Effects of Electronic Cigarette Vaping on Cardiac and Vascular Function, and Post-myocardial Infarction Remodeling in Rats.

The effect of electronic cigarette (E-cig) vaping on cardiac and vascular function during the healing phase of myocardial infarction (MI), and post-MI remodeling was investigated. Sprague Dawley rats were subjected to left coronary artery ligation to induce MI. One week later, rats were randomized to receive either 12 weeks of exposure to purified air (n = 37) or E-cig vapor (15 mg/ml of nicotine) (n = 32). At 12 weeks, cardiac and vascular function, and post-MI remodeling were assessed. Baseline blood flow in the femoral artery did not differ between groups, but peak reperfusion blood flow was blunted in the E-cig group (1.59 ± 0.15 ml/min) vs. the air group (2.11 ± 0.18 ml/min; p = 0.034). Femoral artery diameter after reperfusion was narrower in the E-cig group (0.54 ± 0.02 mm) compared to the air group (0.60 ± 0.02 mm; p = 0.023). Postmortem left ventricular (LV) volumes were similar in the E-cig (0.69 ± 0.04 ml) and air groups (0.73 ± 0.04 ml; p = NS); and myocardial infarct expansion index did not differ between groups (1.4 ± 0.1 in E-cig group versus 1.3 ± 0.1 in air group; p = NS). LV fractional shortening by echo did not differ between groups at 12 weeks (E-cig at 29 ± 2% and air at 27 ± 1%; p = NS). Exposure to E-cig during the healing phase of MI was associated with altered vascular function with reduced femoral artery blood flow and diameter at reperfusion, but not with worsened LV dilation or worsened cardiac function.

Implementation of pharmacist-led services for sexual and gender minorities: A multisite descriptive report.

PURPOSE: This paper compares and contrasts the implementation of pharmacist-led services for 3 different sexual and gender minority populations across California, Mississippi, and Florida. SUMMARY: Implementation of pharmacist-led services tailored to sexual and gender minorities may be a potential mechanism to address health disparities in these populations. Clinical pharmacists have the potential to provide care with cultural humility and improve health outcomes by optimizing medication regimens, reducing adverse drug events, enhancing medication acquisition, and improving medication adherence. CONCLUSION: The services provided by clinical pharmacists varied across sites and included management of gender-affirming hormone therapy, HIV antiretroviral medication adherence programming, primary care and chronic disease state management, and involvement in care related to mental health, psychiatry, and substance use as well as sexual health. Various legislative and regulatory barriers and differences in scope of practice for pharmacists were also identified. This paper advocates for the expansion of pharmacy-led services and the adoption of a culturally humble approach to patient care.

Flavoring Agents in E-cigarette Liquids: A Comprehensive Analysis of Multiple Health Risks.

The availability of a wide range of flavored e-cigarettes is one of the primary reasons for vaping initiation and persistent use among adolescents and young people. This plethora of flavors available on the market are crafted using different flavoring agents such as cinnamaldehyde, vanillin, benzaldehyde, ethyl maltol, menthol, and dimethylpyrazine. Recent studies have brought to light the potential risks associated with e-cigarette flavoring agents and their effects on various organ systems, both with and without nicotine. Research has demonstrated that flavoring agents can induce inflammation, endothelial dysfunction, epithelial barrier disruption, oxidative stress, DNA damage, electrophysiological alterations, immunomodulatory effects, and behavioral changes, even independently of nicotine. Notably, these negative outcomes adversely affect cardiovascular system by reducing cell viability, decreasing endothelial nitric oxide synthase, nitric oxide bioavailability, soluble guanylyl cyclase activity and cyclic guanosine monophosphate accumulation, impairing endothelial proliferation and tube formation, and altering vasoreactivity resulting in vascular dysfunction. In the heart, these agents decrease parasympathetic activity, induce depolarization of resting membrane potential, loss of rhythmicity, increase isovolumic relaxation time, and change in ventricular repolarization and ventricular tachyarrhythmias. It is found that the specific response elicited by flavoring agents in different organ systems varies depending on the flavor used, the concentration of the flavoring agent, and the duration of exposure. However, the literature on the effects of flavoring agents is currently limited, emphasizing the need for more preclinical and randomized clinical trials to gain a deeper understanding and provide further evidence of the harmful effects of flavored e-cigarette use. In summary, recent research suggests that flavoring agents themselves can have detrimental effects on the body. To fully comprehend these effects, additional preclinical and clinical studies are needed to explore the risks associated with flavored e-cigarette usage.

