A causal inference study: The impact of the combined administration of Donepezil and Memantine on decreasing hospital and emergency department visits of Alzheimer's disease patients.

Alzheimer's disease is the most common type of dementia that currently affects over 6.5 million people in the U.S. Currently there is no cure and the existing drug therapies attempt to delay the mental decline and improve cognitive abilities. Two of the most commonly prescribed such drugs are Donepezil and Memantine. We formally tested and confirmed the presence of a beneficial drug-drug interaction of Donepezil and Memantine using a causal inference analysis. We applied doubly robust estimators to one of the largest and high-quality medical databases to estimate the effect of two commonly prescribed Alzheimer's disease (AD) medications, Donepezil and Memantine, on the average number of hospital or emergency department visits per year among patients diagnosed with AD. Our results show that, compared to the absence of medication scenario, the Memantine monotherapy, and the Donepezil monotherapy, the combined use of Donepezil and Memantine treatment significantly reduces the average number of hospital or emergency department visits per year by 0.078 (13.8%), 0.144 (25.5%), and 0.132 days (23.4%), respectively. The assessed decline in the average number of hospital or emergency department visits per year is consequently associated with a substantial reduction in medical costs. As of 2022, according to the Alzheimer's Disease Association, there were over 6.5 million individuals aged 65 and older living with AD in the US alone. If patients who are currently on no drug treatment or using either Donepezil or Memantine alone were switched to the combined used of Donepezil and Memantine therapy, the average number of hospital or emergency department visits could decrease by over 613 thousand visits per year. This, in turn, would lead to a remarkable reduction in medical expenses associated with hospitalization of AD patients in the US, totaling over 940 million dollars per year.

Feasibility and Utility of Routine Point-of-Care Gastric Ultrasonography in Patients Undergoing Upper Gastrointestinal Endoscopy Procedures: A Prospective Cohort Study.

OBJECTIVES: Previous studies have indicated that point-of-care ultrasonography (POCUS) of the gastric antrum can predict the adequacy of fasting before surgery and anesthesia. The aim of this study was to evaluate the utility of gastric POCUS in patients undergoing upper gastrointestinal (GI) endoscopy procedures. METHODS: We performed a single-center cohort study in patients undergoing upper GI endoscopy. Consenting patient's gastric antrum was scanned before anesthetic care for endoscopy to determine the cross-sectional area (CSA) and qualitatively determine safe and unsafe contents. Further, an estimate of residual gastric volume was determined using the formula and the nomogram methods. Subsequently, gastric secretions aspirated during endoscopy were quantified and further correlated with nomogram and formula-based assessments. No patient required a change in the primary anesthetic plan except for using rapid sequence induction in those with unsafe contents on POCUS scans. RESULTS: Qualitative ultrasound measurements consistently determined safe and unsafe gastric residual contents in 83 patients enrolled in the study. Unsafe contents were determined by qualitative scans in 4 out of 83 cases (5%) despite adequate fasting status. Quantitatively, only a moderate correlation was demonstrated between measured gastric volumes and nomogram (r = .40, 95% CI: 0.20, 0.57; P = .0002) or formula-based (r = .38, 95% CI: 0.17, 0.55; P = .0004) determinations of residual gastric volumes. CONCLUSION: In daily clinical practice, qualitative POCUS determination of residual gastric content is a feasible and useful technique to identify patients at risk of aspiration before upper GI endoscopy procedures.

Predicting suicidal and self-injurious events in a correctional setting using AI algorithms on unstructured medical notes and structured data.

Suicidal and self-injurious incidents in correctional settings deplete the institutional and healthcare resources, create disorder and stress for staff and other inmates. Traditional statistical analyses provide some guidance, but they can only be applied to structured data that are often difficult to collect and their recommendations are often expensive to act upon. This study aims to extract information from medical and mental health progress notes using AI algorithms to make actionable predictions of suicidal and self-injurious events to improve the efficiency of triage for health care services and prevent suicidal and injurious events from happening at California's Orange County Jails. The results showed that the notes data contain more information with respect to suicidal or injurious behaviors than the structured data available in the EHR database at the Orange County Jails. Using the notes data alone (under-sampled to 50%) in a Transformer Encoder model produced an AUC-ROC of 0.862, a Sensitivity of 0.816, and a Specificity of 0.738. Incorporating the information extracted from the notes data into traditional Machine Learning models as a feature alongside structured data (under-sampled to 50%) yielded better performance in terms of Sensitivity (AUC-ROC: 0.77, Sensitivity: 0.89, Specificity: 0.65). In addition, under-sampling is an effective approach to mitigating the impact of the extremely imbalanced classes.

