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Abstract Plasmon-driven chemical conversion is gaining burgeoning interest in the field of heterogeneous catalysis. Herein, we study the reactivity of N-methyl-4-sulfanylbenzamide (NMSB) at nanocavities of gold and silver nanoparticle aggregates under plasmonic excitation to gain understanding of the respective reaction mechanism. NMSB is a secondary amide, which is a frequent binding motive found in peptides and a common coupling product of organic molecules and biomolecules. Surface-enhanced Raman scattering (SERS) is used as a two-in-one in-situ spectroscopic tool to initiate the molecular transformation process and simultaneously monitor and analyze the reaction products. Supported by dissociative electron attachment (DEA) studies with the gas phase molecule, a hot electron-mediated conversion of NMSB to p-mercaptobenzamide and p-mercaptobenzonitrile is proposed at the plasmonic nanocavities. The reaction rate showed negligible dependence on the external temperature, ruling out the dominant role of heat in the chemical transformation at the plasmonic interface. This is reflected in the absence of a superlinear relationship between the reaction rate constant and the laser power density, and DEA and SERS studies indicate a hot-electron mediated pathway. We conclude that the overall reaction rate is limited by the availability of energetic hot electrons to the NMSB molecule.

Abstract Background Sheep and goat pox (SGP) caused by sheep poxvirus (SPV) and goat poxvirus (GPV) respectively; are transboundary and World Organisation for Animal Health (WOAH)-notifiable viral diseases. There is barely any coherent information about the distribution and prevalence of SGP for Uganda. We therefore conducted this study to describe the temporal and spatial distribution of SGP suspected outbreaks in Uganda for the period 2011–2020 as well as serologically confirm presence of SGP antibodies in suspected SGP outbreaks reported in 2021–2022. Results Thirty-seven [37] SGP outbreaks were reported across the country during the study period. North-eastern region [that comprises of Karamoja region] had the highest number of outbreaks [n = 17, 45%]; followed by Central [n = 9, 2.4%], Northern [n = 8, 2.2%] and Western region [n = 3, 0.08%]. Reports from district veterinary personnel indicate that the prevalence of; and mortality rate and case fatality rate associated with SGP were 0.06%, 0.02% and 32% respectively. There was a steady increase in the number of reported SGP outbreaks [x̄ = 4] over the study period. Seropositivity of SGPV antibodies in outbreak sheep and goats that were investigated during the study period [2021–2022] was [n = 41, 27%, 95 CI;] Conclusion Our analyses of SGPV passive and active reports indicate that SGP is present in Uganda with a decade long average of four outbreaks per annum. During this period, about a third of all SGPV-clinically infected animals died. SPG is therefore a major constraint to small ruminant health and productivity in Uganda. Introduction of animals from infected herds and breach in farm biosecurity were the most important predictors of SGP outbreaks. In addition to the already existing SGP commercial vaccines, small ruminant screening for SGPV before introducing them to naïve herds and ensuring on farm biosecurity should be part of the SGP control tool pack for Ugandan small ruminant farmers.

The Internet of Things (IoT) is a complex technology with various applications that have become a vital part of our daily life. The number of connected devices and the Internet of Things continues to increase. In terms of bandwidth, service availability, security controls, cyberattacks, and privacy problems, transporting the huge data created by these IoT devices to the cloud offers concern and challenges comprising intermittent connection, service unavailability, data loss at rest, in use, and in motion, unhardened device and server, unpatched device and server, and exploitation vulnerabilities. Mobile computing (MC) is a strategic solution to tackle these difficulties by offering flexible data processing and storage to end users, increase security controls and with customized IoT devices for varied geographic locations. This paper provides a complete description of the components of the IoT architecture. After that, it elaborates on similar security threats and potential cyberattacks in the context of mobile computing-based IoT and suggests solutions. In conclusion, we provide a secure mobile computing architecture design for IoT applications.

Abstract Background Prior to the first recorded outbreak of Rift Valley fever (RVF) in Uganda, in March 2016, earlier studies done until the 1970’s indicated the presence of the RVF virus (RVFV) in the country, without any recorded outbreaks in either man or animals. While severe outbreaks of RVF occurred in the neighboring countries, none were reported in Uganda despite forecasts that placed some parts of Uganda at similar risk. The Ministry of Agriculture, Animal Industry and Fisheries (MAAIF) undertook studies to determine the RVF sero-prevalence in risk prone areas. Three datasets from cattle sheep and goats were obtained; one from retrospective samples collected in 2010–2011 from the northern region; the second from the western region in 2013 while the third was from a cross-sectional survey done in 2016 in the south-western region. Laboratory analysis involved the use of the Enzyme Linked Immunosorbent Assays (ELISA). Data were subjected to descriptive statistical analyses, including non-parametric chi-square tests for comparisons between districts and species in the regions. Results During the Yellow Fever outbreak investigation of 2010–2011 in the northern region, a total sero-prevalence of 6.7% was obtained for anti RVFV reacting antibodies (IgG and IgM) among the domestic ruminant population. The 2013 sero-survey in the western region showed a prevalence of 18.6% in cattle and 2.3% in small ruminants. The 2016 sero-survey in the districts of Kabale, Kanungu, Kasese, Kisoro and Rubirizi, in the south-western region, had the respective district RVF sero-prevalence of 16.0, 2.1, 0.8, 15.1and 2.7% among the domestic ruminants combined for this region; bovines exhibited the highest cumulative sero-prevalence of 15.2%, compared to 5.3 and 4.0% respectively for sheep and goats per species for the region. Conclusions The absence of apparent outbreaks in Uganda, despite neighboring enzootic areas, having minimal restrictions to the exchange of livestock and their products across borders, suggest an unexpected RVF activity in the study areas that needs to be unraveled. Therefore, more in-depth studies are planned to mitigate the risk of an overt RVF outbreak in humans and animals as has occurred in neighboring countries.

