Socioeconomic Disparities and the Prevalence of Antimicrobial Resistance.

BACKGROUND: The increased prevalence of antimicrobial resistant (AMR) infections is a significant global health threat, resulting in increased morbidity, mortality, and costs. The drivers of AMR are complex and potentially impacted by socioeconomic factors. We investigated the relationships between geographic and socioeconomic factors and AMR. METHODS: We collected select patient bacterial culture results from 2015 to 2020 from electronic health records (EHR) of two expansive healthcare systems within the Dallas-Fort Worth, TX (DFW) metropolitan area. Among individuals with EHR records who resided in the four most populus counties in DFW, culture data were aggregated. Case counts for each organism studied were standardized per 1,000 persons per area population. Using residential addresses, the cultures were geocoded and linked to socioeconomic index values. Spatial autocorrelation tests identified geographic clusters of high and low AMR organism prevalence and correlations with established socioeconomic indices. RESULTS: We found significant clusters of AMR organisms in areas with high levels of deprivation, as measured by the Area Deprivation Index (ADI). We found a significant spatial autocorrelation between ADI and the prevalence of AMR organisms, particularly for AmpC and MRSA with 14% and 13%, respectively, of the variability in prevalence rates being attributable to their relationship with the ADI values of the neighboring locations. CONCLUSIONS: We found that areas with a high ADI are more likely to have higher rates of AMR organisms. Interventions that improve socioeconomic factors such as poverty, unemployment, decreased access to healthcare, crowding, and sanitation in these areas of high prevalence may reduce the spread of AMR.

The modern alchemy of clinical pathology: turning the output of microbiology laboratory operations into gold.

The clinical microbiology laboratory generates a huge amount of high-quality data that play a vital role in clinical care. With proper extraction, cleaning, analysis, and validation pipelines, these data can serve multiple other purposes that include supporting laboratory operations, understanding local epidemiology, informing hospital-specific policies, and public health surveillance. In this review, I use one of the core activities of the microbiology laboratory, antimicrobial susceptibility testing (AST), to illustrate several potential applications of next-generation data analytics. The first involves continuous monitoring of commercial AST systems using comparisons of minimum inhibitory concentration (MIC) distributions over time to trigger re-verification when statistically significant differences are detected. An extension of this is temporal analysis of joint MIC distributions to understand performance for multidrug-resistant organisms. More sophisticated analyses involve linking microbiologic data to clinical metadata to gain insight into the clinical validity of AST data and to inform treatment policies. The elements of a robust, validated analysis engine using routine data streams already exist, but numerous challenges must be overcome to make it a reality. Most importantly, it will require the sustained collaboration and advocacy of hospital leadership, microbiologists, clinicians, antimicrobial stewardship, data scientists, and regulatory agencies. Though no small feat, achieving this vision would provide an important resource for microbiology laboratories facing a rapidly evolving practice landscape and further cement its role as an integral part of a learning health system.

Cycle threshold dynamics of non-severe acute respiratory coronavirus virus 2 (SARS-CoV-2) respiratory viruses.

OBJECTIVE: Many providers use severe acute respiratory coronavirus virus 2 (SARS-CoV-2) cycle thresholds (Ct values) as approximate measures of viral burden in association with other clinical data to inform decisions about treatment and isolation. We characterized temporal changes in Ct values for non-SARS-CoV-2 respiratory viruses as a first step to determine whether cycle thresholds could play a similar role in the management of non-SARS-CoV-2 respiratory viruses. DESIGN: Retrospective cohort study. SETTING: Brigham and Women's Hospital, Boston. METHODS: We retrospectively identified all adult patients with positive nasopharyngeal PCRs for influenza, respiratory syncytial virus (RSV), parainfluenza, human metapneumovirus (HMPV), rhinovirus, or adenovirus between January 2022 and March 2023. We plotted Ct distributions relative to days since symptom onset, and we assessed whether distributions varied by immunosuppression and other comorbidities. RESULTS: We analyzed 1,863 positive samples: 506 influenza, 502 rhinovirus, 430 RSV, 219 HMPV, 180 parainfluenza, 26 adenovirus. Ct values were generally 25-30 on the day of symptom onset, lower over the ensuing 1-3 days, and progressively higher thereafter with Ct values ≥30 after 1 week for most viruses. Ct values were generally higher and more stable over time for rhinovirus. There was no association between immunocompromised status and median intervals from symptom onset until Ct values were ≥30. CONCLUSIONS: Ct values relative to symptom onset for influenza, RSV, and other non-SARS-CoV-2 respiratory viruses generally mirror patterns seen with SARS-CoV-2. Further data on associations between Ct values and viral viability, transmissibility, host characteristics, and response to treatment for non-SARS-CoV-2 respiratory viruses are needed to determine how clinicians and infection preventionists might integrate Ct values into treatment and isolation decisions.

