Professors of racial medicine: imperialism and race in nineteenth-century United States medical schools.

This article examines some of the racist features of nineteenth-century medical school curricula in the United States and the imperial networks necessary to acquire the data and specimens that underpinned this part of medical education, which established hierarchies between human races and their relationship to the natural environment. It shows how, in a world increasingly linked by trade and colonialism, medical schools were founded in the United States and grew as the country developed its own imperial ambitions. Taking advantage of the global reach of empires, a number of medical professors in different states, such as Daniel Drake, Josiah Nott and John Collins Warren, who donated his anatomical collection to Harvard Medical School on his retirement in 1847, began to develop racial theories that naturalised slavery and emerging imperialism as part of their medical teaching.

Slavery and Its Afterlives in US Psychiatry.

Antecedents of racist treatments of Black patients by the psychiatric profession in the United States affect the way they view treatment today. Specifically, in this essay, we explore the enduring consequences of racial science on various treatment practices. We examined a range of primary sources on the history of racial theories about the mind, medical and psychiatric publications, and hospitals. We contextualize this analysis by examining the secondary literature in the history and sociology of psychiatry. Through analyzing racial thinking from the antebellum through the Jim Crow periods, we show how US medicine and psychiatry have roots in antebellum racial science and how carceral logics underpinned the past and present politics of Black mental health. Changing this trajectory requires practitioners to interrogate the historical foundations of racist psychiatric concepts. This essay urges them to reject biological racial realism, which bears reminiscences to 19th-century racial science, and embrace the variable of race as a social construct to study social inequalities in health as a first step toward moving away from the legacies of past injustices in medicine. (Am J Public Health. 2024;114(S3):S250-S257. https://doi.org/10.2105/AJPH.2023.307554).

Monotherapy Anticoagulation to Expedite Home Treatment of Patients Diagnosed With Venous Thromboembolism in the Emergency Department: A Pragmatic Effectiveness Trial.

BACKGROUND: The objective was to test if low-risk emergency department patients with vitamin K antagonist (venous thromboembolism [VTE]; including venous thrombosis and pulmonary embolism [PE]) can be safely and effectively treated at home with direct acting oral (monotherapy) anticoagulation in a large-scale, real-world pragmatic effectiveness trial. METHODS: This was a single-arm trial, conducted from 2016 to 2019 in accordance with the Standards for Reporting Implementation Studies guideline in 33 emergency departments in the United States. Participants had newly diagnosed VTE with low risk of death based upon either the modified Hestia criteria, or physician judgment plus the simplified PE severity index score of zero, together with nonhigh bleeding risk were eligible. Patients had to be discharged within 24 hours of triage and treated with either apixaban or rivaroxaban. Effectiveness was defined by the primary efficacy and safety outcomes, image-proven recurrent VTE and bleeding requiring hospitalization >24 hours, respectively, with an upper limit of the 95% CI for the 30-day frequency of VTE recurrence below 2.0% for both outcomes. RESULTS: We enrolled 1421 patients with complete outcomes data, including 903 with venous thrombosis and 518 with PE. The recurrent VTE requiring hospitalization occurred in 14/1421 (1.0% [95% CI, 0.5%-1.7%]), and bleeding requiring hospitalization occurred in 12/1421 (0.8% [0.4%-1.5%). The rate of severe bleeding using International Society for Thrombosis and Haemostasis criteria was 2/1421 (0.1% [0%-0.5%]). No patient died, and serious adverse events occurred in 2.5% of venous thrombosis patients and 2.3% of patients with PE. Medication nonadherence was reported by patients in 8.0% (6.6%-9.5%) and was associated with a risk ratio of 6.0 (2.3-15.2) for VTE recurrence. Among all patients diagnosed with VTE in the emergency department during the period of study, 18% of venous thrombosis patients and 10% of patients with PE were enrolled. CONCLUSIONS: Monotherapy treatment of low-risk patients with venous thrombosis or PE in the emergency department setting produced a low rate of bleeding and VTE recurrence, but may be underused. Patients with venous thrombosis and PE should undergo risk-stratification before home treatment. Improved patient adherence may reduce rate of recurrent VTE. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03404635.

Study protocol for a multicentre implementation trial of monotherapy anticoagulation to expedite home treatment of patients diagnosed with venous thromboembolism in the emergency department.

