Initiation of Buprenorphine Treatment of Opioid Use Disorder in Pediatric Emergency Departments.

Pediatric emergency departments (EDs) in the United States are facing a rise in the number of children and adolescents who present with opioid use disorder (OUD), often driven by illicitly manufactured fentanyl. Medication treatment of pediatric OUD in the ED setting is often limited to symptomatic treatment of opioid withdrawal. Pediatric patients are rarely offered medications for OUD, especially in the ED setting. Buprenorphine is a partial opioid agonist that is Food and Drug Administration-approved for the treatment of OUD in patients aged 16 years and older. Adult studies have demonstrated that ED initiation of medication for OUD such as buprenorphine is feasible, safely treats withdrawal symptoms, and can improve patient compliance with outpatient follow-up. However, initiation of buprenorphine in the ED has not been well-studied in the pediatric population. We present 2 cases of adolescent patients, a 16-year-old male and 17-year-old female, who presented to the ED with opioid withdrawal. They were both diagnosed with severe OUD because of their use of counterfeit pills containing fentanyl. Both patients were successfully started on buprenorphine/naloxone in the pediatric ED before transitioning to an outpatient addiction clinic for continued treatment. The case series demonstrates the feasibility of ED-based buprenorphine initiation for adolescents, an important and timely intervention for adolescents with OUD.

Comparative Study on Elder Abuse and Neglect Among Geriatric Population in the Rural and Urban Field Practice Areas of a Medical College.

Background: Elder abuse is a multidimensional problem of public importance. According to the World Health Organization (WHO), 16% of older people were victims of elder abuse. A study conducted by HelpAge India in 2018 showed that Mangaluru ranks the highest in elder abuse (47%). Given the scarce literature, this study sought to determine the prevalence of elder abuse and its associated sociodemographic factors. Material and Methods: A community-based cross-sectional study was conducted among the senior population in the rural and urban field practice a medical college in Mangaluru for one and a half years. The sample size was 280. Results: Most of the study population was in the age group of fewer than 75 years (75.4%), with 50.4% females, 60% Hindus, 56.4% married, 39.3% illiterate, and 88.9% of them retired. The prevalence of elder abuse was 44.6% (rural = 50.7% and urban = 38.6%). Binary logistic regression showed that elder abuse was statistically significant among the unemployed, extended family members, and staying with children. Conclusions: The study brings to light the sociodemographic factors that play a role in detecting elder abuse. It also shows the importance of awareness of elder mistreatment among older people. These elements must be considered for implementing and enforcing laws and legislation to help curb elder abuse.

Adaptive laboratory evolution in S. cerevisiae highlights role of transcription factors in fungal xenobiotic resistance.

In vitro evolution and whole genome analysis were used to comprehensively identify the genetic determinants of chemical resistance in Saccharomyces cerevisiae. Sequence analysis identified many genes contributing to the resistance phenotype as well as numerous amino acids in potential targets that may play a role in compound binding. Our work shows that compound-target pairs can be conserved across multiple species. The set of 25 most frequently mutated genes was enriched for transcription factors, and for almost 25 percent of the compounds, resistance was mediated by one of 100 independently derived, gain-of-function SNVs found in a 170 amino acid domain in the two Zn2C6 transcription factors YRR1 and YRM1 (p < 1 × 10-100). This remarkable enrichment for transcription factors as drug resistance genes highlights their important role in the evolution of antifungal xenobiotic resistance and underscores the challenge to develop antifungal treatments that maintain potency.

Isolation and characterization of Streptomyces bacteriophages and Streptomyces strains encoding biosynthetic arsenals.

