Retinoic acid from the meninges regulates cortical neuron generation.

Extrinsic signals controlling generation of neocortical neurons during embryonic life have been difficult to identify. In this study we demonstrate that the dorsal forebrain meninges communicate with the adjacent radial glial endfeet and influence cortical development. We took advantage of Foxc1 mutant mice with defects in forebrain meningeal formation. Foxc1 dosage and loss of meninges correlated with a dramatic reduction in both neuron and intermediate progenitor production and elongation of the neuroepithelium. Several types of experiments demonstrate that retinoic acid (RA) is the key component of this secreted activity. In addition, Rdh10- and Raldh2-expressing cells in the dorsal meninges were either reduced or absent in the Foxc1 mutants, and Rdh10 mutants had a cortical phenotype similar to the Foxc1 null mutants. Lastly, in utero RA treatment rescued the cortical phenotype in Foxc1 mutants. These results establish RA as a potent, meningeal-derived cue required for successful corticogenesis.

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.

Anticoagulation reversal for intracranial hemorrhage in the era of the direct oral anticoagulants.

PURPOSE OF REVIEW: This review focuses on recent relevant literature that examines the reversal of direct oral anticoagulants (DOACs) in patients with intracranial hemorrhage (ICH). The aim of this review is to provide an insightful description of available reversal agents and their clinical utility. RECENT FINDINGS: Increases in prescribing of DOACs has led to the introduction of drug-specific reversal agents. The clinical trials that evaluated these agents did not include a comparator arm making it difficult to determine if they are clinically superior to nonspecific reversal agents. SUMMARY: Numerous options for reversal of DOAC-associated ICH are currently available. Recent clinical trials have demonstrated drug-specific reversal agents are effective in this setting, but additional research is needed to determine whether these agents should be routinely preferred over nonspecific reversal agents.

CAR T-Cell-Associated Neurotoxicity: Current Management and Emerging Treatment Strategies.

Axicabtagene ciloleucel and tisagenlecleucel are 2 chimeric antigen receptor (CAR) T-cell immunotherapies targeting CD19 for the treatment of B-cell acute lymphoblastic leukemia and non-Hodgkin lymphoma. Two commonly recognized complications associated with CAR T-cell therapies are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). ICANS can occur in isolation or concomitantly with CRS following CAR T-cell therapy and may be due to disruption of the blood-brain barrier and the effects of elevated cytokine levels on the central nervous system. Presently, the optimum management of ICANS remains elusive, as there lacks consensus guidelines. The objective of this review is to provide a comprehensive summary of ICANS and strategies for prompt identification and management of patients presenting to the intensive care unit with this syndrome.

Scalable Synthesis of Enantiopure Bis-3,4-diazaphospholane Ligands for Asymmetric Catalysis.

An optimized route to enantiopure tetra-carboxylic acid and tetra-carboxamide bis(diazaphospholane) ligands that obviates chromatographic purification is presented. This synthesis, which is demonstrated on 15 and 100 g scales, features a scalable classical resolution of tetra-carboxylic acid enantiomers with recycling of the resolving agent. When paired with a rhodium metal center, these bis(diazaphospholane) ligands are highly active and selective in asymmetric hydroformylation applications.

Evaluation of Posttransplantation Diabetes Mellitus After Liver Transplantation: Assessment of Insulin Administration as a Risk Factor.

BACKGROUND: Impaired glucose regulation posttransplantation can affect allograft survival and may lead to the development of posttransplant diabetes mellitus (PTDM). OBJECTIVES: The primary purpose of this study is to assess the difference in insulin burden between liver transplant patients who develop PTDM and patients who do not. METHODS: This was a single-center, retrospective study. Adult liver transplant recipients transplanted between January 1, 2005, and August 1, 2013, were included. PTDM was defined as: (1) use of an oral antihyperglycemic agent for ≥30 consecutive days after transplant, (2) use of insulin ≥30 consecutive days after transplant, or (3) hemoglobin A1C≥6.5 any time after transplant. RESULTS: Of the 114 patients included, 48 (42%) developed PTDM. The average 24-hour insulin requirement on the medical floors was 17.2 ± 14.5 units in the PTDM group and 11.3 ± 12.2 units in the PTDM-free group;P= 0.02. The average blood glucose level on the medical floor was 184.7 ± 31.5 mg/dL in the PTDM group and 169.3 ± 31.4 mg/dL in the PTDM-free group;P= 0.013. Multivariate analysis revealed that experiencing rejection was positively associated with the development of PTDM: adjusted odds ratio (AOR) = 3.237; 95% CI = 1.214-8.633. Basiliximab was negatively associated with the development of PTDM: AOR = 0.182; 95% CI = 0.040-0.836. CONCLUSION: Univariate analyses suggest that insulin burden is a positive risk factor for the development of PTDM; this association is lost in multivariate analyses. Rejection was a positive predictor, and use of basiliximab was a negative predictor for the development of PTDM.