Point-of-Care Ultrasound (POCUS) for the Cardiothoracic Anesthesiologist.

Point-of-Care Ultrasound (POCUS) is a valuable bedside diagnostic tool for a variety of expeditious clinical assessments or as guidance for a multitude of acute care procedures. Varying aspects of nearly all organ systems can be evaluated using POCUS and, with the increasing availability of affordable ultrasound systems over the past decade, many now refer to POCUS as the 21st-century stethoscope. With the current available and growing evidence for the clinical value of POCUS, its utility across the perioperative arena adds enormous benefit to clinical decision-making. Cardiothoracic anesthesiologists routinely have used portable ultrasound systems for nearly as long as the technology has been available, making POCUS applications a natural extension of existing cardiothoracic anesthesia practice. This narrative review presents a broad discussion of the utility of POCUS for the cardiothoracic anesthesiologist in varying perioperative contexts, including the preoperative clinic, the operating room (OR), intensive care unit (ICU), and others. Furthermore, POCUS-related education, competence, and certification are addressed.

Tracheotomy in the SARS-CoV-2 pandemic.

The severe acute respiratory syndrome (SARS)-CoV-2 pandemic continues to produce a large number of patients with chronic respiratory failure and ventilator dependence. As such, surgeons will be called upon to perform tracheotomy for a subset of these chronically intubated patients. As seen during the SARS and the SARS-CoV-2 outbreaks, aerosol-generating procedures (AGP) have been associated with higher rates of infection of medical personnel and potential acceleration of viral dissemination throughout the medical center. Therefore, a thoughtful approach to tracheotomy (and other AGPs) is imperative and maintaining traditional management norms may be unsuitable or even potentially harmful. We sought to review the existing evidence informing best practices and then develop straightforward guidelines for tracheotomy during the SARS-CoV-2 pandemic. This communication is the product of those efforts and is based on national and international experience with the current SARS-CoV-2 pandemic and the SARS epidemic of 2002/2003.

Design and Synthesis of a Novel Series of Orally Bioavailable, CNS-Penetrant, Isoform Selective Phosphoinositide 3-Kinase γ (PI3Kγ) Inhibitors with Potential for the Treatment of Multiple Sclerosis (MS).

The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kγ, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kγ. This ultimately led to the discovery of 16, an orally bioavailable compound that showed efficacy in murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis.

Discovery of VX-509 (Decernotinib): A Potent and Selective Janus Kinase 3 Inhibitor for the Treatment of Autoimmune Diseases.

While several therapeutic options exist, the need for more effective, safe, and convenient treatment for a variety of autoimmune diseases persists. Targeting the Janus tyrosine kinases (JAKs), which play essential roles in cell signaling responses and can contribute to aberrant immune function associated with disease, has emerged as a novel and attractive approach for the development of new autoimmune disease therapies. We screened our compound library against JAK3, a key signaling kinase in immune cells, and identified multiple scaffolds showing good inhibitory activity for this kinase. A particular scaffold of interest, the 1H-pyrrolo[2,3-b]pyridine series (7-azaindoles), was selected for further optimization in part on the basis of binding affinity (Ki) as well as on the basis of cellular potency. Optimization of this chemical series led to the identification of VX-509 (decernotinib), a novel, potent, and selective JAK3 inhibitor, which demonstrates good efficacy in vivo in the rat host versus graft model (HvG). On the basis of these findings, it appears that VX-509 offers potential for the treatment of a variety of autoimmune diseases.

Hypotensive Resuscitation.