Exposure to environmental airborne particulate matter caused wide-ranged transcriptional changes and accelerated Alzheimer's-related pathology: A mouse study.

Air pollution poses a significant threat to human health, though a clear understanding of its mechanism remains elusive. In this study, we sought to better understand the effects of various sized particulate matter from polluted air on Alzheimer's disease (AD) development using an AD mouse model. We exposed transgenic Alzheimer's mice in their prodromic stage to different sized particulate matter (PM), with filtered clean air as control. After 3 or 6 months of exposure, mouse brains were harvested and analyzed. RNA-seq analysis showed that various PM have differential effects on the brain transcriptome, and these effects seemed to correlate with PM size. Many genes and pathways were affected after PM exposure. Among them, we found a strong activation in mRNA Nonsense Mediated Decay pathway, an inhibition in pathways related to transcription, neurogenesis and survival signaling as well as angiogenesis, and a dramatic downregulation of collagens. Although we did not detect any extracellular Aß plaques, immunostaining revealed that both intracellular Aß1-42 and phospho-Tau levels were increased in various PM exposure conditions compared to the clean air control. NanoString GeoMx analysis demonstrated a remarkable activation of immune responses in the PM exposed mouse brain. Surprisingly, our data also indicated a strong activation of various tumor suppressors including RB1, CDKN1A/p21 and CDKN2A/p16. Collectively, our data demonstrated that exposure to airborne PM caused a profound transcriptional dysregulation and accelerated Alzheimer's-related pathology.

The Penn Medicine COVID-19 Therapeutics Committee-Reflections on a Model for Rapid Evidence Review and Dynamic Practice Recommendations During a Public Health Emergency.

The Penn Medicine COVID-19 Therapeutics Committee-an interspecialty, clinician-pharmacist, and specialist-front line primary care collaboration-has served as a forum for rapid evidence review and the production of dynamic practice recommendations during the 3-year coronavirus disease 2019 public health emergency. We describe the process by which the committee went about its work and how it navigated specific challenging scenarios. Our target audiences are clinicians, hospital leaders, public health officials, and researchers invested in preparedness for inevitable future threats. Our objectives are to discuss the logistics and challenges of forming an effective committee, undertaking a rapid evidence review process, aligning evidence-based guidelines with operational realities, and iteratively revising recommendations in response to changing pandemic data. We specifically discuss the arc of evidence for corticosteroids; the noble beginnings and dangerous misinformation end of hydroxychloroquine and ivermectin; monoclonal antibodies and emerging viral variants; and patient screening and safety processes for tocilizumab, baricitinib, and nirmatrelvir-ritonavir.

Cigarette smoke stimulates clonal expansion of Jak2V617F and Tet2-/- cells.