The threat to public health posed by drug-resistant bacteria is rapidly increasing, as some of healthcare's most potent antibiotics are becoming obsolete. Approximately two-thirds of the world's antibiotics are derived from natural products produced by Streptomyces encoded biosynthetic gene clusters. Thus, to identify novel gene clusters, we sequenced the genomes of four bioactive Streptomyces strains isolated from the soil in San Diego County and used Bacterial Cytological Profiling adapted for agar plate culturing in order to examine the mechanisms of bacterial inhibition exhibited by these strains. In the four strains, we identified 104 biosynthetic gene clusters. Some of these clusters were predicted to produce previously studied antibiotics; however, the known mechanisms of these molecules could not fully account for the antibacterial activity exhibited by the strains, suggesting that novel clusters might encode antibiotics. When assessed for their ability to inhibit the growth of clinically isolated pathogens, three Streptomyces strains demonstrated activity against methicillin-resistant Staphylococcus aureus. Additionally, due to the utility of bacteriophages for genetically manipulating bacterial strains via transduction, we also isolated four new phages (BartholomewSD, IceWarrior, Shawty, and TrvxScott) against S. platensis. A genomic analysis of our phages revealed nearly 200 uncharacterized proteins, including a new site-specific serine integrase that could prove to be a useful genetic tool. Sequence analysis of the Streptomyces strains identified CRISPR-Cas systems and specific spacer sequences that allowed us to predict phage host ranges. Ultimately, this study identified Streptomyces strains with the potential to produce novel chemical matter as well as integrase-encoding phages that could potentially be used to manipulate these strains.

Pacemaker lead related myocardial perforation.

Permanent pacemaker (PPM) insertion is widely used to treat cardiac rhythm disorders; approximately 600,000 pacemakers are implanted annually in the US. Almost 9% of patients who receive a permanent pacemaker, however, experience a variety of medical complications such as infections, battery problems, programming issues, lead migration, or lead fracture. Moreover 1-2% of these patients will encounter severe lead-related problems within 30 days of their pacemaker insertion. In this report, we focus on an uncommon but serious complication of PPM insertion: right ventricular lead perforation leading to a pericardial effusion. Although lead perforation is a relatively rare occurrence, this event can be life-threatening, and should be considered in the differential diagnosis when patients present to the emergency department (ED) with relevant symptoms and recent PPM insertion. Specifically, patients who experience complications from pacemaker insertion may present to the ED with a variety of symptoms such as chest pain, syncope, dyspnea, or even dizziness. Pacemaker complications include pneumothorax, pleural and/or pericardial effusions, and infection, placing the patient at serious risk for significant harm. The evaluation of a lead-related issue typically involves chest radiography to visualize abnormal lead placement and check for a pneumothorax or pleural effusion, and a 12­lead electrocardiogram (ECG) to detect pacing errors. We present the case of a patient who presented to the ED three days after his pacemaker insertion with chest pain and dyspnea; he was subsequently diagnosed with a lead perforation into the pericardial space resulting in a pericardial effusion.

Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway.

A promising new compound class for treating human malaria is the imidazolopiperazines (IZP) class. IZP compounds KAF156 (Ganaplacide) and GNF179 are effective against Plasmodium symptomatic asexual blood-stage infections, and are able to prevent transmission and block infection in animal models. But despite the identification of resistance mechanisms in P. falciparum, the mode of action of IZPs remains unknown. To investigate, we here combine in vitro evolution and genome analysis in Saccharomyces cerevisiae with molecular, metabolomic, and chemogenomic methods in P. falciparum. Our findings reveal that IZP-resistant S. cerevisiae clones carry mutations in genes involved in Endoplasmic Reticulum (ER)-based lipid homeostasis and autophagy. In Plasmodium, IZPs inhibit protein trafficking, block the establishment of new permeation pathways, and cause ER expansion. Our data highlight a mechanism for blocking parasite development that is distinct from those of standard compounds used to treat malaria, and demonstrate the potential of IZPs for studying ER-dependent protein processing.

Rapid Chagas Disease Drug Target Discovery Using Directed Evolution in Drug-Sensitive Yeast.

Recent advances in cell-based, high-throughput phenotypic screening have identified new chemical compounds that are active against eukaryotic pathogens. A challenge to their future development lies in identifying these compounds' molecular targets and binding modes. In particular, subsequent structure-based chemical optimization and target-based screening require a detailed understanding of the binding event. Here, we use directed evolution and whole-genome sequencing of a drug-sensitive S. cerevisiae strain to identify the yeast ortholog of TcCyp51, lanosterol-14-alpha-demethylase (TcCyp51), as the target of MMV001239, a benzamide compound with activity against Trypanosoma cruzi, the etiological agent of Chagas disease. We show that parasites treated with MMV0001239 phenocopy parasites treated with another TcCyp51 inhibitor, posaconazole, accumulating both lanosterol and eburicol. Direct drug-protein binding of MMV0001239 was confirmed through spectrophotometric binding assays and X-ray crystallography, revealing a binding site shared with other antitrypanosomal compounds that target Cyp51. These studies provide a new probe chemotype for TcCyp51 inhibition.