Attitudes, perceptions, and experiences of Western Australians towards vaccine safety surveillance systems following COVID-19 vaccines: A qualitative descriptive study.

OBJECTIVE: Concerns regarding adverse events following immunisation are a barrier to vaccine uptake. Health professionals use vaccine safety surveillance systems (VSSSs) to monitor vaccines and inform the public of safety data. With little known about public attitudes, perceptions, and experiences with VSSS, we examined them in the context of COVID-19 vaccinations in Western Australia. METHODS: Researchers conducted 158 qualitative interviews between March 2021 and May 2022 within the broader [name redacted] project. Data regarding VSSS were coded in NVivo using the deductive and inductive methods. RESULTS: Despite some not knowing about VSSS, participants expected follow-up post COVID-19 vaccination. Vaccine hesitant or refusing participants knew about VSSS and regarded these systems positively. Additional considerations concerned the reliability of data collected by VSSS. CONCLUSION: Perceptions of VSSS signal a lack of understanding about how these systems work. Future studies should further explore the public's understanding of VSSS, whether VSSS improves vaccine confidence, and how governments can better communicate to the public about VSSS. IMPLICATIONS FOR PUBLIC HEALTH: Lack of understanding of how VSSS operate may be stymying attempts to build public vaccine confidence. Healthcare providers and governments could build public knowledge and understanding of VSSS to mitigate concerns of adverse events following immunisation.

Morphological defects in a novel Rdh10 mutant that has reduced retinoic acid biosynthesis and signaling.

Retinoic acid (RA) signaling is necessary for proper patterning and morphogenesis during embryonic development. Tissue-specific RA signaling requires precise spatial and temporal synthesis of RA from retinal by retinaldehyde dehydrogenases (Raldh) and the conversion of retinol to retinal by retinol dehydrogenases (Rdh) of the short-chain dehydrogenase/reducatase gene family (SDR). The SDR, retinol dehydrogenase 10 (RDH10), is a major contributor to retinal biosynthesis during mid-gestation. We have identified a missense mutation in the Rdh10 gene (Rdh10(m366Asp) ) using an N-ethyl-N-nitrosourea-induced forward genetic screen that result in reduced RA levels and signaling during embryonic development. Rdh10(m366Asp) mutant embryos have unique phenotypes, such as edema, a massive midline facial cleft, and neurogenesis defects in the forebrain, that will allow the identification of novel RA functions.

A mutation in the pericentrin gene causes abnormal interneuron migration to the olfactory bulb in mice.

Precise control of neuronal migration is essential for proper function of the brain. Taking a forward genetic screen, we isolated a mutant mouse with defects in interneuron migration. By genetic mapping, we identified a frame shift mutation in the pericentrin (Pcnt) gene. The Pcnt gene encodes a large centrosomal coiled-coil protein that has been implicated in schizophrenia. Recently, frame shift and premature termination mutations in the pericentrin (PCNT) gene were identified in individuals with Seckel syndrome and microcephalic osteodysplastic primordial dwarfism (MOPD II), both of which are characterized by greatly reduced body and brain sizes. The mouse Pcnt mutant shares features with the human syndromes in its overall growth retardation and reduced brain size. We found that dorsal lateral ganglionic eminence (dLGE)-derived olfactory bulb interneurons are severely affected and distributed abnormally in the rostral forebrain in the mutant. Furthermore, mutant interneurons exhibit abnormal migration behavior and RNA interference knockdown of Pcnt impairs cell migration along the rostal migratory stream (RMS) into the olfactory bulb. These findings indicate that pericentrin is required for proper migration of olfactory bulb interneurons and provide a developmental basis for association of pericentrin function with interneuron defects in human schizophrenia.

Development of Pd/C-catalyzed cyanation of aryl halides.

A practical method for palladium-catalyzed cyanation of aryl halides using Pd/C is described. The new method can be applied to a variety of aryl bromide and active aryl chloride substrates to effect efficient conversions. The process features many advantages over existing cyanation conditions and the practical utility of the process has been demonstrated on scale.

Safety and Tolerance of Enteral Nutrition in the Medical and Surgical Intensive Care Unit Patient Receiving Vasopressors.

