy term pregnancies in Toronto, Ontario, Canada. The transplacental transfer of dabigatran and dabigatran etexilate mesylate was separately assessed using the ex vivo dual perfusion of an isolated human placental cotyledon. Dabigatran, at a concentration of 35 ng/mL, was added to the maternal circulation at the start of the experimental phase. Maternal and fetal samples were taken throughout the preexperimental (1 hour) and experimental (3 hours) phases for measurement of dabigatran and markers of placental viability. Separate placenta perfusions with dabigatran etexilate mesylate were conducted at an initial maternal concentration of 3.5 ng/mL. Dabigatran and dabigatran etexilate mesylate were measured using liquid chromatography-tandem mass spectrometry. RESULTS: There was slower transfer of dabigatran compared with antipyrine from the maternal-to-fetal circulation, because the median fetal-to-maternal concentration ratio was 0.33 (interquartile range 0.29-0.38) after 3 hours (n=3). The prodrug, dabigatran etexilate mesylate, had limited placental transfer as characterized by a fetal-to-maternal ratio of 0.17 (interquartile range 0.15-0.17) after 3 hours (n=3). Placental viability markers for all perfusions were within normal ranges. CONCLUSION: This report provides direct evidence of the transfer of dabigatran and its prodrug across the term human placenta from the mother to the fetus. From a clinical perspective, these data suggest that, pending further study, dabigatran should not be used for anticoagulation of pregnant women, because the drug may have an adverse effect on fetal blood coagulation.

The detection and quantification of ethyl glucuronide in placental tissue and placental perfusate by headspace solid-phase microextraction coupled with gas chromatography-mass spectrometry.

BACKGROUND: Ethyl glucuronide (EtG) is arising as a promising biomarker of heavy prenatal alcohol exposure, however its transfer across the human placenta is still unclear and is currently being investigated using the ex vivo placental perfusion model. This model allows for sampling from placental tissue and placental perfusate, which is a surrogate to plasma. OBJECTIVE: To develop a method for detecting and quantifying EtG in placental perfusate and tissue using headspace solid-phase microextraction (HS-SPME) coupled with gas chromatography-mass spectrometry (GC-MS). METHODS: A method was optimized by manipulation of the following components to attain the highest peak counts for the quantifying ions of EtG and its deuterated internal standard on the mass spectrum: cartridges used for solid phase extraction, injection method, derivatizing agent, pre-injection parameters, SPME fiber, GC ramp speed, and GC column flow. RESULTS: The final method utilized involved solid phase extraction of standards via UCT CleanScreen Cartridges, derivatization with heptafluorobutyric acid, and introduction into the GC via HS-SPME with adsorption to a polydimethylsiloxane fiber. The method has improved sensitivity over other methods that quantify EtG in blood using GC-MS, with detection limits of 1.6 ng/mL and 13.7 ng/g for placental perfusate and tissue, respectively. The method was applied to samples collected from the fetal reservoir during the ex vivo placental perfusion model and EtG was detected in the fetal circulation after 20 minutes of perfusion, indicating transfer of EtG. CONCLUSIONS: The present method is sensitive and can be used to quantify EtG transfer during ex vivo placental perfusion experiments.