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Invasive Candida bloodstream infections (candidemia) are a deadly global health threat. Rare Candida species are increasingly important causes of candidemia and phenotypic data, including patterns of antifungal drug resistance, is limited. There is geographic variation in the distribution of Candida species and frequency of antifungal drug resistance, which means that collecting and reporting regional data can have significant clinical value. Here, we report the first survey of species distribution, frequency of antifungal drug resistance, and phenotypic variability of Candida bloodstream isolates from an academic medical center and 5 affiliated hospitals in the Minneapolis-Saint Paul region of Minnesota, collected during an 18-month period from 2019 to 2021. We collected 288 isolates spanning 11 species from 119 patients. C. albicans was the most frequently recovered species, followed by C. glabrata and C. parapsilosis , with 10% of cases representing additional, rare species. We performed antifungal drug susceptibility for the three major drug classes and, concerningly, we identified fluconazole, micafungin and multidrug resistance rates in C. glabrata that were ~ 2 times higher than that reported in other regions of the United States. We report some of the first phenotypic data in rare non- albicans Candida species. Through analysis of serial isolates from individual patients, we identified clinically relevant within-patient differences of MIC values in multiple drug classes. Our results provide valuable clinical data relevant to antifungal stewardship efforts and highlight important areas of future research, including within-patient dynamics of infection and the mechanisms of drug resistance in rare Candida species.

We surveyed 111 institutions' practices for screening and decolonization of Staphylococcus aureus in presurgical patients. Institutions commonly utilize universal, targeted, or no decolonization strategies. Frequently reported products were nasal mupirocin, chlorhexidine gluconate bathing, and nasal povidone-iodine. Practice variability indicates opportunities to define optimal strategies.

Introduction: Nitrous oxide (N2O) is commonly used in pediatric procedural sedation. It is an attractive option to facilitate intravenous line placement, as it does not extend sedation recovery from subsequently administered agents. Although debate exists regarding health consequences of occupational exposure now that scavenging of exhaled gases is common, cooperation of pediatric patients to maximize engineering controls is not guaranteed and can contribute to repeated exposure over the course of a clinician's career. There is no global consensus on personal exposure limits, but the National Institute for Occupational Safety and Health published U.S. guidelines. A dosimetry survey of our sedation team during a short N2O procedure for intravenous line placement exceeded the National Institute for Occupational Safety and Health Recommended Exposure Limit (REL) of 25 parts per million. We designed a process improvement initiative to reduce occupational exposure below the Recommended Exposure Limit on serial surveys., Materials and Methods: A continuous flow, titratable, full-face mask N2O delivery system with scavenging by a central vacuum connection was used. A retrospective chart review of N2O procedures performed before the initial dosimetry survey revealed practice trends in provider behavior during N2O administration. Initiation of N2O gas flow and maintenance of face mask seal on an uncooperative patient were identified as two sources of variability. Two-handed face-masking technique, initiation of N2O gas flow only after masking, and continued masking for 2 min of exhaled scavenging were standardized and socialized as best practices. Subsequent dosimetry surveys of the sedation team were coordinated by Industrial Hygiene., Results: Pre- and post-intervention phases were 17 months each and included 92 and 201 N2O patients, respectively. Six dosimetry surveys occurred in the post phase. Intravenous line placement was the typical procedure surveyed. Dosimetry results for all team members during surveys 1-4 were below the REL, with 14 of 16 samples falling below the level of quantitation. Elevated dosimetry results in survey 5 prompted reevaluation of work practices and equipment. A loose component on the delivery system was discovered, corrected, and incorporated as a pre-procedure check. With no further changes to work practices, dosimetry results were below the REL for survey 6., Conclusion: We layered work practice changes atop engineering controls to reduce occupational exposure levels for medical team members. We utilized dosimetry as a lagging indicator, prompting frequent reassessments of our equipment and processes that we might not otherwise have performed. Pediatric sedation programs are encouraged to consider whether Industrial Hygiene resources might provide synergy to process improvement efforts with inhalational sedation agents., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2024. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: The Infectious Diseases Society of America recommends a screening dilated retinal examination by an ophthalmologist for all patients with candidemia. Conversely, the American Academy of Ophthalmology recommends against routine screening in patients with candidemia without symptoms., Methods: In a collaborative effort between infectious diseases and ophthalmology, we examined the incidence of ocular complications in 308 patients with candidemia and subsequently measured the rate of fundoscopic examinations, risk factors for ocular complications, management changes, and outcomes., Results: Among those who received fundoscopic exams, findings suspicious for ocular candidiasis were found in 12 patients (8%, 12/148). After independent review by ophthalmology and infectious diseases, 3 patients were found to have alternate pathologies that explained their ocular findings. Nine patients (6%, 9/148) were adjudicated as having presumed Candida chorioretinitis. Of these 9 patients, 4 (44%) were asymptomatic, and 2 (22%) were unable to declare symptoms. No patients were definitively determined to have Candida endophthalmitis. Ocular candidiasis was not found to have a statistically significant association with symptoms or comorbidities. Ocular candidiasis was more likely to be found at ophthalmology exams >7 days from first positive Candida blood culture. The number needed to screen to detect presumed Candida chorioretinitis among asymptomatic patients was 20., Conclusions: Based on the available evidence and high risk of morbidity of eye involvement, continued ophthalmological screens seem prudent, but a definitive consensus was found to be challenging given a lack of outcome data. Additional investigations are warranted. Ophthalmology screenings have a higher sensitivity at >7 days from positive blood culture., Competing Interests: Potential conflicts of interest. All authors: no reported conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Candida (Clavispora) lusitaniae is a rare, emerging non- albicans Candida species that can cause life-threatening invasive infections, spread within hospital settings, and rapidly acquire antifungal drug resistance, including multidrug resistance. The frequency and spectrum of mutations causing antifungal drug resistance in C. lusitaniae are poorly understood. Analyses of serial clinical isolates of any Candida species are uncommon and often analyze a limited number of samples collected over months of antifungal therapy with multiple drug classes, limiting the ability to understand relationships between drug classes and specific mutations. Here, we performed comparative genomic and phenotypic analysis of 20 serial C. lusitaniae bloodstream isolates collected daily from an individual patient treated with micafungin monotherapy during a single 11-day hospital admission. We identified isolates with decreased micafungin susceptibility 4 days after initiation of antifungal therapy and a single isolate with increased cross-resistance to micafungin and fluconazole, despite no history of azole therapy in this patient. Only 14 unique single nucleotide polymorphisms (SNPs) were identified between all 20 samples, including three different FKS1 alleles among isolates with decreased micafungin susceptibility and an ERG3 missense mutation found only in the isolate with increased cross-resistance to both micafungin and fluconazole. This is the first clinical evidence of an ERG3 mutation in C. lusitaniae that occurred during echinocandin monotherapy and is associated with cross-resistance to multiple drug classes. Overall, the evolution of multidrug resistance in C. lusitaniae is rapid and can emerge during treatment with only first-line antifungal therapy., Competing Interests: The authors declare no conflict of interest.

Competing Interests: Declaration of competing interest The authors declare no conflicts of interest.