Use of Electronic Clinical Data to Track Incidence and Mortality for SARS-CoV-2-Associated Sepsis.

Importance: Efforts to quantify the burden of SARS-CoV-2-associated sepsis have been limited by inconsistent definitions and underrecognition of viral sepsis. Objective: To describe the incidence and outcomes of SARS-CoV-2-associated sepsis vs presumed bacterial sepsis using objective electronic clinical criteria. Design, Setting, and Participants: This retrospective cohort study included adults hospitalized at 5 Massachusetts hospitals between March 2020 and November 2022. Exposures: SARS-CoV-2-associated sepsis was defined as a positive SARS-CoV-2 polymerase chain reaction test and concurrent organ dysfunction (ie, oxygen support above simple nasal cannula, vasopressors, elevated lactate level, rise in creatine or bilirubin level, and/or decline in platelets). Presumed bacterial sepsis was defined by modified US Centers for Disease Control and Prevention adult sepsis event criteria (ie, blood culture order, sustained treatment with antibiotics, and organ dysfunction using identical thresholds as for SARS-CoV-2-associated sepsis). Main Outcomes and Measures: Trends in the quarterly incidence (ie, proportion of hospitalizations) and in-hospital mortality for SARS-CoV-2-associated and presumed bacterial sepsis were assessed using negative binomial and logistic regression models. Results: This study included 431 017 hospital encounters from 261 595 individuals (mean [SD] age 57.9 [19.8] years, 241 131 (55.9%) females, 286 397 [66.5%] from academic hospital site). Of these encounters, 23 276 (5.4%) were from SARS-CoV-2, 6558 (1.5%) had SARS-CoV-2-associated sepsis, and 30 604 patients (7.1%) had presumed bacterial sepsis without SARS-CoV-2 infection. Crude in-hospital mortality for SARS-CoV-2-associated sepsis declined from 490 of 1469 (33.4%) in the first quarter to 67 of 450 (14.9%) in the last (adjusted odds ratio [aOR], 0.88 [95% CI, 0.85-0.90] per quarter). Crude mortality for presumed bacterial sepsis was 4451 of 30 604 patients (14.5%) and stable across quarters (aOR, 1.00 [95% CI, 0.99-1.01]). Medical record reviews of 200 SARS-CoV-2-positive hospitalizations confirmed electronic health record (EHR)-based SARS-CoV-2-associated sepsis criteria performed well relative to sepsis-3 criteria (90.6% [95% CI, 80.7%-96.5%] sensitivity; 91.2% [95% CI, 85.1%-95.4%] specificity). Conclusions and Relevance: In this retrospective cohort study of hospitalized adults, SARS-CoV-2 accounted for approximately 1 in 6 cases of sepsis during the first 33 months of the COVID-19 pandemic. In-hospital mortality rates for SARS-CoV-2-associated sepsis were high but declined over time and ultimately were similar to presumed bacterial sepsis. These findings highlight the high burden of SARS-CoV-2-associated sepsis and demonstrate the utility of EHR-based algorithms to conduct surveillance for viral and bacterial sepsis.

The diagnostic and clinical utility of microbial cell-free DNA sequencing in a real-world setting.