Introduction: Somatic mutations in myeloid growth factor pathway genes, such as JAK2, and genes involved in epigenetic regulation, such as TET2, in hematopoietic stem cells (HSCs) leads to clonal hematopoiesis of indeterminate potential (CHIP) which presents a risk factor for hematologic malignancy and cardiovascular disease. Smoking behavior has been repeatedly associated with the occurrence of CHIP but whether smoking is an environmental inflammatory stressor in promoting clonal expansion has not been investigated. Methods: We performed in vivo smoke exposures in both wildtype (WT) mice and transplanted mice carrying Jak2V617F mutant and Tet2 knockout (Tet-/-) cells to determine the impact of cigarette smoke (CS) in the HSC compartment as well as favoring mutant cell expansion. Results: WT mice exposed to smoke displayed increased oxidative stress in long-term HSCs and suppression of the hematopoietic stem and progenitor compartment but smoke exposure did not translate to impaired hematopoietic reconstitution in primary bone marrow transplants. Gene expression analysis of hematopoietic cells in the bone marrow identified an imbalance between Th17 and Treg immune cells suggesting a local inflammatory environment. We also observed enhanced survival of Jak2V617F cells exposed to CS in vivo and cigarette smoke extract (CSE) in vitro. WT bone marrow hematopoietic cells from WT/Jak2V617F chimeric mice exposed to CS demonstrated an increase in neutrophil abundance and distinct overexpression of bone marrow stromal antigen 2 (Bst2) and retinoic acid early transcript 1 (Raet1) targets. Bst2 and Raet1 are indicative of increased interferon signaling and cellular stress including oxidative stress and DNA damage, respectively. In chimeric mice containing both WT and Tet2-/- cells, we observed an increased percentage of circulating mutant cells in peripheral blood post-cigarette smoke exposure when compared to pre-exposure levels while this difference was absent in air-exposed controls. Conclusion: Altogether, these findings demonstrate that CS results in an inflamed bone marrow environment that provides a selection pressure for existing CHIP mutations such as Jak2V617F and Tet2 loss-of-function.

Exposure to quasi-ultrafine particulate matter accelerates memory impairment and Alzheimer's disease-like neuropathology in the AppNL-G-F knock-in mouse model.

Exposure to traffic-related air pollution consisting of particulate matter (PM) is associated with cognitive decline leading to Alzheimer's disease (AD). In this study, we sought to examine the neurotoxic effects of exposure to ultrafine PM and how it exacerbates neuronal loss and AD-like neuropathology in wildtype (WT) mice and a knock-in mouse model of AD (AppNL-G-F/+-KI) when the exposure occurs at a prepathologic stage or at a later age with the presence of neuropathology. AppNL-G-F/+-KI and WT mice were exposed to concentrated ultrafine PM from local ambient air in Irvine, California, for 12 weeks, starting at 3 or 9 months of age. Particulate matter-exposed animals received concentrated ultrafine PM up to 8 times above the ambient levels, whereas control animals were exposed to purified air. Particulate matter exposure resulted in a marked impairment of memory tasks in prepathologic AppNL-G-F/+-KI mice without measurable changes in amyloid-ß pathology, synaptic degeneration, and neuroinflammation. At aged, both WT and AppNL-G-F/+-KI mice exposed to PM showed a significant memory impairment along with neuronal loss. In AppNL-G-F/+-KI mice, we also detected an increased amyloid-ß buildup and potentially harmful glial activation including ferritin-positive microglia and C3-positive astrocytes. Such glial activation could promote the cascade of degenerative consequences in the brain. Our results suggest that exposure to PM impairs cognitive function at both ages while exacerbation of AD-related pathology and neuronal loss may depend on the stage of pathology, aging, and/or state of glial activation. Further studies will be required to unveil the neurotoxic role of glial activation activated by PM exposure.

Subchronic co-exposure to particulate matter and fructose-rich-diet induces insulin resistance in male Sprague Dawley rats.

Insulin resistance (IR) and metabolic disorders are non-pulmonary adverse effects induced by fine particulate matter (PM2.5) exposure. The worldwide pandemic of high fructose sweeteners and fat rich modern diets, also contribute to IR development. We investigated some of the underlying effects of IR, altered biochemical insulin action and Insulin/AKT pathway biomarkers. Male Sprague Dawley rats were subchronically exposed to filtered air, PM2.5, a fructose rich diet (FRD), or PM2.5 + FRD. Exposure to PM2.5 or FRD alone did not induce metabolic changes. However, PM2.5 + FRD induced leptin release, systemic hyperinsulinemia, and Insulin/AKT dysregulation in insulin-sensitive tissues preceded by altered AT1R levels. Histological damage and increased HOMA-IR were also observed from PM2.5 + FRD co-exposure. Our results indicate that the concomitant exposure to a ubiquitous environmental pollutant, such as PM2.5, and a metabolic disease risk factor, a FRD, can contribute to the metabolic disorder pandemic occurring in highly polluted locations.