High-level isolation units (HLIUs) are specially designed facilities for care and management of patients with suspected or confirmed high-consequence infectious diseases (HCIDs), equipped with unique infrastructure and operational features. While individual HLIUs have published on their experiences caring for patients with HCIDs and two previous HLIU consensus efforts have outlined key components of HLIUs, we aimed to summarise the existing literature that describes best practices, challenges and core features of these specialised facilities. A narrative review of the literature was conducted using keywords associated with HLIUs and HCIDs. A total of 100 articles were used throughout the manuscript from the literature search or from alternate methods like reference checks or snowballing. Articles were sorted into categories (eg, physical infrastructure, laboratory, internal transport); for each category, a synthesis of the relevant literature was conducted to describe best practices, experiences and operational features. The review and summary of HLIU experiences, best practices, challenges and components can serve as a resource for units continuing to improve readiness, or for hospitals in early stages of developing their HLIU teams and planning or constructing their units. The COVID-19 pandemic, a global outbreak of mpox, sporadic cases of viral haemorrhagic fevers in Europe and the USA, and recent outbreaks of Lassa fever, Sudan Ebolavirus, and Marburg emphasise the need for an extensive summary of HLIU practices to inform readiness and response., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Select circumstances require outpatient parenteral antimicrobial therapy (OPAT). The potency of OPAT agents presents an increased risk of adverse events and unscheduled medical care. We analyzed these outcomes among OPAT recipients as part of the implementation of a collaborative OPAT program., Methods: Adult patients discharged home from an academic hospital with OPAT between January 2019 and June 2021 were included in this retrospective cohort; participants discharged between June 2020 and June 2021 were part of the collaborative OPAT program. Patients with cystic fibrosis were excluded. Data on patient characteristics and outcomes were collected from electronic medical records by two reviewers. Multivariable analysis was conducted to identify predictors of vascular access device (VAD) complications, adverse drug events (ADEs), and OPAT-related emergency department (ED) visits and rehospitalizations., Results: Among 265 patients included in the cohort, 57 (21.5%) patients experienced a VAD complication; obesity [odds ratio (OR): 3.32; 95% confidence interval (CI): 1.38-8.73; p  = 0.01) and multi-drug therapy (OR: 2.56; 95% CI: 1.21-5.39; p  = 0.01) were associated with an increased odds of VAD complication. Eighty-two (30.9%) participants experienced an ADE; 30 (11.3%) experienced a severe/serious ADE. Lipo/glycopeptide receipt, (OR: 5.28; 95% CI: 1.89-15.43; p  < 0.01) and Black/African American race (OR: 4.85; 95% (CI): 1.56-15.45; p  < 0.01) were associated with an increased odds of severe/serious ADE. Inclusion in the OPAT collaborative was associated with a decreased odds of severe/serious ADE (OR: 0.26; 95% CI: 0.08-0.77; p  = 0.01). Fifty-eight (21.9%) patients experienced an OPAT-related ED visit and 53 (20.0%) experienced an OPAT-related rehospitalization. VAD complication (OR: 2.37; 95% (CI): 1.15-4.86, p  = 0.02) and ADEs (OR: 2.19; CI: 1.13-4.22; p  = 0.02) were associated with OPAT-related ED visits. ADE was associated with 90-day OPAT-related rehospitalization (OR: 3.21; (CI): 1.59-6.58; p  < 0.01)., Conclusion: Adverse safety events and OPAT-related unscheduled care occurred often in our cohort. A structured OPAT program that includes ID pharmacist antibiotic reconciliation may reduce rates of ADEs., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: EBH has received advisory board honoraria from Melinta, MeMed, and Merck, and has received research funding from Merck; honoraria and research funding are not directly related to OPAT. No other authors report conflicts of interest., (© The Author(s), 2023.)

Background: The COVID-19 standard of care (SOC) evolved rapidly during 2020 and 2021, but its cumulative effect over time is unclear., Objective: To evaluate whether recovery and mortality improved as SOC evolved, using data from ACTT (Adaptive COVID-19 Treatment Trial)., Design: ACTT is a series of phase 3, randomized, double-blind, placebo-controlled trials that evaluated COVID-19 therapeutics from February 2020 through May 2021. ACTT-1 compared remdesivir plus SOC to placebo plus SOC, and in ACTT-2 and ACTT-3, remdesivir plus SOC was the control group. This post hoc analysis compared recovery and mortality between these comparable sequential cohorts of patients who received remdesivir plus SOC, adjusting for baseline characteristics with propensity score weighting. The analysis was repeated for participants in ACTT-3 and ACTT-4 who received remdesivir plus dexamethasone plus SOC. Trends in SOC that could explain outcome improvements were analyzed. (ClinicalTrials.gov: NCT04280705 [ACTT-1], NCT04401579 [ACTT-2], NCT04492475 [ACTT-3], and NCT04640168 [ACTT-4])., Setting: 94 hospitals in 10 countries (86% U.S. participants)., Participants: Adults hospitalized with COVID-19., Intervention: SOC., Measurements: 28-day mortality and recovery., Results: Although outcomes were better in ACTT-2 than in ACTT-1, adjusted hazard ratios (HRs) were close to 1 (HR for recovery, 1.04 [95% CI, 0.92 to 1.17]; HR for mortality, 0.90 [CI, 0.56 to 1.40]). Comparable patients were less likely to be intubated in ACTT-2 than in ACTT-1 (odds ratio, 0.75 [CI, 0.53 to 0.97]), and hydroxychloroquine use decreased. Outcomes improved from ACTT-2 to ACTT-3 (HR for recovery, 1.43 [CI, 1.24 to 1.64]; HR for mortality, 0.45 [CI, 0.21 to 0.97]). Potential explanatory factors (SOC trends, case surges, and variant trends) were similar between ACTT-2 and ACTT-3, except for increased dexamethasone use (11% to 77%). Outcomes were similar in ACTT-3 and ACTT-4. Antibiotic use decreased gradually across all stages., Limitation: Unmeasured confounding., Conclusion: Changes in patient composition explained improved outcomes from ACTT-1 to ACTT-2 but not from ACTT-2 to ACTT-3, suggesting improved SOC. These results support excluding nonconcurrent controls from analysis of platform trials in rapidly changing therapeutic areas., Primary Funding Source: National Institute of Allergy and Infectious Diseases.

Background: Baricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19., Methods: In this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168., Findings: Between Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012)., Interpretation: In hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered., Funding: National Institute of Allergy and Infectious Diseases., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The National Emerging Special Pathogens Training and Education Center (NETEC) was established in 2015 to improve the capabilities of healthcare facilities to provide safe and effective care to patients with Ebola and other special pathogens in the United States. Through NETEC, a collaborative network of 10 Regional Emerging Special Pathogen Treatment Centers (RESPTCs) undertook readiness activities that included potential respiratory pathogens. These preparations, which took place before the COVID-19 pandemic, established a foundation of readiness that enabled RESPTCs to play a pivotal role in the US COVID-19 pandemic response. As initial COVID-19 cases were detected in the United States, RESPTCs provided essential isolation capacity, supplies, and subject matter expertise that allowed for additional time for healthcare systems to prepare. Through the Special Pathogen Research Network, RESPTCs rapidly enrolled patients into early clinical trials. During periods of high community transmission, RESPTCs provided educational, clinical, and logistical support to a wide range of healthcare and nonhealthcare settings. In this article, we describe how NETEC and the RESPTC network leveraged this foundation of special pathogen readiness to strengthen the national healthcare system's response to the COVID-19 pandemic. NETEC and the RESPTC network have proven to be an effective model that can support the national response to future emerging special pathogens.