Microbial cell free DNA sequencing is increasingly used for diagnosis of infection but few studies describe its utility in real-world settings. We performed a single-center retrospective case series of microbial cell free DNA testing using the Karius assay from 29 patient samples to define the clinical reasoning and the impact of testing. Indications fell into 3 categories, identifying a causative pathogen in patients with an infectious syndrome and negative microbiologic workup (15/29, 52%), seeking another pathogen when organisms identified by traditional diagnostics failed to explain the clinical presentation (9/29, 31%) and to "rule out" infection in patients with nonspecific symptoms and negative microbiologic workup (5/29, 17%). Clinical impact was positive in 13/29 (45%) and all were for patients with high pretest probability for infection. Impact was negative in 3/29 (10%) cases. There was no impact in 15/29 (52%) cases. Further work is needed to define the optimal timing accounting for test performance, and patient characteristics.

Predictors of low spike antibody response in patients with systemic rheumatic disease after an initial course of COVID-19 vaccination.

BACKGROUND: Patients with rheumatic disease may mount a suboptimal serologic response to COVID-19 vaccination. We evaluated predictors of low antibody response in a clinic-based cohort. METHODS: We conducted a cross-sectional study using electronic health record (EHR) data at Brigham and Women's Hospital, Boston, MA. Patients with systemic rheumatic disease that had SARS-CoV-2 spike antibody (Ab) tested using the Roche Elecsys immunoassay, February-August 2021, after 2 doses of mRNA vaccine or 1 dose of adenovirus vector vaccine were identified. Demographics, systemic rheumatic disease, vaccination dates, and disease-modifying antirheumatic drugs (DMARDs) were extracted. The primary outcome was low spike Ab (≤ 200 U/mL). Logistic regression models estimated predictors of low spike Ab. RESULTS: Among 382 patients, the mean age was 57 years, 77% were female, and 37% had low spike Ab. Older age (OR 1.03, 95% CI [1.02, 1.05]), SLE (OR 4.81 [2.08, 8.43], reference: inflammatory arthritis), prednisone (OR 1.67 [1.03, 2.74]), and rituximab (OR 22.91 [9.85, 53.29]) were significantly associated with higher odds of low spike Ab. Use of csDMARD monotherapy (OR 0.12 [0.04, 0.33]) and JAK inhibitors (OR 0.41 [0.18, 0.92]) were associated with significantly lower odds for low spike Ab. After adjusting for systemic rheumatic disease and DMARDs, SLE and rituximab remained significantly associated with low spike Ab. CONCLUSIONS: Over a third of patients with systemic rheumatic disease with spike Ab tested in routine care had low spike Ab after 2 doses of mRNA or 1 dose of adenovirus vector COVID-19 vaccine. SLE and rituximab were significant risk factors for low spike Ab. KEY POINTS: • More than one-third of patients with systemic rheumatic disease that had spike Ab tested in routine care had low spike Ab after 2 doses of mRNA or 1 dose of adenovirus vector COVID-19 vaccine. • Diagnosis of SLE, use of prednisone, and use of rituximab were significantly associated with greater odds of low spike antibodies. • These data underscore the importance of additional doses of COVID-19 vaccine and prophylactic Evusheld in immunosuppressed patients with systemic rheumatic disease as recommended by the US Centers for Disease Control.

The 2022 RSV surge was driven by multiple viral lineages.

The US experienced an early and severe respiratory syncytial virus (RSV) surge in autumn 2022. Despite the pressure this has put on hospitals and care centers, the factors promoting the surge in cases are unknown. To investigate whether viral characteristics contributed to the extent or severity of the surge, we sequenced 105 RSV-positive specimens from symptomatic patients diagnosed with RSV who presented to the Massachusetts General Hospital (MGH) and its outpatient practices in the Greater Boston Area. Genomic analysis of the resulting 77 genomes (54 with >80% coverage, and 23 with >5% coverage) demonstrated that the surge was driven by multiple lineages of RSV-A (91%; 70/77) and RSV-B (9%; 7/77). Phylogenetic analysis of all US RSV-A revealed 12 clades, 4 of which contained Massachusetts and Washington genomes. These clades individually had times to most recent common ancestor (tMRCA) between 2014 and 2017, and together had a tMRCA of 2009, suggesting that they emerged well before the COVID-19 pandemic. Similarly, the RSV-B genomes had a tMRCA between 2016 and 2019. We found that the RSV-A and RSV-B genomes in our sample did not differ statistically from the estimated clock rate of the larger phylogenetic tree (10.6 and 12.4 substitutions per year, respectively). In summary, the polyphyletic nature of viral genomes sequenced in the US during the autumn 2022 surge is inconsistent with the emergence of a single, highly transmissible causal RSV lineage.