Effects of Electronic Cigarette Exposure on Myocardial Infarction and No-Reflow, and Cardiac Function in a Rat Model.

PURPOSE: We investigated the effects of exposure to electronic cigarettes (E-cig) vapor on the sizes of the no-reflow and myocardial infarction regions, and cardiovascular function compared to exposure to purified air and standard cigarette smoke. METHODS AND RESULTS: Sprague Dawley rats (both male and female, 6 weeks old) were successfully exposed to filtered air (n = 32), E-cig with nicotine (E-cig Nic+, n = 26), E-cig without nicotine (E-cig Nic-, n = 26), or standard cigarette smoke (1R6F reference, n = 31). All rats were exposed to inhalation exposure for 8 weeks, prior to being subjected to 30 minutes of left coronary artery occlusion followed by 3 hours of reperfusion. Exposure to E-cig vapor with or without nicotine or exposure to standard cigarettes did not increase myocardial infarct size or worsen the no-reflow phenomenon. Exposure to E-cig Nic+ reduced the body weight gain, and increased the LV weight normalized to body weight and LV wall thickness and enhanced the collagen deposition within the LV wall. E-cig exposure led to cardiovascular dysfunction, such as reductions in cardiac output, LV positive and negative dp/dt, suggesting a reduction in contractility and relaxation, and increased systemic arterial resistance after coronary artery occlusion and reperfusion in rats compared to air or cigarette exposure. CONCLUSIONS: E-cig exposure did not increase myocardial infarct size or worsen the no-reflow phenomenon, but induced deleterious changes in LV structure leading to cardiovascular dysfunction and increased systemic arterial resistance after coronary artery occlusion followed by reperfusion.

Crystal structures of polymerized lithium chloride and dimethyl sulfoxide in the form of {2LiCl·3DMSO} n and {LiCl·DMSO} n.

Two novel LiCl·DMSO polymer structures were created by combining dry LiCl salt with dimethyl sulfoxide (DMSO), namely, catena-poly[[chlorido-lithium(I)]-µ-(dimethyl sulfoxide)-κ2 O:O-[chlorido-lithium(I)]-di-µ-(dimethyl sulfoxide)-κ4 O:O], [Li2Cl2(C2H6OS)3] n , and catena-poly[lithium(I)-µ-chlorido-µ-(dimethyl sulfoxide)-κ2 O:O], [LiCl(C2H6OS)] n . The initial synthesized phase had very small block-shaped crystals (<0.08 mm) with monoclinic symmetry and a 2 LiCl: 3 DMSO ratio. As the solution evaporated, a second phase formed with a plate-shaped crystal morphology. After about 20 minutes, large (>0.20 mm) octa-hedron-shaped crystals formed. The plate crystals and the octa-hedron crystals are the same tetra-gonal structure with a 1 LiCl: 1 DMSO ratio. These structures are reported and compared to other known LiCl·solvent compounds.

Evolving Primary Care Utilization of Transgender and Gender-Nonconforming People at a Community Sexual Health Clinic.

Purpose: Prior research has found that transgender people are less likely to have access to health care and health insurance than their cisgender peers and are more likely to delay seeking care due to systemic discrimination and stigma. To this end, this study seeks to measure transgender and gender-nonconforming (TGNC) clients' primary care utilization and compare them to their cisgender peers. Methods: Demographic data and self-reported primary care utilization from 14,372 clients attending a community health center in Los Angeles, CA, from 2018 to 2020 were examined. Descriptive statistics and multivariable regression analyses were used to examine correlates of gender identity on primary care utilization metrics-Hepatitis A, Hepatitis B, and Human Papillomavirus (HPV) vaccinations and recent primary care visits. Results: Of TGNC clients, 38.0% reported being vaccinated for Hepatitis A compared to 49.2% of cisgender clients (p<0.01) and 42.6% reported being vaccinated for Hepatitis B compared to 51.6% of cisgender clients (p<0.01). TGNC clients had higher odds of engaging with the HPV vaccination series than their cisgender peers (adjusted odds ratio [aOR]=1.28, 95% confidence interval [CI] 1.03-1.59). TGNC clients had higher odds of seeing their primary care provider within the preceding 2 years (aOR=1.72, 95% CI 1.01-2.93) compared to non-TGNC clients. Conclusions: This study's results found that TGNC clients were more likely to access certain primary care services more often than their cisgender counterparts. Our results support the efficacy of such interventions, such as a health care setting designed to support the health of gender minority people, and see similar, if not greater, primary care engagement in transgender persons compared to their cisgender peers.

