Faculty Bibliography

IMPORTANCE/UNASSIGNED:Babesiosis is a worldwide emerging tick-borne disease with an expanding geographic range in the US, Europe, and Asia. Red blood cell exchange transfusion (ET) is often used as an adjunctive treatment for severe illness from babesiosis, particularly in patients with high parasitemia, acute organ injury, or severe hemolytic anemia. Data supporting its clinical effectiveness, however, are lacking. OBJECTIVE/UNASSIGNED:To test whether ET improves clinical outcomes among hospitalized adult patients with severe babesiosis. DESIGN, SETTINGS, AND PARTICIPANTS/UNASSIGNED:This target trial emulation used data from a multicenter cohort study of 3233 consecutive adults hospitalized with babesiosis from 2010 to 2024 at 82 sites across the northeastern US. Patients were eligible if they had parasitemia greater than 10%, or 5% to 10% with either acute organ injury or severe hemolytic anemia. Data were analyzed from April to August 2025. EXPOSURE/UNASSIGNED:Treatment with ET in the first 7 days of hospitalization. MAIN OUTCOMES AND MEASURES/UNASSIGNED:A composite of in-hospital death or 30-day readmission. Outcomes were compared between patients who received ET within the first 7 days of admission and those who did not. The analysis used logistic regression, with inverse probability of treatment weighting (IPTW) to adjust for potential confounders. RESULTS/UNASSIGNED:The analysis included 629 patients (median [IQR] age, 71 [63-79] years; 446 male [70.9%]), among whom 209 (33.2%) received ET in the first 7 days of hospitalization. Patients treated with ET were more severely ill at baseline than those not treated with ET (median parasitemia, 14.0% vs 7.2%); however, severity of illness characteristics were well balanced after applying IPTW. In the main analysis, the primary end point occurred in 3.6% of patients who received ET and in 9.8% who did not (adjusted odds ratio, 0.22; 95% CI, 0.09-0.51). The benefit of ET was confirmed in multiple sensitivity analyses. CONCLUSIONS AND RELEVANCE/UNASSIGNED:This multicenter cohort study found that among severely ill adults hospitalized with babesiosis, the adjusted risk of in-hospital death or 30-day readmission was nearly 5-fold lower in those treated with ET vs those not treated with ET. These data support ET for severely ill patients with babesiosis, although the findings may be susceptible to unmeasured confounding. Further research is needed to identify which patients are most likely to benefit.

Rapid molecular assays guiding treatment of methicillin-resistant Staphylococcus aureus (MRSA) detect SCCmec (Xpert) or the SCCmec-orfX junction (BCID2). Sequence variation in this region can disrupt primer binding, yielding false-negative results. Investigation of a missed bloodstream infection linked escape to a CRISPR-Cas-associated SCCmec variant, leading to identification of 64 variants from 45 patients-2% of 2,432 screened. Misdiagnosis was restricted to clonal complex 5, a hospital-associated lineage; 11 of 40 SCCmec/junctions evaded detection by BCID2 or Xpert. Variants had mecA instability and circulated in healthcare settings. Our findings reveal a unique escape mechanism and underscore a threat to diagnostic accuracy.

Staphylococcus aureus causes approximately 80% of skin and soft tissue infections (SSTIs). Collagen is the most abundant human extracellular matrix protein with critical roles in wound healing, and S. aureus encodes a collagen binding adhesin (Cna). The role of this protein during skin infections is unknown. Here we report that inability to bind collagen results in worsened pathology of intradermal Δcna S. aureus infection. WT/Cna+ S. aureus shows reduced infection severity, aggregate formation, and significantly improves clearance of bacteria. Cna binds to the collagen-like domain of serum C1q protein to reduce its opsonophagocytic functions. We demonstrate that infection of C1qKO mice with WT bacteria show results similar to the Δcna group. Conversely, inability to bind collagen results in an amplified inflammatory response caused in part by macrophage and neutrophil small molecule mediators released at the infection site (MMP-9, MMP-12, LTB₄), leading to increased immune cell infiltration and death.

