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Objective: This study aimed to determine health care disparities in evaluation and admission among underserved racial and ethnic minority groups presenting with cardiovascular complaints during the first postpartum year according to patient and provider demographics., Study Design: A retrospective cohort study was performed on all postpartum patients who sought emergency care between February 2012 and October 2020 in a large urban care center in Southeastern Texas. Patient information was collected according to International Classification of Diseases 10th Revision codes and individual chart analysis. Race, ethnicity, and gender information were self-reported for both patients on hospital enrollment forms and emergency department (ED) providers on their employment records. Statistical analysis was performed with logistic regression and Pearson's chi-square test., Results: Of 47,976 patients who delivered during the study period, 41,237 (85.9%) were black, Hispanic, or Latina and 490 (1.1%) presented to the ED with cardiovascular complaints. Baseline characteristics were similar between groups; however, Hispanic or Latina patients were more likely to have had gestational diabetes mellitus during the index pregnancy (6.2 vs. 18.3%). There was no difference in hospital admission between groups (17.9% black vs. 16.2% Latina or Hispanic patients). There was no difference in the hospital admission rate by provider race or ethnicity overall ( p  = 0.82). There was no difference in the hospital admission rate when a patient was evaluated by a provider of a different race or ethnicity (relative risk [RR] = 1.08, CI: 0.6-1.97). There was no difference in the rate of admission according to the self-reported gender of the provider (RR = 0.97, CI: 0.66-1.44)., Conclusion: This study illustrates that disparities did not exist in the management of racial and ethnic minority groups who presented to the ED with cardiovascular complaints during the first postpartum year. Patient-provider discordance in race or gender was not a significant source of bias or discrimination during the evaluation and treatment of these patients., Key Points: · Adverse postpartum outcomes disproportionately affect minorities.. · There was no difference in admissions between minority groups.. · There was no difference in admissions by provider race and ethnicity.., Competing Interests: None declared., (Thieme. All rights reserved.)

Starting from the MLPCN probe compound ML300, a structure-based optimization campaign was initiated against the recent severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CL pro ). X-ray structures of SARS-CoV-1 and SARS-CoV-2 3CL pro enzymes in complex with multiple ML300-based inhibitors, including the original probe ML300, were obtained and proved instrumental in guiding chemistry toward probe compound 41 (CCF0058981). The disclosed inhibitors utilize a noncovalent mode of action and complex in a noncanonical binding mode not observed by peptidic 3CL pro inhibitors. In vitro DMPK profiling highlights key areas where further optimization in the series is required to obtain useful in vivo probes. Antiviral activity was established using a SARS-CoV-2-infected Vero E6 cell viability assay and a plaque formation assay. Compound 41 demonstrates nanomolar activity in these respective assays, comparable in potency to remdesivir. These findings have implications for antiviral development to combat current and future SARS-like zoonotic coronavirus outbreaks.

Background: There are alternative transfemoral (TF) socket interface designs that have not been compared with the standard of care, ischial ramus containment (IRC). The interface directly affects performance., Objectives: To compare 3 TF interface designs, IRC, dynamic socket (DS), and subischial (Sub-I), regarding gait, balance, mobility, and preference. The authors hypothesized that these more active users may experience gait, mobility, and preference benefits from the less intrusive DS and Sub-I interface designs., Study Design: Single-blind, repeated-measures, 3-period randomized controlled crossover clinical trial., Methods: People with unilateral TF amputation with 1 year or longer prosthesis use experience, independent community ambulatory status, 18 to 60 years of age, of any race or ethnicity, with a body mass of 45 to 125 kg, and with a self-reported ability to walk for 20 minutes continuously were included in the study. Each participant was fit in all 3 interface designs., Results: Thirteen participants completed the clinical trial. Velocity, cadence, mobility, and balance were not statistically different between the 3 socket conditions. The DS demonstrated significantly greater symmetry in swing, stance, single support percentage, and toe angle compared with IRC and Sub-I. Sixty days after study completion, 7 participants changed interfaces, trending away from IRC., Conclusions: Large differences were not observed. Small differences in spatiotemporal gait measures combined with patient preference may make a meaningful difference to individual patients and should be considered., (Copyright © 2021 International Society for Prosthetics and Orthotics.)