We have used a crossed electron molecular beam setup to investigate the behavior of the anticancer drug temozolomide (TMZ) upon the attachment of low-energy electrons (0–14 eV) in the gas phase. Upon a single electron attachment, eight anionic fragments are observed, the most intense being an anion with mass of 109 u at a resonance energy of 0 eV. Quantum chemical calculations suggest that this ion is generated after the tetrazine ring opens along a N–N bond and its fragments leave the molecule, forming an imidazole-carboxamide species. This ion represents the most abundant fragment, with further fragments following from its dissociation. The tetrazine ring cleavage reaction forming N2 is thus the driving force of TMZ reactivity upon electron attachment.

Abstract Background Rabies is a deadly preventable viral disease that affects all warm-blooded animals and widespread in many regions including Africa. The disease remains of major public health importance in Uganda. The purpose of this study was to establish Knowledge, Attitude, Practice (KAP) of Rabies in Moyo and Ntoroko districts and to characterize Rabies virus (RABV) strains from seven districts of Uganda with consistent prevalence of rabies. Methods KAP survey data were collected based on animal biting history by interviewing the head of the veterinary departments, the medical centers and selected households from the study sites. Data were obtained from 84 households in Ntoroko and Moyo districts. Thirty-five (35) brain samples were collected from bovine, dogs, goats, foxes, jackals ad sheep between 2011 and 2013. Samples were tested using fluorescent antibody test (FAT), One step RT-PCR (following RNA extraction) and partial RABV N gene was sequenced by Sanger method before phylogenetic and phylogeographic analyses of sequences. Results Scarcity of post-exposure prophylaxis services in the health centers was noted. Poor attitude of wound washing and deficiency of knowledge on how to handle wounds related to dog bites and the significance among household participants lacked. There is a high risk of rabies infection due to a limited dog’s vaccination. Dog biting episodes in humans were of 75.00 and 62.50% in Moyo and Ntoroko districts respectively. Twenty-seven (27) samples tested positive for rabies by FAT and PCR. Ugandan sequences were closely related (97% nucleotide id) to the rabies virus sequences from Tanzania, Rwanda, Burundi, Nigeria, Central African Republic and Sudan with both the “Africa 1A” and “Africa 1B” RABV clades represented. A putative new clade 1D was also detected. Conclusions Rabies remains a public health hazard in Uganda. There is urgent need to establish advocacy programs in both schools and communities to curtail the spread of rabies. Increasing the knowledge regarding wound washing, post-exposure prophylaxis and dogs vaccination would enhance prevention of rabies. A strong collaboration between medical and veterinary sectors under a one health platform is required to ensure sufficient preventative services to the communities.

Background: The United States Food and Drug Administration (FDA) maintains a black-box warning for antidepressants warning of an increased risk of suicidality in children and young adults that is based on proprietary clinical trial data from study sponsors that were submitted for regulatory approval. This article aimed to assess whether the black-box warning for antidepressants is still valid today using recent drug safety data., Methods: Post-marketing adverse drug event data were obtained from the US FDA's Adverse Event Reporting System (FAERS) for the years 2017 through 2023. Logistic regression analysis was conducted using the case versus non-case methodology and adjusted for gender, age group, drug role (primary drug, secondary drug, interacting drug, and concomitant drug), initial FDA reporting year, reporter country, and a drug*gene*age group interaction., Results: In the multivariate analysis, compared to fluoxetine and patients aged 25 to 64 years, children [adjusted reporting odds ratio (aROR) = 7.38, 95% CI, 6.02-9.05] and young adults (aROR = 3.49, 95% CI, 2.65-4.59) were associated with an increased risk of reporting suicidality, but not for the elderly (aROR = 0.76, 95% CI, 0.53-1.09). Relative to fluoxetine, esketamine was associated with the highest rate of reporting suicidality in children (aROR = 3.20, 95% CI, 2.25-4.54); however, esketamine was associated with a lower risk of reporting suicidality in young adults (aROR = 0.59, 95% CI, 0.41-0.84), but not significantly in the elderly (aROR = 0.77, 95% CI, 0.48-1.23). For country-specific findings, relative to the USA, the Slovak Republic, India, and Canada had the lowest risk of reporting suicidality. For the overall study population, desvenlafaxine (aROR = 0.61, 95% CI, 0.46-0.81) and vilazodone (aROR = 0.56, 95% CI, 0.32-0.99) were the only two antidepressants associated with a reduced risk of reporting suicidality., Conclusion: This study shows that with recent antidepressant drug safety data, the US FDA's black-box warning for prescribing antidepressants to children and young adults is valid today in the USA. However, relative to the USA, 15 countries had a significantly lower risk of reporting suicidality, while 16 countries had a higher risk of reporting suicidality from 38 antidepressants and lithium., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Eugene.)

Background.  Various in vitro studies have shown fluoxetine inhibits multiple variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen causing the coronavirus disease 2019 (COVID-19) worldwide pandemic and multiple observational clinical studies have shown that patients receiving fluoxetine experienced clinical benefit by lowering the risk of intubation and death. The aim of this study is to conduct population pharmacokinetic dosing simulations to quantify the percentage of patients achieving a trough level for the effective concentration resulting in 50% (EC50) and 90% (EC90) inhibition of SARS-CoV-2 as reported in Calu-3 human lung cells. Methods.  Pharmacometric parameter estimates used in this study were obtained from the U.S. FDA website from a new drug application for fluoxetine hydrochloride. A population of 1,000 individuals were simulated at standard fluoxetine antidepressant doses (20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, and 60 mg/day) to estimate the percentage of the patients achieving a trough plasma level for the EC50 and EC90 SARS-CoV-2 inhibition. All analyses were conducted in R. Results.  By day-10 at 20 mg/day, 93.2% and 47% of the population will achieve the trough target plasma EC50 and EC90 concentrations, respectively, which translates to a lung tissue distribution coefficient of 60-times higher EC50 (283.6 ng/ml [0.82 mM]) and EC90 (1390.1 ng/ml [4.02 mM]). Further, by day-10 at an ideal dose of 40 mg/day, 99% and 93% of patients will reach the trough EC50 and EC90 concentrations, respectfully. Lastly, only a dose of 60 mg/day will reach the SARS-CoV-2 EC90 inhibitory concentration in the brain at pharmacokinetic steady-state. Conclusion. Overall, with a minimum treatment period of 10-days and a minimum dose of 20 mg/day, this study corroborates in vitro studies reporting fluoxetine inhibiting SARS-CoV-2 titers and also multiple observational clinical studies showing therapeutic benefit of fluoxetine in COVID-19 patients., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Eugene AR.)