Asymptomatic carriers of antimicrobial-resistant organisms (AMROs) can unwittingly transmit these pathogens in hospitals, contributing to the burden of healthcare-associated infections (HAIs). Surveillance in hospitals can involve different types of observations; however, a framework to coherently synthesize these datasets to identify AMRO carriers is lacking. Here, we develop a new inference framework combining a data-driven mechanistic transmission model and multimodal observations from clinical cultures, electronic health records, patient mobility, and genomic data. Using extensive simulated outbreaks, we validate the inference framework for AMROs with various levels of community importation and hospital transmission and evaluate the utility of different combinations of data sources. Inference results show that using multimodal observations consistently improves the accuracy in identifying AMRO carriers. We apply the inference framework to carbapenem-resistant Klebsiella pneumoniae (CRKP) at an urban quaternary care hospital in New York City, United States and find that the addition of even sparsely sampled genome sequence data to patient characteristics supports more accurate identification of CRKP carriers. Model simulations suggest that inference-guided targeted isolation leads to a greater reduction of AMRO burdens compared to alternative, heuristic approaches. Thus, the synergistic effect of utilizing multimodal observations for estimating AMRO carriage risk may inform improved interventions in hospital settings.

BACKGROUND:Despite decreased mortality over the past several decades, the prognosis of brain abscesses remains dependent on intracranial location and causative organism. Deep-seated brain abscesses carry a risk of intraventricular rupture, an event with reported mortality near 80%. Coccidioidomycosis from the fungus Coccidioides immitis, endemic to the American Southwest, is growing in incidence but uncommonly produces deep brain abscesses, making management unclear.The authors report the diagnosis and management of a solitary thalamic Coccidioides abscess without meningitis. OBSERVATIONS/METHODS:A 59-year-old female presented with 1 week of gait instability, left facial weakness, dysarthria, and intermittent headache, but no meningismus. Cranial imaging was consistent with abscess or, less likely, a neoplasm, and a stereotactic brain biopsy was pursued. Despite negative fungal cultures and lack of serum antibody detection, findings of pathognomonic spherules in pathology tissue with confirmatory polymerase chain reaction testing helped diagnose coccidioidomycosis. The patient's symptoms resolved 3 weeks postoperatively with a dexamethasone taper and, due to relapse risk, planned lifelong fluconazole therapy. The patient self-discontinued fluconazole at 11 months postoperatively but remained disease free at 1 year. LESSONS/CONCLUSIONS:C. immitis can present as solitary brain abscesses despite negative fungal cultures. Postoperative dexamethasone and long-term fluconazole can clear the pathogen and suppress recurrence. https://thejns.org/doi/10.3171/CASE25381.

We recently described the evolution of a community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) USA300 variant responsible for an outbreak of skin and soft tissue infections. Acquisition of a mosaic version of the Φ11 prophage (mΦ11) that increases skin abscess size was an early step in CA-MRSA adaptation that primed the successful spread of the clone. The present report shows how prophage mΦ11 exerts its effect on virulence for skin infection without encoding a known toxin or fitness genes. Abscess size and skin inflammation were associated with DNA methylase activity of an mΦ11-encoded adenine methyltransferase (designated pamA). pamA increased expression of fibronectin-binding protein A (fnbA; FnBPA), and inactivation of fnbA eliminated the effect of pamA on abscess virulence without affecting strains lacking pamA. Thus, fnbA is a pamA-specific virulence factor. Mechanistically, pamA was shown to promote biofilm formation in vivo in skin abscesses, a phenotype linked to FnBPA's role in biofilm formation. Collectively, these data reveal a critical mechanism-epigenetic regulation of staphylococcal gene expression-by which phage can regulate virulence to drive adaptive leaps by S. aureus.

