Severe Infective Endocarditis Caused by Bartonella rochalimae.

A 22-year-old man from Guatemala sought care for subacute endocarditis and mycotic brain aneurysm after living in good health in the United States for 15 months. Bartonella rochalimae, a recently described human and canine pathogen, was identified by plasma microbial cell-free DNA testing. The source of infection is unknown.

The double-stranded RNA binding protein RDE-4 can act cell autonomously during feeding RNAi in C. elegans.

Long double-stranded RNA (dsRNA) can silence genes of matching sequence upon ingestion in many invertebrates and is therefore being developed as a pesticide. Such feeding RNA interference (RNAi) is best understood in the worm Caenorhabditis elegans, where the dsRNA-binding protein RDE-4 initiates silencing by recruiting an endonuclease to process long dsRNA into short dsRNA. These short dsRNAs are thought to move between cells because muscle-specific rescue of rde-4 using repetitive transgenes enables silencing in other tissues. Here, we extend this observation using additional promoters, report an inhibitory effect of repetitive transgenes, and discover conditions for cell-autonomous silencing in animals with tissue-specific rescue of rde-4. While expression of rde-4(+) in intestine, hypodermis, or neurons using a repetitive transgene can enable silencing also in unrescued tissues, silencing can be inhibited wihin tissues that express a repetitive transgene. Single-copy transgenes that express rde-4(+) in body-wall muscles or hypodermis, however, enable silencing selectively in the rescued tissue but not in other tissues. These results suggest that silencing by the movement of short dsRNA between cells is not an obligatory feature of feeding RNAi in C. elegans. We speculate that similar control of dsRNA movement could modulate tissue-specific silencing by feeding RNAi in other invertebrates.

Extracellular RNA is transported from one generation to the next in Caenorhabditis elegans.

Experiences during the lifetime of an animal have been proposed to have consequences for subsequent generations. Although it is unclear how such intergenerational transfer of information occurs, RNAs found extracellularly in animals are candidate molecules that can transfer gene-specific regulatory information from one generation to the next because they can enter cells and regulate gene expression. In support of this idea, when double-stranded RNA (dsRNA) is introduced into some animals, the dsRNA can silence genes of matching sequence and the silencing can persist in progeny. Such persistent gene silencing is thought to result from sequence-specific interaction of the RNA within parents to generate chromatin modifications, DNA methylation, and/or secondary RNAs, which are then inherited by progeny. Here, we show that dsRNA can be directly transferred between generations in the worm Caenorhabditis elegans Intergenerational transfer of dsRNA occurs even in animals that lack any DNA of matching sequence, and dsRNA that reaches progeny can spread between cells to cause gene silencing. Surprisingly, extracellular dsRNA can also reach progeny without entry into the cytosol, presumably within intracellular vesicles. Fluorescently labeled dsRNA is imported from extracellular space into oocytes along with yolk and accumulates in punctate structures within embryos. Subsequent entry into the cytosol of early embryos causes gene silencing in progeny. These results demonstrate the transport of extracellular RNA from one generation to the next to regulate gene expression in an animal and thus suggest a mechanism for the transmission of experience-dependent effects between generations.

Predictors of Nonadherence Among Patients With Infectious Complications of Substance Use Who Are Discharged on Parenteral Antimicrobial Therapy.

Background: The management of invasive infections related to substance use disorder (SUD) needing parenteral antimicrobial therapy is challenging and may have poor treatment outcomes including nonadherence and lack of completion of parenteral antimicrobial therapy. Methods: In this retrospective cohort of 201 patients with invasive infections related to SUD, we looked at frequency and determinants of unfavorable outcomes including nonadherence. Results: Seventy-nine percent of patients with SUD-related infection completed parenteral antibiotic therapy in skilled nursing facilities. A total of 21.5% of patient episodes had documentation of nonadherence. Nonadherence was higher in patients with active injection drug use (IDU) (28.5% versus 15% in non IDU; adjusted odds ratio [OR] 2.36; 95% confidence interval [CI], 1.1-5.5; P = .024), patients with active SUD in the prior year (24.5% vs 11%, P = .047), patients with use of more than 1 illicit substance (30.3% vs 17%, P = .031), as well as in people experiencing homelessness (32.8% vs 15.7% in stably housed, P = .005). In a multivariate model, nonadherence was significantly associated with IDU (OR, 2.38; 95% CI, 1.03-5.5) and homelessness (OR, 2.25; 95% CI, 1.01-4.8) Medication for opioid use disorder was prescribed at discharge in 68% of overall cohort and was not associated with improved outcomes for any of the above groups. Conclusions: Nonadherence to parenteral antimicrobial therapy is high in the most vulnerable patients with unstable high-risk SUD and adverse social determinants of health.

The UTH-UMB Global Health Education Collaboration: Building a Bidirectional Exchange Based on Equity and Reciprocity.

The global health exchange program between the University Teaching Hospitals (UTH) of Lusaka, Zambia and the University of Maryland, Baltimore (UMB) has been operating since 2015. As trainees and facilitators of this exchange program, we describe our experiences working in Lusaka and Baltimore, and strengths and challenges of the partnership. Since 2015, we have facilitated rotations for 71 UMB trainees, who spent four weeks on the Infectious Disease (ID) team at UTH. Since 2019 with funding from UMB, nine UTH ID trainee physicians spent up to six weeks each rotating on various ID consult services at University of Maryland Medical Center (UMMC). Challenges in global health rotations can include inadequate preparation or inappropriate expectations among high-income country trainees, low-value experiences for low- and middle-income country trainees, lack of appropriate mentorship at sites, and power imbalances in research collaborations. We try to mitigate these issues by ensuring pre-departure and on-site orientation for UMB trainees, cross-cultural mentored experiences for all trainees, and intentional sharing of authorship and credit on scientific collaborations. We present a description of our medical education collaboration as a successful model for building equitable and reciprocal collaborations between low- and middle-income countries and high-income countries, and offer suggestions for future program initiatives to enhance global health education equity among participants and organizations.