Hidden in plain sight: urinary Cryptococcus neoformans missed by routine diagnostics in a patient with acute leukemia.

Cryptococcuria is a rare manifestation of localized cryptococcal disease. We present a case of Cryptococcus neoformans urinary tract infection in an immunocompromised host missed by routine laboratory workup. The patient had negative blood cultures, a negative serum cryptococcal antigen (CrAg), and "non-Candida yeast" growing in urine culture that was initially dismissed as non-pathogenic. The diagnosis was ultimately made by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) from a repeat urine culture after transfer to a tertiary care center. Cryptococcus should be considered in the differential of refractory urinary tract infections growing non-Candida yeast.

Prevalence, Clinical Characteristics, and Outcomes of Sepsis Caused by Severe Acute Respiratory Syndrome Coronavirus 2 Versus Other Pathogens in Hospitalized Patients With COVID-19.

The prevalence and causes of sepsis in patients hospitalized with COVID-19 are poorly characterized. OBJECTIVES: To investigate the prevalence, clinical characteristics, and outcomes of sepsis caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) versus other pathogens in patients hospitalized with COVID-19. DESIGN SETTING AND PARTICIPANTS: Cross-sectional, retrospective chart review of 200 randomly selected patients hospitalized with COVID-19 at four Massachusetts hospitals between March 2020 and March 2021. MAIN OUTCOMES AND MEASURES: The presence or absence of sepsis was determined per Sepsis-3 criteria (infection leading to an increase in Sequential Organ Failure Assessment score by ≥ 2 points above baseline). Sepsis episodes were assessed as caused by SARS-CoV-2, other pathogens, or both. Rates of organ dysfunction and in-hospital death were also assessed. RESULTS: Sepsis was present in 65 of 200 COVID-19 hospitalizations (32.5%), of which 46 of 65 sepsis episodes (70.8%) were due to SARS-CoV-2 alone, 17 of 65 (26.2%) were due to both SARS-CoV-2 and non-SARS-CoV-2 infections, and two of 65 (3.1%) were due to bacterial infection alone. SARS-CoV-2-related organ dysfunction in patients with sepsis occurred a median of 1 day after admission (interquartile range, 0-2 d) and most often presented as respiratory (93.7%), neurologic (46.0%), and/or renal (39.7%) dysfunctions. In-hospital death occurred in 28 of 200 COVID-19 hospitalizations (14.0%), including two of 135 patients without sepsis (1.5%), 16 of 46 patients with sepsis (34.8%) due to SARS-CoV-2 alone, and 10 of 17 patients with sepsis (58.8%) due to both SARS-CoV-2 and bacterial pathogens. CONCLUSIONS: Sepsis occurred in one in three patients hospitalized with COVID-19 and was primarily caused by SARS-CoV-2 itself, although bacterial infection also contributed in a quarter of sepsis cases. Mortality in COVID-19 patients with sepsis was high, especially in patients with mixed SARS-CoV-2 and bacterial sepsis. These findings affirm SARS-CoV-2 as an important cause of sepsis and highlight the need to improve surveillance, recognition, prevention, and treatment of both viral and bacterial sepsis in hospitalized patients with COVID-19.

Inter-species geographic signatures for tracing horizontal gene transfer and long-term persistence of carbapenem resistance.