Background.   Recent in vitro studies have shown fluoxetine inhibits the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen, including variants B.1.1.7 and B.1.351, SARS-CoV-2 spike mutations (E484K, K417N, N501Y), and one retrospective clinical study reported fluoxetine exposure at a median dose of 20 mg in patients with the SARS-CoV-2 coronavirus disease 2019 (COVID-19) had a significantly lower risk of intubation and death. The aim of this study is to conduct in silico population pharmacokinetic dosing simulations to quantify the percentage of patients achieving a trough level for the effective concentration resulting in 90% inhibition (EC90) of SARS-CoV-2 as reported in Calu-3 human lung cells.  Methods.   Population pharmacokinetic parameter estimates for a structural one-compartment model with first-order absorption were used to simulate fluoxetine pharmacokinetic data. A population of 1,000 individuals were simulated at standard fluoxetine doses (20 mg/day, 40 mg/day, and 60 mg/day) to estimate the percentage of the patients achieving a trough plasma level for the EC90 SARS-CoV-2 inhibitory concentration for a 10 day treatment period. All analyses were conducted via statistical programming in R.  Results.   Standard fluoxetine antidepressant doses resulted in a range of 81% to 97% of the patient population achieving a trough target plasma concentration of 23.2 ng/ml at day 10 and translates to a lung-tissue distribution coefficient of 60-times higher (EC90 of 4.02 mM). At a dose of 40 mg per day, at least 87% of patients will reach the trough target EC90 concentration within three days.   Conclusion.  Overall, the findings of this population pharmacokinetic dosing study corroborates in vitro and observational clinical studies reporting the first selective serotonin reuptake inhibitor fluoxetine inhibits the SARS-CoV-2 pathogen at commonly treated doses in the practice of psychiatry., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Eugene AR.)

Objective: Antipsychotic compounds are known to induce sedation somnolence and have expanded clinical indications beyond schizophrenia to regulatory approval in bipolar disorder, treatment-resistant depression, and is being repurposed in infectious diseases and oncology. However, the medical sciences literature lacks a comprehensive association between sedation and somnolence among a wide-range of antipsychotic compounds. The objective of this study is to assess the disproportionality of sedation and somnolence among thirty-seven typical and atypical antipsychotics. Materials and Methods: Patient adverse drug reactions (ADR) cases were obtained from the United States Food and Drug Administration Adverse Events Reporting System (FAERS) between January 01, 2004 and September 30, 2020 for a wide-array of clinical indications and off-label use of antipsychotics. An assessment of disproportionality were based on cases of sedation and somnolence and calculated using the case/non-case methodology. Statistical analysis resulting in the reporting odds-ratio (ROR) with corresponding 95% confidence intervals (95% CI) were conducted using the R statistical programming language. Results: Throughout the reporting period, there were a total of 9,373,236 cases with 99,251 specific ADRs reporting sedation and somnolence. Zuclopenthixol ( n = 224) ROR = 13.3 (95% CI, 11.6-15.3) was most strongly associated of sedation and somnolence and haloperidol decanoate long-acting injection (LAI) was not statistically associated sedation and somnolence. Further, among atypical antipsychotic compounds, tiapride and asenapine were the top two compounds most strongly associated with sedation and somnolence. Comprehensively, the typical antipsychotics ROR = 5.05 (95%CI, 4.97-5.12) had a stronger association with sedation and somnolence when compared to atypical antipsychotics ROR = 4.65 (95%CI, 4.47-4.84). Conclusion: We conducted a head-to-head comparison of thirty-seven antipsychotics and ranked the compounds based on the association of sedation and somnolence from ADR data collected throughout 16 years from the FAERS. The results are informative and with recent interests in repurposing phenothiazine antipsychotics in infectious disease and oncology provides an informative assessment of the compounds during repurposing and in psychopharmacology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Eugene, Eugene, Masiak and Masiak.)