Transmission of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is possible among symptom-free individuals. Patients are avoiding medically necessary healthcare visits for fear of becoming infected in the healthcare setting. We screened 489 symptom-free healthcare workers for SARS-CoV-2 and found no positive results, strongly suggesting that the prevalence of SARS-CoV-2 was <1%.

Background: Monitoring COVID-19 infection risk among health care workers (HCWs) is a public health priority. We examined the seroprevalence of SARS-CoV-2 among HCWs following the fall infection surge in Minnesota, and before and after COVID-19 vaccination. Additionally, we assessed demographic and occupational risk factors for SARS-CoV-2 infection., Methods: We conducted two rounds of seroprevalence testing among a cohort of HCWs: samples in round 1 were collected from 11/22/20-02/21/21 and in round 2 from 12/18/20-02/15/21. Demographic and occupational exposures assessed with logistic regression were age, sex, healthcare role and setting, and number of children in the household. The primary outcome was SARS-CoV-2 IgG seropositivity. A secondary outcome, SARS-CoV-2 infection, included both seropositivity and self-reported SARS-CoV-2 test positivity., Results: In total, 459 HCWs were tested. 43/454 (9.47%) had a seropositive sample 1 and 75/423 (17.7%) had a seropositive sample 2. By time of sample 2 collection, 54% of participants had received at least one vaccine dose and seroprevalence was 13% among unvaccinated individuals. Relative to physicians, the odds of SARS-CoV-2 infection in other roles were increased (Nurse Practitioner: OR[95%CI] 1.93[0.57,6.53], Physician's Assistant: 1.69[0.38,7.52], Nurse: 2.33[0.94,5.78], Paramedic/EMTs: 3.86[0.78,19.0], other: 1.68[0.58,4.85]). The workplace setting was associated with SARS-CoV-2 infection (p = 0.04). SARS-CoV-2 seroprevalence among HCWs reporting duties in the ICU vs. those working in an ambulatory clinic was elevated: OR[95%CI] 2.17[1.01,4.68]., Conclusions: SARS-CoV-2 seroprevalence in HCW increased during our study period which was consistent with community infection rates. HCW role and setting-particularly working in the ICU-is associated with higher risk for SARS-CoV-2 infection., Competing Interests: Dr. Baumgartner is employed by Quansys Biosciences (Utah, USA), the manufacturer and testing site of the assays used. There are no patents, products in development, or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Most SARS-CoV-2 antibody assays cannot distinguish between antibodies that developed after natural infection and those that developed after vaccination. We assessed the accuracy of a nucleocapsid-containing assay in identifying natural infection among vaccinated individuals. A longitudinal cohort composed of health care workers in the Minneapolis/St. Paul area was enrolled. Two rounds of seroprevalence studies separated by 1 month were conducted from November 2020 to January 2021 among 81 participants. Capillary blood from rounds 1 and 2 was tested for IgG antibodies against spike proteins by enzyme-linked immunosorbent assay (spike-only assay). During round 2, IgGs reactive to SARS-CoV-2 nucleocapsid protein (nucleocapsid-containing assay) were assessed. Vaccination status at round 2 was determined by self-report. Area under the curve was computed to determine the discriminatory ability of the nucleocapsid-containing assay for identification of recent infection. Participants had a mean age of 40 years (range, 23 to 66 years); 83% were female. Round 1 seroprevalence was 9.5%. Before round 2 testing, 46% reported vaccination. Among those not recently infected, in comparing vaccinated vs unvaccinated individuals, elevated levels of spike 1 (P<.001) and spike 2 (P=.01) were observed, whereas nucleocapsid levels were not statistically significantly different (P=.90). Among all participants, nucleocapsid response predicted recent infection with an area under the curve of 0.93 (95% CI, 0.88 to 0.99). Among individuals vaccinated more than 10 days before antibody testing, the specificity of the nucleocapsid-containing assay was 92%, whereas the specificity of the spike-only assay was 0%. An IgG assay identifying reactivity to nucleocapsid protein is an accurate predictor of natural infection among a partially vaccinated population, whereas a spike-only assay performed poorly., (Copyright © 2022 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Staphylococcus aureus (SA) colonization has significant implications in healthcare-associated infections. Here we describe a prospective study conducted in pre-surgical outpatients, done with the aim of identifying demographic and clinical risk factors for SA colonization. We found younger age to be a potential predictor of SA colonization., Competing Interests: The authors declare that there are no conflicts of interest., (© 2022 The Authors.)

Background: Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19., Methods: We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 μg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04492475., Findings: Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87-1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3-7%) in the interferon beta-1a plus remdesivir group and 3% (2-6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69-2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group., Interpretation: Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo., Funding: The National Institute of Allergy and Infectious Diseases (USA)., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Coronavirus disease 2019 (COVID-19) outcomes are linked to host immune responses and may be affected by antiviral therapy. We investigated antibody and cytokine responses in ACTT-1 study participants enrolled at our center. We studied serum specimens from 19 hospitalized adults with COVID-19 randomized to treatment with remdesivir or placebo. We assessed severe acute respiratory syndrome coronavirus 2 antibody responses and identified cytokine signatures, using hierarchical clustering. We identified no clear immunologic trends attributable to remdesivir treatment. Seven participants were initially seronegative at study enrollment, and all 4 deaths occurred in this group with more recent symptom onset. We identified 3 dominant cytokine signatures, demonstrating different disease trajectories., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Importance: Identification of SARS-CoV-2 infection via antibody assays is important for monitoring natural infection rates. Most antibody assays cannot distinguish natural infection from vaccination., Objective: To assess the accuracy of a nucleocapsid-containing assay in identifying natural infection among vaccinated individuals., Design: A longitudinal cohort comprised of healthcare workers (HCW) in the Minneapolis/St. Paul metropolitan area was enrolled. Two rounds of seroprevalence studies separated by one month were conducted from 11/2020-1/2021. Capillary blood from round 1 and 2 was tested for IgG antibodies against SARS-CoV-2 spike proteins with a qualitative chemiluminescent ELISA (spike-only assay). In a subsample of participants (n=82) at round 2, a second assay was performed that measured IgGs reactive to SARS-CoV-2 nucleocapsid protein (nucleocapsid-containing assay). Round 1 biospecimen collections occurred prior to vaccination in all participants. Vaccination status at round 2 was determined via self-report., Setting: The Minneapolis/St. Paul, Minnesota metropolitan area., Participants: HCW age 18-80 years., Exposures: Round 1 recent SARS-CoV-2 infection assessed via a spike-only assay and participant self-report., Outcomes: Round 2 SARS-CoV-2 infection assessed via the nucleocapsid-containing assay. Area under the curve (AUC) was computed to determine the discriminatory ability of round 2 IgG reactivity to nucleocapsid for identification of recent infection determined during round 1., Results: Participants had a mean age of 40 (range=23-66) years, 83% were female, 46% reported vaccination prior to the round 2 testing. Round 1 seroprevalence was 9.5%. Among those not recently infected, when comparing vaccinated vs. unvaccinated individuals, elevated levels of spike 1 (p<0.001) and spike 2 (p=0.01) were observed while nucleocapsid levels were not statistically significantly different (p=0.90). Among all participants, nucleocapsid response predicted recent infection with an AUC(95%CI) of 0.93(0.88,0.99). Among individuals vaccinated >10 days prior to antibody testing, the specificity of the nucleocapsid-containing assay was 92% and while the specificity of the spike-only assay was 0%., Conclusions and Relevance: An IgG assay identifying reactivity to nucleocapsid protein is an accurate predictor of natural infection among vaccinated individuals while a spike-only assay performed poorly. In the era of SARS-CoV-2 vaccination, seroprevalence studies monitoring natural infection will require assays that do not rely on spike-protein response alone.