BACKGROUND: Multiple societal guidelines recommend enteral nutrition (EN) be initiated within 24 to 48 hours of admission to the intensive care unit (ICU) once a patient is hemodynamically stable. Gastrointestinal intolerance and occurrence of bowel ischemia have been a concern for patients receiving vasopressors while concurrently receiving luminal nutrients. The study objective was to determine whether patients receiving vasopressors while concomitantly receiving enteral nutrients had more incidences of bowel ischemia and intolerance than those receiving EN without vasopressor agents. METHODS: This retrospective study included 319 medical and surgical ICU patients from a level 1 trauma center. The patients were either receiving vasopressors simultaneously with EN (n = 178) or EN alone (n = 141). Data regarding gastric residual volume (GRV), new abdominal pain, emesis, and bowel ischemia were collected. RESULTS: There were more patients who had elevated GRV in the group that received vasopressors than patients who did not (20% vs 7%; P-value < .01). There were no differences between rates of bowel ischemia, emesis, or new abdominal pain between the 2 groups. CONCLUSION: Based on our findings, EN is generally well tolerated and safe for those patients simultaneously receiving vasopressors.

Perpetrator Risk Markers for Intimate Terrorism and Situational Couple Violence: A Meta-Analysis.

Johnson developed a typology of intimate partner violence (IPV) which includes two different categories of violence: situational couple violence (SCV) and intimate terrorism (IT). Johnson proposed that IT is more likely to be found in clinical samples (e.g., batterer intervention programs or domestic violence shelters) compared to nonclinical (general population) samples. This meta-analysis (n = 149 studies; k = 216 effect sizes) examines differences in the strengths of IPV risk markers in clinical and nonclinical samples of male perpetrators and female victims. All variables (communication and conflict resolution, demand-withdraw patterns, relationship dissatisfaction, controlling behaviors, jealousy, patriarchal beliefs, power in the relationship, and stalking) were expected to be significantly related to IPV for both clinical and nonclinical populations. However, specific variables indicative of IT (control, jealousy, patriarchal beliefs, power, and stalking) were expected to be more strongly associated with clinical samples compared to nonclinical samples. As expected, most variables were significant for clinical and nonclinical populations, and IT risk markers (control, power, jealousy, and patriarchal beliefs) were significantly stronger risk markers for IPV in clinical samples. These results indicate that Johnson's typology may be conceptualized as representing a continuum of violence, with IT being more severe due to the controlling nature of the violence. Sample type needs to be considered when research about IPV is disseminated, as different degrees of IPV (IT vs. SCV) may be present depending on sample type. Implications from this study include the need to differentiate the level of violence and to tailor intervention for IPV appropriately.

Continuous Platform to Generate Nitroalkanes On-Demand (in situ) using Peracetic Acid-Mediated Oxidation in a PFA Pipes-in-Series Reactor.

The synthetic utility of the aza-Henry reaction can be diminished on scale by potential hazards associated with the use of peracid to prepare nitroalkane substrates, and the nitroalkanes themselves. In response, a continuous and scalable chemistry platform to prepare aliphatic nitroalkanes on-demand is reported, using the oxidation of oximes with peracetic acid and direct reaction of the nitroalkane intermediate in an aza-Henry reaction. A uniquely designed pipes-in-series plug flow tube reactor addresses a range of process challenges including stability and safe handling of peroxides and nitroalkanes. The subsequent continuous extraction generates a solution of purified nitroalkane which can be directly used in the following enantioselective aza-Henry chemistry to furnish valuable chiral diamine precursors in high selectivity, thus, completely avoiding isolation of potentially unsafe low molecular weight nitroalkane intermediate. A continuous campaign (16 h) established that these conditions were effective in processing 100 g of the oxime and furnishing 1.4 L of nitroalkane solution.

A focused and efficient genetic screening strategy in the mouse: identification of mutations that disrupt cortical development.

Although the mechanisms that regulate development of the cerebral cortex have begun to emerge, in large part through the analysis of mutant mice (Boncinelli et al. 2000; Molnar and Hannan 2000; Walsh and Goffinet 2000), many questions remain unanswered. To provide resources for further dissecting cortical development, we have carried out a focused screen for recessive mutations that disrupt cortical development. One aim of the screen was to identify mutants that disrupt the tangential migration of interneurons into the cortex. At the same time, we also screened for mutations that altered the growth or morphology of the cerebral cortex. We report here the identification of thirteen mutants with defects in aspects of cortical development ranging from the establishment of epithelial polarity to the invasion of thalamocortical axons. Among the collection are three novel alleles of genes for which mutant alleles had already been used to explore forebrain development, and four mutants with defects in interneuron migration. The mutants that we describe here will aid in deciphering the molecules and mechanisms that regulate cortical development. Our results also highlight the utility of focused screens in the mouse, in addition to the large-scale and broadly targeted screens that are being carried out at mutagenesis centers.

Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions.