The σ 1 receptor is implicated in regulating a diverse range of physiology and is a target for developing therapies for cancer, pain management, neural degradation, and COVID-19. This report describes 36 phenethylamine-containing 3-amino-chromane ligands, which bind to σ 1 with low nM affinities. The family consists of 18 distinct compounds and each enantiomer was independently assayed. Three compounds with the greatest affinity bind in the 2 nM K i range (∼8.7 p K i ). Furthermore, ligands with the (3 R ,4 R ) absolute stereochemistry on the 3-amino-chromane core have a higher affinity and greater σ 1 versus TMEM97 selectivity. The most promising ligands were assayed in 661W cells, which did not show significant protective effects., Competing Interests: The authors declare the following competing financial interest(s): M.R.P. and J.J.T. filed US patent No. 16/428,343, submitted 5/31/2019., (© 2020 American Chemical Society.)

The phenethylamine backbone is a privileged substructure found in a wide variety of G protein-coupled receptor (GPCR) ligands. This includes both endogenous neurotransmitters and active pharmaceutical agents. More than 20 structurally unique heterocyclic phenethylamine derivatives were broadly evaluated for GPCR affinity. Selective ligands for the 5-HT 2B , 5-HT 7 , and σ 1 receptors were identified, each with low nanomolar binding affinities. The σ 1 receptor affinity was supported in a cellular assay that provided evidence for increased cell survival under oxidative stress., Competing Interests: The authors declare the following competing financial interest(s): A provisional patent has been filed by the University of Minnesota on the substructure disclosed in this report; M.R.P. and J.J.T. filed US patent No. 16/428,343, submitted 5/31/2019, on the compounds in this article., (Copyright © 2019 American Chemical Society.)

The predictable and controllable interaction of small organic or peptidic molecules with biological substrates is the primary reason most pharmaceuticals are narrowly decorated carbon frameworks. The inhibition or activation binding models are measurable and without side reactions that can cause pathological angst. Yet many diseases, especially those involving rapid proliferation of cells (i.e., cancer) or aggregation of peptides (e.g., heart disease, Alzheimer's disease) have not yet been cured by inhibition therapeutics. Additionally, interventional medicine is often required to alleviate such maladies by physical removal first, followed by molecular-level therapy as a second stage. Thus, there appears to be a niche for more aggressive therapeutics that may employ harsher chemical processes to realize clinical efficacy, albeit without causing catastrophic side effects. Molecules that may be considered for this challenge are not typically biomimetic, nor do they fit the traditional pharmaceutical paradigm. They may have unusual modes of action or undesired reactivity that can be lethal if not controlled. These are the outliers; potential pharmacophores that biology does not know how to manage or adapt to. This is why they may be an intriguing class of agents that needs continuous development. In this Account, we connect the under-developed enediyne family of compounds and our metalloenediyne derivatives to existing radical-based therapeutics such as bleomycin and doxorubicin to illustrate that controlled diradical reactivity, although an outlier mechanism, has a place in the therapeutic portfolio. This is self-evident in that of the 11 natural product enediynes known, 2 have clinical impact, a strong ratio. We expand on the chemical diversity of potential enediyne constructs and focus on the accessible trigger mechanisms to activate diradical formation as a method to control toxicity. Moreover, we further illustrate how electromagnetic fields can be employed to activate both molecular and larger nanomaterial constructs that carry highly concentrated payloads of reactive reagent. Finally, we describe how controlled diradical reactivity can reach beyond traditional therapeutic targets such as DNA, to peptide aggregates found in blood clots, neural fibrils, and membrane scaffolds. It is our belief that cleverly constructed frameworks with well-designed and controlled activation/reaction schemes can lead to novel therapeutics that can challenge evolving viral and bacterial invaders. From this evangelical perspective, our hope is that the conceptual framework, if not the specific designs in this Account, stimulate the readership to develop out-of-the-box therapeutic designs that may combat resistant disease targets.