A Cross-sectional Analysis of Linezolid in Combination with Methadone or Buprenorphine as a Cause of Serotonin Toxicity.

Background: Serotonin toxicity (also referred to as serotonin syndrome) results from medications that affect the neurotransmitter serotonin. The antibiotic linezolid and the opioids methadone and buprenorphine are all reported to cause serotonin toxicity, but the degree of risk with use of linezolid in combination with methadone or buprenorphine is unknown. Methods: We conducted a retrospective cross-sectional analysis of adult patients hospitalized from November 2015 to October 2019 who were administered linezolid in combination with methadone and/or buprenorphine within 24 hours and a subgroup that received the combination for ≥3 days. Cases of serotonin toxicity were identified from the clinical notes in the electronic medical record and were classified as possible or definite based on the clinical record. The Hunter diagnostic criteria were retrospectively applied. Results: There were 494 encounters in which linezolid was administered concurrently with methadone and buprenorphine. The mean patient age was 42.5 years, and 52.4% of encounters were of female patients. The mean duration of concurrent administration was 1.9 days. There were 106 encounters with a duration of concurrent administration ≥3 days (mean, 5.4 days). Two cases of possible serotonin toxicity and 0 cases of definite serotonin toxicity occurred; neither possible case met the Hunter criteria from the available information. Possible cases occurred in 0.40% of all encounters and 1.89% of encounters with ≥3 days of overlap (upper 1-sided 95% CI, 0.87% and 4.06%). Conclusions: Serotonin toxicity occurring during the administration of linezolid in combination with methadone and/or buprenorphine occurred rarely among 494 hospital encounters, including 106 encounters with ≥3 days of overlap. Limitations include potential missed diagnoses of serotonin toxicity and short durations of overlap. Further study evaluating the short-term risk of this combination is needed.

Medication for opioid use disorder at hospital discharge is not associated with intravenous antibiotic completion in post-acute care facilities.

Background: People with opioid use disorder and severe infections may complete their prolonged courses of outpatient parenteral antimicrobial therapy at a post-acute care facility due to adherence and safety concerns. We hypothesized that treatment with medications for opioid use disorder, such as methadone and buprenorphine, would increase antibiotic completion in these facilities. Methods: We performed a retrospective cohort study of people with opioid use disorder and severe infections who were discharged from the University of Maryland Medical Center to a post-acute care facility to complete intravenous antibiotic therapy. The primary outcome was completion of outpatient parenteral antimicrobial therapy. We compared the rate of antibiotic completion between patients prescribed and not prescribed medication for opioid use disorder at discharge from the acute care hospital. Results: A total of 161 patient encounters were included; the mean age was 43.4 years and 56% of patients were male. In 48% of the encounters, the patient was homeless and in 68% they recently injected drugs. The most common infectious syndrome was osteoarticular (44.1%). Medication for opioid use disorder was prescribed at discharge in 103 of 161 encounters and was newly started in 27 encounters. Similar rates of outpatient parenteral antimicrobial therapy completion were found in those who received (65/103) and did not receive (33/58) medication for opioid use disorder at discharge (odds ratio: 1.29; 95% confidence interval: 0.68-2.54; p = 0.44). Conclusion: Medication for opioid use disorder prescription at discharge was not associated with completion of outpatient parenteral antimicrobial therapy in a post-acute care facility. Our study is limited by possible selection bias and infrequent initiation of medication for opioid use disorder, which may have minimized the effect on antibiotic completion.

Pulmonary aspergillosis and cryptococcosis as a complication of COVID-19.

Invasive fungal infections may complicate infection by SARS-CoV-2 and increase morbidity and mortality. A 59-year-old man with multiple medical comorbidities was transferred to our hospital for worsening hypoxic respiratory failure due to COVID-19 and received high-dose corticosteroids and 2 doses of cyclophosphamide. He was diagnosed with pulmonary aspergillosis and cryptococcosis by culture of a bronchoalveolar lavage sample. This patient's secondary infections were likely due to treatment with immunosuppressants, his comorbidities, and his prolonged critical illness.

Acute Limb Ischemia Caused by Inadvertent Arterial Drug Self-Injection: A Case Report.

BACKGROUND A predictable consequence of long-term injection drug use is the destruction of the native venous system; as a consequence, people who inject drugs may eventually move to injection into skin and subcutaneous tissue, wounds, muscles, and arteries. These practices put people who inject drugs at risk for injection-related soft-tissue infection, vascular damage, ischemia, and compartment syndrome, all of which have overlapping presenting symptoms. CASE REPORT A 35-year-old man who injects drugs presented with foot swelling and discoloration initially concerning for necrotizing fasciitis or compartment syndrome. After progression despite appropriate antimicrobial and surgical treatment for soft-tissue infection, he was diagnosed with arterial insufficiency and resultant distal ischemia. This diagnosis was discovered only after obtaining additional history of the patient's drug use practices. Just prior to his symptoms, he had unintentionally injected a formed thrombus into his dorsalis pedis artery. CONCLUSIONS Intra-arterial injection of drugs can cause ischemia through a variety of mechanisms, including direct vessel trauma, arterial spasm, toxicity from the drug of abuse or an adulterant, embolism of particulate matter, and as proposed here, direct injection of preformed thrombus. Medical providers should be aware of the steps of injection drug use and their associated risks so that they can ask appropriate questions to focus their differential diagnosis, increase their understanding of common or current local injection practices, and develop rapport with the patient. Patient education on safe injection techniques may also reduce the risk of serious complications.