INTRODUCTION: In the USA, many emergency departments (EDs) have established protocols to treat patients with newly diagnosed deep vein thrombosis (DVT) as outpatients. Similar treatment of patients with pulmonary embolism (PE) has been proposed, but no large-scale study has been published to evaluate a comprehensive, integrated protocol that employs monotherapy anticoagulation to treat patients diagnosed with DVT and PE in the ED. METHODS AND ANALYSIS: This protocol describes the implementation of the Monotherapy Anticoagulation To expedite Home treatment of Venous ThromboEmbolism (MATH-VTE) study at 33 hospitals in the USA. The study was designed and executed to meet the requirements for the Standards for Reporting Implementation Studies guideline. The study was funded by investigator-initiated awards from industry, with Indiana University as the sponsor. The study principal investigator and study associates travelled to each site to provide on-site training. The protocol identically screens patients with both DVT or PE to determine low risk of death using either the modified Hestia criteria or physician judgement plus a negative result from the simplified PE severity index. Patients must be discharged from the ED within 24 hours of triage and treated with either apixaban or rivaroxaban. Overall effectiveness is based upon the primary efficacy and safety outcomes of recurrent VTE and bleeding requiring hospitalisation respectively. Target enrolment of 1300 patients was estimated with efficacy success defined as the upper limit of the 95% CI for the 30-day frequency of VTE recurrence below 2.0%. Thirty-three hospitals in 17 states were initiated in 2016-2017. ETHICS AND DISSEMINATION: All sites had Institutional Review Board approval. We anticipate completion of enrolment in June 2020; study data will be available after peer-reviewed publication. MATH-VTE will provide information from a large multicentre sample of US patients about the efficacy and safety of home treatment of VTE with monotherapy anticoagulation.

"His Native, Hot Country"1: Racial Science and Environment in Antebellum American Medical Thought.

Relying on a close reading of more than 4,000 medicals student theses, this essay explores the evolving medical approaches to race and environment in the early national and antebellum United States and highlights the role that medical school pedagogy played in disseminating and elaborating racial theory. Specifically, it considers the influence of racial science on medical concepts of the relationship of bodies to climates. At their core, monogenesis-belief in a single, unified human race-and polygenesis-the belief that each race was created separately-were theories about the human body's connections to the natural world. As polygenesis became influential in Atlantic medical thought, physicians saw environmental treatments as a matter of matching bodies to their natural ecology. In the first decades of the nineteenth century, Atlantic physicians understood bodies and places as in constant states of flux. Through proper treatment, people and environments could suffer either degradation or improvement. Practitioners saw African Americans and whites as the same species with their differences being largely superficial and produced by climate. However, by the 1830s and 1840s medical students were learning that each race was inherently different and unalterable by time or temperature. In this paradigm, medical students articulated a vision of racial health rooted in organic relationships between bodies and climates.

Vereckei criteria used as a diagnostic tool by emergency medicine residents to distinguish between ventricular tachycardia and supra-ventricular tachycardia with aberrancy.

BACKGROUND: Accurate electrocardiographic (ECG) differentiation of ventricular tachycardia (VT) from supraventricular tachycardia with aberrancy (SVT-A) on ECG is key to therapeutic decision-making in the emergency department (ED) setting. OBJECTIVE: The goal of this study was to test the accuracy and agreement of emergency medicine residents to differentiate VT from SVT-A using the Vereckei criteria. METHODS: Six emergency medicine residents volunteered to participate in the review of 114 ECGs from 86 patients with a diagnosis of either VT or SVT-A based on an electrophysiology study. The resident reviewers initially read 12-lead ECGs blinded to clinical information, and then one week later reviewed a subset of the same 12-lead ECGs unblinded to clinical information. RESULTS: One reviewer was excluded for failing to follow study protocol and one reviewer was excluded for reviewing less than 50 blinded ECGs. The remaining four reviewers each read 114 common ECGs blinded to clinical data and their diagnostic accuracy for VT was 74% (sensitivity 70%, specificity 80%), 75% (sensitivity 76%, specificity 73%), 61% (sensitivity 81%, specificity 25%), and 68% (sensitivity 84%, specificity 40%). The intraclass correlation coefficient (ICC) was 0.31 (95% CI 0.22-0.42). Eliminating two of the four reviewers who left a disproportionately high number of ECGs unclassified resulted in an increase in overall mean diagnostic accuracy (70-74%) and agreement (0.31-0.50) in the two remaining reviewers. Three reviewers read 45 common ECGs unblinded to clinical information and had accuracies for VT 93%, 93% and 78%. CONCLUSION: The new single lead Vereckei criteria, when applied by emergency medicine residents achieved only fair-to-good individual accuracy and moderate agreement. The addition of clinical information resulted in substantial improvement in test characteristics. Further improvements (accuracy and simplification) of algorithms for differentiating VT from SVT-A would be helpful prior to clinical implementation.

ECG of the month. Bigeminal rhythm VIII. Sinus rhythm with normal antegrade atrioventricular (A-V) conduction and slow retrograde conduction back to the atria, producing atrial reentry or echo complexes and suggesting dual A-V nodal pathways or an accessory A-V pathway that conducts slowly from the ventricles to the atria.

A 55-year-old woman came to the emergency department because of an episode of post-prandial upper abdominal pain radiating to her back and associated with nausea and vomiting. The pain had been recurring intermittently for approximately six months. While in the emergency department, she had another episode of pain and felt lightheaded. Her pulse rate at that point was between 30 and 40 beats per minute, and an electrocardiogram was recorded (Figure).

An analysis of the results from Two-Generation Reproduction Toxicity Studies to assess the value of mating animals of the second (F1) generation for the detection of adverse treatment-related effects on reproductive performance.