Background: Severe coronavirus disease 2019 (Covid-19) is associated with dysregulated inflammation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not known., Methods: We conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15., Results: A total of 1033 patients underwent randomization (with 515 assigned to combination treatment and 518 to control). Patients receiving baricitinib had a median time to recovery of 7 days (95% confidence interval [CI], 6 to 8), as compared with 8 days (95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P = 0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, -5.0 percentage points; 95% CI, -9.8 to -0.3; P = 0.03), as were new infections (5.9% vs. 11.2%; difference, -5.3 percentage points; 95% CI, -8.7 to -1.9; P = 0.003)., Conclusions: Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04401579.)., (Copyright © 2020 Massachusetts Medical Society.)

Background: Transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is possible among symptom-free individuals and some patients are avoiding medically necessary healthcare visits for fear of becoming infected in the healthcare setting. Limited data are available on the point prevalence of SARS-CoV-2 infection in symptom-free U.S. healthcare workers (HCW)., Methods: A cross-sectional convenience sample of symptom-free HCWs from the metropolitan area surrounding Minneapolis and St. Paul, Minnesota was enrolled between April 20 th and June 24 th , 2020. A participant self-collected nasopharyngeal swab (NPS) was obtained. SARS-CoV-2 infection was assessed via polymerase chain reaction. Participants were queried about their willingness to repeat a self-collection NPS for diagnostic purposes. We had >95% power to detect at least one positive test if the true underlying prevalence of SARS-CoV2 was ≥1%., Results: Among n=489 participants 80% were female and mean age±SD was 41±11. Participants reported being physicians (14%), nurse practitioners (8%), physician's assistants (4%), nurses (51%), medics (3%), or other which predominantly included laboratory technicians and administrative roles (22%). Exposure to a known/suspected COVID-19 case in the 14 days prior to enrollment was reported in 40% of participants. SARS-CoV-2 was not detected in any participant. Over 95% of participants reported a willingness to repeat a self-collected NP swab in the future., Conclusions: The point prevalence of SARS-CoV-2 infection was likely <1% in a convenience sample of symptom-free Minnesota healthcare workers from April 20 th and June 24 th , 2020. Self-collected NP swabs are well-tolerated and a viable alternative to provider-collected swabs to preserve PPE.

Background: Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), no antiviral agents have yet been shown to be efficacious., Methods: We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only., Results: A total of 1062 patients underwent randomization (with 541 assigned to remdesivir and 521 to placebo). Those who received remdesivir had a median recovery time of 10 days (95% confidence interval [CI], 9 to 11), as compared with 15 days (95% CI, 13 to 18) among those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; P<0.001, by a log-rank test). In an analysis that used a proportional-odds model with an eight-category ordinal scale, the patients who received remdesivir were found to be more likely than those who received placebo to have clinical improvement at day 15 (odds ratio, 1.5; 95% CI, 1.2 to 1.9, after adjustment for actual disease severity). The Kaplan-Meier estimates of mortality were 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% with remdesivir and 15.2% with placebo by day 29 (hazard ratio, 0.73; 95% CI, 0.52 to 1.03). Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients who received placebo (31.6%)., Conclusions: Our data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 ClinicalTrials.gov number, NCT04280705.)., (Copyright © 2020 Massachusetts Medical Society.)

On May 1, 2020, the US Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) to allow use of the antiviral drug remdesivir to treat patients with severe coronavirus disease-2019 (COVID-19). Remdesivir is an investigational drug studied in clinical trials for COVID-19 and is available to children and pregnant women through compassionate-use access but is not yet FDA approved. In early May, the US Department of Health and Human Services began to distribute remdesivir, donated by Gilead Sciences, Inc., to hospitals and state health departments for emergency use; multiple shipments have since been distributed. This process has raised questions of how remdesivir should be allocated. The Minnesota Department of Health has collaborated with the Minnesota COVID Ethics Collaborative and multiple clinical experts to issue an Ethical Framework for May 2020 Allocation of Remdesivir in the COVID-19 Pandemic. The framework builds on extensive ethical guidance developed for public health emergencies in Minnesota before the COVID-19 crisis. The Minnesota remdesivir allocation framework specifies an ethical approach to distributing the drug to facilities across the state and then among COVID-19 patients within each facility. This article describes the process of developing the framework and adjustments in the framework over time with emergence of new data, analyzes key issues addressed, and suggests next steps. Sharing this framework and the development process can encourage transparency and may be useful to other states formulating and refining their approach to remdesivir EUA allocation., (Copyright © 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

We evaluated the association between infectious disease consultation and bloodstream infection outcomes, including methicillin-resistant Staphylococcus aureus , Candida , and Pseudomonas. No infectious diseases consultation was associated with over 4-fold increased hazard of death at 3 months and 6-fold increased hazard of death in hospital., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The goals of the present study were (a) to create positively charged organo-uranyl complexes with general formula [UO 2 (R)] + (eg, R═CH 3 and CH 2 CH 3 ) by decarboxylation of [UO 2 (O 2 C─R)] + precursors and (b) to identify the pathways by which the complexes, if formed, dissociate by collisional activation or otherwise react when exposed to gas-phase H 2 O. Collision-induced dissociation (CID) of both [UO 2 (O 2 C─CH 3 )] + and [UO 2 (O 2 C─CH 2 CH 3 )] + causes H + transfer and elimination of a ketene to leave [UO 2 (OH)] + . However, CID of the alkoxides [UO 2 (OCH 2 CH 3 )] + and [UO 2 (OCH 2 CH 2 CH 3 )] + produced [UO 2 (CH 3 )] + and [UO 2 (CH 2 CH 3 )] + , respectively. Isolation of [UO 2 (CH 3 )] + and [UO 2 (CH 2 CH 3 )] + for reaction with H 2 O caused formation of [UO 2 (H 2 O)] + by elimination of ·CH 3 and ·CH 2 CH 3 : Hydrolysis was not observed. CID of the acrylate and benzoate versions of the complexes, [UO 2 (O 2 C─CH═CH 2 )] + and [UO 2 (O 2 C─C 6 H 5 )] + , caused decarboxylation to leave [UO 2 (CH═CH 2 )] + and [UO 2 (C 6 H 5 )] + , respectively. These organometallic species do react with H 2 O to produce [UO 2 (OH)] + , and loss of the respective radicals to leave [UO 2 (H 2 O)] + was not detected. Density functional theory calculations suggest that formation of [UO 2 (OH)] + , rather than the hydrated U V O 2 + , cation is energetically favored regardless of the precursor ion. However, for the [UO 2 (CH 3 )] + and [UO 2 (CH 2 CH 3 )] + precursors, the transition state energy for proton transfer to generate [UO 2 (OH)] + and the associated neutral alkanes is higher than the path involving direct elimination of the organic neutral to form [UO 2 (H 2 O)] + . The situation is reversed for the [UO 2 (CH═CH 2 )] + and [UO 2 (C 6 H 5 )] + precursors: The transition state for proton transfer is lower than the energy required for creation of [UO 2 (H 2 O)] + by elimination of CH═CH 2 or C 6 H 5 radical., (© 2019 John Wiley & Sons, Ltd.)

