The History of Flow Chemistry at Eli Lilly and Company.

Flow chemistry was initially used for speed to early phase material delivery in the development laboratories, scaling up chemical transformations that we would not or could not scale up batch for safety reasons. Some early examples included a Newman Kwart Rearrangement, Claisen rearrangement, hydroformylation, and thermal imidazole cyclization. Next, flow chemistry was used to enable safe scale up of hazardous chemistries to manufacturing plants. Examples included high pressure hydrogenation, aerobic oxidation, and Grignard formation reactions. More recently, flow chemistry was used in Small Volume Continuous (SVC) processes, where highly potent oncolytic molecules were produced by fully continuous processes at about 10 kg/day including reaction, extraction, distillation, and crystallization, using disposable equipment contained in fume hoods.

Development of Liquid Chromatography-Tandem Mass Spectrometry Analytical Methods for the Study of Whole-Body, Head, and Trunk Uptake and Elimination of Methamphetamine in 5-Day Postfertilization Zebrafish Larvae Using the Quick, Easy, Cheap, Effective, Rugged, and Safe Technique.

Synthetic cathinones are drugs of abuse substituted for amphetamine-like stimulant drugs such as methamphetamine. In this study, methamphetamine was studied as a prototypical amphetamine-like drug as a first step toward establishing methods to study this entire drug class. The internal concentration of methamphetamine in zebrafish larvae was determined using matrix-matched calibration along with extraction and purification of samples using the quick, easy, cheap, effective, rugged, and safe technique in liquid chromatography-tandem mass spectrometry. Whole-body and head/trunk uptake and elimination in 5-day postfertilization zebrafish larvae were determined. A gradient method was developed using 5 mM ammonium formate with 0.1% formic acid and methanol with 0.1% formic acid as mobile phases, 10 min of total run time, and a 0.3 mL/min flow rate. The limit of quantification was 60 ng/mL, linearity with r2 = 0.9991, and recovery values from 92% to 120%. The internal concentration of methamphetamine was quantifiable in whole-body homogenates within 15 min of uptake analysis. The internal concentration increased with time, whereas a biphasic elimination pattern was shown. With increasing length of exposure, a higher accumulation of drugs was found in the head than in the trunk.

Heterozygous and homozygous gene knockout of the 5-HT1B receptor have different effects on methamphetamine-induced behavioral sensitization.

The psychostimulant drug methamphetamine (METH) causes euphoria in humans and locomotor hyperactivity in rodents by acting on the mesolimbic dopamine (DA) pathway and has severe abuse and addiction liability. Behavioral sensitization, an increased behavioral response to a drug with repeated administration, can persist for many months after the last administration. Research has shown that the serotonin 1B (5-HT1B) receptor plays a critical role in the development and maintenance of drug addiction, as well as other addictive behaviors. This study examined the role of 5-HT1B receptors in METH-induced locomotor sensitization using 5-HT1B knockout (KO) mice. To clarify the action of METH in 5-HT1B KO mice the effects of METH on extracellular levels of DA (DAec) and 5-HT (5-HTec) in the caudate putamen (CPu) and the nucleus accumbens (NAc) were examined. Locomotor sensitization and extracellular monoamine levels were determined in wild-type mice (5-HT1B +/+), heterozygous 5-HT1B receptor KO (5-HT1B +/-) mice and homozygous 5-HT1B receptor KO mice (5-HT1B -/-). Behavioral sensitization to METH was enhanced in 5-HT1B -/- mice compared to 5-HT1B +/+ mice but was attenuated in 5-HT1B +/- mice compared to 5-HT1B +/+ and 5-HT1B -/- mice. In vivo, microdialysis demonstrated that acute administration of METH increases DAec levels in the CPu and NAc of 5-HT1B KO mice compared to saline groups. In 5-HT1B +/- mice, METH increased 5-HTec levels in the CPu, and DAec levels in the NAc were higher than in others.5-HT1B receptors play an important role in regulating METH-induced behavioral sensitization.

