Subcutaneous Sweet Syndrome Successfully Treated With Ustekinumab in a Patient With Ulcerative Colitis.

Ustekinumab, an inhibitor of the interleukin-12/23 pathway, received Food and Drug Administration (FDA) approval in 2019 for induction and maintenance therapy in patients with moderate-to-severe ulcerative colitis (UC). Data regarding the efficacy of ustekinumab in the treatment of extraintestinal manifestations of UC are unclear. Sweet syndrome, an acute febrile neutrophilic dermatosis, is a cutaneous manifestation of inflammatory bowel disease that parallels disease activity. In this study, we present the first case of subcutaneous Sweet syndrome with sterile osteomyelitis in a patient with UC successfully treated with ustekinumab.

A Comparative Analysis of Nonthumb Metacarpal Fracture Treatments in New York City Civilians and Incarcerated Individuals.

Nonthumb metacarpal (NTMC) fractures are common in the incarcerated and the underinsured civilian populations. However, certain social challenges contribute to high rates of follow-up noncompliance and complications in these unique populations. We conducted a retrospective review of the treatments, outcomes, and complications in the incarcerated and civilian patient population who were treated at a tertiary public hospital for NTMC fractures. Even though incarcerated patients were more likely than their civilian counterparts to undergo operative interventions, both populations showed similar complication profiles as well as low rates of treatment compliance and follow-up. This article affirms that incarcerated individuals do not receive inferior care compared with civilians, and both the incarcerated and underinsured civilians would benefit from careful consideration of treatment algorithms and additional access to hand therapy.

Chasing the storm: Recruiting non-hospitalized patients for a multi-site randomized controlled trial in the United States during the COVID-19 pandemic.

Randomized controlled trials (RCTs) remain the gold standard to evaluate clinical interventions, producing the highest level of evidence while minimizing potential bias. Inadequate recruitment is a commonly encountered problem that undermines the completion and generalizability of RCTs-and is even more challenging when enrolling amidst a pandemic. Here, we reflect on our experiences with virtual recruitment of non-hospitalized patients in the United States for ColCorona, an international, multicenter, randomized, placebo-controlled coronavirus disease 2019 (COVID-19) drug trial. Recruitment challenges during a pandemic include constraints created by shelter-in-place policies and targeting enrollment according to national and local fluctuations in infection rate. Presenting a study to potential participants who are sick with COVID-19 and may be frightened, overwhelmed, or mistrusting of clinical research remains a challenge. Strategies previously reported to improve recruitment include transparency, patient and site education, financial incentives, and person-to-person outreach. Active measures taken during ColCorona to optimize United States recruitment involved rapid expansion of sites, adjustment of recruitment scripts, assessing telephone calls versus text messages for initial contact with participants, institutional review board-approved financial compensation, creating an infrastructure to systematically identify potentially eligible patients, partnering with testing sites, appealing to both self-interest and altruism, and large-scale media efforts with varying degrees of success.

Anti-inflammatory therapy for COVID-19 infection: the case for colchicine.

The search for effective COVID-19 management strategies continues to evolve. Current understanding of SARS-CoV-2 mechanisms suggests a central role for exaggerated activation of the innate immune system as an important contributor to COVID-19 adverse outcomes. The actions of colchicine, one of the oldest anti-inflammatory therapeutics, target multiple mechanisms associated with COVID-19 excessive inflammation. While many COVID-19 trials have sought to manipulate SARS-CoV-2 or dampen the inflammatory response once patients are hospitalised, few examine therapeutics to prevent the need for hospitalisation. Colchicine is easily administered, generally well tolerated and inexpensive, and holds particular promise to reduce the risk of hospitalisation and mortality due to COVID-19 in the outpatient setting. Successful outpatient treatment of COVID-19 could greatly reduce morbidity, mortality and the demand for rare or expensive care resources (front-line healthcare workers, hospital beds, ventilators, biological therapies), to the benefit of both resource-replete and resource-poor regions.

Investigating the reaction and substrate preference of indole-3-acetaldehyde dehydrogenase from the plant pathogen Pseudomonas syringae PtoDC3000.