Background: In Minnesota and North Dakota, a clonal strain of bla KPC-3 -producing Enterobacter cloacae complex has been reported with increasing frequency., Methods: Between July 2015 and February 2016, 13 carbapenem-resistant E. cloacae complex isolates were identified at our institution. Five bla KPC -positive isolates were identified by polymerase chain reaction and underwent pulsed-field gel electrophoresis and whole genome sequencing. Medical records of these patients were reviewed., Results: All 5 case-isolates belonged to sequence type 171 and were bla KPC-3 -positive. Three pulsed-field gel electrophoresis patterns with >90% similarity were identified in the 5 case-isolates. We identified overlaps in time and location between case patients. Plasmid types and resistance genes were nearly identical between the isolates. Whole genome sequencing showed isolates A, B, and D to be closely related with <10 core single-nucleotide polymorphisms differences. Isolates C and E were also closely related to each other, but more distantly to A, B, and D; all belonged to the clonal lineage of the major circulating E. cloacae complex strain in Minnesota and North Dakota. Despite having overlapping hospital stays, isolates for patients C and D were not identical., Conclusions: Isolates A and D were nearly identical, indicating possible transmission during hospitalization. Transmission of the other isolates may have occurred elsewhere. This report highlights the importance of using both epidemiologic and molecular data to track the spread of carbapenemase-producers., (Copyright © 2018 Association for Professionals in Infection Control and Epidemiology, Inc. All rights reserved.)

Background: Our center initiated an electronic Sepsis Best Practice Alert (sBPA) protocol to aid in early sepsis detection and treatment. However, surgery alters peri-operative physiology, which may trigger an sBPA for noninfectious causes. This study aimed to provide early evaluation of automated sBPA utility in surgical patients. Methods: This study was a retrospective review of the outcomes of patients admitted to the University of Minnesota Medical Center (but not to the intensive care unit) from August 2015-March 2016 and compared how the sBPA performed in those having and not having surgery. An sBPA prompted nursing to draw blood for an immediate lactate assay if two modified systemic inflammatory response syndrome (mSIRS) criteria or three mSIRS criteria within 24 hours after surgery were met. Physicians were notified if the lactate concentration was >2 mmol/L. Further review was performed of data collected prospectively on the surgical patients. Results: A total of 10,335 patients were admitted (2,158 surgery and 8,177 non-surgery). Of these, 33% of the surgery patients and 35% of the patients not having surgery triggered sBPAs. In surgery patients, 13% of lactate concentrations were >2 mmol/L versus 25% in patients not having surgery. An sBPA was triggered more frequently after procedures with a wound class of 4 (5% vs. 2%), emergency operation (23% vs. 10%), and longer operations (280 min vs. 222 min (p < 0.05 for all). Surgery patients triggering sBPAs had longer hospital stays (9.6 vs. 4.4 days; p < 0.05), more surgical site infections (7% vs. 2%; p < 0.05), and a similar mortality rate (3% vs. 4%; p = 0.15) than those who did not trigger an sBPA. Conclusion: An sBPA fired in a third of all inpatients, and an sBPA that prompted lactate measurements was less likely to be abnormal in surgery patients than in those not having surgery. There was no difference in the mortality rate in surgical patients who fired and those who did not; however, the sBPA did identify patients with a more complicated post-operative course. Further refinements of the electronic trigger should increase BPA specificity.

The 2013-2016 epidemic of Ebola virus disease (EVD) that originated in West Africa underscored many of the challenges to conducting clinical research during an ongoing infectious disease epidemic, both in the most affected countries of Guinea, Liberia, and Sierra Leone, as well as in the United States and Europe, where a total of 27 patients with EVD received care in biocontainment units. The Special Pathogens Research Network (SPRN) was established in the United States in November 2016 to provide an organizational structure to leverage the expertise of the 10 Regional Ebola and Other Special Pathogen Treatment Centers (RESPTCs); it was intended to develop and support infrastructure to improve readiness to conduct clinical research in the United States. The network enables the rapid activation and coordination of clinical research in the event of an epidemic and facilitates opportunities for multicenter research when the RESPTCs are actively caring for patients requiring a biocontainment unit. Here we provide an overview of opportunities identified in the clinical research infrastructure during the West Africa EVD epidemic and the SPRN activities to meet the ongoing challenges in the context of Ebola virus and other special pathogens.

Objective: We developed a decision analytic model to evaluate the impact of a preoperative Staphylococcus aureus decolonization bundle on surgical site infections (SSIs), health-care-associated costs (HCACs), and deaths due to SSI., Methods: Our model population comprised US adults undergoing elective surgery. We evaluated 3 self-administered preoperative strategies: (1) the standard of care (SOC) consisting of 2 disinfectant soap showers; (2) the "test-and-treat" strategy consisting of the decolonization bundle including chlorhexidine gluconate (CHG) soap, CHG mouth rinse, and mupirocin nasal ointment for 5 days) if S. aureus was found at any of 4 screened sites (nasal, throat, axillary, perianal area), otherwise the SOC; and (3) the "treat-all" strategy consisting of the decolonization bundle for all patients, without S. aureus screening. Model parameters were derived primarily from a randomized controlled trial that measured the efficacy of the decolonization bundle for eradicating S. aureus., Results: Under base-case assumptions, the treat-all strategy yielded the fewest SSIs and the lowest HCACs, followed by the test-and-treat strategy. In contrast, the SOC yielded the most SSIs and the highest HCACs. Consequently, relative to the SOC, the average savings per operation was $217 for the treat-all strategy and $123 for the test-and-treat strategy, and the average savings per per SSI prevented was $21,929 for the treat-all strategy and $15,166 for the test-and-treat strategy. All strategies were sensitive to the probability of acquiring an SSI and the increased risk if SSI if the patient was colonized with SA., Conclusion: We predict that the treat-all strategy would be the most effective and cost-saving strategy for preventing SSIs. However, because this strategy might select more extensively for mupirocin-resistant S. aureus and cause more medication adverse effects than the test-and-treat approach or the SOC, additional studies are needed to define its comparative benefits and harms.

Objective: To determine the efficacy in eradicating Staphylococcus aureus (SA) carriage of a 5-day preoperative decolonization bundle compared to 2 disinfectant soap showers, with both regimens self-administered at home., Design: Open label, single-center, randomized clinical trial., Setting: Ambulatory orthopedic, urologic, neurologic, colorectal, cardiovascular, and general surgery clinics at a tertiary-care referral center in the United States.ParticipantsPatients at the University of Minnesota Medical Center planning to have elective surgery and not on antibiotics., Methods: Consenting participants were screened for SA colonization using nasal, throat, axillary, and perianal swab cultures. Carriers of SA were randomized, stratified by methicillin resistance status, to a decolonization bundle group (5 days of nasal mupirocin, chlorhexidine gluconate [CHG] bathing, and CHG mouthwash) or control group (2 preoperative showers with antiseptic soap). Colonization status was reassessed preoperatively. The primary endpoint was absence of SA at all 4 screened body sites., Results: Of 427 participants screened between August 31, 2011, and August 9, 2016, 127 participants (29.7%) were SA carriers. Of these, 121 were randomized and 110 were eligible for efficacy analysis (57 decolonization bundle group, 53 control group). Overall, 90% of evaluable participants had methicillin-susceptible SA strains. Eradication of SA at all body sites was achieved for 41 of 57 participants (71.9%) in the decolonization bundle group and for 13 of 53 participants (24.5%) in the control group, a difference of 47.4% (95% confidence interval [CI], 29.1%-65.7%; P<.0001)., Conclusion: An outpatient preoperative antiseptic decolonization bundle aimed at 4 body sites was significantly more effective in eradicating SA than the usual disinfectant showers (ie, the control).Trial RegistrationClinicalTrials.gov identifier: NCT02182115.