Associations between adverse childhood experiences and obstetrical outcomes in a predominantly Black-identifying and low-income pregnant population.

BACKGROUND: Recent literature indicates that adverse childhood experiences have been associated with poor obstetrical outcomes, including pregnancy loss, preterm birth, and low birthweight. Several studies have been conducted in primarily self-identified White individuals who report middle to high income levels. Less is known about the impact of adverse childhood experiences on obstetrical outcomes in minority-identifying and low-income populations, who are known to experience a greater number of adverse childhood experiences and are at higher risk of maternal morbidity. OBJECTIVE: This study aimed to examine associations between adverse childhood experiences and a broad range of obstetrical outcomes among predominantly Black-identifying pregnant persons who have low income and live in an urban area. STUDY DESIGN: This is a single-center retrospective cohort study of pregnant persons referred to a mental healthcare manager because of elevated psychosocial risks identified by screening tools or provider concerns during the study period from April 2018 to May 2021. Pregnant persons aged <18 years and those who did not speak English were excluded. Patients completed validated mental and behavioral health screening tools including the Adverse Childhood Experiences Questionnaire. Medical charts were reviewed for obstetrical outcomes, including preterm birth, low birthweight, hypertensive disorders of pregnancy, gestational diabetes mellitus, chorioamnionitis, sexually transmitted infection, maternal group B streptococcus carrier status, type of delivery, and attendance of a postpartum visit. Associations between high (≥4) and very high (≥6) of 10 adverse childhood experience score and obstetrical outcomes were analyzed using bivariate analysis and multivariate logistic regression, adjusting for confounding factors (significant at P<.05 in bivariate analysis). RESULTS: Our cohort included 192 pregnant persons, of whom 176 (91.7%) self-identified as Black or African American and 181 (94.8%) had public insurance (used as a proxy for low income). Adverse childhood experience score ≥4 was reported by 91 (47.4%) individuals and score ≥6 by 50 (26%). On univariate analysis, adverse childhood experience score ≥4 was associated with preterm birth (odds ratio, 2.17; 95% confidence interval, 1.02-4.61). Adverse childhood experience score ≥6 was associated with hypertensive disorders of pregnancy (odds ratio, 2.09; 95% confidence interval, 1.05-4.15) and preterm birth (odds ratio, 2.29; 95% confidence interval, 1.05-4.96). After accounting for chronic hypertension, associations between adverse childhood experience score and obstetrical outcomes were no longer significant. CONCLUSION: Approximately half of the pregnant persons referred to a mental healthcare manager had a high adverse childhood experience score, underscoring the high burden of childhood trauma on populations facing long-standing systemic racism and barriers to healthcare access. High and very high adverse childhood experience score may be associated with chronic health conditions that predate pregnancy and can alter obstetrical outcomes. Obstetrical care providers have a unique opportunity to mitigate risk of associated poor health outcomes during preconception and prenatal care by screening for adverse childhood experiences.

Multicenter Phase II Trial of the PARP Inhibitor Olaparib in Recurrent IDH1- and IDH2-mutant Glioma.

Purpose: Isocitrate dehydrogenase (IDH) 1 and IDH2 mutations (IDH1/2mt) are frequent in glioma. Preclinical studies suggest IDH1/2mts confer "BRCAness" phenotype, a vulnerability that can be targeted through PARP inhibition. To test this hypothesis, we conducted a multicenter study of olaparib monotherapy in patients with IDH1/2mt gliomas. Methods: Patients with recurrent, contrast-enhancing IDH1/2mt gliomas were enrolled in a two-step phase II trial; the primary endpoint was overall response rate per Response Assessment in Neuro-Oncology (RANO) criteria. Olaparib 300 mg orally twice daily was given. Results: A total of 15 evaluable patients were enrolled. Histology was astrocytoma (N = 12) and oligodendroglioma (N = 3). Most toxicities were grade 1 or 2. Best response was stable disease (SD) in 9 (60%) patients. Median progression-free survival (PFS) was 3.63 months and median overall survival was 20.7 months. For patients with SD, median PFS was 5.53 months; 4 patients had SD for >6 months. Among patients with best response progressive disease (N = 6), 5 had grade 4 tumor and 4 had known CDKN2A alteration. PFS was 5.23 months for grades 2 or 3 tumors (N = 10) versus 1.8 months for grade 4 (N = 5; P = 0.0013). Conclusion: The study did not meet the prespecified response-based activity threshold for moving to step 2. However, prolonged SD was observed in patients with grades 2 and 3 histologies, suggesting olaparib monotherapy could be of clinical benefit in select populations. Grade 4 tumors per 2021 World Health Organization classification defined by histology or CDKN2A alteration derived no benefit from this drug, highlighting the usefulness of this classification for future patient stratification and trial design. Significance: A single-arm phase II trial of olaparib in IDH-mutant glioma demonstrated clinically significant prolonged SD for select patients with grade 2/3 disease, suggesting potential benefit of olaparib in IDH-mutant gliomas.