Allylic azides are known to undergo the Winstein rearrangement and are often isolated as an equilibrating mixture of isomers. While this process has been known for almost 60 years, very few synthetic applications of this process have been reported. The absence of methods exploiting these intermediates likely stems from a paucity of approaches for gaining the required selectivity to differentiate the isomers. Our lab has made some progress in leveraging this unusual reaction into practical synthetic methodology. Presented herein is a summary of our lab's recent accomplishments in selectively trapping allylic azides.

This report describes the stereoselective synthesis of 3-azido-tetralins, -chromanes, and -tetrahydroquinolines via a tandem allylic azide rearrangement/Friedel-Crafts alkylation. Exposure of allylic azides with a pendant trichloroacetimidate to catalytic quantities of AgSbF 6 proved optimal for this transformation. This cascade successfully differentiates the equilibrating azide isomers, providing products in excellent yield and selectivity (>25 examples, up to 94% yield and >25:1 dr). In many cases, the reactive isomer is only a trace fraction of the equilibrium mixture, keenly illustrating the dynamic nature of these systems. We demonstrate the utility of this process via a synthesis of hasubanan.

A series of M(PyED)·X (X = 2Cl - , SO 4 2- ) pyridine-metalloenediyne complexes [M = Cu(II), Fe(II), or Zn(II)] and their independently synthesized, cyclized analogs have been prepared to investigate their potential as radical-generating DNA-damaging agents. All complexes possess a 1:1 metal-to-ligand stoichiometry as determined by electronic absorption spectroscopy and X-ray diffraction. Solution structural analysis reveals a pπ Cl [Formula: see text] Cu(II) LMCT (22,026 cm -1 ) for Cu(PyED)·2Cl, indicating three nitrogens and a chloride in the psuedo-equatorial plane with the remaining pyridine nitrogen and solvent in axial positions. EPR spectra of the Cu(II) complexes exhibit an axially elongated octahedron. This spectroscopic evidence, together with density functional theory computed geometries, suggest six-coordinate structures for Cu(II) and Fe(II) complexes and a five-coordinate environment for Zn(II) analogs. Bergman cyclization via thermal activation of these constructs yields benzannulated product indicative of diradical generation in all complexes within 3 h at 37 °C. A significant metal dependence on the rate of the reaction is observed [Cu(II) > Fe(II) > Zn(II)], which is mirrored in in vitro DNA-damaging outcomes. Whereas in situ chelation of PyED leads to considerable degradation in the presence of all metals within 1 h under hyperthermia conditions, Cu(II) activation produces >50% compromised DNA within 5 min. Additionally, Cu(II) chelated PyED outcompetes DNA polymerase I to successfully inhibit template strand extension. Exposure of HeLa cells to Cu(PyBD)·SO 4 (IC 50  = 10 μM) results in a G2/M arrest compared with untreated samples, indicating significant DNA damage. These results demonstrate metal-controlled radical generation for degradation of biopolymers under physiologically relevant temperatures on short timescales., Competing Interests: The authors declare no conflict of interest.