Background: Sleep is one of the most essential processes required to maintain a healthy human life, and patients experiencing psychiatric illness often experience an inability to sleep. The aim of this study is to test the hypothesis that antidepressant compounds with strong binding affinities for the serotonin 5-HT2C receptor, histamine H1 receptors, or norepinephrine transporter (NET) will be associated with the highest odds of somnolence., Methods: Post-marketing cases of patient adverse drug reactions were obtained from the United States Food and Drug Administration Adverse Events Reporting System (FAERS) during the reporting window of January 2004 to September 2019. Disproportionality analyses of antidepressants reporting somnolence were calculated using the case/non-case method. The reporting odds-ratios (ROR) and corresponding 95% confidence interval (95% CI) were computed and all computations and graphing conducted in R., Results: There were a total of 69,196 reported cases of somnolence out of a total of 7,366,864 cases reported from January 2004 to September 2019. Among the 30 antidepressants assessed, amoxapine ( n  = 16) reporting odds-ratio (ROR) = 7.1 (95% confidence interval [CI] [4.3-11.7]), atomoxetine ( n = 1,079) ROR = 6.6 (95% CI [6.2-7.1]), a compound generally approved for attention deficit hyperactivity disorder (ADHD), and maprotiline ( n  = 18) ROR = 6.3 (95% CI, 3.9-10.1) were the top three compounds ranked with the highest reporting odds of somnolence. In contrast, vortioxetine ( n  = 52) ROR = 1.3 (95% CI [1.0-1.8]), milnacipran ( n  = 58) ROR = 2.1 (95% CI [1.7-2.8]), and bupropion ( n = 1,048) ROR = 2.2 (95% CI [2.1-2.4]) are least significantly associated with somnolence. Moreover, levomilnacipran ( n  = 1) ROR = 0.4 (95% CI [0.1-2.9]) was not associated with somnolence., Conclusion: Among the thirty tested antidepressants, consistent with the original hypothesis, amoxepine has strongest 5-HT2C receptor binding affinity and has the highest reporting odds of somnolence. Atomoxetine, ranked second in reporting odds of somnolence overall, binds to the NET with with the strongest binding affinity among the thirty compounds. Mirtazapine, a tetracyclic antidepressant, was ranked 11th in reporting odds of somnolence and had the strongest H1 receptor binding affinity. This study provides an informative ranking of somnolence among thirty antidepressant compounds with an already wide array of clinical indications as well as provides insight into potential drug repurposing in psychopharmacology., Competing Interests: The author declares there are no competing interests., (©2020 Eugene.)

We previously reported that testis-specific Y-encoded-like protein (TSPYLs) are transcription regulators for CYP3A4, CYP2C9, and CYP2C19. Here, we observed dual roles for TSPYLs in mediating serotonin transport and the metabolism of selective serotonin reuptake inhibitors (SSRIs) in patients with major depressive disorder (MDD). The widely prescribed SSRIs, citalopram, and escitalopram are metabolized mainly by CYP2C19. The TSPYL1 rs3828743 single nucleotide polymorphism (SNP), which decreases its suppression of CYP2C19 expression, was associated with rapid escitalopram metabolism and worse treatment response in the Mayo PGRN-AMPS clinical trial. We also found that TSPYLs can regulate expression of the serotonin transporter protein, SLC6A4, and, in turn, serotonin transport into cells. The SNPs in tight linkage disequilibrium with the TSPYL1 rs10223646 SNP were significantly correlated with baseline severity of depression in patients with MDD in the Sequenced Treatment Alternatives to Relieve Depression and International SSRI Pharmacogenomics Consortium clinical trials. Our findings suggest that genetic variation in TSPYL genes may be novel indicators for baseline severity of depression and SSRI poor response., (© 2019 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Selective serotonin reuptake inhibitors (SSRIs) are among the most widely prescribed class of drugs in the practice of psychiatry. Cytochrome P450 (CYP) 2C19 and CYP2D6 are established as clinically relevant drug metabolizing enzymes (DMEs) that influence the pharmacokinetics of SSRIs and may either be grouped as being primarily metabolized by CYP2C19 or CYP2D6. The aim of this study is to test the hypothesis that the primary drug metabolizing pathway for SSRI antidepressants are associated with adverse drug reactions (ADRs) related to physiological modulation of organs with the highest gene tissue expression., Methods: Post-marketing ADR cases were obtained from the United States Food and Drug Administration's Adverse Events Reporting System from each of the four quarters for the years 2016 and 2017. Cases were grouped based on one of two primary pharmacokinetic pharmacogenomic pathway biomarkers CYP2C19 and CYP2D6. Citalopram, escitalopram, and sertraline were grouped as CYP2C19 substrates and fluvoxamine, fluoxetine, and paroxetine as CYP2D6 substrates. Logistic regression was computed for the reported SSRI ADRs associated with one of two aforementioned DMEs. All data homogenization and computations were performed in R for statistical programming., Results: The most commonly reported ADR among the SSRIs was anxiety ( n = 3,332). The top two ADRs associated with SSRIs metabolized by CYP2D6 are: nightmare ( n = 983) reporting odds-ratio (OR) = 4.37 (95% confidence interval (CI) [3.67-5.20]) and panic attack ( n = 1,243) OR = 2.43 (95% CI [2.11-2.79]). Contrastingly, the top two ADRs for CYP2C19 metabolized SSRIs are: electrocardiogram QT prolonged ( n = 351) OR = 0.18 (95% CI [0.13-0.24]) and small for dates baby ( n = 306) OR = 0.19 (95% CI [0.14-0.26]). The study tested and produced 40 statistically significant CYP2C19- and CYP2D6-biased ADRs. In overall context, the results suggest that CYPC19 SSRI substrates are associated with ADRs related to modulation of the autonomic nervous system, seizure, pain, erectile-dysfunction, and absorption. Contrastingly, CYP2D6 SSRI substrates are associated with ADRs related to nightmares, withdrawal syndrome, and de-realization of cognitive processes. The results of this study may aid as guidance to optimize drug selection in psychopharmacology., Competing Interests: The author declares no competing interests., (© 2019 Eugene.)