BACKGROUND: Carbapenem-resistant Enterobacterales (CRE) are an urgent global health threat. Inferring the dynamics of local CRE dissemination is currently limited by our inability to confidently trace the spread of resistance determinants to unrelated bacterial hosts. Whole-genome sequence comparison is useful for identifying CRE clonal transmission and outbreaks, but high-frequency horizontal gene transfer (HGT) of carbapenem resistance genes and subsequent genome rearrangement complicate tracing the local persistence and mobilization of these genes across organisms. METHODS: To overcome this limitation, we developed a new approach to identify recent HGT of large, near-identical plasmid segments across species boundaries, which also allowed us to overcome technical challenges with genome assembly. We applied this to complete and near-complete genome assemblies to examine the local spread of CRE in a systematic, prospective collection of all CRE, as well as time- and species-matched carbapenem-susceptible Enterobacterales, isolated from patients from four US hospitals over nearly 5 years. RESULTS: Our CRE collection comprised a diverse range of species, lineages, and carbapenem resistance mechanisms, many of which were encoded on a variety of promiscuous plasmid types. We found and quantified rearrangement, persistence, and repeated transfer of plasmid segments, including those harboring carbapenemases, between organisms over multiple years. Some plasmid segments were found to be strongly associated with specific locales, thus representing geographic signatures that make it possible to trace recent and localized HGT events. Functional analysis of these signatures revealed genes commonly found in plasmids of nosocomial pathogens, such as functions required for plasmid retention and spread, as well survival against a variety of antibiotic and antiseptics common to the hospital environment. CONCLUSIONS: Collectively, the framework we developed provides a clearer, high-resolution picture of the epidemiology of antibiotic resistance importation, spread, and persistence in patients and healthcare networks.

Analysis of multiple bacterial species and antibiotic classes reveals large variation in the association between seasonal antibiotic use and resistance.

Understanding how antibiotic use drives resistance is crucial for guiding effective strategies to limit the spread of resistance, but the use-resistance relationship across pathogens and antibiotics remains unclear. We applied sinusoidal models to evaluate the seasonal use-resistance relationship across 3 species (Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae) and 5 antibiotic classes (penicillins, macrolides, quinolones, tetracyclines, and nitrofurans) in Boston, Massachusetts. Outpatient use of all 5 classes and resistance in inpatient and outpatient isolates in 9 of 15 species-antibiotic combinations showed statistically significant amplitudes of seasonality (false discovery rate (FDR) < 0.05). While seasonal peaks in use varied by class, resistance in all 9 species-antibiotic combinations peaked in the winter and spring. The correlations between seasonal use and resistance thus varied widely, with resistance to all antibiotic classes being most positively correlated with use of the winter peaking classes (penicillins and macrolides). These findings challenge the simple model of antibiotic use independently selecting for resistance and suggest that stewardship strategies will not be equally effective across all species and antibiotics. Rather, seasonal selection for resistance across multiple antibiotic classes may be dominated by use of the most highly prescribed antibiotic classes, penicillins and macrolides.

The Effect of Vaccine Type and SARS-CoV-2 Lineage on Commercial SARS-CoV-2 Serologic and Pseudotype Neutralization Assays in mRNA Vaccine Recipients.