One of the key concerns with the development of radical-generating reactive therapeutics is the ability to control the activation event within a biological environment. To that end, a series of quinoline-metal-loenediynes of the form M( QuiED )·2Cl (M = Cu(II), Fe(II), Mg(II), or Zn(II)) and their independently synthesized cyclized analogs have been prepared in an effort to elucidate Bergman cyclization (BC) reactivity differences in solution. HRMS(ESI) establishes a solution stoichiometry of 1:1 metal to ligand with coordination of one chloride counter ion to the metal center. EPR spectroscopy of Cu( QuiED )·2Cl and Cu ( QuiBD )·2Cl denotes an axially-elongated tetragonal octahedron ( g ║ > g ⊥ > 2.0023) with a d x 2 - y 2 ground state, while the electronic absorption spectrum reveals a pπ Cl→Cu(II) LMCT feature at 19,000 cm -1 , indicating a solution structure with three nitrogens and a chloride in the equatorial plane with the remaining quinoline nitrogen and solvent in the axial positions. Investigations into the BC activity reveal formation of the cyclized product from the Cu(II) and Fe(II) complexes after 12 h at 45 °C in solution, while no product is observed for the Mg(II) or Zn(II) complexes under identical conditions. The basis of this reactivity difference has been found to be a steric effect leading to metal-ligand bond elongation and thus, a retardation of solution reactivity. These results demonstrate how careful consideration of ligand and complex structure may allow for a degree of control and selective activation of these reactive agents.

Current approaches toward modulation of metal-induced Aβ aggregation pathways involve the development of small molecules that bind metal ions, such as Cu(ii) and Zn(ii), and interact with Aβ. For this effort, we present the enediyne-containing ligand ( Z )- N , N '-bis[1-pyridin-2-yl-meth( E )-ylidene]oct-4-ene-2,6-diyne-1,8-diamine ( PyED ), which upon chelation of Cu(ii) and Zn(ii) undergoes Bergman-cyclization to yield diradical formation. The ability of this chelation-triggered diradical to modulate Aβ aggregation is evaluated relative to the non-radical generating control pyridine-2-ylmethyl-(2-{[(pyridine-2-ylmethylene)-amino]-methyl}-benzyl)-amine ( PyBD ). Variable-pH, ligand UV-vis titrations reveal p K a = 3.81(2) for PyBD , indicating it exists mainly in the neutral form at experimental pH. Lipinski's rule parameters and evaluation of blood-brain barrier (BBB) penetration potential by the PAMPA-BBB assay suggest that PyED may be CNS+ and penetrate the BBB. Both PyED and PyBD bind Zn(ii) and Cu(ii) as illustrated by bathochromic shifts of their UV-vis features. Speciation diagrams indicate that Cu(ii)- PyBD is the major species at pH 6.6 with a nanomolar K d , suggesting the ligand may be capable of interacting with Cu(ii)-Aβ species. In the presence of Aβ 40/42 under hyperthermic conditions (43 °C), the radical-generating PyED demonstrates markedly enhanced activity (2-24 h) toward the modulation of Aβ species as determined by gel electrophoresis. Correspondingly, transmission electron microscopy images of these samples show distinct morphological changes to the fibril structure that are most prominent for Cu(ii)-Aβ cases. The loss of CO 2 from the metal binding region of Aβ in MALDI-TOF mass spectra further suggests that metal-ligand-Aβ interaction with subsequent radical formation may play a role in the aggregation pathway modulation.

The susceptibility of a prototypical hydrogen phosphonate to undergo P-H activation upon treatment with alkynylgold complexes has been studied. Dynamic solution behavior was observed during reactions involving triphenylphosphine ligated substrates and was attributed to rapid phosphine exchange between the alkynylgold starting material and the gold phosphonate product. The use of bulky biaryldialkylphosphine ligands eliminated the fluxional behavior, but did not significantly slow the rate of P-H activation. Similarly, changing the supporting ligand to an N-heterocyclic carbene did not significantly slow the rate of the reaction. Despite a number of reports outlining the functionalization of propargyl alcohols using gold catalysts, incorporating these groups into the architecture of the alkynylgold substrates did not alter the product distributions. Although the chemistry tolerated a range of supporting ligands, incorporating electron donating groups into the alkyne increased the rate of the reaction while electron-withdrawing groups slowed the reaction. A possible mechanism for the process includes a transition state containing significant pi-contribution from the alkyne. Due to the high yields of gold phosphonates obtained in this chemistry as well as the mild conditions of the reactions, the interception of intermediates/catalysts by substrates or ligands containing labile P-H donors is an issue that must be circumvented when designing or developing a gold catalyzed reaction that proceeds through alkynylgold intermediates.