Real-Time Analysis of Bioenergetics in Primary Human Retinal Pigment Epithelial Cells Using High-Resolution Respirometry.

Metabolic dysfunction of retinal pigment epithelial cells (RPE) is a key pathogenic driver of retinal diseases such as age-related macular degeneration (AMD) and proliferative vitreoretinopathy (PVR). Since RPE are highly metabolically-active cells, alterations in their metabolic status reflect changes in their health and function. High-resolution respirometry allows for real-time kinetic analysis of the two major bioenergetic pathways, glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), through quantification of the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR), respectively. The following is an optimized protocol for conducting high-resolution respirometry on primary human retinal pigment epithelial cells (H-RPE). This protocol provides a detailed description of the steps involved in producing bioenergetic profiles of RPE to define their basal and maximal OXPHOS and glycolytic capacities. Exposing H-RPE to different drug injections targeting the mitochondrial and glycolytic machinery results in defined bioenergetic profiles, from which key metabolic parameters can be calculated. This protocol highlights the enhanced response of BAM15 as an uncoupling agent compared to carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) to induce the maximal respiration capacity in RPE. This protocol can be utilized to study the bioenergetic status of RPE under different disease conditions and test the efficacy of novel drugs in restoring the basal metabolic status of RPE.

A preliminary study evaluating self-reported effects of cannabis and cannabinoids on neuropathic pain and pain medication use in people with spinal cord injury.

Approximately 60% of individuals with a spinal cord injury (SCI) experience neuropathic pain, which often persists despite the use of various pharmacological treatments. Increasingly, the potential analgesic effects of cannabis and cannabinoid products have been studied; however, little research has been conducted among those with SCI-related neuropathic pain. Therefore, the primary objective of the study was to investigate the perceived effects of cannabis and cannabinoid use on neuropathic pain among those who were currently or had previously used these approaches. Additionally, the study aimed to determine if common pain medications are being substituted by cannabis and cannabinoids. Participants (N = 342) were recruited from existing opt-in listserv sources within the United States. Of those, 227 met the inclusion criteria and were enrolled in the study. The participants took part in an anonymous online survey regarding past and current use of cannabis and their perceived effects on neuropathic pain, including the use of pain medication. Those in the sample reported average neuropathic pain intensity scores over the past week of 6.8 ± 2.1 (0 to 10 scale), reflecting a high moderate to severe level of pain. Additionally, 87.9% noted that cannabis reduced their neuropathic pain intensity by more than 30%, and 92.3% reported that cannabis helped them to better deal with their neuropathic pain symptoms. Most participants (83.3%) also reported substituting their pain medications with cannabis, with the most substituted medication categories being opioids (47.0%), gabapentinoids (42.8%) and over-the-counter pain medications (42.2%). These preliminary results suggest that cannabis and cannabinoids may be effective in reducing neuropathic pain among those with SCI and may help to limit the need for certain pain medications.

Evaluation of Restrictions on Tobacco Sales to Youth Younger Than 21 Years in Cleveland, Ohio, Area.