Purpose of Review: Infections in children with Mycobacterium abscessus complex represent a particular challenge for clinicians. Increasing incidence of these infections worldwide has necessitated focused attention to improve both diagnostic as well as treatment modalities. Published medical literature was reviewed, with emphasis on material published in the past 5 years., Recent Findings: Increasing availability of new diagnostic tools, such as matrix-assisted laser desorption ionization-time of flight mass spectrometry and custom PCRs, has provided unique insights into the subspecies within the complex and improved diagnostic certainty. Microbiological review of all recent isolates at the University of Minnesota Medical Center was also conducted, with description of the antimicrobial sensitivity patterns encountered in our center, and compared with those published from other centers in the recent literature. A discussion of conventional antimicrobial treatment regimens, alongside detailed description of the relevant antimicrobials, is derived from recent publications. Antimicrobial therapy, combined with surgical intervention in some cases, remains the mainstay of pediatric care. Ongoing questions remain regarding the transmission mechanics, immunologic vulnerabilities exploited by these organisms in the host, and the optimal antimicrobial regimens necessary to enable a reliable cure. Updated treatment guidelines based on focused clinical studies in children and accounting especially for the immunocompromised children at greatest risk are very much needed.

BACKGROUND In 2011, pediatric hematopoietic stem cell transplant (HSCT) patients were moved from an older hospital to a new children's hospital. To minimize bacterial growth in the new hospital's water during construction, the plumbing system was flushed and disinfected before occupancy. However, 6 months after occupancy, an increased incidence of rapidly growing mycobacteria (RGM) was detected in clinical cultures. Over 10 months, 15 pediatric HSCT patients were infected, while no pediatric HSCT patients had been infected in the preceding 12 months. OBJECTIVE To determine the cause of the outbreak and to interrupt patient acquisition of RGM. METHODS Water samples were collected from water entering the hospital and from drinking water and ice machines (DWIMs) from the old and new hospitals. Total heterotrophic plate counts (HPCs, CFU/mL) of water were undertaken, and select isolates were identified as RGM. RESULTS The cause of the outbreak was increased bacterial levels in the water (including RGM) in the DWIMs in the new (2011) hospital. Tests revealed higher HPCs in drinking water and ice from the DWIMs in the new hospital than in the DWIMs in the old hospital. Ultimately, HPCs were reduced by several different interventions. CONCLUSION In response to an RGM outbreak, HSCT patients were banned from ingesting DWIM ice and water and bottled water was provided. Since this interverntion 4 years ago, no additional RGM isolates have been identified in HSCT patient cultures. Our measures to reduce HPCs to goal levels in drinking water from DWIMs were successful, but the HPCs for ice have not consistently reached the goal of <500 CFU/mL. Infect Control Hosp Epidemiol 2017;38:792-800.

Background: In October 2014, the United States began actively monitoring all persons who had traveled from Guinea, Liberia, and Sierra Leone in the previous 21 days. State public health departments were responsible for monitoring all travelers; Minnesota has the largest Liberian population in the United States. The MDH Ebola Clinical Team (ECT) was established to assess travelers with symptoms of concern for Ebola virus disease (EVD), coordinate access to healthcare at appropriate facilities including Ebola Assessment and Treatment Units (EATU), and provide guidance to clinicians., Methods: Minnesota Department of Health (MDH) began receiving traveler information collected by U.S. Customs and Border Control and Centers for Disease Control and Prevention staff on October 21, 2014 via encrypted electronic communication. All travelers returning from Liberia, Sierra Leone, and Guinea during 10/21/14-5/15/15 were monitored by MDH staff in the manner recommended by CDC based on the traveler's risk categorization as "low (but not zero)", "some" and "high" risk. When a traveler reported symptoms or a temperature ≥100.4° F at any time during their 21-day monitoring period, an ECT member would speak to the traveler and perform a clinical assessment by telephone or via video-chat. Based on the assessment the ECT member would recommend 1) continued clinical monitoring while at home with frequent telephone follow-up by the ECT member, 2) outpatient clinical evaluation at an outpatient site agreed upon by all parties, or 3) inpatient clinical evaluation at one of four Minnesota EATUs. ECT members assessed and approved testing for Ebola virus infection at MDH. Traveler data, calls to the ECT and clinical outcomes were logged on a secure server at MDH., Results: During 10/21/14-5/15/15, a total of 783 travelers were monitored; 729 (93%) traveled from Liberia, 30 (4%) Sierra Leone, and 24 (3%) Guinea. The median number monitored per week was 59 (range 45-143). The median age was 35 years; 136 (17%) were aged <18 years. Thirteen of 256 women of reproductive age (5%) were pregnant. The country of passport issuance was known for 720 of the travelers. The majority of monitored travelers (478 [66%]) used a non-U.S. passport including 442 (61%) Liberian nationals. A total of 772 (99%) travelers were "low (but not zero)" risk; 11 (1%) were "some" risk. Among monitored travelers, 43 (5%) experienced illness symptoms; 29 (67%) had a symptom consistent with EVD. Two were tested for Ebola virus disease and had negative results. Most frequently reported symptoms were fever (20/43, 47%) and abdominal pain (12/43, 28%). During evaluation, 16 (37%) of 43 travelers reported their symptoms began prior to travel; chronic health conditions in 24 travelers including tumors/cancer, pregnancy, and orthopedic conditions were most common. Infectious causes in 19 travelers included upper respiratory infection, malaria, and gastrointestinal infections., Discussion: Prior to 2014, no similar active monitoring program for travelers had been performed in Minnesota; assessment and management of symptomatic travelers was a new activity for MDH. Ensuring safe entrance into healthcare was particularly challenging for children, and pregnant women, as well as those without an established connection to healthcare. Unnecessary inpatient evaluations were successfully avoided by close clinical follow-up by phone. Before similar monitoring programs are considered in the future, careful thought must be given to necessary resources and the impact on affected populations, public health, and the healthcare system., Competing Interests: The authors have declared that no competing interests exist.