Exposure to environmentally relevant concentrations of ambient fine particulate matter (PM2.5) depletes the ovarian follicle reserve and causes sex-dependent cardiovascular changes in apolipoprotein E null mice.

BACKGROUND: Fine particulate matter (PM2.5) exposure accelerates atherosclerosis and contains known ovotoxic chemicals. However, effects of exposure to PM2.5 on the finite ovarian follicle pool have hardly been investigated, nor have interactions between ovarian and cardiovascular effects. We hypothesized that subchronic inhalation exposure to human-relevant concentrations of PM2.5 results in destruction of ovarian follicles via apoptosis induction, as well as accelerated recruitment of primordial follicles into the growing pool. Further, we hypothesized that destruction of ovarian follicles enhances the adverse cardiovascular effects of PM2.5 in females. RESULTS: Hyperlipidemic apolipoprotein E (Apoe) null ovary-intact or ovariectomized female mice and testis-intact male mice were exposed to concentrated ambient PM2.5 or filtered air for 12 weeks, 5 days/week for 4 h/day using a versatile aerosol concentration enrichment system. Primordial, primary, and secondary ovarian follicle numbers were decreased by 45%, 40%, and 17%, respectively, in PM2.5-exposed ovary-intact mice compared to controls (P < 0.05). The percentage of primary follicles with granulosa cells positive for the mitosis marker Ki67 was increased in the ovaries from PM2.5-exposed females versus controls (P < 0.05), consistent with increased recruitment of primordial follicles into the growing pool. Exposure to PM2.5 increased the percentages of primary and secondary follicles with DNA damage, assessed by γH2AX immunostaining (P < 0.05). Exposure to PM2.5 increased the percentages of apoptotic antral follicles, determined by TUNEL and activated caspase 3 immunostaining (P < 0.05). Removal of the ovaries and PM2.5-exposure exacerbated the atherosclerotic effects of hyperlipidemia in females (P < 0.05). While there were statistically significant changes in blood pressure and heart rate variability in PM2.5-compared to Air-exposed gonad-intact males and females and ovariectomized females, the changes were not consistent between exposure years and assessment methods. CONCLUSIONS: These results demonstrate that subchronic PM2.5 exposure depletes the ovarian reserve by increasing recruitment of primordial follicles into the growing pool and increasing apoptosis of growing follicles. Further, PM2.5 exposure and removal of the ovaries each increase atherosclerosis progression in Apoe-/- females. Premature loss of ovarian function is associated with increased risk of osteoporosis, cardiovascular disease and Alzheimer's disease in women. Our results thus support possible links between PM2.5 exposure and other adverse health outcomes in women.

3-Quinuclidinyl benzilate (agent BZ) toxicokinetics in rats.

3-Quinuclidinyl benzilate (BZ) ranks among incapacitating military warfare agents. It acts as a competitive inhibitor on muscarinic receptors leading to non-lethal mental impairment. The present study aimed to investigate toxicokinetics of BZ in rats. Moreover, BZ can be exploited to produce a pharmacological model of Alzheimer's disease; thus, this paper focuses mainly on the BZ distribution to the brain. Wistar rats were administered i.p. with BZ (2 and 10 mg/kg). The BZ concentration was determined using LC-MS/MS in plasma, urine, bile, brain, kidney and liver. The sample preparation was based on a solid phase extraction (liquids) or protein precipitation (organ homogenates). The plasma concentration peaked at 3 min (204.5 ± 55.4 and 2185.5 ± 465.4 ng/ml). The maximal concentration in the brain was reached several minutes later. Plasma elimination half-life was 67.9 ± 3.4 in the 2 mg/kg group and 96.6 ± 27.9 in the 10 mg/kg group. BZ concentrations remained steady in the brain, with slow elimination (t1/2 506.9 ± 359.5 min). Agent BZ is excreted mainly via the urine. Steady BZ concentration in the brain could explain the previously published duration of the significant impairment in passive avoidance tasks in rats after an injection of BZ.