Aldehyde dehydrogenases (ALDHs) catalyze the conversion of various aliphatic and aromatic aldehydes into corresponding carboxylic acids. Traditionally considered as housekeeping enzymes, new biochemical roles are being identified for members of ALDH family. Recent work showed that AldA from the plant pathogen Pseudomonas syringae strain PtoDC3000 (PtoDC3000) functions as an indole-3-acetaldehyde dehydrogenase for the synthesis of indole-3-acetic acid (IAA). IAA produced by AldA allows the pathogen to suppress salicylic acid-mediated defenses in the model plant Arabidopsis thaliana. Here we present a biochemical and structural analysis of the AldA indole-3-acetaldehyde dehydrogenase from PtoDC3000. Site-directed mutants targeting the catalytic residues Cys302 and Glu267 resulted in a loss of enzymatic activity. The X-ray crystal structure of the catalytically inactive AldA C302A mutant in complex with IAA and NAD+ showed the cofactor adopting a conformation that differs from the previously reported structure of AldA. These structures suggest that NAD+ undergoes a conformational change during the AldA reaction mechanism similar to that reported for human ALDH. Site-directed mutagenesis of the IAA binding site indicates that changes in the active site surface reduces AldA activity; however, substitution of Phe169 with a tryptophan altered the substrate selectivity of the mutant to prefer octanal. The present study highlights the inherent biochemical versatility of members of the ALDH enzyme superfamily in P. syringae.

Management and Complications of Non-Thumb Metacarpal Fractures in the Incarcerated Population.

We reviewed the patient demographics, injury mechanisms, fracture characteristics, treatment modalities, and outcomes of incarcerated patients who were referred for metacarpal fracture evaluation and treatment to our high-volume tertiary care center from a New York City Department of Correction infirmary facility. There is a scarcity of information in the orthopedic and plastic surgery literature on treating these common fractures in this vulnerable population. We conducted a basic statistical analysis and discuss the potential implications of these findings. We found a high incidence of stiffness that may relate to the high rates of follow-up noncompliance coupled with prolonged immobilization. Awareness of these findings may influence treating hand specialists to use less restrictive immobilization devices such as functional bracing, elastic bandage, or neighbor strapping as an effort to promote bony union without the risk of developing stiffness and the potential to compromise general hand function when treating non-thumb metacarpal fractures.

Trends in Mortality From Human Immunodeficiency Virus Infection, 1984-2016: An Autopsy-Based Study.

CONTEXT.­: With increasing use and efficacy of antiretroviral therapy for human immunodeficiency virus (HIV) infection, deaths from acquired immunodeficiency syndrome (AIDS)-defining conditions have decreased. OBJECTIVE.­: To examine trends in the cause of death of HIV-infected patients who underwent autopsy at a major New York City hospital from 1984 to 2016, a period including the major epochs of the AIDS epidemic. DESIGN.­: Retrospective review of autopsy records and charts with modeling of trends by logistic regression using polynomial models. RESULTS.­: We identified 252 autopsies in adult patients with AIDS (by 1982 definition) or HIV infection. Prior to widespread use of highly active antiretroviral therapy, in 1984-1995, on average 13 autopsies per year were done. Post-highly active antiretroviral therapy, the average number of autopsies declined to 4.5 per year. The fitted mean age at death was 35 years in 1984 and increased curvilinearly to 46 years (95% CI, 43-49) in 2016 (P < .001). By regression analysis, mean CD4+ T-cell count increased from 6 in 1992 to 64 in 2016 (P = .01). The proportion of AIDS-defining opportunistic infections decreased, from 79% in 1984-1987 to 41% in 2008-2011 and 29% in 2012-2016 (P = .04). The frequency of nonopportunistic infections, however, increased from 37% in 1984-1987 to 73% in 2008-2011 and 57% in 2012-2016 (P = .001). The frequency of AIDS-defining and other malignancies did not change significantly during the study period. The prevalence of atherosclerosis at autopsy rose dramatically, from 21% in 1988-1991 to 54% in 2008-2011 (P < .001). CONCLUSIONS.­: Despite limitations of autopsy studies, many trends in the evolution of the HIV/AIDS epidemic are readily discernable.

Activation and allosteric modulation of a muscarinic acetylcholine receptor.