Staphylococcus aureus is a global health concern, resulting in significant disease burden in both hospital and community settings. To establish infection, the bacteria must contend with a multitude of host defense mechanisms, including "nutritional immunity", in which nutrients are sequestered away from invading pathogens. Importantly, S. aureus requires iron for growth during infection, which it acquires through the lysis of erythrocytes (hemolysis). HlgAB, a secreted bi-component pore forming toxin, contributes to the ability of S. aureus to lyse erythrocytes to release heme iron. HlgAB consists of two subunits, the S-subunit HlgA and the F-subunit HlgB. Prior work has shown that the hemolytic activity of HlgAB is dependent on the binding of HlgA to the host receptor Duffy Antigen Receptor for Chemokines (DARC). Here we show that HlgB binds the surface of erythrocytes independently of DARC or HlgA. Our comparative genomic analysis reveals high conservation of hlgA and hlgB genes across S. aureus lineages. By performing structure-function studies, we identified a series of loops within the rim domain of HlgB that are required for the binding of HlgB to erythrocytes and erythrocyte lysis by HlgAB. The importance of HlgB-mediated host targeting was validated in a tissue culture model of S. aureus-mediated lysis of primary human erythrocytes, in an in vivo murine model of intoxication, and during in vivo systemic infection. Altogether, these findings expand our mechanistic insights into how S. aureus overcomes nutritional immunity, and the role of HlgB in S. aureus pathophysiology.

The T300A substitution in ATG16L1 associated with Crohn's disease impairs autophagy, yet up to 50% of humans are heterozygous for this allele. Here, we demonstrate that heterozygosity for the analogous substitution in mice (Atg16L1^T316A), but not homozygosity, protects against lethal Salmonella enterica Typhimurium infection. One copy of Atg16L1^T316A was sufficient to enhance cytokine production through inflammasome activation, which was necessary for protection. In contrast, two copies of Atg16L1^T316A inhibited the autophagy-related process of LC3-associated phagocytosis (LAP) and increased susceptibility. Macrophages from human donors heterozygous for ATG16L1^T300A displayed elevated inflammasome activation while homozygosity impaired LAP, similar to mice. These results clarify how the T300A substitution impacts ATG16L1 function and suggest it can be beneficial to heterozygous carriers, providing an explanation for its prevalence within the human population.

Gastrointestinal (GI) colonization by methicillin-resistant Staphylococcus aureus (MRSA) is associated with a high risk of transmission and invasive disease in vulnerable populations. The immune and microbial factors that permit GI colonization remain unknown. Male sex is correlated with enhanced Staphylococcus aureus nasal carriage, skin and soft tissue infections, and bacterial sepsis. Here, we established a mouse model of sexual dimorphism during GI colonization by MRSA. Our results show that in contrast to male mice that were susceptible to persistent colonization, female mice rapidly cleared MRSA from the GI tract following oral inoculation in a manner dependent on the gut microbiota. This colonization resistance displayed by female mice was mediated by an increase in IL-17A+ CD4+ T cells (Th17) and dependent on neutrophils. Ovariectomy of female mice increased MRSA burden, but gonadal female mice that have the Y chromosome retained enhanced Th17 responses and colonization resistance. Our study reveals a novel intersection between sex and gut microbiota underlying colonization resistance against a major widespread pathogen.

BACKGROUND/UNASSIGNED:Global study data show injection drug use is driving upwards of 79% of all new hepatitis C virus (HCV) cases in high-income countries. Low-threshold models can engage vulnerable populations in treatment to achieve HCV elimination targets. We examined the implementation of low-threshold models for HCV care in New York State, which has a robust HCV elimination program. METHODS/UNASSIGNED:We conducted semi-structured interviews with 16 healthcare providers in 2022. Included providers either self-described as "low-threshold," had a clinical focus on marginalized populations, or practiced in non-traditional settings. Interviews focused on the implementation of low-threshold HCV care. Transcripts were analyzed using thematic analysis and were categorized into themes guided by the Exploration, Preparation, Implementation, Sustainment (EPIS) framework. RESULTS/UNASSIGNED:Providers implemented low-threshold HCV care by facilitating access (e.g., having walk-in or telemedicine HCV services). Point-of-care testing and peer support were other important features. The inner context was driven by provider and organization values and involved providing low-threshold HCV care within health systems that were not themselves "low-threshold." Adequate staffing was crucial for the extensive care coordination and outreach activities needed to engage persons who inject drugs (PWID). The outer context was characterized by a limited funding environment, restrictive insurance policies, and the high impact of patients' unmet social needs. Providers relied on care coordination and integrated care models to overcome these barriers. CONCLUSIONS/UNASSIGNED:Low-threshold HCV care incorporates operational flexibility and patient navigation but is challenged by patients' unmet social needs. Jurisdictions can support implementation by providing adequate funding for substantial outreach activities needed to engage vulnerable populations.