This study examines the hypothesis that effective parental influence stems from the qualities of the parent-adolescent relationship rather than from explicit efforts to alter adolescents' behaviors. Adolescents' versus parents' perceptions of parental influence as predictors of parent-adolescent relationship quality and of adolescents' social functioning are examined using observational and multireporter data obtained from a sample of 167 adolescents (90 female, 77 male; age M = 13.34 years, SD = 0.65), their parents, and their same-sex peers. Analyses revealed that adolescents' and parents' perceptions of parental influence were uncorrelated with one another and were differentially related to qualities of adolescents' relationships with parents and friends. Adolescents' perceptions of high parental influence were linked to observations and self-reports of warm, supportive relationships with parents (particularly mothers). In contrast, parents' reports of high influence were linked to lower levels of adolescent autonomy with parents and friends and less relatedness with mothers and friends.

Adolescents' susceptibility to peer influence was examined as a marker of difficulties in the general process of autonomy development that was likely to be related to deficits across multiple domains of psychosocial functioning. A laboratory-based assessment of susceptibility to peer influence in interactions with a close friend was developed and examined in relation to corollary reports obtained from adolescents, their mothers, and close peers at ages 13 and 14. As hypothesized, observed susceptibility to peer influence with a close friend predicted future responses to negative peer pressure, but it was also related to broader markers of problems in functioning, including decreases in popularity, and increasing levels of depressive symptoms, over time. Susceptibility to peer influence was also linked to higher concurrent levels of substance use, externalizing behavior, and sexual activity. Results are interpreted as reflecting the central role of establishing autonomy with peers in psychosocial development.

Depressive symptoms not only impair quality of life in cancer patients but constitute an independent risk factor for increased mortality. In order to accurately and efficiently identify depression in cancer patients, the authors developed a biostatistical strategy to identify items of the 21-item, observer-rated Hamilton Rating Scale for Depression (Ham-D) that would optimize the diagnosis of depression among cancer patients. Exhibiting a relatively high sensitivity and specificity, our most optimal diagnostic tool contained six Ham-D items (late insomnia, agitation, psychic anxiety, diurnal mood variation, depressed mood, and genital symptoms). This study may serve as a prototype to generate valid instruments accurate for the diagnosis of major depression in other populations of cancer patients.

This study used longitudinal, multimethod data to examine specific patterns of behavioral interaction with parents and peers that were hypothesized to predict increasing levels of depressive symptoms in early adolescence. Adolescents' struggles in establishing autonomy and relatedness in interactions with mothers, and a withdrawn, angry, or dependent pattern of behavior with a best friend, were assessed with observational and peer-report methods in a community sample of 143 adolescents, who were also assessed for levels of depressive symptoms at age 13 and with whom the authors followed up 1 year later. Study hypotheses were confirmed, with dysfunctional interaction patterns with parents and peers combining additively to account for substantial change variance in depressive symptoms over time. Results are interpreted as highlighting specific behavioral patterns that may be promising to address via psychosocial interventions targeting adolescent depression., (Copyright (c) 2006 APA, all rights reserved.)

This study assessed the hypothesis that popularity in adolescence takes on a twofold role, marking high levels of concurrent adaptation but predicting increases over time in both positive and negative behaviors sanctioned by peer norms. Multimethod, longitudinal data, on a diverse community sample of 185 adolescents (13 to 14 years), addressed these hypotheses. As hypothesized, popular adolescents displayed higher concurrent levels of ego development, secure attachment, and more adaptive interactions with mothers and best friends. Longitudinal analyses supported a popularity-socialization hypothesis, however, in which popular adolescents were more likely to increase behaviors that receive approval in the peer group (e.g., minor levels of drug use and delinquency) and decrease behaviors unlikely to be well received by peers (e.g., hostile behavior with peers).