Hypotensive resuscitation is a component of damage control resuscitation, the evolving approach to resuscitation in severely injured trauma patients. Resuscitation strategies used in treating severely injured trauma patients have changed dramatically over the last 20 years. The purpose of this review is to examine the current literature pertaining to hypotensive resuscitation, explore its use in damage control resuscitation, and examine blood pressure management in the setting of severe trauma.

Inflammatory response to trauma: implications for coagulation and resuscitation.

PURPOSE OF REVIEW: Recent studies have changed our understanding of the timing and interactions of the inflammatory processes and coagulation cascade following severe trauma. This review highlights this information and correlates its impact on the current clinical approach for fluid resuscitation and treatment of coagulopathy for trauma patients. RECENT FINDINGS: Severe trauma is associated with a failure of multiple biologic emergency response systems that includes imbalanced inflammatory response, acute coagulopathy of trauma, and endovascular glycocalyx degradation with microcirculatory compromise. These abnormalities are all interlinked and related. Recent observations show that after severe trauma: proinflammatory and anti-inflammatory responses are concomitant, not sequential and resolution of the inflammatory response is an active process, not a passive one. Understanding these interrelated processes is considered extremely important for the development of future therapies for severe trauma in humans. SUMMARY: Traumatic injuries continue to be a significant cause of mortality worldwide. Recent advances in understanding the mechanisms of end-organ failure, and modulation of the inflammatory response has important clinical implications regarding fluid resuscitation and treatment of coagulopathy.

Design, synthesis, and evaluation of a novel dual FMS-like tyrosine kinase 3/stem cell factor receptor (FLT3/c-KIT) inhibitor for the treatment of acute myelogenous leukemia.

A high-throughput screen of our compound archive revealed a novel class of dual FMS-like tyrosine kinase 3 (FLT3)/c-KIT inhibitors. With the help of molecular modeling, this class was rapidly optimized for both potency against FLT3 and FLT3/c-KIT and excellent potency in cell-based assays, leading to dose-dependent cell death in acute myelogenous leukemia (AML) patient blast samples. Ultimately, the AML patient blast data defined the preferred target profile as we designed and evaluated a set of FLT3 selective and FLT3/c-KIT dual molecules. Further optimization for pharmacokinetic properties resulted in the selection of the dual FLT3/c-KIT inhibitor, N(3)-(4-(trans-4-morpholinocyclohexyl)phenyl)-1-(pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine, VX-322 (compound 37), to move forward to preclinical evaluation.

A novel chemotype of kinase inhibitors: Discovery of 3,4-ring fused 7-azaindoles and deazapurines as potent JAK2 inhibitors.

Pictet-Spengler condensation of aldehydes or alpha-keto-esters with 4-(2-anilinophenyl)-7-azaindole (11) or deazapurine (12) gave high yields of the 3,4-fused cyclic compounds. SAR studies, by varying the substituted benzaldehyde components, lead to the discovery of a series of potent JAK2 kinase inhibitors.

Janus kinase 2 inhibitors. Synthesis and characterization of a novel polycyclic azaindole.

The synthesis and characterization of a novel polycyclic azaindole based derivative is disclosed, and its binding to JAK2 is described. The compound is further evaluated for its ability to block the EPO/JAK2 signaling cascade in vitro and in vivo.

2-Aminopyrazolo[1,5-a]pyrimidines as potent and selective inhibitors of JAK2.

Constitutive activation of the EPO/JAK2 signaling cascade has recently been implicated in a variety of myeloproliferative disorders including polycythemia vera, essential thrombocythemia and myelofibrosis. In an effort to uncover therapeutic potential of blocking the EPO/JAK2 signaling cascade, we sought to discover selective inhibitors that block the kinase activity of JAK2. Herein, we describe the discovery and structure based optimization of a novel series of 2-amino-pyrazolo[1,5-a]pyrimidines that exhibit potent inhibition of JAK2.

Structure-based design of 3-aryl-6-amino-triazolo[4,3-b]pyridazine inhibitors of Pim-1 kinase.

