In this review, we discuss all sulfur-containing FDA-approved drugs and their structures. The second section of the review is dedicated to structural analysis and is divided into 14 subsections, each ...focusing on one type of sulfur-containing moiety. A concise graphical representation of each class features drugs that are organized on the basis of structural similarity, evolutionary relevance, and medical indication. This review offers a unique and comprehensive overview of the structural features of all sulfur-containing FDA-approved drugs to date.
Phenols and phenolic ethers are significant scaffolds recurring both in nature and among approved small-molecule pharmaceuticals. This compendium presents the first comprehensive compilation and ...analysis of the structures of U.S. FDA-approved molecules containing phenol or phenolic ether fragments. This dataset comprises 371 structures, which are strongly represented by natural products. A total of 55 of the compounds described here are on the World Health Organization’s list of essential medicines. Structural analysis reveals significant differences in the physicochemical properties imparted by phenols versus phenol ethers, each having benefits and drawbacks for drug developability. Despite trends over the past decade to increase the fraction of sp3 centers in drug leads, thereby “escaping flatland”, phenols and phenolic ethers are represented in 62% of small-molecule drugs approved in 2020, suggesting that this aromatic moiety holds a special place in drugs and natural products.
The ST-4821 complex (cc4821) is a leading cause of serogroup C and serogroup B invasive meningococcal disease in China where diverse strains in two phylogenetic groups (groups 1 and 2) have acquired ...fluoroquinolone resistance. cc4821 was recently prevalent among carriage isolates in men who have sex with men in New York City (USA). Genome-level population studies have thus far been limited to Chinese isolates. The aim of the present study was to build upon these with an extended panel of international cc4821 isolates.
Genomes of isolates from Asia (1972 to 2017), Europe (2011 to 2018), North America (2007), and South America (2014) were sequenced or obtained from the PubMLST Neisseria database. Core genome comparisons were performed in PubMLST.
Four lineages were identified. Western isolates formed a distinct, mainly serogroup B sublineage with alleles associated with fluoroquinolone susceptibility (MIC <0.03 mg/L) and reduced penicillin susceptibility (MIC 0.094 to 1 mg/L). A third of these were from anogenital sites in men who have sex with men and had unique denitrification gene alleles. Generally 4CMenB vaccine strain coverage was reliant on strain-specific NHBA peptides.
The previously identified cc4821 group 2 was resolved into three separate lineages. Clustering of western isolates was surprising given the overall diversity of cc4821. Possible association of this cluster with the anogenital niche is worthy of monitoring given concerns surrounding antibiotic resistance and potential subcapsular vaccine escape.
Serotonin syndrome is a rare, frequently misdiagnosed, serious condition with high morbidity.
This review highlights the pearls and pitfalls of serotonin syndrome, including diagnosis, initial ...resuscitation, and management in the emergency department (ED) based on current evidence.
Serotonin syndrome is a potentially deadly toxidrome marked by excess serotonin receptor activity or neurotransmission. Features of serotonin syndrome include 1) neuromuscular excitation such as tremor, hyperreflexia, and clonus; 2) autonomic dysfunction such as tachycardia, hypertension/hypotension, and hyperthermia; and 3) altered mental status such as agitation, delirium, and coma. Although serotonin syndrome may be more obvious in patients who have overdosed on serotonergic agents such as serotonin reuptake inhibitors (SSRIs), multiple other medications may also cause serotonin syndrome. Alternative diagnoses such as sepsis, neuroleptic malignant syndrome, and decompensated hyperthyroidism should be considered. The primary components of therapy include stopping the offending agent and supportive care, which focuses on agitation control, monitoring for and treating hyperthermia, and managing autonomic instability.
An understanding of serotonin syndrome can assist emergency clinicians in diagnosing and managing this disease.
Cerebral venous thrombosis (CVT) is an uncommon neurologic emergency associated with significant morbidity and mortality that can be difficult to differentiate from other conditions. It is important ...for the emergency clinician to be familiar with this disease as it requires a high index of suspicion, and early diagnosis and management can lead to improved outcomes.
This narrative review provides an evidence-based update concerning the presentation, evaluation, and management of CVT for the emergency clinician.