Objective: This study investigated whether cancer patients with and without major depression exhibit immune system abnormalities similar to those reported in medically healthy, depressed subjects without cancer., Method: The study subjects consisted of patients diagnosed with pancreatic, esophageal, or breast cancer. Other groups consisted of subjects with major depression (without cancer) and healthy comparison subjects. Subjects' diagnoses were made with the Structured Clinical Interview for DSM-III-R. Severity of depression was measured with the Hamilton Depression Rating Scale. Plasma concentrations of interleukin-6 (IL-6) and postdexamethasone cortisol were measured., Results: Cancer patients with depression had markedly higher plasma concentrations of IL-6 than healthy comparison subjects and cancer patients without depression. Although significant correlations were found between Hamilton depression scale scores and plasma concentrations of postdexamethasone cortisol, no significant correlations were found between plasma IL-6 and postdexamethasone cortisol concentrations., Conclusions: Higher than normal plasma IL-6 concentrations were associated with a diagnosis of major depression in cancer patients. IL-6 may contribute to sickness behavior that has overlapping symptoms with major depression.

Objective: This study investigated whether depressed patients exhibit exaggerated platelet reactivity., Method: In vivo platelet activation, secretion, and dose-response aggregation were measured in 12 depressed patients and eight normal comparison subjects after overnight bed rest and following orthostatic challenge., Results: The depressed patients exhibited increased platelet activation at baseline, demonstrated by increased binding of monoclonal antibody (moAb) annexin V protein reacting with prothrombinase complex binding sites. Following orthostatic challenge, the depressed patients exhibited increases in binding of moAbs PAC1 and anti-LIBS1 against activated glycoprotein IIb/IIIa and GE12 against P-selectin expressed upon secretion. The normal comparison subjects exhibited increases in platelet activation only with GE12., Conclusions: Depressed patients exhibit enhanced baseline platelet activation and responsiveness in comparison with normal subjects. Heightened susceptibility to platelet activation may be a mechanism by which depression is a significant risk factor for ischemic heart and cerebrovascular disease and/or mortality after myocardial infarction.

This article reviews the challenge of diagnosing depression in patients with cancer. Major depression and depressive symptoms, although commonly encountered in medical populations, are frequently underdiagnosed and undertreated. This is especially true for patients with cancer in whom the diagnosis of major depression is clouded by neurovegetative symptoms that may be secondary to either cancer or depression. Well-established biological markers for major depression are proposed as diagnostic adjuncts in patients with cancer. Studies using biological markers in depressed patients with and without cancer are reviewed, and the implications of diminished immune function in depressed patients with cancer are discussed. The limited database on treatment of depression in patients with cancer also is reviewed. Treatment of depression in these patients improves their dysphoria and other signs and symptoms of depression, improves quality of life, and may improve immune function and survival time. Guidelines for future research are proposed.

The casts of five patients whose kinematic mandibular axes had been previously located and tatooed on the face were mounted on six articulators (two of Denar D4-A, two of Whip-Mix, and two of Hanau model 130-28). The horizontal and lateral condylar guidances of all articulators were adjusted by using 15 interocclusal records (five protrusive and 10 right and left lateral) made in cold-curing acrylic resin. The adjustments for each articulator were repeated 20 times within five days. The lateral condylar guidances as adjusted by the interocclusal records were compared with those established by Hanau's formula. A significant difference in the means of the condylar readings occurred when the Hanau articulator was adjusted with a lateral interocclusal record and the Hanau formula. The range of means of lateral condylar guidances of Hanau articulators using the Hanau formula was small. This small possibility of variation in the lateral condylar guidance would suggest the use of lateral interocclusal records when precise restorative procedures are necessary. The Hanau formula is the only formula available at this time to determine the average lateral condylar guidance as related to the horizontal condylar guidance.