A series of substituted 3-aryl-6-amino-triazolo[4,3-b]pyridazines were identified as highly selective inhibitors of Pim-1 kinase. Initial exploration identified compound 24 as a potent, selective inhibitor, limited in its utility by poor solubility and permeability. Understanding the unusual ATP-binding site of the Pim kinases and X-ray crystallographic data on compound 24 led to design improvements in this class of inhibitor. This resulted in compound 29, a selective, soluble and permeable inhibitor of Pim-1.

Docking study yields four novel inhibitors of the protooncogene Pim-1 kinase.

To supplement the hits from a high throughput screen, docking was performed against Pim-1 kinase. Glide docking was augmented with a filter to require traditional or aromatic CH..O hydrogen bonds to the kinase hinge. Four diverse actives, of 96 molecules assayed, had K(i) values between 0.091 and 4.5 microM. This gives a 14-fold enrichment over the earlier HTS run, and the two crystal structures solved confirmed the binding modes predicted by docking.

Anesthesia for laparoscopic donor nephrectomy: is nitrous oxide contraindicated?

PURPOSE: We performed this study to test the hypothesis that nitrous oxide produces clinically significant bowel distention during laparoscopic abdominal surgery. MATERIALS AND METHODS: Laparoscopic kidney donors were randomized into 2 groups. Group 1 received N2O and oxygen inhalation through anesthesia, and group 2 received a mixture of air and oxygen. All patients received the same preanesthetic and anesthetic medications. The surgeon was blinded to the use of N2O. The surgeon was given the option to discontinue N2O use (if it was used) if he/she thought that the bowel distention was increasing surgical risk. Postoperative data were collected on bowel symptoms, pain and recovery. RESULTS: A total of 28 patients were enrolled in the study, 12 of whom received N2O (group 1) and 16 who did not receive N2O (group 2). Mild to moderate bowel distention was reported by the surgeons in 6 patients (50%) in group 1 and 1 patient only in group 2 (6%, p=0.007). Severe bowel distention was encountered in 4 patients, 3 of whom received N2O (25% of group 1). Nausea and vomiting on postoperative day 1 was reported by 50% of patients in group 1 and 25% of group 2. There was no difference in the pain scores between the 2 groups. No intraoperative or postoperative complications were encountered. CONCLUSIONS: The use of N2O anesthetic causes bowel distention in 50% of abdominal laparoscopic donor nephrectomy operations. The distention was severe enough to interfere with the progress of surgery in 25% of cases and the use of N2O had to be discontinued.

CH...O and CH...N hydrogen bonds in ligand design: a novel quinazolin-4-ylthiazol-2-ylamine protein kinase inhibitor.

Aryl CH hydrogen bonds play an important role in the binding of several analogues of a pyrazol-3-ylquinazolin-4-ylamine inhibitor of glycogen synthase kinase 3 (GSK3). Understanding the importance of these CH...O and CH...N hydrogen bonds allowed the design of a novel quinazolin-4-ylthiazol-2-ylamine inhibitor of GSK3 with a structurally confirmed CH...O hydrogen bond to the protein.

BREED: Generating novel inhibitors through hybridization of known ligands. Application to CDK2, p38, and HIV protease.

In this work we describe BREED, a method for the generation of novel inhibitors from structures of known ligands bound to a common target. The method is essentially an automation of the common medicinal chemistry practice of joining fragments of two known ligands to generate a new inhibitor. The ligand-bound target structures are overlaid, all overlapping bonds in all pairs of ligands are found, and the fragments on each side of each matching bond are swapped to generate the new molecules. Since the method is automated, it can be applied recursively to generate all possible combinations of known ligands. In an application of this method to HIV protease inhibitors and protein kinase inhibitors, hundreds of new molecular structures were generated. These included known inhibitor scaffolds not included in the initial set, entirely novel scaffolds, and novel substituents on known scaffolds. The method is fast, and since all of the ligand functional groups are known to bind the target in the precise position and orientation present in the novel ligand, the success rate of this method should be superior to more traditional de novo design techniques. In an era of increasingly high-throughput structural biology, such methods for high-throughput utilization of structural information will become increasingly valuable.