The use of anti-spike (S) serologic assays as surrogate measurements of SARS-CoV-2 vaccine induced immunity will be an important clinical and epidemiological tool. The characteristics of a commercially available anti-S antibody assay (Roche Elecsys anti-SARS-CoV-2 S) were evaluated in a cohort of vaccine recipients. Levels were correlated with pseudotype neutralizing antibodies (NAb) across SARS-CoV-2 variants. We recruited adults receiving a two-dose series of mRNA-1273 or BNT162b2 and collected serum at scheduled intervals up to 8 months post-first vaccination. Anti-S and NAb levels were measured, and correlation was evaluated by (i) vaccine type and (ii) SARS-CoV-2 variant (wild-type, Alpha, Beta, Gamma, and three constructs Day 146*, Day 152*, and RBM-2). Forty-six mRNA vaccine recipients were enrolled. mRNA-1273 vaccine recipients had higher peak anti-S and NAb levels compared with BNT162b2 (P < 0.001 for anti-S levels; P < 0.05 for NAb levels). When anti-S and NAb levels were compared, there was good correlation (all r values ≥ 0.85) in both BNT162b2 and mRNA-1273 vaccine recipients across all evaluated variants; however, these correlations were nonlinear in nature. Lower correlation was identified between anti-S and NAb for the Beta variant (r = 0.88) compared with the wild-type (WT) strain (r = 0.94). Finally, the degree of neutralizing activity at any given anti-S level was lower for each variant compared with that of the WT strain, (P < 0.001). Although the Roche anti-S assay correlates well with NAb levels, this association is affected by vaccine type and SARS-CoV-2 variant. These variables must be considered when interpreting anti-S levels. IMPORTANCE We evaluated anti-spike antibody concentrations in healthy mRNA vaccinated individuals and compared these concentrations to values obtained from pseudotype neutralization assays targeting SARS-CoV-2 variants of concern to determine how well anti-spike antibodies correlate with neutralizing titers, which have been used as a marker of immunity from COVID-19 infection. We found high peak anti-spike concentrations in these individuals, with significantly higher levels seen in mRNA-1273 vaccine recipients. When we compared anti-spike and pseudotype neuralization titers, we identified good correlation; however, this correlation was affected by both vaccine type and variant, illustrating the difficulty of applying a "one size fits all" approach to anti-spike result interpretation. Our results support CDC recommendations to discourage anti-spike antibody testing to assess for immunity after vaccination and cautions providers in their interpretations of these results as a surrogate of protection in COVID-vaccinated individuals.

Structural basis for continued antibody evasion by the SARS-CoV-2 receptor binding domain.

Many studies have examined the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants on neutralizing antibody activity after they have become dominant strains. Here, we evaluate the consequences of further viral evolution. We demonstrate mechanisms through which the SARS-CoV-2 receptor binding domain (RBD) can tolerate large numbers of simultaneous antibody escape mutations and show that pseudotypes containing up to seven mutations, as opposed to the one to three found in previously studied variants of concern, are more resistant to neutralization by therapeutic antibodies and serum from vaccine recipients. We identify an antibody that binds the RBD core to neutralize pseudotypes for all tested variants but show that the RBD can acquire an N-linked glycan to escape neutralization. Our findings portend continued emergence of escape variants as SARS-CoV-2 adapts to humans.

Safety of Live-Attenuated Measles, Mumps, and Rubella Vaccine Administered Within 2 Years of Hematopoietic Cell Transplant.

BACKGROUND: Measles, mumps, and rubella (MMR) vaccine is a live-attenuated vaccine usually contraindicated within the first 2 years of hematopoietic cell transplant (HCT). The objective of this study was to assess the safety of MMR vaccine when administered within 2 years of HCT. METHODS: We conducted a retrospective review of patients who received MMR vaccination within 2 years of an autologous or allogeneic HCT, mostly in the context of the 2019 measles outbreak. Adverse reactions were collected for 42 days postvaccination, and all hospitalizations and deaths following vaccination were reviewed. RESULTS: A total of 129 patients (75 autologous and 54 allogeneic HCT) were vaccinated 300-729 days after HCT (median, 718 days), and 39 (30%) of these were vaccinated earlier than 23 months post-transplant. Ten adverse reactions in 7 patients (5%) were identified within 42 days of vaccination: 6 respiratory tract infections (3 with fever) and 1 rash. The rash was seen in a 37-year-old female who had an allogeneic HCT 542 days before vaccination. She presented with a centrifugal maculopapular rash, confirmed to be caused by the vaccine strain rubella virus. She fully recovered. No other vaccine-associated illness was identified in the cohort after a median follow-up of 676 days. CONCLUSIONS: MMR vaccine appears to be well tolerated in select HCT recipients when given between 300 and 729 days after transplant. An uncomplicated case of vaccine-associated rubella illness was seen after vaccination. Assessment of potential risks and benefits of MMR vaccination given within 2 years of HCT remains important.