The need to routinely perform a two-generation study to assess reproductive performance is under debate. This review has analysed the results from 22 consecutive Two-Generation Reproduction Toxicity Studies performed within our laboratories, to determine the value of mating each generation in the detection of treatment-related effects on reproductive performance. The chemicals included 13 agrochemicals, 5 industrial chemicals and 4 food additives. Four chemicals (all from the agrochemical group) were found to have clear treatment-related effects and in three studies effects were confined to the second (F1) generation. For the three studies with second (F1) generation effects, we applied the triggers, proposed by the Agricultural Chemical Safety Assessment (ASCA) Technical Committee of HESI, for extension of the one-generation study and found that mating of the second (F1) generation would have been triggered in these studies by effects on the F1 offspring growth and sexual maturation. No effects were seen in the original parental (F0) generation which would have activated the change from a one- to a two-generation study.

Identification of a nonpeptidic and conformationally restricted bradykinin B1 receptor antagonist with anti-inflammatory activity.

We report the discovery of chroman 28, a potent and selective antagonist of human, nonhuman primate, rat, and rabbit bradykinin B1 receptors (0.4-17 nM). At 90 mg/kg s.c., 28 decreased plasma extravasation in two rodent models of inflammation. A novel method to calculate entropy is introduced and ascribed approximately 30% of the gained affinity between "flexible" 4 (Ki = 132 nM) and "rigid" 28 (Ki = 0.77 nM) to decreased conformational entropy.

Modeling aided design of potent glycogen phosphorylase inhibitors.

Molecular modeling has been used to assist in the development of a novel series of potent glycogen phosphorylase inhibitors based on a phenyl diacid lead, compound 1. In the absence of suitable competitive binding assays, compound 1 was predicted to bind at the AMP allosteric site based on superposition onto known inhibitors which bind at different sites in the enzyme and analyses of the surrounding protein environment associated with these distinct sites. Possible docking modes of compound 1 at the AMP allosteric site were further explored using the crystal structure of rabbit muscle glycogen phosphorylase complexed with a Bayer diacid compound W1807 (PDB entry 3AMV). Compound 1 was predicted to interact with positively charged arginines at the AMP allosteric site in the docking model. Characterization of the binding pocket by a grid-based surface calculation of the docking model revealed a large unfilled hydrophobic region near the central phenyl ring, suggesting that compounds with larger hydrophobic groups in this region would improve binding. A series of naphthyl diacid compounds were designed and synthesized to access this hydrophobic cleft, and showed significantly improved potency.

Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 2: Discovery of potent, selective, and orally bioavailable compounds.

Modifications of the alkyl acetic acid portion and the phenyl on pyrrolidine in our lead pyrazole compound 1 afforded the isopropyl compound 9. This compound is a potent CCR5 antagonist showing good in vitro antiviral activity against HIV-1, an excellent selectivity profile, and good oral bioavailability in three animal species. During this investigation, a new method for the preparation of alpha-(pyrrolidin-1-yl)-alpha,alpha-dialkyl acetic acid from a pyrrolidine and alpha-bromo-alpha,alpha-dialkyl acetic acid using silver triflate was discovered. This allowed us to prepare compounds such as 24 and 25 for the first time. A novel Pd-mediated N-dealkylation of alpha-(pyrrolidin-1-yl)acetic acid was also uncovered.

A new class of glycogen phosphorylase inhibitors.

A new class of diacid analogues that binds at the AMP site not only are very potent but have approximately 10-fold selectivity in liver versus muscle glycogen phosphorylase (GP) in the in vitro assay. The synthesis, structure, and in vitro and in vivo biological evaluation of these liver selective glycogen phosphorylase inhibitors are discussed.

1,3,4 Trisubstituted pyrrolidine CCR5 receptor antagonists bearing 4-aminoheterocycle substituted piperidine side chains.

A new class of 4-(aminoheterocycle)piperidine derived 1,3,4 trisubstituted pyrrolidine CCR5 antagonists is reported. Compound 4a is shown to have good binding affinity (1.8 nM) and antiviral activity in PBMC's (IC(95)=50 nM). Compound 4a also has improved PK properties relative to 1.

1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists: modifications of the arylpropylpiperidine side chains.

The 4-(3-phenylprop-1-yl)piperidine moiety of the 1,3,4-trisubstituted pyrrolidine CCR5 antagonist 1 was modified with electron deficient aromatics as well as replacement of the benzylic methylene with sulfones, gem-difluoromethylenes and alcohols in an effort to balance the antiviral potency with reasonable pharmacokinetics.

Discovery of potent, selective human granzyme B inhibitors that inhibit CTL mediated apoptosis.

A novel class of small molecule human granzyme B inhibitors is reported. Compound 20 has a K(i) of 7 nM against human granzyme B and blocks CTL mediated apoptosis with an IC(50) of 3 micromolar.

Combinatorial synthesis of 3-(amidoalkyl) and 3-(aminoalkyl)-2-arylindole derivatives: discovery of potent ligands for a variety of G-protein coupled receptors.

Preparation and screening of mixture libraries based on a 2-arylindole scaffold resulted in the discovery of potent ligands for a variety of G-protein coupled receptors.