Purpose: Clopidogrel is a thienopyridine prodrug that inhibits platelet aggregation. It is prescribed to prevent atherothrombotic and thromboembolic events in patients receiving a stent implant in carotid, vertebral, or cranial arteries. The influence of cytochrome P-450 (CYP) 2C19 on the response to clopidogrel has been widely studied; however, the effect of other genes involved in clopidogrel absorption and metabolism has not been established in this cohort of patients., Methods: This observational retrospective study assessed the antiplatelet response and the prevalence of hemorrhagic or ischemic events after percutaneous neurointervention in clopidogrel-treated patients, related to 35 polymorphisms in the genes encoding the clopidogrel-metabolizing enzymes (CYP2C19, CYP1A2, CYP2B6, CYP2C9, CYP2C9, CYP3A4, CYP3A5, carboxylesterase-1 [CES1], and paraoxonase-1 [PON1]), P-glycoprotein transporter (ABCB1), and platelet receptor P2Y 12 . Polymorphisms were analyzed by quantitative real-time polymerase chain reaction and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry. Antiplatelet response was documented with the VerifyNow system (Accriva, San Diego, California)., Findings: We confirmed that CYP2C19 is the most important enzyme involved in clopidogrel response. The carriage of the CYP2C19*2 allele was strongly associated with hyporesponse to clopidogrel, while the CYP2C19*17 allele was a protective factor for the development of ischemic events (odds ratio = 0.149; P = 0.002) but a risk factor for bleeding (odds ratio = 3.60; P = 0.038). Patients carrying ABCB1 mutated alleles showed lower aggregation values, suggesting that clopidogrel absorption is influenced by P-glycoprotein. In fact, the percentage of responders was significantly higher in the group carrying the mutated haplotype compared to the wild type (80.8% vs 43.3%; P = 0.009). Patients with the CES1 G143E C/T genotype showed a considerably lower, aggregation value versus wild-type patients, although the difference was not significant likely due to the small sample size (59.0 [21.2] vs 165.2 [86.0] PRU; P = 0.084), which suggests an increased active metabolite formation. No relationship was found between polymorphisms in other CYP genes, PON1, or P2RY12 and response to clopidogrel in patients subjected to neurointervention procedures., Implications: Therapeutic guidelines recommend that CYP2C19 intermediate and poor metabolizers with acute coronary syndromes undergoing percutaneous coronary intervention receive an alternative antiplatelet therapy; however, genotype-guided therapy is not a standard recommendation for neurovascular conditions. This is the first study to carry out a joint analysis of CYP2C19 and other genes involved in clopidogrel treatment in patients receiving percutaneous neurointervention. Our findings support routine genotyping in clopidogrel-treated patients. Moreover, we encourage considering an alternative antiplatelet therapy in CYP2C19 intermediate, poor and ultrarapid metabolizers. Additionally, ABCB1 polymorphisms could be considered for a better pharmacogenetic approach., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Adverse drug reactions (ADRs) are a major cause of hospital admissions, prolonged hospital stays, morbidity, and drug-related mortality. In this study, we sought to identify the most frequently reported medications and associated side effects in adolescent-aged patients in an effort to prioritize clinical pharmacology consultation efforts for hospitals seeking to improve patient safety.   Methods: Quarterly reported data were obtained from the United States Food and Drug Administration Adverse Events Reporting System (FAERS) from the third quarter of 2014 and ending in the third quarter of 2017. We then used the GeneCards database to map the pharmacogenomic biomarkers associated with the most reported FAERS drugs. Data homogenization and statistics analysis were all conducted in R for statistical programming. Results: We identified risperidone (10.64%) as the compound with the most reported ADRs from all reported cases. Males represented 90.1% of reported risperidone cases with gynecomastia being the most reported ADR. Ibuprofen OR=188 (95% CI, 105.00 - 335.00) and quetiapine fumarate OR=116 (95% CI, 48.40 - 278.00) were associated with the highest odds of completed suicide in teenagers. Ondansetron hydrochloride OR=7.12 (95% CI, 1.59 - 31.9) resulted in the highest odds of pneumothorax. Lastly, olanzapine (8.96%) represented the compound with the most reported drug-drug interactions cases, while valproic acid OR=221 (95% CI, 93.900 - 522.00) was associated with the highest odds of drug-drug interactions. Conclusion: Despite any data limitations, physicians prescribing risperidone in males should be aware of the high rates of adverse drug events and an alternative psychotropic should be considered in male patients. Further, patients with a history of pneumothorax or genetically predisposed to pneumothorax should be considered for an alternative antiemetic to ondansetron hydrochloride, due to increased odds associated with the drug and adverse event., Competing Interests: No competing interests were disclosed.

Background: We sought to test the hypothesis that transcriptiome-level genes signatures are differentially expressed between male and female bipolar patients, prior to lithium treatment, in a patient cohort who later were clinically classified as lithium treatment responders. Methods: Gene expression study data was obtained from the Lithium Treatment-Moderate dose Use Study data accessed from the National Center for Biotechnology Information's Gene Expression Omnibus via accession number GSE4548. Differential gene expression analysis was conducted using the Linear Models for Microarray and RNA-Seq (limma) package and the Random Forests machine learning algorithm in R. Results: In pre-treatment lithium responders, the following genes were found having a greater than 0.5 fold-change, and differentially expressed indicating a male bias: RBPMS2, SIDT2, CDH23, LILRA5, and KIR2DS5; while the female-biased genes were: HLA-H, RPS23, FHL3, RPL10A, NBPF14, PSTPIP2, FAM117B, CHST7, and ABRACL. Conclusions: Using machine learning, we developed a pre-treatment gender- and gene-expression-based predictive model selective for lithium responders with an ROC AUC of 0.92 for men and an ROC AUC of 1 for women., Competing Interests: No competing interests were disclosed.

Background: Gender differences in treatment response rates for patients treated with antipsychotics are known. However, the literature lacks a pharmacodynamic model to allow for gender-based clinical trial simulations from modelling parameters for Olanzapine and dopamine D2 receptor occupancy. Thus, the primary aim of this analysis is to test and quantify the effect of gender on the pharmacodynamics of Olanzapine., Methods: Population pharmacodynamic modelling was performed using non-linear mixed effects modelling in MONOLIX, while the Clinical Trial Simulations were performed using R for statistical programming. The pharmacometric analysis is based on a pooled data approach from three clinical studies where patients were diagnosed with schizophrenia and one clinical study where the patients were diagnosed with bipolar disorder., Results: Olanzapine D2RO was modelled using an E max model in a study population of 70 patients. Population pharmacodynamic parameters were estimated to be: E max  = 85.6% (RSE = 3%), ED50-Men = 5.15 mg/day (RSE = 14) and ED50-Women = 2.38 mg/day (RSE = 34%), with the p-value = 0.037 for the gender-stratified ED50 results., Conclusion: The pharmacometrics analysis and model-based dosing simulations suggest that, in order to achieve 70% D2RO, women require a 10 mg/day dose and men require approximately a 20 mg/day dose of Olanzapine. Further, clinical implications exist suggesting that clinicians should factor patient gender when considering both a starting dose, as well a, a maintenance dose for patients prescribed Olanzapine due to quantifiable gender-differences of striatal dopamine D2 receptor occupancy.