CVT is due to thrombosis of the cerebral veins resulting in obstruction of venous outflow and increased intracranial pressure. Early recognition is important but difficult as the clinical presentation can mimic more common disease patterns. The most common patient population affected includes women under the age of 50. Risk factors for CVT include pregnancy, medications (oral contraceptives), inherited thrombophilia, prior venous thromboembolic event, malignancy, recent infection, and neurosurgery. CVT can present in a variety of ways, but the most common symptom is headache, followed by focal neurologic deficit, seizure, and altered mental status. Imaging studies such as computed tomography (CT) venography or magnetic resonance (MR) venography should be obtained in patients with concern for CVT, as non-contrast CT will be normal or have non-specific findings in most patients. Treatment includes anticoagulation, treating seizures and elevated ICP aggressively, and neurosurgical or interventional radiology consultation in select cases.
CVT can be a challenging diagnosis. Knowledge of the risk factors, patient presentation, evaluation, and management can assist emergency clinicians.
Radiation injury from medical, accidental, or intentional sources can induce acute and long-term hepatic dysregulation, fibrosis, and cancer. This long-term hepatic dysregulation decreases quality of ...life and may lead to death. Our goal in this study is to determine acute changes in biological pathways and discover potential RNA biomarkers predictive of radiation injury. We performed whole transcriptome microarray analysis of mouse liver tissue (C57BL/6 J) 48 h after whole-body irradiation with 1, 2, 4, 8, and 12 Gray to identify significant expression changes in mRNAs, lncRNAs, and miRNAs, We also validated changes in specific RNAs through qRT-PCR. We used Ingenuity Pathway Analysis (IPA) to identify pathways associated with gene expression changes. We observed significant dysregulation of multiple mRNAs across all doses. In contrast, miRNA dysregulation was observed upwards of 2 Gray. The most significantly upregulated mRNAs function as tumor suppressors: Cdkn1a, Phlda3, and Eda2r. The most significantly downregulated mRNAs were involved in hemoglobin synthesis, inflammation, and mitochondrial function including multiple members of Hbb and Hba. The most significantly upregulated miRNA included: miR-34a-5p, miR-3102-5p, and miR-3960, while miR-342-3p, miR-142a-3p, and miR-223-3p were most significantly downregulated. IPA predicted activation of cell cycle checkpoint control pathways and inhibition of pathways relevant to inflammation and erythropoietin. Clarifying expression of mRNA, miRNA and lncRNA at a short time point (48 h) offers insight into potential biomarkers, including radiation markers shared across organs and animal models. This information, once validated in human models, can aid in development of bio-dosimetry biomarkers, and furthers our understanding of acute pathway dysregulation.
Reversible Cerebral Vasoconstriction Syndrome (RCVS) is a rare cause of severe headache that can mimic other causes of sudden, severe headache and result in frequent emergency department (ED) visits.
...This narrative review provides an evidence-based update concerning the presentation, evaluation, and management of RCVS for the emergency clinician.
RCVS can present as recurrent, severe headaches that may be maximal in onset, known as a thunderclap headache. Distinguishing from other causes of thunderclap headache such as aneurysmal subarachnoid hemorrhage, cerebral venous thrombosis, and posterior reversible encephalopathy syndrome is challenging. Risk factors for RCVS include use of vasoactive substances, exertion, coughing, showering, sexual activity, and cervical artery dissection. Diagnosis relies on clinical features and imaging. Cerebral catheter digital subtraction angiography (DSA) is considered the gold standard imaging modality; however, computed tomography angiography or magnetic resonance angiography are reliable non-invasive diagnostic modalities. Treatment focuses on avoiding or removing the offending agent, administration of calcium channel blockers such as nimodipine, and reversing anticoagulation if bleeding is present. Although most cases have a benign course and resolve within 3 months, focal subarachnoid hemorrhage, intracerebral hemorrhage, permanent neurologic disability, or death can occur in a minority of cases.
Diagnosis and appropriate management of RCVS can be aided by understanding key aspects of the history and examination. The emergency clinician can then obtain indicated imaging, confirming the diagnosis and allowing for appropriate management.
...according to data reported by Janssen, eight cases of CVT or thrombosis with thrombocytopenia have been associated with the Ad26Cov2.S vaccine 4. ...from the studies discussed, all patients had ...positive PF-4 assays (if the assay was available). ...as this is a rapidly evolving field, involvement of a multidisciplinary team is recommended to manage a patient with TTS, including hematology, and as discussed in our paper, neurology, neurosurgery, or interventional radiology depending on local practice.Acknowledgements AT, BL, KRS, and AK conceived the idea for this manuscript and contributed substantially to the writing and editing of the review.
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