Importance: Tobacco 21 (T21) policies raise the minimum legal age to purchase tobacco from 18 to 21 years to curb youth access to tobacco products. While some studies have found that T21 is associated with reducing prevalence of youth tobacco use, little is known about the impact it may have on youth of different racial and ethnic identities. Objective: To evaluate the association of T21 policy with the prevalence of high school youth tobacco use across sex, race, and ethnicity. Design, Setting, and Participants: This survey study used representative survey data collected from the local biennial Youth Risk Behavior Survey from 2013 to 2017 comparing Cleveland, Ohio (which has a T21 policy), to proximal jurisdictions in the first-ring suburbs in Cuyahoga County (which do not have T21 policies). Within-Cleveland demographic information was also collected for 2013 to 2019. Overall high school youth tobacco use rates were compared between Cleveland and the first-ring suburbs and then examined within Cleveland among Hispanic, non-Hispanic Black, and non-Hispanic White high school students. Percentage data were adjusted to more closely align with local population demographics. Data were analyzed from January to June 2022. Exposures: T21 was implemented in Cleveland in 2016 and not adopted in proximal jurisdictions or at the state and federal level until at least 1 year later. Main Outcomes and Measures: The main outcomes were prevalence of past 30-day cigarette, cigar product, or e-cigarette use, measured using geographically representative high school youth survey data from 2013 to 2015 (prelegislation) and 2017 to 2019 (postlegislation) and compared using a difference-in-differences analysis. Results: The unweighted sample included 12 616 high school students (27.0% [95% CI, 26.9%-28.0%] in 10th grade; 50.9% [95% CI, 50.3%-51.6%] females) participating in 1 or more Youth Risk Behavior Surveys from 2013 to 2019, including 7064 students in Cleveland and 5552 students in the first-ring suburbs. Compared with the first-ring suburbs, Cleveland had a greater proportion of younger students (1623 [28.5%] ninth grade students vs 2179 [34.0%] ninth grade students) and Hispanic students (436 students [1.1%] vs 1433 students [12.6%]) and non-Hispanic Black students (2000 students [53.1%] vs 3971 students [75.1%]). Cigars were the most commonly used tobacco product in Cleveland, with use reported by 6201 students (19.8%) in 2013, 5877 students (21.3%) in 2015, and 5784 students (16.8%) in 2019. Compared with the first-ring suburbs, there was a greater decline in prevalence of use of cigars in Cleveland (ß = 0.18 [SE, 0.05]; P < .001). The disparity across race, ethnicity, and sex decreased for all current tobacco product use. For example, the maximum difference between demographic subpopulations in current cigarette use was 11.6 (95% CI, 9.5-13.7) percentage points in 2013 between White females (16.1% [95% CI, 11.3%-20.8%]) and Black males (4.5% [95% CI, 3.5%-5.4%]). This maximum difference in current cigarette use decreased significantly to 5.1 (95% CI, 3.5-6.7) percentage points in 2019 between White females (6.9% [95% CI, 3.4%-10.3%]) and Black females (1.8% [95% CI, 0.7%-2.8%]). Conclusions and Relevance: This survey study found that there was a decline in youth-reported tobacco use across every tobacco product category from 2013 to 2019. This decline changed the trajectory of use among several demographic groups and brought the youth populations with the highest tobacco product use to similar rates of others.

Dimethyl Fumarate Blocks Tumor Necrosis Factor-Alpha-Driven Inflammation and Metabolic Rewiring in the Retinal Pigment Epithelium.