Despite recent advances in crystallography and the availability of G-protein-coupled receptor (GPCR) structures, little is known about the mechanism of their activation process, as only the ß2 adrenergic receptor (ß2AR) and rhodopsin have been crystallized in fully active conformations. Here we report the structure of an agonist-bound, active state of the human M2 muscarinic acetylcholine receptor stabilized by a G-protein mimetic camelid antibody fragment isolated by conformational selection using yeast surface display. In addition to the expected changes in the intracellular surface, the structure reveals larger conformational changes in the extracellular region and orthosteric binding site than observed in the active states of the ß2AR and rhodopsin. We also report the structure of the M2 receptor simultaneously bound to the orthosteric agonist iperoxo and the positive allosteric modulator LY2119620. This structure reveals that LY2119620 recognizes a largely pre-formed binding site in the extracellular vestibule of the iperoxo-bound receptor, inducing a slight contraction of this outer binding pocket. These structures offer important insights into the activation mechanism and allosteric modulation of muscarinic receptors.

Novel structural and functional insights into M3 muscarinic receptor dimer/oligomer formation.

Class A G protein-coupled receptors (GPCRs) are able to form homodimers and/or oligomeric arrays. We recently proposed, based on bioluminescence resonance energy transfer studies with the M3 muscarinic receptor (M3R), a prototypic class A GPCR, that the M3R is able to form multiple, structurally distinct dimers that are probably transient in nature (McMillin, S. M., Heusel, M., Liu, T., Costanzi, S., and Wess, J. (2011) J. Biol. Chem. 286, 28584-28598). To provide more direct experimental support for this concept, we employed a disulfide cross-linking strategy to trap various M3R dimeric species present in a native lipid environment (transfected COS-7 cells). Disulfide cross-linking studies were carried out with many mutant M3Rs containing single cysteine (Cys) substitutions within two distinct cytoplasmic M3R regions, the C-terminal portion of the second intracellular loop (i2) and helix H8 (H8). The pattern of cross-links that we obtained, in combination with molecular modeling studies, was consistent with the existence of two structurally distinct M3R dimer interfaces, one involving i2/i2 contacts (TM4-TM5-i2 interface) and the other one characterized by H8-H8 interactions (TM1-TM2-H8 interface). Specific H8-H8 disulfide cross-links led to significant impairments in M3R-mediated G protein activation, suggesting that changes in the structural orientation or mobility of H8 are critical for efficient receptor-G protein coupling. Our findings provide novel structural and functional insights into the mechanisms involved in M3R dimerization (oligomerization). Because the M3R shows a high degree of sequence similarity with many other class A GPCRs, our findings should be of considerable general interest.

Muscarinic receptors as model targets and antitargets for structure-based ligand discovery.

G protein-coupled receptors (GPCRs) regulate virtually all aspects of human physiology and represent an important class of therapeutic drug targets. Many GPCR-targeted drugs resemble endogenous agonists, often resulting in poor selectivity among receptor subtypes and restricted pharmacologic profiles. The muscarinic acetylcholine receptor family exemplifies these problems; thousands of ligands are known, but few are receptor subtype-selective and nearly all are cationic in nature. Using structure-based docking against the M2 and M3 muscarinic receptors, we screened 3.1 million molecules for ligands with new physical properties, chemotypes, and receptor subtype selectivities. Of 19 docking-prioritized molecules tested against the M2 subtype, 11 had substantial activity and 8 represented new chemotypes. Intriguingly, two were uncharged ligands with low micromolar to high nanomolar Ki values, an observation with few precedents among aminergic GPCRs. To exploit a single amino-acid substitution among the binding pockets between the M2 and M3 receptors, we selected molecules predicted by docking to bind to the M3 and but not the M2 receptor. Of 16 molecules tested, 8 bound to the M3 receptor. Whereas selectivity remained modest for most of these, one was a partial agonist at the M3 receptor without measurable M2 agonism. Consistent with this activity, this compound stimulated insulin release from a mouse ß-cell line. These results support the ability of structure-based discovery to identify new ligands with unexplored chemotypes and physical properties, leading to new biologic functions, even in an area as heavily explored as muscarinic pharmacology.