Escherichia coli sequence type 13 (ST131), an emergent cause of multidrug-resistant extraintestinal infections, has important phylogenetic subsets, notably the H30 and H30Rx subclones, with distinctive resistance profiles and, possibly, clinical associations. To clarify the local prevalence of these ST131 subclones and their associations with antimicrobial resistance, ecological source, and virulence traits, we extensively characterized 233 consecutive E. coli clinical isolates (July and August 2013) from the University of Minnesota Medical Center-Fairview Infectious Diseases and Diagnostic Laboratory, Minneapolis, MN, which serves three adjacent facilities (a children's hospital and low- and high-acuity adult facilities). ST131 accounted for 26% of the study isolates (more than any other clonal group), was distributed similarly by facility, and was closely associated with ciprofloxacin resistance and extended-spectrum β-lactamase (ESBL) production. The H30 and H30Rx subclones accounted for most ST131 isolates and for the association of ST131 with fluoroquinolone resistance and ESBL production. Unlike ST131 per se, these subclones were distributed differentially by hospital, being most prevalent at the high-acuity adult facility and were absent from the children's hospital. The virulence gene profiles of ST131 and its subclones were distinctive and more extensive than those of other fluoroquinolone-resistant or ESBL-producing isolates. Within ST131, bla CTX-M-15 was confined to H30Rx isolates and other bla CTX-M variants to non-Rx H30 isolates. Pulsed-field gel electrophoresis documented a predominance of globally distributed pulsotypes and no local outbreak pattern. These findings help clarify the epidemiology, ecology, and bacterial correlates of the H30 and H30Rx ST131 subclones by documenting a high overall prevalence but significant segregation by facility, strong associations with fluoroquinolone resistance and specific ESBL variants, and distinctive virulence gene associations that may confer fitness advantages over other resistant E. coli., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Background: The purpose of this study was to evaluate the safety of a novel silver-impregnated Foley catheter system designed to prevent catheter-associated bacteriuria and funguria, assess recruitment feasibility for a future pivotal trial, and preliminarily assess efficacy., Methods: This single-center, randomized controlled trial at a university hospital involved adult neurosurgical patients expected to have a urinary catheter for ≥24 hours. Subjects were randomized to a novel silver-impregnated (test) Foley catheter system or a control system. They were followed for 30 days (or until discharge) while catheterized and for up to 48 hours after catheter removal, with daily bacteriuria testing and assessment for symptoms of infection and catheter intolerance., Results: Ninety-five subjects were randomized (intention-to-treat [ITT] population). Of these, 61 subjects (64%) had a catheter for ≥24 hours without perioperative antibiotics beyond 24 hours (evaluable population). In the ITT population, 11 of 95 (12%) subjects had an asymptomatic bacteriuria (ABU) event. Compared with controls, test system recipients had a trend toward longer time to ABU in the ITT population (P = .08, log-rank test) and a longer time to ABU in the evaluable population (P = .03). All 6 ABU events caused by gram-negative bacilli occurred in the control group., Conclusion: In this pilot randomized trial the test system was well tolerated and seemingly effective in preventing catheter-associated bacteriuria, especially with gram-negative bacilli. A pivotal study is warranted., (Copyright © 2015 Association for Professionals in Infection Control and Epidemiology, Inc. All rights reserved.)

Background: Rapidly growing mycobacteria (RGM) have a predilection for those with immunocompromised states. We report increased isolation of RGM among pediatric hematopoietic cell transplant patients that was traced to the hospital water supply., Methods: Cases of RGM-positive patients were differentiated based on whether they were community-acquired or nosocomial, colonized or infected based on predefined criteria. Medical records of all RGM-positive patients were reviewed and data extracted. Infection control outbreak measures were instituted and an environmental investigation was conducted., Results: Between July 2011 and April 2012, 16 RGM isolates were identified among 15 hematopoietic cell transplant patients, compared with none in the preceding year. After environmental samples were initially grown on media for heterotrophic counts and further speciated, RGM species were identified in the hospital water supply., Conclusions: This outbreak of RGM was traced to an environmental source and was successfully controlled through institution of infection control measures.

We surveyed the Society for Healthcare Epidemiology of America Research Network, the Minnesota Association for Professionals in Infection Control and Epidemiology, and the Minnesota Hospital Association to assess presurgical Staphylococcus aureus screening and decolonization practices. The practices varied widely among responding facilities. The majority of respondents (63%) did not screen for S. aureus preoperatively.

Background: This study examined risk factors for extended-spectrum β-lactamase (ESBL) infection in patients at the University of Minnesota Medical Center, Fairview., Methods: Laboratory-confirmed cases of ESBL infection between January 2005 and June 2008 were evaluated in a case-control study. Risk factors were assessed based on source of infection, either health facility-acquired (HFA) or community-acquired (CA). Cases were identified through hospital infection control department ESBL surveillance records. Controls were selected from the patient population present within the same facility as the cases., Results: Our evaluation revealed that 60.6% of the health facility-acquired ESBL infections were due to Escherichia coli. Risk factors included previous antibiotic use (odds ratio [OR], 23.7; P < .0001), recurrent urinary tract infection (OR, 7.0; P < .022), venous or arterial catheter use (OR, 12.5; P < .0001), and long-term care facility residence (OR, 7.7; P = .043). For each day of antibiotic use, the risk of infection increased by 2%. Similarly, 76.5% of the community-acquired ESBL infections were due to E coli. Risk factors included previous antibiotic use (OR, 5.1; P = .0005) and recurrent urinary tract infection (OR, 9.1; P = .0098). For each day of antibiotic use, the risk of infection increased by 1%., Conclusions: Developing policies and methods to promote good antibiotic stewardship and reduce the incidence of urinary tract infections will decrease the risk of ESBL infection., (Copyright © 2012 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Mosby, Inc. All rights reserved.)

Babesiosis is a tick- and transfusion-borne disease caused by intraerythrocytic Babesia parasites. In 2009, a 61-year-old Minnesota woman with chronic lymphocytic leukemia and a history of recent chemotherapy and numerous blood transfusions for gastrointestinal bleeding became febrile and anemic 12 days postsplenectomy. Babesia were visualized on blood smears, confirmed by polymerase chain reaction as B. microti. She developed respiratory failure despite initiation of clindamycin and quinine, and required 12 weeks of azithromycin and atovaquone before blood smear and polymerase chain reaction findings were negative. Serologic evidence of B. microti infection was identified in 1 associated blood donor and 1 other recipient of that donor's blood. Babesia infection can be asymptomatic or cause mild to fulminant disease resulting in multiorgan failure or death. Patients with advanced age, asplenia, or other immune compromise are at risk for severe babesiosis and may require prolonged treatment to eradicate parasitemia. Incidence of transfusion-transmitted babesiosis has increased over the past decade., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Spinal cysticercosis is an uncommon manifestation of neurocysticercosis (NCC). We present a case of isolated lumbar intradural-extramedullary NCC. The patient was treated successfully with the surgical removal of the cyst. Spinal NCC should be considered in the differential diagnosis in high-risk populations with new symptoms suggestive of a spinal mass lesion., (© 2011 International Society of Travel Medicine.)

A 44-year-old woman with long-standing common variable immunodeficiency who was receiving intravenous immune globulin suddenly had paralysis of all four limbs and the respiratory muscles, resulting in death. Type 2 vaccine-derived poliovirus was isolated from stool. The viral capsid protein VP1 region had diverged from the vaccine strain at 12.3% of nucleotide positions, and the two attenuating substitutions had reverted to the wild-type sequence. Infection probably occurred 11.9 years earlier (95% confidence interval [CI], 10.9 to 13.2), when her child received the oral poliovirus vaccine. No secondary cases were identified among close contacts or 2038 screened health care workers. Patients with common variable immunodeficiency can be chronically infected with poliovirus, and poliomyelitis can develop despite treatment with intravenous immune globulin.