The retinal pigment epithelium (RPE) acts as a metabolic gatekeeper between photoreceptors and the choroidal vasculature to maintain retinal function. RPE dysfunction is a key feature of age-related macular degeneration (AMD), the leading cause of blindness in developed countries. Inflammation is a key pathogenic mechanism in AMD and tumor necrosis factor-alpha (TNFα) has been implicated as a pro-inflammatory cytokine involved in AMD. While mitochondrial dysfunction has been implicated in AMD pathogenesis, the interplay between inflammation and cellular metabolism remains elusive. The present study explores how the pro-inflammatory cytokine, TNFα, impacts mitochondrial morphology and metabolic function in RPE. Matured human primary RPE (H-RPE) were treated with TNFα (10 ng/ml) for up to 5 days. TNFα-induced upregulation of IL-6 secretion and inflammatory genes (IL-6, IL-8, MCP-1) was accompanied by increased oxidative phosphorylation (OXPHOS) and reduced glycolysis, leading to an increase in cellular adenosine triphosphate (ATP) content. Transmission electron microscopy (TEM) revealed defects in mitochondrial morphology with engorged mitochondria and loss of cristae integrity following TNFα treatment. Pre-treatment with the anti-inflammatory drug, 80 µM dimethyl fumarate (DMFu), blocked TNFα-induced inflammatory activation of RPE (IL-6, IL-8, MCP-1, CFH, CFB, C3) and normalized their bioenergetic profile to control levels by regulating PFKFB3 and PKM2 gene expression. Furthermore, DMFu prevented TNFα-induced mitochondrial dysfunction and morphological anomalies. Thus, our results indicate that DMFu serves as a novel therapeutic avenue for combating inflammatory activation and metabolic dysfunction of RPE in AMD.

A Continuous Flow Process for LSN647712 via Double Organometallic Additions to Dimethylcarbamyl Chloride.

The ketone intermediate LSN647712 is a key synthetic intermediate for the drug substance lasmiditan manufacturing process. A three-step connected continuous flow process utilizing a Turbo Grignard reagent, N-methylpiperidin-4-ylmagnesium chloride, and lithiated 2,6-dibromopyridine sequentially added to double electrophile (O═C(++) synthon dimethylcarbamyl chloride (DMCC) was developed to deliver the ketone intermediate in a high chemical yield (>85%). This highly productive (>100 g/h lab system) and intensified process (τ ∼ 3 min) yields the product in high purity upon batch reactive crystallization to form a corresponding hydrobromide salt. In addition to the connected plug flow reactor system, the Grignard reagent, N-methylpiperidin-4-ylmagnesium chloride, was also prepared continuously in CSTR as a more soluble LiCl adduct in THF (Turbo Grignard).

Associations Between Adverse Childhood Experiences and Prenatal Mental Health and Substance Use Among Urban, Low-Income Women.

This study examined associations between Adverse Childhood Experiences (ACEs) and perinatal mental health and substance use among 98 low-income women (mean age 25.4 years; 93% Black/African American) referred to a mental health care manager in an urban women's clinic. Self-report and retrospective chart review data were utilized. Chi-squared and Fisher's Exact tests were performed to assess bivariate relationships between ACEs and mental health and substance use outcomes. Multivariate logistic regressions were used to examine the impact of ACEs on mental health and substance use, adjusting for marital status, education, and age. Findings indicate high levels of childhood adversity, specifically childhood abuse, are associated with negative perinatal mental health and substance use outcomes, including suicidal thoughts, anxiety, mood dysregulation, and tobacco and marijuana use. Inquiring about ACEs during prenatal care and/or in community health clinics may help identify patients' overall risk and provide opportunities for intervention for mothers and their infants.

Tunable and Cooperative Catalysis for Enantioselective Pictet-Spengler Reaction with Varied Nitrogen-Containing Heterocyclic Carboxaldehydes.

Herein we report an organocatalytic enantioselective functionalization of heterocyclic carboxaldehydes via the Pictet-Spengler reaction. Through careful pairing of novel squaramide and Brønsted acid catalysts, our method tolerates a breadth of heterocycles, enabling preparation of a series of heterocycle conjugated ß-(tetrahydro)carbolines in good yield and enantioselectivity. Careful selection of carboxylic acid co-catalyst is essential for toleration of a variety of regioisomeric heterocycles. Utility is demonstrated via the three-step stereoselective preparation of pyridine-containing analogues of potent selective estrogen receptor downregulator and U.S. FDA approved drug Tadalafil.