Determination of K869, a Novel Oxime Reactivator of Acetylcholinesterase, in Rat Body Fluids and Tissues by Liquid-Chromatography Methods: Pharmacokinetic Study.

Oxime reactivators of acetylcholinesterase (AChE) represent an integral part of standard antidote treatment of organophosphate poisoning. Oxime K869 is a novel bisquaternary non-symmetric pyridinium aldoxime with two pyridinium rings connected by a tetramethylene bridge where two chlorines modify the pyridinium ring bearing the oxime moiety. Based on in vitro assays, K869 is a potent AChE and butyrylcholinesterase (BChE) reactivator. For the investigation of the basic pharmacokinetic properties of K869 after its intramuscular application, new HPLC-UV and LC-MS/MS methods were developed and validated for its determination in rat body fluids and tissues. In this study, the SPE procedure for sample pretreatment was optimized as an alternative to routine protein precipitation widely used in oxime pharmacokinetics studies. K869 oxime is quickly absorbed into the central compartment reaching its maximum in plasma (39 ± 4 µg/mL) between 15 and 20 min. The majority of K869 was eliminated by kidneys via urine when compared with biliary excretion. However, only a limited amount of K869 (65 ± 4 ng/g of brain tissue) was found in the brain 30 min after oxime administration. Regarding the brain/plasma ratio calculated (less than 1%), the penetration of K869 into the brain did not exceed conventionally used oximes.

Survey to determine the relative importance of clinical factors used to make empiric antibiotic decisions.

A cross-sectional survey study of inpatient prescribers in a university health system was performed to assess the importance they place on different clinical risk factors when making empiric antibiotic decisions. Our findings show that these clinical risk factors were weighted differently based on the clinical scenario and the type of prescriber.

E-cigarette or Vaping Product Use-Associated Lung Injury Produced in an Animal Model From Electronic Cigarette Vapor Exposure Without Tetrahydrocannabinol or Vitamin E Oil.

E-cigarette or vaping product use-associated lung injury was recognized in the United States in the summer of 2019 and is typified by acute respiratory distress, shortness of breath, chest pain, cough, and fever, associated with vaping. It can mimic many of the manifestations of coronavirus disease 2019 (COVID-19). Some investigators have suggested that E-cigarette or vaping product use-associated lung injury was due to tetrahydrocannabinol or vitamin E acetate oil mixed with the electronic cigarette liquid. In experimental rodent studies initially designed to study the effect of electronic cigarette use on the cardiovascular system, we observed an E-cigarette or vaping product use-associated lung injury-like condition that occurred acutely after use of a nichrome heating element at high power, without the use of tetrahydrocannabinol, vitamin E, or nicotine. Lung lesions included thickening of the alveolar wall with foci of inflammation, red blood cell congestion, obliteration of alveolar spaces, and pneumonitis in some cases; bronchi showed accumulation of fibrin, inflammatory cells, and mucus plugs. Electronic cigarette users should be cautioned about the potential danger of operating electronic cigarette units at high settings; the possibility that certain heating elements may be deleterious; and that E-cigarette or vaping product use-associated lung injury may not be dependent upon tetrahydrocannabinol, vitamin E, or nicotine.

E-Cigarette Exposure Decreases Bone Marrow Hematopoietic Progenitor Cells.