Enhanced Virus Detection and Metagenomic Sequencing in Patients with Meningitis and Encephalitis.

Meningitis and encephalitis are leading causes of central nervous system (CNS) disease and often result in severe neurological compromise or death. Traditional diagnostic workflows largely rely on pathogen-specific tests, sometimes over days to weeks, whereas metagenomic next-generation sequencing (mNGS) profiles all nucleic acid in a sample. In this single-center, prospective study, 68 hospitalized patients with known (n = 44) or suspected (n = 24) CNS infections underwent mNGS from RNA and DNA to identify potential pathogens and also targeted sequencing of viruses using hybrid capture. Using a computational metagenomic classification pipeline based on KrakenUniq and BLAST, we detected pathogen nucleic acid in cerebrospinal fluid (CSF) from 22 subjects, 3 of whom had no clinical diagnosis by routine workup. Among subjects diagnosed with infection by serology and/or peripheral samples, we demonstrated the utility of mNGS to detect pathogen nucleic acid in CSF, importantly for the Ixodes scapularis tick-borne pathogens Powassan virus, Borrelia burgdorferi, and Anaplasma phagocytophilum. We also evaluated two methods to enhance the detection of viral nucleic acid, hybrid capture and methylated DNA depletion. Hybrid capture nearly universally increased viral read recovery. Although results for methylated DNA depletion were mixed, it allowed the detection of varicella-zoster virus DNA in two samples that were negative by standard mNGS. Overall, mNGS is a promising approach that can test for multiple pathogens simultaneously, with efficacy similar to that of pathogen-specific tests, and can uncover geographically relevant infectious CNS disease, such as tick-borne infections in New England. With further laboratory and computational enhancements, mNGS may become a mainstay of workup for encephalitis and meningitis. IMPORTANCE Meningitis and encephalitis are leading global causes of central nervous system (CNS) disability and mortality. Current diagnostic workflows remain inefficient, requiring costly pathogen-specific assays and sometimes invasive surgical procedures. Despite intensive diagnostic efforts, 40 to 60% of people with meningitis or encephalitis have no clear cause of CNS disease identified. As diagnostic uncertainty often leads to costly inappropriate therapies, the need for novel pathogen detection methods is paramount. Metagenomic next-generation sequencing (mNGS) offers the unique opportunity to circumvent these challenges using unbiased laboratory and computational methods. Here, we performed comprehensive mNGS from 68 prospectively enrolled patients with known (n = 44) or suspected (n = 24) CNS viral infection from a single center in New England and evaluated enhanced methods to improve the detection of CNS pathogens, including those not traditionally identified in the CNS by nucleic acid detection. Overall, our work helps elucidate how mNGS can become integrated into the diagnostic toolkit for CNS infections.

Trajectory Inspection: A Method for Iterative Clinician-Driven Design of Reinforcement Learning Studies.

Reinforcement learning (RL) has the potential to significantly improve clinical decision making. However, treatment policies learned via RL from observational data are sensitive to subtle choices in study design. We highlight a simple approach, trajectory inspection, to bring clinicians into an iterative design process for model-based RL studies. We identify where the model recommends unexpectedly aggressive treatments or expects surprisingly positive outcomes from its recommendations. Then, we examine clinical trajectories simulated with the learned model and policy alongside the actual hospital course. Applying this approach to recent work on RL for sepsis management, we uncover a model bias towards discharge, a preference for high vasopressor doses that may be linked to small sample sizes, and clinically implausible expectations of discharge without weaning off vasopressors. We hope that iterations of detecting and addressing the issues unearthed by our method will result in RL policies that inspire more confidence in deployment.

Prospective Clinical Assessments of Hospitalized Patients With Positive SARS-CoV-2 PCR Tests for Necessity of Isolation.

We prospectively assessed 536 hospitalized patients with positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction tests for infectiousness based on symptoms, cycle thresholds, and SARS-CoV-2 history, with repeat testing and serologies in select cases. One hundred forty-eight (28%) patients were deemed noninfectious, most with evidence of prior infection, and managed on standard precautions without evidence of transmission.