We describe here a clinical daptomycin treatment failure in a patient with recurrent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia in whom daptomycin was administered after a failed empirical treatment course with vancomycin and piperacillin-tazobactam. We had the opportunity to compare the genome sequences of an isogenic pair of daptomycin-susceptible and -resistant MRSA isolates obtained before and after initiation of daptomycin therapy, respectively. The genotype of both isolates was USA800, ST5, SCCmec type IV, agr type II. There was no increase in cell wall thickness in the daptomycin-resistant strain despite having decreased susceptibility to both vancomycin and daptomycin. By comparing the genome sequences by pyrosequencing, we identified a polymorphism (S337L) in the tenth transmembrane segment of the multiple peptide resistance factor, MprF, encoding lysyl phosphatidylglycerol transferase. This enzyme has been shown previously to promote repulsion of daptomycin at the cell surface by addition of positively charged lysine to phosphatidylglycerol. Also, the hlb open reading frame (ORF) encoding the β-toxin was interrupted by a prophage in the daptomycin-susceptible strain; this phage was missing in the daptomycin-resistant isolate and the hlb ORF was restored. Loss of the phage in the resistant isolate also resulted in loss of the virulence factor genes clpP, scn, and sak. This is the first study to use pyrosequencing to compare the genomes of a daptomycin-susceptible/resistant MRSA isolate pair obtained during failed daptomycin therapy in humans.

For millions of people around the world, tuberculosis (TB) is a cause of significant morbidity and mortality. It continues to affect the well-being of Minnesotans as well. This article reviews one Minnesota hospital's experience withTB. Through retrospective reviews of charts at the University of Minnesota Medical Center, we found that patients who tested positive for TB were more likely to be foreign-born than U.S.-born, that foreign-born patients who tested positive for TB were younger than those who tested positive and were born in the United States, and that foreign-born patients were more likely to have extrapulmonary disease than pulmonary TB.

Purpose: The primary objective of this study was to inform the development of measures of pain impact appropriate for all respondents, including homeless individuals, so that they can be used in clinical research and practice. The secondary objective was to increase understanding about the unique experience of homeless people with pain., Methods: Seventeen homeless individuals with chronic health conditions (often associated with pain) participated in cognitive interviews to test the functioning of 56 pain measurement items and provided information about their experience living with and accessing treatment for pain., Results: The most common problems identified with items were that they lacked clarity or were irrelevant in the context of homelessness. Items that were unclear, irrelevant and/or had other identified problems made it difficult for participants to respond. Participants also described multiple ways in which their pain was exacerbated by conditions of homelessness and identified barriers to accessing appropriate treatment., Conclusions: Results suggested that the majority of items were problematic for the homeless and require substantial modifications to make the pain impact bank relevant to this population. Additional recommendations include involving homeless in future item bank development, conducting research on the topic of pain and homelessness, and using cognitive interviewing in other types of health disparities research.

Given that the public uses the media to learn about adoption as a family form, this study analyzes U.S. television news coverage of adoption between 2001 and 2005 (N = 309 stories), to identify the types of news events covered about adoption. A majority of news stories covered fraud, crime, legal disputes, and negative international adoption cases. Adoptees as defective or unhealthy were depicted more in negative news event stories, birth parents appeared less overall, and adoptive parents were most likely to have healthy depictions in positively oriented adoption experience, big family, and reunion stories. Although three quarters of the stories used primary adoption participants as news sources, one-third of the negative event stories did not contain healthy depictions of adoption participants. The authors discuss ways journalists and researchers might improve adoption news coverage.

The purpose of this study was to examine perceptions of fairness of a computer-administered quiz as a function of the anthropomorphic features of the help agent offered within the quiz environment. The addition of simple anthropomorphic cues to a computer help agent reduced the perceived friendliness of the agent, perceived intelligence of the agent, and the perceived fairness of the quiz. These differences were observed only for male anthropomorphic cues, but not for female anthropomorphic cues. The results were not explained by the social attraction of the anthropomorphic agents used in the quiz or by gender identification with the agents. Priming of visual cues provides the best account of the data. Practical implications of the study are discussed.

All eukaryotes rely on multi-protein assemblies, called kinetochores, to direct the segregation of their chromosomes in mitosis. The list of known kinetochore components has been growing rapidly in the post-genomic era: in animal cells, there are presently more than 80 proteins that show either exclusive or partial localization at kinetochores during mitosis. The future challenge is to elucidate how these proteins contribute to kinetochore structure, spindle microtubule attachment, regulation of microtubule dynamics, and the detection, signaling, and correction of microtubule attachment errors. Cultured human tumor cells, especially HeLa cells, are widely used for the study of kinetochores. Recently, the experimental advantages offered by the nematode Caenorhabditis elegans have been exploited for functional analysis of kinetochore components in the first embryonic division. Here, we discuss basic methods, largely based on fluorescence imaging, to study kinetochore structure and function in these two metazoan model systems.

Background: Studying mitosis requires a system in which the dramatic movements of chromosomes and spindle microtubules can be visualized. PtK cells, due to their flat morphology and their small number of large chromosomes, allow microscopic visualizations to be readily performed., Results: By performing RNAi in PtK cells, we can explore the function of many proteins important for spindle assembly and chromosome segregation. Although it is difficult to transfect DNA into PtK cells (efficiency approximately 10%), we have transfected a fluorescent siRNA at nearly 100% efficiency. Using a cDNA expression library, we then isolated a complete PtK MCAK (P-MCAK) cDNA. P-MCAK shares 81% identity to Human-MCAK (H-MCAK) protein and 66% identity to H-MCAK DNA. Knockdown of P-MCAK by RNAi caused defects in chromosome congression and defective spindle organization. Live imaging revealed that chromosomes had defects in congression and segregation, similar to what we found after microinjection of inhibitory anti-MCAK antibodies. Because it is laborious to isolate full-length clones, we explored using RT-PCR with degenerate primers to yield cDNA fragments from PtK cells from which to design siRNAs. We isolated a cDNA fragment of the mitotic kinesin Eg5 from PtK cells. This fragment is 93% identical to H-Eg5 protein and 87% identical to H-Eg5 DNA. A conserved 21 bp siRNA was used for RNAi in both HeLa and PtK cells in which Eg5 knockdown resulted in an increased mitotic index and cells with monopolar spindles. In addition, we used RT-PCR to isolate fragments of 5 additional genes, whose sequence identity ranged from 76 to 90% with human, mouse, or rat genes, suggesting that this strategy is feasible to apply to any gene of interest., Conclusion: This approach will allow us to effectively probe mitotic defects from protein knockdowns by combining genomic information from other organisms with the tractable morphology of PtK cells.

During cell division, kinetochores form the primary chromosomal attachment sites for spindle microtubules. We previously identified a network of 10 interacting kinetochore proteins conserved between Caenorhabditis elegans and humans. In this study, we investigate three proteins in the human network (hDsn1Q9H410, hNnf1PMF1, and hNsl1DC31). Using coexpression in bacteria and fractionation of mitotic extracts, we demonstrate that these proteins form a stable complex with the conserved kinetochore component hMis12. Human or chicken cells depleted of Mis12 complex subunits are delayed in mitosis with misaligned chromosomes and defects in chromosome biorientation. Aligned chromosomes exhibited reduced centromere stretch and diminished kinetochore microtubule bundles. Consistent with this, localization of the outer plate constituent Ndc80HEC1 was severely reduced. The checkpoint protein BubR1, the fibrous corona component centromere protein (CENP) E, and the inner kinetochore proteins CENP-A and CENP-H also failed to accumulate to wild-type levels in depleted cells. These results indicate that a four-subunit Mis12 complex plays an essential role in chromosome segregation in vertebrates and contributes to mitotic kinetochore assembly.