The vasodilatory mechanism of Nntroglycerin (NTG) is similar to sodium nitroprusside (SNP) in regard to action on guanosine 3'5'-monophosphate (cyclic GMP) via nitric oxide. However, it is unknown whether NTG can achieve the same magnitude of vasodilation in the forearm as SNP. Therefore, the purpose of the study was to evaluate the differences in forearm blood flow (FBF) and forearm vascular conductance (FVC) during escalating infusions of NTG vs. SNP at similar concentration doses and rates. We measured FBF using venous occlusion plethysmography (VOP) and Doppler ultrasound in eight young, healthy participants (mean age = 28 ± 2 yr) during four forearm volume (FAV)-specific doses (0.25, 0.5, 1, and 2 µg·100 ml FAV -1 ·min -1 ) of SNP and NTG infused via a brachial artery catheter. There was a significant difference in FVC of SNP vs. NTG only at the higher doses, as measured by VOP (14.9 ± 1.4 and 18.3 ± 1.5 vs. 11.6 ± 1.2 and 12.5 ± 1.2 ml/dl FAV -1 ·min -1 ·100 mmHg -1 ). FVC as measured by Doppler ultrasound unadjusted for FAV was significantly different at the lowest and the higher two doses of SNP compared with NTG (202.1 ± 25.8, 329.4 ± 46.7, and 408 ± 63.5 vs. 142.9 ± 22.4, 217.2 ± 18.8, and 247.5 ± 18.2 ml·min -1 ·100 mmHg -1 ). SNP induces significantly higher vasodilatory actions compared with NTG. However, NTG is comparable in eliciting equivalent vasodilator effects to SNP during low concentration doses when measured by VOP. Importantly, for forearm pharmacology studies, NTG can elicit marked endothelium-independent forearm vasodilation. NEW & NOTEWORTHY We compared the vasodilatory capacities of NTG vs. SNP at similar concentration doses and rates into the forearm. Based on the results of the study, it may be feasible to use intra-arterial NTG as a measure of endothelial-independent vasodilator in research studies. However, NTG dosing may need to be higher if used as an endothelial-independent vasodilator due to significant differences in the vasodilatory effects during higher doses of SNP compared with NTG., (Copyright © 2017 the American Physiological Society.)

We tested the hypotheses that: (1) carotid body size can be measured by computed tomographic angiography (CTA) with high inter-observer agreement, and (2) patients with sleep apnea exhibit larger carotid bodies than those without sleep apnea. A chart review was conducted from patients who underwent neck CTA and polysomnography at the Mayo Clinic between January 2000 and February 2015. Widest axial measurements of the carotid bodies, performed independently by two radiologists, were possible in 81% of patients. Intra-class correlation coefficients ranged from 0.93 to 0.95 (Right carotid body: 0.93; Left: 0.94; Average: 0.95). Widest axial measurements of the carotid bodies were greater in patients with sleep apnea (n=32) compared to controls (n=46, P-value range 0.02-0.04). After adjusting for age, no differences in carotid body size were observed between the patient groups (P-value range 0.45-0.59). We conclude carotid body size can be detected by CTA with high inter-observer agreement; however, carotid body size is not increased in patients with sleep apnea., Competing Interests: All authors report no conflicts of interest., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: This article seeks to test the hypothesis that repeated 1mg intravenous epinephrine dosing intervals of 3-minutes and 5-minutes results in differences in the total drug exposure and the maximum epinephrine concentration using simulated cardiopulmonary resuscitation (CPR) dosing., Methods: Published population pharmacokinetic parameters were identified in the literature and pharmacokinetic dosing simulations were conducted according to the 2015 American Heart Association guidelines for CPR in adults. The stochastic pharmacokinetic simulations were conducted in MATLAB and R for statistical programming., Results: A total of 5000 simulations were conducted in MATLAB while 90,000 data points for the 3-minute dosing interval and 150,000 data points for the 5-minute epinephrine dosing interval resulted from pharmacokinetic simulations in R. The difference between the 3-minute and 5-minute dosing intervals for patients with a SAP score of 30, were found to be: Male ΔAUC=2416 and ΔCmax=71, Female ΔAUC=1422 and ΔCmax=41, and for a 70kg patient ΔAUC=2968 and ΔCmax=90. While in virtual healthy participants, the differences were calculated to be ΔAUC=2658 and ΔCmax=81 for 3-minute and 5-minute dosing frequencies., Conclusions: Epinephrine plasma levels during a simulated CPR scenario in a virtual patient population are dependent upon intravenous dosing intervals of either 3-minutes or 5-minutes. Based on the results of this clinical trial simulation, implications may exist that may require clinical studies investigating the influence of the 1mg epinephrine dosing frequency on the return of spontaneous circulation., Competing Interests: Conflicts of Interest: The author declares no conflict of interest.