Advances in drug potency and tailored therapeutics are promoting pharmaceutical manufacturing to transition from a traditional batch paradigm to more flexible continuous processing. Here we report the development of a multistep continuous-flow CGMP (current good manufacturing practices) process that produced 24 kilograms of prexasertib monolactate monohydrate suitable for use in human clinical trials. Eight continuous unit operations were conducted to produce the target at roughly 3 kilograms per day using small continuous reactors, extractors, evaporators, crystallizers, and filters in laboratory fume hoods. Success was enabled by advances in chemistry, engineering, analytical science, process modeling, and equipment design. Substantial technical and business drivers were identified, which merited the continuous process. The continuous process afforded improved performance and safety relative to batch processes and also improved containment of a highly potent compound.

A selective estrogen receptor modulator for the treatment of hot flushes.

A selective estrogen receptor modulator (SERM) for the potential treatment of hot flushes is described. (R)-(+)-7,9-difluoro-5-[4-(2-piperidin-1-ylethoxy)phenyl]-5H-6-oxachrysen-2-ol, LSN2120310, potently binds ERalpha and ERbeta and is an antagonist in MCF-7 breast adenocarcinoma and Ishikawa uterine cancer cell lines. The compound is a potent estrogen antagonist in the rat uterus. In ovariectomized rats, the compound lowers cholesterol, maintains bone mineral density, and is efficacious in a morphine dependent rat model of hot flush efficacy.

Development of an Intermittent-Flow Enantioselective Aza-Henry Reaction Using an Arylnitromethane and Homogeneous Brønsted Acid-Base Catalyst with Recycle.

A stereoselective aza-Henry reaction between an arylnitromethane and Boc-protected aryl aldimine using a homogeneous Brønsted acid-base catalyst was translated from batch format to an automated intermittent-flow process. This work demonstrates the advantages of a novel intermittent-flow setup with product crystallization and slow reagent addition which is not amenable to the standard continuous equipment: plug flow tube reactor (PFR) or continuous stirred tank reactor (CSTR). A significant benefit of this strategy was the integration of an organocatalytic enantioselective reaction with straightforward product separation, including recycle of the catalyst, resulting in increased intensity of the process by maintaining high catalyst concentration in the reactor. A continuous campaign confirmed that these conditions could effectively provide high throughput of material using an automated system while maintaining high selectivity, thereby addressing nitroalkane safety and minimizing catalyst usage.

Genetic mechanisms control the linear scaling between related cortical primary and higher order sensory areas.

In mammals, the neocortical layout consists of few modality-specific primary sensory areas and a multitude of higher order ones. Abnormal layout of cortical areas may disrupt sensory function and behavior. Developmental genetic mechanisms specify primary areas, but mechanisms influencing higher order area properties are unknown. By exploiting gain-of and loss-of function mouse models of the transcription factor Emx2, we have generated bi-directional changes in primary visual cortex size in vivo and have used it as a model to show a novel and prominent function for genetic mechanisms regulating primary visual area size and also proportionally dictating the sizes of surrounding higher order visual areas. This finding redefines the role for intrinsic genetic mechanisms to concomitantly specify and scale primary and related higher order sensory areas in a linear fashion.

A mutation in mouse Pak1ip1 causes orofacial clefting while human PAK1IP1 maps to 6p24 translocation breaking points associated with orofacial clefting.

Orofacial clefts are among the most common birth defects and result in an improper formation of the mouth or the roof of the mouth. Monosomy of the distal aspect of human chromosome 6p has been recognized as causative in congenital malformations affecting the brain and cranial skeleton including orofacial clefts. Among the genes located in this region is PAK1IP1, which encodes a nucleolar factor involved in ribosomal stress response. Here, we report the identification of a novel mouse line that carries a point mutation in the Pak1ip1 gene. Homozygous mutants show severe developmental defects of the brain and craniofacial skeleton, including a median orofacial cleft. We recovered this line of mice in a forward genetic screen and named the allele manta-ray (mray). Our findings prompted us to examine human cases of orofacial clefting for mutations in the PAK1IP1 gene or association with the locus. No deleterious variants in the PAK1IP1 gene coding region were recognized, however, we identified a borderline association effect for SNP rs494723 suggesting a possible role for the PAK1IP1 gene in human orofacial clefting.

Rhodium-catalyzed and zinc(II)-triflate-promoted asymmetric hydrogenation of tetrasubstituted α,ß-unsaturated ketones.

The asymmetric hydrogenation of tetrasubstituted α,ß-unsaturated ketones has been accomplished using an in situ formed rhodium-Josiphos catalyst. The reaction is enhanced by addition of catalytic zinc(II) triflate, which significantly improves turnover frequency while suppressing epimerization of the products.