Electronic cigarettes (E-cigs) generate nicotine containing aerosols for inhalation and have emerged as a popular tobacco product among adolescents and young adults, yet little is known about their health effects due to their relatively recent introduction. Few studies have assessed the long-term effects of inhaling E-cigarette smoke or vapor. Here, we show that two months of E-cigarette exposure causes suppression of bone marrow hematopoietic stem and progenitor cells (HSPCs). Specifically, the common myeloid progenitors and granulocyte-macrophage progenitors were decreased in E-cig exposed animals compared to air exposed mice. Competitive reconstitution in bone marrow transplants was not affected by two months of E-cig exposure. When air and E-cig exposed mice were challenged with an inflammatory stimulus using lipopolysaccharide (LPS), competitive fitness between the two groups was not significantly different. However, mice transplanted with bone marrow from E-cigarette plus LPS exposed mice had elevated monocytes in their peripheral blood at five months post-transplant indicating a myeloid bias similar to responses of aged hematopoietic stem cells (HSC) to an acute inflammatory challenge. We also investigated whether E-cigarette exposure enhances the selective advantage of hematopoietic cells with myeloid malignancy associated mutations. E-cigarette exposure for one month slightly increased JAK2V617F mutant cells in peripheral blood but did not have an impact on TET2-/- cells. Altogether, our findings reveal that chronic E-cigarette exposure for two months alters the bone marrow HSPC populations but does not affect HSC reconstitution in primary transplants.

In vitro and in vivo metabolism of 3-quinuclidinyl benzilate by high-resolution mass spectrometry.

3-Quinuclidinyl benzilate (QNB) is an anticholinergic compound that affects the nervous system. Its hallucinogenic action has led to its potential utility as an incapacitating warfare agent, and it is listed in Schedule 2 by the Organization for the Prohibition of Chemical Weapons. Although this compound has been known for a long time, limited information is available regarding its metabolism and mass spectrometric data of the metabolites, the information that could facilitate the identification of QNB in case of suspected intoxication. To the best of our knowledge, the analytical methods previously described in the literature are based on outdated procedures, which may result in a significantly lower number of observable metabolites. The aim of this work was to obtain deeper insight into QNB biotransformation using a combination of in vitro and in vivo approach. The development of a suitable method for the separation and detection of metabolites using mass spectrometry together with the identification of reliable diagnostic fragments for the unambiguous identification of QNB metabolites in the different biological matrices are also presented in this work. A screening of rat plasma, urine and tissue homogenates revealed 26 new metabolites related to the cytochrome P450 biotransformation pathway, which involves N-oxidation and hydroxylation(s) followed by O-methylation and O-glucuronosylation within phase II of the metabolism. A study showed that the brain is not metabolically active in the case of QNB and that the metabolites do not cross the blood-brain barrier; thus, the toxicodynamic effects are due to QNB itself. In addition, in vitro experiments performed using isolated human liver microsomes revealed N-oxidation as the principal metabolic pathway in human tissue. In light of current global events, the abuse of QNB by terrorists or para-military groups is a real possibility, and our findings may improve the detection systems used in laboratories involved in postexposure investigations.

Interventions for paternal perinatal depression: A systematic review.

BACKGROUND: The prevalence of paternal perinatal depression (PPD) is approximately 10%. Despite this epidemiology and what is known about the importance of paternal mental health to family functioning, there is limited research on evidence-based interventions for PPD. This systematic review aimed to investigate the literature for randomized-controlled trials (RCT) of interventions for PPD. METHODS: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Databases searched included Medline, EMBASE, EBM Reviews, PubMed, PsycInfo, and CINAHL. Search terms included depression, depressive disorder, fathers, pregnancy, and peripartum period, etc. RESULTS: The search strategy identified 2949 items. A total of 10 interventions over the course of 25 years of research met inclusion criteria. Three of the included studies found a small but significant effect on paternal depression scores. However, none of the included studies exclusively targeted paternal mental health. Instead, they addressed paternal well-being indirectly by focusing on the mother, infant, or couple relationship. LIMITATIONS: Studies did not require fathers to meet criteria for depression at baseline. This may have resulted in a selection bias, whereby the included fathers may not have required any treatment. We were also unable to perform additional statistical analyses because of the limited research available as well as the inconsistent outcome measures. CONCLUSIONS: There remains limited research on interventions assessing paternal depressive symptomatology, and none have targeted diagnosed PPD. Because of the prevalence and impact of this disorder, it is imperative to identify and offer treatments and interventions specifically tailored towards this population.