Introduction: Numerous studies have emerged over the course of several decades describing the properties of drugs eliciting vasodilatory or vasoconstrictor responses in the human vasculature. During drug development, decisions to move forward with testing with a new chemical entity are very costly. To fund or not to fund development, go or no-go, decisions are often limited by efficacy comparisons with the current products on the market. The primary aim of this paper is to use dose-response modeling and simulations to quantify differences in blood flow to Acetylcholine, Albuterol, ATP, Bradykinin, 17β-Estradiol, Glyceryl Trinitrate, L-NMMA, Nevibolol, Norepinephrine, Sodium Nitroprusside, Substance P, and Verapamil., Methods: Five studies were identified in the literature that included a total of 12 compounds. Infusion doses were normalized to nmol/min and forearm blood flow values were normalized and scaled to the percent increase or decrease in forearm blood flow from baseline resting values. The original published studies were mathematically modeled using the Emax model or Sigmoid Emax model equation parameters. Lastly, dose-response simulations of higher doses using a virtual population were produced to account for population variability., Results: The gender difference between the Emax estimates, interpreted as the %Change from Baseline resting forearm blood flow, were found to be: Albuterol 253%, Acetylcholine 231%, Substance P 159%, Verapamil 145%, Bradykinin 42%, Sodium Nitroprusside 41%, and Glyceryl Trinitrate 26%. Contrastingly, Norepinephrine and L-NMMA Emax gender difference resulted in a 6% and 7% difference, respectively., Conclusion: These results provide insight into the differences in men and women seen in anti-hypertensive patient management. Further, the modeling estimates provide pharmacometricians evaluating new compounds with mathematical parameters for comparative efficacy studies through the various phases of drug development., Competing Interests: Conflicts of Interests: The author declares no conflict of interests.

Recent meta-analyses and publications over the past 15 years have provided evidence showing there are considerable gender differences in the pharmacokinetics of metoprolol. Throughout this time, there have not been any research articles proposing a gender stratified dose-adjustment resulting in an equivalent total drug exposure. Metoprolol pharmacokinetic data was obtained from a previous publication. Data was modeled using nonlinear mixed effect modeling using the MONOLIX software package to quantify metoprolol concentration-time data. Gender-stratified dosing simulations were conducted to identify equivalent total drug exposure based on a 100 mg dose in adults. Based on the pharmacokinetic modeling and simulations, a 50 mg dose in adult women provides an approximately similar metoprolol drug exposure to a 100 mg dose in adult men., Competing Interests: The author declares no conflict of interest.

Introduction: Sodium Nitroprusside has successfully been an excellent choice when considering a decrease in systemic vascular resistance in the critical care setting. However, reflex tachycardia and ventilation-perfusion mismatch are possible side effects of this agent. To maintaining cardiac output, cerebral perfusion pressure, and concurrently drop SVR, low-dose epinephrine or dopamine are viable options. The aim of this paper is to conduct dose-response simulations to identify the equivalent dopamine, epinephrine, and nitroprusside infusion doses to decrease the systemic vascular resistance by 20% and by 40% from baseline resting values., Methods: Three studies were identified in the literature with reported epinephrine, dopamine, and sodium nitroprusside infusion doses with corresponding systemic vascular resistance responses. Infusion doses were normalized to mcg/kg/min and SVR values were normalized and scaled to the percent decrease (%SVR) in SVR from baseline resting values. The original published studies were mathematically modeled and the Hill equation parameters used for further dose-response simulations of a virtual population. One-hundred patients were simulated various doses resulting in corresponding %SVR responses for each of the three drugs., Results: Equivalent infusion doses achieving in an approximate 20-25% decrease in SVR, from baseline, were identified for epinephrine, dopamine, and sodium nitroprusside. Moreover, equivalent infusion doses were identified for epinephrine and nitroprusside to decrease the SVR by 40% from baseline., Conclusion: Even though sodium nitroprusside is traditionally used in decreasing SVR, low doses of dopamine or epinephrine are viable alternatives to patients with contraindications to nitroprusside infusions or who will require prolonged infusions to avoid toxicity. The multiple comparisons procedure-modeling approach is an excellent methodology for dose-finding exercises and has enabled identification of equivalent pharmacodynamic responses for epinephrine, dopamine, and sodium nitroprusside through mathematic simulations.

Propranolol, a non-selective β-blocker, has been found to have a tremendous array of indications. Recent evidence has suggested that propranolol may be effective in patients suffering from post-traumatic stress disorder by suppressing activity in the amygdala and thereby inhibiting emotional memory formation. Dosage requirements have been well established in the pediatric and adult population, however, there has been no definitive geriatric dose recommended in the package inserts made available to the public. The aim of this paper is to use pharmacokinetic simulations in order to establish a pharmacokinetic profile dosage equivalent for the elderly as has been found in young patients. After completing the Monte-Carlo simulations for the elderly and young patients, a single 10mg dose in the elderly has shown comparable pharmacokinetic profiles as found in young patients administered a 40mg single dose.

Trigeminal Neuralgia is a disorder that is characterized with electrical-type shocking pain in the face and jaw. This pain may either present as sharp unbearable pain unilateral or bilaterally. There is no definite etiology for this condition. There are various treatment methods that are currently being used to relieve the pain. One of the pharmacological treatments is Carbamazepine and the most prevalent surgical treatments include Gamma Knife Surgery (GKS), Microvascular Decompression (MVD) and Radiofrequency Lesioning (RFL). Although, MVD is the most used surgical method it is not an option for all the patients due to the intensity of the procedure. RFL is used when MVD is not suitable. In this paper we present the various treatments and Monte-Carlo based pharmacokinetic simulations of Carbamazepine in treatment of Trigeminal Neuralgia.