Optimism Bias, Pessimism Bias, Magical Beliefs, and Conspiracy Theory Beliefs Related to COVID-19 among the Jordanian Population.

The outbreak of the novel SARS-CoV-2 virus has an enormous impact on health. People's views about the virus impact public health efforts to mitigate the pandemic. In this study, we measured misconceptions toward coronavirus in the Jordanian population; 2,544 participants from the Jordanian population completed an online survey. Questions in the survey addressed misconceptions divided into four categories: optimism bias, pessimism bias, magical beliefs, and conspiracy theory beliefs. Questions were evaluated on a Likert scale, and average/median scores for each category were evaluated ("one" high misconception to "five" low misconception). Overall, the most common misconceptions involved conspiracy theory beliefs (2.68 ± 0.83), whereas the least common involved magical beliefs (2.25 ± 0.75). Females had more misconceptions than males (2.52 versus 2.47, P = 0.04). Participants who had attended a lecture on coronavirus, had a higher level of education, worked in a medical field, lived in urban area, or resided in Amman or northern Jordan had fewer misconceptions about SARS-CoV-2/COVID-19 (2.64, 2.34, 2.33, 2.50 and 2.50 versus 2.53, 2.73, 2.72, 2.64, and 2.66, respectively, P < 0.001). The use of social media appeared to be an important factor influencing the likelihood of false beliefs (2.61 versus 2.38, P < 0.001). Understanding of the factors influencing public perceptions surrounding the SARS-CoV-2/COVID-19 pandemic will help public health authorities improve public understanding and compliance with public health recommendations directed at combatting the virus, including the use of surgical masks, thorough handwashing, and avoiding close contact. These messages will be better received by the public through correcting misconceptions surrounding COVID-19.

Dual actions of 5-MeO-DIPT at the serotonin transporter and serotonin 5-HT1A receptor in the mouse striatum and prefrontal cortex.

AIMS: 5-Methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) is a synthetic orally active hallucinogenic tryptamine analogue. The present study examined whether the effects of 5-MeO-DIPT involve the serotonin transporter (SERT) and serotonin 5-hydroxytryptamine-1A (5-HT1A ) receptor in the striatum and prefrontal cortex (PFC). METHODS: We investigated the effects of 5-MeO-DIPT on extracellular 5-HT (5-HTex ) and dopamine (DAex ) levels in the striatum and PFC in wildtype and SERT knockout (KO) mice using in vivo microdialysis, and for comparison the effects of the 5-HT1A receptor antagonist WAY100635 and the 5-HT1A receptor agonist 8-OH-DPAT on 5-HTex . RESULTS: 5-MeO-DIPT decreased 5-HTex levels in the striatum, but not PFC. In SERT-KO mice, 5-MeO-DIPT did not affect 5-HTex levels in the striatum or PFC. In the presence of WAY100635, 5-MeO-DIPT substantially increased 5-HTex levels, suggesting that 5-MeO-DIPT acts on SERT and these effects are masked by its 5-HT1A actions in the absence of WAY100635. 8-OH-DPAT decreased 5-HTex levels in the striatum and PFC in wildtype mice. WAY100635 antagonized the 8-OH-DPAT-induced decrease in 5-HTex levels. In SERT-KO mice, 8-OH-DPAT did not decrease 5-HTex levels in the striatum and PFC. 5-MeO-DIPT dose-dependently increased DAex levels in the PFC, but not striatum, in wildtype and SERT-KO mice. The increase in DAex levels that was induced by 5-MeO-DIPT was not antagonized by WAY100635. CONCLUSION: 5-MeO-DIPT influences both 5-HTex and DAex levels in the striatum and PFC. 5-MeO-DIPT dually acts on SERT and 5-HT1A receptors so that elevations in 5-HTex levels produced by reuptake inhibition are limited by actions of the drug on 5-HT1A receptors.

Peptide Isolation via Spray Drying: Particle Formation, Process Design and Implementation for the Production of Spray Dried Glucagon.

PURPOSE: Spray drying plays an important role in the pharmaceutical industry for product development of sensitive bio-pharmaceutical formulations. Process design, implementation and optimisation require in-depth knowledge of process-product interactions. Here, an integrated approach for the rapid, early-stage spray drying process development of trehalose and glucagon on lab-scale is presented. METHODS: Single droplet drying experiments were used to investigate the particle formation process. Process implementation was supported using in-line process analytical technology within a data acquisition framework recording temperature, humidity, pressure and feed rate. During process implementation, off-line product characterisation provided additional information on key product properties related to residual moisture, solid state structure, particle size/morphology and peptide fibrillation/degradation. RESULTS: A psychrometric process model allowed the identification of feasible operating conditions for spray drying trehalose, achieving high yields of up to 84.67%, and significantly reduced levels of residual moisture and particle agglomeration compared to product obtained during non-optimal drying. The process was further translated to produce powders of glucagon and glucagon-trehalose formulations with yields of >83.24%. Extensive peptide aggregation or degradation was not observed. CONCLUSIONS: The presented data-driven process development concept can be applied to address future isolation problems on lab-scale and facilitate a systematic implementation of spray drying for the manufacturing of sensitive bio-pharmaceutical formulations.

Current and Future Roles of Artificial Intelligence in Medicinal Chemistry Synthesis.

Artificial intelligence and machine learning have demonstrated their potential role in predictive chemistry and synthetic planning of small molecules; there are at least a few reports of companies employing in silico synthetic planning into their overall approach to accessing target molecules. A data-driven synthesis planning program is one component being developed and evaluated by the Machine Learning for Pharmaceutical Discovery and Synthesis (MLPDS) consortium, comprising MIT and 13 chemical and pharmaceutical company members. Together, we wrote this perspective to share how we think predictive models can be integrated into medicinal chemistry synthesis workflows, how they are currently used within MLPDS member companies, and the outlook for this field.

Critically High Carboxyhemoglobin Level following Extensive Hysteroscopic Myomectomy.

Studies have demonstrated that during hysteroscopic myomectomy with bipolar diathermy, carbon monoxide is produced and enters the patient's circulation. However, little is known regarding the immediate or long-term sequelae of transient rises in carboxyhemoglobin levels during hysteroscopic surgery. This paper aims to suggest recommendations for acute evaluation, management, patient counseling, and future research. We present a case of a 36-year-old woman (Gravida 0, Para 0) with abnormal uterine bleeding-leiomyoma and resultant anemia, undergoing hysteroscopic resection of a large submucous myoma. During surgery, the patient was found to have a critically elevated level of carboxyhemoglobin and accompanying electrocardiogram derangements. She was managed with prolonged intubation, 100% O2, and trending of her carboxyhemoglobin levels before extubation. This demonstrates the importance of being cognizant of the potentially toxic gaseous byproducts of bipolar resection and of including intravasation of these byproducts in one's consideration of patient safety during extensive resections. Bipolar hysteroscopic resection of large leiomyomas may result in critically high carboxyhemoglobin levels, which can impair end-organ oxygen delivery with resultant ischemia; the risks of myocardial ischemia should be discussed with the anesthesia team before attempting an extensive resection. Electrocardiogram changes indicative of ischemia should prompt discontinuation of the case. Finally, carboxyhemoglobin poisoning should be included in the differential diagnosis of patients who demonstrate longer-than-expected anesthesia recovery times after bipolar resection of large submucous leiomyomas, and they should be managed with repeat evaluation of carboxyhemoglobin levels, supplemental oxygen, and cardiac monitoring.

Disaster Training Needs and Expectations Among Turkish Emergency Medicine Physicians - A National Survey.