Sleep is an important component of human life, yet many people do not understand the relationship between the brain and the process of sleeping. Sleep has been proven to improve memory recall, regulate metabolism, and reduce mental fatigue. A minimum of 7 hours of daily sleep seems to be necessary for proper cognitive and behavioral function. The emotional and mental handicaps associated with chronic sleep loss as well as the highly hazardous situations which can be contributed to the lack of sleep is a serious concern that people need to be aware of. When one sleeps, the brain reorganizes and recharges itself, and removes toxic waste byproducts which have accumulated throughout the day. This evidence demonstrates that sleeping can clear the brain and help maintain its normal functioning. Multiple studies have been done to determine the effects of total sleep deprivation; more recently some have been conducted to show the effects of sleep restriction, which is a much more common occurrence, have the same effects as total sleep deprivation. Each phase of the sleep cycle restores and rejuvenates the brain for optimal function. When sleep is deprived, the active process of the glymphatic system does not have time to perform that function, so toxins can build up, and the effects will become apparent in cognitive abilities, behavior, and judgment. As a background for this paper we have reviewed literature and research of sleep phases, effects of sleep deprivation, and the glymphatic system of the brain and its restorative effect during the sleep cycle.

Introduction: The purpose of this electrophysiological neuroimaging study was to provide a deeper mechanistic understanding of both olanzapine and risperidone pharmacodynamics relative to gender. In doing so, we age-matched 22 men and women and evaluated their resting-state EEG recordings and later used standard low resolution brain Electrotomography to visualize the differences in brain activity amongst the two patient groups., Methods: In this investigation, electroencephalogram (EEG) data were analyzed from male and female schizophrenia patients treated with either olanzapine or risperidone, both atypical antipsychotics, during their in-patient stay at the Department of Psychiatry. Twenty-two males and females were age-matched and EEG recordings were analyzed from 19 Ag/AgCl electrodes. Thirty-seconds of resting EEG were spectrally transformed in standardized low resolution electromagnetic tomography (sLORETA). 3D statistical non-paramentric maps for the sLORETA Global Field Power within each band were finally computed., Results: The results indicated that, relative to males patients, females schizophrenia patients had increased neuronal synchronization in delta frequency, slow-wave, EEG band located in the dorsolateral prefrontal cortex, within the middle frontal gyrus (t= -2.881, p < 0.03580). These findings suggest that females experience greater dopamine (D2) receptor and serotonin (5-HT2) receptor neuronal blockade relative to age-matched males. Further, our finding provided insight to the pharmacodynamics of second-generation antipsychotics olanzapine and risperidone., Conclusion: When compared to male patients, female patients, suffering from schizophrenia, have D2 and 5-HT2 receptors that are blocked more readily than age-matched male schizophrenia patients. Clinically, this may translate into a quicker time to treatment-response in females as compared to male patients.

In this retrospective analysis of electroencephalograms were to identify a surrogate biomarker for the Dopamine D2 receptors in the brain by comparing patients diagnosed with Schizophrenia taking Atypical Antipsychotics to Depressive patients medicated with Selective Serotonin Reuptake Inhibitors. To achieve this, thirty-seconds of resting EEG were spectrally transformed in sLORETA. Three-dimensional statistical non-paramentric maps (SnPM) for the sLORETA Global Field Power within each band were then computed. Our results illustrated that the Right Superior Frontal Gyrus (t=2.049, p=0.007), along the dopamine mesolimbic pathway, had higher neuronal oscillations in the delta frequency band in the 100 Schizophrenia patients as compared to the 32-depressive female patients. The comparisons with both the 48 depressive patient cohort or the sixteen male depressive patient cohort did not yield any statistically significant findings. We conclude that the Superior Frontal Gyrus should be investigated as a possible surrogate biomarker for preclinical and clinical drug discovery in neuropharmacology.

Anorexia Nervosa (AN) is characterized by Diagnostic and Statistical Manual of Mental Disorders Volume 4 (DSM IV), as one's refusal to maintain a body weight that is above the calculated limit, which is determined by an algorithm involving one's height and weight. As more emphasis in society is placed on one's body image and appearance there has been an increase in the prevalence of this disease. Previously, the sole diagnostic imaging modality was fMRI. Studies determined that there was reduced blood flood in the Parahippocampal Gyrus, and Left Fusiform Gyrus, of those afflicted with AN. Electroencephalography (EEG) was utilized as an alternative imaging modality that was more cost effect. It was determined that the activated regions localized on the fMRI study coincided with those highlighted on the EEG report and previous fMRI studies. The goal of this study was to determine a more cost effective way to earlier detect a diagnosis of AN. The desired outcome would be for patients afflicted with AN to be diagnosed and treated at an earlier stage, increasing their overall long-term survival.

Introduction: The purpose of this investigatory neuroimaging analysis was done to better understand the pharmacodynamics of Lithium by isolating the norepinephrine pathway in the brain. To accomplish this, we compared patients with Bipolar Disorder treated with Lithium to patients diagnosed with Major Depression or Depressive Disorder who are treated with Selective Serotonin Reuptake Inhibitors (SSRIs)., Methodology: We used Standardized Low Resolution Brain Electrotomography to calculate the whole brain, voxel-by-voxel, unpaired t-tests Statistical non-Parametric Maps. For our first electrophysiological neuroimaging investigation, we compared 46 patients (average age = 34 ± 16.5) diagnosed with Bipolar Affective Disorder to three patient groups all diagnosed with Major Depression or Depressive Episode. The first is with 48 patients diagnosed with Major Depression or Depressive Episode (average age = 49 ± 12.9), the second to 16 male depressive patients (average age = 45 ± 15.1), and the final comparison to 32 depressive females (average age = 50 ± 11.7)., Results: The results of sLORETA three-dimensional statistical non-parametric maps illustrated that Lithium influenced an increase in neurotransmission in the right Superior Temporal Gyrus (t=1.403, p=0.00780), Fusiform Gyrus (t=1.26), and Parahippocampal Gyrus (t=1.29). Moreover, an increased in neuronal function was found was also identified at the Cingulate Gyrus (t=1.06, p=0.01200)., Conclusion: We are proposing a translational clinical biological marker for patients diagnosed with Bipolar Disorder to guide physicians during the course of Lithium therapy and have identified neuroanatomical structures influenced by norepinephrine.