OBJECTIVES: Earthquakes, landslides, and floods are the most frequent natural disasters in Turkey. The country has also recently experienced an increased number of terrorist attacks. The purpose of this study is to understand the expectations and training of Turkish emergency medicine attending physicians in disaster medicine. METHODS: An online questionnaire was administered to the 937 members of the Emergency Medicine Association of Turkey, of which 191 completed the survey (20%). RESULTS: Most participants (68%) worked at a Training and Research Hospital (TRH) or a University Hospital (UH), and 69% had practiced as an attending for 5 years or less. Mass immigration, refugee problems, and war/terror attacks were considered to be the highest perceived risk topics. Most (95%) agreed that disaster medicine trainings should occur during residency training. Regular disaster drills and exercises and weekly or monthly trainings were the most preferred educational modalities. Most respondents (85%) were interested in advanced training in disaster medicine, and this was highest for those working less than 5 years as an attending. UH and TRH residency training programs were not considered in themselves to be sufficient for learning disaster medicine. CONCLUSIONS: Turkish emergency medicine residency training should include more disaster medicine education and training.

Lithium Pharmacology and a Potential Role of Lithium on Methamphetamine Abuse and Dependence.

BACKGROUND: The effectiveness of lithium salts in neuropsychiatric disorders such as bipolar disorder, Alzheimer's disease, and treatment-resistant depression has been documented in an extensive scientific literature. Lithium inhibits inositol monophosphatase, inositol polyphosphate 1- phosphatase, and glycogen synthase kinase-3 and decreases expression level of tryptophan hydroxylase 2, conceivably underlying the mood stabilizing effects of lithium, as well as procognitive and neuroprotective effects. However, the exact molecular mechanisms of action of lithium on mood stabilizing and pro-cognitive effects in humans are still largely unknown. OBJECTIVE: On the basis of the known aspects of lithium pharmacology, this review will discuss the possible mechanisms underlying the therapeutic effects of lithium on positive symptoms of methamphetamine abuse and dependence. CONCLUSION: It is possible that lithium treatment reduces the amount of newly synthesized phosphatidylinositol, potentially preventing or reversing neuroadaptations contributing to behavioral sensitization induced by methamphetamine. In addition, it is suggested that exposure to repeated doses of methamphetamine induces hyperactivation of glycogen synthase kinase-3ß in the nucleus accumbens and in dorsal hippocampus, resulting in a long-term alterations in synaptic plasticity underlying behavioral sensitization as well as other behavioral deficits in memory-related behavior. Therefore it is clear that glycogen synthase kinase-3ß inhibitors can be considered as a potential candidate for the treatment of methamphetamine abuse and dependence.

Larger Numbers of Glial and Neuronal Cells in the Periaqueductal Gray Matter of µ-Opioid Receptor Knockout Mice.

Background: µ-opioid receptor knockout (MOP-KO) mice display baseline hyperalgesia. We have recently identified changes in tissue volume in the periaqueductal gray matter (PAG) using magnetic resonance imaging voxel-based morphometry. Changes in the structure and connectivity of this region might account for some behavior phenotypes in MOP-KO mice, including hyperalgesia. Methods: Adult male MOP-KO and wild-type (WT) mice were studied. Immunohistochemistry was performed to detect microglia, astrocytes, and neurons in the PAG using specific markers: ionized calcium-binding adaptor molecule 1 (Iba-1) for microglia, glial fibrillary acidic protein (GFAP) for astrocytes, and the neuronal nuclei antigen (NeuN; product of the Rbfox3 gene) for neurons, respectively. Cell counting was performed in the four parallel longitudinal columns of the PAG (dorsomedial, dorsolateral, lateral, and ventrolateral) at three different locations from bregma (-3.5, -4.0, and -4.5 mm). Results: The quantitative analysis showed larger numbers of well-distributed Iba1-IR cells (microglia), NeuN-IR cells (neurons), and GFAP-IR areas (astrocytes) at all the anatomically distinct regions examined, namely, the dorsomedial (DM) PAG, dorsolateral (DL) PAG, lateral (L) PAG, and ventrolateral (VL) PAG, in MOP-KO mice than in control mice. Conclusions: The cellular changes in the PAG identified in this paper may underlie aspects of the behavioral alterations produced by MOP receptor deletion, and suggest that alterations in the cellular structure of the PAG may contribute to hyperalgesic states.